WO2023246873A1 - Amino-substituted heteroaryl derivatives and use thereof - Google Patents

Amino-substituted heteroaryl derivatives and use thereof Download PDF

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WO2023246873A1
WO2023246873A1 PCT/CN2023/101740 CN2023101740W WO2023246873A1 WO 2023246873 A1 WO2023246873 A1 WO 2023246873A1 CN 2023101740 W CN2023101740 W CN 2023101740W WO 2023246873 A1 WO2023246873 A1 WO 2023246873A1
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compound
alkyl
cycloalkyl
alkoxy
pharmaceutically acceptable
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PCT/CN2023/101740
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French (fr)
Chinese (zh)
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姜奋
刘笑
张杨
陈新海
张丽
张浩宇
王晶晶
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2023246873A1 publication Critical patent/WO2023246873A1/en

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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
    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D405/14—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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to a series of amino-substituted heteroaryl derivatives and their applications, specifically to the compounds represented by formula (P) and their pharmaceutically acceptable salts.
  • Protein arginine methylation is a post-translational modification process that is widespread in mammalian cells and can regulate many biological activities. In humans, this process is mainly catalyzed by nine arginine methyltransferases (PRMTs), which transfer the methyl group on SAM (S-adenosylmethionine) to the protein substrate arginine residue.
  • PRMT5 protein arginine methyltransferase 5
  • SAM S-adenosylmethionine
  • PRMT5 plays an important role in regulating key cellular activities such as DNA repair, cell cycle, transcriptional regulation and RNA splicing.
  • the development of inhibitors targeting PRMT5 has become a hot topic in the field of anti-tumor drugs, and many inhibitors have entered clinical research.
  • GSK-3326595 which acts on the PRMT5 substrate binding pocket, is the first PRMT5 inhibitor to enter clinical research.
  • PRMT5 can inhibit the function of PRMT5 very well. However, due to lack of selectivity, it inhibits PRMT5 in tumor cells and also inhibits normal PRMT5. PRMT5 in cells has a greater risk of clinical side effects such as anemia.
  • MTAP Metalthioadenosine Phosphorylase
  • MTA methylthioadenosine
  • the MTAP gene often co-deletes with CDKN2A, a common tumor suppressor gene in the body. The proportion of this co-deletion in tumors can reach 9% to 15%.
  • the deletion of the MTAP gene can lead to the accumulation of MTA in cells.
  • MTA can compete with SAM to bind to PRMT5 to form a PRMT5 ⁇ MTA complex and inhibit the activity of PRMT5.
  • Inhibitors developed for the PRMT5 ⁇ MTA complex can selectively inhibit PRMT5 in MTAP-deficient tumor cells and have little effect on PRMT5 in normal cells, thereby selectively killing MTAP-deficient tumor cells to achieve better results. safety.
  • AMG-193 and MRTX1719 are inhibitors targeting the PRMT5 ⁇ MTA complex that are in or about to be in clinical research. Therefore, the development of inhibitors targeting the PRMT5 ⁇ MTA complex has important clinical significance for the treatment of MTAP-deficient tumors.
  • the present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
  • T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
  • T 5 is selected from C, CR 6 and N;
  • T 6 , T 7 and T 8 are independently selected from CR 6 and N;
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
  • Each R 3 is independently selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1 , 2 or 3 R c substitutions;
  • T 9 is C, is a double bond, R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitutions;
  • T 9 is selected from C and N, Selected from single bonds and double bonds, R 4 and T 5 are linked together to form a structural unit The structural unit Selected from
  • Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl.
  • the one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R f ;
  • R 5 is selected from C 1-3 alkylthio, C 2-5 alkenyl, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy -C 3-7 cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkyl Amino-C 3-7 cycloalkyl, the C 1-3 alkylthio group, C 2-5 alkenyl, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl , -C 1-3 alkoxy-C 3-7 cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl
  • R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R g replaced;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from H, D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl- OH, the C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F or D;
  • Each R f is independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
  • Each R g is independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
  • n is selected from 0, 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl, 8-12-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl independently represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  • each of the above R a is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
  • each of the above R a is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
  • each of the above R b is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
  • each of the above R b is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
  • each of the above R c is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
  • each of the above R c is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
  • each of the above R d is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
  • each R d mentioned above is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
  • each of the above R e is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
  • each of the above R e is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
  • R 1 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently optionally substituted by 1, 2 or 3 R a , other variables are as follows defined by the present invention.
  • R 1 is selected from CH 3 and cyclopropyl, and other variables are as defined in the present invention.
  • R 1 is CH 3 , and other variables are as defined in the present invention.
  • the above R 2 is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl, and the pyridinyl, pyrimidinyl , pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl and oxazolyl are independently optionally substituted by 1, 2 or 3 R b , other variables are as follows defined by the present invention.
  • R 3 is selected from F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 ,
  • the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 are independently optionally substituted by 1, 2 or 3 R c , and other variables are as follows defined by the present invention.
  • R 3 is selected from CH 3 and CF 3 , and other variables are as defined in the present invention.
  • R 4 is selected from F, Cl, Br, I, CH 3 and CD 3 , and other variables are as defined in the present invention.
  • the above R 5 is selected from SCH 3 , SCH 2 CH 3 , ethynyl,
  • the above R 5 is selected from SCH 3 , SCH 2 CH 3 , ethynyl,
  • R 5 is selected from SCH 2 CH 3 .
  • Other variables are as defined in the present invention.
  • the above-mentioned R 5 is selected from C 2-5 alkynyl, C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 2-5 alkynyl, C 8-12 cycloalkyl
  • the alkyl group and the 8-12 membered heterocycloalkyl group are each independently optionally substituted by 1, 2 or 3 Re , and other variables are as defined in the present invention.
  • R 5 is selected from C 2-5 alkynyl group, and the C 2-5 alkynyl group is optionally substituted by 1, 2 or 3 Re , and other variables are as defined in the present invention.
  • the above-mentioned R 5 is selected from ethynyl, and the ethynyl is optionally substituted by Re , and other variables are as defined in the present invention.
  • R 5 is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently Optionally substituted by 1, 2 or 3 Re , other variables are as defined in the present invention.
  • R 6 is selected from H, F, Cl, Br, I, CH 3 and OCH 3 , and other variables are as defined in the present invention.
  • R 4 and T 5 are connected together to make the structural unit for The structural unit Selected from Other variables are as defined in the present invention.
  • the compound of the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
  • T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 , T 9 , R 4 , R b and Re are as defined in the present invention.
  • the compound of the above formula (P-1) or a pharmaceutically acceptable salt thereof is selected from,
  • the structural unit T 1 , T 2 , T 6 , T 7 , T 8 , R 4 , R b and Re are as defined in the present invention.
  • the carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound of the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
  • Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
  • R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-7 ring Alkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 cycloalkyl Alkyl group, the C 1-3 alkylthio group, C 2-5 alkynyl group, C 8-12 cycloalkyl group, 8-12 membered heterocycloalkyl group, -C 1-3 alkoxy group-C 3-7 Cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 The
  • T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
  • R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, The C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl and 8-12-membered heterocycloalkyl independently represents 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and N heteroatoms or heteroatom groups.
  • the compound of the above formula (P2) or a pharmaceutically acceptable salt thereof is selected from:
  • Ring B is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R e replaced;
  • T 1 , T 2 , T 5 , T 6 , T 7 , T 8 , R 3 , R 4 , R b , Re and n are as defined in the present invention.
  • the carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound of the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b ;
  • n is selected from 0, 1, 2 and 3;
  • n is selected from 1, 2 and 3
  • each R 3 is independently selected from H, halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkyl Oxygen group, wherein at least one R 3 is selected from C 2-5 alkenyl and C 2-5 alkynyl, said C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1 -3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
  • Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl.
  • the one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R e ;
  • T 3 , T 4 and T 5 are independently selected from CR 4 and N;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
  • the compound of the above formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
  • Ring A and R c are as defined in the invention.
  • the present invention also provides a compound represented by formula (P2) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
  • Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
  • R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-7 ring Alkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 cycloalkyl Alkyl group, the C 1-3 alkylthio group, C 2-5 alkynyl group, C 8-12 cycloalkyl group, 8-12 membered heterocycloalkyl group, -C 1-3 alkoxy group-C 3-7 Cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 The
  • T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
  • T 5 , T 6 , T 7 and T 8 are independently selected from CR 6 and N;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, The C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl and 8-12-membered heterocycloalkyl independently represents 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and N heteroatoms or heteroatom groups.
  • each R a , each R b , each R c , each R d and each Re is independently selected from D , F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH are independently Optionally substituted by 1, 2 or 3 F, other variables are as defined in the present invention.
  • each R a , each R b , each R c , each R d and each Re is independently selected from D , F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from Other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from Other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof wherein R 3 is selected from F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3. CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 are respectively independent. is optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
  • R 5 is selected from SCH 2 CH 3
  • Other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof wherein T 1 , T 2 , T 3 and T 4 are each independently selected from CH, and other variables are as in the present invention defined.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof wherein the structural unit Selected from R3 and other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof wherein the structural unit Selected from R 6 and other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof is selected from,
  • Ring A is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R e replaced;
  • T 1 , T 2 , T 5 , T 6 , T 7 , T 8 , R 3 , R 4 , R b , Re and n are as defined in the present invention.
  • Carbon atoms with "*" are chiral carbon atoms, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof is selected from,
  • T 1 , T 2 , T 5 , T 6 , T 7 , T 8 , R 3 , R 4 , R b , Re and n are as defined in the present invention.
  • the compound of formula (P2) or a pharmaceutically acceptable salt thereof is selected from,
  • Ring A is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R e replaced;
  • T 1 , T 2 , R 3 , R 4 , Re and n are as defined in the present invention.
  • the compound of formula (P2-I-1) or a pharmaceutically acceptable salt thereof is selected from,
  • ring A, T 1 , T 2 , R 3 , R 4 , Re and n are as defined in the present invention.
  • the present invention also provides compounds represented by formula (P2-I) or pharmaceutically acceptable salts thereof,
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
  • Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, wherein C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • the 5-6-membered heteroaryl and 8-12-membered heterocycloalkyl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from -O-, -NH-, -S- and N or heteroatoms.
  • the present invention also provides a compound represented by formula (P2) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
  • Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
  • R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
  • R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-7 ring Alkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 cycloalkyl Alkyl group, the C 1-3 alkylthio group, C 2-5 alkynyl group, C 8-12 cycloalkyl group, 8-12 membered heterocycloalkyl group, -C 1-3 alkoxy group-C 3-7 Cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 The
  • T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
  • T 5 , T 6 , T 7 and T 8 are independently selected from CR 6 and N;
  • R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, wherein C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
  • n is selected from 0, 1, 2 and 3;
  • hetero of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl and 8-12-membered heterocycloalkyl independently represents 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and N heteroatoms or heteroatom groups.
  • the present invention also provides the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b ;
  • Each R 3 is independently selected from H, halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy, the C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c ;
  • T 3 , T 4 and T 5 are independently selected from CR 4 and N;
  • T 6 and T 7 are independently selected from CH and N;
  • R 4 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitution;
  • each R a , each R b , each R c , each R d and each R e are independently selected From H, F, Cl, OH, NH2 and CH3 , other variables are as defined in the present invention.
  • the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from Other variables are as defined in the present invention.
  • each R 3 is independently selected from H, F, Cl, Br, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , said CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 is each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
  • each R 3 is independently selected from F, Cl, Br, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , said CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 is each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
  • the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof wherein the structural unit Selected from At this time, n is 1, and R 3 is selected from C 2-5 alkenyl and C 2-5 alkynyl.
  • the C 2-5 alkenyl and C 2-5 alkynyl are independently optionally substituted by 1, 2 or 3 R c substitutions, each R c and other variables are as defined in the present invention.
  • the compound of formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
  • Ring A, R 3 and n are as defined in the invention.
  • the compound of formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
  • the structural unit T 1 , T 2 , R 3 and n are as defined in the present invention.
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
  • Structural units Selected from Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1 or 2 R e ;
  • T 3 , T 4 and T 5 are independently selected from CR 4 and N;
  • T 6 and T 7 are independently selected from CH and N;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from halogen, OH, NH 2 and CH 3 ;
  • n is selected from 0, 1, 2 and 3;
  • the 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl
  • the groups are independently optionally substituted by 1, 2 or 3 R a ;
  • R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b ;
  • Each R 3 is independently selected from halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy, the C 1-3 alkyl, C 2 -5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 R c ;
  • each R 3 is independently selected from C 2-5 alkenyl and C 2-5 alkynyl, and the C 2-5 alkenyl and C 2-5 alkynyl are independently optionally substituted by 1, 2 or 3 R c substitutions;
  • Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl.
  • the one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R e ;
  • T 6 and T 7 are independently selected from CH and N;
  • R 4 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitution;
  • Each R a , each R b , each R c , each R d and each Re are independently selected from H, halogen, OH, NH 2 and CH 3 ;
  • n is selected from 0, 1, 2 and 3;
  • the present invention also provides compounds represented by the following formula or pharmaceutically acceptable salts thereof,
  • the compound is selected from,
  • Example 1 of the present invention SFC detection (chromatographic column: Chiralcel OJ-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: Phase A: CO 2 , Phase B: methanol (0.05% diethylamine); gradient: B%: 5% ⁇ 40%, flow rate: 3mL/min), the retention time of compound 1a is 1.471min.
  • Example 5 of the present invention after SFC detection (chromatographic column: Chiralpak IC-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: A phase: CO 2 , B phase: [66.67% (methanol-0.05% diethylamine) )+33.33% (acetonitrile-diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min), the retention time of compound 5a is 1.003min.
  • Example 7 of the present invention SFC detection (chromatographic column: Chiralpak AY-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: A phase: CO 2 , B phase: [66.67% (methanol 0.05% diethylamine) +33.33% (acetonitrile-0.05% diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min), the retention time of compound 7a is 0.967min.
  • Example 8 of the present invention after SFC detection (chromatographic column: Chiralpak IC-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: Phase A: CO 2 , Phase B: 75% isopropyl alcohol + 25% acetonitrile (0.05 % diethylamine); gradient: B%: 50% isopropanol + acetonitrile (0.05% diethylamine), flow rate: 3mL/min), the retention time of compound 8a is 1.385min; the retention of its enantiomers The time is 2.037min.
  • Example 9 of the present invention after SFC detection (chromatographic column: (S, S) Whelk-O1 50 ⁇ 4.6mm ID, 3.5 ⁇ m; mobile phase: A phase: CO 2 , B phase: isopropanol (0.05% Diethylamine); gradient: B%: 5%-40%, flow rate: 3mL/min), the retention time of compound 9a is 0.991min; the retention time of its enantiomer is 1.195min.
  • the present invention also provides the use of the above compounds or pharmaceutically acceptable salts thereof in preparing PRMT5 inhibitor-related drugs.
  • the present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in preparing drugs for treating diseases related to PRMT5 inhibitors.
  • the invention also provides the following synthesis methods:
  • R 5 is selected from C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 4-7 cycloalkyl and -C 1-3 alkylamino-C 4 -7 cycloalkyl, the C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 4-7 cycloalkyl and -C 1-3 alkylamino- C 4-7 cycloalkyl groups are independently optionally substituted by 1, 2 or 3 Re ;
  • Each R e is independently selected from F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH;
  • R5 is selected from
  • the invention also provides the following test methods:
  • Test method 1 PRMT5 enzyme inhibitory activity test
  • Buffer preparation Take 10 ml as an example.
  • 10mM MTA Add 10 mg MTA to 3296 ⁇ l DMSO, dissolve, aliquot and store at -80°C. On the day of the experiment, it was configured for immediate use. The configuration plan is shown in Table 1 and Table 2.
  • the concentration of PRMT5 is 7.6nM
  • the concentration of polypeptide H4(1-21) is 0.32 ⁇ M
  • the concentration of SAM is 2.6 ⁇ M.
  • This experiment uses PE Company’s time-resolved fluorescence resonance energy transfer technology ( Ultra) for testing.
  • Ultra time-resolved fluorescence resonance energy transfer technology
  • two antibodies are added.
  • Ultra-Europium anti-methyl histone H4 arginine 3 (H4R3me) antibody serves as an energy donor and can specifically bind to the methylation site on peptide H4 (1-21), while Ulight serves as an energy acceptor and can bind to peptide H4 ( 1-21) specifically binds to the biotin tag carried on it. If a laser with a certain wavelength (the excitation wavelength of this experiment is 340nm) is used for excitation, the energy donor can emit light with a wavelength of 615nm.
  • Use LANCE buffer to prepare antibody mixture solution The concentration of Ultra Europium-anti-methyl-Histone H4 Arginine 3(H4R3me) Antibody is 4nM and the concentration of Ulight is 53.3nM.
  • Use an electric multi-channel pipette to add the detection solution to the positive control, negative control and compound wells of the experimental plate in a volume of 10 ⁇ L per well, centrifuge and incubate at room temperature for one hour, and read using a plate reader Envision 2104.
  • Use the interpolation method to calculate the compound inhibition rate, and use the four-parameter Logis equation curve and XLfit software to make the compound inhibition curve and calculate related parameters, including the minimum inhibition rate, maximum inhibition rate and IC 50 .
  • the formula for calculating the inhibition rate is:
  • the compound of the present invention has a good binding effect with the PRMT5 ⁇ MTA complex, has good inhibitory activity against MTAP-deficient HCT116 tumor cells, and has weak inhibitory activity against wild-type HCT116 tumor cells, showing excellent selectivity;
  • the compound of the present invention showed a lower clearance rate and a higher drug exposure, and had good pharmacokinetic properties in vivo; the compound of the present invention also showed excellent anti-tumor drugs in vivo It is effective, and the body weight of mice is maintained well after administration.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
  • diastereomer refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
  • wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center
  • using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line
  • wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
  • the terms “enriched in an isomer,” “enantiomerically enriched,” “enriched in an enantiomer,” or “enantiomerically enriched” refer to one of the isomers or enantiomers.
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, enantiomers and Separation of diastereomers is usually accomplished by the use of chromatography using a chiral stationary phase, optionally combined with chemical derivatization methods (eg carbamate generation from amines).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs.
  • the bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon.
  • deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • the direction of connection is arbitrary, for example, The middle linking group L is -MW-.
  • -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction to the reading order from left to right.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-3 alkylthio means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom.
  • the C 1-3 alkylthio group includes C 1-2 , C 3 and C 2 alkylthio groups, etc.
  • Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , and the like.
  • C 4-6 cycloalkenyl by itself or in combination with another term respectively means a partially unsaturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond.
  • the group includes single-ring and double-ring systems, wherein the double-ring system includes spiro ring, paracyclic ring and bridged ring. Any ring in this system is non-aromatic.
  • the C 4-6 cycloalkenyl group includes C 4-5 or C 5-6 cycloalkenyl group, etc.; it can be monovalent, divalent or multivalent.
  • the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond. , 1, 2, 3 or 4 of its ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally quaternized. Oxidation (i.e. NO and S(O) p , p is 1 or 2). It includes single-ring and bicyclic systems. The bicyclic system includes spiro ring, paracyclic ring and bridged ring.
  • azolyl group, etc. imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyrid
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
  • Figure 16 Mouse body weight change curve in the human large cell lung cancer LU99 subcutaneous xenograft tumor model.
  • the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the molecular docking process is by using Maestro ( Performed with Glide SP [1] precision and default options in version 2021-2).
  • the crystal structure of PRMT5 in the PDB database (PDB ID: 7S1S) was selected as the docking template.
  • hydrogen atoms were added using the Protein Preparation Wizard module of Maestro [2] and energy minimization was performed using the OPLS4 force field.
  • LigPrep [3] was used to generate the three-dimensional structure of the molecule, and the OPLS4 force field was used for energy minimization [3] .
  • reaction solution was filtered, and the filtrate was prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Waters Xbridge C18 150*50mm*10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40 %-70%) to obtain compound 1-8a.
  • the mixture was stirred and reacted under microwave conditions at 120°C. 1.5 hours.
  • the reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure.
  • the crude product was purified by preparative high-performance liquid phase separation (separation conditions: chromatographic column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile%: 13%-43%) to obtain compound 2a .
  • reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Racemization occurred during the reaction, and the crude product was successively separated by preparative high-performance liquid phase (separation conditions: chromatographic column: Waters 53%) and SFC separation and purification (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [25% acetonitrile + 75% isopropyl alcohol, after mixing Add 0.1% ammonia water]; B%: 40%-40%) to obtain compounds 3a and 3b.
  • reaction solution was filtered, and the filtrate was prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Waters Xbridge C18 150*50mm*10 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 29 %-59%) to obtain compound 4.
  • MS m/z 424.3[M+H] + .
  • reaction solution was concentrated under reduced pressure, and the filtrate was prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: DAICEL CHIRALCEL OX (250mm*30mm, 10 ⁇ m); mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; Acetonitrile%: 3%-66%), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AS (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [60% isopropanol +30% acetonitrile +10% (ethanol-1% ammonia)]; B%: 70%-70%) to obtain compound 6a.
  • chromatographic column: DAICEL CHIRALCEL OX 250mm*30mm, 10 ⁇ m
  • mobile phase [water (10mM ammonium bicarbonate)-acetonitrile]; Acetonitrile%: 3%-66%
  • the filtrate is prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Waters Xbridge 150*25mm *5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 23%-53%), and then separated by SFC (separation conditions: column: DAICEL CHIRALPAK AY-H (250mm*30mm, 10 ⁇ m ); Mobile phase: A phase: CO 2 , B phase: [75% methanol + 15% acetonitrile + 10% (1% ammonia ethanol solution)]; B%: 70%-70%) to obtain compound 7a.
  • reaction solution was diluted with water (15 mL), extracted with ethyl acetate (15 mL ⁇ 4), the organic phases were combined, washed with saturated sodium chloride solution (15 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 8 -7.
  • compound 11-1 was obtained without SFC chiral resolution.
  • a solution of compound 11-1 (200.00 mg, 508.55 ⁇ mol) in triethylamine (5 mL) a solution of propyne in N,N-dimethylformamide (1 M, 7.63 mL) and copper iodide (9.69 mg) were added in sequence. , 50.85 ⁇ mol) and dichlorobis(triphenylphosphine)palladium(II) (35.69 mg, 50.85 ⁇ mol), and the mixture was stirred at 120°C under microwave conditions for 12 hours.
  • the reaction solution was filtered through diatomaceous earth, the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 2), the organic phases were combined, washed with saturated brine (30 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. concentrate.
  • N,N-diisopropylethylamine (167.5 mg, 1.30 mmol, 226 ⁇ L) and p-methoxy were added to a solution of compound 12-5 (0.12 g, 432.08 ⁇ mol) in tetrahydrofuran (15 mL).
  • benzylamine (1.30 mmol, 168 ⁇ L) then the temperature was raised to 80°C, and stirring was continued for 12 hours.
  • p-methoxybenzylamine (1.30 mmol, 168 ⁇ L) was added to the reaction solution, and the reaction was continued with stirring at 80°C for 12 hours. Reaction liquid decreases Pressure concentration.
  • the racemate is separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [60% methanol + 30% acetonitrile + 10% (ethanol- 1% ammonia water)]; B%: 40%-40%) to obtain two crude compounds.
  • the crude products of these two compounds were separately purified by preparative high-performance liquid phase separation (chromatographic column: Waters Xbridge C18 150*50mm*10 ⁇ m; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 32%-62% ) to obtain compound 12a and compound 12b.
  • Compound 12-2 (1.3g, 4.69mmol) was dissolved in 1.4-dioxane (13mL)/water (3.25mL), and potassium carbonate (1.77g, 12.79mmol) and tetrakistriphenylphosphine palladium (492.80 mg, 426.46 ⁇ mol) and 13-2 (1.04 g, 4.26 mmol), stir at 90°C for 12 hours under nitrogen protection.
  • reaction solution was diluted with water (10mL), extracted with dichloromethane (10mL*3), the organic phase was washed with saturated brine (10mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a small amount of racemic compound. 15-5, used directly for the next step.
  • reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16-5.
  • reaction solution was diluted with water (25 mL), extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17-6.
  • HCT116 MTAP KO cells or HCT116 wt cells were seeded in an ultra-low adsorption 96-well U-shaped plate, with 80 ⁇ L of cell suspension per well containing 1,000 cells. The cell plate was cultured overnight in a carbon dioxide incubator.
  • the concentration of compounds transferred into the cell plate ranged from 5 ⁇ M to 0.305 nM.
  • the cell plate was cultured in a carbon dioxide incubator for 10 days. Prepare another cell plate, and read the signal value on the day of adding the drug as the maximum value (Max value in the equation below) to participate in data analysis.
  • IV intravenous injection
  • PO oral administration
  • C 0 instantaneous required concentration after intravenous injection
  • C max the highest blood drug concentration after administration
  • T max required to reach peak drug concentration after administration time
  • T 1/2 the time required for the blood drug concentration to decrease by half
  • V dss apparent volume of distribution, which refers to the proportional constant between the amount of drug in the body and the blood drug concentration when the drug reaches dynamic equilibrium in the body.
  • Cl clearance rate, refers to the apparent distribution volume of the drug cleared from the body per unit time
  • AUC 0-last area under the drug-time curve, refers to the area surrounded by the blood drug concentration curve against the time axis
  • F bioavailability.
  • the compounds of the present invention exhibit low clearance and high drug exposure, and have good pharmacokinetic properties in vivo.
  • mice Female BALB/c nude mice were subcutaneously inoculated with human large cell lung cancer LU99 cell line. After inoculation, they were randomly divided into groups according to body weight and tumor volume, with 6 animals in each group. After inoculation, administration will begin when the tumor volume is 180-230mm3 .
  • the administration treatment method is as follows:
  • Control group Start administration when the tumor volume is 207 ⁇ 9mm after inoculation. Once a day (QD), the vehicle (5% DMSO/10% Solutol/85% double distilled water) is administered (po) at a dose of 0.1mL/10g. .
  • Treatment Group 2 Administration was started when the tumor volume after inoculation was 207 ⁇ 16 mm. Compounds were administered by gavage once a day at a dose of 100 mg/kg (the test compound was dissolved in 5% DMSO/10% Solutol/85% double distilled water ).
  • This experiment evaluated the efficacy of the compound of the present invention on the human large cell lung cancer LU99 subcutaneous xenograft tumor model, using the solvent control group as a reference.
  • the body weight change curve of mice in each group is shown in Figure 16, and the average tumor volume of each group at different time points is shown in Figure 17.
  • the TGI was calculated based on the average tumor volume on day 29 after administration.
  • the specific experimental results are shown in Table 5.

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Abstract

Disclosed in the present application are a series of amino-substituted heteroaryl derivatives and a use thereof. In particular, disclosed are a compound represented by formula (P) and a pharmaceutically acceptable salt thereof.

Description

氨基取代的杂芳基衍生物及其应用Amino-substituted heteroaryl derivatives and their applications
本发明主张如下优先权：The present invention claims the following priority:
CN202210725456.9，申请日2022年06月23日；CN202210725456.9, application date is June 23, 2022;
CN202210743843.5，申请日2022年06月27日；CN202210743843.5, application date: June 27, 2022;
CN202211161527.3，申请日2022年08月29日；CN202211161527.3, application date: August 29, 2022;
CN202211074176.2，申请日2022年09月02日。CN202211074176.2, application date: September 2, 2022.
技术领域Technical field
本发明涉及一系列氨基取代的杂芳基衍生物及其应用，具体涉及了式(P)所示化合物及其药学上可接受的盐。The present invention relates to a series of amino-substituted heteroaryl derivatives and their applications, specifically to the compounds represented by formula (P) and their pharmaceutically acceptable salts.
背景技术Background technique
蛋白精氨酸甲基化是哺乳动物细胞中广泛存在的一种翻译后修饰过程，可以调节许多生物学活动。在人类中这一过程主要由9个精氨酸甲基转移酶(PRMTs)催化，将SAM(S-腺苷甲硫氨酸)上的甲基转移到蛋白底物精氨酸残基上。PRMT5(蛋白质精氨酸甲基转移酶5)是一种II型精氨酸甲基转移酶，可以催化精氨酸单甲基化和对称双甲基化(sDMA)过程。作为主要的sDMA催化酶，PRMT5在调节DNA修复，细胞周期，转录调控和RNA剪接等关键细胞活动中起着重要作用。研究表明，PRMT5在多种不同的肿瘤中高表达，包括结直肠癌、肺癌、卵巢癌、***癌、淋巴瘤、白血病和胶质母细胞瘤等，因此抑制PRMT5有望成为这些肿瘤的新型治疗手段。近年来，靶向PRMT5的抑制剂开发成为抗肿瘤药物领域的热点，目前已有多个抑制剂进入临床研究。作用于PRMT5底物结合口袋的GSK-3326595是第一个进入临床研究的PRMT5抑制剂，其可以很好的抑制PRMT5的功能，但是由于缺乏选择性，在抑制肿瘤细胞PRMT5的同时也会抑制正常细胞中的PRMT5，导致临床出现贫血等副作用的风险较大。MTAP(甲硫腺苷磷酸化酶)是甲硫氨酸和嘌呤合成补救途径的第一个酶,专门司职催化多胺代谢的副产物MTA(甲基硫代腺苷)的代谢。MTAP基因常与体内常见的抑癌基因CDKN2A发生共缺失现象，这种共缺失现象在肿瘤中的比例可达9％～15％。MTAP基因的缺失可导致细胞内MTA蓄积，MTA可以与SAM竞争结合PRMT5形成PRMT5·MTA复合物并抑制PRMT5的活性。针对PRMT5·MTA复合物开发的抑制剂可以选择性的抑制MTAP缺失肿瘤细胞中的PRMT5，对正常细胞中的PRMT5影响较小，以此来选择性杀死MTAP缺失的肿瘤细胞，达到更好的安全性。针对PRMT5·MTA复合物的抑制剂目前仅有AMG-193和MRTX1719开展或即将开展临床研究。因此，针对PRMT5·MTA复合物来开发抑制剂对于MTAP缺失的肿瘤治疗具有重要的临床意义。Protein arginine methylation is a post-translational modification process that is widespread in mammalian cells and can regulate many biological activities. In humans, this process is mainly catalyzed by nine arginine methyltransferases (PRMTs), which transfer the methyl group on SAM (S-adenosylmethionine) to the protein substrate arginine residue. PRMT5 (protein arginine methyltransferase 5) is a type II arginine methyltransferase that can catalyze the arginine monomethylation and symmetric dimethylation (sDMA) processes. As the main sDMA catalytic enzyme, PRMT5 plays an important role in regulating key cellular activities such as DNA repair, cell cycle, transcriptional regulation and RNA splicing. Studies have shown that PRMT5 is highly expressed in a variety of different tumors, including colorectal cancer, lung cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, and glioblastoma. Therefore, inhibiting PRMT5 is expected to become a new treatment method for these tumors. In recent years, the development of inhibitors targeting PRMT5 has become a hot topic in the field of anti-tumor drugs, and many inhibitors have entered clinical research. GSK-3326595, which acts on the PRMT5 substrate binding pocket, is the first PRMT5 inhibitor to enter clinical research. It can inhibit the function of PRMT5 very well. However, due to lack of selectivity, it inhibits PRMT5 in tumor cells and also inhibits normal PRMT5. PRMT5 in cells has a greater risk of clinical side effects such as anemia. MTAP (Methylthioadenosine Phosphorylase) is the first enzyme in the salvage pathway for the synthesis of methionine and purine. It specifically catalyzes the metabolism of MTA (methylthioadenosine), a by-product of polyamine metabolism. The MTAP gene often co-deletes with CDKN2A, a common tumor suppressor gene in the body. The proportion of this co-deletion in tumors can reach 9% to 15%. The deletion of the MTAP gene can lead to the accumulation of MTA in cells. MTA can compete with SAM to bind to PRMT5 to form a PRMT5·MTA complex and inhibit the activity of PRMT5. Inhibitors developed for the PRMT5·MTA complex can selectively inhibit PRMT5 in MTAP-deficient tumor cells and have little effect on PRMT5 in normal cells, thereby selectively killing MTAP-deficient tumor cells to achieve better results. safety. Currently, only AMG-193 and MRTX1719 are inhibitors targeting the PRMT5·MTA complex that are in or about to be in clinical research. Therefore, the development of inhibitors targeting the PRMT5·MTA complex has important clinical significance for the treatment of MTAP-deficient tumors.
发明内容Contents of the invention
本发明提供了式(P)所示化合物或其药学上可接受的盐，
The present invention provides a compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
其中，in,
T1、T2、T3和T4分别独立地选自CH和N； T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
T5选自C、CR6和N；T 5 is selected from C, CR 6 and N;
T6、T7和T8分别独立地选自CR6和N；T 6 , T 7 and T 8 are independently selected from CR 6 and N;
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
各R3分别独立地选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1 , 2 or 3 R c substitutions;
T9为C，为双键，R4选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；T 9 is C, is a double bond, R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitutions;
或者，T9选自C和N，选自单键和双键，R4与T5连接在一起形成结构单元所述结构单元选自 Alternatively, T 9 is selected from C and N, Selected from single bonds and double bonds, R 4 and T 5 are linked together to form a structural unit The structural unit Selected from
环A选自5-6元杂芳基、C4-6环烯基和5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基和5-6元杂环烯基分别独立地任选被1或2个Rf取代；Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl. The 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R f ;
R5选自C1-3烷硫基、C2-5烯基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基，所述C1-3烷硫基、C2-5烯基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基分别独立地任选被1、2或3个Re取代；R 5 is selected from C 1-3 alkylthio, C 2-5 alkenyl, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy -C 3-7 cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkyl Amino-C 3-7 cycloalkyl, the C 1-3 alkylthio group, C 2-5 alkenyl, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl , -C 1-3 alkoxy-C 3-7 cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl The -C 1-3 alkylamino-C 3-7 cycloalkyl group is each independently optionally substituted by 1, 2 or 3 R e ;
R6选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rg取代；R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R g replaced;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自H、D、卤素、OH、NH2、C1-3烷基和-C1-3烷基-OH，所述C1-3烷基和-C1-3烷基-OH分别独立地任选被1、2或3个F或D取代；Each R a , each R b , each R c , each R d and each Re are independently selected from H, D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl- OH, the C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F or D;
各Rf分别独立地选自H、D、卤素、OH、NH2、CH3、CF3和CD3；Each R f is independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
各Rg分别独立地选自H、D、卤素、OH、NH2、CH3、CF3和CD3；Each R g is independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基、3-7元杂环烷基、8-12元杂环烷基和5-6元杂环烯基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl, 8-12-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl independently represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
本发明的一些方案中，上述各Ra分别独立地选自D、F、Cl、OH、NH2、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH分别独立地任选被1、2或3个F或D取代，其他变量如本发明所定义。In some aspects of the present invention, each of the above R a is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Ra分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH，其他变量如本发明所定义。In some solutions of the present invention, each of the above R a is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rb分别独立地选自D、F、Cl、OH、NH2、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH分别独立地任选被1、2或3个F或D取代，其他变量如本发明所定义。In some aspects of the invention, each of the above R b is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rb分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH，其他变量如本发明所定义。 In some solutions of the present invention, each of the above R b is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rc分别独立地选自D、F、Cl、OH、NH2、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH分别独立地任选被1、2或3个F或D取代，其他变量如本发明所定义。In some aspects of the invention, each of the above R c is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rc分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH，其他变量如本发明所定义。In some solutions of the present invention, each of the above R c is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rd分别独立地选自D、F、Cl、OH、NH2、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH分别独立地任选被1、2或3个F或D取代，其他变量如本发明所定义。In some aspects of the invention, each of the above R d is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Rd分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH，其他变量如本发明所定义。In some solutions of the present invention, each R d mentioned above is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Re分别独立地选自D、F、Cl、OH、NH2、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH分别独立地任选被1、2或3个F或D取代，其他变量如本发明所定义。In some aspects of the present invention, each of the above R e is independently selected from D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , - CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, - CH 2 CH 2 OH and -C(CH 3 ) 2 OH are each independently optionally substituted by 1, 2 or 3 F or D, and other variables are as defined in the present invention.
本发明的一些方案中，上述各Re分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH，其他变量如本发明所定义。In some solutions of the present invention, each of the above R e is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
本发明的一些方案中，上述R1选自CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己基，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己基分别独立地任选被1、2或3个Ra取代，其他变量如本发明所定义。In some aspects of the invention, the above R 1 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH (CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are each independently optionally substituted by 1, 2 or 3 R a , other variables are as follows defined by the present invention.
本发明的一些方案中，上述R1选自CH3和环丙基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R 1 is selected from CH 3 and cyclopropyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述R1为CH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R2选自吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基和噁唑基，所述吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基和噁唑基分别独立地任选被1、2或3个Rb取代，其他变量如本发明所定义。In some embodiments of the present invention, the above R 2 is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl, and the pyridinyl, pyrimidinyl , pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl and oxazolyl are independently optionally substituted by 1, 2 or 3 R b , other variables are as follows defined by the present invention.
本发明的一些方案中，上述R2选自其他变量如本发明所定义。In some solutions of the present invention, the above R 2 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述R2选自其他变量如本发明所定义。In some solutions of the present invention, the above R 2 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述R3选自F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3分别独立地任选被1、2或3个Rc取代，其他变量如本发明所定义。In some aspects of the invention, the above R 3 is selected from F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 are independently optionally substituted by 1, 2 or 3 R c , and other variables are as follows defined by the present invention.
本发明的一些方案中，上述R3选自CH3和CF3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 3 is selected from CH 3 and CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R4选自F、Cl、Br、I、CH3和CD3，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R 4 is selected from F, Cl, Br, I, CH 3 and CD 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自SCH3、SCH2CH3、乙炔基、 所述SCH3、SCH2CH3、乙炔基、 分别独立地任选被1、2或3个Re取代，其他变量如本发明所定义。In some aspects of the invention, the above R 5 is selected from SCH 3 , SCH 2 CH 3 , ethynyl, The SCH 3 , SCH 2 CH 3 , ethynyl, Each is independently optionally substituted by 1, 2 or 3 Re , and other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自SCH3、SCH2CH3、乙炔基、 所述SCH3、SCH2CH3、乙炔基、 分别独立地任选被1、2或3个Re取代，其他变量如本发明所定义。In some aspects of the invention, the above R 5 is selected from SCH 3 , SCH 2 CH 3 , ethynyl, The SCH 3 , SCH 2 CH 3 , ethynyl, Each is independently optionally substituted by 1, 2 or 3 Re , and other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自SCH2CH3、 其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 5 is selected from SCH 2 CH 3 , Other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自C2-5炔基、C8-12环烷基和8-12元杂环烷基，所述C2-5炔基、C8-12环烷基和8-12元杂环烷基分别独立地任选被1、2或3个Re取代，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 5 is selected from C 2-5 alkynyl, C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 2-5 alkynyl, C 8-12 cycloalkyl The alkyl group and the 8-12 membered heterocycloalkyl group are each independently optionally substituted by 1, 2 or 3 Re , and other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自C2-5炔基，所述C2-5炔基任选被1、2或3个Re取代，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R 5 is selected from C 2-5 alkynyl group, and the C 2-5 alkynyl group is optionally substituted by 1, 2 or 3 Re , and other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自乙炔基，所述乙炔基任选被Re取代，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned R 5 is selected from ethynyl, and the ethynyl is optionally substituted by Re , and other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自其他变量如本发明所定义。In some solutions of the present invention, the above R 5 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自C8-12环烷基和8-12元杂环烷基，所述C8-12环烷基和8-12元杂环烷基分别独立地任选被1、2或3个Re取代，其他变量如本发明所定义。In some embodiments of the present invention, the above R 5 is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently Optionally substituted by 1, 2 or 3 Re , other variables are as defined in the present invention.
本发明的一些方案中，上述R5选自其他变量如本发明所定义。In some solutions of the present invention, the above R 5 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述R6选自H、F、Cl、Br、I、CH3和OCH3，其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 6 is selected from H, F, Cl, Br, I, CH 3 and OCH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自 其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元选自 其他变量如本发明所定义。In some solutions of the present invention, the above structural units Selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述R4与T5连接在一起使结构单元为所述结构单元选自 其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R 4 and T 5 are connected together to make the structural unit for The structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述式(P)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
其中，T1、T2、T3、T4、T5、T6、T7、T8、T9、R4、Rb和Re如本发明所定义。Among them, T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 , T 9 , R 4 , R b and Re are as defined in the present invention.
本发明的一些方案中，上述式(P-1)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of the above formula (P-1) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元T1、T2、T6、T7、T8、R4、Rb和Re如本发明所定义；Among them, the structural unit T 1 , T 2 , T 6 , T 7 , T 8 , R 4 , R b and Re are as defined in the present invention;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明的一些方案中，上述式(P)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
各R3分别独立地选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代； Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
R4选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
R5选自C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基，所述C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基分别独立地任选被1、2或3个Re取代；R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-7 ring Alkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 cycloalkyl Alkyl group, the C 1-3 alkylthio group, C 2-5 alkynyl group, C 8-12 cycloalkyl group, 8-12 membered heterocycloalkyl group, -C 1-3 alkoxy group-C 3-7 Cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 The cycloalkyl groups are independently optionally substituted by 1, 2 or 3 Re ;
T1、T2、T3和T4分别独立地选自CH和N；T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
T5、T6、T7和T8分别独立地选自CR6和N；T 5 , T 6 , T 7 and T 8 are independently selected from CR 6 and N;
R6选自H、卤素、C1-3烷基和C1-3烷氧基；R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自D、卤素、OH、NH2、C1-3烷基和-C1-3烷基-OH，所述C1-3烷基和-C1-3烷基-OH分别独立地任选被1、2或3个F取代；Each R a , each R b , each R c , each R d and each Re are independently selected from D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, The C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基、3-7元杂环烷基和8-12元杂环烷基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl and 8-12-membered heterocycloalkyl independently represents 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and N heteroatoms or heteroatom groups.
本发明的一些方案中，上述式(P2)化合物或其药学上可接受的盐，其化合物选自：
In some aspects of the present invention, the compound of the above formula (P2) or a pharmaceutically acceptable salt thereof is selected from:
其中，in,
环B选自C8-12环烷基和8-12元杂环烷基，所述C8-12环烷基和8-12元杂环烷基分别独立地任选被1、2或3个Re取代；Ring B is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R e replaced;
T1、T2、T5、T6、T7、T8、R3、R4、Rb、Re和n如本发明所定义；T 1 , T 2 , T 5 , T 6 , T 7 , T 8 , R 3 , R 4 , R b , Re and n are as defined in the present invention;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明的一些方案中，上述式(P)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1或2个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b ;
各R3分别独立地选自H、卤素、C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基，所述C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from H, halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy, the C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c ;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
结构单元选自 Structural units Selected from
或者，结构单元选自此时，n选自1、2和3，各R3分别独立地选自H、卤素、C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基，其中至少有一个R3选自C2-5烯基和C2-5炔基，所述C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Or, structural unit Selected from At this time, n is selected from 1, 2 and 3, and each R 3 is independently selected from H, halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkyl Oxygen group, wherein at least one R 3 is selected from C 2-5 alkenyl and C 2-5 alkynyl, said C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1 -3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
环A选自5-6元杂芳基、C4-6环烯基和5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基和5-6元杂环烯基分别独立地任选被1或2个Re取代；Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl. The 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R e ;
T3、T4和T5分别独立地选自CR4和N；T 3 , T 4 and T 5 are independently selected from CR 4 and N;
T6和T7分别独立地选自CH和N；T 6 and T 7 are independently selected from CH and N;
R4选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitution;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自H、D、卤素、OH、NH2、CH3、CF3和CD3；Each R a , each R b , each R c , each R d and each Re are independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
所述5-6元杂芳基或5-6元杂环烯基的“杂”表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl or 5-6-membered heterocyclenyl group represents 1, 2, 3 or 4 heteroatoms independently selected from -O-, -NH-, -S- and N or heteroatom groups.
本发明的一些方案中，上述式(P4)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of the above formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元选自 Among them, the structural unit Selected from
环A和Rc如本发明所定义；Ring A and R c are as defined in the invention;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明还提供了式(P2)所示化合物或其药学上可接受的盐，
The present invention also provides a compound represented by formula (P2) or a pharmaceutically acceptable salt thereof,
其中，in,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
各R3分别独立地选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
R4选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
R5选自C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基，所述C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基分别独立地任选被1、2或3个Re取代；R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-7 ring Alkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 cycloalkyl Alkyl group, the C 1-3 alkylthio group, C 2-5 alkynyl group, C 8-12 cycloalkyl group, 8-12 membered heterocycloalkyl group, -C 1-3 alkoxy group-C 3-7 Cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 The cycloalkyl groups are independently optionally substituted by 1, 2 or 3 Re ;
T1、T2、T3和T4分别独立地选自CH和N；T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
T5、T6、T7和T8分别独立地选自CR6和N；T 5 , T 6 , T 7 and T 8 are independently selected from CR 6 and N;
R6选自H、卤素、C1-3烷基和C1-3烷氧基；R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自D、卤素、OH、NH2、C1-3烷基和-C1-3烷基-OH，所述C1-3烷基和-C1-3烷基-OH分别独立地任选被1、2或3个F取代；Each R a , each R b , each R c , each R d and each Re are independently selected from D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, The C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
n选自0、1、2和3； n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基、3-7元杂环烷基和8-12元杂环烷基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl and 8-12-membered heterocycloalkyl independently represents 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and N heteroatoms or heteroatom groups.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自D、F、Cl、OH、NH2、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、-CH2OH、-CH2CH2OH和-C(CH3)2OH分别独立地任选被1、2或3个F取代，其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein each R a , each R b , each R c , each R d and each Re is independently selected from D , F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH 2 OH, -CH 2 CH 2 OH and -C(CH 3 ) 2 OH are independently Optionally substituted by 1, 2 or 3 F, other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH，其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein each R a , each R b , each R c , each R d and each Re is independently selected from D , F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R1选自CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己基，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己基分别独立地任选被1、2或3个Ra取代，Ra及其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are independently is optionally replaced by 1, 2 or 3 Ra , and Ra and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R1选自CH3和环丙基，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 and cyclopropyl, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R2选自吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基和噁唑基，所述吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基和噁唑基分别独立地任选被1、2或3个Rb取代，Rb及其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, Pyrrolyl, thiazolyl and oxazolyl, the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl and oxazolyl groups are independently is optionally replaced by 1, 2 or 3 R b , R b and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R2选自其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R2选自其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R3选自F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3分别独立地任选被1、2或3个Rc取代，Rc及其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3. CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 are respectively independent. is optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R3选自CH3和CF3，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from CH 3 and CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R4选自F、Cl、Br、I、CH3和CD3，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from F, Cl, Br, I, CH 3 and CD 3 , and other variables are as defined in the present invention .
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R4选自F、Cl、Br、I和CH3，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from F, Cl, Br, I and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R4选自CH3，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R5选自SCH3、SCH2CH3、乙炔基、 所述SCH3、SCH2CH3、乙炔基、 分别独立地任选被1、2或3个Re取代，其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from SCH 3 , SCH 2 CH 3 , ethynyl, The SCH 3 , SCH 2 CH 3 , ethynyl, Each is independently optionally substituted by 1, 2 or 3 Re , and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R5选自SCH3、SCH2CH3、乙炔基、 所述乙炔基、 分别独立地任选被1、2或3个Re取代，Re及其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from SCH 3 , SCH 2 CH 3 , ethynyl, The ethynyl group, Each is independently optionally substituted by 1, 2 or 3 Re , and Re and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R5选自SCH2CH3、 其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from SCH 2 CH 3 , Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，R6选自H、F、Cl、Br、I、CH3和OCH3，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H, F, Cl, Br, I, CH 3 and OCH 3 , and other variables are as in the present invention defined.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，T1选自CH，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein T 1 is selected from CH, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，T1、T2、T3和T4分别独立地选自选自N，其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein T 1 , T 2 , T 3 and T 4 are each independently selected from N, and other variables are as in the present invention defined.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，T1、T2、T3和T4分别独立地选自选自CH，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein T 1 , T 2 , T 3 and T 4 are each independently selected from CH, and other variables are as in the present invention defined.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，T2选自N，其他变量如本发明所定义。In some embodiments of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein T 2 is selected from N, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，T5、T6、T7和T8分别独立地选自选自CH、CF、C(CH3)和N，其他变量如本发明所定义。 In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein T 5 , T 6 , T 7 and T 8 are independently selected from the group consisting of CH, CF, C(CH 3 ) and N, other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，结构单元选自R3及其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from R3 and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，结构单元选自其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，结构单元选自其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，结构单元选自R6及其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from R 6 and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，结构单元选自 其他变量如本发明所定义。In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其中，结构单元选自其他变量如本发明所定义。 In some aspects of the present invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其选自，
In some aspects of the invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
环A选自C8-12环烷基和8-12元杂环烷基，所述C8-12环烷基和8-12元杂环烷基分别独立地任选被1、2或3个Re取代；Ring A is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R e replaced;
T1、T2、T5、T6、T7、T8、R3、R4、Rb、Re和n如本发明所定义；T 1 , T 2 , T 5 , T 6 , T 7 , T 8 , R 3 , R 4 , R b , Re and n are as defined in the present invention;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在Carbon atoms with "*" are chiral carbon atoms, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
在本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其选自，

In some aspects of the invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof is selected from,

其中，T1、T2、T5、T6、T7、T8、R3、R4、Rb、Re和n如本发明所定义。Among them, T 1 , T 2 , T 5 , T 6 , T 7 , T 8 , R 3 , R 4 , R b , Re and n are as defined in the present invention.
在本发明的一些方案中，所述式(P2)化合物或其药学上可接受的盐，其选自，
In some aspects of the invention, the compound of formula (P2) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
环A选自C8-12环烷基和8-12元杂环烷基，所述C8-12环烷基和8-12元杂环烷基分别独立地任选被1、2或3个Re取代；Ring A is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R e replaced;
T1、T2、R3、R4、Re和n如本发明所定义。T 1 , T 2 , R 3 , R 4 , Re and n are as defined in the present invention.
在本发明的一些方案中，所述式(P2-I-1)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of formula (P2-I-1) or a pharmaceutically acceptable salt thereof is selected from,
其中，环A、T1、T2、R3、R4、Re和n如本发明所定义。Among them, ring A, T 1 , T 2 , R 3 , R 4 , Re and n are as defined in the present invention.
本发明还提供了式(P2-I)所示化合物或其药学上可接受的盐，
The present invention also provides compounds represented by formula (P2-I) or pharmaceutically acceptable salts thereof,
其中，in,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
各R3分别独立地选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
R4选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
R5选自C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C4-7环烷基、-C1-3烷硫基-C4-7环烷基和-C1-3烷氨基-C4-7环烷基，所述C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C4-7环烷基、-C1-3烷硫基-C4-7环烷基和-C1-3烷氨基-C4-7环烷基分别独立地任选被1、2或3个Re取代；T1和T2分别独立地选自CH和N；R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 4-7 ring Alkyl, -C 1-3 alkylthio-C 4-7 cycloalkyl and -C 1-3 alkylamino-C 4-7 cycloalkyl, the C 1-3 alkylthio, C 2-5 Alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 4-7 cycloalkyl, -C 1-3 alkylthio-C 4-7 Cycloalkyl and -C 1-3 alkylamino-C 4-7 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Re ; T 1 and T 2 are each independently selected from CH and N;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自卤素、OH、NH2、C1-3烷基和-C1-3烷基-OH，所述C1-3烷基和-C1-3烷基-OH分别独立地任选被1、2或3个F取代；Each R a , each R b , each R c , each R d and each Re are independently selected from halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, wherein C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基和8-12元杂环烷基分别独立地包含1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The 5-6-membered heteroaryl and 8-12-membered heterocycloalkyl groups each independently contain 1, 2, 3 or 4 heteroatoms independently selected from -O-, -NH-, -S- and N or heteroatoms.
本发明还提供了式(P2)所示化合物或其药学上可接受的盐，
The present invention also provides a compound represented by formula (P2) or a pharmaceutically acceptable salt thereof,
其中，in,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
各R3分别独立地选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
R4选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
R5选自C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基，所述C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基分别独立地任选被1、2或3个Re取代；R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-7 ring Alkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 cycloalkyl Alkyl group, the C 1-3 alkylthio group, C 2-5 alkynyl group, C 8-12 cycloalkyl group, 8-12 membered heterocycloalkyl group, -C 1-3 alkoxy group-C 3-7 Cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 The cycloalkyl groups are independently optionally substituted by 1, 2 or 3 Re ;
T1、T2、T3和T4分别独立地选自CH和N；T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
T5、T6、T7和T8分别独立地选自CR6和N；T 5 , T 6 , T 7 and T 8 are independently selected from CR 6 and N;
R6选自H、卤素、C1-3烷基和C1-3烷氧基；R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自卤素、OH、NH2、C1-3烷基和-C1-3烷基-OH，所述C1-3烷基和-C1-3烷基-OH分别独立地任选被1、2或3个F取代； Each R a , each R b , each R c , each R d and each Re are independently selected from halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, wherein C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基、3-7元杂环烷基和8-12元杂环烷基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl and 8-12-membered heterocycloalkyl independently represents 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and N heteroatoms or heteroatom groups.
本发明还提供了式(P4)所示化合物或其药学上可接受的盐，
The present invention also provides the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1或2个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b ;
各R3分别独立地选自H、卤素、C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基，所述C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from H, halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy, the C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c ;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
结构单元选自 Structural units Selected from
或者，结构单元选自此时，n选自1、2和3，各R3分别独立地选自H、卤素、C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基，其中至少有一个R3选自C2-5烯基和C2-5炔基，所述C1-3烷基、C2- 5烯基、C2-5炔基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Or, structural unit Selected from At this time, n is selected from 1, 2 and 3, and each R 3 is independently selected from H, halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkyl Oxygen group, wherein at least one R 3 is selected from C 2-5 alkenyl and C 2-5 alkynyl, said C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1 -3 alkoxy groups are independently optionally substituted by 1, 2 or 3 R c ;
环A选自5-6元杂芳基、C4-6环烯基和5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基和5-6元杂环烯基分别独立地任选被1或2个Re取代；Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl. The 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R e ;
T3、T4和T5分别独立地选自CR4和N；T 3 , T 4 and T 5 are independently selected from CR 4 and N;
T6和T7分别独立地选自CH和N；T 6 and T 7 are independently selected from CH and N;
R4选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitution;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自H、D、卤素、OH、NH2、CH3、CF3和CD3；Each R a , each R b , each R c , each R d and each Re are independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
所述5-6元杂芳基或5-6元杂环烯基的“杂”表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl or 5-6-membered heterocyclenyl group represents 1, 2, 3 or 4 heteroatoms independently selected from -O-, -NH-, -S- and N or heteroatom groups.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自H、D、F、Cl、OH、NH2、CH3、CF3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R a , each R b , each R c , each R d and each R e are independently selected From H, D, F, Cl, OH, NH2 , CH3 , CF3 and CD3 , other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自H、F、Cl、OH、NH2和CH3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R a , each R b , each R c , each R d and each R e are independently selected From H, F, Cl, OH, NH2 and CH3 , other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自F、Cl、OH、NH2和CH3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R a , each R b , each R c , each R d and each R e are independently selected From F, Cl, OH, NH2 and CH3 , other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，R1选自CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己 基，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己基分别独立地任选被1、2或3个Ra取代，Ra及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl base, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl The base, cyclobutyl, cyclopentyl and cyclohexyl are each independently optionally substituted by 1, 2 or 3 R a , and R a and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，R1选自CH3和环丙基，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 and cyclopropyl, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，R1选自CH3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，R2选自吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基和噁唑基，所述吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基和噁唑基分别独立地任选被1或2个Rb取代，Rb及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazole base, pyrrolyl, thiazolyl, thienyl, furyl and oxazolyl, the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, Furyl and oxazolyl are each independently optionally substituted by 1 or 2 R b , and R b and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，R2选自其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自H、F、Cl、Br、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3分别独立地任选被1、2或3个Rc取代，Rc及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from H, F, Cl, Br, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , said CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 is each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自F、Cl、Br、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3分别独立地任选被1、2或3个Rc取代，Rc及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from F, Cl, Br, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 are each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自F、Cl、Br、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3分别独立地任选被1、2或3个Rc取代，Rc及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from F, Cl, Br, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 , said CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 is each independently optionally substituted by 1, 2 or 3 R c , and R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自H、F和CF3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from H, F and CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，R3选自CF3，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自各R3分别独立地选自H和所述任选被1、2或3个Rc取代，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from H and each R 3 is independently selected from H and described Optionally substituted by 1, 2 or 3 Rc , other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自H、其他变量如本发明所定义。本发明的一些方案中，所述各R3分别独立地选自C2-5烯基和C2-5炔基，所述C2-5烯基和C2-5炔基分别独立地任选被1、2或3个Rc取代，各Rc及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from H, Other variables are as defined in the present invention. In some aspects of the present invention, each R 3 is independently selected from C 2-5 alkenyl and C 2-5 alkynyl, and the C 2-5 alkenyl and C 2-5 alkynyl are independently selected from any group. Choose to be replaced by 1, 2 or 3 R c , each R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自C2-5炔基，所述C2-5炔基任选被1、2或3个Rc取代，各Rc及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from C 2-5 alkynyl, and the C 2-5 alkynyl Optionally substituted by 1, 2 or 3 R c , each R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自所述任选被1、2或3个Rc取代，各Rc及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from described Optionally substituted by 1, 2 or 3 R c , each R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，各R3分别独立地选自其他变量如本发明所定义。 In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，R4选自H，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，T3、T4和T5分别独立地选自CH，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein T 3 , T 4 and T 5 are each independently selected from CH, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，T3选自CH，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein T 3 is selected from CH, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，T4选自CH，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein T 4 is selected from CH, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，T5选自CH，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein T 5 is selected from CH, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，T6为N，T7为CH，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein T 6 is N, T 7 is CH, and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，环A选自吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基、噁唑基、环丁烯基、环戊烯基、环己烯基、氧杂环戊烯基、氧杂环己烯基、氮杂环戊烯基和氮杂环己烯基，所述吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基、噁唑基、环丁烯基、环戊烯基、环己烯基、氧杂环戊烯基、氧杂环己烯基、氮杂环戊烯基和氮杂环己烯基分别独立地任选被1或2个Re取代，Re及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazole base, pyrrolyl, thiazolyl, thienyl, furyl, oxazolyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxolenyl, oxanyl, nitrogen heterocycle Pentenyl and azacyclohexenyl, the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl, oxazolyl, Cyclobutenyl, cyclopentenyl, cyclohexenyl, oxolenyl, oxalenyl, azeparenyl and azeparenyl are each independently optionally substituted by 1 or 2 Re substitutions, Re and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，环A选自吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基和噁唑基，所述吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基和噁唑基分别独立地任选被1或2个Re取代，Re及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazole base, pyrrolyl, thiazolyl, thienyl, furyl and oxazolyl, the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, Furyl and oxazolyl are each independently optionally substituted by 1 or 2 Re , and Re and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，结构单元选自其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中结构单元选自各R3分别独立地选自C2-5烯基和C2-5炔基，所述C2-5烯基和C2-5炔基分别独立地任选被1、2或3个Rc取代，各Rc及其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Each R 3 is independently selected from C 2-5 alkenyl and C 2-5 alkynyl, and the C 2-5 alkenyl and C 2-5 alkynyl are independently optionally substituted by 1, 2 or 3 R c is substituted, each R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，结构单元选自此时，n为1，R3选自C2-5烯基和C2-5炔基，所述C2-5烯基和C2-5炔基分别独立地任选被1、2或3个Rc取代，各Rc及其他变量如本发明所定义。 In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from At this time, n is 1, and R 3 is selected from C 2-5 alkenyl and C 2-5 alkynyl. The C 2-5 alkenyl and C 2-5 alkynyl are independently optionally substituted by 1, 2 or 3 R c substitutions, each R c and other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，结构单元选自 其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，结构单元选自其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，结构单元选自其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)所示化合物或其药学上可接受的盐，其中，结构单元选自 其他变量如本发明所定义。In some aspects of the present invention, the compound represented by formula (P4) or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Other variables are as defined in the present invention.
本发明的一些方案中，所述式(P4)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元选自 Among them, the structural unit Selected from
环A和Rc如本发明所定义；Ring A and R c are as defined in the invention;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明的一些方案中，所述式(P4)或(P4-II-1)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of formula (P4) or (P4-II-1) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
结构单元选自 Structural units Selected from
环A和Rc如本发明所定义。Ring A and Rc are as defined herein.
本发明的一些方案中，所述式(P4)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元选自 Among them, the structural unit Selected from
环A、R3和n如本发明所定义；Ring A, R 3 and n are as defined in the invention;
带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。 The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
本发明的一些方案中，所述式(P4)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元选自 Among them, the structural unit Selected from
环A、R3和n如本发明所定义。Ring A, R3 and n are as defined herein.
本发明的一些方案中，所述式(P4)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元T1、T2、R3和n如本发明所定义。Among them, the structural unit T 1 , T 2 , R 3 and n are as defined in the present invention.
本发明的一些方案中，所述式(P4)化合物或其药学上可接受的盐，其选自，
In some aspects of the present invention, the compound of formula (P4) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元T1、T2、R3和n如本发明所定义。Among them, the structural unit T 1 , T 2 , R 3 and n are as defined in the present invention.
本发明还提供了式(P4-I)所示化合物或其药学上可接受的盐，
The present invention also provides the compound represented by formula (P4-I) or a pharmaceutically acceptable salt thereof,
其中， in,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1或2个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b ;
各R3分别独立地选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
结构单元选自环A选自5-6元杂芳基，所述5-6元杂芳基任选被1或2个Re取代；Structural units Selected from Ring A is selected from 5-6 membered heteroaryl groups, and the 5-6 membered heteroaryl groups are optionally substituted by 1 or 2 R e ;
T3、T4和T5分别独立地选自CR4和N；T 3 , T 4 and T 5 are independently selected from CR 4 and N;
T6和T7分别独立地选自CH和N；T 6 and T 7 are independently selected from CH and N;
R4选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitution;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自卤素、OH、NH2和CH3；Each R a , each R b , each R c , each R d and each Re are independently selected from halogen, OH, NH 2 and CH 3 ;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基包含1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The 5-6 membered heteroaryl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
本发明还提供了式(P4-I)所示化合物或其药学上可接受的盐，
The present invention also provides the compound represented by formula (P4-I) or a pharmaceutically acceptable salt thereof,
其中，in,
R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
R2选自5-6元杂芳基，所述5-6元杂芳基任选被1或2个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1 or 2 R b ;
各R3分别独立地选自卤素、C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基，所述C1-3烷基、C2-5烯基、C2-5炔基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from halogen, C 1-3 alkyl, C 2-5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy, the C 1-3 alkyl, C 2 -5 alkenyl, C 2-5 alkynyl and C 1-3 alkoxy are each independently optionally substituted by 1, 2 or 3 R c ;
结构单元选自 Structural units Selected from
或者，结构单元选自此时，各R3分别独立地选自C2-5烯基和C2-5炔基，所述C2-5烯基和C2-5炔基分别独立地任选被1、2或3个Rc取代；Or, structural unit Selected from At this time, each R 3 is independently selected from C 2-5 alkenyl and C 2-5 alkynyl, and the C 2-5 alkenyl and C 2-5 alkynyl are independently optionally substituted by 1, 2 or 3 R c substitutions;
环A选自5-6元杂芳基、C4-6环烯基和5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基和5-6元杂环烯基分别独立地任选被1或2个Re取代；Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl. The 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R e ;
T3、T4和T5分别独立地选自CR4和N；T 3 , T 4 and T 5 are independently selected from CR 4 and N;
T6和T7分别独立地选自CH和N； T 6 and T 7 are independently selected from CH and N;
R4选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；R 4 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitution;
各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自H、卤素、OH、NH2和CH3；Each R a , each R b , each R c , each R d and each Re are independently selected from H, halogen, OH, NH 2 and CH 3 ;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
所述5-6元杂芳基或5-6元杂环烯基的“杂”表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl or 5-6-membered heterocyclenyl group represents 1, 2, 3 or 4 heteroatoms independently selected from -O-, -NH-, -S- and N or heteroatom groups.
本发明还有一些方案由上述变量任意组合而来。There are also some solutions of the present invention derived from any combination of the above variables.
本发明还提供了下式所示化合物或其药学上可接受的盐，


The present invention also provides compounds represented by the following formula or pharmaceutically acceptable salts thereof,


在本发明的一些方案中，所述化合物选自，





In some aspects of the invention, the compound is selected from,





本发明的实施例1中，经SFC检测(色谱柱:Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:甲醇(0.05％二乙胺)；梯度:B％:5％～40％,流速:3mL/min)，化合物1a的保留时间为1.471min。In Example 1 of the present invention, SFC detection (chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3 μm; mobile phase: Phase A: CO 2 , Phase B: methanol (0.05% diethylamine); gradient: B%: 5% ~ 40%, flow rate: 3mL/min), the retention time of compound 1a is 1.471min.
本发明的实施例5中，经SFC检测(色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[66.67％(甲醇-0.05％二乙胺)+33.33％(乙腈-二乙胺)]；梯度:B％:60％,流速:3mL/min)，化合物5a的保留时间为1.003min。In Example 5 of the present invention, after SFC detection (chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3 μm; mobile phase: A phase: CO 2 , B phase: [66.67% (methanol-0.05% diethylamine) )+33.33% (acetonitrile-diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min), the retention time of compound 5a is 1.003min.
本发明的实施例6中，经SFC检测(色谱柱:Cellulose-4 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[66.67％(异丙醇-0.05％二乙胺)+33.33％(乙腈-0.05％二乙胺)]；梯度:B％:60％,流速:3mL/min)，化合物6a的保留时间为2.825min。In Example 6 of the present invention, after SFC detection (chromatographic column: Cellulose-4 50×4.6mm ID, 3 μm; mobile phase: A phase: CO 2 , B phase: [66.67% (isopropanol-0.05% diethyl Amine) + 33.33% (acetonitrile-0.05% diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min), the retention time of compound 6a is 2.825min.
本发明的实施例7中，经SFC检测(色谱柱:Chiralpak AY-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[66.67％(甲醇0.05％二乙胺)+33.33％(乙腈-0.05％二乙胺)]；梯度:B％:60％,流速:3mL/min)，化合物7a的保留时间为0.967min。In Example 7 of the present invention, SFC detection (chromatographic column: Chiralpak AY-3 50×4.6mm ID, 3 μm; mobile phase: A phase: CO 2 , B phase: [66.67% (methanol 0.05% diethylamine) +33.33% (acetonitrile-0.05% diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min), the retention time of compound 7a is 0.967min.
本发明的实施例8中，经SFC检测(色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:75％异丙醇+25％乙腈(0.05％二乙胺)；梯度:B％:50％异丙醇+乙腈(0.05％二乙胺),流速:3mL/min)，化合物8a的保留时间为1.385min；其对映异构体的保留时间为2.037min。In Example 8 of the present invention, after SFC detection (chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3 μm; mobile phase: Phase A: CO 2 , Phase B: 75% isopropyl alcohol + 25% acetonitrile (0.05 % diethylamine); gradient: B%: 50% isopropanol + acetonitrile (0.05% diethylamine), flow rate: 3mL/min), the retention time of compound 8a is 1.385min; the retention of its enantiomers The time is 2.037min.
本发明的实施例9中，经SFC检测(色谱柱:(S,S)Whelk-O1 50×4.6mm I.D.,3.5μm；流动相:A相:CO2,B相:异丙醇(0.05％二乙胺)；梯度:B％:5％-40％,流速:3mL/min)，化合物9a的保留时间为0.991min；其对映异构体的保留时间为1.195min。In Example 9 of the present invention, after SFC detection (chromatographic column: (S, S) Whelk-O1 50×4.6mm ID, 3.5μm; mobile phase: A phase: CO 2 , B phase: isopropanol (0.05% Diethylamine); gradient: B%: 5%-40%, flow rate: 3mL/min), the retention time of compound 9a is 0.991min; the retention time of its enantiomer is 1.195min.
本发明的实施例10中，经SFC检测(色谱柱:Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相:A相:二氧化碳,B相:乙醇(0.05％二乙胺)；梯度:B％:40％),流速:3mL/min)，化合物10a的保留时间为1.332min。In Example 10 of the present invention, SFC detection (chromatographic column: Chiralpak IG-3 50×4.6mm I.D., 3 μm; mobile phase: phase A: carbon dioxide, phase B: ethanol (0.05% diethylamine); gradient: B %: 40%), flow rate: 3mL/min), the retention time of compound 10a is 1.332min.
本发明的实施例11中，经SFC检测(色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:二氧化碳,B相:异丙醇(0.05％二乙胺)；梯度:B％:40％),流速:3mL/min)，化合物11a的保留时间为1.115min；其对映异构体的保留时间为1.347min。In Example 11 of the present invention, SFC detection (chromatographic column: Chiralpak AD-3 50×4.6mm I.D., 3 μm; mobile phase: phase A: carbon dioxide, phase B: isopropyl alcohol (0.05% diethylamine); gradient :B%: 40%), flow rate: 3mL/min), the retention time of compound 11a is 1.115min; the retention time of its enantiomer is 1.347min.
本发明还提供了上述化合物或其药学上可接受的盐在制备PRMT5抑制剂相关药物上的应用。The present invention also provides the use of the above compounds or pharmaceutically acceptable salts thereof in preparing PRMT5 inhibitor-related drugs.
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗PRMT5抑制剂相关疾病的药物上的应用。The present invention also provides the use of the above-mentioned compound or a pharmaceutically acceptable salt thereof in preparing drugs for treating diseases related to PRMT5 inhibitors.
本发明还提供了下列合成方法：The invention also provides the following synthesis methods:
方法1：
method 1:
方法2：
Method 2:
其中，R5选自C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C4-7环烷基和-C1-3烷氨基-C4-7环烷基，所述C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C4-7环烷基和-C1-3烷氨基-C4-7环烷基分别独立地任选被1、2或3个Re取代；Among them, R 5 is selected from C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 4-7 cycloalkyl and -C 1-3 alkylamino-C 4 -7 cycloalkyl, the C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 4-7 cycloalkyl and -C 1-3 alkylamino- C 4-7 cycloalkyl groups are independently optionally substituted by 1, 2 or 3 Re ;
各Re分别独立地选自F、Cl、CH3、CF3和-C(CH3)2OH；Each R e is independently selected from F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH;
优选地，R5选自 Preferably, R5 is selected from
本发明还提供了下列测试方法：The invention also provides the following test methods:
测试方法1：PRMT5酶抑制活性试验Test method 1: PRMT5 enzyme inhibitory activity test
实验目的：测试小分子化合物对PRMT5·MTA的抑制作用Experimental purpose: test the inhibitory effect of small molecule compounds on PRMT5·MTA
实验材料：PRMT5/MEP50，多肽H4(1-21)，超铕抗甲基组蛋白H4精氨酸3(H4R3me)抗体，Ulight链霉亲和素，LANCE检测缓冲溶液，SAM(腺苷甲硫氨酸)，猪皮胶原蛋白，MTA(甲硫腺苷)Experimental materials: PRMT5/MEP50, peptide H4(1-21), Ultra-Europium anti-methyl histone H4 arginine 3 (H4R3me) antibody, Ulight streptavidin, LANCE detection buffer solution, SAM (adenosylmethionine), porcine skin collagen, MTA (methylthioadenosine) )
实验方法：experimental method:
(1)缓冲液配制：以10毫升为例。10mM MTA：将10毫克MTA加入3296微升DMSO中，溶解后分装并置于-80℃保存。实验当天先配现用，配置方案见表1和表2。(1) Buffer preparation: Take 10 ml as an example. 10mM MTA: Add 10 mg MTA to 3296 μl DMSO, dissolve, aliquot and store at -80°C. On the day of the experiment, it was configured for immediate use. The configuration plan is shown in Table 1 and Table 2.
表1添加MTA的缓冲液配制方案
Table 1 Buffer preparation scheme for adding MTA
表2不添加MTA的缓冲液配制方案
Table 2 Buffer preparation scheme without adding MTA
(2)化合物准备(2) Compound preparation
将化合物溶解于DMSO得到化合物母液，浓度为10mM。在化合物稀释板中进行梯度稀释，得到四个化合物孔，浓度依次为：1mM，37.037μM，1.3717μM，0.0508μM。将这四个浓度的化合物转移到化合物转移板中，转移体积为每个浓度8μL。另将DMSO加入至化合物转移板上空的孔中备用。使用微量液体转移器Echo550的连续稀释功能转移液体至实验板中，液体转移完成后就得到实验板。Dissolve the compound in DMSO to obtain a compound stock solution with a concentration of 10mM. Perform gradient dilution in the compound dilution plate to obtain four compound wells, the concentrations of which are: 1mM, 37.037μM, 1.3717μM, 0.0508μM. Transfer these four concentrations of compounds to the compound transfer plate in a transfer volume of 8 μL for each concentration. Add DMSO to the empty wells on the compound transfer plate for later use. Use the serial dilution function of the micro liquid transfer device Echo550 to transfer the liquid to the experimental plate. After the liquid transfer is completed, the experimental plate is obtained.
(3)反应(3)Reaction
使用缓冲液配制酶溶液与底物混合溶液，PRMT5浓度为7.6nM，多肽H4(1-21)浓度为0.32μM，SAM浓度为2.6μM。Use buffer to prepare a mixed solution of enzyme solution and substrate. The concentration of PRMT5 is 7.6nM, the concentration of polypeptide H4(1-21) is 0.32μM, and the concentration of SAM is 2.6μM.
使用电动多通道移液器以每孔5μL的体积将PRMT5溶液添加至实验板的化合物孔以及阴性对照孔中，在阳性对照孔中添加同等体积的缓冲液。使用离心机以1000转每分钟的转速离心一分钟，随后将实验板置于恒温孵育箱中以25℃孵育30分钟。之后用同样的方法将底物混合溶液添加至实验板的阳性对照，阴性对照以及化合物孔中，离心并以25℃孵育90分钟。Use an electric multi-channel pipette to add the PRMT5 solution to the compound wells and negative control wells of the experimental plate at a volume of 5 μL per well, and add an equal volume of buffer to the positive control wells. Use a centrifuge to centrifuge at 1000 rpm for one minute, and then place the test plate in a constant temperature incubator and incubate at 25°C for 30 minutes. Then use the same method to add the substrate mixed solution to the positive control, negative control and compound wells of the experimental plate, centrifuge and incubate at 25°C for 90 minutes.
(4)检测和结果计算(4)Detection and result calculation
原理：本实验采用PE公司的时间分辨荧光共振能量转移技术(Ultra)进行检测。反应过程中，当PRMT将底物多肽H4(1-21)甲基化以后加入两种抗体，其中超铕抗甲基组蛋白H4精氨酸3(H4R3me)抗体作为能量供体能与多肽H4(1-21)上的甲基化位点特异性结合，而Ulight作为能量受体能与多肽H4(1-21)上携带的生物素标签特异性结合。若使用一定波长的激光(本实验的激发光波长为340nm)激发，能量供体能发射出615nm波长的发射光，同时当能量供体与能量受体的空间距离足够接近时(即两个抗体同时连接在多肽H4(1-21)上)，能量供体与能量受体之间能发生能量转移，使得能量受体发射出665nm波长的发射光。使用读板机对两个发射光进行检测并求出665nm与615nm两种信号的比值，通过作图和计算即可求出待测样品的相关参数。Principle: This experiment uses PE Company’s time-resolved fluorescence resonance energy transfer technology ( Ultra) for testing. During the reaction, when PRMT methylates the substrate polypeptide H4 (1-21), two antibodies are added. Ultra-Europium anti-methyl histone H4 arginine 3 (H4R3me) antibody serves as an energy donor and can specifically bind to the methylation site on peptide H4 (1-21), while Ulight serves as an energy acceptor and can bind to peptide H4 ( 1-21) specifically binds to the biotin tag carried on it. If a laser with a certain wavelength (the excitation wavelength of this experiment is 340nm) is used for excitation, the energy donor can emit light with a wavelength of 615nm. At the same time, when the spatial distance between the energy donor and the energy acceptor is close enough (that is, the two antibodies simultaneously Connected to polypeptide H4(1-21)), energy transfer can occur between the energy donor and the energy acceptor, causing the energy acceptor to emit light with a wavelength of 665nm. Use a plate reader to detect the two emitted lights and find the ratio of the two signals, 665nm and 615nm. The relevant parameters of the sample to be tested can be found through drawing and calculation.
使用LANCE缓冲液配制抗体混合溶液，Ultra Europium-anti-methyl-Histone H4 Arginine 3(H4R3me)Antibody浓度为4nM，Ulight浓度为53.3nM。使用电动多通道移液器以每孔10μL的体积将检测溶液添加至实验板的阳性对照，阴性对照以及化合物孔中，离心并在室温孵育一小时，使用读板机Envision 2104读数。使用内插法计算化合物抑制率，将抑制率使用四参数罗吉斯方程曲线和XLfit软件作出化合物抑制曲线图和计算相关参数，包括最小抑制率，最大抑制率及IC50。抑制率计算公式为：
Use LANCE buffer to prepare antibody mixture solution, The concentration of Ultra Europium-anti-methyl-Histone H4 Arginine 3(H4R3me) Antibody is 4nM and the concentration of Ulight is 53.3nM. Use an electric multi-channel pipette to add the detection solution to the positive control, negative control and compound wells of the experimental plate in a volume of 10 μL per well, centrifuge and incubate at room temperature for one hour, and read using a plate reader Envision 2104. Use the interpolation method to calculate the compound inhibition rate, and use the four-parameter Logis equation curve and XLfit software to make the compound inhibition curve and calculate related parameters, including the minimum inhibition rate, maximum inhibition rate and IC 50 . The formula for calculating the inhibition rate is:
技术效果Technical effect
本发明化合物与PRMT5·MTA复合物有较好的结合作用，对MTAP缺失的HCT116肿瘤细胞有很好的抑制活性，对野生型HCT116肿瘤细胞的抑制活性较弱，表现出优秀的选择性；在小鼠药代动力学评价测试中，本发明化合物展现了较低的清除率和较高的药物暴露量，具有良好的体内药物代谢动力学性质；本发明化合物还表现出优秀的体内抗肿瘤药效，且给药后小鼠体重维持良好。The compound of the present invention has a good binding effect with the PRMT5·MTA complex, has good inhibitory activity against MTAP-deficient HCT116 tumor cells, and has weak inhibitory activity against wild-type HCT116 tumor cells, showing excellent selectivity; In the mouse pharmacokinetic evaluation test, the compound of the present invention showed a lower clearance rate and a higher drug exposure, and had good pharmacokinetic properties in vivo; the compound of the present invention also showed excellent anti-tumor drugs in vivo It is effective, and the body weight of mice is maintained well after administration.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。 Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear in the absence of a specific definition, but should be understood in its ordinary meaning. Where a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in pure solution or in a suitable inert solvent. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereoisomers isomer, the (D)-isomer, the (L)-isomer, as well as their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to the present invention. within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the term "cis-trans isomers" or "geometric isomers" refers to the inability of the double bonds or single bonds of the carbon atoms in the ring to rotate freely.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise stated, the term "diastereomer" refers to stereoisomers whose molecules have two or more chiral centers and are in a non-mirror image relationship between the molecules.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise stated, "(+)" means right-handed, "(-)" means left-handed, and "(±)" means racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键或楔形虚线键或用波浪线表示直形实线键或直形虚线键 Unless otherwise stated, use wedge-shaped solid line keys and wedge-shaped dotted keys Represents the absolute configuration of a three-dimensional center, using straight solid line keys and straight dotted keys Represent the relative configuration of the three-dimensional center with a wavy line Represents wedge-shaped solid line key or wedge-shaped dotted key or use tilde Represents a straight solid line key or straight dotted key
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise stated, the terms "enriched in an isomer," "enantiomerically enriched," "enriched in an enantiomer," or "enantiomerically enriched" refer to one of the isomers or enantiomers. The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise stated, the term "isomeric excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和 非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The optically active (R)- and (S)-isomers as well as the D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with a suitable optically active acid or base, and then the salt is formed by conventional methods known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, enantiomers and Separation of diastereomers is usually accomplished by the use of chromatography using a chiral stationary phase, optionally combined with chemical derivatization methods (eg carbamate generation from amines). The compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound. For example, compounds can be labeled with radioactive isotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C). For another example, deuterated drugs can be replaced by heavy hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce side effects and increase drug stability. , enhance efficacy, extend drug biological half-life and other advantages. All variations in the isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optionally" or "optionally" mean that the subsequently described event or condition may, but need not, occur, and that the description includes instances in which the stated event or condition occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e. =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (e.g., R) occurs more than once in the composition or structure of a compound, its definition in each instance is independent. Thus, for example, if a group is substituted by 0-2 R, then said group may optionally be substituted by up to two R's, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR)0-，表示该连接基团为单键。When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R)0表示该结构实际上是-A。When the number of a substituent is 0, it means that the substituent is not present. For example, -A-(R) 0 means that the structure is actually -A.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups it is connected to are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When the bond of a substituent can be cross-linked to two or more atoms in a ring, the substituent can be bonded to any atom in the ring, e.g., structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom thereof. For example, a pyridyl group as a substituent can be bonded through any one of the pyridine rings. The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When the listed linking groups do not specify the direction of connection, the direction of connection is arbitrary, for example, The middle linking group L is -MW-. At this time, -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction to the reading order from left to right. Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时， 该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括 这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。Unless otherwise specified, when a certain group has one or more attachable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the connection mode of the chemical bond is non-positioned and there is an H atom in the connectable site, then when the chemical bond is connected, The number of H atoms at this site will decrease correspondingly with the number of connected chemical bonds and become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express. For example, the straight solid line bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group; The straight dotted bond in means that it is connected to other groups through both ends of the nitrogen atoms in the group; The wavy lines in indicate that the phenyl group is connected to other groups through the 1 and 2 carbon atoms in the phenyl group; Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least In these four connection methods, even if H atoms are drawn on -N-, still includes For groups with this type of connection, only when a chemical bond is connected, the H at that position will be reduced by one and become the corresponding monovalent piperidinyl group.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1-3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C 1-3 alkyl" is used to mean a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
除非另有规定，“C2-5烯基”本身或者与其他术语联合分别表示直链或支链的包含至少一个碳-碳双键的由2至5个碳原子组成的碳氢基团，碳-碳双键可以位于该基团的任何位置上。所述C2-5烯基包括C2-4、C2-3、C5、C4、C3和C2烯基等；其可以是一价、二价或者多价。C2-5烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、戊烯基、己烯基、丁间二烯基、戊间二烯基等。Unless otherwise specified, "C 2-5 alkenyl" by itself or in combination with other terms respectively means a straight-chain or branched hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon double bond, The carbon-carbon double bond can be located anywhere in the group. The C 2-5 alkenyl group includes C 2-4 , C 2-3 , C 5 , C 4 , C 3 and C 2 alkenyl groups, etc.; it can be monovalent, divalent or multivalent. Examples of C 2-5 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, hexenyl, butadienyl, piperylene, and the like.
除非另有规定，“C2-5炔基”用于表示直链或支链的包含至少一个碳-碳三键的由2至5个碳原子组成的碳氢基团，碳-碳三键可以位于该基团的任何位置上。所述C2-5炔基包括C2-4、C2-3、C5、C4、C3和C2炔基等。其可以是一价、二价或者多价。C2-5炔基的实例包括但不限于乙炔基、丙炔基、丁炔基、戊炔基等。Unless otherwise specified, "C 2-5 alkynyl" is used to mean a straight-chain or branched hydrocarbon group consisting of 2 to 5 carbon atoms containing at least one carbon-carbon triple bond. Can be located anywhere on the group. The C 2-5 alkynyl group includes C 2-4 , C 2-3 , C 5 , C 4 , C 3 and C 2 alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C 2-5 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
除非另有规定，术语“C1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氧基包括C1-2、C2-3、C3和C2烷氧基等。C1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。Unless otherwise specified, the term "C 1-3 alkoxy" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups, etc. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“C1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷氨基包括C1-2、C3和C2烷氨基等。C1-3烷氨基的实例包括但不限于-NHCH3、-N(CH3)2、-NHCH2CH3、-N(CH3)CH2CH3、-NHCH2CH2CH3、-NHCH(CH3)2等。Unless otherwise specified, the term "C 1-3 alkylamino" means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. The C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups, etc. Examples of C 1-3 alkylamino groups include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH(CH 3 ) 2 etc.
除非另有规定，术语“C1-3烷硫基”表示通过一个硫原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C1-3烷硫基包括C1-2、C3和C2烷硫基等。C1-3烷硫基的实例包括但不限于-SCH3、-SCH2CH3、-SCH2CH2CH3、-SCH(CH3)2等。Unless otherwise specified, the term "C 1-3 alkylthio" means those alkyl groups containing 1 to 3 carbon atoms that are attached to the remainder of the molecule through a sulfur atom. The C 1-3 alkylthio group includes C 1-2 , C 3 and C 2 alkylthio groups, etc. Examples of C 1-3 alkylthio groups include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH(CH 3 ) 2 , and the like.
除非另有规定，“C3-7环烷基”本身或者与另一术语联合，用于表示由3至7个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C3-7环烷基包括C3-5、C3-6、C4-5、C4-6、C4-7和C5-6环烷基等；其可以是一价、二价或者多价。C3-7环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, "C 3-7 cycloalkyl", by itself or in combination with another term, is used to represent a saturated cyclic hydrocarbon group consisting of 3 to 7 carbon atoms, which is a monocyclic and bicyclic system, The C 3-7 cycloalkyl group includes C 3-5 , C 3-6 , C 4-5 , C 4-6 , C 4-7 and C 5-6 cycloalkyl group, etc.; it can be monovalent, Bivalent or polyvalent. Examples of C 3-7 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，“C3-6环烷基”本身或者与另一术语联合，用于表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C3-6环烷基包括C3-5、C4-5和C5-6环烷基等；其可以是一价、二价或者多价。C3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。Unless otherwise specified, "C 3-6 cycloalkyl" by itself or in combination with another term is used to represent a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, The C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl groups, etc.; it can be monovalent, divalent or multivalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，“C4-7环烷基”本身或者与另一术语联合，用于表示由4至7个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C4-7环烷基包括C4、C5、C6、C7、C4-5、C4-6和C5-7环烷基等；其可以是一价、二价或者多价。C4-7环烷基的实例包括，但不限于，环丁基、环戊基、环己基等。Unless otherwise specified, "C 4-7 cycloalkyl" by itself or in combination with another term is used to represent a saturated cyclic hydrocarbon group consisting of 4 to 7 carbon atoms, which is a monocyclic and bicyclic system, The C 4-7 cycloalkyl group includes C 4 , C 5 , C 6 , C 7 , C 4-5 , C 4-6 and C 5-7 cycloalkyl, etc.; it can be monovalent, divalent or Multivalent. Examples of C 4-7 cycloalkyl include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，“C8-12环烷基”本身或者与另一术语联合，用于表示由8至12个碳原子组成的饱和环状碳氢基团，其为单环、双环和三环体系，所述C8-12环烷基包括C9-12、C10-12、C8-10、C9-10、C10、C9和C8环烷基等；其可以是一价、二价或者多价。C8-12环烷基的实例包括，但不限于，环辛基、环壬基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷、螺[2.5]辛烷等。Unless otherwise specified, "C 8-12 cycloalkyl" by itself or in combination with another term is used to represent a saturated cyclic hydrocarbon group consisting of 8 to 12 carbon atoms, which is a monocyclic, bicyclic or tricyclic hydrocarbon group. Ring system, the C 8-12 cycloalkyl group includes C 9-12 , C 10-12 , C 8-10 , C 9-10 , C 10 , C 9 and C 8 cycloalkyl group, etc.; it can be a valence, bivalence or polyvalence. Examples of C 8-12 cycloalkyl include, but are not limited to, cyclooctyl, cyclononyl, norbornyl, [2.2.2]bicyclooctane, [4.4.0]bicyclodecane, spiro[ 2.5] Octane etc.
除非另有规定，“C4-6环烯基”本身或者与另一术语联合分别表示包含至少一个碳-碳双键的由4至6个碳原子组成的部分不饱和的环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。所述C4-6环烯基包括C4-5或C5-6环烯基等；其可以是一价、二价或者多价。C4-6环烯基的实例包括但不限于，环丁烯基、环戊烯基、环戊二烯基、环己烯基、环己二烯基等。Unless otherwise specified, "C 4-6 cycloalkenyl" by itself or in combination with another term respectively means a partially unsaturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond. The group includes single-ring and double-ring systems, wherein the double-ring system includes spiro ring, paracyclic ring and bridged ring. Any ring in this system is non-aromatic. The C 4-6 cycloalkenyl group includes C 4-5 or C 5-6 cycloalkenyl group, etc.; it can be monovalent, divalent or multivalent. Examples of C 4-6 cycloalkenyl include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.
除非另有规定，术语“8-12元杂环烷基”本身或者与其他术语联合分别表示由8至12个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。所述8-12元杂环烷基包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“8-12元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-12元杂环烷基包括8-10元、8-11元、9-10元、9-11元、9-12元、8元、9元、10元、11元和12元杂环烷基等。8-12元杂环烷基的实例包括但不限于等。Unless otherwise specified, the term "8-12 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 8 to 12 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 8-12 membered heterocycloalkyl group includes monocyclic, bicyclic and tricyclic systems, wherein the bicyclic and tricyclic systems include spirocyclic, paracyclic and bridged rings. Furthermore, in the case of the "8-12 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 3-12 yuan heterocycloalkyl group includes 8-10 yuan, 8-11 yuan, 9-10 yuan, 9-11 yuan, 9-12 yuan, 8 yuan, 9 yuan, 10 yuan, 11 yuan and 12 yuan Heterocycloalkyl, etc. Examples of 8-12 membered heterocycloalkyl groups include, but are not limited to wait.
除非另有规定，术语“3-7元杂环烷基”本身或者与其他术语联合分别表示由3至7个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-7元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-7元杂环烷基包括4-6元、5-6元、4元、5元、6元和7元杂环烷基等。3-7元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基等。4-7Unless otherwise specified, the term "3-7 membered heterocycloalkyl" by itself or in combination with other terms means a saturated cyclic group consisting of 3 to 7 ring atoms, with 1, 2, 3 or 4 ring atoms. are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes single-ring and double-ring systems, where the double-ring system includes spiro rings, parallel rings and bridged rings. Furthermore, in the case of the "3-7 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 3-7-membered heterocycloalkyl group includes 4-6-membered, 5-6-membered, 4-membered, 5-membered, 6-membered and 7-membered heterocycloalkyl groups, etc. Examples of 3-7 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- Piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl, 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperazinyl Aldinyl etc. 4-7
除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外， 就该“5-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于 Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond. , 1, 2, 3 or 4 of its ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, in which the nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally quaternized. Oxidation (i.e. NO and S(O) p , p is 1 or 2). It includes single-ring and bicyclic systems. The bicyclic system includes spiro ring, paracyclic ring and bridged ring. Any ring in this system is non-aromatic. also, In the case of the "5- to 6-membered heterocycloalkenyl", the heteroatom may occupy the attachment position of the heterocycloalkenyl to the rest of the molecule. The 5-6 membered heterocyclic alkenyl group includes 5-membered and 6-membered heterocyclic alkenyl groups. Examples of 5-6 membered heterocyclenyl groups include, but are not limited to
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。Unless otherwise specified, the terms "5-6 membered heteroaromatic ring" and "5-6 membered heteroaryl" may be used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means 5 to 6 ring atoms. It consists of a monocyclic group with a conjugated π electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atoms are optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include but are not limited to pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl). azolyl group, etc.), imidazolyl group (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazolyl) Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-thienyl, etc.) -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and methods well known to those skilled in the art. Equivalent alternatives and preferred embodiments include, but are not limited to, embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal. The light source is CuKα radiation. The scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。The solvent used in the present invention is commercially available. Compounds are named according to conventional naming principles in the field or use For software naming, commercially available compounds adopt supplier catalog names.
附图说明Description of the drawings
图1.化合物A与PRMT5·MTA复合物的结合模式图。Figure 1. Binding mode diagram of compound A and PRMT5·MTA complex.
图2.化合物B与PRMT5·MTA复合物的结合模式图。Figure 2. Binding mode diagram of compound B and PRMT5·MTA complex.
图3.化合物C与PRMT5·MTA复合物的结合模式图。Figure 3. Binding mode diagram of compound C and PRMT5·MTA complex.
图4.化合物D与PRMT5·MTA复合物的结合模式图。Figure 4. Binding mode diagram of compound D and PRMT5·MTA complex.
图5.化合物E与PRMT5·MTA复合物的结合模式图。Figure 5. Binding mode diagram of compound E and PRMT5·MTA complex.
图6.化合物F与PRMT5·MTA复合物的结合模式图。Figure 6. Binding mode diagram of compound F and PRMT5·MTA complex.
图7.化合物G与PRMT5·MTA复合物的结合模式图。Figure 7. Binding mode diagram of compound G and PRMT5·MTA complex.
图8.化合物H与PRMT5·MTA复合物的结合模式图。Figure 8. Binding mode diagram of compound H and PRMT5·MTA complex.
图9.化合物I与PRMT5·MTA复合物的结合模式图。Figure 9. Binding mode diagram of compound I and PRMT5·MTA complex.
图10.化合物J与PRMT5·MTA复合物的结合模式图。Figure 10. Binding mode diagram of compound J and PRMT5·MTA complex.
图11.化合物K与PRMT5·MTA复合物的结合模式图。Figure 11. Binding mode diagram of compound K and PRMT5·MTA complex.
图12.化合物L与PRMT5·MTA复合物的结合模式图。 Figure 12. Binding mode diagram of compound L and PRMT5·MTA complex.
图13.化合物M与PRMT5·MTA复合物的结合模式图。Figure 13. Binding mode diagram of compound M and PRMT5·MTA complex.
图14.化合物N与PRMT5·MTA复合物的结合模式图。Figure 14. Binding mode diagram of compound N and PRMT5·MTA complex.
图15.化合物O与PRMT5·MTA复合物的结合模式图。Figure 15. Binding mode diagram of compound O and PRMT5·MTA complex.
图16.人大细胞肺癌LU99皮下异种移植肿瘤模型中小鼠体重变化曲线图。Figure 16. Mouse body weight change curve in the human large cell lung cancer LU99 subcutaneous xenograft tumor model.
图17.人大细胞肺癌LU99皮下异种移植肿瘤模型中不同时间点的平均肿瘤体积。Figure 17. Average tumor volume at different time points in the human large cell lung cancer LU99 subcutaneous xenograft tumor model.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。在本发明具体实施例方式中，带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The present invention is described in detail below through examples, which do not mean any adverse limitations to the present invention. The present invention has been described in detail herein, and its specific embodiments are also disclosed. For those skilled in the art, various changes and improvements can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention. will be obvious. In specific embodiments of the present invention, the carbon atom with "*" is a chiral carbon atom, which exists in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
计算例1

Calculation example 1

本发明化合物与PRMT5·MTA复合物的结合模式预测：分子对接过程是通过使用Maestro(版本2021-2)中的Glide SP[1]精度和默认选项进行的。选取PDB数据库中PRMT5的晶体结构(PDB ID:7S1S)作为对接模板。为了准备蛋白质，使用Maestro[2]的蛋白质准备向导模块添加氢原子，并使用OPLS4力场进行能量最小化。对于配体的准备，使用LigPrep[3]生成了分子的三维结构，并使用OPLS4力场进行能量最小化[3]，使用confgen模块对小分子构象进行采样。以7S1S的配体作为质心生成了边长为 的正方体对接网格，在分子对接过程中放置实例化合物。分析蛋白质与实例化合物的相互作用，然后根据计算得到的docking score以及结合模式，选择并保存了合理对接构象。化合物A～O的结合模式见附图1～15。Prediction of the binding mode of the compound of the present invention and the PRMT5·MTA complex: the molecular docking process is by using Maestro ( Performed with Glide SP [1] precision and default options in version 2021-2). The crystal structure of PRMT5 in the PDB database (PDB ID: 7S1S) was selected as the docking template. To prepare the protein, hydrogen atoms were added using the Protein Preparation Wizard module of Maestro [2] and energy minimization was performed using the OPLS4 force field. For the preparation of ligands, LigPrep [3] was used to generate the three-dimensional structure of the molecule, and the OPLS4 force field was used for energy minimization [3] . The confgen module was used to sample the small molecule conformation. Taking the ligand of 7S1S as the center of mass, a side length of Cube docking grid for placing example compounds during molecular docking. The interaction between the protein and the example compound was analyzed, and then a reasonable docking conformation was selected and saved based on the calculated docking score and binding mode. The binding modes of compounds A to O are shown in Figures 1 to 15.
[1]Glide,LLC,New York,NY,2021.[1]Glide, LLC,New York,NY,2021.
[2]Maestro,LLC,New York,NY,2021.[2]Maestro, LLC,New York,NY,2021.
[3]LigPrep,LLC,New York,NY,2021.[3]LigPrep, LLC,New York,NY,2021.
结论：本发明系列化合物分子中胺基与Glu435和Glu444形成2个氢键相互作用；三并环位于Phe327和Trp579中间形成pi-pi相互作用；酰胺羰基与Phe580的主链NH形成氢键相互作用，三氟吡啶环提供疏水相互作用；化合物D、I、J、K、L中三并环结构的五元环上的①号氮原子，化合物F中三并环结构的呋喃环上氧原子，化合物H中三并环结构的①号氮原子可以与Lys333形成氢键。本发明系列化合物与PRMT5·MTA复合物有较好的结合作用。Conclusion: In the molecules of the series of compounds of the present invention, the amine group forms two hydrogen bond interactions with Glu435 and Glu444; the tricyclic ring is located between Phe327 and Trp579 to form a pi-pi interaction; the amide carbonyl group forms a hydrogen bond interaction with the main chain NH of Phe580 , the trifluoropyridine ring provides hydrophobic interactions; the nitrogen atom No. 1 on the five-membered ring of the tricyclic ring structure in compounds D, I, J, K, and L, the oxygen atom on the furan ring of the tricyclic ring structure in compound F, The nitrogen atom No. 1 of the tricyclic ring structure in compound H can form a hydrogen bond with Lys333. The series of compounds of the present invention have better binding effect with the PRMT5·MTA complex.
参考例1中间体A的合成
Reference Example 1 Synthesis of Intermediate A
向化合物A-1(3g,24.57mmol)和化合物A-2(5.22g,24.57mmol)的二氯甲烷(30mL)溶液中加入醋酸钾(2.89g,29.48mmol)，在15℃搅拌反应30分钟，然后向其中加入醋酸硼氢化钠(6.77g,31.93mmol)，继续搅拌1小时。反应液加水稀释(30mL)，加稀盐酸(1M,20mL)调节pH至2，二氯甲烷萃取(30mL×1)，分层，水相用10％氢氧化钠水溶液调节pH至12，二氯甲烷萃取(20mL×3)，并合并有机相，有机相经无水硫酸钠干燥，过滤，滤液减压浓缩。粗品先经制备型高效液相分离纯化(色谱柱:Kromasil Eternity XT250*80mm*10μm；流动相:[水(0.05％氨水)-乙腈]；乙腈％:20％-50％)，然后经SFC分离纯化(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:甲醇(0.1％氨水)；B％:25％-25％) 得到中间体A。SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:甲醇(0.05％二乙胺)；梯度:B％:5％～40％,流速:3mL/min，保留时间为0.950min，ee＝100％。MS:m/z 283.2[M+H]+。Potassium acetate (2.89g, 29.48mmol) was added to a solution of compound A-1 (3g, 24.57mmol) and compound A-2 (5.22g, 24.57mmol) in dichloromethane (30mL), and the reaction was stirred at 15°C for 30 minutes. , then add sodium acetate borohydride (6.77g, 31.93mmol), and continue stirring for 1 hour. The reaction solution was diluted with water (30mL), dilute hydrochloric acid (1M, 20mL) was added to adjust the pH to 2, extracted with dichloromethane (30mL×1), separated into layers, and the aqueous phase was adjusted to pH 12 with 10% sodium hydroxide aqueous solution. Extract with methane (20 mL×3), and combine the organic phases. The organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product is first purified by preparative high-performance liquid phase separation (chromatographic column: Kromasil Eternity XT250*80mm*10μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile%: 20%-50%), and then separated by SFC Purification (chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: methanol (0.1% ammonia); B%: 25%-25%) Intermediate A is obtained. SFC detection conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: methanol (0.05% diethylamine); gradient: B%: 5% ~ 40% , flow rate: 3mL/min, retention time 0.950min, ee=100%. MS: m/z 283.2[M+H] + .
实施例1
Example 1
第一步first step
将化合物1-1(5g,22.37mmol)和化合物1-2(2.73g,22.37mmol)溶在无水二氯甲烷(50mL)中，加入醋酸钾(2.63g,26.85mmol)，反应液在20℃下搅拌30分钟。加入三乙酰氧基硼氢化钠(6.16g,29.08mmol)，反应液在20℃搅拌反应1.5小时。向反应液中加入水(15mL)，混合液减压浓缩除去二氯甲烷溶液，经高效液相色谱法制备分离纯化(分离条件：色谱柱:Kromasil Eternity XT 250*80mm*10μm；流动相:[水(0.05％氨水)-乙腈；乙腈％:15％-45％)，然后再通过SFC分离(分离条件：色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:(0.1％氨水)乙醇；梯度:B％:35％-35％)得到化合物1-3a。SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:乙醇(0.05％二乙胺)；梯度:B％:5％～40％,流速:3mL/min，保留时间为1.459min，ee＝100％，其异构体的保留时间为1.692min。MS:m/z 292.9,295.0[M+H]+。Compound 1-1 (5g, 22.37mmol) and compound 1-2 (2.73g, 22.37mmol) were dissolved in anhydrous dichloromethane (50mL), potassium acetate (2.63g, 26.85mmol) was added, and the reaction solution was heated at 20 Stir for 30 minutes at ℃. Sodium triacetoxyborohydride (6.16g, 29.08mmol) was added, and the reaction solution was stirred and reacted at 20°C for 1.5 hours. Water (15 mL) was added to the reaction solution, and the mixture was concentrated under reduced pressure to remove the methylene chloride solution, and was separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Kromasil Eternity XT 250*80mm*10μm; mobile phase: [ Water (0.05% ammonia)-acetonitrile; acetonitrile%: 15%-45%), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: Phase A: CO 2 , B phase: (0.1% ammonia water) ethanol; gradient: B%: 35%-35%) to obtain compound 1-3a. SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; Mobile phase: Phase A: CO 2 , Phase B: ethanol (0.05% diethylamine); Gradient: B%: 5% ~ 40% , flow rate: 3mL/min, retention time is 1.459min, ee=100%, and the retention time of its isomer is 1.692min. MS: m/z 292.9,295.0[M+H] + .
第二步Step 2
将化合物1-3a(1g,3.41mmol)溶在无水二氯甲烷(20mL)中，加入N,N-二异丙基乙胺(881.7mg,6.82mmol,1.19mL)和碳酸酐二叔丁酯(893.4mg,4.09mmol,940μL)，反应液在20℃下搅拌12小时。将反应液减压浓缩，经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝1/1)纯化得到化合物1-4a。MS:m/z 393.0,395.0[M+H]+。Compound 1-3a (1g, 3.41mmol) was dissolved in anhydrous dichloromethane (20mL), and N,N-diisopropylethylamine (881.7mg, 6.82mmol, 1.19mL) and di-tert-butyl carbonic anhydride were added. ester (893.4 mg, 4.09 mmol, 940 μL), and the reaction solution was stirred at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to obtain compound 1-4a. MS: m/z 393.0,395.0[M+H] + .
第三步third step
将化合物1-4a(0.3g,762.82μmol)和三甲基硅乙炔(2g,20.36mmol,2.82mL)溶在三乙胺(10mL)中，氮气保护下加入碘化亚铜(29mg,152.56μmol)和二氯双(三苯基膦)钯(107mg,152.56μmol)，反应液在微波100℃下搅拌10小时。将反应液减压浓缩，经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝1/1)纯化得到化合 物1-5a。MS:m/z 411.2[M+H]+。Compound 1-4a (0.3g, 762.82μmol) and trimethylsilyl acetylene (2g, 20.36mmol, 2.82mL) were dissolved in triethylamine (10mL), and copper iodide (29mg, 152.56μmol) was added under nitrogen protection. ) and dichlorobis(triphenylphosphine)palladium (107 mg, 152.56 μmol), the reaction solution was stirred under microwave at 100°C for 10 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to obtain the compound. Things 1-5a. MS: m/z 411.2[M+H] + .
第四步the fourth step
将化合物1-5a(0.21g,511.47μmol)溶在无水二氯甲烷(5mL)中，加入盐酸/二氧六环溶液(4M,1.28mL)，反应液在20℃下搅拌2小时。将反应液减压浓缩，经高效液相色谱法制备分离纯化(分离条件：色谱柱:3_Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:20％-40％)得到化合物1-6a(盐酸盐)。MS:m/z 311.2[M+H]+。Compound 1-5a (0.21g, 511.47μmol) was dissolved in anhydrous dichloromethane (5mL), hydrochloric acid/dioxane solution (4M, 1.28mL) was added, and the reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure and separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 20 %-40%) to obtain compound 1-6a (hydrochloride). MS: m/z 311.2[M+H] + .
第五步the fifth step
将化合物1-7(70mg,346.18μmol)溶于无水N,N-二甲基甲酰胺(2mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,138mg,363.19μmol)和N,N-二异丙基乙胺(134mg,1.04mmol,180.7μL)，在20℃下搅拌30分钟，加入化合物1-6a(0.12g,盐酸盐)，在50℃下搅拌12小时。将反应液过滤，滤液经高效液相色谱法制备分离纯化(分离条件：色谱柱:Waters Xbridge C18 150*50mm*10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:40％-70％)得到化合物1-8a。MS:m/z 495.2[M+H]+。Compound 1-7 (70 mg, 346.18 μmol) was dissolved in anhydrous N,N-dimethylformamide (2 mL), and 2-(7-azabenzotriazole)-N,N,N' was added , N'-tetramethylurea hexafluorophosphate (HATU, 138 mg, 363.19 μmol) and N, N-diisopropylethylamine (134 mg, 1.04 mmol, 180.7 μL), stir for 30 minutes at 20°C, and add Compound 1-6a (0.12g, hydrochloride), stirred at 50°C for 12 hours. The reaction solution was filtered, and the filtrate was prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 40 %-70%) to obtain compound 1-8a. MS: m/z 495.2[M+H] + .
第六步Step 6
将化合物1-8a(60mg,121.30μmol)溶在无水甲醇(2mL)中，加入碳酸钾(50.3mg,363.89μmol)。反应液在20℃搅拌1小时。将反应液过滤，滤液经高效液相色谱法制备分离纯化(分离条件：色谱柱Waters Xbridge 150*25mm*5μm；流动相:[水(0.05％氨水)-乙腈]；乙腈％:22％-52％)得到化合物1a。SFC检测条件：色谱柱:Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:甲醇(0.05％二乙胺)；梯度:B％:5％～40％,流速:3mL/min，保留时间为1.471min，ee＝100％。MS:m/z 423.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.78(d,J＝4.0Hz,2H),8.54(s,1H),7.80(d,J＝8.0Hz,2H),7.69-7.55(m,1H),7.53-7.45(m,1H),7.39(t,J＝4.0Hz,1H),7.34(d,J＝8.0Hz,2H),6.49(s,2H),5.40(s,1H),4.85(d,J＝16.0Hz,1H),4.39(s,2H),2.21(s,3H),1.58(d,J＝8.0Hz,3H)。Compound 1-8a (60 mg, 121.30 μmol) was dissolved in anhydrous methanol (2 mL), and potassium carbonate (50.3 mg, 363.89 μmol) was added. The reaction solution was stirred at 20°C for 1 hour. The reaction solution was filtered, and the filtrate was prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column Waters Xbridge 150*25mm*5μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile%: 22%-52 %) to obtain compound 1a. SFC detection conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: methanol (0.05% diethylamine); gradient: B%: 5% ~ 40% , flow rate: 3mL/min, retention time 1.471min, ee=100%. MS: m/z 423.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.78 (d, J = 4.0Hz, 2H), 8.54 (s, 1H), 7.80 (d, J = 8.0Hz, 2H), 7.69-7.55 (m, 1H),7.53-7.45(m,1H),7.39(t,J＝4.0Hz,1H),7.34(d,J＝8.0Hz,2H),6.49(s,2H),5.40(s,1H), 4.85 (d, J = 16.0 Hz, 1H), 4.39 (s, 2H), 2.21 (s, 3H), 1.58 (d, J = 8.0 Hz, 3H).
实施例2
Example 2
第一步first step
将化合物1-7(0.48g,2.37mmol)溶于无水N,N-二甲基甲酰胺(10mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(947.7mg,2.49mmol)和N,N-二异丙基乙胺(613.6mg,4.75mmol,827μL)，在20℃下搅拌30分钟。加入化合物1-3a(904.7mg,3.09mmol)，在50℃下搅拌2小时。将反应液倒入水(30mL)中，用乙酸乙酯(30mL*3)萃取，合并的有机相用饱和食盐水(30mL*3)洗涤，无水硫酸钠 干燥，过滤，滤液减压浓缩，硅胶柱层析纯化(洗脱剂：二氯甲烷/甲醇＝20/1)后得到粗品，再经高效液相色谱法制备分离纯化(分离条件：色谱柱：Waters Xbridge 150*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:28％-58％)得到化合物2-1a。MS m/z:477.1,479.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.78(d,J＝4.8Hz,2H),8.56(s,1H),7.94(dd,J＝8.4Hz,2.0Hz,1H),7.80(brs,2H),7.58(brs,1H),7.48(brs,1H),7.40(t,J＝4.8Hz,1H),7.31(d,J＝8.4Hz,1H),6.48(brs,2H),5.39(brs,1H),4.80(d,J＝16.8Hz,1H),4.33(d,J＝16.0Hz,1H),2.21(s,3H),1.58(brd,J＝5.1Hz,3H)。Compound 1-7 (0.48g, 2.37mmol) was dissolved in anhydrous N,N-dimethylformamide (10mL), and 2-(7-azabenzotriazole)-N,N,N was added ',N'-tetramethylurea hexafluorophosphate (947.7mg, 2.49mmol) and N,N-diisopropylethylamine (613.6mg, 4.75mmol, 827μL), stirred at 20°C for 30 minutes. Compound 1-3a (904.7 mg, 3.09 mmol) was added and stirred at 50°C for 2 hours. Pour the reaction solution into water (30mL) and extract with ethyl acetate (30mL*3). The combined organic phases are washed with saturated brine (30mL*3) and anhydrous sodium sulfate. Dry, filter, and concentrate the filtrate under reduced pressure. Purify by silica gel column chromatography (eluent: methylene chloride/methanol = 20/1) to obtain the crude product, which is then prepared, separated, and purified by high-performance liquid chromatography (separation conditions: chromatography column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 28%-58%) to obtain compound 2-1a. MS m/z:477.1,479.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.78 (d, J = 4.8Hz, 2H), 8.56 (s, 1H), 7.94 (dd, J = 8.4Hz, 2.0Hz, 1H), 7.80 (brs ,2H),7.58(brs,1H),7.48(brs,1H),7.40(t,J＝4.8Hz,1H),7.31(d,J＝8.4Hz,1H),6.48(brs,2H),5.39 (brs,1H),4.80(d,J＝16.8Hz,1H),4.33(d,J＝16.0Hz,1H),2.21(s,3H),1.58(brd,J＝5.1Hz,3H).
第二步Step 2
向化合物2-1a(100mg,209.49μmol)和化合物2-2(27.4mg,314.23μmol)的四氢呋喃(2mL)溶液中加入叔丁醇钠(50.3mg,523.72μmol)，甲烷磺酸(2-二环己基膦-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-甲胺基-1,1-联苯-2-基)钯(II)(38.6mg,41.90μmol)和2-双环己基膦-2,6-二异丙氧基-1,1-联苯(19.6mg,41.90μmol)，混合物于微波120℃条件下搅拌反应1.5小时。反应液经硅藻土过滤，滤液减压浓缩。粗品经制备型高效液相分离纯化(分离条件：色谱柱：Waters Xbridge 150*25mm*5μm；流动相:[水(0.05％氨水)-乙腈]；乙腈％:13％-43％)得到化合物2a。SFC检测条件：色谱柱:Chiralcel OJ-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:甲醇(0.05％二乙胺)；梯度:B％:5％～40％,流速:3mL/min，保留时间为1.662min，ee＝100％。MS:m/z 484.4[M+H]+。1H NMR(400MHz,CD3OD)δ8.64(brs,2H),7.93-7.65(m,5H),7.21-7.23(m,1H),7.10(d,J＝8.4Hz,1H),6.90(d,J＝6.8Hz,1H),5.49-5.37(m,1H),4.89-4.80(m,2H),4.65-4.63(m,1H),4.39-4.36(m,3H),3.31(d,J＝7.2Hz,2H),3.22-3.16(m,1H),2.20(s,3H),1.55(br s,3H)。To a solution of compound 2-1a (100 mg, 209.49 μmol) and compound 2-2 (27.4 mg, 314.23 μmol) in tetrahydrofuran (2 mL), sodium tert-butoxide (50.3 mg, 523.72 μmol), methane sulfonic acid (2-di Cyclohexylphosphine-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-methylamino-1,1-biphenyl-2-yl)palladium (II) (38.6 mg, 41.90 μmol) and 2-bicyclohexylphosphine-2,6-diisopropoxy-1,1-biphenyl (19.6 mg, 41.90 μmol). The mixture was stirred and reacted under microwave conditions at 120°C. 1.5 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid phase separation (separation conditions: chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (0.05% ammonia)-acetonitrile]; acetonitrile%: 13%-43%) to obtain compound 2a . SFC detection conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: methanol (0.05% diethylamine); gradient: B%: 5% ~ 40% , flow rate: 3mL/min, retention time 1.662min, ee=100%. MS: m/z 484.4[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.64 (brs, 2H), 7.93-7.65 (m, 5H), 7.21-7.23 (m, 1H), 7.10 (d, J = 8.4Hz, 1H), 6.90 (d,J＝6.8Hz,1H),5.49-5.37(m,1H),4.89-4.80(m,2H),4.65-4.63(m,1H),4.39-4.36(m,3H),3.31(d ,J＝7.2Hz,2H),3.22-3.16(m,1H),2.20(s,3H),1.55(br s,3H).
实施例3
Example 3
向化合物2-1a(50mg,104.74μmol)和化合物3-1(环丙基甲胺,11.2mg,157.12μmol)的四氢呋喃(2mL)溶液中加入叔丁醇钠(25.2mg,261.86μmol)，甲烷磺酸(2-二环己基膦-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-甲胺基-1,1-联苯-2-基)钯(II)(19.3mg,20.95μmol)和2-(二环己基膦基)-3,6-二甲氧基-2-4-6-三异丙基-1,1-联苯(11.2mg,20.95μmol)，混合物于微波120℃条件下搅拌反应1小时。反应液经硅藻土过滤，滤液减压浓缩。反应过程中发生消旋，粗品先后经制备型高效液相(分离条件：色谱柱:Waters Xbridge 150*25mm*5μm；流动相:[水(0.05％氨水)-乙腈]；乙腈％:23％-53％)和SFC分离纯化(分离条件：色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:[25％乙腈+75％异丙醇，混合后再加0.1％氨水]；B％:40％-40％)得到化合物3a和3b。To a solution of compound 2-1a (50 mg, 104.74 μmol) and compound 3-1 (cyclopropylmethylamine, 11.2 mg, 157.12 μmol) in tetrahydrofuran (2 mL) was added sodium tert-butoxide (25.2 mg, 261.86 μmol), methane Sulfonic acid (2-dicyclohexylphosphine-3,6-dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-methylamino-1,1-biphenyl -2-yl)palladium(II) (19.3 mg, 20.95 μmol) and 2-(dicyclohexylphosphino)-3,6-dimethoxy-2-4-6-triisopropyl-1,1 -Biphenyl (11.2 mg, 20.95 μmol), the mixture was stirred and reacted under microwave conditions at 120°C for 1 hour. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. Racemization occurred during the reaction, and the crude product was successively separated by preparative high-performance liquid phase (separation conditions: chromatographic column: Waters 53%) and SFC separation and purification (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [25% acetonitrile + 75% isopropyl alcohol, after mixing Add 0.1% ammonia water]; B%: 40%-40%) to obtain compounds 3a and 3b.
化合物3a：SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[20％(乙腈-0.05％二乙胺)+80％(异丙醇-0.05％二乙胺)]；梯度:B％:40％,流速:3mL/min，保留时间为1.647 min，ee＝100％。1H NMR(400MHz,CD3OD)δ8.72(brs,2H),7.89-7.41(m,5H),7.35-7.25(m,1H),7.22-7.13(m,1H),7.03-6.91(m,1H),5.61-5.32(m,1H),4.59(brs,2H),2.93(d,J＝6.8Hz,2H),2.28(s,3H),1.63(br s,3H),1.08-1.05(m,1H),0.56-0.42(m,2H),0.26-0.22(m,2H)。MS:m/z 468.1[M+H]+。Compound 3a: SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: [20% (acetonitrile-0.05% diethylamine) + 80% ( Isopropyl alcohol-0.05% diethylamine)]; gradient: B%: 40%, flow rate: 3mL/min, retention time is 1.647 min,ee=100%. 1 H NMR (400MHz, CD 3 OD) δ8.72(brs,2H),7.89-7.41(m,5H),7.35-7.25(m,1H),7.22-7.13(m,1H),7.03-6.91( m,1H),5.61-5.32(m,1H),4.59(brs,2H),2.93(d,J＝6.8Hz,2H),2.28(s,3H),1.63(br s,3H),1.08- 1.05(m,1H),0.56-0.42(m,2H),0.26-0.22(m,2H). MS:m/z 468.1[M+H] + .
化合物3b：SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[20％(乙腈-0.05％二乙胺)+80％(异丙醇-0.05％二乙胺)]；梯度:B％:40％,流速:3mL/min，保留时间为1.926min，ee＝95.62％。1H NMR(400MHz,CD3OD)δ8.74(brs,2H),7.89-7.45(m,5H),7.38-7.28(m,1H),7.22-7.16(m,1H),7.01-6.95(m,1H),5.63-5.37(m,1H),4.58(s,2H),2.95(d,J＝6.8Hz,2H),2.29(br s,3H),1.64(br s,3H),1.14-1.02(m,1H),0.57-0.54(m,2H),0.28-0.23(m,2H)。MS:m/z 468.2[M+H]+。Compound 3b: SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: [20% (acetonitrile-0.05% diethylamine) + 80% ( Isopropyl alcohol-0.05% diethylamine)]; gradient: B%: 40%, flow rate: 3mL/min, retention time is 1.926min, ee=95.62%. 1 H NMR (400MHz, CD 3 OD) δ8.74(brs,2H),7.89-7.45(m,5H),7.38-7.28(m,1H),7.22-7.16(m,1H),7.01-6.95( m,1H),5.63-5.37(m,1H),4.58(s,2H),2.95(d,J＝6.8Hz,2H),2.29(br s,3H),1.64(br s,3H),1.14 -1.02(m,1H),0.57-0.54(m,2H),0.28-0.23(m,2H). MS: m/z 468.2[M+H] + .
实施例4
Example 4
第一步first step
将化合物4-2(734mg,6.01mmol)溶在无水四氢呋喃(25mL)中，冷却至0℃，加入钠氢(240.4mg,6.01mmol,60％含量)，反应液在0℃下搅拌30分钟。将化合物4-1(1.1g,6.01mmol)加入到反应液中，反应液在0～10℃反应12小时。向反应液中加入饱和氯化铵水溶液(25mL)，用乙酸乙酯(25mL*3)萃取，合并的有机相用饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析纯化(洗脱剂：石油醚/乙酸乙酯＝2:1)得到化合物4-3。MS:m/z 225.1[M+H]+。Compound 4-2 (734 mg, 6.01 mmol) was dissolved in anhydrous tetrahydrofuran (25 mL), cooled to 0°C, sodium hydrogen (240.4 mg, 6.01 mmol, 60% content) was added, and the reaction solution was stirred at 0°C for 30 minutes. . Compound 4-1 (1.1g, 6.01mmol) was added to the reaction solution, and the reaction solution was reacted at 0 to 10°C for 12 hours. Add saturated aqueous ammonium chloride solution (25 mL) to the reaction solution, extract with ethyl acetate (25 mL*3), wash the combined organic phase once with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate and purify through silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 2:1) to obtain compound 4-3. MS: m/z 225.1[M+H] + .
第二步Step 2
将化合物4-3(1g,4.46mmol)溶在甲醇(10mL)中，氩气保护下加入钯碳(0.1g,446.02μmol,10％含 量)。置换三次氩气，三次氢气，反应液在氢气氛围(50psi)80℃下搅拌12小时。将反应液直接过滤，滤液减压浓缩得到化合物4-4。MS:m/z 229.1[M+H]+。Compound 4-3 (1g, 4.46mmol) was dissolved in methanol (10mL), and palladium on carbon (0.1g, 446.02μmol, 10% containing quantity). Argon gas was replaced three times and hydrogen gas was replaced three times, and the reaction solution was stirred at 80°C in a hydrogen atmosphere (50 psi) for 12 hours. The reaction solution was directly filtered, and the filtrate was concentrated under reduced pressure to obtain compound 4-4. MS: m/z 229.1[M+H] + .
第三步third step
将化合物4-4(1.3g,5.70mmol)和化合物1-2(650mg,5.32mmol)溶于无水二氯甲烷(5mL)中，加入醋酸钾(626.8mg,6.39mmol)，在20℃下搅拌0.5小时，加入三乙酰氧基硼氢化钠(1.47g,6.92mmol)，反应液在20℃下搅拌1小时。向反应液中加入饱和氯化铵水溶液(25mL)，用二氯甲烷(25mL*3)萃取，合并的有机相用饱和食盐水(50mL)洗涤一次，无水硫酸钠干燥，过滤，滤液减压浓缩，经硅胶柱层析(洗脱剂：乙酸乙酯)纯化得到化合物4-5粗品。Compound 4-4 (1.3g, 5.70mmol) and compound 1-2 (650mg, 5.32mmol) were dissolved in anhydrous dichloromethane (5mL), potassium acetate (626.8mg, 6.39mmol) was added, and the mixture was heated at 20°C. Stir for 0.5 hours, add sodium triacetoxyborohydride (1.47g, 6.92mmol), and stir the reaction solution at 20°C for 1 hour. Add saturated aqueous ammonium chloride solution (25 mL) to the reaction solution, extract with dichloromethane (25 mL*3), wash the combined organic phases once with saturated brine (50 mL), dry over anhydrous sodium sulfate, filter, and depressurize the filtrate Concentrate and purify through silica gel column chromatography (eluent: ethyl acetate) to obtain crude compound 4-5.
第四步the fourth step
将化合物1-7(78.6mg,388.80μmol)溶于无水N,N-二甲基甲酰胺(3mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(147.8mg,388.80μmol)和N,N-二异丙基乙胺(150.8mg,1.17mmol,203μL)，在20℃下搅拌30分钟，加入化合物4-5(130mg,388.80μmol)，在50℃下搅拌12小时。将反应液过滤，滤液经高效液相色谱法制备分离纯化(分离条件：色谱柱:Waters Xbridge C18 150*50mm*10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:29％-59％)得到化合物4。Compound 1-7 (78.6 mg, 388.80 μmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), and 2-(7-azabenzotriazole)-N,N,N was added ',N'-Tetramethylurea hexafluorophosphate (147.8mg, 388.80μmol) and N,N-diisopropylethylamine (150.8mg, 1.17mmol, 203μL), stir at 20°C for 30 minutes, add Compound 4-5 (130 mg, 388.80 μmol), stirred at 50°C for 12 hours. The reaction solution was filtered, and the filtrate was prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 29 %-59%) to obtain compound 4.
第五步the fifth step
化合物4通过SFC分离(分离条件：色谱柱:DAICEL CHIRALPAK IC(250mm*30mm,10μm)；流动相:A相:CO2,B相:[60％甲醇+30％乙腈+10％(1％氨水乙醇溶液)]；B％:60％-60％)得到化合物4a和化合物4b。Compound 4 was separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [60% methanol + 30% acetonitrile + 10% (1% ammonia water) Ethanol solution)]; B%: 60%-60%) to obtain compound 4a and compound 4b.
化合物4a：SFC检测条件：色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[80％(甲醇-0.05％二乙胺)+20％(乙腈-0.05％二乙胺)]；梯度:B％:60％,流速:3mL/min，保留时间1.408min，ee＝99.99％。MS:m/z 519.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.79(d,J＝8.0Hz,2H),8.15(brs,1H),7.79(brs,2H),7.58(brs,1H),7.48(brs,1H),7.39(t,J＝4.0Hz,1H),7.34-7.26(m,2H),6.45(s,2H),5.56-5.32(m,1H),4.86-4.72(m,1H),4.31-4.14(m,1H)，4.09(d,J＝8.0Hz,2H),2.72-2.68(m,3H),2.37-2.33(m,2H),2.22(s,3H),1.55(d,J＝8.0Hz,3H)。Compound 4a: SFC detection conditions: Chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: [80% (methanol-0.05% diethylamine) + 20% ( Acetonitrile-0.05% diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min, retention time 1.408min, ee=99.99%. MS:m/z 519.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.79 (d, J = 8.0Hz, 2H), 8.15 (brs, 1H), 7.79 (brs, 2H), 7.58 (brs, 1H), 7.48 (brs, 1H ),7.39(t,J＝4.0Hz,1H),7.34-7.26(m,2H),6.45(s,2H),5.56-5.32(m,1H),4.86-4.72(m,1H),4.31- 4.14(m,1H), 4.09(d,J＝8.0Hz,2H),2.72-2.68(m,3H),2.37-2.33(m,2H),2.22(s,3H),1.55(d,J＝ 8.0Hz,3H).
化合物4b：SFC检测条件：色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[80％(甲醇-0.05％二乙胺)+20％(乙腈-0.05％二乙胺)]；梯度:B％:60％,流速:3mL/min，保留时间2.009min，ee＝100％。MS:m/z 519.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.79(d,J＝8.0Hz,2H),8.15(brs,1H),7.79(brs,2H),7.58(brs,1H),7.49(brs,1H),7.39(t,J＝4.0Hz,1H),7.34-7.26(m,2H),6.46(brs,2H),5.51-5.33(m,1H),4.87-4.71(m,1H),4.27-4.17(m,1H),5.09(d,J＝8.0Hz,2H),2.78-2.68(m,3H),2.45-2.28(m,3H),1.56(d,J＝8.0Hz,3H)。Compound 4b: SFC detection conditions: Chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: [80% (methanol-0.05% diethylamine) + 20% ( Acetonitrile-0.05% diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min, retention time 2.009min, ee=100%. MS:m/z 519.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.79 (d, J = 8.0Hz, 2H), 8.15 (brs, 1H), 7.79 (brs, 2H), 7.58 (brs, 1H), 7.49 (brs, 1H),7.39(t,J＝4.0Hz,1H),7.34-7.26(m,2H),6.46(brs,2H),5.51-5.33(m,1H),4.87-4.71(m,1H),4.27 -4.17(m,1H),5.09(d,J＝8.0Hz,2H),2.78-2.68(m,3H),2.45-2.28(m,3H),1.56(d,J＝8.0Hz,3H).
实施例5
Example 5
第一步first step
将化合物1-4a(0.3g,762.82μmol)和化合物5-1(1.71g,20.36mmol,1.99mL)加入微波管中，氮气保护下，加入三乙胺(10mL)、碘化亚铜(29mg,152.56μmol)和二氯双(三苯基膦)钯(107mg,152.56μmol)。微波100℃下搅拌10小时。将反应液减压浓缩，经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝1/1)纯化得到化合物5-2a。MS:m/z 397.3[M+H]+。Add compound 1-4a (0.3g, 762.82μmol) and compound 5-1 (1.71g, 20.36mmol, 1.99mL) into a microwave tube. Under nitrogen protection, add triethylamine (10mL) and copper iodide (29mg , 152.56 μmol) and bis(triphenylphosphine)palladium dichloride (107 mg, 152.56 μmol). Microwave at 100°C and stir for 10 hours. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to obtain compound 5-2a. MS: m/z 397.3[M+H] + .
第二步Step 2
将化合物5-2a(0.23g,580.10μmol)溶在乙酸乙酯(2mL)中，加入盐酸/二氧六环溶液(4M,1.45mL)，反应液在20℃下搅拌0.5小时。将反应液减压浓缩,经高效液相色谱法制备分离纯化(分离条件：色谱柱:3_Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:0％-22％)得到化合物5-3a(盐酸盐)。MS:m/z 297.1[M+H]+。Compound 5-2a (0.23g, 580.10μmol) was dissolved in ethyl acetate (2mL), hydrochloric acid/dioxane solution (4M, 1.45mL) was added, and the reaction solution was stirred at 20°C for 0.5 hours. The reaction solution was concentrated under reduced pressure and separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 0 %-22%) to obtain compound 5-3a (hydrochloride). MS: m/z 297.1[M+H] + .
第三步third step
将化合物1-7(48mg,236.19μmol)溶于无水N,N-二甲基甲酰胺(3mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(98.8mg,259.81μmol)和N,N-二异丙基乙胺(91.6mg,708.58μmol,123μL)，在20℃下搅拌30分钟，加入化合物5-3a(70mg,盐酸盐)，在50℃下搅拌4小时。将反应液减压浓缩，经高效液相色谱法制备分离纯化(分离条件：色谱柱:Waters Xbridge 150*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:23％-53％)，再经SFC分离(分离条件：色谱柱:DAICEL CHIRALPAK IC(250mm*30mm,10μm)；流动相:A相:CO2,B相:[60％甲醇+30％乙腈+10％(1％氨水乙醇溶液)]；B％:60％-60％)得到化合物5a。SFC检测条件：色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[66.67％(甲醇-0.05％二乙胺)+33.33％(乙腈-二乙胺)]；梯度:B％:60％,流速:3mL/min，保留时间为1.003min，ee＝100％。LCMS m/z:481.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ8.78(d,J＝4.8Hz,2H),8.44(s,1H),7.89-7.65(m,3H),7.61(brs,1H),7.56-7.45(m,1H),7.39(t,J＝4.8Hz,1H),7.30(br d,J＝8.0Hz,1H),6.51(br s,2H),5.54(s,1H),5.41(br s,1H),4.86(br d,J＝17.2Hz,1H),4.39(br d,J＝15.6Hz,1H),2.22(br s,3H),1.57(br d,J＝6.8Hz,3H),1.47(s,6H)。Compound 1-7 (48 mg, 236.19 μmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), and 2-(7-azabenzotriazole)-N,N,N' was added , N'-tetramethylurea hexafluorophosphate (98.8 mg, 259.81 μmol) and N, N-diisopropylethylamine (91.6 mg, 708.58 μmol, 123 μL), stir for 30 minutes at 20°C, and add the compounds 5-3a (70 mg, hydrochloride), stir at 50°C for 4 hours. The reaction solution was concentrated under reduced pressure and separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 23 %-53%), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK IC (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [60% methanol + 30% acetonitrile + 10 % (1% ammonia ethanol solution)]; B%: 60%-60%) to obtain compound 5a. SFC detection conditions: Chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: [66.67% (methanol-0.05% diethylamine) + 33.33% (acetonitrile-diethylamine) Ethylamine)]; gradient: B%: 60%, flow rate: 3mL/min, retention time: 1.003min, ee=100%. LCMS m/z:481.2[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ8.78 (d, J = 4.8 Hz, 2H), 8.44 (s, 1H), 7.89-7.65 (m, 3H), 7.61 (brs, 1H), 7.56- 7.45(m,1H),7.39(t,J＝4.8Hz,1H),7.30(br d,J＝8.0Hz,1H),6.51(br s,2H),5.54(s,1H),5.41(br s,1H),4.86(br d,J＝17.2Hz,1H),4.39(br d,J＝15.6Hz,1H),2.22(br s,3H),1.57(br d,J＝6.8Hz,3H ),1.47(s,6H).
实施例6
Example 6
第一步first step
将化合物1-4a(0.3g,762.82μmol)和化合物6-1(169mg,1.14mmol)溶在无水二氧六环(10mL)中，氮气保护下，加入三(二亚苄基丙酮)二钯(139.7mg,152.56μmol)，(±)-2,2-双(二苯膦基)-11-联萘(95mg,152.56μmol)和碳酸铯(745.6mg,2.29mmol)，反应液在氮气保护下80℃搅拌12小时。将反应液过滤，滤液减压浓缩，经薄层色谱(展开剂：石油醚/乙酸乙酯＝1/1)纯化后再经高效液相色谱法制备分离纯化(分离条件：色谱柱3_Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:22％-42％)得到化合物6-2a。MS:m/z 424.3[M+H]+。Compound 1-4a (0.3g, 762.82μmol) and compound 6-1 (169mg, 1.14mmol) were dissolved in anhydrous dioxane (10mL), and tris(dibenzylideneacetone)dioxanol was added under nitrogen protection. Palladium (139.7mg, 152.56μmol), (±)-2,2-bis(diphenylphosphino)-11-binaphthyl (95mg, 152.56μmol) and cesium carbonate (745.6mg, 2.29mmol), the reaction solution was in nitrogen Stir at 80°C for 12 hours under protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure, purified by thin layer chromatography (developing solvent: petroleum ether/ethyl acetate = 1/1), and then separated and purified by high performance liquid chromatography (separation conditions: chromatography column 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 22%-42%) to obtain compound 6-2a. MS: m/z 424.3[M+H] + .
第二步Step 2
将化合物6-2a(65mg,153.46μmol)溶在乙酸乙酯(2mL)中，加入盐酸/二氧六环溶液(4M,2mL)，反应液在20℃下搅拌1小时。将反应液减压浓缩得到化合物6-3a(盐酸盐)。MS:m/z 324.2[M+H]+。Compound 6-2a (65 mg, 153.46 μmol) was dissolved in ethyl acetate (2 mL), hydrochloric acid/dioxane solution (4 M, 2 mL) was added, and the reaction solution was stirred at 20°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 6-3a (hydrochloride). MS: m/z 324.2[M+H] + .
第三步third step
将化合物1-7(34mg,170.05μmol)溶于无水N,N-二甲基甲酰胺(3mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(71mg,187.05μmol)和N,N-二异丙基乙胺(66mg,510.15μmol,89μL)，在20℃下搅拌30分钟，加入化合物6-3a(55mg,盐酸盐)，在50℃下搅拌4小时。将反应液减压浓缩，滤液经高效液相色谱法制备分离纯化(分离条件：色谱柱:DAICEL CHIRALCEL OX(250mm*30mm,10μm)；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:3％-66％)，再经SFC分离(分离条件：色谱柱:DAICEL CHIRALPAK AS(250mm*30mm,10μm)；流动相:A相:CO2,B相:[60％异丙醇+30％乙腈+10％(乙醇-1％氨水)]；B％:70％-70％)得到化合物6a。SFC检测条件：色谱柱:Cellulose-4 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[66.67％(异丙醇-0.05％二乙胺)+33.33％(乙腈-0.05％二乙胺)]；梯度:B％:60％,流速:3mL/min，保留时间为2.825min，ee＝99.19％。MS:m/z 508.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.78(d,J＝4.8Hz,2H),8.15(brs,1H),7.78(brs,2H),7.57(brs,1H),7.48(brs,1H),7.39(t,J＝4.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.15(d,J＝8.4Hz,1H),6.46(brs,2H),5.38(brs,1H),4.78(brs,1H),4.20(brs,1H),3.22(t,J＝4.8Hz,4H),2.21(s,3H),1.56(d,J＝6.8Hz,3H),1.45(t,J＝5.2Hz,4H),0.34(s,4H)。Compound 1-7 (34 mg, 170.05 μmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), and 2-(7-azabenzotriazole)-N,N,N' was added , N'-tetramethylurea hexafluorophosphate (71 mg, 187.05 μmol) and N, N-diisopropylethylamine (66 mg, 510.15 μmol, 89 μL), stir at 20°C for 30 minutes, and add compound 6- 3a (55 mg, hydrochloride), stir at 50°C for 4 hours. The reaction solution was concentrated under reduced pressure, and the filtrate was prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; Acetonitrile%: 3%-66%), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AS (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [60% isopropanol +30% acetonitrile +10% (ethanol-1% ammonia)]; B%: 70%-70%) to obtain compound 6a. SFC detection conditions: Chromatographic column: Cellulose-4 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: [66.67% (isopropyl alcohol-0.05% diethylamine) + 33.33% (acetonitrile- 0.05% diethylamine)]; gradient: B%: 60%, flow rate: 3mL/min, retention time is 2.825min, ee=99.19%. MS: m/z 508.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.78 (d, J = 4.8Hz, 2H), 8.15 (brs, 1H), 7.78 (brs, 2H), 7.57 (brs, 1H), 7.48 (brs, 1H),7.39(t,J＝4.8Hz,1H),7.27(d,J＝8.0Hz,1H),7.15(d,J＝8.4Hz,1H),6.46(brs,2H),5.38(brs, 1H),4.78(brs,1H),4.20(brs,1H),3.22(t,J＝4.8Hz,4H),2.21(s,3H),1.56(d,J＝6.8Hz,3H),1.45( t,J＝5.2Hz,4H),0.34(s,4H).
实施例7
Example 7
第一步first step
将化合物1-4a(0.3g,762.82μmol)和化合物7-1(95mg,839.10μmol)溶在无水二氧六环(5mL)中，氮气保护下，加入三(二亚苄基丙酮)二钯(139.7mg,152.56μmol)，(±)-2,2-双(二苯膦基)-11-联萘(95mg,152.56μmol)和碳酸铯(745.6mg,2.29mmol)，反应液在氮气保护下80℃搅拌12小时。将反应液过滤，滤液减压浓缩，经制备薄层色谱(展开剂：石油醚/乙酸乙酯＝1/1)分离纯化得到化合物7-2a。MS:m/z 426.3[M+H]+。第二步Compound 1-4a (0.3g, 762.82μmol) and compound 7-1 (95mg, 839.10μmol) were dissolved in anhydrous dioxane (5mL). Under nitrogen protection, tris(dibenzylideneacetone) di Palladium (139.7mg, 152.56μmol), (±)-2,2-bis(diphenylphosphino)-11-binaphthyl (95mg, 152.56μmol) and cesium carbonate (745.6mg, 2.29mmol), the reaction solution was in nitrogen Stir at 80°C for 12 hours under protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The compound 7-2a was separated and purified by preparative thin layer chromatography (developing solvent: petroleum ether/ethyl acetate = 1/1). MS: m/z 426.3[M+H] + . Step 2
将化合物7-2a(80mg,188.00μmol)溶在乙酸乙酯(2mL)中，加入盐酸/二氧六环溶液(4M,2mL)，反应液在20℃下搅拌12小时。将反应液减压浓缩，经高效液相色谱法制备分离(分离条件：色谱柱:3_Phenomenex Luna C18 75*30mm*3μm；流动相:[水(0.05％盐酸)-乙腈]；乙腈％:0％-17％)得到化合物7-3a(盐酸盐)。MS:m/z 326.1[M+H]+。Compound 7-2a (80 mg, 188.00 μmol) was dissolved in ethyl acetate (2 mL), hydrochloric acid/dioxane solution (4 M, 2 mL) was added, and the reaction solution was stirred at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure and separated by high performance liquid chromatography (separation conditions: chromatographic column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 0% -17%) to obtain compound 7-3a (hydrochloride). MS: m/z 326.1[M+H] + .
第三步third step
将化合物1-7(31mg,153.65μmol)溶于无水N,N-二甲基甲酰胺(3mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(64mg,169.02μmol)和N,N-二异丙基乙胺(59mg,460.96μmol,80μL)，在20℃下搅拌30分钟。加入化合物7-3a(50mg,盐酸盐)，在50℃下搅拌4小时，将反应液减压浓缩，滤液经高效液相色谱法制备分离纯化(分离条件：色谱柱:Waters Xbridge 150*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；乙腈％:23％-53％)，再通过SFC分离(分离条件：色谱柱:DAICEL CHIRALPAK AY-H(250mm*30mm,10μm)；流动相:A相:CO2,B相:[75％甲醇+15％乙腈+10％(1％氨水乙醇溶液)]；B％:70％-70％)得到化合物7a。SFC检测条件：色谱柱:Chiralpak AY-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[66.67％(甲醇0.05％二乙胺)+33.33％(乙腈-0.05％二乙胺)]；梯度:B％:60％,流速:3mL/min，保留时间为0.967min，ee＝100％。MS:m/z 510.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.79(d,J＝4.8Hz,2H),8.06(brs,1H),7.78(brs,2H),7.55(brs,1H),7.44(brs,1H),7.40(t,J＝4.8Hz,1H),7.17(s,2H),6.46(brs,2H),5.37(brs,1H),4.79(brs,1H),4.43(s,2H),4.18(brs,1H),3.43-3.39(m,2H),2.81(d,J＝10.4Hz,2H),2.21(s,3H),1.84(s,4H),1.56(d,J＝6.0Hz,3H)。Compound 1-7 (31 mg, 153.65 μmol) was dissolved in anhydrous N,N-dimethylformamide (3 mL), and 2-(7-azabenzotriazole)-N,N,N' was added , N'-tetramethylurea hexafluorophosphate (64 mg, 169.02 μmol) and N, N-diisopropylethylamine (59 mg, 460.96 μmol, 80 μL), stirred at 20°C for 30 minutes. Add compound 7-3a (50 mg, hydrochloride), stir at 50°C for 4 hours, and concentrate the reaction solution under reduced pressure. The filtrate is prepared, separated and purified by high performance liquid chromatography (separation conditions: chromatographic column: Waters Xbridge 150*25mm *5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; acetonitrile%: 23%-53%), and then separated by SFC (separation conditions: column: DAICEL CHIRALPAK AY-H (250mm*30mm, 10μm ); Mobile phase: A phase: CO 2 , B phase: [75% methanol + 15% acetonitrile + 10% (1% ammonia ethanol solution)]; B%: 70%-70%) to obtain compound 7a. SFC detection conditions: Chromatographic column: Chiralpak AY-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: [66.67% (methanol 0.05% diethylamine) + 33.33% (acetonitrile-0.05% Diethylamine)]; Gradient: B%: 60%, flow rate: 3mL/min, retention time is 0.967min, ee=100%. MS: m/z 510.3[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.79 (d, J = 4.8Hz, 2H), 8.06 (brs, 1H), 7.78 (brs, 2H), 7.55 (brs, 1H), 7.44 (brs, 1H),7.40(t,J＝4.8Hz,1H),7.17(s,2H),6.46(brs,2H),5.37(brs,1H),4.79(brs,1H),4.43(s,2H), 4.18(brs,1H),3.43-3.39(m,2H),2.81(d,J＝10.4Hz,2H),2.21(s,3H),1.84(s,4H),1.56(d,J＝6.0Hz ,3H).
实施例8

Example 8

第一步first step
在0℃条件下，向化合物8-1(10g,56.45mmol)的四氢呋喃(150mL)溶液中加入二(三甲基硅)氨基锂(1M四氢呋喃溶液,62.10mL)，搅拌30分钟，然后降温至-78℃，再向其中加入氘代碘甲烷(9.62g,67.74mmol)，缓慢升温至15℃，继续搅拌15小时。在冰浴条件下，反应液加稀盐酸淬灭(1.5M,200mL)，二氯甲烷萃取(150mL×3)，合并有机相，饱和氯化钠溶液洗涤(150mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝3:1～0:1)得到化合物8-2。1H NMR(400MHz,CDCl3)δ＝4.33-4.19(m,4H),3.05-2.81(m,1H),1.46-1.34(m,6H)。At 0°C, add lithium bis(trimethylsilyl)amide (1M tetrahydrofuran solution, 62.10 mL) to a solution of compound 8-1 (10 g, 56.45 mmol) in tetrahydrofuran (150 mL), stir for 30 minutes, and then cool to -78°C, then add deuterated methyl iodide (9.62g, 67.74mmol), slowly raise the temperature to 15°C, and continue stirring for 15 hours. Under ice bath conditions, the reaction solution was quenched with dilute hydrochloric acid (1.5M, 200mL), extracted with dichloromethane (150mL×3), combined organic phases, washed with saturated sodium chloride solution (150mL×2), and anhydrous sodium sulfate Dry, filter, and concentrate the filtrate under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 ~ 0:1) to obtain compound 8-2. 1 H NMR (400MHz, CDCl 3 ) δ = 4.33-4.19 (m, 4H), 3.05-2.81 (m, 1H), 1.46-1.34 (m, 6H).
第二步Step 2
0℃下，向化合物8-2(758.64mg,3.91mmol)的四氢呋喃(10mL)溶液中加入钠氢(167.44mg,4.19mmol,60％纯度)，搅拌30分钟，然后向其中加入化合物8-3(0.5g,2.79mmol,)的四氢呋喃(10mL)溶液，然后升温至25℃，继续搅拌2小时。反应液加饱和氯化铵溶液淬灭(20mL)，乙酸乙酯萃取(15mL×2)，合并有机相，饱和氯化钠溶液洗涤(15mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝5:1～0:1)，然后经制备型薄层层析分离纯化(石油醚：乙酸乙酯＝0:1)，得到化合物8-4。MS:m/z 220.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.28-8.25(m,1H),7.92(dd,J＝2.0,8.4Hz,1H),7.87(s,1H),7.48(d,J＝8.4Hz,1H),6.74-6.67(m,2H),3.85(s,3H)。To a solution of compound 8-2 (758.64 mg, 3.91 mmol) in tetrahydrofuran (10 mL), sodium hydrogen (167.44 mg, 4.19 mmol, 60% purity) was added at 0°C, stirred for 30 minutes, and then compound 8-3 was added thereto. (0.5g, 2.79mmol,) in tetrahydrofuran (10mL), then warmed to 25°C and continued stirring for 2 hours. The reaction solution was quenched by adding saturated ammonium chloride solution (20mL), extracted with ethyl acetate (15mL×2), combined the organic phases, washed with saturated sodium chloride solution (15mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced to Pressure concentration. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 0:1), and then separated and purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 0:1) to obtain the compound 8-4. MS: m/z 220.1[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ＝8.28-8.25(m,1H),7.92(dd,J＝2.0,8.4Hz,1H),7.87(s,1H),7.48(d,J＝8.4Hz ,1H),6.74-6.67(m,2H),3.85(s,3H).
第三步third step
向化合物8-4(0.576g,2.63mmol)的甲醇(10mL)，四氢呋喃(10mL)和水(5mL)的溶液中加入一水合氢氧化锂(330.73mg,7.88mmol)，反应液升温至45℃，搅拌12小时。反应液减压浓缩，加水稀释(15mL)，加乙酸乙酯萃取(15mL×1)，水相加稀盐酸(2M)调节pH至6，析出固体，过滤，滤饼干燥得到化合物8-5。MS:m/z 206.2[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.19(d,J＝2.0Hz,1H),7.92(dd,J＝2.0,8.8Hz,1H),7.82(s,1H),7.42(d,J＝8.8Hz,1H),6.53(brs,2H)。To a solution of compound 8-4 (0.576g, 2.63mmol) in methanol (10mL), tetrahydrofuran (10mL) and water (5mL) was added lithium hydroxide monohydrate (330.73mg, 7.88mmol), and the reaction solution was heated to 45°C. , stir for 12 hours. The reaction solution was concentrated under reduced pressure, diluted with water (15 mL), and extracted with ethyl acetate (15 mL × 1). Add dilute hydrochloric acid (2M) to the aqueous phase to adjust the pH to 6. The solid was precipitated, filtered, and the filter cake was dried to obtain compound 8-5. MS: m/z 206.2[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.19 (d, J = 2.0Hz, 1H), 7.92 (dd, J = 2.0, 8.8Hz, 1H), 7.82 (s, 1H), 7.42 (d, J =8.8Hz,1H),6.53(brs,2H).
第四步the fourth step
在25℃条件下，向化合物8-5(0.075g,365.45μmol)的N,N-二甲基甲酰胺(4mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(208.43mg,548.17μmol)和N,N-二异丙基乙胺(94.46mg,730.90μmol)，搅拌10分钟，然后向其中加入化合物1-6a(113.46mg,365.45μmol)，升温至45℃，继续搅拌24小时。反应中发生部分消旋。反应液加水稀释(15mL)，乙酸乙酯萃取(15mL×4)，合并有机相，经饱和氯化钠溶液洗涤(15mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物8-7。MS:m/z498.3[M+H]+。At 25°C, 2-(7-azabenzotriazole)-N was added to a solution of compound 8-5 (0.075g, 365.45μmol) in N,N-dimethylformamide (4mL). ,N,N',N'-tetramethylurea hexafluorophosphate (208.43mg, 548.17μmol) and N,N-diisopropylethylamine (94.46mg, 730.90μmol), stir for 10 minutes, and then add Compound 1-6a (113.46 mg, 365.45 μmol) was added, the temperature was raised to 45°C, and stirring was continued for 24 hours. Partial racemization occurs during the reaction. The reaction solution was diluted with water (15 mL), extracted with ethyl acetate (15 mL × 4), the organic phases were combined, washed with saturated sodium chloride solution (15 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 8 -7. MS:m/z498.3[M+H] + .
第五步 the fifth step
在25℃条件下，向化合物8-7(0.18g,361.68μmol)的甲醇(5mL)溶液中加入碳酸钾(74.98mg,542.52μmol)，继续搅拌15分钟。粗品经硅胶柱层析分离纯化(石油醚：乙酸乙酯＝3:1～0:1,然后乙酸乙酯：甲醇＝10:1)，再经制备型高效液相分离纯化(色谱柱:Waters Xbridge C18 150*50mm*10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度(乙腈)％:24％-54％)，然后再经SFC分离纯化(色谱柱:DAICEL CHIRALPAK IC(250mm*30mm,10μm)；流动相:A相:CO2,B相:[乙腈/异丙醇(0.1％氨水)]；梯度(B)％:55％-55％)，得到化合物8a。SFC检测条件：色谱柱:Chiralpak IC-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:75％异丙醇+25％乙腈(0.05％二乙胺)；梯度:B％:50％异丙醇+乙腈(0.05％二乙胺),流速:3mL/min，化合物8a的保留时间为1.385min，ee＝100％，其对映异构体的保留时间为2.037min。MS:m/z 426.3[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.78(d,J＝4.8Hz,2H),8.54(brs,1H),8.01-7.95(m,1H),7.94-7.90(m,1H),7.81(brd,J＝8.0Hz,1H),7.70-7.65(m,1H),7.60-7.55(m,1H),7.39(t,J＝4.8Hz,1H),7.33(d,J＝8.0Hz,1H),5.36(brs,1H),4.89–4.76(m,1H),4.39(s,2H),1.58(br d,J＝6.4Hz,3H)。At 25°C, potassium carbonate (74.98 mg, 542.52 μmol) was added to a solution of compound 8-7 (0.18 g, 361.68 μmol) in methanol (5 mL), and stirring was continued for 15 minutes. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 3:1 ~ 0:1, then ethyl acetate: methanol = 10:1), and then purified by preparative high performance liquid phase (chromatography column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient (acetonitrile)%: 24%-54%), and then separated and purified by SFC (chromatographic column: DAICEL CHIRALPAK IC ( 250mm*30mm, 10μm); mobile phase: phase A: CO 2 , phase B: [acetonitrile/isopropyl alcohol (0.1% ammonia)]; gradient (B)%: 55%-55%) to obtain compound 8a. SFC detection conditions: Chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: 75% isopropyl alcohol + 25% acetonitrile (0.05% diethylamine); gradient: B%: 50% isopropyl alcohol + acetonitrile (0.05% diethylamine), flow rate: 3mL/min, the retention time of compound 8a is 1.385min, ee=100%, and the retention time of its enantiomer is 2.037min . MS: m/z 426.3[M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.78 (d, J = 4.8Hz, 2H), 8.54 (brs, 1H), 8.01-7.95 (m, 1H), 7.94-7.90 (m, 1H), 7.81 (brd,J＝8.0Hz,1H),7.70-7.65(m,1H),7.60-7.55(m,1H),7.39(t,J＝4.8Hz,1H),7.33(d,J＝8.0Hz, 1H), 5.36 (brs, 1H), 4.89–4.76 (m, 1H), 4.39 (s, 2H), 1.58 (br d, J = 6.4Hz, 3H).
实施例9
Example 9
第一步first step
向化合物9-1(5g,28.90mmol)的三氯甲烷(200mL)溶液中依次加入偶氮二异丁腈(949.13mg,5.78mmol) 和N-溴代丁二酰亚胺(5.14g,28.90mmol)，反应液在氮气保护下，25℃搅拌10分钟，然后加热至80℃反应2小时。反应液过滤，滤液减压浓缩得到粗品，粗品经硅胶柱层析(洗脱剂：石油醚/乙酸乙酯＝6/1～3/1)纯化得到化合物9-2。To a solution of compound 9-1 (5g, 28.90mmol) in chloroform (200mL) was added azobisisobutyronitrile (949.13mg, 5.78mmol) in sequence and N-bromosuccinimide (5.14g, 28.90mmol). The reaction solution was stirred at 25°C for 10 minutes under nitrogen protection, and then heated to 80°C for 2 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 6/1 to 3/1) to obtain compound 9-2.
第二步Step 2
将化合物9-2(0.9g,3.57mmol)溶在无水二氧六环(20mL)中，逐滴加入氨甲醇溶液(7M,10mL)，反应液在氮气保护下，25℃搅拌2小时。反应液过滤，滤液减压浓缩得到化合物9-3，直接用于下一步。Compound 9-2 (0.9g, 3.57mmol) was dissolved in anhydrous dioxane (20mL), ammonia methanol solution (7M, 10mL) was added dropwise, and the reaction solution was stirred at 25°C for 2 hours under nitrogen protection. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-3, which was directly used in the next step.
第三步third step
向化合物9-3(0.9g,4.79mmol)和化合物1-2(584.56mg,4.79mmol)的二氯甲烷(20mL)溶液中加入乙酸钾(563.71mg,5.74mmol)，反应液在25℃下搅拌0.5小时，然后向反应体系中加入醋酸硼氢化钠(1.32g,6.22mmol)，反应液在25℃下搅拌32.5小时。10℃下，将反应液缓慢加入到冰水(10mL)中淬灭，然后用二氯甲烷(5mL×2)萃取，合并有机相，用饱和食盐水(15mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物9-4。MS:m/z 294.1,296.1[M+H]+。To a solution of compound 9-3 (0.9g, 4.79mmol) and compound 1-2 (584.56mg, 4.79mmol) in dichloromethane (20mL) was added potassium acetate (563.71mg, 5.74mmol), and the reaction solution was heated at 25°C. Stir for 0.5 hours, then add sodium acetate borohydride (1.32g, 6.22mmol) to the reaction system, and stir the reaction solution at 25°C for 32.5 hours. At 10°C, the reaction solution was slowly added to ice water (10 mL) to quench, and then extracted with dichloromethane (5 mL × 2). The organic phases were combined, washed with saturated brine (15 mL × 2), and anhydrous sodium sulfate. Dry, filter and concentrate under reduced pressure to obtain compound 9-4. MS: m/z 294.1,296.1[M+H] + .
第四步the fourth step
将化合物9-4(0.72g,2.45mmol)溶在二氯甲烷(5mL)中，依次加入三乙胺(495.37mg,4.90mmol)和二碳酸二叔丁酯(1.07g,4.90mmol)，反应液在25℃下搅拌1小时。将反应液减压浓缩得到化合物9-5。MS:m/z 394.0,396.0[M+H]+。Dissolve compound 9-4 (0.72g, 2.45mmol) in dichloromethane (5mL), add triethylamine (495.37mg, 4.90mmol) and di-tert-butyl dicarbonate (1.07g, 4.90mmol) in sequence, and react. The solution was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 9-5. MS: m/z 394.0,396.0[M+H] + .
第五步the fifth step
将化合物9-5(0.58g,1.47mmol)溶于三乙胺(15mL)中，依次加入三甲基乙炔基硅(173.39mg,1.77mmol)，碘化亚铜(11.21mg,58.84μmol)和双三苯基磷二氯化钯(20.65mg,29.42μmol)，反应液在25℃下搅拌10分钟，然后加热至70℃搅拌12小时。20℃下，将反应液缓慢加入到冰水(15mL)中淬灭，然后用二氯甲烷(10mL×2)萃取，合并有机相，用饱和食盐水(5mL×2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物9-6。Compound 9-5 (0.58g, 1.47mmol) was dissolved in triethylamine (15mL), and trimethylethynylsilane (173.39mg, 1.77mmol), copper iodide (11.21mg, 58.84μmol) and Bistriphenylphosphine palladium dichloride (20.65 mg, 29.42 μmol), the reaction solution was stirred at 25°C for 10 minutes, then heated to 70°C and stirred for 12 hours. At 20°C, the reaction solution was slowly added to ice water (15 mL) to quench, and then extracted with dichloromethane (10 mL × 2). Combine the organic phases, wash with saturated brine (5 mL × 2), and anhydrous sodium sulfate. Dry, filter and concentrate under reduced pressure to obtain compound 9-6.
第六步Step 6
将化合物9-6(0.34g,826.10μmol)溶在无水甲醇(10mL)中，加入碳酸钾(342.53mg,2.48mmol)。反应液在25℃搅拌12小时。将反应液过滤，滤液减压浓缩得到化合物9-7。Compound 9-6 (0.34g, 826.10 μmol) was dissolved in anhydrous methanol (10 mL), and potassium carbonate (342.53 mg, 2.48 mmol) was added. The reaction solution was stirred at 25°C for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-7.
第七步Step 7
向化合物9-7(0.21g,618.76μmol)的乙酸乙酯(2mL)溶液中加入盐酸乙酸乙酯溶液(4M,3mL)，25℃搅拌12小时。反应液减压浓酸得到化合物9-8的盐酸盐。To a solution of compound 9-7 (0.21 g, 618.76 μmol) in ethyl acetate (2 mL) was added hydrochloric acid ethyl acetate solution (4 M, 3 mL), and the mixture was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of compound 9-8.
第八步Step 8
将化合物1-7(50mg,247.27μmol)和三乙胺(75.06mg,741.81μmol)溶于无水N,N-二甲基甲酰胺(3mL)中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(141.03mg,370.91μmol)，在10℃下搅拌30分钟。加入化合物9-8(59.17mg,盐酸盐)的N,N-二甲基甲酰胺(2mL)溶液，在25℃下搅拌2小时。反应液加水(10mL)稀释，然后用二氯甲烷(10mL*2)萃取，合并有机相，用饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，减压浓缩得到化合物9。 Compound 1-7 (50 mg, 247.27 μmol) and triethylamine (75.06 mg, 741.81 μmol) were dissolved in anhydrous N,N-dimethylformamide (3 mL), and 2-(7-azabenzo Triazole)-N,N,N',N'-tetramethylurea hexafluorophosphate (141.03 mg, 370.91 μmol), stirred at 10°C for 30 minutes. A solution of compound 9-8 (59.17 mg, hydrochloride) in N,N-dimethylformamide (2 mL) was added and stirred at 25°C for 2 hours. The reaction solution was diluted with water (10 mL), and then extracted with dichloromethane (10 mL*2). The organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 9.
第九步Step 9
化合物9(83mg,196.00μmol)经制备型高效液相色谱(分离条件：色谱柱:UniSil 3-100C18UItra150*25mm*3μm；流动相:[水(0.025％甲酸)-乙腈]；乙腈％:15％-35％)纯化，再经SFC分离(分离条件：色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:[0.1％氨水-乙醇]；B％:25％-25％)，得到化合物9a和9b。Compound 9 (83 mg, 196.00 μmol) was analyzed by preparative high performance liquid chromatography (separation conditions: column: UniSil 3-100C18UItra150*25mm*3μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; acetonitrile%: 15% -35%) purification, and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [0.1% ammonia water-ethanol]; B% :25%-25%) to obtain compounds 9a and 9b.
化合物9a:SFC检测条件：色谱柱:(S,S)Whelk-O1 50×4.6mm I.D.,3.5μm；流动相:A相:CO2,B相:异丙醇(0.05％二乙胺)；梯度:B％:5％-40％,流速:3mL/min，保留时间为0.991min，ee＝94.72％。MS:m/z 424.1[M+H]+。1H NMR(400MHz,CD3OD)δ＝8.73(br s,2H),8.50(br s,1H),8.37(br s,1H),7.95(br s,1H),7.79(br s,2H),7.65(br s,1H),7.33(br s,1H),5.44(br s,1H),4.63(br d,J＝15.5Hz,2H),3.73(s,1H),2.33(br s,3H),1.67(br d,J＝7.0Hz,3H)。Compound 9a: SFC detection conditions: chromatographic column: (S, S) Whelk-O1 50×4.6mm ID, 3.5μm; mobile phase: phase A: CO 2 , phase B: isopropyl alcohol (0.05% diethylamine); Gradient: B%: 5%-40%, flow rate: 3mL/min, retention time is 0.991min, ee=94.72%. MS: m/z 424.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ = 8.73 (br s, 2H), 8.50 (br s, 1H), 8.37 (br s, 1H), 7.95 (br s, 1H), 7.79 (br s, 2H ),7.65(br s,1H),7.33(br s,1H),5.44(br s,1H),4.63(br d,J＝15.5Hz,2H),3.73(s,1H),2.33(br s ,3H),1.67(br d,J=7.0Hz,3H).
化合物9b:SFC检测条件：色谱柱:(S,S)Whelk-O1 50×4.6mm I.D.,3.5μm；流动相:A相:CO2,B相:异丙醇(0.05％二乙胺)；梯度:B％:5％-40％,流速:3mL/min，保留时间为1.195min，ee＝100.00％。MS:m/z424.1[M+H]+。1H NMR(400MHz,CD3OD)δ＝8.74(br s,2H),8.50(br s,1H),8.34(br s,1H),7.99(br s,1H),7.81(br s,2H),7.67(br s,1H),7.33(br s,1H),5.43(br s,1H),4.97(br s,1H),4.63(br d,J＝15.8Hz,1H),3.74(s,1H),2.39-2.30(m,3H),1.67(d,J＝7.0Hz,3H)。Compound 9b: SFC detection conditions: Chromatographic column: (S, S) Whelk-O1 50×4.6mm ID, 3.5μm; mobile phase: Phase A: CO 2 , Phase B: isopropyl alcohol (0.05% diethylamine); Gradient: B%: 5%-40%, flow rate: 3mL/min, retention time: 1.195min, ee=100.00%. MS:m/z424.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ = 8.74 (br s, 2H), 8.50 (br s, 1H), 8.34 (br s, 1H), 7.99 (br s, 1H), 7.81 (br s, 2H ),7.67(br s,1H),7.33(br s,1H),5.43(br s,1H),4.97(br s,1H),4.63(br d,J＝15.8Hz,1H),3.74(s ,1H),2.39-2.30(m,3H),1.67(d,J＝7.0Hz,3H).
实施例10
Example 10
第一步first step
向化合物10-1(300mg,914.34μmol)和化合物10-2(263.49mg,1.37mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入碘化亚铜(34.83mg,182.87μmol)，混合物在油浴120℃下搅拌16小时。反应混合液过滤，滤液用乙酸乙酯(5mL*2)萃取，合并有机相，用水(5mL*2)和饱和食盐水(5mL*2)洗涤，无水硫酸钠干燥，过滤之后减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Phenomenex luna C18 150*25mm*10μm；流动相:[水(0.025％甲酸)-乙腈]；梯度：B％:25％-55％)，得到化合物10-3。MS:m/z 271.1[M+H]+。To a solution of compound 10-1 (300 mg, 914.34 μmol) and compound 10-2 (263.49 mg, 1.37 mmol) in N,N-dimethylformamide (5 mL) was added copper iodide (34.83 mg, 182.87 μmol) , the mixture was stirred in an oil bath at 120°C for 16 hours. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate (5mL*2). The organic phases were combined, washed with water (5mL*2) and saturated brine (5mL*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid phase separation (chromatographic column: Phenomenex luna C18 150*25mm*10μm; mobile phase: [water (0.025% formic acid)-acetonitrile]; gradient: B%: 25%-55%) to obtain the compound 10-3. MS: m/z 271.1[M+H] + .
第二步Step 2
向化合物10-3(40mg,148.03μmol)的甲醇(2mL)，水(2mL)和四氢呋喃(1mL)混合溶液中加入一水合 氢氧化锂(12.42mg,296.07μmol)，反应混合液在室温25℃搅拌3小时。向反应混合液中滴加2M稀盐酸调节pH至6-7，混合液搅拌5分钟，过滤，滤饼用水(5mL*3)淋洗，滤饼减压干燥。得到化合物10-4。MS:m/z 257.0[M+H]+。To a mixed solution of compound 10-3 (40 mg, 148.03 μmol) in methanol (2 mL), water (2 mL) and tetrahydrofuran (1 mL) was added monohydrate Lithium hydroxide (12.42 mg, 296.07 μmol), the reaction mixture was stirred at room temperature 25°C for 3 hours. Add 2M dilute hydrochloric acid dropwise to the reaction mixture to adjust the pH to 6-7, stir the mixture for 5 minutes, filter, rinse the filter cake with water (5mL*3), and dry the filter cake under reduced pressure. Compound 10-4 was obtained. MS: m/z 257.0[M+H] + .
第三步third step
向化合物10-4(40mg,156.14μmol)的N,N-二甲基甲酰胺(3mL)溶液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(HATU,59.37mg,156.14μmol)和N,N-二异丙基乙胺(40.36mg,312.28μmol,)，混合物在室温25℃下搅拌2小时，然后向其中加入化合物1-6a(53.32mg,171.75μmol)，混合物继续在油浴50℃下搅拌18小时。向混合物中加入水(3mL)，然后用乙酸乙酯(3mL*3)萃取，合并有机相，用水(3mL*3)和饱和食盐水(3mL*3)洗涤，无水硫酸钠干燥，过滤之后减压浓缩。得到化合物10-5。MS:m/z 549.1[M+H]+。To a solution of compound 10-4 (40 mg, 156.14 μmol) in N,N-dimethylformamide (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N , N-tetramethylurea hexafluorophosphonium salt (HATU, 59.37mg, 156.14μmol) and N,N-diisopropylethylamine (40.36mg, 312.28μmol,), the mixture was stirred at room temperature 25°C for 2 hours. Compound 1-6a (53.32 mg, 171.75 μmol) was then added thereto, and the mixture was continued to be stirred at 50° C. in an oil bath for 18 hours. Add water (3mL) to the mixture, then extract with ethyl acetate (3mL*3), combine the organic phases, wash with water (3mL*3) and saturated brine (3mL*3), dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure. Compound 10-5 was obtained. MS: m/z 549.1[M+H] + .
第四步the fourth step
向化合物10-5(80mg,145.82μmol)的甲醇(3mL)溶液中加入碳酸钾(40.31mg,291.63μmol)，混合物在室温25℃下搅拌1小时。混合物过滤，滤液减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters xbridge 150*25mm 10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度：B％:34％-64％)，得到化合物10a。SFC检测条件：色谱柱:Chiralpak IG-3 50×4.6mm I.D.,3μm；流动相:A相:二氧化碳,B相:乙醇(0.05％二乙胺)；梯度:B％:40％),流速:3mL/min，保留时间为1.332min，ee＝100％。MS:m/z 477.1[M+H]+。1H NMR(400MHz,CD3OD)δ＝8.73(br s,2H),8.50(s,1H),8.10(br s,1H),7.95-7.75(m,2H),7.67(br s,1H),7.42(br d,J＝5.6Hz,1H),7.37-7.29(m,2H),5.44(br s,1H),4.99(br d,J＝16.0Hz,1H),4.64(br d,J＝16.2Hz,1H),3.72(s,1H),1.68(d,J＝7.0Hz,3H)。To a solution of compound 10-5 (80 mg, 145.82 μmol) in methanol (3 mL) was added potassium carbonate (40.31 mg, 291.63 μmol), and the mixture was stirred at room temperature 25°C for 1 hour. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid phase separation (chromatographic column: Waters xbridge 150*25mm 10 μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient: B%: 34%-64%) to obtain compound 10a . SFC detection conditions: Chromatographic column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethylamine); gradient: B%: 40%), flow rate: 3mL/min, retention time is 1.332min, ee=100%. MS:m/z 477.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ = 8.73 (br s, 2H), 8.50 (s, 1H), 8.10 (br s, 1H), 7.95-7.75 (m, 2H), 7.67 (br s, 1H) ),7.42(br d,J＝5.6Hz,1H),7.37-7.29(m,2H),5.44(br s,1H),4.99(br d,J＝16.0Hz,1H),4.64(br d, J=16.2Hz, 1H), 3.72 (s, 1H), 1.68 (d, J=7.0Hz, 3H).
实施例11
Example 11
第一步 first step
参考实施例1的第一步和第二步，不经过SFC手性拆分得到化合物11-1。向化合物11-1(200.00mg,508.55μmol)的三乙胺(5mL)溶液中依次加入丙炔的N,N-二甲基甲酰胺溶液(1M,7.63mL)，碘化亚铜(9.69mg,50.85μmol)和二氯双(三苯基膦)钯(II)(35.69mg,50.85μmol)，混合物在微波条件下120℃搅拌12小时。反应混合液过滤，滤液加入水(5mL)，用乙酸乙酯(5mL*3)萃取，合并有机相，用水(5mL*3)和饱和食盐水(5mL*3)洗涤，无水硫酸钠干燥，过滤之后减压浓缩。粗品经柱层析(洗脱剂：石油醚/乙酸乙酯＝10/1～3/1)，得到化合物11-2。MS:m/z 353.2[M+H]+。Referring to the first and second steps of Example 1, compound 11-1 was obtained without SFC chiral resolution. To a solution of compound 11-1 (200.00 mg, 508.55 μmol) in triethylamine (5 mL), a solution of propyne in N,N-dimethylformamide (1 M, 7.63 mL) and copper iodide (9.69 mg) were added in sequence. , 50.85 μmol) and dichlorobis(triphenylphosphine)palladium(II) (35.69 mg, 50.85 μmol), and the mixture was stirred at 120°C under microwave conditions for 12 hours. The reaction mixture was filtered, water (5mL) was added to the filtrate, extracted with ethyl acetate (5mL*3), the organic phases were combined, washed with water (5mL*3) and saturated brine (5mL*3), and dried over anhydrous sodium sulfate. After filtration, the mixture was concentrated under reduced pressure. The crude product was subjected to column chromatography (eluent: petroleum ether/ethyl acetate = 10/1~3/1) to obtain compound 11-2. MS: m/z 353.2[M+H] + .
第二步Step 2
将化合物11-2(130mg,368.87μmol)溶解于乙酸乙酯(3mL)中，加入盐酸乙酸乙酯(10mL)，反应混合液在室温25℃搅拌1.5小时。反应混合液直接减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge C18 150*50mm*10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度：B％:1％-30％)，得到化合物11-3。MS:m/z 253.2[M+H]+。Compound 11-2 (130 mg, 368.87 μmol) was dissolved in ethyl acetate (3 mL), ethyl acetate hydrochloride (10 mL) was added, and the reaction mixture was stirred at room temperature 25°C for 1.5 hours. The reaction mixture was directly concentrated under reduced pressure. The crude product was purified by preparative high-performance liquid phase separation (chromatographic column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient: B%: 1%-30%) to obtain Compound 11-3. MS: m/z 253.2[M+H] + .
第三步third step
向化合物1-7(35.00mg,173.09μmol)的N,N-二甲基甲酰胺(3mL)溶液中加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(65.81mg,173.09μmol)和N,N-二异丙基乙胺(44.74mg,346.18μmol)，混合物在室温25℃下搅拌1小时，然后向其中加入化合物11-3(43.67mg,173.09μmol)，混合物继续在油浴50℃下搅拌16小时。向混合物中加入水(5mL)，然后用乙酸乙酯(10mL*3)萃取，合并有机相，用水(10mL*3)和饱和食盐水(10mL*3)洗涤，无水硫酸钠干燥，过滤之后减压浓缩。粗品经制备型高效液相分离纯化(色谱柱:Waters xbridge 150*25mm 10μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度：B％:30％-60％)，得到化合物11。To a solution of compound 1-7 (35.00 mg, 173.09 μmol) in N,N-dimethylformamide (3 mL) was added O-(7-azabenzotriazol-1-yl)-N,N, The mixture of N,N-tetramethylurea hexafluorophosphonium salt (65.81mg, 173.09μmol) and N,N-diisopropylethylamine (44.74mg, 346.18μmol) was stirred at room temperature 25°C for 1 hour, and then added to Compound 11-3 (43.67 mg, 173.09 μmol) was added, and the mixture was continued to stir in an oil bath at 50°C for 16 hours. Add water (5mL) to the mixture, then extract with ethyl acetate (10mL*3), combine the organic phases, wash with water (10mL*3) and saturated brine (10mL*3), dry over anhydrous sodium sulfate, and filter. Concentrate under reduced pressure. The crude product was purified by preparative high-performance liquid phase separation (chromatographic column: Waters xbridge 150*25mm 10μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient: B%: 30%-60%) to obtain compound 11 .
第四步the fourth step
化合物11经SFC分离纯化(分离条件，色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相：CO2,B相：[0.1％氨水-异丙醇]；B％:50％-50％)，得到化合物11a和11b。Compound 11 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [0.1% ammonia water-isopropyl alcohol]; B%: 50 %-50%) to obtain compounds 11a and 11b.
化合物11a：SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:二氧化碳,B相:异丙醇(0.05％二乙胺)；梯度:B％:40％),流速:3mL/min，保留时间为1.115min，ee＝100％。MS:m/z 437.1[M+H]+。1H NMR(400MHz,CD3OD)δ＝8.72(br s,2H),8.38(s,1H),7.96-7.77(m,2H),7.68(br d,J＝7.4Hz,2H),7.62-7.48(m,1H),7.40-7.24(m,2H),5.48(br s,1H),4.69-4.52(m,2H),2.28(br s,3H),2.05(s,3H),1.65(br d,J＝6.8Hz,3H)。Compound 11a: SFC detection conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: carbon dioxide, phase B: isopropyl alcohol (0.05% diethylamine); gradient: B%: 40 %), flow rate: 3mL/min, retention time: 1.115min, ee=100%. MS:m/z 437.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ = 8.72 (br s, 2H), 8.38 (s, 1H), 7.96-7.77 (m, 2H), 7.68 (br d, J = 7.4Hz, 2H), 7.62 -7.48(m,1H),7.40-7.24(m,2H),5.48(br s,1H),4.69-4.52(m,2H),2.28(br s,3H),2.05(s,3H),1.65 (br d,J=6.8Hz,3H).
化合物11b：SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:二氧化碳,B相:异丙醇(0.05％二乙胺)；梯度:B％:40％),流速:3mL/min，保留时间为1.347min，ee＝97.11％。MS:m/z437.1[M+H]+。1H NMR(400MHz,CD3OD)δ＝8.73(br s,2H),8.38(s,1H),7.96-7.77(m,2H),7.69(br d,J＝2.8Hz,2H),7.62-7.54(m,1H),7.41-7.31(m,2H),5.48(br s,1H),4.67-4.54(m,2H),2.30(br s,3H),2.05(s,3H),1.66(br d,J＝6.8Hz,3H)。Compound 11b: SFC detection conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: carbon dioxide, phase B: isopropyl alcohol (0.05% diethylamine); gradient: B%: 40 %), flow rate: 3mL/min, retention time: 1.347min, ee=97.11%. MS:m/z437.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ = 8.73 (br s, 2H), 8.38 (s, 1H), 7.96-7.77 (m, 2H), 7.69 (br d, J = 2.8Hz, 2H), 7.62 -7.54(m,1H),7.41-7.31(m,2H),5.48(br s,1H),4.67-4.54(m,2H),2.30(br s,3H),2.05(s,3H),1.66 (br d,J=6.8Hz,3H).
实施例12
Example 12
第一步first step
在氮气氛围下，将化合物12-1(5g,21.73mmol)，双联频哪醇硼酸酯(11.04g,43.47mmol)，醋酸钾(6.40g,65.20mmol)和1,1-双(二苯基膦)二茂铁氯化钯二氯甲烷混合物(1.77g,2.17mmol)的二氧六环(100mL)溶液置于100℃搅拌反应14小时。反应液经硅藻土过滤，滤液减压浓缩。粗品经柱层析分离纯化(石油醚：乙酸乙酯＝10:1～3:1)得到化合物12-2。MS:m/z 278.2[M+H]+。Under a nitrogen atmosphere, compound 12-1 (5g, 21.73mmol), bis-pinacol borate (11.04g, 43.47mmol), potassium acetate (6.40g, 65.20mmol) and 1,1-bis(di A solution of phenylphosphine)ferrocene palladium chloride and dichloromethane mixture (1.77g, 2.17mmol) in dioxane (100mL) was stirred at 100°C for 14 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 10:1 to 3:1) to obtain compound 12-2. MS: m/z 278.2[M+H] + .
第二步Step 2
将化合物12-2(470mg,1.70mmol)，化合物12-3(0.25g,1.13mmol)，碳酸钾(312.6mg,2.26mmol)和1,1-双(二苯基膦)二茂铁氯化钯二氯甲烷混合物(92.4mg,113.09μmol)的N,N-二甲基甲酰胺(10mL)和水(2mL)溶液置于110℃搅拌14小时。反应液经硅藻土过滤，滤液加水稀释(30mL)，乙酸乙酯萃取(30mL×2)，合并有机相，饱和食盐水洗涤(30mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析分离纯化(先石油醚：乙酸乙酯＝5:1～0:1，然后乙酸乙酯：甲醇＝10:1)得到化合物12-4。1H NMR(400MHz,DMSO-d6)δ12.09(brs,1H),8.35(d,J＝2.0Hz,1H),8.04(dd,J＝8.0Hz,J＝2.0Hz,1H),7.87(d,J＝5.4Hz,1H),7.62(d,J＝5.4Hz,1H),7.51(d,J＝8.0Hz,1H),3.90(s,3H).MS:m/z 260.0[M+H]+。Compound 12-2 (470 mg, 1.70 mmol), compound 12-3 (0.25 g, 1.13 mmol), potassium carbonate (312.6 mg, 2.26 mmol) and 1,1-bis(diphenylphosphine)ferrocene were chlorinated A solution of the palladium dichloromethane mixture (92.4 mg, 113.09 μmol) in N,N-dimethylformamide (10 mL) and water (2 mL) was stirred at 110°C for 14 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was diluted with water (30 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, washed with saturated brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. concentrate. The crude product was separated and purified by column chromatography (first petroleum ether: ethyl acetate = 5:1 to 0:1, then ethyl acetate: methanol = 10:1) to obtain compound 12-4. 1 H NMR (400MHz, DMSO-d 6 ) δ12.09 (brs, 1H), 8.35 (d, J = 2.0Hz, 1H), 8.04 (dd, J = 8.0Hz, J = 2.0Hz, 1H), 7.87 (d,J＝5.4Hz,1H),7.62(d,J＝5.4Hz,1H),7.51(d,J＝8.0Hz,1H),3.90(s,3H).MS:m/z 260.0[M +H] + .
第三步third step
在25℃条件下，向化合物12-4(0.08g,308.55μmol)的乙腈(5mL)溶液中分别加入N,N-二异丙基乙胺(3.09mmol,537μL)和三氯氧磷(1.54mmol,143.4μL)，然后升温至45℃，继续搅拌反应16小时。后升温至100℃，搅拌反应12小时。反应液减压浓缩。粗品经柱层析分离纯化(石油醚：乙酸乙酯＝5:1～0:1)得到化合物12-5。MS:m/z 278.0[M+H]+。At 25°C, N,N-diisopropylethylamine (3.09mmol, 537μL) and phosphorus oxychloride (1.54 mmol, 143.4 μL), then the temperature was raised to 45°C, and the reaction was continued with stirring for 16 hours. Then the temperature was raised to 100°C, and the reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 to 0:1) to obtain compound 12-5. MS: m/z 278.0[M+H] + .
第四步the fourth step
在20℃条件下，向化合物12-5(0.12g,432.08μmol)的四氢呋喃(15mL)溶液中分别加入N,N-二异丙基乙胺(167.5mg,1.30mmol,226μL)和对甲氧基苄胺(1.30mmol,168μL)，然后升温至80℃，继续搅拌12小时。再向反应液中加入对甲氧基苄胺(1.30mmol,168μL)，继续于80℃条件搅拌反应12小时。反应液减 压浓缩。粗品经柱层析分离纯化(石油醚:乙酸乙酯＝10:1～3:1)得到化合物12-6。MS:m/z 379.1[M+H]+。At 20°C, N,N-diisopropylethylamine (167.5 mg, 1.30 mmol, 226 μL) and p-methoxy were added to a solution of compound 12-5 (0.12 g, 432.08 μmol) in tetrahydrofuran (15 mL). benzylamine (1.30 mmol, 168 μL), then the temperature was raised to 80°C, and stirring was continued for 12 hours. Then, p-methoxybenzylamine (1.30 mmol, 168 μL) was added to the reaction solution, and the reaction was continued with stirring at 80°C for 12 hours. Reaction liquid decreases Pressure concentration. The crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=10:1~3:1) to obtain compound 12-6. MS: m/z 379.1[M+H] + .
第五步the fifth step
在15℃条件下，向化合物12-6(0.06g,158.54μmol)的甲醇(10mL)和水(2mL)溶液中加入一水合氢氧化锂(20mg,475.63μmol)，反应液搅拌1小时，然后向其中加入四氢呋喃(4mL)，升温至45℃，继续搅拌12小时。反应液加乙酸乙酯(10mL)和水(10mL)稀释，加稀盐酸调节pH至5～6，乙酸乙酯萃取(10mL×2)，合并有机相，饱和食盐水洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物12-7。MS:m/z 365.1[M+H]+。Lithium hydroxide monohydrate (20 mg, 475.63 μmol) was added to a solution of compound 12-6 (0.06 g, 158.54 μmol) in methanol (10 mL) and water (2 mL) at 15°C, and the reaction solution was stirred for 1 hour, and then Tetrahydrofuran (4 mL) was added thereto, the temperature was raised to 45°C, and stirring was continued for 12 hours. The reaction solution was diluted with ethyl acetate (10 mL) and water (10 mL), and dilute hydrochloric acid was added to adjust the pH to 5-6. Extract with ethyl acetate (10 mL × 2). Combine the organic phases and wash with saturated brine (10 mL × 2). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 12-7. MS: m/z 365.1[M+H] + .
第六步Step 6
在15℃条件下，向化合物12-7(51.6mg,141.71μmol)的N,N-二甲基甲酰胺(4mL)溶液中分别加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,64.7mg,170.05μmol)和N,N-二异丙基乙胺(354.28μmol,61.71μL)，搅拌10分钟，然后向其中加入中间体A(0.042g,148.80μmol)，继续搅拌30分钟，然后升温至50℃，继续搅拌12小时。反应液加水稀释(15mL)，乙酸乙酯萃取(10mL×3)，合并有机相，饱和食盐水洗涤(10mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。粗品经柱层析分离纯化(石油醚：乙酸乙酯＝3:1～0:1)得到化合物12-8。MS:m/z 629.2[M+H]+。At 15°C, 2-(7-azabenzotriazole)-N was added to a solution of compound 12-7 (51.6 mg, 141.71 μmol) in N,N-dimethylformamide (4 mL). ,N,N',N'-tetramethylurea hexafluorophosphate (HATU, 64.7mg, 170.05μmol) and N,N-diisopropylethylamine (354.28μmol, 61.71μL), stir for 10 minutes, then Intermediate A (0.042g, 148.80 μmol) was added thereto, stirring was continued for 30 minutes, then the temperature was raised to 50°C, and stirring was continued for 12 hours. The reaction solution was diluted with water (15 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1 ~ 0:1) to obtain compound 12-8. MS: m/z 629.2[M+H] + .
第七步Step 7
将化合物12-8(50.0mg,79.53μmol)的三氟乙酸(5mL)溶液置于50℃条件下搅拌反应12小时。反应液缓慢倒入饱和碳酸氢钠溶液(50mL)中，乙酸乙酯萃取(25mL×3)，合并有机相，饱和氯化钠溶液洗涤(25mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩后经柱层析分离纯化(石油醚：乙酸乙酯＝3:1～0:1，然后乙酸乙酯：甲醇＝10:1)得到粗品，经SFC检测为消旋体。消旋体经SFC分离(分离条件:色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:[60％甲醇+30％乙腈+10％(乙醇-1％氨水)]；B％:40％-40％)得到两个化合物粗品。这两个化合物粗品分别再经过制备型高效液相分离纯化(色谱柱:Waters Xbridge C18 150*50mm*10μm；流动相:[水(碳酸氢铵)-乙腈]；乙腈％:32％-62％)得到化合物12a和化合物12b。A solution of compound 12-8 (50.0 mg, 79.53 μmol) in trifluoroacetic acid (5 mL) was stirred and reacted at 50°C for 12 hours. The reaction solution was slowly poured into saturated sodium bicarbonate solution (50mL), extracted with ethyl acetate (25mL×3), the organic phases were combined, washed with saturated sodium chloride solution (25mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate After concentration under reduced pressure, the product was separated and purified by column chromatography (petroleum ether: ethyl acetate = 3:1 to 0:1, then ethyl acetate: methanol = 10:1) to obtain a crude product, which was detected as a racemate by SFC. The racemate is separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [60% methanol + 30% acetonitrile + 10% (ethanol- 1% ammonia water)]; B%: 40%-40%) to obtain two crude compounds. The crude products of these two compounds were separately purified by preparative high-performance liquid phase separation (chromatographic column: Waters Xbridge C18 150*50mm*10μm; mobile phase: [water (ammonium bicarbonate)-acetonitrile]; acetonitrile%: 32%-62% ) to obtain compound 12a and compound 12b.
化合物12a：SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[80％(甲醇-0.05％二乙胺)+20％(乙腈-0.05％二乙胺)]；梯度:B％:40％,流速:3mL/min，保留时间为0.699min，ee＝100％。1H NMR(400MHz,CD3OD)δ8.83–8.73(m,3H),8.34–8.25(m,1H),8.10–7.99(m,1H),7.84–7.70(m,3H),7.67–7.55(m,2H),7.36(t,J＝4.8Hz,1H),5.61–5.47(m,1H),5.15–5.01(m,2H),1.70(d,J＝6.8Hz,3H)。MS:m/z 509.0[M+H]+。Compound 12a: SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: [80% (methanol-0.05% diethylamine) + 20% ( Acetonitrile-0.05% diethylamine)]; gradient: B%: 40%, flow rate: 3mL/min, retention time 0.699min, ee=100%. 1 H NMR (400MHz, CD 3 OD) δ8.83–8.73(m,3H),8.34–8.25(m,1H),8.10–7.99(m,1H),7.84–7.70(m,3H),7.67– 7.55(m,2H),7.36(t,J＝4.8Hz,1H),5.61–5.47(m,1H),5.15–5.01(m,2H),1.70(d,J＝6.8Hz,3H). MS: m/z 509.0[M+H] + .
化合物12b：SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:[80％(甲醇-0.05％二乙胺)+20％(乙腈-0.05％二乙胺)]；梯度:B％:40％,流速:3mL/min，保留时间为1.065min，ee＝100％。1H NMR(400MHz,CD3OD)δ8.83–8.72(m,3H),8.28–8.19(m,1H),8.11–7.97(m,1H),7.79–7.66(m,3H),7.67–7.55(m,2H),7.36(t,J＝4.8Hz,1H),5.62–5.53(m,1H),5.18–4.97(m,2H),1.70(d,J＝6.8Hz,3H)。MS:m/z 509.2[M+H]+。Compound 12b: SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: [80% (methanol-0.05% diethylamine) + 20% ( Acetonitrile-0.05% diethylamine)]; gradient: B%: 40%, flow rate: 3mL/min, retention time is 1.065min, ee=100%. 1 H NMR (400MHz, CD 3 OD) δ8.83–8.72(m,3H),8.28–8.19(m,1H),8.11–7.97(m,1H),7.79–7.66(m,3H),7.67– 7.55(m,2H),7.36(t,J＝4.8Hz,1H),5.62–5.53(m,1H),5.18–4.97(m,2H),1.70(d,J＝6.8Hz,3H). MS: m/z 509.2[M+H] + .
实施例13
Example 13
第一步first step
将化合物13-1(1g,9.00mmol)溶于二氯甲烷(10mL)，-78℃缓慢加入三氟甲磺酸酐(2.79g,9.90mmol,)和N,N-二异丙基乙胺(1.74g,13.50mmol)后搅拌1小时。加入二氯甲烷(50mL)稀释，用水(100mL)洗涤，饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物13-2，直接用于下一步。Compound 13-1 (1g, 9.00mmol) was dissolved in dichloromethane (10mL), and trifluoromethanesulfonic anhydride (2.79g, 9.90mmol,) and N,N-diisopropylethylamine () were slowly added at -78°C. 1.74g, 13.50mmol) and then stirred for 1 hour. Add dichloromethane (50 mL) to dilute, wash with water (100 mL), wash with saturated brine (100 mL × 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 13-2, which is used directly in the next step.
第二步Step 2
将化合物12-2(1.3g,4.69mmol)溶于1.4-二氧六环(13mL)/水(3.25mL)中，加入碳酸钾(1.77g,12.79mmol),四三苯基膦钯(492.80mg,426.46μmol)和13-2(1.04g,4.26mmol)，氮气保护下90℃搅拌12小时。反应液减压浓缩后加入乙酸乙酯(10mL)和水(10mL)在25℃下搅拌30分钟，过滤，滤饼用乙酸乙酯(5mL)和二氯甲烷(5mL,2％MeOH)淋洗，得到化合物13-3。MS:m/z 244.9[M+H]+。Compound 12-2 (1.3g, 4.69mmol) was dissolved in 1.4-dioxane (13mL)/water (3.25mL), and potassium carbonate (1.77g, 12.79mmol) and tetrakistriphenylphosphine palladium (492.80 mg, 426.46 μmol) and 13-2 (1.04 g, 4.26 mmol), stir at 90°C for 12 hours under nitrogen protection. After the reaction solution was concentrated under reduced pressure, ethyl acetate (10 mL) and water (10 mL) were added, stirred at 25°C for 30 minutes, filtered, and the filter cake was rinsed with ethyl acetate (5 mL) and dichloromethane (5 mL, 2% MeOH). , compound 13-3 was obtained. MS: m/z 244.9[M+H] + .
第三步third step
将化合物13-3(830mg,3.40mmol)溶于甲醇(8.5mL)/水(8.5mL)/四氢呋喃(8.5mL)，加入氢氧化锂(325.55mg,13.59mmol)，在75℃搅拌3个小时。将反应液浓缩后加入1.5M盐酸调pH至6，过滤，滤饼用甲醇(3mL)淋洗，干燥后得到化合物13-4。MS:m/z 230.9[M+H]+。Compound 13-3 (830 mg, 3.40 mmol) was dissolved in methanol (8.5 mL)/water (8.5 mL)/tetrahydrofuran (8.5 mL), lithium hydroxide (325.55 mg, 13.59 mmol) was added, and stirred at 75°C for 3 hours. . After the reaction solution was concentrated, 1.5M hydrochloric acid was added to adjust the pH to 6, filtered, and the filter cake was rinsed with methanol (3 mL) and dried to obtain compound 13-4. MS: m/z 230.9[M+H] + .
第五步the fifth step
将化合物13-4(70.96mg,308.24umol)溶于N,N-二甲基乙酰胺(3mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,127.86mg,336.27μmol)和N,N-二异丙基乙胺(1.12mmol,195.24μL)，在80℃下搅拌1小时，加入1-6a(87mg,280.22μmol)继续反应11小时。反应液用乙酸乙酯(20mL)稀释，有机相用水(20mL x 2)洗，饱和食盐水(20mL x 2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干燥得到部分消旋的化合物13-5，直接用于下一步。MS:m/z 523.2[M+H]+。Compound 13-4 (70.96mg, 308.24umol) was dissolved in N,N-dimethylacetamide (3mL), and 2-(7-azobenzotriazole)-N,N,N' was added, N'-tetramethylurea hexafluorophosphate (HATU, 127.86mg, 336.27μmol) and N,N-diisopropylethylamine (1.12mmol, 195.24μL), stir at 80°C for 1 hour, add 1- 6a (87 mg, 280.22 μmol) was continued to react for 11 hours. The reaction solution was diluted with ethyl acetate (20 mL), and the organic phase was washed with water (20 mL x 2) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and dried to obtain a partially racemic compound. 13-5, used directly for the next step. MS: m/z 523.2[M+H] + .
第六步Step 6
将化合物13-5(150mg,580.63μmol)溶于甲醇(3mL)中，加入碳酸钾(439.38mg,870.94μmol)在25℃下搅拌12小时。向反应液中加入乙酸乙酯(20mL)稀释，有机相用水(20mL x 2)洗，饱和食盐水(20mL x 2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干燥得到粗品。粗品经制备HPLC(柱子:Welch Xtimate C18 80*40mm*3μm；流动相:[5％氨水+10mM碳酸氢铵)-乙腈]；梯度：(乙腈)％:0％-30％)纯化，再经SFC(色谱柱:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:[0.1％氨水-异丙 醇]；梯度：B％:45％-45％)拆分，得到化合物13a。1H NMR(CDCl3,400MHz):8.68-8.69(m,2H),8.55-8.58(m,1H),7.68-7.82(m,4H),7.35(d,J＝8.0Hz,1H),7.18(t,J＝4.8Hz,1H),5.40-5.46(m,2H),5.00-5.08(m,4H),4.62-4.70(m,1H),3.18(s,1H),1.62(d,J＝3.26Hz,3H)；MS:m/z 451.2[M+H]+。Compound 13-5 (150 mg, 580.63 μmol) was dissolved in methanol (3 mL), potassium carbonate (439.38 mg, 870.94 μmol) was added, and the mixture was stirred at 25°C for 12 hours. Add ethyl acetate (20 mL) to the reaction solution to dilute, wash the organic phase with water (20 mL x 2) and saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to dryness to obtain a crude product. The crude product was purified by preparative HPLC (column: Welch SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [0.1% ammonia water-isopropyl Alcohol]; gradient: B%: 45%-45%) was resolved to obtain compound 13a. 1 H NMR (CDCl 3 , 400MHz): 8.68-8.69 (m, 2H), 8.55-8.58 (m, 1H), 7.68-7.82 (m, 4H), 7.35 (d, J = 8.0Hz, 1H), 7.18 (t,J＝4.8Hz,1H),5.40-5.46(m,2H),5.00-5.08(m,4H),4.62-4.70(m,1H),3.18(s,1H),1.62(d,J =3.26Hz, 3H); MS: m/z 451.2[M+H] + .
SFC检测条件：色谱柱:Chiralpak AD(250mm*30mm,10μm)；流动相:[0.1％氨水异丙醇]；B％:45％-45％；流动相:A相:CO2,B相:异丙醇(0.05％二乙胺)；梯度:B％:45％,流速:4mL/min，化合物13a保留时间为0.837min，ee＝100％；对映异构体保留时间为1.205min。SFC detection conditions: chromatographic column: Chiralpak AD (250mm*30mm, 10μm); mobile phase: [0.1% ammonia isopropanol]; B%: 45%-45%; mobile phase: A phase: CO 2 , B phase: Isopropyl alcohol (0.05% diethylamine); gradient: B%: 45%, flow rate: 4mL/min, compound 13a retention time is 0.837min, ee=100%; enantiomer retention time is 1.205min.
实施例14
Example 14
第一步first step
将化合物14-1(1.43g,5.14mmol)溶于1.4-二氧六环(14mL)/水(3.5mL)中，加入碳酸钾(3.97g,18.71mmol),四三苯基膦钯(331.18mg,467.72μmol)和化合物12-2(870mg,4.68mmol)，氮气保护下90℃搅拌48小时。反应液减压浓缩后加入乙酸乙酯(100mL)和水(100mL)在25℃下搅拌30分钟，过滤，滤饼用乙酸乙酯(5mL)和二氯甲烷(5mL,2％MeOH)淋洗，干燥滤饼得到化合物14-2。MS:m/z 256.9[M+H]+。Compound 14-1 (1.43g, 5.14mmol) was dissolved in 1.4-dioxane (14mL)/water (3.5mL), and potassium carbonate (3.97g, 18.71mmol) and tetrakistriphenylphosphine palladium (331.18 mg, 467.72 μmol) and compound 12-2 (870 mg, 4.68 mmol), stirred at 90°C for 48 hours under nitrogen protection. After the reaction solution was concentrated under reduced pressure, ethyl acetate (100 mL) and water (100 mL) were added, stirred at 25°C for 30 minutes, filtered, and the filter cake was rinsed with ethyl acetate (5 mL) and dichloromethane (5 mL, 2% MeOH). , dry the filter cake to obtain compound 14-2. MS: m/z 256.9[M+H] + .
第二步Step 2
将化合物14-2(700mg,2.73mmol)溶于甲醇(7mL)/水(7mL)/四氢呋喃(7mL)，加入氢氧化锂(261.67mg,10.93mmol)，在75℃搅拌3个小时。将反应液浓缩加入1.5M盐酸调pH至6，过滤，滤饼用甲醇(3mL)淋洗，干燥滤饼得到化合物14-3。MS:m/z 242.9[M+H]+。Compound 14-2 (700 mg, 2.73 mmol) was dissolved in methanol (7 mL)/water (7 mL)/tetrahydrofuran (7 mL), lithium hydroxide (261.67 mg, 10.93 mmol) was added, and the mixture was stirred at 75°C for 3 hours. The reaction solution was concentrated and 1.5M hydrochloric acid was added to adjust the pH to 6, filtered, the filter cake was rinsed with methanol (3 mL), and the filter cake was dried to obtain compound 14-3. MS: m/z 242.9[M+H] + .
第三步third step
将化合物14-3(68.66mg,283.44μmol)溶于N,N-二甲基乙酰胺(3mL)中，加入2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU,117.57mg,309.21μmol)和N,N-二异丙基乙胺(133.21mg,1.03mmol)在50℃下搅拌1小时，加入1-6a(80mg,257.68μmol)继续反应11小时。反应液用乙酸乙酯(20mL)稀释，有机相用水(20mL x 2)洗，饱和食盐水(20mL x 2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干燥得到部分消旋的化合物14-4，直接用于下一步。MS:m/z 535.9[M+H]+。Compound 14-3 (68.66 mg, 283.44 μmol) was dissolved in N,N-dimethylacetamide (3 mL), and 2-(7-azobenzotriazole)-N,N,N' was added, N'-tetramethylurea hexafluorophosphate (HATU, 117.57 mg, 309.21 μmol) and N, N-diisopropylethylamine (133.21 mg, 1.03 mmol) were stirred at 50°C for 1 hour, and 1-6a was added (80 mg, 257.68 μmol) and continue the reaction for 11 hours. The reaction solution was diluted with ethyl acetate (20 mL), and the organic phase was washed with water (20 mL x 2) and saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure and dried to obtain a partially racemic compound. 14-4, used directly for the next step. MS: m/z 535.9[M+H] + .
第四步the fourth step
将化合物14-4(120mg,224.43μmol)溶于甲醇(2mL)中，加入碳酸钾(124.07mg,897.72μmol)在25℃下搅拌2小时。原料反应完全后，向反应液中加入乙酸乙酯(20mL)稀释，有机相用水(20mL x 2)洗，饱和食盐水(20mL x 2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干燥得到粗品。粗品经制备 HPLC(柱子:Welch Xtimate C18 80*40mm*3μm；流动相:[5％氨水+10mM碳酸氢铵)-乙腈]；梯度：(乙腈)％:30％-60％)纯化，再经SFC(柱子:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:[0.1％氨水-异丙醇]；梯度：B％:60％-60％)拆分，得到化合物14a。1H NMR(CDCl3,400MHz):8.74-8.75(m,2H),8.57(s,1H),8.11-8.32(m,2H),7.79-7.84(m,1H),7.53-7.67(m,2H),7.43-7.45(m,1H),7.33(t,J＝4.4Hz,1H),5.51-5.76(m,1H),5.05-4.99(m,1H),4.57-4.71(m,1H),4.39(s,3H),3.72(s,1H),1.68(d,J＝5.2Hz,3H)；MS:m/z 463.2[M+H]+。Compound 14-4 (120 mg, 224.43 μmol) was dissolved in methanol (2 mL), potassium carbonate (124.07 mg, 897.72 μmol) was added, and the mixture was stirred at 25°C for 2 hours. After the raw material reaction is complete, add ethyl acetate (20 mL) to the reaction solution to dilute, wash the organic phase with water (20 mL x 2), wash with saturated brine (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Drying gives crude product. The crude product was prepared HPLC (Column: Welch :DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [0.1% ammonia water-isopropyl alcohol]; gradient: B%: 60%-60%) to obtain the compound 14a. 1 H NMR (CDCl 3 ,400MHz):8.74-8.75(m,2H),8.57(s,1H),8.11-8.32(m,2H),7.79-7.84(m,1H),7.53-7.67(m, 2H),7.43-7.45(m,1H),7.33(t,J＝4.4Hz,1H),5.51-5.76(m,1H),5.05-4.99(m,1H),4.57-4.71(m,1H) ,4.39(s,3H),3.72(s,1H),1.68(d,J＝5.2Hz,3H); MS: m/z 463.2[M+H] + .
SFC检测条件：色谱柱:Chiralpak AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:[0.1％氨水-乙醇]；梯度：B％:60％，流速:4mL/min，化合物14a保留时间为3.931min，ee＝100％；对映异构体保留时间为5.499min。SFC detection conditions: chromatographic column: Chiralpak AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [0.1% ammonia water-ethanol]; gradient: B%: 60%, flow rate: 4mL/min , the retention time of compound 14a is 3.931min, ee=100%; the enantiomer retention time is 5.499min.
实施例15
Example 15
第一步first step
将化合物12-2(800mg,4.30mmol)加入到二氧六环(16mL)和水(1.6mL)的混合溶剂中，然后加入化合物15-1(953.49mg,3.44mmol)，碳酸钾(1.78g,12.90mmol)，四(三苯基膦)钯(496.99mg,430.09μmol)，氮气置换三次，反应液在80℃下搅拌12小时。反应液直接减压浓缩，然后加入乙酸乙酯(5mL)和水(5mL)，搅拌30分钟，有固体析出，过滤，滤饼经乙酸乙酯(3mL*2)洗涤，干燥得到化合物15-2。1H NMR(400MHz,DMSO-d6):δ8.15(s,1H),7.81(dd,J＝2.01,8.53Hz,1H),7.59-7.65(m,1H),6.85(d,J＝8.78Hz,1H),6.18(s,2H),3.77(s,3H),3.66(s,3H)。Compound 12-2 (800 mg, 4.30 mmol) was added to a mixed solvent of dioxane (16 mL) and water (1.6 mL), and then compound 15-1 (953.49 mg, 3.44 mmol) and potassium carbonate (1.78 g were added ,12.90mmol), tetrakis(triphenylphosphine)palladium (496.99mg, 430.09μmol), nitrogen was substituted three times, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was directly concentrated under reduced pressure, then added ethyl acetate (5mL) and water (5mL), stirred for 30 minutes, solid precipitated, filtered, the filter cake was washed with ethyl acetate (3mL*2), and dried to obtain compound 15-2 . 1 H NMR (400MHz, DMSO-d 6 ): δ8.15 (s, 1H), 7.81 (dd, J＝2.01, 8.53Hz, 1H), 7.59-7.65 (m, 1H), 6.85 (d, J＝ 8.78Hz,1H),6.18(s,2H),3.77(s,3H),3.66(s,3H).
第二步Step 2
将化合物15-2(300mg,1.17mmol)加入到二甲基亚砜(0.5mL)中，反应液在110℃下搅拌12小时。反应液直接过滤，滤饼干燥得到化合物15-3。MS:m/z 256.9[M+H]+。Compound 15-2 (300 mg, 1.17 mmol) was added to dimethyl sulfoxide (0.5 mL), and the reaction solution was stirred at 110°C for 12 hours. The reaction solution was directly filtered, and the filter cake was dried to obtain compound 15-3. MS: m/z 256.9[M+H] + .
第三步third step
向化合物15-3(200mg,780.46μmol)溶于四氢呋喃(1.5mL)，甲醇(1.5mL)和水(1.5mL)的混合溶剂中，然后加入一水合氢氧化锂(131.00mg,3.12mmol)，反应液在75℃下搅拌3小时。反应液直接减压浓缩，然后加入稀盐酸(1M,1mL)和甲醇(1mL)，室温下搅拌10分钟，过滤，滤饼干燥后得到化合物15-4，直接用于下一步。Compound 15-3 (200 mg, 780.46 μmol) was dissolved in a mixed solvent of tetrahydrofuran (1.5 mL), methanol (1.5 mL) and water (1.5 mL), and then lithium hydroxide monohydrate (131.00 mg, 3.12 mmol) was added, The reaction solution was stirred at 75°C for 3 hours. The reaction solution was directly concentrated under reduced pressure, then dilute hydrochloric acid (1M, 1mL) and methanol (1mL) were added, stirred at room temperature for 10 minutes, filtered, and the filter cake was dried to obtain compound 15-4, which was used directly in the next step.
第四步 the fourth step
将化合物15-4(46.81mg,193.26μmol)和1-6a(50mg,161.05μmol)溶于N,N-二甲基乙酰胺(2mL)中，加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(HATU,73.48mg,193.26μmol)和N,N-二异丙基乙胺(83.26mg,644.19μmol)，反应液在25℃下搅拌24小时。反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到少量消旋的化合物15-5，直接用于下一步。Compounds 15-4 (46.81 mg, 193.26 μmol) and 1-6a (50 mg, 161.05 μmol) were dissolved in N,N-dimethylacetamide (2 mL), and O-(7-azabenzotriazole) was added Azol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt (HATU, 73.48mg, 193.26μmol) and N,N-diisopropylethylamine (83.26mg, 644.19μmol) , the reaction solution was stirred at 25°C for 24 hours. The reaction solution was diluted with water (10mL), extracted with dichloromethane (10mL*3), the organic phase was washed with saturated brine (10mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a small amount of racemic compound. 15-5, used directly for the next step.
第五步the fifth step
将化合物15-5(70.00mg,130.92μmol)溶于甲醇(1mL)中，加入碳酸钾(54.28mg,392.75μmo)，反应液在25℃下搅拌1小时。反应结束后，反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，粗品经制备HPLC(柱子：O-Welch C18 150*30mm*5μm；流动相:[水(0.255％甲酸)-乙腈]；梯度：(乙腈)％:0％-35％)纯化得到产物15a。1H NMR(400MHz,CD3OD):δ8.76(br d,J＝4.77Hz,2H),8.49(br s,1H),8.32(s,1H),7.58-8.05(m,4H),7.39(br d,J＝7.78Hz,1H),7.35(t,J＝4.89Hz,1H),5.60(br s,1H),4.87-5.01(m,3H),4.46(br d,J＝12.55Hz,2H),3.73(s,1H),1.68(br d,J＝7.03Hz,3H)；MS:m/z 463.1[M+H]+。Compound 15-5 (70.00 mg, 130.92 μmol) was dissolved in methanol (1 mL), potassium carbonate (54.28 mg, 392.75 μmol) was added, and the reaction solution was stirred at 25°C for 1 hour. After the reaction, the reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. , the crude product was purified by preparative HPLC (column: O-Welch C18 150*30mm*5μm; mobile phase: [water (0.255% formic acid)-acetonitrile]; gradient: (acetonitrile)%: 0%-35%) to obtain product 15a. 1 H NMR (400MHz, CD 3 OD): δ8.76 (br d, J = 4.77Hz, 2H), 8.49 (br s, 1H), 8.32 (s, 1H), 7.58-8.05 (m, 4H), 7.39(br d,J＝7.78Hz,1H),7.35(t,J＝4.89Hz,1H),5.60(br s,1H),4.87-5.01(m,3H),4.46(br d,J＝12.55 Hz, 2H), 3.73 (s, 1H), 1.68 (br d, J = 7.03Hz, 3H); MS: m/z 463.1[M+H] + .
SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:异丙醇(0.05％二乙醇胺)；梯度:B％5％-40％-5％,流速:4mL/min，化合物15a保留时间为2.245min，ee＝85.1％；其对映异构体保留时间为2.530min。SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: isopropyl alcohol (0.05% diethanolamine); gradient: B% 5%-40% -5%, flow rate: 4mL/min, compound 15a retention time is 2.245min, ee=85.1%; its enantiomer retention time is 2.530min.
实施例16
Example 16
第一步first step
将化合物16-1(3g,11.34mmo)加入到二氧六环(45mL)中，然后加入双联频哪醇硼酸酯(5.76g,22.68mmol)，醋酸钾(3.34g,34.03mmol)，1,1-双(二苯基磷)二茂铁氯化钯(829.90mg,1.13mmol)，氮气置换三次，反应液在100℃下搅拌12小时。反应液直接减压浓缩，粗品经硅胶柱层析(石油醚:乙酸乙酯＝0:1)纯化得到粗品，粗品加入乙酸乙酯(20mL)，过滤，滤液浓缩得到化合物16-2。MS:m/z 311.9[M+H]+。Compound 16-1 (3g, 11.34mmo) was added to dioxane (45mL), and then bis-pinaccol borate (5.76g, 22.68mmol) and potassium acetate (3.34g, 34.03mmol) were added. 1,1-Bis(diphenylphosphorus)ferrocene palladium chloride (829.90 mg, 1.13 mmol) was replaced with nitrogen three times, and the reaction solution was stirred at 100°C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 0:1) to obtain a crude product. Ethyl acetate (20 mL) was added to the crude product, filtered, and the filtrate was concentrated to obtain compound 16-2. MS: m/z 311.9[M+H] + .
第二步Step 2
将化合物13-2(500mg,2.06mmol)加入到二氧六环(10mL)和水(1mL)的混合溶剂中，然后加入化合物16-2(512.53mg,1.65mmol)，磷酸钾(1.31g,6.17mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(167.92mg,205.63μmol)，氮气置换三次，反应液在80℃下搅拌12小时。反应液直接浓缩，然后加入乙酸乙酯(5mL)和水(5mL)，搅拌30分钟，有固体析出，过滤，滤饼经乙酸乙酯(3mL*2)洗涤，干燥得到化合物16-3。 MS:m/z 278.9[M+H]+。Compound 13-2 (500 mg, 2.06 mmol) was added to a mixed solvent of dioxane (10 mL) and water (1 mL), and then compound 16-2 (512.53 mg, 1.65 mmol) and potassium phosphate (1.31 g, 6.17 mmol), [1,1-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane (167.92 mg, 205.63 μmol), nitrogen was substituted three times, and the reaction solution was stirred at 80°C for 12 hours. The reaction solution was concentrated directly, then ethyl acetate (5mL) and water (5mL) were added, stirred for 30 minutes, solid precipitated, filtered, the filter cake was washed with ethyl acetate (3mL*2), and dried to obtain compound 16-3. MS: m/z 278.9[M+H] + .
第三步third step
向化合物16-3(190mg,681.76μmol)溶于四氢呋喃(2mL)，甲醇(2mL)和水(2mL)的混合溶剂中，然后加入一水合氢氧化锂(114.44mg,2.73mmol)，反应液在75℃下搅拌2小时。反应液直接浓缩，然后加入稀盐酸(1M,5mL)和甲醇(2mL)，室温下搅拌10分钟，过滤，滤饼干燥后得到化合物16-4。1H NMR(400MHz,DMSO-d6)δ8.04(s,1H),7.64(s,1H),5.37(br s,2H),5.01(br s,2H)；MS:m/z 265.4[M+H]+。Compound 16-3 (190 mg, 681.76 μmol) was dissolved in a mixed solvent of tetrahydrofuran (2 mL), methanol (2 mL) and water (2 mL), and then lithium hydroxide monohydrate (114.44 mg, 2.73 mmol) was added, and the reaction solution was Stir at 75°C for 2 hours. The reaction solution was directly concentrated, then dilute hydrochloric acid (1M, 5mL) and methanol (2mL) were added, stirred at room temperature for 10 minutes, filtered, and the filter cake was dried to obtain compound 16-4. 1 H NMR (400MHz, DMSO-d 6 ) δ8.04 (s, 1H), 7.64 (s, 1H), 5.37 (br s, 2H), 5.01 (br s, 2H); MS: m/z 265.4[ M+H] + .
第四步the fourth step
将化合物16-4(81.84mg,309.21μmol)和1-6a(80mg,257.68μmol)溶于N,N-二甲基乙酰胺(2mL)中，加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(HATU,117.57mg,309.21μmol)和N,N-二异丙基乙胺(133.21mg,1.03mmol)，反应液在25℃下搅拌12小时。反应少量消旋。反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物16-5。Compounds 16-4 (81.84 mg, 309.21 μmol) and 1-6a (80 mg, 257.68 μmol) were dissolved in N,N-dimethylacetamide (2 mL), and O-(7-azabenzotriazole) was added Azol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt (HATU, 117.57mg, 309.21μmol) and N,N-diisopropylethylamine (133.21mg, 1.03mmol) , the reaction solution was stirred at 25°C for 12 hours. The reaction was slightly racemic. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16-5.
第五步the fifth step
将化合物16-5(100mg,179.50μmol)溶于甲醇(2mL)中，加入碳酸钾(74.42mg,538.49μmol)，反应液在25℃下搅拌1小时。反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤浓缩得到粗品，粗品经制备HPLC(柱子:O-Welch C18 150*30mm*5μm；流动相:[水(0.225％甲酸)-乙腈]；梯度：(乙腈)％:0％-40％)纯化得到化合物16a。1H NMR(400MHz,CD3OD):δ8.72(d,J＝4.77Hz,2H),8.48(d,J＝1.26Hz,1H),7.85(dd,J＝1.88,8.16Hz,1H),7.74(s,1H),7.54-7.60(m,2H),7.34(t,J＝4.77Hz,1H),5.30-5.37(m,1H),5.14-5.21(m,2H),5.05-5.11(m,4H),3.73(s,1H),1.62(d,J＝7.03Hz,3H)；MS:m/z 485.1[M+H]+。Compound 16-5 (100 mg, 179.50 μmol) was dissolved in methanol (2 mL), potassium carbonate (74.42 mg, 538.49 μmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was diluted with water (10mL), extracted with dichloromethane (10mL*3), the organic phase was washed with saturated brine (10mL*2), dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was subjected to preparative HPLC (column: O-Welch C18 150*30mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: (acetonitrile)%: 0%-40%) to obtain compound 16a. 1 H NMR (400MHz, CD 3 OD): δ8.72 (d, J = 4.77Hz, 2H), 8.48 (d, J = 1.26Hz, 1H), 7.85 (dd, J = 1.88, 8.16Hz, 1H) ,7.74(s,1H),7.54-7.60(m,2H),7.34(t,J＝4.77Hz,1H),5.30-5.37(m,1H),5.14-5.21(m,2H),5.05-5.11 (m, 4H), 3.73 (s, 1H), 1.62 (d, J = 7.03Hz, 3H); MS: m/z 485.1[M+H] + .
SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:乙醇(0.05％二乙醇胺)；梯度:B％:40％,流速:4mL/min，化合物16a保留时间为0.833min，ee＝80.16％；对映异构体保留时间为3.406min。SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; Mobile phase: Phase A: CO 2 , Phase B: ethanol (0.05% diethanolamine); Gradient: B%: 40%, flow rate: 4mL /min, the retention time of compound 16a is 0.833min, ee=80.16%; the enantiomer retention time is 3.406min.
实施例17
Example 17
第一步first step
0℃下，向化合物17-1(20g,118.24mmol)的乙腈(200mL)溶液中缓慢加入N-溴代丁二酰亚胺(21.04g,118.24mmol)，混合物在室温25℃下搅拌16小时。向反应液中加入水(100mL)，用乙酸乙酯(100mL*3)萃取，合并有机相，用饱和氯化钠水溶液(50mL*3)洗涤，无水硫酸钠干燥，过滤之后滤液减压浓缩。粗品经 柱层析(硅胶，石油醚：乙酸乙酯＝3:1)，得到化合物17-2。MS:m/z 248.0/250.0[M+H]+。To a solution of compound 17-1 (20g, 118.24mmol) in acetonitrile (200mL), N-bromosuccinimide (21.04g, 118.24mmol) was slowly added at 0°C, and the mixture was stirred at room temperature 25°C for 16 hours. . Add water (100mL) to the reaction solution, extract with ethyl acetate (100mL*3), combine the organic phases, wash with saturated sodium chloride aqueous solution (50mL*3), dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure . Crude Classics Column chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) gave compound 17-2. MS: m/z 248.0/250.0[M+H] + .
第二步Step 2
0℃下，向化合物17-2(5.00g,20.16mmol)和双联嚬哪醇硼酸酯(6.14g,24.19mmol)的二氧六环(50mL)溶液中加入乙酸钾(5.93g,60.47mmol)，1,1-双(二苯基膦)二茂铁氯化钯(737.47mg,1.01mmol)，混合物在100℃下搅拌20小时。混合物通过硅藻土过滤，滤液减压浓缩。粗品经柱层析(硅胶，石油醚：乙酸乙酯＝20:1)，得到化合物17-3。MS:m/z 296.2[M+H]+。Potassium acetate (5.93g, 60.47) was added to a solution of compound 17-2 (5.00g, 20.16mmol) and bis-zalcohol borrate (6.14g, 24.19mmol) in dioxane (50mL) at 0°C. mmol), 1,1-bis(diphenylphosphine)ferrocene palladium chloride (737.47 mg, 1.01 mmol), and the mixture was stirred at 100°C for 20 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The crude product was subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 20:1) to obtain compound 17-3. MS: m/z 296.2[M+H] + .
第三步third step
向化合物15-1(1g,5.38mmol)和化合物17-3(1.59g,5.38mmol)的二氧六环(16mL)和水(4mL)溶液中加入磷酸钾(667.55mg,4.83mmol)和二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(761.33mg,1.08mmol)，混合物在油浴90℃下搅拌6小时。反应液经硅藻土过滤，滤液减压浓缩。粗品通过柱层析(硅胶，二氯甲烷：甲醇＝10：1)纯化，得到化合物17-4。MS:m/z 275.0[M+H]+。To a solution of compound 15-1 (1 g, 5.38 mmol) and compound 17-3 (1.59 g, 5.38 mmol) in dioxane (16 mL) and water (4 mL) was added potassium phosphate (667.55 mg, 4.83 mmol) and dioxane. Chlorobis[di-tert-butyl-(4-dimethylaminophenyl)phosphine]palladium(II) (761.33 mg, 1.08 mmol), the mixture was stirred in an oil bath at 90°C for 6 hours. The reaction solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=10:1) to obtain compound 17-4. MS: m/z 275.0[M+H] + .
第四步the fourth step
向化合物17-4(510mg,1.86mmol)的水(5mL)，甲醇(5mL)和四氢呋喃(5mL)溶液中加入一水合氢氧化锂(156.06mg,3.72mmol)，混合物在室温25℃下搅拌19小时。向反应混合物中加入2mol/L的稀盐酸调节pH至5-6，混合物搅拌5分钟，过滤，滤饼用水(10mL*3)洗涤，而后滤饼减压干燥。得到化合物17-5。MS:m/z 261.0[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.76-8.69(m,1H),8.27(s,1H),7.50(br s,2H),7.28-7.23(m,1H),4.38(s,3H)。To a solution of compound 17-4 (510 mg, 1.86 mmol) in water (5 mL), methanol (5 mL) and tetrahydrofuran (5 mL) was added lithium hydroxide monohydrate (156.06 mg, 3.72 mmol), and the mixture was stirred at room temperature 25°C for 19 Hour. Add 2 mol/L dilute hydrochloric acid to the reaction mixture to adjust the pH to 5-6, stir the mixture for 5 minutes, filter, wash the filter cake with water (10 mL*3), and then dry the filter cake under reduced pressure. Compound 17-5 was obtained. MS: m/z 261.0[M+H] + . 1 H NMR (400MHz, DMSO-d 6 )δ=8.76-8.69(m,1H),8.27(s,1H),7.50(br s,2H),7.28-7.23(m,1H),4.38(s, 3H).
第五步the fifth step
将化合物17-5(69.15mg,265.73μmol)溶于N,N-二甲基乙酰胺(6mL)中，依次加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(HATU,137.78.57mg,362.36μmol)和N,N-二异丙基乙胺(62.44mg,483.14μmol)和化合物1-6a(75mg,241.57μmol)，反应液在50℃下搅拌12小时。反应液加入水(25mL)稀释，乙酸乙酯(20mL*3)萃取，有机相经饱和食盐水(20mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物17-6。Compound 17-5 (69.15 mg, 265.73 μmol) was dissolved in N,N-dimethylacetamide (6 mL), and O-(7-azabenzotriazol-1-yl)-N was added in sequence. N,N,N-tetramethylurea hexafluorophosphine salt (HATU, 137.78.57mg, 362.36μmol) and N,N-diisopropylethylamine (62.44mg, 483.14μmol) and compound 1-6a (75mg, 241.57 μmol), the reaction solution was stirred at 50°C for 12 hours. The reaction solution was diluted with water (25 mL), extracted with ethyl acetate (20 mL*3), the organic phase was washed with saturated brine (20 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17-6.
第六步Step 6
将化合物17-6(176mg,318.45μmol)溶于甲醇(5mL)中，加入碳酸钾(66.02mg,477.68μmol)，反应液在25℃下搅拌1小时。反应液浓缩得到粗品，粗品经制备HPLC(柱子:Waters Xbridge 150*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度：(乙腈)％:25％-55％)纯化，再经SFC(柱子:DAICEL CHIRALCEL OX(250mm*30mm,10μm)；流动相:A相:CO2,B相:[0.1％氨水-乙醇]；梯度：B％:50％-50％)拆分，再经制备HPLC(柱子:Waters Xbridge 150*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度：(乙腈)％:25％-55％)纯化，得到化合物17a。MS:m/z 481.1[M+H]+。1H NMR(400MHz,DMSO-d6)δ＝8.78(br s,2H),8.54(s,1H),8.36(br d,J＝7.5Hz,1H),8.25(s,1H),7.86(br d,J＝6.6Hz,1H),7.40(br d,J＝4.4Hz,2H),7.29(br s,1H),5.32(q,J＝6.8Hz,1H),4.95(br d,J＝16.6Hz,1H),4.84-4.65(m,1H),4.30(br s,3H),4.19(s,1H),1.60-1.52(m,3H)。Compound 17-6 (176 mg, 318.45 μmol) was dissolved in methanol (5 mL), potassium carbonate (66.02 mg, 477.68 μmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated to obtain a crude product, which was purified by preparative HPLC (column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient: (acetonitrile)%: 25%-55%) , and then separated by SFC (column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [0.1% ammonia water-ethanol]; gradient: B%: 50%-50%) separated, and then purified by preparative HPLC (column: Waters . MS: m/z 481.1[M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ = 8.78 (br s, 2H), 8.54 (s, 1H), 8.36 (br d, J = 7.5Hz, 1H), 8.25 (s, 1H), 7.86 ( br d,J＝6.6Hz,1H),7.40(br d,J＝4.4Hz,2H),7.29(br s,1H),5.32(q,J＝6.8Hz,1H),4.95(br d,J ＝16.6Hz,1H),4.84-4.65(m,1H),4.30(br s,3H),4.19(s,1H),1.60-1.52(m,3H).
SFC检测条件：色谱柱:Chiralpak OX-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:乙醇(0.05％二乙胺)；梯度:B％:40％,流速:3mL/min，化合物17a保留时间为2.288min，ee＝100.00％。SFC detection conditions: Chromatographic column: Chiralpak OX-3 50×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: ethanol (0.05% diethylamine); gradient: B%: 40%, flow rate: 3mL/min, the retention time of compound 17a is 2.288min, ee=100.00%.
实施例18
Example 18
第一步first step
将化合物13-2(100mg,411.25μmol)加入到二氧六环(2mL)和水(0.2mL)的混合溶剂中，然后加入化合物17-3(97.09mg,329.00μmol)，磷酸钾(261.89mg,1.23mmo)，1,1-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(33.58mg,41.13μmol)，氮气置换三次，反应液在80℃下搅拌12小时。反应液直接浓缩，然后加入乙酸乙酯(5mL)和水(5mL)，搅拌30分钟，有固体析出，过滤，滤饼经乙酸乙酯(3mL*2)洗涤，干燥滤饼得到化合物18-1。1H NMR(400MHz,DMSO-d6)δ8.05(d,J＝8.13Hz,1H),7.27(d,J＝13.38Hz,1H),7.11(br s,2H),5.36(t,J＝3.31Hz,2H),4.99(br s,2H),3.86(s,3H)。Compound 13-2 (100 mg, 411.25 μmol) was added to a mixed solvent of dioxane (2 mL) and water (0.2 mL), and then compound 17-3 (97.09 mg, 329.00 μmol) and potassium phosphate (261.89 mg were added ,1.23mmo), 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride(II) dichloromethane complex (33.58mg, 41.13μmol), nitrogen was replaced three times, and the reaction solution was stirred at 80°C 12 hours. The reaction solution was concentrated directly, then ethyl acetate (5mL) and water (5mL) were added, stirred for 30 minutes, solid precipitated, filtered, the filter cake was washed with ethyl acetate (3mL*2), and the filter cake was dried to obtain compound 18-1 . 1 H NMR (400MHz, DMSO-d 6 ) δ8.05(d,J＝8.13Hz,1H),7.27(d,J＝13.38Hz,1H),7.11(br s,2H),5.36(t,J =3.31Hz,2H),4.99(br s,2H),3.86(s,3H).
第二步Step 2
将化合物18-1(50mg,190.67μmol)溶于四氢呋喃(0.5mL)，甲醇(0.5mL)和水(0.5mL)的混合溶剂中，然后加入一水合氢氧化锂(32.00mg,762.67μmol)，反应液在75℃下搅拌2小时。反应液直接浓缩，然后加入稀盐酸(1M,1mL)和甲醇(1mL)，室温下搅拌10分钟，过滤，滤饼干燥后得到化合物18-2。MS:m/z 248.8[M+H]+。Compound 18-1 (50 mg, 190.67 μmol) was dissolved in a mixed solvent of tetrahydrofuran (0.5 mL), methanol (0.5 mL) and water (0.5 mL), and then lithium hydroxide monohydrate (32.00 mg, 762.67 μmol) was added. The reaction solution was stirred at 75°C for 2 hours. The reaction solution was directly concentrated, then dilute hydrochloric acid (1M, 1mL) and methanol (1mL) were added, stirred at room temperature for 10 minutes, filtered, and the filter cake was dried to obtain compound 18-2. MS: m/z 248.8[M+H] + .
第三步third step
将1-6a(28.78mg,115.95μmol)和化合物18-2(30mg,96.63μmol)溶于N,N-二甲基乙酰胺(1mL)中，加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(HATU,44.09mg,115.95μmol)和N,N-二异丙基乙胺(49.95mg,386.51μmol)，反应液在25℃下搅拌12小时。反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物18-3。MS:m/z 541.3[M+H]+。Dissolve 1-6a (28.78 mg, 115.95 μmol) and compound 18-2 (30 mg, 96.63 μmol) in N,N-dimethylacetamide (1 mL), and add O-(7-azabenzotriazole) Azol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt (HATU, 44.09 mg, 115.95 μmol) and N,N-diisopropylethylamine (49.95 mg, 386.51 μmol) , the reaction solution was stirred at 25°C for 12 hours. The reaction solution was diluted with water (10 mL), extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 18-3. MS: m/z 541.3[M+H] + .
第四步the fourth step
将化合物18-3(30mg,55.49μmol)溶于甲醇(1mL)中，加入碳酸钾(23.01mg,166.46μmol)，反应液在25℃下搅拌1小时。反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经制备HPLC(柱子:Waters Xbridge 150*25mm*5μm；流动相:[水(0.225％甲酸)-乙腈]；梯度：(乙腈)％:5％-45％)纯化得到化合物18a。MS:m/z 469.0[M+H]+。MS:m/z 469.0[M+H]+。1H NMR(400MHz,CD3OD)δ8.76(d,J＝5.00Hz,1H),8.70(br d,J＝4.88Hz,2H), 8.50(s,1H),7.83(br d,J＝6.88Hz,2H),7.38-7.42(m,1H),7.30-7.34(m,1H),5.43(br s,1H),5.21-5.27(m,2H),5.12(br s,2H),5.07(br s,2H),3.74(s,1H),1.64(d,J＝7.00Hz,3H)。SFC检测条件：色谱柱:Chiralpak AD-350×4.6mm I.D.,3μm；流动相:A相:CO2,B相:异丙醇(0.05％二乙胺)；梯度:B％:5％-40％,流速:4mL/min，化合物18a保留时间为2.187min，ee＝80.00％，其对映异构体保留时间为2.716min。Compound 18-3 (30 mg, 55.49 μmol) was dissolved in methanol (1 mL), potassium carbonate (23.01 mg, 166.46 μmol) was added, and the reaction solution was stirred at 25°C for 1 hour. The reaction solution was diluted with water (10mL), extracted with dichloromethane (10mL*3), the organic phase was washed with saturated brine (10mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was analyzed by preparative HPLC ( Column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: (acetonitrile)%: 5%-45%) to obtain compound 18a. MS: m/z 469.0[M+H] + . MS: m/z 469.0[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.76 (d, J = 5.00Hz, 1H), 8.70 (br d, J = 4.88Hz, 2H), 8.50(s,1H),7.83(br d,J＝6.88Hz,2H),7.38-7.42(m,1H),7.30-7.34(m,1H),5.43(br s,1H),5.21-5.27( m,2H),5.12(br s,2H),5.07(br s,2H),3.74(s,1H),1.64(d,J＝7.00Hz,3H). SFC detection conditions: chromatographic column: Chiralpak AD-350×4.6mm ID, 3μm; mobile phase: A phase: CO 2 , B phase: isopropyl alcohol (0.05% diethylamine); gradient: B%: 5%-40 %, flow rate: 4mL/min, compound 18a retention time is 2.187min, ee=80.00%, and its enantiomer retention time is 2.716min.
实施例19
Example 19
第一步first step
将化合物19-1(10g,92.51mmol)溶于N,N-二甲基乙酰胺(100mL)中，加入碳酸铯(33.15g,101.76mmol)，反应液降温至0℃，然后缓慢滴加氘代碘甲烷(14.08g,97.13mmol)，反应液在0℃下搅拌6小时。反应液直接浓缩，然后加入二氯甲烷(100mL)，搅拌30分钟，过滤。滤饼经二氯甲烷(10mL*2)洗涤，收集滤饼干燥后加入乙酸乙酯(200mL)，搅拌30分钟，过滤，滤饼经乙酸乙酯(10mL*2)洗涤，滤液浓缩得到化合物19-2。1H NMR(400MHz,DMSO-d6)δ8.01(s,1H),5.51(s,2H)。Dissolve compound 19-1 (10g, 92.51mmol) in N,N-dimethylacetamide (100mL), add cesium carbonate (33.15g, 101.76mmol), cool the reaction solution to 0°C, and then slowly add deuterium dropwise Methyl iodide (14.08g, 97.13mmol), the reaction solution was stirred at 0°C for 6 hours. The reaction solution was directly concentrated, then dichloromethane (100 mL) was added, stirred for 30 minutes, and filtered. The filter cake was washed with dichloromethane (10 mL*2). The filter cake was collected and dried, then ethyl acetate (200 mL) was added, stirred for 30 minutes, filtered, the filter cake was washed with ethyl acetate (10 mL*2), and the filtrate was concentrated to obtain compound 19. -2. 1 H NMR (400MHz, DMSO-d 6 ) δ 8.01 (s, 1H), 5.51 (s, 2H).
第二步Step 2
将化合物19-2(1g,7.99mmol)加入到水(30mL)中，然后加入氢溴酸(40％纯度,21.81g,107.83mmol)，反应液降温至0℃，然后缓慢滴加亚硝酸钠(827.03mg,11.99mmol)的水(2mL)溶液，然后分批加入溴化亚铜(1.83g,12.79mmol)，反应液在0℃下搅拌4小时，转至25℃下继续搅拌12小时。反应液在0℃下加入水(60mL)搅拌2小时，过滤，滤饼经水(20mL*2)洗涤，然后收集滤饼经减压干燥得到化合物19-3。MS: m/z 188.8,190.8[M+H]+。Add compound 19-2 (1g, 7.99mmol) to water (30mL), then add hydrobromic acid (40% purity, 21.81g, 107.83mmol), cool the reaction solution to 0°C, and then slowly add sodium nitrite dropwise (827.03 mg, 11.99 mmol) in water (2 mL), then copper bromide (1.83 g, 12.79 mmol) was added in batches. The reaction solution was stirred at 0°C for 4 hours, and then transferred to 25°C to continue stirring for 12 hours. The reaction solution was stirred for 2 hours by adding water (60 mL) at 0°C, and filtered. The filter cake was washed with water (20 mL*2), and then the filter cake was collected and dried under reduced pressure to obtain compound 19-3. MS: m/z 188.8,190.8[M+H] + .
第三步third step
将化合物19-3(1g,5.29mmol)加入到二氧六环(20mL)和水(2mL)的混合溶剂中，然后加入化合物12-2(1.17g,4.23mmol)，磷酸钾(3.37g,15.87mmol)，1,1-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物(432.02mg,529.02μmol)，氮气置换三次，反应液在80℃下搅拌12小时。反应液直接浓缩，然后加入乙酸乙酯(5mL)和水(5mL)，搅拌30分钟，有固体析出，过滤，滤饼经乙酸乙酯(3mL*2)洗涤，干燥得到化合物19-4。MS:m/z 259.9[M+H]+。Compound 19-3 (1g, 5.29mmol) was added to a mixed solvent of dioxane (20mL) and water (2mL), then compound 12-2 (1.17g, 4.23mmol) and potassium phosphate (3.37g, 15.87mmol), 1,1-bis(diphenylphosphino)ferrocene palladium(II) dichloride dichloromethane complex (432.02mg, 529.02μmol), nitrogen was replaced three times, and the reaction solution was stirred at 80°C for 12 Hour. The reaction solution was concentrated directly, then ethyl acetate (5mL) and water (5mL) were added, stirred for 30 minutes, solid precipitated, filtered, the filter cake was washed with ethyl acetate (3mL*2), and dried to obtain compound 19-4. MS: m/z 259.9[M+H] + .
第四步the fourth step
将化合物19-4(300mg,1.16mmol)溶于四氢呋喃(3mL)，甲醇(3mL)和水(3mL)的混合溶剂中，然后加入一水合氢氧化锂(194.22mg,4.63mmol)，反应液在75℃下搅拌2小时。反应液直接浓缩，然后加入1M的稀盐酸(5mL)和甲醇(1mL)，室温下搅拌10分钟，过滤，滤饼干燥后得到化合物19-5。MS:m/z 245.9[M+H]+。Compound 19-4 (300 mg, 1.16 mmol) was dissolved in a mixed solvent of tetrahydrofuran (3 mL), methanol (3 mL) and water (3 mL), and then lithium hydroxide monohydrate (194.22 mg, 4.63 mmol) was added, and the reaction solution was Stir at 75°C for 2 hours. The reaction solution was directly concentrated, then 1M dilute hydrochloric acid (5 mL) and methanol (1 mL) were added, stirred at room temperature for 10 minutes, filtered, and the filter cake was dried to obtain compound 19-5. MS: m/z 245.9[M+H] + .
第五步the fifth step
参考实施例1的步骤1～4，未拆分中间体得到消旋得化合物19-6。将19-6(50mg,161.05μmol)和化合物19-5(47.40mg,193.26μmol)溶于N,N-二甲基乙酰胺(1mL)中，加入O-(7-氮杂苯并三氮唑-1-基)-N,N,N,N-四甲基脲六氟膦盐(73.48mg,193.26μmol)和N,N-二异丙基乙胺(83.25mg,644.19μmol)，反应液在25℃下搅拌24小时。向反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物19-7。MS:m/z 538.2[M+H]+。Referring to steps 1 to 4 of Example 1, the intermediate was not resolved to obtain racemic compound 19-6. Dissolve 19-6 (50 mg, 161.05 μmol) and compound 19-5 (47.40 mg, 193.26 μmol) in N,N-dimethylacetamide (1 mL), and add O-(7-azabenzotriazole) Azol-1-yl)-N,N,N,N-tetramethylurea hexafluorophosphonium salt (73.48mg, 193.26μmol) and N,N-diisopropylethylamine (83.25mg, 644.19μmol), reaction The solution was stirred at 25°C for 24 hours. The reaction solution was diluted by adding water (10 mL), extracted with dichloromethane (10 mL*3), the organic phase was washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 19-7. MS: m/z 538.2[M+H] + .
第六步Step 6
将化合物19-7(50mg,92.99μmol)溶于甲醇(1mL)中，加入碳酸钾(38.55mg,278.96μmol)，反应液在25℃下搅拌1小时。向反应液加入水(10mL)稀释，二氯甲烷(10mL*3)萃取，有机相经饱和食盐水(10mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品，粗品经硅胶柱层析(二氯甲烷/甲醇＝1/0-10/1)纯化得到化合物19。MS:m/z 466.2[M+H]+。Compound 19-7 (50 mg, 92.99 μmol) was dissolved in methanol (1 mL), potassium carbonate (38.55 mg, 278.96 μmol) was added, and the reaction solution was stirred at 25°C for 1 hour. Add water (10mL) to the reaction solution to dilute, extract with dichloromethane (10mL*3), wash the organic phase with saturated brine (10mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain a crude product, which is passed through a silica gel column Compound 19 was purified by chromatography (dichloromethane/methanol=1/0-10/1). MS: m/z 466.2[M+H] + .
第七步Step 7
化合物19(28mg,60.15μmol)经SFC(柱子:DAICEL CHIRALPAK AD(250mm*30mm,10μm)；流动相:A相:CO2,B相:[0.1％氨水-异丙醇]；梯度：B％:50％-50％)拆分得到化合物19a和19b。Compound 19 (28 mg, 60.15 μmol) was analyzed by SFC (column: DAICEL CHIRALPAK AD (250mm*30mm, 10 μm); mobile phase: A phase: CO 2 , B phase: [0.1% ammonia water-isopropyl alcohol]; gradient: B% :50%-50%) to obtain compounds 19a and 19b.
化合物19a:SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:异丙醇(0.05％二乙胺)；梯度:B％:40％,流速:4mL/min，保留时间为0.680min，ee＝100％。MS:m/z 466.2[M+H]+。1H NMR(400MHz,CD3OD)δ8.76(br d,J＝4.52Hz,2H),8.49(br s,1H),8.30(s,1H),7.89(br d,J＝8.28Hz,1H),7.62-7.83(m,3H),7.33-7.44(m,2H),5.60(br s,1H),4.92-5.00(m,2H),3.71-3.77(m,1H),1.69(br d,J＝6.78Hz,3H)。Compound 19a: SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: isopropyl alcohol (0.05% diethylamine); gradient: B%: 40%, flow rate: 4mL/min, retention time: 0.680min, ee=100%. MS: m/z 466.2[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.76 (br d, J＝4.52Hz, 2H), 8.49 (br s, 1H), 8.30 (s, 1H), 7.89 (br d, J＝8.28Hz, 1H),7.62-7.83(m,3H),7.33-7.44(m,2H),5.60(br s,1H),4.92-5.00(m,2H),3.71-3.77(m,1H),1.69(br d,J＝6.78Hz,3H).
化合物19b:SFC检测条件：色谱柱:Chiralpak AD-3 50×4.6mm I.D.,3μm；流动相:A相:CO2,B相:异丙醇(0.05％二乙胺)；梯度:B％:40％,流速:4mL/min，保留时间为0.998min，ee＝98.14％。MS:m/z 466.2[M+H]+。1H NMR(400MHz,CD3OD)δ8.76(br d,J＝5.02Hz,2H),8.44-8.70(m,2H),8.21(s,1H),7.59-7.87(m,3H),7.41(d,J＝8.03Hz,1H),7.34(t,J＝4.89Hz,1H),5.66(br s,1H),4.91-5.02(m,2H),3.73(s,1H),1.69(br d,J＝6.78Hz,3H)。 Compound 19b: SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: Phase A: CO 2 , Phase B: isopropyl alcohol (0.05% diethylamine); gradient: B%: 40%, flow rate: 4mL/min, retention time: 0.998min, ee=98.14%. MS: m/z 466.2[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ8.76 (br d, J＝5.02Hz, 2H), 8.44-8.70 (m, 2H), 8.21 (s, 1H), 7.59-7.87 (m, 3H), 7.41(d,J＝8.03Hz,1H),7.34(t,J＝4.89Hz,1H),5.66(br s,1H),4.91-5.02(m,2H),3.73(s,1H),1.69( br d,J＝6.78Hz,3H).
生物测试数据Biological test data
实验例1：化合物对HCT116MTAP KO细胞和HCT116wt细胞的增殖抑制活性测试Experimental Example 1: Test of the proliferation inhibitory activity of compounds on HCT116 MTAP KO cells and HCT116 wt cells
实验材料：Experimental Materials:
McCoy's 5A培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。3D CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。HCT116MTAP KO细胞系和HCT116wt细胞系购自Horizon公司。Envision多标记分析仪(PerkinElmer)。McCoy's 5A medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal calf serum was purchased from Biosera. 3D CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega. HCT116 MTAP KO cell line and HCT116 wt cell line were purchased from Horizon Company. Envision multi-label analyzer (PerkinElmer).
实验方法：experimental method:
将HCT116MTAP KO细胞或HCT116wt细胞种于超低吸附96孔U型板中，80μL细胞悬液每孔，其中包含1000个细胞。细胞板置于二氧化碳培养箱中过夜培养。HCT116 MTAP KO cells or HCT116 wt cells were seeded in an ultra-low adsorption 96-well U-shaped plate, with 80 μL of cell suspension per well containing 1,000 cells. The cell plate was cultured overnight in a carbon dioxide incubator.
将待测化合物用排枪4倍稀释至第9个浓度，即从1mM稀释至61.04nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是5μM至0.305nM。细胞板置于二氧化碳培养箱中培养10天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向细胞板中加入每100μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。Dilute the compound to be tested 4 times to the ninth concentration, that is, from 1mM to 61.04nM, using a volute gun, and set up a double well experiment. Add 78 μL of culture medium to the middle plate, then transfer 2 μL of the gradient dilution compound per well to the middle plate according to the corresponding position, mix well, and transfer 20 μL of each well to the cell plate. The concentration of compounds transferred into the cell plate ranged from 5 μM to 0.305 nM. The cell plate was cultured in a carbon dioxide incubator for 10 days. Prepare another cell plate, and read the signal value on the day of adding the drug as the maximum value (Max value in the equation below) to participate in data analysis. Add 100 μL of cell viability chemiluminescence detection reagent to the cell plate and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Take multi-label analyzer readings.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。表3提供了本发明化合物对HCT116MTAP KO细胞和HCT116wt细胞增殖的抑制活性。Use the equation (Sample-Min)/(Max-Min)*100% to convert the original data into an inhibition rate. The value of IC 50 can be obtained by curve fitting with four parameters ("log(inhibitor) vs." in GraphPad Prism. response--Variable slope" mode). Table 3 provides the inhibitory activity of the compounds of the present invention on the proliferation of HCT116 MTAP KO cells and HCT116 wt cells.
表3本发明化合物对HCT116MTAP KO细胞和HCT116wt细胞增殖抑制活性测试结果

注：“—”表示未测试。Table 3 Test results of the inhibitory activity of the compounds of the present invention on HCT116 MTAP KO cells and HCT116 wt cells

Note: "—" means not tested.
结论：本发明化合物对MTAP缺失的HCT116肿瘤细胞有很好的抑制活性，对野生型HCT116肿瘤细胞的抑制活性较弱，表现出优秀的选择性。Conclusion: The compound of the present invention has good inhibitory activity against MTAP-deficient HCT116 tumor cells, but has weak inhibitory activity against wild-type HCT116 tumor cells, showing excellent selectivity.
实验例2：小鼠药代动力学评价 Experimental Example 2: Evaluation of Pharmacokinetics in Mouse
实验方法：experimental method:
受试化合物与5％DMSO/10％聚乙二醇-15羟基硬脂酸酯/85％水混合，涡旋并超声，制备得到0.2mg/mL澄清溶液，微孔滤膜过滤后备用。选取18至20克的Balb/c雄性小鼠，静脉注射给予候选化合物溶液，剂量1mg/kg；口服给予候选化合物溶液，剂量为2mg/kg。收集一定时间的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin软件(美国Pharsight公司)计算药代参数。The test compound was mixed with 5% DMSO/10% polyethylene glycol-15 hydroxystearate/85% water, vortexed and ultrasonicated to prepare a 0.2 mg/mL clear solution, which was filtered through a microporous membrane for later use. Balb/c male mice weighing 18 to 20 grams were selected, and the candidate compound solution was administered intravenously at a dose of 1 mg/kg; the candidate compound solution was administered orally at a dose of 2 mg/kg. Whole blood was collected for a certain period of time, plasma was prepared, drug concentration was analyzed by LC-MS/MS method, and pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight Company, USA).
各参数定义：IV：静脉注射；PO：口服；C0：静脉注射后瞬时的需要浓度；Cmax：给药后出现的血药浓度最高值；Tmax：给药后达到药峰浓度所需的时间；T1/2：血药浓度下降一半所需的时间；Vdss：表观分布容积，指药物在体内达到动态平衡时体内药量与血药浓度的比例常数。Cl：清除率，指单位时间从体内清除的药物表观分布容积数；AUC0-last：药时曲线下面积，指血药浓度曲线对时间轴所包围的面积；F：生物利用度。Definition of each parameter: IV: intravenous injection; PO: oral administration; C 0 : instantaneous required concentration after intravenous injection; C max : the highest blood drug concentration after administration; T max : required to reach peak drug concentration after administration time; T 1/2 : the time required for the blood drug concentration to decrease by half; V dss : apparent volume of distribution, which refers to the proportional constant between the amount of drug in the body and the blood drug concentration when the drug reaches dynamic equilibrium in the body. Cl: clearance rate, refers to the apparent distribution volume of the drug cleared from the body per unit time; AUC 0-last : area under the drug-time curve, refers to the area surrounded by the blood drug concentration curve against the time axis; F: bioavailability.
实验结果：实验结果见表4。Experimental results: The experimental results are shown in Table 4.
表4本发明化合物血浆中的PK测试结果

“--”是指未测试或未获得数据。Table 4 PK test results of the compounds of the present invention in plasma

"--" means no testing or no data obtained.
结论：本发明化合物展现了较低的清除率和较高的药物暴露量，具有良好的体内药物代谢动力学性质。Conclusion: The compounds of the present invention exhibit low clearance and high drug exposure, and have good pharmacokinetic properties in vivo.
实验例3：化合物在BALB/c裸小鼠皮下异种移植肿瘤模型上的抗肿瘤活性测试Experimental Example 3: Test of anti-tumor activity of compounds on BALB/c nude mouse subcutaneous xenograft tumor model
实验目的：Purpose:
在人大细胞肺癌LU99皮下异种移植肿瘤模型上考察待测化合物的抑瘤效果Examining the anti-tumor effect of the compounds to be tested on the human large cell lung cancer LU99 subcutaneous xenograft tumor model
实验方法：experimental method:
在雌性BALB/c裸小鼠皮下接种人大细胞肺癌LU99细胞株，接种后按照体重和肿瘤体积随机分组，每组6只动物。接种后当肿瘤体积为180-230mm3时开始给药，给药处理方式如下：Female BALB/c nude mice were subcutaneously inoculated with human large cell lung cancer LU99 cell line. After inoculation, they were randomly divided into groups according to body weight and tumor volume, with 6 animals in each group. After inoculation, administration will begin when the tumor volume is 180-230mm3 . The administration treatment method is as follows:
对照组：接种后肿瘤体积为207±9mm3时开始给药，每天一次(QD)按照0.1mL/10g的剂量灌胃(p.o.)溶媒(5％DMSO/10％Solutol/85％二次蒸馏水)。Control group: Start administration when the tumor volume is 207±9mm after inoculation. Once a day (QD), the vehicle (5% DMSO/10% Solutol/85% double distilled water) is administered (po) at a dose of 0.1mL/10g. .
治疗组1：接种后肿瘤体积为207±9mm3时开始给药，每天一次按照50mg/kg的剂量灌胃给药化合物(待测化合物溶解于5％DMSO/10％Solutol/85％二次蒸馏水)。Treatment Group 1: After inoculation, the tumor volume was 207±9mm. Administration was started when the tumor volume was 207±9mm. The compound was administered by gavage once a day at a dose of 50 mg/kg (the compound to be tested was dissolved in 5% DMSO/10% Solutol/85% double distilled water). ).
治疗组2：接种后肿瘤体积为207±16mm3时开始给药，每天一次按照100mg/kg的剂量灌胃给药化合物(待测化合物溶解于5％DMSO/10％Solutol/85％二次蒸馏水)。Treatment Group 2: Administration was started when the tumor volume after inoculation was 207 ± 16 mm. Compounds were administered by gavage once a day at a dose of 100 mg/kg (the test compound was dissolved in 5% DMSO/10% Solutol/85% double distilled water ).
实验分组后，每周二次称量小鼠体重，并用游标卡尺测量肿瘤直径，并按照长径×宽径2/2的公式计算 肿瘤体积。再计算肿瘤生长抑制率(TGI)，计算公式：TGI(％)＝[1-(Ti-T0)/(Ci-C0)]×100,其中Ti为某一天某给药组的平均肿瘤体积，T0为此给药组在开始给药时的平均肿瘤体积；Ci为某一天(与Ti同一天)对照组的平均肿瘤体积，C0为对照组在给开始药时的平均肿瘤体积。After the experimental grouping, the mice were weighed twice a week, and the tumor diameter was measured with a vernier caliper and calculated according to the formula of length × width 2/2 Tumor volume. Then calculate the tumor growth inhibition rate (TGI), the calculation formula: TGI (%) = [1-(T i -T 0 )/(C i -C 0 )] × 100, where T i is a certain dosage group on a certain day The average tumor volume of average tumor volume.
实验给药后第29天安乐死小鼠并采样。The mice were euthanized and sampled on the 29th day after experimental administration.
实验结果：Experimental results:
本实验评价了本发明化合物在人大细胞肺癌LU99皮下异种移植肿瘤模型上的药效，以溶剂对照组为参照。各组小鼠体重变化曲线如图16所示，各组在不同时间点的平均肿瘤体积如图17所示。基于给药后第29天的平均肿瘤体积计算得出TGI，具体实验结果见表5。This experiment evaluated the efficacy of the compound of the present invention on the human large cell lung cancer LU99 subcutaneous xenograft tumor model, using the solvent control group as a reference. The body weight change curve of mice in each group is shown in Figure 16, and the average tumor volume of each group at different time points is shown in Figure 17. The TGI was calculated based on the average tumor volume on day 29 after administration. The specific experimental results are shown in Table 5.
表5本发明化合物对LU99细胞皮下异种移植肿瘤模型的抑瘤药效评价
Table 5 Evaluation of the anti-tumor efficacy of the compounds of the present invention on the LU99 cell subcutaneous xenograft tumor model
实验结论：本发明化合物表现出优秀的体内抗肿瘤药效，且给药后小鼠体重维持良好。 Experimental conclusion: The compound of the present invention exhibits excellent anti-tumor efficacy in vivo, and the body weight of mice is maintained well after administration.

Claims (18)

  1. 式(P)所示化合物或其药学上可接受的盐，
    A compound represented by formula (P) or a pharmaceutically acceptable salt thereof,
    其中，in,
    T1、T2、T3和T4分别独立地选自CH和N；T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
    T5选自C、CR6和N；T 5 is selected from C, CR 6 and N;
    T6、T7和T8分别独立地选自CR6和N；T 6 , T 7 and T 8 are independently selected from CR 6 and N;
    R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
    R2选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
    各R3分别独立地选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1 , 2 or 3 R c substitutions;
    T9为C，为双键，R4选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代；T 9 is C, is a double bond, R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d substitutions;
    或者，T9选自C和N，选自单键和双键，R4与T5连接在一起形成结构单元所述结构单元选自 Alternatively, T 9 is selected from C and N, Selected from single bonds and double bonds, R 4 and T 5 are linked together to form a structural unit The structural unit Selected from
    环A选自5-6元杂芳基、C4-6环烯基和5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基和5-6元杂环烯基分别独立地任选被1或2个Rf取代；Ring A is selected from the group consisting of 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 membered heterocycloalkenyl. The 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1 or 2 R f ;
    R5选自C1-3烷硫基、C2-5烯基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基，所述C1-3烷硫基、C2-5烯基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基分别独立地任选被1、2或3个Re取代；R 5 is selected from C 1-3 alkylthio, C 2-5 alkenyl, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy -C 3-7 cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkyl Amino-C 3-7 cycloalkyl, the C 1-3 alkylthio group, C 2-5 alkenyl, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl , -C 1-3 alkoxy-C 3-7 cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl The -C 1-3 alkylamino-C 3-7 cycloalkyl group is each independently optionally substituted by 1, 2 or 3 R e ;
    R6选自H、卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rg取代；R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R g replaced;
    各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自H、D、卤素、OH、NH2、C1-3烷基和-C1-3烷基-OH，所述C1-3烷基和-C1-3烷基-OH分别独立地任选被1、2或3个F或D取代；Each R a , each R b , each R c , each R d and each Re are independently selected from H, D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl- OH, the C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F or D;
    各Rf分别独立地选自H、D、卤素、OH、NH2、CH3、CF3和CD3；Each R f is independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
    各Rg分别独立地选自H、D、卤素、OH、NH2、CH3、CF3和CD3；Each R g is independently selected from H, D, halogen, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
    n选自0、1、2和3； n is selected from 0, 1, 2 and 3;
    所述5-6元杂芳基、3-7元杂环烷基、8-12元杂环烷基和5-6元杂环烯基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl, 8-12-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl independently represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，各Ra分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH；或者，各Rb分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH；或者，各Rc分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH；或者，各Rd分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH；或者，各Re分别独立地选自D、F、Cl、CH3、CF3和-C(CH3)2OH。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH; or, each R a R b is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH; alternatively, each R c is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH; alternatively, each R d is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH; alternatively, each R e is independently selected from D, F, Cl, CH 3 , CF 3 and -C(CH 3 ) 2 OH.
  3. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R1选自CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己基，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3、OCH(CH3)2、环丙基、环丁基、环戊基和环己基分别独立地任选被1、2或3个Ra取代；或者，R1选自CH3和环丙基；或者，R1为CH3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 , OCH 2 CH 3. OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH( CH 3 ) 2 , OCH 3 , OCH 2 CH 3 , OCH 2 CH 2 CH 3 , OCH(CH 3 ) 2 , cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl are independently optionally substituted by 1, 2 Or 3 R a substituted; alternatively, R 1 is selected from CH 3 and cyclopropyl; alternatively, R 1 is CH 3 .
  4. 根据权利要求3所述化合物或其药学上可接受的盐，其中，R2选自吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基和噁唑基，所述吡啶基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、吡咯基、噻唑基、噻吩基、呋喃基和噁唑基分别独立地任选被1、2或3个Rb取代；或者，R2选自或者，R2选自 The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl and oxazolyl. Azolyl group, the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl and oxazolyl groups are independently optionally substituted by 1, 2 or 3 R b substitutions; alternatively, R 2 is selected from Alternatively, R 2 is selected from
  5. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R3选自F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3和OCH2CH3分别独立地任选被1、2或3个Rc取代；或者，R3选自CH3和CF3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from F, Cl, Br, I, CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2. OCH 3 and OCH 2 CH 3. The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , OCH 3 and OCH 2 CH 3 are independently optionally selected from 1 and 2. Or 3 R c substitutions; alternatively, R 3 is selected from CH 3 and CF 3 .
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R4选自F、Cl、Br、I、CH3和CD3。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from F, Cl, Br, I, CH 3 and CD 3 .
  7. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R5选自SCH3、SCH2CH3、乙炔基、 所述SCH3、SCH2CH3、乙炔基、 分别独立地任选被1、2或3个Re取代；或者，R5选自SCH2CH3、 或者，R5选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from SCH 3 , SCH 2 CH 3 , ethynyl, The SCH 3 , SCH 2 CH 3 , ethynyl, Each independently optionally substituted by 1, 2 or 3 R e ; alternatively, R 5 is selected from SCH 2 CH 3 , Alternatively, R 5 is selected from
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R6选自H、F、Cl、Br、I、CH3和OCH3。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from H, F, Cl, Br, I, CH 3 and OCH 3 .
  9. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元选自 或者，结构单元选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Or, structural unit Selected from
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元选自或者，结构单元选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Or, structural unit Selected from
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R4与T5连接在一起使结构单元为所述结构单元选自 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 and T 5 are connected together to form a structural unit for The structural unit Selected from
  12. 根据权利要求1～11任意一项所述的式(P)化合物或其药学上可接受的盐，其选自，
    The compound of formula (P) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 11, which is selected from,
    其中，T1、T2、T3、T4、T5、T6、T7、T8、T9、R4、Rb和Re如权利要求1～11任意一项所定义。Among them, T 1 , T 2 , T 3 , T 4 , T 5 , T 6 , T 7 , T 8 , T 9 , R 4 , R b and Re are as defined in any one of claims 1 to 11.
  13. 根据权利要求12所述式(P-1)化合物或其药学上可接受的盐，其选自，
    The compound of formula (P-1) according to claim 12 or a pharmaceutically acceptable salt thereof, which is selected from,
    其中，结构单元T1、T2、T6、T7、T8、R4、Rb和Re如权利要求12所定义；Among them, the structural unit T 1 , T 2 , T 6 , T 7 , T 8 , R 4 , R b and Re are as defined in claim 12;
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  14. 根据权利要求1所述式(P)化合物或其药学上可接受的盐，其选自，
    The compound of formula (P) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from,
    其中，in,
    R1选自C1-3烷基、C1-3烷氧基和C3-6环烷基，所述C1-3烷基、C1-3烷氧基和C3-6环烷基分别独立地任选被1、2或3个Ra取代；R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl The groups are independently optionally substituted by 1, 2 or 3 R a ;
    R2选自5-6元杂芳基，所述5-6元杂芳基任选被1、2或3个Rb取代；R 2 is selected from 5-6 membered heteroaryl, and the 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R b ;
    各R3分别独立地选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rc取代；Each R 3 is independently selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R c substitutions;
    R4选自卤素、C1-3烷基和C1-3烷氧基，所述C1-3烷基和C1-3烷氧基分别独立地任选被1、2或3个Rd取代； R 4 is selected from halogen, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are independently optionally substituted by 1, 2 or 3 R d replace;
    R5选自C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基，所述C1-3烷硫基、C2-5炔基、C8-12环烷基、8-12元杂环烷基、-C1-3烷氧基-C3-7环烷基、-C1-3烷硫基-C3-7环烷基、-C1-3烷氨基-3-7元杂环烷基和-C1-3烷氨基-C3-7环烷基分别独立地任选被1、2或3个Re取代；R 5 is selected from C 1-3 alkylthio, C 2-5 alkynyl, C 8-12 cycloalkyl, 8-12 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-7 ring Alkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 cycloalkyl Alkyl group, the C 1-3 alkylthio group, C 2-5 alkynyl group, C 8-12 cycloalkyl group, 8-12 membered heterocycloalkyl group, -C 1-3 alkoxy group-C 3-7 Cycloalkyl, -C 1-3 alkylthio-C 3-7 cycloalkyl, -C 1-3 alkylamino-3-7 membered heterocycloalkyl and -C 1-3 alkylamino-C 3-7 The cycloalkyl groups are independently optionally substituted by 1, 2 or 3 Re ;
    T1、T2、T3和T4分别独立地选自CH和N；T 1 , T 2 , T 3 and T 4 are independently selected from CH and N;
    T5、T6、T7和T8分别独立地选自CR6和N；T 5 , T 6 , T 7 and T 8 are independently selected from CR 6 and N;
    R6选自H、卤素、C1-3烷基和C1-3烷氧基；R 6 is selected from H, halogen, C 1-3 alkyl and C 1-3 alkoxy;
    各Ra、各Rb、各Rc、各Rd和各Re分别独立地选自D、卤素、OH、NH2、C1-3烷基和-C1-3烷基-OH，所述C1-3烷基和-C1-3烷基-OH分别独立地任选被1、2或3个F取代；Each R a , each R b , each R c , each R d and each Re are independently selected from D, halogen, OH, NH 2 , C 1-3 alkyl and -C 1-3 alkyl-OH, The C 1-3 alkyl and -C 1-3 alkyl-OH are each independently optionally substituted by 1, 2 or 3 F;
    n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
    所述5-6元杂芳基、3-7元杂环烷基和8-12元杂环烷基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "hetero" of the 5-6-membered heteroaryl, 3-7-membered heterocycloalkyl and 8-12-membered heterocycloalkyl independently represents 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and N heteroatoms or heteroatom groups.
  15. 根据权利要求14所述的式(P2)化合物或其药学上可接受的盐，其化合物选自：
    The compound of formula (P2) according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from:
    其中， in,
    环B选自C8-12环烷基和8-12元杂环烷基，所述C8-12环烷基和8-12元杂环烷基分别独立地任选被1、2或3个Re取代；Ring B is selected from C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl, and the C 8-12 cycloalkyl and 8-12 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R e replaced;
    T1、T2、T5、T6、T7、T8、R3、R4、Rb、Re和n如权利要求14所定义；T 1 , T 2 , T 5 , T 6 , T 7 , T 8 , R 3 , R 4 , R b , Re and n are as defined in claim 14;
    带“*”碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。The carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  16. 下列所示化合物或其药学上可接受的盐，


    The following compounds or pharmaceutically acceptable salts thereof,


  17. 根据权利要求16所述化合物或其药学上可接受的盐，其选自，





    The compound according to claim 16 or a pharmaceutically acceptable salt thereof, which is selected from,





  18. 根据权利要求1～17任意一项所述的化合物或其药学上可接受的盐在制备治疗PRMT5抑制剂相关疾病的药物上的应用。 Use of the compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating diseases related to PRMT5 inhibitors.
PCT/CN2023/101740 2022-06-23 2023-06-21 Amino-substituted heteroaryl derivatives and use thereof WO2023246873A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163344A1 (en) * 2020-02-12 2021-08-19 Amgen Inc. Novel prmt5 inhibitors
WO2022115377A1 (en) * 2020-11-24 2022-06-02 Amgen Inc. Tricyclic carboxamide derivatives as prmt5 inhibitors
WO2022256806A1 (en) * 2021-06-02 2022-12-08 Ideaya Biosciences, Inc. Combination therapy comprising a mat2a inhibitor and a type ii prmt inhibitor

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021163344A1 (en) * 2020-02-12 2021-08-19 Amgen Inc. Novel prmt5 inhibitors
WO2022115377A1 (en) * 2020-11-24 2022-06-02 Amgen Inc. Tricyclic carboxamide derivatives as prmt5 inhibitors
WO2022256806A1 (en) * 2021-06-02 2022-12-08 Ideaya Biosciences, Inc. Combination therapy comprising a mat2a inhibitor and a type ii prmt inhibitor

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