WO2023217018A1 - Ezh2 inhibitor and use thereof in medicine - Google Patents

Ezh2 inhibitor and use thereof in medicine Download PDF

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WO2023217018A1
WO2023217018A1 PCT/CN2023/092449 CN2023092449W WO2023217018A1 WO 2023217018 A1 WO2023217018 A1 WO 2023217018A1 CN 2023092449 W CN2023092449 W CN 2023092449W WO 2023217018 A1 WO2023217018 A1 WO 2023217018A1
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alkyl
compound
cycloalkyl
aryl
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PCT/CN2023/092449
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Chinese (zh)
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吴颢
徐人奇
路渊
郑航
张洪波
王冬
陆镜禾
王泽�
杜亚军
柏英
王国建
陈小平
周全
兰宏
王家炳
丁列明
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贝达药业股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—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 linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the invention belongs to the field of medicine, and in particular relates to an EZH2 inhibitor, which has cancer therapeutic activity.
  • the present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing the same.
  • Enhancer of zeste homolog 2 is a member of the Polycomb group genes (PcGs) family
  • polycomb repressive complex 2 is one of two PcG protein core complexes that are mainly mediated by regulating chromatin structure.
  • Gene silencing. EZH2 is the core catalytic subunit of PRC2.
  • H3K27 histone H3 trimethylation
  • EZH2 is highly expressed in various solid tumors such as prostate cancer, ovarian cancer, bladder cancer, and lung cancer. It often undergoes activating mutations in hematological tumors such as lymphoma, which ultimately leads to increased H3K27me3 levels.
  • Histone lysine methyltransferase EZH2 catalyzes the transfer of the active methyl group of the cofactor S adenosylmethionine (SAM) to the ⁇ -NH2 of lysine 27 (H3K27) on histone H3, resulting in the trisomy of H3K27.
  • SAM cofactor S adenosylmethionine
  • H3K27me3 and subsequent transcriptional silencing of target genes regulate various life activities such as cancer progression and stem cell stemness maintenance.
  • EZH2 can also function by methylating non-histone proteins in a manner that is independent of PRC2; or it can form a transcription complex with other factors to activate the transcription of downstream target genes and increase the expression of target genes. ; It can also regulate the stemness maintenance and generational differentiation of Ganxipao. Therefore, the signaling pathway mediated by EZH2 is considered to be an intrinsic cause of various pathological processes such as cancer. Inhibition of aberrant EZH2 activity may be an attractive new strategy for treating cancer. A number of targeted small molecule drugs have been successfully developed targeting the SET region of EZH2 methyltransferase for the treatment of lymphoma and various solid tumors.
  • Drugs targeting EZH2 are still one of the current hot areas of drug research and development.
  • the world's first EZH2 inhibitor Tazemetostat was launched.
  • the first EZH1 and EZH2 dual inhibitor Valemetostat was approved for marketing in Japan.
  • major international pharmaceutical companies also have plans.
  • problems such as CYP induction in the drugs on the market, and it is still necessary to conduct research and improvements to meet clinical needs.
  • the present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
  • X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 , O or S;
  • X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 , O or S;
  • X 3 is selected from C or N;
  • R 2 is selected from absence, H, hydroxyl, amino, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl , -NR a R b , or halogen;
  • R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl
  • R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 ring Alkyl group, 3-12 membered heterocyclyl group, C 6-12 aryl group, 5-12 membered heteroaryl group, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 R c ; wherein,
  • R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
  • R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
  • R 7 and R 8 together with the carbon atom to which they are connected form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclyl group; wherein, the C 3-12 cycloalkyl group or 3-12 membered heterocyclyl group The group is optionally further substituted by one or more independent R a ;
  • R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkane
  • R b , R c or R d are each independently selected from hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl Base, H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
  • R 1 and R 6 are selected from one of the following groups:
  • R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b , the C 1-8 alkyl group
  • R 3 ' is each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl or -NR a R b , the C 1-8 alkoxy group, C 1-8 alkyl group, C 1-8 haloalkoxy group, C 1 -8 haloalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally further substituted by one or more independent R a ;
  • R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl The group is optionally further substituted by one or more independent R a ;
  • X 4 , X 5 , and X 6 are selected from C(R 9 ) m , N, NR 9 , O or S;
  • R 6 ' is selected from H, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
  • R 9 is selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
  • R 1 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5- 12-membered heteroaryl, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl group or 5-12 membered heteroaryl group is optionally further substituted by at least one R a .
  • formula (I) is selected from compounds represented by general formula (II):
  • R 1 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5- 12-membered heteroaryl, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl
  • the base or 5-12 membered heteroaryl group is optionally further substituted by at least one R a ;
  • R 2 is selected from absence, H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl or halogen ;
  • R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 ring Alkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, oxo group, -CN, -NO 2 , -OR b , -SR b , -SOR b , - SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , - NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 R
  • R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
  • X 1 is selected from -CO-, C(R 7 ) 2 , N or O;
  • X 2 is selected from -CO-, C(R 8 ) 2 , N or O;
  • X 3 is selected from C or N;
  • X 4 , X 5 , and X 6 are selected from C(R 9 ) m , N, NR 9 , O or S;
  • R 6 ' is selected from H, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
  • R 7 , R 8 , and R 9 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1 -8 haloalkoxy;
  • R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl
  • n is each independently selected from 1 or 2;
  • n is selected from 0, 1, 2, 3 or 4;
  • R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12
  • R b , R c or R d are each independently selected from H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkene base, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
  • R12 of formula (I) is selected from H.
  • formula (I) is selected from compounds represented by general formula (IIA):
  • R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl or halogen;
  • R 1 , R 3 , R 4 , R 5 , R 6 ', X 4 , X 5 , X 6 and n are the same as in formula (II).
  • formula (I) is selected from compounds represented by general formula (IIB):
  • R 1 , R 3 , R 4 , R 5 , R 6 ', X 4 , X 5 , X 6 and n are the same as those in formula (II).
  • R 1 in formula (II) is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, and the C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a selected from H, halogen, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, -OR b or -NR b R c .
  • R 1 in formula (II) is selected from
  • R 1 in formula (II) is selected from
  • R 2 in formula (II) is selected from H or C 1-8 alkyl.
  • R 4 in formula (II) is selected from H, halogen or C 1-8 alkyl.
  • R 6 ' in formula (II) is selected from H, halogen or C 1-8 alkyl, preferably methyl.
  • X 4 in formula (II) is selected from O, C(R 9 ) m , NR 9 or S.
  • X 5 in formula (II) is selected from C(R 9 ) m , O, S or N.
  • Formula (II) X6 is selected from N or C( R9 ) m .
  • R 9 in formula (II) is selected from H or halogen.
  • n in formula (II) is selected from 0 or 1, with 0 being preferred.
  • formula (II) describes Selected from
  • formula (I) is selected from compounds represented by general formula (III):
  • R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b ; wherein, the C 1-8 al
  • R 1 ' and R 2 ' and the carbon atoms they are jointly connected to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5-12 membered heteroaryl group; wherein, The C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
  • R 3 ' is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, -NR a R b , C 1-8 haloalkoxy, or C 1-8 haloalkyl;
  • R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
  • R 3 , R 4 , and R 5 are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2 -8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or
  • R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl
  • the group is optionally further substituted by at least one R a ;
  • X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 or O;
  • X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 or O;
  • X 3 is selected from C or N;
  • R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
  • R 12 is selected from H
  • R a , R b or R c are each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, -OR a , -SR a , -SO 2 R a , -COR a , CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c , -NR a SO 2 R b , - (CH 2 ) 0-3 Si(C 1-4 alkyl) 3 , C 3-12 cycloalky
  • formula (I) is selected from compounds represented by general formula (III):
  • R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b , the C 1-8 alkyl group
  • R 3 ' is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, -NR a R b , C 1-8 haloalkoxy, or C 1-8 haloalkyl;
  • R 3 , R 4 , and R 5 are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2 -8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or
  • R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
  • R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered
  • the heteroaryl group is optionally further substituted by at least one R ;
  • X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 or O;
  • X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 or O;
  • X 3 is selected from C or N;
  • R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
  • R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
  • R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl
  • R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12
  • R b , R c or R d are each independently selected from hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl Base, H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
  • the compound of formula (III) is selected from the group consisting of compounds of the following formula:
  • R 1 '-R 3 ' and R 2 -R 8 are the same as in formula (III).
  • R 1 ' in formula (III) is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered hetero Ring group, C 6-12 aryl group, 5-12 membered heteroaryl group, oxo group, -NR a R b , -OR a , -NR a CO 2 R b , -NR a SO 2 R b or -COR a ; wherein, the C 1-8 alkyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, -NR a R b , -OR a or -COR a is optionally further substituted by at least one member selected from halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl
  • R 1 ' in formula (III) is selected from H, halogen, C 1-8 alkyl, -COR a , -NR a CO 2 R b , -NR a SO 2 R b , -NR a R b , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-8 alkyl, -NR a CO 2 R b , -NR a SO 2 R b , -NR a R b , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optionally further At least one is selected from halogen, C 1-8 alkyl, hydroxyl, C 1-8 alkoxy, -OR a , oxo or -CN substituent.
  • R 1 ' in formula (III) is selected from H, methyl,
  • R 2 ' in formula (III) is selected from H, C 1-8 alkyl or -NR a R b ; preferably from H, methyl,
  • the group formed after R 1 ' and R 2 ' in formula (III) and the carbon atoms they are jointly connected to form a ring are selected from since
  • R 3 ' in formula (III) is selected from H, methyl,
  • R2 in formula (III) is selected from methyl or -CF3 .
  • R in formula (III) is selected from Among them, the Optionally further selected from at least one group selected from H, -OH, C 1-8 alkyl, C 1-8 haloalkoxy, oxo, -(CH 2 ) 0-3 CN, -NO 2 , -OR b , -SR b or C 1-8 haloalkyl substituent.
  • R in formula (III) is selected from
  • R 4 in formula (III) is selected from H, halogen, C 1-8 alkyl or C 1-8 alkoxy.
  • R 4 in formula (III) is selected from H, F, methyl, or -OCH 3 .
  • R 4 and R 12 in formula (III) together form a 5-8-membered heterocyclyl group, and the 5-8-membered heterocyclyl group is optionally further substituted by at least one R a .
  • formula (I) is selected from compounds represented by general formula (IV):
  • X 1 is selected from -C(R 7 ) 2 -, -NR 7 - or -O-;
  • X 2 is selected from -C(R 8 ) 2 -, -NR 8 - or -O-;
  • X 3 is selected from C or -N-;
  • R 1 ' is selected from H, C 1-8 alkyl, C 1-8 haloalkyl or C 1-8 alkoxy;
  • R 2 ' is selected from H, C 1-8 alkyl, C 1-8 haloalkyl or C 1-8 alkoxy;
  • R 1 ' , R 2 ' and the carbon atom to which they are connected form a 3-6-membered heterocyclic group; wherein, the 3-6-membered heterocyclic group can be further substituted by one or more independent R a ;
  • R 3 ' is each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl or -NR a R b ; wherein, the C 1-8 alkoxy group, C 1-8 alkyl group, C 1-8 haloalkoxy group, C 1-8 haloalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally further substituted by one or more independent R a ;
  • X 7 is selected from C(R 10 ) 2 , NR 10 or O;
  • R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
  • R 3 and R 5 are each independently selected from H, -CN, -NO 2 , hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the C 1-8 alkoxy group, C 1-8 alkyl, C 1-8 hydroxyl group Alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optionally further substituted by one or more independent R a ;
  • R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered Heteroaryl is optionally further substituted by one or more independent R ;
  • R 7 , R 8 , and R 10 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1 -8 haloalkoxy;
  • R a or R b are each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl.
  • the compound of formula (IV) is selected from the group consisting of compounds of the following formula:
  • R 1 ', R 2 ', R 3 ', R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are as described in formula (IV);
  • X 7 is selected from -C(H) 2 - or -O-.
  • R 3 ' in formula (IV) is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered hetero Ring group, -NR a R b ; wherein, the C 1-8 alkoxy group, C 1-8 alkyl group, C 3-12 cycloalkyl group, -NR a R b or 3-12 membered heterocyclyl group is any Optionally further substituted by one or more R a ; each of the R a or R b is independently selected from H, hydroxyl, halogen, -CN, oxo group, C 1-8 alkyl, C 1-8 Alkoxy group, C 3-12 cycloalkyl group, 3-12 membered heterocyclyl group or C 1-8 haloalkyl group.
  • R 3 ' in formula (IV) is selected from H, methyl,
  • R 1 ' in formula (IV) is selected from H or C 1-8 alkyl; said R 2 is selected from H or C 1-8 alkyl.
  • R 1 ', R 2 ' in formula (IV) and the carbon atoms to which they are connected form a 3-6-membered heterocyclic group; wherein, the 3-6-membered heterocyclic group can be further substituted by one or more Substituted by two independent R a ; the R a is selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo group, C 1-8 alkyl or C 1-8 alkoxy group.
  • R 2 in formula (IV) is selected from C 1-8 alkyl or C 1-8 haloalkyl; preferably methyl or -CF 3 .
  • formula (IV) is the structure shown in formula (V):
  • R 3 , R 5 and R 6 are as described in formula (IV).
  • R 6 in formula (IV) is selected from 3-12-membered heterocyclyl or 5-12-membered heteroaryl; wherein, the 3-12-membered heterocyclyl or 5-12-membered heteroaryl Optionally further substituted by one or more independent R a selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 Alkoxy or -SC 1-8 alkyl.
  • R in formula (IV) is selected from Among them, the Optionally further substituted by one or more independent R a selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 Alkoxy or -SC 1-8 alkyl.
  • R in formula (IV) is selected from
  • R 3 in formula (IV) is selected from H, halogen or C 1-8 alkyl; preferably methyl.
  • R 5 in formula (IV) is selected from H, halogen or C 1-8 alkyl; preferably Cl.
  • the compound in formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt is selected from:
  • the compound of the present invention can effectively inhibit the function of EZH2 protein, and has a strong inhibitory effect in experiments on various types of EZH2 mutated or amplified hematological tumors and solid tumor cells.
  • this type of compound has excellent oral absorption in various animal models, which is much higher than the second-generation EZH2 inhibitors currently on the market, and is expected to achieve better clinical efficacy.
  • the compound of the present invention has the advantages of low toxicity and large safety window.
  • the present invention also provides a pharmaceutical composition, which is characterized in that the pharmaceutical composition contains a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable auxiliary material.
  • the present invention further provides a pharmaceutical composition, characterized in that the mass percentage of the therapeutically effective amount of at least one compound represented by formula (I) and pharmaceutically acceptable excipients is 0.0001:1-10.
  • the present invention provides the use of compounds or pharmaceutical compositions represented by structural formula (I) in the preparation of medicines.
  • the application is in the preparation of drugs for the treatment and/or prevention of cancer.
  • the application is the application of preparing drugs for treating diseases mediated by EZH2.
  • the disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • the present invention also provides a method for treating and/or preventing diseases, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same.
  • the present invention also provides a method for treating and/or preventing diseases mediated by EZH2, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same.
  • the present invention also provides a method for treating cancer, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same.
  • the EZH2-mediated disease is cancer.
  • the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • alkyl includes linear or branched monovalent saturated hydrocarbon groups.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc.
  • the " 1-8 " in "C 1-8 alkyl” refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain. group.
  • Alkoxy refers to the oxygen ether form of the aforementioned linear or branched alkyl group, that is, -O-alkyl.
  • alkylene refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the alkylene's point of attachment to the rest of the compound. Similarly, “C 1-3 " in C 1-3 alkylene refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
  • compositions comprising "a” pharmaceutically acceptable excipient may be interpreted to mean that the composition includes “one or more” pharmaceutically acceptable excipients.
  • haloalkyl refers to an alkyl group in which one or more H's have been replaced by a halogen atom.
  • haloalkoxy refers to the group -O-haloalkyl.
  • oxo or "oxo” refers to an oxygen atom in the form of a divalent substituent which, when attached to C, forms a carbonyl group and which, when attached to a heteroatom, forms a sulfoxide or sulfone or N-oxide group group.
  • aromatic ring means having aromatic characteristics (having (4n+2) delocalized ⁇ electrons, where n is Integer) polyunsaturated ring carbocyclic or heterocyclic ring.
  • aryl in the present invention, unless otherwise stated, refers to an unsubstituted or substituted single atom including a carbocyclic ring. Ring or fused ring aromatic groups. A C 6-12 aryl group is preferred, and a C 6-10 monocyclic or bicyclic aromatic ring group is more preferred. Preferred are phenyl and naphthyl. Most preferred is phenyl.
  • the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, where the ring attached to the parent structure is an aryl ring, non-limiting examples include but are not limited to benzocyclopentyl.
  • heterocyclyl refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic atom selected from N, O and/or S.
  • the heterocyclyl group may include monocyclic or polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). Heterocyclyl groups can be connected to other parts of the compound via ring carbon atoms or ring heteroatoms.
  • 3-12-membered heterocyclic groups and "3-12-membered" in 3-12-membered heterocyclic groups refers to heterocyclic groups containing 3-12 C, N, O or S ring-forming atoms; more preferably 3-8 membered heterocyclyl group, more preferably 3-6 membered heterocyclyl group.
  • the nitrogen or sulfur heteroatoms can be selectively oxidized, and the nitrogen heteroatoms can be selectively quaternized.
  • heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydroxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydrogen Oxadiazolyl.
  • the heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is the heterocyclyl group.
  • heteroaryl in the present invention, unless otherwise stated, refers to a monocyclic or polycyclic (such as fused bicyclic) aromatic heterocyclic ring with at least one heteroatom selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatoms can be selectively oxidized and the nitrogen heteroatoms can be selectively quaternized.
  • heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolyl or isoquinolyl.
  • the heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
  • cycloalkyl refers to a ring system having at least one cyclized alkyl group.
  • C 3-12 cycloalkyl is preferred, where "C 3-12 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms.
  • Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.).
  • the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, where it is connected to the parent structure The rings joined together are cycloalkyl.
  • substituted means that one or more hydrogen atoms in the group are replaced by the same or different substituents, respectively.
  • the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy group, tert-butoxy group, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C(OCH 3 ), cyano group, nitro group, -CF 3 , -OCF 3 , amino group, dimethyl group amino, methylthio, sulfonyl and acetyl groups.
  • substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxolylmethyl and piperazinylmethyl.
  • substituted alkoxy examples include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
  • salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low prices), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low prices), potassium, sodium, and zinc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred.
  • Nontoxic organic bases capable of being derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines.
  • non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine Acid, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
  • ion exchange resins and arginine betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylamin
  • the compound provided by the present invention is a base
  • its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids.
  • acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, parapexic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydriodic acid, perchloric acid, cyclohexane sulfonic acid, salicylic acid, 2-naphthalene sulfonic acid, saccharinic
  • a certain purity is used, for example, at least 60% Purity, preferably a purity of at least 75%, particularly preferably a purity of at least 98% (% is a weight ratio).
  • prodrugs of the compounds of the present invention are included in the protection scope of the present invention.
  • the prodrug refers to a functional derivative that is easily converted into the desired compound in the body.
  • any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite after administration to the recipient; Residues.
  • the compounds described in the present invention may contain one or more asymmetric centers, and diastereoisomers and optical isomers may arise therefrom.
  • the present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
  • the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as their mixtures.
  • substitution of compounds of formula (I) with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
  • the present invention includes any possible solvates and polymorphic forms.
  • the type of solvent used to form the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable.
  • water, ethanol, propanol, acetone and other similar solvents can be used.
  • composition is meant to include products containing specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of specified amounts of each specified ingredient. Accordingly, pharmaceutical compositions containing compounds of the invention as active ingredients as well as methods of preparing the compounds of the invention are also part of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also within the scope of the present invention.
  • composition refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients.
  • the purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
  • the pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with appropriate pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, Topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • treatment generally refers to obtaining a desired pharmacological and/or physiological effect.
  • the effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease.
  • treatment encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
  • the term "effective amount” means (i) treating or preventing a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described in .
  • the amount of a compound of the present application that constitutes a "therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
  • Step A Compound II-1 and compound II-2 are subjected to acid-amine condensation under basic conditions such as DIEA and a condensation reagent such as HATU to obtain compound II-3;
  • Step B Compound II-3 is reduced by hydrogenation to obtain the target compound II.
  • TosCl p-toluenesulfonyl chloride
  • DIPEA/DIEA N,N-diisopropylethylamine
  • PE petroleum ether
  • CD 3 OD deuterated methanol
  • TEA triethylamine
  • HATU 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate
  • TMSCH 2 N 2 trimethylsilylated diazomethane
  • Pd(DPEPhos)Cl 2 bis(diphenylphosphinephenyl ether)palladium(II) dichloride;
  • CPME cyclopentyl methyl ether
  • LiOH.H 2 O lithium hydroxide monohydrate
  • HATU N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate
  • HOAc acetic acid/glacial acetic acid
  • Ru 3 (CO) 12 triruthenium dodecacarbonyl
  • TFA trifluoroacetic acid
  • LiOH.H 2 O lithium hydroxide monohydrate
  • Chloroform-d deuterated chloroform
  • Dess-martin Dess-Martin oxidant
  • DMF-DMA N,N-dimethylformamide dimethyl acetal
  • NIS N-iodosuccinimide
  • prep-TLC thin layer chromatography preparative separation
  • intermediate M1 refers to the synthesis of intermediate 9 in patent WO2019204490.
  • intermediate M4-2 (0.910g) was dissolved in 10.0mL anhydrous methanol, and then anhydrous potassium carbonate (0.920g) and (1-diazo-2-oxopropyl)phosphine were added in sequence Acid dimethyl ester (0.960g), react at room temperature for 2 hours.
  • 1 H NMR 500MHz, Chloroform-d
  • Example 1 Compound (R)-7-chloro-2-((1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl Base-N-((7-methyl-5-oxo-5,6-dihydro-1H-pyrrole[2,3-c]pyridin-4-yl)methyl)benzo[d][1, 3] Synthesis of dioxin-5-carboxamide
  • Example 60 7-chloro-2-(1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-(4 -Methyl-6-oxo-5,6-dihydropyrrolo[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxole- Synthesis of 5-carboxamide
  • compound 60-9 (0.50g) and bis(triphenylphosphine)cyclopentadienylruthenium chloride (174.58mg) were dissolved in pyridine (2.0mL), and N2 replaced 2-3 After several times, react at 75°C for 8 hours.
  • LC-MS monitors the complete reaction of raw materials. The solvent was evaporated from the reaction solution under reduced pressure, and the solvent was evaporated again after being redissolved in DCM. The product was purified by column chromatography to obtain 0.30 g of a white solid product, namely compound 60-10.
  • Example 62 Compound 7-chloro-2-(1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-( 7-Methyl-5-oxo-5,6-dihydropyrazolo[3,4-c]pyridin-4-yl)methyl)benzo[d][1,3]dioxola Synthesis of ene-5-carboxamide
  • Dissolve intermediate 62-7 (55 mg) in 5.00 mL DCM, then add 1.00 mL TFA, react at room temperature for 0.5 h, directly concentrate the reaction solution, redissolve 5.00 mL DCM and concentrate again, and prepare liquid phase separation and purification to obtain light 2.9 mg of yellow powder, namely compound 62.
  • Example 93 Compound 7-chloro-2-(3-(dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-N-(6-methyl Synthesis of methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxin-5-carboxamide
  • Dissolve 93-1 (100mg) in 5.00mL DCM, then add 1.00mL TFA, react at room temperature for 0.5h, directly concentrate the reaction solution, redissolve 5.00mL DCM and concentrate again, then dissolve 5.00mL methanol, add 37% Formaldehyde aqueous solution (24.6mg), react at room temperature for 30 minutes. Then add sodium cyanoborohydride (21.3 mg) and react at room temperature for 10 minutes. LCMS monitors the completion of the reaction. The reaction solution was directly concentrated, and the preparative liquid phase was separated to obtain 16.9 mg of compound 93. ESI-MS m/z:518[M+H] + .
  • Example 117 Compound 9-chloro-6-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(3-(dimethyl Aminomethyl)bicyclo[1.1.1]pent-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxetane[4,5-g]isoquin Synthesis of pholin-5(6H)-one
  • Step 1 Synthesis of Compound 117-1
  • Example 138 Compound 9-chloro-2-(3-(dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-6-(6-methyl methyl-4-methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro-[1,3]dioxetane[4,5 -Synthesis of isoquinolin-5(6H)-one
  • Step 1 Synthesis of Compound 138-1
  • Example 139 Compound 10-chloro-2-(3-((dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-6-(( 6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6,7,8,9-tetrahydro-5H-[1, 3] Synthesis of dioxetane[4',5':4,5]benzo[1,2-c]azaline-5-one
  • Step 1 Synthesis of Compound 139-1
  • compound 139-1 (3.2g), (E)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) Allyl) tert-butyl carbamate (3.67g), PdCl 2 (dppf) (0.63g), potassium carbonate (3.58g), dioxane (50mL), and water (10mL) were added to a 100mL three-necked bottle. Then react at 100°C for 12 hours under N2 protection conditions and stop the reaction. Cool the reaction solution to room temperature, add 100 mL of water, and extract twice with 150 mL of EA each time.
  • Step 8 Synthesis of Compound 139-8
  • Example 194 Compound 7-chloro-2-(3-(dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-N-(4-methyl base-6-oxo-5,6-dihydrofuran[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxetane-5-carboxamide synthesis
  • Dissolve intermediate 194-3 (50mg) in 5.00mL DCM, then add 1.00mL TFA, react at room temperature for 0.5h, directly concentrate the reaction solution, redissolve 5.00mL DCM and concentrate again, then dissolve 5.00mL methanol, add 37 % formaldehyde aqueous solution (13.0 mg), react at room temperature for 30 minutes. Then add sodium cyanoborohydride (11.0 mg) and react at room temperature for 10 minutes. LCMS monitors the completion of the reaction. Add 10 mL of saturated sodium bicarbonate solution to the reaction solution to quench the reaction. Then 10 mL of DCM was added for extraction three times. The organic phase was collected, dried over anhydrous sodium sulfate and filtered.
  • Example 195 Compound 7-chloro-2-(1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-( 7-Methyl-5-oxo-4,5-dihydropyrrolo[3,2-b]pyridin-6-yl)methyl)benzo[d][1,3]dioxole -Synthesis of 5-carboxamide
  • Example 196 7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-N-((6-methyl-4 Synthesis of -(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide
  • Example 197 7-chloro-2-(6-((dimethylamino)methyl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methyl) Synthesis of thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide
  • Example 198 7-chloro-2-(2-((dimethylamino)methyl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methyl) Synthesis of thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide
  • Example 198 The synthetic route of Example 198 is the same as that of Example 197.
  • Step 1 Synthesis of Compound 199-1
  • Example 200 Compound 7-chloro-2-(4-(1-(dimethylamino)cyclopropyl)phenyl)-2,4-dimethyl-N-((6-methyl-4- Synthesis of (methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxolane-5-carboxamide
  • reaction solution was directly concentrated and separated and purified by column chromatography (DCM-MeOH, 10% MeOH peak) to obtain 58.0 mg of light yellow solid, namely compound 200-6.
  • Example 201 Compound (R)-7-chloro-2-((1r,4R)-4-((4-fluorophenyl)(methyl)amine)cyclohexyl)-2,4-dimethyl- N-((4-methyl-6-oxo-5,6-dihydrofuran[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxolane -Synthesis of 5-carboxamide
  • Step 1 Synthesis of Compound 201-1
  • Methyl(R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxolane-5-carboxamide (150.0 mg ) and p-fluorobenzylamine (121.9 mg) were added to a mixed solvent of tetrahydrofuran (4 mL) and methanol (4 mL), protected by nitrogen, and stirred at room temperature for 2 hours. Then place the reaction bottle at -70°C, add lithium borohydride (19.3 mg), keep stirring for 0.5 hours, and perform TLC Monitor the reaction for completion.
  • Example 202 Compound (2R)-7-chloro-2,4-dimethyl-N-((4-methyl-6-oxo-5,6-dihydrofuran[3,2-c]pyridine- 7-yl)methyl)-2-((1r,4R)-4-(tetrahydro-1H-furan[3,4-c]pyrrole-5(3H)-yl)cyclohexyl)benzo[d] Synthesis of [1,3]dioxolane-5-carboxamide
  • Methyl(R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxolane-5-carboxamide (200.0 mg ) and hexahydro-1H-furan[3,4-c]pyrrole (133.6 mg) were added to a mixed solvent of tetrahydrofuran (4 mL) and methanol (4 mL), protected by nitrogen, and stirred at room temperature for 2 hours. Then the reaction bottle was placed at -70°C, lithium borohydride (25.7 mg) was added, kept stirring for 0.5 hours, and TLC monitored the reaction to completion.
  • Step 1 Synthesis of Compound 203-1
  • Dissolve compound 204-2 (5.3g) in THF (60.0mL), cool to 0°C, slowly add 2 mol/L diisobutylaluminum hydride in n-hexane solution (10.5mL), and react at 0°C for 2 hours. Add saturated ammonium chloride solution to the reaction solution to quench, add 40 mL H 2 O and 100 mL EA to the reaction solution, stir and separate the layers, extract the aqueous phase with EA three times, combine the organic phases, wash, dry, and concentrate to dryness , the concentrate does not require purification and is directly put into the next step to obtain the target compound 204-3 (3.8g, yield 88.2%). ESI-MS m/z:263.1[M+H] + .
  • Step 8 Synthesis of Compound 204
  • Example 205 7-chloro-6-methoxy-2-((1r,4r)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-di Methyl-N-((4-methyl-6-oxo-5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3] Synthesis of dioxola-5-carboxamide
  • Step 1 Synthesis of Compound 205-1
  • the above compound 205-6 (0.87g) was dissolved in DMF (10 mL), potassium carbonate (0.68g) and methyl iodide (0.52g) were added, and the reaction was carried out at room temperature overnight. Add 10 mL H 2 O and 10 mL EA to the reaction solution, stir and separate layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness. The concentrate does not need to be purified and is directly added to the next step to obtain the target compound. 205-7 (0.8g, yield 88.6%).
  • Example 206 7-chloro-6-fluoro-2-((1r,4r)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl -N-((4-methyl-6-oxo-5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxo Synthesis of heterocyclopent-5-carboxamide
  • Step 1 Synthesis of Compound 206-1
  • Example 207 Compound 7-chloro-4-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl Synthesis of )-2-(((1-methylpiperidin-4-yl)methyl ester)-3-oxoisoindoline-5-carboxamide
  • Step 1 Synthesis of Compound 207-1
  • Step 1 Synthesis of Compound 208-1
  • the methyltransferase kit MTase-Glo Kit (Promage, V7602) was used to detect the methyltransferase activity of PRC2-EZH2.
  • the reaction buffer is 20mM Tris-HCl [pH 8.0], 50mM NaCl, 1mM EDTA, 3mM MgCl 2 , 0.1mg/ml BSA, 1mM DTT.
  • Pfeiffer EZH2 (A677G) cells were spread in a low-adsorption 96-well plate at a cell density of 5,000 cells/well, placed in a cell culture incubator, and after the cells were stabilized for 1-3 hours, the compound to be tested was added at a final concentration of 1,000, 333.33, and 111.11 , 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0nM (the final concentration of DMSO is 0.1%) was added to the 96-well plate. The cell plate was cultured in a 37°C, 5% CO2 cell incubator for 7 days and then 50 ⁇ L was added to each well.
  • Inhibition percentage (maximum value - measured value) / (maximum value - Blank) ⁇ 100
  • Compound D1 Purchased from MCE (MedChemExpress), the trade name is Valemetostat, its structure is as follows:
  • mice were divided into two groups, with 3 mice in each group, all of which were female.
  • Compounds were administered via a single intragastric administration of 10 mg/kg; blood was collected through the fundus venous plexus at designated time points, and the plasma was separated and placed into Store in -80°C refrigerator.
  • mice Nine Balb/c mice were divided into three groups, with three mice in each group, all of which were female.
  • Compound D1 was administered at a dose of 10 mg/kg by intragastric administration at a single time; blood was collected from the fundus venous plexus at designated time points, and the plasma was separated and released. Store in -80°C refrigerator.

Abstract

Provided is a compound having a structure of formula (I), which has cancer treatment activity. Further provided are a preparation method for the compound of formula (I), and a pharmaceutical composition comprising the compound.

Description

EZH2抑制剂及其在医药上的应用EZH2 inhibitors and their applications in medicine 技术领域Technical field
本发明属于医药领域，尤其涉及一种EZH2抑制剂，其具有癌症治疗活性。本发明还涉及这些化合物的制备方法以及包含其的药物组合物。The invention belongs to the field of medicine, and in particular relates to an EZH2 inhibitor, which has cancer therapeutic activity. The present invention also relates to methods for the preparation of these compounds and pharmaceutical compositions containing the same.
背景技术Background technique
DNA的甲基化和去甲基化等表观遗传学修饰在基因表达中发挥重要作用，同时也是癌症发生发展的重要原因之一。zeste同源物2增强子(EZH2)是多梳群基因(PcGs)家族的成员，多梳抑制复合物2(PRC2)是两种PcG蛋白核心复合物之一，主要通过调节染色质结构介导基因沉默。EZH2是PRC2的核心催化亚基，与PRC2另外两个主要的非催化亚基EED和SUZ12形成络合物后具有稳定的甲基转移酶活性，催化组蛋白H3上27号位的赖氨酸(H3K27)三甲基化诱导染色体凝集，进而抑制靶基因的转录，参与调控细胞周期，细胞衰老，细胞分化及癌症等生理或病理过程。大量研究表明EZH2在***癌、卵巢癌、膀胱癌、肺癌等多种实体瘤中高表达，在淋巴瘤等血液瘤中常发生激活突变，最终均导致H3K27me3水平升高。Epigenetic modifications such as DNA methylation and demethylation play an important role in gene expression and are also one of the important causes of cancer development. Enhancer of zeste homolog 2 (EZH2) is a member of the Polycomb group genes (PcGs) family, and polycomb repressive complex 2 (PRC2) is one of two PcG protein core complexes that are mainly mediated by regulating chromatin structure. Gene silencing. EZH2 is the core catalytic subunit of PRC2. It forms a complex with the other two main non-catalytic subunits of PRC2, EED and SUZ12, and has stable methyltransferase activity, catalyzing the removal of lysine at position 27 on histone H3 ( H3K27) trimethylation induces chromosome condensation, thereby inhibiting the transcription of target genes and participating in the regulation of physiological or pathological processes such as cell cycle, cell senescence, cell differentiation and cancer. A large number of studies have shown that EZH2 is highly expressed in various solid tumors such as prostate cancer, ovarian cancer, bladder cancer, and lung cancer. It often undergoes activating mutations in hematological tumors such as lymphoma, which ultimately leads to increased H3K27me3 levels.
组蛋白赖氨酸甲基转移酶EZH2催化辅助因子S腺苷甲硫氨酸(SAM)活性甲基转移到组蛋白H3上27号位赖氨酸(H3K27)的ξ-NH2，导致H3K27的三甲基化(H3K27me3)和随后的靶基因的转录沉默，从而调控癌症进展及干细胞干性维持等多种生命活动。研究表明，依赖EZH2的组蛋白甲基化是造成抑癌基因沉默的一种潜在机制。此外，EZH2也可以通过一种不依赖于PRC2的方式对非组蛋白进行甲基化来发挥功能；或是与其他因子一起构成转录复合体来激活下游靶基因的转录，提高靶基因的表达量；还可以对干细跑的干性维持及世代分化进行调控。因此，由EZH2所介导的信号通路被认为是造成诸如癌症等多种病理过程产生的内在原因。异常EZH2活性的抑制可能是用于治疗癌症有吸引力的新策略。针对EZH2甲基转移酶SET区域已成功开发出多个靶向小分子药物，用于淋巴瘤、多种实体瘤的治疗。Histone lysine methyltransferase EZH2 catalyzes the transfer of the active methyl group of the cofactor S adenosylmethionine (SAM) to the ξ-NH2 of lysine 27 (H3K27) on histone H3, resulting in the trisomy of H3K27. Methylation (H3K27me3) and subsequent transcriptional silencing of target genes regulate various life activities such as cancer progression and stem cell stemness maintenance. Studies have shown that EZH2-dependent histone methylation is a potential mechanism responsible for silencing tumor suppressor genes. In addition, EZH2 can also function by methylating non-histone proteins in a manner that is independent of PRC2; or it can form a transcription complex with other factors to activate the transcription of downstream target genes and increase the expression of target genes. ; It can also regulate the stemness maintenance and generational differentiation of Ganxipao. Therefore, the signaling pathway mediated by EZH2 is considered to be an intrinsic cause of various pathological processes such as cancer. Inhibition of aberrant EZH2 activity may be an attractive new strategy for treating cancer. A number of targeted small molecule drugs have been successfully developed targeting the SET region of EZH2 methyltransferase for the treatment of lymphoma and various solid tumors.
靶向EZH2的药物仍然是当前药物研发热点领域之一，2020年，全球首个EZH2抑制剂Tazemetostat上市，2022年，首个EZH1，EZH2双抑制剂Valemetostat在日本获批上市。除此之外，国际上各大药企也均有布局。然而上市的药品存在着CYP诱导等问题，仍有必要进行研究改进，以适应临床需求。 Drugs targeting EZH2 are still one of the current hot areas of drug research and development. In 2020, the world's first EZH2 inhibitor Tazemetostat was launched. In 2022, the first EZH1 and EZH2 dual inhibitor Valemetostat was approved for marketing in Japan. In addition, major international pharmaceutical companies also have plans. However, there are problems such as CYP induction in the drugs on the market, and it is still necessary to conduct research and improvements to meet clinical needs.
发明内容Contents of the invention
本发明提供一种通式(I)所示的化合物、其立体异构体、互变异构体、氘代物或药用盐：
The present invention provides a compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
其中，in,
X1选自-CO-、C(R7)2、NR7、O或S；X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 , O or S;
X2选自-CO-、C(R8)2、NR8、O或S；X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 , O or S;
X3选自C或N；X 3 is selected from C or N;
R2选自不存在、H、羟基、氨基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素；R 2 is selected from absence, H, hydroxyl, amino, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl , -NR a R b , or halogen;
R12选自H、C1-8烷基或C1-8卤代烷基；R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl;
R3、R4、R5各自独立选自H、卤素、C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc；其中，所述C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 ring Alkyl group, 3-12 membered heterocyclyl group, C 6-12 aryl group, 5-12 membered heteroaryl group, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 R c ; wherein, the C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optionally further substituted by at least one R a ;
或者，R4也可以与R12共同形成一个5-12元的杂环基；其中，所述5-12元的杂环基任选地进一步被至少一个Ra取代；Alternatively, R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
R7、R8各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
或者，R7和R8与其所连接的碳原子一起形成C3-12环烷基、3-12元杂环基；其中，所述C3-12环烷基、3-12元杂环基基任选地进一步被一个或多个独立的Ra所取代；Alternatively, R 7 and R 8 together with the carbon atom to which they are connected form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclyl group; wherein, the C 3-12 cycloalkyl group or 3-12 membered heterocyclyl group The group is optionally further substituted by one or more independent R a ;
Ra各自独立地选自H、卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc或-NRbSO2Rc，所述C1-8烷 基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、6-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc取代基所取代；R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkane Optionally further _ _ Selected from halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 6 -12-membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 R c substituent substituted;
Rb、Rc或Rd各自独立地选自羟基、卤素、-CN、-NO2、氧代基、C1-8烷氧基、-N-C1-8烷基、-S-C1-8烷基、H、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；R b , R c or R d are each independently selected from hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl Base, H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
其中，R1、R6的定义选自下组中的一种：Among them, the definition of R 1 and R 6 is selected from one of the following groups:
1)当R1中C3-12环烷基为时：1) When C 3-12 cycloalkyl in R 1 is hour:
其中，in,
R1’、R2’各自独立地选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb或-NRaSO2Rb，所述C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b , the C 1-8 alkyl group, C 1-8 alkoxy group, C 1-8 haloalkyl group Oxygen group, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclyl group, C 6 -12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
或者，R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；Alternatively, R 1 ' and R 2 ' and the carbon atoms they are connected together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5-12 membered heteroaryl group, wherein C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
R3’各自独立地选自H、羟基、卤素、-CN、-NO2、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基、3-12元杂环基或-NRaRb，所述C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基或3-12元杂环基任选地进一步被一个或多个独立的Ra所取代；R 3 ' is each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl or -NR a R b , the C 1-8 alkoxy group, C 1-8 alkyl group, C 1-8 haloalkoxy group, C 1 -8 haloalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally further substituted by one or more independent R a ;
R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代；R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl The group is optionally further substituted by one or more independent R a ;
2)当R6为时： 2) When R 6 is hour:
其中，in,
选自单键或双键； Selected from single or double bonds;
X4、X5、X6选自C(R9)m、N、NR9、O或S；X 4 , X 5 , and X 6 are selected from C(R 9 ) m , N, NR 9 , O or S;
R6’选自H、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 6 ' is selected from H, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
R9选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 9 is selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
R1选自C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代。R 1 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5- 12-membered heteroaryl, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl group or 5-12 membered heteroaryl group is optionally further substituted by at least one R a .
一些实施方式中，式(I)选自通式(II)所示的化合物：
In some embodiments, formula (I) is selected from compounds represented by general formula (II):
其中，in,
R1选自C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5- 12-membered heteroaryl, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl The base or 5-12 membered heteroaryl group is optionally further substituted by at least one R a ;
R2选自不存在、H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基或卤素；R 2 is selected from absence, H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl or halogen ;
R3、R4、R5各自独立选自H、卤素、C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc；其中，所述C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 ring Alkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, oxo group, -CN, -NO 2 , -OR b , -SR b , -SOR b , - SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , - NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 R c ; wherein, the C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group , C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optionally further substituted by at least one R a ;
R4也可以与R12共同形成一个5-12元的杂环基；其中，所述5-12元的杂环基任选地进一步被至少一个Ra取代； R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
X1选自-CO-、C(R7)2、N或O；X 1 is selected from -CO-, C(R 7 ) 2 , N or O;
X2选自-CO-、C(R8)2、N或O；X 2 is selected from -CO-, C(R 8 ) 2 , N or O;
X3选自C或N；X 3 is selected from C or N;
X4、X5、X6选自C(R9)m、N、NR9、O或S；X 4 , X 5 , and X 6 are selected from C(R 9 ) m , N, NR 9 , O or S;
R6’选自H、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 6 ' is selected from H, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
R7、R8、R9各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 , R 8 , and R 9 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1 -8 haloalkoxy;
R12选自H、C1-8烷基或C1-8卤代烷基；R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl;
m各自独立选自1或2；m is each independently selected from 1 or 2;
n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
选自单键或双键； Selected from single or double bonds;
Ra各自独立地选自H、卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc或-NRbSO2Rc，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、6-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc取代基所取代；R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further selected from Halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 6-12 membered Heteroaryl, oxo, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 Substituted by R c substituent;
Rb、Rc或Rd各自独立地选自H、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；R b , R c or R d are each independently selected from H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkene base, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
一些实施方式中，式(I)所述的R12选自H。In some embodiments, R12 of formula (I) is selected from H.
一些实施方式中，式(I)选自通式(IIA)所示的化合物：
In some embodiments, formula (I) is selected from compounds represented by general formula (IIA):
其中，R2选自H、羟基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基或卤素；Wherein, R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl or halogen;
R1、R3、R4、R5、R6’、X4、X5、X6、n的定义同式(II)。The definitions of R 1 , R 3 , R 4 , R 5 , R 6 ', X 4 , X 5 , X 6 and n are the same as in formula (II).
一些实施方式中，式(I)选自通式(IIB)所示的化合物：
In some embodiments, formula (I) is selected from compounds represented by general formula (IIB):
其中，R1、R3、R4、R5、R6’、X4、X5、X6、n的定义同式(II)。Among them, the definitions of R 1 , R 3 , R 4 , R 5 , R 6 ', X 4 , X 5 , X 6 and n are the same as those in formula (II).
一些实施方式中，式(II)所述R1选自C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代，所述Ra选自H、卤素、C1-8烷基、C3-12环烷基、3-12元杂环基、-ORb或-NRbRc。In some embodiments, R 1 in formula (II) is selected from C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, and the C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a selected from H, halogen, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, -OR b or -NR b R c .
一些实施方式中，式(II)所述R1选自 In some embodiments, R 1 in formula (II) is selected from
一些实施方式中，式(II)所述R1选自 In some embodiments, R 1 in formula (II) is selected from
一些实施方式中，式(II)所述R2选自H或C1-8烷基。In some embodiments, R 2 in formula (II) is selected from H or C 1-8 alkyl.
一些实施方式中，式(II)所述R4选自H、卤素或C1-8烷基。In some embodiments, R 4 in formula (II) is selected from H, halogen or C 1-8 alkyl.
一些实施方式中，式(II)所述R6’选自H、卤素或C1-8烷基，优选甲基。In some embodiments, R 6 ' in formula (II) is selected from H, halogen or C 1-8 alkyl, preferably methyl.
一些实施方式中，式(II)所述X4选自O、C(R9)m、NR9或S。 In some embodiments, X 4 in formula (II) is selected from O, C(R 9 ) m , NR 9 or S.
一些实施方式中，式(II)所述X5选自C(R9)m、O、S或N。In some embodiments, X 5 in formula (II) is selected from C(R 9 ) m , O, S or N.
一些实施方式中，式(II)X6选自N或C(R9)m。In some embodiments, Formula (II) X6 is selected from N or C( R9 ) m .
一些实施方式中，式(II)所述R9选自H或卤素。In some embodiments, R 9 in formula (II) is selected from H or halogen.
一些实施方式中，式(II)所述n选自0或1，优选0。In some embodiments, n in formula (II) is selected from 0 or 1, with 0 being preferred.
一些实施方式中，式(II)所述选自 In some embodiments, formula (II) describes Selected from
一些实施方式中，式(I)选自通式(III)所示的化合物：
In some embodiments, formula (I) is selected from compounds represented by general formula (III):
其中，in,
R1’、R2’各自独立地选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb或-NRaSO2Rb；其中，所述C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b ; wherein, the C 1-8 alkyl group, C 1-8 alkoxy group, C 1- 8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
或者，R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；Alternatively, R 1 ' and R 2 ' and the carbon atoms they are jointly connected to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5-12 membered heteroaryl group; wherein, The C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
R3’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、-NRaRb、C1-8卤代烷氧基、或C1-8卤代烷基；R 3 ' is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, -NR a R b , C 1-8 haloalkoxy, or C 1-8 haloalkyl;
R2选自H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素； R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
R3、R4、R5各自独立选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C2- 8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc或-NRaSO2Rb，所述C1-8烷基、C1- 8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2 -8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b , the C 1-8 alkyl, C 1-8 hydroxyalkyl Optionally further _ _ Replaced by at least one R a ;
R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra所取代；R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl The group is optionally further substituted by at least one R a ;
X1选自-CO-、C(R7)2、NR7或O；X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 or O;
X2选自-CO-、C(R8)2、NR8或O；X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 or O;
X3选自C或N；X 3 is selected from C or N;
R7、R8各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
R12选自H；R 12 is selected from H;
Ra、Rb或Rc各自独立地选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、-ORa、-SRa、-SO2Ra、-CORa、CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc、-NRaSO2Rb、-(CH2)0-3Si(C1-4烷基)3、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、-ORa、-SRa、-CORa、-SO2Ra、CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc、-NRaSO2Rb、-(CH2)0-3Si(C1-4烷基)3、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个选自H、卤素、-OH、-CN、-NO2、C1-8烷基、氧代基、-(CH2)0-3CN、C1-8羟基烷基、C1-8卤代烷氧基或C1-8卤代烷基的取代基所取代；R a , R b or R c are each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, -OR a , -SR a , -SO 2 R a , -COR a , CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c , -NR a SO 2 R b , - (CH 2 ) 0-3 Si(C 1-4 alkyl) 3 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, so Said C 1-8 alkyl group, C 1-8 haloalkoxy group, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, -OR a , - SR a , -COR a , -SO 2 R a , CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c , -NR a SO 2 R b , -(CH 2 ) 0-3 Si(C 1-4 alkyl) 3 , C 3-12 cycloalkyl, 3-12 The one-membered heterocyclyl group, C 6-12 aryl group or 5-12 membered heteroaryl group is optionally further substituted by at least one member selected from H, halogen, -OH, -CN, -NO 2 , C 1-8 alkyl group, oxygen Substituted with substituents of substituents, -(CH 2 ) 0-3 CN, C 1-8 hydroxyalkyl, C 1-8 haloalkoxy or C 1-8 haloalkyl;
且通式(III)的化合物不为 And the compound of general formula (III) is not
一些实施方式中，式(I)选自通式(III)所示的化合物：
In some embodiments, formula (I) is selected from compounds represented by general formula (III):
其中，in,
R1’、R2’各自独立地选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb或-NRaSO2Rb，所述C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b , the C 1-8 alkyl group, C 1-8 alkoxy group, C 1-8 haloalkyl group Oxygen group, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclyl group, C 6 -12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
或者，R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；Alternatively, R 1 ' and R 2 ' and the carbon atoms they are connected together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5-12 membered heteroaryl group, wherein C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
R3’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、-NRaRb、C1-8卤代烷氧基、或C1-8卤代烷基；R 3 ' is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, -NR a R b , C 1-8 haloalkoxy, or C 1-8 haloalkyl;
R3、R4、R5各自独立选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C2- 8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc或-NRaSO2Rb；其中，所述C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2 -8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b ; wherein, the C 1-8 alkyl group, C 1-8 Hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optional Ground is further replaced by at least one R a ;
或者，R4也可以与R12共同形成一个5-12元的杂环基；其中，所述5-12元的杂环基任选地进一步被至少一个Ra取代；Alternatively, R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra所取代；R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered The heteroaryl group is optionally further substituted by at least one R ;
X1选自-CO-、C(R7)2、NR7或O；X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 or O;
X2选自-CO-、C(R8)2、NR8或O；X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 or O;
X3选自C或N； X 3 is selected from C or N;
R2选自H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素；R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
R7、R8各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
R 12选自H、C1-8烷基或C1-8卤代烷基；R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl;
Ra各自独立地选自H、卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc或-NRbSO2Rc，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、6-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc取代基所取代；R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further selected from Halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 6-12 membered Heteroaryl, oxo, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 Substituted by R c substituent;
Rb、Rc或Rd各自独立地选自羟基、卤素、-CN、-NO2、氧代基、C1-8烷氧基、-N-C1-8烷基、-S-C1-8烷基、H、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；R b , R c or R d are each independently selected from hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl Base, H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
一些实施方式中，所述式(III)化合物选自下式化合物：
In some embodiments, the compound of formula (III) is selected from the group consisting of compounds of the following formula:
R1’-R3’、R2-R8的定义同式(III)。 The definitions of R 1 '-R 3 ' and R 2 -R 8 are the same as in formula (III).
一些实施方式中，式(III)中的R1’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-NRaRb、-ORa、-NRaCO2Rb、-NRaSO2Rb或-CORa；其中，所述C1-8烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-NRaRb、-ORa或-CORa任选地进一步被至少一个选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、6-12元杂芳基、氧代基、-ORa、-CN或-NO2取代基所取代。In some embodiments, R 1 ' in formula (III) is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered hetero Ring group, C 6-12 aryl group, 5-12 membered heteroaryl group, oxo group, -NR a R b , -OR a , -NR a CO 2 R b , -NR a SO 2 R b or -COR a ; wherein, the C 1-8 alkyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, -NR a R b , -OR a or -COR a is optionally further substituted by at least one member selected from halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 Substituted with a 6-membered heterocyclic group, C 6-12 aryl group, 6-12 membered heteroaryl group, oxo group, -OR a , -CN or -NO 2 substituent.
一些实施方式中，式(III)中的R1’选自H、卤素、C1-8烷基、-CORa、-NRaCO2Rb、-NRaSO2Rb、-NRaRb、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、-NRaCO2Rb、-NRaSO2Rb、-NRaRb、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个选自卤素、C1-8烷基、羟基、C1-8烷氧基、-ORa、氧代基或-CN取代基所取代。In some embodiments, R 1 ' in formula (III) is selected from H, halogen, C 1-8 alkyl, -COR a , -NR a CO 2 R b , -NR a SO 2 R b , -NR a R b , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 1-8 alkyl, -NR a CO 2 R b , -NR a SO 2 R b , -NR a R b , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, optionally further At least one is selected from halogen, C 1-8 alkyl, hydroxyl, C 1-8 alkoxy, -OR a , oxo or -CN substituent.
一些实施方式中，式(III)中的R1’选自H、甲基、 In some embodiments, R 1 ' in formula (III) is selected from H, methyl,
一些实施方式中，式(III)中的R2’选自H、C1-8烷基或-NRaRb；优选自H、甲基、 In some embodiments, R 2 ' in formula (III) is selected from H, C 1-8 alkyl or -NR a R b ; preferably from H, methyl,
一些实施方式中，式(III)中的R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个选自H、羟基、卤素、C1-8烷基、C1-8烷氧基、氧代基、-CN、-ORa、-NRaRb或C1-8卤代烷基的取代基所取代；In some embodiments, R 1 ' and R 2 ' in formula (III) and the carbon atoms they are connected together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5 -12-membered heteroaryl; wherein, the C 3-12 cycloalkyl, 3-12-membered heterocyclyl, C 6-12 aryl or 5-12-membered heteroaryl is optionally further selected from at least one H, substituted by hydroxyl, halogen, C 1-8 alkyl, C 1-8 alkoxy, oxo, -CN, -OR a , -NR a R b or C 1-8 haloalkyl substituents;
一些实施方式中，式(III)中的R1’与R2’和其共同连接的碳原子形成环后形成的基团选 自 In some embodiments, the group formed after R 1 ' and R 2 ' in formula (III) and the carbon atoms they are jointly connected to form a ring are selected from since
一些实施方式中，式(III)中的R3’选自H、甲基、 In some embodiments, R 3 ' in formula (III) is selected from H, methyl,
一些实施方式中，式(III)中的R2选自甲基或-CF3。In some embodiments, R2 in formula (III) is selected from methyl or -CF3 .
一些实施方式中，式(III)中的R6选自 其中，所述 任选地进一步被至少一个选自H、-OH、C1-8烷基、C1-8卤代烷氧基、氧代基、-(CH2)0-3CN、-NO2、-ORb、-SRb或C1-8卤代烷基的取代基所取代。In some embodiments, R in formula (III) is selected from Among them, the Optionally further selected from at least one group selected from H, -OH, C 1-8 alkyl, C 1-8 haloalkoxy, oxo, -(CH 2 ) 0-3 CN, -NO 2 , -OR b , -SR b or C 1-8 haloalkyl substituent.
一些实施方式中，式(III)中的R6选自 In some embodiments, R in formula (III) is selected from
一些实施方式中，式(III)中的R4选自H、卤素、C1-8烷基或C1-8烷氧基。In some embodiments, R 4 in formula (III) is selected from H, halogen, C 1-8 alkyl or C 1-8 alkoxy.
一些实施方式中，式(III)中的R4选自H、F、甲基或-OCH3。 In some embodiments, R 4 in formula (III) is selected from H, F, methyl, or -OCH 3 .
一些实施方式中，式(III)中的R4与R12共同形成一个5-8元的杂环基，所述5-8元的杂环基任选地进一步被至少一个Ra取代。In some embodiments, R 4 and R 12 in formula (III) together form a 5-8-membered heterocyclyl group, and the 5-8-membered heterocyclyl group is optionally further substituted by at least one R a .
一些实施方式中，式(I)选自通式(IV)所示的化合物：
In some embodiments, formula (I) is selected from compounds represented by general formula (IV):
其中，in,
X1选自-C(R7)2-、-NR7-或-O-；X 1 is selected from -C(R 7 ) 2 -, -NR 7 - or -O-;
X2选自-C(R8)2-、-NR8-或-O-；X 2 is selected from -C(R 8 ) 2 -, -NR 8 - or -O-;
X3选自C或-N-；X 3 is selected from C or -N-;
R1’选自H、C1-8烷基、C1-8卤代烷基或C1-8烷氧基；R 1 ' is selected from H, C 1-8 alkyl, C 1-8 haloalkyl or C 1-8 alkoxy;
R2’选自H、C1-8烷基、C1-8卤代烷基或C1-8烷氧基；R 2 ' is selected from H, C 1-8 alkyl, C 1-8 haloalkyl or C 1-8 alkoxy;
或者R1’、R2’与其所连接的碳原子形成3-6元杂环基；其中，所述3-6元杂环基可以进一步被一个或多个独立的Ra所取代；Or R 1 ' , R 2 ' and the carbon atom to which they are connected form a 3-6-membered heterocyclic group; wherein, the 3-6-membered heterocyclic group can be further substituted by one or more independent R a ;
R3’各自独立地选自H、羟基、卤素、-CN、-NO2、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基、3-12元杂环基或-NRaRb；其中，所述C1-8烷氧基、C1- 8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基或3-12元杂环基任选地进一步被一个或多个独立的Ra所取代；R 3 ' is each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl or -NR a R b ; wherein, the C 1-8 alkoxy group, C 1-8 alkyl group, C 1-8 haloalkoxy group, C 1-8 haloalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally further substituted by one or more independent R a ;
X7选自C(R10)2、NR10或O；X 7 is selected from C(R 10 ) 2 , NR 10 or O;
R2选自H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素；R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
R3、R5各自独立选自H、-CN、-NO2、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代；R 3 and R 5 are each independently selected from H, -CN, -NO 2 , hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the C 1-8 alkoxy group, C 1-8 alkyl, C 1-8 hydroxyl group Alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optionally further substituted by one or more independent R a ;
R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代； R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered Heteroaryl is optionally further substituted by one or more independent R ;
R7、R8、R10各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 , R 8 , and R 10 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1 -8 haloalkoxy;
Ra或Rb各自独立地选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8烷氧基、-N-C1-8烷基、-S-C1-8烷基、C3-12环烷基或3-12元杂环基。R a or R b are each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl.
一些实施方式中，所述式(IV)化合物选自下式化合物：
In some embodiments, the compound of formula (IV) is selected from the group consisting of compounds of the following formula:
其中，R1’，R2’，R3’，R2，R3，R5，R6，R7，R8如式(IV)所述；X7选自-C(H)2-或-O-。Among them, R 1 ', R 2 ', R 3 ', R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are as described in formula (IV); X 7 is selected from -C(H) 2 - or -O-.
一些实施方式中，式(IV)中的R3’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C3-12环烷基、3-12元杂环基、-NRaRb；其中，所述C1-8烷氧基、C1-8烷基、C3-12环烷基、-NRaRb或3-12元杂环基任选地进一步被一个或多个Ra的所取代；所述Ra或Rb各自独立地选自H、羟基、卤素、-CN、氧代基、C1-8烷基、C1-8烷氧基、C3-12环烷基、3-12元杂环基或C1- 8卤代烷基。In some embodiments, R 3 ' in formula (IV) is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered hetero Ring group, -NR a R b ; wherein, the C 1-8 alkoxy group, C 1-8 alkyl group, C 3-12 cycloalkyl group, -NR a R b or 3-12 membered heterocyclyl group is any Optionally further substituted by one or more R a ; each of the R a or R b is independently selected from H, hydroxyl, halogen, -CN, oxo group, C 1-8 alkyl, C 1-8 Alkoxy group, C 3-12 cycloalkyl group, 3-12 membered heterocyclyl group or C 1-8 haloalkyl group.
一些实施方式中，式(IV)中的R3’选自H、甲基、 In some embodiments, R 3 ' in formula (IV) is selected from H, methyl,
一些实施方式中，式(IV)中的R1’选自H或C1-8烷基；所述R2选自H或C1-8烷基。In some embodiments, R 1 ' in formula (IV) is selected from H or C 1-8 alkyl; said R 2 is selected from H or C 1-8 alkyl.
一些实施方式中，式(IV)中的R1’、R2’与其所连接的碳原子形成3-6元杂环基；其中，所述3-6元杂环基可以进一步被一个或多个独立的Ra所取代；所述Ra选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基或C1-8烷氧基。In some embodiments, R 1 ', R 2 ' in formula (IV) and the carbon atoms to which they are connected form a 3-6-membered heterocyclic group; wherein, the 3-6-membered heterocyclic group can be further substituted by one or more Substituted by two independent R a ; the R a is selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo group, C 1-8 alkyl or C 1-8 alkoxy group.
一些实施方式中，式(IV)中的R2选自C1-8烷基或C1-8卤代烷基；优选为甲基或-CF3。In some embodiments, R 2 in formula (IV) is selected from C 1-8 alkyl or C 1-8 haloalkyl; preferably methyl or -CF 3 .
一些实施方式中，式(IV)中为式(V)所示结构：
In some embodiments, formula (IV) is the structure shown in formula (V):
其中，R3，R5，R6的定义如式(IV)所述。Among them, the definitions of R 3 , R 5 and R 6 are as described in formula (IV).
一些实施方式中，式(IV)中的R6选自3-12元杂环基或5-12元杂芳基；其中，所述3-12元杂环基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代，所述Ra选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8烷氧基或-S-C1-8烷基。In some embodiments, R 6 in formula (IV) is selected from 3-12-membered heterocyclyl or 5-12-membered heteroaryl; wherein, the 3-12-membered heterocyclyl or 5-12-membered heteroaryl Optionally further substituted by one or more independent R a selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 Alkoxy or -SC 1-8 alkyl.
一些实施方式中，式(IV)中的R6选自 其中，所述 任选地进一步被一个或多个独立的Ra所取代，所述Ra选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8烷氧基或-S-C1-8烷基。 In some embodiments, R in formula (IV) is selected from Among them, the Optionally further substituted by one or more independent R a selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 Alkoxy or -SC 1-8 alkyl.
一些实施方式中，式(IV)中的R6选自 In some embodiments, R in formula (IV) is selected from
一些实施方式中，式(IV)中的R3选自H、卤素或C1-8烷基；优选为甲基。In some embodiments, R 3 in formula (IV) is selected from H, halogen or C 1-8 alkyl; preferably methyl.
一些实施方式中，式(IV)中的R5选自H、卤素或C1-8烷基；优选为Cl。In some embodiments, R 5 in formula (IV) is selected from H, halogen or C 1-8 alkyl; preferably Cl.
一些实施方式中，式(I)中的化合物、其立体异构体、互变异构体、氘代物或药用盐，其选自：




In some embodiments, the compound in formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt is selected from:




本发明化合物可以高效抑制EZH2蛋白功能，在各类EZH2突变或扩增的血液瘤、实体瘤细胞实验中具有强效抑制效果。另一方面，该类化合物在各种属动物模型中，均具有优秀的口服吸收，远高于目前上市的二代EZH2抑制剂，有望取得更好的临床疗效。其次，本发明化合物具有毒性小、安全窗大的优点。The compound of the present invention can effectively inhibit the function of EZH2 protein, and has a strong inhibitory effect in experiments on various types of EZH2 mutated or amplified hematological tumors and solid tumor cells. On the other hand, this type of compound has excellent oral absorption in various animal models, which is much higher than the second-generation EZH2 inhibitors currently on the market, and is expected to achieve better clinical efficacy. Secondly, the compound of the present invention has the advantages of low toxicity and large safety window.
本发明还提供了一种药物组合物，其特征在于，所述药物组合物包含治疗有效量的至少一种式(I)所示的化合物和至少一种药学上可接受的辅料。The present invention also provides a pharmaceutical composition, which is characterized in that the pharmaceutical composition contains a therapeutically effective amount of at least one compound represented by formula (I) and at least one pharmaceutically acceptable auxiliary material.
本发明进一步提供了一种药物组合物，其特征在于，所述的治疗有效量的至少一种式(I)所示的化合物和药学上可接受的辅料的质量百分比为0.0001:1-10。The present invention further provides a pharmaceutical composition, characterized in that the mass percentage of the therapeutically effective amount of at least one compound represented by formula (I) and pharmaceutically acceptable excipients is 0.0001:1-10.
本发明提供了结构式(I)所示化合物或药物组合物在制备药物中的应用。The present invention provides the use of compounds or pharmaceutical compositions represented by structural formula (I) in the preparation of medicines.
本发明进一步提供了所述应用的优选技术方案：The present invention further provides preferred technical solutions for the application:
作为优选，所述应用为制备治疗和/或预防癌症药物中的应用。Preferably, the application is in the preparation of drugs for the treatment and/or prevention of cancer.
作为优选，所述应用为制备用于治疗由EZH2介导的疾病的药物的应用。作为优选，所述疾病是癌症。Preferably, the application is the application of preparing drugs for treating diseases mediated by EZH2. Preferably, the disease is cancer.
作为优选，所述癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic lung cancer, ovarian cancer, esophageal cancer Carcinoma, melanoma, colorectal cancer, hepatoma, head and neck tumors, cholangiocarcinoma, myelodysplastic syndrome, glioblastoma, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
本发明还提供了一种治疗和/或预防疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。 The present invention also provides a method for treating and/or preventing diseases, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same.
本发明还提供了一种治疗和/或预防由EZH2介导的疾病的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating and/or preventing diseases mediated by EZH2, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same.
本发明还提供了一种治疗癌症的方法，包括向治疗对象施用治疗有效量的至少任意一种结构式(I)所示化合物或含其的药物组合物。The present invention also provides a method for treating cancer, which includes administering to a treatment subject a therapeutically effective amount of at least any compound represented by structural formula (I) or a pharmaceutical composition containing the same.
作为优选，在上述方法中，所述EZH2介导的疾病是癌症。Preferably, in the above method, the EZH2-mediated disease is cancer.
作为优选，在上述方法中，所述的癌症选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。Preferably, in the above method, the cancer is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non-small cell lung cancer, small cell lung cancer, polymorphic Lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck tumors, hepatocholangiocarcinoma, myelodysplastic syndrome, malignant glioma, prostate cancer, thyroid cancer, Xuwang cell tumor, squamous cell carcinoma of the lung, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer, or liposarcoma.
除非另有说明，所述结构通式中使用的一般化学术语具有通常的含义。Unless otherwise stated, general chemical terms used in the structural formulas have their ordinary meanings.
例如，除非另有说明，本发明所用的术语“卤素”是指氟、氯、溴或碘。For example, unless otherwise stated, the term "halogen" as used herein refers to fluorine, chlorine, bromine or iodine.
在本发明中，除非另有说明，“烷基”包括直链或支链的一价饱和烃基。例如，烷基包括甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、3-(2-甲基)丁基、2-戊基、2-甲基丁基、新戊基、正己基、2-己基、2-甲基戊基等。类似的，“C1-8烷基”中的“1-8”是指包含有1、2、3、4、5、6、7或8个碳原子的直链或支链形式排列的基团。In the present invention, unless otherwise stated, "alkyl" includes linear or branched monovalent saturated hydrocarbon groups. For example, alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 3-(2-methyl)butyl, 2 -Pentyl, 2-methylbutyl, neopentyl, n-hexyl, 2-hexyl, 2-methylpentyl, etc. Similarly, the " 1-8 " in "C 1-8 alkyl" refers to a group containing 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms arranged in a straight or branched chain. group.
“烷氧基”是指前述的直链或支链烷基的氧醚形式，即-O-烷基。"Alkoxy" refers to the oxygen ether form of the aforementioned linear or branched alkyl group, that is, -O-alkyl.
术语“亚烷基”是指二价烷基连接基团。亚烷基在形式上是指两个C-H键替换为亚烷基与化合物其余部分的连接点的烷烃。类似的，C1-3亚烷基中的“C1-3”是指含有1、2或3个碳原子的亚烷基，包括但不限于亚甲基、1,2-亚乙基、1,3-亚丙基或1,2-亚异丙基。The term "alkylene" refers to a divalent alkyl linking group. Alkylene formally refers to an alkane in which the two CH bonds are replaced by the alkylene's point of attachment to the rest of the compound. Similarly, "C 1-3 " in C 1-3 alkylene refers to an alkylene group containing 1, 2 or 3 carbon atoms, including but not limited to methylene, 1,2-ethylene, 1,3-propylene or 1,2-isopropylene.
在本发明中，“一”、“一个”、“该”、“至少一个”和“一个或多个”可互换使用。因此，例如，包含“一种”药学上可接受的赋形剂的组合物可以被解释为表示该组合物包括“一种或多种”药学上可接受的赋形剂。In the present invention, "a", "an", "the", "at least one" and "one or more" are used interchangeably. Thus, for example, a composition comprising "a" pharmaceutically acceptable excipient may be interpreted to mean that the composition includes "one or more" pharmaceutically acceptable excipients.
术语“卤代烷基”是指一个或多个H已经被卤素原子置换的烷基。The term "haloalkyl" refers to an alkyl group in which one or more H's have been replaced by a halogen atom.
术语“卤代烷氧基”是指-O-卤代烷基的基团。The term "haloalkoxy" refers to the group -O-haloalkyl.
术语“氧代”或“氧代基”是指呈二价取代基形式的氧原子，其与C连接时形成羰基，其与杂原子连接时形成亚砜基或砜基或N-氧化物基团。The term "oxo" or "oxo" refers to an oxygen atom in the form of a divalent substituent which, when attached to C, forms a carbonyl group and which, when attached to a heteroatom, forms a sulfoxide or sulfone or N-oxide group group.
本发明中，除另有说明，术语“芳香环”、“芳香族环”或“芳香族杂环”即为具有芳香族特征(具有(4n+2)个非定域π电子，其中n为整数)的多不饱和环的碳环或杂环。In the present invention, unless otherwise stated, the term "aromatic ring", "aromatic ring" or "aromatic heterocycle" means having aromatic characteristics (having (4n+2) delocalized π electrons, where n is Integer) polyunsaturated ring carbocyclic or heterocyclic ring.
术语“芳基”，在本发明中，除非另有说明，是指未取代或取代的包括碳环的原子的单 环或稠环芳香基团。优选C6-12芳基，更优选芳基为C6-10的单环或双环的芳香环基团。优选为苯基、萘基。最优选为苯基。所述芳基环可以稠合于杂芳基、杂环基或环烷基上，其中与母体结构连接在一起的环为芳基环，非限制性实例包括但不限于苯并环戊基。The term "aryl", in the present invention, unless otherwise stated, refers to an unsubstituted or substituted single atom including a carbocyclic ring. Ring or fused ring aromatic groups. A C 6-12 aryl group is preferred, and a C 6-10 monocyclic or bicyclic aromatic ring group is more preferred. Preferred are phenyl and naphthyl. Most preferred is phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl group, where the ring attached to the parent structure is an aryl ring, non-limiting examples include but are not limited to benzocyclopentyl.
术语“杂环基”是指具有至少一个含有杂环子的环化烷基或环化烯基的环***，所述杂原子选自N、O和/或S。所述杂环基可以包括单环或多环(例如具有2、3或4个稠合环、螺环、桥环等)。杂环基可以经由成环碳原子或成环杂原子与化合物其他部分相连接。优选3-12元杂环基，3-12元杂环基中的“3-12元”是指含有3-12个C、N、O或S的成环原子组成的杂环基；更优选3-8元杂环基，更更优选3-6元杂环基。其中氮或硫杂原子可以选择性地被氧化，并且氮杂原子可以选择性地被季铵化。这些杂环基的实例包括但不限于氮杂环丁烷基、吡咯烷基、哌啶基、哌嗪基、氧代哌嗪基、氧代哌啶基、四氢呋喃基、二氧戊环基、四氢咪唑基、四氢噻唑基、四氢恶唑基、四氢吡喃基、吗啉基、硫代吗啉基、硫代吗啉基亚砜、硫代吗啉基砜基和四氢恶二唑基。所述杂环基可以稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基。The term "heterocyclyl" refers to a ring system having at least one cyclized alkyl or cyclized alkenyl group containing a heterocyclic atom selected from N, O and/or S. The heterocyclyl group may include monocyclic or polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). Heterocyclyl groups can be connected to other parts of the compound via ring carbon atoms or ring heteroatoms. Preferred are 3-12-membered heterocyclic groups, and "3-12-membered" in 3-12-membered heterocyclic groups refers to heterocyclic groups containing 3-12 C, N, O or S ring-forming atoms; more preferably 3-8 membered heterocyclyl group, more preferably 3-6 membered heterocyclyl group. Wherein the nitrogen or sulfur heteroatoms can be selectively oxidized, and the nitrogen heteroatoms can be selectively quaternized. Examples of these heterocyclyl groups include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, oxopiperazinyl, oxopiperidinyl, tetrahydrofuranyl, dioxolanyl, Tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydroxazolyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone and tetrahydrogen Oxadiazolyl. The heterocyclyl group may be fused to an aryl, heteroaryl or cycloalkyl ring, where the ring attached to the parent structure is the heterocyclyl group.
术语“杂芳基”，在本发明中，除非另有说明，是指具有至少一个杂原子的单环或多环(例如稠合双环)芳香族杂环，所述杂原子选自N、O和/或S，并且其中所述氮或硫杂原子可以选择性地被氧化，所述氮杂原子可以选择性地被季铵化。优选5-18元杂芳基，其中5-18元杂芳基中的“5-18元”是指含有5-18个C、N、O或S的成环原子组成的杂芳基。更优选的是5-10元杂芳基；更更优选的是5-6元杂芳基。杂芳基的实例包括但不限于噻吩基、呋喃基、咪唑基、异恶唑基、恶唑基、吡唑基、吡咯基、噻唑基、噻二唑基、***基、吡啶基、哒嗪基、吲哚基、氮杂吲哚基、吲唑基、苯并咪唑基、苯并呋喃基、苯并噻吩基、苯并异恶唑基、苯并噻唑基、苯并噻唑基、苯并噻二唑基、苯并***基腺嘌呤、喹啉基或异喹啉基。所述杂芳基可以稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环。The term "heteroaryl" in the present invention, unless otherwise stated, refers to a monocyclic or polycyclic (such as fused bicyclic) aromatic heterocyclic ring with at least one heteroatom selected from N, O and/or S, and wherein the nitrogen or sulfur heteroatoms can be selectively oxidized and the nitrogen heteroatoms can be selectively quaternized. Preferred are 5-18-membered heteroaryl groups, wherein the "5-18-membered" in 5-18-membered heteroaryl groups refers to heteroaryl groups containing 5-18 C, N, O or S ring-forming atoms. More preferred is a 5-10 membered heteroaryl group; even more preferred is a 5-6 membered heteroaryl group. Examples of heteroaryl groups include, but are not limited to, thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl, pyridyl, pyridyl Azinyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzothiazolyl, benzothiazolyl, benzene Thiadiazolyl, benzotriazolyladenine, quinolyl or isoquinolyl. The heteroaryl group may be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is the heteroaryl ring.
术语“环烷基”是指具有至少一个环化烷基的环***。优选C3-12环烷基，其中的“C3-12”是指环烷基可以具有3、4、5、6、7、8、9、10、11或12个成环原子。环烷基可以包括单环和多环(例如具有2、3或4个稠合环、螺环、桥环等)。一些实施例中环烷基包括但不限于环丙基、环丁基、环戊基等；所述环烷基还可以稠合于芳基、杂环基或杂芳基环上，其中与母体结构连接在一起的环为环烷基。The term "cycloalkyl" refers to a ring system having at least one cyclized alkyl group. C 3-12 cycloalkyl is preferred, where "C 3-12 " means that the cycloalkyl group may have 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms. Cycloalkyl groups can include monocyclic and polycyclic rings (eg, having 2, 3 or 4 fused rings, spiro rings, bridged rings, etc.). In some embodiments, the cycloalkyl group includes but is not limited to cyclopropyl, cyclobutyl, cyclopentyl, etc.; the cycloalkyl group can also be fused to an aryl, heterocyclyl or heteroaryl ring, where it is connected to the parent structure The rings joined together are cycloalkyl.
术语“取代的”是指基团中的一个或多个氢原子分别被相同的或者不同的取代基所取代。典型的取代基包括但不限于卤素(F、Cl、Br或I)、C1-8烷基、C3-12环烷基、-OR1、-SR1、 ＝O、＝S、-C(O)R1、-C(S)R1、＝NR1、-C(O)OR1、-C(S)OR1、-NR1R2、-C(O)NR1R2、氰基、硝基、-S(O)2R1、-O-S(O2)OR1、-O-S(O)2R1、-OP(O)(OR1)(OR2)；其中R1和R2独立地选自-H、C1-6烷基、C1-6卤代烷基或C3-6环烷基。在一些实施例中，取代基独立地选自包含-F、-Cl、-Br、-I、-OH、三氟甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、-SCH3、-SC2H5、甲醛基、-C(OCH3)、氰基、硝基、-CF3、-OCF3、氨基、二甲基氨基、甲硫基、磺酰基和乙酰基的基团。The term "substituted" means that one or more hydrogen atoms in the group are replaced by the same or different substituents, respectively. Typical substituents include but are not limited to halogen (F, Cl, Br or I), C 1-8 alkyl, C 3-12 cycloalkyl, -OR 1 , -SR 1 , =O, =S, -C(O)R 1 , -C(S)R 1 , =NR 1 , -C(O)OR 1 , -C(S)OR 1 , -NR 1 R 2 , -C (O)NR 1 R 2 , cyano, nitro, -S(O) 2 R 1 , -OS(O 2 )OR 1 , -OS(O) 2 R 1 , -OP(O)(OR 1 ) (OR 2 ); wherein R 1 and R 2 are independently selected from -H, C 1-6 alkyl, C 1-6 haloalkyl or C 3-6 cycloalkyl. In some embodiments, the substituents are independently selected from the group consisting of -F, -Cl, -Br, -I, -OH, trifluoromethoxy, ethoxy, propoxy, isopropoxy, n-butoxy group, isobutoxy group, tert-butoxy group, -SCH 3 , -SC 2 H 5 , formaldehyde group, -C(OCH 3 ), cyano group, nitro group, -CF 3 , -OCF 3 , amino group, dimethyl group amino, methylthio, sulfonyl and acetyl groups.
取代烷基的实例包括但不限于2,3-二羟基丙基、2-氨基乙基、2-羟乙基、五氯乙基、三氟甲基、甲氧基甲基、五氟乙基、苯基甲基、二恶茂基甲基和哌嗪基甲基。Examples of substituted alkyl groups include, but are not limited to, 2,3-dihydroxypropyl, 2-aminoethyl, 2-hydroxyethyl, pentachloroethyl, trifluoromethyl, methoxymethyl, pentafluoroethyl , phenylmethyl, dioxolylmethyl and piperazinylmethyl.
取代烷氧基的实例包括但不限于2-羟基乙氧基、2-氟乙氧基、2,2-二氟乙氧基、2-甲氧基乙氧基、2-氨基乙氧基、2,3-二羟基丙氧基、环丙基甲氧基、氨基甲氧基、三氟甲氧基、2-二乙基氨基乙氧基、2-乙氧基羰基乙氧基、3-羟基丙氧基。Examples of substituted alkoxy include, but are not limited to, 2-hydroxyethoxy, 2-fluoroethoxy, 2,2-difluoroethoxy, 2-methoxyethoxy, 2-aminoethoxy, 2,3-dihydroxypropoxy, cyclopropylmethoxy, aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3- Hydroxypropoxy.
术语“药用盐”是指从药学上可接受的无毒的碱或酸制备的盐。The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids.
当本发明提供的化合物是酸时，可以从药学上可接受的无毒的碱，包括无机碱和有机碱，方便地制得其相应的盐。从无机碱衍生的盐包括铝、铵、钙、铜(高价和低价)、三价铁、亚铁、锂、镁、锰(高价和低价)、钾、钠、锌之类的盐。特别优选铵、钙、镁、钾和钠的盐。能够衍生成药学上可接受的盐的无毒有机碱包括伯胺、仲胺和叔胺，也包括环胺及含有取代基的胺，如天然存在的和合成的含取代基的胺。能够成盐的其他药学上可接受的无毒有机碱，包括离子交换树脂以及精氨酸、甜菜碱、咖啡因、胆碱、N',N'-二苄乙二胺、二乙胺、2-二乙氨基乙醇、2-二甲胺基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、还原葡萄糖胺、氨基葡萄糖、组氨酸、异丙胺、赖氨酸，甲基葡萄糖胺、吗啉、哌嗪、哌啶、多胺树脂、普鲁卡因、氯普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨丁三醇等。When the compound provided by the present invention is an acid, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include salts of aluminum, ammonium, calcium, copper (high and low prices), ferric iron, ferrous iron, lithium, magnesium, manganese (high and low prices), potassium, sodium, and zinc. Ammonium, calcium, magnesium, potassium and sodium salts are particularly preferred. Nontoxic organic bases capable of being derivatized into pharmaceutically acceptable salts include primary, secondary and tertiary amines, as well as cyclic amines and substituted amines, such as naturally occurring and synthetic substituted amines. Other pharmaceutically acceptable non-toxic organic bases capable of forming salts, including ion exchange resins and arginine, betaine, caffeine, choline, N',N'-dibenzylethylenediamine, diethylamine, 2 -Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, reduced glucosamine, glucosamine, histidine, isopropylamine, lysine Acid, methylglucosamine, morpholine, piperazine, piperidine, polyamine resin, procaine, chloroprocaine, purine, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine wait.
当本发明提供的化合物是碱时，可以从药学上可接受的无毒的酸，包括无机酸和有机酸，方便制得其相应的盐。这样的酸包括，如，醋酸、苯磺酸、苯甲酸、樟脑磺酸、柠檬酸、乙磺酸、甲酸、富马酸、葡萄糖酸、谷氨酸、氢溴酸、盐酸、羟乙磺酸、乳酸、马来酸、苹果酸、扁桃酸、甲磺酸、黏酸、硝酸、扑酸、泛酸、磷酸、琥珀酸、硫酸、草酸、丙酸、乙醇酸、氢碘酸、高氯酸、环己氨磺酸、水杨酸、2-萘磺酸、糖精酸、三氟乙酸、酒石酸和对甲苯磺酸等。较优地，柠檬酸、氢溴酸、甲酸、盐酸、马来酸、磷酸、硫酸和酒石酸。更优地，甲酸和盐酸。When the compound provided by the present invention is a base, its corresponding salt can be conveniently prepared from pharmaceutically acceptable non-toxic acids, including inorganic acids and organic acids. Such acids include, for example, acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, formic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid , lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, parapexic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, oxalic acid, propionic acid, glycolic acid, hydriodic acid, perchloric acid, cyclohexane sulfonic acid, salicylic acid, 2-naphthalene sulfonic acid, saccharinic acid, trifluoroacetic acid, tartaric acid and p-toluenesulfonic acid, etc. Preferably, citric acid, hydrobromic acid, formic acid, hydrochloric acid, maleic acid, phosphoric acid, sulfuric acid and tartaric acid. More preferably, formic acid and hydrochloric acid.
由于式(I)所示化合物将作为药物应用，较优地，使用一定纯度，例如，至少为60％ 纯度，比较合适的纯度为至少75％，特别合适地纯度为至少98％(％是重量比)。Since the compound represented by formula (I) will be used as a medicine, preferably, a certain purity is used, for example, at least 60% Purity, preferably a purity of at least 75%, particularly preferably a purity of at least 98% (% is a weight ratio).
本发明化合物的药物前体包含在本发明的保护范围内。通常，所述药物前体是指很容易在体内转化成所需化合物的功能性衍生物。例如，本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物，其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。The prodrugs of the compounds of the present invention are included in the protection scope of the present invention. Generally, the prodrug refers to a functional derivative that is easily converted into the desired compound in the body. For example, any pharmaceutically acceptable salt, ester, ester salt or other derivative of the compound of the present application, which can directly or indirectly provide the compound of the present application or its pharmaceutically active metabolite after administration to the recipient; Residues.
本发明所述化合物可能含有一个或多个不对称中心，并可能由此产生非对映异构体和光学异构体。本发明包括所有可能的非对映异构体及其外消旋混合物、其基本上纯的拆分对映异构体、所有可能的几何异构体及其药用盐。The compounds described in the present invention may contain one or more asymmetric centers, and diastereoisomers and optical isomers may arise therefrom. The present invention includes all possible diastereoisomers and their racemic mixtures, their substantially pure resolved enantiomers, all possible geometric isomers and their pharmaceutically acceptable salts.
当式(I)所示化合物存在互变异构体时，除非特别声明，本发明包括任何可能的互变异构体和其药用盐，及它们的混合物。When there are tautomers of the compound represented by formula (I), unless otherwise stated, the present invention includes any possible tautomers and pharmaceutically acceptable salts thereof, as well as their mixtures.
当式(I)所示化合物用较重的同位素(例如氘)替代可能提供某些治疗优势，这是由于更大的代谢稳定性，例如增加体内半衰期或减少剂量要求。Substitution of compounds of formula (I) with heavier isotopes such as deuterium may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements.
当式(I)所示化合物及其药学上可接受的盐存在溶剂化物或多晶型时，本发明包括任何可能的溶剂化物和多晶型。形成溶剂化物的溶剂类型没有特别的限定，只要该溶剂是药学上可以接受的。例如，水、乙醇、丙醇、丙酮等类似的溶剂都可以采用。When the compound represented by formula (I) and its pharmaceutically acceptable salts exist in solvates or polymorphic forms, the present invention includes any possible solvates and polymorphic forms. The type of solvent used to form the solvate is not particularly limited as long as the solvent is pharmaceutically acceptable. For example, water, ethanol, propanol, acetone and other similar solvents can be used.
术语“组合物”，在本发明中，是指包括包含指定量的各指定成分的产品，以及直接或间接地由指定量的各指定成分的组合生产的任何产品。因此，含有本发明的化合物作为活性成分的药物组合物以及制备本发明化合物的方法也是本发明的一部分。此外，化合物的一些结晶形式可以多晶型存在，并且此多晶型包括在本发明中。另外，一些化合物可以与水(即水合物)或常见的有机溶剂形成溶剂化物，并且此类溶剂化物也落入本发明的范围内。The term "composition", as used herein, is meant to include products containing specified amounts of each of the specified ingredients, as well as any product produced directly or indirectly from a combination of specified amounts of each specified ingredient. Accordingly, pharmaceutical compositions containing compounds of the invention as active ingredients as well as methods of preparing the compounds of the invention are also part of the present invention. Furthermore, some crystalline forms of the compounds may exist as polymorphs, and such polymorphs are included in the present invention. Additionally, some compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also within the scope of the present invention.
术语“药物组合物”是指一种或多种本申请的化合物或其药用盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipients. The purpose of pharmaceutical compositions is to facilitate administration to an organism of the compounds of the present application.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients that have no obvious irritating effect on the organism and do not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, etc.
本发明的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present invention can be prepared by combining the compound of the present application with appropriate pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, and powders. , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本发明化合物或其药用盐或其药物组合物的典型途径包括但不限于口服、直肠、 局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of the compounds of the present invention or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof include, but are not limited to, oral, rectal, Topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
术语“治疗”一般是指获得需要的药理和/或生理效应。该效应根据部分或完全稳定或治愈疾病和/或由于疾病产生的副作用，可以是治疗性的。本文使用的“治疗”涵盖了对患者疾病的任何治疗，包括：(a)抑制疾病的症状，即阻止其发展；或(b)缓解疾病的症状，即，导致疾病或症状退化。The term "treatment" generally refers to obtaining a desired pharmacological and/or physiological effect. The effect may be therapeutic in terms of partial or complete stabilization or cure of the disease and/or side effects due to the disease. As used herein, "treatment" encompasses any treatment of a patient's disease that: (a) inhibits the symptoms of the disease, i.e., prevents their progression; or (b) alleviates the symptoms of the disease, i.e., causes regression of the disease or symptoms.
术语“有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "effective amount" means (i) treating or preventing a specified disease, condition, or disorder, (ii) reducing, ameliorating, or eliminating one or more symptoms of a specified disease, condition, or disorder, or (iii) preventing or delaying An amount of a compound of the present application that is associated with the onset of one or more symptoms of a particular disease, condition, or disorder described in . The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by one skilled in the art. based on its own knowledge and the contents of this disclosure.
合成方案：
Synthesis plan:
步骤A：化合物II-1与化合物II-2在碱性条件如DIEA和缩合试剂如HATU的作用下，通过酸胺缩合得到化合物II-3；Step A: Compound II-1 and compound II-2 are subjected to acid-amine condensation under basic conditions such as DIEA and a condensation reagent such as HATU to obtain compound II-3;
步骤B：化合物II-3经过氢化还原即可得到目标化合物II。Step B: Compound II-3 is reduced by hydrogenation to obtain the target compound II.
具体实施方式Detailed ways
为使上述内容更清楚、明确，本发明将用以下实施例来进一步阐述本发明的技术方案。以下实施例仅用于说明本发明的具体实施方式，以使本领域的技术人员能够理解本发明，但不用于限制本发明的保护范围。本发明的具体实施方式中，未作特别说明的技术手段或方法等为本领域的常规技术手段或方法等。In order to make the above content clearer and clearer, the present invention will use the following examples to further illustrate the technical solution of the present invention. The following examples are only used to illustrate specific implementations of the present invention so that those skilled in the art can understand the present invention, but are not used to limit the scope of the present invention. In the specific embodiments of the present invention, technical means or methods that are not specifically described are conventional technical means or methods in the art.
除非另有说明，本发明所有的一部分和百分比均按重量计算，所有温度均指摄氏度。Unless otherwise stated, all parts and percentages herein are by weight and all temperatures are in degrees Celsius.
实施例中使用了下列缩略语：The following abbreviations are used in the examples:
THF：四氢呋喃；THF: tetrahydrofuran;
DMF：N,N-二甲基甲酰胺；DMF: N,N-dimethylformamide;
(Boc)2O：二碳酸二叔丁酯；(Boc) 2 O: di-tert-butyl dicarbonate;
NaH：氢化钠； NaH: sodium hydride;
TosCl：对甲苯磺酰氯；TosCl: p-toluenesulfonyl chloride;
DIPEA/DIEA：N,N-二异丙基乙胺；DIPEA/DIEA: N,N-diisopropylethylamine;
EA：乙酸乙酯；EA: ethyl acetate;
PE：石油醚；PE: petroleum ether;
CD3OD：氘代甲醇；CD 3 OD: deuterated methanol;
CDCl3：氘代氯仿；CDCl 3 : deuterated chloroform;
DCM：二氯甲烷；DCM: dichloromethane;
MeOH：甲醇；MeOH: methanol;
TEA：三乙胺；TEA: triethylamine;
HATU：2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯；HATU: 2-(7-azobenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate;
Pd(OAc)2：醋酸钯；Pd(OAc) 2 : palladium acetate;
PPh3：三苯基膦；PPh 3 : triphenylphosphine;
Ac2O：乙酸酐；Ac 2 O: acetic anhydride;
TMSCH2N2：三甲基硅烷化重氮甲烷；TMSCH 2 N 2 : trimethylsilylated diazomethane;
Pd(DPEPhos)Cl2：双(二苯基膦苯基醚)二氯化钯(II)；Pd(DPEPhos)Cl 2 : bis(diphenylphosphinephenyl ether)palladium(II) dichloride;
CPME：环戊基甲醚；CPME: cyclopentyl methyl ether;
LiOH.H2O：一水合氢氧化锂；LiOH.H 2 O: lithium hydroxide monohydrate;
HATU：N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲；HATU: N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate;
HOAc：乙酸/冰醋酸；HOAc: acetic acid/glacial acetic acid;
Ru3(CO)12：十二羰基三钌；Ru 3 (CO) 12 : triruthenium dodecacarbonyl;
TFA：三氟乙酸；TFA: trifluoroacetic acid;
NaBH3CN：氰基硼氢化钠；NaBH 3 CN: sodium cyanoborohydride;
LiOH.H2O：一水合氢氧化锂；LiOH.H 2 O: lithium hydroxide monohydrate;
Chloroform-d：氘代氯仿；Chloroform-d: deuterated chloroform;
Dess-martin：戴斯-马丁氧化剂；Dess-martin: Dess-Martin oxidant;
DMF-DMA：N,N-二甲基甲酰胺二甲基缩醛；DMF-DMA: N,N-dimethylformamide dimethyl acetal;
NIS：N-碘代丁二酰亚胺；NIS: N-iodosuccinimide;
prep-HPLC：高效液相制备分离；prep-HPLC: high performance liquid phase preparative separation;
prep-TLC：薄层色谱制备分离； prep-TLC: thin layer chromatography preparative separation;
中间体M1的合成：
Synthesis of intermediate M1:
中间体M1的合成参考专利WO2019204490中间体9的合成。The synthesis of intermediate M1 refers to the synthesis of intermediate 9 in patent WO2019204490.
中间体M2的合成
Synthesis of intermediate M2
步骤1：化合物M2-1的合成Step 1: Synthesis of Compound M2-1
将6-溴-1,2,3,4-四氢异喹啉(3.0g)溶解于THF(30mL)中，加入碳酸氢钠(2.38g)的水溶液(6mL)，室温下向反应液中分批加入(Boc)2O(3.4g)，室温反应2小时。将反应液直接浓缩，柱层析分离纯化(PE-EA，10％EA出峰)，得黄色液体4.05g，即化合物M2-1。ESI-MS m/z:312[M+H]+。Dissolve 6-bromo-1,2,3,4-tetrahydroisoquinoline (3.0g) in THF (30mL), add an aqueous solution (6mL) of sodium bicarbonate (2.38g), and add it to the reaction solution at room temperature. Add (Boc) 2 O (3.4g) in batches and react at room temperature for 2 hours. The reaction solution was directly concentrated and separated and purified by column chromatography (PE-EA, 10% EA peak) to obtain 4.05g of yellow liquid, namely compound M2-1. ESI-MS m/z:312[M+H] + .
步骤2：化合物M2-2的合成Step 2: Synthesis of compound M2-2
将M2-1(1.4g)，双三苯基膦二氯化钯(0.31g)，碘化亚铜(0.17g)依次加入TEA(20mL)中，氮气保护，室温下向反应液中加入三甲基硅基乙炔(0.77mL)，80℃反应过夜。将反应液直接浓缩，柱层析分离纯化(PE-EA，5％EA出峰)，得黄色液体1.3g，即化合物M2-2。ESI-MS m/z:330[M+H]+。M2-1 (1.4g), bistriphenylphosphine palladium dichloride (0.31g), and copper iodide (0.17g) were added to TEA (20 mL) in sequence, under nitrogen protection, and triphenylphosphine palladium dichloride (0.31g) was added to the reaction solution at room temperature. Methylsilyl acetylene (0.77 mL), react at 80°C overnight. The reaction solution was directly concentrated and separated and purified by column chromatography (PE-EA, peak of 5% EA) to obtain 1.3 g of yellow liquid, namely compound M2-2. ESI-MS m/z:330[M+H] + .
步骤3：化合物M2-3的合成Step 3: Synthesis of compound M2-3
将M2-2(1.0g)，碳酸钾(1.05g)依次加入甲醇(15mL)中，室温反应12小时。将反应液抽滤，滤液直接浓缩，得淡黄色液体0.51g，即化合物M2-3。化合物无需纯化，直接进行下一步反应。ESI-MS m/z:258[M+H]+。M2-2 (1.0g) and potassium carbonate (1.05g) were added to methanol (15mL) in sequence and reacted at room temperature for 12 hours. The reaction solution was suction-filtered, and the filtrate was directly concentrated to obtain 0.51g of light yellow liquid, namely compound M2-3. The compound does not need to be purified and can be directly used in the next reaction. ESI-MS m/z:258[M+H] + .
步骤4：化合物M2-4的合成Step 4: Synthesis of Compound M2-4
将2-甲基-3,4-二羟基-5-氯苯甲酸甲酯(300.0mg)，十二羰基三钌(37.3mg)，三苯基膦(30.6mg)加入甲苯(4mL)中，氮气保护，升温至120℃搅拌0.5小时。加入M2-3(378.8 mg)的甲苯溶液(2mL)，继续反应12h。将反应液直接浓缩，柱层析分离纯化(PE-EA，5％EA出峰)，得淡黄色液体180.1mg，即化合物M2-4。ESI-MS m/z:474[M+H]+。Add 2-methyl-3,4-dihydroxy-5-chlorobenzoic acid methyl ester (300.0 mg), triruthenium dodecacarbonyl (37.3 mg), and triphenylphosphine (30.6 mg) into toluene (4 mL). Under nitrogen protection, the temperature was raised to 120°C and stirred for 0.5 hours. Join M2-3 (378.8 mg) in toluene solution (2 mL), and continue the reaction for 12 h. The reaction solution was directly concentrated and separated and purified by column chromatography (PE-EA, 5% EA peak) to obtain 180.1 mg of light yellow liquid, namely compound M2-4. ESI-MS m/z:474[M+H] + .
步骤5：化合物M2的合成Step 5: Synthesis of Compound M2
将M2-4(90.0mg)，一水合氢氧化锂(79.7mg)加入甲醇(1.6mL)和水(0.4mL)中，升温至70℃反应2小时。向反应液中加入饱和柠檬酸水溶液至pH＝6，析出淡黄色固体，抽滤，滤饼水洗，烘干，得淡黄色粉末87.4mg，即化合物M2。化合物无需纯化，直接进行下一步反应。ESI-MS m/z:460[M+H]+。M2-4 (90.0 mg) and lithium hydroxide monohydrate (79.7 mg) were added to methanol (1.6 mL) and water (0.4 mL), and the temperature was raised to 70°C for 2 hours. Add a saturated citric acid aqueous solution to the reaction solution until pH=6, and precipitate a light yellow solid. It is filtered with suction, and the filter cake is washed with water and dried to obtain 87.4 mg of light yellow powder, which is compound M2. The compound does not need to be purified and can be directly used in the next reaction. ESI-MS m/z:460[M+H] + .
中间体M3的合成：
Synthesis of intermediate M3:
步骤1：中间体M3-1的合成Step 1: Synthesis of intermediate M3-1
将2-羟基-4，6-二甲基烟腈(1.00g)溶于10.0mL甲苯中，依次加入溴化苄(0.79mL)，氧化银(1.54g)，110℃反应12h，反应完毕后硅藻土过滤，减压浓缩，浓缩物经柱层析纯化(PE:EA＝5:1)得1.50g中间体M3-1。ESI-MS m/z:239[M+H]+；Dissolve 2-hydroxy-4,6-dimethylnicotinonitrile (1.00g) in 10.0mL toluene, add benzyl bromide (0.79mL) and silver oxide (1.54g) in sequence, and react at 110°C for 12 hours. After the reaction is completed Filter through diatomaceous earth and concentrate under reduced pressure. The concentrate is purified by column chromatography (PE:EA=5:1) to obtain 1.50g of intermediate M3-1. ESI-MS m/z:239[M+H] + ;
步骤2：中间体M3-2的合成Step 2: Synthesis of intermediate M3-2
冰浴下，将中间体M3-1(1.40g)溶于20.0mL DCM中，加入二异丁基氢化铝(1mol/L，6.0mL)，自然升高至室温反应1h，向反应液中滴加1N HCl水溶液(5.0mL)搅拌30min淬灭反应，然后加入4N NaOH水溶液(1.25mL)，硅藻土过滤除去不溶性杂质，滤饼用20.0mL DCM洗脱3次，收集滤液萃取收集有机相，无水硫酸钠干燥，过滤后减压蒸除溶剂，柱层析纯化得到化合物0.95g，即中间体M3-2。ESI-MS m/z:242[M+H]+；Dissolve intermediate M3-1 (1.40g) in 20.0mL DCM under ice bath, add diisobutylaluminum hydride (1mol/L, 6.0mL), naturally raise to room temperature and react for 1h, then drop it into the reaction solution Add 1N HCl aqueous solution (5.0mL) and stir for 30 minutes to quench the reaction, then add 4N NaOH aqueous solution (1.25mL), filter through diatomaceous earth to remove insoluble impurities, and elute the filter cake with 20.0mL DCM three times. Collect the filtrate and extract the organic phase. Dry over anhydrous sodium sulfate, filter, evaporate the solvent under reduced pressure, and purify by column chromatography to obtain 0.95g of the compound, which is intermediate M3-2. ESI-MS m/z:242[M+H] + ;
步骤3：中间体M3-3的合成Step 3: Synthesis of intermediate M3-3
冰浴下，将中间体M3-2(0.95g)溶于10.0mL MeOH中，加入硼氢化钠(210mg)，冰浴下反应1.0h，反应液减压蒸除溶剂，加入适量乙酸乙酯与饱和碳酸氢钠溶液萃取，收集有机相，无水硫酸钠干燥，减压蒸除溶剂后柱层析纯化，得到0.914g产物，即中间体M3-3。ESI-MS m/z:244[M+H]+； Under an ice bath, dissolve intermediate M3-2 (0.95g) in 10.0 mL MeOH, add sodium borohydride (210 mg), and react under an ice bath for 1.0 h. The solvent is evaporated from the reaction solution under reduced pressure, and an appropriate amount of ethyl acetate and Extract with saturated sodium bicarbonate solution, collect the organic phase, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure and then purify by column chromatography to obtain 0.914g of the product, intermediate M3-3. ESI-MS m/z:244[M+H] + ;
步骤4：中间体M3的合成Step 4: Synthesis of intermediate M3
-40℃下，将中间体M3-3(0.90g)溶于10.0mLDCM中，加入氯化亚砜(0.41mL)，低温反应0.5h，反应液滴加至饱和碳酸氢钠溶液中淬灭，加入DCM萃取，收集有机相，无水硫酸钠干燥，减压蒸除溶剂后柱层析纯化，得到0.850g产物，即中间体M3。ESI-MS m/z:262[M+H]+；Dissolve intermediate M3-3 (0.90g) in 10.0mL DCM at -40°C, add thionyl chloride (0.41mL), and react at low temperature for 0.5h. The reaction solution is added dropwise to saturated sodium bicarbonate solution to quench. DCM was added for extraction, the organic phase was collected, dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure and then purified by column chromatography to obtain 0.850g of the product, intermediate M3. ESI-MS m/z:262[M+H] + ;
中间体M4的合成：
Synthesis of intermediate M4:
步骤1：中间体M4-1的合成Step 1: Synthesis of intermediate M4-1
0℃下，将3-(((叔丁氧羰基)氨基)甲基)双环[1.1.1]戊烷-1-羧酸(1.00g)与二甲羟胺盐酸盐(0.510g)溶于10.0mL DCM中，然后依次加入N,N-二异丙基乙胺(2.17mL)，N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(2.99g)，室温反应3h，向反应液缓慢加入50mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗3遍，无水硫酸钠干燥，减压蒸除溶剂后得1.40g无色油状产物，即中间体M4-1。ESI-MS m/z:285[M+H]+；1H NMR(500MHz,Chloroform-d)δ4.51(s,1H),3.66(s,3H),3.18(s,3H),2.80(s,2H),2.02(s,6H),1.44(s,9H).Dissolve 3-(((tert-butoxycarbonyl)amino)methyl)bicyclo[1.1.1]pentane-1-carboxylic acid (1.00g) and dimethylhydroxylamine hydrochloride (0.510g) at 0°C. In 10.0mL DCM, then add N,N-diisopropylethylamine (2.17mL), N,N,N',N'-tetramethyl-O-(7-azabenzotriazole-1 -base) urea hexafluorophosphate (2.99g), react at room temperature for 3 hours, slowly add 50 mL saturated sodium bicarbonate solution to the reaction solution to quench, extract with EA 3 times, combine the organic phases, wash with saturated sodium chloride 3 times, and anhydrous sulfuric acid After drying over sodium, the solvent was evaporated under reduced pressure to obtain 1.40g of colorless oily product, namely intermediate M4-1. ESI-MS m/z:285[M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ4.51(s,1H),3.66(s,3H),3.18(s,3H),2.80( s,2H),2.02(s,6H),1.44(s,9H).
步骤2：中间体M4-2的合成Step 2: Synthesis of intermediate M4-2
将中间体M4-1(1.40g)溶于20.0mL THF中，冷却至-40℃，加入四氢铝锂(0.330g)，自然升高至室温反应2h，反应液降低温度至0℃，然后向反应液中依次逐渐滴加0.33mL水，0.33mL 15％NaOH溶液和0.33mL水，搅拌30min后硅藻土过滤除去不溶性杂质，滤饼用20.0mL EA洗脱3次，收集滤液并无水硫酸钠干燥，过滤减压蒸出溶剂后得到0.910g淡黄色油状产物，即中间体M4-2。1H NMR(500MHz,Chloroform-d)δ9.50(s,1H),4.50(s,1H),3.15(s,2H),1.88(s,6H),1.38(s,9H).Dissolve intermediate M4-1 (1.40g) in 20.0mL THF, cool to -40°C, add lithium aluminum tetrahydrogen (0.330g), naturally raise to room temperature and react for 2 hours, then lower the temperature of the reaction solution to 0°C, and then Gradually add 0.33 mL water, 0.33 mL 15% NaOH solution and 0.33 mL water to the reaction solution. After stirring for 30 minutes, filter through diatomaceous earth to remove insoluble impurities. The filter cake is eluted with 20.0 mL EA three times. The filtrate is collected and anhydrous. After drying over sodium sulfate, filtering and evaporating the solvent under reduced pressure, 0.910g of light yellow oily product, namely intermediate M4-2, was obtained. 1 H NMR (500MHz, Chloroform-d) δ9.50 (s, 1H), 4.50 (s, 1H), 3.15 (s, 2H), 1.88 (s, 6H), 1.38 (s, 9H).
步骤3：中间体M4的合成Step 3: Synthesis of intermediate M4
N2保护下，中间体M4-2(0.910g)溶于10.0mL无水甲醇中，然后依次加入无水碳酸钾(0.920g)，(1-重氮基-2-氧代丙基)膦酸二甲酯(0.960g)，室温反应2h。反应液旋干后柱层析分离纯化(PE:EA＝5:1)，得0.480g白色固体，即中间体M4。1H NMR(500MHz,Chloroform-d)δ4.47(s,1H),3.16(s,2H),2.09(s,1H),1.97(s,6H),1.44(s,9H).Under N2 protection, intermediate M4-2 (0.910g) was dissolved in 10.0mL anhydrous methanol, and then anhydrous potassium carbonate (0.920g) and (1-diazo-2-oxopropyl)phosphine were added in sequence Acid dimethyl ester (0.960g), react at room temperature for 2 hours. The reaction solution was spin-dried and then separated and purified by column chromatography (PE:EA=5:1) to obtain 0.480g of white solid, which is intermediate M4. 1 H NMR (500MHz, Chloroform-d) δ4.47(s,1H),3.16(s,2H),2.09(s,1H),1.97(s,6H),1.44(s,9H).
中间体M5的合成：
Synthesis of intermediate M5:
步骤1：中间体M5-1的合成Step 1: Synthesis of intermediate M5-1
将中间体M6(2.50g)，十二羰基三钌(213mg)，三苯基膦(534mg)加入500.0mL三口瓶中，N2保护下加入50.0mL甲苯，120℃下反应20min后加入中间体M4(2.48g)的甲苯(20.0mL)溶液，120℃下反应12h，反应液旋干后柱层析分离纯化(PE:EA＝2:1)，得化合物1.68g，即中间体M5-1。ESI-MS m/z:449[M+H]+。Add intermediate M6 (2.50g), triruthenium dodecacarbonyl (213mg), and triphenylphosphine (534mg) into a 500.0mL three-necked flask, add 50.0mL toluene under N2 protection, react at 120°C for 20 minutes, and then add the intermediate A solution of M4 (2.48g) in toluene (20.0mL) was reacted at 120°C for 12 hours. The reaction solution was spin-dried and then separated and purified by column chromatography (PE:EA=2:1) to obtain 1.68g of compound, which is intermediate M5-1. . ESI-MS m/z:449[M+H] + .
步骤2：中间体M5-2的合成Step 2: Synthesis of intermediate M5-2
将中间体M5-1(1.68g)溶于20.00mL DCM中，然后加入4.00mL TFA，室温反应0.5h，将反应液直接浓缩，5.00mL DCM复溶后再次浓缩得到化合物三氟乙酸盐1.75g，即中间体M5-2。化合物无需纯化，直接进行下一步反应。ESI-MS m/z:349[M+H]+。Dissolve intermediate M5-1 (1.68g) in 20.00mL DCM, then add 4.00mL TFA, react at room temperature for 0.5h, directly concentrate the reaction solution, redissolve 5.00mL DCM and concentrate again to obtain compound trifluoroacetate 1.75 g, that is, intermediate M5-2. The compound does not need to be purified and can be directly used in the next reaction. ESI-MS m/z:349[M+H] + .
步骤3：中间体M5的合成Step 3: Synthesis of intermediate M5
将中间体M5-2(1.75g)，溶于25.00mL MeOH中，加入37％的甲醛水溶液(4.30g)，加入N,N-二异丙基乙胺(0.368mL)和一滴乙酸，室温反应30分钟。再添加氰基硼氢化钠(249mg)，室温反应30分钟，LCMS监测反应完成。向反应液中加入10mL饱和碳酸氢钠溶液淬灭反应，然后加入10mL DCM萃取三次，收集有机相，无水硫酸钠干燥后过滤，减压蒸出溶剂后柱层析纯化(DCM:CH3OH＝10:1)得到产物得淡黄色粉末988mg，即中间体M5。ESI-MS m/z:377[M+H]+。Dissolve intermediate M5-2 (1.75g) in 25.00mL MeOH, add 37% formaldehyde aqueous solution (4.30g), add N,N-diisopropylethylamine (0.368mL) and a drop of acetic acid, and react at room temperature 30 minutes. Then add sodium cyanoborohydride (249 mg) and react at room temperature for 30 minutes. LCMS monitors the completion of the reaction. Add 10 mL of saturated sodium bicarbonate solution to the reaction solution to quench the reaction, then add 10 mL of DCM for extraction three times, collect the organic phase, dry it over anhydrous sodium sulfate and filter, evaporate the solvent under reduced pressure and purify by column chromatography (DCM: CH 3 OH =10:1) to obtain 988 mg of light yellow powder, namely intermediate M5. ESI-MS m/z:377[M+H] + .
中间体M6的合成：
Synthesis of intermediate M6:
步骤1：中间体M6-1的合成Step 1: Synthesis of intermediate M6-1
将3，4-二羟基-2-甲基苯甲酸甲酯(5.0g)溶解于DMF(50.0mL)中，依次添加碳酸钾(18.9g)和碘甲烷(5.1mL)。添加完成后，将混合物在常温下搅拌过夜。用乙酸乙酯和水稀释反应产物，并萃取有机层。萃取的有机层用无水硫酸钠干燥，通过减压蒸出溶剂后获得化合物5.4g，即中间体M6-1，其无需进一步纯化即可使用。ESI-MS m/z:211[M+H]+。Methyl 3,4-dihydroxy-2-methylbenzoate (5.0g) was dissolved in DMF (50.0mL), and potassium carbonate (18.9g) and methyl iodide (5.1mL) were added in sequence. After the addition was complete, the mixture was stirred at room temperature overnight. The reaction product was diluted with ethyl acetate and water, and the organic layer was extracted. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 5.4 g of compound, namely intermediate M6-1, which could be used without further purification. ESI-MS m/z:211[M+H] + .
步骤2：中间体M6-2的合成Step 2: Synthesis of intermediate M6-2
将中间体M6-1(5.4g)加入甲醇/水(1/1，54.0mL)混合液后添加氢氧化钠(3.30g)，加热回流4小时完成反应。低温冷却反应液后，用6.0N的盐酸水溶液酸化至Ph＝1。将生成的固体在低温下搅拌1小时后，过滤回收，并用水洗涤，干燥获得化合物5.0g，即中间体M6-2。ESI-MS m/z:197[M+H]+。Intermediate M6-1 (5.4g) was added to the methanol/water (1/1, 54.0mL) mixture, sodium hydroxide (3.30g) was added, and the reaction was completed by heating and refluxing for 4 hours. After cooling the reaction liquid at low temperature, it was acidified to Ph=1 with 6.0N hydrochloric acid aqueous solution. The resulting solid was stirred at low temperature for 1 hour, filtered, recovered, washed with water, and dried to obtain 5.0 g of compound, namely intermediate M6-2. ESI-MS m/z:197[M+H]+.
步骤3：中间体M6-3的合成Step 3: Synthesis of intermediate M6-3
将中间体M6-2(5.0g)与氨基乙醛缩二甲醇(3.31g)溶于DMF(50.0mL)中，依次加入N,N-二异丙基乙胺(12.65mL)，N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(11.05g)，室温反应1h完成反应。用乙酸乙酯和水稀释反应产物，并萃取有机层。萃取的有机层用无水硫酸钠干燥，通过减压蒸出溶剂后获得化合物5.5g，即中间体M6-3，其无需进一步纯化即可使用。ESI-MS m/z:284[M+H]+。Dissolve intermediate M6-2 (5.0g) and aminoacetaldehyde dimethyl acetal (3.31g) in DMF (50.0mL), add N,N-diisopropylethylamine (12.65mL), N,N ,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (11.05g), react at room temperature for 1 hour to complete the reaction. The reaction product was diluted with ethyl acetate and water, and the organic layer was extracted. The extracted organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 5.5 g of compound, namely intermediate M6-3, which could be used without further purification. ESI-MS m/z:284[M+H] + .
步骤4：中间体M6-4的合成Step 4: Synthesis of intermediate M6-4
将中间体M6-3(5.5g)添加到浓硫酸(27.5mL)后，将温度升温至60℃后搅拌2小时。将反应液冷却至常温后，倒入冰水搅拌30分钟。过滤收集生成的固体，并用过量的水洗涤，干燥获得化合物3.3g，即中间体M6-4，其无需进一步纯化即可使用。ESI-MS m/z:220[M+H]+。After adding intermediate M6-3 (5.5 g) to concentrated sulfuric acid (27.5 mL), the temperature was raised to 60°C and stirred for 2 hours. After the reaction solution was cooled to room temperature, ice water was poured into it and stirred for 30 minutes. The resulting solid was collected by filtration, washed with excess water, and dried to obtain 3.3 g of compound, intermediate M6-4, which could be used without further purification. ESI-MS m/z:220[M+H] + .
步骤5：中间体M6-5的合成Step 5: Synthesis of intermediate M6-5
将中间体M6-4(3.3g)溶于50.0mL甲醇中，加入10％Pd/C(1.7g)，升温至50℃反应过夜，LCMS监测反应完成。硅藻土过滤，滤饼分别用甲醇和乙醇洗脱数次，滤液蒸出溶 剂后柱层析纯化，得到化合物2.3g，即中间体M6-5。ESI-MS m/z:222[M+H]+。Intermediate M6-4 (3.3g) was dissolved in 50.0 mL methanol, 10% Pd/C (1.7g) was added, the temperature was raised to 50°C and the reaction was completed overnight. LCMS monitored the reaction to completion. Filter through diatomaceous earth, elute the filter cake with methanol and ethanol several times, and evaporate the filtrate to remove the solution. After purification by column chromatography, 2.3g of compound was obtained, namely intermediate M6-5. ESI-MS m/z:222[M+H]+.
步骤6：中间体M6-6的合成Step 6: Synthesis of intermediate M6-6
将中间体M6-5(2.30g)溶于50.0mL DCM中，加入磺酰氯(3.0mL)，50℃反应30分钟，LCMS监测反应完成。反应液降低温度至室温后，滴加至饱和碳酸氢钠溶液中，加入DCM萃取数次，收集有机相，减压蒸除溶剂后柱层析纯化，得化合物1.6g，即中间体M6-6。ESI-MS m/z:256[M+H]+。Dissolve intermediate M6-5 (2.30g) in 50.0mL DCM, add sulfonyl chloride (3.0mL), and react at 50°C for 30 minutes. LCMS monitors the reaction to be completed. After the temperature of the reaction solution was lowered to room temperature, it was added dropwise to a saturated sodium bicarbonate solution, and DCM was added for extraction several times. The organic phase was collected, the solvent was evaporated under reduced pressure and then purified by column chromatography to obtain 1.6g of the compound, which is intermediate M6-6. . ESI-MS m/z:256[M+H] + .
步骤7：中间体M6的合成Step 7: Synthesis of intermediate M6
冰浴下，将中间体M6-6(1.6g)溶于20.0mL DCM中，加入2.50mL三溴化硼，室温反应0.5h，监控反应完毕后，向反应液中加入水淬灭，体系中有固体析出，搅拌30min后过滤，用水和DCM洗脱数次后收集滤饼并干燥，得到中间体M6。ESI-MS m/z:228[M+H]+。1H NMR(500MHz,DMSO-d6)δ9.63(s,1H),8.70(s,1H),7.74(d,J＝3.7Hz,1H),3.22(td,J＝6.3,3.1Hz,2H),2.80(t,J＝6.5Hz,2H),2.42(s,3H).Dissolve intermediate M6-6 (1.6g) in 20.0mL DCM under ice bath, add 2.50mL boron tribromide, and react at room temperature for 0.5h. After monitoring the reaction, add water to the reaction solution to quench the system. If a solid precipitates, stir for 30 minutes and then filter. Elute with water and DCM several times, collect the filter cake and dry it to obtain intermediate M6. ESI-MS m/z:228[M+H] + . 1 H NMR (500MHz, DMSO-d 6 ) δ9.63 (s, 1H), 8.70 (s, 1H), 7.74 (d, J = 3.7Hz, 1H), 3.22 (td, J = 6.3, 3.1Hz, 2H), 2.80 (t, J = 6.5Hz, 2H), 2.42 (s, 3H).
中间体M7的合成
Synthesis of intermediate M7
步骤1：化合物M7-1的合成Step 1: Synthesis of Compound M7-1
250mL单口瓶中加入化合物4-羟基-6-甲基-2-氧代-1,2-二氢吡啶-3-腈(15.6g)，溶于POCl3(100mL)，加入DMF(2mL)混合均匀，在N2保护油浴120℃下回流反应3h。冷却至室温，反应液直接蒸干，浓缩物溶于DCM，用饱和碳酸氢钠洗涤，干燥，浓缩至干，柱层析分离产物(PE:EA＝10:1),得12.8g黄色固体，即化合物M7-1。Add compound 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-nitrile (15.6g) into a 250mL single-neck bottle, dissolve it in POCl 3 (100mL), add DMF (2mL) and mix Evenly, reflux the reaction in an N2 protected oil bath at 120°C for 3 hours. Cool to room temperature, directly evaporate the reaction solution to dryness, dissolve the concentrate in DCM, wash with saturated sodium bicarbonate, dry, concentrate to dryness, and separate the product by column chromatography (PE:EA=10:1) to obtain 12.8g of yellow solid. That is compound M7-1.
步骤2：化合物M7-2的合成Step 2: Synthesis of compound M7-2
250mL单口瓶中加入化合物M7-1(7.8g)，溶于甲醇(100mL)，加入甲醇钠(11.26g)， 碘化钾(6.92g)，回流反应过夜。冷却至室温，反应液直接蒸干，柱层析分离纯化(PE:EA＝10:1)，得7.1g类白色固体，即化合物M7-2。Add compound M7-1 (7.8g) to a 250mL single-neck bottle, dissolve it in methanol (100mL), add sodium methoxide (11.26g), Potassium iodide (6.92g), reflux and react overnight. After cooling to room temperature, the reaction solution was directly evaporated to dryness and separated and purified by column chromatography (PE:EA=10:1) to obtain 7.1g of off-white solid, namely compound M7-2.
步骤3：化合物M7-3的合成Step 3: Synthesis of Compound M7-3
250mL单口瓶中加入化合物M7-2(6.4g)，溶于DCM(80mL)和TFA(20mL)，加入N-碘代丁二酰亚胺，室温反应过夜。将反应液倒入饱和亚硫酸钠溶液中淬灭后，加入适量水,分液，水相用DCM萃取，合并有机相，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝10:1),得8.8g白色固体，即化合物M7-3。Add compound M7-2 (6.4g) to a 250mL single-neck bottle, dissolve it in DCM (80mL) and TFA (20mL), add N-iodosuccinimide, and react at room temperature overnight. Pour the reaction solution into saturated sodium sulfite solution to quench, add an appropriate amount of water, separate the liquids, extract the aqueous phase with DCM, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=10: 1), 8.8g of white solid was obtained, namely compound M7-3.
步骤4：化合物M7-4的合成Step 4: Synthesis of Compound M7-4
250mL单口瓶中加入化合物M7-3(8.8g)，溶于DMF(100mL)，加入三甲基硅基乙炔(12.27mL),CuI(1.1g)，PdCl2(PPh3)2(2.03g)，DIEA(14.35mL),N2保护50℃反应1h。冷却至室温，向反应液中加入倒入适量水和EA，分液，水相用EA萃取，合并有机相，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝10:1),得6.7g白色固体，即化合物M7-4。Add compound M7-3 (8.8g) to a 250mL single-neck bottle, dissolve in DMF (100mL), add trimethylsilyl acetylene (12.27mL), CuI (1.1g), PdCl 2 (PPh 3 ) 2 (2.03g) , DIEA (14.35mL), reaction at 50°C for 1 hour under N 2 protection. Cool to room temperature, add an appropriate amount of water and EA to the reaction solution, separate the liquids, extract the water phase with EA, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=10:1 ), 6.7g of white solid was obtained, namely compound M7-4.
步骤5：化合物M7-5的合成Step 5: Synthesis of Compound M7-5
250mL单口瓶中加入化合物M7-4(6.7g)，溶于DMF(50mL),加入DABCO(8.29g)，100℃反应4h。无需后处理，直接投下一步。Add compound M7-4 (6.7g) to a 250mL single-neck bottle, dissolve it in DMF (50mL), add DABCO (8.29g), and react at 100°C for 4 hours. No post-processing required, just go to the next step.
步骤6：化合物M7-6的合成Step 6: Synthesis of Compound M7-6
向化合物M7-5的反应液中加入CuI(4.61g)，100℃反应过夜。冷却至室温，向反应液中倒入适量水和EA，分液，水相用EA萃取，合并有机相，有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝8:1),得2.2g白色固体，即化合物M7-6。CuI (4.61g) was added to the reaction solution of compound M7-5, and the reaction was carried out at 100°C overnight. Cool to room temperature, pour an appropriate amount of water and EA into the reaction solution, separate the liquids, extract the water phase with EA, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=8:1) , 2.2g of white solid was obtained, namely compound M7-6.
步骤7：化合物M7-7的合成Step 7: Synthesis of Compound M7-7
50mL单口瓶中加入化合物M7-6(2.2g)，溶于7M NH3/MeOH(15mL)，加入EA(15mL),雷尼镍(2.0g)，通入氢气后，室温反应2h。反应液过滤，滤液直接蒸干，得2.1g淡黄色固体，即为化合物M7-7。Add compound M7-6 (2.2g) to a 50mL single-neck bottle, dissolve it in 7M NH 3 /MeOH (15mL), add EA (15mL) and Raney nickel (2.0g), add hydrogen, and react at room temperature for 2h. The reaction solution was filtered, and the filtrate was directly evaporated to dryness to obtain 2.1g of light yellow solid, which was compound M7-7.
步骤8：化合物M7的合成Step 8: Synthesis of Compound M7
50mL单口瓶中加入化合物M7-7(2.1g)，溶于4M HCI(40mL)，加热至100℃，反应过夜。反应液直接旋干，得1.9g淡黄色固体，即化合物M7。Add compound M7-7 (2.1g) to a 50mL single-neck bottle, dissolve it in 4M HCI (40mL), heat to 100°C, and react overnight. The reaction solution was directly spun to dryness to obtain 1.9g of light yellow solid, namely compound M7.
中间体M8的合成：
Synthesis of intermediate M8:
步骤1：化合物M8-1的合成Step 1: Synthesis of Compound M8-1
将2-甲基-3,4-二羟基-5-氯苯甲酸甲酯(200mg)，十二羰基三钌(29.6mg)，三苯基膦(24.2mg)加入50.0mL三口瓶中，N2保护下加入5.00mL甲苯，120℃下反应10min后加入M4(0.240g)的甲苯(5.00mL)溶液，120℃下反应12h，反应液浓缩后柱层析分离纯化(PE:EA＝4:1)得0.130g化合物M8-1。1H NMR(500MHz,CDCl3)δ7.53(s,1H),4.46(s,1H),3.85(s,3H),3.20(s,2H),2.39(s,3H),1.70(s,6H),1.67(s,3H),1.43(s,9H)。Add 2-methyl-3,4-dihydroxy-5-chlorobenzoic acid methyl ester (200mg), triruthenium dodecacarbonyl (29.6mg), triphenylphosphine (24.2mg) into a 50.0mL three-necked bottle, N 2. Add 5.00mL toluene under protection, react at 120°C for 10 minutes, then add a solution of M4 (0.240g) in toluene (5.00mL), react at 120°C for 12h, concentrate the reaction solution and then separate and purify by column chromatography (PE:EA=4: 1) Obtain 0.130g of compound M8-1. 1 H NMR (500MHz, CDCl 3 ) δ7.53(s,1H),4.46(s,1H),3.85(s,3H),3.20(s,2H),2.39(s,3H),1.70(s, 6H),1.67(s,3H),1.43(s,9H).
步骤2：化合物M8的合成Step 2: Synthesis of Compound M8
将M8-1(130mg)，一水合氢氧化锂(118mg)溶于5.00mL甲醇和1.00mL水中，升温至50℃反应3小时。向反应液中加入饱和柠檬酸水溶液至pH＝6，析出淡黄色固体，抽滤，滤饼用水洗涤，烘干，得到120mg化合物M8。化合物无需纯化，直接进行下一步反应。ESI-MS m/z:424[M+H]+。Dissolve M8-1 (130 mg) and lithium hydroxide monohydrate (118 mg) in 5.00 mL methanol and 1.00 mL water, raise the temperature to 50°C and react for 3 hours. Saturated citric acid aqueous solution was added to the reaction solution until pH=6, a light yellow solid precipitated, and was filtered with suction. The filter cake was washed with water and dried to obtain 120 mg of compound M8. The compound does not need to be purified and can be directly used in the next reaction. ESI-MS m/z:424[M+H] + .
中间体M9的合成：
Synthesis of intermediate M9:
步骤1：化合物M9-1的合成Step 1: Synthesis of Compound M9-1
在室温下，将3-溴-2-氟-6-甲基吡啶(10g)加入250mL三口瓶中，N2保护下加入50mL THF，加入苯甲醇(5.98g)，冷却至0℃，缓慢加入钠氢(6.82g)，0℃反应1h，然后恢复到室温反应12h。反应液过滤后收集滤液直接浓缩。浓缩物经柱层析分离纯化(PE: EA＝10:1)得15.1g化合物M9-1。ESI-MS m/z:278[M+H]+。At room temperature, add 3-bromo-2-fluoro-6-methylpyridine (10g) into a 250mL three-necked flask, add 50mL THF under N2 protection, add benzyl alcohol (5.98g), cool to 0°C, and slowly add Sodium hydrogen (6.82g) was reacted at 0°C for 1 hour, then returned to room temperature for 12 hours. The reaction solution was filtered and the filtrate was collected and concentrated directly. The concentrate was separated and purified by column chromatography (PE: EA=10:1) to obtain 15.1g of compound M9-1. ESI-MS m/z:278[M+H] + .
步骤2：化合物M9-2的合成Step 2: Synthesis of Compound M9-2
化合物M9-1(15.1g)加入250mL单口瓶，冷却至0℃，滴入25mL浓硝酸，恢复到室温反应12h。反应液加入20mL水稀释，加入碳酸氢钠粉末调节pH至7，有固体析出。过滤收集滤饼，滤饼用10mL水洗涤。将滤饼加入250mL单口瓶，加入10mL EA打浆30min，过滤，滤饼烘干得12.75g化合物M9-2。ESI-MS m/z:233[M+H]+。1H NMR(500MHz,CD3OD-d4)δ8.59(s,1H),2.67(s,3H)。Compound M9-1 (15.1g) was added to a 250mL single-neck bottle, cooled to 0°C, 25mL of concentrated nitric acid was added dropwise, and the reaction was returned to room temperature for 12h. The reaction solution was diluted by adding 20 mL of water, and sodium bicarbonate powder was added to adjust the pH to 7. A solid precipitated. The filter cake was collected by filtration and washed with 10 mL of water. Add the filter cake to a 250 mL single-neck bottle, add 10 mL EA and beat for 30 minutes, filter, and dry the filter cake to obtain 12.75 g of compound M9-2. ESI-MS m/z:233[M+H] + . 1 H NMR (500MHz, CD 3 OD-d 4 ) δ8.59 (s, 1H), 2.67 (s, 3H).
步骤3：化合物M9-3的合成Step 3: Synthesis of compound M9-3
化合物M9-2(11g)加入250mL三口瓶，加入碳酸银(14.32g)，N2保护下加入60mL甲苯，加入苄溴(6.05g)，升温至100℃反应12h。反应液过滤后收集滤液直接浓缩。浓缩物经柱层析分离纯化(PE:EA＝20:1)，得6.05g化合物M9-3。1H NMR(500MHz,CDCl3-d)δ8.55(s,1H),7.49(d,J＝7.2Hz,2H),7.42-7.33(m,3H),5.54(s,2H),2.80(s,3H)。Compound M9-2 (11g) was added to a 250mL three-necked flask, silver carbonate (14.32g) was added, 60mL toluene was added under N2 protection, benzyl bromide (6.05g) was added, and the temperature was raised to 100°C for 12h. The reaction solution was filtered and the filtrate was collected and concentrated directly. The concentrate was separated and purified by column chromatography (PE:EA=20:1) to obtain 6.05g of compound M9-3. 1 H NMR (500MHz, CDCl 3 -d) δ8.55 (s, 1H), 7.49 (d, J = 7.2Hz, 2H), 7.42-7.33 (m, 3H), 5.54 (s, 2H), 2.80 ( s,3H).
步骤4：化合物M9-4的合成Step 4: Synthesis of Compound M9-4
化合物M9-3(1g)加入100mL三口瓶，N2保护下加入50mL THF，乙醇干冰浴冷却至-60℃，加入乙烯基溴化镁(15.7mL,1M/THF)，升温至-50℃反应1h，向反应液缓慢加入20mL饱和氯化铵溶液猝灭，EA萃取，取有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝3:1),得163.0mg化合物M9-4。ESI-MS m/z:317/319[M+H]+。1H NMR(500MHz,CDCl3-d)δ8.16(s,1H),7.54(m,2H),7.39-7.32(m,3H),7.27(s,1H),6.51(dd,J＝3.1,2.1Hz,1H),5.51(s,2H),2.60(s,3H)。Compound M9-3 (1g) was added to a 100mL three-necked flask, 50mL THF was added under N2 protection, cooled to -60°C in an ethanol dry ice bath, vinyl magnesium bromide (15.7mL, 1M/THF) was added, and the temperature was raised to -50°C for reaction. For 1 hour, slowly add 20 mL of saturated ammonium chloride solution to the reaction solution to quench, extract with EA, take the organic phase and dry it over anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=3:1) to obtain 163.0 mg of compound M9-4. . ESI-MS m/z:317/319[M+H] + . 1 H NMR (500MHz, CDCl 3 -d) δ8.16 (s, 1H), 7.54 (m, 2H), 7.39-7.32 (m, 3H), 7.27 (s, 1H), 6.51 (dd, J = 3.1 ,2.1Hz,1H),5.51(s,2H),2.60(s,3H).
步骤5：化合物M9-5的合成Step 5: Synthesis of Compound M9-5
化合物M9-4(0.2g)加入10mL蛋形瓶，N2保护，加入4mL DMF，冰水浴下加入钠氢(40mg),搅拌20min后加入TosCl(0.18mg)，回到室温搅拌30min。向反应液缓慢加入20mL饱和氯化铵溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，湿法上样柱层析分离产物(PE:EA＝20:1),得214mg化合物M9-5。ESI-MS m/z:471/473[M+H]+。Compound M9-4 (0.2g) was added to a 10mL egg-shaped flask under N2 protection, 4mL of DMF was added, sodium hydrogen (40mg) was added in an ice water bath, stirred for 20min, then TosCl (0.18mg) was added, returned to room temperature and stirred for 30min. Slowly add 20 mL of saturated ammonium chloride solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and separate the product by wet loading column chromatography (PE:EA=20 :1), 214 mg of compound M9-5 was obtained. ESI-MS m/z:471/473[M+H] + .
步骤6：化合物M9-6的合成Step 6: Synthesis of Compound M9-6
化合物M9-5(0.1g)加入5mL微波管，加入2mL DMF，随后加入氰化亚铜(0.1g),微波加热搅拌2h后回到室温。向反应液缓慢加入20mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，湿法上样柱层析分离产物(PE: EA＝10:1),得90mg化合物M9-6。ESI-MS m/z:417[M+H]+。Compound M9-5 (0.1g) was added to a 5mL microwave tube, 2mL of DMF was added, then copper cyanide (0.1g) was added, heated under microwave and stirred for 2 hours before returning to room temperature. Slowly add 20 mL of saturated sodium bicarbonate solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and separate the product by wet loading column chromatography (PE: EA=10:1), 90 mg of compound M9-6 was obtained. ESI-MS m/z:417[M+H] + .
步骤7：化合物M9-7的合成Step 7: Synthesis of Compound M9-7
化合物M9-6(90mg)加入25mL反应瓶中，N2保护，加入10mL甲醇，随后加入氢氧化钾固体(240mg),室温搅拌1小时。向反应液缓慢加入20mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，湿法上样柱层析分离产物(PE:EA＝2:1),得45mg化合物M9-7。ESI-MS m/z:264[M+H]+。Compound M9-6 (90 mg) was added to a 25 mL reaction flask, protected by N2 , 10 mL of methanol was added, then potassium hydroxide solid (240 mg) was added, and stirred at room temperature for 1 hour. Slowly add 20 mL of saturated sodium bicarbonate solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and separate the product by wet loading column chromatography (PE:EA=2 :1), 45 mg of compound M9-7 was obtained. ESI-MS m/z:264[M+H] + .
步骤8：化合物M9的合成Step 8: Synthesis of Compound M9
化合物M9-7(20mg)加入10mL反应瓶中，N2保护，加入3mL四氢呋喃，随后加入0.15mL 1M硼烷二甲硫醚的四氢呋喃溶液，加热60℃反应30min。冷至室温，向体系中加入甲醇淬灭。回流解离将络合的硼完全解离，冷至室温，向反应液缓慢加入20mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗涤，无水硫酸钠干燥，旋干后得18mg粗品，即化合物M9。ESI-MS m/z:268[M+H]+。未经纯化直接用于下一步反应。Compound M9-7 (20 mg) was added to a 10 mL reaction flask under N2 protection, 3 mL of tetrahydrofuran was added, and then 0.15 mL of 1M borane dimethyl sulfide in tetrahydrofuran solution was added, and the reaction was heated at 60°C for 30 min. Cool to room temperature, add methanol to the system to quench. Reflux dissociation to completely dissociate the complexed boron, cool to room temperature, slowly add 20 mL saturated sodium bicarbonate solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, and dry with anhydrous sodium sulfate , after spin drying, 18 mg of crude product was obtained, namely compound M9. ESI-MS m/z:268[M+H] + . It was used directly in the next reaction without purification.
中间体M10的合成：
Synthesis of intermediate M10:
步骤1：中间体M10-1的合成Step 1: Synthesis of intermediate M10-1
将3-氰基-4,6-二甲基-2-羟基吡啶(1.00g)溶于10.0mL甲苯中，依次加入溴化苄(0.79mL)，氧化银(1.54g)，110℃反应12h，反应完毕后硅藻土过滤，减压蒸除溶剂柱层析纯化，得1.40g白色固体产物，即中间体M10-1。ESI-MS m/z:271[M+H]+；Dissolve 3-cyano-4,6-dimethyl-2-hydroxypyridine (1.00g) in 10.0mL toluene, add benzyl bromide (0.79mL) and silver oxide (1.54g) in sequence, and react at 110°C for 12h , after the reaction is completed, filter through diatomaceous earth, evaporate the solvent under reduced pressure and purify by column chromatography to obtain 1.40g of white solid product, namely intermediate M10-1. ESI-MS m/z:271[M+H] + ;
步骤2：中间体M10-2的合成Step 2: Synthesis of intermediate M10-2
冰浴下，将中间体M10-1(1.40g)溶于20.0mL DCM中，加入二异丁基氢化铝(1mol/L，6.0mL)，自然升高至室温反应1h，向反应液中滴加1N HCl水溶液(5.0mL)搅拌30min淬灭反应，然后加入4N NaOH水溶液(1.25mL)，硅藻土过滤除去不溶性杂质，滤饼用20.0Ml DCM洗脱3次，收集滤液萃取收集有机相，无水硫酸钠干燥，过滤后 减压蒸除溶剂，柱层析纯化得到化合物0.58g，即中间体M10-2。ESI-MS m/z:274[M+H]+；Dissolve intermediate M10-1 (1.40g) in 20.0mL DCM under ice bath, add diisobutylaluminum hydride (1mol/L, 6.0mL), naturally raise to room temperature and react for 1h, then drop it into the reaction solution Add 1N HCl aqueous solution (5.0mL) and stir for 30 minutes to quench the reaction, then add 4N NaOH aqueous solution (1.25mL), filter through diatomaceous earth to remove insoluble impurities, and elute the filter cake with 20.0Ml DCM three times. Collect the filtrate and extract the organic phase. Dry over anhydrous sodium sulfate and filter The solvent was evaporated under reduced pressure and purified by column chromatography to obtain 0.58g of compound, namely intermediate M10-2. ESI-MS m/z:274[M+H] + ;
步骤3：中间体M10-3的合成Step 3: Synthesis of intermediate M10-3
冰浴下，将中间体M10-2(0.58g)溶于10.0mLMeOH中，加入硼氢化钠(92mg)，冰浴下反应1.0h，反应液减压蒸除溶剂，加入适量乙酸乙酯与饱和碳酸氢钠溶液萃取，收集有机相，无水硫酸钠干燥，减压蒸除溶剂后柱层析纯化，得到0.54g产物，即中间体M10-3。ESI-MS m/z:276[M+H]+；Dissolve intermediate M10-2 (0.58g) in 10.0 mL MeOH under ice bath, add sodium borohydride (92 mg), react under ice bath for 1.0 h, evaporate the solvent from the reaction solution under reduced pressure, add an appropriate amount of ethyl acetate and saturated Extract with sodium bicarbonate solution, collect the organic phase, dry with anhydrous sodium sulfate, evaporate the solvent under reduced pressure and then purify by column chromatography to obtain 0.54g of the product, intermediate M10-3. ESI-MS m/z:276[M+H] + ;
步骤4：中间体M10的合成Step 4: Synthesis of intermediate M10
-40℃下，将中间体M10-3(0.54g)溶于10.0mL DCM中，加入氯化亚砜(0.20mL)，低温反应0.5h，反应液滴加至饱和碳酸氢钠溶液中淬灭，加入DCM萃取，收集有机相，无水硫酸钠干燥，减压蒸除溶剂后柱层析纯化，得到0.23g产物，即中间体M10。Dissolve intermediate M10-3 (0.54g) in 10.0mL DCM at -40°C, add thionyl chloride (0.20mL), react at low temperature for 0.5h, and add the reaction solution dropwise to saturated sodium bicarbonate solution to quench. , add DCM for extraction, collect the organic phase, dry it over anhydrous sodium sulfate, evaporate the solvent under reduced pressure and then purify by column chromatography to obtain 0.23g of product, intermediate M10.
ESI-MS m/z:294[M+H]+；ESI-MS m/z:294[M+H] + ;
中间体M11的合成：
Synthesis of intermediate M11:
步骤1：化合物M11-1的合成Step 1: Synthesis of Compound M11-1
常温下，将双环[1.1.1]戊烷-1,3-二羧酸,1-甲酯(3g)溶于THF(20mL)中，冷却至0℃,加入硼烷二甲硫醚(3.54mL,10mol/L)，缓慢升温至室温反应2小时。将反应液滴入20mL甲醇，搅拌至无气泡冒出，减压浓缩。浓缩物经柱层析(PE:EA＝70:30)分离纯化得到化合物M11-1(2.54g，92％产率)。Dissolve bicyclo[1.1.1]pentane-1,3-dicarboxylic acid, 1-methyl ester (3g) in THF (20mL) at room temperature, cool to 0°C, and add borane dimethyl sulfide (3.54 mL, 10mol/L), slowly warm to room temperature and react for 2 hours. Add 20 mL of methanol dropwise into the reaction solution, stir until no bubbles appear, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=70:30) to obtain compound M11-1 (2.54g, 92% yield).
步骤2：化合物M11-2的合成Step 2: Synthesis of Compound M11-2
常温下，将M11-1(1.65g)溶于DCM(10mL)中，冷却至0℃,加入咪唑(1.44g)，叔丁基二甲基氯硅烷(2.39g)，缓慢升温至室温反应2小时。向反应液中加入20mL水，用20mL DCM萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝90:10)分离纯化得到化合物M11-2(2.79g，97％产率)。1H NMR(500MHz,Chloroform-d)δ3.64(s,3H),3.57(s,2H),1.92(s,6H),0.86(s,9H),-0.00(s,6H). Dissolve M11-1 (1.65g) in DCM (10mL) at room temperature, cool to 0°C, add imidazole (1.44g), tert-butyldimethylsilyl chloride (2.39g), slowly warm to room temperature, react 2 Hour. Add 20 mL of water to the reaction solution, extract three times with 20 mL of DCM, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=90:10) to obtain compound M11-2 (2.79g, 97% yield). 1 H NMR (500MHz, Chloroform-d) δ3.64 (s, 3H), 3.57 (s, 2H), 1.92 (s, 6H), 0.86 (s, 9H), -0.00 (s, 6H).
步骤3：化合物M11-3的合成Step 3: Synthesis of Compound M11-3
常温下，将M11-2(1.5g)溶于THF(10mL)中，冷却至0℃,加入硼氢化钠(0.63g)，将反应混合物升温至50℃，加入甲醇(3mL),反应2小时。向反应液中加入20mL水，用20ml乙酸乙酯萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝70:30)分离纯化得到化合物M11-3(1.25g，93％产率)。1H NMR(500MHz,Chloroform-d)δ3.57(s,2H),1.56(s,6H),0.86(s,9H),0.00(s,6H).Dissolve M11-2 (1.5g) in THF (10mL) at room temperature, cool to 0°C, add sodium borohydride (0.63g), heat the reaction mixture to 50°C, add methanol (3mL), and react for 2 hours. . Add 20 mL of water to the reaction solution, extract three times with 20 ml of ethyl acetate, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=70:30) to obtain compound M11-3 (1.25g, 93% yield). 1 H NMR (500MHz, Chloroform-d) δ3.57 (s, 2H), 1.56 (s, 6H), 0.86 (s, 9H), 0.00 (s, 6H).
步骤4：化合物M11-4的合成Step 4: Synthesis of Compound M11-4
常温下，将M11-3(400mg)溶于DCM(5mL)中，冷却至0℃,加入Dess-martin氧化剂(744mg)，缓慢升温至室温反应1小时。反应混合物过滤，滤液加入10mL饱和碳酸氢钠溶液,搅拌10分钟。用20ml DCM萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。得到M11-4(380mg，95％产率)，无需纯化直接进行下一步。Dissolve M11-3 (400 mg) in DCM (5 mL) at room temperature, cool to 0°C, add Dess-martin oxidant (744 mg), slowly warm to room temperature and react for 1 hour. The reaction mixture was filtered, 10 mL of saturated sodium bicarbonate solution was added to the filtrate, and stirred for 10 minutes. Extract three times with 20 ml DCM, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. M11-4 (380 mg, 95% yield) was obtained and was directly carried to the next step without purification.
步骤5：化合物M11的合成Step 5: Synthesis of Compound M11
常温下，将M11-4(380mg)溶于DCM(10mL)中，加入碳酸钾(1.3g)，搅拌10分钟，加入(1-重氮-2-氧代-丙醇)-膦酸二甲酯(0.25mL)，室温反应12小时。反应混合物过滤，滤液加入20mL水，用20ml DCM萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝80:20)分离纯化得到化合物M11(240mg，61％产率)。1H NMR(500MHz,Chloroform-d)δ3.53(s,2H),2.07(s,1H),1.95(s,6H),0.86(s,9H),-0.00(s,6H).Dissolve M11-4 (380mg) in DCM (10mL) at room temperature, add potassium carbonate (1.3g), stir for 10 minutes, add (1-diazo-2-oxo-propanol)-dimethylphosphonate Ester (0.25 mL), react at room temperature for 12 hours. The reaction mixture was filtered, 20 mL of water was added to the filtrate, extracted three times with 20 ml of DCM, the organic layers were combined, and the organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=80:20) to obtain compound M11 (240 mg, 61% yield). 1 H NMR (500MHz, Chloroform-d) δ3.53 (s, 2H), 2.07 (s, 1H), 1.95 (s, 6H), 0.86 (s, 9H), -0.00 (s, 6H).
实施例1：化合物(R)-7-氯-2-((1r，4R)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2,4-二甲基-N-((7-甲基-5-氧代-5,6-二氢-1H-吡咯[2,3-c]吡啶-4-基)甲基)苯并[d][1,3]二恶英-5-甲酰胺的合成
Example 1: Compound (R)-7-chloro-2-((1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl Base-N-((7-methyl-5-oxo-5,6-dihydro-1H-pyrrole[2,3-c]pyridin-4-yl)methyl)benzo[d][1, 3] Synthesis of dioxin-5-carboxamide
步骤1：化合物1-1的合成Step 1: Synthesis of Compound 1-1
在室温下，将3-溴-2-氟-6-甲基吡啶(10g)加入250mL三口瓶中，N2保护下加入50mL THF，加入苯甲醇(5.98g)，冷却至0℃，缓慢加入钠氢(6.82g)，0℃反应1h，然后恢复到室温反应12h。反应液过滤后收集滤液直接浓缩。浓缩物经柱层析分离纯化(PE:EA＝10:1)得15.1g无色油状液体，即化合物1-1。ESI-MS m/z:278[M+H]+。At room temperature, add 3-bromo-2-fluoro-6-methylpyridine (10g) into a 250mL three-necked flask, add 50mL THF under N2 protection, add benzyl alcohol (5.98g), cool to 0°C, and slowly add Sodium hydrogen (6.82g) was reacted at 0°C for 1 hour, then returned to room temperature for 12 hours. The reaction solution was filtered and the filtrate was collected and concentrated directly. The concentrate was separated and purified by column chromatography (PE:EA=10:1) to obtain 15.1g of colorless oily liquid, namely compound 1-1. ESI-MS m/z:278[M+H] + .
步骤2：化合物1-2的合成Step 2: Synthesis of Compound 1-2
化合物1-1(15.1g)加入250mL单口瓶，冷却至0℃，滴入25mL浓硝酸，恢复到室温反应12h。反应液加入20mL水稀释，加入碳酸氢钠粉末调节pH至7，有固体析出。过滤收集滤饼，滤饼用10mL水洗涤。将滤饼加入250mL单口瓶，加入10mL EA打浆30min，过滤，滤饼烘干得12.75g黄褐色固体，即化合物1-2。ESI-MS m/z:233[M+H]+。1H NMR(500MHz,CD3OD-d4)δ8.59(s,1H),2.67(s,3H)。Compound 1-1 (15.1g) was added to a 250mL single-neck bottle, cooled to 0°C, 25mL of concentrated nitric acid was added dropwise, and the reaction was returned to room temperature for 12h. The reaction solution was diluted by adding 20 mL of water, and sodium bicarbonate powder was added to adjust the pH to 7. A solid precipitated. The filter cake was collected by filtration and washed with 10 mL of water. Add the filter cake to a 250 mL single-neck bottle, add 10 mL EA and beat for 30 minutes, filter, and dry the filter cake to obtain 12.75 g of a yellow-brown solid, which is compound 1-2. ESI-MS m/z:233[M+H] + . 1 H NMR (500MHz, CD 3 OD-d 4 ) δ8.59 (s, 1H), 2.67 (s, 3H).
步骤3：化合物1-3的合成Step 3: Synthesis of Compounds 1-3
化合物1-2(11g)加入250mL三口瓶，加入碳酸银(14.32g)，N2保护下加入60mL甲苯，加入苄溴(6.05g)，升温至100℃反应12h。反应液过滤后收集滤液直接浓缩。浓缩物经柱层析分离纯化(PE:EA＝20:1)，得6.05g淡黄色固体，即化合物1-3。1H NMR(500MHz,CDCl3-d)δ8.55(s,1H),7.49(d,J＝7.2Hz,2H),7.42-7.33(m,3H),5.54(s,2H),2.80(s,3H)。Compound 1-2 (11g) was added to a 250mL three-necked flask, silver carbonate (14.32g) was added, 60mL toluene was added under N2 protection, benzyl bromide (6.05g) was added, and the temperature was raised to 100°C for 12h. The reaction solution was filtered and the filtrate was collected and concentrated directly. The concentrate was separated and purified by column chromatography (PE:EA=20:1) to obtain 6.05g of light yellow solid, namely compound 1-3. 1 H NMR (500MHz, CDCl 3 -d) δ8.55 (s, 1H), 7.49 (d, J = 7.2Hz, 2H), 7.42-7.33 (m, 3H), 5.54 (s, 2H), 2.80 ( s,3H).
步骤4：化合物1-4的合成 Step 4: Synthesis of Compounds 1-4
化合物1-3(1g)加入100mL三口瓶，N2保护下加入50mL THF，乙醇干冰浴冷却至-60℃，加入乙烯基溴化镁(15.7mL,1M in THF)，升温至-50℃反应1h，向反应液缓慢加入20mL饱和氯化铵溶液猝灭，EA萃取，取有机相无水硫酸钠干燥，柱层析分离产物(PE:EA＝3:1),得163.0mg黄色固体，即化合物1-4。ESI-MS m/z:317/319[M+H]+。1H NMR(500MHz,CDCl3-d)δ8.16(s,1H),7.54(m,2H),7.39-7.32(m,3H),7.27(s,1H),6.51(dd,J＝3.1,2.1Hz,1H),5.51(s,2H),2.60(s,3H)。Compound 1-3 (1g) was added to a 100mL three-necked flask, 50mL THF was added under N2 protection, cooled to -60°C in an ethanol dry ice bath, vinyl magnesium bromide (15.7mL, 1M in THF) was added, and the temperature was raised to -50°C for reaction. 1h, slowly add 20mL saturated ammonium chloride solution to the reaction solution to quench, extract with EA, take the organic phase and dry it with anhydrous sodium sulfate, and separate the product by column chromatography (PE:EA=3:1) to obtain 163.0mg of yellow solid, that is Compounds 1-4. ESI-MS m/z:317/319[M+H] + . 1 H NMR (500MHz, CDCl 3 -d) δ8.16 (s, 1H), 7.54 (m, 2H), 7.39-7.32 (m, 3H), 7.27 (s, 1H), 6.51 (dd, J = 3.1 ,2.1Hz,1H),5.51(s,2H),2.60(s,3H).
步骤5：化合物1-5的合成Step 5: Synthesis of Compounds 1-5
化合物1-4(0.2g)加入10mL蛋形瓶，N2保护，加入4mL DMF，冰水浴下加入钠氢(40mg),搅拌20min后加入TosCl(0.18mg)，回到室温搅拌30min。向反应液缓慢加入20mL饱和氯化铵溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗，无水硫酸钠干燥，湿法上样柱层析分离产物(PE:EA＝20:1),得214mg无色油状物，即化合物1-5。ESI-MS m/z:471/473[M+H]+。Compound 1-4 (0.2g) was added to a 10mL egg-shaped flask under N2 protection, 4mL of DMF was added, sodium hydrogen (40mg) was added in an ice water bath, stirred for 20min, then TosCl (0.18mg) was added, returned to room temperature and stirred for 30min. Slowly add 20 mL of saturated ammonium chloride solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and separate the product by wet loading column chromatography (PE:EA=20 :1), 214 mg of colorless oil was obtained, namely compound 1-5. ESI-MS m/z:471/473[M+H] + .
步骤6：化合物1-6的合成Step 6: Synthesis of Compounds 1-6
化合物1-5(0.1g)加入5mL微波管，加入2mL DMF，随后加入氰化亚铜(0.1g),微波加热搅拌2h后回到室温。向反应液缓慢加入20mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗，无水硫酸钠干燥，湿法上样柱层析分离产物(PE:EA＝10:1),得90mg黄色固物，即化合物1-6。ESI-MS m/z:417[M+H]+。Compound 1-5 (0.1g) was added to a 5mL microwave tube, 2mL of DMF was added, then copper cyanide (0.1g) was added, heated in the microwave and stirred for 2 hours before returning to room temperature. Slowly add 20 mL of saturated sodium bicarbonate solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and separate the product by wet loading column chromatography (PE:EA=10 :1), 90 mg of yellow solid was obtained, namely compound 1-6. ESI-MS m/z:417[M+H] + .
步骤7：化合物1-7的合成Step 7: Synthesis of Compounds 1-7
化合物1-6(90mg)加入25mL反应瓶中，N2保护，加入10mL甲醇，随后加入氢氧化钾固体(240mg),室温搅拌1小时。向反应液缓慢加入20mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗，无水硫酸钠干燥，湿法上样柱层析分离产物(PE:EA＝2:1),得45mg黄色固物，即化合物1-7。ESI-MS m/z:264[M+H]+。Compound 1-6 (90 mg) was added to a 25 mL reaction flask, protected by N2 , 10 mL of methanol was added, then potassium hydroxide solid (240 mg) was added, and stirred at room temperature for 1 hour. Slowly add 20 mL of saturated sodium bicarbonate solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride, dry with anhydrous sodium sulfate, and separate the product by wet loading column chromatography (PE:EA=2 :1), 45 mg of yellow solid was obtained, namely compound 1-7. ESI-MS m/z:264[M+H] + .
步骤8：化合物1-8的合成Step 8: Synthesis of Compounds 1-8
化合物1-7(20mg)加入10mL反应瓶中，N2保护，加入3mL四氢呋喃，随后加入0.15mL 1M硼烷二甲硫醚的四氢呋喃溶液，加热60℃反应30min。冷至室温，向体系中加入甲醇淬灭。回流解离将络合的硼完全解离，冷至室温，向反应液缓慢加入20mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗，无水硫酸钠干燥，旋干后得18mg粗品，即化合物1-8。ESI-MS m/z:268[M+H]+。未经纯化直接投下一步。Compound 1-7 (20 mg) was added to a 10 mL reaction flask under N2 protection, 3 mL of tetrahydrofuran was added, and then 0.15 mL of 1M borane dimethyl sulfide in tetrahydrofuran solution was added, and the reaction was heated at 60°C for 30 min. Cool to room temperature, add methanol to the system to quench. Reflux dissociation to completely dissociate the complexed boron, cool to room temperature, slowly add 20 mL saturated sodium bicarbonate solution to the reaction solution to quench, extract 3 times with EA, combine the organic phases, wash with saturated sodium chloride, and dry with anhydrous sodium sulfate , after spin drying, 18 mg of crude product was obtained, namely compound 1-8. ESI-MS m/z:268[M+H] + . It was used directly in the next step without purification.
步骤9：化合物1-9的合成Step 9: Synthesis of Compounds 1-9
化合物1-8(18mg)加入10mL反应瓶中，加入中间体1(26mg)，HATU(28mg)，随 后加入3mL DMF，DIPEA(0.04mL)，室温搅拌30min。向反应液缓慢加入20mL饱和碳酸氢钠溶液猝灭，EA萃取3次，合并有机相，饱和氯化钠洗3遍，无水硫酸钠干燥，旋干后湿法上样柱层析分离产物(DCM:MeOH＝10:1),得20mg白色固物，即化合物1-9。ESI-MS m/z:645[M+H]+。Compound 1-8 (18mg) was added to a 10mL reaction bottle, intermediate 1 (26mg) and HATU (28mg) were added, followed by Then add 3 mL DMF and DIPEA (0.04 mL), and stir at room temperature for 30 min. Slowly add 20 mL of saturated sodium bicarbonate solution to the reaction solution to quench, extract with EA three times, combine the organic phases, wash with saturated sodium chloride three times, dry with anhydrous sodium sulfate, spin dry, and then apply wet method to column chromatography to separate the product ( DCM:MeOH=10:1), and 20 mg of white solid was obtained, namely compound 1-9. ESI-MS m/z:645[M+H] + .
步骤10：化合物1的合成Step 10: Synthesis of Compound 1
化合物1-9(20mg)加入10mL反应瓶中，加入甲醇(1mL)，乙酸乙酯(5mL)，随后加入10％Pd/C(25mg)，抽换氢气3次，室温搅拌2h。过滤除去钯碳，滤液浓缩得粗品，HPLC分离得5mg白色固物，即化合物1。ESI-MS m/z:555[M+H]+。1H NMR(500MHz,CD3OD-d4)δ7.91(d,J＝2.5Hz,1H),6.96(s,1H),6.75(d,J＝2.5Hz,1H),4.69(s,2H),4.41-4.38(m,1H),4.32-4.20(m,2H),4.07-4.01(m,2H),3.37-3.33(m,3H),3.16-3.10(m,1H),2.78(s,3H),2.18(s,3H),2.12-1.92(m,5H),1.63(s,3H),1.30-1.18(m,4H)。Compound 1-9 (20 mg) was added to a 10 mL reaction flask, methanol (1 mL), ethyl acetate (5 mL), then 10% Pd/C (25 mg) was added, hydrogen was replaced three times, and the mixture was stirred at room temperature for 2 h. The palladium carbon was removed by filtration, and the filtrate was concentrated to obtain a crude product, which was separated by HPLC to obtain 5 mg of white solid, namely compound 1. ESI-MS m/z:555[M+H] + . 1 H NMR (500MHz, CD 3 OD-d 4 ) δ7.91 (d, J＝2.5Hz, 1H), 6.96 (s, 1H), 6.75 (d, J＝2.5Hz, 1H), 4.69 (s, 2H),4.41-4.38(m,1H),4.32-4.20(m,2H),4.07-4.01(m,2H),3.37-3.33(m,3H),3.16-3.10(m,1H),2.78( s,3H),2.18(s,3H),2.12-1.92(m,5H),1.63(s,3H),1.30-1.18(m,4H).
实施例9：(R)-7-氯-2-((1r，4R)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2,4-二甲基-N-((4-甲基-6-氧代-5,6-二氢氟[3,2-c]吡啶-7-基)甲基)苯并[d][1,3]二氧杂环戊-5-甲酰胺的合成
Example 9: (R)-7-chloro-2-((1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl -N-((4-methyl-6-oxo-5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxo Synthesis of heterocyclopent-5-carboxamide
步骤1：化合物9-1的合成Step 1: Synthesis of compound 9-1
将上述化合物(R)-7-氯-2,4-二甲基-2-(4-氧代环己基)苯并[d][1,3]二氧杂环戊-5-羧酸甲酯(100.0mg)，溶于THF(2mL)，加入甲醇(2mL)，3-甲氧基-氮杂环丁烷(121.6m g)，室温反应1h后，降温至-70℃，加入硼氢化锂(43.7mg)，继续反应3h。升温至室温，向反应液中倒入适量水和EA，分液，水相用EA萃取，合并有机相，有机相无水硫酸钠干燥，经柱层析(DCM:MeOH＝10:1)分离纯化得到目标产物9-1(98.5mg，产率81.4％)。ESI-MS m/z:410.3[M+H]+。The above compound (R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxola-5-carboxylic acid methyl Ester (100.0mg), dissolved in THF (2mL), add methanol (2mL), 3-methoxy-azetidine (121.6m g), react at room temperature for 1 hour, then cool to -70°C, add lithium borohydride (43.7mg), continue the reaction for 3h. Warm up to room temperature, pour an appropriate amount of water and EA into the reaction solution, separate the liquids, extract the aqueous phase with EA, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and separate by column chromatography (DCM:MeOH=10:1) Purification gave the target product 9-1 (98.5 mg, yield 81.4%). ESI-MS m/z:410.3[M+H] + .
步骤2：化合物9-2的合成Step 2: Synthesis of compound 9-2
将上述化合物9-1(98.5mg)，溶于甲醇(3mL)，加入水(0.5mL)，氢氧化锂(32.2 mg)，加热至70℃反应3h。降温至室温，向反应液中加入1M盐酸溶液，调节溶液pH至2-3后，向反应液中加入10mL H2O和10mL DCM，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物9-2(77.2mg，产率81.4％)。ESI-MS m/z:396.2[M+H]+。Dissolve the above compound 9-1 (98.5mg) in methanol (3mL), add water (0.5mL), lithium hydroxide (32.2 mg), heated to 70°C for 3 hours. Cool to room temperature, add 1M hydrochloric acid solution to the reaction solution, adjust the pH of the solution to 2-3, add 10mL H 2 O and 10mL DCM to the reaction solution, stir and separate the layers, extract the water phase three times with DCM, and combine the organic phases. The organic phase was washed, dried, and concentrated to dryness. The concentrate did not require purification and was directly put into the next step to obtain target compound 9-2 (77.2 mg, yield 81.4%). ESI-MS m/z:396.2[M+H] + .
步骤3：化合物9的合成Step 3: Synthesis of Compound 9
将上述化合物9-2(77.2mg)，溶于DMF(3mL)，加入DIEA(0.1mL)，M7(41.7mg)，HATU(111.2mg)，室温反应1h。向反应液中加入10mL H2O和10mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物反相色谱柱层析分离产物(CH3CN/H2O＝30％-55％)，得到目标化合物9(53.7mg，产率49.5％)。ESI-MS m/z:556.4[M+H]+。1H NMR(500MHz,DMSO)δ11.93(s,1H),8.26(t,J＝4.8Hz,1H),7.66(d,J＝2.3Hz,1H),6.88(s,1H),6.84(d,J＝2.4Hz,1H),4.35(d,J＝4.8Hz,2H),3.90–3.80(m,1H),3.42(d,J＝7.0Hz,2H),3.12(s,3H),2.70(t,J＝6.3Hz,2H),2.38(s,3H),2.12(s,3H),1.89–1.72(m,6H),1.59(s,3H),1.13(dd,J＝24.9,12.4Hz,2H),0.87(dd,J＝23.6,11.0Hz,2H).Dissolve the above compound 9-2 (77.2 mg) in DMF (3 mL), add DIEA (0.1 mL), M7 (41.7 mg), HATU (111.2 mg), and react at room temperature for 1 h. Add 10 mL H 2 O and 10 mL EA to the reaction solution, stir and separate the layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness, and the concentrate is separated by reverse-phase chromatography column chromatography to separate the product (CH 3 CN/H 2 O=30%-55%) to obtain target compound 9 (53.7 mg, yield 49.5%). ESI-MS m/z:556.4[M+H]+. 1H NMR (500MHz, DMSO) δ11.93(s,1H),8.26(t,J＝4.8Hz,1H),7.66(d,J＝2.3Hz,1H),6.88(s,1H),6.84(d ,J＝2.4Hz,1H),4.35(d,J＝4.8Hz,2H),3.90–3.80(m,1H),3.42(d,J＝7.0Hz,2H),3.12(s,3H),2.70 (t,J＝6.3Hz,2H),2.38(s,3H),2.12(s,3H),1.89–1.72(m,6H),1.59(s,3H),1.13(dd,J＝24.9,12.4 Hz, 2H), 0.87 (dd, J = 23.6, 11.0Hz, 2H).
实施例60：7-氯-2-(1r，4R)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2，4-二甲基-N-(4-甲基-6-氧代-5，6-二氢吡咯并[3，2-c]吡啶-7-基)甲基)苯并[d][1，3]二氧杂环戊烯-5-甲酰胺的合成
Example 60: 7-chloro-2-(1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-(4 -Methyl-6-oxo-5,6-dihydropyrrolo[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxole- Synthesis of 5-carboxamide
步骤1：化合物60-1的合成 Step 1: Synthesis of Compound 60-1
冰浴下，将丙二腈(5.00g)溶于四氢呋喃(50.00mL)中，分批加入氢化钠(3.03g,60％)，冰浴下反应30min后加入4-亚甲基氧杂环丁烷-2-酮(6.36g)，-10℃反应1h。TLC监控原料反应完毕。向反应液中加入4mol/L HCl水溶液淬灭反应，然后减压蒸除溶剂得到粗品11.36g，即化合物60-1，直接用于下一步。Under ice bath, dissolve malononitrile (5.00g) in tetrahydrofuran (50.00mL), add sodium hydride (3.03g, 60%) in batches, react under ice bath for 30 minutes, and then add 4-methyleneoxetane. Alkan-2-one (6.36g), reacted at -10°C for 1 hour. TLC monitors the completion of the raw material reaction. 4mol/L HCl aqueous solution was added to the reaction solution to quench the reaction, and then the solvent was evaporated under reduced pressure to obtain 11.36g of crude product, namely compound 60-1, which was used directly in the next step.
步骤2：化合物60-2的合成Step 2: Synthesis of Compound 60-2
冰浴下，将化合物60-1(11.36g)溶于4mol/L HCl(50.0mL)水溶液中，加热回流搅拌3h。LC-MS监控原料反应完全。反应液冷却至室温后过滤，分别用100mL水，100mL乙醇，100mL甲叔醚洗脱滤饼，收集滤饼干燥得到7.2g产物，即化合物60-2。MS m/z:151[M+H]+ Under ice bath, compound 60-1 (11.36g) was dissolved in 4mol/L HCl (50.0mL) aqueous solution, heated to reflux and stirred for 3h. LC-MS monitors the complete reaction of raw materials. The reaction solution was cooled to room temperature and then filtered. The filter cake was eluted with 100 mL of water, 100 mL of ethanol, and 100 mL of methyl tertiary ether. The filter cake was collected and dried to obtain 7.2 g of product, namely compound 60-2. MS m/z:151[M+H] +
步骤3：化合物60-3的合成Step 3: Synthesis of Compound 60-3
室温下，将化合物60-2(7.2g)溶于三氯氧磷(40.0mL)中，加入DMF(0.07mL)，加热至115℃搅拌2h。LC-MS监控原料反应完全。反应液冷却至室温后减压蒸出溶剂，DCM复溶后再次蒸出溶剂，柱层析纯化得到5.30g淡黄色固体产物，即化合物60-3。MS m/z:187[M+H]+；1H NMR(500MHz,Chloroform-d)δ7.31(s,1H),2.62(s,3H).Compound 60-2 (7.2g) was dissolved in phosphorus oxychloride (40.0mL) at room temperature, DMF (0.07mL) was added, and the mixture was heated to 115°C and stirred for 2 hours. LC-MS monitors the complete reaction of raw materials. The reaction solution was cooled to room temperature, and then the solvent was evaporated under reduced pressure. After redissolving in DCM, the solvent was evaporated again. Purification by column chromatography yielded 5.30 g of a light yellow solid product, namely compound 60-3. MS m/z: 187[M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ7.31 (s, 1H), 2.62 (s, 3H).
步骤4：化合物60-4的合成Step 4: Synthesis of Compound 60-4
冰浴下，将化合物60-3(5.0g)溶于DMF(20.0mL)中，依次加入三乙胺(3.72mL)，对甲氧基苄胺(3.49mL)，冰浴下搅拌2h。。反应液中加入100mL水淬灭反应，然后加入20mLEA萃取三次，收集有机相，蒸出溶剂后柱层析纯化得到3.50g白色固体产物，即化合物60-4。MS m/z:288[M+H]+；1H NMR(500MHz,Chloroform-d)δ7.25–7.19(m,2H),6.95–6.89(m,2H),6.36(s,1H),5.41(s,1H),4.38(d,J＝5.3Hz,2H),3.82(s,3H),2.41(s,3H).Dissolve compound 60-3 (5.0g) in DMF (20.0 mL) under ice bath, add triethylamine (3.72 mL) and p-methoxybenzylamine (3.49 mL) in sequence, and stir for 2 hours under ice bath. . 100 mL of water was added to the reaction solution to quench the reaction, and then 20 mL of EA was added for extraction three times. The organic phase was collected, the solvent was evaporated, and then purified by column chromatography to obtain 3.50 g of a white solid product, namely compound 60-4. MS m/z:288[M+H] + ; 1 H NMR(500MHz,Chloroform-d)δ7.25–7.19(m,2H),6.95–6.89(m,2H),6.36(s,1H), 5.41(s,1H),4.38(d,J＝5.3Hz,2H),3.82(s,3H),2.41(s,3H).
步骤5：化合物60-5的合成Step 5: Synthesis of Compound 60-5
室温下，将化合物60-4(1.8g)溶于甲醇(20.0mL)中，依次加入碘化钾(2.06g)，甲醇钠(3.35g)，加热至95℃搅拌5h。LC-MS监控原料反应完全。反应液冷却至室温后减压蒸出溶剂，DCM复溶后再次蒸出溶剂，柱层析纯化得到1.65g淡黄色固体产物，即化合物60-5。MS m/z:284[M+H]+ Dissolve compound 60-4 (1.8g) in methanol (20.0 mL) at room temperature, add potassium iodide (2.06g) and sodium methoxide (3.35g) in sequence, heat to 95°C and stir for 5 hours. LC-MS monitors the complete reaction of raw materials. The reaction solution was cooled to room temperature, and then the solvent was evaporated under reduced pressure. After redissolving in DCM, the solvent was evaporated again. Purification by column chromatography gave 1.65 g of a light yellow solid product, namely compound 60-5. MS m/z:284[M+H] +
步骤6：化合物60-6的合成Step 6: Synthesis of Compound 60-6
室温下，将化合物60-5(1.4g)溶于三氟乙酸(30.0mL)中，加热至80℃搅拌2h。LC-MS监控原料反应完全。反应液冷却至室温后减压蒸出溶剂，DCM复溶后再次蒸出溶剂，柱层析纯化得到0.7g淡黄色固体产物，即化合物60-6。MS m/z:164[M+H]+；Compound 60-5 (1.4 g) was dissolved in trifluoroacetic acid (30.0 mL) at room temperature, heated to 80°C and stirred for 2 h. LC-MS monitors the complete reaction of raw materials. The reaction solution was cooled to room temperature, and then the solvent was evaporated under reduced pressure. After redissolving in DCM, the solvent was evaporated again. Purification by column chromatography yielded 0.7 g of a light yellow solid product, namely compound 60-6. MS m/z:164[M+H] + ;
步骤7：化合物60-7的合成Step 7: Synthesis of Compound 60-7
室温下，将化合物60-6(0.7g)溶于三氟乙酸(10.0mL)与DCM(10.0mL)的混 合溶液中，加入N-碘代丁二酰亚胺(1.25g)，室温反应搅拌2h。LC-MS监控原料反应完全。反应液减压蒸出溶剂，DCM复溶后再次蒸出溶剂，柱层析纯化得到1.23g淡黄色固体产物，即化合物60-7。MS m/z:290[M+H]+；1H NMR(500MHz,Chloroform-d)δ5.50–5.25(m,2H),3.97(s,3H),2.63(s,3H).Compound 60-6 (0.7g) was dissolved in a mixture of trifluoroacetic acid (10.0mL) and DCM (10.0mL) at room temperature. To the combined solution, N-iodosuccinimide (1.25g) was added, and the reaction was stirred at room temperature for 2 h. LC-MS monitors the complete reaction of raw materials. The solvent was evaporated from the reaction solution under reduced pressure, and the solvent was evaporated again after redissolving in DCM. Purification by column chromatography yielded 1.23 g of a light yellow solid product, namely compound 60-7. MS m/z:290[M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ5.50–5.25(m,2H),3.97(s,3H),2.63(s,3H).
步骤8：化合物60-8的合成Step 8: Synthesis of Compound 60-8
室温N2保护下，将化合物60-7(1.2g)，双三苯基膦二氯化钯(284mg)，碘化亚铜(154mg)溶于DMF(10.0mL)中，加入DIPEA(2.11mL)，三甲基硅基乙炔(0.86mL)，N2置换2-3次后，50℃反应1h。LC-MS监控原料反应完全。向反应液中加入50mL水淬灭反应，然后加入20mL EA萃取三次，合并有机相后减压蒸出溶剂，柱层析纯化得到0.93g黄色固体产物，即化合物60-8。MS m/z:260[M+H]+；1H NMR(500MHz,Chloroform-d)δ5.33(s,2H),3.97(d,J＝1.9Hz,3H),2.50(d,J＝1.8Hz,3H),0.27(d,J＝1.7Hz,9H).Under N2 protection at room temperature, dissolve compound 60-7 (1.2g), bistriphenylphosphine palladium dichloride (284mg), and copper iodide (154mg) in DMF (10.0mL), and add DIPEA (2.11mL ), trimethylsilyl acetylene (0.86 mL), after N 2 replacement 2-3 times, react at 50°C for 1 hour. LC-MS monitors the complete reaction of raw materials. Add 50 mL of water to the reaction solution to quench the reaction, then add 20 mL of EA for extraction three times, combine the organic phases, evaporate the solvent under reduced pressure, and purify by column chromatography to obtain 0.93 g of a yellow solid product, namely compound 60-8. MS m/z: 260[M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ5.33 (s, 2H), 3.97 (d, J＝1.9Hz, 3H), 2.50 (d, J＝ 1.8Hz, 3H), 0.27 (d, J = 1.7Hz, 9H).
步骤9：化合物60-9的合成Step 9: Synthesis of Compound 60-9
室温N2保护下，将化合物60-8(0.93g)，溶于THF(10.0mL)中，加入TBAF(5.11mL，1mol/L)，室温反应1h。LC-MS监控原料反应完全。反应液减压蒸出溶剂，柱层析纯化得到0.61g黄色固体产物，即化合物60-9。MS m/z:188[M+H]+；1H NMR(500MHz,Chloroform-d)δ5.38(s,2H),3.98(s,3H),3.65(s,1H),2.52(s,3H).Under N2 protection at room temperature, compound 60-8 (0.93g) was dissolved in THF (10.0 mL), TBAF (5.11 mL, 1 mol/L) was added, and the reaction was carried out at room temperature for 1 h. LC-MS monitors the complete reaction of raw materials. The solvent was evaporated under reduced pressure from the reaction solution and purified by column chromatography to obtain 0.61g of a yellow solid product, namely compound 60-9. MS m/z:188[M+H] + ; 1 H NMR(500MHz,Chloroform-d)δ5.38(s,2H),3.98(s,3H),3.65(s,1H),2.52(s, 3H).
步骤10：化合物60-10的合成Step 10: Synthesis of Compound 60-10
室温N2保护下，将化合物60-9(0.50g)，二(三苯基膦)环戊二烯基氯化钌(174.58mg)溶于吡啶(2.0mL)中，N2置换2-3次后，75℃反应8h。LC-MS监控原料反应完全。反应液减压蒸出溶剂，DCM复溶后再次蒸出溶剂，柱层析纯化得到0.30g白色固体产物，即化合物60-10。MS m/z:188[M+H]+；1H NMR(500MHz,Chloroform-d)δ9.11(s,1H),7.14(dd,J＝3.4,2.1Hz,1H),6.57(dd,J＝3.4,2.0Hz,1H),4.08(s,3H),2.69(s,3H).Under the protection of N2 at room temperature, compound 60-9 (0.50g) and bis(triphenylphosphine)cyclopentadienylruthenium chloride (174.58mg) were dissolved in pyridine (2.0mL), and N2 replaced 2-3 After several times, react at 75°C for 8 hours. LC-MS monitors the complete reaction of raw materials. The solvent was evaporated from the reaction solution under reduced pressure, and the solvent was evaporated again after being redissolved in DCM. The product was purified by column chromatography to obtain 0.30 g of a white solid product, namely compound 60-10. MS m/z: 188[M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ9.11 (s, 1H), 7.14 (dd, J = 3.4, 2.1Hz, 1H), 6.57 (dd, J＝3.4,2.0Hz,1H),4.08(s,3H),2.69(s,3H).
步骤11：化合物60-11的合成Step 11: Synthesis of Compound 60-11
室温下，将化合物60-10(0.30g)溶于NH3的MeOH溶液(5.0mL，7mol/L)中，加入雷尼镍(150mg)，H2置换2-3次后，室温反应1h。LC-MS监控原料反应完全。硅藻土过滤除去催化剂，DCM与MeOH混合溶剂(体积比1:1)多次洗脱滤饼后。收集滤液，减压蒸除溶剂，柱层析纯化得到230mg黄色固体产物，即化合物60-11。MS m/z:192[M+H]+；1H NMR(500MHz,DMSO-d6)δ7.21(d,J＝3.3Hz,1H),6.45(d,J＝3.2Hz,1H),3.88(d,J＝4.5Hz,5H),2.54(s,3H).Compound 60-10 (0.30g) was dissolved in NH 3 in MeOH solution (5.0 mL, 7 mol/L) at room temperature, Raney nickel (150 mg) was added, H2 was replaced 2-3 times, and the reaction was carried out at room temperature for 1 h. LC-MS monitors the complete reaction of raw materials. The catalyst was removed by diatomaceous earth filtration, and the filter cake was eluted with a mixed solvent of DCM and MeOH (volume ratio 1:1) several times. The filtrate was collected, the solvent was evaporated under reduced pressure, and purified by column chromatography to obtain 230 mg of a yellow solid product, namely compound 60-11. MS m/z: 192[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ7.21 (d, J = 3.3 Hz, 1H), 6.45 (d, J = 3.2 Hz, 1H), 3.88(d,J＝4.5Hz,5H),2.54(s,3H).
步骤12：化合物60-12的合成 Step 12: Synthesis of Compound 60-12
室温下，将化合物60-11(0.23g)溶于浓HCl溶液(20.0mL)中，120℃反应5h。LC-MS监控原料反应完全。反应液冷却至室温后加入50mL水，冷冻干燥得到180mg黄色固体产物，即化合物60-12。MS m/z:178[M+H]+；Compound 60-11 (0.23g) was dissolved in concentrated HCl solution (20.0 mL) at room temperature, and reacted at 120°C for 5 hours. LC-MS monitors the complete reaction of raw materials. After the reaction solution was cooled to room temperature, 50 mL of water was added and freeze-dried to obtain 180 mg of a yellow solid product, namely compound 60-12. MS m/z:178[M+H] + ;
步骤13：化合物60的合成Step 13: Synthesis of Compound 60
将化合物60-12(50mg)，中间体M1(72.6mg)溶于2.00mL DMF中，依次加入N,N-二异丙基乙胺(0.16mL)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(84.0mg)，室温反应30分钟，LCMS监测反应完成。向反应液中加入20.0mL水，然后加入10mL EA萃取三次，收集有机相，无水硫酸钠干燥后过滤，收集滤液并减压蒸出溶剂后制备液相分离纯化，得到白色固体产物14.3mg，即化合物60。ESI-MS m/z:555[M+H]+；1H NMR(500MHz,Methanol-d4)δ7.40(d,J＝3.3Hz,1H),6.97(s,1H),6.71(d,J＝3.4Hz,1H),4.69(s,2H),4.38(d,J＝9.2Hz,1H),4.29(s,2H),4.05(d,J＝12.9Hz,2H),3.13(d,J＝13.1Hz,1H),2.71(d,J＝1.5Hz,3H),2.25–2.02(m,7H),1.95(s,1H),1.63(s,3H),1.35(d,J＝14.4Hz,2H),1.28–1.16(m,2H).Compound 60-12 (50 mg) and intermediate M1 (72.6 mg) were dissolved in 2.00 mL DMF, and N, N-diisopropylethylamine (0.16 mL) and N, N, N', N'- were added in sequence. Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (84.0 mg), react at room temperature for 30 minutes, and monitor the reaction completion with LCMS. Add 20.0 mL of water to the reaction solution, and then add 10 mL of EA for extraction three times. Collect the organic phase, dry it over anhydrous sodium sulfate and filter. Collect the filtrate and evaporate the solvent under reduced pressure and then prepare liquid phase separation and purification to obtain 14.3 mg of the white solid product. That is compound 60. ESI-MS m/z: 555[M+H] + ; 1 H NMR (500MHz, Methanol-d 4 ) δ7.40 (d, J = 3.3Hz, 1H), 6.97 (s, 1H), 6.71 (d ,J＝3.4Hz,1H),4.69(s,2H),4.38(d,J＝9.2Hz,1H),4.29(s,2H),4.05(d,J＝12.9Hz,2H),3.13(d ,J＝13.1Hz,1H),2.71(d,J＝1.5Hz,3H),2.25–2.02(m,7H),1.95(s,1H),1.63(s,3H),1.35(d,J＝ 14.4Hz,2H),1.28–1.16(m,2H).
实施例62：化合物7-氯-2-(1r，4R)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2，4-二甲基-N-(7-甲基-5-氧代-5，6-二氢吡唑并[3，4-c]吡啶-4-基)甲基)苯并[d][1，3]二氧杂环戊烯-5-甲酰胺的合成
Example 62: Compound 7-chloro-2-(1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-( 7-Methyl-5-oxo-5,6-dihydropyrazolo[3,4-c]pyridin-4-yl)methyl)benzo[d][1,3]dioxola Synthesis of ene-5-carboxamide
步骤1：化合物62-1的合成Step 1: Synthesis of Compound 62-1
将2-羟基-4,6-二甲基-5-硝基烟腈(10.0g)溶于100.0mL甲苯中，依次加入溴化苄(7.38mL)，氧化银(17.1g)，120℃反应10h。反应完毕后硅藻土过滤，减压蒸出溶剂，柱层析纯化(PE:EA＝5:1)，得13.0g淡黄色固体产物，即中间体62-1。MS m/z:284[M+H]+；1H NMR(500MHz,Chloroform-d)δ7.52–7.45(m,2H),7.43–7.32(m,3H),5.54(s,2H),2.55 (s,3H),2.51(s,3H).Dissolve 2-hydroxy-4,6-dimethyl-5-nitrononitrile (10.0g) in 100.0mL toluene, add benzyl bromide (7.38mL) and silver oxide (17.1g) in sequence, and react at 120°C 10h. After the reaction is completed, filter through diatomaceous earth, evaporate the solvent under reduced pressure, and purify by column chromatography (PE:EA=5:1) to obtain 13.0g of light yellow solid product, namely intermediate 62-1. MS m/z:284[M+H] + ; 1 H NMR(500MHz,Chloroform-d)δ7.52–7.45(m,2H),7.43–7.32(m,3H),5.54(s,2H), 2.55 (s,3H),2.51(s,3H).
步骤2：化合物62-2的合成Step 2: Synthesis of Compound 62-2
将化合物62-1(2.0g)溶于20.0mL乙醇中，依次加入Fe粉(2.20g)，氯化铵(4.21g)的水溶液(4.00mL)，90℃反应1.0h。反应完毕后硅藻土过滤，减压蒸出溶剂，柱层析纯化(PE:EA＝3:1)，得1.0g淡黄色固体产物，即中间体62-2。MS m/z:254[M+H]+；Compound 62-1 (2.0g) was dissolved in 20.0mL ethanol, Fe powder (2.20g), aqueous solution of ammonium chloride (4.21g) (4.00mL) were added in sequence, and the reaction was carried out at 90°C for 1.0h. After the reaction is completed, filter through diatomaceous earth, evaporate the solvent under reduced pressure, and purify by column chromatography (PE:EA=3:1) to obtain 1.0g of light yellow solid product, namely intermediate 62-2. MS m/z:254[M+H] + ;
步骤3：化合物62-3的合成Step 3: Synthesis of Compound 62-3
将化合物62-2(0.80g)溶于10.0mL甲苯中，加入乙酸酐(0.90mL)，100℃反应3h。反应完毕后，蒸出溶剂直接用于下一步，得0.9g淡黄色固体产物，即中间体62-3。MS m/z:296[M+H]+；Compound 62-2 (0.80g) was dissolved in 10.0 mL toluene, acetic anhydride (0.90 mL) was added, and the reaction was carried out at 100°C for 3 hours. After the reaction was completed, the solvent was evaporated and used directly in the next step to obtain 0.9 g of a light yellow solid product, namely intermediate 62-3. MS m/z:296[M+H] + ;
步骤4：化合物62-4的合成Step 4: Synthesis of Compound 62-4
将化合物62-3(0.80g)溶于10.0mL氯仿中，依次加入乙酸酐(0.99mL)，乙酸钾(0.28g)，最后滴加亚硝酸异戊脂(0.98mL)，100℃反应12h。反应完毕后，蒸出溶剂柱层析纯化(PE:EA＝10:1)，得0.12g淡黄色固体产物，即化合物62-4。MS m/z:307[M+H]+；Dissolve compound 62-3 (0.80g) in 10.0mL chloroform, add acetic anhydride (0.99mL), potassium acetate (0.28g), and finally add isopentyl nitrite (0.98mL) dropwise, and react at 100°C for 12h. After the reaction was completed, the solvent was evaporated and purified by column chromatography (PE:EA=10:1) to obtain 0.12g of a light yellow solid product, namely compound 62-4. MS m/z:307[M+H] + ;
步骤5：化合物62-5的合成Step 5: Synthesis of Compound 62-5
将化合物62-4(0.12g)溶于10.0Ml MeOH中，加入1mol/L的NaOH水溶液(1.0mL)，室温反应1.0h。反应完毕后，加入水10mL，加入10mLDCM萃取三次，收集有机相后无水硫酸钠干燥，过滤并蒸出溶剂柱层析纯化(PE:EA＝3:1)，得0.10g淡黄色固体产物，即中间体62-5。MS m/z:265[M+H]+；Compound 62-4 (0.12g) was dissolved in 10.0Ml MeOH, 1 mol/L NaOH aqueous solution (1.0mL) was added, and the reaction was carried out at room temperature for 1.0h. After the reaction is completed, add 10 mL of water, add 10 mL of DCM for extraction three times, collect the organic phase, dry it over anhydrous sodium sulfate, filter and evaporate the solvent for column chromatography purification (PE:EA=3:1) to obtain 0.10g of light yellow solid product. That is intermediate 62-5. MS m/z:265[M+H] + ;
步骤6：化合物62-6的合成Step 6: Synthesis of Compound 62-6
将化合物62-5(0.10g)溶于5.00mL四氢呋喃中，加入硼烷二甲硫醚(1.89mL，10mol/L)，60℃反应1.0h。反应完毕后，反应冷却至室温后滴加入5mL盐酸甲醇淬灭反应，DIPEA调节pH至碱性，减压蒸出溶剂后直接用于下一步，得90mg黄色油状产物，即中间体62-6。MS m/z:269[M+H]+；Compound 62-5 (0.10g) was dissolved in 5.00mL tetrahydrofuran, borane dimethyl sulfide (1.89mL, 10mol/L) was added, and the reaction was carried out at 60°C for 1.0h. After the reaction was completed, the reaction was cooled to room temperature and 5 mL of methanol hydrochloric acid was added dropwise to quench the reaction. DIPEA was used to adjust the pH to alkaline. The solvent was evaporated under reduced pressure and used directly in the next step to obtain 90 mg of a yellow oily product, namely intermediate 62-6. MS m/z:269[M+H] + ;
步骤7：化合物62-7的合成Step 7: Synthesis of Compound 62-7
将化合物62-6(50mg)，中间体M1(45.0mg)溶于2.00mL DMF中，依次加入N,N-二异丙基乙胺(0.05mL)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(53mg)，室温反应30分钟，LCMS监测反应完成。向反应液中加入20.0mL水，然后加入10mL EA萃取，收集有机相，无水硫酸钠干燥后过滤，收集滤液并减压蒸出溶剂得到55mg油状产物粗品，直接用于下一步，即化合物62-7。ESI-MS m/z:646[M+H]+。Compound 62-6 (50 mg) and intermediate M1 (45.0 mg) were dissolved in 2.00 mL DMF, and N, N-diisopropylethylamine (0.05 mL) and N, N, N', N'- were added in sequence. Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (53 mg) was reacted at room temperature for 30 minutes, and LCMS monitored the reaction to completion. Add 20.0 mL of water to the reaction solution, then add 10 mL of EA for extraction, collect the organic phase, dry it over anhydrous sodium sulfate and filter, collect the filtrate and evaporate the solvent under reduced pressure to obtain 55 mg of crude oily product, which can be used directly in the next step, namely compound 62 -7. ESI-MS m/z:646[M+H] + .
步骤8：化合物62的合成 Step 8: Synthesis of Compound 62
将中间体62-7(55mg)溶于5.00mL DCM中，然后加入1.00mL TFA，室温反应0.5h，将反应液直接浓缩，5.00mL DCM复溶后再次浓缩，制备液相分离纯化，得淡黄色粉末2.9mg，即化合物62。ESI-MS m/z:556[M+H]+。1H NMR(500MHz,Methanol-d4)δ8.12(s,1H),6.87(s,1H),4.71(s,2H),4.00(p,J＝5.7Hz,1H),3.59(td,J＝6.3,1.9Hz,2H),3.25(s,3H),3.01(dd,J＝8.6,5.6Hz,2H),2.69(s,3H),2.14(s,3H),2.08(td,J＝9.8,8.5,5.5Hz,1H),1.97–1.79(m,5H),1.60(s,3H),1.23(ddd,J＝16.3,10.3,6.9Hz,2H),1.05–0.94(m,2H).Dissolve intermediate 62-7 (55 mg) in 5.00 mL DCM, then add 1.00 mL TFA, react at room temperature for 0.5 h, directly concentrate the reaction solution, redissolve 5.00 mL DCM and concentrate again, and prepare liquid phase separation and purification to obtain light 2.9 mg of yellow powder, namely compound 62. ESI-MS m/z:556[M+H] + . 1 H NMR (500MHz, Methanol-d 4 ) δ8.12 (s, 1H), 6.87 (s, 1H), 4.71 (s, 2H), 4.00 (p, J = 5.7Hz, 1H), 3.59 (td, J＝6.3,1.9Hz,2H),3.25(s,3H),3.01(dd,J＝8.6,5.6Hz,2H),2.69(s,3H),2.14(s,3H),2.08(td,J ＝9.8,8.5,5.5Hz,1H),1.97–1.79(m,5H),1.60(s,3H),1.23(ddd,J＝16.3,10.3,6.9Hz,2H),1.05–0.94(m,2H ).
实施例93：化合物7-氯-2-(3-(二甲氨基)甲基)双环[1.1.1]戊烷-1-基)-2,4-二甲基-N-(6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)苯并[d][1,3]二恶英-5-甲酰胺的合成
Example 93: Compound 7-chloro-2-(3-(dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-N-(6-methyl Synthesis of methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxin-5-carboxamide
步骤1：化合物93-1的合成Step 1: Synthesis of Compound 93-1
将M8(120mg)，3-氨甲基-4-硫甲基-6-甲基-1H-吡啶-2-酮(57.0mg)溶于5.0mL DMF中，室温搅拌2分钟，然后依次加入N,N-二异丙基乙胺(0.15mL)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(145mg)，室温反应15分钟。向反应液中加入20.0mL水，过滤得到体系中析出的固体，经柱层析分离纯化(DCM-MeOH，10％MeOH出峰)，得100mg化合物93-1。ESI-MS m/z:590[M+H]+。Dissolve M8 (120 mg), 3-aminomethyl-4-thiomethyl-6-methyl-1H-pyridin-2-one (57.0 mg) in 5.0 mL DMF, stir at room temperature for 2 minutes, then add N successively , N-diisopropylethylamine (0.15mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (145mg ), react at room temperature for 15 minutes. 20.0 mL of water was added to the reaction solution, filtered to obtain the solid precipitated in the system, and separated and purified by column chromatography (DCM-MeOH, 10% MeOH peak) to obtain 100 mg of compound 93-1. ESI-MS m/z:590[M+H] + .
步骤2：化合物93的合成Step 2: Synthesis of Compound 93
将93-1(100mg)溶于5.00mL DCM中，然后加入1.00mL TFA，室温反应0.5h，将反应液直接浓缩，5.00mL DCM复溶后再次浓缩，然后5.00mL甲醇溶解，加入37％的甲醛水溶液(24.6mg)，室温反应30分钟。再添加氰基硼氢化钠(21.3mg)，室温反应10分钟，LCMS监测反应完成。将反应液直接浓缩，制备液相分离，得到16.9mg化合物93。ESI-MS m/z:518[M+H]+。1H NMR(500MHz,CD3OD)δ6.89(s,1H),6.27(d,J＝1.0Hz,1H),4.48(s,2H),2.56(s,2H),2.52(s,3H),2.32(s,6H),2.29(d,J＝0.8Hz,3H),2.19(s,3H),1.80(s,6H),1.64(s,3H).Dissolve 93-1 (100mg) in 5.00mL DCM, then add 1.00mL TFA, react at room temperature for 0.5h, directly concentrate the reaction solution, redissolve 5.00mL DCM and concentrate again, then dissolve 5.00mL methanol, add 37% Formaldehyde aqueous solution (24.6mg), react at room temperature for 30 minutes. Then add sodium cyanoborohydride (21.3 mg) and react at room temperature for 10 minutes. LCMS monitors the completion of the reaction. The reaction solution was directly concentrated, and the preparative liquid phase was separated to obtain 16.9 mg of compound 93. ESI-MS m/z:518[M+H] + . 1 H NMR (500MHz, CD 3 OD) δ6.89 (s, 1H), 6.27 (d, J = 1.0Hz, 1H), 4.48 (s, 2H), 2.56 (s, 2H), 2.52 (s, 3H ),2.32(s,6H),2.29(d,J＝0.8Hz,3H),2.19(s,3H),1.80(s,6H),1.64(s,3H).
实施例117：化合物9-氯-6-(4，6-二甲基-2-氧代-1，2-二氢吡啶-3-基)甲基)-2-(3-(二甲基氨基甲基)双环[1.1.1]戊-1-基)-2，4-二甲基-7，8-二氢-[1，3]二氧杂环[4，5-g]异喹啉-5(6H)-酮的合成
Example 117: Compound 9-chloro-6-(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-(3-(dimethyl Aminomethyl)bicyclo[1.1.1]pent-1-yl)-2,4-dimethyl-7,8-dihydro-[1,3]dioxetane[4,5-g]isoquin Synthesis of pholin-5(6H)-one
步骤1：化合物117-1的合成Step 1: Synthesis of Compound 117-1
冰浴下，将中间体M5(85.0mg)溶于1.00mL DMF中，加入叔丁醇钾(25.0mg)搅拌10min后加入化合物2-(苄氧基)-3-(氯甲基)-4,6-二甲基吡啶(54.0mg)，室温反应0.5h，反应液中加入DCM与水萃取，收集有机相，无水硫酸钠钠干燥，过滤后减压浓缩，柱层析纯化(DCM:CH3OH＝10:1)得化合物110mg，即化合物117-1。ESI-MS m/z:602[M+H]+。Under ice bath, dissolve intermediate M5 (85.0 mg) in 1.00 mL DMF, add potassium tert-butoxide (25.0 mg), stir for 10 min, and then add compound 2-(benzyloxy)-3-(chloromethyl)-4 , 6-lutidine (54.0mg), react at room temperature for 0.5h, add DCM and water to the reaction solution for extraction, collect the organic phase, dry it over anhydrous sodium sulfate, filter, concentrate under reduced pressure, and purify by column chromatography (DCM: CH 3 OH = 10:1) to obtain 110 mg of compound, namely compound 117-1. ESI-MS m/z:602[M+H] + .
步骤2：化合物117的合成Step 2: Synthesis of Compound 117
冰浴下，将化合物117-1(110mg)溶于3.00mL DCM中，加入1.00mL TFA，50℃反应1.0h，反应液直接浓缩后送样制备纯化得到产物52.7mg，即化合物117。ESI-MS m/z:512[M+H]+。1H NMR(500MHz,Methanol-d4)δ6.12(s,1H),4.71(d,J＝1.9Hz,2H),3.39(t,J＝6.4Hz,2H),2.88(s,6H),2.82(q,J＝6.4Hz,2H),2.43(s,3H),2.26(s,3H),2.26–2.23(m,3H),1.97(s,6H),1.68(s,3H).Dissolve compound 117-1 (110 mg) in 3.00 mL DCM under an ice bath, add 1.00 mL TFA, and react at 50°C for 1.0 h. The reaction solution is directly concentrated and sent to sample preparation and purification to obtain 52.7 mg of product, namely compound 117. ESI-MS m/z:512[M+H] + . 1 H NMR (500MHz, Methanol-d 4 ) δ6.12 (s, 1H), 4.71 (d, J = 1.9 Hz, 2H), 3.39 (t, J = 6.4 Hz, 2H), 2.88 (s, 6H) ,2.82(q,J＝6.4Hz,2H),2.43(s,3H),2.26(s,3H),2.26–2.23(m,3H),1.97(s,6H),1.68(s,3H).
实施例138：化合物9-氯-2-(3-(二甲基氨基)甲基)双环[1.1.1]戊-1-基)-2，4-二甲基-6-(6-甲基-4-甲硫基)-2-氧代-1，2-二氢吡啶-3-基)甲基)-7，8-二氢-[1，3]二氧杂环[4，5-g]异喹啉-5(6H)-酮的合成
Example 138: Compound 9-chloro-2-(3-(dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-6-(6-methyl methyl-4-methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-7,8-dihydro-[1,3]dioxetane[4,5 -Synthesis of isoquinolin-5(6H)-one
步骤1：化合物138-1的合成Step 1: Synthesis of Compound 138-1
将中间体M6(250mg)，十二羰基三钌(21.3mg)，三苯基膦(53.4mg)加入50.0mL三 口瓶中，N2保护下加入5.00mL甲苯，120℃下反应20min后加入中间体M4(248mg)的甲苯(5.00mL)溶液，120℃下反应12h，反应液旋干后柱层析分离纯化，得化合物13800mg，即化合物138-1。ESI-MS m/z:449[M+H]+。Add intermediate M6 (250mg), triruthenium dodecacarbonyl (21.3mg) and triphenylphosphine (53.4mg) into 50.0mL triruthenium. In the bottle, add 5.00mL toluene under N2 protection, react at 120℃ for 20min, then add a solution of intermediate M4 (248mg) in toluene (5.00mL), react at 120℃ for 12h, spin the reaction solution to dryness and then separate and purify by column chromatography. , compound 13800 mg was obtained, namely compound 138-1. ESI-MS m/z:449[M+H] + .
步骤2：化合物138-2的合成Step 2: Synthesis of Compound 138-2
将化合物138-1(100mg)溶于5.00mL DCM中，然后加入1.00mL TFA，室温反应0.5h，将反应液直接浓缩，5.00mL DCM复溶后再次浓缩得到化合物三氟乙酸盐100mg，即化合物138-2。化合物无需纯化，直接进行下一步反应。ESI-MS m/z:349[M+H]+。Dissolve compound 138-1 (100 mg) in 5.00 mL DCM, then add 1.00 mL TFA, and react at room temperature for 0.5 h. The reaction solution is directly concentrated. After redissolving in 5.00 mL DCM, it is concentrated again to obtain 100 mg of compound trifluoroacetate, namely Compound 138-2. The compound does not need to be purified and can be directly used in the next reaction. ESI-MS m/z:349[M+H] + .
步骤3：化合物138-3的合成Step 3: Synthesis of Compound 138-3
将化合物138-2(100mg)，溶于5.00mL MeOH中，加入37％的甲醛水溶液(24.6mg)，加入N,N-二异丙基乙胺(0.021mL)和一滴乙酸，室温反应30分钟。再添加氰基硼氢化钠(14.2mg)，室温反应30分钟，LCMS监测反应完成。将反应液直接浓缩，制备液相分离，得淡黄色粉末44mg，即化合物138-3。ESI-MS m/z:378[M+H]+。Dissolve compound 138-2 (100 mg) in 5.00 mL MeOH, add 37% formaldehyde aqueous solution (24.6 mg), add N, N-diisopropylethylamine (0.021 mL) and a drop of acetic acid, and react at room temperature for 30 minutes. . Then add sodium cyanoborohydride (14.2 mg) and react at room temperature for 30 minutes. LCMS monitors the completion of the reaction. The reaction solution was directly concentrated, and the preparative liquid phase was separated to obtain 44 mg of light yellow powder, namely compound 138-3. ESI-MS m/z:378[M+H] + .
步骤4：化合物138-4的合成Step 4: Synthesis of Compound 138-4
冰浴下，将化合物138-3(44mg)溶于1.00mL DMF中，加入叔丁醇钾(16.0mg)搅拌10min后加入中间体M3，室温反应0.5h，反应液中加入DCM与水萃取，收集有机相，无水硫酸钠钠干燥，过滤后减压浓缩，柱层析纯化得化合物31mg，即化合物138-4。ESI-MS m/z:634[M+H]+。Dissolve compound 138-3 (44 mg) in 1.00 mL DMF under ice bath, add potassium tert-butoxide (16.0 mg) and stir for 10 min, then add intermediate M3, react at room temperature for 0.5 h, add DCM and water to the reaction solution for extraction. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 31 mg of compound, namely compound 138-4. ESI-MS m/z:634[M+H] + .
步骤5：化合物138的合成Step 5: Synthesis of Compound 138
冰浴下，将化合物138-4(31mg)溶于3.00mL DCM中，加入1.00mL TFA，50℃反应1.0h，反应液直接浓缩后送样制备纯化得到产物12.9mg，即化合物138。ESI-MS m/z:544[M+H]+。1H NMR(500MHz,Methanol-d4)δ6.31(s,1H),4.77(d,J＝2.7Hz,2H),3.32(s,2H),3.24(t,J＝6.5Hz,2H),2.89(s,6H),2.82(dt,J＝10.7,6.4Hz,2H),2.49(s,3H),2.44(s,3H),2.31(d,J＝0.7Hz,3H),1.98(s,6H),1.69(s,3H).Dissolve compound 138-4 (31 mg) in 3.00 mL DCM under an ice bath, add 1.00 mL TFA, and react at 50°C for 1.0 h. The reaction solution is directly concentrated and sent to sample preparation and purification to obtain 12.9 mg of product, namely compound 138. ESI-MS m/z:544[M+H] + . 1 H NMR (500MHz, Methanol-d 4 ) δ6.31 (s, 1H), 4.77 (d, J = 2.7Hz, 2H), 3.32 (s, 2H), 3.24 (t, J = 6.5Hz, 2H) ,2.89(s,6H),2.82(dt,J＝10.7,6.4Hz,2H),2.49(s,3H),2.44(s,3H),2.31(d,J＝0.7Hz,3H),1.98( s,6H),1.69(s,3H).
实施例139：化合物10-氯-2-(3-((二甲基氨基)甲基)双环[1.1.1]戊烷-1-基)-2,4-二甲基-6-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-6,7,8,9-四氢-5H-[1,3]二氧杂环[4',5':4,5]苯并[1，2-c]氮杂啉-5-酮的合成
Example 139: Compound 10-chloro-2-(3-((dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-6-(( 6-Methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6,7,8,9-tetrahydro-5H-[1, 3] Synthesis of dioxetane[4',5':4,5]benzo[1,2-c]azaline-5-one
步骤1：化合物139-1的合成Step 1: Synthesis of Compound 139-1
N2保护下，将原料5-氯-3,4-二甲氧基-2-甲基苯甲酸甲酯(3.2g)，DCM(50mL),三氟甲磺酸银(6.72g)加入到100mL三口瓶中，0℃下加入碘(13.28g),升至室温搅拌3h。用亚硫酸钠水溶液淬灭反应，分层，水层用100mL DCM萃取一次，合并有机相，用100mL饱和食盐水滤洗涤一次，无水硫酸钠干燥，将滤液浓缩。浓缩物经柱层析(PE:EA＝10:1)分离纯化得到目标产物139-1(4.55g，产率93.9％)。ESI-MS m/z:371.2[M+H]+。Under N2 protection, add the raw materials 5-chloro-3,4-dimethoxy-2-methylbenzoic acid methyl ester (3.2g), DCM (50mL), and silver triflate (6.72g). In a 100mL three-necked flask, add iodine (13.28g) at 0°C, raise to room temperature and stir for 3 hours. The reaction was quenched with a sodium sulfite aqueous solution, and the layers were separated. The aqueous layer was extracted once with 100 mL of DCM. The organic phases were combined, filtered and washed once with 100 mL of saturated brine, dried over anhydrous sodium sulfate, and the filtrate was concentrated. The concentrate was separated and purified by column chromatography (PE:EA=10:1) to obtain the target product 139-1 (4.55g, yield 93.9%). ESI-MS m/z:371.2[M+H] + .
步骤2：化合物139-2的合成Step 2: Synthesis of Compound 139-2
在室温下，将化合物139-1(3.2g)，(E)-(3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)烯丙基)氨基甲酸叔丁酯(3.67g),PdCl2(dppf)(0.63g),碳酸钾(3.58g),二氧六环(50mL),水(10mL)加入到100mL三口瓶中，然后N2保护条件下，100℃反应12h，停止反应。反应液冷至室温，加100mL水,用EA萃取二次，每次用150mL EA，合并有机相，用100mL饱和食盐水洗涤一次，无水硫酸钠干燥，将滤液浓缩。浓缩物经柱层析(PE:EA＝10:1)分离纯化得到目标产物139-2(3.4g，产率98.5％)。ESI-MS m/z:400.2[M+H]+。At room temperature, compound 139-1 (3.2g), (E)-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl) Allyl) tert-butyl carbamate (3.67g), PdCl 2 (dppf) (0.63g), potassium carbonate (3.58g), dioxane (50mL), and water (10mL) were added to a 100mL three-necked bottle. Then react at 100°C for 12 hours under N2 protection conditions and stop the reaction. Cool the reaction solution to room temperature, add 100 mL of water, and extract twice with 150 mL of EA each time. Combine the organic phases, wash once with 100 mL of saturated brine, dry over anhydrous sodium sulfate, and concentrate the filtrate. The concentrate was separated and purified by column chromatography (PE:EA=10:1) to obtain the target product 139-2 (3.4 g, yield 98.5%). ESI-MS m/z:400.2[M+H] + .
步骤3：化合物139-3的合成Step 3: Synthesis of Compound 139-3
在室温下，将化合物139-2(4.0g)溶于到EA(60mL)和MeOH(30mL)的混合溶液中，然后加入Pd/C(1.6g)，在氢气氛围下室温搅拌3h，停止反应。抽滤，MeOH(100mL)淋洗，浓缩，抽干，得到目标产物139-3(3.7g，产率92.0％)。ESI-MS m/z:402.2[M+H]+。Dissolve compound 139-2 (4.0g) into a mixed solution of EA (60mL) and MeOH (30mL) at room temperature, then add Pd/C (1.6g), stir at room temperature for 3h under a hydrogen atmosphere, and stop the reaction. . Filtered with suction, rinsed with MeOH (100 mL), concentrated, and drained to obtain the target product 139-3 (3.7 g, yield 92.0%). ESI-MS m/z:402.2[M+H] + .
步骤4：化合物139-4的合成Step 4: Synthesis of Compound 139-4
在室温下，将化合物139-3(3.7g)，4M HCl二氧六环(20mL)，室温下加入到100mL 单口瓶中，室温搅拌1h，停止反应。浓缩，抽干，得到目标产物139-4(2.8g，产率90.7％)。ESI-MS m/z:302.2[M+H]+。At room temperature, compound 139-3 (3.7g), 4M HCl dioxane (20 mL) was added to 100 mL at room temperature. In a single-neck bottle, stir at room temperature for 1 hour to stop the reaction. Concentrate and drain to obtain the target product 139-4 (2.8 g, yield 90.7%). ESI-MS m/z:302.2[M+H] + .
步骤5：化合物139-5的合成Step 5: Synthesis of Compound 139-5
在室温下，将化合物139-4(2.8g)，DCE(30mL)，室温下加入到100mL三口瓶中，氮气保护，0℃下滴加AlMe3(13.92mL),升温至80℃搅拌4h，停止反应。降至室温，将反应液倒入冰的1.5M酒石酸钠钾(30mL)中淬灭反应，EA萃取三次，每次EA(100mL),无水硫酸钠干燥，浓缩，抽干，得到目标产物139-5(1.84g，产率73.5％)。ESI-MS m/z:270.1[M+H]+。Add compound 139-4 (2.8g) and DCE (30mL) into a 100mL three-necked flask at room temperature, under nitrogen protection, add AlMe 3 (13.92mL) dropwise at 0°C, raise the temperature to 80°C and stir for 4 hours. Stop reacting. Cool to room temperature, pour the reaction solution into ice-cold 1.5M sodium potassium tartrate (30 mL) to quench the reaction, extract with EA three times, each time with EA (100 mL), dry over anhydrous sodium sulfate, concentrate, and drain to obtain the target product 139 -5 (1.84g, yield 73.5%). ESI-MS m/z:270.1[M+H] + .
步骤6：化合物139-6的合成Step 6: Synthesis of Compound 139-6
在室温下，将化合物139-5(1.64g)，DCM(30mL)，室温下加入到100mL三口瓶中，氮气保护，0℃下滴加BBr3(24.32mL),0℃搅拌2h，停止反应。降至0℃，向反应液中滴加MeOH(50mL)，浓缩，抽干，用乙醇(10mL)打浆得到目标产物139-6(1.40g，产率91.5％)。ESI-MS m/z:242.1[M+H]+。Add compound 139-5 (1.64g) and DCM (30mL) to a 100mL three-necked flask at room temperature, under nitrogen protection, add BBr 3 (24.32mL) dropwise at 0°C, stir at 0°C for 2 hours, and stop the reaction. . Lower to 0°C, add MeOH (50 mL) dropwise to the reaction solution, concentrate, drain, and slurry with ethanol (10 mL) to obtain the target product 139-6 (1.40 g, yield 91.5%). ESI-MS m/z:242.1[M+H] + .
步骤7：化合物139-7的合成Step 7: Synthesis of Compound 139-7
在室温下，将化合物139-6(0.65g)，十二羰基三钌(0.17g),三苯基膦(0.14g),甲苯(30mL)加入到100mL三口瓶中，然后N2保护条件下，升至110℃，搅拌30min,滴加M11(1.14g)的甲苯溶液,110℃反应48h，停止反应。反应液冷至室温，将滤液浓缩。浓缩物经柱层析(PE:EA＝1:1)分离纯化得到目标产物139-7(粗品1.4g)。ESI-MS m/z:478.2[M+H]+。At room temperature, add compound 139-6 (0.65g), triruthenium dodecacarbonyl (0.17g), triphenylphosphine (0.14g), and toluene (30mL) into a 100mL three-necked flask, and then under N 2 protection conditions , raised to 110°C, stirred for 30min, added dropwise the toluene solution of M11 (1.14g), reacted at 110°C for 48h, and stopped the reaction. The reaction solution was cooled to room temperature, and the filtrate was concentrated. The concentrate was separated and purified by column chromatography (PE:EA=1:1) to obtain the target product 139-7 (crude product 1.4g). ESI-MS m/z:478.2[M+H] + .
步骤8：化合物139-8的合成Step 8: Synthesis of Compound 139-8
在室温下，将化合物139-7(1.4g)，THF(15mL)加入到100mL三口瓶中，室温下加入1M TBAF(7.32mL)，室温搅拌2h,停止反应。向反应液中加入EA(200mL),用饱和食盐水洗涤三次，每次用食盐水(100mL)，无水硫酸钠干燥，浓缩。浓缩物经柱层析(DCM:MeOH＝10:1)分离纯化得到目标产物139-8(粗品0.86g)。ESI-MS m/z:364.2[M+H]+。Add compound 139-7 (1.4g) and THF (15mL) to a 100mL three-necked flask at room temperature, add 1M TBAF (7.32mL) at room temperature, and stir for 2 hours at room temperature to stop the reaction. EA (200 mL) was added to the reaction solution, washed three times with saturated brine (100 mL) each time, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain the target product 139-8 (crude product 0.86g). ESI-MS m/z:364.2[M+H] + .
步骤9：化合物139-9的合成Step 9: Synthesis of Compound 139-9
在室温下，将化合物139-8(0.84g)，DCM(20mL)加入到100mL三口瓶中，氮气保护，0℃下分批加入Dess-martin(0.98g),0℃下搅拌2h,停止反应。向反应液中加入DCM(100mL),用饱和碳酸氢钠溶液洗涤三次，每次用饱和碳酸氢钠溶液(100mL)，再用饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩。浓缩物抽干得到目标产物139-9(粗品0.9g)。ESI-MS m/z:362.2[M+H]+。 At room temperature, add compound 139-8 (0.84g) and DCM (20mL) into a 100mL three-necked flask under nitrogen protection. Add Dess-martin (0.98g) in batches at 0°C, stir for 2 hours at 0°C, and stop the reaction. . DCM (100 mL) was added to the reaction solution, washed three times with saturated sodium bicarbonate solution (100 mL) each time, and once with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated. The concentrate was drained to obtain the target product 139-9 (crude product 0.9g). ESI-MS m/z:362.2[M+H] + .
步骤10：化合物139-10的合成Step 10: Synthesis of Compound 139-10
将化合物139-9(0.9g)，MeOH(30mL)加入到100mL三口瓶中，氮气保护，室温下加入二甲胺-THF(2.5mL,2M),AcOH(15mg),室温搅拌15min,加入氰基硼氢化钠(0.3g)，室温搅拌16h,停止反应。向反应液中加入EA(100mL),用饱和食盐水洗涤三次，每次用食盐水(60mL)，无水硫酸钠干燥，浓缩。浓缩物经柱层析分离纯化(DCM:MeOH＝10:1)得到目标产物139-10(粗品0.43g)。ESI-MS m/z:391.2[M+H]+。Add compound 139-9 (0.9g) and MeOH (30mL) into a 100mL three-necked flask under nitrogen protection. Add dimethylamine-THF (2.5mL, 2M) and AcOH (15mg) at room temperature. Stir at room temperature for 15min. Add cyanide. Sodium borohydride (0.3g) was added and stirred at room temperature for 16 hours to stop the reaction. EA (100 mL) was added to the reaction solution, washed three times with saturated brine (60 mL) each time, dried over anhydrous sodium sulfate, and concentrated. The concentrate was separated and purified by column chromatography (DCM:MeOH=10:1) to obtain the target product 139-10 (crude product 0.43g). ESI-MS m/z:391.2[M+H] + .
步骤11：化合物139-11的合成Step 11: Synthesis of Compound 139-11
将化合物139-10(50mg)，DMF(3mL)加入到50mL三口瓶中，氮气保护，0℃下加入叔丁醇钾(21.53mg),0℃搅拌10min,加入2-(苄氧基)-3-(氯甲基)-6-甲基-4-(甲硫基)吡啶(45.1mg)，升至室温搅拌0.5h,停止反应。向反应液中缓慢滴加水(10mL)，搅拌均匀，抽滤，水洗(50mL)，PE(50mL)淋洗,抽干得到目标产物139-11(粗品60mg)。ESI-MS m/z:648.2[M+H]+。Add compound 139-10 (50 mg) and DMF (3 mL) into a 50 mL three-necked flask under nitrogen protection. Add potassium tert-butoxide (21.53 mg) at 0°C, stir for 10 min at 0°C, and add 2-(benzyloxy)- 3-(Chloromethyl)-6-methyl-4-(methylthio)pyridine (45.1 mg), raised to room temperature and stirred for 0.5h to stop the reaction. Slowly add water (10 mL) dropwise to the reaction solution, stir evenly, filter with suction, wash with water (50 mL), rinse with PE (50 mL), and drain to obtain the target product 139-11 (crude product 60 mg). ESI-MS m/z:648.2[M+H] + .
步骤12：化合物139的合成Step 12: Synthesis of Compound 139
在室温下，将化合物139-11(60mg)，二氯甲烷(5.0mL)加入到50mL单口瓶中，室温下加入三氟乙酸(1.0mL)，升温至50℃反应2h，停止反应。将反应液直接浓缩，向其中加入100mL DCM，用饱和碳酸氢钠溶液洗涤三次，每次用饱和碳酸氢钠溶液(60mL)，再用饱和食盐水(100mL)洗涤一次，无水硫酸钠干燥，浓缩。浓缩物经柱层析[DCM:CH3OH(NH3)＝10:1]分离纯化得到目标产物139(14.9mg，产率27.6％)。ESI-MS m/z:558.2[M+H]+。1H NMR(500MHz,DMSO-d6)δ11.64(s,1H),6.13(s,1H),4.77-4.50(m,2H),3.11-2.95(m,2H),2.77-2.68(m,1H),2.46(s,3H),2.33-2.13(m,13H),1.71-1.42(m,12H)。At room temperature, compound 139-11 (60 mg) and dichloromethane (5.0 mL) were added to a 50 mL single-neck bottle, trifluoroacetic acid (1.0 mL) was added at room temperature, and the temperature was raised to 50°C for 2 h to stop the reaction. Concentrate the reaction solution directly, add 100 mL DCM to it, wash it three times with saturated sodium bicarbonate solution (60 mL) each time, and wash once with saturated brine (100 mL), and dry over anhydrous sodium sulfate. concentrate. The concentrate was separated and purified by column chromatography [DCM:CH 3 OH (NH 3 )=10:1] to obtain the target product 139 (14.9 mg, yield 27.6%). ESI-MS m/z:558.2[M+H] + . 1 H NMR (500MHz, DMSO-d 6 ) δ11.64(s,1H),6.13(s,1H),4.77-4.50(m,2H),3.11-2.95(m,2H),2.77-2.68(m ,1H),2.46(s,3H),2.33-2.13(m,13H),1.71-1.42(m,12H).
实施例194：化合物7-氯-2-(3-(二甲基氨基)甲基)双环[1.1.1]戊-1-基)-2，4-二甲基-N-(4-甲基-6-氧代-5，6-二氢呋喃[3，2-c]吡啶-7-基)甲基)苯并[d][1，3]二氧杂环-5-甲酰胺的合成
Example 194: Compound 7-chloro-2-(3-(dimethylamino)methyl)bicyclo[1.1.1]pentan-1-yl)-2,4-dimethyl-N-(4-methyl base-6-oxo-5,6-dihydrofuran[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxetane-5-carboxamide synthesis
步骤1：化合物194-1的合成Step 1: Synthesis of Compound 194-1
将2-甲基-3,4-二羟基-5-氯苯甲酸甲酯(200mg)，十二羰基三钌(29.6mg)，三苯基膦(24.2mg)加入50.0mL三口瓶中，N2保护下加入5.00mL甲苯，120℃下反应10min后加入中间体M4(0.240g)的甲苯(5.00mL)溶液，120℃下反应12h，反应液旋干后柱层析分离纯化(PE:EA＝4:1)，得0.180g白色固体，即化合物194-1。1H NMR(500MHz,Chloroform-d)δ7.53(s,1H),4.46(s,1H),3.85(s,3H),3.20(s,2H),2.39(s,3H),1.70(s,6H),1.67(s,3H),1.43(s,9H).Add 2-methyl-3,4-dihydroxy-5-chlorobenzoic acid methyl ester (200mg), triruthenium dodecacarbonyl (29.6mg), triphenylphosphine (24.2mg) into a 50.0mL three-necked bottle, N 2. Add 5.00mL toluene under protection, react at 120°C for 10 minutes, then add a solution of intermediate M4 (0.240g) in toluene (5.00mL), react at 120°C for 12h, spin the reaction solution to dryness and then separate and purify by column chromatography (PE:EA =4:1), and 0.180g of white solid was obtained, namely compound 194-1. 1H NMR (500MHz, Chloroform-d) δ7.53 (s, 1H), 4.46 (s, 1H), 3.85 (s, 3H), 3.20(s,2H),2.39(s,3H),1.70(s,6H),1.67(s,3H),1.43(s,9H).
步骤2：化合物194-2的合成Step 2: Synthesis of Compound 194-2
将化合物194-1(180mg)，一水合氢氧化锂(164mg)溶于5.00mL甲醇和1.00mL水中，升温至70℃反应3小时，LCMS监测反应完成。向反应液中加入饱和柠檬酸水溶液至pH＝6，析出淡黄色固体，抽滤，滤饼水洗，烘干，得淡黄色粉末150mg，即化合物194-2。化合物无需纯化，直接进行下一步反应。ESI-MS m/z:424[M+H]+。Compound 194-1 (180 mg) and lithium hydroxide monohydrate (164 mg) were dissolved in 5.00 mL methanol and 1.00 mL water, and the temperature was raised to 70°C for 3 hours. The reaction was monitored by LCMS. Add saturated citric acid aqueous solution to the reaction solution until pH=6, and precipitate a light yellow solid. Filter it with suction, wash the filter cake with water, and dry it to obtain 150 mg of light yellow powder, namely compound 194-2. The compound does not need to be purified and can be directly used in the next reaction. ESI-MS m/z:424[M+H] + .
步骤3：化合物194-3的合成Step 3: Synthesis of Compound 194-3
将194-2(150mg)，7-氨甲基-4-甲基呋喃并[3，2-c]吡啶-6(5H)酮(63.0mg)溶于5.0mL DMF中，室温搅拌2分钟，然后依次加入N,N-二异丙基乙胺(0.19mL)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(181mg)，室温反应15分钟，LCMS监测反应完成。向反应液中加入20.0mL水，过滤得到体系中析出的固体，经柱层析纯化(DCM:MeOH＝10:1)得淡黄色固体119mg，即化合物194-3。ESI-MS m/z:584[M+H]+。Dissolve 194-2 (150mg), 7-aminomethyl-4-methylfuro[3,2-c]pyridin-6(5H)one (63.0mg) in 5.0mL DMF, and stir at room temperature for 2 minutes. Then N,N-diisopropylethylamine (0.19mL) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluoro Urea phosphate (181 mg), react at room temperature for 15 minutes, and monitor the reaction completion with LCMS. 20.0 mL of water was added to the reaction solution, filtered to obtain the solid precipitated in the system, and purified by column chromatography (DCM:MeOH=10:1) to obtain 119 mg of light yellow solid, namely compound 194-3. ESI-MS m/z:584[M+H] + .
步骤4：化合物194的合成Step 4: Synthesis of Compound 194
将中间体194-3(50mg)溶于5.00mL DCM中，然后加入1.00mL TFA，室温反应0.5h，将反应液直接浓缩，5.00mL DCM复溶后再次浓缩，然后5.00mL甲醇溶解，加入37％的甲醛水溶液(13.0mg)，室温反应30分钟。再添加氰基硼氢化钠(11.0mg)，室温反应10分钟，LCMS监测反应完成。向反应液中加入10mL饱和碳酸氢钠溶液淬灭反应， 然后加入10mL DCM萃取三次，收集有机相，无水硫酸钠干燥后过滤，制备液相分离，得白色粉末11.9mg，即化合物194。ESI-MS m/z:512[M+H]+。1H NMR(500MHz,Methanol-d4)δ7.60(t,J＝2.3Hz,1H),6.94(s,1H),6.82(t,J＝2.3Hz,1H),4.59(s,2H),2.89(s,6H),2.53(d,J＝1.6Hz,3H),2.18(s,3H),1.97(s,6H),1.67(s,3H).Dissolve intermediate 194-3 (50mg) in 5.00mL DCM, then add 1.00mL TFA, react at room temperature for 0.5h, directly concentrate the reaction solution, redissolve 5.00mL DCM and concentrate again, then dissolve 5.00mL methanol, add 37 % formaldehyde aqueous solution (13.0 mg), react at room temperature for 30 minutes. Then add sodium cyanoborohydride (11.0 mg) and react at room temperature for 10 minutes. LCMS monitors the completion of the reaction. Add 10 mL of saturated sodium bicarbonate solution to the reaction solution to quench the reaction. Then 10 mL of DCM was added for extraction three times. The organic phase was collected, dried over anhydrous sodium sulfate and filtered. The preparative liquid phase was separated to obtain 11.9 mg of white powder, namely compound 194. ESI-MS m/z:512[M+H] + . 1 H NMR (500MHz, Methanol-d 4 ) δ7.60 (t, J = 2.3 Hz, 1H), 6.94 (s, 1H), 6.82 (t, J = 2.3 Hz, 1H), 4.59 (s, 2H) ,2.89(s,6H),2.53(d,J＝1.6Hz,3H),2.18(s,3H),1.97(s,6H),1.67(s,3H).
实施例195：化合物7-氯-2-(1r，4R)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2，4-二甲基-N-(7-甲基-5-氧代-4，5-二氢吡咯并[3，2-b]吡啶-6-基)甲基)苯并[d][1，3]二氧杂环戊烯-5-甲酰胺的合成
Example 195: Compound 7-chloro-2-(1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl-N-( 7-Methyl-5-oxo-4,5-dihydropyrrolo[3,2-b]pyridin-6-yl)methyl)benzo[d][1,3]dioxole -Synthesis of 5-carboxamide
步骤1：化合物195-1的合成Step 1: Synthesis of Compound 195-1
在冰浴下，将2-羟基-4，6-二甲基烟腈(15.0g)溶于冰醋酸(100.0mL)中，加热至50℃后加入浓硝酸(13.5mL)与乙酸酐(13.5mL)的混合溶液，有大量棕色气体产生，搅拌30min后LC-MS监控原料反应完全。将反应液降至室温后滴加至冰水(300mL)中有淡黄色固体析出，过滤并用100mL水洗涤三遍，收集滤饼得化合物13.1g，即化合物195-1。ESI-MS m/z:194[M+H]+。1H NMR(500MHz,DMSO-d6)δ13.22(s,1H),2.44(s,3H),2.43(s,3H).Dissolve 2-hydroxy-4,6-dimethylnicotinonitrile (15.0g) in glacial acetic acid (100.0mL) under ice bath, heat to 50°C, then add concentrated nitric acid (13.5mL) and acetic anhydride (13.5 mL) of the mixed solution, a large amount of brown gas was produced. After stirring for 30 minutes, LC-MS monitored that the raw material reaction was complete. The reaction solution was cooled to room temperature and then added dropwise to ice water (300 mL). A light yellow solid precipitated, filtered and washed three times with 100 mL of water. The filter cake was collected to obtain 13.1 g of compound, namely compound 195-1. ESI-MS m/z:194[M+H] + . 1 H NMR (500MHz, DMSO-d 6 ) δ13.22(s,1H),2.44(s,3H),2.43(s,3H).
步骤2：化合物195-2的合成Step 2: Synthesis of Compound 195-2
将化合物195-1(13.1g)溶于150.0mL甲苯中，依次加入溴化苄(9.67mL)，氧化银(18.9g)，120℃反应3h，反应完毕后硅藻土过滤，减压蒸除溶剂，柱层析纯化(PE:EA＝5:1)，得16.5g淡黄色固体产物，即中间体195-2。MS m/z:284[M+H]+；1H NMR(500MHz,Chloroform-d)δ7.52–7.45(m,2H),7.43–7.32(m,3H),5.54(s,2H),2.55(s,3H),2.51(s,3H).Dissolve compound 195-1 (13.1g) in 150.0mL toluene, add benzyl bromide (9.67mL) and silver oxide (18.9g) in sequence, and react at 120°C for 3 hours. After the reaction is completed, filter through diatomaceous earth and evaporate under reduced pressure. Solvent and purify by column chromatography (PE:EA=5:1) to obtain 16.5g of light yellow solid product, namely intermediate 195-2. MS m/z:284[M+H] + ; 1 H NMR(500MHz,Chloroform-d)δ7.52–7.45(m,2H),7.43–7.32(m,3H),5.54(s,2H), 2.55(s,3H),2.51(s,3H).
步骤3：化合物195-3的合成Step 3: Synthesis of Compound 195-3
将化合物195-2(16.5g)溶于100.0mL DMF中，加入DMF-DMA(184mL)，室温反应4h。向反应液中1000mL水淬灭反应，加入200mL EA萃取三次，收集有机相后，减压蒸除溶剂，柱层析纯化(PE:EA＝3:1)，得4.7g淡黄色固体产物，即中间体195-3。MS m/z:339[M+H]+；1H NMR(500MHz,Chloroform-d)δ7.81(d,J＝12.1Hz,1H),7.45– 7.41(m,2H),7.40–7.35(m,2H),7.34–7.29(m,1H),5.47(s,2H),5.09(d,J＝12.1Hz,1H),3.01(d,J＝119.0Hz,6H),2.39(s,3H).Compound 195-2 (16.5g) was dissolved in 100.0 mL DMF, DMF-DMA (184 mL) was added, and the reaction was carried out at room temperature for 4 h. Quench the reaction with 1000mL of water in the reaction solution, add 200mL of EA for extraction three times, collect the organic phase, evaporate the solvent under reduced pressure, and purify by column chromatography (PE:EA=3:1) to obtain 4.7g of a light yellow solid product, namely Intermediate 195-3. MS m/z: 339[M+H] + ; 1 H NMR (500MHz, Chloroform-d) δ7.81 (d, J＝12.1Hz, 1H), 7.45– 7.41(m,2H),7.40–7.35(m,2H),7.34–7.29(m,1H),5.47(s,2H),5.09(d,J＝12.1Hz,1H),3.01(d,J＝ 119.0Hz,6H),2.39(s,3H).
步骤4：化合物195-4的合成Step 4: Synthesis of Compound 195-4
将化合物195-3(4.70g)溶于MeOH(150.00mL)中，依次加入冰醋酸(3.18mL)，Pd/C(4.30g,5.5％)，用H2置换2-3次后，室温反应2h，LC-MS监控原料反应完毕。硅藻土过滤并用胺的甲醇溶液与DCM等体积比的混合溶剂洗脱滤饼，收集滤液后减压蒸除溶剂得到产物3.7g，即中间体195-4。MS m/z:174[M+H]+；1H NMR(500MHz,DMSO-d6)δ11.71(s,2H),7.81(d,J＝2.9Hz,1H),6.14(d,J＝2.8Hz,1H),2.53(s,3H).Dissolve compound 195-3 (4.70g) in MeOH (150.00mL), add glacial acetic acid (3.18mL), Pd/C (4.30g, 5.5%) in sequence, replace with H 2-3 times, and react at room temperature 2h, LC-MS monitors that the raw material reaction is completed. Filter through diatomaceous earth and elute the filter cake with a mixed solvent of equal volume ratio of amine methanol solution and DCM. Collect the filtrate and evaporate the solvent under reduced pressure to obtain 3.7g of product, namely intermediate 195-4. MS m/z: 174[M+H] + ; 1 H NMR (500MHz, DMSO-d 6 ) δ11.71 (s, 2H), 7.81 (d, J = 2.9 Hz, 1H), 6.14 (d, J =2.8Hz,1H),2.53(s,3H).
步骤5：化合物195-5的合成Step 5: Synthesis of Compound 195-5
将化合物195-4(0.10g)溶于NH3的MeOH溶液(5.0mL，7mol/L)中，加入雷尼镍(0.10g)，H2置换2-3次后，室温反应1h，LC-MS监控原料反应完毕。硅藻土过滤并用甲醇洗脱滤饼，收集滤液后减压蒸除溶剂得到产物0.1g，即中间体195-5。ESI-MS m/z:178[M+H]+ Dissolve compound 195-4 (0.10g) in NH 3 MeOH solution (5.0 mL, 7 mol/L), add Raney nickel (0.10g), replace H 2 to 3 times, react at room temperature for 1 h, LC- MS monitors the completion of raw material reaction. Filter through diatomaceous earth and elute the filter cake with methanol. Collect the filtrate and evaporate the solvent under reduced pressure to obtain 0.1g of the product, namely intermediate 195-5. ESI-MS m/z:178[M+H] +
步骤6：化合物195的合成Step 6: Synthesis of Compound 195
将195-5(100mg)，中间体M1(223.0mg)溶于5.0mL DMF中，室温搅拌2分钟，然后依次加入N,N-二异丙基乙胺(0.19mL)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(181mg)，室温反应15分钟，LCMS监测反应完成。向反应液中加入20.0mL水，过滤得到体系中析出的固体，经制备液相分离纯化得白色固体32.0mg，即化合物195。ESI-MS m/z:555[M+H]+。1H NMR(500MHz,Methanol-d4)δ7.22(d,J＝2.9Hz,1H),6.88(s,1H),6.15(d,J＝3.0Hz,1H),4.55(s,2H),4.04(p,J＝5.7Hz,1H),3.76–3.66(m,2H),3.26(s,3H),3.20–3.13(m,2H),2.59(s,3H),2.24(d,J＝11.9Hz,1H),2.16(s,3H),1.94(t,J＝12.6Hz,4H),1.89–1.80(m,1H),1.60(s,3H),1.25(dd,J＝21.5,7.7Hz,2H),1.08–0.94(m,2H).Dissolve 195-5 (100mg) and intermediate M1 (223.0mg) in 5.0mL DMF, stir at room temperature for 2 minutes, then add N,N-diisopropylethylamine (0.19mL) and N,N,N in sequence ',N'-Tetramethyl-O-(7-azebenzotriazol-1-yl)urea hexafluorophosphate (181 mg), react at room temperature for 15 minutes, and monitor the reaction completion with LCMS. 20.0 mL of water was added to the reaction solution, and the solid precipitated in the system was obtained by filtration. After preparative liquid phase separation and purification, 32.0 mg of white solid, namely compound 195, was obtained. ESI-MS m/z:555[M+H] + . 1 H NMR (500MHz, Methanol-d 4 ) δ7.22 (d, J = 2.9 Hz, 1H), 6.88 (s, 1H), 6.15 (d, J = 3.0 Hz, 1H), 4.55 (s, 2H) ,4.04(p,J＝5.7Hz,1H),3.76–3.66(m,2H),3.26(s,3H),3.20–3.13(m,2H),2.59(s,3H),2.24(d,J ＝11.9Hz,1H),2.16(s,3H),1.94(t,J＝12.6Hz,4H),1.89–1.80(m,1H),1.60(s,3H),1.25(dd,J＝21.5, 7.7Hz,2H),1.08–0.94(m,2H).
实施例196：7-氯-2-(4-(二甲氨基)双环[2.2.2]辛烷-1-基)-2，4-二甲基-N-((6-甲基-4-(甲硫基)-2-氧代-1，2-二氢吡啶-3-基)甲基)苯并[d][1，3]二氧杂环戊烯-5-甲酰胺的合成
Example 196: 7-chloro-2-(4-(dimethylamino)bicyclo[2.2.2]octan-1-yl)-2,4-dimethyl-N-((6-methyl-4 Synthesis of -(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide
步骤1：化合物196-1的合成Step 1: Synthesis of Compound 196-1
常温下，将5-氯-3,4-二羟基-2-甲基苯甲酸甲酯(150mg)溶于甲苯(5mL)中，加入N-{4-乙炔基双环[2.2.2]辛烷-1-基}氨基甲酸叔丁酯；N-(4-乙炔基-1-双环[2.2.2]辛基)氨基甲酸叔丁酯(207mg),Ru3(CO)12(22mg),三苯基磷(18mg)，然后N2保护条件下将反应混合物升温至120℃，回流反应24小时。将反应液冷却后，减压浓缩，向其中加30mL乙酸乙酯溶解，30mL水洗涤，有机相再用饱和食盐水洗涤1次后，用无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝90:10)分离纯化得到化合物196-1(58mg，18％产率)。ESI-MS m/z:466.1[M+H]+。Dissolve 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester (150 mg) in toluene (5 mL) at room temperature, and add N-{4-ethynylbicyclo[2.2.2]octane -1-yl}carbamic acid tert-butyl ester; N-(4-ethynyl-1-bicyclo[2.2.2]octyl)carbamate tert-butyl ester (207mg), Ru 3 (CO) 12 (22mg), tris Phenylphosphorus (18 mg), then the reaction mixture was heated to 120°C under N2 protection, and the reaction was refluxed for 24 hours. After the reaction solution was cooled, it was concentrated under reduced pressure, 30 mL of ethyl acetate was added to dissolve, and washed with 30 mL of water. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=90:10) to obtain compound 196-1 (58 mg, 18% yield). ESI-MS m/z:466.1[M+H] + .
步骤2：化合物196-2的合成Step 2: Synthesis of Compound 196-2
常温下，将196-1(58mg)溶于DCM(2mL)中,加入4M HCl/Dioxane(2mL)，室温反应1小时。反应液减压浓缩，向其中加10mL甲醇溶解，再用饱和碳酸氢钠溶液调至pH>8。用20mL二氯甲烷萃取3次，合并有机层，无水硫酸钠干燥，减压浓缩。得196-2(41mg,90％产率)，无需纯化直接进行下一步。ESI-MS m/z:366.1[M+H]+。Dissolve 196-1 (58mg) in DCM (2mL) at room temperature, add 4M HCl/Dioxane (2mL), and react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of methanol was added to dissolve it, and then saturated sodium bicarbonate solution was used to adjust the pH to >8. Extract with 20 mL of methylene chloride three times, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 196-2 (41 mg, 90% yield) was obtained, and the next step was carried out directly without purification. ESI-MS m/z:366.1[M+H] + .
步骤3：化合物196-3的合成Step 3: Synthesis of Compound 196-3
常温下，将196-2(41mg)溶于甲醇中,依次加入氰基硼氢化钠(18mg)，甲醛-水溶液(30mg)，室温反应1小时。向反应液中加入5mL水，用5mL二氯甲烷萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(DCM:MeOH＝90:10)分离纯化得到化合物196-3(30mg，68％产率)。ESI-MS m/z:393.7[M+H]+。Dissolve 196-2 (41 mg) in methanol at room temperature, add sodium cyanoborohydride (18 mg) and formaldehyde-aqueous solution (30 mg) in sequence, and react at room temperature for 1 hour. Add 5 mL of water to the reaction solution, extract three times with 5 mL of methylene chloride, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (DCM:MeOH=90:10) to obtain compound 196-3 (30 mg, 68% yield). ESI-MS m/z:393.7[M+H] + .
步骤4：化合物196-4的合成Step 4: Synthesis of Compound 196-4
常温下，将196-3(30mg)溶于甲醇(2mL)和水(1mL)中,加入LiOH(32mg),然后将反应混合物升温至70℃，反应2小时。将反应液冷却后，加入5mL水稀释，1M HCl调节pH到4,用5ml二氯甲烷萃取3次，合并有机层，无水硫酸钠干燥，减压浓缩。得到196-4(25mg)，无需纯化直接进行下一步.ESI-MS m/z:379.8[M+H]+。 Dissolve 196-3 (30 mg) in methanol (2 mL) and water (1 mL) at room temperature, add LiOH (32 mg), then heat the reaction mixture to 70°C and react for 2 hours. After cooling the reaction solution, add 5 mL of water to dilute, adjust the pH to 4 with 1 M HCl, extract three times with 5 ml of methylene chloride, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 196-4 (25 mg) was obtained, and the next step was carried out directly without purification. ESI-MS m/z: 379.8[M+H] + .
步骤5：化合物196的合成Step 5: Synthesis of Compound 196
常温下，将196-4(25mg)和3-(氨基甲基)-6-甲基-4-(甲硫基)吡啶-2(1H)-酮(15mg)溶于DMF中,加入HATU(18mg),DIEA(0.03mL)，室温反应2小时。向反应液中加入5mL水，用5mL乙酸乙酯萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。制备色谱分离得到196(2mg,12％产率)。1H NMR(500MHz,Methanol-d4)δ6.91(s,1H),6.29(s,1H),4.48(s,2H),2.78(s,6H),2.53(s,3H),2.29(s,3H),2.19(s,4H),1.88(d,J＝4.7Hz,12H),1.56(s,3H).Dissolve 196-4 (25 mg) and 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one (15 mg) in DMF at room temperature, and add HATU ( 18mg), DIEA (0.03mL), react at room temperature for 2 hours. Add 5 mL of water to the reaction solution, extract three times with 5 mL of ethyl acetate, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Preparative chromatography afforded 196 (2 mg, 12% yield). 1 H NMR (500MHz, Methanol-d 4 ) δ6.91(s,1H),6.29(s,1H),4.48(s,2H),2.78(s,6H),2.53(s,3H),2.29( s,3H),2.19(s,4H),1.88(d,J＝4.7Hz,12H),1.56(s,3H).
实施列197：7-氯-2-(6-((二甲氨基)甲基)吡啶-3-基)-2，4-二甲基-N-((6-甲基-4-(甲硫基)-2-氧代-1，2-二氢吡啶-3-基)甲基)苯并[d][1，3]二氧杂环戊烯-5-甲酰胺的合成
Example 197: 7-chloro-2-(6-((dimethylamino)methyl)pyridin-3-yl)-2,4-dimethyl-N-((6-methyl-4-(methyl) Synthesis of thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide
步骤1：化合物197-1的合成Step 1: Synthesis of Compound 197-1
常温下，将(5-碘2-吡啶基)氨基甲酸叔丁酯(1.5g)溶于TEA(15mL)中，加入CuI(0.2g)，Pd(PPh3)2Cl2(0.37g),然后N2保护条件下加入三甲基硅基乙炔(3.72mL)，将反应混合物升温至80℃，反应2小时。将反应液冷却后，减压浓缩，向其中加30mL乙酸乙酯溶解，30mL水洗涤，有机相再用饱和食盐水洗涤1次后，用无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝90:10)分离纯化得到化合物197-1(1.51g，94％产率)。ESI-MS m/z:305.3[M+H]+。Dissolve (5-iodo2-pyridyl)carbamic acid tert-butyl ester (1.5g) in TEA (15mL) at room temperature, add CuI (0.2g), Pd(PPh 3 ) 2 Cl 2 (0.37g), Then trimethylsilyl acetylene (3.72 mL) was added under N2 protection, and the reaction mixture was heated to 80°C and reacted for 2 hours. After the reaction solution was cooled, it was concentrated under reduced pressure, 30 mL of ethyl acetate was added to dissolve, and washed with 30 mL of water. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=90:10) to obtain compound 197-1 (1.51 g, 94% yield). ESI-MS m/z:305.3[M+H] + .
步骤2：化合物197-2的合成Step 2: Synthesis of Compound 197-2
常温下，将197-1(1.51g)溶于甲醇(5mL)中，加入碳酸钾(1.71g)，室温反应2小时。反应液过滤，收集滤液，减压浓缩。浓缩物经柱层析(PE:EA＝85:15)分离纯化得到化合物197-2(820mg，71％产率)。ESI-MS m/z:233.2[M+H]+。 Dissolve 197-1 (1.51g) in methanol (5 mL) at room temperature, add potassium carbonate (1.71g), and react at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was collected and concentrated under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=85:15) to obtain compound 197-2 (820 mg, 71% yield). ESI-MS m/z:233.2[M+H]+.
步骤3：化合物197-3的合成Step 3: Synthesis of Compound 197-3
常温下，将197-2(820mg),5-氯-3,4-二羟基-2-甲基苯甲酸甲酯(800mg)溶于甲苯(10mL)中，加入Ru3(CO)12(110mg),三苯基磷(90mg)，然后N2保护条件下将反应混合物升温至120℃，回流反应24小时。将反应液冷却后，减压浓缩，向其中加30mL乙酸乙酯溶解，30mL水洗涤，有机相再用饱和食盐水洗涤1次后，用无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝85:15)分离纯化得到化合物197-3(254mg，18％产率)。ESI-MS m/z:448.9[M+H]+。Dissolve 197-2 (820mg), 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester (800mg) in toluene (10mL) at room temperature, and add Ru 3 (CO) 12 (110mg ), triphenylphosphonium (90 mg), then the reaction mixture was heated to 120°C under N2 protection, and the reaction was refluxed for 24 hours. After the reaction solution was cooled, it was concentrated under reduced pressure, 30 mL of ethyl acetate was added to dissolve, and washed with 30 mL of water. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=85:15) to obtain compound 197-3 (254 mg, 18% yield). ESI-MS m/z:448.9[M+H] + .
步骤4：化合物197-4的合成Step 4: Synthesis of Compound 197-4
常温下，将197-3(245mg)溶于甲醇(5mL)和水(5mL)中,加入LiOH(181mg),然后将反应混合物升温至70℃，反应2小时。将反应液冷却后，加入10mL水稀释，1M HCl调节pH到4,用20mL二氯甲烷萃取3次，合并有机层，无水硫酸钠干燥，减压浓缩，得到197-4(201mg,85％产率)，无需纯化直接进行下一步。ESI-MS m/z:434.8[M+H]+。Dissolve 197-3 (245 mg) in methanol (5 mL) and water (5 mL) at room temperature, add LiOH (181 mg), then heat the reaction mixture to 70°C and react for 2 hours. After cooling the reaction solution, add 10 mL of water to dilute, adjust the pH to 4 with 1 M HCl, extract 3 times with 20 mL of methylene chloride, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain 197-4 (201 mg, 85% Yield), proceed directly to the next step without purification. ESI-MS m/z:434.8[M+H] + .
步骤5：化合物197-5的合成Step 5: Synthesis of Compound 197-5
常温下，将197-4(201mg)和3-(氨基甲基)-6-甲基-4-(甲硫基)吡啶-2(1H)-酮(93mg)溶于DMF(3mL)中,加入HATU(210mg)，DIEA(0.31mL)，室温反应2小时。向反应液中加入10mL水，用10mL乙酸乙酯萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(DCM:MeOH＝90:10)分离纯化得到化合物197-5(188mg，68％产率)。ESI-MS m/z:601.1[M+H]+。Dissolve 197-4 (201mg) and 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one (93mg) in DMF (3mL) at room temperature. Add HATU (210 mg) and DIEA (0.31 mL) and react at room temperature for 2 hours. Add 10 mL of water to the reaction solution, extract three times with 10 mL of ethyl acetate, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (DCM:MeOH=90:10) to obtain compound 197-5 (188 mg, 68% yield). ESI-MS m/z:601.1[M+H] + .
步骤6：化合物197-6的合成Step 6: Synthesis of Compound 197-6
常温下，将197-5(90mg)溶于DCM(3mL)中,加入4M HCl/Dioxane(2mL)，室温反应1小时。反应液减压浓缩，向其中加10mL甲醇溶解，再用饱和碳酸氢钠溶液调至pH>8。用20mL二氯甲烷萃取3次，合并有机层，无水硫酸钠干燥，减压浓缩。得到197-6(70mg，93％产率)，无需纯化直接进行下一步。ESI-MS m/z:501.4[M+H]+。Dissolve 197-5 (90mg) in DCM (3mL) at room temperature, add 4M HCl/Dioxane (2mL), and react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of methanol was added to dissolve it, and then saturated sodium bicarbonate solution was used to adjust the pH to >8. Extract with 20 mL of methylene chloride three times, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 197-6 (70 mg, 93% yield) was obtained and was directly carried to the next step without purification. ESI-MS m/z:501.4[M+H]+.
步骤7：化合物197的合成Step 7: Synthesis of Compound 197
常温下，将197-6(70mg)溶于甲醇中,依次加入氰基硼氢化钠(50mg)，甲醛-水溶液(258mg)，室温反应1小时。向反应液中加入10mL水，用10mL二氯甲烷萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。制备色谱分离得到197(25mg,29％产率)。1H NMR(500MHz,Methanol-d4)δ8.91(dd,J＝2.3,0.8Hz,1H),8.12(dd,J＝8.1,2.4Hz,1H),7.52(dd,J＝8.1,0.8Hz,1H),6.97(s,1H),6.27(d,J ＝0.9Hz,1H),4.51(s,2H),4.48(d,J＝1.3Hz,2H),2.93(s,6H),2.52(s,3H),2.29(d,J＝0.8Hz,3H),2.27(s,3H),2.10(s,3H).Dissolve 197-6 (70mg) in methanol at room temperature, add sodium cyanoborohydride (50mg) and formaldehyde-aqueous solution (258mg) in sequence, and react at room temperature for 1 hour. Add 10 mL of water to the reaction solution, extract three times with 10 mL of methylene chloride, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. Preparative chromatography afforded 197 (25 mg, 29% yield). 1 H NMR (500MHz, Methanol-d 4 ) δ8.91 (dd, J＝2.3, 0.8Hz, 1H), 8.12 (dd, J＝8.1, 2.4Hz, 1H), 7.52 (dd, J＝8.1, 0.8 Hz,1H),6.97(s,1H),6.27(d,J ＝0.9Hz,1H),4.51(s,2H),4.48(d,J＝1.3Hz,2H),2.93(s,6H),2.52(s,3H),2.29(d,J＝0.8Hz,3H ),2.27(s,3H),2.10(s,3H).
实施列198：7-氯-2-(2-((二甲氨基)甲基)嘧啶-5-基)-2，4-二甲基-N-((6-甲基-4-(甲硫基)-2-氧代-1，2-二氢吡啶-3-基)甲基)苯并[d][1，3]二氧杂环戊烯-5-甲酰胺的合成Example 198: 7-chloro-2-(2-((dimethylamino)methyl)pyrimidin-5-yl)-2,4-dimethyl-N-((6-methyl-4-(methyl) Synthesis of thio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxole-5-carboxamide
实施列198的合成路线同实施列197。1H NMR(500MHz,Methanol-d4)δ9.09(s,2H),6.99(s,1H),6.27(s,1H),4.66(s,2H),4.49(d,J＝3.6Hz,2H),3.03(s,6H),2.52(s,3H),2.29(s,3H),2.27(s,3H),2.15(s,3H),1.31(d,J＝21.9Hz,6H).The synthetic route of Example 198 is the same as that of Example 197. 1 H NMR (500MHz, Methanol-d 4 ) δ9.09 (s, 2H), 6.99 (s, 1H), 6.27 (s, 1H), 4.66 (s, 2H), 4.49 (d, J = 3.6Hz, 2H),3.03(s,6H),2.52(s,3H),2.29(s,3H),2.27(s,3H),2.15(s,3H),1.31(d,J=21.9Hz,6H).
实施列199:(2R)-7-氯-2，4-二甲基-N-((4-甲基-6-氧代-5，6-二氢呋喃并[3，2-c]吡啶-7-基)甲基)-2-(4-((1R，5S，6S)-6-(N-甲基乙酰胺)-3-氮杂双环[3.1.0]己烷-3-基)环己基)苯并[d][1，3]二氧杂环戊烯-5-甲酰胺的合成
Example 199: (2R)-7-chloro-2,4-dimethyl-N-((4-methyl-6-oxo-5,6-dihydrofuro[3,2-c]pyridine -7-yl)methyl)-2-(4-((1R,5S,6S)-6-(N-methylacetamide)-3-azabicyclo[3.1.0]hexan-3-yl Synthesis of )cyclohexyl)benzo[d][1,3]dioxole-5-carboxamide
步骤1：化合物199-1的合成Step 1: Synthesis of Compound 199-1
常温下，将(1R,5s,6s)-6-氨基-3-氮杂双环[3.1.0]己烷-3-羧酸叔丁酯(900mg)溶于DCM(5mL)中，加入TEA(1.58mL)，乙酸酐(0.72mL)，室温反应2小时。向反应液中加入10mL水，用20ml DCM萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝90:10)分离纯化得到化合物199-1(700mg，83％产率)。ESI-MS m/z:240.3[M+H]+。Dissolve (1R,5s,6s)-6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylic acid tert-butyl ester (900mg) in DCM (5mL) at room temperature, add TEA ( 1.58mL), acetic anhydride (0.72mL), react at room temperature for 2 hours. Add 10 mL of water to the reaction solution, extract three times with 20 ml of DCM, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=90:10) to obtain compound 199-1 (700 mg, 83% yield). ESI-MS m/z:240.3[M+H] + .
步骤2：化合物199-2的合成Step 2: Synthesis of Compound 199-2
常温下，将199-1(378mg)溶于THF(5mL)中，N2保护条件下将反应混合物冷却至0℃，加入NaH(125mg)，反应10分钟，然后加入碘甲烷(0.18mL),室温反应2小 时。向反应液中加入10mL饱和氯化铵溶液，用20ml乙酸乙酯萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(PE:EA＝90:10)分离纯化得到化合物199-2(343mg，86％产率)。ESI-MS m/z:254.3[M+H]+。Dissolve 199-1 (378mg) in THF (5mL) at room temperature, cool the reaction mixture to 0°C under N2 protection, add NaH (125mg), react for 10 minutes, then add methyl iodide (0.18mL), Room temperature reaction 2 hours hour. Add 10 mL of saturated ammonium chloride solution to the reaction solution, extract three times with 20 ml of ethyl acetate, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (PE:EA=90:10) to obtain compound 199-2 (343 mg, 86% yield). ESI-MS m/z:254.3[M+H] + .
步骤3：化合物199-3的合成Step 3: Synthesis of Compound 199-3
常温下，将199-2(300mg)溶于DCM(5mL)中，加入HCl/Dioxane(5mL)，室温反应1小时。反应液减压浓缩，向其中加10mL甲醇溶解，再用饱和碳酸氢钠溶液调至pH>8。用20mL二氯甲烷萃取三次，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。得到199-3(198mg，95％产率)，无需纯化直接进行下一步。ESI-MS m/z:154.1[M+H]+。Dissolve 199-2 (300 mg) in DCM (5 mL) at room temperature, add HCl/Dioxane (5 mL), and react at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 10 mL of methanol was added to dissolve it, and then saturated sodium bicarbonate solution was used to adjust the pH to >8. Extract three times with 20 mL of methylene chloride, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 199-3 (198 mg, 95% yield) was obtained and was directly carried to the next step without purification. ESI-MS m/z:154.1[M+H] + .
步骤4：化合物199-4的合成Step 4: Synthesis of Compound 199-4
常温下，将(R)-7-氯-2,4-二甲基-2-(4-氧代环己基)苯并[d][1,3]二氧杂环戊-5-羧酸甲酯(95mg)溶于THF(3mL)中,加入199-3(108mg)，DIEA(0.23mL)，1M ZnCl2(0.84mL)，室温反应1小时，然后加入氰基硼氢化钠(53mg)，反应2小时。向反应液中加入10mL水，用10mL二氯甲烷萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(DCM:MeOH＝90:10)分离纯化得到化合物199-4(95mg，71％产率)。ESI-MS m/z:477.0[M+H]+。At room temperature, (R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxola-5-carboxylic acid Dissolve methyl ester (95mg) in THF (3mL), add 199-3 (108mg), DIEA (0.23mL), 1M ZnCl 2 (0.84mL), react at room temperature for 1 hour, then add sodium cyanoborohydride (53mg) , react for 2 hours. Add 10 mL of water to the reaction solution, extract three times with 10 mL of methylene chloride, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (DCM:MeOH=90:10) to obtain compound 199-4 (95 mg, 71% yield). ESI-MS m/z:477.0[M+H] + .
步骤5：化合物199-5的合成Step 5: Synthesis of Compound 199-5
常温下，将199-4(95mg)溶于甲醇(2mL)和水(1mL)中,加入LiOH(82mg),然后将反应混合物升温至70℃，反应2小时。将反应液冷却后，加入5mL水稀释，1M HCl调节pH到4,用5mL二氯甲烷萃取3次，合并有机层，无水硫酸钠干燥，减压浓缩。得到199-5(75mg)，无需纯化直接进行下一步.ESI-MS m/z:463.2[M+H]+。Dissolve 199-4 (95 mg) in methanol (2 mL) and water (1 mL) at room temperature, add LiOH (82 mg), then heat the reaction mixture to 70°C and react for 2 hours. After cooling the reaction solution, add 5 mL of water to dilute, adjust the pH to 4 with 1 M HCl, extract three times with 5 mL of methylene chloride, combine the organic layers, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. 199-5 (75mg) was obtained, and the next step was carried out directly without purification. ESI-MS m/z: 463.2[M+H] + .
步骤6：化合物199的合成Step 6: Synthesis of Compound 199
常温下，将199-5(70mg)和M7(52mg)溶于DMF(2mL)中,加入HATU(47mg),DIEA(0.07mL)，室温反应1小时。向反应液中加入10mL水，用10mL乙酸乙酯萃取3次，合并有机层，有机相再用饱和食盐水洗涤1次后，无水硫酸钠干燥，减压浓缩。浓缩物经柱层析(DCM:MeOH＝90:10)分离纯化得到化合物199(65mg,68％产率)。ESI-MS m/z:623.1[M+H]+。1H NMR(500MHz,Methanol-d4)δ7.58(d,J＝2.5Hz,1H),6.91(s,1H),6.79(d,J＝2.5Hz,1H),5.34(dd,J＝5.5,4.2Hz,2H),3.18(d,J＝9.4Hz,2H),2.86(s,3H),2.51(s,3H),2.16(d,J＝3.5Hz,6H),2.02(d,J＝8.3Hz,4H),1.92(d,J＝10.6Hz,3H),1.87(q,J＝2.0Hz,2H),1.60(s,3H),1.30(m,6H). Dissolve 199-5 (70 mg) and M7 (52 mg) in DMF (2 mL) at room temperature, add HATU (47 mg) and DIEA (0.07 mL), and react at room temperature for 1 hour. Add 10 mL of water to the reaction solution, extract three times with 10 mL of ethyl acetate, combine the organic layers, wash the organic phase once with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The concentrate was separated and purified by column chromatography (DCM:MeOH=90:10) to obtain compound 199 (65 mg, 68% yield). ESI-MS m/z:623.1[M+H]+. 1 H NMR (500MHz, Methanol-d 4 ) δ7.58 (d, J＝2.5Hz, 1H), 6.91 (s, 1H), 6.79 (d, J＝2.5Hz, 1H), 5.34 (dd, J＝ 5.5,4.2Hz,2H),3.18(d,J＝9.4Hz,2H),2.86(s,3H),2.51(s,3H),2.16(d,J＝3.5Hz,6H),2.02(d, J＝8.3Hz,4H),1.92(d,J＝10.6Hz,3H),1.87(q,J＝2.0Hz,2H),1.60(s,3H),1.30(m,6H).
实施例200：化合物7-氯-2-(4-(1-(二甲基氨基)环丙基)苯基)-2,4-二甲基-N-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)苯并[d][1,3]二氧戊环-5-甲酰胺的合成
Example 200: Compound 7-chloro-2-(4-(1-(dimethylamino)cyclopropyl)phenyl)-2,4-dimethyl-N-((6-methyl-4- Synthesis of (methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl)benzo[d][1,3]dioxolane-5-carboxamide
步骤1：化合物200-1的合成Step 1: Synthesis of Compound 200-1
将1-(4-溴苯基)环丙烷-1-羧酸(2.2g)溶解于叔丁醇(150mL)中，添加三乙胺(2.54mL)和分子筛(1.83g)，氮气保护，室温下向反应液中加入叠氮磷酸二苯酯(2.36mL)，室温反应1小时，升温至110℃继续反应12h。将反应液直接浓缩，柱层析分离纯化(DCM-MeOH，3％MeOH出峰)，得白色粉末2.03g，即化合物200-1。ESI-MS m/z:213[M+H]+。Dissolve 1-(4-bromophenyl)cyclopropane-1-carboxylic acid (2.2g) in tert-butanol (150mL), add triethylamine (2.54mL) and Molecular sieve (1.83g), nitrogen protection, add diphenyl phosphoryl azide (2.36mL) to the reaction solution at room temperature, react at room temperature for 1 hour, then raise the temperature to 110°C and continue the reaction for 12 hours. The reaction solution was directly concentrated and separated and purified by column chromatography (DCM-MeOH, 3% MeOH peak) to obtain 2.03 g of white powder, namely compound 200-1. ESI-MS m/z:213[M+H] + .
步骤2：化合物200-2的合成Step 2: Synthesis of Compound 200-2
将化合物200-1(760.0mg)，双三苯基膦二氯化钯(170.8mg)，碘化亚铜(92.7mg)依次加入TEA(20mL)中，氮气保护，室温下向反应液中加入三甲基硅基乙炔(0.42mL)，80℃反应过夜，LCMS监测反应完成。将反应液直接浓缩，柱层析分离纯化(PE-EA，10％EA出峰)，得化合物200-2(593.0mg)。ESI-MS m/z:230[M+H]+。Compound 200-1 (760.0 mg), bistriphenylphosphine palladium dichloride (170.8 mg), and copper iodide (92.7 mg) were added to TEA (20 mL) in sequence, under nitrogen protection, and added to the reaction solution at room temperature. Trimethylsilyl acetylene (0.42 mL) was reacted at 80°C overnight, and LCMS monitored the reaction to completion. The reaction solution was directly concentrated and separated and purified by column chromatography (PE-EA, 10% EA peak emitted) to obtain compound 200-2 (593.0 mg). ESI-MS m/z:230[M+H] + .
步骤3：化合物200-3的合成Step 3: Synthesis of Compound 200-3
将200-2(593.0mg)，碳酸钾(621.8mg)依次加入甲醇(10mL)中，室温反应12小时，TLC监测反应完成。将反应液直接浓缩，柱层析分离纯化(PE-EA，20％EA出峰)，得白色固体375.2mg，即化合物200-3。ESI-MS m/z:202[M+H]+。200-2 (593.0 mg) and potassium carbonate (621.8 mg) were added to methanol (10 mL) in sequence, and the reaction was carried out at room temperature for 12 hours. TLC monitored the reaction to completion. The reaction solution was directly concentrated and separated and purified by column chromatography (PE-EA, 20% EA peak) to obtain 375.2 mg of white solid, namely compound 200-3. ESI-MS m/z:202[M+H] + .
步骤4：化合物200-4的合成Step 4: Synthesis of Compound 200-4
将2-甲基-3,4-二羟基-5-氯苯甲酸甲酯(260.0mg)，十二羰基三钌(38.4mg)，三苯基膦(31.5mg)加入甲苯(4mL)中，氮气保护，升温至120℃搅拌0.5小时。添加200-3(375.2mg)的甲苯溶液(2mL)，继续反应12h，TLC监测反应完成。将反应液直接浓缩，柱层析分离纯化(PE-EA，10％EA出峰)，得淡黄色液体96.0mg，即化合物200-4。ESI-MS m/z:418[M+H]+。Add 2-methyl-3,4-dihydroxy-5-chlorobenzoic acid methyl ester (260.0 mg), triruthenium dodecacarbonyl (38.4 mg), and triphenylphosphine (31.5 mg) to toluene (4 mL). Under nitrogen protection, the temperature was raised to 120°C and stirred for 0.5 hours. Add a toluene solution (2 mL) of 200-3 (375.2 mg) and continue the reaction for 12 hours. TLC monitors the completion of the reaction. The reaction solution was directly concentrated and separated and purified by column chromatography (PE-EA, 10% EA peak) to obtain 96.0 mg of light yellow liquid, namely compound 200-4. ESI-MS m/z:418[M+H] + .
步骤5：化合物200-5的合成Step 5: Synthesis of Compound 200-5
将200-4(96.0mg)，一水合氢氧化锂(85.0mg)加入甲醇(1.6mL)和水(0.4mL)中，升温至70℃反应2小时，LCMS监测反应完成。向反应液中加入饱和柠檬酸水溶液至pH＝ 6，DCM/iPrOH(4：1)萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析分离纯化(PE-EA，10％EA出峰)，得白色固体56.1mg，即化合物200-5。ESI-MS m/z:404[M+H]+。Add 200-4 (96.0 mg) and lithium hydroxide monohydrate (85.0 mg) to methanol (1.6 mL) and water (0.4 mL), heat to 70°C and react for 2 hours. LCMS monitors the reaction to be completed. Add saturated citric acid aqueous solution to the reaction solution until pH = 6. Extract with DCM/ i PrOH (4:1), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate and purify by column chromatography (PE-EA, 10% EA peak) to obtain 56.1 mg of white solid. That is compound 200-5. ESI-MS m/z:404[M+H] + .
步骤6：化合物200-6的合成Step 6: Synthesis of Compound 200-6
将200-5(56.1mg)，3-氨甲基-4-硫甲基-6-甲基-1H-吡啶-2-酮(26.9mg)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(69.5mg)溶解于DMF(2.0mL)中，室温搅拌2分钟，添加N,N-二异丙基乙胺(0.1mL)，室温反应15分钟，LCMS监测反应完成。将反应液直接浓缩，柱层析分离纯化(DCM-MeOH，10％MeOH出峰)，得淡黄色固体58.0mg，即化合物200-6。ESI-MS m/z:626[M+H]+。200-5 (56.1 mg), 3-aminomethyl-4-thiomethyl-6-methyl-1H-pyridin-2-one (26.9 mg) and N,N,N',N'-tetramethyl -O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (69.5 mg) was dissolved in DMF (2.0 mL), stirred at room temperature for 2 minutes, and N,N-diisopropylethyl ethyl was added Amine (0.1 mL) was reacted at room temperature for 15 minutes, and LCMS monitored the reaction to completion. The reaction solution was directly concentrated and separated and purified by column chromatography (DCM-MeOH, 10% MeOH peak) to obtain 58.0 mg of light yellow solid, namely compound 200-6. ESI-MS m/z:626[M+H] + .
步骤7：化合物200的合成Step 7: Synthesis of Compound 200
将200-6(58.0mg)溶解于三氟乙酸(1mL)中，室温反应5分钟。将反应液直接浓缩，然后加入DCM(1mL)和TEA(1mL)，室温反应5分钟。将反应液再次浓缩，甲醇(1mL)溶解，然后加入37％的甲醛水溶液(17.1mg)和冰醋酸(2滴)，室温反应30分钟。再添加氰基硼氢化钠(10.8mg)，室温反应10分钟，LCMS监测反应完成。将反应液直接浓缩，制备液相分离，得白色粉末10.1mg，即化合物200。ESI-MS m/z:554[M+H]+。1H NMR(500MHz,DMSO)δ11.53(s,1H),8.05(t,J＝4.5Hz,1H),7.55(dd,J＝6.5Hz,2.0Hz,2H),7.34(dd,J＝6.0Hz,1.5Hz,2H),6.90(s,1H),6.08(s,1H),4.26(d,J＝4.5Hz,2H),2.44(s,3H),2.20(s,3H),2.16(s,3H),2.11(s,6H),2.05(s,3H),0.83(m,2H),0.72(m,2H)。Dissolve 200-6 (58.0 mg) in trifluoroacetic acid (1 mL) and react at room temperature for 5 minutes. The reaction solution was directly concentrated, then DCM (1 mL) and TEA (1 mL) were added, and the reaction was carried out at room temperature for 5 minutes. The reaction solution was concentrated again, methanol (1 mL) was dissolved, then 37% formaldehyde aqueous solution (17.1 mg) and glacial acetic acid (2 drops) were added, and the reaction was carried out at room temperature for 30 minutes. Then add sodium cyanoborohydride (10.8 mg) and react at room temperature for 10 minutes. LCMS monitors the completion of the reaction. The reaction solution was directly concentrated, and the preparative liquid phase was separated to obtain 10.1 mg of white powder, namely compound 200. ESI-MS m/z:554[M+H] + . 1 H NMR (500MHz, DMSO) δ11.53 (s, 1H), 8.05 (t, J = 4.5Hz, 1H), 7.55 (dd, J = 6.5Hz, 2.0Hz, 2H), 7.34 (dd, J = 6.0Hz,1.5Hz,2H),6.90(s,1H),6.08(s,1H),4.26(d,J＝4.5Hz,2H),2.44(s,3H),2.20(s,3H),2.16 (s,3H),2.11(s,6H),2.05(s,3H),0.83(m,2H),0.72(m,2H).
实施例201：化合物(R)-7-氯-2-((1r,4R)-4-((4-氟苯基)(甲基)胺)环己基)-2,4-二甲基-N-((4-甲基-6-氧-5,6-二氢呋喃[3,2-c]吡啶-7-基)甲基)苯并[d][1,3]二氧戊环-5-甲酰胺的合成
Example 201: Compound (R)-7-chloro-2-((1r,4R)-4-((4-fluorophenyl)(methyl)amine)cyclohexyl)-2,4-dimethyl- N-((4-methyl-6-oxo-5,6-dihydrofuran[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxolane -Synthesis of 5-carboxamide
步骤1：化合物201-1的合成Step 1: Synthesis of Compound 201-1
将甲基(R)-7-氯-2,4-二甲基-2-(4-氧环己基)苯并[d][1,3]二氧戊环-5-甲酰胺(150.0mg)和对氟苄胺(121.9mg)加入四氢呋喃(4mL)和甲醇(4mL)的混合溶剂中，氮气保护，室温搅拌2小时。然后将反应瓶置于-70℃，加入硼氢化锂(19.3mg)，保温搅拌0.5小时，TLC 监测反应完成。向反应液中加入水和DCM，DCM萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析分离纯化(DCM-MeOH，10％MeOH出峰)，得白色固体190.0mg，即化合物201-1。ESI-MS m/z:448[M+H]+。Methyl(R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxolane-5-carboxamide (150.0 mg ) and p-fluorobenzylamine (121.9 mg) were added to a mixed solvent of tetrahydrofuran (4 mL) and methanol (4 mL), protected by nitrogen, and stirred at room temperature for 2 hours. Then place the reaction bottle at -70°C, add lithium borohydride (19.3 mg), keep stirring for 0.5 hours, and perform TLC Monitor the reaction for completion. Add water and DCM to the reaction solution, extract with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate and purify by column chromatography (DCM-MeOH, 10% MeOH peak) to obtain 190.0 mg of white solid, namely Compound 201-1. ESI-MS m/z:448[M+H] + .
步骤2：化合物201-2的合成Step 2: Synthesis of Compound 201-2
将甲基(R)-7-氯-2,4-二甲基-2-(4-氧环己基)苯并[d][1,3]二氧戊环-5-甲酰胺(190.0mg)和甲醛水溶液(0.5mL)加入甲醇(4mL)中，室温搅拌2小时。添加氰基硼氢化钠(65.0mg)，继续反应0.5小时，TLC监测反应完成。向反应液中加入水和DCM，DCM萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析分离纯化(DCM-MeOH，10％MeOH出峰)，得白色固体170.8mg，即化合物201-2。ESI-MS m/z:462[M+H]+。Methyl(R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxolane-5-carboxamide (190.0 mg ) and formaldehyde aqueous solution (0.5 mL) were added to methanol (4 mL), and stirred at room temperature for 2 hours. Sodium cyanoborohydride (65.0 mg) was added, the reaction was continued for 0.5 hours, and TLC monitored the reaction to completion. Add water and DCM to the reaction solution, extract with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate and purify by column chromatography (DCM-MeOH, 10% MeOH peak) to obtain 170.8 mg of white solid, namely Compound 201-2. ESI-MS m/z:462[M+H] + .
步骤3：化合物201-3的合成Step 3: Synthesis of Compound 201-3
将201-2(170.8mg)，一水合氢氧化锂(155.2mg)加入甲醇(4mL)和水(1mL)中，升温至70℃反应2小时，LCMS监测反应完成。向反应液中加入饱和柠檬酸水溶液至pH＝6，DCM/iPrOH(4：1)萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析分离纯化(PE-EA，10％EA出峰)，得白色固体132.1mg，即化合物201-3。ESI-MS m/z:448[M+H]+。Add 201-2 (170.8 mg) and lithium hydroxide monohydrate (155.2 mg) to methanol (4 mL) and water (1 mL), raise the temperature to 70°C and react for 2 hours. LCMS monitors the reaction to be completed. Add saturated citric acid aqueous solution to the reaction solution to pH=6, extract with DCM/ i PrOH (4:1), wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and purify by column chromatography (PE-EA, 10 %EA peak), and 132.1 mg of white solid was obtained, namely compound 201-3. ESI-MS m/z:448[M+H] + .
步骤4：化合物201的合成Step 4: Synthesis of Compound 201
将201-3(80.0mg)，7-(氨甲基)-4-甲基呋喃[3,2-c]吡啶-6(5H)-酮(38.2mg)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(81.5mg)溶解于DMF(2.0mL)中，室温搅拌2分钟，添加N,N-二异丙基乙胺(0.15mL)，室温反应15分钟，LCMS监测反应完成。将反应液直接浓缩，制备液相分离，得白色粉末50.4mg，即化合物201。ESI-MS m/z:608[M+H]+。1H NMR(500MHz,DMSO)δ7.60(d,J＝2.5Hz,1H),7.55-7.53(m,2H),7.24(t,J＝8.5Hz,2H),6.95(s,1H),6.81(d,J＝2.5Hz,1H),4.59(s,1H),4.50(d,J＝13.0Hz,1H),4.16(d,J＝13.0Hz,1H),2.71(s,3H),2.52(s,3H),2.24-2.13(m,4H),2.05-2.01(m,2H),1.75-1.70(m,3H),1.64(s,3H),1.46-1.37(m,3H)。201-3 (80.0 mg), 7-(aminomethyl)-4-methylfuran[3,2-c]pyridin-6(5H)-one (38.2 mg) and N,N,N',N '-Tetramethyl-O-(7-azabenzotriazol-1-yl)urea hexafluorophosphate (81.5 mg) was dissolved in DMF (2.0 mL), stirred at room temperature for 2 minutes, and N,N-bis Isopropylethylamine (0.15 mL), react at room temperature for 15 minutes, and monitor the reaction with LCMS to complete. The reaction solution was directly concentrated, and the preparative liquid phase was separated to obtain 50.4 mg of white powder, namely compound 201. ESI-MS m/z:608[M+H] + . 1 H NMR (500MHz, DMSO) δ7.60 (d, J＝2.5Hz, 1H), 7.55-7.53 (m, 2H), 7.24 (t, J＝8.5Hz, 2H), 6.95 (s, 1H), 6.81(d,J＝2.5Hz,1H),4.59(s,1H),4.50(d,J＝13.0Hz,1H),4.16(d,J＝13.0Hz,1H),2.71(s,3H), 2.52(s,3H),2.24-2.13(m,4H),2.05-2.01(m,2H),1.75-1.70(m,3H),1.64(s,3H),1.46-1.37(m,3H).
实施例202：化合物(2R)-7-氯-2,4-二甲基-N-((4-甲基-6-氧-5,6-二氢呋喃[3,2-c]吡啶-7-基)甲基)-2-((1r,4R)-4-(四氢-1H-呋喃[3,4-c]吡咯-5(3H)-基)环己基)苯并[d][1,3]二氧戊环-5-甲酰胺的合成
Example 202: Compound (2R)-7-chloro-2,4-dimethyl-N-((4-methyl-6-oxo-5,6-dihydrofuran[3,2-c]pyridine- 7-yl)methyl)-2-((1r,4R)-4-(tetrahydro-1H-furan[3,4-c]pyrrole-5(3H)-yl)cyclohexyl)benzo[d] Synthesis of [1,3]dioxolane-5-carboxamide
步骤1：化合物202-1的合成Step 1: Synthesis of Compound 202-1
将甲基(R)-7-氯-2,4-二甲基-2-(4-氧环己基)苯并[d][1,3]二氧戊环-5-甲酰胺(200.0mg) 和六氢-1H-呋喃[3,4-c]吡咯(133.6mg)加入四氢呋喃(4mL)和甲醇(4mL)的混合溶剂中，氮气保护，室温搅拌2小时。然后将反应瓶置于-70℃，加入硼氢化锂(25.7mg)，保温搅拌0.5小时，TLC监测反应完成。向反应液中加入水和DCM，DCM萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析分离纯化(DCM-MeOH，10％MeOH出峰)，得白色固体40.0mg，即化合物202-1。ESI-MS m/z:436[M+H]+。Methyl(R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxolane-5-carboxamide (200.0 mg ) and hexahydro-1H-furan[3,4-c]pyrrole (133.6 mg) were added to a mixed solvent of tetrahydrofuran (4 mL) and methanol (4 mL), protected by nitrogen, and stirred at room temperature for 2 hours. Then the reaction bottle was placed at -70°C, lithium borohydride (25.7 mg) was added, kept stirring for 0.5 hours, and TLC monitored the reaction to completion. Add water and DCM to the reaction solution, extract with DCM, wash the organic phase with saturated brine, dry with anhydrous sodium sulfate, concentrate, and separate and purify by column chromatography (DCM-MeOH, 10% MeOH peak) to obtain 40.0 mg of white solid, namely Compound 202-1. ESI-MS m/z:436[M+H] + .
步骤2：化合物202-2的合成Step 2: Synthesis of Compound 202-2
将202-1(40.0mg)，一水合氢氧化锂(38.5mg)加入甲醇(4mL)和水(1mL)中，升温至70℃反应2小时，LCMS监测反应完成。向反应液中加入饱和柠檬酸水溶液至pH＝6，DCM/iPrOH(4：1)萃取，有机相饱和食盐水洗，无水硫酸钠干燥，浓缩，柱层析分离纯化(DCM-MeOH，10％MeOH出峰)，得白色固体30.1mg，即化合物202-2。ESI-MS m/z:422[M+H]+。Add 202-1 (40.0 mg) and lithium hydroxide monohydrate (38.5 mg) to methanol (4 mL) and water (1 mL), raise the temperature to 70°C and react for 2 hours. LCMS monitors the reaction to be completed. Add saturated citric acid aqueous solution to the reaction solution to pH=6, extract with DCM/ i PrOH (4:1), wash the organic phase with saturated brine, dry over anhydrous sodium sulfate, concentrate, and purify by column chromatography (DCM-MeOH, 10 %MeOH peak), and 30.1 mg of white solid was obtained, namely compound 202-2. ESI-MS m/z:422[M+H] + .
步骤3：化合物202的合成Step 3: Synthesis of Compound 202
将202-2(30.1mg)，中间体M7(19.1mg)和N,N,N’,N’-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(40.7mg)溶解于DMF(2.0mL)中，室温搅拌2分钟，添加N,N-二异丙基乙胺(0.1mL)，室温反应15分钟，LCMS监测反应完成。将反应液直接浓缩，制备液相分离，得白色粉末9.4mg，即化合物202。ESI-MS m/z:582[M+H]+。1H NMR(500MHz,DMSO)δ7.59(d,J＝2.5Hz,1H),6.94(s,1H),6.80(d,J＝3.0Hz,1H),4.59(s,2H),3.97-3.93(m,2H),3.58-3.55(m,2H),3.07-3.02(m,2H),2.80-2.76(m,2H),2.52(s,3H),2.28-2.21(m,3H),2.18(s,3H),2.10-2.07(m,3H),1.99-1.93(m,2H),1.63(s,3H),1.54-1.39(m,4H)。202-2 (30.1 mg), intermediate M7 (19.1 mg) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)hexafluorophosphoric acid Dissolve urea (40.7 mg) in DMF (2.0 mL), stir at room temperature for 2 minutes, add N,N-diisopropylethylamine (0.1 mL), react at room temperature for 15 minutes, and monitor the reaction with LCMS to complete. The reaction solution was directly concentrated, and the preparative liquid phase was separated to obtain 9.4 mg of white powder, namely compound 202. ESI-MS m/z:582[M+H] + . 1 H NMR (500MHz, DMSO) δ7.59(d,J＝2.5Hz,1H),6.94(s,1H),6.80(d,J＝3.0Hz,1H),4.59(s,2H),3.97- 3.93(m,2H),3.58-3.55(m,2H),3.07-3.02(m,2H),2.80-2.76(m,2H),2.52(s,3H),2.28-2.21(m,3H), 2.18(s,3H),2.10-2.07(m,3H),1.99-1.93(m,2H),1.63(s,3H),1.54-1.39(m,4H).
实施例203：(R)-7-氯-2-((1r，4R)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2,4-二甲基-N-((4-甲基-6-氧代-5,6-二氢氟[3,2-c]吡啶-7-基)甲基)苯并[d][1,3]二氧杂环戊-5-甲酰胺的合成
Example 203: (R)-7-chloro-2-((1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl -N-((4-methyl-6-oxo-5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxo Synthesis of heterocyclopent-5-carboxamide
步骤1：化合物203-1的合成 Step 1: Synthesis of Compound 203-1
将上述化合物(R)-7-氯-2,4-二甲基-2-(4-氧代环己基)苯并[d][1,3]二氧杂环戊-5-羧酸甲酯(100.0mg)，溶于THF(2mL)，加入甲醇(2mL)，3-甲氧基-3-甲基氮杂丁烷(133.2mg)，室温反应1h后，降温至-70℃，加入硼氢化锂(43.7mg)，继续反应3h。升温至室温，向反应液中倒入适量水和EA，分液，水相用EA萃取，合并有机相，有机相无水硫酸钠干燥，经柱层析(DCM:MeOH＝10:1)分离纯化得到目标产物203-1(92.8mg，产率74.2％)。ESI-MS m/z:424.3[M+H]+。The above compound (R)-7-chloro-2,4-dimethyl-2-(4-oxocyclohexyl)benzo[d][1,3]dioxola-5-carboxylic acid methyl Ester (100.0mg), dissolved in THF (2mL), add methanol (2mL), 3-methoxy-3-methylazetidine (133.2mg), react at room temperature for 1 hour, then cool to -70°C, add Lithium borohydride (43.7 mg), continue the reaction for 3 hours. Warm up to room temperature, pour an appropriate amount of water and EA into the reaction solution, separate the liquids, extract the aqueous phase with EA, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and separate by column chromatography (DCM:MeOH=10:1) Purification gave the target product 203-1 (92.8 mg, yield 74.2%). ESI-MS m/z:424.3[M+H] + .
步骤2：化合物203-2的合成Step 2: Synthesis of Compound 203-2
将上述化合物203-1(92.8mg)，溶于甲醇(3mL)，加入水(0.5mL)，氢氧化锂(26.3mg)，加热至70℃反应3h。降温至室温，向反应液中加入1M盐酸溶液，调节溶液pH至2-3后，向反应液中加入10mL H2O和10mL DCM，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物203-2(67.1mg，产率74.8％)。ESI-MS m/z:410.5[M+H]+。The above compound 203-1 (92.8 mg) was dissolved in methanol (3 mL), water (0.5 mL) and lithium hydroxide (26.3 mg) were added, and the mixture was heated to 70°C for 3 h. Cool to room temperature, add 1M hydrochloric acid solution to the reaction solution, adjust the pH of the solution to 2-3, add 10mL H 2 O and 10mL DCM to the reaction solution, stir and separate the layers, extract the water phase three times with DCM, and combine the organic phases. The organic phase was washed, dried, and concentrated to dryness. The concentrate did not require purification and was directly put into the next step to obtain target compound 203-2 (67.1 mg, yield 74.8%). ESI-MS m/z:410.5[M+H] + .
步骤3：化合物203的合成Step 3: Synthesis of Compound 203
将上述化合物203-2(67.1mg)，溶于DMF(3mL)，加入DIEA(0.1mL)，M7(35.0mg)，HATU(93.3mg)，室温反应1h。向反应液中加入10mL H2O和10mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物反相色谱柱层析分离产物(CH3CN/H2O＝30％-55％)，得到目标化合物203(38.4mg，产率41.2％)。ESI-MS m/z:570.2[M+H]+。1H NMR(500MHz,DMSO)δ11.94(s,1H),8.26(t,J＝4.9Hz,1H),7.66(d,J＝2.3Hz,1H),6.88(s,1H),6.84(d,J＝2.4Hz,1H),4.35(d,J＝4.9Hz,2H),3.09–3.00(m,4H),2.85(s,2H),2.39(s,3H),2.12(s,3H),1.92–1.70(m,6H),1.59(s,3H),1.33(s,3H),1.20–1.07(m,2H),0.89(dd,J＝23.9,11.5Hz,2H).Dissolve the above compound 203-2 (67.1 mg) in DMF (3 mL), add DIEA (0.1 mL), M7 (35.0 mg), and HATU (93.3 mg), and react at room temperature for 1 h. Add 10 mL H 2 O and 10 mL EA to the reaction solution, stir and separate the layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness, and the concentrate is separated by reverse-phase chromatography column chromatography to separate the product (CH 3 CN/H 2 O=30%-55%) to obtain target compound 203 (38.4 mg, yield 41.2%). ESI-MS m/z:570.2[M+H]+. 1H NMR (500MHz, DMSO) δ11.94(s,1H),8.26(t,J＝4.9Hz,1H),7.66(d,J＝2.3Hz,1H),6.88(s,1H),6.84(d ,J＝2.4Hz,1H),4.35(d,J＝4.9Hz,2H),3.09–3.00(m,4H),2.85(s,2H),2.39(s,3H),2.12(s,3H) ,1.92–1.70(m,6H),1.59(s,3H),1.33(s,3H),1.20–1.07(m,2H),0.89(dd,J＝23.9,11.5Hz,2H).
实施例204：(R)-7-氯-2-((1r，4R)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2,4-二甲基-N-((4-甲基-6-氧代-5,6-二氢氟[3,2-c]吡啶-7-基)甲基)苯并[d][1,3]二氧杂环戊-5-甲酰胺的合成
Example 204: (R)-7-chloro-2-((1r,4R)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl -N-((4-methyl-6-oxo-5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxo Synthesis of heterocyclopent-5-carboxamide
步骤1：化合物204-2的合成Step 1: Synthesis of Compound 204-2
将原料204-1(5.0g)溶于DMF(50.0mL)中，加入DIEA(7.8mL)，二甲羟胺盐酸盐(3.5g)，HATU(10.2g)，室温反应过夜。向反应液中加入100mL H2O和100mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物204-2(5.3g，产率91.4％)。ESI-MS m/z:322.2[M+H]+。Dissolve raw material 204-1 (5.0g) in DMF (50.0mL), add DIEA (7.8mL), dimethylhydroxylamine hydrochloride (3.5g), HATU (10.2g), and react at room temperature overnight. Add 100mL H 2 O and 100mL EA to the reaction solution, stir and separate layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness. The concentrate does not need to be purified and is directly added to the next step to obtain the target compound. 204-2 (5.3g, yield 91.4%). ESI-MS m/z:322.2[M+H] + .
步骤2：化合物204-3的合成Step 2: Synthesis of Compound 204-3
将化合物204-2(5.3g)溶于THF(60.0mL),冷却降温至0℃，缓慢加入2mol/L的二异丁基氢化铝的正己烷溶液(10.5mL)，0℃反应2h。向反应液中加入饱和氯化铵溶液淬灭，向反应液中加入40mL H2O和100mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物204-3(3.8g，产率88.2％)。ESI-MS m/z:263.1[M+H]+。Dissolve compound 204-2 (5.3g) in THF (60.0mL), cool to 0°C, slowly add 2 mol/L diisobutylaluminum hydride in n-hexane solution (10.5mL), and react at 0°C for 2 hours. Add saturated ammonium chloride solution to the reaction solution to quench, add 40 mL H 2 O and 100 mL EA to the reaction solution, stir and separate the layers, extract the aqueous phase with EA three times, combine the organic phases, wash, dry, and concentrate to dryness , the concentrate does not require purification and is directly put into the next step to obtain the target compound 204-3 (3.8g, yield 88.2%). ESI-MS m/z:263.1[M+H] + .
步骤3：化合物204-4的合成Step 3: Synthesis of Compound 204-4
将上述化合物204-3(3.8g)溶于MeOH(50.0mL),加入碳酸钾(6.0g)，(1-重氮基-2-氧代丙基)膦酸二甲酯(5.6g),室温反应过夜。向反应液中加入50mL H2O和50mL DCM，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物经柱层析(PE:EA＝4:1)分离纯化得到目标产物204-4(2.2g，产率58.6％)。ESI-MS m/z:259.4[M+H]+。Dissolve the above compound 204-3 (3.8g) in MeOH (50.0mL), add potassium carbonate (6.0g), (1-diazo-2-oxopropyl)phosphonic acid dimethyl ester (5.6g), Reaction was carried out at room temperature overnight. Add 50 mL H 2 O and 50 mL DCM to the reaction solution, stir and separate the layers, extract the aqueous phase three times with DCM, combine the organic phases, wash the organic phases, dry, and concentrate to dryness, and the concentrate is subjected to column chromatography (PE:EA=4 :1) Isolate and purify to obtain the target product 204-4 (2.2g, yield 58.6%). ESI-MS m/z:259.4[M+H] + .
步骤4：化合物204-5的合成Step 4: Synthesis of Compound 204-5
将上述化合物5-氯-3,4-二羟基-2-甲基苯甲酸甲酯(0.8g)溶于甲苯(15mL)，加入PPh3(0.19g),十二羰基三钌(0.23g)，在N2保护油浴115℃下回流反应1h后，加入 204-4(1.72g)，继续反应12h。冷却至室温，反应液直接蒸干，经柱层析(PE:EA＝5:1)分离纯化得到目标产物204-5(1.3g，产率73.2％)。ESI-MS m/z:475.3[M+H]+。Dissolve the above compound 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester (0.8g) in toluene (15mL), add PPh 3 (0.19g), triruthenium dodecacarbonyl (0.23g) , after 1 hour of reflux reaction in an N2 protected oil bath at 115°C, add 204-4 (1.72g), continue the reaction for 12 hours. After cooling to room temperature, the reaction solution was directly evaporated to dryness and separated and purified by column chromatography (PE:EA=5:1) to obtain the target product 204-5 (1.3g, yield 73.2%). ESI-MS m/z:475.3[M+H] + .
步骤5：化合物204-6的合成Step 5: Synthesis of Compound 204-6
将上述化合物204-5(1.3g)溶于DCM(10.0mL),加入三氟乙酸(2.5mL)，室温反应1h，反应液浓缩，浓缩物无需纯化，直接投下一步，得到目标产物204-6(0.95g，产率92.4％)。ESI-MS m/z:375.4[M+H]+。Dissolve the above compound 204-5 (1.3g) in DCM (10.0mL), add trifluoroacetic acid (2.5mL), and react at room temperature for 1 hour. The reaction solution is concentrated. The concentrate does not need to be purified and is directly added to the next step to obtain the target product 204-6. (0.95g, yield 92.4%). ESI-MS m/z:375.4[M+H] + .
步骤6：化合物204-7的合成Step 6: Synthesis of Compound 204-7
将上述化合物204-6(0.95g)溶于甲醇(10mL)，加入37％wt的甲醛水溶液(1mL),室温反应0.5h后，加入氰基硼氢化钠(0.32g)，室温反应1h。向反应液中加入10mL H2O和10mL DCM，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，经柱层析(DCM:MeOH＝10:1)分离纯化得到目标产物204-7(0.72g，产率73.1％)。ESI-MS m/z:389.2[M+H]+。Dissolve the above compound 204-6 (0.95g) in methanol (10mL), add 37% wt formaldehyde aqueous solution (1mL), react at room temperature for 0.5h, then add sodium cyanoborohydride (0.32g), and react at room temperature for 1h. Add 10 mL H 2 O and 10 mL DCM to the reaction solution, stir and separate the layers, extract the aqueous phase three times with DCM, combine the organic phases, wash the organic phases, dry, concentrate to dryness, and perform column chromatography (DCM:MeOH=10:1 ) was separated and purified to obtain the target product 204-7 (0.72g, yield 73.1%). ESI-MS m/z:389.2[M+H] + .
步骤7：化合物204-8的合成Step 7: Synthesis of Compound 204-8
将上述化合物204-7(0.2g)，溶于甲醇(5mL)，加入水(1mL)，氢氧化锂(72.0mg)，加热至70℃反应3h。降温至室温，向反应液中加入1M盐酸溶液，调节溶液pH至2-3后，向反应液中加入10mL H2O和10mL DCM，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物204-8(0.17g，产率89.5％)。ESI-MS m/z:375.3[M+H]+。The above compound 204-7 (0.2g) was dissolved in methanol (5mL), water (1mL) and lithium hydroxide (72.0mg) were added, and the mixture was heated to 70°C for 3 hours. Cool to room temperature, add 1M hydrochloric acid solution to the reaction solution, adjust the pH of the solution to 2-3, add 10mL H 2 O and 10mL DCM to the reaction solution, stir and separate the layers, extract the water phase three times with DCM, and combine the organic phases. The organic phase was washed, dried, and concentrated to dryness. The concentrate did not require purification and was directly put into the next step to obtain target compound 204-8 (0.17 g, yield 89.5%). ESI-MS m/z:375.3[M+H] + .
步骤8：化合物204的合成Step 8: Synthesis of Compound 204
将上述化合物204-8(58.2mg)，溶于DMF(3mL)，加入DIEA(0.1mL)，M7(33.2mg)，HATU(88.5mg)，室温反应1h。向反应液中加入10mL H2O和10mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物反相色谱柱层析分离产物(CH3CN/H2O＝30％-55％)，得到目标化合物204(29.7mg，产率35.8％)。1H NMR(500MHz,DMSO)δ12.01(s,1H),10.19(s,1H),8.68(d,J＝2.0Hz,1H),8.32(t,J＝5.0Hz,1H),7.94(d,J＝1.9Hz,1H),7.66(d,J＝2.4Hz,1H),6.98(s,1H),6.85(d,J＝2.4Hz,1H),4.56(d,J＝15.5Hz,1H),4.35(d,J＝5.0Hz,3H),3.69(s,2H),3.38(d,J＝15.1Hz,2H),3.15(dd,J＝11.7,5.8Hz,2H),2.98(s,3H),2.40(s,3H),2.21(s,3H),2.09(d,J＝19.6Hz,3H).Dissolve the above compound 204-8 (58.2 mg) in DMF (3 mL), add DIEA (0.1 mL), M7 (33.2 mg), HATU (88.5 mg), and react at room temperature for 1 h. Add 10 mL H 2 O and 10 mL EA to the reaction solution, stir and separate the layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness, and the concentrate is separated by reverse-phase chromatography column chromatography to separate the product (CH 3 CN/H 2 O=30%-55%) to obtain the target compound 204 (29.7 mg, yield 35.8%). 1H NMR (500MHz, DMSO) δ12.01(s,1H),10.19(s,1H),8.68(d,J＝2.0Hz,1H),8.32(t,J＝5.0Hz,1H),7.94(d ,J＝1.9Hz,1H),7.66(d,J＝2.4Hz,1H),6.98(s,1H),6.85(d,J＝2.4Hz,1H),4.56(d,J＝15.5Hz,1H ),4.35(d,J＝5.0Hz,3H),3.69(s,2H),3.38(d,J＝15.1Hz,2H),3.15(dd,J＝11.7,5.8Hz,2H),2.98(s ,3H),2.40(s,3H),2.21(s,3H),2.09(d,J＝19.6Hz,3H).
实施例205：7-氯-6-甲氧基-2-((1r，4r)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2,4-二甲基-N-((4-甲基-6-氧代-5,6-二氢氟[3,2-c]吡啶-7-基)甲基)苯并[d][1,3]二氧杂环戊-5-甲酰胺的合成
Example 205: 7-chloro-6-methoxy-2-((1r,4r)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-di Methyl-N-((4-methyl-6-oxo-5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3] Synthesis of dioxola-5-carboxamide
步骤1：化合物205-1的合成Step 1: Synthesis of Compound 205-1
将原料5-氯-3,4-二羟基-2-甲基苯甲酸甲酯(5.0g)溶于DMF(50.0mL)中，加入碳酸钾(12.7g)，碘甲烷(9.8g)，室温反应过夜。向反应液中加入100mL H2O和100mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物205-1(5.3g，产率90.0％)。Dissolve the raw material 5-chloro-3,4-dihydroxy-2-methylbenzoic acid methyl ester (5.0g) in DMF (50.0mL), add potassium carbonate (12.7g), iodomethane (9.8g), and keep at room temperature Reaction was allowed to take place overnight. Add 100mL H 2 O and 100mL EA to the reaction solution, stir and separate layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness. The concentrate does not need to be purified and is directly added to the next step to obtain the target compound. 205-1 (5.3g, yield 90.0%).
步骤2：化合物205-2的合成Step 2: Synthesis of Compound 205-2
将化合物205-1(5.3g)溶于DCM(60.0mL),冷却降温至0℃，加入三氟乙酸酐(15.0mL)，HNO3(1.8mL),保温反应4h。向反应液中滴加饱和碳酸钠溶液淬灭，待无气泡产生后，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩，浓缩物经柱层析(PE:EA＝10:1)分离纯化得到目标产物205-2(5.2g，产率82.6％)。Compound 205-1 (5.3g) was dissolved in DCM (60.0mL), cooled to 0°C, trifluoroacetic anhydride (15.0mL) and HNO 3 (1.8mL) were added, and the reaction was incubated for 4h. Add saturated sodium carbonate solution dropwise to the reaction solution to quench. After no bubbles are generated, stir and separate the layers. The aqueous phase is extracted three times with DCM. The organic phases are combined. The organic phases are washed, dried, and concentrated. The concentrate is subjected to column chromatography (PE :EA=10:1) was separated and purified to obtain the target product 205-2 (5.2g, yield 82.6%).
步骤3：化合物205-3的合成Step 3: Synthesis of Compound 205-3
将上述化合物205-2(5.2g)溶于EtOH(50.0mL),加入氯化铵(9.6g)，水(50.0mL),铁粉(5.0g)，加热至70℃，反应2h。停止加热，降温至室温，反应液浓缩，向浓缩物中加入30mL饱和碳酸氢钠溶液和100mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩。浓缩物经柱层析(PE:EA＝10:1)分离纯化得到目标产物205-3(4.1g，产率88.3％)。ESI-MS m/z:260.4[M+H]+。Dissolve the above compound 205-2 (5.2g) in EtOH (50.0mL), add ammonium chloride (9.6g), water (50.0mL), and iron powder (5.0g), heat to 70°C, and react for 2 hours. Stop heating, cool to room temperature, concentrate the reaction solution, add 30 mL saturated sodium bicarbonate solution and 100 mL EA to the concentrate, stir and separate the layers, extract the aqueous phase three times with EA, combine the organic phases, wash, dry and concentrate. The concentrate was separated and purified by column chromatography (PE:EA=10:1) to obtain the target product 205-3 (4.1 g, yield 88.3%). ESI-MS m/z:260.4[M+H] + .
步骤4：化合物205-4的合成Step 4: Synthesis of Compound 205-4
冰浴下，将上述化合物205-3(4.1g)溶于四氟硼酸(50.0mL)中，加入水(5.0mL)，亚硝酸钠(1.6g)，反应1h后，302nm汞灯照射，室温反应24h。向反应中加入适量DCM与水淬灭，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩，浓缩物经柱层析(PE:EA＝10:1)分离纯化得到目标产物205-4(0.96g，产率23.3％)。ESI- MS m/z:259.2[M-H]+。Dissolve the above compound 205-3 (4.1g) in tetrafluoroboric acid (50.0mL) under an ice bath, add water (5.0mL) and sodium nitrite (1.6g), react for 1 hour, and then irradiate with a 302nm mercury lamp at room temperature. Reaction 24h. Add an appropriate amount of DCM and water to the reaction to quench, stir and separate the layers, extract the aqueous phase with DCM three times, combine the organic phases, wash, dry, and concentrate, and the concentrate is separated by column chromatography (PE:EA=10:1) Purification gave the target product 205-4 (0.96g, yield 23.3%). ESI- MS m/z:259.2[MH] + .
步骤5：化合物205-5的合成Step 5: Synthesis of Compound 205-5
将上述化合物205-4(0.96g)溶于DCM(10.0mL),加入三溴化硼(1.4mL)，室温反应1h，向反应液中加入5mL甲醇淬灭，反应液浓缩，浓缩物无需纯化，直接投下一步，得到目标产物205-5(0.8g，产率93.6％)。ESI-MS m/z:231.3[M-H]+。Dissolve the above compound 205-4 (0.96g) in DCM (10.0mL), add boron tribromide (1.4mL), react at room temperature for 1 hour, add 5mL of methanol to the reaction solution to quench, and the reaction solution is concentrated. The concentrate does not require purification. , directly invest in the next step, and obtain the target product 205-5 (0.8g, yield 93.6%). ESI-MS m/z:231.3[MH] + .
步骤6：化合物205-6的合成Step 6: Synthesis of Compound 205-6
将上述化合物205-5(0.8g)溶于甲苯(15mL)，加入PPh3(0.18g),十二羰基三钌(0.22g)，在N2保护油浴115℃下回流反应1h后，加入4-乙炔基环己烷-1-酮(0.84g)，继续反应12h。冷却至室温，反应液直接蒸干，经柱层析(PE:EA＝5:1)分离纯化得到目标产物205-6(0.87g，产率70.9％)。ESI-MS m/z:353.2[M-H]+。Dissolve the above compound 205-5 (0.8g) in toluene (15mL), add PPh 3 (0.18g), triruthenium dodecacarbonyl (0.22g), reflux and react in an N 2 protective oil bath at 115°C for 1 hour, then add 4-Ethynylcyclohexan-1-one (0.84g), continue the reaction for 12h. After cooling to room temperature, the reaction solution was directly evaporated to dryness and separated and purified by column chromatography (PE:EA=5:1) to obtain the target product 205-6 (0.87g, yield 70.9%). ESI-MS m/z:353.2[MH] + .
步骤7：化合物205-7的合成Step 7: Synthesis of Compound 205-7
将上述化合物205-6(0.87g)溶于DMF(10mL)，加入碳酸钾(0.68g)，碘甲烷(0.52g)，室温反应过夜。向反应液中加入10mL H2O和10mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物205-7(0.8g，产率88.6％)。The above compound 205-6 (0.87g) was dissolved in DMF (10 mL), potassium carbonate (0.68g) and methyl iodide (0.52g) were added, and the reaction was carried out at room temperature overnight. Add 10 mL H 2 O and 10 mL EA to the reaction solution, stir and separate layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness. The concentrate does not need to be purified and is directly added to the next step to obtain the target compound. 205-7 (0.8g, yield 88.6%).
步骤8：化合物205-8的合成Step 8: Synthesis of Compound 205-8
将上述化合物205-7(0.8g)，溶于THF(5mL)，加入甲醇(5mL)，3-甲氧基-氮杂环丁烷(0.94g)，室温反应1h后，降温至-70℃，加入硼氢化锂(0.47g)，继续反应3h。升温至室温，向反应液中倒入适量水和EA，分液，水相用EA萃取，合并有机相，有机相无水硫酸钠干燥，经柱层析(DCM:MeOH＝10:1)分离纯化得到目标产物205-8(0.81g，产率85.4％)。ESI-MS m/z:440.2[M+H]+。Dissolve the above compound 205-7 (0.8g) in THF (5mL), add methanol (5mL) and 3-methoxy-azetidine (0.94g), react at room temperature for 1 hour, and then cool to -70°C. , add lithium borohydride (0.47g), and continue the reaction for 3 hours. Warm up to room temperature, pour an appropriate amount of water and EA into the reaction solution, separate the liquids, extract the aqueous phase with EA, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and separate by column chromatography (DCM:MeOH=10:1) After purification, the target product 205-8 (0.81 g, yield 85.4%) was obtained. ESI-MS m/z:440.2[M+H] + .
步骤9：化合物205-9的合成Step 9: Synthesis of Compound 205-9
将上述化合物205-8(0.5g)，溶于甲醇(5mL)，加入水(1mL)，氢氧化锂(0.27g)，加热至70℃反应3h。降温至室温，向反应液中加入1M盐酸溶液，调节溶液pH至2-3后，向反应液中加入10mL H2O和10mL DCM，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物205-9(0.44g，产率91.2％)。ESI-MS m/z:426.3[M+H]+。The above compound 205-8 (0.5g) was dissolved in methanol (5mL), water (1mL) and lithium hydroxide (0.27g) were added, and the mixture was heated to 70°C for 3 hours. Cool to room temperature, add 1M hydrochloric acid solution to the reaction solution, adjust the pH of the solution to 2-3, add 10mL H 2 O and 10mL DCM to the reaction solution, stir and separate the layers, extract the water phase three times with DCM, and combine the organic phases. The organic phase was washed, dried, and concentrated to dryness. The concentrate did not require purification and was directly put into the next step to obtain target compound 205-9 (0.44 g, yield 91.2%). ESI-MS m/z:426.3[M+H] + .
步骤10：化合物205的合成Step 10: Synthesis of Compound 205
将上述化合物205-9(100.0mg)，溶于DMF(3mL)，加入DIEA(0.1mL)，M7(50.2mg)，HATU(133.9mg)，室温反应3h。向反应液中加入10mL H2O和10mL EA，搅 拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物反相色谱柱层析分离产物(CH3CN/H2O＝30％-55％)，得到目标化合物205(73.1mg，产率53.1％)。ESI-MS m/z:586.6[M+H]+。1H NMR(500MHz,MeOD)δ7.65(s,1H),6.85(s,1H),4.63(s,2H),4.42-4.15(m,4H),4.10–3.94(m,2H),3.67(s,3H),3.34(d,J＝10.7Hz,2H),3.31(d,J＝7.7Hz,3H),3.18-3.08(m,1H),2.51(s,3H),2.17–2.06(m,3H),2.03(s,3H),1.93(d,J＝7.5Hz,1H),1.59(s,3H),1.40-1.14(m,4H).Dissolve the above compound 205-9 (100.0 mg) in DMF (3 mL), add DIEA (0.1 mL), M7 (50.2 mg), and HATU (133.9 mg), and react at room temperature for 3 hours. Add 10mL H 2 O and 10mL EA to the reaction solution, stir Stir the layers, extract the aqueous phase three times with EA, combine the organic phases, wash, dry, and concentrate to dryness. The concentrate is separated by reverse-phase column chromatography (CH 3 CN/H 2 O = 30%-55%). , the target compound 205 (73.1 mg, yield 53.1%) was obtained. ESI-MS m/z:586.6[M+H] + . 1H NMR(500MHz,MeOD)δ7.65(s,1H),6.85(s,1H),4.63(s,2H),4.42-4.15(m,4H),4.10–3.94(m,2H),3.67( s,3H),3.34(d,J＝10.7Hz,2H),3.31(d,J＝7.7Hz,3H),3.18-3.08(m,1H),2.51(s,3H),2.17–2.06(m ,3H),2.03(s,3H),1.93(d,J＝7.5Hz,1H),1.59(s,3H),1.40-1.14(m,4H).
实施例206：7-氯-6-氟-2-((1r，4r)-4-(3-甲氧基氮杂环丁烷-1-基)环己基)-2,4-二甲基-N-((4-甲基-6-氧代-5,6-二氢氟[3,2-c]吡啶-7-基)甲基)苯并[d][1,3]二氧杂环戊-5-甲酰胺的合成
Example 206: 7-chloro-6-fluoro-2-((1r,4r)-4-(3-methoxyazetidin-1-yl)cyclohexyl)-2,4-dimethyl -N-((4-methyl-6-oxo-5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxo Synthesis of heterocyclopent-5-carboxamide
步骤1：化合物206-1的合成Step 1: Synthesis of Compound 206-1
冰浴下，将上述化合物205-3(2.0g)溶于四氟硼酸(25.0mL)中，加入水(2.5mL)，亚硝酸钠(0.8g)，反应1h后，302nm汞灯照射，室温反应24h。向反应中加入适量DCM与水淬灭，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩，浓缩物经柱层析(PE:EA＝10:1)分离纯化得到目标产物206-1(0.36g，产率17.8％)。Dissolve the above compound 205-3 (2.0g) in tetrafluoroboric acid (25.0mL) under ice bath, add water (2.5mL) and sodium nitrite (0.8g), react for 1 hour, irradiate with 302nm mercury lamp, room temperature Reaction 24h. Add an appropriate amount of DCM and water to the reaction to quench, stir and separate the layers, extract the aqueous phase with DCM three times, combine the organic phases, wash, dry, and concentrate, and the concentrate is separated by column chromatography (PE:EA=10:1) After purification, the target product 206-1 (0.36g, yield 17.8%) was obtained.
步骤2：化合物206-2的合成Step 2: Synthesis of Compound 206-2
将上述化合物206-1(0.36g)溶于DCM(5mL),加入三溴化硼(0.5mL)，室温反应1h，向反应液中加入5mL甲醇淬灭，反应液浓缩，浓缩物无需纯化，直接投下一步，得到目标产物206-2(0.29g，产率91.2％)。ESI-MS m/z:233.2[M-H]+。Dissolve the above compound 206-1 (0.36g) in DCM (5mL), add boron tribromide (0.5mL), react at room temperature for 1 hour, add 5mL of methanol to the reaction solution to quench, and the reaction solution is concentrated. The concentrate does not require purification. Directly transfer to the next step to obtain the target product 206-2 (0.29g, yield 91.2%). ESI-MS m/z:233.2[MH] + .
步骤3：化合物206-3的合成Step 3: Synthesis of Compound 206-3
将上述化合物206-2(290.0mg)溶于甲苯(10mL)，加入PPh3(65.3mg),十二羰基三钌(79.7mg)，在N2保护油浴115℃下回流反应1h后，加入4-乙炔基环己烷-1-酮(304.5mg)，继续反应12h。冷却至室温，反应液直接蒸干，经柱层析(PE:EA＝5:1)分离纯化得到目标产物206-3(312.4mg，产率70.8％)。Dissolve the above compound 206-2 (290.0 mg) in toluene (10 mL), add PPh 3 (65.3 mg), triruthenium dodecacarbonyl (79.7 mg), reflux and react in an N 2 protected oil bath at 115°C for 1 hour, then add 4-Ethynylcyclohexan-1-one (304.5mg), continue the reaction for 12h. After cooling to room temperature, the reaction solution was directly evaporated to dryness and separated and purified by column chromatography (PE:EA=5:1) to obtain the target product 206-3 (312.4 mg, yield 70.8%).
步骤4：化合物206-4的合成 Step 4: Synthesis of Compound 206-4
将上述化合物206-3(200.0mg)，溶于THF(2mL)，加入甲醇(2mL)，3-甲氧基-氮杂环丁烷(235.1mg)，室温反应1h后，降温至-70℃，加入硼氢化锂(117.5mg)，继续反应3h。升温至室温，向反应液中倒入适量水和EA，分液，水相用EA萃取，合并有机相，有机相无水硫酸钠干燥，经柱层析(DCM:MeOH＝10:1)分离纯化得到目标产物206-4(206.2mg，产率85.9％)。ESI-MS m/z:428.4[M+H]+。Dissolve the above compound 206-3 (200.0 mg) in THF (2 mL), add methanol (2 mL) and 3-methoxy-azetidine (235.1 mg), react at room temperature for 1 hour, and then cool to -70°C. , add lithium borohydride (117.5 mg), and continue the reaction for 3 hours. Warm up to room temperature, pour an appropriate amount of water and EA into the reaction solution, separate the liquids, extract the aqueous phase with EA, combine the organic phases, dry the organic phase over anhydrous sodium sulfate, and separate by column chromatography (DCM:MeOH=10:1) After purification, the target product 206-4 (206.2 mg, yield 85.9%) was obtained. ESI-MS m/z:428.4[M+H] + .
步骤5：化合物206-5的合成Step 5: Synthesis of Compound 206-5
将上述化合物206-4(100.0mg)，溶于甲醇(3mL)，加入水(0.5mL)，氢氧化锂(54.1mg)，加热至70℃反应3h。降温至室温，向反应液中加入1M盐酸溶液，调节溶液pH至2-3后，向反应液中加入10mL H2O和10mL DCM，搅拌分层，水相用DCM萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物无需纯化，直接投下一步，得到目标化合物206-5(84.2mg，产率87.1％)。ESI-MS m/z:414.3[M+H]+。The above compound 206-4 (100.0 mg) was dissolved in methanol (3 mL), water (0.5 mL) and lithium hydroxide (54.1 mg) were added, and the mixture was heated to 70°C for 3 h. Cool to room temperature, add 1M hydrochloric acid solution to the reaction solution, adjust the pH of the solution to 2-3, add 10mL H 2 O and 10mL DCM to the reaction solution, stir and separate the layers, extract the water phase three times with DCM, and combine the organic phases. The organic phase was washed, dried, and concentrated to dryness. The concentrate did not require purification and was directly put into the next step to obtain target compound 206-5 (84.2 mg, yield 87.1%). ESI-MS m/z:414.3[M+H]+.
步骤6：化合物206的合成Step 6: Synthesis of Compound 206
将上述化合物206-5(60.6mg)，溶于DMF(3mL)，加入DIEA(0.1mL)，M7(30.4mg)，HATU(81.1mg)，室温反应3h。向反应液中加入10mL H2O和10mL EA，搅拌分层，水相用EA萃取三次，合并有机相，有机相洗涤，干燥，浓缩至干，浓缩物反相色谱柱层析分离产物(CH3CN/H2O＝30％-55％)，得到目标化合物206(40.2mg，产率47.8％)。ESI-MS m/z:574.3[M+H]+。1H NMR(500MHz,Methanol-d4)δ7.59(d,J＝2.5Hz,1H),6.80(dd,J＝2.5,1.0Hz,1H),5.49(d,J＝1.0Hz,1H),4.62(d,J＝5.8Hz,2H),4.39(t,J＝8.9Hz,1H),4.28(t,J＝9.3Hz,2H),4.20(s,1H),4.05(d,J＝11.9Hz,2H),3.38–3.33(m,2H),3.13(d,J＝14.6Hz,1H),2.51(s,3H),2.24–2.01(m,7H),1.93(s,1H),1.69–1.58(m,3H),1.33(s,2H).Dissolve the above compound 206-5 (60.6 mg) in DMF (3 mL), add DIEA (0.1 mL), M7 (30.4 mg), and HATU (81.1 mg), and react at room temperature for 3 hours. Add 10mL H2O and 10mL EA to the reaction solution, stir and separate the layers, extract the aqueous phase three times with EA, combine the organic phases, wash the organic phases, dry, and concentrate to dryness, and the concentrate is separated by reverse-phase chromatography column chromatography to separate the product (CH3CN/H2O =30%-55%), and the target compound 206 (40.2 mg, yield 47.8%) was obtained. ESI-MS m/z:574.3[M+H]+. 1H NMR(500MHz,Methanol-d4)δ7.59(d,J＝2.5Hz,1H),6.80(dd,J＝2.5,1.0Hz,1H),5.49(d,J＝1.0Hz,1H),4.62 (d,J＝5.8Hz,2H),4.39(t,J＝8.9Hz,1H),4.28(t,J＝9.3Hz,2H),4.20(s,1H),4.05(d,J＝11.9Hz ,2H),3.38–3.33(m,2H),3.13(d,J＝14.6Hz,1H),2.51(s,3H),2.24–2.01(m,7H),1.93(s,1H),1.69– 1.58(m,3H),1.33(s,2H).
实施例207：化合物7-氯-4-甲基-N-((6-甲基-4-(甲硫基)-2-氧代-1,2-二氢吡啶-3-基)甲基)-2-(((1-甲基哌啶-4-基)甲酯)-3-氧代异吲哚啉-5-甲酰胺的合成
Example 207: Compound 7-chloro-4-methyl-N-((6-methyl-4-(methylthio)-2-oxo-1,2-dihydropyridin-3-yl)methyl Synthesis of )-2-(((1-methylpiperidin-4-yl)methyl ester)-3-oxoisoindoline-5-carboxamide
步骤1：化合物207-1的合成Step 1: Synthesis of Compound 207-1
向化合物3-氯-2-甲基苯甲酸甲酯(5.1g)的四氯化碳(50ml)中，加入NBS(N-溴代丁二酰亚胺)，BPO(过氧化苯甲酰)，氮气保护，90度下反应2h。反应液冷却至室温，加入50mL冰水中，补加50mLDCM，分出有机相，有机相饱和食盐水洗1次，干燥，过滤，减压浓缩。得到化合物207-1(7.2g)。ESI-MS m/z:280[M+18]+。To the compound 3-chloro-2-methylbenzoic acid methyl ester (5.1g) in carbon tetrachloride (50ml), NBS (N-bromosuccinimide) and BPO (benzoyl peroxide) were added , nitrogen protection, reaction at 90 degrees for 2 hours. The reaction solution was cooled to room temperature, 50 mL of ice water was added, and 50 mL of DCM was added. The organic phase was separated, and the organic phase was washed once with saturated brine, dried, filtered, and concentrated under reduced pressure. Compound 207-1 (7.2g) was obtained. ESI-MS m/z:280[M+18] + .
步骤2：化合物207-2的合成Step 2: Synthesis of Compound 207-2
向化合物207-1(7.3g)，化合物(1-甲基哌啶-4-基)甲胺(3.73g)，碳酸钾(11.49g)的甲苯(150.00mL)中，升温至100℃下反应2h。反应液冷却至室温，加入150mL清水中，加入150mL EA，分出有机相，有机相干燥，过滤，减压浓缩。得到4.9g,淡黄色油状物，冰箱过夜变为棕色固体。即化合物207-2，直接投下步。ESI-MS m/z:279.30[M+H]+。Add compound 207-1 (7.3g), compound (1-methylpiperidin-4-yl)methanamine (3.73g), and potassium carbonate (11.49g) in toluene (150.00mL), and react at 100°C. 2h. Cool the reaction solution to room temperature, add 150 mL of clean water, add 150 mL of EA, separate the organic phase, dry the organic phase, filter and concentrate under reduced pressure. 4.9 g of light yellow oil was obtained, which turned into a brown solid after being refrigerated overnight. That is compound 207-2, directly throw it into the next step. ESI-MS m/z:279.30[M+H] + .
步骤3：化合物207-3的合成Step 3: Synthesis of Compound 207-3
向化合物207-2(4.9g)的H2SO4/浓硫酸(30.00mL)中，降温至-10℃，滴加HNO3/硝酸(3748.51mg,65％,38.67mmol)(1.4g/ml)，然后20℃下反应1h。反应液冰水冷却，加入100mL冰水中，淬灭时内温低于10℃，变为浑浊液，析出很难过滤的固体，用冷的浓NaOH溶液(约45g)调PH至8-9，用氯仿/异丙醇＝3：1(3*100ml)萃取。有机相干燥，过滤，减压浓缩。得到化合物207-3(5.5g)，冰箱放置成固体。ESI-MS m/z:324.10[M+H]+。To compound 207-2 (4.9g) in H 2 SO 4 / concentrated sulfuric acid (30.00 mL), cool to -10°C, and add HNO3 / nitric acid (3748.51 mg, 65%, 38.67mmol) (1.4g/ml) dropwise. , and then reacted at 20°C for 1 hour. Cool the reaction solution with ice water and add 100 mL of ice water. During quenching, the internal temperature will be lower than 10°C and it will turn into a turbid liquid. A solid that is difficult to filter will precipitate. Use cold concentrated NaOH solution (about 45g) to adjust the pH to 8-9. Extract with chloroform/isopropyl alcohol = 3:1 (3*100ml). The organic phase was dried, filtered and concentrated under reduced pressure. Compound 207-3 (5.5 g) was obtained, and was placed in a refrigerator to become solid. ESI-MS m/z:324.10[M+H] + .
步骤4：化合物207-4的合成Step 4: Synthesis of Compound 207-4
向化合物207-3(5.5g)的EtOH(110.00mL)和H2O(22.00mL)中，加入铁粉(4.74g,84.94mmol)，NH4Cl(9.09g,169.87mmol),升温至80℃下反应4h。反应液硅藻土过滤，滤液直接减压浓缩得固体，加入60mL乙醇，打浆0.5h，过滤，滤液再减压浓缩。得到化合物207-4(5.90g,产率118.22％)。ESI-MS m/z:294.40[M+H]+。To compound 207-3 (5.5g) in EtOH (110.00mL) and H 2 O (22.00mL), add iron powder (4.74g, 84.94mmol) and NH 4 Cl (9.09g, 169.87mmol), and heat to 80 React at ℃ for 4 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was directly concentrated under reduced pressure to obtain a solid. 60 mL of ethanol was added, beaten for 0.5 h, filtered, and the filtrate was concentrated under reduced pressure. Compound 207-4 (5.90 g, yield 118.22%) was obtained. ESI-MS m/z:294.40[M+H] + .
步骤5：化合物207-5的合成Step 5: Synthesis of Compound 207-5
向化合物207-4(2.7g,9.19mmol)的冰醋酸(25.00mL)中，加入NIS(2.48g,11.03mmol)，然后20℃下反应0.5h。反应液加入50mL水中，4M氢氧化钠(约120ml)调PH＝8-9，氯仿/异丙醇＝3：1(萃取2次)，合并有机相，有机相干燥，过滤，浓缩。得到化合物207-5(3.8g,产率98.52％)。ESI-MS m/z:420.30[M+H]+。To compound 207-4 (2.7g, 9.19mmol) in glacial acetic acid (25.00mL), NIS (2.48g, 11.03mmol) was added, and then reacted at 20°C for 0.5h. Add 50 mL of water to the reaction solution, adjust pH to 8-9 with 4M sodium hydroxide (approximately 120 ml), chloroform/isopropyl alcohol = 3:1 (extract twice), combine the organic phases, dry the organic phases, filter and concentrate. Compound 207-5 (3.8 g, yield 98.52%) was obtained. ESI-MS m/z:420.30[M+H] + .
步骤6：化合物207-6的合成Step 6: Synthesis of Compound 207-6
向化合物207-5(2.0g),草酸(1.5g),Pd(OAc)2(212mg),PPh3(750mg),DIPEA/N,N-二异丙基乙胺(2.46g),Ac2O(1.94g)的DMF(24mL)中，氮气保护，100℃下密封反应2h。反应液加入60ml清水中，碳酸钠调PH至9-10，分离水相，水相再用4M盐酸调PH至6-7， 冻干，甲醇：DCM＝2：1(40ml)搅拌，过滤，滤液减压浓缩，prep-HPLC纯化得到化合物207-6(360.00mg,产率22.36％)。ESI-MS m/z:338.30[M+H]+。To compound 207-5 (2.0g), oxalic acid (1.5g), Pd(OAc) 2 (212mg), PPh 3 (750mg), DIPEA/N, N-diisopropylethylamine (2.46g), Ac 2 O (1.94g) in DMF (24mL), protected by nitrogen, and sealed for 2 hours at 100°C. Add 60 ml of clean water to the reaction solution, adjust the pH to 9-10 with sodium carbonate, separate the water phase, and adjust the pH to 6-7 with 4M hydrochloric acid in the water phase. Lyophilize, stir with methanol:DCM=2:1 (40 ml), filter, concentrate the filtrate under reduced pressure, and purify by prep-HPLC to obtain compound 207-6 (360.00 mg, yield 22.36%). ESI-MS m/z:338.30[M+H] + .
步骤7：化合物207-7的合成Step 7: Synthesis of Compound 207-7
向化合物207-6(300.00mg,0.89mmol)的THF(22.50mL)和MeOH(7.50mL)中，加入TMSCH2N2(0.89mL,2.00mol/L,1.78mmol)，氮气保护，20℃下反应1h。反应液减压浓缩，残留物过柱纯化(MeOH：DCM＝1％-15％)得到化合物207-7(200.00mg,产率64.01％)。ESI-MS m/z:352.30[M+H]+。To compound 207-6 (300.00mg, 0.89mmol) in THF (22.50mL) and MeOH (7.50mL), add TMSCH 2 N 2 (0.89mL, 2.00mol/L, 1.78mmol), under nitrogen protection, at 20°C Reaction 1h. The reaction solution was concentrated under reduced pressure, and the residue was purified by column (MeOH: DCM=1%-15%) to obtain compound 207-7 (200.00 mg, yield 64.01%). ESI-MS m/z:352.30[M+H] + .
步骤8：化合物207-8的合成Step 8: Synthesis of Compound 207-8
向化合物207-7(200.00mg,0.57mmol)的乙腈(20.00mL)中(混悬液)，加入亚硝酸异戊酯(99.91mg,0.85mmol)，CuBr2(152.37mg,0.68mmol)，升温至50℃下反应1h。反应液冷却至室温，过滤，滤液减压浓缩。加入3mL甲醇，打浆0.5h，过滤，滤饼为产品较干净(217mg)，滤液浓缩，残留物prep-TLC纯化(MeOH:DCM＝1:10)。合并得到化合物207-8(220.00mg,产率93.09％)。ESI-MS m/z:415.20[M+H]+。To compound 207-7 (200.00 mg, 0.57 mmol) in acetonitrile (20.00 mL) (suspension), isoamyl nitrite (99.91 mg, 0.85 mmol) and CuBr 2 (152.37 mg, 0.68 mmol) were added, and the temperature was raised. React at 50°C for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Add 3 mL of methanol, beat for 0.5 h, and filter. The filter cake is a relatively clean product (217 mg). The filtrate is concentrated, and the residue is purified by prep-TLC (MeOH:DCM=1:10). Combined, compound 207-8 (220.00 mg, yield 93.09%) was obtained. ESI-MS m/z:415.20[M+H] + .
步骤9：化合物207-9的合成Step 9: Synthesis of Compound 207-9
向化合物207-8(240.00mg,0.58mmol)，三甲基环三硼氧烷(434.81mg,50％,1.73mmol)(50％/THF)，K3PO4(367.62mg,1.73mmol)，Pd(DPEPhos)Cl2(82.69mg,0.12mmol)的CPME(24.00mL)和H2O(4.80mL)中，氮气保护，升温至80℃下反应1.0h。加入25mL EA，25mL水，分出有机相，有机相干燥，过滤，浓缩，残留物prep-TLC(MeOH:DCM＝1:10)纯化。得到化合物207-9(50.00mg,24.69％)。ESI-MS m/z:351.30[M+H]+。To compound 207-8 (240.00mg, 0.58mmol), trimethylcyclotriboroxane (434.81mg, 50%, 1.73mmol) (50%/THF), K 3 PO 4 (367.62mg, 1.73mmol), Pd(DPEPhos)Cl 2 (82.69 mg, 0.12 mmol) was placed in CPME (24.00 mL) and H 2 O (4.80 mL) under nitrogen protection, and the temperature was raised to 80°C and reacted for 1.0 h. Add 25 mL of EA and 25 mL of water, separate the organic phase, dry, filter, and concentrate, and the residue is purified by prep-TLC (MeOH:DCM=1:10). Compound 207-9 (50.00 mg, 24.69%) was obtained. ESI-MS m/z:351.30[M+H] + .
步骤10：化合物207-10的合成Step 10: Synthesis of Compound 207-10
向化合物207-9(10.00mg,0.03mmol)的MeOH(2.00mL)中，加入LiOH.H2O(11.96mg,0.28mmol)的H2O(0.40mL)溶液，20℃下反应0.5h。反应液冰水冷却，2M盐酸调PH至6-7，减压浓缩。得到化合物207-10(8.00mg,83.34％)，直接投下步缩合。ESI-MS m/z:337.20[M+H]+。To compound 207-9 (10.00 mg, 0.03 mmol) in MeOH (2.00 mL), a solution of LiOH.H 2 O (11.96 mg, 0.28 mmol) in H 2 O (0.40 mL) was added, and the reaction was carried out at 20°C for 0.5 h. The reaction solution was cooled with ice water, adjusted to pH 6-7 with 2M hydrochloric acid, and concentrated under reduced pressure. Compound 207-10 (8.00 mg, 83.34%) was obtained, which was directly put into the next step of condensation. ESI-MS m/z:337.20[M+H] + .
步骤11：化合物207的合成Step 11: Synthesis of Compound 207
向化合物207-10(9.00mg,0.03mmol)，3-(氨基甲基)-6-甲基-4-(甲硫基)吡啶-2(1H)-酮(5.90mg,0.03mmol)，HATU(12.17mg,0.03mmol)的DMF(1.50mL)中，加入DIPEA(0.02mL,0.09mmol)，20℃下反应2h。反应液加水1.5mL，加入EA 5mL萃取，产物留在水相，水相pre-HPLC纯化，得到化合物207(0.60mg,4.60％)。ESI-MS m/z:503.10[M+H]+。1H NMR(500MHz,MEOH-d4)δ7.51(s,1H),6.27(s,1H),4.44(s,2H),3.51- 3.50(m,2H),2.96-2.94(m,2H),2.69(s,3H),2.54(s,3H),2.29(s,3H),2.26(s,3H),2.20-2.17(m,1H),2.03-2.02(m,4H),1.74-1.71(m,2H),1.60-1.59(m,2H).To compound 207-10 (9.00 mg, 0.03 mmol), 3-(aminomethyl)-6-methyl-4-(methylthio)pyridin-2(1H)-one (5.90 mg, 0.03 mmol), HATU (12.17 mg, 0.03 mmol) in DMF (1.50 mL), add DIPEA (0.02 mL, 0.09 mmol), and react at 20°C for 2 hours. 1.5 mL of water was added to the reaction solution, and 5 mL of EA was added for extraction. The product remained in the aqueous phase, and the aqueous phase was purified by pre-HPLC to obtain compound 207 (0.60 mg, 4.60%). ESI-MS m/z:503.10[M+H] + . 1 H NMR (500MHz, MEOH-d 4 ) δ7.51(s,1H),6.27(s,1H),4.44(s,2H),3.51- 3.50(m,2H),2.96-2.94(m,2H),2.69(s,3H),2.54(s,3H),2.29(s,3H),2.26(s,3H),2.20-2.17(m, 1H),2.03-2.02(m,4H),1.74-1.71(m,2H),1.60-1.59(m,2H).
实施例208:(2R)-6,7-二氯-2-(4-(二甲基氨基)环己基)-2,4-二甲基-N-((4-甲基-6-氧代-5,6-二氢氟[3,2-c]吡啶-7-基)甲基)苯并[d][1,3]二氧杂环戊-5-甲酰胺的合成
Example 208: (2R)-6,7-dichloro-2-(4-(dimethylamino)cyclohexyl)-2,4-dimethyl-N-((4-methyl-6-oxo) Synthesis of 5,6-dihydrofluoro[3,2-c]pyridin-7-yl)methyl)benzo[d][1,3]dioxola-5-carboxamide
步骤1：化合物208-1的合成Step 1: Synthesis of Compound 208-1
向化合物3,4-二羟基-2-甲基苯甲酸甲酯(2000.00mg,10.98mmol)的HOAc(20.00mL)中，室温下，加入SO2Cl2(4.5g,33.02mmol)，20℃反应1h。反应液分批加入冰水中，然后用饱和碳酸钠溶液调PH至7-8，析出棕色沉淀，加入30mL DCM,分出有机相，水相DCM萃取1次，合并有机相，有机相干燥，过滤，浓缩。得到化合物208-1(2400.00mg,87.07％)，直接投下步。ESI-MS m/z:251.20[M+H]+。To compound 3,4-dihydroxy-2-methylbenzoic acid methyl ester (2000.00 mg, 10.98 mmol) in HOAc (20.00 mL), add SO 2 Cl 2 (4.5 g, 33.02 mmol) at room temperature, 20°C Reaction 1h. Add the reaction solution to ice water in batches, then adjust the pH to 7-8 with saturated sodium carbonate solution to precipitate brown precipitate, add 30 mL DCM, separate the organic phase, extract the aqueous phase with DCM once, combine the organic phases, dry the organic phase and filter ,concentrate. Compound 208-1 (2400.00 mg, 87.07%) was obtained and was directly added to the next step. ESI-MS m/z:251.20[M+H] + .
步骤2：化合物208-2的合成Step 2: Synthesis of Compound 208-2
向化合物208-1(200.00mg,0.80mmol),(1R，4R)-4-乙炔基环己基)氨基甲酸叔丁酯(266.83mg,1.19mmol),Ru3(CO)12(25.45mg,0.04mmol),PPh3(20.91mg,0.08mmol)中，加入甲苯(4.00mL)，115℃下反应16h。反应液加入15mL水中，EA萃取2次，有机相干燥，过滤，减压浓缩，残留物过柱纯化(EA:PE＝1％to 25％).得到化合物208-2(218.00mg,57.69％)。ESI-MS m/z:474.30[M+H]+。To compound 208-1 (200.00mg, 0.80mmol), (1R, 4R)-4-ethynylcyclohexyl)carbamic acid tert-butyl ester (266.83mg, 1.19mmol), Ru 3 (CO) 12 (25.45mg, 0.04 mmol), PPh 3 (20.91 mg, 0.08 mmol), add toluene (4.00 mL), and react at 115°C for 16 hours. The reaction solution was added to 15 mL of water, and extracted with EA twice. The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified through column (EA: PE=1% to 25%). Compound 208-2 (218.00 mg, 57.69%) was obtained. . ESI-MS m/z:474.30[M+H] + .
步骤3：化合物208-3的合成Step 3: Synthesis of Compound 208-3
向化合物208-2(200.00mg,0.42mmol)的DCM(6.00mL)中，加入TFA(1.57mL,21.08mmol)，20℃下反应1h。反应液加入饱和碳酸氢钠溶液中，补加DCM 10mL，分出有机相，有机相干燥，浓缩。得到化合物208-3(150.00mg,95.06％)。ESI-MS m/z:374.10[M+H]+。To compound 208-2 (200.00 mg, 0.42 mmol) in DCM (6.00 mL), TFA (1.57 mL, 21.08 mmol) was added, and the reaction was carried out at 20°C for 1 h. The reaction solution was added to saturated sodium bicarbonate solution, and 10 mL of DCM was added. The organic phase was separated, dried and concentrated. Compound 208-3 (150.00 mg, 95.06%) was obtained. ESI-MS m/z:374.10[M+H] + .
步骤4：化合物208-4的合成Step 4: Synthesis of Compound 208-4
向化合物208-3(158.00mg,0.42mmol)的MeOH(10.00mL)中，加入甲醛水溶液37％(342.32mg,37％,4.22mmol)，20℃下反应5分钟，加NaBH3CN(79.59mg,1.27mmol)， 然后20℃下反应1h。反应液加入15mL水中，加入15mL DCM，分出有机相，水相用少许DCM萃取1次，水相无产品弃，合并有机相，干燥，过滤，浓缩，残留物过柱纯化(MEOH:DCM＝1％to 15％，7M氨甲醇)得到化合物208-4(86.00mg,50.63％)。ESI-MS m/z:402.30[M+H]+。To compound 208-3 (158.00 mg, 0.42 mmol) in MeOH (10.00 mL), add formaldehyde aqueous solution 37% (342.32 mg, 37%, 4.22 mmol), react at 20°C for 5 minutes, add NaBH 3 CN (79.59 mg ,1.27mmol), Then react at 20°C for 1 hour. The reaction solution was added to 15 mL of water, and 15 mL of DCM was added to separate the organic phase. The aqueous phase was extracted once with a little DCM. There was no product in the aqueous phase and discarded. The organic phases were combined, dried, filtered, concentrated, and the residue was purified through column (MEOH:DCM= 1% to 15%, 7M ammonia methanol) to give compound 208-4 (86.00 mg, 50.63%). ESI-MS m/z:402.30[M+H] + .
步骤5：化合物208-5的合成Step 5: Synthesis of Compound 208-5
向化合物208-4(86.00mg,0.21mmol)的MeOH(4.00mL)中，加入含有LiOH.H2O(89.71mg,2.14mmol)的H2O(0.80mL)，反应液加入10mL水中，4M盐酸调PH至6-7，5mlEA萃取，LCMS 85％为未水解的原料，自留，产品在水相，因此，水相用氯仿/异丙醇萃取3次，合并有机相，干燥，过滤，减压浓缩得到化合物208-5(60.00mg,72.28％)。ESI-MS m/z:388.20[M+H]+。To compound 208-4 (86.00 mg, 0.21 mmol) in MeOH (4.00 mL), H 2 O (0.80 mL) containing LiOH.H 2 O (89.71 mg, 2.14 mmol) was added, and the reaction solution was added to 10 mL of water, 4M Adjust pH to 6-7 with hydrochloric acid, extract with 5ml EA, LCMS 85% is unhydrolyzed raw material, retained, and the product is in the aqueous phase. Therefore, the aqueous phase is extracted 3 times with chloroform/isopropyl alcohol, combine the organic phases, dry and filter. Concentrate under reduced pressure to obtain compound 208-5 (60.00 mg, 72.28%). ESI-MS m/z:388.20[M+H] + .
步骤6：化合物208的合成Step 6: Synthesis of Compound 208
向化合物208-5(32.00mg,0.08mmol)，中间体M7(22.02mg,0.12mmol)，HATU(37.60mg,0.10mmol)的DMF(1.00mL)中，加入DIPEA(0.06mL,0.33mmol)，20℃下反应0.5h。反应液加入15mL水中，10mlEA萃取1次，水相氯仿/异丙醇萃取6次(6*10mL)，干燥，过滤，减压浓缩，残留物HPLC纯化得到化合物208(10.60mg,98.26％,23.05％)，甲酸盐。ESI-MS m/z:548.20[M+H]+。1H NMR(500MHz,MEOH-d4)δ7.61(s,1H),6.81(s,1H),4.64(s,2H),3.18-3.13(m,1H),2.72(s,3H),2.67(s,6H),2.53(s,3H),2.21(s,3H),1.69-1.65(m,8H),1.46-1.39(m,1H).To compound 208-5 (32.00mg, 0.08mmol), intermediate M7 (22.02mg, 0.12mmol), HATU (37.60mg, 0.10mmol) in DMF (1.00mL), add DIPEA (0.06mL, 0.33mmol), React for 0.5h at 20°C. The reaction solution was added to 15 mL of water, extracted once with 10 ml of EA, and extracted with aqueous chloroform/isopropyl alcohol for 6 times (6*10 mL). Dry, filter, and concentrate under reduced pressure. The residue was purified by HPLC to obtain compound 208 (10.60 mg, 98.26%, 23.05 %), formate. ESI-MS m/z:548.20[M+H] + . 1 H NMR (500MHz, MEOH-d 4 ) δ7.61 (s, 1H), 6.81 (s, 1H), 4.64 (s, 2H), 3.18-3.13 (m, 1H), 2.72 (s, 3H), 2.67(s,6H),2.53(s,3H),2.21(s,3H),1.69-1.65(m,8H),1.46-1.39(m,1H).
下述的实施例采用上述方法合成，或使用相应中间体的类似方法合成。





The following examples were synthesized using the above method, or similar methods using corresponding intermediates.





药理实验Pharmacological experiments
药理实验1:PRC2-EZH2体外酶学活性检测 Pharmacological experiment 1: PRC2-EZH2 in vitro enzymatic activity detection
实验使用甲基转移酶试剂盒MTase-Glo Kit(Promage，V7602)检测PRC2-EZH2的甲基转移酶活性。反应缓冲液为20mM Tris-HCl[pH 8.0]，50mM NaCl，1mM EDTA，3mM MgCl2，0.1mg/ml BSA，1mM DTT。将2uL PRC2-EZH2蛋白溶液和4uL梯度稀释的待测化合物溶液加入384孔反应板中，25℃孵育15min，再加入2uL组蛋白H3和SAM混合溶液，使8uL反应体系各组分终浓度分别为50nM PRC2-EZH2蛋白，5nM组蛋白H3，1uM SAM，待测化合物终浓度为1000，333.33，111.11，37.04，12.35，4.12，1.37，0.46，0.15，0.05，0nM，DMSO终浓度为1％，25℃孵育60min，向反应板各孔中加入2uL MTase-Glo Reagent溶液，25℃孵育30min，最后再加入MTase-Glo Detection试剂，25℃避光孵育30min，在Envision(Perkin Elmer)上读取Luminescence发光值(RLU值)，收集原始数据。In the experiment, the methyltransferase kit MTase-Glo Kit (Promage, V7602) was used to detect the methyltransferase activity of PRC2-EZH2. The reaction buffer is 20mM Tris-HCl [pH 8.0], 50mM NaCl, 1mM EDTA, 3mM MgCl 2 , 0.1mg/ml BSA, 1mM DTT. Add 2uL PRC2-EZH2 protein solution and 4uL gradient diluted test compound solution into the 384-well reaction plate, incubate at 25°C for 15 minutes, then add 2uL histone H3 and SAM mixed solution, so that the final concentration of each component of the 8uL reaction system is 50nM PRC2-EZH2 protein, 5nM histone H3, 1uM SAM, the final concentration of the compound to be tested is 1000, 333.33, 111.11, 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0.05, 0nM, the final concentration of DMSO is 1%, 25 Incubate at ℃ for 60 minutes, add 2uL MTase-Glo Reagent solution to each well of the reaction plate, incubate at 25℃ for 30 minutes, finally add MTase-Glo Detection reagent, incubate at 25℃ in the dark for 30 minutes, and read Luminescence on Envision (Perkin Elmer) value (RLU value), collect raw data.
将RLU值转化为Inhibition％值：Convert RLU value to Inhibition% value:
各孔的抑制百分比(％inh)＝100*(最大值-所测值)/(最大值-Blank)Inhibition percentage of each well (%inh)=100*(maximum value-measured value)/(maximum value-Blank)
(“最大值”来自1％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物反应孔)。(The "maximum value" comes from the 1% DMSO control well, the "Blank" comes from the blank control well, and the "measured value" comes from the compound reaction well).
利用GraphPad Prism软件进行曲线拟合并获取IC50值。Use GraphPad Prism software to perform curve fitting and obtain IC 50 values.
表1

Table 1

药理实验2：Pfeiffer细胞增殖实验Pharmacological experiment 2: Pfeiffer cell proliferation assay
将Pfeiffer EZH2(A677G)细胞按5000个/孔的细胞密度铺于低吸附96孔板中，置于细胞培养箱待细胞稳定1-3h后，将待测化合物按照终浓度为1000，333.33，111.11，37.04，12.35，4.12，1.37，0.46，0.15，0nM(DMSO终浓度均为0.1％)加入96孔板中，细胞板于37℃，5％CO2细胞培养箱中培养7days后向各孔加入50μL Cell-titer GLO工作液，震荡混匀后室温孵育10min，在Envision(Perkin Elmer)上读取Luminescence发光值(RLU值)，将RLU值计算转换为抑制百分数。并根据以下公式，计算细胞增殖抑制百分数：Pfeiffer EZH2 (A677G) cells were spread in a low-adsorption 96-well plate at a cell density of 5,000 cells/well, placed in a cell culture incubator, and after the cells were stabilized for 1-3 hours, the compound to be tested was added at a final concentration of 1,000, 333.33, and 111.11 , 37.04, 12.35, 4.12, 1.37, 0.46, 0.15, 0nM (the final concentration of DMSO is 0.1%) was added to the 96-well plate. The cell plate was cultured in a 37°C, 5% CO2 cell incubator for 7 days and then 50 μL was added to each well. Cell-titer GLO working solution, shake and mix well, incubate at room temperature for 10 minutes, read the Luminescence value (RLU value) on Envision (Perkin Elmer), and convert the RLU value into a percentage of inhibition. And calculate the percentage of cell proliferation inhibition according to the following formula:
抑制百分数＝(最大值-所测值)/(最大值-Blank)×100Inhibition percentage = (maximum value - measured value) / (maximum value - Blank) × 100
(“最大值”来自0.1％DMSO对照孔，“Blank”来自空白对照孔，“所测值”来自化合物反应孔)。(The "maximum value" comes from the 0.1% DMSO control well, the "Blank" comes from the blank control well, and the "measured value" comes from the compound reaction well).
利用GraphPad Prism软件进行曲线拟合并获取GI50值见表1。Use GraphPad Prism software to perform curve fitting and obtain the GI 50 value shown in Table 1.
药理实验3：药代动力学测试Pharmacological Experiment 3: Pharmacokinetic Test
化合物D1:购买于MCE(MedChemExpress)，商品名为Valemetostat，其结构如下：
Compound D1: Purchased from MCE (MedChemExpress), the trade name is Valemetostat, its structure is as follows:
化合物D2：CPI-0209，其结构如下：
Compound D2: CPI-0209, its structure is as follows:
Balb/c小鼠6只，分为两组，每组3只，均为雌性，单次灌胃10mg/kg给药化合物；分别在指定的时间点通过眼底静脉丛采血，分离血浆，放入-80℃冰箱保存。6 Balb/c mice were divided into two groups, with 3 mice in each group, all of which were female. Compounds were administered via a single intragastric administration of 10 mg/kg; blood was collected through the fundus venous plexus at designated time points, and the plasma was separated and placed into Store in -80℃ refrigerator.
上述血浆样品，乙腈沉淀蛋白，取上清用水稀释1倍，同时配制相同基质的标准曲线、质控样品，进样量10μL至LC-MS/MS检测，试验数据如表2所示：For the above plasma sample, the protein was precipitated with acetonitrile, and the supernatant was diluted 1-fold with water. At the same time, a standard curve and quality control sample of the same matrix were prepared. A sample volume of 10 μL was injected into LC-MS/MS for detection. The test data are shown in Table 2:
表2化合物的药代动力学测试结果

Table 2 Pharmacokinetic test results of compounds

Balb/c小鼠9只，分为三组，每组3只，均为雌性，单次灌胃10mg/kg给药化合物D1；分别在指定的时间点通过眼底静脉丛采血，分离血浆，放入-80℃冰箱保存。Nine Balb/c mice were divided into three groups, with three mice in each group, all of which were female. Compound D1 was administered at a dose of 10 mg/kg by intragastric administration at a single time; blood was collected from the fundus venous plexus at designated time points, and the plasma was separated and released. Store in -80℃ refrigerator.
上述血浆样品，乙腈沉淀蛋白，取上清用水稀释1倍，同时配制相同基质的标准曲线、质控样品，进样量10μL至LC-MS/MS检测，试验数据如表3所示：For the above plasma sample, the protein was precipitated with acetonitrile, and the supernatant was diluted 1-fold with water. At the same time, a standard curve and quality control sample of the same matrix were prepared. A sample volume of 10 μL was injected into LC-MS/MS for detection. The test data are shown in Table 3:
表3化合物D1的药代动力学测试结果
Table 3 Pharmacokinetic test results of compound D1
由以上结果可知，本发明化合物在Balb/c小鼠上口服吸收非常优秀，无论是最大血药浓度(Cmax)抑或是暴露量(AUC)均远高于阳性化合物D1或D2，有望取得更好的药效结果。It can be seen from the above results that the oral absorption of the compound of the present invention is very good in Balb/c mice. Both the maximum blood concentration (Cmax) and the exposure (AUC) are much higher than the positive compounds D1 or D2, and it is expected to achieve better results. efficacy results.
虽然本发明已通过其实施方式进行了全面的描述，但是值得注意的是，各种变化和修改对于本领域技术人员都是显而易见的。这样的变化和修改都应该包括在本发明所附权利要求的范围内。 While the invention has been fully described in terms of embodiments thereof, it is to be noted that various changes and modifications will be apparent to those skilled in the art. Such changes and modifications should be included within the scope of the appended claims of the present invention.

Claims (56)

  1. 一种通式(I)所示的化合物、其立体异构体、互变异构体、氘代物或药用盐：
    A compound represented by general formula (I), its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt:
    其中，in,
    X1选自-CO-、C(R7)2、NR7、O或S；X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 , O or S;
    X2选自-CO-、C(R8)2、NR8、O或S；X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 , O or S;
    X3选自C或N；X 3 is selected from C or N;
    R2选自不存在、H、羟基、氨基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素；R 2 is selected from absence, H, hydroxyl, amino, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl , -NR a R b , or halogen;
    R12选自H、C1-8烷基或C1-8卤代烷基；R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl;
    R3、R4、R5各自独立选自H、卤素、C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc；其中，所述C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 ring Alkyl group, 3-12 membered heterocyclyl group, C 6-12 aryl group, 5-12 membered heteroaryl group, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 R c ; wherein, the C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2- 8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optionally further substituted by at least one R a ;
    或者，R4也可以与R12共同形成一个5-12元的杂环基；其中，所述5-12元的杂环基任选地进一步被至少一个Ra取代；Alternatively, R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
    R7、R8各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
    或者，R7和R8与其所连接的碳原子一起形成C3-12环烷基、3-12元杂环基；其中，所述C3-12环烷基、3-12元杂环基基任选地进一步被一个或多个独立的Ra所取代；Alternatively, R 7 and R 8 together with the carbon atom to which they are connected form a C 3-12 cycloalkyl group or a 3-12 membered heterocyclyl group; wherein, the C 3-12 cycloalkyl group or 3-12 membered heterocyclyl group The group is optionally further substituted by one or more independent R a ;
    Ra各自独立地选自H、卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc或-NRbSO2Rc，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳 基、6-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc取代基所取代；R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further selected from Halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aromatic Base, 6-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d Or substituted by -NR b SO 2 R c substituent;
    Rb、Rc或Rd各自独立地选自羟基、卤素、-CN、-NO2、氧代基、C1-8烷氧基、-N-C1-8烷基、-S-C1-8烷基、H、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；R b , R c or R d are each independently selected from hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl Base, H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
    其中，R1、R6的定义选自下组中的一种：Among them, the definition of R 1 and R 6 is selected from one of the following groups:
    1)当R1中C3-12环烷基为时：1) When C 3-12 cycloalkyl in R 1 is hour:
    其中，in,
    R1’、R2’各自独立地选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb或-NRaSO2Rb，所述C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b , the C 1-8 alkyl group, C 1-8 alkoxy group, C 1-8 haloalkyl group Oxygen group, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclyl group, C 6 -12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
    或者，R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；Alternatively, R 1 ' and R 2 ' and the carbon atoms they are connected together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5-12 membered heteroaryl group, wherein C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
    R3’各自独立地选自H、羟基、卤素、-CN、-NO2、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基、3-12元杂环基或-NRaRb，所述C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基或3-12元杂环基任选地进一步被一个或多个独立的Ra所取代；R 3 ' is each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl or -NR a R b , the C 1-8 alkoxy group, C 1-8 alkyl group, C 1-8 haloalkoxy group, C 1 -8 haloalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally further substituted by one or more independent R a ;
    R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代；R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl The group is optionally further substituted by one or more independent R a ;
    2)当R6为时：2) When R 6 is hour:
    其中， in,
    选自单键或双键； Selected from single or double bonds;
    X4、X5、X6选自C(R9)m、N、NR9、O或S；X 4 , X 5 , and X 6 are selected from C(R 9 ) m , N, NR 9 , O or S;
    R6’选自H、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 6 ' is selected from H, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
    R9选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 9 is selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
    R1选自C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代。R 1 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5- 12-membered heteroaryl, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl group or 5-12 membered heteroaryl group is optionally further substituted by at least one R a .
  2. 根据权利要求1所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，其选自通式(II)所示的化合物
    The compound according to claim 1, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that it is selected from the compounds represented by the general formula (II)
    其中，in,
    R1选自C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 is selected from C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5- 12-membered heteroaryl, the C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl The base or 5-12 membered heteroaryl group is optionally further substituted by at least one R a ;
    R2选自不存在、H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基或卤素；R 2 is selected from absence, H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl or halogen ;
    R3、R4、R5各自独立选自H、卤素、C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc；其中，所述C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, halogen, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 ring Alkyl group, 3-12 membered heterocyclic group, C 6-12 aryl group, 5-12 membered heteroaryl group, oxo group, -CN, -NO 2 , -OR b , -SR b , -SOR b , - SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , - NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 R c ; wherein, the C 1-8 alkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group , C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optionally further substituted by at least one R a ;
    R4也可以与R12共同形成一个5-12元的杂环基；其中，所述5-12元的杂环基任选地进一步被至少一个Ra取代； R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
    X1选自-CO-、C(R7)2、N或O；X 1 is selected from -CO-, C(R 7 ) 2 , N or O;
    X2选自-CO-、C(R8)2、N或O；X 2 is selected from -CO-, C(R 8 ) 2 , N or O;
    X3选自C或N；X 3 is selected from C or N;
    X4、X5、X6选自C(R9)m、N、NR9、O或S；X 4 , X 5 , and X 6 are selected from C(R 9 ) m , N, NR 9 , O or S;
    R6’选自H、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 6 ' is selected from H, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkoxy;
    R7、R8、R9各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 , R 8 , and R 9 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1 -8 haloalkoxy;
    R12选自H、C1-8烷基或C1-8卤代烷基；R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl;
    m各自独立选自1或2；m is each independently selected from 1 or 2;
    n选自0、1、2、3或4；n is selected from 0, 1, 2, 3 or 4;
    选自单键或双键； Selected from single or double bonds;
    Ra各自独立地选自H、卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc或-NRbSO2Rc，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、6-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc取代基所取代；R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further selected from Halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 6-12 membered Heteroaryl, oxo, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 Substituted by R c substituent;
    Rb、Rc或Rd各自独立地选自H、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；R b , R c or R d are each independently selected from H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkene base, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
  3. 根据权利要求2所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R12选自H。The compound according to claim 2, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 12 is selected from H.
  4. 根据权利要求2-3任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，其选自通式(IIA)所示的化合物：

    The compound according to any one of claims 2-3, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that it is selected from the compounds represented by the general formula (IIA):

    其中，R2选自H、羟基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基或卤素；Wherein, R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl or halogen;
    R1、R3、R4、R5、R6’、X4、X5、X6、n的定义同权利要求2。The definitions of R 1 , R 3 , R 4 , R 5 , R 6 ', X 4 , X 5 , X 6 and n are the same as in claim 2.
  5. 根据权利要求2-3任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，其选自通式(IIB)所示的化合物：
    The compound according to any one of claims 2-3, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that it is selected from the compounds represented by the general formula (IIB):
    其中，R1、R3、R4、R5、R6’、X4、X5、X6、n的定义同权利要求2。Among them, the definitions of R 1 , R 3 , R 4 , R 5 , R 6 ', X 4 , X 5 , X 6 and n are the same as in claim 2.
  6. 根据权利要求2-5任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代，所述Ra选自H、卤素、C1-8烷基、C3-12环烷基、3-12元杂环基、-ORb或-NRbRc。The compound according to any one of claims 2 to 5, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 1 is selected from C 3-12 cycloalkyl , 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, the C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5 -12- membered heteroaryl is optionally further substituted by at least one R a selected from H, halogen, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, -OR b or -NR b R c .
  7. 根据权利要求2-6任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自 The compound according to any one of claims 2 to 6, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R1 is selected from
  8. 根据权利要求2-7任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1选自 The compound according to any one of claims 2 to 7, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R1 is selected from
  9. 根据权利要求2-4、6-8任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R2选自H或C1-8烷基。 The compound according to any one of claims 2-4 and 6-8, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R2 is selected from H or C 1-8 alkyl.
  10. 根据权利要求2-9任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R4选自H、卤素或C1-8烷基。The compound according to any one of claims 2 to 9, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 4 is selected from H, halogen or C 1- 8 alkyl.
  11. 根据权利要求2-10任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R6’选自H、卤素或C1-8烷基，优选甲基。The compound according to any one of claims 2 to 10, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 6 ' is selected from H, halogen or C 1 -8 alkyl, preferably methyl.
  12. 根据权利要求2-11任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述X4选自O、C(R9)m、NR9或S。The compound according to any one of claims 2-11, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the X 4 is selected from O, C (R 9 ) m , NR 9 or S.
  13. 根据权利要求2-12任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述X5选自C(R9)m、O、S或N。The compound according to any one of claims 2-12, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the X 5 is selected from C(R 9 ) m , O, S or N.
  14. 根据权利要求2-13任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述X6选自N或C(R9)m。The compound according to any one of claims 2 to 13, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the X 6 is selected from N or C (R 9 ) m .
  15. 根据权利要求2-14任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R9选自H或卤素。The compound according to any one of claims 2-14, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 9 is selected from H or halogen.
  16. 根据权利要求2-15任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述n选自0或1，优选0。The compound according to any one of claims 2 to 15, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said n is selected from 0 or 1, preferably 0.
  17. 根据权利要求2-16任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述选自 The compound according to any one of claims 2 to 16, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, Selected from
  18. 根据权利要求1所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，其选自通式(III)所示的化合物：
    The compound according to claim 1, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that it is selected from the compounds represented by the general formula (III):
    其中，in,
    R1’、R2’各自独立地选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳 基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb或-NRaSO2Rb；其中，所述C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl Base, 5-12 membered heteroaryl group, oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b ; wherein, the C 1-8 alkyl group, C 1 -8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl , 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
    或者，R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；Alternatively, R 1 ' and R 2 ' and the carbon atoms they are jointly connected to form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5-12 membered heteroaryl group; wherein, The C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
    R3’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、-NRaRb、C1-8卤代烷氧基、或C1-8卤代烷基；R 3 ' is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, -NR a R b , C 1-8 haloalkoxy, or C 1-8 haloalkyl;
    R2选自H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素；R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
    R3、R4、R5各自独立选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C2- 8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc或-NRaSO2Rb，所述C1-8烷基、C1- 8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2 -8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b , the C 1-8 alkyl, C 1-8 hydroxyalkyl Optionally further _ _ Replaced by at least one R a ;
    R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra所取代；R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, said 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl The group is optionally further substituted by at least one R a ;
    X1选自-CO-、C(R7)2、NR7或O；X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 or O;
    X2选自-CO-、C(R8)2、NR8或O；X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 or O;
    X3选自C或N；X 3 is selected from C or N;
    R7、R8各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
    R12选自H；R 12 is selected from H;
    Ra、Rb或Rc各自独立地选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、-ORa、-SRa、-SO2Ra、-CORa、CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc、-NRaSO2Rb、-(CH2)0-3Si(C1-4烷基)3、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、 -ORa、-SRa、-CORa、-SO2Ra、CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc、-NRaSO2Rb、-(CH2)0-3Si(C1-4烷基)3、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个选自H、卤素、-OH、-CN、-NO2、C1-8烷基、氧代基、-(CH2)0-3CN、C1-8羟基烷基、C1-8卤代烷氧基或C1-8卤代烷基的取代基所取代；R a , R b or R c are each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, -OR a , -SR a , -SO 2 R a , -COR a , CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c , -NR a SO 2 R b , - (CH 2 ) 0-3 Si(C 1-4 alkyl) 3 , C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl, so The following C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, -OR a , -SR a , -COR a , -SO 2 R a , CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , - NR a SONR b R c , -NR a SO 2 NR b R c , -NR a SO 2 R b , -(CH 2 ) 0-3 Si(C 1-4 alkyl) 3 , C 3-12 cycloalkyl base, 3-12-membered heterocyclyl, C 6-12 aryl or 5-12-membered heteroaryl optionally further selected from at least one member selected from H, halogen, -OH, -CN, -NO 2 , C 1- Substituted with substituents of 8 alkyl, oxo, -(CH 2 ) 0-3 CN, C 1-8 hydroxyalkyl, C 1-8 haloalkoxy or C 1-8 haloalkyl;
    且通式(III)的化合物不为 And the compound of general formula (III) is not
  19. 根据权利要求1所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，其选自通式(III)所示的化合物：
    The compound according to claim 1, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that it is selected from the compounds represented by the general formula (III):
    其中，in,
    R1’、R2’各自独立地选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb或-NRaSO2Rb，所述C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 1 ', R 2 ' are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1 -8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl , oxo group, -CN, -NO 2 , -OR a , -SR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b or -NR a SO 2 R b , the C 1-8 alkyl group, C 1-8 alkoxy group, C 1-8 haloalkyl group Oxygen group, C 1-8 haloalkyl group, C 1-8 hydroxyalkyl group, C 2-8 alkenyl group, C 2-8 alkynyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclyl group, C 6 -12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
    或者，R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；Alternatively, R 1 ' and R 2 ' and the carbon atoms they are connected together form a C 3-12 cycloalkyl group, a 3-12 membered heterocyclyl group, a C 6-12 aryl group or a 5-12 membered heteroaryl group, wherein C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one R a ;
    R3’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、-NRaRb、C1-8卤代烷氧基、或C1-8卤代烷基； R 3 ' is selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, -NR a R b , C 1-8 haloalkoxy, or C 1-8 haloalkyl;
    R3、R4、R5各自独立选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C2- 8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORa、-SRa、-SORa、-SO2Ra、-SO2NRaRb、-CORa、-CO2Ra、-CONRaRb、-NRaRb、-NRaCORb、-NRaCO2Rb、-NRaSONRbRc、-NRaSO2NRbRc或-NRaSO2Rb；其中，所述C1-8烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra取代；R 3 , R 4 , and R 5 are each independently selected from H, hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2 -8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR a , -SR a , -SOR a , -SO 2 R a , -SO 2 NR a R b , -COR a , -CO 2 R a , -CONR a R b , -NR a R b , -NR a COR b , -NR a CO 2 R b , -NR a SONR b R c , -NR a SO 2 NR b R c or -NR a SO 2 R b ; wherein, the C 1-8 alkyl group, C 1-8 Hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optional Ground is further replaced by at least one R a ;
    或者，R4也可以与R12共同形成一个5-12元的杂环基；其中，所述5-12元的杂环基任选地进一步被至少一个Ra取代；Alternatively, R 4 can also form a 5-12-membered heterocyclic group together with R 12 ; wherein, the 5-12-membered heterocyclic group is optionally further substituted by at least one R a ;
    R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个Ra所取代；R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered The heteroaryl group is optionally further substituted by at least one R ;
    X1选自-CO-、C(R7)2、NR7或O；X 1 is selected from -CO-, C(R 7 ) 2 , NR 7 or O;
    X2选自-CO-、C(R8)2、NR8或O；X 2 is selected from -CO-, C(R 8 ) 2 , NR 8 or O;
    X3选自C或N；X 3 is selected from C or N;
    R2选自H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素；R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
    R7、R8各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 and R 8 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1-8 haloalkyl Oxygen;
    R12选自H、C1-8烷基或C1-8卤代烷基；R 12 is selected from H, C 1-8 alkyl or C 1-8 haloalkyl;
    Ra各自独立地选自H、卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc或-NRbSO2Rc，所述C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、6-12元杂芳基、氧代基、-CN、-NO2、-ORb、-SRb、-SORb、-SO2Rb、-SO2NRbRc、-CORb、-CO2Rb、-CONRbRc、-NRbRc、-NRbCORc、-NRbCO2Rc、-NRbSONRcRd、-NRbSO2NRcRd或-NRbSO2Rc取代基所取代；R a is each independently selected from H, halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6 -12 aryl, 5-12 membered heteroaryl, oxo group, -CN, -NO 2 , -OR b , -SR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c or -NR b SO 2 R c , the C 1-8 alkyl group, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl is optionally further selected from Halogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 6-12 membered Heteroaryl, oxo, -CN, -NO 2 , -OR b , -SR b , -SOR b , -SO 2 R b , -SO 2 NR b R c , -COR b , -CO 2 R b , -CONR b R c , -NR b R c , -NR b COR c , -NR b CO 2 R c , -NR b SONR c R d , -NR b SO 2 NR c R d or -NR b SO 2 Substituted by R c substituent;
    Rb、Rc或Rd各自独立地选自羟基、卤素、-CN、-NO2、氧代基、C1-8烷氧基、-N-C1-8烷基、-S-C1-8烷基、H、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；R b , R c or R d are each independently selected from hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl Base, H, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 2-8 alkenyl, C 2-8 alkynyl, C 3 -12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl;
  20. 根据权利要求18或19所述的化合物、其立体异构体、互变异构体、氘代物或药用 盐，其特征在于，所述式(III)化合物选自下式化合物：
    The compound according to claim 18 or 19, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable Salt, characterized in that the compound of formula (III) is selected from the group consisting of compounds of the following formula:
    R1’-R3’、R2-R8的定义同权利要求18或19。The definitions of R 1 ' to R 3 ' and R 2 to R 8 are the same as in claim 18 or 19.
  21. 根据权利要求18-20任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R1’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、氧代基、-NRaRb、-ORa、-NRaCO2Rb、-NRaSO2Rb或-CORa；其中，所述C1-8烷基、C3-12环烷基、3-12元杂环基、C6-12芳基、5-12元杂芳基、-NRaRb、-ORa或-CORa任选地进一步被至少一个选自卤素、C1-8烷基、C2-8烯基、C2-8炔基、C3-12环烷基、3-12元杂环基、C6-12芳基、6-12元杂芳基、氧代基、-ORa、-CN或-NO2取代基所取代。The compound according to any one of claims 18 to 20, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 1 ' is selected from H, hydroxyl, halogen, C 1 -8 alkoxy, C 1-8 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, oxo group, -NR a R b , -OR a , -NR a CO 2 R b , -NR a SO 2 R b or -COR a ; wherein, the C 1-8 alkyl group, C 3-12 cycloalkyl group, 3-12 One-membered heterocyclyl, C 6-12 aryl, 5-12 membered heteroaryl, -NR a R b , -OR a or -COR a is optionally further optionally further substituted by at least one member selected from halogen, C 1-8 alkyl , C 2-8 alkenyl, C 2-8 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl, 6-12 membered heteroaryl, oxo group, Substituted with -OR a , -CN or -NO 2 substituent.
  22. 根据权利要求21所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R1’选自H、卤素、C1-8烷基、-CORa、-NRaCO2Rb、-NRaSO2Rb、-NRaRb、C3- 12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基，所述C1-8烷基、-NRaCO2Rb、-NRaSO2Rb、-NRaRb、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个选自卤素、C1-8烷基、羟基、C1-8烷氧基、-ORa、氧代基或-CN取代基所取代。The compound according to claim 21, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 1 ' is selected from H, halogen, C 1-8 alkyl, -COR a , -NR a CO 2 R b , -NR a SO 2 R b , -NR a R b , C 3-12 cycloalkyl group, 3-12 membered heterocyclyl group, C 6-12 aryl group or 5-12 Heteroaryl group, the C 1-8 alkyl group, -NR a CO 2 R b , -NR a SO 2 R b , -NR a R b , C 3-12 cycloalkyl group, 3-12 membered heterocyclic ring group, C 6-12 aryl or 5-12 membered heteroaryl is optionally further substituted by at least one member selected from halogen, C 1-8 alkyl, hydroxyl, C 1-8 alkoxy, -OR a , oxo substituted by -CN substituent.
  23. 根据权利要求22所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R1’选自H、甲基、 The compound according to claim 22, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 1 ' is selected from H, methyl,
  24. 根据权利要求18-23任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R2’选自H、C1-8烷基或-NRaRb；优选自H、甲基、 The compound according to any one of claims 18-23, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 2 ' is selected from H, C 1-8 alkyl or -NR a R b ; preferably from H, methyl,
  25. 根据权利要求18-24任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R1’与R2’和其共同连接的碳原子形成C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被至少一个选自H、羟基、卤素、C1-8烷基、C1-8烷氧基、氧代基、-CN、-ORa、-NRaRb或C1-8卤代烷基的取代基所取代；The compound according to any one of claims 18 to 24, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 1 ' and R 2 ' and the carbon they are jointly connected to Atoms form C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the C 3-12 cycloalkyl, 3-12 membered heterocyclyl The ring group, C 6-12 aryl group or 5-12 membered heteroaryl group is optionally further substituted by at least one member selected from H, hydroxyl, halogen, C 1-8 alkyl group, C 1-8 alkoxy group, oxo group , -CN, -OR a , -NR a R b or substituted by a substituent of C 1-8 haloalkyl;
  26. 根据权利要求25所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R1’与R2’和其共同连接的碳原子形成环后形成的基团选自 The compound according to claim 25, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 1 ' and R 2 ' and the carbon atoms they are commonly connected form a ring to form The groups are selected from
  27. 根据权利要求18-26任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R3’选自H、甲基、 The compound according to any one of claims 18 to 26, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 3 ' is selected from H, methyl,
  28. 根据权利要求18-27任一项所述的化合物、其立体异构体、互变异构体、氘代物或 药用盐，其特征在于，R2选自甲基或-CF3。The compound according to any one of claims 18-27, its stereoisomer, tautomer, deuterated product or Pharmaceutically acceptable salt, characterized in that R 2 is selected from methyl or -CF 3 .
  29. 根据权利要求18-28任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R6选自 其中，所述 任选地进一步被至少一个选自H、-OH、C1-8烷基、C1-8卤代烷氧基、氧代基、-(CH2)0-3CN、-NO2、-ORb、-SRb或C1-8卤代烷基的取代基所取代。The compound according to any one of claims 18-28, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 6 is selected from Among them, the Optionally further selected from at least one group selected from H, -OH, C 1-8 alkyl, C 1-8 haloalkoxy, oxo, -(CH 2 ) 0-3 CN, -NO 2 , -OR b , -SR b or C 1-8 haloalkyl substituent.
  30. 根据权利要求29所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R6选自 The compound according to claim 29, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that, R 6 is selected from
  31. 根据权利要求1-30任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R4选自H、卤素、C1-8烷基或C1-8烷氧基。The compound according to any one of claims 1-30, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 4 is selected from H, halogen, C 1- 8 alkyl or C 1-8 alkoxy.
  32. 根据权利要求1-31任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R4选自H、F、甲基或-OCH3。The compound according to any one of claims 1-31, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 4 is selected from H, F, methyl or -OCH 3 .
  33. 根据权利要求1-32任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R4与R12共同形成一个5-8元的杂环基，所述5-8元的杂环基任选地进一步被至少一个Ra取代。The compound according to any one of claims 1-32, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 4 and R 12 together form a 5-8 The 5- to 8-membered heterocyclyl group is optionally further substituted by at least one R a .
  34. 根据权利要求1所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，其选自通式(IV)所示的化合物：
    The compound according to claim 1, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that it is selected from the compounds represented by the general formula (IV):
    其中，in,
    X1选自-C(R7)2-、-NR7-或-O-；X 1 is selected from -C(R 7 ) 2 -, -NR 7 - or -O-;
    X2选自-C(R8)2-、-NR8-或-O-；X 2 is selected from -C(R 8 ) 2 -, -NR 8 - or -O-;
    X3选自C或-N-；X 3 is selected from C or -N-;
    R1’选自H、C1-8烷基、C1-8卤代烷基或C1-8烷氧基；R 1 ' is selected from H, C 1-8 alkyl, C 1-8 haloalkyl or C 1-8 alkoxy;
    R2’选自H、C1-8烷基、C1-8卤代烷基或C1-8烷氧基；R 2 ' is selected from H, C 1-8 alkyl, C 1-8 haloalkyl or C 1-8 alkoxy;
    或者R1’、R2’与其所连接的碳原子形成3-6元杂环基；其中，所述3-6元杂环基可以进一步被一个或多个独立的Ra所取代；Or R 1 ' , R 2 ' and the carbon atom to which they are connected form a 3-6-membered heterocyclic group; wherein, the 3-6-membered heterocyclic group can be further substituted by one or more independent R a ;
    R3’各自独立地选自H、羟基、卤素、-CN、-NO2、C1-8烷氧基、C1-8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基、3-12元杂环基或-NRaRb；其中，所述C1-8烷氧基、C1- 8烷基、C1-8卤代烷氧基、C1-8卤代烷基、C3-12环烷基或3-12元杂环基任选地进一步被一个或多个独立的Ra所取代；R 3 ' is each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , C 1-8 alkoxy, C 1-8 alkyl, C 1-8 haloalkoxy, C 1-8 haloalkyl , C 3-12 cycloalkyl, 3-12 membered heterocyclyl or -NR a R b ; wherein, the C 1-8 alkoxy group, C 1-8 alkyl group, C 1-8 haloalkoxy group, C 1-8 haloalkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl is optionally further substituted by one or more independent R a ;
    X7选自C(R10)2、NR10或O；X 7 is selected from C(R 10 ) 2 , NR 10 or O;
    R2选自H、羟基、C1-8烷基、C1-8烷氧基、C1-8卤代烷氧基、C1-8卤代烷基、C1-8羟基烷基、-NRaRb、或卤素；R 2 is selected from H, hydroxyl, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkoxy, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, -NR a R b , or halogen;
    R3、R5各自独立选自H、-CN、-NO2、羟基、卤素、C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述C1-8烷氧基、C1-8烷基、C1-8羟基烷基、C3-12环烷基、3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代；R 3 and R 5 are each independently selected from H, -CN, -NO 2 , hydroxyl, halogen, C 1-8 alkoxy, C 1-8 alkyl, C 1-8 hydroxyalkyl, C 3-12 ring Alkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the C 1-8 alkoxy group, C 1-8 alkyl, C 1-8 hydroxyl group Alkyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl are optionally further substituted by one or more independent R a ;
    R6选自3-12元杂环基、C6-12芳基或5-12元杂芳基；其中，所述3-12元杂环基、C6-12芳基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代；R 6 is selected from 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered heteroaryl; wherein, the 3-12 membered heterocyclyl, C 6-12 aryl or 5-12 membered Heteroaryl is optionally further substituted by one or more independent R ;
    R7、R8、R10各自独立选自H、羟基、卤素、C1-8烷基、C1-8卤代烷基、C1-8羟基烷基、C1-8烷氧基或C1-8卤代烷氧基；R 7 , R 8 , and R 10 are each independently selected from H, hydroxyl, halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 1-8 hydroxyalkyl, C 1-8 alkoxy or C 1 -8 haloalkoxy;
    Ra或Rb各自独立地选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8烷氧基、-N-C1-8烷基、-S-C1-8烷基、C3-12环烷基或3-12元杂环基。 R a or R b are each independently selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 alkoxy, -NC 1-8 alkyl, -SC 1-8 alkyl, C 3-12 cycloalkyl or 3-12 membered heterocyclyl.
  35. 根据权利要求33或34所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述式(IV)化合物选自下式化合物：
    The compound according to claim 33 or 34, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that the compound of formula (IV) is selected from the group consisting of compounds of the following formula:
    其中，R1’，R2’，R3’，R2，R3，R5，R6，R7，R8如权利要求34所述；X7选自-C(H)2-或-O-。Wherein, R 1 ', R 2 ', R 3 ', R 2 , R 3 , R 5 , R 6 , R 7 and R 8 are as described in claim 34; X 7 is selected from -C(H) 2 - or -O-.
  36. 根据权利要求34或35任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R3’选自H、羟基、卤素、C1-8烷氧基、C1-8烷基、C3-12环烷基、3-12元杂环基、-NRaRb；其中，所述C1-8烷氧基、C1-8烷基、C3-12环烷基、-NRaRb或3-12元杂环基任选地进一步被一个或多个Ra的所取代；所述Ra或Rb各自独立地选自H、羟基、卤素、-CN、氧代基、C1-8烷基、C1-8烷氧基、C3-12环烷基、3-12元杂环基或C1-8卤代烷基。The compound according to any one of claims 34 or 35, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 3 ' is selected from H, hydroxyl, halogen, C 1-8 alkoxy group, C 1-8 alkyl group, C 3-12 cycloalkyl group, 3-12 membered heterocyclic group, -NR a R b ; wherein, the C 1-8 alkoxy group, C 1-8 alkyl, C 3-12 cycloalkyl, -NR a R b or 3-12 membered heterocyclyl are optionally further substituted by one or more R a ; each of the R a or R b Independently selected from H, hydroxyl, halogen, -CN, oxo, C 1-8 alkyl, C 1-8 alkoxy, C 3-12 cycloalkyl, 3-12 membered heterocyclyl or C 1 -8 Haloalkyl.
  37. 根据权利要求36所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R3’选自H、甲基、 The compound according to claim 36, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 3 ' is selected from H, methyl,
  38. 根据权利要求34-37任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1’选自H或C1-8烷基；所述R2选自H或C1-8烷基。 The compound according to any one of claims 34 to 37, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 1 ' is selected from H or C 1-8 Alkyl; the R 2 is selected from H or C 1-8 alkyl.
  39. 根据权利要求34-38任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R1’、R2’与其所连接的碳原子形成3-6元杂环基；其中，所述3-6元杂环基可以进一步被一个或多个独立的Ra所取代；所述Ra选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基或C1-8烷氧基。The compound according to any one of claims 34 to 38, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 1 ', R 2 ' and their connected The carbon atoms form a 3-6-membered heterocyclic group; wherein the 3-6-membered heterocyclic group can be further substituted by one or more independent R a ; the R a is selected from H, hydroxyl, halogen, -CN , -NO 2 , oxo group, C 1-8 alkyl group or C 1-8 alkoxy group.
  40. 根据权利要求34-39任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，所述R2选自C1-8烷基或C1-8卤代烷基；优选为甲基或-CF3。The compound according to any one of claims 34 to 39, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that said R 2 is selected from C 1-8 alkyl or C 1-8 haloalkyl; preferably methyl or -CF 3 .
  41. 根据权利要求34-40任一项所述得化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，其为式(V)所示结构：
    The compound, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt according to any one of claims 34 to 40, characterized in that it has a structure represented by formula (V):
    其中，R3，R5，R6的定义如权利要求34-40任一项所述。Wherein, R 3 , R 5 and R 6 are as defined in any one of claims 34 to 40.
  42. 根据权利要求34-41任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R6选自3-12元杂环基或5-12元杂芳基；其中，所述3-12元杂环基或5-12元杂芳基任选地进一步被一个或多个独立的Ra所取代，所述Ra选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8烷氧基或-S-C1-8烷基。The compound according to any one of claims 34 to 41, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 6 is selected from 3-12 membered heterocyclyl or 5 -12-membered heteroaryl; wherein, the 3-12-membered heterocyclyl or 5-12-membered heteroaryl is optionally further substituted by one or more independent R a , and the R a is selected from H, Hydroxy, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl, C 1-8 alkoxy or -SC 1-8 alkyl.
  43. 根据权利要求42所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R6选自 其中，所述 任选地进一步被一个或多个独 立的Ra所取代，所述Ra选自H、羟基、卤素、-CN、-NO2、氧代基、C1-8烷基、C1-8烷氧基或-S-C1-8烷基。The compound according to claim 42, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 6 is selected from Among them, the optionally further by one or more independent Replaced by a standing R a selected from H, hydroxyl, halogen, -CN, -NO 2 , oxo, C 1-8 alkyl , C 1-8 alkoxy or -SC 1-8 alkyl.
  44. 根据权利要求43所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R6选自 The compound according to claim 43, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 6 is selected from
  45. 根据权利要求1-44任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R3选自H、卤素或C1-8烷基；优选为甲基。The compound according to any one of claims 1-44, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 3 is selected from H, halogen or C 1-8 alkane group; preferably methyl.
  46. 根据权利要求1-45任一项所述的化合物、其立体异构体、互变异构体、氘代物或药用盐，其特征在于，R5选自H、卤素或C1-8烷基；优选为Cl。The compound according to any one of claims 1-45, its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt, characterized in that R 5 is selected from H, halogen or C 1-8 alkane group; preferably Cl.
  47. 一种化合物、其立体异构体、互变异构体、氘代物或药用盐，其选自：




    A compound, its stereoisomer, tautomer, deuterate or pharmaceutically acceptable salt, selected from:




  48. 一种药物组合物，其特征在于，所述药物组合物含有治疗有效量的权利要求1-47任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐和至少一种药学上可接受的辅料。A pharmaceutical composition, characterized in that the pharmaceutical composition contains a therapeutically effective amount of the compound described in any one of claims 1-47 or its stereoisomer, tautomer, deuterated product or medicinal salt and at least one pharmaceutically acceptable excipient.
  49. 权利要求1-47任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐或权利要求48所述的药物组合物在制备药物中的应用。Use of the compound according to any one of claims 1 to 47 or its stereoisomer, tautomer, deuterated product or pharmaceutically acceptable salt or the pharmaceutical composition according to claim 48 in the preparation of medicines.
  50. 根据权利要求49所述的应用，其特征在于，所述制备药物为在制备治疗和/或预防癌症的药物中的应用。The application according to claim 49, characterized in that the preparation of drugs is an application in the preparation of drugs for the treatment and/or prevention of cancer.
  51. 根据权利要求49或50所述的应用，其特征在于，所述制备药物为在制备治疗和/或预防由EZH2介导的疾病的药物中的应用。The application according to claim 49 or 50, characterized in that the preparation of the medicine is an application in the preparation of medicines for treating and/or preventing diseases mediated by EZH2.
  52. 根据权利要求49-51任一项所述的应用，其特征在于，所述癌症或疾病选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。The application according to any one of claims 49 to 51, wherein the cancer or disease is selected from the group consisting of breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, non- Small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatoma, head and neck cancer, hepatocellular carcinoma, myelodysplastic syndrome, malignant glioma , prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
  53. 一种治疗和/或预防疾病的方法，其特征在于，包括向治疗对象施用治疗有效量的权利要求1-47任一项所述的化合物或其立体异构体、互变异构体、氘代物或药用盐或权利要求48所述的药物组合物。A method for treating and/or preventing diseases, characterized by comprising administering to a treatment subject a therapeutically effective amount of the compound of any one of claims 1-47 or its stereoisomer, tautomer, deuterium substitute or pharmaceutically acceptable salt or the pharmaceutical composition of claim 48.
  54. 根据权利要求53所述的方法，其特征在于，所述治疗和/或预防的疾病为癌症。 The method of claim 53, wherein the disease to be treated and/or prevented is cancer.
  55. 根据权利要求53或54所述的方法，其特征在于，所述治疗和/或预防的疾病为由EZH2介导的疾病The method according to claim 53 or 54, characterized in that the disease treated and/or prevented is a disease mediated by EZH2
  56. 根据权利要求53-55任一项所述的方法，其特征在于，所述的癌症或疾病选自乳腺癌、多发性骨髓瘤、膀胱癌、子宫内膜癌、胃癌、***、横纹肌肉瘤、非小细胞肺癌、小细胞肺癌、多形性肺癌、卵巢癌、食管癌、黑色素瘤、结肠直肠癌、肝细胞瘤、头颈部肿瘤、肝胆管细胞癌、骨髓增生异常综合征、恶性胶质瘤、***癌、甲状腺癌、徐旺氏细胞瘤、肺鳞状细胞癌、苔藓样角化病、滑膜肉瘤、皮肤癌、胰腺癌、睾丸癌或脂肪肉瘤。 The method according to any one of claims 53-55, wherein the cancer or disease is selected from breast cancer, multiple myeloma, bladder cancer, endometrial cancer, gastric cancer, cervical cancer, rhabdomyosarcoma, Non-small cell lung cancer, small cell lung cancer, pleomorphic lung cancer, ovarian cancer, esophageal cancer, melanoma, colorectal cancer, hepatocellular carcinoma, head and neck tumors, hepatobiliary cell carcinoma, myelodysplastic syndrome, malignant glioma tumour, prostate cancer, thyroid cancer, Schwann cell tumor, lung squamous cell carcinoma, lichenoid keratosis, synovial sarcoma, skin cancer, pancreatic cancer, testicular cancer or liposarcoma.
PCT/CN2023/092449 2022-05-07 2023-05-06 Ezh2 inhibitor and use thereof in medicine WO2023217018A1 (en)

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WO2015077193A1 (en) * 2013-11-19 2015-05-28 Bristol-Myers Squibb Company Inhibitors of lysine methyl transferase
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