WO2024002263A1 - Amino-substituted heteroaryl derivative and use thereof - Google Patents

Amino-substituted heteroaryl derivative and use thereof Download PDF

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Publication number
WO2024002263A1
WO2024002263A1 PCT/CN2023/103995 CN2023103995W WO2024002263A1 WO 2024002263 A1 WO2024002263 A1 WO 2024002263A1 CN 2023103995 W CN2023103995 W CN 2023103995W WO 2024002263 A1 WO2024002263 A1 WO 2024002263A1
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alkoxy
alkyl
independently
optionally substituted
present
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PCT/CN2023/103995
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French (fr)
Chinese (zh)
Inventor
姜奋
刘笑
张杨
高娜
张丽
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 WO2024002263A1 publication Critical patent/WO2024002263A1/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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—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 (IV) and their pharmaceutically acceptable salts.
  • PRMT5 protein arginine methyltransferase 5
  • SAM S-adenosylmethionine
  • sDMA symmetric dimethylarginylation
  • PRMT5 can combine with MEP50 (methyl body protein 50) to form a heterooctamer complex, which is a component of the methyl body and can methylate a variety of substrates, including spliceosomal Sm protein, nucleolus proteins, p53, histones H2A, H3 and H4, SPT5 transcription elongation factor and MBD2, etc.
  • the PRMT5-MEP50 complex plays an important role in mammalian cell survival.
  • multiple inhibitors targeting PRMT5 have entered clinical stage research (such as GSK3326595, JNJ64619178, PF06939999, PRT543, PRT811).
  • PRMT5 also plays an important role in regulating hematopoietic function.
  • PRMT5 inhibitors have dose-limiting blood system side effects such as thrombocytopenia, anemia and neutropenia in clinical practice, which limits their clinical application prospects. Therefore, selectively inhibiting PRMT5 function in tumor cells without inhibiting PRMT5 activity in normal cells is expected to improve the therapeutic index of PRMT5 inhibitors and is a new direction for PRMT5 inhibitor research.
  • MTAP methylthioadenosine phosphorylase
  • CDKN2A a common tumor suppressor gene in the body.
  • MTA combines with PRMT5 to form a catalytically inactive PRMT5-MEP50 ⁇ MTA (PRMT5 ⁇ MTA) complex, resulting in a reduced ability of PRMT5 to bind SAM. , thereby inhibiting the methylation process in MTAP-deficient cells.
  • PRMT5 ⁇ MTA catalytically inactive PRMT5-MEP50 ⁇ MTA
  • MTAP-deficient tumor cells will be significantly more dependent on PRMT5.
  • the development of inhibitors that can specifically bind to the PRMT5 ⁇ MTA complex is expected to inhibit PRMT5 activity in MTAP-deficient tumor cells while reducing the impact on PRMT5 in MTAP-wild-type cells, thereby improving the targeting and safety of the compounds. sex.
  • the present invention provides compounds represented by formula (IV) or pharmaceutically acceptable salts thereof,
  • E 1 is selected from CH 2 , NH and O;
  • Each R 1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively Independently optionally substituted by 1, 2 or 3 R a ;
  • two R 1 on the same atom are connected to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 Re ;
  • R 6 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, C 1-3 alkylamino, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-6 cycloalkyl, -C 1-3 alkylamino-C 3-6 cycloalkyl, -C 1-3 alkoxy-4-6-membered heterocycloalkyl and -C 1-3 alkylamino-4-6-membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy Base, C 2-4 alkynyl, C 2-4 alkenyl, C 1-3 alkylamino, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-6 cycloalkyl, -C 1-3 alkylamino
  • Ring A is selected from 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 membered heterocycloalkenyl, said 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6
  • the one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
  • Ring B is selected from phenyl and 5-10 membered heteroaryl
  • T 1 and T 2 are independently selected from C, CR 3 or N;
  • T 3 , T 4 and T 5 are independently selected from CR 4 and N;
  • R 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
  • R 4 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R d ;
  • Each R a , each R c , each R d and each Re are independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
  • Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R substitution;
  • Each R is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
  • n is selected from 0, 1, 2 and 3;
  • n is selected from 0, 1, 2, 3 and 4;
  • Ring B is a bicyclic 8-10 membered heteroaryl, or structural unit Selected from The "hetero" of the 5-6-membered heteroaryl, 5-6-membered heterocycloalkenyl, 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl or bicyclic 8-10-membered heteroaryl are respectively Represents 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof is selected from,
  • E 1 is selected from O;
  • Each R 1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively Independently optionally substituted by 1, 2 or 3 R a ;
  • two R 1 on the same atom are connected to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 Re ;
  • R 6 is selected from C 2-4 alkynyl, which is optionally substituted by 1, 2 or 3 R b ;
  • Ring A is selected from 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 membered heterocycloalkenyl, said 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6
  • the one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
  • Ring B is selected from phenyl and 5-10 membered heteroaryl
  • T 1 and T 2 are independently selected from C, CR 3 or N;
  • T 3 , T 4 and T 5 are independently selected from CR 4 and N;
  • R 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
  • R 4 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
  • Each R 5 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R d ;
  • Each R a , each R c and each R d are independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
  • Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R substitution;
  • Each R is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
  • n is selected from 0, 1 and 2;
  • n is chosen from 0 and 1.
  • each R a is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
  • each R c is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
  • each R d is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
  • each R e is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof wherein each R b is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, the CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1 , 2 or 3 R substitutions, and other variables are as defined in the present invention.
  • each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 , N(CH 3 ) 2 ,
  • R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 , N(CH 3 ) 2 ,
  • R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 , N(CH 3 ) 2 ,
  • Other variables are as defined in the present invention.
  • each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 and N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof wherein said R 1 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , 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 and OCH(CH 3 ) 2 are each independently optionally selected from 1, 2 or 3 R a substitutions, and other variables are as defined in the present invention.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof wherein R 3 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , 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 and OCH(CH 3 ) 2 are independently optionally substituted by 1, 2 or 3 R d .
  • Other variables are as follows: defined by invention.
  • Other variables are as follows: defined by invention.
  • each R 5 is independently selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , said 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 and OCH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , Other variables are as defined in the present invention.
  • each R 5 is independently selected from H, F, Cl, Br and CH 3 , and other variables are as follows defined by invention.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein said R 6 is selected from Other variables are as defined in the present invention.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein said R 6 is selected from Other variables are as defined in the present invention.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, Benzopyrazolyl and benzimidazolyl, other variables are as defined in the present invention.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof wherein the ring A is selected from the group consisting of 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, cycl
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof wherein the ring A is selected from the group consisting of imidazolyl, pyrazolyl, oxolenyl and azelene base, the imidazolyl, pyrazolyl, oxolenyl and azeolenyl groups are independently optionally substituted by 1, 2 or 3 R c , and other variables are as defined in the present invention.
  • the ring A is selected from the group consisting of imidazolyl and pyrazolyl, and the imidazolyl and pyrazolyl are independently optional.
  • the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof is selected from,
  • R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
  • Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, and the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
  • the compound represented by the above formula (P) or a pharmaceutically acceptable salt thereof wherein said R 2 is selected from H, F, Cl, CH 3 , CH 2 CH 3 and CH (CH 3 ) 2.
  • R 2 is selected from H, F, Cl, CH 3 , CH 2 CH 3 and CH (CH 3 ) 2.
  • the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R b , and each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 and N(CH 3 ) 2 , other variables are as defined in the present invention.
  • the compound represented by the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
  • the structural unit R 1 , R 2 and R 4 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;
  • R 1 is not H
  • the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • the compound represented by the above formula (P-1) or a pharmaceutically acceptable salt thereof is selected from,
  • the structural unit R 1 , R 2 and R 4 are as defined in the present invention.
  • the present invention also provides compounds represented by formula (II) or pharmaceutically acceptable salts thereof,
  • Each R 1 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 a substitutions;
  • R 6 is selected from 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 b ;
  • R 2 is selected from H, halogen, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
  • E 1 is selected from CH 2 , NH and O;
  • T 1 and T 2 are independently selected from CR 3 and N, Selected from double bonds;
  • 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, 2 or 3 R c ;
  • T 3 , T 4 and T 5 are independently selected from CR 4 and N;
  • T 6 , T 7 , T 8 and T 9 are independently selected from CR 5 and N;
  • R 3 , R 4 and R 5 are each 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 selected.
  • R is optionally replaced by 1, 2 or 3 R d ;
  • Each R a , each R b , each R c and each R d are independently selected from H, D, halogen, OH, NH 2 , CH 3 and CD 3 ;
  • n is selected from 0, 1, 2 and 3;
  • the condition is that when R 6 is selected from 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 when 3 R b are substituted, the structural unit Selected from and the compound is not
  • 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.
  • the present invention also provides compounds represented by formula (I) or pharmaceutically acceptable salts thereof,
  • Each R 1 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 a substitutions;
  • R 2 is selected from H, halogen, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
  • E 1 is selected from CH 2 , NH and O;
  • T 1 and T 2 are independently selected from CR 3 and N;
  • 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, 2 or 3 R c ;
  • T 3 , T 4 and T 5 are independently selected from CR 4 and N;
  • T 6 , T 7 , T 8 and T 9 are independently selected from CR 5 and N;
  • R 3 , R 4 and R 5 are each 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 selected.
  • R is optionally replaced by 1, 2 or 3 R d ;
  • Each R a , each R b , each R c and each R d are independently selected from H, halogen, OH, NH 2 and CH 3 ;
  • n is selected from 0, 1, 2 and 3;
  • each R a , each R b , each R c and each R d mentioned above are independently selected from H, F, Cl, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • each of the above R a is independently selected from H, F, Cl, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • each of the above R c is independently selected from H, F, Cl, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • each R d mentioned above is independently selected from H, F, Cl, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • each of the above R e is independently selected from H, F, Cl, OH, NH 2 and CH 3 , and other variables are as defined in the present invention.
  • each of the above R b is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3.
  • N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted by 1, 2 or 3 R, and other variables are as defined in the present invention.
  • each of the above R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 , N(CH 3 ) 2 ,
  • Other variables are as defined in the present invention.
  • each of the above R b is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD 3 , and other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 said 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention.
  • R 1 is selected from F, CH 3 and CD 3 , and other variables are as defined in the present invention.
  • R 1 is selected from CH 3 and CD 3 , and other variables are as defined in the present invention.
  • R 1 is selected from F and CH 3 , and other variables are as defined in the present invention.
  • the two R 1's on the same atom are connected to form a cyclopropyl group, and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , so
  • the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 is selected from H and Other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
  • R 3 is selected from H, F, Cl, Br and CH 3 , and other variables are as defined in the present invention.
  • R 4 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
  • R 4 is selected from H, F, Cl, Br and CH 3 , and other variables are as defined in the present invention.
  • each R 5 mentioned above is independently selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , said 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
  • each R 5 mentioned above is independently selected from H, F, Cl, Br and CH 3 , and other variables are as defined in the present invention.
  • the above R 6 is selected from C 2-4 alkynyl, C 2-4 alkenyl, NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , azetidinyl, pyrrolidinyl , morpholinyl, piperazinyl, piperidinyl and -OCH 2 -C 3-6 cycloalkyl, the C 2-4 alkynyl, C 2-4 alkenyl, NHCH 3 , NHCH 2 CH 3 , N (CH 3 ) 2 , azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl and -OCH 2 -C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3
  • Each R b is replaced, and other variables are as defined in the present invention.
  • R 6 is selected from ethynyl, propynyl, vinyl, NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 3 )CH 2 CH 3 , -O- CH 2 -cyclopropyl, -O-CH 2 -cyclobutyl, -NH-CH 2 -cyclopropyl and -NH-CH 2 -cyclobutyl, the ethynyl, propynyl, vinyl, NHCH 3.
  • NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 3 )CH 2 CH 3 , -O-CH 2 -cyclopropyl, -O-CH 2 -cyclobutyl, -NH-CH 2 - Cyclopropyl and -NH-CH 2 -cyclobutyl are each independently optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 6 is selected from CH 3 and CF 3 and other variables are as defined in the present invention.
  • R 6 is selected from CH 3 and CF 3 , and other variables are as defined in the present invention.
  • the above-mentioned R 6 is selected from ethynyl, propynyl and vinyl, and the ethynyl, propynyl and vinyl are independently optionally substituted by 1, 2 or 3 R b , and the others Variables are as defined herein.
  • T 1 is selected from C, C(CH 3 ) and C(CD 3 ), and other variables are as defined in the present invention.
  • T 2 is selected from C, CH and N, and other variables are as defined in the present invention.
  • T 3 is CH, and other variables are as defined in the present invention.
  • T 4 is selected from CH, CF, CCl, C(CH 3 ) and N, and other variables are as defined in the present invention.
  • T 5 is N, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzopyrazolyl and benzimidazolyl, and other variables are as in the present invention defined.
  • the above-mentioned ring B is selected from pyridyl, and other variables are as defined in the present invention.
  • the above-mentioned Ring B is selected from benzothiazolyl and benzopyrazolyl, and other variables are as defined in the present invention.
  • T 6 is selected from CH and N, and other variables are as defined in the present invention.
  • T 6 is N, and other variables are as defined in the present invention.
  • T 7 is selected from CH, and other variables are as defined in the present invention.
  • T 8 is selected from CH, and other variables are as defined in the present invention.
  • T 9 is selected from CH, and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from a 5-6-membered heteroaryl group or a 5-6-membered heterocyclic alkenyl group, and the 5-6-membered heteroaryl group or 5-6-membered heterocyclic alkenyl group are independently Optionally substituted by 1, 2 or 3 Rc , other variables are as defined in the present invention.
  • the above-mentioned Ring A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl, oxazolyl, ring Butenyl, cyclopentenyl, cyclohexenyl, oxolenyl, oxanyl, azolidenyl and azacyclohexenyl, the pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl, oxazolyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxolyl Alkenyl,
  • the above-mentioned E 1 is selected from O and NH, and other variables are as defined in the present invention.
  • E 1 is selected from O, and other variables are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • Example 1 of the present invention through SFC chiral analysis (analysis method: chromatographic column: Chiralcel OX-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 1b is 1.760min.
  • Example 2 of the present invention through SFC chiral analysis (analysis method: chromatographic column: (S.S) Whelk-O1 50 ⁇ 4.6mm I.D., 3.5 ⁇ m; mobile phase: A phase: carbon dioxide, B phase: [66.67% (Isopropyl alcohol-0.05% diethylamine) + 33.33% (acetonitrile-0.05% diethylamine)]; gradient (B%): 50%), the retention time of compound 2a is 0.849 min.
  • Example 3 of the present invention through SFC chiral analysis (analysis method: chromatographic column: Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl amine); gradient: 40% ethanol (0.05% diethylamine), flow rate: 3mL/min), the retention time of compound 3b was 1.636min.
  • Example 4 of the present invention through SFC chiral analysis (analysis method: chromatographic column: Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 4a is 3.396min.
  • Example 5 of the present invention through SFC chiral analysis (analysis method: chromatographic column: Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 5a is 2.682min.
  • Example 6 of the present invention through SFC chiral analysis (analysis method: chromatographic column: Chiralcel OD-3 150 ⁇ 4.6mm I.D., 3 ⁇ m; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 6a is 3.737min.
  • the present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicines for treating diseases related to PRMT5 inhibitors.
  • the present invention also provides the use of the above compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for treating PRMT5-related diseases.
  • the invention also provides the following synthesis methods:
  • R 2 is selected from H, halogen, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
  • Each R b is independently selected from H, halogen, OH, NH 2 and CH 3 ;
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R b ;
  • R 2 is selected from H and
  • the carbon atoms with "*" are chiral carbon atoms, which exist in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  • R 6 is selected from CH 3 and CF 3 ;
  • 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 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. Prepare for immediate use on the day of the experiment. The preparation 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 significant anti-proliferative activity on LU99 cells, has good inhibitory activity on MTAP-deficient HCT116 tumor cells, and has relatively low inhibitory activity on wild-type HCT116 tumor cells. Weak, showing excellent selectivity; in the mouse pharmacokinetic evaluation test, the compound of the present invention showed a longer half-life, higher tissue distribution and higher drug exposure, and has good drug metabolism kinetics in the body chemical properties; the compound of the present invention also exhibits excellent anti-tumor efficacy in vivo, 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 may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent.
  • 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, and their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to this 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 For example, express and mixture, express and mixture.
  • carbon atoms with an "*" are chiral carbon atoms that exist in the form of (R) or (S) as a single enantiomer or enriched in one enantiomer. For example, express or or may be present enriched in one enantiomeric form.
  • 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 body. 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, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • 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.
  • 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.
  • 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.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can be bonded through any atom thereof.
  • 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.
  • 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.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • connection mode of the chemical bond is non-positioned and there are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group.
  • the chemical bond connecting the site to other groups can be a straight solid line bond straight dashed key or wavy lines express.
  • 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;
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-3 alkyl by itself or in combination with other terms means, respectively, a linear or branched 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.
  • C 2-4 alkenyl by itself or in combination with other terms is used to refer to a linear or branched hydrocarbon radical composed of 2 to 4 carbon atoms containing at least one carbon-carbon double bond.
  • the carbon-carbon double bond can be located anywhere in the group.
  • the C 2-4 alkenyl group includes C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; the C 2-4 alkenyl group can be monovalent, divalent or multivalent. Examples of C 2-4 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, butadienyl, and the like.
  • C 2-4 alkynyl by itself or in combination with other terms is used to represent a straight-chain or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond. Group, the carbon-carbon triple bond can be located at any position of the group.
  • the C 2-4 alkynyl group includes C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C 2-4 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
  • C 1-3 alkoxy by itself or in combination with other terms 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.
  • C 1-3 alkylamino by itself or in combination with other terms respectively means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through a nitrogen atom.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups, etc. It can be monovalent, bivalent or polyvalent.
  • the C 1-3 alkylamino group includes -NH-C 1-3 alkyl group, such as -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 and -NHCH 2 (CH 3 ) 2 , and also includes di Alkylamino, for example -N(CH 3 ) 2 and -N(CH 3 )CH 2 CH 3 .
  • C 3-6 cycloalkyl by itself or in combination with another term respectively means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic ring 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.
  • C 4-6 cycloalkenyl by itself or in combination with another term respectively means a partially unsaturated monocyclic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond. group.
  • 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.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms means a saturated monocyclic group consisting of 4 to 6 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, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and nitrogen and thia Atoms may optionally be oxidized (i.e. NO and S(O) p , p is 1 or 2).
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 4-6-membered heterocycloalkyl group includes 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc. It can be monovalent, bivalent or polyvalent.
  • Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( 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, isothiazolidin
  • the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms means a partially unsaturated monocyclic 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).
  • the 5-6 membered heterocyclic alkenyl group includes 5-membered and 6-membered heterocyclic alkenyl groups. It can be monovalent, bivalent or polyvalent. Examples of 5-6 membered heterocyclenyl groups include, but are not limited to
  • 5-10 membered heteroaromatic ring and “5-10 membered heteroaryl” in the present invention can be used interchangeably.
  • the term “5-10 membered heteroaryl” means a ring consisting of 5 to 10 rings.
  • 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- to 10-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10-membered heteroaryl group includes 8-10-membered, 5-8-membered, 5-7-membered, 5-6-membered, 5-membered and 6-membered heteroaryl groups, etc. It can be monovalent, bivalent or polyvalent.
  • Examples of the 5-10 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.), pyrid
  • bicyclic 8-10 membered heteroaryl refers to a bicyclic group composed of 8 to 10 ring atoms with a conjugated ⁇ electron system, and each of its rings is aromatic. 1, 2, 3 or 4 of its ring atoms are heteroatoms independently selected from O, S and N, and the remainder 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).
  • the bicyclic 8-10 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • bicyclic 8-10 membered heteroaryl groups include, but are not limited to, benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzo Oxazolyl group, indolyl group (including 5-indolyl group, etc.), isoquinolyl group (including 1-isoquinolyl group and 5-isoquinolyl group, etc.), quinoxalinyl group (including 2-quinoxaline group) base and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolinyl, 6-quinolinyl, etc.).
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” may be used interchangeably in the present invention
  • the term “5-6 membered heteroaryl” means 5 to 6 ring atoms. It consists of a monocyclic group with a conjugated ⁇ 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. It can be monovalent, bivalent or polyvalent.
  • 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.), pyrid
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group also known as N atom protecting group, refers to a protecting group suitable for preventing side reactions at the nitrogen position of the amino group.
  • Representative amino protecting groups include, but are not limited to: acyl, such as alkanoyl (such as formyl, acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) , Allyloxycarbonyl (Alloc); Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), trityl (Trt), 1,1-bis-(4'-methoxyphenyl)methyl; silyl group, such as Trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); sulfonyl groups, such as p-to
  • hydroxyl protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB),
  • 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 D8venture 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 9 Mouse body weight change curve in the human large cell lung cancer LU99 subcutaneous xenograft tumor model.
  • Figure 10 Average tumor volume at different time points in the human large cell lung cancer LU99 subcutaneous xenograft tumor model.
  • 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] .
  • 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 H are shown in Figures 1 to 8.
  • the series of compounds of the present invention have a good binding effect with the PRMT5 ⁇ MTA complex.
  • the amine group in the compound forms two hydrogen bond interactions with Glu435 and Glu444.
  • the amide carbonyl group forms a hydrogen bond interaction with the main chain NH of Phe580.
  • the nitrogen atom of the substituted pyridine ring can form a hydrogen bond with the side chain NH of Gln309 and replaces the pyridine.
  • the quinoline ring of compound A and the tricyclic rings of compounds B, C, D, E, F, G, and H are located between Phe327 and Trp579 to form pi-pi interactions, and compounds C, D,
  • the non-quinoline heteroatom on the tricyclic ring in E can form a hydrogen bond with the Lys333 side chain
  • the 1 nitrogen atom in the tricyclic structure of compounds F, G, and H can form a hydrogen bond with the Lys333 side chain.
  • reaction solution was then filtered, the filter cake was washed with ice water (50 mL), and the filtrate was washed with dichloromethane. (50mL*3) extraction, combine the organic phases, wash with saturated aqueous sodium chloride solution (30mL*3), combine the organic phases and filter cake and concentrate under reduced pressure to obtain compound 1-2, which is directly used in the next step.
  • Compound 1 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALCEL OX (250mm*30mm, 10 ⁇ m); mobile phase: phase A: carbon dioxide, phase B: acetonitrile/ethanol/ethanol containing 1% ammonia (volume ratio is 60 %:30%:10%); gradient: B%:45%-45%), the crude products of compound 1a and compound 1b were obtained, and then were purified by preparative high-performance liquid phase separation (chromatographic column: Waters Xbridge 150*25mm* 5 ⁇ m; mobile phase: [0.05% ammonia water-acetonitrile]; gradient: (acetonitrile%): 26%-56%) to obtain compound 1a and compound 1b.
  • SFC separation conditions, chromatographic column: DAICEL CHIRALCEL OX (250mm*30mm, 10 ⁇ m); mobile phase: phase A: carbon dioxide, phase B: acetonitrile/ethanol/ethanol containing 1% ammonia (volume ratio
  • Compound 2 was separated and purified by SFC (separation conditions, chromatographic column: REGIS (S, S) WHELK-O1 (250 mm ⁇ 25 mm, 10 ⁇ m); mobile phase: [Phase A: carbon dioxide, phase B: 25% acetonitrile + 75% isopropyl alcohol, mix and then add 0.1% ammonia]; gradient (B%): 60%-60%) to obtain compound 2a and compound 2b.
  • SFC separation conditions, chromatographic column: REGIS (S, S) WHELK-O1 (250 mm ⁇ 25 mm, 10 ⁇ m); mobile phase: [Phase A: carbon dioxide, phase B: 25% acetonitrile + 75% isopropyl alcohol, mix and then add 0.1% ammonia]; gradient (B%): 60%-60%) to obtain compound 2a and compound 2b.
  • the crude product was purified by preparative high-performance liquid phase separation (chromatographic column: Waters Xbridge 150*25mm*5 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient (acetonitrile)%: 24%-54%) to obtain the compound 3.
  • Compound 3 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALPAK AD 250 ⁇ 30mm, 10 ⁇ m; mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia v/v)]; B%: 50% ) to obtain compound 3a and compound 3b.
  • SFC separation conditions, chromatographic column: DAICEL CHIRALPAK AD 250 ⁇ 30mm, 10 ⁇ m; mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia v/v)]; B%: 50% ) to obtain compound 3a and compound 3b.
  • Compound 4 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALPAK AD (250mm ⁇ 30mm, 10 ⁇ m); mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia v/v)]; B%: 50%) to obtain compound 4a and compound 4b.
  • SFC separation conditions, chromatographic column: DAICEL CHIRALPAK AD (250mm ⁇ 30mm, 10 ⁇ m); mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia v/v)]; B%: 50%) to obtain compound 4a and compound 4b.
  • Compound 5 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALPAK AD (250mm ⁇ 30mm, 10 ⁇ m); mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia)]; B%: 45%) , compound 5a and compound 5b were obtained.
  • SFC separation conditions, chromatographic column: DAICEL CHIRALPAK AD (250mm ⁇ 30mm, 10 ⁇ m); mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia)]; B%: 45%) , compound 5a and compound 5b were obtained.
  • 1640 medium penicillin/streptomycin antibiotics were purchased from Gibco, and fetal calf serum was purchased from Biosera.
  • CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega.
  • LU99 cell line was purchased from JCRB, Envision multi-label analyzer (PerkinElmer).
  • Cell proliferation and viability detection Add 100 ⁇ L of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 30 minutes to stabilize the luminescence signal. Take multi-label analyzer readings.
  • the compounds of the present invention have significant anti-proliferative activity on LU99 cells.
  • McCoy's 5A medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal calf serum was purchased from Biosera.
  • HCT116 MTAP KO cell line and HCT116 wt cell line were purchased from Horizon Company. Envision multi-label analyzer (PerkinElmer).
  • 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.
  • 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.
  • 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 of 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 or 50 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).
  • 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 compound of the present invention exhibits a longer half-life, higher tissue distribution and higher drug exposure, and has 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, when the tumor volume is 150-200mm3 , start drug administration.
  • the drug administration treatment method is as follows:
  • Control group Administration was started when the tumor volume reached 174 ⁇ 8mm3 after inoculation, and vehicle (5% DMSO/10% Solutol/85% twice distilled water) was administered once a day at a dose of 0.1 mL/10 g.
  • Treatment group After inoculation, administration was started when the tumor volume was 172 ⁇ 8 mm 3 , and the compound (to be tested) was administered orally (PO) at a dose of 15 mg/kg once a day (QD) (the test compound was dissolved in 5% DMSO/10% Solutol /85% double distilled water).
  • TGI tumor growth inhibition rate
  • T 0 is the average tumor volume of the drug group at the beginning of drug administration
  • C i is the average tumor volume of the control group on a certain day (the same day as T i )
  • C 0 is the average tumor volume of the control group at the beginning of drug administration.
  • Average tumor volume at drug initiation is the average tumor volume of the drug group at the beginning of drug administration.
  • mice were euthanized and sampled on the 22nd day after experimental administration.
  • 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 9, and the average tumor volume of each group at different time points is shown in Figure 10.
  • TGI was calculated based on the average tumor volume on day 22 postdose.
  • the compound of the present invention exhibits excellent anti-tumor efficacy in vivo, and the body weight of mice is maintained well after administration.
  • test compound and warfarin plasma sample to the administration end of each dialysis hole, and add blank dialysis buffer to the corresponding receiving end of the dialysis hole. Then the dialysis plate was sealed with a breathable membrane and placed in a humidified 5% CO 2 incubator, and incubated for 4 hours at 37°C and 100 rpm shaking. After dialysis, transfer 50 ⁇ L of the dialyzed buffer sample and the dialyzed plasma sample to a new sample receiving plate. Add a corresponding volume of corresponding blank plasma or buffer to the sample so that the final volume of each sample well is 100 ⁇ L, and the volume ratio of plasma:dialysis buffer is 1:1.
  • PPB_Unbound (%) 100* FC / TC , where F C is the concentration of the compound at the buffer end of the dialysis plate; T C is the concentration of the compound at the plasma end of the dialysis plate; T 0 is the concentration of the compound in the plasma sample at time zero.
  • the compound of the present invention has a reasonable plasma protein binding rate in both humans and mice.
  • MDCKII-MDR1 monolayer cell test system Use the MDCKII-MDR1 monolayer cell test system to evaluate the permeability and efflux ratio of the compound to be tested to determine the potential of the compound to cross the blood-brain barrier and be effluxed by the P-GP transporter.
  • MDR1-MDCKII cells (from Netherlands Cancer Institute) were seeded on 96 plates (from Corning) at a cell density of 2.5 ⁇ 10 cells/ml and cultured for 4-7 days to form a copolymerized cell monolayer.
  • Hank's balanced salt buffer pH 7.40 ⁇ 0.05
  • 10mM 4-hydroxyethylpiperazineethanesulfonic acid was used as the transport buffer.
  • the bidirectional transport of the test compound at a concentration of 50 ⁇ M was tested, and the concentration of DMSO in the incubation system was controlled below 1%. After adding the sample, incubate the cell plate at 37 ⁇ 1°C, 5% CO2 and saturated humidity for 150 minutes. All samples were quantitatively analyzed using LC-MS/MS method. Use the following formula to calculate the apparent permeability coefficient (P app , cm/s) and efflux ratio.
  • dC r /d t is the cumulative concentration of the compound at the receiving end per unit time ( ⁇ M/s)
  • V r is the volume of the receiving end solution (the solution volumes at the top and basal ends are 0.075mL and 0.250mL respectively)
  • A is the cell
  • C 0 is the initial concentration of the test substance at the administration end (nM) or the peak area ratio of the reference substance.
  • Liver microsomes purchased from Corning or Xenotech, stored in -80°C refrigerator;
  • NADPH Reduced nicotinamide adenine dinucleotide phosphate
  • Control compounds testosterone, diclofenac, propafenone.
  • T60 incubation plate Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
  • microsomal working solution live microsomal protein concentration is 0.56 mg/mL
  • test product or control compound working solution After the pre-incubation, add 5 ⁇ L of test product or control compound working solution to the T60 incubation plate and NCF60 incubation plate respectively, and mix well. Add 50 ⁇ L potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction; add 180 ⁇ L stop solution (containing 200ng/mL tolbutamide (tolbutamide) and 200ng/mL labetalol (labetalol)) to the T0 stop plate. Acetonitrile solution) and 6 ⁇ L of NADPH regeneration system working solution, take 54 ⁇ L of sample from the T60 incubation plate to the T0 stop plate (TO sample generation).
  • stop solution containing 200ng/mL tolbutamide (tolbutamide) and 200ng/mL labetalol (labetalol)
  • stop solution acetonitrile solution containing 200ng/mL tolbutamide and 200ng/mL labetalol

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Abstract

Disclosed are a series of amino-substituted heteroaryl and use thereof, and in particular, disclosed are a compound represented by formula (IV) 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
本申请主张如下优先权：This application claims the following priority rights:
CN202210771404.5，申请日2022年06月30日；CN202210771404.5, application date is June 30, 2022;
CN202211067793.X，申请日2022年09月01日；CN202211067793.X, application date is September 1, 2022;
CN202211364327.8，申请日2022年11月02日；CN202211364327.8, application date November 2, 2022;
CN202310179692.X，申请日2023年02月28日。CN202310179692.X, application date: February 28, 2023.
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(IV)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 (IV) and their pharmaceutically acceptable salts.
背景技术Background technique
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，可将SAM(S-腺苷甲硫氨酸)上的甲基转移至其底物蛋白的精氨酸残基上，使底物蛋白对称二甲基精氨酸化(sDMA)。PRMT5可以与MEP50(甲基体蛋白50)结合形成异八聚体复合物，该复合物是甲基小体的一个组成部分，可甲基化多种底物，包括剪接体Sm蛋白，核仁素，p53，组蛋白H2A、H3和H4，SPT5转录延伸因子以及MBD2等。因此，PRMT5-MEP50复合物对哺乳动物细胞存活具有重要作用。研究表明PRMT5高表达于结直肠癌、肺癌、卵巢癌、前列腺癌、淋巴瘤、白血病和胶质母细胞瘤等多种肿瘤细胞。抑制PRMT5有望为这些肿瘤的治疗带来新的突破。目前已有多个靶向PRMT5的抑制剂进入了临床阶段研究(如GSK3326595,JNJ64619178,PF06939999,PRT543,PRT811)。然而PRMT5在调节造血功能时同样发挥重要作用，上述PRMT5抑制剂在临床上存在剂量限制性的血小板减少、贫血和中性粒细胞减少等血液系统副作用，限制了其临床应用前景。因此，选择性抑制肿瘤细胞中PRMT5功能而不抑制正常细胞中PRMT5的活性有望改善PRMT5抑制剂的治疗指数，是PRMT5抑制剂研究的新方向。MTAP(甲基硫腺苷磷酸化酶)是甲硫氨酸补救途径的关键酶，MTAP基因常与体内常见的抑癌基因CDKN2A发生共缺失现象。多个独立研究表明，MTAP缺失会导致细胞内MTA(甲硫腺苷)蓄积，MTA与PRMT5结合形成无催化活性的PRMT5-MEP50·MTA(PRMT5·MTA)复合物，致使PRMT5结合SAM的能力降低，从而抑制MTAP缺失细胞内的甲基化过程。MTAP缺失肿瘤细胞为了维持正常的生理活动，对PRMT5的依赖性会大幅提高。综上，开发能够特异性结合PRMT5·MTA复合物的抑制剂有望在抑制MTAP缺失肿瘤细胞中的PRMT5活性的同时降低对MTAP-野生型细胞中PRMT5的影响，从而提高化合物的靶向性和安全性。靶向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。PRMT5 (protein arginine methyltransferase 5) is a type II arginine methyltransferase that can transfer the methyl group on SAM (S-adenosylmethionine) to the sperm of its substrate protein. symmetric dimethylarginylation (sDMA) of substrate proteins on amino acid residues. PRMT5 can combine with MEP50 (methyl body protein 50) to form a heterooctamer complex, which is a component of the methyl body and can methylate a variety of substrates, including spliceosomal Sm protein, nucleolus proteins, p53, histones H2A, H3 and H4, SPT5 transcription elongation factor and MBD2, etc. Therefore, the PRMT5-MEP50 complex plays an important role in mammalian cell survival. Studies have shown that PRMT5 is highly expressed in various tumor cells such as colorectal cancer, lung cancer, ovarian cancer, prostate cancer, lymphoma, leukemia and glioblastoma. Inhibiting PRMT5 is expected to bring new breakthroughs in the treatment of these tumors. Currently, multiple inhibitors targeting PRMT5 have entered clinical stage research (such as GSK3326595, JNJ64619178, PF06939999, PRT543, PRT811). However, PRMT5 also plays an important role in regulating hematopoietic function. The above-mentioned PRMT5 inhibitors have dose-limiting blood system side effects such as thrombocytopenia, anemia and neutropenia in clinical practice, which limits their clinical application prospects. Therefore, selectively inhibiting PRMT5 function in tumor cells without inhibiting PRMT5 activity in normal cells is expected to improve the therapeutic index of PRMT5 inhibitors and is a new direction for PRMT5 inhibitor research. MTAP (methylthioadenosine phosphorylase) is a key enzyme in the methionine salvage pathway. The MTAP gene is often co-deleted with CDKN2A, a common tumor suppressor gene in the body. Multiple independent studies have shown that the loss of MTAP will lead to the accumulation of MTA (methylthioadenosine) in cells. MTA combines with PRMT5 to form a catalytically inactive PRMT5-MEP50·MTA (PRMT5·MTA) complex, resulting in a reduced ability of PRMT5 to bind SAM. , thereby inhibiting the methylation process in MTAP-deficient cells. In order to maintain normal physiological activities, MTAP-deficient tumor cells will be significantly more dependent on PRMT5. In summary, the development of inhibitors that can specifically bind to the PRMT5·MTA complex is expected to inhibit PRMT5 activity in MTAP-deficient tumor cells while reducing the impact on PRMT5 in MTAP-wild-type cells, thereby improving the targeting and safety of the compounds. sex. 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(IV)所示化合物或其药学上可接受的盐，
The present invention provides compounds represented by formula (IV) or pharmaceutically acceptable salts thereof,
其中，in,
E1选自CH2、NH和O；E 1 is selected from CH 2 , NH and O;
各R1分别独立地选自H、F、Cl、Br、I、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Ra取代； Each R 1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively Independently optionally substituted by 1, 2 or 3 R a ;
或者，相同原子上的两个R1连接形成C3-6环烷基，所述C3-6环烷基任选被1、2或3个Re取代；Alternatively, two R 1 on the same atom are connected to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 Re ;
R6选自H、F、Cl、Br、I、C1-3烷基、C1-3烷氧基、C2-4炔基、C2-4烯基、C1-3烷氨基、C3-6环烷基、4-6元杂环烷基、-C1-3烷氧基-C3-6环烷基、-C1-3烷氨基-C3-6环烷基、-C1-3烷氧基-4-6元杂环烷基和-C1-3烷氨基-4-6元杂环烷基，所述C1-3烷基、C1-3烷氧基、C2-4炔基、C2-4烯基、C1-3烷氨基、C3-6环烷基、4-6元杂环烷基、-C1-3烷氧基-C3-6环烷基、-C1-3烷氨基-C3-6环烷基、-C1-3烷氧基-4-6元杂环烷基和-C1-3烷氨基-4-6元杂环烷基分别独立地任选被1、2或3个Rb取代；R 6 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, C 1-3 alkylamino, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-6 cycloalkyl, -C 1-3 alkylamino-C 3-6 cycloalkyl, -C 1-3 alkoxy-4-6-membered heterocycloalkyl and -C 1-3 alkylamino-4-6-membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy Base, C 2-4 alkynyl, C 2-4 alkenyl, C 1-3 alkylamino, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-6 cycloalkyl, -C 1-3 alkylamino-C 3-6 cycloalkyl, -C 1-3 alkoxy-4-6 membered heterocycloalkyl and -C 1-3 alkylamino-4 -6-membered heterocycloalkyl groups are independently optionally substituted by 1, 2 or 3 R b ;
结构单元选自 Structural units Selected from
环A选自5-6元杂芳基、C4-6环烯基或5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基或5-6元杂环烯基分别独立地任选被1、2或3个Rc取代；Ring A is selected from 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 membered heterocycloalkenyl, said 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
环B选自苯基和5-10元杂芳基；Ring B is selected from phenyl and 5-10 membered heteroaryl;
T1和T2分别独立地选自C、CR3或N；T 1 and T 2 are independently selected from C, CR 3 or N;
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;
R3选自H、F、Cl、Br、I、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 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
R4选自H、F、Cl、Br、I、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, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
各R5分别独立地选自H、F、Cl、Br、I、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；Each R 5 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R d ;
各Ra、各Rc、各Rd和各Re分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R a , each R c , each R d and each Re are independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
各Rb分别独立地选自H、D、F、Cl、Br、I、OH、NH2、C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基，所述C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基分别独立地任选被1、2或3个R取代；Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R substitution;
各R分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R is independently selected from H, D, F, Cl, Br, I, 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;
m选自0、1、2、3和4；m is selected from 0, 1, 2, 3 and 4;
条件是，当R6选自H、F、Cl、Br、I、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个卤素取代时，环B为双环的8-10元杂芳基，或者，结构单元选自所述5-6元杂芳基、5-6元杂环烯基、4-6元杂环烷基、5-10元杂芳基或双环的8-10元杂芳基的“杂”分别表示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 condition is that when R 6 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are respectively When independently optionally substituted by 1, 2 or 3 halogens, Ring B is a bicyclic 8-10 membered heteroaryl, or structural unit Selected from The "hetero" of the 5-6-membered heteroaryl, 5-6-membered heterocycloalkenyl, 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl or bicyclic 8-10-membered heteroaryl are respectively 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，上述式(IV)所示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 represented by the above formula (IV) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
E1选自O； E 1 is selected from O;
各R1分别独立地选自H、F、Cl、Br、I、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Ra取代；Each R 1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively Independently optionally substituted by 1, 2 or 3 R a ;
或者，相同原子上的两个R1连接形成C3-6环烷基，所述C3-6环烷基任选被1、2或3个Re取代；Alternatively, two R 1 on the same atom are connected to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 Re ;
R6选自C2-4炔基，所述C2-4炔基任选被1、2或3个Rb取代；R 6 is selected from C 2-4 alkynyl, which is optionally substituted by 1, 2 or 3 R b ;
结构单元选自 Structural units Selected from
环A选自5-6元杂芳基、C4-6环烯基或5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基或5-6元杂环烯基分别独立地任选被1、2或3个Rc取代；Ring A is selected from 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 membered heterocycloalkenyl, said 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
环B选自苯基和5-10元杂芳基；Ring B is selected from phenyl and 5-10 membered heteroaryl;
T1和T2分别独立地选自C、CR3或N；T 1 and T 2 are independently selected from C, CR 3 or N;
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;
R3选自H、F、Cl、Br、I、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 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
R4选自H、F、Cl、Br、I、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, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
各R5分别独立地选自H、F、Cl、Br、I、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；Each R 5 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R d ;
各Ra、各Rc和各Rd分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R a , each R c and each R d are independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
各Rb分别独立地选自H、D、F、Cl、Br、I、OH、NH2、C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基，所述C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基分别独立地任选被1、2或3个R取代；Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R substitution;
各R分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
n选自0、1和2；n is selected from 0, 1 and 2;
m选自0和1。m is chosen from 0 and 1.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各Ra分别独立地选自H、D、F、Cl、OH、NH2、CH3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R a is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各Rc分别独立地选自H、D、F、Cl、OH、NH2、CH3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R c is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各Rd分别独立地选自H、D、F、Cl、OH、NH2、CH3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R d is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各Re分别独立地选自H、D、F、Cl、OH、NH2、CH3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R e is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各Rb分别独立地选自H、D、F、Cl、OH、NH2、CH3、CH2CH3、OCH3、OCH2CH3、NHCH3、NHCH2CH3、N(CH3)2、吡咯烷基、哌啶基、哌嗪基和吗啡啉基，所述CH3、CH2CH3、OCH3、OCH2CH3、NHCH3、NHCH2CH3、N(CH3)2、吡咯烷基、哌啶基、哌嗪基和吗啡啉基分别独立地任选被1、2或3个R取代，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, the CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are each independently optionally substituted by 1 , 2 or 3 R substitutions, and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各Rb分别独立地选自H、D、F、OH、NH2、CH3、CD3、CF3、N(CH3)2、其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 , N(CH 3 ) 2 , Other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各Rb分别独立地选自H、D、F、OH、NH2、CH3、CD3、CF3和N(CH3)2，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 and N(CH 3 ) 2 , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R1选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、 CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2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 present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein said R 1 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , 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 and OCH(CH 3 ) 2 are each independently optionally selected from 1, 2 or 3 R a substitutions, and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R1选自F、CH3和CD3，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from F, CH 3 and CD 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中相同原子上的两个R1连接形成环丙基，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein two R 1 on the same atom are connected to form a cyclopropyl group, and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示的化合物或其药学上可接受的盐，其中，所述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 the above formula (IV) 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，上述式(IV)所示的化合物或其药学上可接受的盐，其中，所述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 the above formula (IV) 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，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R3选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2分别独立地任选被1、2或3个Rd取代，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , 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 and OCH(CH 3 ) 2 are independently optionally substituted by 1, 2 or 3 R d . Other variables are as follows: defined by invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R3选自H、F、Cl、Br、CH3和CD3，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F, Cl, Br, CH 3 and CD 3 , and other variables are as in the present invention defined.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R4选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2分别独立地任选被1、2或3个Rd取代，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , 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 and OCH(CH 3 ) 2 are independently optionally substituted by 1, 2 or 3 R d . Other variables are as follows: defined by invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R4选自H、F、Cl、Br、CD3和CH3，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from H, F, Cl, Br, CD 3 and CH 3 , and other variables are as in the present invention defined.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R3选自H、F、Cl、Br、CH3和CD3，R4选自H、F、Cl、Br、CD3和CH3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F, Cl, Br, CH 3 and CD 3 and R 4 is selected from H , F, Cl, Br, CD 3 and CH 3 , other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各R5分别独立地选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2分别独立地任选被1、2或3个Rd取代，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , said 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 and OCH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , Other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述各R5分别独立地选自H、F、Cl、Br和CH3，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein each R 5 is independently selected from H, F, Cl, Br and CH 3 , and other variables are as follows defined by invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R6选自C2-4炔基、C2-4烯基、NHCH3、NHCH2CH3、N(CH3)2、氮杂环丁基、吡咯烷基、吗啡啉基、哌嗪基、哌啶基和-OCH2-C3-6环烷基，所述C2-4炔基、C2-4烯基、NHCH3、NHCH2CH3、N(CH3)2、氮杂环丁基、吡咯烷基、吗啡啉基、哌嗪基、哌啶基和-OCH2-C3-6环烷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 aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 2-4 alkynyl, C 2-4 alkenyl, NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl and -OCH 2 -C 3-6 cycloalkyl, the C 2-4 Alkynyl, C 2-4 alkenyl, NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl and -OCH 2 -C 3-6 cycloalkyl is independently optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R6选自C2-4炔基，所述C2-4炔基任选被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 compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 2-4 alkynyl, and the C 2-4 alkynyl is optionally replaced by 1 , 2 or 3 R b substitutions, and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R6选自 其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein said R 6 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述R6选自 其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein said R 6 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述环B选自吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并噻唑基、苯并吡唑基和苯并咪唑基，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, Benzopyrazolyl and benzimidazolyl, other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述环B选自吡啶基，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein the ring B is selected from pyridyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述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 the above formula (IV) 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，上述式(IV)所示化合物或其药学上可接受的盐，其中所述环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、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 the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from the group consisting of 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, 2 or 3 R c substitutions, other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述环A选自咪唑基、吡唑基、氧杂环戊烯基和氮杂环戊烯基，所述咪唑基、吡唑基、氧杂环戊烯基和氮杂环戊烯基分别独立地任选被1、2或3个Rc取代，其他变量如本发明所定义。In some embodiments of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from the group consisting of imidazolyl, pyrazolyl, oxolenyl and azelene base, the imidazolyl, pyrazolyl, oxolenyl and azeolenyl groups are independently optionally substituted by 1, 2 or 3 R c , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述环A选自咪唑基和吡唑基，所述咪唑基和吡唑基分别独立地任选被1、2或3个Rc取代，其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) or a pharmaceutically acceptable salt thereof, wherein the ring A is selected from the group consisting of imidazolyl and pyrazolyl, and the imidazolyl and pyrazolyl are independently optional. Choose to be replaced by 1, 2 or 3 R c , and other variables are as defined in the present invention.
本发明的一些方案中，上述式(IV)所示化合物或其药学上可接受的盐，其中所述结构单元选自 其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) 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，上述式(IV)所示化合物或其药学上可接受的盐，其中所述结构单元选自 其他变量如本发明所定义。In some aspects of the present invention, the compound represented by the above formula (IV) 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，上述式(IV)所示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 represented by the above formula (IV) or a pharmaceutically acceptable salt thereof is selected from,
其中，in,
R2选自H、卤素和C1-3烷基，所述C1-3烷基任选被1、2或3个Rb取代；R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
各Rb分别独立地选自H、D、F、Cl、Br、I、OH、NH2、C1-3烷基、C1-3烷氧基和C1-3烷氨基，所述C1-3烷基、C1-3烷氧基和C1-3烷氨基分别独立地任选被1、2或3个R取代；Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, and the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
结构单元各R、各R1、R4如本发明所定义。Structural units Each R, each R 1 and R 4 are as defined in the present invention.
本发明的一些方案中，上述式(P)所示化合物或其药学上可接受的盐，其中所述R2选自H、F、Cl、CH3、CH2CH3和CH(CH3)2，所述CH3、CH2CH3和CH(CH3)2分别独立地任选被1、2或3个Rb取代，各Rb分别独立地选自H、D、F、OH、NH2、CH3、CD3、CF3和N(CH3)2，其他变量如本发明所定义。 In some aspects of the present invention, the compound represented by the above formula (P) or a pharmaceutically acceptable salt thereof, wherein said R 2 is selected from H, F, Cl, CH 3 , CH 2 CH 3 and CH (CH 3 ) 2. The CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R b , and each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 and N(CH 3 ) 2 , other variables are as defined in the present invention.
本发明的一些方案中，上述式(P)所示化合物或其药学上可接受的盐，其中所述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 the above formula (P) 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，上述式(P)所示化合物或其药学上可接受的盐，其中，所述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 the above formula (P) 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，上述式(P)所示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 represented by the above formula (P) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元R1、R2和R4如本发明所定义；Among them, the structural unit R 1 , R 2 and R 4 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;
R1不为H时，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。When R 1 is not H, the carbon atom with "#" is a chiral carbon atom, existing 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-1)所示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 represented by the above formula (P-1) or a pharmaceutically acceptable salt thereof is selected from,
其中，结构单元R1、R2和R4如本发明所定义。Among them, the structural unit R 1 , R 2 and R 4 are as defined in the present invention.
本发明还提供了式(II)所示化合物或其药学上可接受的盐，
The present invention also provides compounds represented by formula (II) or pharmaceutically acceptable salts thereof,
其中，in,
各R1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Ra取代；Each R 1 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 a substitutions;
R6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Rb取代；R 6 is selected from 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 b ;
R2选自H、卤素、OH、NH2和C1-3烷基，所述C1-3烷基任选被1、2或3个Rb取代；R 2 is selected from H, halogen, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
E1选自CH2、NH和O；E 1 is selected from CH 2 , NH and O;
环A不存在，T1和T2分别独立地选自CR3和N，选自双键；Ring A is absent, T 1 and T 2 are independently selected from CR 3 and N, Selected from double bonds;
或者，结构单元选自环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、2或3个Rc取代；Or, 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 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
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、T7、T8和T9分别独立地选自CR5和N；T 6 , T 7 , T 8 and T 9 are independently selected from CR 5 and N;
R3、R4和R5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Rd取代；R 3 , R 4 and R 5 are each 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 selected. R is optionally replaced by 1, 2 or 3 R d ;
各Ra、各Rb、各Rc和各Rd分别独立地选自H、D、卤素、OH、NH2、CH3和CD3；Each R a , each R b , each R c and each R d are independently selected from H, D, halogen, OH, NH 2 , CH 3 and CD 3 ;
n选自0、1、2和3；n is selected from 0, 1, 2 and 3;
条件是，当R6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Rb取代时，结构单元选自且所述化合物不为所述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 condition is that when R 6 is selected from 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 when 3 R b are substituted, the structural unit Selected from and the compound is not 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.
本发明还提供了式(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 (I) or pharmaceutically acceptable salts thereof,
其中，in,
各R1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Ra取代；Each R 1 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 a substitutions;
R2选自H、卤素、OH、NH2和C1-3烷基，所述C1-3烷基任选被1、2或3个Rb取代；R 2 is selected from H, halogen, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
E1选自CH2、NH和O；E 1 is selected from CH 2 , NH and O;
环A不存在，T1和T2分别独立地选自CR3和N；Ring A does not exist, and T 1 and T 2 are independently selected from CR 3 and N;
或者，结构单元选自环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、2或3个Rc取代；Or, 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 5-6 membered heteroaryl, C 4-6 cycloalkenyl and 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
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、T7、T8和T9分别独立地选自CR5和N；T 6 , T 7 , T 8 and T 9 are independently selected from CR 5 and N;
R3、R4和R5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Rd取代；R 3 , R 4 and R 5 are each 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 selected. R is optionally replaced by 1, 2 or 3 R d ;
各Ra、各Rb、各Rc和各Rd分别独立地选自H、卤素、OH、NH2和CH3；Each R a , each R b , each R c and each R d 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.
本发明的一些方案中，上述各Ra、各Rb、各Rc和各Rd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 solutions of the present invention, each R a , each R b , each R c and each R d mentioned above are independently selected from H, F, Cl, OH, NH 2 and CH 3 , 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H、F、Cl、OH、NH2和CH3，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 H, F, Cl, OH, NH 2 and CH 3 , 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H、F、Cl、OH、NH2和CH3，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 H, F, Cl, OH, NH 2 and CH 3 , 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H、F、Cl、OH、NH2和CH3，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 H, F, Cl, OH, NH 2 and CH 3 , 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H、F、Cl、OH、NH2和CH3，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 H, F, Cl, OH, NH 2 and CH 3 , 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H、D、F、Cl、OH、NH2、CH3、CH2CH3、OCH3、OCH2CH3、NHCH3、NHCH2CH3、N(CH3)2、吡咯烷基、哌啶基、哌嗪基和吗啡啉基，所述CH3、CH2CH3、OCH3、OCH2CH3、NHCH3、NHCH2CH3、N(CH3)2、吡咯烷基、哌啶基、哌嗪基和吗啡啉基分别独立地任选被1、2或3个R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 H, D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, said CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3. N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted by 1, 2 or 3 R, 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H、D、F、OH、NH2、CH3、CD3、CF3、N(CH3)2、其他变量如本发明所定义。In some aspects of the present invention, each of the above R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 , N(CH 3 ) 2 , 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H、D、F、Cl、OH、NH2、CH3和CD3，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 H, D, F, Cl, OH, NH 2 , 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R1选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2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 H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , said 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 Ra , and other variables are as defined in the present invention.
本发明的一些方案中，上述R1选自F、CH3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from F, 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R1选自CH3和CD3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 1 is selected from 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R1选自F和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 selected from F and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述相同原子上的两个R1连接形成环丙基，其他变量如本发明所定义。 In some embodiments of the present invention, the two R 1's on the same atom are connected to form a cyclopropyl group, and other variables are as defined in the present invention.
本发明的一些方案中，上述R2选自H、F、Cl、Br、I、OH、NH2、CH3、CH2CH3、CH2CH2CH3和CH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3和CH(CH3)2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 aspects of the invention, the above R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , so The CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
本发明的一些方案中，上述R2选自H和其他变量如本发明所定义。In some aspects of the present invention, the above R 2 is selected from H and Other variables are as defined in the present invention.
本发明的一些方案中，上述R3选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2分别独立地任选被1、2或3个Rd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 H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
本发明的一些方案中，上述R3选自H、F、Cl、Br和CH3，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 H, F, Cl, Br and CH 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H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2分别独立地任选被1、2或3个Rd取代，其他变量如本发明所定义。In some aspects of the invention, the above R 4 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
本发明的一些方案中，上述R4选自H、F、Cl、Br和CH3，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned R 4 is selected from H, F, Cl, Br and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述各R5分别独立地选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2分别独立地任选被1、2或3个Rd取代，其他变量如本发明所定义。In some aspects of the present invention, each R 5 mentioned above is independently selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , said 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 and OCH (CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R d , and other variables are as defined in the present invention.
本发明的一些方案中，上述各R5分别独立地选自H、F、Cl、Br和CH3，其他变量如本发明所定义。In some aspects of the present invention, each R 5 mentioned above is independently selected from H, F, Cl, Br and CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R6选自C2-4炔基、C2-4烯基、NHCH3、NHCH2CH3、N(CH3)2、氮杂环丁基、吡咯烷基、吗啡啉基、哌嗪基、哌啶基和-OCH2-C3-6环烷基，所述C2-4炔基、C2-4烯基、NHCH3、NHCH2CH3、N(CH3)2、氮杂环丁基、吡咯烷基、吗啡啉基、哌嗪基、哌啶基和-OCH2-C3-6环烷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 6 is selected from C 2-4 alkynyl, C 2-4 alkenyl, NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , azetidinyl, pyrrolidinyl , morpholinyl, piperazinyl, piperidinyl and -OCH 2 -C 3-6 cycloalkyl, the C 2-4 alkynyl, C 2-4 alkenyl, NHCH 3 , NHCH 2 CH 3 , N (CH 3 ) 2 , azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl and -OCH 2 -C 3-6 cycloalkyl are each independently optionally substituted by 1, 2 or 3 Each R b is replaced, and other variables are as defined in the present invention.
本发明的一些方案中，上述R6选自乙炔基、丙炔基、乙烯基、NHCH3、NHCH2CH3、N(CH3)2、N(CH3)CH2CH3、-O-CH2-环丙基、-O-CH2-环丁基、-NH-CH2-环丙基和-NH-CH2-环丁基，所述乙炔基、丙炔基、乙烯基、NHCH3、NHCH2CH3、N(CH3)2、N(CH3)CH2CH3、-O-CH2-环丙基、-O-CH2-环丁基、-NH-CH2-环丙基和-NH-CH2-环丁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 aspects of the invention, the above R 6 is selected from ethynyl, propynyl, vinyl, NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 3 )CH 2 CH 3 , -O- CH 2 -cyclopropyl, -O-CH 2 -cyclobutyl, -NH-CH 2 -cyclopropyl and -NH-CH 2 -cyclobutyl, the ethynyl, propynyl, vinyl, NHCH 3. NHCH 2 CH 3 , N(CH 3 ) 2 , N(CH 3 )CH 2 CH 3 , -O-CH 2 -cyclopropyl, -O-CH 2 -cyclobutyl, -NH-CH 2 - Cyclopropyl and -NH-CH 2 -cyclobutyl are each independently optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
本发明的一些方案中，上述R6选自 其他变量如本发明所定义。In some solutions of the present invention, the above R 6 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CH3和CF3，其他变量如本发明所定义。In some solutions of the present invention, the above R 6 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R6选自其他变量如本发明所定义。In some solutions of the present invention, the above R 6 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 6 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R6选自乙炔基、丙炔基和乙烯基，所述乙炔基、丙炔基和乙烯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-mentioned R 6 is selected from ethynyl, propynyl and vinyl, and the ethynyl, propynyl and vinyl are independently optionally substituted by 1, 2 or 3 R b , and the others Variables are as defined herein.
本发明的一些方案中，上述R6选自 其他变量如本发明所定义。 In some solutions of the present invention, the above R 6 is selected from Other variables are as defined in the present invention.
本发明的一些方案中，上述T1选自C、C(CH3)和C(CD3)，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned T 1 is selected from C, C(CH 3 ) and C(CD 3 ), and other variables are as defined in the present invention.
本发明的一些方案中，上述T2选自C、CH和N，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned T 2 is selected from C, CH and N, and other variables are as defined in the present invention.
本发明的一些方案中，上述T3为CH，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned T 3 is CH, and other variables are as defined in the present invention.
本发明的一些方案中，上述T4选自CH、CF、CCl、C(CH3)和N，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned T 4 is selected from CH, CF, CCl, C(CH 3 ) and N, and other variables are as defined in the present invention.
本发明的一些方案中，上述T5为N，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned T 5 is N, and other variables are as defined in the present invention.
本发明的一些方案中，上述环B选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并噻唑基、苯并吡唑基和苯并咪唑基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring B is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzothiazolyl, benzopyrazolyl and benzimidazolyl, and other variables are as in the present invention defined.
本发明的一些方案中，上述环B选自吡啶基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring B is selected from pyridyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述环B选自苯并噻唑基和苯并吡唑基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned Ring B is selected from benzothiazolyl and benzopyrazolyl, 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T6选自CH和N，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned T 6 is selected from CH and N, and other variables are as defined in the present invention.
本发明的一些方案中，上述T6为N，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned T 6 is N, and other variables are as defined in the present invention.
本发明的一些方案中，上述T7选自CH，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned T 7 is selected from CH, and other variables are as defined in the present invention.
本发明的一些方案中，上述T8选自CH，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned T 8 is selected from CH, and other variables are as defined in the present invention.
本发明的一些方案中，上述T9选自CH，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned T 9 is selected from CH, 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，上述环A选自5-6元杂芳基或5-6元杂环烯基，所述5-6元杂芳基或5-6元杂环烯基分别独立地任选被1、2或3个Rc取代，其他变量如本发明所定义。In some aspects of the present invention, the above-mentioned ring A is selected from a 5-6-membered heteroaryl group or a 5-6-membered heterocyclic alkenyl group, and the 5-6-membered heteroaryl group or 5-6-membered heterocyclic alkenyl group are independently 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，上述环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、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-mentioned Ring A is selected from the group consisting of pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl, oxazolyl, ring Butenyl, cyclopentenyl, cyclohexenyl, oxolenyl, oxanyl, azolidenyl and azacyclohexenyl, the pyridyl, pyrimidinyl, Pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl, oxazolyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxolyl Alkenyl, oxanyl, azepanyl and azepanyl are each independently optionally substituted by 1, 2 or 3 R c , 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 are 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，上述结构单元为其他变量如本发明所定义。 In some solutions of the present invention, the above structural units for Other variables are as defined in the present invention.
本发明的一些方案中，上述E1选自O和NH，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned E 1 is selected from O and NH, and other variables are as defined in the present invention.
本发明的一些方案中，上述E1选自O，其他变量如本发明所定义。In some solutions of the present invention, the above-mentioned E 1 is selected from O, 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.
本发明还提供了下列化合物或其药学上可接受的盐，








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








本发明的一些方案中，上述化合物或其药学上可接受的盐选自，

































In some embodiments of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,

































在本发明的实施例1中，通过SFC手性分析(分析方法：色谱柱:Chiralcel OX-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％)，化合物1b的保留时间为1.760min。In Example 1 of the present invention, through SFC chiral analysis (analysis method: chromatographic column: Chiralcel OX-3 50×4.6mm I.D., 3μm; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 1b is 1.760min.
在本发明的实施例2中，通过SFC手性分析(分析方法：色谱柱:(S.S)Whelk-O1 50×4.6mm I.D.,3.5μm；流动相:A相:二氧化碳,B相:[66.67％(异丙醇-0.05％二乙胺)+33.33％(乙腈-0.05％二乙胺)]；梯度(B％):50％)，化合物2a的保留时间为0.849min。In Example 2 of the present invention, through SFC chiral analysis (analysis method: chromatographic column: (S.S) Whelk-O1 50×4.6mm I.D., 3.5μm; mobile phase: A phase: carbon dioxide, B phase: [66.67% (Isopropyl alcohol-0.05% diethylamine) + 33.33% (acetonitrile-0.05% diethylamine)]; gradient (B%): 50%), the retention time of compound 2a is 0.849 min.
在本发明的实施例3中，通过SFC手性分析(分析方法：色谱柱:Chiralpak AD-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:40％乙醇(0.05％二乙胺)，流速:3mL/min)，化合物3b的保留时间为1.636min。In Example 3 of the present invention, through SFC chiral analysis (analysis method: chromatographic column: Chiralpak AD-3 50×4.6mm I.D., 3μm; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl amine); gradient: 40% ethanol (0.05% diethylamine), flow rate: 3mL/min), the retention time of compound 3b was 1.636min.
在本发明的实施例4中，通过SFC手性分析(分析方法：色谱柱:Chiralpak AD-3 150×4.6mm 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％)，化合物4a的保留时间为3.396min。In Example 4 of the present invention, through SFC chiral analysis (analysis method: chromatographic column: Chiralpak AD-3 150×4.6mm I.D., 3 μm; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 4a is 3.396min.
在本发明的实施例5中，通过SFC手性分析(分析方法：色谱柱:Chiralpak AD-3 150×4.6mm 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％)，化合物5a的保留时间为2.682min。In Example 5 of the present invention, through SFC chiral analysis (analysis method: chromatographic column: Chiralpak AD-3 150×4.6mm I.D., 3 μm; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 5a is 2.682min.
在本发明的实施例6中，通过SFC手性分析(分析方法：色谱柱:Chiralcel OD-3 150×4.6mm 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％)，化合物6a的保留时间为3.737min。In Example 6 of the present invention, through SFC chiral analysis (analysis method: chromatographic column: Chiralcel OD-3 150×4.6mm I.D., 3μm; mobile phase: A phase: carbon dioxide, B phase: ethanol (0.05% diethyl Amine); gradient: B%: 40%), the retention time of compound 6a is 3.737min.
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中的应用。The present invention also provides the use of the above-mentioned compounds or pharmaceutically acceptable salts thereof in the preparation of medicines for treating diseases related to PRMT5 inhibitors.
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相关疾病的药物中的应用。The present invention also provides the use of the above compounds or pharmaceutically acceptable salts thereof in the preparation of drugs for treating PRMT5-related diseases.
本发明还提供了下列合成方法：The invention also provides the following synthesis methods:
方法1(中间体)：
Method 1 (intermediate):
方法2：
Method 2:
方法3：
Method 3:
方法4：
Method 4:
方法5：
Method 5:
方法6：
Method 6:
方法7：
Method 7:
其中，上述合成方法1～7中，Among them, in the above synthesis methods 1 to 7,
R2选自H、卤素、OH、NH2和C1-3烷基，所述C1-3烷基任选被1、2或3个Rb取代；R 2 is selected from H, halogen, OH, NH 2 and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
各Rb分别独立地选自H、卤素、OH、NH2和CH3；Each R b is independently selected from H, halogen, OH, NH 2 and CH 3 ;
优选的，R2选自H、F、Cl、Br、I、OH、NH2、CH3、CH2CH3、CH2CH2CH3和CH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3和CH(CH3)2分别独立地任选被1、2或3个Rb取代；Preferably, R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are each independently optionally substituted by 1, 2 or 3 R b ;
进一步优选的，R2选自H和 Further preferably, R 2 is selected from H and
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.
方法8：
Method 8:
方法9：
Method 9:
其中，上述合成方法8或9中，R6选自CH3和CF3；Among them, in the above synthesis method 8 or 9, R 6 is selected from CH 3 and CF 3 ;
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，配制方案见表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. Prepare for immediate use on the day of the experiment. The preparation 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 Che In the compound transfer plate, the transfer volume is 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LU99细胞具有显著的抗增殖活性，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长的半衰期、较高的组织分布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 significant anti-proliferative activity on LU99 cells, has good inhibitory activity on MTAP-deficient HCT116 tumor cells, and has relatively low inhibitory activity on wild-type HCT116 tumor cells. Weak, showing excellent selectivity; in the mouse pharmacokinetic evaluation test, the compound of the present invention showed a longer half-life, higher tissue distribution and higher drug exposure, and has good drug metabolism kinetics in the body chemical properties; the compound of the present invention also exhibits excellent anti-tumor efficacy in vivo, 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。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 the compound of the present invention contains a relatively basic functional group, Acid addition salts may be obtained by contacting such compounds with a sufficient amount of acid in pure solution or in a suitable inert solvent.
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, and their racemic mixtures and other mixtures, such as enantiomeric or diastereomerically enriched mixtures, all of which belong to this 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例如，表示与的混合物，表示与的混合物。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 For example, express and mixture, express and mixture.
除非另有说明，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。例如，表示或者或者富含一种对映体形式存在。Unless otherwise stated, carbon atoms with an "*" are chiral carbon atoms that exist in the form of (R) or (S) as a single enantiomer or enriched in one enantiomer. For example, express or or may be present enriched in one enantiomeric form.
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 body. 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, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate). 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.
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用表示，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。Unless otherwise stated, when there are double bond structures in the compound, such as carbon-carbon double bonds, carbon-nitrogen double bonds, and nitrogen-nitrogen double bonds, and each atom on the double bond is connected to two different substituents (including nitrogen atoms In the double bond, a lone pair of electrons on the nitrogen atom is regarded as a substituent connected to it), if there is a link between the atom on the double bond and its substituent in the compound means the (Z) isomer, (E) isomer or a mixture of the two isomers of the compound.
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。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.
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“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 "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.
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。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 substituents do not specify which atom is connected to the substituted group, 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. 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 are H atoms at the connectable site, when the chemical bond is connected, the number of H atoms at the site will be reduced correspondingly with the number of connected chemical bonds and become the corresponding valence. group. 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”本身或者与其他术语联合分别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" by itself or in combination with other terms means, respectively, a linear or branched 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，“C2-4烯基”本身或者与其他术语联合分别用于表示直链或支链的包含至少一个碳-碳双键的由2至4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C2-4烯基包括C2-3、C4、C3和C2烯基等；所述C2-4烯基可以是一价、二价或者多价。C2-4烯基的实例包括但不限于乙烯基、丙烯基、丁烯基、丁间二烯基等。Unless otherwise specified, "C 2-4 alkenyl" by itself or in combination with other terms is used to refer to a linear or branched hydrocarbon radical composed of 2 to 4 carbon atoms containing at least one carbon-carbon double bond. The carbon-carbon double bond can be located anywhere in the group. The C 2-4 alkenyl group includes C 2-3 , C 4 , C 3 and C 2 alkenyl groups, etc.; the C 2-4 alkenyl group can be monovalent, divalent or multivalent. Examples of C 2-4 alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, butadienyl, and the like.
除非另有规定，“C2-4炔基”本身或者与其他术语联合分别用于表示直链或支链的包含至少一个碳-碳三键的由2至4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C2-4炔基包括C2-3、C4、C3和C2炔基等。其可以是一价、二价或者多价。C2-4炔基的实例包括但不限于乙炔基、丙炔基、丁炔基等。Unless otherwise specified, "C 2-4 alkynyl" by itself or in combination with other terms is used to represent a straight-chain or branched hydrocarbon group consisting of 2 to 4 carbon atoms containing at least one carbon-carbon triple bond. Group, the carbon-carbon triple bond can be located at any position of the group. The C 2-4 alkynyl group includes C 2-3 , C 4 , C 3 and C 2 alkynyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of C 2-4 alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, and the like.
除非另有规定，术语“C1-3烷氧基”本身或者与其他术语联合分别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" by itself or in combination with other terms 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”本身或者与其他术语联合分别表示通过氮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烷氨基包括C1-2、C3和C2烷氨基等。其可以是一价、二价或者多价。所述C1-3烷氨基包括-NH-C1-3烷基，例如-NHCH3、-NHCH2CH3、-NHCH2CH2CH3和-NHCH2(CH3)2，还包括二烷基氨基，例如-N(CH3)2和-N(CH3)CH2CH3。Unless otherwise specified, the term "C 1-3 alkylamino" by itself or in combination with other terms respectively means those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through a nitrogen atom. The C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups, etc. It can be monovalent, bivalent or polyvalent. The C 1-3 alkylamino group includes -NH-C 1-3 alkyl group, such as -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 and -NHCH 2 (CH 3 ) 2 , and also includes di Alkylamino, for example -N(CH 3 ) 2 and -N(CH 3 )CH 2 CH 3 .
除非另有规定，“C3-6环烷基”本身或者与另一术语联合分别表示由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 respectively means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic ring 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，“C4-6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单环碳氢基团。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 monocyclic hydrocarbon group consisting of 4 to 6 carbon atoms containing at least one carbon-carbon double bond. group. 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“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和单环基团，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，碳原子任选地被氧代(即C(O))，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)。此外，就该“4-6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4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。其可以是一价、二价或者多价。4-6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-噻嗪基或六氢哒嗪基等。Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms means a saturated monocyclic group consisting of 4 to 6 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, wherein the carbon atoms are optionally oxo (i.e., C(O)), the nitrogen atoms are optionally quaternized, and nitrogen and thia Atoms may optionally be oxidized (i.e. NO and S(O) p , p is 1 or 2). Furthermore, in the case of the "4-6 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 4-6-membered heterocycloalkyl group includes 5-6-membered, 4-membered, 5-membered and 6-membered heterocycloalkyl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl ( 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 or hexahydropyridazinyl, etc.
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)。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。其可以是一价、二价或者多价。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 monocyclic 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). In addition, in the case of the "5- to 6-membered heterocycloalkenyl group", a heteroatom may occupy the attachment position of the heterocycloalkenyl group to the rest of the molecule. The 5-6 membered heterocyclic alkenyl group includes 5-membered and 6-membered heterocyclic alkenyl groups. It can be monovalent, bivalent or polyvalent. Examples of 5-6 membered heterocyclenyl groups include, but are not limited to
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，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。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。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)。5-10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5-10元杂芳基包括8-10元、5-8元、5-7元、5-6元、5元和6元杂芳基等。其可以是一价、二价或者多价。所述5-10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)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、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、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。Unless otherwise specified, the terms "5-10 membered heteroaromatic ring" and "5-10 membered heteroaryl" in the present invention can be used interchangeably. The term "5-10 membered heteroaryl" means a ring consisting of 5 to 10 rings. A cyclic group composed of atoms with a conjugated π electron system, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. It can be a monocyclic, fused bicyclic or fused tricyclic system, in which each ring is aromatic. 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- to 10-membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-10-membered heteroaryl group includes 8-10-membered, 5-8-membered, 5-7-membered, 5-6-membered, 5-membered and 6-membered heteroaryl groups, etc. It can be monovalent, bivalent or polyvalent. Examples of the 5-10 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, pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.), benzothiazolyl (including 5-benzothiazolyl, etc.) , Purine group, benzimidazolyl group (including 2-benzimidazolyl group, etc.), benzoxazolyl group, indolyl group (including 5-indolyl group, etc.), isoquinolyl group (including 1-isoquinolyl group) and 5-isoquinolinyl, etc.), quinoxalinyl (including 2-quinoxalinyl and 5-quinoxalinyl, etc.) or quinolinyl (including 3-quinolinyl, 6-quinolinyl, etc.) .
除非另有规定，本发明术语“双环的8-10元杂芳基”表示由8至10个环原子组成的具有共轭π电子体系的双环基团，其各个环均为芳香性的。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)。所述双环的8-10元杂芳基可通过杂原子或碳原子连接到分子的其余部分。其可以是一价、二价或者多价。所述 双环的8-10元杂芳基的实例包括但不限于苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。Unless otherwise specified, the term "bicyclic 8-10 membered heteroaryl" in the present invention refers to a bicyclic group composed of 8 to 10 ring atoms with a conjugated π electron system, and each of its rings is aromatic. 1, 2, 3 or 4 of its ring atoms are heteroatoms independently selected from O, S and N, and the remainder 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). The bicyclic 8-10 membered heteroaryl group may be attached to the remainder of the molecule through a heteroatom or a carbon atom. It can be monovalent, bivalent or polyvalent. described Examples of bicyclic 8-10 membered heteroaryl groups include, but are not limited to, benzothiazolyl (including 5-benzothiazolyl, etc.), purinyl, benzimidazolyl (including 2-benzimidazolyl, etc.), benzo Oxazolyl group, indolyl group (including 5-indolyl group, etc.), isoquinolyl group (including 1-isoquinolyl group and 5-isoquinolyl group, etc.), quinoxalinyl group (including 2-quinoxaline group) base and 5-quinoxalinyl, etc.) or quinolyl (including 3-quinolinyl, 6-quinolinyl, etc.).
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。其可以是一价、二价或者多价。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)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、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. It can be monovalent, bivalent or polyvalent. 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.).
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”也称为N原子保护基团，是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：酰基，例如链烷酰基(如甲酰基、乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)、烯丙氧羰基(Alloc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、对甲氧基苄基(PMB)、3,4-二甲氧苄基(DMB)、三苯甲基(Trt)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)；磺酰基，如对甲苯磺酰基(Tos)、邻硝基苯磺酰基(Nos)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)、对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group", also known as N atom protecting group, refers to a protecting group suitable for preventing side reactions at the nitrogen position of the amino group. Representative amino protecting groups include, but are not limited to: acyl, such as alkanoyl (such as formyl, acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) , Allyloxycarbonyl (Alloc); Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMB), trityl (Trt), 1,1-bis-(4'-methoxyphenyl)methyl; silyl group, such as Trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); sulfonyl groups, such as p-toluenesulfonyl (Tos), o-nitrobenzenesulfonyl (Nos), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
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 D8venture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 D8venture 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：Picture description:
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.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 9. Mouse body weight change curve in the human large cell lung cancer LU99 subcutaneous xenograft tumor model.
图10.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 10. 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。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.
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～H的结合模式见附图1～8。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 H are shown in Figures 1 to 8.
[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：本发明系列化合物与PRMT5·MTA复合物有较好的结合作用。化合物中的胺基与Glu435和Glu444形成2个氢键相互作用，酰胺羰基与Phe580的主链NH形成氢键相互作用，取代吡啶环的氮原子可以与Gln309侧链NH形成氢键，且取代吡啶可以提供疏水相互作用；其中，化合物A的喹啉环以及化合物B、C、D、E、F、G、H的三并环位于Phe327和Trp579中间形成pi-pi相互作用，化合物C、D、E中三并环上的非喹啉杂原子可以与Lys333侧链形成氢键，化合物F、G、H中三并环结构中的①号氮原子可以与Lys333侧链形成氢键。Conclusion: The series of compounds of the present invention have a good binding effect with the PRMT5·MTA complex. The amine group in the compound forms two hydrogen bond interactions with Glu435 and Glu444. The amide carbonyl group forms a hydrogen bond interaction with the main chain NH of Phe580. The nitrogen atom of the substituted pyridine ring can form a hydrogen bond with the side chain NH of Gln309 and replaces the pyridine. It can provide hydrophobic interactions; among them, the quinoline ring of compound A and the tricyclic rings of compounds B, C, D, E, F, G, and H are located between Phe327 and Trp579 to form pi-pi interactions, and compounds C, D, The non-quinoline heteroatom on the tricyclic ring in E can form a hydrogen bond with the Lys333 side chain, and the ① nitrogen atom in the tricyclic structure of compounds F, G, and H can form a hydrogen bond with the Lys333 side chain.
参考例1中间体A的合成

Reference Example 1 Synthesis of Intermediate A

第一步first step
向化合物A-1(10g,53.76mmol)和三甲基乙炔基硅(10.56g,107.52mmol)的四氢呋喃(100mL)溶液中加入三乙胺(9.79g,96.77mmol)，二氯双(三苯基膦)钯(II)(754.71mg,1.08mmol)，碘化亚铜(409.56mg,2.15mmol)，混合物在80℃下搅拌19小时。混合物减压浓缩得到粗品。粗品经柱层析纯化(硅胶，石油醚：乙酸乙酯＝50:1)，得到化合物A-2。MS:m/z 204.1[M+H]+。To a solution of compound A-1 (10g, 53.76mmol) and trimethylethynylsilane (10.56g, 107.52mmol) in tetrahydrofuran (100mL), triethylamine (9.79g, 96.77mmol), dichlorobis(triphenyl) were added Phosphine) palladium (II) (754.71 mg, 1.08 mmol), copper iodide (409.56 mg, 2.15 mmol), and the mixture was stirred at 80°C for 19 hours. The mixture was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50:1) to obtain compound A-2. MS: m/z 204.1[M+H] + .
第二步Step 2
0℃下，向化合物A-3(2g,26.63mmol)的N,N-二甲基乙酰胺(40mL)溶液中缓慢加入钠氢(1.17g,29.29mmol,60％纯度)，混合物在25℃下搅拌3小时，然后0℃下向混合物中缓慢滴加三丁基(碘甲基)锡烷(11.48g,26.63mmol)，加完之后反应液自然升温至25℃继续搅拌18小时。将反应液降温至0℃，缓慢加入饱和氯化铵水溶液(20mL)淬灭，用二氯甲烷(20mL*3)萃取，合并有机相，用水(20mL*3)和饱和氯化钠水溶液(20mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品A-4，直接用于下一步。MS:m/z 380.1[M+H]+。To a solution of compound A-3 (2g, 26.63mmol) in N,N-dimethylacetamide (40mL), sodium hydrogen (1.17g, 29.29mmol, 60% purity) was slowly added at 0°C, and the mixture was heated at 25°C. Stir for 3 hours at 0°C, and then slowly dropwise add tributyl (iodomethyl)stannane (11.48g, 26.63mmol) into the mixture at 0°C. After the addition, the reaction solution is naturally heated to 25°C and stirred for 18 hours. Cool the reaction solution to 0°C, slowly add saturated aqueous ammonium chloride solution (20mL) to quench, extract with dichloromethane (20mL*3), combine the organic phases, add water (20mL*3) and saturated aqueous sodium chloride solution (20mL *3) Wash, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product A-4, which is directly used in the next step. MS: m/z 380.1[M+H] + .
第三步third step
向化合物A-4(2.26g,11.11mmol)和4A分子筛(29.12g)的二氯甲烷(50mL)混合体系中加入化合物A-2(4.2g,11.11mmol)，混合物在25℃下搅拌20小时。反应液过滤，滤液减压浓缩得到粗品A-5，直接用于下一步。MS:m/z 565.2[M+H]+。Compound A-2 (4.2g, 11.11mmol) was added to a mixed system of compound A-4 (2.26g, 11.11mmol) and 4A molecular sieve (29.12g) in dichloromethane (50mL), and the mixture was stirred at 25°C for 20 hours. . The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain crude product A-5, which was directly used in the next step. MS: m/z 565.2[M+H] + .
第四步the fourth step
向(S,S)-2,2-异丙亚基双(4-苯基-2-噁唑啉)(350.15mg,1.05mmol)，(R,R)-2,2-异丙亚基双(4-苯基-2-噁唑啉)(350.15mg,1.05mmol)的六氟异丙醇(10mL)溶液中加入三氟甲磺酸铜(757.41mg,2.09mmol)，混合物在25℃下搅拌2小时，然后将该混合物加到化合物A-5(5.9g,10.47mmol)的六氟异丙醇(30mL)溶液中，混合物在25℃下继续搅拌19小时。向反应混合物中加入氨水/饱和氯化钠水溶液(v/v＝1:1,20mL)，搅拌1小时，然后向混合物中加入二氯甲烷(15mL)和饱和氯化钠水溶液(15mL)，分液，水相用二氯甲烷(20mL*3)萃取，合并有机相，用无水硫酸钠干燥，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:Welch Ultimate XB-SiOH 250*70*10μm；流动相:[A相：正庚烷；B相：乙醇(0.1％氨水)]；梯度：B％:1％-15％)，得到中间体化合物A。MS:m/z 275.1[M+H]+。To (S,S)-2,2-isopropylidene bis(4-phenyl-2-oxazoline) (350.15mg, 1.05mmol), (R,R)-2,2-isopropylidene Copper triflate (757.41 mg, 2.09 mmol) was added to a solution of bis(4-phenyl-2-oxazoline) (350.15 mg, 1.05 mmol) in hexafluoroisopropanol (10 mL), and the mixture was heated at 25°C. The mixture was stirred at 25°C for 2 hours, and then the mixture was added to a solution of compound A-5 (5.9g, 10.47mmol) in hexafluoroisopropanol (30mL), and the mixture was continued to stir at 25°C for 19 hours. Add ammonia/saturated sodium chloride aqueous solution (v/v=1:1, 20mL) to the reaction mixture, stir for 1 hour, then add methylene chloride (15mL) and saturated sodium chloride aqueous solution (15mL) to the mixture, and divide liquid, the aqueous phase was extracted with dichloromethane (20mL*3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative high performance liquid phase separation (chromatographic column: Welch Ultimate XB-SiOH 250*70*10μm; mobile phase: [Phase A: n-heptane; Phase B: ethanol (0.1% ammonia)]; gradient: B% :1%-15%) to obtain intermediate compound A. MS: m/z 275.1[M+H] + .
参考例2中间体B的合成
Reference Example 2 Synthesis of Intermediate B
第一步first step
0℃下，向化合物B-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，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B-2。MS:m/z 248.0/250.0[M+H]+。To a solution of compound B-1 (20g, 118.24mmol) in acetonitrile (200mL) at 0°C, N-bromosuccinimide (21.04g, 118.24 mmol), 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 aqueous sodium chloride solution (50mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure . The crude product was subjected to column chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain compound B-2. MS: m/z 248.0/250.0[M+H] + .
第二步Step 2
0℃下，向化合物B-2(5.00g,20.16mmol)和化合物B-3(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)，得到中间体化合物B。MS:m/z 296.2[M+H]+。At 0°C, potassium acetate (5.93g, 60.47mmol) was added to a solution of compound B-2 (5.00g, 20.16mmol) and compound B-3 (6.14g, 24.19mmol) in dioxane (50mL), 1 , 1-bis(diphenylphosphine)ferrocene palladium chloride (737.47 mg, 1.01 mmol), the mixture was stirred at 100°C for 20 hours. The mixture was filtered, 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 intermediate compound B. MS: m/z 296.2[M+H] + .
参考例3中间体C的合成
Reference Example 3 Synthesis of Intermediate C
第一步first step
0℃下，向化合物C-1(2g,26.63mmol)和三乙胺(5.39g,53.26mmol)的二氯甲烷(10mL)溶液中缓慢滴加三苯基甲基氯(7.42g,26.63mmol)的二氯甲烷(10mL)溶液，滴加完毕后混合物自然升至室温25℃下搅拌17小时。向反应液中加入水(20mL)，分液，水相用二氯甲烷(20mL*3)萃取，合并有机相，用饱和氯化钠水溶液(20mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品通过柱层析(硅胶，石油醚：乙酸乙酯＝10：1到石油醚：乙酸乙酯＝5：1)纯化，得到化合物C-2。1H NMR(400MHz,CDCl3)δ＝7.47(d,J＝7.4Hz,6H),7.31-7.26(m,6H),7.23-7.18(m,3H),3.87-3.77(m,1H),2.88-2.70(m,1H),2.20-2.16(m,2H),2.05(s,1H),1.12(d,J＝6.2Hz,3H)。To a solution of compound C-1 (2g, 26.63mmol) and triethylamine (5.39g, 53.26mmol) in dichloromethane (10mL) at 0°C, triphenylmethyl chloride (7.42g, 26.63mmol) was slowly added dropwise ) in dichloromethane (10 mL). After the dropwise addition, the mixture naturally rose to room temperature and was stirred at 25°C for 17 hours. Add water (20mL) to the reaction solution, separate the layers, extract the aqueous phase with dichloromethane (20mL*3), combine the organic phases, wash with saturated sodium chloride aqueous solution (20mL*3), dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to petroleum ether: ethyl acetate = 5:1) to obtain compound C-2. 1 H NMR (400MHz, CDCl 3 ) δ = 7.47 (d, J = 7.4Hz, 6H), 7.31-7.26 (m, 6H), 7.23-7.18 (m, 3H), 3.87-3.77 (m, 1H), 2.88-2.70(m,1H),2.20-2.16(m,2H),2.05(s,1H),1.12(d,J＝6.2Hz,3H).
第二步Step 2
0℃下，向钠氢(378.01mg,9.45mmol,60％纯度)的N,N-二甲基乙酰胺(10mL)悬浮液中加入化合物C-2(2g,6.30mmol)的N,N-二甲基乙酰胺(10mL)溶液，反应液自然升至室温25℃搅拌1小时，然后0℃下，向反应液中缓慢滴加化合物C-3(三丁基(碘甲基)锡烷，2.72g,6.30mmol)，反应液自然升至室温25℃搅拌19小时。0℃下，向反应液中缓慢加入饱和氯化铵水溶液(10mL)淬灭，水相用乙酸乙酯(20mL*3)萃取，合并有机相，用水(20mL*3)和饱和氯化钠水溶液(20mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品通过柱层析(硅胶，石油醚：乙酸乙酯＝10：1到石油醚：乙酸乙酯＝5：1)纯化，得到化合物C-4。1H NMR(400MHz,CDCl3)δ＝7.52-7.45(m,6H),7.35-7.28(m,5H),7.25(s,1H),7.21-7.16(m,3H),3.71(d,J＝9.8Hz,1H),3.46(d,J＝9.8Hz,1H),3.36(br s,1H),2.27-2.21(m,1H),2.19-2.07(m,2H),1.57-1.44(m,6H),1.31-1.23(m,6H),1.15-1.10(m,3H),0.75-0.97(m,15H)。To a suspension of sodium hydrogen (378.01 mg, 9.45 mmol, 60% purity) in N,N-dimethylacetamide (10 mL) was added N,N- of compound C-2 (2 g, 6.30 mmol) at 0°C. Dimethylacetamide (10 mL) solution, the reaction solution was naturally raised to room temperature 25°C and stirred for 1 hour, then compound C-3 (tributyl (iodomethyl) stannane) was slowly added dropwise to the reaction solution at 0°C. 2.72g, 6.30mmol), the reaction solution was naturally raised to room temperature 25°C and stirred for 19 hours. At 0°C, slowly add saturated aqueous ammonium chloride solution (10mL) to the reaction solution to quench, extract the aqueous phase with ethyl acetate (20mL*3), combine the organic phases, add water (20mL*3) and saturated aqueous sodium chloride solution. (20mL*3), washed with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to petroleum ether: ethyl acetate = 5:1) to obtain compound C-4. 1 H NMR (400MHz, CDCl 3 ) δ = 7.52-7.45 (m, 6H), 7.35-7.28 (m, 5H), 7.25 (s, 1H), 7.21-7.16 (m, 3H), 3.71 (d, J ＝9.8Hz,1H),3.46(d,J＝9.8Hz,1H),3.36(br s,1H),2.27-2.21(m,1H),2.19-2.07(m,2H),1.57-1.44(m ,6H),1.31-1.23(m,6H),1.15-1.10(m,3H),0.75-0.97(m,15H).
第三步third step
将化合物C-4(2g,3.22mmo)溶解于二氯甲烷(21mL)，三氟乙醇(6mL)，冰醋酸(3mL)混合溶液中，反应液在室温25℃下搅拌15小时。向反应混合物中加入饱和碳酸钾水溶液调节pH至8左右，分液，水相 用二氯甲烷(20mL*3)萃取，合并有机相，用水(20mL*3)和饱和氯化钠水溶液(20mL*3)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品通过柱层析(硅胶，石油醚：乙酸乙酯＝5：1到二氯甲烷：甲醇＝10：1)纯化。得到化合物C-5。MS:m/z 380.2[M+H]+。1H NMR(400MHz,CDCl3)δ＝3.84(d,J＝9.8Hz,1H),3.55(d,J＝9.8Hz,1H),3.23(dt,J＝3.8,6.8Hz,1H),2.78(dd,J＝3.6,13.2Hz,1H),2.62(dd,J＝7.4,13.0Hz,2H),2.54(br s,1H),1.56-1.47(m,6H),1.34-1.28(m,6H),1.10(d,J＝6.2Hz,3H),0.93-0.88(m,15H)。Compound C-4 (2g, 3.22mmo) was dissolved in a mixed solution of dichloromethane (21mL), trifluoroethanol (6mL), and glacial acetic acid (3mL). The reaction solution was stirred at room temperature 25°C for 15 hours. Add saturated potassium carbonate aqueous solution to the reaction mixture to adjust the pH to about 8, separate the liquids, and separate the aqueous phase. Extract with dichloromethane (20mL*3), combine the organic phases, wash with water (20mL*3) and saturated sodium chloride aqueous solution (20mL*3), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 5:1 to dichloromethane: methanol = 10:1). Compound C-5 was obtained. MS: m/z 380.2[M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ = 3.84 (d, J = 9.8 Hz, 1H), 3.55 (d, J = 9.8 Hz, 1H), 3.23 (dt, J = 3.8, 6.8 Hz, 1H), 2.78 (dd,J＝3.6,13.2Hz,1H),2.62(dd,J＝7.4,13.0Hz,2H),2.54(br s,1H),1.56-1.47(m,6H),1.34-1.28(m, 6H), 1.10 (d, J = 6.2Hz, 3H), 0.93-0.88 (m, 15H).
第四步the fourth step
向化合物C-5(723mg,1.91mmo)和4A分子筛(3.9g)的二氯甲烷(15mL)溶液中加入化合物A-2(388.69mg,1.91mmol)，混合物在室温25℃下搅拌12小时。反应液过滤，滤饼用二氯甲烷(20mL*3)淋洗，滤液减压浓缩。粗品通过柱层析(硅胶，石油醚：乙酸乙酯＝10：1到石油醚：乙酸乙酯＝5：1)纯化。得到化合物C-6。MS:m/z 565.2[M+H]+。To a solution of compound C-5 (723 mg, 1.91 mmol) and 4A molecular sieve (3.9 g) in dichloromethane (15 mL) was added compound A-2 (388.69 mg, 1.91 mmol), and the mixture was stirred at room temperature 25°C for 12 hours. The reaction solution was filtered, the filter cake was rinsed with dichloromethane (20mL*3), and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1 to petroleum ether: ethyl acetate = 5:1). Compound C-6 was obtained. MS: m/z 565.2[M+H] + .
第五步the fifth step
向(S,S)-2,2-异丙亚基双(4-苯基-2-噁唑啉)(54.13mg,161.85μmo)，(R,R)-2,2-异丙亚基双(4-苯基-2-噁唑啉)(54.13mg,161.85μmol)的六氟异丙醇(5mL)溶液中加入三氟甲磺酸铜(117.08mg,323.70μmol)，混合物在室温25℃下搅拌3小时，然后将该混合物加到化合物C-6(912mg,1.62mmol)的六氟异丙醇(5mL)溶液中，混合物在室温25℃下继续搅拌17小时。向反应混合物中加入氨水/饱和氯化钠水溶液(v/v＝1:1,10mL)，混合物搅拌1小时，然后向混合物中加入二氯甲烷(10mL)和饱和氯化钠水溶液(10mL)，分液，水相用二氯甲烷(10mL*3)萃取，合并有机相，用无水硫酸钠干燥，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:Phenomenex luna C18(250*70mm,10μm)；流动相:[水(甲酸)-乙腈]；乙腈％:25％-55％)，得到中间体化合物C。MS:m/z 275.1[M+H]+。To (S,S)-2,2-isopropylidene bis(4-phenyl-2-oxazoline) (54.13mg, 161.85μmo), (R,R)-2,2-isopropylidene Copper triflate (117.08 mg, 323.70 μmol) was added to a solution of bis(4-phenyl-2-oxazoline) (54.13 mg, 161.85 μmol) in hexafluoroisopropanol (5 mL), and the mixture was heated at room temperature 25 The mixture was stirred at 25° C. for 3 hours, and then the mixture was added to a solution of compound C-6 (912 mg, 1.62 mmol) in hexafluoroisopropanol (5 mL), and the mixture was stirred at room temperature at 25° C. for 17 hours. Add ammonia/saturated sodium chloride aqueous solution (v/v=1:1, 10mL) to the reaction mixture, stir the mixture for 1 hour, then add methylene chloride (10mL) and saturated sodium chloride aqueous solution (10mL) to the mixture, Separate the liquids, extract the aqueous phase with dichloromethane (10mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by preparative high-performance liquid phase separation (chromatographic column: Phenomenex luna C18 (250*70mm, 10μm); mobile phase: [water (formic acid)-acetonitrile]; acetonitrile%: 25%-55%) to obtain the intermediate compound C. MS: m/z 275.1[M+H] + .
参考例4中间体D的合成
Reference Example 4 Synthesis of Intermediate D
第一步first step
将化合物D-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D-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，干燥滤饼得到化合物D-3。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 D-2 (800 mg, 4.30 mmol) was added to a mixed solvent of dioxane (16 mL) and water (1.6 mL), and then compound D-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 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 the filter cake was dried to obtain compound D- 3. 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D-3(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。反应液过滤，滤饼干燥得到化合物D-4。MS:m/z 256.9[M+H]+。Compound D-3 (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 filtered, and the filter cake was dried to obtain compound D-4. MS: m/z 256.9[M+H] + .
第三步third step
向化合物D-4(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，滤饼干燥后得到中间体化合物D，直接用于下一步。 Compound D-4 (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 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 intermediate compound D, which was directly used in the next step.
参考例5中间体E的合成
Reference Example 5 Synthesis of Intermediate E
第一步first step
将中间体A-4(983.69mg,5.29mmol)和无水硫酸镁(1.91g,15.87mmol)溶于甲苯(20mL)溶液中，加入化合物A-1(2g,5.29mmol)，反应液在氮气保护下在70℃下搅拌24小时。将反应液冷却至室温，过滤，收集滤液，减压浓缩得到化合物E-1，直接用于下一步。Intermediate A-4 (983.69mg, 5.29mmol) and anhydrous magnesium sulfate (1.91g, 15.87mmol) were dissolved in toluene (20mL) solution, compound A-1 (2g, 5.29mmol) was added, and the reaction solution was heated under nitrogen Stir at 70°C for 24 hours under protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain compound E-1, which was used directly in the next step.
第二步Step 2
将(R,R)-2,2-异丙亚基双(4-苯基-2-噁唑啉)(171.44mg,512.66μmol)和(S,S)-2,2-异丙亚基双(4-苯基-2-噁唑啉)(171.44mg,512.66μmol)溶于六氟异丙醇(6mL)中，加入三氟甲磺酸铜(370.84mg,1.03mmol)，反应液在25℃下搅拌2小时，将反应液加入到中间体E-1(2.8g,5.13mmol)的六氟异丙醇(18mL)溶液中，反应液在氮气保护下在25℃下搅拌60小时。向反应液中加入氨水和饱和氯化钠的混合溶液(1:1,10mL)，搅拌1小时，然后再向其中加入二氯甲烷(30mL)和饱和氯化钠水溶液(30mL)，分液，水相用二氯甲烷萃取(30mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经柱层析纯化(硅胶，0～60％乙酸乙酯/石油醚)得到中间体化合物E。MS:m/z 256.9/259.0[M+H]+。Combine (R,R)-2,2-isopropylidene bis(4-phenyl-2-oxazoline) (171.44mg, 512.66μmol) and (S,S)-2,2-isopropylidene Bis(4-phenyl-2-oxazoline) (171.44 mg, 512.66 μmol) was dissolved in hexafluoroisopropanol (6 mL), copper trifluoromethanesulfonate (370.84 mg, 1.03 mmol) was added, and the reaction solution was Stir at 25°C for 2 hours, add the reaction solution to a solution of intermediate E-1 (2.8g, 5.13mmol) in hexafluoroisopropanol (18mL), and stir the reaction solution at 25°C for 60 hours under nitrogen protection. Add a mixed solution of ammonia water and saturated sodium chloride (1:1, 10mL) to the reaction solution, stir for 1 hour, then add methylene chloride (30mL) and saturated sodium chloride aqueous solution (30mL), and separate the layers. The aqueous phase was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel, 0-60% ethyl acetate/petroleum ether) to obtain intermediate compound E. MS: m/z 256.9/259.0[M+H] + .
实施例1
Example 1
第一步first step
0-5℃下，向化合物1-1(1g,8.19mmol)的水(15mL)溶液中缓慢加入溴化氢(24.84g,122.82mmol,40％的水溶液)和亚硝酸钠(847.47mg,12.28mmol)的水(15mL)溶液，然后向混合液中加入溴化亚铜(1.88g,13.10mmol)，加完之后反应液继续在0-5℃下搅拌3小时，而后自然升温至25℃继续搅拌18小时。反应液降温至0-5℃，向反应液中加入冰水(60mL)并在0-5℃下搅拌1小时，而后反应液过滤，滤饼用冰水(50mL)洗涤，滤液用二氯甲烷(50mL*3)萃取，合并有机相，用饱和氯化钠水溶液(30mL*3)洗涤，有机相和滤饼合并一起减压浓缩得到化合物1-2，直接用于下一步。MS:m/z 186.0/187.9[M+H]+。To a solution of compound 1-1 (1g, 8.19mmol) in water (15mL) at 0-5°C, hydrogen bromide (24.84g, 122.82mmol, 40% aqueous solution) and sodium nitrite (847.47mg, 12.28 mmol) in water (15 mL), and then add copper bromide (1.88 g, 13.10 mmol) to the mixed solution. After the addition, the reaction solution continues to stir at 0-5°C for 3 hours, and then naturally warms to 25°C to continue. Stir for 18 hours. The reaction solution was cooled to 0-5°C, ice water (60 mL) was added to the reaction solution and stirred at 0-5°C for 1 hour. The reaction solution was then filtered, the filter cake was washed with ice water (50 mL), and the filtrate was washed with dichloromethane. (50mL*3) extraction, combine the organic phases, wash with saturated aqueous sodium chloride solution (30mL*3), combine the organic phases and filter cake and concentrate under reduced pressure to obtain compound 1-2, which is directly used in the next step. MS: m/z 186.0/187.9[M+H] + .
第二步 Step 2
向化合物1-2(1g,5.38mmol)和中间体B(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1-3。MS:m/z 275.0[M+H]+。To a solution of compound 1-2 (1g, 5.38mmol) and intermediate B (1.59g, 5.38mmol) in dioxane (16mL) and water (4mL) was added potassium phosphate (667.55mg, 4.83mmol) and dichloride Bis[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, 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 1-3. MS: m/z 275.0[M+H] + .
第三步third step
向化合物1-3(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，滤饼减压干燥得到化合物1-4。MS:m/z261.0[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 1-3 (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 dry the filter cake under reduced pressure to obtain compound 1-4. MS:m/z261.0[M+H] + . 1 H 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) ).
第四步the fourth step
向化合物1-4(60mg,230.57μmol)和中间体A(63.28mg,230.57μmol)的二氯甲烷(30mL)溶液中加入三乙胺(23.33mg,230.57μmol)，然后加入2-氯-1-甲基吡啶(盐)碘化物(70.69mg,276.69μmol)，混合物在45℃下搅拌4小时。反应混合液加水(20mL)洗涤，收集有机相减压浓缩得到粗品化合物1-5，直接用于下一步。MS:m/z 517.2[M+H]+。To a solution of compound 1-4 (60 mg, 230.57 μmol) and intermediate A (63.28 mg, 230.57 μmol) in dichloromethane (30 mL) was added triethylamine (23.33 mg, 230.57 μmol), followed by 2-chloro-1 -Picoline (salt) iodide (70.69 mg, 276.69 μmol), the mixture was stirred at 45°C for 4 hours. The reaction mixture was washed with water (20 mL), and the organic phase was collected and concentrated under reduced pressure to obtain crude compound 1-5, which was used directly in the next step. MS: m/z 517.2[M+H] + .
第五步the fifth step
将化合物1-5(76mg,147.10μmo)溶解于甲醇(5mL)溶液中，加入碳酸钾(30.50mg,220.66μmol)，混合物在25℃下搅拌4小时。反应混合物减压浓缩，粗品经制备型高效液相分离纯化(色谱柱:UniSil 3-100C18UItra(150*25mm*3μm)；流动相:[水(0.255％甲酸)-乙腈]；梯度：(乙腈％):21％-41％)得到化合物1。Compound 1-5 (76 mg, 147.10 μmol) was dissolved in methanol (5 mL) solution, potassium carbonate (30.50 mg, 220.66 μmol) was added, and the mixture was stirred at 25°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was purified by preparative high-performance liquid phase separation (chromatographic column: UniSil 3-100C18UItra (150*25mm*3μm); mobile phase: [water (0.255% formic acid)-acetonitrile]; gradient: (acetonitrile% ):21%-41%) to obtain compound 1.
第六步Step 6
化合物1经SFC分离纯化(分离条件，色谱柱:DAICEL CHIRALCEL OX(250mm*30mm,10μm)；流动相:A相：二氧化碳，B相：乙腈/乙醇/含1％氨水的乙醇(体积比为60％:30％:10％)；梯度：B％:45％-45％)，得到化合物1a和化合物1b的粗品，再分别经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150*25mm*5μm；流动相:[0.05％氨水-乙腈]；梯度：(乙腈％):26％-56％)，得到化合物1a和化合物1b。Compound 1 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALCEL OX (250mm*30mm, 10μm); mobile phase: phase A: carbon dioxide, phase B: acetonitrile/ethanol/ethanol containing 1% ammonia (volume ratio is 60 %:30%:10%); gradient: B%:45%-45%), the crude products of compound 1a and compound 1b were obtained, and then were purified by preparative high-performance liquid phase separation (chromatographic column: Waters Xbridge 150*25mm* 5 μm; mobile phase: [0.05% ammonia water-acetonitrile]; gradient: (acetonitrile%): 26%-56%) to obtain compound 1a and compound 1b.
化合物1a：SFC检测条件：色谱柱:Chiralcel OX-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％，保留时间为1.391min，ee＝89.11％。MS:m/z 445.2[M+H]+。1H NMR(400MHz,CD3OD)δppm 8.69(s,1H),8.49(br s,1H),8.26(s,1H),7.88(br d,J＝8.08Hz,1H),7.65(br d,J＝7.34Hz,1H),7.50-7.39(m,1H),6.15–5.44(m,1H),5.36(br s,1H),4.45(s,3H),3.99-3.74(m,4H),3.72(br s,1H),0.89(br d,J＝7.22Hz,3H)。Compound 1a: SFC detection conditions: Chromatographic column: Chiralcel OX-3 50×4.6mm ID, 3μm; Mobile phase: Phase A: carbon dioxide, Phase B: ethanol (0.05% diethylamine); Gradient: B%: 40%, The retention time is 1.391min, ee=89.11%. MS: m/z 445.2[M+H] + . 1 H NMR (400MHz, CD 3 OD) δppm 8.69 (s, 1H), 8.49 (br s, 1H), 8.26 (s, 1H), 7.88 (br d, J = 8.08Hz, 1H), 7.65 (br d ,J＝7.34Hz,1H),7.50-7.39(m,1H),6.15–5.44(m,1H),5.36(br s,1H),4.45(s,3H),3.99-3.74(m,4H) ,3.72(br s,1H),0.89(br d,J＝7.22Hz,3H).
化合物1b：SFC检测条件：色谱柱:Chiralcel OX-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％，保留时间为1.760min，ee＝95.09％。MS:m/z 445.2[M+H]+。1H NMR(400MHz,CD3OD)δppm 8.68(s,1H),8.49(br s,1H),8.25(s,1H),7.87(br d,J＝7.84Hz,1H),7.64(br d,J＝7.46Hz,1H),7.42(br d,J＝11.26Hz,1H),6.20–5.43(m,1H),5.35(s,1H),4.44(s,3H),4.00–3.74(m,4H),3.69(br s,1H),0.88(br d,J＝6.98Hz,3H)。Compound 1b: SFC detection conditions: Chromatographic column: Chiralcel OX-3 50×4.6mm ID, 3μm; Mobile phase: Phase A: carbon dioxide, Phase B: ethanol (0.05% diethylamine); Gradient: B%: 40%, The retention time is 1.760min, ee=95.09%. MS: m/z 445.2[M+H] + . 1 H NMR (400MHz, CD 3 OD) δppm 8.68 (s, 1H), 8.49 (br s, 1H), 8.25 (s, 1H), 7.87 (br d, J＝7.84Hz, 1H), 7.64 (br d ,J＝7.46Hz,1H),7.42(br d,J＝11.26Hz,1H),6.20–5.43(m,1H),5.35(s,1H),4.44(s,3H),4.00–3.74(m ,4H),3.69(br s,1H),0.88(br d,J＝6.98Hz,3H).
实施例2
Example 2
第一步first step
向化合物1-4(30mg,115.29μmol)的N,N-二甲基甲酰胺(5mL)溶液中加入O-(7-氮杂苯并三氮唑-1-YL)-N,N,N,N-四甲基脲六氟膦盐(87.67mg,230.57μmol)和N,N-二异丙基乙胺(29.80mg,230.57μmol)，混合物在室温25℃下搅拌1小时，然后向其中加入中间体C(31.64mg,115.29μmol)，混合物继续在油浴50℃下搅拌21小时。向混合物中加入水(10mL)，然后用乙酸乙酯(10mL*3)萃取，合并有机相，用无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物2-1粗品。MS:m/z 517.2[M+H]+。To a solution of compound 1-4 (30 mg, 115.29 μmol) in N,N-dimethylformamide (5 mL) was added O-(7-azabenzotriazole-1-YL)-N,N,N , N-tetramethylurea hexafluorophosphonium salt (87.67mg, 230.57μmol) and N,N-diisopropylethylamine (29.80mg, 230.57μmol), the mixture was stirred at room temperature 25°C for 1 hour, and then added Intermediate C (31.64 mg, 115.29 μmol) was added, and the mixture continued to stir in an oil bath at 50°C for 21 hours. Water (10 mL) was added to the mixture, and then extracted with ethyl acetate (10 mL*3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 2-1. MS: m/z 517.2[M+H] + .
第二步Step 2
将中间体2-1(50mg,粗品)溶解于甲醇(2mL)溶液中，加入碳酸钾(26.75mg,193.56μmol)，混合物在室温25℃下搅拌1小时。反应混合物过滤，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×5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度(乙腈)％:30％-60％)，得到化合物2。第三步Intermediate 2-1 (50 mg, crude product) was dissolved in methanol (2 mL) solution, potassium carbonate (26.75 mg, 193.56 μmol) was added, and the mixture was stirred at room temperature 25°C for 1 hour. The reaction 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 Compound 2. third step
化合物2经SFC分离纯化(分离条件，色谱柱:REGIS(S,S)WHELK-O1(250mm×25mm,10μm)；流动相:[A相：二氧化碳，B相：25％乙腈+75％异丙醇，混合后再加0.1％氨水]；梯度(B％):60％-60％)，得到化合物2a和化合物2b。Compound 2 was separated and purified by SFC (separation conditions, chromatographic column: REGIS (S, S) WHELK-O1 (250 mm × 25 mm, 10 μm); mobile phase: [Phase A: carbon dioxide, phase B: 25% acetonitrile + 75% isopropyl alcohol, mix and then add 0.1% ammonia]; gradient (B%): 60%-60%) to obtain compound 2a and compound 2b.
化合物2a：SFC检测条件：色谱柱:(S.S)Whelk-O1 50×4.6mm I.D.,3.5μm；流动相:A相:二氧化碳,B相:[66.67％(异丙醇-0.05％二乙胺)+33.33％(乙腈-0.05％二乙胺)]；梯度(B％):50％)，保留时间为0.849min，ee＝100％。MS:m/z 445.1[M+H]+。1H NMR(400MHz,CD3OD)δ＝8.67(s,1H),8.41(s,2H),7.88(br d,J＝3.8Hz,1H),7.62-7.48(m,2H),5.46(br s,1H),4.40(br s,3H),4.27(br d,J＝4.0Hz,3H),4.09(br s,2H),3.78(s,1H),1.35-1.27(m,3H)。Compound 2a: SFC detection conditions: Chromatographic column: (SS) Whelk-O1 50×4.6mm ID, 3.5μm; mobile phase: Phase A: carbon dioxide, phase B: [66.67% (isopropyl alcohol-0.05% diethylamine) +33.33% (acetonitrile-0.05% diethylamine)]; gradient (B%): 50%), retention time is 0.849min, ee=100%. MS:m/z 445.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ = 8.67 (s, 1H), 8.41 (s, 2H), 7.88 (br d, J = 3.8Hz, 1H), 7.62-7.48 (m, 2H), 5.46 ( br s,1H),4.40(br s,3H),4.27(br d,J＝4.0Hz,3H),4.09(br s,2H),3.78(s,1H),1.35-1.27(m,3H) .
化合物2b：SFC检测条件：色谱柱:(S.S)Whelk-O1 50×4.6mm I.D.,3.5μm；流动相:A相:二氧化碳,B相:[66.67％(异丙醇-0.05％二乙胺)+33.33％(乙腈-0.05％二乙胺)]；梯度:(B％):50％，保留时间为1.487min，ee＝97.12％。MS:m/z 445.1[M+H]+。1H NMR(400MHz,CD3OD)δ＝8.66(s,1H),8.44(s,2H),7.88(br d,J＝5.8Hz,1H),7.66-7.47(m,2H),5.45(br s,1H),4.41(br s,3H),4.27(br d,J＝3.8Hz,3H),4.09(br s,2H),3.78(s,1H),1.33-1.27(m,3H)。Compound 2b: SFC detection conditions: Chromatographic column: (SS) Whelk-O1 50×4.6mm ID, 3.5μm; mobile phase: Phase A: carbon dioxide, phase B: [66.67% (isopropanol-0.05% diethylamine) +33.33% (acetonitrile-0.05% diethylamine)]; gradient: (B%): 50%, retention time is 1.487min, ee=97.12%. MS:m/z 445.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δ = 8.66 (s, 1H), 8.44 (s, 2H), 7.88 (br d, J = 5.8Hz, 1H), 7.66-7.47 (m, 2H), 5.45 ( br s,1H),4.41(br s,3H),4.27(br d,J＝3.8Hz,3H),4.09(br s,2H),3.78(s,1H),1.33-1.27(m,3H) .
实施例3
Example 3
第一步first step
向化合物D(125mg,516.03μmol)和化合物A(141.62mg,516.03μmo)的二氯甲烷(30mL)溶液中，加入三乙胺(52.22mg,516.03μmol)和2-氯-1-甲基吡啶(盐)碘化物(158.20mg,619.24μmol)，升温至45℃反应4小时。反应液经水洗涤(15mL*3)，过滤，浓缩有机层，得到粗品。粗品经制备型高效液相分离纯化(色谱柱:Waters Xbridge 150*25mm*5μm；流动相:[水(10mM碳酸氢铵)-乙腈]；梯度(乙腈)％:24％-54％)得到化合物3。To a solution of compound D (125 mg, 516.03 μmol) and compound A (141.62 mg, 516.03 μmol) in dichloromethane (30 mL), triethylamine (52.22 mg, 516.03 μmol) and 2-chloro-1-methylpyridine were added (Salt) Iodide (158.20 mg, 619.24 μmol), heated to 45°C and reacted for 4 hours. The reaction solution was washed with water (15mL*3), filtered, and the organic layer was concentrated to obtain crude product. The crude product was purified by preparative high-performance liquid phase separation (chromatographic column: Waters Xbridge 150*25mm*5μm; mobile phase: [water (10mM ammonium bicarbonate)-acetonitrile]; gradient (acetonitrile)%: 24%-54%) to obtain the compound 3.
第二步Step 2
化合物3经SFC分离纯化(分离条件，色谱柱:DAICEL CHIRALPAK AD 250×30mm,10μm；流动相:[A相：二氧化碳，B相：乙醇(0.1％氨水v/v)]；B％:50％)，得到化合物3a和化合物3b。Compound 3 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALPAK AD 250×30mm, 10μm; mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia v/v)]; B%: 50% ) to obtain compound 3a and compound 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:二氧化碳,B相:乙醇(0.05％二乙胺)；梯度(B％):40％，保留时间为0.884min，ee＝98.3％。MS:m/z 427.1[M+H]+。Compound 3a: SFC detection conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: carbon dioxide, phase B: ethanol (0.05% diethylamine); gradient (B%): 40% , retention time is 0.884min, ee=98.3%. MS: m/z 427.1[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:二氧化碳,B相:乙醇(0.05％二乙胺)；梯度:40％乙醇(0.05％二乙胺)，流速:3mL/min，保留时间为1.636min，ee＝99.0％。MS:m/z427.1[M+H]+。Compound 3b: SFC detection conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: carbon dioxide, phase B: ethanol (0.05% diethylamine); gradient: 40% ethanol (0.05% Diethylamine), flow rate: 3mL/min, retention time: 1.636min, ee=99.0%. MS:m/z427.1[M+H] + .
实施例4
Example 4
第一步first step
将中间体E(100mg,388.91μmol)和化合物4-1(98.14mg,1.17mmol)溶于三乙胺(2mL)中，加入二氯双(三苯基膦)钯(II)(54.60mg,77.78μmol)和碘化亚酮(14.81mg,77.78μmol)，反应液在氮气保护下在75℃下搅拌3小时。向反应液中加入乙酸乙酯(10mL)稀释，过滤，滤饼用乙酸乙酯(10mL×2)淋洗，收集滤液，用水(10mL×2)洗，饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经柱层析纯化(硅胶，0～10％甲醇/二氯甲烷)。得到化合物4-2。MS:m/z 260.9[M+H]+。Intermediate E (100 mg, 388.91 μmol) and compound 4-1 (98.14 mg, 1.17 mmol) were dissolved in triethylamine (2 mL), and dichlorobis(triphenylphosphine)palladium (II) (54.60 mg) was added. 77.78 μmol) and ketone iodide (14.81 mg, 77.78 μmol). The reaction solution was stirred at 75°C for 3 hours under nitrogen protection. Add ethyl acetate (10 mL) to the reaction solution to dilute, filter, and rinse the filter cake with ethyl acetate (10 mL × 2). Collect the filtrate, wash with water (10 mL × 2), wash with saturated brine (10 mL), and anhydrous. Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel, 0-10% methanol/dichloromethane). Compound 4-2 was obtained. MS: m/z 260.9[M+H] + .
第二步Step 2
将化合物4-2(40mg,153.65μmol)和化合物1-4(39.98mg,153.65μmol)溶于二氯甲烷(3mL)中，加入三乙胺(15.55mg,153.65μmol)和2-氯-1-甲基吡啶(盐)碘化物(47.11mg,184.38μmol)，反应液在氮气保护下在45℃下搅拌4小时。向反应液中加入水(10mL)，用二氯甲烷(10mL×3)萃取，合并有机相，用水(10mL) 洗，饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经柱层析纯化(硅胶，0～10％甲醇/二氯甲烷)。得到化合物4。MS:m/z 503.1[M+H]+。Compound 4-2 (40 mg, 153.65 μmol) and compound 1-4 (39.98 mg, 153.65 μmol) were dissolved in dichloromethane (3 mL), and triethylamine (15.55 mg, 153.65 μmol) and 2-chloro-1 were added. -Picoline (salt) iodide (47.11 mg, 184.38 μmol), the reaction solution was stirred at 45°C for 4 hours under nitrogen protection. Add water (10 mL) to the reaction solution, extract with dichloromethane (10 mL × 3), combine the organic phases, and add water (10 mL) Wash with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel, 0-10% methanol/dichloromethane). Compound 4 was obtained. MS: m/z 503.1[M+H] + .
第三步third step
化合物4经SFC分离纯化(分离条件，色谱柱:DAICEL CHIRALPAK AD(250mm×30mm,10μm)；流动相:[A相：二氧化碳，B相：乙醇(0.1％氨水v/v)]；B％:50％)，得到化合物4a和化合物4b。Compound 4 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALPAK AD (250mm×30mm, 10μm); mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia v/v)]; B%: 50%) to obtain compound 4a and compound 4b.
化合物4a：SFC检测条件：色谱柱:Chiralpak AD-3 150×4.6mm 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％，保留时间为3.396min，ee＝100.00％。MS:m/z 503.0[M+H]+。1H NMR(400MHz,CD3OD)δppm 8.61(s,1H)8.44(br s,1H)8.21(s,1H)7.80(br d,J＝8.13Hz,1H)7.62(br d,J＝8.50Hz,1H)7.38(br d,J＝11.51Hz,1H)4.90(br s,1H)4.79-4.86(m,2H)4.44(s,3H)3.78-3.96(m,2H)3.74(br s,1H)1.58(s,6H)0.89(br d,J＝6.88Hz,3H)。Compound 4a: SFC detection conditions: Chromatographic column: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: Phase A: carbon dioxide, Phase B: ethanol (0.05% diethylamine); Gradient: B%: 40%, The retention time is 3.396min, ee=100.00%. MS: m/z 503.0[M+H] + . 1 H NMR (400MHz, CD 3 OD) δppm 8.61 (s, 1H) 8.44 (br s, 1H) 8.21 (s, 1H) 7.80 (br d, J = 8.13Hz, 1H) 7.62 (br d, J = 8.50 Hz,1H)7.38(br d,J＝11.51Hz,1H)4.90(br s,1H)4.79-4.86(m,2H)4.44(s,3H)3.78-3.96(m,2H)3.74(br s, 1H) 1.58 (s, 6H) 0.89 (br d, J = 6.88Hz, 3H).
化合物4b：SFC检测条件：色谱柱:Chiralpak AD-3 150×4.6mm 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％，保留时间为4.497min，ee＝98.58％。MS:m/z 503.1[M+H]+。1H NMR(400MHz,CD3OD)δppm 8.61(s,1H)8.45(br s,1H)8.20(s,1H)7.80(br d,J＝7.00Hz,1H)7.62(br d,J＝7.13Hz,1H)7.38(br d,J＝11.26Hz,1H)4.90-4.96(m,1H)4.80-4.85(m,2H)4.44(s,3H)3.81-3.96(m,2H)3.74(br s,1H)1.58(s,6H)0.89(br d,J＝6.88Hz,3H)。Compound 4b: SFC detection conditions: Chromatographic column: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: Phase A: carbon dioxide, Phase B: ethanol (0.05% diethylamine); Gradient: B%: 40%, The retention time is 4.497min, ee=98.58%. MS: m/z 503.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δppm 8.61 (s, 1H) 8.45 (br s, 1H) 8.20 (s, 1H) 7.80 (br d, J = 7.00Hz, 1H) 7.62 (br d, J = 7.13 Hz,1H)7.38(br d,J＝11.26Hz,1H)4.90-4.96(m,1H)4.80-4.85(m,2H)4.44(s,3H)3.81-3.96(m,2H)3.74(br s ,1H)1.58(s,6H)0.89(br d,J＝6.88Hz,3H).
实施例5
Example 5
第一步first step
将化合物E(100mg,388.91μmol)和化合物5-1(96.99mg,1.17mmol)溶于三乙胺(2mL)中，加入二氯双(三苯基膦)钯(II)(54.60mg,77.78μmol)和碘化亚酮(14.81mg,77.78μmol)，反应液在氮气保护下在75℃下搅拌3小时。向反应液中加入乙酸乙酯(10mL)稀释，过滤，滤饼用乙酸乙酯(10mL×3)淋洗，收集滤液，有机相用水(10mL×2)洗，饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经柱层析纯化(硅胶，0～10％甲醇/二氯甲烷)。得到化合物5-2。MS:m/z 260.0[M+H]+。Compound E (100 mg, 388.91 μmol) and compound 5-1 (96.99 mg, 1.17 mmol) were dissolved in triethylamine (2 mL), and dichlorobis(triphenylphosphine)palladium (II) (54.60 mg, 77.78 μmol) and ketone iodide (14.81 mg, 77.78 μmol). The reaction solution was stirred at 75°C for 3 hours under nitrogen protection. Add ethyl acetate (10 mL) to the reaction solution to dilute, filter, and rinse the filter cake with ethyl acetate (10 mL × 3). Collect the filtrate, wash the organic phase with water (10 mL × 2), and wash with saturated brine (10 mL). Dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography (silica gel, 0-10% methanol/dichloromethane). Compound 5-2 was obtained. MS: m/z 260.0[M+H] + .
第二步Step 2
将化合物5-2(55mg,212.07μmol)和化合物1-4(55.19mg,212.07μmol)溶于二氯甲烷(3mL)中，加入三乙胺(21.46mg,212.07μmol)和2-氯-1-甲基吡啶(盐)碘化物(65.02mg,254.49μmol)，反应液在氮气保护下在45℃下搅拌4小时。向反应液中加入水(10mL)，用二氯甲烷(10mL×3)萃取，合并有机相，用水(10mL)洗，饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品经柱层析纯化(硅胶，0～10％甲醇/二氯甲烷)。得到化合物5。MS:m/z 502.2[M+H]+。Compound 5-2 (55 mg, 212.07 μmol) and compound 1-4 (55.19 mg, 212.07 μmol) were dissolved in dichloromethane (3 mL), and triethylamine (21.46 mg, 212.07 μmol) and 2-chloro-1 were added. -Picoline (salt) iodide (65.02 mg, 254.49 μmol), the reaction solution was stirred at 45°C for 4 hours under nitrogen protection. Add water (10 mL) to the reaction solution, extract with dichloromethane (10 mL Concentrate to obtain crude product. The crude product was purified by column chromatography (silica gel, 0-10% methanol/dichloromethane). Compound 5 was obtained. MS: m/z 502.2[M+H] + .
第三步third step
化合物5经SFC分离纯化(分离条件，色谱柱:DAICEL CHIRALPAK AD(250mm×30mm,10μm)；流动相:[A相：二氧化碳，B相：乙醇(0.1％氨水)]；B％:45％)，得到化合物5a和化合物5b。Compound 5 was separated and purified by SFC (separation conditions, chromatographic column: DAICEL CHIRALPAK AD (250mm×30mm, 10μm); mobile phase: [Phase A: carbon dioxide, phase B: ethanol (0.1% ammonia)]; B%: 45%) , compound 5a and compound 5b were obtained.
化合物5a：SFC检测条件：色谱柱:Chiralpak AD-3 150×4.6mm 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％，保留时间为2.682min，ee＝100.00％。MS:m/z 502.1[M+H]+。1H NMR(400MHz,CD3OD)δppm 8.66(s,1H)8.45(br s,1H)8.21(s,1H)7.85(br s,1H)7.65(br s,1H)7.39(br d,J＝11.80Hz,1H)4.92(br s,1H)4.80(s,2H)4.44(s,3H)3.81-3.99(m,2H)3.74(s,1H)3.58(s,2H)2.43(s,6H)0.90(br d,J＝6.53Hz,3H)。Compound 5a: SFC detection conditions: Chromatographic column: Chiralpak AD-3 150×4.6mm ID, 3μm; mobile phase: Phase A: carbon dioxide, phase B: Ethanol (0.05% diethylamine); gradient: B%: 40%, retention time is 2.682min, ee=100.00%. MS: m/z 502.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δppm 8.66 (s, 1H) 8.45 (br s, 1H) 8.21 (s, 1H) 7.85 (br s, 1H) 7.65 (br s, 1H) 7.39 (br d, J ＝11.80Hz,1H)4.92(br s,1H)4.80(s,2H)4.44(s,3H)3.81-3.99(m,2H)3.74(s,1H)3.58(s,2H)2.43(s,6H )0.90(br d,J=6.53Hz,3H).
化合物5b：SFC检测条件：色谱柱:Chiralpak AD-3 150×4.6mm 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％，保留时间为3.653min，ee＝98.80％。MS:m/z 502.1[M+H]+。1H NMR(400MHz,CD3OD)δppm 8.65(s,1H)8.45(br s,1H)8.20(s,1H)7.83(br s,1H)7.64(br s,1H)7.38(br d,J＝11.26Hz,1H)4.94(br s,1H)4.80(br s,2H)4.43(br s,3H)3.79-3.98(m,2H)3.73(br s,1H)3.54(s,2H)2.39(s,6H)0.89(br d,J＝6.13Hz,3H)。Compound 5b: SFC detection conditions: Chromatographic column: Chiralpak AD-3 150×4.6mm ID, 3μm; Mobile phase: Phase A: carbon dioxide, Phase B: ethanol (0.05% diethylamine); Gradient: B%: 40%, The retention time is 3.653min, ee=98.80%. MS: m/z 502.1[M+H] + . 1 H NMR (400MHz, CD 3 OD) δppm 8.65 (s, 1H) 8.45 (br s, 1H) 8.20 (s, 1H) 7.83 (br s, 1H) 7.64 (br s, 1H) 7.38 (br d, J ＝11.26Hz,1H)4.94(br s,1H)4.80(br s,2H)4.43(br s,3H)3.79-3.98(m,2H)3.73(br s,1H)3.54(s,2H)2.39( s, 6H) 0.89 (br d, J = 6.13Hz, 3H).
实施例6
Example 6
第一步first step
将中间体E(1g,3.89mmol)和化合物1-4(1.11g,4.28mmol)溶于二氯甲烷(30mL)中，加入三乙胺(1.57g,15.56mmol)和2-氯-1-甲基吡啶(盐)碘化物(1.49g,5.83mmol)，反应液在45℃下搅拌12小时。反应液中加入水(10mL)，然后加入二氯甲烷(10mL×3)萃取，有机相合并经饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，滤液干燥得到粗品，粗品经快速硅胶柱纯化(0～10％甲醇/二氯甲烷)得到化合物6-1。MS:m/z[M+H]+499.0/501.0。Intermediate E (1g, 3.89mmol) and compound 1-4 (1.11g, 4.28mmol) were dissolved in dichloromethane (30mL), and triethylamine (1.57g, 15.56mmol) and 2-chloro-1- were added. Picoline (salt) iodide (1.49g, 5.83mmol), the reaction solution was stirred at 45°C for 12 hours. Water (10 mL) was added to the reaction solution, and then dichloromethane (10 mL × 3) was added for extraction. The organic phases were combined and washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product, which was Fast silica gel column purification (0-10% methanol/dichloromethane) gave compound 6-1. MS:m/z[M+H] + 499.0/501.0.
第二步Step 2
将化合物6-1(150mg,300.40μmol)溶于二氯甲烷(5mL)，然后加入4-二甲氨基吡啶(36.70mg,300.40μmol)，三乙胺(91.19mg,901.20μmol)和二碳酸二叔丁酯(262.25mg,1.20mmol)，反应在25℃搅拌16小时。减压浓缩得到粗品，粗品经快速硅胶柱纯化(0～5％甲醇/二氯甲烷)，得到化合物6-2。MS:m/z[M+H]+699.1/701.1。Compound 6-1 (150 mg, 300.40 μmol) was dissolved in dichloromethane (5 mL), and then 4-dimethylaminopyridine (36.70 mg, 300.40 μmol), triethylamine (91.19 mg, 901.20 μmol) and dicarbonate were added. tert-Butyl ester (262.25 mg, 1.20 mmol), the reaction was stirred at 25°C for 16 hours. Concentrate under reduced pressure to obtain a crude product, which is purified by flash silica gel column (0-5% methanol/dichloromethane) to obtain compound 6-2. MS:m/z[M+H] + 699.1/701.1.
第三步third step
氮气氛围下，将化合物6-2(210mg,300.19μmol)和3-氨基-3-甲基-1-丁炔(249.55mg,3.00mmol)溶于三乙胺(6mL)，然后加入二氯双(三苯基膦)钯(II)(31.60mg,45.03μmol)和碘化亚铜(8.58mg,45.03μmol)， 75℃搅拌6小时。将反应液过滤，滤饼用乙酸乙酯(10mL×2)荡洗，收集滤液，减压浓缩，加入乙酸乙酯(10mL)稀释，有机相用水(10mL×2)洗，饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，粗品经制备TLC纯化(二氯甲烷:甲醇＝50:1)得化合物6-3。MS:m/z[M+H]+702.3。Under nitrogen atmosphere, compound 6-2 (210 mg, 300.19 μmol) and 3-amino-3-methyl-1-butyne (249.55 mg, 3.00 mmol) were dissolved in triethylamine (6 mL), and then dichlorobis was added. (Triphenylphosphine)palladium(II) (31.60mg, 45.03μmol) and copper iodide (8.58mg, 45.03μmol), Stir at 75°C for 6 hours. The reaction solution was filtered, and the filter cake was washed with ethyl acetate (10 mL ), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was purified by preparative TLC (dichloromethane:methanol=50:1) to obtain compound 6-3. MS:m/z[M+H] + 702.3.
第四步the fourth step
氮气氛围下，将化合物6-3(120mg,170.99μmol)溶于三氟乙醇(2mL)，加入多聚甲醛(10.27mg,341.98μmol)，25℃搅拌1小时，然后加入醋酸硼氢化钠(72.48mg,341.98μmol)，加热至80℃搅拌6小时。向反应液中加入水(5mL)淬灭，乙酸乙酯(10mL×3)萃取，饱和食盐水(10mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品，粗品经制备TLC纯化(二氯甲烷:甲醇＝50:1)得到化合物6-4。Under nitrogen atmosphere, dissolve compound 6-3 (120 mg, 170.99 μmol) in trifluoroethanol (2 mL), add paraformaldehyde (10.27 mg, 341.98 μmol), stir at 25°C for 1 hour, and then add sodium acetate borohydride (72.48 mg, 341.98 μmol), heated to 80°C and stirred for 6 hours. Add water (5 mL) to the reaction solution to quench, extract with ethyl acetate (10 mL Purification (dichloromethane:methanol=50:1) gave compound 6-4.
第四步the fourth step
将化合物6-4(90mg,348.35μmol)溶于二氯甲烷(2mL)，滴加三氟乙酸(781.15mg,6.85mmol)，25℃搅拌2小时。向反应液中滴加水(5mL)，加入饱和碳酸氢钠溶液调pH>7，加入乙酸乙酯(5mL×3)萃取，饱和食盐水(5mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，粗品经制备TLC纯化(二氯甲烷:甲醇＝50:1)，得到化合物6。MS:m/z[M+H]+530.3。Compound 6-4 (90 mg, 348.35 μmol) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (781.15 mg, 6.85 mmol) was added dropwise, and the mixture was stirred at 25°C for 2 hours. Add water (5mL) dropwise to the reaction solution, add saturated sodium bicarbonate solution to adjust pH>7, add ethyl acetate (5mL×3) for extraction, wash with saturated brine (5mL), dry over anhydrous sodium sulfate, filter, and reduce the filtrate to Concentrate under pressure to obtain a crude product, which is purified by preparative TLC (dichloromethane:methanol=50:1) to obtain compound 6. MS:m/z[M+H] + 530.3.
第五步the fifth step
化合物6(60mg,113.29μmol)经SFC分离纯化(分离条件，色谱柱:ChiralPak IH,250×30mm,10μm；流动相:[A相：二氧化碳，B相：异丙醇(0.1％氨水)]；B％:45％)，得到化合物6a和化合物6b。Compound 6 (60 mg, 113.29 μmol) was separated and purified by SFC (separation conditions, chromatographic column: ChiralPak IH, 250×30 mm, 10 μm; mobile phase: [Phase A: carbon dioxide, phase B: isopropyl alcohol (0.1% ammonia)]; B%: 45%) to obtain compound 6a and compound 6b.
化合物6a：SFC检测条件：色谱柱:Chiralcel OD-3 150×4.6mm 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％，保留时间为3.737min，ee＝100％。MS:m/z[M+H]+530.2。1H NMR(400MHz,DMSO-d6)δppm 8.65(br s,1H),8.30(br d,J＝7.0Hz,1H),8.26(s,1H),7.89(br s,1H),7.63-7.54(m,1H),7.40-7.35(m,1H),7.33(br s,2H),4.38(br s,3H),3.76(br s,2H),3.69(br s,2H),2.38(br s,6H),1.46(br s,6H),0.79(br s,3H)Compound 6a: SFC detection conditions: chromatographic column: Chiralcel OD-3 150×4.6mm ID, 3μm; mobile phase: phase A: carbon dioxide, phase B: ethanol (0.05% diethylamine); gradient: B%: 40%, The retention time is 3.737min, ee=100%. MS:m/z[M+H] + 530.2. 1 H NMR (400MHz, DMSO-d 6 ) δppm 8.65 (br s, 1H), 8.30 (br d, J = 7.0Hz, 1H), 8.26 (s, 1H), 7.89 (br s, 1H), 7.63- 7.54(m,1H),7.40-7.35(m,1H),7.33(br s,2H),4.38(br s,3H),3.76(br s,2H),3.69(br s,2H),2.38( br s,6H),1.46(br s,6H),0.79(br s,3H)
化合物6b：SFC检测条件：色谱柱:Chiralcel OD-3 150×4.6mm 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％,保留时间为4.255min，ee＝100％。MS:m/z[M+H]+530.2。1H NMR(400MHz,DMSO-d6)δppm 8.64(br s,1H),8.30(br d,J＝6.0Hz,1H),8.26(br s,1H),7.87(br s,1H),7.58(br s,1H),7.39-7.33(m,1H),7.31(br s,2H),4.38(br s,3H),3.76(br s,2H),3.69(br d,J＝1.5Hz,2H),2.31(br s,6H),1.43(br s,6H),0.79(br s,3H)。Compound 6b: SFC detection conditions: Chromatographic column: Chiralcel OD-3 150×4.6mm ID, 3μm; Mobile phase: Phase A: carbon dioxide, Phase B: ethanol (0.05% diethylamine); Gradient: B%: 40%, The retention time is 4.255min, ee=100%. MS:m/z[M+H] + 530.2. 1 H NMR (400MHz, DMSO-d 6 ) δppm 8.64 (br s, 1H), 8.30 (br d, J = 6.0Hz, 1H), 8.26 (br s, 1H), 7.87 (br s, 1H), 7.58 (br s,1H),7.39-7.33(m,1H),7.31(br s,2H),4.38(br s,3H),3.76(br s,2H),3.69(br d,J＝1.5Hz, 2H),2.31(br s,6H),1.43(br s,6H),0.79(br s,3H).
生物测试数据Biological test data
实验例1：LU99细胞增殖抑制试验Experimental Example 1: LU99 cell proliferation inhibition test
实验目的：Purpose:
测试本发明化合物对LU99细胞的抗增殖活性。Compounds of the invention were tested for antiproliferative activity on LU99 cells.
实验材料：Experimental Materials:
1640培养基，盘尼西林/链霉素抗生素购自Gibco，胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。LU99细胞系购自JCRB，Envision多标记分析仪(PerkinElmer)。1640 medium, penicillin/streptomycin antibiotics were purchased from Gibco, and fetal calf serum was purchased from Biosera. CellTiter-Glo (cell viability chemiluminescence detection reagent) reagent was purchased from Promega. LU99 cell line was purchased from JCRB, Envision multi-label analyzer (PerkinElmer).
实验操作：Experimental operation:
1)细胞培养：将LU99细胞种于超低吸附96孔黑壁板中，80μL细胞悬液每孔，其中包含1000个LU99细胞。细胞板置于二氧化碳培养箱中过夜培养。1) Cell culture: LU99 cells were seeded in an ultra-low adsorption 96-well black wall plate, with 80 μL of cell suspension per well containing 1,000 LU99 cells. The cell plate was cultured overnight in a carbon dioxide incubator.
2)给药：将待测化合物用排枪经DMSO 5倍稀释8个浓度，即从2mM稀释至25.6nM，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10μM至0.128nM。细胞板置于二氧化碳培养箱中培养6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。2) Administration: Use a volley gun to dilute the compound to be tested 5 times with DMSO to 8 concentrations, that is, from 2mM to 25.6nM, and set up a double well experiment. Add 78 μL of culture medium to the middle plate, then transfer 2 μL of gradient dilution compound per well to the middle plate according to the corresponding position, and mix. After homogenization, transfer 20 μL per well to the cell plate. The concentration of compounds transferred into the cell plate ranged from 10 μM to 0.128 nM. The cell plate was cultured in a carbon dioxide incubator for 6 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.
3)细胞增殖活检测：向细胞板的每个孔中加入100μL的细胞活率化学发光检测试剂，室温孵育30分钟使发光信号稳定。采用多标记分析仪读数。3) Cell proliferation and viability detection: Add 100 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 30 minutes to stabilize the luminescence signal. Take multi-label analyzer readings.
4)数据分析：利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC50的值即可通过参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。4) Data analysis: 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 parameters ("log(" in GraphPad Prism inhibitor) vs. response--Variable slope" model).
实验结果见表3。The experimental results are shown in Table 3.
表3本发明化合物对LU99细胞的抗增殖活性结果
Table 3 Anti-proliferative activity results of compounds of the present invention on LU99 cells
结论：本发明化合物对LU99细胞具有显著的抗增殖活性。Conclusion: The compounds of the present invention have significant anti-proliferative activity on LU99 cells.
实验例2：化合物对HCT116MTAP KO细胞和HCT116wt细胞的增殖抑制活性测试Experimental Example 2: 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)。实验结果见表4。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). The experimental results are shown in Table 4.
表4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
Table 4 Test results of the inhibitory activity of the compounds of the present invention on HCT116 MTAP KO cells and HCT116 wt cells
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3：小鼠药代动力学评价Experimental Example 3: Evaluation of Mouse Pharmacokinetics
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或50mg/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 of 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 or 50 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。实验结果见表5。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. The experimental results are shown in Table 5.
表5本发明化合物血浆中的PK测试结果
Table 5 PK test results of the compounds of the present invention in plasma
“--”是指未测试或未获得数据。"--" means no testing or no data obtained.
结论：本发明化合物展现了较长的半衰期、较高的组织分布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 compound of the present invention exhibits a longer half-life, higher tissue distribution and higher drug exposure, and has good pharmacokinetic properties in vivo.
实验例4：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 4: 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 tumor inhibitory effect of the test compound 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150-200mm3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, when the tumor volume is 150-200mm3 , start drug administration. The drug administration treatment method is as follows:
对照组：接种后当肿瘤体积为174±8mm3时开始给药，每天一次按照0.1mL/10g的剂量灌胃溶媒(5％DMSO/10％Solutol/85％二次蒸馏水)。Control group: Administration was started when the tumor volume reached 174± 8mm3 after inoculation, and vehicle (5% DMSO/10% Solutol/85% twice distilled water) was administered once a day at a dose of 0.1 mL/10 g.
治疗组：接种后当肿瘤体积为172±8mm3时开始给药，每天一次(QD)按照15mg/kg的剂量灌胃给药(P.O.)化合物(待测化合物溶解于5％DMSO/10％Solutol/85％二次蒸馏水)。Treatment group: After inoculation, administration was started when the tumor volume was 172 ± 8 mm 3 , and the compound (to be tested) was administered orally (PO) at a dose of 15 mg/kg once a day (QD) (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)，用下列公式计算：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 experiment was divided into groups, the mice were weighed twice a week, the tumor diameter was measured with a vernier caliper, and the tumor volume was calculated according to the formula of length × width 2 /2. Then calculate the tumor growth inhibition rate (TGI) using the following formula: TGI (%) = [1-(T i -T 0 )/(C i -C 0 )] × 100, where T i is a certain dose on a certain day. The average tumor volume of the drug group, T 0 is the average tumor volume of the drug group at the beginning of drug administration; C i is the average tumor volume of the control group on a certain day (the same day as T i ), and C 0 is the average tumor volume of the control group at the beginning of drug administration. Average tumor volume at drug initiation.
实验给药后第22天安乐死小鼠并采样。The mice were euthanized and sampled on the 22nd 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9所示，各组在不同时间点的平均肿瘤体积如图10所示。基于给药后第22天的平均肿瘤体积计算得出TGI。 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 9, and the average tumor volume of each group at different time points is shown in Figure 10. TGI was calculated based on the average tumor volume on day 22 postdose.
具体实验结果见表6。The specific experimental results are shown in Table 6.
表6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 6 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.
实验例5：血浆蛋白结合率(PPB)测定Experimental Example 5: Plasma protein binding rate (PPB) measurement
取人、SD大鼠及CD-1小鼠的空白血浆796μL(血浆购买自BioreclamationIVT)，加入受试化合物工作溶液或华法林工作溶液，使血浆样品中受试化合物与华法林终浓度均为2μM。将样品充分混合。有机相DMSO的终浓度为0.5％；移取50μL受试化合物和华法林血浆样品到样品接收板中，立即加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1：1，然后向这些样品中加入终止液，此样品将作为T0样品用于回收率及稳定性测定。将受试化合物和华法林血浆样品加入到每个透析孔的给药端，在透析孔对应的接收端中加入空白透析缓冲液。然后将透析板封上透气膜后置于湿润的5％CO2的培养箱中，在37℃、100rpm振荡孵育4小时。透析结束后，移取50μL透析后的缓冲液样品和透析后的血浆样品到新的样品接收板。在样品中加入相应体积的对应空白血浆或缓冲液，使得每个样品孔的终体积为100μL，血浆：透析缓冲液的体积比为1：1。所有样品经过蛋白沉淀后进行LC/MS/MS分析，并通过以下公式计算化合物的游离率：PPB_Unbound(％)＝100*FC/TC，其中FC是透析板缓冲液端化合物的浓度；TC是透析板血浆端化合物的浓度；T0是零时刻血浆样品中化合物的浓度。Take 796 μL of blank plasma from humans, SD rats, and CD-1 mice (plasma was purchased from Bioreclamation IVT), and add the test compound working solution or warfarin working solution to make the final concentrations of the test compound and warfarin in the plasma sample uniform. is 2μM. Mix the sample thoroughly. The final concentration of DMSO in the organic phase is 0.5%; pipet 50 μL of the test compound and warfarin plasma sample into the sample receiving plate, and immediately add the corresponding volume of corresponding blank plasma or buffer so that the final volume of each sample well is 100 μL. , the volume ratio of plasma:dialysis buffer is 1:1, and then add stop solution to these samples. This sample will be used as T 0 sample for recovery and stability determination. Add the test compound and warfarin plasma sample to the administration end of each dialysis hole, and add blank dialysis buffer to the corresponding receiving end of the dialysis hole. Then the dialysis plate was sealed with a breathable membrane and placed in a humidified 5% CO 2 incubator, and incubated for 4 hours at 37°C and 100 rpm shaking. After dialysis, transfer 50 μL of the dialyzed buffer sample and the dialyzed plasma sample to a new sample receiving plate. Add a corresponding volume of corresponding blank plasma or buffer to the sample so that the final volume of each sample well is 100 μL, and the volume ratio of plasma:dialysis buffer is 1:1. All samples were analyzed by LC/MS/MS after protein precipitation, and the free rate of the compound was calculated by the following formula: PPB_Unbound (%) = 100* FC / TC , where F C is the concentration of the compound at the buffer end of the dialysis plate; T C is the concentration of the compound at the plasma end of the dialysis plate; T 0 is the concentration of the compound in the plasma sample at time zero.
实验结果见表7。The experimental results are shown in Table 7.
表7.血浆蛋白结合率测试结果
Table 7. Plasma protein binding rate test results
实验结论：本发明化合物在人、小鼠中都具有合理的血浆蛋白结合率。Experimental conclusion: The compound of the present invention has a reasonable plasma protein binding rate in both humans and mice.
实验例6：体外MDCKII-MDR1单层细胞渗透性测试Experimental Example 6: In vitro MDCKII-MDR1 monolayer cell permeability test
实验目的：Purpose:
使用MDCKII-MDR1单层细胞测试体系，评估待测化合物的渗透性和外排比，以判断化合物穿过血脑屏障的潜力和被P-GP转运体外排的潜力。Use the MDCKII-MDR1 monolayer cell test system to evaluate the permeability and efflux ratio of the compound to be tested to determine the potential of the compound to cross the blood-brain barrier and be effluxed by the P-GP transporter.
实验方法：experimental method:
将MDR1-MDCKII细胞(来自荷兰癌症研究所)接种在96板(来自康宁)上，细胞密度是2.5x 105细胞/毫升，培养4-7天，形成共聚细胞单层。采用含10mM 4-羟乙基哌嗪乙磺酸的Hank’s平衡盐缓冲液(pH7.40±0.05)为转运缓冲液。测试受试化合物在50μM浓度下的双向转运，孵育体系中DMSO的浓度控制在1％以下。加样后，将细胞板置于37±1℃，5％CO2及饱和湿度条件下孵育150分钟。所有的样品采用LC-MS/MS方法进行所有样品的定量分析。采用如下公式计算表观渗透系数(Papp,cm/s)，外排比。MDR1-MDCKII cells (from Netherlands Cancer Institute) were seeded on 96 plates (from Corning) at a cell density of 2.5× 10 cells/ml and cultured for 4-7 days to form a copolymerized cell monolayer. Hank's balanced salt buffer (pH 7.40±0.05) containing 10mM 4-hydroxyethylpiperazineethanesulfonic acid was used as the transport buffer. The bidirectional transport of the test compound at a concentration of 50 μM was tested, and the concentration of DMSO in the incubation system was controlled below 1%. After adding the sample, incubate the cell plate at 37±1°C, 5% CO2 and saturated humidity for 150 minutes. All samples were quantitatively analyzed using LC-MS/MS method. Use the following formula to calculate the apparent permeability coefficient (P app , cm/s) and efflux ratio.
表观渗透系数(Papp,cm/s)采用如下公式计算：Papp＝(dCr/dt)×Vr/(A×C0)。其中，dCr/dt是化合物在单位时间内接收端的累积浓度(μM/s)；Vr是接收端溶液的体积(顶端和基底端的溶液体积分别为0.075mL和0.250mL)；A是胞单层的相对表面积(0.0804cm2)；C0是给药端供试品的起始浓度(nM)或对照品的峰面积比值。外排比采用如下公式计算：外排比＝Papp(BA)/Papp(AB)。The apparent permeability coefficient (P app ,cm/s) is calculated using the following formula: P app =(dC r /d t )×V r /(A×C 0 ). Among them, dC r /d t is the cumulative concentration of the compound at the receiving end per unit time (μM/s); V r is the volume of the receiving end solution (the solution volumes at the top and basal ends are 0.075mL and 0.250mL respectively); A is the cell The relative surface area of the monolayer (0.0804cm 2 ); C 0 is the initial concentration of the test substance at the administration end (nM) or the peak area ratio of the reference substance. The efflux ratio is calculated using the following formula: efflux ratio = P app (BA)/P app (AB).
实验结果见表8。 The experimental results are shown in Table 8.
表8 MDCKII-MDR1细胞渗透性测试结果
Table 8 MDCKII-MDR1 cell permeability test results
结论：在MDCKII-MDR1单层细胞(高表达人源p-gp)渗透性实验中，本发明化合物渗透性良好。Conclusion: In the permeability experiment of MDCKII-MDR1 monolayer cells (highly expressing human p-gp), the compound of the present invention has good permeability.
实验例7：化合物体外微粒体稳定性实验Experimental Example 7: In vitro microsomal stability test of compounds
实验材料Experimental Materials
肝微粒体：购买于Corning或Xenotech，储存于-80℃冰箱；Liver microsomes: purchased from Corning or Xenotech, stored in -80°C refrigerator;
还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)，供应商：Chem-impex international，货号：00616；Reduced nicotinamide adenine dinucleotide phosphate (NADPH), supplier: Chem-impex international, product number: 00616;
对照化合物：睾酮，双氯芬酸，普罗帕酮。Control compounds: testosterone, diclofenac, propafenone.
实验步骤Experimental steps
2.1工作液的配制2.1 Preparation of working fluid
储备液：10mM DMSO溶液Stock solution: 10mM DMSO solution
工作浓度配制：100％乙腈稀释到100μM(有机相含量：99％乙腈，1％DMSO)Working concentration preparation: 100% acetonitrile diluted to 100 μM (organic phase content: 99% acetonitrile, 1% DMSO)
2.2实验步骤2.2 Experimental steps
准备2块96孔孵育板，分别命名为T60孵育板和NCF60孵育板。Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
在T60孵育板和NCF60孵育板上分别加入445μL微粒体工作液(肝微粒体蛋白浓度为0.56mg/mL)，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。Add 445 μL of microsomal working solution (liver microsomal protein concentration is 0.56 mg/mL) to the T60 incubation plate and NCF60 incubation plate respectively, and then place the above-mentioned incubation plate in a 37°C water bath for pre-incubation for about 10 minutes.
预孵育结束后，在T60孵育板和NCF60孵育板上分别加入5μL供试品或对照化合物工作液，混匀。在NCF60孵育板上每孔添加50μL磷酸钾盐缓冲液启动反应；在T0终止板中加入180μL的终止液(含200ng/mL tolbutamide(甲苯磺丁尿)和200ng/mL labetalol(拉贝洛尔)的乙腈溶液)和6μL的NADPH再生体系工作液，从T60孵育板中取出54μL样品至T0终止板(T0样品产生)。在T60孵育板上每孔添加44μL NADPH再生体系工作液启动反应。在空白板中只添加54μL微粒体工作液、6uL的NADPH再生体系工作液和180μL的终止液。因此，在供试品或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)。After the pre-incubation, add 5 μL of test product or control compound working solution to the T60 incubation plate and NCF60 incubation plate respectively, and mix well. Add 50 μL potassium phosphate buffer to each well of the NCF60 incubation plate to start the reaction; add 180 μL stop solution (containing 200ng/mL tolbutamide (tolbutamide) and 200ng/mL labetalol (labetalol)) to the T0 stop plate. Acetonitrile solution) and 6 μL of NADPH regeneration system working solution, take 54 μL of sample from the T60 incubation plate to the T0 stop plate (TO sample generation). Add 44 μL of NADPH regeneration system working solution to each well of the T60 incubation plate to start the reaction. Add only 54 μL of microsome working solution, 6 μL of NADPH regeneration system working solution, and 180 μL of stop solution to the blank plate. Therefore, in the sample of the test product or control compound, the final concentration of the compound, testosterone, diclofenac and propafenone in the reaction is 1 μM, the concentration of liver microsomes is 0.5 mg/mL, and the final concentration of DMSO and acetonitrile in the reaction system 0.01% (v/v) and 0.99% (v/v) respectively.
孵育适当时间(如5、15、30、45和60分钟)后，分别在每个终止板的样品孔中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)，之后从T60孵育板中取出60μL样品以终止反应。After incubating for an appropriate time (such as 5, 15, 30, 45 and 60 minutes), add 180 μL of stop solution (acetonitrile solution containing 200ng/mL tolbutamide and 200ng/mL labetalol) to the sample wells of each stop plate. Remove 60 μL of sample from the T60 incubation plate to stop the reaction.
所有样品板摇匀并在3220×g离心20分钟，然后每孔取80μL上清液稀释到240μL纯水中用于液相色谱串联质谱分析。实验结果见表9。All sample plates were shaken and centrifuged at 3220 × g for 20 minutes, and then 80 μL of the supernatant from each well was diluted into 240 μL of pure water for liquid chromatography-tandem mass spectrometry analysis. The experimental results are shown in Table 9.
表9：本发明化合物肝微粒体稳定性试验结果
Table 9: Liver microsome stability test results of the compounds of the present invention
结论：本发明化合物在人肝微粒体测试中表现出中等代谢。 Conclusion: The compounds of the present invention exhibit moderate metabolism in human liver microsome tests.

Claims (19)

  1. 式(IV)所示化合物或其药学上可接受的盐，
    The compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
    其中，in,
    E1选自CH2、NH和O；E 1 is selected from CH 2 , NH and O;
    各R1分别独立地选自H、F、Cl、Br、I、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Ra取代；Each R 1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively Independently optionally substituted by 1, 2 or 3 R a ;
    或者，相同原子上的两个R1连接形成C3-6环烷基，所述C3-6环烷基任选被1、2或3个Re取代；Alternatively, two R 1 on the same atom are connected to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 Re ;
    R6选自H、F、Cl、Br、I、C1-3烷基、C1-3烷氧基、C2-4炔基、C2-4烯基、C1-3烷氨基、C3-6环烷基、4-6元杂环烷基、-C1-3烷氧基-C3-6环烷基、-C1-3烷氨基-C3-6环烷基、-C1-3烷氧基-4-6元杂环烷基和-C1-3烷氨基-4-6元杂环烷基，所述C1-3烷基、C1-3烷氧基、C2-4炔基、C2-4烯基、C1-3烷氨基、C3-6环烷基、4-6元杂环烷基、-C1-3烷氧基-C3-6环烷基、-C1-3烷氨基-C3-6环烷基、-C1-3烷氧基-4-6元杂环烷基和-C1-3烷氨基-4-6元杂环烷基分别独立地任选被1、2或3个Rb取代；R 6 is selected from H, F, Cl, Br, I, C 1-3 alkyl, C 1-3 alkoxy, C 2-4 alkynyl, C 2-4 alkenyl, C 1-3 alkylamino, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-6 cycloalkyl, -C 1-3 alkylamino-C 3-6 cycloalkyl, -C 1-3 alkoxy-4-6-membered heterocycloalkyl and -C 1-3 alkylamino-4-6-membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy Base, C 2-4 alkynyl, C 2-4 alkenyl, C 1-3 alkylamino, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, -C 1-3 alkoxy-C 3-6 cycloalkyl, -C 1-3 alkylamino-C 3-6 cycloalkyl, -C 1-3 alkoxy-4-6 membered heterocycloalkyl and -C 1-3 alkylamino-4 -6-membered heterocycloalkyl groups are independently optionally substituted by 1, 2 or 3 R b ;
    结构单元选自 Structural units Selected from
    环A选自5-6元杂芳基、C4-6环烯基或5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基或5-6元杂环烯基分别独立地任选被1、2或3个Rc取代；Ring A is selected from 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 membered heterocycloalkenyl, said 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
    环B选自苯基和5-10元杂芳基；Ring B is selected from phenyl and 5-10 membered heteroaryl;
    T1和T2分别独立地选自C、CR3或N；T 1 and T 2 are independently selected from C, CR 3 or N;
    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;
    R3选自H、F、Cl、Br、I、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 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
    R4选自H、F、Cl、Br、I、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, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
    各R5分别独立地选自H、F、Cl、Br、I、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；Each R 5 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R d ;
    各Ra、各Rc、各Rd和各Re分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R a , each R c , each R d and each Re are independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
    各Rb分别独立地选自H、D、F、Cl、Br、I、OH、NH2、C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基，所述C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基分别独立地任选被1、2或3个R取代；各R分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R substitution; each R is independently selected from H, D, F, Cl, Br, I, 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;
    m选自0、1、2、3和4； m is selected from 0, 1, 2, 3 and 4;
    条件是，当R6选自H、F、Cl、Br、I、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个卤素取代时，环B为双环的8-10元杂芳基，或者，结构单元选自 The condition is that when R 6 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are respectively When independently optionally substituted by 1, 2 or 3 halogens, Ring B is a bicyclic 8-10 membered heteroaryl, or structural unit Selected from
    所述5-6元杂芳基、5-6元杂环烯基、4-6元杂环烷基、5-10元杂芳基或双环的8-10元杂芳基的“杂”分别表示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, 5-6-membered heterocycloalkenyl, 4-6-membered heterocycloalkyl, 5-10-membered heteroaryl or bicyclic 8-10-membered heteroaryl are respectively 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，其选自，
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from,
    其中，in,
    E1选自O；E 1 is selected from O;
    各R1分别独立地选自H、F、Cl、Br、I、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Ra取代；Each R 1 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively Independently optionally substituted by 1, 2 or 3 R a ;
    或者，相同原子上的两个R1连接形成C3-6环烷基，所述C3-6环烷基任选被1、2或3个Re取代；Alternatively, two R 1 on the same atom are connected to form a C 3-6 cycloalkyl group, and the C 3-6 cycloalkyl group is optionally substituted by 1, 2 or 3 Re ;
    R6选自C2-4炔基，所述C2-4炔基任选被1、2或3个Rb取代；R 6 is selected from C 2-4 alkynyl, which is optionally substituted by 1, 2 or 3 R b ;
    结构单元选自 Structural units Selected from
    环A选自5-6元杂芳基、C4-6环烯基或5-6元杂环烯基，所述5-6元杂芳基、C4-6环烯基或5-6元杂环烯基分别独立地任选被1、2或3个Rc取代；Ring A is selected from 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 membered heterocycloalkenyl, said 5-6 membered heteroaryl, C 4-6 cycloalkenyl or 5-6 The one-membered heterocyclic alkenyl groups are independently optionally substituted by 1, 2 or 3 R c ;
    环B选自苯基和5-10元杂芳基；Ring B is selected from phenyl and 5-10 membered heteroaryl;
    T1和T2分别独立地选自C、CR3或N；T 1 and T 2 are independently selected from C, CR 3 or N;
    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;
    R3选自H、F、Cl、Br、I、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 3 is selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
    R4选自H、F、Cl、Br、I、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, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy are independently optional Replaced by 1, 2 or 3 R d ;
    各R5分别独立地选自H、F、Cl、Br、I、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；Each R 5 is independently selected from H, F, Cl, Br, I, C 1-3 alkyl and C 1-3 alkoxy, and the C 1-3 alkyl and C 1-3 alkoxy are respectively independently optionally substituted by 1, 2 or 3 R d ;
    各Ra、各Rc、各Rd和各Re分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R a , each R c , each R d and each Re are independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
    各Rb分别独立地选自H、D、F、Cl、Br、I、OH、NH2、C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基，所述C1-3烷基、C1-3烷氧基、C1-3烷氨基和4-6元杂环烷基分别独立地任选被1、2或3个R取代；Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl, the C 1-3 alkyl, C 1-3 alkoxy, C 1-3 alkylamino and 4-6 membered heterocycloalkyl are independently optionally substituted by 1, 2 or 3 R substitution;
    各R分别独立地选自H、D、F、Cl、Br、I、OH、NH2、CH3、CF3和CD3；Each R is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , CH 3 , CF 3 and CD 3 ;
    n选自0、1和2；n is selected from 0, 1 and 2;
    m选自0和1。m is chosen from 0 and 1.
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，各Ra、各Rc、各Rd和各Re分别独立地选自H、D、F、Cl、OH、NH2、CH3和CD3。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each R a , each R c , each R d and each R e are independently selected from H, D, F, Cl, OH, NH 2 , CH 3 and CD 3 .
  4. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，各Rb分别独立地选自H、D、F、Cl、OH、NH2、CH3、CH2CH3、OCH3、OCH2CH3、NHCH3、NHCH2CH3、N(CH3)2、吡咯烷基、哌啶基、哌嗪基和吗啡啉基，所述CH3、CH2CH3、OCH3、OCH2CH3、NHCH3、NHCH2CH3、N(CH3)2、吡咯烷基、哌啶基、哌嗪基和吗啡啉基分别独立地任选被1、2或3个R取代；或者，各Rb分别独立地选自H、D、F、OH、NH2、CH3、CD3、CF3、N(CH3)2、 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein each R b is independently selected from H, D, F, Cl, OH, NH 2 , CH 3 , CH 2 CH 3 , OCH 3. OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, the CH 3 , CH 2 CH 3 , OCH 3 , OCH 2 CH 3 , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl are independently optionally substituted by 1, 2 or 3 R ; Or, each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 , N(CH 3 ) 2 ,
  5. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R1选自H、F、Cl、Br、I、CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2，所述CH3、CH2CH3、CH2CH2CH3、CH(CH3)2、OCH3、OCH2CH3、OCH2CH2CH3和OCH(CH3)2分别独立地任选被1、2或3个Ra取代；或者，R1选自F、CH3和CD3；或者，相同原子上的两个R1连接形成环丙基。The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, F, Cl, Br, I, 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 and OCH(CH 3 ) 2 , said 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 and OCH (CH 3 ) 2 are independently optionally substituted by 1, 2 or 3 R a ; alternatively, R 1 is selected from F, CH 3 and CD 3 ; Alternatively, two R 1 on the same atom are joined to form a cyclopropyl group.
  6. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，R3选自H、F、Cl、Br、CH3和CD3，R4选自H、F、Cl、Br、CD3和CH3。The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from H, F, Cl, Br, CH 3 and CD 3 , and R 4 is selected from H, F, Cl, Br, CD 3 and CH 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，R6选自C2-4炔基、C2-4烯基、NHCH3、NHCH2CH3、N(CH3)2、氮杂环丁基、吡咯烷基、吗啡啉基、哌嗪基、哌啶基和-OCH2-C3-6环烷基，所述C2- 4炔基、C2-4烯基、NHCH3、NHCH2CH3、N(CH3)2、氮杂环丁基、吡咯烷基、吗啡啉基、哌嗪基、哌啶基和-OCH2-C3-6环烷基分别独立地任选被1、2或3个Rb取代。The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 2-4 alkynyl, C 2-4 alkenyl, NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl , piperidinyl and -OCH 2 -C 3-6 cycloalkyl, the C 2-4 alkynyl, C 2-4 alkenyl , NHCH 3 , NHCH 2 CH 3 , N(CH 3 ) 2 , azetidinyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl and -OCH 2 -C 3-6 cycloalkyl respectively Independently optionally substituted by 1, 2 or 3 R b .
  8. 根据权利要求2或7所述化合物或其药学上可接受的盐，其中，R6选自 The compound according to claim 2 or 7 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from
  9. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，结构单元选自 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from
  10. 根据权利要求1或2所述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、2或3个Rc取代。 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein ring A is selected from pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl , thienyl, furyl, oxazolyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, oxolenyl, oxanyl, azacyclonyl and azacyclo Hexenyl, the pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrrolyl, thiazolyl, thienyl, furyl, oxazolyl, cyclobutenyl, cyclopentenyl Alkenyl, cyclohexenyl, oxalenyl, oxalenyl, azelanyl and azalane are each independently optionally substituted by 1, 2 or 3 R c .
  11. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，结构单元选自 The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from
  12. 根据权利要求2所述化合物或其药学上可接受的盐，其选自，
    The compound according to claim 2 or a pharmaceutically acceptable salt thereof, which is selected from,
    其中，in,
    R2选自H、卤素和C1-3烷基，所述C1-3烷基任选被1、2或3个Rb取代；R 2 is selected from H, halogen and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b ;
    各Rb分别独立地选自H、D、F、Cl、Br、I、OH、NH2、C1-3烷基、C1-3烷氧基和C1-3烷氨基，所述C1-3烷基、C1-3烷氧基和C1-3烷氨基分别独立地任选被1、2或3个R取代；Each R b is independently selected from H, D, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, and the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R;
    结构单元各R、各R1、R4和n如权利要求2所定义。Structural units Each R, each R 1 , R 4 and n are as defined in claim 2.
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其中，R2选自H、F、Cl、CH3、CH2CH3和CH(CH3)2，所述CH3、CH2CH3和CH(CH3)2分别独立地任选被1、2或3个Rb取代，各Rb分别独立地选自H、D、F、OH、NH2、CH3、CD3、CF3和N(CH3)2。The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, F, Cl, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are independently optionally substituted by 1, 2 or 3 R b , and each R b is independently selected from H, D, F, OH, NH 2 , CH 3 , CD 3 , CF 3 and N(CH 3 ) 2 .
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其中，结构单元选自 The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from
  15. 根据权利要求12～14任意一项所述化合物或其药学上可接受的盐，其选自，
    The compound according to any one of claims 12 to 14 or a pharmaceutically acceptable salt thereof, which is selected from,
    其中，in,
    结构单元R1、R2和R4如权利要求12～14任意一项所定义；Structural units R 1 , R 2 and R 4 are as defined in any one of claims 12 to 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；Carbon atoms with "*" are chiral carbon atoms, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer;
    R1不为H时，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。When R 1 is not H, the carbon atom with "#" is a chiral carbon atom, existing in the form of (R) or (S) single enantiomer or enriched in one enantiomer.
  16. 根据权利要求15所述化合物或其药学上可接受的盐，其选自，
    The compound according to claim 15 or a pharmaceutically acceptable salt thereof, which is selected from,
    其中，结构单元R1、R2和R4如权利要求15所定义。Among them, the structural unit R 1 , R 2 and R 4 are as defined in claim 15.
  17. 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,








  18. 根据权利要求17所述化合物或其药学上可接受的盐，其选自，

































    The compound according to claim 17 or a pharmaceutically acceptable salt thereof, which is selected from,

































  19. 权利要求1～18任意一项所述化合物或其药学上可接受的盐在制备治疗PRMT5相关疾病的药物中的应用。 Use of the compound of any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating PRMT5-related diseases.
PCT/CN2023/103995 2022-06-30 2023-06-29 Amino-substituted heteroaryl derivative and use thereof WO2024002263A1 (en)

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WO2024153128A1 (en) * 2023-01-18 2024-07-25 Shanghai Antengene Corporation Limited Prmt5 inhibiting compounds and uses thereof
WO2024213044A1 (en) * 2023-04-14 2024-10-17 Beijing Double-Crane Runchuang Technology Co., Ltd. Azacyclo-carbonyl-fused ring derivatives and use thereof
WO2024220917A1 (en) * 2023-04-21 2024-10-24 Gilead Sciences, Inc. Prmt5 inhibitors and uses thereof

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CN113045543A (en) * 2019-12-26 2021-06-29 石药集团中奇制药技术（石家庄）有限公司 PRMT5 inhibitor and application thereof
WO2022132914A1 (en) * 2020-12-16 2022-06-23 Amgen Inc. Prmts inhibitors
WO2023034786A1 (en) * 2021-08-30 2023-03-09 Amgen Inc. Process for synthesizing naphthyridine derivatives and intermediates thereof

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CN113045543A (en) * 2019-12-26 2021-06-29 石药集团中奇制药技术（石家庄）有限公司 PRMT5 inhibitor and application thereof
WO2022132914A1 (en) * 2020-12-16 2022-06-23 Amgen Inc. Prmts inhibitors
WO2023034786A1 (en) * 2021-08-30 2023-03-09 Amgen Inc. Process for synthesizing naphthyridine derivatives and intermediates thereof

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WO2024153128A1 (en) * 2023-01-18 2024-07-25 Shanghai Antengene Corporation Limited Prmt5 inhibiting compounds and uses thereof
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