WO2024002263A1 - Dérivé hétéroaryle amino-substitué et son utilisation - Google Patents

Dérivé hétéroaryle amino-substitué et son utilisation 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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English (en)
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/fr

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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

L'invention concerne une série de dérivés hétéroaryle amino-substitués et son utilisation, et en particulier, l'invention concerne un composé représenté par la formule (IV) et un sel pharmaceutiquement acceptable de celui-ci.
PCT/CN2023/103995 2022-06-30 2023-06-29 Dérivé hétéroaryle amino-substitué et son utilisation WO2024002263A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045543A (zh) * 2019-12-26 2021-06-29 石药集团中奇制药技术（石家庄）有限公司 一种prmt5抑制剂及其应用
WO2022132914A1 (fr) * 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2023034786A1 (fr) * 2021-08-30 2023-03-09 Amgen Inc. Procédé de synthèse de dérivés de naphtyridine et d'intermédiaires de ceux-ci

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113045543A (zh) * 2019-12-26 2021-06-29 石药集团中奇制药技术（石家庄）有限公司 一种prmt5抑制剂及其应用
WO2022132914A1 (fr) * 2020-12-16 2022-06-23 Amgen Inc. Inhibiteurs de prmts
WO2023034786A1 (fr) * 2021-08-30 2023-03-09 Amgen Inc. Procédé de synthèse de dérivés de naphtyridine et d'intermédiaires de ceux-ci

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