WO2023217184A2 - Substituted pyridine or pyrimidine derivative, pharmaceutical composition thereof, preparation method, and use - Google Patents

Substituted pyridine or pyrimidine derivative, pharmaceutical composition thereof, preparation method, and use Download PDF

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WO2023217184A2
WO2023217184A2 PCT/CN2023/093248 CN2023093248W WO2023217184A2 WO 2023217184 A2 WO2023217184 A2 WO 2023217184A2 CN 2023093248 W CN2023093248 W CN 2023093248W WO 2023217184 A2 WO2023217184 A2 WO 2023217184A2
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formula
compound
pharmaceutically acceptable
acceptable salt
alkyl
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PCT/CN2023/093248
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French (fr)
Chinese (zh)
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WO2023217184A3 (en
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栾林波
姚元山
陈永凯
王朝东
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上海美悦生物科技发展有限公司
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Publication of WO2023217184A2 publication Critical patent/WO2023217184A2/en
Publication of WO2023217184A3 publication Critical patent/WO2023217184A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present disclosure belongs to the field of medicine, and specifically relates to a substituted pyridine or pyrimidine derivative and its pharmaceutical composition, preparation method and use.
  • Mitogen-activated protein kinase MAPK mitogen-activated protein kinase
  • MAPK mitogen-activated protein kinase
  • p38 MAPK responds to external signals and inflammatory cytokines in cells. After p38 MAPK is activated, it phosphorylates and activates a variety of downstream protein kinases and transcription factors, thus playing a complex biological role. effect.
  • p38 MAPK includes four members, namely p38 ⁇ , p38 ⁇ , p38 ⁇ and p38 ⁇ . Among them, p38 ⁇ is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isoforms have not been fully discovered, but they have pleiotropic effects.
  • MAP Kinase Kinase 3 mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38 ⁇ to play an role in the proliferation and survival of advanced colorectal cancer (CRC) cells.
  • MAP Kinase Kinase 3 mitogen-activated protein kinase MKK3
  • CRC colorectal cancer
  • p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152),924], so selectively inhibiting the activation of downstream effectors of p38 MAPK is to avoid side effects caused by the overall inhibition of p38 MAPK / Main strategy for insufficient drug efficacy.
  • MAPK-activated protein kinase 2 (MK2) is a direct substrate downstream of p38 MAPK and can be activated by p38 ⁇ and p38 ⁇ . As the first p38 MAPK substrate discovered, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thereby playing an important role in the regulation of multiple inflammatory diseases.
  • MK2 can increase the expression of inflammatory factors such as TNF- ⁇ , IL-6, IL-8 and COX-2 by stabilizing the AU-rich element of mRNA.
  • MK2 inhibitors can reduce the expression of inflammatory factors such as MIP-1 ⁇ , TNF- ⁇ , IL-6 and IL-1 ⁇ .
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • X is N or CH
  • Y is N or CH
  • R 1 , R 2 , R 3 and R 4 are the same or different, and are each independently selected from H, D, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl Oxygen group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, cyano group and 3 to 8 membered cycloalkyl group;
  • R 1 and R 2 together with the carbon atom to which they are connected form a 3 to 12-membered cycloalkyl group or a 3 to 12-membered heterocyclyl group, and the 3 to 12-membered cycloalkyl group or 3 to 12-membered heterocyclyl group is optionally Substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino and hydroxyl;
  • R 3 and R 4 together with the carbon atom to which they are connected form a 3 to 12-membered cycloalkyl group or a 3 to 12-membered heterocyclyl group, and the 3 to 12-membered cycloalkyl group or 3 to 12-membered heterocyclyl group is optionally Substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino and hydroxyl;
  • R 5 is selected from H, halogen and C 1-6 alkyl
  • R 6 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 deuterated alkyl;
  • R 7 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
  • R 8 is selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • Z is selected from O, S and NH
  • Ring A is a 5- to 6-membered heteroaryl group
  • R 9 and R 10 are the same or different, and are each independently selected from H, D, halogen and C 1-6 alkyl;
  • Each R 11 is the same or different, and each is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyl Alkyl, cyano, hydroxyl, amino, nitro and 3 to 8-membered cycloalkyl;
  • n is selected from 0, 1, 2, 3 and 4.
  • the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.
  • the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 1-6 deuterated alkyl.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are the same or different, and each is independently selected from H, F, OH, hydroxymethyl, methyl, ethyl;
  • R 1 and R 2 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl or tetrahydro-2H-pyranyl, and the cyclopropyl , cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl can be optionally substituted by one or more F or methyl;
  • R 3 and R 4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl or tetrahydro-2H-pyranyl; the cyclopropyl , cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl may be optionally substituted by one or more F or methyl groups.
  • the present disclosure provides compounds of formula (I), wherein Z is O, or a pharmaceutically acceptable salt thereof.
  • the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 11 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; n is 0, 1 or 2.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 11 is the same or different, and each is independently selected from F, Cl, methyl, ethyl and Trifluoromethyl; n is 0, 1 or 2.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is O; Ring A is pyridyl; each R 11 is the same or different, and each is independently selected from Halogen, C 1-6 alkyl and C 1-6 haloalkyl; n is 0, 1 or 2.
  • the compound represented by formula (I) provided by the present disclosure has a structure represented by formula (II),
  • R 11a and R 11b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, hydroxyl, amino, nitro and 3 to 8 membered cycloalkyl;
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined in formula (I).
  • the compound represented by formula (I) has a structure represented by formula (II-1) or formula (II-2),
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , X and Y are as defined in formula (II).
  • the compound represented by formula (I) has the structure represented by formula (III),
  • R 11a and R 11b are the same or different, and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, cyano, hydroxyl, amino, nitro and 3 to 8 membered cycloalkyl;
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined in formula (I).
  • the compound represented by formula (I) has a structure represented by formula (III-1) or formula (III-2),
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , X and Y are as defined in formula (III).
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from:
  • G 1 is selected from O, NR 12a or CR 13a R 14a ;
  • G 2 is selected from O, NR 12b or CR 13b R 14b ;
  • R 12a and R 12b are the same or different, and are each independently selected from H or C 1-6 alkyl;
  • R 13a , R 14a , R 13b and R 14b are the same or different, and each is independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • p 0, 1, 2, 3 or 4;
  • q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time;
  • j 0, 1, 2, 3 or 4;
  • k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time.
  • the present disclosure provides a compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
  • G 1 is selected from O, NR 12a or CR 13a R 14a ;
  • R 12a is H or C 1-6 alkyl
  • R 13a and R 14a are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • p 0, 1, 2, 3 or 4;
  • q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time.
  • the present disclosure provides a compound represented by formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
  • G 2 is selected from O, NR 12b or CR 13b R 14b ;
  • R 12b is H or C 1-6 alkyl
  • R 13b and R 14b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • j 0, 1, 2, 3 or 4;
  • k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time.
  • the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from:
  • the present disclosure provides a compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
  • the present disclosure provides a compound represented by formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
  • the compound represented by formula (I) has a structure represented by formula (IV) or formula (V),
  • G 1 is selected from O, NR 12a or CR 13a R 14a ;
  • R 12a is H or C 1-6 alkyl
  • R 13a and R 14a are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • p 0, 1, 2, 3 or 4;
  • q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and X are as defined in formula (II).
  • the compound represented by formula (I) has a structure represented by formula (VI) or formula (VII),
  • G 2 is selected from O, NR 12b or CR 13b R 14b ;
  • R 12b is H or C 1-6 alkyl
  • R 13b and R 14b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
  • j 0, 1, 2, 3 or 4;
  • k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time;
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and X are as defined in formula (III).
  • the present disclosure provides compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (IV) or formula (V) or pharmaceutical compounds thereof.
  • acceptable salt which Selected from:
  • the present disclosure provides compounds represented by formula (I), formula (III), formula (III-1), formula (III-2), formula (VI) or formula (VII) or pharmaceutical compounds thereof.
  • acceptable salt which Selected from:
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein X is N.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein X is CH.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), or Formula (III- 2)
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), or Formula (III- 2)
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 5 is H or F.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 5 is F.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halogen, methyl, ethyl, trifluoromethyl radical, difluoromethyl, CH 2 F and CD 3.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R is selected from Cl, F, methyl, ethyl, tris Fluoromethyl, difluoromethyl and CD 3 .
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halogen, methyl, ethyl and trifluoromethyl base .
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from Cl, methyl and ethyl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is Cl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is ethyl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is F.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is trifluoromethyl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is difluoromethyl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is CD 3 .
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is CH 2 F.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from Cl, methyl, ethyl, methoxy , ethoxy and trifluoromethyl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 7 is Cl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halogen, C 1-3 alkyl or C 1-3 haloalkyl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from methyl, ethyl and Cl.
  • the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are the same or different, and each is independently H or D.
  • the present disclosure provides Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula ( IV), a compound represented by formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 11a and R 11b are the same or different, and each is independently selected from halogen, C 1- 6 alkyl and C 1-6 haloalkyl.
  • the present disclosure provides Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula ( IV), a compound represented by formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 11a and R 11b are the same or different, and each is independently selected from F, Cl, base, ethyl and trifluoromethyl.
  • exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table A below:
  • exemplary specific compounds of the compound represented by formula (I) also include, but are not limited to, the structures in Table B below:
  • formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III) are provided -2), isotope labels represented by formula (IV), formula (V), formula (VI), formula (VII), or compounds shown in Table A or Table B.
  • the isotope label is preferably deuterium ( D or 2H ) replaces hydrogen ( 1H ).
  • the present disclosure provides a compound of formula (IA) or a salt thereof,
  • R 5 , R 6 , R 0 and Y are as defined in formula (I).
  • the present disclosure provides a compound of formula (IIA) or a salt thereof,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (II).
  • the present disclosure provides a compound of formula (IIA-1) or formula (IIA-2) or a salt thereof,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (II).
  • the present disclosure provides a compound of formula (IVA) or formula (VA) or a salt thereof,
  • R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a and R 11b are as defined in formula (II).
  • the present disclosure provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • the compound of formula (IB) undergoes a ring-closing reaction with the compound of formula (IA) to obtain the compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • X is N
  • R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined in formula (I).
  • the present disclosure provides a method for preparing the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • the compound of formula (IIB) undergoes a ring-closing reaction with the compound of formula (IIA) to obtain the compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • X is N
  • R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (II).
  • the compound of formula (IIB) undergoes a ring-closing reaction with the compound of formula (IIA-1) or formula (IIA-2) respectively to obtain the formula ( II-1) or a compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof, wherein X is N; R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y have the definitions stated above.
  • the present disclosure provides a method for preparing the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • the compound of formula (IIIB) undergoes a ring-closing reaction with the compound of formula (IIA) to obtain the compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
  • X is N
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (III).
  • the compound of formula (IIIB) undergoes a ring-closing reaction with the compound of formula (IIA-1) or formula (IIA-2) respectively to obtain the formula ( III-1) or a compound represented by formula (III-2) or a pharmaceutically acceptable salt thereof, wherein X is N; R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (III).
  • the present disclosure provides a method for preparing the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which includes the following steps:
  • the compound of formula (IVB) undergoes a ring-closing reaction with the compound of formula (IVA) to obtain the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
  • X is N
  • G 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , p and q are as defined in formula (IV).
  • the compound represented by formula (IVB) undergoes a ring-closing reaction with formula (VA) respectively to obtain the compound represented by formula (V) or its pharmaceutically acceptable salt.
  • Acceptable salts where X is N; G1 , R5 , R6 , R7 , R8 , R9 , R10 , R11a , R11b , p and q are as defined in formula (V).
  • formula (VIB) Refer to the method for preparing the compound represented by formula (IV) or its pharmaceutically acceptable salt, formula (VIB)
  • the compound of formula (IVA) or formula (VA) undergoes a ring-closing reaction respectively, correspondingly obtaining the compound represented by formula (VI) or (VII) or a pharmaceutically acceptable salt thereof, wherein X is N; G 2 , R 5 , R6 , R7 , R8 , R9 , R10 , R11a , R11b , j and k are as defined in formula (VI).
  • the present disclosure provides a pharmaceutical composition
  • a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the present disclosure also provides formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2 ), the use of compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them, for Preparation of p38 kinase inhibitor drugs.
  • the present disclosure also provides formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula ( IV), formula (V), formula (VI), formula (VII), a compound shown in Table A or Table B or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used in the preparation of prevention and/or Or use in medicines for treating p38 kinase-mediated diseases or conditions; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway.
  • the present disclosure also provides formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula ( IV), formula (V), formula (VI), formula (VII), a compound shown in Table A or Table B or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used in the preparation of prevention and/or Or use in medicines for treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer; preferably, it is used in the preparation of drugs for preventing and/or treating arthritis, psoriasis, systemic erythema Use in medicines for lupus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.
  • the present disclosure also provides a method for inhibiting p38 kinase, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III) ), compounds shown in formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI), formula (VII), table A or table B, or pharmaceutically acceptable compounds thereof
  • a method for inhibiting p38 kinase which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III) ), compounds shown in formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI), formula (VII), table A or table B, or pharmaceutically acceptable compounds thereof
  • the present disclosure also provides a method for preventing and/or treating p38 kinase-mediated diseases or conditions, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table
  • the present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (I), Formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI ), the compound shown in formula (VII), Table A or Table B or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition containing the same.
  • the present disclosure also provides a method for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, animal Methods for atherosclerosis and Alzheimer's disease, which include administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III) ), compounds shown in formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI), formula (VII), table A or table B, or pharmaceutically acceptable compounds thereof salt or the aforementioned pharmaceutical composition containing the same.
  • the present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or their pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions are used as medicines.
  • the present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2),
  • the compound shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition is used as a p38 kinase inhibitor.
  • the present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions containing them, which are used for the prevention and / Or a drug for treating p38 kinase-mediated diseases or conditions; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway.
  • the present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions containing them, which are used for the prevention and /or drugs to treat autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer.
  • the present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions containing them, which are used for the prevention and /or medications to treat arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.
  • the p38 kinase-mediated diseases described in the present disclosure are selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer.
  • the p38 kinase-mediated diseases described in the present disclosure are selected from the group consisting of arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.
  • the unit dosage of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), Compounds shown in Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceuticals thereof acceptable salts or isotopic labels thereof.
  • the pharmaceutical composition contains 0.1-99.9% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), the compound shown in Table A or Table B or a pharmaceutically acceptable salt thereof Isotopic markers.
  • the pharmaceutical composition contains 0.5%-99.5% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), Compounds shown in Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B, or pharmaceutically acceptable salts thereof or its isotopic label.
  • the pharmaceutical composition contains 1%-99% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), Compounds shown in Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B, or pharmaceutically acceptable salts thereof or its isotopic label.
  • the pharmaceutical composition contains 0.01% to 99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1% to 99% of one or more pharmaceutically acceptable excipients.
  • the compounds of the present disclosure may be administered in the form of pharmaceutical compositions.
  • These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area treated. May be administered topically (e.g., transdermal, cutaneous, ocular, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal), Oral or parenteral administration.
  • topically e.g., transdermal, cutaneous, ocular, and mucosal including intranasal, vaginal, and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal
  • Oral or parenteral administration e.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intracerebroventricular administration.
  • the administration may be parenteral as a single bolus or may be administered, for example, by a continuous infusion pump.
  • the active ingredients are generally mixed with excipients, and the compositions may be in the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, and suspensions , emulsions, solutions, syrups, aerosols (solid or dissolved in liquid vehicles), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders .
  • Excipients refer to ingredients other than active ingredients, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
  • pharmaceutically acceptable salts of the compounds described in the present disclosure may be inorganic salts or organic salts, which may form acid addition salts if they have a basic center or acid addition salts if they have an acidic center. They can form base addition salts; if these compounds contain both acidic centers (eg carboxyl) and basic centers (eg amino), they can also form internal salts.
  • compounds of the present disclosure may exist in specific geometric or stereoisomeric forms.
  • cis and trans isomers (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers isomer, the (L)-isomer, racemic mixtures and other mixtures, as well as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure.
  • Alkyl and other substituents may exist Additional asymmetric carbon atoms. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • the bond Indicates that the configuration is not specified, Represents the absolute configuration, i.e. if there are chiral isomers in the chemical structure, the bond can be or both Two configurations, Indicates the presence of axial chirality.
  • Tautomers refer to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also called proton transfer tautomers
  • proton migration tautomers include tautomers via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam isomerization. Isomerization of imides. All tautomeric forms of all compounds in this disclosure are within the scope of this disclosure. The name of a compound named in a single way does not exclude any tautomers.
  • the present disclosure also includes compounds of the present disclosure that have the same structure as described herein, but are isotopically labeled with one or more atoms replaced by atoms of an atomic weight or mass number different from those typically found in nature.
  • isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
  • deuterium when a position is specifically designated as deuterium (D), that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10 % deuterium incorporation).
  • Examples of compounds having a natural abundance greater than deuterium may be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials may be used in the preparation of deuterated forms of the compounds, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran. , Deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • the "therapeutically effective amount” of this disclosure refers to the amount of active compound or drug that researchers, veterinarians, physicians or other clinicians seek to cause a biological or medical response in tissues, systems, animals, individuals or humans, and it includes One or more of the following: (1) Prevention of disease: e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibition of disease: e.g., inhibition of a disease, disorder, or condition (i.e., preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing pathology or symptoms of the disease, disorder, or condition.
  • Prevention of disease e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease.
  • Inhibition of disease e.g., inhibition of a disease, disorder, or condition (i.e
  • a "therapeutically effective amount” refers to a non-toxic amount of the drug or agent that is sufficient to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • “Pharmaceutically acceptable” in this disclosure means those compounds, materials, compositions and/or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reactions or other problems or complications, have a reasonable benefit/risk ratio, and be effective for the intended use.
  • Patient in the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably people.
  • the present disclosure provides a small molecule compound represented by formula (I) with a ⁇ -hydroxyl structure, which can be used as a p38 MAPK/MK2 pathway inhibitor, such as formula (II), formula (II) with a ⁇ -hydroxyl structure -1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI), formula (VII), Compounds shown in Table A or Table B, such compounds or pharmaceutical compositions can be used to effectively treat or prevent diseases mediated by the p38 MAPK/MK2 pathway.
  • This type of ⁇ -hydroxy structural compound inhibits p38 MAPK-dependent MK2 activity while maintaining selectivity for ATF2 and MK5; in addition, this type of compound also has good in vivo pharmacokinetic properties.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups of carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms (C 1-6 alkyl).
  • alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and Various branched chain isomers, etc. Alkyl groups may be substituted or un replaced.
  • alkoxy refers to -O-(alkyl), where alkyl is as defined herein, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (C 1-12 alkoxy), more preferably an alkoxy group containing 1 to 6 carbon atoms (C 1-6 alkoxy).
  • alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be substituted or unsubstituted.
  • cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g. 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably containing 3 to 6 carbon atoms.
  • Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
  • spirocycloalkyl refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between each single ring in the system, which may contain one or more double bonds.
  • a spiro atom a carbon atom shared between each single ring in the system, which may contain one or more double bonds.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spirocycloalkyl group is divided into a single spirocycloalkyl group, a double spirocycloalkyl group or a polyspirocycloalkyl group, and is preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocyclic alkyl group.
  • spirocycloalkyl groups include:
  • fused cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 1/5-membered and 6-membered/6-membered bicycloalkyl groups.
  • fused cycloalkyl groups include:
  • bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly connected, and may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • the cycloalkyl ring includes a cycloalkyl group (including monocyclic, spiro, fused and bridged rings) as described herein fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein with the parent
  • the rings linked together by the structure are cycloalkyl, non-limiting examples include etc; preferred
  • the cycloalkyl group may be substituted or unsubstituted.
  • heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur,
  • the sulfur may optionally be oxosubstituted (i.e., to form a sulfoxide or sulfone), but does not include the -OO-, -OS- or -SS- ring moiety, and the remaining ring atoms are carbon.
  • Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazine base, etc.
  • Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
  • spiroheterocyclyl refers to a polycyclic heterocyclic group with 5 to 20 members, each single ring in the system shares one atom (called a spiro atom), in which one or more ring atoms are selected from nitrogen, Heteroatoms of oxygen and sulfur, the sulfur may be optionally oxo-substituted (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group.
  • spiroheterocyclyl include:
  • fused heterocyclyl refers to a polycyclic heterocyclic group with 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxo-substituted (ie, forming sulfoxide or sulfone), and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 One-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups.
  • fused heterocyclyl groups include:
  • bridged heterocyclyl refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, one or more of which are ring atoms. is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxo-substituted (ie, forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan).
  • bridged heterocyclyl groups preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocyclyl groups include:
  • the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) as described herein fused to an aryl, heteroaryl or cycloalkyl ring, wherein
  • the ring attached to the parent structure is a heterocyclyl group, non-limiting examples of which include:
  • the heterocyclyl group may be substituted or unsubstituted.
  • aryl refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated ⁇ electron system, preferably 6 to 10 members , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl or cycloalkyl ring as described herein, where the ring attached to the parent structure is an aryl ring, which is not limited to Examples include:
  • Aryl groups may be substituted or unsubstituted.
  • heteroaryl refers to a heteroaromatic system containing from 1 to 4 (eg, 1, 2, 3, and 4) heteroatoms, and from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen.
  • the heteroaryl group is preferably 5 to 10 yuan (such as 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • yuan such as 5, 6, 7, 8, 9 or 10 yuan
  • 6 yuan such as furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described herein, where the ring attached to the parent structure is a heteroaryl ring, which is not limited to sexual examples include:
  • Heteroaryl groups may be substituted or unsubstituted.
  • alkyl alkoxy
  • cycloalkyl heterocyclyl
  • aryl and “heteroaryl” as used herein may be substituted or unsubstituted; when substituted When it is used, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano , one or more identical or different substituents in amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • cycloalkyl, heterocyclyl, aryl and heteroaryl include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same or two different ring atoms of the parent. Derivatized residues, namely "bivalent cycloalkyl”, “bivalent heterocyclyl", “arylene”, “heteroaryl”.
  • cycloalkyloxy refers to cycloalkyl-O-, where cycloalkyl is as defined herein.
  • heterocyclyloxy refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.
  • haloalkyl refers to an alkyl group substituted with one or more halogens, where alkyl is as defined herein.
  • haloalkoxy refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined herein.
  • hydroxyalkyl refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined herein.
  • halogen refers to F, Cl, Br or I.
  • hydroxy refers to -OH.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • carboxylate refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined herein.
  • heterocycloalkyl group optionally substituted by alkyl means that alkyl groups may but need not be present, and this description includes the case where the heterocycloalkyl group is substituted by an alkyl group and the heterocycloalkyl group is not substituted by an alkyl group. replacement situation.
  • Substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
  • the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts ( ⁇ ) are given in units of 10 -6 (ppm). NMR was measured using a Bruker Avance III 400MHz nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was tetrahydrofuran. Methylsilane (TMS).
  • Mass spectrometry was measured by Waters 2767 HPLC/Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC/Waters liquid phase mass spectrometer.
  • Thin layer chromatography silica gel plate is used in Cheng Chemical (Shanghai) Co., Ltd. GF254 silica gel plate.
  • the specification of silica gel plate used in thin layer chromatography (TLC) is 0.2 ⁇ 0.25mm.
  • the specification of thin layer chromatography separation and purification products is 0.4 ⁇ 0.5mm.
  • Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 liter.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.
  • reaction temperature is room temperature, and the temperature range is 20°C-30°C.
  • the resolved chiral compounds can be distinguished by the order of their retention times in the chiral chromatographic column. Therefore, the chiral compounds that have been resolved successively according to their retention times are distinguished by the number suffixes P1 and P2. . That is, the suffix P1 corresponds to the chiral structure separated first, and the suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of a compound is listed in the structural formula, it does not mean that it corresponds to the compounds with the number suffix P1 and P2, but only indicates the two existence forms of the absolute configuration. The absolute configurations of compounds with number suffixes P1 and P2 are based on the absolute configurations objectively corresponding to specific retention times.
  • reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL), and extracted with ethyl acetate (300 mL ⁇ 3). The combined organic phases were washed with saturated brine (300 mL 1) Purify to obtain compound A2-2 (6.6g, yield: 30%). MS m/z(ESI):185.1[M+1] + .
  • Bistriphenylphosphine palladium dichloride (1.56g, 2.22mmol) was added to compound A2-4 (8.4g, 22.2mmol) and tributyl(1-ethoxyethylene)tin (10.21g, 24.2mmol)
  • 1,4-dioxane 100 mL
  • the reaction mixture was heated to 130°C and stirred at this temperature for 4 hours.
  • the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure.
  • Tetrahydrofuran 100 mL was added to the residue to dissolve, and then 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour.
  • N,N-dimethylformamide dimethyl acetal (0.85g, 7.2mmol) was added to the N,N- of compound A2-6 (1.3g, 3.1mmol).
  • the reaction mixture was heated to 100°C in dimethylformamide (15 mL) and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL ⁇ 3). The combined organic phases were washed with saturated brine (30 mL Compound A2 (900 mg, yield: 78%) was purified. MS m/z(ESI):474.9[M+H] + .
  • Diphenylphosphoryl azide (23.5g, 0.085mol) was added to a mixture of compound A3-1 (10g, 0.057mol) and triethylamine (17.3g, 0.17mol) in tert-butanol/toluene (50mL/50mL). In solution, the reaction mixture was heated at 110°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane (200 mL ⁇ 3). The combined organic phases were washed with water (150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent.
  • methylboronic acid 530mg, 8.8mmol
  • cesium carbonate 8.96g, 27.5mmol
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride 450mg , 0.55 mmol
  • N,N-dimethylformamide dimethyl acetal 600 mg, 5.0 mmol was added to a solution of compound A3-11 (1.08 g, 2.5 mmol) in N, N-dimethylformamide (15 mL). The reaction was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL ⁇ 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent.
  • Bistriphenylphosphine palladium dichloride (146 mg, 0.21 mmol) was added to 1 of compound A4-4 (900 mg, 2.09 mmol) and tributyl(1-ethoxyethylene)tin (2.64 g, 7.3 mmol).
  • 4-dioxane 20 mL
  • the reaction mixture was heated to 130°C and stirred at this temperature for 1.5 hours.
  • the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • Tetrahydrofuran (20 mL) was added to the residue to dissolve, and then 2 mL of concentrated hydrochloric acid was added dropwise, and the resulting mixture was stirred for 1 hour.
  • 1,1-Bis(diphenylphosphine)ferrocene palladium dichloride (1.59g, 1.96mmol) was added to compound A7-1 (5g, 19.6mmol) and triethylboron tetrahydrofuran solution (25.5mL, 25.5 mmol) and cesium carbonate (38.32 g, 117.6 mmol) in tetrahydrofuran (100 mL), the reaction mixture was heated to 55°C under nitrogen protection and stirred for 16 hours.
  • 1,4-dibromobutane (21g, 97.2mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (29.61g, 194.5mmol) were added to the compound in sequence
  • DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
  • reaction solution was diluted with water (400mL), and Extract with ethyl acetate (200 mL ⁇ 3), wash the combined organic phases with saturated brine (200 mL ⁇ 3), dry with anhydrous sodium sulfate and filter, filter and concentrate under reduced pressure to obtain compound 10b (10 g, yield: 61%).
  • Compound 10 was purified by supercritical fluid chiral chromatography ((equipment: SFC Thar prep 80, column: CHIRALPAK AD- H 250mm*20mm, 5 ⁇ m, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min), compound 10-P1 (20mg, yield 16%) and 10- P2 (20 mg, yield 16%).
  • Lithium diisopropylamide (29.2 mL, 58.4 mmol) was added to a solution of compound 15a (3.41 g, 48.7 mmol) in tetrahydrofuran (50 mL) at -60°C, and the reaction mixture was stirred at -60°C for 1 hour, and then Acetonitrile (2.4g, 58.4mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. At the end of the reaction, the reaction solution was quenched by adding saturated ammonium chloride solution (10 mL). The quenching solution was concentrated under reduced pressure to remove tetrahydrofuran.
  • Compound 53 was purified by supercritical fluid chiral chromatography (equipment : SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5 ⁇ m, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min).
  • Compound 53-P1 27.1 mg, yield 9.76%) and compound 53-P2 (24.6 mg, yield 8.84%).
  • Example 18 (Compound 65, 65-P1 or 65-P2 or 65-P3 or 65-P4, 65-P2 or 65-P1 or 65-P3 or 65-P4, 65-P3 or 65-P4 or 65-P1 or 65-P2, 65-P4 or 65-P1 or 65-P2 or 65-P3) synthesis
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride 134 mg, 0.18 mmol was added to compound 65b (450 mg, 0.92 mmol), isopropenylboronic acid pinacol
  • ester 154 mg, 0.92 mmol
  • potassium carbonate 381 mg, 2.75 mmol
  • 1,4-dioxane and water 10 mL/2 mL
  • Step 4 Synthesis of compounds 65-P1, 65-P2, 65-P3, 65-P4
  • Isopropenylboronic acid pinacol ester (41.5 mg, 0.25 mmol, CAS: 126726-62-3), potassium carbonate (62 mg, 0.45 mmol) and [1,1'-bis(diphenylphosphino)bis Ferrocene]palladium(II) dichloride dichloromethane complex (18.3 mg, 0.022 mmol) was added to compound 67a (120 mg, 0.225 mmol) mixed with 1,4-dioxane and water (10 mL/1 mL) In solution, the reaction mixture was heated to 90°C under a nitrogen atmosphere and stirred at this temperature for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (5 mg, 0.006 mmol) was added to compound 68b (236 mg, 1.2 mmol), compound In a mixed solution of A6 (300 mg, 0.6 mmol) and potassium carbonate (165 mg, 1.2 mmol) in 1,4-dioxane and water (10 mL/1 mL), the reaction mixture was heated to 90°C under a nitrogen atmosphere and at this temperature Stir for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure.
  • Step 2 Synthesis of compounds 88-P1 and 88-P2
  • Step 2 Synthesis of compounds 89-P1 and 89-P2
  • Example 25 Synthesis of Example 25 (Compound 108, 108-P1 or 108-P2 and 108-P2 or 108-P1)
  • Example 27 Synthesis of Example 27 (Compound 111, 111-P1 or 111-P2 and 111-P2 or 111-P1)
  • Test Example 1 Determination of p38 MAPK/MK2 activity in vitro
  • the inhibitory effect of compounds on p38 MAPK/MK2 was detected using Z-LYTE kinase detection kit (Thermo, PV3177). Dissolve test compounds in DMSO to 10mM stock solution and store at -20°C until use.
  • the starting concentration of the compound is 10 ⁇ M, 1% DMSO, 5-fold dilution, 8 concentrations, double wells; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA is used as reaction buffer to prepare 2x active p38a/inactive MK2/Ser/Thr 4 mixture, the final 10 ⁇ L reaction system was carried out in a 384-well plate (Corning, 4514), containing 500ng/mL inactive MK2 (abcam, 79910), 8ng/mL active p38a (Carna, 04-152), 2 ⁇ M Ser/Thr 4; after reacting at 20°C for 1 hour, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 ⁇ L of stop buffer solution to terminate the reaction, and detect with a microplate reader (Ex.
  • Test Example 2 In vitro activity measurement of TNF- ⁇ in human PBMC cell supernatant
  • the experimental protocol for the inhibitory effect of compounds on TNF- ⁇ in human PBMC cell supernatants was tested using Elisa detection kit (Beyotime, PI518). Dissolve test compounds in DMSO to 10mM stock solution and store at -20°C until use. The starting concentration of the compound is 2 ⁇ M, 5-fold dilution, 6 concentrations, cells are plated in double wells, Elisa detection is single well, the final concentration of DMSO is 0.4%, the starting concentration of the compound can also be changed according to the actual situation of compound screening. , dilution ratio, number of gradient concentrations and number of duplicate wells.
  • PBMC peripheral blood mononuclear cells
  • the compounds of the present disclosure have good inhibitory effects on TNF- ⁇ in human PBMC cells.

Abstract

The present disclosure relates to a substituted pyridine or pyrimidine derivative and a use thereof. Specifically, provided are a substituted pyridine or pyrimidine compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which can be used for preparing a drug, and particularly for preparing a drug for preventing and/or treating a p38 MAPK/MK2 pathway-mediated disease or disorder. Each group in formula (I) is as defined in the description.

Description

取代的吡啶或嘧啶类衍生物及其药物组合物、制备方法和用途Substituted pyridine or pyrimidine derivatives and pharmaceutical compositions, preparation methods and uses thereof
本公开要求享有：This disclosure request enjoys:
于2022年5月12日向中国国家知识产权局提交的，专利申请号为202210533240.2，名称为“取代的吡啶或嘧啶类衍生物及其药物组合物、制备方法和用途”的在先申请的优先权；Submitted to the State Intellectual Property Office of China on May 12, 2022, the patent application number is 202210533240.2, and the priority is the priority of the earlier application titled "Substituted pyridine or pyrimidine derivatives and pharmaceutical compositions, preparation methods and uses thereof" ;
于2022年9月19日向中国国家知识产权局提交的，专利申请号为202211139876.5，名称为“取代的吡啶或嘧啶类衍生物及其药物组合物、制备方法和用途”的在先申请的优先权；Submitted to the State Intellectual Property Office of China on September 19, 2022, the patent application number is 202211139876.5, and the priority is the priority of the earlier application titled "Substituted pyridine or pyrimidine derivatives and pharmaceutical compositions, preparation methods and uses thereof" ;
上述在先申请的全文通过引用的方式结合于本申请中。The entire contents of the above-mentioned prior applications are incorporated into this application by reference.
技术领域Technical field
本公开属于医药领域，具体涉及一种取代的吡啶或嘧啶类衍生物及其药物组合物、制备方法和用途。The present disclosure belongs to the field of medicine, and specifically relates to a substituted pyridine or pyrimidine derivative and its pharmaceutical composition, preparation method and use.
背景技术Background technique
生物信号转导涉及特异性的蛋白-蛋白相互作用和翻译后修饰、调节遗传和表观遗传过程以应对内外环境的作用。丝裂原活化蛋白激酶MAPK(mitogen-activated protein kinase)是一组能被不同的细胞内外部应激激活的丝氨酸-苏氨酸蛋白激酶，是信号从细胞表面传导到细胞核内部的重要传递者。应激因素包括细胞因子、神经递质、激素、细胞应激和细胞黏附等。Biological signal transduction involves specific protein-protein interactions and post-translational modifications, regulating genetic and epigenetic processes in response to the effects of internal and external environments. Mitogen-activated protein kinase MAPK (mitogen-activated protein kinase) is a group of serine-threonine protein kinases that can be activated by different intracellular and external stresses. It is an important transmitter of signals from the cell surface to the interior of the nucleus. Stress factors include cytokines, neurotransmitters, hormones, cell stress and cell adhesion.
作为MAPK家族的一个亚族，p38 MAPK在细胞对外界信号和炎性细胞因子的作用做出响应，p38 MAPK被激活后磷酸化并激活下游多种蛋白激酶和转录因子，从而发挥复杂的生物学作用。p38 MAPK包括四个成员，即p38α、p38β、p38γ和p38δ。其中，p38α被认为在炎症过程的信号通路中起着重要作用，而其它异构体的生物学功能尚未完全被发现，但它们具有多效性。研究表明，p38β在细胞保护机制中起着重要的作用，而丝裂原活化蛋白激酶MKK3(MAP Kinase Kinase 3)介导p38δ对晚期结直肠癌(CRC)细胞的增殖和存活有作用。作为药物开发领域一个有吸引力的靶点，p38 MAPK有多个抑制剂药物进入临床研究，截至目前还没有药物被批准上市。根据***息，部分候选化合物在临床研究阶段失败。因此，开发一款安全有效的p38 MAPK抑制剂是目前该领域药物开发面临的主要挑战。As a subfamily of the MAPK family, p38 MAPK responds to external signals and inflammatory cytokines in cells. After p38 MAPK is activated, it phosphorylates and activates a variety of downstream protein kinases and transcription factors, thus playing a complex biological role. effect. p38 MAPK includes four members, namely p38α, p38β, p38γ and p38δ. Among them, p38α is considered to play an important role in the signaling pathway of the inflammatory process, while the biological functions of other isoforms have not been fully discovered, but they have pleiotropic effects. Studies have shown that p38β plays an important role in cell protection mechanisms, and mitogen-activated protein kinase MKK3 (MAP Kinase Kinase 3) mediates p38δ to play an role in the proliferation and survival of advanced colorectal cancer (CRC) cells. As an attractive target in the field of drug development, multiple inhibitor drugs of p38 MAPK have entered clinical research, but so far no drug has been approved for marketing. According to public information, some candidate compounds failed in the clinical research stage. Therefore, developing a safe and effective p38 MAPK inhibitor is a major challenge currently facing drug development in this field.
p38 MAPK可调控超过60种底物并行使不同的生理学功能[Cell 2013(152),924]，所以选择性地抑制p38 MAPK下游效应物的激活，是避免由于p38 MAPK的整体抑制而导致的副作用/药效不足的主要策略。MAPK激活蛋白激酶2(MAPK-activated protein kinase 2，MK2)是p38 MAPK下游的直接作用底物，可被p38α和p38β激活。作为第一个被发现的p38 MAPK底物，MK2可在转录和转录后水平调节炎症因子的表达，从而在多个炎症性疾病的调节中发挥重要作用。研究表明，MK2可通过稳定mRNA的AU-rich元件，从而使TNF-α、IL-6、IL-8和COX-2等炎症因子表达增加。在小鼠的术后肠梗阻模型中[The Journal of surgical research 2013(185),102]，MK2抑制剂可减少炎症因子MIP-1α、TNF-α、IL-6和IL-1β等的表达，同时发现多形核白细胞、肥大细胞、单核巨噬细胞浸润的减少和肠平滑肌收缩性能的改善。在小鼠的胶原诱发性关节炎(CIA)模型中[Journal of immunology 2006(177),1913]，敲除MK2基因可以减少胶原诱发性关节炎的发生，与野生型小鼠相比，MK2-/-和MK2+/-小鼠胶原诱发性关节炎的发病率减少、严重程度降低，且炎症因子TNF-α和IL-6表达也有不同程度的减少。在MK2敲除的高胆固醇血症小鼠模型中[Circ Res 2007(101),1104]，小鼠的大动脉的脂质沉积和巨噬细胞减少，而且VCAM-1和MCP-1等炎症因子表达减少。另外，有研究表明抑制MK2可以用于抗肿瘤药物的开发[Cancer cell 2007(11),175]。因此，需要寻找新的小分子抑制剂，通过选择性的调控p38 MAPK/MK2通路，在抑制p38 MAPK依赖性的MK2活性同时保持p38 MAPK其它底物的选择性(例如ATF2和MK5)，在保持治疗效果的同时提高药物的安全性。p38 MAPK can regulate more than 60 substrates and perform different physiological functions [Cell 2013(152),924], so selectively inhibiting the activation of downstream effectors of p38 MAPK is to avoid side effects caused by the overall inhibition of p38 MAPK / Main strategy for insufficient drug efficacy. MAPK-activated protein kinase 2 (MK2) is a direct substrate downstream of p38 MAPK and can be activated by p38α and p38β. As the first p38 MAPK substrate discovered, MK2 can regulate the expression of inflammatory factors at the transcriptional and post-transcriptional levels, thereby playing an important role in the regulation of multiple inflammatory diseases. Studies have shown that MK2 can increase the expression of inflammatory factors such as TNF-α, IL-6, IL-8 and COX-2 by stabilizing the AU-rich element of mRNA. In the mouse postoperative intestinal obstruction model [The Journal of surgical research 2013(185),102], MK2 inhibitors can reduce the expression of inflammatory factors such as MIP-1α, TNF-α, IL-6 and IL-1β, At the same time, it was found that the infiltration of polymorphonuclear leukocytes, mast cells, and mononuclear macrophages was reduced and the contractile properties of intestinal smooth muscle were improved. In the mouse collagen-induced arthritis (CIA) model [Journal of immunology 2006(177),1913], knocking out the MK2 gene can reduce the occurrence of collagen-induced arthritis. Compared with wild-type mice, MK2- The incidence and severity of collagen-induced arthritis in /- and MK2+/- mice were reduced, and the expression of inflammatory factors TNF-α and IL-6 was also reduced to varying degrees. In the MK2 knockout mouse model of hypercholesterolemia [Circ Res 2007(101),1104], the lipid deposition and macrophages in the aorta of mice were reduced, and inflammatory factors such as VCAM-1 and MCP-1 were expressed. reduce. In addition, some studies have shown that inhibiting MK2 can be used for the development of anti-tumor drugs [Cancer cell 2007(11),175]. Therefore, there is a need to find new small molecule inhibitors that can inhibit p38 MAPK-dependent MK2 activity while maintaining the selectivity of other p38 MAPK substrates (such as ATF2 and MK5) by selectively regulating the p38 MAPK/MK2 pathway. While improving the therapeutic effect, the safety of the drug is improved.
发明内容Contents of the invention
本公开提供了一种式(I)所示化合物或其药学上可接受的盐，
The present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
其中：in:
X为N或CH；X is N or CH;
Y为N或CH；Y is N or CH;
R1、R2、R3和R4相同或不同，且各自独立地选自H、D、卤素、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基和3至8元环烷基；R 1 , R 2 , R 3 and R 4 are the same or different, and are each independently selected from H, D, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl Oxygen group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, cyano group and 3 to 8 membered cycloalkyl group;
或者R1和R2与其相连的碳原子一起形成3至12元环烷基或3至12元杂环基，所述的3至12元环烷基或3至12元杂环基任选被选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基和羟基中的一个或多个取代基所取代；Or R 1 and R 2 together with the carbon atom to which they are connected form a 3 to 12-membered cycloalkyl group or a 3 to 12-membered heterocyclyl group, and the 3 to 12-membered cycloalkyl group or 3 to 12-membered heterocyclyl group is optionally Substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino and hydroxyl;
或者R3和R4与其相连的碳原子一起形成3至12元环烷基或3至12元杂环基，所述的3至12元环烷基或3至12元杂环基任选被选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基和羟基中的一个或多个取代基所取代；Or R 3 and R 4 together with the carbon atom to which they are connected form a 3 to 12-membered cycloalkyl group or a 3 to 12-membered heterocyclyl group, and the 3 to 12-membered cycloalkyl group or 3 to 12-membered heterocyclyl group is optionally Substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino and hydroxyl;
R5选自H、卤素和C1-6烷基；R 5 is selected from H, halogen and C 1-6 alkyl;
R6选自卤素、C1-6烷基、C1-6卤代烷基和C1-6氘代烷基；R 6 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 deuterated alkyl;
R0为 R 0 is
R7选自H、卤素、C1-6烷基、C1-6烷氧基和C1-6卤代烷基；R 7 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
R8选自H、卤素、C1-6烷基和C1-6卤代烷基；R 8 is selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
Rt为 R t is
Z选自O、S和NH；Z is selected from O, S and NH;
环A为5至6元杂芳基；Ring A is a 5- to 6-membered heteroaryl group;
R9和R10相同或不同，且各自独立地选自H、D、卤素和C1-6烷基；R 9 and R 10 are the same or different, and are each independently selected from H, D, halogen and C 1-6 alkyl;
各个R11相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；Each R 11 is the same or different, and each is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyl Alkyl, cyano, hydroxyl, amino, nitro and 3 to 8-membered cycloalkyl;
n选自0、1、2、3和4。n is selected from 0, 1, 2, 3 and 4.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中R6选自卤素、C1-6烷基和C1-6卤代烷基。In some embodiments, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中R6选自C1-6氘代烷基。In some embodiments, the present disclosure provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from C 1-6 deuterated alkyl.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中R1、R2、R3和R4相同或不同，且各自独立地选自H、F、OH、羟甲基、甲基、乙基；In some embodiments, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are the same or different, and each is independently selected from H, F, OH, hydroxymethyl, methyl, ethyl;
或者R1和R2与其相连的碳原子一起形成环丙基、环丁基、氧杂环丁烷基、环戊基、环己基或四氢-2H-吡喃基，所述的环丙基、环丁基、氧杂环丁烷基、环戊基、环己基、四氢-2H-吡喃基可以任选被一个或多个F或甲基取代；Or R 1 and R 2 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl or tetrahydro-2H-pyranyl, and the cyclopropyl , cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl can be optionally substituted by one or more F or methyl;
或者R3和R4与其相连的碳原子一起形成环丙基、环丁基、氧杂环丁烷基、环戊基、环己基或四氢-2H-吡喃基；所述的环丙基、环丁基、氧杂环丁烷基、环戊基、环己基、四氢-2H-吡喃基可以任选被一个或多个F或甲基取代。 Or R 3 and R 4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl or tetrahydro-2H-pyranyl; the cyclopropyl , cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl may be optionally substituted by one or more F or methyl groups.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中Z为O。In some embodiments, the present disclosure provides compounds of formula (I), wherein Z is O, or a pharmaceutically acceptable salt thereof.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中环A为吡啶基。In some embodiments, the present disclosure provides a compound represented by formula (I), or a pharmaceutically acceptable salt thereof, wherein ring A is pyridyl.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中各个R11相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；n为0、1或2。In some embodiments, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 11 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; n is 0, 1 or 2.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中各个R11相同或不同，且各自独立地选自F、Cl、甲基、乙基和三氟甲基；n为0、1或2。In some embodiments, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein each R 11 is the same or different, and each is independently selected from F, Cl, methyl, ethyl and Trifluoromethyl; n is 0, 1 or 2.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中Z为O；环A为吡啶基；各个R11相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；n为0、1或2。In some embodiments, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Z is O; Ring A is pyridyl; each R 11 is the same or different, and each is independently selected from Halogen, C 1-6 alkyl and C 1-6 haloalkyl; n is 0, 1 or 2.
在一些实施方式中，本公开提供的式(I)所示化合物具有式(II)所示的结构，
In some embodiments, the compound represented by formula (I) provided by the present disclosure has a structure represented by formula (II),
其中：in:
R11a和R11b相同或不同，且各自独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；R 11a and R 11b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, hydroxyl, amino, nitro and 3 to 8 membered cycloalkyl;
R1、R2、R5、R6、R7、R8、R9、R10、X和Y如式(I)中所定义。R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined in formula (I).
在一些实施方式中，式(I)所示化合物具有式(II-1)或式(II-2)所示的结构，
In some embodiments, the compound represented by formula (I) has a structure represented by formula (II-1) or formula (II-2),
其中：加粗的化学键表示化合物存在轴手性；Among them: Bold chemical bonds indicate the presence of axial chirality in the compound;
R1、R2、R5、R6、R7、R8、R9、R10、R11a、R11b、X和Y如式(II)中所定义。R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , X and Y are as defined in formula (II).
在一些实施方式中，式(I)所示化合物具有式(III)所示的结构，
In some embodiments, the compound represented by formula (I) has the structure represented by formula (III),
其中：R11a和R11b相同或不同，且各自独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；Wherein: R 11a and R 11b are the same or different, and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, cyano, hydroxyl, amino, nitro and 3 to 8 membered cycloalkyl;
R3、R4、R5、R6、R7、R8、R9、R10、X和Y如式(I)中所定义。R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined in formula (I).
在一些实施方式中，式(I)所示化合物具有式(III-1)或式(III-2)所示的结构，
In some embodiments, the compound represented by formula (I) has a structure represented by formula (III-1) or formula (III-2),
其中：加粗的化学键表示化合物存在轴手性；Among them: Bold chemical bonds indicate the presence of axial chirality in the compound;
R3、R4、R5、R6、R7、R8、R9、R10、R11a、R11b、X和Y如式(III)中所定义。R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , X and Y are as defined in formula (III).
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中选自：
In some embodiments, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from:
G1选自O、NR12a或CR13aR14a；G 1 is selected from O, NR 12a or CR 13a R 14a ;
G2选自O、NR12b或CR13bR14b；G 2 is selected from O, NR 12b or CR 13b R 14b ;
R12a和R12b相同或不同，且各自独立地选自H或C1-6烷基； R 12a and R 12b are the same or different, and are each independently selected from H or C 1-6 alkyl;
R13a、R14a、R13b和R14b相同或不同，且各自独立地选自H、卤素、C1-6烷基或C1-6卤代烷基；R 13a , R 14a , R 13b and R 14b are the same or different, and each is independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
p为0、1、2、3或4；p is 0, 1, 2, 3 or 4;
q为0、1、2、3或4；条件是p和q不同时为0；q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time;
j为0、1、2、3或4；j is 0, 1, 2, 3 or 4;
k为0、1、2、3或4；条件是j和k不同时为0。k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time.
在一些实施方式中，本公开提供了式(II)、式(II-1)或式(II-2)所示化合物或其药学上可接受的盐，其中选自： In some embodiments, the present disclosure provides a compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
G1选自O、NR12a或CR13aR14a；G 1 is selected from O, NR 12a or CR 13a R 14a ;
R12a为H或C1-6烷基；R 12a is H or C 1-6 alkyl;
R13a和R14a相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13a and R 14a are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
p为0、1、2、3或4；p is 0, 1, 2, 3 or 4;
q为0、1、2、3或4；条件是p和q不同时为0。q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time.
在一些实施方式中，本公开提供了式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中选自： In some embodiments, the present disclosure provides a compound represented by formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
G2选自O、NR12b或CR13bR14b；G 2 is selected from O, NR 12b or CR 13b R 14b ;
R12b为H或C1-6烷基；R 12b is H or C 1-6 alkyl;
R13b和R14b相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13b and R 14b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
j为0、1、2、3或4；j is 0, 1, 2, 3 or 4;
k为0、1、2、3或4；条件是j和k不同时为0。k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time.
在一些实施方式中，本公开提供了式(I)所示化合物或其药学上可接受的盐，其中选自：
In some embodiments, the present disclosure provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, wherein Selected from:
在一些实施方式中，本公开提供了式(II)、式(II-1)或式(II-2)所示化合物或其药学上可接受的盐，其中 选自： In some embodiments, the present disclosure provides a compound represented by formula (II), formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
在一些实施方式中，本公开提供了式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中选自： In some embodiments, the present disclosure provides a compound represented by formula (III), formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof, wherein Selected from:
在一些实施方式中，式(I)所示化合物具有式(IV)或式(V)所示的结构，
In some embodiments, the compound represented by formula (I) has a structure represented by formula (IV) or formula (V),
其中：in:
G1选自O、NR12a或CR13aR14a；G 1 is selected from O, NR 12a or CR 13a R 14a ;
R12a为H或C1-6烷基；R 12a is H or C 1-6 alkyl;
R13a和R14a相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13a and R 14a are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
p为0、1、2、3或4；p is 0, 1, 2, 3 or 4;
q为0、1、2、3或4；条件是p和q不同时为0；q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time;
R5、R6、R7、R8、R9、R10、R11a、R11b和X如式(II)中所定义。R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and X are as defined in formula (II).
在一些实施方式中，式(I)所示化合物具有式(VI)或式(VII)所示的结构，
In some embodiments, the compound represented by formula (I) has a structure represented by formula (VI) or formula (VII),
其中：in:
G2选自O、NR12b或CR13bR14b；G 2 is selected from O, NR 12b or CR 13b R 14b ;
R12b为H或C1-6烷基；R 12b is H or C 1-6 alkyl;
R13b和R14b相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13b and R 14b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
j为0、1、2、3或4；j is 0, 1, 2, 3 or 4;
k为0、1、2、3或4；条件是j和k不同时为0；k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time;
R5、R6、R7、R8、R9、R10、R11a、R11b和X如式(III)中所定义。R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and X are as defined in formula (III).
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(IV)或式(V)所示化合物或其药学上可接受的盐，其中选自： In some embodiments, the present disclosure provides compounds represented by formula (I), formula (II), formula (II-1), formula (II-2), formula (IV) or formula (V) or pharmaceutical compounds thereof. acceptable salt, which Selected from:
在一些实施方式中，本公开提供了式(I)、式(III)、式(III-1)、式(III-2)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中选自： In some embodiments, the present disclosure provides compounds represented by formula (I), formula (III), formula (III-1), formula (III-2), formula (VI) or formula (VII) or pharmaceutical compounds thereof. acceptable salt, which Selected from:
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中X为N。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein X is N.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中X为CH。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein X is CH.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中Y为N。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), or Formula (III- 2) The compound shown or a pharmaceutically acceptable salt thereof, wherein Y is N.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)或式(III-2)所示化合物或其药学上可接受的盐，其中Y为CH。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), or Formula (III- 2) The compound shown or a pharmaceutically acceptable salt thereof, wherein Y is CH.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R5为H或F。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 5 is H or F.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R5为H。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 5 is H.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R5为F。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 5 is F.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6选自卤素、甲基、乙基、三氟甲基、二氟甲基、CH2F和CD3。 In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halogen, methyl, ethyl, trifluoromethyl radical, difluoromethyl, CH 2 F and CD 3.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6选自Cl、F、甲基、乙基、三氟甲基、二氟甲基和CD3。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R is selected from Cl, F, methyl, ethyl, tris Fluoromethyl, difluoromethyl and CD 3 .
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6选自卤素、甲基、乙基和三氟甲基。 In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halogen, methyl, ethyl and trifluoromethyl base .
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6选自Cl、甲基和乙基。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from Cl, methyl and ethyl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为甲基。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为Cl。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is Cl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为乙基。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is ethyl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为F。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is F.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为三氟甲基。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is trifluoromethyl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为二氟甲基。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is difluoromethyl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为CD3。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is CD 3 .
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R6为CH2F。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 6 is CH 2 F.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R7选自Cl、甲基、乙基、甲氧基、乙氧基和三氟甲基。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from Cl, methyl, ethyl, methoxy , ethoxy and trifluoromethyl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R7为Cl。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 7 is Cl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R8选自H、卤素、C1-3烷基或C1-3卤代烷基。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halogen, C 1-3 alkyl or C 1-3 haloalkyl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R8选自甲基、乙基和Cl。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from methyl, ethyl and Cl.
在一些实施方式中，本公开提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R9和R10相同或不同，且各自独立地为H或D。In some embodiments, the present disclosure provides Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III- 2), a compound represented by formula (IV), formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are the same or different, and each is independently H or D.
在一些实施方式中，本公开提供了式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R11a和R11b相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。In some embodiments, the present disclosure provides Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula ( IV), a compound represented by formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 11a and R 11b are the same or different, and each is independently selected from halogen, C 1- 6 alkyl and C 1-6 haloalkyl.
在一些实施方式中，本公开提供了式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)或式(VII)所示化合物或其药学上可接受的盐，其中R11a和R11b相同或不同，且各自独立地选自F、Cl、甲基、乙基和三氟甲基。In some embodiments, the present disclosure provides Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula ( IV), a compound represented by formula (V), formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof, wherein R 11a and R 11b are the same or different, and each is independently selected from F, Cl, base, ethyl and trifluoromethyl.
在一些实施方式中，式(I)所示化合物的示例性的具体化合物包括，但不限于下表A中的结构：In some embodiments, exemplary specific compounds of the compound represented by formula (I) include, but are not limited to, the structures in Table A below:
表A






















Table A






















在一些实施方式中，式(I)所示化合物的示例性的具体化合物还包括，但不限于下表B中的结构：In some embodiments, exemplary specific compounds of the compound represented by formula (I) also include, but are not limited to, the structures in Table B below:
表B







Table B







在本公开的另一方面中，提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)所示的、或表A或表B所示化合物的同位素标记物，所述的同位素标记优选为氘(D或2H)取代氢(1H)。In another aspect of the present disclosure, formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III) are provided -2), isotope labels represented by formula (IV), formula (V), formula (VI), formula (VII), or compounds shown in Table A or Table B. The isotope label is preferably deuterium ( D or 2H ) replaces hydrogen ( 1H ).
本公开另一方面，提供了一种式(IA)化合物或其盐，
In another aspect, the present disclosure provides a compound of formula (IA) or a salt thereof,
其中：R5、R6、R0和Y如式(I)中所定义。Among them: R 5 , R 6 , R 0 and Y are as defined in formula (I).
本公开另一方面，提供了一种式(IIA)化合物或其盐，
In another aspect, the present disclosure provides a compound of formula (IIA) or a salt thereof,
其中：R5、R6、R7、R8、R9、R10、R11a、R11b和Y如式(II)中所定义。Wherein: R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (II).
本公开另一方面，提供了一种式(IIA-1)或式(IIA-2)化合物或其盐，
In another aspect, the present disclosure provides a compound of formula (IIA-1) or formula (IIA-2) or a salt thereof,
其中：加粗的化学键表示化合物存在轴手性；R5、R6、R7、R8、R9、R10、R11a、R11b和Y如式(II)中所定义。Among them: the bold chemical bonds indicate the existence of axial chirality in the compound; R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (II).
本公开另一方面，提供了一种式(IVA)或式(VA)化合物或其盐，
In another aspect, the present disclosure provides a compound of formula (IVA) or formula (VA) or a salt thereof,
其中：R5、R6、R7、R8、R9、R10、R11a和R11b如式(II)中所定义。Wherein: R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a and R 11b are as defined in formula (II).
本公开另一方面，提供了一种制备式(I)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
On the other hand, the present disclosure provides a method for preparing a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, which includes the following steps:
式(IB)的化合物与式(IA)化合物发生关环反应，得到式(I)所示的化合物或其药学上可接受的盐，The compound of formula (IB) undergoes a ring-closing reaction with the compound of formula (IA) to obtain the compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
其中：X为N；Among them: X is N;
R0、R1、R2、R3、R4、R5、R6和Y如式(I)中所定义。R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and Y are as defined in formula (I).
本公开另一方面，提供了一种制备式(II)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
On the other hand, the present disclosure provides a method for preparing the compound represented by formula (II) or a pharmaceutically acceptable salt thereof, which includes the following steps:
式(IIB)的化合物与式(IIA)化合物发生关环反应，得到式(II)所示的化合物或其药学上可接受的盐，The compound of formula (IIB) undergoes a ring-closing reaction with the compound of formula (IIA) to obtain the compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
其中：X为N；Among them: X is N;
R1、R2、R5、R6、R7、R8、R9、R10、R11a、R11b和Y如式(II)中所定义。R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (II).
参照制备式(II)所示化合物或其药学上可接受的盐的方法，式(IIB)的化合物分别与式(IIA-1)或式(IIA-2)化合物发生关环反应，得到式(II-1)或式(II-2)所示的化合物或其药学上可接受的盐，其中X为N；R1、R2、R5、R6、R7、R8、R9、R10、R11a、R11b和Y具有上文所述的定义。Referring to the method for preparing the compound represented by formula (II) or its pharmaceutically acceptable salt, the compound of formula (IIB) undergoes a ring-closing reaction with the compound of formula (IIA-1) or formula (IIA-2) respectively to obtain the formula ( II-1) or a compound represented by formula (II-2) or a pharmaceutically acceptable salt thereof, wherein X is N; R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y have the definitions stated above.
本公开另一方面，提供了一种制备式(III)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
On the other hand, the present disclosure provides a method for preparing the compound represented by formula (III) or a pharmaceutically acceptable salt thereof, which includes the following steps:
式(IIIB)的化合物与式(IIA)化合物发生关环反应，得到式(III)所示的化合物或其药学上可接受的盐，The compound of formula (IIIB) undergoes a ring-closing reaction with the compound of formula (IIA) to obtain the compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
其中：X为N；Among them: X is N;
R3、R4、R5、R6、R7、R8、R9、R10、R11a、R11b和Y如式(III)中所定义。R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (III).
参照制备式(III)所示化合物或其药学上可接受的盐的方法，式(IIIB)的化合物分别与式(IIA-1)或式(IIA-2)化合物发生关环反应，得到式(III-1)或式(III-2)所示的化合物或其药学上可接受的盐，其中X为N；R1、R2、R5、R6、R7、R8、R9、R10、R11a、R11b和Y如式(III)中所定义。Referring to the method for preparing the compound represented by formula (III) or its pharmaceutically acceptable salt, the compound of formula (IIIB) undergoes a ring-closing reaction with the compound of formula (IIA-1) or formula (IIA-2) respectively to obtain the formula ( III-1) or a compound represented by formula (III-2) or a pharmaceutically acceptable salt thereof, wherein X is N; R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and Y are as defined in formula (III).
本公开另一方面，提供了一种制备式(IV)所示化合物或其药学上可接受的盐的方法，其包含如下步骤：
On the other hand, the present disclosure provides a method for preparing the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof, which includes the following steps:
式(IVB)的化合物与式(IVA)化合物发生关环反应，得到式(IV)所示的化合物或其药学上可接受的盐，The compound of formula (IVB) undergoes a ring-closing reaction with the compound of formula (IVA) to obtain the compound represented by formula (IV) or a pharmaceutically acceptable salt thereof,
其中：X为N；Among them: X is N;
G1、R5、R6、R7、R8、R9、R10、R11a、R11b、p和q如式(IV)中所定义。G 1 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , p and q are as defined in formula (IV).
参照制备式(IV)所示化合物或其药学上可接受的盐的方法，式(IVB)的化合物分别与式(VA)发生关环反应，得到式(V)所示的化合物或其药学上可接受的盐，其中X为N；G1、R5、R6、R7、R8、R9、R10、R11a、R11b、p和q如式(V)中所定义。Referring to the method for preparing the compound represented by formula (IV) or its pharmaceutically acceptable salt, the compound represented by formula (IVB) undergoes a ring-closing reaction with formula (VA) respectively to obtain the compound represented by formula (V) or its pharmaceutically acceptable salt. Acceptable salts where X is N; G1 , R5 , R6 , R7 , R8 , R9 , R10 , R11a , R11b , p and q are as defined in formula (V).
参照制备式(IV)所示化合物或其药学上可接受的盐的方法，式(VIB)的化合物分别与式(IVA)或式(VA)发生关环反应，相应得到式(VI)或(VII)所示的化合物或其药学上可接受的盐，其中X为N；G2、R5、R6、R7、R8、R9、R10、R11a、R11b、j和k如式(VI)中所定义。Refer to the method for preparing the compound represented by formula (IV) or its pharmaceutically acceptable salt, formula (VIB) The compound of formula (IVA) or formula (VA) undergoes a ring-closing reaction respectively, correspondingly obtaining the compound represented by formula (VI) or (VII) or a pharmaceutically acceptable salt thereof, wherein X is N; G 2 , R 5 , R6 , R7 , R8 , R9 , R10 , R11a , R11b , j and k are as defined in formula (VI).
本公开另一方面，提供了一种药物组合物，其包括至少一种治疗有效量的前述的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的赋形剂。In another aspect, the present disclosure provides a pharmaceutical composition comprising at least a therapeutically effective amount of the aforementioned compound or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
本公开另一方面，还提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或包含其的药物组合物的用途，用于制备p38激酶抑制剂的药物。On the other hand, the present disclosure also provides formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2 ), the use of compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or pharmaceutical compositions containing them, for Preparation of p38 kinase inhibitor drugs.
本公开还提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或包含其的药物组合物，其在制备用于预防和/或治疗p38激酶介导的疾病或病症的药物中的用途；优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病。The present disclosure also provides formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula ( IV), formula (V), formula (VI), formula (VII), a compound shown in Table A or Table B or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used in the preparation of prevention and/or Or use in medicines for treating p38 kinase-mediated diseases or conditions; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway.
本公开还提供了式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或包含其的药物组合物，其在制备用于预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经***疾病和癌症的药物中的用途；优选地，其在制备用于预防和/或治疗关节炎、银屑病、***性红斑狼疮、糖尿病、白血病、淋巴瘤、动脉粥样硬化和阿尔兹海默症的药物中的用途。The present disclosure also provides formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula ( IV), formula (V), formula (VI), formula (VII), a compound shown in Table A or Table B or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same, which is used in the preparation of prevention and/or Or use in medicines for treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer; preferably, it is used in the preparation of drugs for preventing and/or treating arthritis, psoriasis, systemic erythema Use in medicines for lupus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.
本公开还提供了一种抑制p38激酶的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述同位素标记物或前述包含其的药物组合物。The present disclosure also provides a method for inhibiting p38 kinase, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III) ), compounds shown in formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI), formula (VII), table A or table B, or pharmaceutically acceptable compounds thereof The salt or the aforementioned isotope label or the aforementioned pharmaceutical composition containing the same.
本公开还提供了一种预防和/或治疗p38激酶介导的疾病或病症的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述同位素标记物或前述包含其的药物组合物；优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病。The present disclosure also provides a method for preventing and/or treating p38 kinase-mediated diseases or conditions, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table The compound represented by B or a pharmaceutically acceptable salt thereof or the aforementioned isotope label or the aforementioned pharmaceutical composition containing the same; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway.
本公开还提供了一种预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经***疾病和癌症的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物。The present disclosure also provides a method for preventing and/or treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer, which includes administering to a patient in need a therapeutically effective amount of Formula (I), Formula (I), Formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI ), the compound shown in formula (VII), Table A or Table B or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition containing the same.
本公开还提供了一种预防和/或治疗关节炎、银屑病、***性红斑狼疮、糖尿病、白血病、淋巴瘤、动 脉粥样硬化和阿尔兹海默症的方法，其包括给予所需患者治疗有效量的式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物。The present disclosure also provides a method for preventing and/or treating arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, animal Methods for atherosclerosis and Alzheimer's disease, which include administering to a patient in need a therapeutically effective amount of Formula (I), Formula (II), Formula (II-1), Formula (II-2), Formula (III) ), compounds shown in formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI), formula (VII), table A or table B, or pharmaceutically acceptable compounds thereof salt or the aforementioned pharmaceutical composition containing the same.
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述药物组合物，其用作药物。The present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or their pharmaceutically acceptable salts or the aforementioned pharmaceutical compositions are used as medicines.
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述药物组合物，其用作p38激酶抑制剂。The present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), The compound shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition is used as a p38 kinase inhibitor.
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物，其用作预防和/或治疗p38激酶介导的疾病或病症的药物；优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病。The present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions containing them, which are used for the prevention and / Or a drug for treating p38 kinase-mediated diseases or conditions; preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway.
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物，其用作预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经***疾病和癌症的药物。The present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions containing them, which are used for the prevention and /or drugs to treat autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer.
本公开还提供了一种式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或前述包含其的药物组合物，其用作预防和/或治疗关节炎、银屑病、***性红斑狼疮、糖尿病、白血病、淋巴瘤、动脉粥样硬化和阿尔兹海默症的药物。The present disclosure also provides a formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), formula (III-2), Compounds shown in Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceutically acceptable salts thereof or the aforementioned pharmaceutical compositions containing them, which are used for the prevention and /or medications to treat arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.
本公开所述的p38激酶介导的疾病选自自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经***疾病和癌症。The p38 kinase-mediated diseases described in the present disclosure are selected from autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer.
本公开所述的p38激酶介导的疾病选自关节炎、银屑病、***性红斑狼疮、糖尿病、白血病、淋巴瘤、动脉粥样硬化和阿尔兹海默症。The p38 kinase-mediated diseases described in the present disclosure are selected from the group consisting of arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, atherosclerosis, and Alzheimer's disease.
在一些实施方式中，所述的药物组合物的单位剂量为0.001mg-1000mg。In some embodiments, the unit dosage of the pharmaceutical composition is 0.001 mg-1000 mg.
在一些实施方式中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或其同位素标记物。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐其同位素标记物。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或其同位素标记物。在某些实施方案中，所述的药物组合物含有1％-99％的前述式(I)、式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示化合物或其药学上可接受的盐或其同位素标记物。In some embodiments, based on the total weight of the composition, the pharmaceutical composition contains 0.01-99.99% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), Compounds shown in Formula (III), Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B or pharmaceuticals thereof acceptable salts or isotopic labels thereof. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), the compound shown in Table A or Table B or a pharmaceutically acceptable salt thereof Isotopic markers. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), Compounds shown in Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B, or pharmaceutically acceptable salts thereof or its isotopic label. In certain embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned formula (I), formula (II), formula (II-1), formula (II-2), formula (III), Compounds shown in Formula (III-1), Formula (III-2), Formula (IV), Formula (V), Formula (VI), Formula (VII), Table A or Table B, or pharmaceutically acceptable salts thereof or its isotopic label.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的一种或多种赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的一种或多种赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的一种或多种赋形剂。In certain embodiments, the pharmaceutical composition contains 0.01% to 99.99% of one or more pharmaceutically acceptable excipients, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1% to 99.9% of one or more pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1% to 99% of one or more pharmaceutically acceptable excipients.
作为药物时，可按药物组合物的形式给予本公开化合物。可按药剂领域中熟知的方式制备这些组合物，可通过多种途径给予，这取决于是否需要局部或全身治疗和所治疗的区域。可局部(例如，透皮、皮肤、眼和粘膜包括鼻内、***和直肠递药)、肺(例如，通过吸入或吹入粉末或气雾剂，包括通过喷雾器；气管内、鼻内)、口服或肠胃外给药。肠胃外给药包括静脉内、动脉内、皮下、腹膜内或肌内注射或输注；或颅内例如鞘内或脑室内给药。可按单次大剂量形式肠胃外给药，或可通过例如连续灌注泵给药。As pharmaceuticals, the compounds of the present disclosure may be administered in the form of pharmaceutical compositions. These compositions may be prepared in a manner well known in the pharmaceutical art and may be administered by a variety of routes, depending on whether local or systemic treatment is desired and the area treated. May be administered topically (e.g., transdermal, cutaneous, ocular, and mucosal including intranasal, vaginal, and rectal delivery), pulmonary (e.g., by inhalation or insufflation of a powder or aerosol, including by nebulizer; intratracheal, intranasal), Oral or parenteral administration. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, such as intrathecal or intracerebroventricular administration. The administration may be parenteral as a single bolus or may be administered, for example, by a continuous infusion pump.
在制备本公开的组合物时，通常将活性成分与赋形剂混合，组合物可以是以下形式：片剂、丸剂、散剂、锭剂、小药囊、扁囊剂、酏剂、混悬剂、乳剂、溶液剂、糖浆剂、气雾剂(固体或溶于液体溶媒)、含例如高达10％重量活性化合物的软膏剂、软和硬明胶胶囊、栓剂、无菌注射溶液和无菌包装粉末。In preparing the compositions of the present disclosure, the active ingredients are generally mixed with excipients, and the compositions may be in the following forms: tablets, pills, powders, lozenges, sachets, cachets, elixirs, and suspensions , emulsions, solutions, syrups, aerosols (solid or dissolved in liquid vehicles), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders .
本公开所述的“赋形剂”是指除活性成分以外的成分，例如包括稀释剂、填充剂、吸收剂、润湿剂、粘合剂、崩解剂和润滑剂等。"Excipients" as used in this disclosure refer to ingredients other than active ingredients, including, for example, diluents, fillers, absorbents, wetting agents, binders, disintegrants, lubricants, and the like.
另一方面，本公开中所述化合物的药学上可接受的盐可为无机盐或有机盐，如果这些化合物具有碱性中心，则其可以形成酸加成盐；如果这些化合物具有酸性中心，则其可以形成碱加成盐；如果这些化合物既包含酸性中心(例如羧基)又包含碱性中心(例如氨基)，则其还可以形成内盐。On the other hand, pharmaceutically acceptable salts of the compounds described in the present disclosure may be inorganic salts or organic salts, which may form acid addition salts if they have a basic center or acid addition salts if they have an acidic center. They can form base addition salts; if these compounds contain both acidic centers (eg carboxyl) and basic centers (eg amino), they can also form internal salts.
另一方面，本公开化合物可以存在特定的几何或立体异构体形式。例如顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，外消旋混合物和其他混合物，以及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公开的范围之内。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，均包括在本公开的范围之内。On the other hand, compounds of the present disclosure may exist in specific geometric or stereoisomeric forms. For example, cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers isomer, the (L)-isomer, racemic mixtures and other mixtures, as well as enantiomeric or diastereomerically enriched mixtures, all of which are within the scope of the present disclosure. Alkyl and other substituents may exist Additional asymmetric carbon atoms. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
本公开所述化合物的化学结构中，键表示未指定构型，表示绝对构型，即如果化学结构中存在手性异构体，键可以为或者同时包含两种构型，表示存在轴手性。In the chemical structure of the compounds described in this disclosure, the bond Indicates that the configuration is not specified, Represents the absolute configuration, i.e. if there are chiral isomers in the chemical structure, the bond can be or both Two configurations, Indicates the presence of axial chirality.
键表示未指定构型，包括顺式(E)或反式(Z)构型。key Indicates unspecified configuration, including cis (E) or trans (Z) configuration.
另外，本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。“互变异构体”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇异构化、亚胺-烯胺异构化和内酰胺-内酰亚胺异构化。本公开中的所有化合物的所有的互变异构形式均在本公开的范围内。用单一方式命名的化合物的名称不排除任何互变异构体。Additionally, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. "Tautomers" refer to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also called proton transfer tautomers) include tautomers via proton migration, such as keto-enol isomerization, imine-enamine isomerization, and lactam-lactam isomerization. Isomerization of imides. All tautomeric forms of all compounds in this disclosure are within the scope of this disclosure. The name of a compound named in a single way does not exclude any tautomers.
本公开还包括一些与本文中记载的结构相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。本公开的化合物的所有同位素组成的变换，无论放射性与否，都包括在本公开的范围之内。The present disclosure also includes compounds of the present disclosure that have the same structure as described herein, but are isotopically labeled with one or more atoms replaced by atoms of an atomic weight or mass number different from those typically found in nature. Examples of isotopes that may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc. All variations in the isotopic composition of the compounds of the present disclosure, whether radioactive or not, are included within the scope of the present disclosure.
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的化合物。在制备氘代形式的化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。Unless otherwise stated, when a position is specifically designated as deuterium (D), that position is understood to have an abundance of deuterium that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 10 % deuterium incorporation). Examples of compounds having a natural abundance greater than deuterium may be at least 1000 times the abundance of deuterium, at least 2000 times the abundance of deuterium, at least 3000 times the abundance of deuterium, at least 4000 times the abundance of deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to relevant literature to synthesize deuterated forms of compounds. Commercially available deuterated starting materials may be used in the preparation of deuterated forms of the compounds, or they may be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated borane, trideuterated borane in tetrahydrofuran. , Deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
本公开的“治疗有效量”是指研究人员、兽医、医师或其它临床医师等在组织、***、动物、个体或人中寻找的引起生物学或医学反应的活性化合物或药物的量，它包括以下一项或多项：(1)预防疾病：例如在易感染疾病、紊乱或病症但尚未经历或出现疾病病理或症状的个体中预防疾病、紊乱或病症。(2)抑制疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中抑制疾病、紊乱或病症(即阻止病理和/或症状的进一步发展)。(3)缓解疾病：例如在正经历或出现疾病、紊乱或病症的病理或症状的个体中缓解疾病、紊乱或病症(即逆转病理和/或症状)。针对药物或药理学活性剂而言，“治疗有效量”是指无毒的但能达到预期效果的药物或药剂的足够用量。有效量的确定因人而异，取决于受体的年龄和一般情况，也取决于具体的活性物质，个案中合适的有效量可以由本领域技术人员根据常规试验确定。The "therapeutically effective amount" of this disclosure refers to the amount of active compound or drug that researchers, veterinarians, physicians or other clinicians seek to cause a biological or medical response in tissues, systems, animals, individuals or humans, and it includes One or more of the following: (1) Prevention of disease: e.g., prevention of a disease, disorder, or condition in an individual who is susceptible to the disease, disorder, or condition but who has not yet experienced or developed the pathology or symptoms of the disease. (2) Inhibition of disease: e.g., inhibition of a disease, disorder, or condition (i.e., preventing further progression of pathology and/or symptoms) in an individual who is experiencing or developing pathology or symptoms of the disease, disorder, or condition. (3) Disease amelioration: e.g., alleviation of a disease, disorder, or condition (i.e., reversal of the pathology and/or symptoms) in an individual who is experiencing or developing the pathology or symptoms of the disease, disorder, or condition. For a drug or pharmacologically active agent, a "therapeutically effective amount" refers to a non-toxic amount of the drug or agent that is sufficient to achieve the desired effect. The determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
本公开“药学上可接受的”是指这些化合物、材料、组合物和/或剂型，在合理的医学判断范围内，适用于与患者组织接触而没有过度毒性、刺激性、过敏反应或其他问题或并发症，具有合理的获益/风险比，并且对预期的用途是有效。"Pharmaceutically acceptable" in this disclosure means those compounds, materials, compositions and/or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with patient tissue without undue toxicity, irritation, allergic reactions or other problems or complications, have a reasonable benefit/risk ratio, and be effective for the intended use.
本公开的“患者”是指包括哺乳动物在内的任何动物，优选小鼠、大鼠、其它啮齿类动物、兔、狗、猫、猪、牛、羊、马或灵长类动物，最优选人。"Patient" in the present disclosure refers to any animal including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, pigs, cattle, sheep, horses or primates, most preferably people.
有益效果beneficial effects
本公开提供了一种具有β-羟基类结构的式(I)所示的小分子化合物，可作为p38 MAPK/MK2通路抑制剂，例如具有β-羟基类结构的式(II)、式(II-1)、式(II-2)、式(III)、式(III-1)、式(III-2)、式(IV)、式(V)、式(VI)、式(VII)、表A或表B所示的化合物，该类化合物或药物组合物可以用于有效治疗或预防p38 MAPK/MK2通路介导的疾病。这类β-羟基类结构化合物在抑制p38 MAPK依赖性的MK2活性同时保持了对ATF2和MK5的选择性；此外，这类化合物也具有良好的体内药代动力学性质。The present disclosure provides a small molecule compound represented by formula (I) with a β-hydroxyl structure, which can be used as a p38 MAPK/MK2 pathway inhibitor, such as formula (II), formula (II) with a β-hydroxyl structure -1), formula (II-2), formula (III), formula (III-1), formula (III-2), formula (IV), formula (V), formula (VI), formula (VII), Compounds shown in Table A or Table B, such compounds or pharmaceutical compositions can be used to effectively treat or prevent diseases mediated by the p38 MAPK/MK2 pathway. This type of β-hydroxy structural compound inhibits p38 MAPK-dependent MK2 activity while maintaining selectivity for ATF2 and MK5; in addition, this type of compound also has good in vivo pharmacokinetic properties.
术语定义与说明Definitions and explanations of terms
除非有相反陈述，否则在说明书和权利要求书中使用的术语具有下述含义。Unless stated to the contrary, the terms used in the specification and claims have the following meanings.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷基，更优选含有1至6个碳原子的烷基(C1-6烷基)。烷基的非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基，及其各种支链异构体等。烷基可以是取代的或未 取代的。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably 1 to 12 (e.g. 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) alkyl groups of carbon atoms, more preferably alkyl groups containing 1 to 6 carbon atoms (C 1-6 alkyl). Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl -2-Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and Various branched chain isomers, etc. Alkyl groups may be substituted or un replaced.
术语“烷氧基”指-O-(烷基)，其中烷基的定义如本文中所述，优选含有1至12个(例如1、2、3、4、5、6、7、8、9、10、11和12个)碳原子的烷氧基(C1-12烷氧基)，更优选含有1至6个碳原子的烷氧基(C1-6烷氧基)。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基和丁氧基。烷氧基可以是取代的或未取代的。The term "alkoxy" refers to -O-(alkyl), where alkyl is as defined herein, preferably containing 1 to 12 (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) carbon atoms (C 1-12 alkoxy), more preferably an alkoxy group containing 1 to 6 carbon atoms (C 1-6 alkoxy). Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be substituted or unsubstituted.
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基，环烷基环包含3至20个碳原子，优选包含3至12个碳原子或3至8个(例如3、4、5、6、7和8个)碳原子，更优选包含3至6个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环庚三烯基、环辛基等；多环环烷基包括螺环、稠环和桥环的环烷基。The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms or 3 to 8 (e.g. 3, 4, 5, 6, 7 and 8) carbon atoms, more preferably containing 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene base, cyclooctyl, etc.; polycyclic cycloalkyl includes spiro ring, fused ring and bridged ring cycloalkyl.
术语“螺环烷基”指5至20元，***中的每个单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括：
The term "spirocycloalkyl" refers to a 5- to 20-membered polycyclic group with one carbon atom (called a spiro atom) shared between each single ring in the system, which may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the rings, the spirocycloalkyl group is divided into a single spirocycloalkyl group, a double spirocycloalkyl group or a polyspirocycloalkyl group, and is preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocyclic alkyl group. Non-limiting examples of spirocycloalkyl groups include:
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元的双环烷基。稠环烷基的非限制性实例包括：
The term "fused cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, one or more of which may contain one or more rings. Multiple double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 1/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused cycloalkyl groups include:
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更优选为双环或三环。桥环烷基的非限制性实例包括：
The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly connected, and may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
所述环烷基环包括如本文中所述的环烷基(包括单环、螺环、稠环和桥环)稠合于芳基、杂芳基或杂环烷基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括 等；优选所述环烷基可以是取代的或未取代的。The cycloalkyl ring includes a cycloalkyl group (including monocyclic, spiro, fused and bridged rings) as described herein fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein with the parent The rings linked together by the structure are cycloalkyl, non-limiting examples include etc; preferred The cycloalkyl group may be substituted or unsubstituted.
术语“杂环基”指饱和或部分不饱和单环或多环环状取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个(例如3、4、5、6、7、8、9、10、11和12个)环原子，其中1～4个(例如1、2、3和4个)是杂原子；更优选包含3至8个环原子(例如3、4、5、6、7和8个)，其中 1-3个(例如1、2和3个)是杂原子；更优选包含3至6个环原子，其中1-3个是杂原子；最优选包含5或6个环原子，其中1-3个是杂原子。单环杂环基的非限制性实例包括吡咯烷基、四氢吡喃基、1,2,3,6-四氢吡啶基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic substituent containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen and sulfur, The sulfur may optionally be oxosubstituted (i.e., to form a sulfoxide or sulfone), but does not include the -OO-, -OS- or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably it contains 3 to 12 (eg 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12) ring atoms, of which 1 to 4 (eg 1, 2, 3 and 4) are hetero atoms; more preferably containing 3 to 8 ring atoms (e.g. 3, 4, 5, 6, 7 and 8), where 1-3 (e.g., 1, 2, and 3) are heteroatoms; more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 One is a heteroatom. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine base, homopiperazine base, etc. Polycyclic heterocyclyl groups include spirocyclic, fused cyclic and bridged cyclic heterocyclyl groups.
术语“螺杂环基”指5至20元，***中的每个单环之间共用一个原子(称螺原子)的多环杂环基团，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。其可以含有一个或多个双键。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基，优选为单螺杂环基和双螺杂环基。更优选为3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括：
The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, each single ring in the system shares one atom (called a spiro atom), in which one or more ring atoms are selected from nitrogen, Heteroatoms of oxygen and sulfur, the sulfur may be optionally oxo-substituted (i.e., forming sulfoxide or sulfone), and the remaining ring atoms are carbon. It may contain one or more double bonds. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of shared spiro atoms between the rings, the spiroheterocyclyl group is divided into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a polyspiroheterocyclyl group, and is preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably, it is a 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiroheterocyclic group. Non-limiting examples of spiroheterocyclyl include:
术语“稠杂环基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团，一个或多个环可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基，优选为双环或三环，更优选为3元/4元、3元/5元、3元/6元、4元/4元、4元/5元、4元/6元、5元/4元、5元/5元、5元/6元、6元/3元、6元/4元、6元/5元和6元/6元双环稠杂环基。稠杂环基的非限制性实例包括：
The term "fused heterocyclyl" refers to a polycyclic heterocyclic group with 5 to 20 members, each ring in the system shares an adjacent pair of atoms with other rings in the system, and one or more rings may contain one or more Double bonds, in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxo-substituted (ie, forming sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered , 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/4 yuan, 5 yuan/5 yuan, 5 yuan/6 yuan, 6 yuan/3 yuan, 6 yuan/4 yuan, 6 One-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclyl groups include:
术语“桥杂环基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环基团，其可以含有一个或多个双键，其中一个或多个环原子为选自氮、氧和硫的杂原子，所述的硫可任选被氧代(即形成亚砜或砜)，其余环原子为碳。优选为6至14元，更优选为7至10元(例如7、8、9或10元)。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基，优选为双环、三环或四环，更优选为双环或三环。桥杂环基的非限制性实例包括：
The term "bridged heterocyclyl" refers to a 5- to 14-membered polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected. It may contain one or more double bonds, one or more of which are ring atoms. is a heteroatom selected from nitrogen, oxygen and sulfur, the sulfur may be optionally oxo-substituted (ie, forming a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:
所述杂环基环包括如本文中所述的杂环基(包括单环、螺杂环、稠杂环和桥杂环)稠合于芳基、杂芳基或环烷基环上，其中与母体结构连接在一起的环为杂环基，其非限制性实例包括：The heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) as described herein fused to an aryl, heteroaryl or cycloalkyl ring, wherein The ring attached to the parent structure is a heterocyclyl group, non-limiting examples of which include:
等。所述杂环基可以是取代的或未取代的。 wait. The heterocyclyl group may be substituted or unsubstituted.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(稠合多环是共享毗邻碳原子对的环)基团，优选为6至10元，例如苯基和萘基。所述芳基环包括如本文中所述的芳基环稠合于杂芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括： The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (fused polycyclic is a ring that shares adjacent pairs of carbon atoms) group having a conjugated π electron system, preferably 6 to 10 members , such as phenyl and naphthyl. The aryl ring includes an aryl ring fused to a heteroaryl, heterocyclyl or cycloalkyl ring as described herein, where the ring attached to the parent structure is an aryl ring, which is not limited to Examples include:
芳基可以是取代的或未取代的。 Aryl groups may be substituted or unsubstituted.
术语“杂芳基”指包含1至4个(例如1、2、3和4个)杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为5至10元(例如5、6、7、8、9或10元)，更优选为5元或6元，例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、嘧啶基、吡嗪基、哒嗪基、咪唑基、吡唑基、***基、四唑基等。所述杂芳基环包括如本文中所述的杂芳基稠合于芳基、杂环基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 (eg, 1, 2, 3, and 4) heteroatoms, and from 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl group is preferably 5 to 10 yuan (such as 5, 6, 7, 8, 9 or 10 yuan), more preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkyl pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described herein, where the ring attached to the parent structure is a heteroaryl ring, which is not limited to Sexual examples include:
杂芳基可以是取代的或未取代的。 Heteroaryl groups may be substituted or unsubstituted.
本文中的术语“烷基”、“烷氧基”、“环烷基”、“杂环基”、“芳基”和“杂芳基”等可以是取代的或未取代的；当被取代时，其可以在任何可使用的连接点上被取代，所述取代基优选独立地任选选自卤素、烷基、烷氧基、卤代烷基、卤代烷氧基、羟基、羟烷基、氰基、氨基、硝基、环烷基、杂环基、芳基和杂芳基中的一个或多个相同或不同的取代基。The terms "alkyl", "alkoxy", "cycloalkyl", "heterocyclyl", "aryl" and "heteroaryl" as used herein may be substituted or unsubstituted; when substituted When it is used, it may be substituted at any available point of attachment, and the substituents are preferably independently selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, hydroxyl, hydroxyalkyl, cyano , one or more identical or different substituents in amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
上述环烷基、杂环基、芳基和杂芳基包括从母体环原子上除去一个氢原子所衍生的残基，或从母体的相同或两个不同的环原子上除去两个氢原子所衍生的残基，即“二价环烷基”、“二价杂环基”、“亚芳基”、“亚杂芳基”。The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl include residues derived by removing one hydrogen atom from the parent ring atom, or removing two hydrogen atoms from the same or two different ring atoms of the parent. Derivatized residues, namely "bivalent cycloalkyl", "bivalent heterocyclyl", "arylene", "heteroaryl".
术语“环烷基氧基”指环烷基-O-，其中环烷基如本文中所定义。The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined herein.
术语“杂环基氧基”指杂环基-O-，其中杂环基如本文中所定义。The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined herein.
术语“卤代烷基”指烷基被一个或多个卤素取代，其中烷基如本文中所定义。The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where alkyl is as defined herein.
术语“卤代烷氧基”指烷氧基被一个或多个卤素取代，其中烷氧基如本文中所定义。The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, where alkoxy is as defined herein.
术语“羟烷基”指烷基被一个或多个羟基取代，其中烷基如本文中所定义。The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, where alkyl is as defined herein.
术语“卤素”指F、Cl、Br或I。The term "halogen" refers to F, Cl, Br or I.
术语“羟基”指-OH。The term "hydroxy" refers to -OH.
术语“氨基”指-NH2。The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO2。The term "nitro" refers to -NO2 .
术语“氧代基”或“氧代”指“＝O”。The term "oxo" or "oxo" refers to "=O".
术语“羰基”指C＝O。The term "carbonyl" refers to C=O.
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“羧酸酯基”指-C(O)O(烷基)、-C(O)O(环烷基)、(烷基)C(O)O-或(环烷基)C(O)O-，其中烷基和环烷基如本文中所定义。The term "carboxylate" refers to -C(O)O(alkyl), -C(O)O(cycloalkyl), (alkyl)C(O)O- or (cycloalkyl)C(O )O-, wherein alkyl and cycloalkyl are as defined herein.
“任选”或“任选地”意味着随后所描述地事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生地场合。例如，“任选被烷基取代的杂环烷基团”意味着烷基可以但不必须存在，该说明包括杂环烷基团被烷基取代的情形和杂环烷基团不被烷基取代的情形。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance does or does not occur. For example, "heterocycloalkyl group optionally substituted by alkyl" means that alkyl groups may but need not be present, and this description includes the case where the heterocycloalkyl group is substituted by an alkyl group and the heterocycloalkyl group is not substituted by an alkyl group. replacement situation.
“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。例如，具有游离氢的氨基或羟基与具有不饱和(如烯属)键的碳原子结合时可能是不稳定的。"Substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, are independently substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and the person skilled in the art is able to determine (either experimentally or theoretically) possible or impossible substitutions without undue effort. For example, an amino or hydroxyl group with a free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.
具体实施方式Detailed ways
下文将结合具体实施例对本公开的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本公开，而不应被解释为对本公开保护范围的限制。凡基于本公开上述内容所实现的技术 均涵盖在本公开旨在保护的范围内。The technical solution of the present disclosure will be further described in detail below with reference to specific embodiments. It should be understood that the following examples are only illustrative and explain the present disclosure, and should not be construed as limiting the scope of the present disclosure. Any technology implemented based on the above contents of this disclosure All are covered by the scope of protection intended by this disclosure.
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。Experimental methods that do not indicate specific conditions in the following examples should be selected according to conventional methods and conditions, or according to product specifications.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker Avance III 400MHz核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)，氘代氯仿(CDCl3)，氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). NMR was measured using a Bruker Avance III 400MHz nuclear magnetic instrument. The measurement solvents were deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), and deuterated methanol (CD 3 OD). The internal standard was tetrahydrofuran. Methylsilane (TMS).
质谱(MS)是通过Waters 2767 HPLC/Waters SQD，Waters H-class UPLC-SQD2，Agilent HPLC/Waters液相质谱联用仪测定的。Mass spectrometry (MS) was measured by Waters 2767 HPLC/Waters SQD, Waters H-class UPLC-SQD2, and Agilent HPLC/Waters liquid phase mass spectrometer.
手性HPLC分析测定使用Shimadzu LC-20AD。Chiral HPLC analysis was performed using Shimadzu LC-20AD.
薄层层析硅胶板使用于成化工(上海)有限公司GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.2～0.25mm,薄层层析分离纯化产品采用的规格是0.4～0.5mm。Thin layer chromatography silica gel plate is used in Cheng Chemical (Shanghai) Co., Ltd. GF254 silica gel plate. The specification of silica gel plate used in thin layer chromatography (TLC) is 0.2~0.25mm. The specification of thin layer chromatography separation and purification products is 0.4～0.5mm.
柱层析一般使用于成化工(上海)有限公司100～200目硅胶为载体。Column chromatography generally uses 100-200 mesh silica gel from Cheng Chemical (Shanghai) Co., Ltd. as the carrier.
高效液相制备使用Waters HPLC、Gilson HPLC和Biotage MPLC制备型色谱仪。High performance liquid chromatography was performed using Waters HPLC, Gilson HPLC and Biotage MPLC preparative chromatographs.
手性分离柱层析使用GilsonGX-281制备型HPLC。Chiral separation column chromatography used Gilson GX-281 preparative HPLC.
实施例中如无特殊说明，反应均在氮气氛下进行。Unless otherwise stated in the examples, the reactions were all carried out under nitrogen atmosphere.
氮气氛是指反应瓶连接一个约1升容积的氮气气球。Nitrogen atmosphere means that the reaction bottle is connected to a nitrogen balloon with a volume of about 1 liter.
氢气氛是指反应瓶连接一个约1升容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a volume of about 1 liter.
实施例中如无特殊说明，反应温度均为室温，温度范围是20℃-30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, and the temperature range is 20°C-30°C.
本领域技术人员应当理解，拆分的手性化合物可以通过在手性色谱柱中的保留时间的先后进行区分，因此，针对保留时间先后拆分出来的手性化合物以编号后缀P1、P2对应区分。即后缀P1对应先拆分出来的手性结构，后缀P2对应后拆分出来的手性结构。结构式中若有列出化合物的绝对构型，则其不意味着与编号后缀P1、P2的化合物一一对应，仅是示意绝对构型的两种存在形式。编号后缀P1、P2的化合物的绝对构型以特定保留时间客观对应的绝对构型为准。Those skilled in the art should understand that the resolved chiral compounds can be distinguished by the order of their retention times in the chiral chromatographic column. Therefore, the chiral compounds that have been resolved successively according to their retention times are distinguished by the number suffixes P1 and P2. . That is, the suffix P1 corresponds to the chiral structure separated first, and the suffix P2 corresponds to the chiral structure separated later. If the absolute configuration of a compound is listed in the structural formula, it does not mean that it corresponds to the compounds with the number suffix P1 and P2, but only indicates the two existence forms of the absolute configuration. The absolute configurations of compounds with number suffixes P1 and P2 are based on the absolute configurations objectively corresponding to specific retention times.
中间体化合物A1的合成
Synthesis of intermediate compound A1
第一步：化合物A1-2的合成Step One: Synthesis of Compound A1-2
将氯化亚砜(22.43g,0.19mol)缓慢滴加到化合物A1-1(20g,0.13mol)的乙醇(60mL)溶液中，反应混合物加热至60℃并在该温度下搅拌3小时。反应结束后，反应液减压浓缩，得到化合物A1-2(20g,粗品)。产物不经纯化直接进行下一步反应。MS m/z(ESI):187.9[M+1]+。Thionyl chloride (22.43g, 0.19mol) was slowly added dropwise to a solution of compound A1-1 (20g, 0.13mol) in ethanol (60mL), and the reaction mixture was heated to 60°C and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound A1-2 (20 g, crude product). The product was directly used in the next reaction without purification. MS m/z(ESI):187.9[M+1] + .
第二步：化合物A1-3的合成Step 2: Synthesis of Compound A1-3
0℃下，将硼氢化钠(6.48g,0.17mol)分批加入化合物A1-2(16g,0.086mol)的乙醇(60mL)溶液中。反应混合物缓慢升至室温，并在室温下搅拌3小时。反应结束后，反应液减压浓缩，所得残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/5)纯化得化合物A1-3(16g,收率：73.5％)。MS m/z(ESI):146.1[M+1]+。At 0°C, sodium borohydride (6.48g, 0.17mol) was added in portions to a solution of compound A1-2 (16g, 0.086mol) in ethanol (60mL). The reaction mixture was slowly warmed to room temperature and stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/5) to obtain compound A1-3 (16 g, yield: 73.5%). MS m/z(ESI):146.1[M+1] + .
第三步：化合物A1的合成Step 3: Synthesis of Compound A1
将5滴N,N-二甲基甲酰胺加入化合物A1-3(1.80g,12.4mmol)的二氯甲烷(50mL)溶液中，反应混合物搅拌十分钟。室温下，将氯化亚砜(1.77g,14.88mmol)缓慢加入上述溶液中。所得混合物在室温下搅拌1小时。反应结束后，反应液中加入4M的氯化铵溶液至pH＝7，用二氯甲烷萃取(60mL×3)。合并有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～5/1)纯化得到化合物A1(1.80g,收率：84.7％)。1HNMR(400MHz,CDCl3)δ8.35(d,J＝2.4Hz,1H),7.26(ddd,J＝9.1,8.0,2.6Hz,1H),4.72(d,J＝2.1Hz,2H)。Five drops of N,N-dimethylformamide were added to a solution of compound A1-3 (1.80 g, 12.4 mmol) in dichloromethane (50 mL), and the reaction mixture was stirred for ten minutes. At room temperature, thionyl chloride (1.77g, 14.88mmol) was slowly added to the above solution. The resulting mixture was stirred at room temperature for 1 hour. After the reaction, 4M ammonium chloride solution was added to the reaction solution to pH=7, and the mixture was extracted with dichloromethane (60 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~5/1) to obtain compound A1 (1.80g, Yield: 84.7%). 1 HNMR (400MHz, CDCl 3 ) δ 8.35 (d, J = 2.4 Hz, 1H), 7.26 (ddd, J = 9.1, 8.0, 2.6 Hz, 1H), 4.72 (d, J = 2.1 Hz, 2H).
中间体化合物A2的合成
Synthesis of intermediate compound A2
第一步：化合物A2-2的合成Step One: Synthesis of Compound A2-2
-78℃下，将双(三甲基硅基)胺基锂的四氢呋喃溶液(141mL,141mmol)缓慢加入到化合物A2-1(20g,141mmol)的四氢呋喃(500mL)溶液中，反应混合物在-78℃下搅拌1小时后再慢慢滴加乙酰氯(6.6g,844mmol)，得到的混合物在-78℃下继续搅拌1小时。反应结束后，反应液缓慢倒入饱和氯化铵水溶液中(500mL),用乙酸乙酯萃取(300mL×3)。合并的有机相用饱和食盐水洗涤(300mL×2)，无水硫酸钠干燥并过滤，过滤液减压浓缩，所得残余物经柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物A2-2(6.6g,收率：30％)。MS m/z(ESI):185.1[M+1]+。At -78°C, a solution of lithium bis(trimethylsilyl)amide in tetrahydrofuran (141 mL, 141 mmol) was slowly added to a solution of compound A2-1 (20 g, 141 mmol) in tetrahydrofuran (500 mL). The reaction mixture was at -78°C. After stirring at -78°C for 1 hour, acetyl chloride (6.6g, 844mmol) was slowly added dropwise, and the resulting mixture was continued to stir at -78°C for 1 hour. After the reaction, the reaction solution was slowly poured into a saturated aqueous ammonium chloride solution (500 mL), and extracted with ethyl acetate (300 mL × 3). The combined organic phases were washed with saturated brine (300 mL 1) Purify to obtain compound A2-2 (6.6g, yield: 30%). MS m/z(ESI):185.1[M+1] + .
第二步：化合物A2-3的合成Step 2: Synthesis of Compound A2-3
将化合物A2-2(8.98g,48.7mmol)和2-氯-4-氨基-5-甲基吡啶(4.63g,32.5mmol,CAS：79055-62-2)的1,4-二氧六环(150mL)溶液加热至90℃并在该温度下搅拌3.5小时。反应液自然冷却至室温后，加入甲磺酸(3.12g,32.5mmol)，然后反应加热至50℃继续搅拌3小时。反应结束后，反应液自然冷却到室温并过滤，滤饼收集后干燥得到化合物A2-3(5.6g，收率：69％)。MS m/z(ESI):251.0[M+1]+。Compound A2-2 (8.98g, 48.7mmol) and 2-chloro-4-amino-5-methylpyridine (4.63g, 32.5mmol, CAS: 79055-62-2) were dissolved in 1,4-dioxane (150 mL) solution was heated to 90°C and stirred at this temperature for 3.5 hours. After the reaction solution was naturally cooled to room temperature, methanesulfonic acid (3.12g, 32.5mmol) was added, and then the reaction was heated to 50°C and stirred for 3 hours. After the reaction, the reaction solution was naturally cooled to room temperature and filtered. The filter cake was collected and dried to obtain compound A2-3 (5.6 g, yield: 69%). MS m/z(ESI):251.0[M+1] + .
第三步：化合物A2-4的合成Step 3: Synthesis of Compound A2-4
将化合物A1(4.01g,24.6mmol)加入化合物A2-3(5.60g,22.3mmol)、碳酸钾(7.69g,55.7mmol)和18-冠-6(1.18g,4.4mmol)的N,N-二甲基甲酰胺(80mL)溶液中。反应混合物在室温下搅拌16小时。反应结束后，反应液加水(100mL)稀释,乙酸乙酯萃取(80mL×3)。合并有机相经饱和食盐水洗涤(20mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物A2-4(8.40g,收率：99.5％)。产物不经纯化直接进行下一步反应。MS m/z(ESI):378.0[M+1]+。Compound A1 (4.01g, 24.6mmol) was added to the N,N- Dimethylformamide (80 mL) solution. The reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was diluted with water (100 mL), and extracted with ethyl acetate (80 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain compound A2-4 (8.40 g, yield: 99.5%). The product was directly used in the next reaction without purification. MS m/z(ESI):378.0[M+1] + .
第四步：化合物A2-5的合成Step 4: Synthesis of Compound A2-5
将双三苯基膦二氯化钯(1.56g,2.22mmol)加到化合物A2-4(8.4g,22.2mmol)和三丁基(1-乙氧基乙烯)锡(10.21g,24.2mmol)的1,4-二氧六环(100mL)溶液中，反应混合物加热至130℃并在该温度下搅拌4小时。反应结束后，反应液过滤，滤液直接减压浓缩，残余物中加入四氢呋喃(100mL)溶解，再滴入5mL浓盐酸并搅拌1小时。反应结束后，反应液减压浓缩，所得残余物经柱层析(石油醚/乙酸乙酯＝1/1～0/1)纯化得到化合物A2-5(5g,收率：60％)。MS m/z(ESI):386.0[M+1]+。Bistriphenylphosphine palladium dichloride (1.56g, 2.22mmol) was added to compound A2-4 (8.4g, 22.2mmol) and tributyl(1-ethoxyethylene)tin (10.21g, 24.2mmol) In a solution of 1,4-dioxane (100 mL), the reaction mixture was heated to 130°C and stirred at this temperature for 4 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure. Tetrahydrofuran (100 mL) was added to the residue to dissolve, and then 5 mL of concentrated hydrochloric acid was added dropwise and stirred for 1 hour. After the reaction, the reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to obtain compound A2-5 (5 g, yield: 60%). MS m/z(ESI):386.0[M+1] + .
第五步：化合物A2-6的合成Step 5: Synthesis of Compound A2-6
将醋酸(2mL)滴加到化合物A2-5(5g,13mmol)和N-氯代丁二酰亚胺(1.9g,14.3mmol)的异丙醇(100mL)溶液中，反应混合物加热至60℃并在该温度下搅拌16小时。反应结束后，反应液减压浓缩，残余物经柱层析(石油醚/乙酸乙酯＝1/1～0/1)纯化得到化合物A2-6(3.6g,收率：70％)。MS m/z(ESI):420.0[M+1]+。Acetic acid (2mL) was added dropwise to a solution of compound A2-5 (5g, 13mmol) and N-chlorosuccinimide (1.9g, 14.3mmol) in isopropyl alcohol (100mL), and the reaction mixture was heated to 60°C. and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to obtain compound A2-6 (3.6 g, yield: 70%). MS m/z(ESI):420.0[M+1] + .
第六步：化合物A2的合成Step Six: Synthesis of Compound A2
将N，N-二甲基甲酰胺二甲基缩醛(0.85g,7.2mmol)加入到化合物A2-6(1.3g,3.1mmol)的N，N- 二甲基甲酰胺(15mL)溶液中，反应混合物加热至100℃并在该温度下搅拌3小时。反应结束后，反应液加水(50mL)稀释,用乙酸乙酯萃取(30mL×3)。合并的有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经柱层析(二氯甲烷/甲醇＝1/0～50/1)纯化得到化合物A2(900mg,收率：78％)。MS m/z(ESI):474.9[M+H]+。N,N-dimethylformamide dimethyl acetal (0.85g, 7.2mmol) was added to the N,N- of compound A2-6 (1.3g, 3.1mmol). The reaction mixture was heated to 100°C in dimethylformamide (15 mL) and stirred at this temperature for 3 hours. After the reaction was completed, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL Compound A2 (900 mg, yield: 78%) was purified. MS m/z(ESI):474.9[M+H] + .
中间体化合物A3的合成：
Synthesis of intermediate compound A3:
第一步：化合物A3-2的合成Step One: Synthesis of Compound A3-2
将叠氮磷酸二苯酯(23.5g,0.085mol)加入到化合物A3-1(10g,0.057mol)和三乙胺(17.3g,0.17mol)的叔丁醇/甲苯(50mL/50mL)的混合溶液中，反应混合物加热在110℃并在该温度下搅拌16小时。反应结束后，将反应液倒入水中，用二氯甲烷(200mL×3)萃取。合并的有机相用水(150mL)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/0～10/1)纯化得到化合物A3-2(3.6g，收率：25％)。MS m/z(ESI):247.0[M+1]+。Diphenylphosphoryl azide (23.5g, 0.085mol) was added to a mixture of compound A3-1 (10g, 0.057mol) and triethylamine (17.3g, 0.17mol) in tert-butanol/toluene (50mL/50mL). In solution, the reaction mixture was heated at 110°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was poured into water and extracted with dichloromethane (200 mL×3). The combined organic phases were washed with water (150 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was passed through silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~10/1). Purification gave compound A3-2 (3.6 g, yield: 25%). MS m/z(ESI):247.0[M+1] + .
第二步：化合物A3-3的合成Step 2: Synthesis of Compound A3-3
将化合物A3-2(3.6g,14.5mol)加入到三氟乙酸/二氯甲烷(15mL/30mL)的混合溶液中，反应混合为在室温下搅拌16小时。反应结束后，反应液减压浓缩除去溶剂，所得残余物经柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物A3-3粗品(3.1g)。MS m/z(ESI):147.0[M+1]+。Compound A3-2 (3.6g, 14.5mol) was added to the mixed solution of trifluoroacetic acid/dichloromethane (15mL/30mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by column chromatography (dichloromethane/methanol=1/0~20/1) to obtain crude compound A3-3 (3.1g). MS m/z(ESI):147.0[M+1] + .
第三步：化合物A3-4的合成Step 3: Synthesis of Compound A3-4
将硫酸银(6.61g,0.02mol)和碘(5.38g,0.02mol)加入到化合物A3-3(3.1g,0.02mol)的乙醇(50mL)溶液中，反应混合为在50℃下搅拌16小时。反应结束后，反应液减压浓缩除去溶剂，得到的残余物通过硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物A3-4(4.9g,收率：65％)。MS m/z(ESI):272.7[M+1]+。Silver sulfate (6.61g, 0.02mol) and iodine (5.38g, 0.02mol) were added to a solution of compound A3-3 (3.1g, 0.02mol) in ethanol (50mL), and the reaction mixture was stirred at 50°C for 16 hours. . After the reaction, the reaction solution was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound A3-4 (4.9g, yield: 65 %). MS m/z(ESI):272.7[M+1] + .
第四步：化合物A3-6的合成Step 4: Synthesis of Compound A3-6
在氮气保护下，将甲基硼酸(530mg,8.8mmol)，碳酸铯(8.96g,27.5mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(450mg,0.55mmol)依次加入到化合物A3-5(1.5g,5.5mmol)的1,4-二氧六环(30mL)溶液中，反应在100℃进行1.5小时。反应结束后，向反应液中加入碳酸氢钠水溶液进行稀释，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水洗一次，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，所得残余物通过硅胶柱层析法(石油醚/乙酸乙酯＝1/0～2/3)纯化得到化合物A3-6(0.43g,收率：48％)。MS m/z(ESI):161.0[M+1]+。Under nitrogen protection, methylboronic acid (530mg, 8.8mmol), cesium carbonate (8.96g, 27.5mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (450mg , 0.55 mmol) was sequentially added to a solution of compound A3-5 (1.5 g, 5.5 mmol) in 1,4-dioxane (30 mL), and the reaction was carried out at 100°C for 1.5 hours. After the reaction, add sodium bicarbonate aqueous solution to the reaction solution to dilute, extract with ethyl acetate (50 mL × 3), wash the combined organic phase once with saturated brine, dry over anhydrous sodium sulfate and filter, and the filtrate is concentrated under reduced pressure. The solvent was removed, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/3) to obtain compound A3-6 (0.43 g, yield: 48%). MS m/z(ESI):161.0[M+1] + .
第五步：化合物A3-7的合成Step 5: Synthesis of Compound A3-7
将化合物A3-6(1.2g,6.88mmol)加入到化合物A2-2(850mg,5.29mmol)的无水1,4-二氧六环(8mL)溶液中，反应混合物加热到110℃并在该温度下搅拌1小时。反应液自然降温至50℃后，加入甲基磺酸(285mg,2.96mmol)，然后反应在50℃继续进行1小时。反应结束后，向反应液中加水(50mL)稀释，用乙酸乙酯萃取(100mL×3)。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并过滤，过滤液通过减压浓 缩除去溶剂，所得残余物经硅胶柱层析(二氯甲烷)纯化得到化合物A3-7(530mg,收率：66％)。MS m/z(ESI):269.0[M+1]+。Compound A3-6 (1.2g, 6.88mmol) was added to a solution of compound A2-2 (850mg, 5.29mmol) in anhydrous 1,4-dioxane (8mL), and the reaction mixture was heated to 110°C and heated at Stir at room temperature for 1 hour. After the reaction solution was naturally cooled to 50°C, methylsulfonic acid (285 mg, 2.96 mmol) was added, and the reaction was continued at 50°C for 1 hour. After the reaction was completed, the reaction solution was diluted with water (50 mL), and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The solvent was condensed and removed, and the resulting residue was purified by silica gel column chromatography (dichloromethane) to obtain compound A3-7 (530 mg, yield: 66%). MS m/z(ESI):269.0[M+1] + .
第六步：化合物A3-8的合成Step 6: Synthesis of Compound A3-8
将碳酸钾(1.14g,8.28mmol)，18-冠-6(175mg,0.66mmol)加入到化合物A1(702mg,4.30mmol)和化合物A3-7(890mg,3.31mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物加热到40℃并在该温度下搅拌16小时。反应结束后，反应液冷却至室温，加入水(50mL行稀释，用乙酸乙酯(50mL×3)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥并过滤，过滤液通过减压浓缩得到化合物A3-8(1.5g,纯度：84％,收率：96％)粗品，该粗品直接用于下一步反应。MS m/z(ESI):395.8[M+1]+。Potassium carbonate (1.14g, 8.28mmol) and 18-crown-6 (175mg, 0.66mmol) were added to the N,N-dimethyl of compound A1 (702mg, 4.30mmol) and compound A3-7 (890mg, 3.31mmol). The reaction mixture was heated to 40°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. The liquid was concentrated under reduced pressure to obtain compound A3-8 (1.5g, purity: 84%, yield: 96%) crude product, which was directly used in the next step of reaction. MS m/z (ESI): 395.8 [M+1] + .
第七步:化合物A3-9的合成Step 7: Synthesis of Compound A3-9
将三丁基(1-乙氧基乙烯)锡(2.01g,5.55mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(257mg,0.37mmol)加入到化合物A3-8(1.45g,3.70mmol)的1,4-二氧六环(20mL)溶液中，反应混合物加热至130℃并在该温度下搅拌1.5小时。反应结束后，反应液直接减压浓缩得到化合物A3-9(3.9g)粗品，该粗品直接用于下一步。MS m/z(ESI):431.9[M+1]+。Tributyl(1-ethoxyethylene)tin (2.01g, 5.55mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (257mg, 0.37mmol) were added To a solution of compound A3-8 (1.45 g, 3.70 mmol) in 1,4-dioxane (20 mL), the reaction mixture was heated to 130°C and stirred at this temperature for 1.5 hours. After the reaction was completed, the reaction solution was directly concentrated under reduced pressure to obtain crude compound A3-9 (3.9g), which was directly used in the next step. MS m/z(ESI):431.9[M+1] + .
第八步:化合物A3-10的合成Step 8: Synthesis of Compound A3-10
将化合物A3-9(1.45g,3.40mmol)加入到四氢呋喃(15mL)和浓盐酸(0.5mL)溶液中，反应在室温搅拌1小时。反应结束后，将反应液减压浓缩除去溶剂，所得残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/0～3/2)纯化得到A3-10(910mg,收率：66％)。MS m/z(ESI):403.9[M+1]+。Compound A3-9 (1.45g, 3.40mmol) was added to a solution of tetrahydrofuran (15mL) and concentrated hydrochloric acid (0.5mL), and the reaction was stirred at room temperature for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~3/2) to obtain A3-10 (910 mg, yield: 66%). ). MS m/z(ESI):403.9[M+1] + .
第九步：化合物A3-11的合成Step 9: Synthesis of Compound A3-11
将N-氯代丁二酰亚胺(330mg,2.48mmol)和冰醋酸(0.2mL)依次加入到化合物A3-10(910mg,2.25mmol)的异丙醇(12mL)溶液中，反应在60℃下搅拌3小时。反应结束后，反应液减压浓缩除去溶剂，所得残余物通过硅胶柱层析法(石油醚/乙酸乙酯＝1/1～0/1)纯化得到化合物A3-11(1.13g)。MS m/z(ESI):437.8[M+1]+。N-Chlorosuccinimide (330 mg, 2.48 mmol) and glacial acetic acid (0.2 mL) were added sequentially to a solution of compound A3-10 (910 mg, 2.25 mmol) in isopropyl alcohol (12 mL), and the reaction was carried out at 60°C Stir for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to remove the solvent, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/1 to 0/1) to obtain compound A3-11 (1.13 g). MS m/z(ESI):437.8[M+1] + .
第十步：化合物A3的合成Step 10: Synthesis of Compound A3
将N,N-二甲基甲酰胺二甲基缩醛(600mg,5.0mmol)加入到化合物A3-11(1.08g,2.5mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应在100℃条件下搅拌3小时。反应结束后，反应液自然冷却至室温，加入水(50mL)稀释，用乙酸乙酯(50mL×3)萃取。合并的有机相用饱和食盐水洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩除去溶剂，得到的残余物通过硅胶柱层析(石油醚/乙酸乙酯＝1/1～2/1)纯化得到化合物A3(900mg,收率：72％)。MS m/z(ESI):492.7[M+1]+。N,N-dimethylformamide dimethyl acetal (600 mg, 5.0 mmol) was added to a solution of compound A3-11 (1.08 g, 2.5 mmol) in N, N-dimethylformamide (15 mL). The reaction was stirred at 100°C for 3 hours. After the reaction was completed, the reaction solution was naturally cooled to room temperature, diluted with water (50 mL), and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to remove the solvent. The resulting residue was passed through silica gel column chromatography (petroleum ether/ethyl acetate = 1/1 to 2/1 ) was purified to obtain compound A3 (900 mg, yield: 72%). MS m/z(ESI):492.7[M+1] + .
中间体化合物A4的合成：
Synthesis of intermediate compound A4:
第一步：化合物A4-2的合成Step One: Synthesis of Compound A4-2
将化合物A2-2(2.0g,10.9mmol)加入到化合物A4-1(1.78g,10.9mmol)的1,4-二氧六环(15mL)溶液中，反应混合物加热至90℃并在该温度下搅拌3.0小时，反应液自然冷却至室温，加入甲磺酸(10mL)，反应混合物加热至50℃并搅拌1小时。反应结束后，反应液冷却到室温并过滤，滤饼干燥得到化合物A4-2(1.6g，收率：61.6％)。MS m/z(ESI):270.9[M+H]+。Compound A2-2 (2.0g, 10.9mmol) was added to a solution of compound A4-1 (1.78g, 10.9mmol) in 1,4-dioxane (15mL), and the reaction mixture was heated to 90°C and at this temperature Stir for 3.0 hours at low temperature. The reaction solution is naturally cooled to room temperature. Methanesulfonic acid (10 mL) is added. The reaction mixture is heated to 50°C and stirred for 1 hour. After the reaction was completed, the reaction solution was cooled to room temperature and filtered, and the filter cake was dried to obtain compound A4-2 (1.6 g, yield: 61.6%). MS m/z(ESI):270.9[M+H] + .
第二步：化合物A4-3的合成Step 2: Synthesis of Compound A4-3
将化合物A1(2.11g,12.88mmol)和碳酸钾(3.18g,23.0mmol)加入到化合物A4-2(2.5g,9.20mmol)的N,N二甲基甲酰胺(30mL)溶液中，反应混合物在65℃下搅拌2小时。反应结束后，反应液加水(100 mL)稀释，乙酸乙酯萃取(50mL×3)，合并有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物A4-3(2.20g，收率：60.0％)MS m/z(ESI):397.8[M+1]+。Compound A1 (2.11g, 12.88mmol) and potassium carbonate (3.18g, 23.0mmol) were added to a solution of compound A4-2 (2.5g, 9.20mmol) in N,N dimethylformamide (30mL), and the reaction mixture Stir at 65°C for 2 hours. After the reaction is completed, water (100 mL), extracted with ethyl acetate (50 mL ~1/1) purification to obtain compound A4-3 (2.20g, yield: 60.0%) MS m/z (ESI): 397.8[M+1] + .
第三步：化合物A4-4的合成Step 3: Synthesis of Compound A4-4
将2mL醋酸滴入化合物A4-3(1.9g，4.77mmol)和N-氯代丁二酰亚胺(0.89mg，6.68mmol)的异丙醇(30mL)溶液中，反应混合物加热到70℃并在该温度下搅拌16小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～0/1)纯化得到化合物A4-4(1.2g，收率：58％)。MS m/z(ESI):431.7，433.7[M+1]+。2 mL acetic acid was dropped into a solution of compound A4-3 (1.9 g, 4.77 mmol) and N-chlorosuccinimide (0.89 mg, 6.68 mmol) in isopropyl alcohol (30 mL). The reaction mixture was heated to 70°C and Stir at this temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0-0/1) to obtain compound A4-4 (1.2 g, yield: 58%). MS m/z(ESI): 431.7, 433.7[M+1] + .
第四步：化合物A4-5的合成Step 4: Synthesis of Compound A4-5
将双三苯基膦二氯化钯(146mg,0.21mmol)加到化合物A4-4(900mg,2.09mmol)和三丁基(1-乙氧基乙烯)锡(2.64g,7.3mmol)的1,4-二氧六环(20mL)溶液中，反应混合物加热到130℃并在该温度下搅拌1.5小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物中加入四氢呋喃(20mL)溶解，再滴入2mL浓盐酸，得到的混合物搅拌1小时。反应液减压浓缩，所得残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～0/1)纯化得到化合物A4-5(1.1g，收率：57％)。MS m/z(ESI):439.7[M+1]+。Bistriphenylphosphine palladium dichloride (146 mg, 0.21 mmol) was added to 1 of compound A4-4 (900 mg, 2.09 mmol) and tributyl(1-ethoxyethylene)tin (2.64 g, 7.3 mmol). , in a solution of 4-dioxane (20 mL), the reaction mixture was heated to 130°C and stirred at this temperature for 1.5 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Tetrahydrofuran (20 mL) was added to the residue to dissolve, and then 2 mL of concentrated hydrochloric acid was added dropwise, and the resulting mixture was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 0/1) to obtain compound A4-5 (1.1 g, yield: 57%). MS m/z(ESI):439.7[M+1] + .
第五步：化合物A4的合成Step 5: Synthesis of Compound A4
将化合物A4-5(500mg,1.14mmol)和N，N-二甲基甲酰胺二甲基缩醛(406mg,3.41mmol)的N,N-二甲基甲酰胺(10mL)溶液加热至100℃并在该温度下搅拌3小时。反应结束后，反应混合液倒入液加水(50mL)稀释，乙酸乙酯萃取(30mL×3)。合并有机相经饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～50/1)纯化得到化合物A4(450mg，收率：80％)。MS m/z(ESI):495.0[M+1]+。A solution of compound A4-5 (500 mg, 1.14 mmol) and N, N-dimethylformamide dimethyl acetal (406 mg, 3.41 mmol) in N, N-dimethylformamide (10 mL) was heated to 100°C. and stirred at this temperature for 3 hours. After the reaction was completed, the reaction mixture was poured into the solution, diluted with water (50 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phases were washed with saturated brine (30 mL Purification gave compound A4 (450 mg, yield: 80%). MS m/z(ESI):495.0[M+1] + .
中间体化合物A5的合成：
Synthesis of intermediate compound A5:
第一步：化合物A5-2的合成Step One: Synthesis of Compound A5-2
将化合物A2-2(1.65g,8.97mmol)加入到化合物A5-1(1.29g,6.9mmol)的1,4-二氧六环(30mL)溶液中，反应混合物在110℃下搅拌3小时后，反应混合物冷却至室温，加入甲磺酸(0.66g,6.9mmol)，反应混合物在50℃下搅拌1小时。反应结束后，反应液加入冰水(80mL)淬灭，所得混合物过滤得到化合物A5-2(1.3g，收率：65％)。MS m/z(ESI):296.8[M+1]+。Compound A2-2 (1.65g, 8.97mmol) was added to a solution of compound A5-1 (1.29g, 6.9mmol) in 1,4-dioxane (30mL), and the reaction mixture was stirred at 110°C for 3 hours. , the reaction mixture was cooled to room temperature, methanesulfonic acid (0.66g, 6.9mmol) was added, and the reaction mixture was stirred at 50°C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding ice water (80 mL), and the resulting mixture was filtered to obtain compound A5-2 (1.3 g, yield: 65%). MS m/z(ESI):296.8[M+1] + .
第二步：化合物A5-3的合成Step 2: Synthesis of Compound A5-3
将化合物A1(1g,6.12mmol)加入到化合物A5-2(1g,3.4mmol)和碳酸钾(0.94g,6.8mmol)的N,N-二甲基甲酰胺(30mL)溶液中，反应混合物在65℃下搅拌3小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到化合物A5-3(0.8g，收率：50％)。MS m/z(ESI):421.7[M+1]+。Compound A1 (1g, 6.12mmol) was added to a solution of compound A5-2 (1g, 3.4mmol) and potassium carbonate (0.94g, 6.8mmol) in N,N-dimethylformamide (30mL), and the reaction mixture was Stir at 65°C for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/2) to obtain compound A5-3 (0.8 g, yield: 50%). MS m/z(ESI):421.7[M+1] + .
第三步：化合物A5的合成Step 3: Synthesis of Compound A5
将N-氯代丁二酰亚胺(0.5g,3.72mmol)加入到化合物A5-3(1.3g,3.1mmol)的异丙醇(40mL)溶液中，反应混合物在90℃下搅拌3小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到化合物A5(1g，收率：64％)。MS m/z(ESI):456.0[M+1]+。N-Chlorosuccinimide (0.5 g, 3.72 mmol) was added to a solution of compound A5-3 (1.3 g, 3.1 mmol) in isopropyl alcohol (40 mL), and the reaction mixture was stirred at 90°C for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/2) to obtain compound A5 (1 g, yield: 64%). MS m/z(ESI):456.0[M+1] + .
中间体化合物A6的合成：
Synthesis of intermediate compound A6:
第一步：化合物A6-2的合成Step One: Synthesis of Compound A6-2
将化合物A6-1(1g,7.9mmol)加入到2-甲基-5-溴苯胺(1.47g,7.9mmol)的邻二氯苯(20mL)溶液中，反应混合物在165℃下搅拌1.5小时。反应结束后，反应液冷却至室温，加入甲苯(30mL)和***(20mL)，析出固体，过滤得到化合物A6-2(0.6g，收率：24％)。MS m/z(ESI):295.8[M+1]+。Compound A6-1 (1 g, 7.9 mmol) was added to a solution of 2-methyl-5-bromoaniline (1.47 g, 7.9 mmol) in o-dichlorobenzene (20 mL), and the reaction mixture was stirred at 165°C for 1.5 hours. After the reaction was completed, the reaction solution was cooled to room temperature, toluene (30 mL) and diethyl ether (20 mL) were added to precipitate a solid, which was filtered to obtain compound A6-2 (0.6 g, yield: 24%). MS m/z(ESI):295.8[M+1] + .
第二步：化合物A6-3的合成Step 2: Synthesis of Compound A6-3
将N-氯代丁二酰亚胺(272.37mg,2.04mmol)加入到化合物A6-2(500mg,1.7mmol)的异丙醇(10mL)的溶液中，反应混合物在80℃下搅拌4小时。反应结束后，反应液减压浓缩经，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物A6-3(450mg，收率：76％)。MS m/z(ESI):327.7,329.8[M+1]+。N-Chlorosuccinimide (272.37 mg, 2.04 mmol) was added to a solution of compound A6-2 (500 mg, 1.7 mmol) in isopropyl alcohol (10 mL), and the reaction mixture was stirred at 80°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound A6-3 (450 mg, yield: 76%). MS m/z(ESI):327.7,329.8[M+1] + .
第三步：化合物A6-4的合成Step 3: Synthesis of Compound A6-4
将化合物A1(312.64mg,1.91mmol)加入到化合物A6-3(450mg,1.37mmol)和碳酸钾(471.78mg,3.41mmol)的N,N-二甲基甲酰胺(20mL)的溶液中，反应混合物在65℃下搅拌3.5小时。反应结束后，反应液加水(100mL)稀释，用乙酸乙酯萃取(50mL×3)，合并有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物A6-4(290mg，收率：44％)。MS m/z(ESI):454.6,456.6[M+1]+。Compound A1 (312.64 mg, 1.91 mmol) was added to a solution of compound A6-3 (450 mg, 1.37 mmol) and potassium carbonate (471.78 mg, 3.41 mmol) in N,N-dimethylformamide (20 mL), and the reaction was carried out The mixture was stirred at 65°C for 3.5 hours. After the reaction, the reaction solution was diluted with water (100 mL), extracted with ethyl acetate (50 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum Ether/ethyl acetate=1/0~1/1) was purified to obtain compound A6-4 (290 mg, yield: 44%). MS m/z(ESI):454.6,456.6[M+1] + .
第四步：化合物A6的合成Step 4: Synthesis of Compound A6
将[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(51.93mg,0.064mmol)加入到化合物A6-4(290mg,0.64mmol)、联硼酸频哪醇酯(177.77mg,0.7mmol)和乙酸钾(187.37mg,1.91mmol)的1,4-二氧六环(10mL)溶液中，反应混合物在氮气气氛下加热至90℃并在该温度下搅拌16小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物A6(160mg，收率：46％)。MS m/z(ESI):502.8[M+1]+。[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (51.93 mg, 0.064 mmol) was added to compound A6-4 (290 mg, 0.64 mmol), pina diboronate In a solution of alcohol ester (177.77 mg, 0.7 mmol) and potassium acetate (187.37 mg, 1.91 mmol) in 1,4-dioxane (10 mL), the reaction mixture was heated to 90°C under a nitrogen atmosphere and stirred at this temperature. 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to obtain compound A6 (160 mg, yield: 46%). MS m/z(ESI):502.8[M+1] + .
中间体化合物A7的合成：
Synthesis of intermediate compound A7:
第一步：化合物A7-2的合成Step One: Synthesis of Compound A7-2
将1,1-双(二苯基膦)二茂铁二氯化钯(1.59g，1.96mmol)加入到化合物A7-1(5g，19.6mmol)、三乙基硼四氢呋喃溶液(25.5mL，25.5mmol)和碳酸铯(38.32g，117.6mmol)的四氢呋喃(100mL)溶液中，反应混合物在氮气保护下加热至55℃并搅拌16小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物A7-2(2.2g，收率：64％)。MS m/z(ESI):157.0[M+1]+。1,1-Bis(diphenylphosphine)ferrocene palladium dichloride (1.59g, 1.96mmol) was added to compound A7-1 (5g, 19.6mmol) and triethylboron tetrahydrofuran solution (25.5mL, 25.5 mmol) and cesium carbonate (38.32 g, 117.6 mmol) in tetrahydrofuran (100 mL), the reaction mixture was heated to 55°C under nitrogen protection and stirred for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to obtain compound A7-2 (2.2 g, yield: 64%). MS m/z(ESI):157.0[M+1] + .
第二步：化合物A7-3的合成Step 2: Synthesis of Compound A7-3
将化合物A7-2(1.4g，8.94mmol)和化合物A2-2(2.14g，11.62mmol)的1,4-二氧六环(30mL)溶液加热至110℃并在该温度下搅拌30分钟。反应液冷却至室温加入甲磺酸(1.12g，11.62mmol)，在50℃下搅拌30分钟。反应结束后，反应液加入冰水(80mL)淬灭，过滤得到化合物A7-3(0.9g，收率：31％)。 MS m/z(ESI):264.9[M+1]+。A solution of compound A7-2 (1.4 g, 8.94 mmol) and compound A2-2 (2.14 g, 11.62 mmol) in 1,4-dioxane (30 mL) was heated to 110°C and stirred at this temperature for 30 minutes. The reaction solution was cooled to room temperature, methanesulfonic acid (1.12g, 11.62mmol) was added, and the mixture was stirred at 50°C for 30 minutes. After the reaction was completed, the reaction solution was quenched by adding ice water (80 mL), and filtered to obtain compound A7-3 (0.9 g, yield: 31%). MS m/z(ESI):264.9[M+1] + .
第三步：化合物A7-4的合成Step 3: Synthesis of Compound A7-4
将碳酸钾(1.17g，8.5mmol)加入到化合物A7-3(900mg，3.4mmol)和化合物A1(778mg，4.76mmol)的N,N-二甲基甲酰胺(10mL)中，反应混合物在65℃下搅拌1小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物A7-4(1.2g，收率：85％)。MS m/z(ESI):391.8[M+1]+。Potassium carbonate (1.17g, 8.5mmol) was added to compound A7-3 (900mg, 3.4mmol) and compound A1 (778mg, 4.76mmol) in N,N-dimethylformamide (10mL), and the reaction mixture was stirred at 65 Stir for 1 hour at ℃. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to obtain compound A7-4 (1.2 g, yield: 85%). MS m/z(ESI):391.8[M+1] + .
第四步：化合物A7-5的合成Step 4: Synthesis of Compound A7-5
将N-氯代丁二酰亚胺(491mg，3.68mmol)加入到化合物A7-4(1.2g，3.06mmol)的异丙醇(30mL)溶液中，反应混合物在80℃下搅拌4小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物A7-5(620mg，收率：45％)。MS m/z(ESI):425.8[M+1]+。N-Chlorosuccinimide (491 mg, 3.68 mmol) was added to a solution of compound A7-4 (1.2 g, 3.06 mmol) in isopropanol (30 mL), and the reaction mixture was stirred at 80°C for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to obtain compound A7-5 (620 mg, yield: 45%). MS m/z(ESI):425.8[M+1] + .
第五步：化合物A7-6的合成Step 5: Synthesis of Compound A7-6
将二(三苯基膦)二氯化钯(102mg,0.15mol)加入到化合物A7-5(620mg,1.45mol)和三丁基(1-乙氧基乙烯)锡(788mg,2.18mol)的1,4-二氧六环(5mL)溶液中，反应混合物在130℃下搅拌2小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物A7-6(0.7g，收率：62％)。MS m/z(ESI):462.0[M+1]+。Bis(triphenylphosphine)palladium dichloride (102 mg, 0.15 mol) was added to compound A7-5 (620 mg, 1.45 mol) and tributyl(1-ethoxyethylene)tin (788 mg, 2.18 mol). In a solution of 1,4-dioxane (5 mL), the reaction mixture was stirred at 130°C for 2 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~2/1) to obtain compound A7-6 (0.7g, yield: 62%). MS m/z(ESI):462.0[M+1] + .
第六步：化合物A7-7的合成Step Six: Synthesis of Compound A7-7
将浓盐酸(2mL)加入到化合物A7-6(0.75g,1.62mmol)的四氢呋喃(10mL)溶液中，反应混合物室温搅拌3小时。反应结束后，反应液减压浓缩后经碳酸氢钠溶液调pH＝7-8，然后用乙酸乙酯(20mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到化合物A7-7(0.45g，收率：61％)。MS m/z(ESI):434.0[M+1]+。Concentrated hydrochloric acid (2 mL) was added to a solution of compound A7-6 (0.75 g, 1.62 mmol) in tetrahydrofuran (10 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, adjusted to pH=7-8 with sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was reduced to The mixture was concentrated under pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/2) to obtain compound A7-7 (0.45 g, yield: 61%). MS m/z(ESI):434.0[M+1] + .
第七步：化合物A7的合成Step Seven: Synthesis of Compound A7
将N,N-二甲基甲酰胺二甲基缩醛(371mg,3.11mmol)加入到化合物A7-7(450mg,1.04mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在100℃下搅拌3小时。反应结束后，反应液加水(10mL)稀释，用乙酸乙酯(20mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物A7(300mg，收率：59％)。MS m/z(ESI):489.1[M+1]+。N,N-dimethylformamide dimethyl acetal (371 mg, 3.11 mmol) was added to a solution of compound A7-7 (450 mg, 1.04 mmol) in N, N-dimethylformamide (5 mL), and the reaction was The mixture was stirred at 100°C for 3 hours. After the reaction, the reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Dichloromethane/methanol=1/0~10/1) was purified to obtain compound A7 (300 mg, yield: 59%). MS m/z(ESI):489.1[M+1] + .
中间体化合物A8的合成：
Synthesis of intermediate compound A8:
第一步：化合物A8-1的合成Step One: Synthesis of Compound A8-1
0℃下，将氘代氢化锂铝(1.35g,32mmol)加入到化合物A1-2(5g,26.7mmol)的四氢呋喃(80mL)溶液中中，反应混合物在0℃下搅拌3小时。反应结束后，反应液依次用水(1.5mL)，15％氢氧化钠溶液(1.5mL)和水(4.5mL)淬灭并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～4/1)纯化得到化合物A8-1(1.6g，收率：38％)。MS m/z(ESI):147.9[M+1]+。Lithium aluminum hydride deuteration (1.35 g, 32 mmol) was added to a solution of compound A1-2 (5 g, 26.7 mmol) in tetrahydrofuran (80 mL) at 0° C., and the reaction mixture was stirred at 0° C. for 3 hours. After the reaction, the reaction solution was quenched with water (1.5 mL), 15% sodium hydroxide solution (1.5 mL) and water (4.5 mL) and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether). /ethyl acetate=1/0~4/1) and purified to obtain compound A8-1 (1.6 g, yield: 38%). MS m/z(ESI):147.9[M+1] + .
第二步：化合物A8的合成Step 2: Synthesis of Compound A8
0℃下，依次将氯化亚砜(485.2mg,4.08mmol)和N,N-二甲基甲酰胺(25mg,0.34mmol)加入到化合物A8-1(500mg,3.4mmol)的二氯甲烷(15mL)溶液中，反应混合物室温搅拌2小时。反应结束后，反应液减压浓缩得到化合物A8(450mg，收率：72％)。At 0°C, thionyl chloride (485.2 mg, 4.08 mmol) and N, N-dimethylformamide (25 mg, 0.34 mmol) were added sequentially to compound A8-1 (500 mg, 3.4 mmol) in dichloromethane ( 15 mL) solution, the reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound A8 (450 mg, yield: 72%).
中间体化合物A9的合成：
Synthesis of intermediate compound A9:
第一步：化合物A9-2的合成Step One: Synthesis of Compound A9-2
将化合物A9-1(1g，6.8mmol)和化合物A2-2(1.63g，8.84mmol)的1,4-二氧六环(10mL)溶液在110℃下搅拌30分钟后加入甲磺酸(3mL)，反应混合物在50℃下继续搅拌30分钟。反应结束后，反应液加入水(30mL)析出固体，过滤得到化合物A9-2(500mg，收率：28％)。MS m/z(ESI):254.8[M+1]+。A solution of compound A9-1 (1g, 6.8mmol) and compound A2-2 (1.63g, 8.84mmol) in 1,4-dioxane (10mL) was stirred at 110°C for 30 minutes and then methanesulfonic acid (3mL ), the reaction mixture was continued to stir at 50°C for 30 minutes. After the reaction was completed, water (30 mL) was added to the reaction solution to precipitate a solid, which was filtered to obtain compound A9-2 (500 mg, yield: 28%). MS m/z(ESI):254.8[M+1] + .
第二步：化合物A9-3的合成Step 2: Synthesis of Compound A9-3
将碳酸钾(977mg，7.07mmol)加入到化合物A9-2(900mg，3.53mmol)和化合物A1(809mg，4.95mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在65℃下搅拌1小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物A9-3(1000mg，收率：70％)。MS m/z(ESI):382.0[M+1]+。Potassium carbonate (977 mg, 7.07 mmol) was added to a solution of compound A9-2 (900 mg, 3.53 mmol) and compound A1 (809 mg, 4.95 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 65 Stir for 1 hour at ℃. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to obtain compound A9-3 (1000 mg, yield: 70%). MS m/z(ESI):382.0[M+1] + .
第三步：化合物A9-4的合成Step 3: Synthesis of Compound A9-4
将N-氯代丁二酰亚胺(420mg，3.14mmol)加入到化合物A9-3(1000mg，2.62mmol)的异丙醇(30mL)溶液中，反应混合物加热到80℃搅拌4小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物A9-4(600mg，收率：52％)。MS m/z(ESI):416.0,418.0[M+1]+。N-Chlorosuccinimide (420 mg, 3.14 mmol) was added to a solution of compound A9-3 (1000 mg, 2.62 mmol) in isopropyl alcohol (30 mL), and the reaction mixture was heated to 80°C and stirred for 4 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to obtain compound A9-4 (600 mg, yield: 52%). MS m/z(ESI):416.0,418.0[M+1] + .
第四步：化合物A9-5的合成Step 4: Synthesis of Compound A9-5
将二(三苯基膦)二氯化钯(101mg,0.14mmol)加入到化合物A9-4(600mg,1.44mmol)和三丁基(1-乙氧基乙烯)锡(781mg,2.16mmol)的1,4-二氧六环(20mL)溶液中，反应混合物130℃下搅拌2小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物A9-5(700mg，收率：97％)。MS m/z(ESI):452.0[M+1]+。Bis(triphenylphosphine)palladium dichloride (101 mg, 0.14 mmol) was added to compound A9-4 (600 mg, 1.44 mmol) and tributyl(1-ethoxyethylene)tin (781 mg, 2.16 mmol). In a solution of 1,4-dioxane (20 mL), the reaction mixture was stirred at 130°C for 2 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~2/1) to obtain compound A9-5 (700 mg, yield: 97 %). MS m/z(ESI):452.0[M+1] + .
第五步：化合物A9-6的合成Step 5: Synthesis of Compound A9-6
将浓盐酸(2mL)加入到化合物A9-5(700mg,1.55mmol)的四氢呋喃(6mL)溶液中，反应混合物室温搅拌3小时。反应结束后，反应液减压浓缩，残余物用碳酸氢钠溶液调pH＝7-8，然后用乙酸乙酯(20mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到化合物A9-6(500mg，收率：76％)。MS m/z(ESI):424.0[M+1]+。Concentrated hydrochloric acid (2 mL) was added to a solution of compound A9-5 (700 mg, 1.55 mmol) in tetrahydrofuran (6 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure. The residue was adjusted to pH=7-8 with sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The liquid was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/2) to obtain compound A9-6 (500 mg, yield: 76%). MS m/z(ESI):424.0[M+1] + .
第六步：化合物A9的合成Step Six: Synthesis of Compound A9
将N,N-二甲基甲酰胺二甲基缩醛(422mg,3.54mmol)加入到化合物A9-6(500mg,1.18mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在100℃下搅拌3小时。反应结束后，反应液加水(10mL)稀释，经乙酸乙酯(20mL×3)萃取，无水硫酸钠干燥并过滤，过滤液减压浓缩后经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物A9(400mg，收率：71％)。MS m/z(ESI):478.8[M+1]+。N,N-dimethylformamide dimethyl acetal (422 mg, 3.54 mmol) was added to a solution of compound A9-6 (500 mg, 1.18 mmol) in N, N-dimethylformamide (5 mL), and the reaction was The mixture was stirred at 100°C for 3 hours. After the reaction, the reaction solution was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel column chromatography (dichloromethane/methanol=1 /0～10/1) to obtain compound A9 (400 mg, yield: 71%). MS m/z(ESI):478.8[M+1] + .
中间体化合物A10的合成：
Synthesis of intermediate compound A10:
第一步：化合物A10-2的合成Step One: Synthesis of Compound A10-2
将化合物A2-2(2.4g,13.3mmol)和化合物A10-1(2.0g,10.2mmol)的1,4-二氧六环(40mL)溶液在110℃下搅拌1小时后加入甲磺酸(0.98g,10.2mmol)。反应混合物在50℃下搅拌1小时。反应完成后，反应液加冰水(80mL)淬灭，过滤，滤饼干燥得到化合物A10-2(2.0g，收率：57.8％)。MS m/z(ESI):305.0[M+1]+。A solution of compound A2-2 (2.4g, 13.3mmol) and compound A10-1 (2.0g, 10.2mmol) in 1,4-dioxane (40mL) was stirred at 110°C for 1 hour and then methanesulfonic acid ( 0.98g, 10.2mmol). The reaction mixture was stirred at 50°C for 1 hour. After the reaction was completed, the reaction solution was quenched by adding ice water (80 mL), filtered, and the filter cake was dried to obtain compound A10-2 (2.0 g, yield: 57.8%). MS m/z(ESI):305.0[M+1] + .
第二步：化合物A10-3的合成Step 2: Synthesis of Compound A10-3
将碳酸钾(1.8g，13.0mmol)加入到化合物A10-2(1.8g，5.9mmol)和化合物A1(1.4g，8.3mmol)的N,N-二甲基甲酰胺(40mL)溶液中，反应混合物在65℃下搅拌3小时。反应结束后，反应液加水(200mL)稀释，经乙酸乙酯萃取(100mL×3)，合并的有机相经饱和食盐水(100mL×1)洗涤并减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物A10-3(2.0g，收率：71.2％)。MS m/z(ESI):432.0[M+1]+。Potassium carbonate (1.8g, 13.0mmol) was added to the solution of compound A10-2 (1.8g, 5.9mmol) and compound A1 (1.4g, 8.3mmol) in N,N-dimethylformamide (40mL), and the reaction was The mixture was stirred at 65°C for 3 hours. After the reaction was completed, the reaction solution was diluted with water (200 mL) and extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 1) and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate=1/0~1/1) was purified to obtain compound A10-3 (2.0g, yield: 71.2%). MS m/z(ESI):432.0[M+1] + .
第三步：化合物A10-4的合成Step 3: Synthesis of Compound A10-4
将N-氯琥珀酰亚胺(0.74g，5.5mmol)加入化合物A10-3(2.0g,4.6mmol)的异丙醇(40mL)溶液中，反应混合物在80℃下搅拌反应3小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物A10-4(2.0g，收率：84.7％)。MS m/z(ESI):466.0[M+1]+。N-Chlorosuccinimide (0.74g, 5.5mmol) was added to a solution of compound A10-3 (2.0g, 4.6mmol) in isopropanol (40mL), and the reaction mixture was stirred at 80°C for 3 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound A10-4 (2.0g, yield: 84.7 %). MS m/z(ESI):466.0[M+1] + .
第四步：化合物A10-5的合成Step 4: Synthesis of Compound A10-5
在氮气气氛下，将二(三苯基膦)二氯化钯(0.3mg,0.4mmol)加入到化合物A10-4(2.0g,4.3mmol)和三丁基(1-乙氧基乙烯)锡(2.1g,5.5mmol)的1,4-二氧六环(50mL)溶液中，反应混合物在120℃下搅拌2小时。反应结束后，反应液加水(100mL)稀释，经乙酸乙酯萃取(50mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物A10-5(1.8g，收率：74.4％)。MS m/z(ESI):502.2[M+1]+。Under a nitrogen atmosphere, bis(triphenylphosphine)palladium dichloride (0.3 mg, 0.4 mmol) was added to compound A10-4 (2.0 g, 4.3 mmol) and tributyl (1-ethoxyethylene) tin (2.1 g, 5.5 mmol) in 1,4-dioxane (50 mL), the reaction mixture was stirred at 120°C for 2 hours. After the reaction, the reaction solution was diluted with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Dichloromethane/methanol=1/0~20/1) was purified to obtain compound A10-5 (1.8 g, yield: 74.4%). MS m/z(ESI):502.2[M+1] + .
第五步：化合物A10-6的合成Step 5: Synthesis of Compound A10-6
将浓盐酸(0.9mL)加入到化合物A10-5(1.4g,2.8mmol)的四氢呋喃(50mL)溶液中，反应混合物室温搅拌2小时。反应结束，反应液用饱和的碳酸氢钠溶液调pH＝7，然后用乙酸乙酯(50mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物A10-6(1.0g，收率：67.8％)。MS m/z(ESI):474.0[M+1]+。Concentrated hydrochloric acid (0.9 mL) was added to a solution of compound A10-5 (1.4 g, 2.8 mmol) in tetrahydrofuran (50 mL), and the reaction mixture was stirred at room temperature for 2 hours. At the end of the reaction, the reaction solution was adjusted to pH=7 with saturated sodium bicarbonate solution, and then extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue Compound A10-6 (1.0 g, yield: 67.8%) was purified by silica gel column chromatography (dichloromethane/methanol = 1/0 to 10/1). MS m/z(ESI):474.0[M+1] + .
第六步：化合物A10的合成Step 6: Synthesis of Compound A10
将N,N-二甲基甲酰胺二甲基缩醛(250mg,2.1mmol)加入到化合物A10-6(500mg,1.0mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在100℃下搅拌3小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物A10(500mg，收率：80.6％)。MS m/z(ESI):529.1[M+1]+。Add N,N-dimethylformamide dimethyl acetal (250 mg, 2.1 mmol) to a solution of compound A10-6 (500 mg, 1.0 mmol) in N, N-dimethylformamide (10 mL), and react The mixture was stirred at 100°C for 3 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound A10 (500 mg, yield: 80.6%). MS m/z(ESI):529.1[M+1] + .
实施例1(化合物1、1-P1或1-P2和1-P2或1-P1)的合成
Synthesis of Example 1 (Compound 1, 1-P1 or 1-P2 and 1-P2 or 1-P1)
第一步：化合物1b的合成Step One: Synthesis of Compound 1b
将羟胺的水溶液(5mL)加入到化合物1a(1g,14.1mmol)的乙醇(20mL)溶液中，反应混合物加热至75℃并在该温度下搅拌12小时。反应结束后，反应液减压浓缩得到化合物1b(1.2g，粗品)。MS m/z(ESI):105.1[M+1]+ An aqueous solution of hydroxylamine (5 mL) was added to a solution of compound 1a (1 g, 14.1 mmol) in ethanol (20 mL), and the reaction mixture was heated to 75 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 1b (1.2 g, crude product). MS m/z(ESI):105.1[M+1] +
第二步：化合物1c的合成Step 2: Synthesis of Compound 1c
将雷尼镍(2.03g,34.5mmol)加入化合物1b(1.2g,11.5mmol)和乙酸(1mL)的甲醇(20mL)溶液中，反应混合物在氢气气氛下室温搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物1c(1g，粗品)。MS m/z(ESI):89.1[M+1]+ Raney Nickel (2.03 g, 34.5 mmol) was added to a solution of compound 1b (1.2 g, 11.5 mmol) and acetic acid (1 mL) in methanol (20 mL), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 1c (1 g, crude product). MS m/z(ESI):89.1[M+1] +
第三步：化合物1-P1和1-P2的合成Step 3: Synthesis of Compounds 1-P1 and 1-P2
将化合物A2(400mg,0.84mmol)加入到化合物1c(445.28mg,5.05mmol)和碳酸钾(814.90mg,5.90mmol)的乙腈(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物1，化合物1经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm×20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物1-P1(16.5mg，收率4.04％)和化合物1-P2(17.8mg，收率4.36％)。Compound A2 (400 mg, 0.84 mmol) was added to a solution of compound 1c (445.28 mg, 5.05 mmol) and potassium carbonate (814.90 mg, 5.90 mmol) in acetonitrile (10 mL). The reaction mixture was heated to 75°C and stirred at this temperature. 12 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 1, which is subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) After separation, compound 1- P1 (16.5 mg, yield 4.04%) and compound 1-P2 (17.8 mg, yield 4.36%).
化合物1-P1：Compound 1-P1:
MS m/z(ESI):499.8[M+1]+。超临界流体色谱SFC：保留时间＝3.16min，UV＝220nm。1H NMR(400MHz,CD3OD)δ8.87-8.76(m,2H),8.44(d,J＝2.4Hz,1H),8.38(s,1H),8.25(d,J＝5.3Hz,1H),7.71-7.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝2.0Hz,2H),4.07(t,J＝6.4Hz,2H),3.19(t,J＝6.4Hz,2H),2.15(s,3H),2.04(d,J＝0.5Hz,3H)。MS m/z(ESI):499.8[M+1] + . Supercritical fluid chromatography SFC: retention time = 3.16min, UV = 220nm. 1 H NMR (400MHz, CD 3 OD) δ8.87-8.76 (m, 2H), 8.44 (d, J = 2.4Hz, 1H), 8.38 (s, 1H), 8.25 (d, J = 5.3Hz, 1H ),7.71-7.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝2.0Hz,2H),4.07(t,J＝6.4Hz,2H),3.19(t ,J＝6.4Hz,2H),2.15(s,3H),2.04(d,J＝0.5Hz,3H).
化合物1-P2：Compound 1-P2:
MS m/z(ESI):499.8[M+1]+。超临界流体色谱SFC：保留时间＝3.91min，UV＝220nm。1H NMR(400MHz,CD3OD)δ8.87-8.76(m,2H),8.44(d,J＝2.4Hz,1H),8.38(s,1H),8.25(d,J＝5.3Hz,1H),7.71-7.69(m,1H),6.81(d,J＝0.5Hz,1H),5.49(d,J＝2.0Hz,2H),4.07(t,J＝6.4Hz,2H),3.19(t,J＝6.4Hz,2H),2.15(s,3H),2.04(d,J＝0.4Hz,3H).MS m/z(ESI):499.8[M+1] + . Supercritical fluid chromatography SFC: retention time=3.91min, UV=220nm. 1 H NMR (400MHz, CD 3 OD) δ8.87-8.76 (m, 2H), 8.44 (d, J = 2.4Hz, 1H), 8.38 (s, 1H), 8.25 (d, J = 5.3Hz, 1H ),7.71-7.69(m,1H),6.81(d,J＝0.5Hz,1H),5.49(d,J＝2.0Hz,2H),4.07(t,J＝6.4Hz,2H),3.19(t ,J＝6.4Hz,2H),2.15(s,3H),2.04(d,J＝0.4Hz,3H).
实施例2(化合物3、3-P1或3-P2和3-P2或3-P1)的合成
Synthesis of Example 2 (Compound 3, 3-P1 or 3-P2 and 3-P2 or 3-P1)
第一步：化合物3b的合成Step One: Synthesis of Compound 3b
将硼氢化钠(0.81mg,21.3mmol)加入到化合物3a(1g,7.1mmol)的四氢呋喃)和水(10mL/10mL)混合溶液中，反应混合物室温搅拌16小时。反应结束后，反应液用2N盐酸调pH＝7，反应液减压浓缩除去四氢呋喃，用乙酸乙酯萃取(20mL×3)，合并有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物3b(0.6g，收率：80％)。1H NMR(400MHz,CDCl3)δ3.55(dd,J＝4.5,1.9Hz,2H),1.48-1.22(m,6H)。Sodium borohydride (0.81 mg, 21.3 mmol) was added to a mixed solution of compound 3a (1 g, 7.1 mmol) in tetrahydrofuran) and water (10 mL/10 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was adjusted to pH=7 with 2N hydrochloric acid. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran. It was extracted with ethyl acetate (20mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. Compound 3b (0.6 g, yield: 80%) was obtained. 1 H NMR (400MHz, CDCl 3 ) δ3.55 (dd, J=4.5, 1.9Hz, 2H), 1.48-1.22 (m, 6H).
第二步：化合物3c的合成Step 2: Synthesis of compound 3c
将羟胺水溶液(2.13g,32.28mmol)加入到化合物3b(0.8g,8.07mmol)的乙醇(20mL)溶液中，反应混合物加热至75℃并在该温度下搅拌16小时。反应结束后，反应液减压浓缩得到化合物3c(1.0g，粗品)。MS m/z(ESI):133.0[M+1]+。Aqueous hydroxylamine solution (2.13 g, 32.28 mmol) was added to a solution of compound 3b (0.8 g, 8.07 mmol) in ethanol (20 mL), and the reaction mixture was heated to 75°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 3c (1.0 g, crude product). MS m/z(ESI):133.0[M+1] + .
第三步：化合物3d的合成Step 3: Synthesis of Compound 3d
将雷尼镍(0.13g,2.27mmol)加入到化合物3c(0.6g,4.54mmol)的甲醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌12小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物3d(0.4g，粗品)。MS m/z(ESI):117.1[M+1]+。Raney Nickel (0.13 g, 2.27 mmol) was added to a solution of compound 3c (0.6 g, 4.54 mmol) in methanol (10 mL), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 3d (0.4 g, crude product). MS m/z(ESI):117.1[M+1] + .
第四步：化合物3-P1和3-P2的合成Step 4: Synthesis of compounds 3-P1 and 3-P2
将化合物A2(300mg,0.63mmol)加入到化合物3d(293.56mg,2.53mmol)，和碳酸钾(174.6mg,1.26mmol)的乙腈(10mL)溶液中，反应混合物加热至90℃并在该温度下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物3，化合物3经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm×20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物3-P1(13.3mg，收率3.8％)和3-P2(18.6mg，收率5.3％)。Compound A2 (300 mg, 0.63 mmol) was added to a solution of compound 3d (293.56 mg, 2.53 mmol) and potassium carbonate (174.6 mg, 1.26 mmol) in acetonitrile (10 mL). The reaction mixture was heated to 90°C and at this temperature Stir for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 3, which was subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) After separation, compound 3- P1 (13.3 mg, yield 3.8%) and 3-P2 (18.6 mg, yield 5.3%).
化合物3-P1：Compound 3-P1:
MS m/z(ESI):527.8[M+1]+。超临界流体色谱SFC：保留时间＝2.43min,UV＝254nm。1H NMR(400MHz,CDCl3)δ8.84(d,J＝5.3Hz,1H),8.76(s,1H),8.42(d,J＝2.3Hz,1H),8.29(d,J＝5.3Hz,1H),8.20(s,1H),7.38-7.28(m,1H),6.44(s,1H),5.43(d,J＝1.7Hz,2H),3.86(d,J＝1.0Hz,2H),2.20(s,3H),2.00(s,3H),1.43(d,J＝1.5Hz,6H)。MS m/z(ESI):527.8[M+1] + . Supercritical fluid chromatography SFC: retention time=2.43min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.84(d,J＝5.3Hz,1H),8.76(s,1H),8.42(d,J＝2.3Hz,1H),8.29(d,J＝5.3Hz ,1H),8.20(s,1H),7.38-7.28(m,1H),6.44(s,1H),5.43(d,J＝1.7Hz,2H),3.86(d,J＝1.0Hz,2H) ,2.20(s,3H),2.00(s,3H),1.43(d,J＝1.5Hz,6H).
化合物3-P2：Compound 3-P2:
MS m/z(ESI):527.8[M+1]+。超临界流体色谱SFC：保留时间＝3.37min,UV＝254nm。1H NMR(400MHz,CDCl3)δ8.82(d,J＝5.2Hz,1H),8.75(s,1H),8.42(d,J＝2.3Hz,1H),8.24(d,J＝5.2Hz,1H),8.19(s,1H),7.39-7.29(m,1H),6.44(s,1H),5.43(d,J＝1.8Hz,2H),3.84(d,J＝5.0Hz,1H),2.20(d,J＝5.8Hz,3H),2.00(d,J＝3.7Hz,3H),1.42(d,J＝4.8Hz,6H)。MS m/z(ESI):527.8[M+1] + . Supercritical fluid chromatography SFC: retention time=3.37min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.82(d,J＝5.2Hz,1H),8.75(s,1H),8.42(d,J＝2.3Hz,1H),8.24(d,J＝5.2Hz ,1H),8.19(s,1H),7.39-7.29(m,1H),6.44(s,1H),5.43(d,J＝1.8Hz,2H),3.84(d,J＝5.0Hz,1H) ,2.20(d,J＝5.8Hz,3H), 2.00(d,J＝3.7Hz,3H), 1.42(d,J＝4.8Hz,6H).
实施例3(化合物5、5-P1或5-P2和5-P2或5-P1)的合成
Synthesis of Example 3 (Compound 5, 5-P1 or 5-P2 and 5-P2 or 5-P1)
第一步：化合物5b的合成Step One: Synthesis of Compound 5b
将硼氢化钠(598mg,15.8mmol)加入到化合物5a(2g,14.4mmol)的甲醇(20mL)溶液中，反应混合物室温搅拌16小时。反应结束后，反应液用2N盐酸调pH＝7，所得溶液减压浓缩除去甲醇，用乙酸乙酯萃取(10mL×3)，合并有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩得到化合物5b(1.0g，收率：64％)。1H NMR(400MHz,CD3OD)δ3.57(s,2H),1.40-1.14(m,2H),1.04-0.80(m,2H)。Sodium borohydride (598 mg, 15.8 mmol) was added to a solution of compound 5a (2 g, 14.4 mmol) in methanol (20 mL), and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was adjusted to pH=7 with 2N hydrochloric acid. The resulting solution was concentrated under reduced pressure to remove methanol, and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. Compound 5b (1.0 g, yield: 64%) was obtained. 1 H NMR (400MHz, CD 3 OD) δ3.57 (s, 2H), 1.40-1.14 (m, 2H), 1.04-0.80 (m, 2H).
第二步：化合物5c的合成Step 2: Synthesis of compound 5c
将羟胺水溶液(3.4g,103mmol)加热到化合物5b(1.0g,10.3mmol)的乙醇(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌16小时。反应结束后，反应液减压浓缩得到化合物5c(1.2g，粗品)。MS m/z(ESI):131.2[M+1]+。Aqueous hydroxylamine (3.4 g, 103 mmol) was heated to a solution of compound 5b (1.0 g, 10.3 mmol) in ethanol (10 mL) and the reaction mixture was heated to 75°C and stirred at this temperature for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 5c (1.2 g, crude product). MS m/z(ESI):131.2[M+1] + .
第三步：化合物5d的合成Step 3: Synthesis of Compound 5d
将雷尼镍(1.32g,15.4mmol)加入到化合物5c(1g,7.68mmol)和乙酸(46mg,0.77mmol)的甲醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌12小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物5d(1.0g，粗品)。MS m/z(ESI):115.2[M+1]+。Raney nickel (1.32 g, 15.4 mmol) was added to a solution of compound 5c (1 g, 7.68 mmol) and acetic acid (46 mg, 0.77 mmol) in methanol (10 mL), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 12 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5d (1.0 g, crude product). MS m/z(ESI):115.2[M+1] + .
第四步：化合物5-P1和5-P2的合成Step 4: Synthesis of compounds 5-P1 and 5-P2
将化合物A2(416mg,0.88mmol)加入到化合物5d(500mg,4.4mmol)，和碳酸钾(1.2g,8.77mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物加热至90℃并在该温度下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物5，化合物5经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm×20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物5-P1(19.4mg，收率0.8％)和5-P2(17.8mg，收率0.76％)。Compound A2 (416 mg, 0.88 mmol) was added to a solution of compound 5d (500 mg, 4.4 mmol) and potassium carbonate (1.2 g, 8.77 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated to 90°C and stirred at this temperature for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 5, which was subjected to supercritical fluid chiral chromatography. ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 5 was obtained by separation -P1 (19.4 mg, yield 0.8%) and 5-P2 (17.8 mg, yield 0.76%).
化合物5-P1：Compound 5-P1:
MS m/z(ESI):526.1[M+1]+。超临界流体色谱SFC：保留时间＝3.1min,UV＝254nm。1H NMR(400MHz,CD3OD)δ8.79-8.73(m,2H),8.44(d,J＝2.4Hz,1H),8.35(s,1H),8.13(d,J＝5.2Hz,1H),7.71-7.69(m,1H),6.81(s,1H),5.49(d,J＝1.8Hz,2H),4.00(dd,J＝29.1,11.6Hz,2H),2.14(s,3H),2.04(s,3H),1.40(d,J＝4.5Hz,2H),1.07(d,J＝3.1Hz,2H)。MS m/z(ESI):526.1[M+1] + . Supercritical fluid chromatography SFC: retention time=3.1min, UV=254nm. 1H NMR (400MHz, CD 3 OD) δ8.79-8.73 (m, 2H), 8.44 (d, J = 2.4Hz, 1H), 8.35 (s, 1H), 8.13 (d, J = 5.2Hz, 1H) ,7.71-7.69(m,1H),6.81(s,1H),5.49(d,J＝1.8Hz,2H),4.00(dd,J＝29.1,11.6Hz,2H),2.14(s,3H), 2.04(s,3H),1.40(d,J=4.5Hz,2H),1.07(d,J=3.1Hz,2H).
化合物5-P2：Compound 5-P2:
MS m/z(ESI):526.2[M+1]+。超临界流体色谱SFC：保留时间＝5.18min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.79-8.74(m,2H),8.44(d,J＝2.4Hz,1H),8.35(s,1H),8.13(d,J＝5.2Hz,1H),7.71-7.69(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),4.00(dd,J＝29.0,11.6Hz,2H),2.14(s,3H),2.04(s,3H),1.40(d,J＝4.5Hz,2H),1.07(d,J＝3.1Hz,2H)。MS m/z(ESI):526.2[M+1] + . Supercritical fluid chromatography SFC: retention time=5.18min, UV=254nm. 1H NMR (400MHz, CD 3 OD) δ8.79-8.74(m,2H),8.44(d,J＝2.4Hz,1H),8.35(s,1H),8.13(d,J＝5.2Hz,1H) ,7.71-7.69(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),4.00(dd,J＝29.0,11.6Hz,2H),2.14(s,3H), 2.04(s,3H),1.40(d,J=4.5Hz,2H),1.07(d,J=3.1Hz,2H).
实施例4(化合物6、6-P1或6-P2和6-P2或6-P1)的合成
Synthesis of Example 4 (Compound 6, 6-P1 or 6-P2 and 6-P2 or 6-P1)
第一步：化合物6b的合成Step One: Synthesis of Compound 6b
0℃下，将硼氢化钠(330mg,8.5mmol)加入到化合物6a(1.2g,7.8mmol)的甲醇(20mL)溶液中，反应混合物室温搅拌5小时。反应结束后，反应液加入饱和氯化铵溶液(10mL)淬灭，用乙酸乙酯萃取(20mL×3)，合并有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩后得到化合物6b(1.0g，收率：80％)。1H NMR(400MHz,CDCl3)δ4.27-4.23(m,2H),2.80-2.73(m,2H),2.58-2.54(m,J＝9.4,8.2,4.2Hz,2H),2.36-2.30(m,2H)。Sodium borohydride (330 mg, 8.5 mmol) was added to a solution of compound 6a (1.2 g, 7.8 mmol) in methanol (20 mL) at 0°C, and the reaction mixture was stirred at room temperature for 5 hours. After the reaction, the reaction solution was quenched by adding saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain compound 6b. (1.0g, yield: 80%). 1 H NMR (400MHz, CDCl 3 ) δ4.27-4.23(m,2H),2.80-2.73(m,2H),2.58-2.54(m,J＝9.4,8.2,4.2Hz,2H),2.36-2.30 (m,2H).
第二步：化合物6c的合成Step 2: Synthesis of compound 6c
将羟胺水溶液(2.97g,90mmol)加入到化合物6b(1.0g,9mmol)的乙醇(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌12小时。反应结束后，反应液减压浓缩得到化合物6c(1.2g，粗品)。MS m/z(ESI):145.1[M+1]+。Aqueous hydroxylamine solution (2.97 g, 90 mmol) was added to a solution of compound 6b (1.0 g, 9 mmol) in ethanol (10 mL), and the reaction mixture was heated to 75 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 6c (1.2 g, crude product). MS m/z(ESI):145.1[M+1] + .
第三步：化合物6d的合成Step 3: Synthesis of Compound 6d
将雷尼镍(2.4g,41.6mmol)加入到化合物6c(1.2g,8.3mmol)和乙酸(50mg,0.83mmol)的甲醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物6d(1.2g，粗品)。MS m/z(ESI):129.0[M+1]+。Raney nickel (2.4 g, 41.6 mmol) was added to a solution of compound 6c (1.2 g, 8.3 mmol) and acetic acid (50 mg, 0.83 mmol) in methanol (10 mL), and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6d (1.2 g, crude product). MS m/z(ESI):129.0[M+1] + .
第四步：化合物6-P1和6-P2的合成Step 4: Synthesis of compounds 6-P1 and 6-P2
将化合物A2(222.3mg,0.47mmol)加入到化合物6d(1.2g,9.36mmol)，和碳酸钾(1.29g,9.36mmol)的乙腈(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌4小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得化合物6，化合物6经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm×20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物6-P1(35mg，收率0.63％)和化合物6-P2(23.5mg，收率0.46％)。Compound A2 (222.3 mg, 0.47 mmol) was added to a solution of compound 6d (1.2 g, 9.36 mmol) and potassium carbonate (1.29 g, 9.36 mmol) in acetonitrile (10 mL). The reaction mixture was heated to 75°C and at this temperature Stir for 4 hours. After the reaction, the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 6, which was subjected to supercritical fluid chiral chromatography. ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 6 was obtained by resolution -P1 (35 mg, yield 0.63%) and compound 6-P2 (23.5 mg, yield 0.46%).
化合物6-P1：Compound 6-P1:
MS m/z(ESI):539.8[M+1]+。超临界流体色谱SFC：保留时间＝3.15min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.85(d,J＝5.2Hz,1H),8.80(s,1H),,8.44(d,J＝2.4Hz,1H),8.36(s,1H),8.22(d,J＝5.2Hz,1H),7.75-7.66(m,1H),6.81(s,1H),5.49(d,J＝1.8Hz,2H),4.03(s,2H),2.67-2.54(m,2H),2.29-2.19(m,2H),2.14(s,3H),2.04(s,3H),1.97-1.86(m,2H)。MS m/z(ESI):539.8[M+1] + . Supercritical fluid chromatography SFC: retention time=3.15min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.85(d,J＝5.2Hz,1H),8.80(s,1H),,8.44(d,J＝2.4Hz,1H),8.36(s,1H) ,8.22(d,J＝5.2Hz,1H),7.75-7.66(m,1H),6.81(s,1H),5.49(d,J＝1.8Hz,2H),4.03(s,2H),2.67- 2.54(m,2H),2.29-2.19(m,2H),2.14(s,3H),2.04(s,3H),1.97-1.86(m,2H).
化合物6-P2：Compound 6-P2:
MS m/z(ESI):540.0[M+1]+。超临界流体色谱SFC：保留时间＝5.03min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.87(d,J＝5.2Hz,1H),8.81(s,1H),8.46(d,J＝2.3Hz,1H),8.38(s,1H),8.24(d,J＝5.2Hz,1H),7.77-7.70(m,1H),6.83(s,1H),5.51(d,J＝1.8Hz,2H),4.04(s,2H),2.68-2.58(m,2H),2.28-2.20(m,2H),2.17(s,3H),2.06(s,3H),2.04-1.75(m,2H)。MS m/z(ESI):540.0[M+1] + . Supercritical fluid chromatography SFC: retention time=5.03min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.87(d,J＝5.2Hz,1H),8.81(s,1H),8.46(d,J＝2.3Hz,1H),8.38(s,1H), 8.24(d,J＝5.2Hz,1H),7.77-7.70(m,1H),6.83(s,1H),5.51(d,J＝1.8Hz,2H),4.04(s,2H),2.68-2.58 (m,2H),2.28-2.20(m,2H),2.17(s,3H),2.06(s,3H),2.04-1.75(m,2H).
实施例5(化合物13、13-P1或13-P2和13-P2或13-P1)的合成
Synthesis of Example 5 (Compound 13, 13-P1 or 13-P2 and 13-P2 or 13-P1)
第一步：化合物13b的合成Step One: Synthesis of Compound 13b
将羟胺的水溶液(2.5mL)加入到化合物13a(500mg,5.04mmol)的乙醇(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌12小时。反应结束后，反应液减压浓缩得到化合物13b(600mg，粗品)。MS m/z(ESI):133.1[M+1]+。An aqueous solution of hydroxylamine (2.5 mL) was added to a solution of compound 13a (500 mg, 5.04 mmol) in ethanol (10 mL), and the reaction mixture was heated to 75 °C and stirred at this temperature for 12 h. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 13b (600 mg, crude product). MS m/z(ESI):133.1[M+1] + .
第二步：化合物13c的合成Step 2: Synthesis of compound 13c
将雷尼镍(0.8g,13.62mmol)加入到化合物13b(300mg,4.54mmol)和乙酸(0.5mL)的甲醇(10mL)溶液中。反应混合物下氢气气氛下室温搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物13c(400mg，粗品)。MS m/z(ESI):117.1[M+1]+ Raney Nickel (0.8 g, 13.62 mmol) was added to a solution of compound 13b (300 mg, 4.54 mmol) and acetic acid (0.5 mL) in methanol (10 mL). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 13c (400 mg, crude product). MS m/z(ESI):117.1[M+1] +
第二步：化合物13-P1和13-P2的合成Step 2: Synthesis of compounds 13-P1 and 13-P2
将化合物A2(350mg,0.74mmol)加入到化合物13c(514mg,4.42mmol)和碳酸钾(713mg,5.16mmol)的乙腈(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到粗品化合物13，粗品化合物13经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm×20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物13-P1(14.9mg，收率3.64％)和13-P2(27.0mg，收率6.59％)。Compound A2 (350 mg, 0.74 mmol) was added to a solution of compound 13c (514 mg, 4.42 mmol) and potassium carbonate (713 mg, 5.16 mmol) in acetonitrile (10 mL). The reaction mixture was heated to 75°C and stirred at this temperature for 12 hours. . After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain crude compound 13. The crude compound 13 was purified by supercritical fluid chromatography. Chromatography ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compounds 13-P1 (14.9 mg, yield 3.64%) and 13-P2 (27.0 mg, yield 6.59%).
化合物13-P1：Compound 13-P1:
MS m/z(ESI):528.0[M+1]+。超临界流体色谱SFC：保留时间＝2.22min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.84(d,J＝5.3Hz,1H),8.80(s,1H),8.44(d,J＝2.4Hz,1H),8.35(s,1H),8.28(d,J＝5.3Hz,1H),7.72-6.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝1.9Hz,2H),3.15(s,2H),2.16(s,3H),2.04(d,J＝0.5Hz,3H),1.26(d,J＝4.3Hz,6H)。MS m/z(ESI):528.0[M+1] + . Supercritical fluid chromatography SFC: retention time = 2.22min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.84(d,J＝5.3Hz,1H),8.80(s,1H),8.44(d,J＝2.4Hz,1H),8.35(s,1H), 8.28(d,J＝5.3Hz,1H),7.72-6.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝1.9Hz,2H),3.15(s,2H ), 2.16 (s, 3H), 2.04 (d, J = 0.5Hz, 3H), 1.26 (d, J = 4.3Hz, 6H).
化合物13-P2：Compound 13-P2:
MS m/z(ESI):528.1[M+1]+。超临界流体色谱SFC：保留时间＝2.84min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.84(d,J＝5.3Hz,1H),8.80(s,1H),8.44(d,J＝2.3Hz,1H),8.36(d,J＝5.0Hz,1H),8.28(d,J＝5.3Hz,1H),7.71-6.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝1.9Hz,2H),3.15(s,2H),2.15(s,3H),2.04(s,3H),1.26(d,J＝3.9Hz,6H)。MS m/z(ESI):528.1[M+1] + . Supercritical fluid chromatography SFC: retention time = 2.84min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.84(d,J＝5.3Hz,1H),8.80(s,1H),8.44(d,J＝2.3Hz,1H),8.36(d,J＝5.0 Hz,1H),8.28(d,J＝5.3Hz,1H),7.71-6.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝1.9Hz,2H), 3.15(s,2H),2.15(s,3H),2.04(s,3H),1.26(d,J=3.9Hz,6H).
实施例6(化合物20、20-P1或20-P2和20-P2或20-P1)的合成
Synthesis of Example 6 (Compound 20, 20-P1 or 20-P2 and 20-P2 or 20-P1)
将化合物A3(350mg,0.71mmol)加入到化合物13c(495mg,4.26mmol)和碳酸钾(687mg,4.97mmol) 的乙腈(10mL)溶液中，反应混合物加热至75℃并在该温度下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到粗品化合物20，粗品化合物20经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm×20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物20-P1(16.5mg，收率4.04％)和20-P2(17.8mg，收率4.36％)。Compound A3 (350 mg, 0.71 mmol) was added to compound 13c (495 mg, 4.26 mmol) and potassium carbonate (687 mg, 4.97 mmol) The reaction mixture was heated to 75°C in acetonitrile (10 mL) and stirred at this temperature for 12 hours. After the reaction, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain crude compound 20. The crude compound 20 was purified by supercritical fluid chromatography. Chromatography ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm×20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compounds 20-P1 (16.5 mg, yield 4.04%) and 20-P2 (17.8 mg, yield 4.36%).
化合物20-P1：Compound 20-P1:
MS m/z(ESI):545.8[M+1]+。超临界流体色谱SFC：保留时间＝6.6min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.93(d,J＝5.3Hz,1H),8.74(s,1H),8.48(d,J＝2.3Hz,1H),8.12(d,J＝5.3Hz,1H),7.84-7.67(m,1H),6.91(s,1H),5.54(d,J＝1.8Hz,2H),3.22(s,2H),2.25(s,3H),2.16(s,3H),1.30(s,6H)。MS m/z(ESI):545.8[M+1] + . Supercritical fluid chromatography SFC: retention time=6.6min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.93 (d, J = 5.3 Hz, 1H), 8.74 (s, 1H), 8.48 (d, J = 2.3 Hz, 1H), 8.12 (d, J = 5.3 Hz,1H),7.84-7.67(m,1H),6.91(s,1H),5.54(d,J＝1.8Hz,2H),3.22(s,2H),2.25(s,3H),2.16(s ,3H),1.30(s,6H).
化合物20-P2：Compound 20-P2:
MS m/z(ESI):545.7[M+1]+。超临界流体色谱SFC：保留时间＝13.54min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.93(d,J＝5.3Hz,1H),8.74(s,1H),8.48(d,J＝1.8Hz,1H),8.12(d,J＝5.3Hz,1H),7.85-7.68(m,1H),6.90(s,1H),5.54(s,2H),3.21(s,2H),2.25(s,3H),2.15(s,3H),1.30(s,6H)。MS m/z(ESI):545.7[M+1] + . Supercritical fluid chromatography SFC: retention time = 13.54min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.93 (d, J = 5.3 Hz, 1H), 8.74 (s, 1H), 8.48 (d, J = 1.8 Hz, 1H), 8.12 (d, J = 5.3 Hz,1H),7.85-7.68(m,1H),6.90(s,1H),5.54(s,2H),3.21(s,2H),2.25(s,3H),2.15(s,3H),1.30 (s,6H).
实施例7(化合物10、10-P1或10-P2和10-P2或10-P1)的合成
Synthesis of Example 7 (Compound 10, 10-P1 or 10-P2 and 10-P2 or 10-P1)
第一步：化合物10b的合成Step One: Synthesis of Compound 10b
将1,4-二溴丁烷(21g,97.2mmol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(DBU)(29.61g,194.5mmol)依次加入到化合物10a(10g,88.4mmol)的N,N-二甲基甲酰胺(200mL溶液中，反应混合物加热至80℃并在该温度下搅拌2小时。反应结束后，反应液加水(400mL)稀释，经乙酸乙酯萃取(200mL×3)，合并有机相经饱和食盐水(200mL×3)洗涤，无水硫酸钠干燥并过滤，过滤减压浓缩得到化合物10b(10g，收率：61％)。1H NMR(400MHz,CDCl3)δ4.28-4.20(m,2H),2.29-2.19(m,4H),1.90-1.79(m,4H),1.31(t,J＝7.1Hz,3H)。1,4-dibromobutane (21g, 97.2mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (29.61g, 194.5mmol) were added to the compound in sequence In a solution of 10a (10g, 88.4mmol) in N,N-dimethylformamide (200mL), the reaction mixture was heated to 80°C and stirred at this temperature for 2 hours. After the reaction was completed, the reaction solution was diluted with water (400mL), and Extract with ethyl acetate (200 mL × 3), wash the combined organic phases with saturated brine (200 mL × 3), dry with anhydrous sodium sulfate and filter, filter and concentrate under reduced pressure to obtain compound 10b (10 g, yield: 61%). 1 H NMR (400MHz, CDCl 3 ) δ4.28-4.20(m,2H), 2.29-2.19(m,4H), 1.90-1.79(m,4H), 1.31(t,J=7.1Hz,3H).
第二步：化合物10c的合成Step 2: Synthesis of compound 10c
依次将氯化钙(2.16g,19.5mmol)和硼氢化钠(1.47g,39mmol)加入到化合物10b(2.5g,15mmol)的乙醇(50mL)溶液中，反应混合物室温搅拌16小时。反应结束后，反应液减压浓缩，残余物用2N盐酸调pH至2-3，用乙酸乙酯萃取(50mL×3)，合并有机相经无水硫酸钠干燥并，过滤液减压浓缩得化合物10c(2g，收率：96％)。1H NMR(400MHz,CDCl3)δ3.62(s,2H),2.16-2.02(m,2H),1.91-1.63(m,6H)。Calcium chloride (2.16g, 19.5mmol) and sodium borohydride (1.47g, 39mmol) were added to a solution of compound 10b (2.5g, 15mmol) in ethanol (50mL) in sequence, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the pH of the residue was adjusted to 2-3 with 2N hydrochloric acid, extracted with ethyl acetate (50 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain Compound 10c (2g, yield: 96%). 1 H NMR (400MHz, CDCl 3 ) δ3.62 (s, 2H), 2.16-2.02 (m, 2H), 1.91-1.63 (m, 6H).
第三步：化合物10d的合成Step 3: Synthesis of Compound 10d
将羟胺的水溶液(527.77mg,15.98mmol加入到化合物10c(500mg,3.99mmol)的乙醇(20mL)中，反应混合物75℃下搅拌16小时。反应结束后，反应液减压浓缩得到化合物10d(600mg，粗品)。MS m/z(ESI):159.0[M+1]+。The aqueous solution of hydroxylamine (527.77 mg, 15.98 mmol) was added to compound 10c (500 mg, 3.99 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 75°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 10d (600 mg , crude product). MS m/z(ESI):159.0[M+1] + .
第四步：化合物10e的合成Step 4: Synthesis of Compound 10e
依次将雷尼镍(185.5mg,3.16mmol)和乙酸(0.5mL)加入到化合物10d(500mg,3.16mmol)的乙醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物10e(500mg，粗品)。MS m/z(ESI):143.1[M+1]+。Raney nickel (185.5 mg, 3.16 mmol) and acetic acid (0.5 mL) were added to a solution of compound 10d (500 mg, 3.16 mmol) in ethanol (10 mL) in sequence, and the reaction mixture was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 10e (500 mg, crude product). MS m/z(ESI):143.1[M+1] + .
第五步：化合物10-P1和10-P2的合成Step 5: Synthesis of Compounds 10-P1 and 10-P2
将化合物10e(120mg,0.84mmol)和碳酸钾(87.32mg,0.63mmol)加入到化合物A2(100mg,0.21mmol)的乙腈(20mL)溶液中，反应混合物在90℃下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩， 残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物10，化合物10经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH0.2％)，总流速：40g/min)拆分得到化合物10-P1(20mg，收率16％)和10-P2(20mg，收率16％)。Compound 10e (120 mg, 0.84 mmol) and potassium carbonate (87.32 mg, 0.63 mmol) were added to a solution of compound A2 (100 mg, 0.21 mmol) in acetonitrile (20 mL), and the reaction mixture was stirred at 90°C for 12 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 10. Compound 10 was purified by supercritical fluid chiral chromatography ((equipment: SFC Thar prep 80, column: CHIRALPAK AD- H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min), compound 10-P1 (20mg, yield 16%) and 10- P2 (20 mg, yield 16%).
化合物10-P1：Compound 10-P1:
MS m/z(ESI):553.8[M+1]+。超临界流体色谱SFC：保留时间＝2.71min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.84(d,J＝5.2Hz,1H),8.79(s,1H),8.44(d,J＝2.4Hz,1H),8.33(s,1H),8.19(d,J＝5.2Hz,1H),7.75-7.66(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),3.87(s,2H),2.29(dd,J＝13.2,5.7Hz,2H),2.15(s,3H),2.04(s,3H),1.84(dd,J＝13.1,6.5Hz,2H),1.76-1.69(m,4H).MS m/z(ESI):553.8[M+1] + . Supercritical fluid chromatography SFC: retention time=2.71min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.84(d,J＝5.2Hz,1H),8.79(s,1H),8.44(d,J＝2.4Hz,1H),8.33(s,1H), 8.19(d,J＝5.2Hz,1H),7.75-7.66(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),3.87(s,2H),2.29(dd ,J＝13.2,5.7Hz,2H),2.15(s,3H),2.04(s,3H),1.84(dd,J＝13.1,6.5Hz,2H),1.76-1.69(m,4H).
化合物10-P2：Compound 10-P2:
MS m/z(ESI):553.8[M+1]+。超临界流体色谱SFC：保留时间＝4.26min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.84(d,J＝5.2Hz,1H),8.79(s,1H),8.44(d,J＝2.4Hz,1H),8.33(s,1H),8.19(d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.81(d,J＝0.5Hz,1H),5.49(d,J＝2.0Hz,2H),3.87(s,2H),2.29(dd,J＝13.2,5.8Hz,2H),2.15(s,3H),2.07-2.01(m,3H),1.92-1.79(m,2H),1.77-1.68(m,4H)。MS m/z(ESI):553.8[M+1] + . Supercritical fluid chromatography SFC: retention time=4.26min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.84(d,J＝5.2Hz,1H),8.79(s,1H),8.44(d,J＝2.4Hz,1H),8.33(s,1H), 8.19(d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.81(d,J＝0.5Hz,1H),5.49(d,J＝2.0Hz,2H ),3.87(s,2H),2.29(dd,J＝13.2,5.8Hz,2H),2.15(s,3H),2.07-2.01(m,3H),1.92-1.79(m,2H),1.77- 1.68(m,4H).
实施例8(化合物15、15-P1或15-P2和15-P2或15-P1)的合成
Synthesis of Example 8 (Compound 15, 15-P1 or 15-P2 and 15-P2 or 15-P1)
第一步：化合物15b的合成Step One: Synthesis of Compound 15b
-60℃下，将二异丙基氨基锂(29.2mL,58.4mmol)加入到化合物15a(3.41g,48.7mmol)的四氢呋喃(50mL)溶液中，反应混合物在-60℃下搅拌1小时，然后加入乙腈(2.4g,58.4mmol)，反应混合物缓慢升至室温并搅拌2小时。反应结束，反应液加入饱和氯化铵溶液(10mL)淬灭，淬灭液减压浓缩去除四氢呋喃，残余物加水(100mL)稀释，用乙酸乙酯萃取(200mL×3)，合并有机相用饱和食盐水(200mL×3)洗涤，无水硫酸钠干燥并过滤，过滤液减压浓缩得化合物15b(3.5g，收率：65％)。1H NMR(400MHz,CDCl3)δ2.65(d,J＝1.5Hz,2H),2.23-2.13(m,4H),1.88-1.78(m,1H),1.65-1.52(m,1H)。Lithium diisopropylamide (29.2 mL, 58.4 mmol) was added to a solution of compound 15a (3.41 g, 48.7 mmol) in tetrahydrofuran (50 mL) at -60°C, and the reaction mixture was stirred at -60°C for 1 hour, and then Acetonitrile (2.4g, 58.4mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 2 hours. At the end of the reaction, the reaction solution was quenched by adding saturated ammonium chloride solution (10 mL). The quenching solution was concentrated under reduced pressure to remove tetrahydrofuran. The residue was diluted with water (100 mL) and extracted with ethyl acetate (200 mL × 3). The organic phases were combined and saturated with ethyl acetate. Wash with brine (200 mL×3), dry over anhydrous sodium sulfate and filter, and the filtrate is concentrated under reduced pressure to obtain compound 15b (3.5 g, yield: 65%). 1 H NMR (400MHz, CDCl 3 ) δ2.65 (d, J = 1.5Hz, 2H), 2.23-2.13 (m, 4H), 1.88-1.78 (m, 1H), 1.65-1.52 (m, 1H).
第二步：化合物15c的合成Step 2: Synthesis of compound 15c
将羟胺的水溶液(0.89g,27mmol)加入到化合物15b(1g,9mmol)的乙醇(20mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液减压浓缩得到化合物15c(1g，收率：61％)。MS m/z(ESI):145.0[M+1]+。An aqueous solution of hydroxylamine (0.89 g, 27 mmol) was added to a solution of compound 15b (1 g, 9 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 75°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 15c (1 g, yield: 61%). MS m/z(ESI):145.0[M+1] + .
第三步：化合物15d的合成Step 3: Synthesis of Compound 15d
将雷尼镍(0.2g,3.45mmol)和乙酸(1mL)加入到化合物15c(1g,6.9mmol)，的乙醇(20mL)溶液中，反应混合物在氢气气氛下温搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物15d(0.8g，收率：72％)。MS m/z(ESI):129.1[M+1]+。Raney nickel (0.2 g, 3.45 mmol) and acetic acid (1 mL) were added to a solution of compound 15c (1 g, 6.9 mmol) in ethanol (20 mL), and the reaction mixture was stirred warmly under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15d (0.8 g, yield: 72%). MS m/z(ESI):129.1[M+1] + .
第四步：化合物15-P1和15-P2的合成Step 4: Synthesis of Compounds 15-P1 and 15-P2
将化合物A2(150mg,0.31mmol)和碳酸钾(130.98mg,0.95mmol)加入到化合物15d(121.47mg,0.95mmol)的乙腈(30mL)溶液中，反应混合物在90℃下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶层析柱(二氯甲烷：甲醇＝1:0～20:1)纯化得到化合物15，化合物15经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物15-P1(25.8mg，收率25％)和15-P2(20.9mg， 收率20％)。Compound A2 (150 mg, 0.31 mmol) and potassium carbonate (130.98 mg, 0.95 mmol) were added to a solution of compound 15d (121.47 mg, 0.95 mmol) in acetonitrile (30 mL), and the reaction mixture was stirred at 90°C for 12 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified through a silica gel chromatography column (dichloromethane: methanol = 1:0 ~ 20:1) to obtain compound 15. Compound 15 is subjected to supercritical fluid chiral chromatography. ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 15 was obtained by separation -P1 (25.8mg, yield 25%) and 15-P2 (20.9mg, Yield 20%).
化合物15-P1：Compound 15-P1:
MS m/z(ESI):539.8[M+1]+。超临界流体色谱SFC：保留时间＝3.61min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.85-8.77(m,2H),8.44(d,J＝2.4Hz,1H),8.36(s,1H),8.28(d,J＝5.3Hz,1H),7.71-7.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝2.0Hz,2H),3.28(d,J＝2.0Hz,2H),2.31-2.23(m,2H),2.16(s,3H),2.12-2.04(m,5H),1.75(d,J＝11.2Hz,1H),1.65-1.50(m,1H)。MS m/z(ESI):539.8[M+1] + . Supercritical fluid chromatography SFC: retention time=3.61min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.85-8.77(m,2H),8.44(d,J＝2.4Hz,1H),8.36(s,1H),8.28(d,J＝5.3Hz,1H ),7.71-7.69(m,1H),6.81(d,J＝0.6Hz,1H),5.49(d,J＝2.0Hz,2H),3.28(d,J＝2.0Hz,2H),2.31-2.23 (m,2H),2.16(s,3H),2.12-2.04(m,5H),1.75(d,J＝11.2Hz,1H),1.65-1.50(m,1H).
化合物15-P2：Compound 15-P2:
MS m/z(ESI):539.8[M+1]+。超临界流体色谱SFC：保留时间＝4.35min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.87-8.76(m,2H),8.44(d,J＝2.4Hz,1H),8.36(s,1H),8.27(d,J＝5.3Hz,1H),7.76-7.65(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),3.27(s,2H),2.31-2.23(m,2H),2.15(s,3H),2.12-2.03(m,5H),1.75(dd,J＝8.7,2.6Hz,1H),1.57(dt,J＝11.2,8.8Hz,1H)。MS m/z(ESI):539.8[M+1] + . Supercritical fluid chromatography SFC: retention time=4.35min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.87-8.76 (m, 2H), 8.44 (d, J = 2.4Hz, 1H), 8.36 (s, 1H), 8.27 (d, J = 5.3Hz, 1H ),7.76-7.65(m,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),3.27(s,2H),2.31-2.23(m,2H),2.15(s, 3H), 2.12-2.03 (m, 5H), 1.75 (dd, J＝8.7, 2.6Hz, 1H), 1.57 (dt, J＝11.2, 8.8Hz, 1H).
实施例9(化合物17、17-P1或17-P2和17-P2或17-P1)的合成
Synthesis of Example 9 (Compound 17, 17-P1 or 17-P2 and 17-P2 or 17-P1)
将化合物3d(1g,8.6mmol)和碳酸钾(166mg,1.2mmol)加入到化合物A3(210mg,0.4mmol)的乙腈(20mL)溶液中，反应混合物在60℃下搅拌4小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷：甲醇＝1:0～20:1)纯化得到化合物17，化合物17经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH0.2％)，总流速：40g/min)拆分得到化合物17-P1(39.5mg，收率17％)和17-P2(41.5mg，收率18％)。Compound 3d (1 g, 8.6 mmol) and potassium carbonate (166 mg, 1.2 mmol) were added to a solution of compound A3 (210 mg, 0.4 mmol) in acetonitrile (20 mL), and the reaction mixture was stirred at 60°C for 4 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane: methanol = 1:0 ~ 20:1) to obtain compound 17. Compound 17 is subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 17 was obtained by resolution -P1 (39.5 mg, yield 17%) and 17-P2 (41.5 mg, yield 18%).
化合物17-P1：Compound 17-P1:
MS m/z(ESI):546.0[M+1]+。超临界流体色谱SFC：保留时间＝2.52min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.90(d,J＝5.2Hz,1H),8.70(s,1H),8.47(d,J＝2.3Hz,1H),8.02(d,J＝5.2Hz,1H),7.78-7.69(m,1H),6.89(s,1H),5.53(d,J＝1.8Hz,2H),3.85(s,2H),2.23(s,3H),2.14(s,3H),1.40(d,J＝0.7Hz,6H)。MS m/z(ESI):546.0[M+1] + . Supercritical fluid chromatography SFC: retention time = 2.52min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.90 (d, J = 5.2 Hz, 1H), 8.70 (s, 1H), 8.47 (d, J = 2.3 Hz, 1H), 8.02 (d, J = 5.2 Hz,1H),7.78-7.69(m,1H),6.89(s,1H),5.53(d,J＝1.8Hz,2H),3.85(s,2H),2.23(s,3H),2.14(s ,3H),1.40(d,J＝0.7Hz,6H).
化合物17-P2：Compound 17-P2:
MS m/z(ESI):546.0[M+1]+。超临界流体色谱SFC：保留时间＝4.17min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.90(d,J＝5.2Hz,1H),8.70(d,J＝0.5Hz,1H),8.47(d,J＝2.4Hz,1H),8.02(d,J＝5.2Hz,1H),7.74-7.71(m,1H),6.89(s,1H),5.53(d,J＝1.9Hz,2H),3.85(s,2H),2.23(s,3H),2.14(s,3H),1.40(d,J＝0.9Hz,6H)。MS m/z(ESI):546.0[M+1] + . Supercritical fluid chromatography SFC: retention time=4.17min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.90(d,J＝5.2Hz,1H),8.70(d,J＝0.5Hz,1H),8.47(d,J＝2.4Hz,1H),8.02( d,J＝5.2Hz,1H),7.74-7.71(m,1H),6.89(s,1H),5.53(d,J＝1.9Hz,2H),3.85(s,2H),2.23(s,3H ), 2.14 (s, 3H), 1.40 (d, J = 0.9Hz, 6H).
实施例10(化合物18、18-P1或18-P2和18-P2或18-P1)的合成
Synthesis of Example 10 (Compound 18, 18-P1 or 18-P2 and 18-P2 or 18-P1)
将化合物5d(301mg,2.64mmol)和碳酸钾(280mg,2.03mmol)加入到化合物A3(200mg,0.41mmol)的乙腈(10mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷：甲醇＝1:0～20:1)纯化得到化合物18，化合物18经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH0.2％)，总流速：40g/min)拆分得到化合物18-P1(7.7mg，收率3.43％)和18-P2(8.5mg，收率3.70％)。Compound 5d (301 mg, 2.64 mmol) and potassium carbonate (280 mg, 2.03 mmol) were added to a solution of compound A3 (200 mg, 0.41 mmol) in acetonitrile (10 mL), and the reaction mixture was stirred at 75°C for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane: methanol = 1:0 ~ 20:1) to obtain compound 18, which was subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 18 was obtained by separation -P1 (7.7 mg, yield 3.43%) and 18-P2 (8.5 mg, yield 3.70%).
化合物18-P1：Compound 18-P1:
MS m/z(ESI):544.0[M+1]+。超临界流体色谱SFC：保留时间＝2.99min，UV＝214nm。1H NMR(400MHz,CDCl3)δ8.74(d,J＝5.2Hz,1H),8.57(d,J＝0.5Hz,1H),8.40(d,J＝2.4Hz,1H),7.91(d,J＝5.2Hz,1H), 7.32-7.25(m,1H),6.44(s,1H),5.42(d,J＝1.8Hz,2H),3.93(d,J＝11.9Hz,1H),3.80(d,J＝12.0Hz,1H),2.21(s,3H),2.03(s,3H),1.45-1.40(m,2H),1.11-1.01(m,2H)。MS m/z(ESI):544.0[M+1] + . Supercritical fluid chromatography SFC: retention time = 2.99min, UV = 214nm. 1 H NMR (400MHz, CDCl 3 ) δ8.74(d,J＝5.2Hz,1H),8.57(d,J＝0.5Hz,1H),8.40(d,J＝2.4Hz,1H),7.91(d ,J＝5.2Hz,1H), 7.32-7.25(m,1H),6.44(s,1H),5.42(d,J＝1.8Hz,2H),3.93(d,J＝11.9Hz,1H),3.80(d,J＝12.0Hz,1H ),2.21(s,3H),2.03(s,3H),1.45-1.40(m,2H),1.11-1.01(m,2H).
化合物18-P2：Compound 18-P2:
MS m/z(ESI):544.0[M+1]+。超临界流体色谱SFC：保留时间＝3.88min，UV＝214nm。1H NMR(400MHz,CDCl3)δ8.74(d,J＝5.2Hz,1H),8.57(d,J＝0.5Hz,1H),8.40(d,J＝2.3Hz,1H),7.91(d,J＝5.2Hz,1H),7.32-7.25(m,1H),6.44(d,J＝0.4Hz,1H),5.42(d,J＝1.9Hz,2H),3.93(d,J＝12.0Hz,1H),3.80(d,J＝12.0Hz,1H),2.21(s,3H),2.03(s,3H),1.45-1.40(m,2H),1.09-0.99(m,2H)。MS m/z(ESI):544.0[M+1] + . Supercritical fluid chromatography SFC: retention time=3.88min, UV=214nm. 1 H NMR (400MHz, CDCl 3 ) δ8.74(d,J＝5.2Hz,1H),8.57(d,J＝0.5Hz,1H),8.40(d,J＝2.3Hz,1H),7.91(d ,J＝5.2Hz,1H),7.32-7.25(m,1H),6.44(d,J＝0.4Hz,1H),5.42(d,J＝1.9Hz,2H),3.93(d,J＝12.0Hz ,1H),3.80(d,J＝12.0Hz,1H),2.21(s,3H),2.03(s,3H),1.45-1.40(m,2H),1.09-0.99(m,2H).
实施例11(化合物29、29-P1或29-P2和29-P2或29-P1)的合成
Synthesis of Example 11 (Compound 29, 29-P1 or 29-P2 and 29-P2 or 29-P1)
将化合物3d(703mg,6.06mmol)加入到化合物A4(150mg,0.30mmol)和碳酸钾(84mg,0.61mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在60℃下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到粗化合物29，化合物29经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物29-P1(16.7mg，收率10.04％)和化合物29-P2(19mg，收率11.43％)。Compound 3d (703 mg, 6.06 mmol) was added to a solution of compound A4 (150 mg, 0.30 mmol) and potassium carbonate (84 mg, 0.61 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated at 60°C. Stir for 12 hours. After the reaction is completed, the reaction liquid is filtered, and the filtrate is concentrated under reduced pressure. The residue is purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain crude compound 29. Compound 29 is purified by supercritical fluid chirality. Chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) was resolved to obtain compound 29 -P1 (16.7 mg, yield 10.04%) and compound 29-P2 (19 mg, yield 11.43%).
化合物29-P1：Compound 29-P1:
MS m/z(ESI):548.1[M+1]+。超临界流体色谱SFC：保留时间＝2.97min，UV＝254nm。1H NMR(400MHz,CDCl3)δ8.92-8.85(m,2H),8.43-8.37(m,2H),8.30(d,J＝5.3Hz,1H),7.34(ddd,J＝9.0,8.0,2.4Hz,1H),6.46(d,J＝0.5Hz,1H),5.44(d,J＝1.8Hz,2H),3.87(s,2H),2.05(s,3H),1.44(d,J＝1.2Hz,6H).MS m/z(ESI):548.1[M+1] + . Supercritical fluid chromatography SFC: retention time=2.97min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.92-8.85(m,2H),8.43-8.37(m,2H),8.30(d,J＝5.3Hz,1H),7.34(ddd,J＝9.0,8.0 ,2.4Hz,1H),6.46(d,J＝0.5Hz,1H),5.44(d,J＝1.8Hz,2H),3.87(s,2H),2.05(s,3H),1.44(d,J =1.2Hz,6H).
化合物29-P2：Compound 29-P2:
MS m/z(ESI):548.1[M+1]+。超临界流体色谱SFC：保留时间＝4.12min，UV＝254nm。1H NMR(400MHz,CDCl3)δ8.96-8.82(m,2H),8.42-8.36(m,2H),8.23(d,J＝5.2Hz,1H),7.36-7.31(m,1H),6.46(s,1H),5.44(d,J＝1.7Hz,2H),3.84(d,J＝3.6Hz,2H),2.06-2.03(m,3H),1.41(s,6H)。MS m/z(ESI):548.1[M+1] + . Supercritical fluid chromatography SFC: retention time=4.12min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.96-8.82(m,2H),8.42-8.36(m,2H),8.23(d,J＝5.2Hz,1H),7.36-7.31(m,1H), 6.46(s,1H),5.44(d,J＝1.7Hz,2H),3.84(d,J＝3.6Hz,2H),2.06-2.03(m,3H),1.41(s,6H).
实施例12(化合物31、31-P1或31-P2和31-P2或31-P1)的合成
Synthesis of Example 12 (Compound 31, 31-P1 or 31-P2 and 31-P2 or 31-P1)
将化合物5d(317mg,2.78mmol)加入到化合物A4(250mg,0.50mmol)和碳酸钾(279mg,2.02mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物31，化合物31经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物31-P1(16.3mg，收率5.81％)和化合物31-P2(17.9mg，收率6.22％)。Compound 5d (317 mg, 2.78 mmol) was added to a solution of compound A4 (250 mg, 0.50 mmol) and potassium carbonate (279 mg, 2.02 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated at 90°C. Stir for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 31, which was subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 31- was obtained by separation. P1 (16.3 mg, yield 5.81%) and compound 31-P2 (17.9 mg, yield 6.22%).
化合物31-P1：Compound 31-P1:
MS m/z(ESI):545.7[M+1]+。超临界流体色谱SFC：保留时间＝3.93min，UV＝214nm。1H NMR(400MHz,CDCl3)δ8.95(s,1H),8.79(d,J＝5.2Hz,1H),8.59(s,1H),8.44(d,J＝2.4Hz,1H),8.16(d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.82(d,J＝0.6Hz,1H),5.49(d,J＝2.0Hz,2H),4.07(d,J＝11.6Hz,1H),3.95(d,J＝11.6Hz,1H),2.08(d,J＝0.5Hz,3H),1.42(dd,J＝6.4,3.4Hz,2H),1.09(dd,J＝6.5,3.3Hz,2H)。MS m/z(ESI):545.7[M+1] + . Supercritical fluid chromatography SFC: retention time=3.93min, UV=214nm. 1 H NMR (400MHz, CDCl 3 ) δ8.95 (s, 1H), 8.79 (d, J = 5.2Hz, 1H), 8.59 (s, 1H), 8.44 (d, J = 2.4Hz, 1H), 8.16 (d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.82(d,J＝0.6Hz,1H),5.49(d,J＝2.0Hz,2H) ,4.07(d,J＝11.6Hz,1H),3.95(d,J＝11.6Hz,1H),2.08(d,J＝0.5Hz,3H),1.42(dd,J＝6.4,3.4Hz,2H) ,1.09(dd,J=6.5,3.3Hz,2H).
化合物31-P2： Compound 31-P2:
MS m/z(ESI):545.7[M+1]+。超临界流体色谱SFC：保留时间＝7.13min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.95(s,1H),8.79(d,J＝5.2Hz,1H),8.59(s,1H),8.44(d,J＝2.4Hz,1H),8.16(d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.82(d,J＝0.7Hz,1H),5.49(d,J＝1.9Hz,2H),4.06(d,J＝11.6Hz,1H),3.95(d,J＝11.6Hz,1H),2.08(s,3H),1.48-1.35(m,2H),1.09(dd,J＝6.4,3.3Hz,2H)。MS m/z(ESI):545.7[M+1] + . Supercritical fluid chromatography SFC: retention time=7.13min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.95 (s, 1H), 8.79 (d, J = 5.2Hz, 1H), 8.59 (s, 1H), 8.44 (d, J = 2.4Hz, 1H), 8.16(d,J＝5.2Hz,1H),7.71(ddd,J＝9.6,8.6,2.4Hz,1H),6.82(d,J＝0.7Hz,1H),5.49(d,J＝1.9Hz,2H ),4.06(d,J＝11.6Hz,1H),3.95(d,J＝11.6Hz,1H),2.08(s,3H),1.48-1.35(m,2H),1.09(dd,J＝6.4, 3.3Hz,2H).
实施例13(化合物32、32-P1或32-P2和32-P2或32-P1)的合成
Synthesis of Example 13 (Compound 32, 32-P1 or 32-P2 and 32-P2 or 32-P1)
将化合物6d(776mg,6.06mmol)加入到化合物A4(150mg,0.30mmol)和碳酸钾(84mg,0.61mmol)的N,N-二甲基甲酰胺(10mL)中，反应混合物在60℃下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物32，化合物32经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物32-P1(29.7mg，收率17.50％)和化合物32-P2(37.6mg，收率22.16％)。Compound 6d (776 mg, 6.06 mmol) was added to compound A4 (150 mg, 0.30 mmol) and potassium carbonate (84 mg, 0.61 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 60°C. 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 32, which was subjected to supercritical fluid chiral chromatography. ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 32 was obtained by resolution -P1 (29.7 mg, yield 17.50%) and compound 32-P2 (37.6 mg, yield 22.16%).
化合物32-P1：Compound 32-P1:
MS m/z(ESI):560.1[M+1]+。超临界流体色谱SFC：保留时间＝3.92min，UV＝254nm。1H NMR(400MHz,CDCl3)δ8.92-8.85(m,2H),8.41(d,J＝1.9Hz,2H),8.27(d,J＝5.3Hz,1H),7.34(dd,J＝6.5,5.3Hz,1H),6.46(d,J＝0.9Hz,1H),5.44(d,J＝2.4Hz,2H),4.10(s,2H),2.81-2.55(m,2H),2.17(d,J＝6.1Hz,2H),2.05(d,J＝0.9Hz,5H)。MS m/z(ESI):560.1[M+1] + . Supercritical fluid chromatography SFC: retention time=3.92min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.92-8.85(m,2H),8.41(d,J＝1.9Hz,2H),8.27(d,J＝5.3Hz,1H),7.34(dd,J＝ 6.5,5.3Hz,1H),6.46(d,J＝0.9Hz,1H),5.44(d,J＝2.4Hz,2H),4.10(s,2H),2.81-2.55(m,2H),2.17( d, J=6.1Hz, 2H), 2.05 (d, J=0.9Hz, 5H).
化合物32-P2：Compound 32-P2:
MS m/z(ESI):560.1[M+1]+。超临界流体色谱SFC：保留时间＝6.39min，UV＝254nm。1H NMR(400MHz,CDCl3)δ8.90-8.85(m,2H),8.41(d,J＝2.7Hz,2H),8.24(d,J＝5.2Hz,1H),7.34-7.32(m,1H),6.46(s,1H),5.44(d,J＝1.8Hz,2H),4.09(s,2H),2.68-2.64(m,2H),2.24-2.08(m,4H),2.05(s,3H)。MS m/z(ESI):560.1[M+1] + . Supercritical fluid chromatography SFC: retention time=6.39min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.90-8.85 (m, 2H), 8.41 (d, J = 2.7Hz, 2H), 8.24 (d, J = 5.2Hz, 1H), 7.34-7.32 (m, 1H),6.46(s,1H),5.44(d,J＝1.8Hz,2H),4.09(s,2H),2.68-2.64(m,2H),2.24-2.08(m,4H),2.05(s ,3H).
实施例14(化合物39、39-P1或39-P2和39-P2或39-P1)的合成
Synthesis of Example 14 (Compound 39, 39-P1 or 39-P2 and 39-P2 or 39-P1)
将碳酸钾(41mg,0.30mmol)加入到化合物13c(123mg,1.06mmol)和化合物A4(150mg,0.30mmol)的N,N-二甲基甲酰胺(10mL)中，反应混合物在90℃下搅拌48小时，反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物39，化合物39经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物39-P1(16.2mg，收率9.6％)和化合物39-P2(18.1mg，收率10.7％)。Potassium carbonate (41 mg, 0.30 mmol) was added to compound 13c (123 mg, 1.06 mmol) and compound A4 (150 mg, 0.30 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 90°C. After 48 hours, the reaction was completed, the reaction liquid was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 39, which was purified by supercritical fluid Chiral chromatography (equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min). Compound 39-P1 (16.2 mg, yield 9.6%) and compound 39-P2 (18.1 mg, yield 10.7%).
化合物39-P1：Compound 39-P1:
MS m/z(ESI):547.7[M+1]+。手性HPLC：保留时间＝6.16min，UV＝214nm。1H NMR(400MHz,CDCl3)δ9.02-8.81(m,2H),8.48-8.23(m,3H),7.33(t,J＝7.6Hz,1H),6.43(s,1H),5.44(s,2H),3.23(s,2H),2.04(s,3H),1.26(d,J＝6.5Hz,6H)。MS m/z(ESI):547.7[M+1] + . Chiral HPLC: retention time=6.16min, UV=214nm. 1 H NMR (400MHz, CDCl 3 ) δ9.02-8.81 (m, 2H), 8.48-8.23 (m, 3H), 7.33 (t, J = 7.6Hz, 1H), 6.43 (s, 1H), 5.44 ( s, 2H), 3.23 (s, 2H), 2.04 (s, 3H), 1.26 (d, J = 6.5Hz, 6H).
化合物39-P2： Compound 39-P2:
MS m/z(ESI):547.7[M+1]+。手性HPLC：保留时间＝9.38min，UV＝214nm。1H NMR(400MHz,CDCl3)δ9.02-8.81(m,2H),8.48-8.23(m,3H),7.42-7.30(m,1H),6.43(s,1H),5.43(s,2H),3.21(s,2H),2.04(s,3H),1.30(s,3H),1.26(d,J＝3.4Hz,3H)。MS m/z(ESI):547.7[M+1] + . Chiral HPLC: retention time=9.38min, UV=214nm. 1 H NMR (400MHz, CDCl 3 ) δ9.02-8.81(m,2H),8.48-8.23(m,3H),7.42-7.30(m,1H),6.43(s,1H),5.43(s,2H ), 3.21 (s, 2H), 2.04 (s, 3H), 1.30 (s, 3H), 1.26 (d, J = 3.4Hz, 3H).
实施例15(化合物41、41-P1或41-P2和41-P2或41-P1)的合成
Synthesis of Example 15 (Compound 41, 41-P1 or 41-P2 and 41-P2 or 41-P1)
将碳酸钾(84mg,0.61mmol)加入到化合物A4(150mg,0.30mmol)和化合物15d(194mg,1.51mmol)的N,N-二甲基甲酰胺(10mL)中，反应混合物在70℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物41，化合物41经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物41-P1(18.4mg，收率10.5％)和化合物416-P2(20.9mg，收率12.3％)。Potassium carbonate (84 mg, 0.61 mmol) was added to compound A4 (150 mg, 0.30 mmol) and compound 15d (194 mg, 1.51 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 70°C. 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 41, which was subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 41- was obtained by separation. P1 (18.4 mg, yield 10.5%) and compound 416-P2 (20.9 mg, yield 12.3%).
化合物41-P1：Compound 41-P1:
MS m/z(ESI):560.0[M+1]+。超临界流体色谱SFC：保留时间＝3.34min，UV＝254nm。1H NMR(400MHz,CDCl3)δ8.89(s,1H),8.83(d,J＝5.3Hz,1H),8.48-8.36(m,2H),8.29(d,J＝5.2Hz,1H),7.41-7.29(m,1H),6.43(s,1H),5.44(s,2H),3.36(s,2H),2.27-2.10(m,2H),2.08-1.97(m,5H),1.84-1.64(m,2H)。MS m/z(ESI):560.0[M+1] + . Supercritical fluid chromatography SFC: retention time = 3.34min, UV = 254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.89 (s, 1H), 8.83 (d, J = 5.3Hz, 1H), 8.48-8.36 (m, 2H), 8.29 (d, J = 5.2Hz, 1H) ,7.41-7.29(m,1H),6.43(s,1H),5.44(s,2H),3.36(s,2H),2.27-2.10(m,2H),2.08-1.97(m,5H),1.84 -1.64(m,2H).
化合物41-P2：Compound 41-P2:
MS m/z(ESI):560.0[M+1]+。超临界流体色谱SFC：保留时间＝6.82min，UV＝254nm。1H NMR(400MHz,CDCl3)δ9.02-8.79(m,2H),8.53-8.36(m,2H),8.28(d,J＝5.2Hz,1H),7.43-7.30(m,1H),6.44(s,1H),5.44(s,2H),3.35(s,2H),2.29-2.10(m,2H),2.10-1.92(m,5H),1.92-1.60(m,2H)。MS m/z(ESI):560.0[M+1] + . Supercritical fluid chromatography SFC: retention time=6.82min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ9.02-8.79 (m, 2H), 8.53-8.36 (m, 2H), 8.28 (d, J = 5.2Hz, 1H), 7.43-7.30 (m, 1H), 6.44(s,1H),5.44(s,2H),3.35(s,2H),2.29-2.10(m,2H),2.10-1.92(m,5H),1.92-1.60(m,2H).
实施例16(化合物53、53-P1或53-P2和53-P2或53-P1)的合成
Synthesis of Example 16 (Compound 53, 53-P1 or 53-P2 and 53-P2 or 53-P1)
将碳酸钾(70mg,0.51mmol)加入到化合物A7(250mg,0.51mmol)和化合物3d(208mg,1.79mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在90℃下搅拌48小时。反应结束后，反应液过滤并减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物53，化合物53经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物53-P1(27.1mg，收率9.76％)和化合物53-P2(24.6mg，收率8.84％)。Potassium carbonate (70 mg, 0.51 mmol) was added to a solution of compound A7 (250 mg, 0.51 mmol) and compound 3d (208 mg, 1.79 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was heated at 90°C. Stir for 48 hours. After the reaction, the reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 53. Compound 53 was purified by supercritical fluid chiral chromatography (equipment : SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min). Compound 53-P1 ( 27.1 mg, yield 9.76%) and compound 53-P2 (24.6 mg, yield 8.84%).
化合物53-P1：Compound 53-P1:
MS m/z(ESI):542.2[[M+1]+。超临界流体色谱SFC：保留时间＝6.85min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.89(d,J＝5.1Hz,2H),8.49(d,J＝2.4Hz,1H),8.36(s,1H),8.25(d,J＝5.2Hz,1H),7.78-7.73(m,1H),6.85(s,1H),5.54(d,J＝1.9Hz,2H),3.90(s,2H),2.64-2.53(m,1H),2.53-2.44(m,1H),2.09(s,3H),1.43(d,J＝1.7Hz,6H),1.25(t,J＝7.6Hz,3H)。MS m/z(ESI):542.2[[M+1] + . Supercritical fluid chromatography SFC: retention time=6.85min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.89 (d, J = 5.1Hz, 2H), 8.49 (d, J = 2.4Hz, 1H), 8.36 (s, 1H), 8.25 (d, J = 5.2 Hz,1H),7.78-7.73(m,1H),6.85(s,1H),5.54(d,J＝1.9Hz,2H),3.90(s,2H),2.64-2.53(m,1H),2.53 -2.44(m,1H),2.09(s,3H),1.43(d,J＝1.7Hz,6H),1.25(t,J＝7.6Hz,3H).
化合物53-P2：Compound 53-P2:
MS m/z(ESI):542.2[[M+1]+。超临界流体色谱SFC：保留时间＝12.48min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.76(d,J＝5.1Hz,2H),8.36(d,J＝2.4Hz,1H),8.24(s,1H),8.13(d,J＝5.2Hz,1H),7.66-7.61(m,1H),6.73(s,1H),5.41(d,J＝1.9Hz,2H),3.78(s,2H),2.49-2.42(m,1H),2.41-2.34(m,1H),1.97(s,3H), 1.30(d,J＝1.6Hz,6H),1.13(t,J＝7.6Hz,3H)。MS m/z(ESI):542.2[[M+1] + . Supercritical fluid chromatography SFC: retention time=12.48min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.76 (d, J = 5.1Hz, 2H), 8.36 (d, J = 2.4Hz, 1H), 8.24 (s, 1H), 8.13 (d, J = 5.2 Hz,1H),7.66-7.61(m,1H),6.73(s,1H),5.41(d,J＝1.9Hz,2H),3.78(s,2H),2.49-2.42(m,1H),2.41 -2.34(m,1H),1.97(s,3H), 1.30(d,J=1.6Hz,6H), 1.13(t,J=7.6Hz,3H).
实施例17(化合物54、54-P1或54-P2和54-P2或54-P1)的合成
Synthesis of Example 17 (Compound 54, 54-P1 or 54-P2 and 54-P2 or 54-P1)
将碳酸钾(28mg,0.20mmol)加入到化合物A7(100mg,0.20mmol)和化合物5d(70mg,0.61mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在90℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物54，化合物54经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物54-P1(12.4mg，收率11.25％)和化合物54-P2(13.1mg，收率11.88％)。Potassium carbonate (28 mg, 0.20 mmol) was added to a solution of compound A7 (100 mg, 0.20 mmol) and compound 5d (70 mg, 0.61 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was heated at 90°C. Stir for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 54, which was subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) After separation, compound 54- P1 (12.4 mg, yield 11.25%) and compound 54-P2 (13.1 mg, yield 11.88%).
化合物54-P1：Compound 54-P1:
MS m/z(ESI):540.2[[M+1]+。超临界流体色谱SFC：保留时间＝5.98min，UV＝254nm。1H NMR(400MHz,CDCl3)δ8.86-8.71(m,2H),8.42(d,J＝2.3Hz,1H),8.18(d,J＝5.2Hz,1H),8.08(s,1H),7.40-7.30(m,1H),6.43(s,1H),5.43(d,J＝1.7Hz,2H),3.93(dd,J＝35.1,12.0Hz,2H),2.57-2.46(m,2H),1.98(s,3H),1.48(d,J＝4.0Hz,2H),1.25(d,J＝7.6Hz,3H),1.11(dd,J＝7.7,5.4Hz,2H)。MS m/z(ESI):540.2[[M+1] + . Supercritical fluid chromatography SFC: retention time=5.98min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.86-8.71 (m, 2H), 8.42 (d, J = 2.3Hz, 1H), 8.18 (d, J = 5.2Hz, 1H), 8.08 (s, 1H) ,7.40-7.30(m,1H),6.43(s,1H),5.43(d,J＝1.7Hz,2H),3.93(dd,J＝35.1,12.0Hz,2H),2.57-2.46(m,2H ), 1.98 (s, 3H), 1.48 (d, J = 4.0Hz, 2H), 1.25 (d, J = 7.6Hz, 3H), 1.11 (dd, J = 7.7, 5.4Hz, 2H).
化合物54-P2：Compound 54-P2:
MS m/z(ESI):540.2[[M+1]+。超临界流体色谱SFC：保留时间＝7.59min，UV＝254nm。1H NMR(400MHz,CDCl3)δ8.83-8.68(m,2H),8.42(d,J＝2.3Hz,1H),8.17(d,J＝5.2Hz,1H),8.08(s,1H),7.36-7.31(m,1H),6.43(s,1H),5.43(d,J＝1.6Hz,2H),3.93(dd,J＝37.0,11.9Hz,2H),2.55-2.48(m,2H),1.98(s,3H),1.54-1.39(m,2H),1.26(d,J＝3.4Hz,3H),1.10(dd,J＝7.9,5.5Hz,2H)。MS m/z(ESI):540.2[[M+1] + . Supercritical fluid chromatography SFC: retention time=7.59min, UV=254nm. 1 H NMR (400MHz, CDCl 3 ) δ8.83-8.68 (m, 2H), 8.42 (d, J = 2.3Hz, 1H), 8.17 (d, J = 5.2Hz, 1H), 8.08 (s, 1H) ,7.36-7.31(m,1H),6.43(s,1H),5.43(d,J＝1.6Hz,2H),3.93(dd,J＝37.0,11.9Hz,2H),2.55-2.48(m,2H ), 1.98 (s, 3H), 1.54-1.39 (m, 2H), 1.26 (d, J = 3.4Hz, 3H), 1.10 (dd, J = 7.9, 5.5Hz, 2H).
实施例18(化合物65、65-P1或65-P2或65-P3或65-P4、65-P2或65-P1或65-P3或65-P4、65-P3或65-P4或65-P1或65-P2、65-P4或65-P1或65-P2或65-P3)的合成
Example 18 (Compound 65, 65-P1 or 65-P2 or 65-P3 or 65-P4, 65-P2 or 65-P1 or 65-P3 or 65-P4, 65-P3 or 65-P4 or 65-P1 or 65-P2, 65-P4 or 65-P1 or 65-P2 or 65-P3) synthesis
第一步：化合物65a的合成Step One: Synthesis of Compound 65a
将碳酸钾(1.75g,12.63mmol)加入到化合物A2(2.0g,4.21mmol)和碳酸胍(2.28g,12.63mmol)的N,N-二甲基甲酰胺(20mL)的溶液中，反应混合物在90℃下搅拌12小时。反应结束后，反应液加水(50 mL)稀释，经乙酸乙酯萃取(30mL×3)。合并的有机相经饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物65a(0.75g，收率：36％)。MS m/z(ESI):470.8[M+1]+。Potassium carbonate (1.75g, 12.63mmol) was added to a solution of compound A2 (2.0g, 4.21mmol) and guanidine carbonate (2.28g, 12.63mmol) in N,N-dimethylformamide (20mL), and the reaction mixture Stir at 90°C for 12 hours. After the reaction is completed, water (50 mL) and extracted with ethyl acetate (30 mL×3). The combined organic phases were washed with saturated brine (30 mL ) was purified to obtain compound 65a (0.75g, yield: 36%). MS m/z(ESI):470.8[M+1] + .
第二步：化合物65b的合成Step 2: Synthesis of Compound 65b
将亚硝酸异戊酯(560mg,4.78mmol)加入到化合物65a(750mg,1.59mmol)、三甲基氯硅烷(260mg,2.39mmol)和四丁基氯化铵(664mg,2.39mmol)的二氯甲烷和N,N-二甲基甲酰胺(13mL/1mL)混合溶液中，反应混合物在50℃下搅拌16小时，反应结束后，反应液减压浓缩，加水(20mL)稀释，经***萃取(10mL×3)。合并的有机相用饱和食盐水洗涤(30mL×3)，无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/乙酸乙酯＝1/0～20/1)纯化得到化合物65b(450mg，收率：55％)。MS m/z(ESI):489.7,491.7[M+1]+。Isoamyl nitrite (560 mg, 4.78 mmol) was added to compound 65a (750 mg, 1.59 mmol), trimethylchlorosilane (260 mg, 2.39 mmol), and tetrabutylammonium chloride (664 mg, 2.39 mmol) in dichloride. In a mixed solution of methane and N,N-dimethylformamide (13mL/1mL), the reaction mixture was stirred at 50°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, diluted with water (20mL), and extracted with ether ( 10mL×3). The combined organic phases were washed with saturated brine (30 mL /1) Purification gave compound 65b (450 mg, yield: 55%). MS m/z(ESI):489.7,491.7[M+1] + .
第三步：化合物65c的合成Step 3: Synthesis of Compound 65c
将[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(134mg,0.18mmol)加入到化合物65b(450mg,0.92mmol)、异丙烯基硼酸频哪醇酯(154mg,0.92mmol)和碳酸钾(381mg,2.75mmol)的1,4-二氧六环和水(10mL/2mL)混合溶液中，反应混合物在90℃下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物65c(240mg，收率：50％)。MS m/z(ESI):495.8[M+1]+。[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (134 mg, 0.18 mmol) was added to compound 65b (450 mg, 0.92 mmol), isopropenylboronic acid pinacol In a mixed solution of ester (154 mg, 0.92 mmol) and potassium carbonate (381 mg, 2.75 mmol) in 1,4-dioxane and water (10 mL/2 mL), the reaction mixture was stirred at 90°C for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 65c (240 mg, yield: 50%). MS m/z(ESI):495.8[M+1] + .
第四步：化合物65-P1,65-P2,65-P3,65-P4的合成Step 4: Synthesis of compounds 65-P1, 65-P2, 65-P3, 65-P4
将四氧化锇(12.3mg,0.048mmol)加入到化合物65c(240mg,0.48mmol)和N-甲基吗啉-N-氧化物(227mg,1.94mmol)的四氢呋喃和水(6mL/6mL)混合溶液中，反应混合物室温搅拌3小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物65，化合物65经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物65-P1(17.3mg，收率6.7％)，65-P2(14.7mg，收率5.7％)，65-P3(14.4mg，收率5.6％)，65-P4(11.8mg，收率4.6％)。65-P1、65-P2、65-P3、65-P4这4个化合物经手性HPLC[设备：GilsonGX-281，柱温：25℃，柱子：chiralpark IA250mm*30mm 10um；流动相：Hex/EtOH＝30/70；流速：25mL/min]分析，保留时间如下所示。Osmium tetroxide (12.3 mg, 0.048 mmol) was added to a mixed solution of compound 65c (240 mg, 0.48 mmol) and N-methylmorpholine-N-oxide (227 mg, 1.94 mmol) in tetrahydrofuran and water (6 mL/6 mL). medium, the reaction mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 65, which was subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) After separation, compound 65- P1 (17.3 mg, yield 6.7%), 65-P2 (14.7 mg, yield 5.7%), 65-P3 (14.4 mg, yield 5.6%), 65-P4 (11.8 mg, yield 4.6%). Chiral HPLC of the four compounds 65-P1, 65-P2, 65-P3, and 65-P4 [equipment: GilsonGX-281, column temperature: 25°C, column: chiralpark IA250mm*30mm 10um; mobile phase: Hex/EtOH＝ 30/70; flow rate: 25mL/min] analysis, the retention times are as follows.
化合物65-P1：Compound 65-P1:
MS m/z(ESI):529.7[[M+1]+。手性HPLC：保留时间＝11.357min，UV＝214nm。1HNMR(400MHz,CD3OD)δ8.95(d,J＝5.2Hz,1H),8.85(s,1H),8.57(s,1H),8.48(d,J＝2.4Hz,1H),8.33(d,J＝5.2Hz,1H),7.80-7.70(m,1H),6.86(s,1H),5.54(d,J＝1.9Hz,2H),4.00(d,J＝11.1Hz,1H),3.81(d,J＝11.1Hz,1H),2.21(s,3H),2.10(s,3H),1.57(s,3H)。MS m/z(ESI):529.7[[M+1] + . Chiral HPLC: retention time=11.357min, UV=214nm. 1 HNMR (400MHz, CD 3 OD) δ8.95(d,J＝5.2Hz,1H),8.85(s,1H),8.57(s,1H),8.48(d,J＝2.4Hz,1H),8.33 (d,J＝5.2Hz,1H),7.80-7.70(m,1H),6.86(s,1H),5.54(d,J＝1.9Hz,2H),4.00(d,J＝11.1Hz,1H) ,3.81(d,J＝11.1Hz,1H),2.21(s,3H),2.10(s,3H),1.57(s,3H).
化合物65-P2：Compound 65-P2:
MS m/z(ESI):529.7[[M+1]+。手性HPLC：保留时间＝11.476min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.94(d,J＝5.2Hz,1H),8.83(s,1H),8.57(s,1H),8.47(d,J＝2.3Hz,1H),8.31(d,J＝5.2Hz,1H),7.79-7.71(m,1H),6.85(s,1H),5.53(d,J＝1.8Hz,2H),3.99(d,J＝11.1Hz,1H),3.80(d,J＝11.1Hz,1H),2.20(s,3H),2.09(s,3H),1.56(s,3H)。MS m/z(ESI):529.7[[M+1] + . Chiral HPLC: retention time=11.476min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.94(d,J＝5.2Hz,1H),8.83(s,1H),8.57(s,1H),8.47(d,J＝2.3Hz,1H), 8.31(d,J＝5.2Hz,1H),7.79-7.71(m,1H),6.85(s,1H),5.53(d,J＝1.8Hz,2H),3.99(d,J＝11.1Hz,1H ), 3.80 (d, J = 11.1Hz, 1H), 2.20 (s, 3H), 2.09 (s, 3H), 1.56 (s, 3H).
化合物65-P3：Compound 65-P3:
MS m/z(ESI):529.7[[M+1]+。手性HPLC：保留时间＝21.744min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.95(d,J＝5.2Hz,1H),8.85(s,1H),8.57(s,1H),8.48(d,J＝2.3Hz,1H),8.33(d,J＝5.2Hz,1H),7.82-7.70(m,1H),6.86(s,1H),5.54(d,J＝1.8Hz,2H),3.99(t,J＝10.8Hz,1H),3.81(d,J＝11.1Hz,1H),2.21(s,3H),2.10(s,3H),1.57(s,3H)。MS m/z(ESI):529.7[[M+1] + . Chiral HPLC: retention time=21.744min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.95 (d, J = 5.2Hz, 1H), 8.85 (s, 1H), 8.57 (s, 1H), 8.48 (d, J = 2.3Hz, 1H), 8.33(d,J＝5.2Hz,1H),7.82-7.70(m,1H),6.86(s,1H),5.54(d,J＝1.8Hz,2H),3.99(t,J＝10.8Hz,1H ), 3.81 (d, J = 11.1Hz, 1H), 2.21 (s, 3H), 2.10 (s, 3H), 1.57 (s, 3H).
化合物65-P4：Compound 65-P4:
MS m/z(ESI):529.7[[M+1]+。手性HPLC：保留时间＝36.167min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.95(d,J＝5.2Hz,1H),8.84(s,1H),8.58(s,1H),8.48(d,J＝2.3Hz,1H),8.32(d,J＝5.2Hz,1H),7.81-7.69(m,1H),6.86(s,1H),5.54(d,J＝1.8Hz,2H),4.00(d,J＝11.1Hz,1H),3.81(d,J＝11.1Hz,1H),2.21(s,3H),2.10(s,3H),1.57(s,3H).MS m/z(ESI):529.7[[M+1] + . Chiral HPLC: retention time=36.167min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.95 (d, J = 5.2Hz, 1H), 8.84 (s, 1H), 8.58 (s, 1H), 8.48 (d, J = 2.3Hz, 1H), 8.32(d,J＝5.2Hz,1H),7.81-7.69(m,1H),6.86(s,1H),5.54(d,J＝1.8Hz,2H),4.00(d,J＝11.1Hz,1H ),3.81(d,J=11.1Hz,1H),2.21(s,3H),2.10(s,3H),1.57(s,3H).
实施例19(化合物67)的合成
Synthesis of Example 19 (Compound 67)
第一步：化合物67a的合成Step One: Synthesis of Compound 67a
依次将2,6-二溴吡啶(228mg,0.96mmol)、六甲基二锡(142mg,0.44mmol)和四(三苯基膦)钯(102mg,0.088mmol)加入到化合物A5(400mg,0.88mmol)的甲苯(20mL)溶液中，反应混合物在氮气气氛下加热至110℃并在该温度下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物67a(110mg，收率：12％)。MS m/z(ESI):533.0，535.0[M+1]+。2,6-Dibromopyridine (228mg, 0.96mmol), hexamethyldistin (142mg, 0.44mmol) and tetrakis(triphenylphosphine)palladium (102mg, 0.088mmol) were added to compound A5 (400mg, 0.88 mmol) in toluene (20 mL), the reaction mixture was heated to 110°C under a nitrogen atmosphere and stirred at this temperature for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound 67a (110 mg, yield: 12%). MS m/z(ESI):533.0,535.0[M+1] + .
第二步：化合物67b的合成Step 2: Synthesis of compound 67b
依次将异丙烯基硼酸频哪醇酯(41.5mg,0.25mmol，CAS:126726-62-3)，碳酸钾(62mg,0.45mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷络合物(18.3mg,0.022mmol)加入到化合物67a(120mg,0.225mmol)的1,4-二氧六环和水(10mL/1mL)混合溶液中，反应混合物在氮气气氛下加热至90℃并在该温度下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物67b(100mg，收率：67％)。MS m/z(ESI):494.8[M+1]+。Isopropenylboronic acid pinacol ester (41.5 mg, 0.25 mmol, CAS: 126726-62-3), potassium carbonate (62 mg, 0.45 mmol) and [1,1'-bis(diphenylphosphino)bis Ferrocene]palladium(II) dichloride dichloromethane complex (18.3 mg, 0.022 mmol) was added to compound 67a (120 mg, 0.225 mmol) mixed with 1,4-dioxane and water (10 mL/1 mL) In solution, the reaction mixture was heated to 90°C under a nitrogen atmosphere and stirred at this temperature for 12 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound 67b (100 mg, yield: 67%). MS m/z(ESI):494.8[M+1] + .
第三步：化合物67的合成Step 3: Synthesis of Compound 67
将四氧化锇(123mg,0.48mmol)加入到化合物67b(120mg,0.24mmol)和N-甲基吗啉-N-氧化物(57mg,0.48mmol)的四氢呋喃和水(5mL/5mL)混合溶液中，反应混合物室温搅拌3小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到粗品化合物67，粗品化合物67经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：40-60％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物67(14mg，收率：11％)。MS m/z(ESI):529.1[M+1]+。1H NMR(400MHz,CD3OD)δ8.76(s,1H),8.48(d,J＝2.3Hz,1H),8.35(d,J＝1.7Hz,1H),8.30(d,J＝7.9Hz,1H),7.95(t,J＝7.9Hz,1H),7.78-7.69(m,2H),6.85(s,1H),5.53(d,J＝1.8Hz,2H),3.87(dd,J＝11.1,2.6Hz,1H),3.75(dd,J＝11.1,2.2Hz,1H),2.17(s,3H),2.10(s,3H),1.54(d,J＝1.2Hz,3H)。Osmium tetroxide (123 mg, 0.48 mmol) was added to a mixed solution of compound 67b (120 mg, 0.24 mmol) and N-methylmorpholine-N-oxide (57 mg, 0.48 mmol) in tetrahydrofuran and water (5 mL/5 mL). , the reaction mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain crude compound 67. The crude compound 67 was subjected to high performance liquid chromatography (chromatography column). : Gemini-C18; 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 67 (14 mg, yield: 11%). MS m/z(ESI):529.1[M+1] + . 1 H NMR (400MHz, CD 3 OD) δ8.76 (s, 1H), 8.48 (d, J = 2.3Hz, 1H), 8.35 (d, J = 1.7Hz, 1H), 8.30 (d, J = 7.9 Hz,1H),7.95(t,J＝7.9Hz,1H),7.78-7.69(m,2H),6.85(s,1H),5.53(d,J＝1.8Hz,2H),3.87(dd,J ＝11.1,2.6Hz,1H),3.75(dd,J＝11.1,2.2Hz,1H),2.17(s,3H),2.10(s,3H),1.54(d,J＝1.2Hz,3H).
实施例20(化合物68)的合成
Synthesis of Example 20 (Compound 68)
第一步：化合物68b的合成Step One: Synthesis of Compound 68b
将[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)(70mg,0.084mmol)加入到化合物68a(2g,8.4mmol)、异丙烯基硼酸频哪醇酯(1.41g,8.4mmol,CAS:126726-62-3)和碳酸钾(2.32g,16.8mmol)的1,4-二氧六环(20mL)的溶液中，反应混合物在氮气气氛下加热至110℃并在该温度下搅拌12小时。反应结束后，反应液过滤并减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～20/1)纯化得到化合物68b(0.8g，收率：38％)。MS m/z(ESI):197.8，199.9[M+1]+。[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (70 mg, 0.084 mmol) was added to compound 68a (2 g, 8.4 mmol), isopropenylboronic acid pinacol In a solution of ester (1.41g, 8.4mmol, CAS: 126726-62-3) and potassium carbonate (2.32g, 16.8mmol) in 1,4-dioxane (20mL), the reaction mixture was heated to 110°C and stirred at this temperature for 12 hours. After the reaction was completed, the reaction solution was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0-20/1) to obtain compound 68b (0.8 g, yield: 38%). MS m/z(ESI):197.8,199.9[M+1] + .
第二步：化合物68c的合成Step 2: Synthesis of compound 68c
将[1,1'-双(二苯基膦基)二茂铁]二氯化钯(II)二氯甲烷络合物(5mg,0.006mmol)加入到化合物68b(236mg,1.2mmol)、化合物A6(300mg,0.6mmol)和碳酸钾(165mg,1.2mmol)的1,4-二氧六环和水(10mL/1mL)混合溶液中，反应混合物在氮气气氛下加热至90℃并在该温度下搅拌12小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物68c(180mg， 收率：61.2％)。MS m/z(ESI):493.8[M+1]+。[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane complex (5 mg, 0.006 mmol) was added to compound 68b (236 mg, 1.2 mmol), compound In a mixed solution of A6 (300 mg, 0.6 mmol) and potassium carbonate (165 mg, 1.2 mmol) in 1,4-dioxane and water (10 mL/1 mL), the reaction mixture was heated to 90°C under a nitrogen atmosphere and at this temperature Stir for 12 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound 68c (180 mg, Yield: 61.2%). MS m/z(ESI):493.8[M+1] + .
第三步：化合物68的合成Step 3: Synthesis of Compound 68
将四氧化锇(463mg,1.8mmol)加入到化合物68c(180mg,0.36mmol)，和N-甲基吗啉-N-氧化物(213mg,1.8mmol)的四氢呋喃和水(5mL/5mL)混合溶液中，反应混合物室温搅拌3小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～5/1)纯化得到粗品化合物68，粗品化合物68通过高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：40-60％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物68(47mg，收率：24％)。MS m/z(ESI):528.0[M+1]+。1H NMR(400MHz,CDCl3)δ8.41(d,J＝2.3Hz,1H),7.97(m,1H),7.83-7.73(m,2H),7.65(d,J＝7.7Hz,1H),7.47(d,J＝7.9Hz,1H),7.38-7.30(m,2H),6.38(s,1H),5.42(d,J＝1.7Hz,2H),3.80(dd,J＝21.1,12.0Hz,2H),2.13(s,3H),2.00(d,J＝3.2Hz,3H),1.53(d,J＝7.7Hz,3H)。Osmium tetroxide (463 mg, 1.8 mmol) was added to a mixed solution of compound 68c (180 mg, 0.36 mmol) and N-methylmorpholine-N-oxide (213 mg, 1.8 mmol) in tetrahydrofuran and water (5 mL/5 mL). medium, the reaction mixture was stirred at room temperature for 3 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~5/1) to obtain crude compound 68. The crude compound 68 was purified by high-performance liquid chromatography (chromatography column). : Gemini-C18; 150×21.2mm, 5μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 40-60%; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar) to obtain compound 68 (47 mg, yield: 24%). MS m/z(ESI):528.0[M+1] + . 1 H NMR (400MHz, CDCl 3 ) δ8.41 (d, J = 2.3Hz, 1H), 7.97 (m, 1H), 7.83-7.73 (m, 2H), 7.65 (d, J = 7.7Hz, 1H) ,7.47(d,J＝7.9Hz,1H),7.38-7.30(m,2H),6.38(s,1H),5.42(d,J＝1.7Hz,2H),3.80(dd,J＝21.1,12.0 Hz, 2H), 2.13 (s, 3H), 2.00 (d, J = 3.2Hz, 3H), 1.53 (d, J = 7.7Hz, 3H).
实施例21(化合物73)的合成
Synthesis of Example 21 (Compound 73)
第一步：化合物73b的合成Step One: Synthesis of Compound 73b
将羟胺的水溶液(993mg,30mmol)加入到化合物73a(400mg,6mmol)的乙醇(10mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液减压浓缩得到化合物73b(500mg，收率：80.14％)。MS m/z(ESI):117.2[M+1]+。An aqueous solution of hydroxylamine (993 mg, 30 mmol) was added to a solution of compound 73a (400 mg, 6 mmol) in ethanol (10 mL), and the reaction mixture was stirred at 75°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 73b (500 mg, yield: 80.14%). MS m/z(ESI):117.2[M+1] + .
第二步：化合物73c的合成Step 2: Synthesis of compound 73c
将雷尼镍(1.5g,25.8mmol)化合物73b(500mg,5.1mmol)和乙酸(50mg,0.83mmol)的甲醇(10mL)溶液中，反应混合物在氢气气氛下室温搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物73c(474mg，收率：74.23％)。MS m/z(ESI):101.1[M+1]+。A solution of Raney Nickel (1.5 g, 25.8 mmol), compound 73b (500 mg, 5.1 mmol) and acetic acid (50 mg, 0.83 mmol) in methanol (10 mL) was stirred at room temperature under a hydrogen atmosphere for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 73c (474 mg, yield: 74.23%). MS m/z(ESI):101.1[M+1] + .
第三步：化合物73d的合成Step 3: Synthesis of Compound 73d
将碳酸钾(276mg,2mmol)加入到化合物73c(500mg,5mmol)和化合物A2(474mg,1mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物73d(130mg，收率：23.6％)。MS m/z(ESI):475.1[M+1]+。Potassium carbonate (276 mg, 2 mmol) was added to a solution of compound 73c (500 mg, 5 mmol) and compound A2 (474 mg, 1 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was stirred at 75°C for 16 hours. . After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 73d (130 mg, yield: 23.6%). MS m/z(ESI):475.1[M+1] + .
第四步：化合物73的合成Step 4: Synthesis of Compound 73
将化合物73d(130mg,0.25mmol)加入到80％硫酸和二氯甲烷(3mL/3mL)混合溶液中，反应混合物在50℃下搅拌16小时。反应结束后，反应液用饱和碳酸氢钠水溶液调节pH＝8，加水(60mL)稀释，经乙酸乙酯萃取(20mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得粗品化合物73，粗品经高效液相制备色谱(色谱柱：Gemini-C18；150×21.2mm，5μm；流动相：乙腈-水(0.1％甲酸)；梯度：32-45％；柱温：25℃；流速：20mL/min；波长：214nm；柱压：80bar)纯化得到化合物73(16.9mg，收率12.6％)MS m/z(ESI):530.0[M+1]+。1H NMR(400MHz,CD3OD)δ8.89(d,J＝5.3Hz,1H),8.84(s,1H),8.49(d,J＝2.3Hz,1H),8.43(s,1H),8.31(t,J＝5.3Hz,1H),7.80-7.72(m,1H),6.86(s,1H),5.54(d,J＝1.8Hz,2H),4.12-3.98(m,4H),3.42(t,1H),2.20(s,3H),2.09(s,3H)。Compound 73d (130 mg, 0.25 mmol) was added to a mixed solution of 80% sulfuric acid and dichloromethane (3 mL/3 mL), and the reaction mixture was stirred at 50°C for 16 hours. After the reaction, the reaction solution was adjusted to pH=8 with saturated sodium bicarbonate aqueous solution, diluted with water (60 mL), and extracted with ethyl acetate (20 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was reduced to The mixture was concentrated under pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain crude compound 73. The crude product was subjected to high performance liquid chromatography (chromatography column: Gemini-C18; 150×21.2mm). , 5 μm; mobile phase: acetonitrile-water (0.1% formic acid); gradient: 32-45%; column temperature: 25°C; flow rate: 20mL/min; wavelength: 214nm; column pressure: 80bar) and purified compound 73 (16.9mg , yield 12.6%) MS m/z (ESI): 530.0[M+1] + . 1 H NMR (400MHz, CD 3 OD) δ8.89(d,J＝5.3Hz,1H),8.84(s,1H),8.49(d,J＝2.3Hz,1H),8.43(s,1H), 8.31(t,J＝5.3Hz,1H),7.80-7.72(m,1H),6.86(s,1H),5.54(d,J＝1.8Hz,2H),4.12-3.98(m,4H),3.42 (t,1H),2.20(s,3H),2.09(s,3H).
实施例22(化合物88)的合成
Synthesis of Example 22 (Compound 88)
第一步：化合物88a的合成Step One: Synthesis of Compound 88a
将碳酸钾(291mg,2.11mmol)加入到化合物A2(200mg,0.42mmol)和化合物3d(245mg,2.11mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌48小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物88a(150mg，收率：71％)。MS m/z(ESI):400.8[M+1]+。Potassium carbonate (291 mg, 2.11 mmol) was added to a solution of compound A2 (200 mg, 0.42 mmol) and compound 3d (245 mg, 2.11 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated at 90°C. Stir for 48 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound 88a (150 mg, yield: 71%). MS m/z(ESI):400.8[M+1] + .
第二步：化合物88-P1和88-P2的合成Step 2: Synthesis of compounds 88-P1 and 88-P2
将碳酸钾(103mg,0.75mmol)加入到化合物88a(150mg,0.37mmol)和化合物A8(93mg,0.56mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在60℃下搅拌3小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物88，化合物88经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物88-P1(17.8mg，收率8.89％)和88-P2(17.2mg，收率8.59％)。Potassium carbonate (103 mg, 0.75 mmol) was added to a solution of compound 88a (150 mg, 0.37 mmol) and compound A8 (93 mg, 0.56 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated at 60°C. Stir for 3 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound 88, which was subjected to supercritical fluid chiral chromatography. ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 88 was obtained by resolution -P1 (17.8 mg, yield 8.89%) and 88-P2 (17.2 mg, yield 8.59%).
化合物88-P1：Compound 88-P1:
MS m/z(ESI):530.0[[M+1]+。超临界流体色谱SFC：保留时间＝4.48min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.86(d,J＝5.2Hz,1H),8.81(s,1H),8.46(d,J＝2.3Hz,1H),8.36(s,1H),8.22(d,J＝5.2Hz,1H),7.75-7.71(m,1H),6.84(d,J＝0.7Hz,1H),3.87(s,2H),2.17(s,3H),2.07(s,3H),1.40(d,J＝1.7Hz,6H)。MS m/z(ESI):530.0[[M+1] + . Supercritical fluid chromatography SFC: retention time=4.48min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.86 (d, J = 5.2 Hz, 1H), 8.81 (s, 1H), 8.46 (d, J = 2.3 Hz, 1H), 8.36 (s, 1H), 8.22(d,J＝5.2Hz,1H),7.75-7.71(m,1H),6.84(d,J＝0.7Hz,1H),3.87(s,2H),2.17(s,3H),2.07(s ,3H),1.40(d,J＝1.7Hz,6H).
化合物88-P2：Compound 88-P2:
MS m/z(ESI):530.0[[M+1]+。超临界流体色谱SFC：保留时间＝5.58min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.86(d,J＝5.2Hz,1H),8.81(s,1H),8.46(d,J＝2.4Hz,1H),8.36(s,1H),8.22(d,J＝5.2Hz,1H),7.75-7.71(m,1H),6.84(d,J＝0.7Hz,1H),3.87(s,2H),2.17(s,3H),2.07(s,3H),1.40(d,J＝1.8Hz,6H)。MS m/z(ESI):530.0[[M+1] + . Supercritical fluid chromatography SFC: retention time=5.58min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.86(d,J＝5.2Hz,1H),8.81(s,1H),8.46(d,J＝2.4Hz,1H),8.36(s,1H), 8.22(d,J＝5.2Hz,1H),7.75-7.71(m,1H),6.84(d,J＝0.7Hz,1H),3.87(s,2H),2.17(s,3H),2.07(s ,3H),1.40(d,J=1.8Hz,6H).
实施例23(化合物89、89-P1或89-P2和89-P2或89-P1)的合成
Synthesis of Example 23 (Compound 89, 89-P1 or 89-P2 and 89-P2 or 89-P1)
第一步：化合物89a的合成Step One: Synthesis of Compound 89a
将碳酸钾(582mg,4.2mmol)加入到化合物A2(200mg,0.42mmol)和化合物5d(240mg,2.1mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在90℃下搅拌48小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到黄色状化合物89a(120mg，收率：57％)。MS m/z(ESI):398.8[M+1]+。Potassium carbonate (582 mg, 4.2 mmol) was added to a solution of compound A2 (200 mg, 0.42 mmol) and compound 5d (240 mg, 2.1 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated at 90°C. Stir for 48 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain yellow compound 89a (120 mg, yield: 57%). ). MS m/z(ESI):398.8[M+1] + .
第二步：化合物89-P1和89-P2的合成Step 2: Synthesis of compounds 89-P1 and 89-P2
将碳酸钾(83mg,0.60mmol)加入到化合物89a(120mg,0.30mmol)和化合物A8(100mg,0.60mmol)的N,N-二甲基甲酰胺(10mL)溶液中，反应混合物在60℃下搅拌3小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物89，化合物89经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物89-P1(16.7mg，收率10.4％)和化合物89-P2(18.6mg，收率11.6％)。Potassium carbonate (83 mg, 0.60 mmol) was added to a solution of compound 89a (120 mg, 0.30 mmol) and compound A8 (100 mg, 0.60 mmol) in N,N-dimethylformamide (10 mL), and the reaction mixture was heated at 60°C. Stir for 3 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound 89. Compound 89 was purified by supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) After separation, compound 89- P1 (16.7 mg, yield 10.4%) and compound 89-P2 (18.6 mg, yield 11.6%).
化合物89-P1：Compound 89-P1:
MS m/z(ESI):528.0[[M+1]+。超临界流体色谱SFC：保留时间＝3.22min，UV＝230nm。1H NMR(400MHz,CD3OD)δ8.86-8.73(m,2H),8.46(d,J＝2.3Hz,1H),8.37(s,1H),8.15(d,J＝5.2Hz,1H),7.75-7.70(m,1H),6.83(d,J＝0.6Hz,1H),4.03(dd,J＝27.1,11.6Hz,2H),2.16(s,3H),2.06(s,3H),1.43(d,J＝4.5Hz,2H),1.10(dd,J＝6.0,2.9Hz,2H)。MS m/z(ESI):528.0[[M+1] + . Supercritical fluid chromatography SFC: retention time = 3.22min, UV = 230nm. 1 H NMR (400MHz, CD 3 OD) δ8.86-8.73 (m, 2H), 8.46 (d, J = 2.3Hz, 1H), 8.37 (s, 1H), 8.15 (d, J = 5.2Hz, 1H ),7.75-7.70(m,1H),6.83(d,J＝0.6Hz,1H),4.03(dd,J＝27.1,11.6Hz,2H),2.16(s,3H),2.06(s,3H) ,1.43(d,J＝4.5Hz,2H), 1.10(dd,J＝6.0,2.9Hz,2H).
化合物89-P2：Compound 89-P2:
MS m/z(ESI):528.0[[M+1]+。超临界流体色谱SFC：保留时间＝3.57min，UV＝230nm。1H NMR(400MHz,CD3OD)δ8.84-8.73(m,2H),8.46(d,J＝2.4Hz,1H),8.37(s,1H),8.16(d,J＝5.2Hz,1H),7.75-7.70(m,1H),6.83(d,J＝0.7Hz,1H),4.03(dd,J＝26.9,11.6Hz,2H),2.16(s,3H),2.06(s,3H),1.43(d,J＝4.5Hz,2H),1.10(d,J＝3.1Hz,2H)。MS m/z(ESI):528.0[[M+1] + . Supercritical fluid chromatography SFC: retention time=3.57min, UV=230nm. 1 H NMR (400MHz, CD 3 OD) δ8.84-8.73 (m, 2H), 8.46 (d, J = 2.4Hz, 1H), 8.37 (s, 1H), 8.16 (d, J = 5.2Hz, 1H ),7.75-7.70(m,1H),6.83(d,J＝0.7Hz,1H),4.03(dd,J＝26.9,11.6Hz,2H),2.16(s,3H),2.06(s,3H) ,1.43(d,J＝4.5Hz,2H), 1.10(d,J＝3.1Hz,2H).
实施例24(化合物95、95-P1或95-P2和95-P2或95-P1)的合成
Synthesis of Example 24 (Compound 95, 95-P1 or 95-P2 and 95-P2 or 95-P1)
第一步：化合物95a的合成Step One: Synthesis of Compound 95a
将碳酸钾(637mg，4.61mmol)加入到化合物A4-2(500mg，1.84mmol)和化合物A8(422mg，2.58mmol)的到N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在65℃下搅拌2小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/1)纯化得到化合物95a(800mg，收率：97％)。MS m/z(ESI):400.0[M+1]+。Potassium carbonate (637 mg, 4.61 mmol) was added to a solution of compound A4-2 (500 mg, 1.84 mmol) and compound A8 (422 mg, 2.58 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was Stir at 65°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 1/1) to obtain compound 95a (800 mg, yield: 97%). MS m/z(ESI):400.0[M+1] + .
第二步：化合物95b的合成Step 2: Synthesis of Compound 95b
将N-氯代丁二酰亚胺(322mg，2.41mmol)加入到化合物95a(800mg，2.01mmol)的异丙醇(30mL)溶液中，反应混合物在80℃下搅拌4小时。反应结束后，反应液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物95b(500mg，收率：54％)。MS m/z(ESI):433.7,435.7[M+1]+。N-Chlorosuccinimide (322 mg, 2.41 mmol) was added to a solution of compound 95a (800 mg, 2.01 mmol) in isopropanol (30 mL), and the reaction mixture was stirred at 80°C for 4 hours. After the reaction, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0 to 2/1) to obtain compound 95b (500 mg, yield: 54%). MS m/z(ESI):433.7,435.7[M+1] + .
第三步：化合物95c的合成Step 3: Synthesis of Compound 95c
将二(三苯基膦)二氯化钯(81mg,0.12mol)加入到化合物95b(500mg,1.15mol)和三丁基(1-乙氧基乙烯)锡(623mg,1.73mol)的1,4-二氧六环(5mL)溶液中，反应混合物在130℃下搅拌2小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～2/1)纯化得到化合物95c(550mg，收率：51％)。MS m/z(ESI):469.7[M+1]+。Bis(triphenylphosphine)palladium dichloride (81 mg, 0.12 mol) was added to compound 95b (500 mg, 1.15 mol) and tributyl(1-ethoxyethylene)tin (623 mg, 1.73 mol) 1, In a solution of 4-dioxane (5 mL), the reaction mixture was stirred at 130°C for 2 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0~2/1) to obtain compound 95c (550 mg, yield: 51%). . MS m/z(ESI):469.7[M+1] + .
第四步：化合物95d的合成Step 4: Synthesis of Compound 95d
将浓盐酸(0.5mL)加入到化合物95c(550mg,1.17mmol)的四氢呋喃(10mL)溶液中，反应混合物在室温下搅拌3小时。反应结束后，反应液减压浓缩后用碳酸氢钠溶液调pH＝7-8，然后经乙酸乙酯(20mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝1/0～1/2)纯化得到化合物95d(350mg，收率：71％)。MS m/z(ESI):441.7[M+1]+。Concentrated hydrochloric acid (0.5 mL) was added to a solution of compound 95c (550 mg, 1.17 mmol) in tetrahydrofuran (10 mL), and the reaction mixture was stirred at room temperature for 3 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, adjusted to pH=7-8 with sodium bicarbonate solution, and then extracted with ethyl acetate (20 mL×3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was reduced to The mixture was concentrated under pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 1/0-1/2) to obtain compound 95d (350 mg, yield: 71%). MS m/z(ESI):441.7[M+1] + .
第五步：化合物95e的合成Step 5: Synthesis of Compound 95e
将N,N-二甲基甲酰胺二甲基缩醛(284mg,2.39mmol)加入到化合物95d(350mg,0.80mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在100℃下搅拌3小时。反应结束后，反应加用水(10mL)稀释，经乙酸乙酯(20mL×3)萃取，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物95e(250mg，收率：60％)。MS m/z(ESI):496.7[M+1]+。N,N-dimethylformamide dimethyl acetal (284 mg, 2.39 mmol) was added to a solution of compound 95d (350 mg, 0.80 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was Stir at 100°C for 3 hours. After the reaction was completed, the reaction was diluted with water (10 mL), extracted with ethyl acetate (20 mL × 3), the combined organic phases were dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Dichloromethane/methanol=1/0~10/1) was purified to obtain compound 95e (250 mg, yield: 60%). MS m/z(ESI):496.7[M+1] + .
第六步：化合物95-P1和95-P2的合成Step Six: Synthesis of Compounds 95-P1 and 95-P2
将碳酸钾(64mg,0.46mmol)加入到化合物95e(230mg,0.46mmol)和化合物5d(158mg,1.39mmol)的N,N-二甲基甲酰胺(5mL)溶液中，反应混合物在65℃下搅拌32小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物95，化合物95经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物95-P1(12.3mg，收率4.61％)和95-P2(11.2mg，收率4.2％)。Potassium carbonate (64 mg, 0.46 mmol) was added to a solution of compound 95e (230 mg, 0.46 mmol) and compound 5d (158 mg, 1.39 mmol) in N,N-dimethylformamide (5 mL), and the reaction mixture was heated at 65°C. Stir for 32 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 95, which was subjected to supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) After separation, compound 95- P1 (12.3 mg, yield 4.61%) and 95-P2 (11.2 mg, yield 4.2%).
化合物95-P1：Compound 95-P1:
MS m/z(ESI):547.7[[M+1]+。超临界流体色谱SFC：保留时间＝3.46min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.97(s,1H),8.81(d,J＝5.2Hz,1H),8.61(s,1H),8.46(d,J＝2.3Hz,1H),8.18(d,J＝5.2Hz,1H),7.76-7.70(m,1H),6.84(d,J＝0.7Hz,1H),4.09(d,J＝11.6Hz,1H),3.97(d,J＝11.6Hz,1H),2.10(s,3H), 1.45-1.43(m,2H),1.15-1.04(m,2H)。MS m/z(ESI):547.7[[M+1] + . Supercritical fluid chromatography SFC: retention time = 3.46min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.97 (s, 1H), 8.81 (d, J = 5.2Hz, 1H), 8.61 (s, 1H), 8.46 (d, J = 2.3Hz, 1H), 8.18(d,J＝5.2Hz,1H),7.76-7.70(m,1H),6.84(d,J＝0.7Hz,1H),4.09(d,J＝11.6Hz,1H),3.97(d,J ＝11.6Hz,1H),2.10(s,3H), 1.45-1.43(m,2H),1.15-1.04(m,2H).
化合物95-P2：Compound 95-P2:
MS m/z(ESI):547.7[[M+1]+。超临界流体色谱SFC：保留时间＝4.66min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.95(s,1H),8.79(d,J＝5.2Hz,1H),8.59(s,1H),8.44(d,J＝2.4Hz,1H),8.16(d,J＝5.2Hz,1H),7.74-7.68(m,1H),6.82(d,J＝0.7Hz,1H),4.06(d,J＝11.7Hz,1H),3.96(d,J＝11.6Hz,1H),2.08(d,J＝0.5Hz,3H),1.43-1.41(m,2H),1.10-1.06(m,2H)。MS m/z(ESI):547.7[[M+1] + . Supercritical fluid chromatography SFC: retention time=4.66min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.95 (s, 1H), 8.79 (d, J = 5.2Hz, 1H), 8.59 (s, 1H), 8.44 (d, J = 2.4Hz, 1H), 8.16(d,J＝5.2Hz,1H),7.74-7.68(m,1H),6.82(d,J＝0.7Hz,1H),4.06(d,J＝11.7Hz,1H),3.96(d,J ＝11.6Hz,1H),2.08(d,J＝0.5Hz,3H),1.43-1.41(m,2H),1.10-1.06(m,2H).
实施例25(化合物108、108-P1或108-P2和108-P2或108-P1)的合成
Synthesis of Example 25 (Compound 108, 108-P1 or 108-P2 and 108-P2 or 108-P1)
将碳酸钾(87mg,0.63mmol)加入到化合物A9(300mg,0.63mmol)和化合物3d(218mg,1.88mmol)的乙腈(10mL)溶液中，反应混合物在75℃下搅拌20小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～10/1)纯化得到化合物108，化合物108经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH0.2％)，总流速：40g/min)拆分得到化合物108-P1(24.2mg，收率7.25％)和108-P2(25.6mg，收率7.66％)。Potassium carbonate (87 mg, 0.63 mmol) was added to a solution of compound A9 (300 mg, 0.63 mmol) and compound 3d (218 mg, 1.88 mmol) in acetonitrile (10 mL), and the reaction mixture was stirred at 75°C for 20 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~10/1) to obtain compound 108. Compound 108 was purified by supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 108 was obtained by resolution -P1 (24.2 mg, yield 7.25%) and 108-P2 (25.6 mg, yield 7.66%).
化合物108-P1：Compound 108-P1:
MS m/z(ESI):532.0[[M+1]+。超临界流体色谱SFC：保留时间＝2.54min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.78(d,J＝5.1Hz,2H),8.51(d,J＝6.1Hz,1H),8.36(d,J＝2.4Hz,1H),8.13(d,J＝5.2Hz,1H),7.65-7.60(m,1H),6.74(s,1H),5.42(d,J＝1.9Hz,2H),3.78(s,2H),2.07(s,3H),1.31(d,J＝1.9Hz,6H)。MS m/z(ESI):532.0[[M+1] + . Supercritical fluid chromatography SFC: retention time = 2.54min, UV = 214nm. 1 H NMR (400MHz, CD 3 OD) δ8.78(d,J＝5.1Hz,2H),8.51(d,J＝6.1Hz,1H),8.36(d,J＝2.4Hz,1H),8.13( d,J＝5.2Hz,1H),7.65-7.60(m,1H),6.74(s,1H),5.42(d,J＝1.9Hz,2H),3.78(s,2H),2.07(s,3H ), 1.31 (d, J = 1.9Hz, 6H).
化合物108-P2：Compound 108-P2:
MS m/z(ESI):532.0[[M+1]+。超临界流体色谱SFC：保留时间＝3.24min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.90(d,J＝5.1Hz,2H),8.63(d,J＝6.1Hz,1H),8.48(d,J＝2.4Hz,1H),8.25(d,J＝5.2Hz,1H),7.79-7.70(m,1H),6.86(s,1H),5.54(d,J＝1.9Hz,2H),3.91(s,2H),2.19(s,3H),1.43(d,J＝1.8Hz,6H)。MS m/z(ESI):532.0[[M+1] + . Supercritical fluid chromatography SFC: retention time=3.24min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.90 (d, J = 5.1Hz, 2H), 8.63 (d, J = 6.1Hz, 1H), 8.48 (d, J = 2.4Hz, 1H), 8.25 ( d,J＝5.2Hz,1H),7.79-7.70(m,1H),6.86(s,1H),5.54(d,J＝1.9Hz,2H),3.91(s,2H),2.19(s,3H ), 1.43 (d, J = 1.8Hz, 6H).
实施例26(化合物110、110-P1或110-P2和110-P2或110-P1)的合成
Synthesis of Example 26 (Compound 110, 110-P1 or 110-P2 and 110-P2 or 110-P1)
将碳酸钾(87mg,0.63mmol)加入到化合物A9(300mg,0.63mmol)和化合物5d(215mg,1.88mmol)的乙腈(5mL)溶液中，反应混合物在75℃下搅拌32小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物110，化合物110经超临界流体手性色谱((设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH 0.2％)，总流速：40g/min)拆分得到化合物110-P1(21.7mg，收率6.46％)和110-P2(21.4mg，收率6.37％)。Potassium carbonate (87 mg, 0.63 mmol) was added to a solution of compound A9 (300 mg, 0.63 mmol) and compound 5d (215 mg, 1.88 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at 75°C for 32 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 110. Compound 110 was purified by supercritical fluid chiral chromatography. ((Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 110 was obtained by separation -P1 (21.7 mg, yield 6.46%) and 110-P2 (21.4 mg, yield 6.37%).
化合物110-P1：Compound 110-P1:
MS m/z(ESI):529.7[[M+1]+。超临界流体色谱SFC：保留时间＝2.83min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.77(s,1H),8.70(d,J＝5.2Hz,1H),8.53(d,J＝6.1Hz,1H),8.36(d,J＝2.3Hz,1H),8.06(d,J＝5.2Hz,1H),7.68-7.59(m,1H),6.74(s,1H),5.42(d,J＝1.8Hz,2H),3.94(dd,J＝33.5,11.6Hz,2H),2.07(s,3H),1.34(dd,J＝6.4,3.4Hz,2H),1.01(dd,J＝6.4,3.4Hz,2H)。MS m/z(ESI):529.7[[M+1] + . Supercritical fluid chromatography SFC: retention time=2.83min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.77(s,1H),8.70(d,J＝5.2Hz,1H),8.53(d,J＝6.1Hz,1H),8.36(d,J＝2.3 Hz,1H),8.06(d,J＝5.2Hz,1H),7.68-7.59(m,1H),6.74(s,1H),5.42(d,J＝1.8Hz,2H),3.94(dd,J ＝33.5,11.6Hz,2H),2.07(s,3H),1.34(dd,J＝6.4,3.4Hz,2H),1.01(dd,J＝6.4,3.4Hz,2H).
化合物110-P2：Compound 110-P2:
MS m/z(ESI):529.7[[M+1]+。超临界流体色谱SFC：保留时间＝3.75min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.76(s,1H),8.69(d,J＝5.2Hz,1H),8.53(d,J＝6.1Hz,1H),8.36(d,J＝2.3Hz,1H),8.06(d,J＝5.2 Hz,1H),7.67-7.57(m,1H),6.73(s,1H),5.42(d,J＝1.8Hz,2H),3.94(dd,J＝34.3,11.6Hz,2H),2.07(s,3H),1.34(dd,J＝6.4,3.5Hz,2H),1.01(dd,J＝6.5,3.4Hz,2H)。MS m/z(ESI):529.7[[M+1] + . Supercritical fluid chromatography SFC: retention time=3.75min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.76 (s, 1H), 8.69 (d, J = 5.2Hz, 1H), 8.53 (d, J = 6.1Hz, 1H), 8.36 (d, J = 2.3 Hz,1H),8.06(d,J＝5.2 Hz,1H),7.67-7.57(m,1H),6.73(s,1H),5.42(d,J＝1.8Hz,2H),3.94(dd,J＝34.3,11.6Hz,2H),2.07(s ,3H), 1.34(dd,J＝6.4,3.5Hz,2H), 1.01(dd,J＝6.5,3.4Hz,2H).
实施例27(化合物111、111-P1或111-P2和111-P2或111-P1)的合成
Synthesis of Example 27 (Compound 111, 111-P1 or 111-P2 and 111-P2 or 111-P1)
将碳酸钾(86mg,0.6mmol)加入到化合物A9(240mg,1.9mmol)和化合物6d(300mg,0.6mmol)的乙腈(5mL)溶液中，反应混合物在80℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物111，化合物111经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％MeOH/CO2(NH4OH0.2％)，总流速：40g/min)拆分得到化合物111-P1(18.2mg，收率5.5％)和111-P2(17.5mg，收率5.3％)。Potassium carbonate (86 mg, 0.6 mmol) was added to a solution of compound A9 (240 mg, 1.9 mmol) and compound 6d (300 mg, 0.6 mmol) in acetonitrile (5 mL), and the reaction mixture was stirred at 80°C for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 111. Compound 111 was purified by supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% MeOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 111 was obtained by separation -P1 (18.2 mg, yield 5.5%) and 111-P2 (17.5 mg, yield 5.3%).
化合物111-P1：Compound 111-P1:
MS m/z(ESI):543.8[[M+1]+。超临界流体色谱SFC：保留时间＝2.65min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.90-8.84(m,2H),8.61(d,J＝6.1Hz,1H),8.43(d,J＝2.4Hz,1H),8.22(d,J＝5.2Hz,1H),7.70(ddd,J＝9.6,8.6,2.4Hz,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),4.03(s,2H),2.67-2.51(m,2H),2.26-2.17(m,2H),2.14(s,3H),2.09-2.00(m,1H),1.96-1.86(m,1H)。MS m/z(ESI):543.8[[M+1] + . Supercritical fluid chromatography SFC: retention time=2.65min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.90-8.84(m,2H),8.61(d,J＝6.1Hz,1H),8.43(d,J＝2.4Hz,1H),8.22(d,J ＝5.2Hz,1H),7.70(ddd,J＝9.6,8.6,2.4Hz,1H),6.81(s,1H),5.49(d,J＝1.9Hz,2H),4.03(s,2H),2.67 -2.51(m,2H),2.26-2.17(m,2H),2.14(s,3H),2.09-2.00(m,1H),1.96-1.86(m,1H).
化合物111-P2：Compound 111-P2:
MS m/z(ESI):543.7[[M+1]+。超临界流体色谱SFC：保留时间＝3.23min，UV＝214nm。1H NMR(400MHz,CD3OD)δ8.94-8.87(m,2H),8.64(d,J＝6.1Hz,1H),8.47(d,J＝2.4Hz,1H),8.25(d,J＝5.2Hz,1H),7.73(ddd,J＝9.7,8.6,2.4Hz,1H),6.84(d,J＝0.7Hz,1H),5.52(d,J＝1.9Hz,2H),4.06(s,2H),2.72-2.56(m,2H),2.30-2.20(m,2H),2.17(s,3H),2.13-2.04(m,1H),1.98-1.90(m,1H)。MS m/z(ESI):543.7[[M+1] + . Supercritical fluid chromatography SFC: retention time=3.23min, UV=214nm. 1 H NMR (400MHz, CD 3 OD) δ8.94-8.87(m,2H),8.64(d,J＝6.1Hz,1H),8.47(d,J＝2.4Hz,1H),8.25(d,J ＝5.2Hz,1H),7.73(ddd,J＝9.7,8.6,2.4Hz,1H),6.84(d,J＝0.7Hz,1H),5.52(d,J＝1.9Hz,2H),4.06(s ,2H),2.72-2.56(m,2H),2.30-2.20(m,2H),2.17(s,3H),2.13-2.04(m,1H),1.98-1.90(m,1H).
实施例28(化合物12、12-P1或12-P2和12-P2或12-P1)的合成
Synthesis of Example 28 (Compound 12, 12-P1 or 12-P2 and 12-P2 or 12-P1)
第一步：化合物12a的合成Step One: Synthesis of Compound 12a
将2,2’-二溴***(6.15g,26.5mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(DBU)(8.08g,53.04mmol)，依次加入到化合物10a(3g,26.5mmol)的N,N-二甲基甲酰胺(30mL)溶液中，反应混合物在80℃下搅拌2小时。反应完成后，反应液冷却至室温，加水(400mL)稀释，用乙酸乙酯萃取(200mL×3)，合并的有机相经饱和食盐水洗(200mL×3)，无水硫酸钠干燥并，过滤液减压浓缩得到化合物12a(2.3g，收率：38％)。1H NMR(400MHz,CDCl3)δ4.30(q,J＝7.1Hz,2H),4.00-3.96(m,2H),3.78-3.72(m,2H),2.18-2.10 (m,2H),2.05-1.99(m,2H),1.34(t,J＝7.1Hz,3H)。Add 2,2'-dibromoethyl ether (6.15g, 26.5mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (8.08g, 53.04mmol) in sequence. Added to a solution of compound 10a (3 g, 26.5 mmol) in N,N-dimethylformamide (30 mL), the reaction mixture was stirred at 80°C for 2 hours. After the reaction is completed, the reaction solution is cooled to room temperature, diluted with water (400 mL), extracted with ethyl acetate (200 mL × 3), the combined organic phases are washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, and filtered. Concentrate under reduced pressure to obtain compound 12a (2.3 g, yield: 38%). 1 H NMR (400MHz, CDCl 3 ) δ4.30 (q, J = 7.1Hz, 2H), 4.00-3.96 (m, 2H), 3.78-3.72 (m, 2H), 2.18-2.10 (m,2H),2.05-1.99(m,2H),1.34(t,J=7.1Hz,3H).
第二步：化合物12b的合成Step 2: Synthesis of Compound 12b
依次将氯化钙(1.53g,13.81mmol)和硼氢化钠(0.95g,25.11mmol)加入到化合物12a(2.3g,12.55mmol)的乙醇(30mL)溶液中，反应混合物室温搅拌16小时。反应结束后，反应液浓缩，用2M盐酸调pH至2-3，混合物经乙酸乙酯萃取(50mL×3)，合并的有机相经无水硫酸钠干燥并过滤，过滤液减压浓缩后得到化合物12b(2g，收率：94％)。1H NMR(400MHz,CDCl3)δ4.01-3.99(m,2H),3.88-3.54(m,4H),1.93-1.87(m,2H),1.70-1.60(m,2H)。Calcium chloride (1.53g, 13.81mmol) and sodium borohydride (0.95g, 25.11mmol) were added to a solution of compound 12a (2.3g, 12.55mmol) in ethanol (30mL) in sequence, and the reaction mixture was stirred at room temperature for 16 hours. After the reaction, the reaction solution was concentrated, and the pH was adjusted to 2-3 with 2M hydrochloric acid. The mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain Compound 12b (2g, yield: 94%). 1 H NMR (400MHz, CDCl 3 ) δ4.01-3.99(m,2H), 3.88-3.54(m,4H), 1.93-1.87(m,2H), 1.70-1.60(m,2H).
第三步：化合物12c的合成Step 3: Synthesis of Compound 12c
将羟胺水溶液(1.68g,51mmol)加入到化合物12b(1.8g,12.75mmol)的乙醇(20mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液减压浓缩得到化合物12c(2.2g，收率：69％)。MS m/z(ESI):175.2[M+1]+。Aqueous hydroxylamine solution (1.68 g, 51 mmol) was added to a solution of compound 12b (1.8 g, 12.75 mmol) in ethanol (20 mL), and the reaction mixture was stirred at 75°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain compound 12c (2.2 g, yield: 69%). MS m/z(ESI):175.2[M+1] + .
第四步：化合物12d的合成Step 4: Synthesis of Compound 12d
将雷尼镍(3.5g,60mmol)加入到化合物12c(2.1g,12mmol)的乙醇(10mL)溶液中，反应混合物在氢气气氛下升温至75℃并在该温度下搅拌16小时。反应结束，反应液过滤，过滤液减压浓缩得到化合物12d(2.0g，收率：84％)。MS m/z(ESI):159.0[M+1]+。Raney Nickel (3.5 g, 60 mmol) was added to a solution of compound 12c (2.1 g, 12 mmol) in ethanol (10 mL), and the reaction mixture was warmed to 75°C under a hydrogen atmosphere and stirred at this temperature for 16 hours. After the reaction was completed, the reaction liquid was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 12d (2.0 g, yield: 84%). MS m/z(ESI):159.0[M+1] + .
第五步：化合物12-P1和12-P2的合成Step 5: Synthesis of Compounds 12-P1 and 12-P2
将化合物A2(200mg,0.42mmol)和碳酸钾(116mg,0.84mmol)加入到化合物12d(333mg,2.11mmol)的乙腈(10mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物12，化合物12经超临界流体手性色谱(设备：SFC Thar prep 80,柱子：CHIRALPAK AD-H 250mm*20mm，5μm，流动相：40％EtOH/CO2(NH4OH0.2％)，总流速：40g/min)拆分得到化合物12-P1(34.3mg，收率13.5％)和化合物12-P2(32.3mg，收率12.8％)。Compound A2 (200 mg, 0.42 mmol) and potassium carbonate (116 mg, 0.84 mmol) were added to a solution of compound 12d (333 mg, 2.11 mmol) in acetonitrile (10 mL), and the reaction mixture was stirred at 75°C for 16 hours. After the reaction, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 12. Compound 12 was purified by supercritical fluid chiral chromatography. (Equipment: SFC Thar prep 80, column: CHIRALPAK AD-H 250mm*20mm, 5μm, mobile phase: 40% EtOH/CO 2 (NH 4 OH 0.2%), total flow rate: 40g/min) Compound 12 was obtained by separation -P1 (34.3 mg, yield 13.5%) and compound 12-P2 (32.3 mg, yield 12.8%).
化合物12-P1:Compound 12-P1:
MS m/z(ESI):570.1[M+1]+。超临界流体色谱SFC：保留时间＝3.12min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.92(d,J＝5.2Hz,1H),8.82(s,1H),8.46(d,J＝2.3Hz,1H),8.34(s,1H),8.26(d,J＝5.2Hz,1H),7.78-7.69(m,1H),6.83(s,1H),5.51(d,J＝1.8Hz,2H),3.89-3.75(m,4H),3.49-3.45(m,2H),2.55(d,J＝14.0Hz,2H),2.17(s,3H),2.06(s,3H),1.89-1.79(m,2H)。MS m/z(ESI):570.1[M+1] + . Supercritical fluid chromatography SFC: retention time=3.12min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.92(d,J＝5.2Hz,1H),8.82(s,1H),8.46(d,J＝2.3Hz,1H),8.34(s,1H), 8.26(d,J＝5.2Hz,1H),7.78-7.69(m,1H),6.83(s,1H),5.51(d,J＝1.8Hz,2H),3.89-3.75(m,4H),3.49 -3.45(m,2H),2.55(d,J＝14.0Hz,2H),2.17(s,3H),2.06(s,3H),1.89-1.79(m,2H).
化合物12-P2:Compound 12-P2:
MS m/z(ESI):570.1[M+1]+。超临界流体色谱SFC：保留时间＝3.92min，UV＝254nm。1H NMR(400MHz,CD3OD)δ8.92(d,J＝5.2Hz,1H),8.82(s,1H),8.46(d,J＝2.3Hz,1H),8.34(s,1H),8.26(d,J＝5.2Hz,1H),7.76-7.70(m,1H),6.82(s,1H),5.51(d,J＝1.7Hz,2H),3.88-3.75(m,4H),3.49-3.45(m,2H),2.55(d,J＝14.1Hz,2H),2.17(s,3H),2.06(s,3H),1.89-1.79(m,2H)。MS m/z(ESI):570.1[M+1] + . Supercritical fluid chromatography SFC: retention time=3.92min, UV=254nm. 1 H NMR (400MHz, CD 3 OD) δ8.92(d,J＝5.2Hz,1H),8.82(s,1H),8.46(d,J＝2.3Hz,1H),8.34(s,1H), 8.26(d,J＝5.2Hz,1H),7.76-7.70(m,1H),6.82(s,1H),5.51(d,J＝1.7Hz,2H),3.88-3.75(m,4H),3.49 -3.45(m,2H),2.55(d,J＝14.1Hz,2H),2.17(s,3H),2.06(s,3H),1.89-1.79(m,2H).
实施例29(化合物143)的合成
Synthesis of Example 29 (Compound 143)
将碳酸钾(73mg,0.52mmol)加入到化合物A10(140mg,0.26mmol)和化合物3d(153mg,1.32mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得化合物143(50mg，收率32.13％)。MS m/z(ESI):582.1[M+1]+。1H NMR(400MHz,CD3OD)δ9.17(s,1H),8.86(d,J＝5.1Hz,1H),8.53(s,1H),8.36(d,J＝2.4Hz,1H),8.24(d,J＝5.1Hz,1H),7.63-7.60(m,1H),6.74(s,1H),5.42(d,J＝1.9Hz,2H),3.79(d,J＝2.7Hz,2H),2.01(s,3H),1.32(d,J＝3.6Hz,6H)Potassium carbonate (73 mg, 0.52 mmol) was added to a solution of compound A10 (140 mg, 0.26 mmol) and compound 3d (153 mg, 1.32 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was heated at 75°C. Stir for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 143 (50 mg, yield 32.13%). MS m/z(ESI):582.1[M+1] + . 1 H NMR (400MHz, CD 3 OD) δ9.17 (s, 1H), 8.86 (d, J = 5.1Hz, 1H), 8.53 (s, 1H), 8.36 (d, J = 2.4Hz, 1H), 8.24(d,J＝5.1Hz,1H),7.63-7.60(m,1H),6.74(s,1H),5.42(d,J＝1.9Hz,2H),3.79(d,J＝2.7Hz,2H ),2.01(s,3H),1.32(d,J＝3.6Hz,6H)
实施例30(化合物145)的合成
Synthesis of Example 30 (Compound 145)
将碳酸钾(73mg,0.52mmol)加入到化合物A10(140mg,0.26mmol)和化合物5d(150mg,1.32mmol)的N,N-二甲基甲酰胺(15mL)溶液中，反应混合物在75℃下搅拌16小时。反应结束后，反应液过滤，过滤液减压浓缩，残余物经硅胶柱层析(二氯甲烷/甲醇＝1/0～20/1)纯化得到化合物145(50mg，收率32.25％)。MS m/z(ESI):580.0[M+1]+。1H NMR(400MHz,DMSO)δ9.36(s,1H),8.96(d,J＝5.1Hz,1H),8.74(s,1H),8.62(d,J＝2.3Hz,1H),8.19(d,J＝5.1Hz,1H),8.11(d,J＝1.5Hz,1H),6.86(s,1H),5.51(s,2H),4.60(s,1H),4.00(d,J＝5.7Hz,2H),2.00(s,3H),1.39(dd,J＝9.1,3.4Hz,1H),1.26(dd,J＝10.6,8.0Hz,1H),1.10(d,J＝3.0Hz,2H)。Potassium carbonate (73 mg, 0.52 mmol) was added to a solution of compound A10 (140 mg, 0.26 mmol) and compound 5d (150 mg, 1.32 mmol) in N,N-dimethylformamide (15 mL), and the reaction mixture was heated at 75°C. Stir for 16 hours. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=1/0~20/1) to obtain compound 145 (50 mg, yield 32.25%). MS m/z(ESI):580.0[M+1] + . 1 H NMR (400MHz, DMSO) δ9.36 (s, 1H), 8.96 (d, J = 5.1Hz, 1H), 8.74 (s, 1H), 8.62 (d, J = 2.3Hz, 1H), 8.19 ( d,J＝5.1Hz,1H),8.11(d,J＝1.5Hz,1H),6.86(s,1H),5.51(s,2H),4.60(s,1H),4.00(d,J＝5.7 Hz,2H),2.00(s,3H),1.39(dd,J＝9.1,3.4Hz,1H),1.26(dd,J＝10.6,8.0Hz,1H),1.10(d,J＝3.0Hz,2H ).
生物学评价biological evaluation
测试例1.p38 MAPK/MK2体外活性的测定Test Example 1. Determination of p38 MAPK/MK2 activity in vitro
化合物对p38 MAPK/MK2的抑制作用采用Z-LYTE激酶检测试剂盒(Thermo,PV3177)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为10μM，1％DMSO,5倍倍比稀释，8个浓度，双复孔；50mM HEPES pH 7.5,10mM MgCl2,0.01％Brij-35,1mM EGTA作为反应缓冲液用来配置2x active p38a/inactive MK2/Ser/Thr 4混合液，最终10μL的反应体系在384孔板(Corning,4514)中进行，含有500ng/mL inactive MK2(abcam,79910),8ng/mL active p38a(Carna,04-152),2μM Ser/Thr 4；20℃反应1小时后，每孔加入稀释2048倍后的Development Reagent A，室温孵育1小时后加入5μL终止缓冲溶液终止反应，酶标仪检测(Ex.400nm,Em.445nm；Ex.400nm,Em.520nm)。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC50。结果如表1所示。The inhibitory effect of compounds on p38 MAPK/MK2 was detected using Z-LYTE kinase detection kit (Thermo, PV3177). Dissolve test compounds in DMSO to 10mM stock solution and store at -20°C until use. The starting concentration of the compound is 10 μM, 1% DMSO, 5-fold dilution, 8 concentrations, double wells; 50mM HEPES pH 7.5, 10mM MgCl 2 , 0.01% Brij-35, 1mM EGTA is used as reaction buffer to prepare 2x active p38a/inactive MK2/Ser/Thr 4 mixture, the final 10μL reaction system was carried out in a 384-well plate (Corning, 4514), containing 500ng/mL inactive MK2 (abcam, 79910), 8ng/mL active p38a (Carna, 04-152), 2 μM Ser/Thr 4; after reacting at 20°C for 1 hour, add Development Reagent A diluted 2048 times to each well, incubate at room temperature for 1 hour, add 5 μL of stop buffer solution to terminate the reaction, and detect with a microplate reader (Ex. 400nm, Em.445nm; Ex.400nm, Em.520nm). Use GraphPad Prism 8 software to fit the concentration-effect curve, and calculate the compound concentration with 50% inhibitory effect, that is, IC 50 . The results are shown in Table 1.
表1

Table 1

从表1可知，本公开的上述化合物对p38 MAPK/MK2具有良好的抑制活性。As can be seen from Table 1, the above-mentioned compounds of the present disclosure have good inhibitory activity against p38 MAPK/MK2.
测试例2.对人PBMC细胞上清TNF-α体外活性测定Test Example 2. In vitro activity measurement of TNF-α in human PBMC cell supernatant
化合物对人PBMC细胞上清TNF-α的抑制作用实验方案用Elisa检测试剂盒(碧云天，PI518)进行检测。DMSO溶解受试化合物至10mM母液，-20℃保存待用。化合物起始浓度为2μM，5倍倍比稀释，6个浓度，细胞铺板双复孔，Elisa检测为单孔，DMSO终浓度为0.4％，也可根据化合物筛选的实际情况，变更化合物起始浓度、倍比稀释倍数、梯度浓度数量和复孔数。The experimental protocol for the inhibitory effect of compounds on TNF-α in human PBMC cell supernatants was tested using Elisa detection kit (Beyotime, PI518). Dissolve test compounds in DMSO to 10mM stock solution and store at -20°C until use. The starting concentration of the compound is 2 μM, 5-fold dilution, 6 concentrations, cells are plated in double wells, Elisa detection is single well, the final concentration of DMSO is 0.4%, the starting concentration of the compound can also be changed according to the actual situation of compound screening. , dilution ratio, number of gradient concentrations and number of duplicate wells.
新鲜人外周血单个核细胞(PBMC)(赛笠生物)以2*10^5的数量铺在96孔板(Corning,3599)中，每孔含有100μL的RPMI-1640(Gibco#A1049101)+10％FBS(Gibco,10099141C),37℃，5％CO2过夜培养；待测化合物已25μL/孔的体积加入96孔培养板中，1h后，加入5μL的LPS，使其终浓度为100ng/mL，阴性对照孔不加LPS及化合物，阳性对照孔中不加化合物，37℃，5％CO2继续培养24h后，500rcf离心8min收集细胞培养上清，按照Elisaa试剂盒中操作手册进行操作，检测TNF-α的浓度。用GraphPad Prism 8软件拟合浓度-效应曲线，并计算50％抑制效果的化合物浓度，即IC50。结果如表2所示。Fresh human peripheral blood mononuclear cells (PBMC) (Sel Bio) were plated in a 96-well plate (Corning, 3599) at a number of 2*10^5, and each well contained 100 μL of RPMI-1640 (Gibco#A1049101)+10 % FBS (Gibco, 10099141C), cultured overnight at 37°C, 5% CO2; the compound to be tested was added to the 96-well culture plate at a volume of 25 μL/well. After 1 hour, 5 μL of LPS was added to make the final concentration 100ng/mL. , no LPS and compounds were added to the negative control wells, and no compounds were added to the positive control wells. After continuing to culture for 24 hours at 37°C and 5% CO 2 , centrifuge at 500 rcf for 8 minutes to collect the cell culture supernatant. Operate and detect according to the operation manual in the Elisaa kit. Concentration of TNF-α. Use GraphPad Prism 8 software to fit the concentration-effect curve, and calculate the compound concentration with 50% inhibitory effect, that is, IC 50 . The results are shown in Table 2.
表2

Table 2

从表2可知，本公开的化合物对人PBMC细胞的TNF-α具有良好的抑制作用。As can be seen from Table 2, the compounds of the present disclosure have good inhibitory effects on TNF-α in human PBMC cells.
以上对本公开技术方案的实施方式进行了示例性的说明。应当理解，本公开的保护范围不拘囿于上述实施方式。凡在本公开的精神和原则之内，本领域技术人员所做的任何修改、等同替换、改进等，均应包含在本申请权利要求书的保护范围之内。 The above has provided an exemplary description of the embodiments of the technical solution of the present disclosure. It should be understood that the protection scope of the present disclosure is not limited to the above-described embodiments. Any modifications, equivalent substitutions, improvements, etc. made by those skilled in the art within the spirit and principles of this disclosure shall be included in the protection scope of the claims of this application.

Claims (30)

  1. 一种如式(I)所示的化合物或其药学上可接受的盐，
    A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
    其中：in:
    X为N或CH；X is N or CH;
    Y为N或CH；Y is N or CH;
    R1、R2、R3和R4相同或不同，且各自独立地选自H、D、卤素、羟基、氨基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基和3至8元环烷基；R 1 , R 2 , R 3 and R 4 are the same or different, and are each independently selected from H, D, halogen, hydroxyl, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkyl Oxygen group, C 1-6 haloalkoxy group, C 1-6 hydroxyalkyl group, cyano group and 3 to 8 membered cycloalkyl group;
    或者R1和R2与其相连的碳原子一起形成3至12元环烷基或3至12元杂环基，所述的3至12元环烷基或3至12元杂环基任选被选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基和羟基中的一个或多个取代基所取代；Or R 1 and R 2 together with the carbon atom to which they are connected form a 3 to 12-membered cycloalkyl group or a 3 to 12-membered heterocyclyl group, and the 3 to 12-membered cycloalkyl group or 3 to 12-membered heterocyclyl group is optionally Substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino and hydroxyl;
    或者R3和R4与其相连的碳原子一起形成3至12元环烷基或3至12元杂环基，所述的3至12元环烷基或3至12元杂环基任选被选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、氨基和羟基中的一个或多个取代基所取代；Or R 3 and R 4 together with the carbon atom to which they are connected form a 3 to 12-membered cycloalkyl group or a 3 to 12-membered heterocyclyl group, and the 3 to 12-membered cycloalkyl group or 3 to 12-membered heterocyclyl group is optionally Substituted with one or more substituents selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, amino and hydroxyl;
    R5选自H、卤素和C1-6烷基；R 5 is selected from H, halogen and C 1-6 alkyl;
    R6选自卤素、C1-6烷基、C1-6卤代烷基和C1-6氘代烷基；R 6 is selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl and C 1-6 deuterated alkyl;
    R0为 R 0 is
    R7选自H、卤素、C1-6烷基、C1-6烷氧基和C1-6卤代烷基；R 7 is selected from H, halogen, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 haloalkyl;
    R8选自H、卤素、C1-6烷基和C1-6卤代烷基；R 8 is selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
    Rt为 R t is
    Z选自O、S和NH；Z is selected from O, S and NH;
    环A为5至6元杂芳基；Ring A is a 5- to 6-membered heteroaryl group;
    R9和R10相同或不同，且各自独立地选自H、D、卤素和C1-6烷基；R 9 and R 10 are the same or different, and are each independently selected from H, D, halogen and C 1-6 alkyl;
    各个R11相同或不同，且各自独立地选自卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；Each R 11 is the same or different, and each is independently selected from halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyl Alkyl, cyano, hydroxyl, amino, nitro and 3 to 8-membered cycloalkyl;
    n选自0、1、2、3和4。n is selected from 0, 1, 2, 3 and 4.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中Z为O。The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is O.
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中环A为吡啶基。The compound according to claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Ring A is pyridyl.
  4. 根据权利要求1至3中任一项所述的化合物或其药学上可接受的盐，其中R1、R2、R3和R4相同或不同，且各自独立地选自H、F、OH、羟甲基、甲基、乙基；The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are the same or different, and each is independently selected from H, F, OH , hydroxymethyl, methyl, ethyl;
    或者R1和R2与其相连的碳原子一起形成环丙基、环丁基、氧杂环丁烷基、环戊基、环己基或四氢-2H-吡喃基，所述的环丙基、环丁基、氧杂环丁烷基、环戊基、环己基、四氢-2H-吡喃基任选被一个或多个F或甲基取代；Or R 1 and R 2 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl or tetrahydro-2H-pyranyl, and the cyclopropyl , cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl are optionally substituted by one or more F or methyl;
    或者R3和R4与其相连的碳原子一起形成环丙基、环丁基、氧杂环丁烷基、环戊基、环己基或四氢-2H-吡喃基；所述的环丙基、环丁基、氧杂环丁烷基、环戊基、环己基、四氢-2H-吡喃基任选被一个或多个F 或甲基取代。Or R 3 and R 4 together with the carbon atoms to which they are connected form cyclopropyl, cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl or tetrahydro-2H-pyranyl; the cyclopropyl , cyclobutyl, oxetanyl, cyclopentyl, cyclohexyl, tetrahydro-2H-pyranyl optionally substituted by one or more F or methyl substitution.
  5. 根据权利要求1至4中任一项所述的化合物或其药学上可接受的盐，其中各个R11相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；n为0、1或2。The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein each R 11 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1-6 Haloalkyl; n is 0, 1 or 2.
  6. 根据权利要求1至5中任一项所述的化合物或其药学上可接受的盐，其中Z为O；环A为吡啶基；各个R11相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；n为0、1或2。The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein Z is O; Ring A is pyridyl; each R 11 is the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1-6 haloalkyl; n is 0, 1 or 2.
  7. 根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐，其为式(II)所示的化合物或其药学上可接受的盐，
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
    其中：in:
    R11a和R11b相同或不同，且各自独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；R 11a and R 11b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 hydroxyalkyl, cyano, hydroxyl, amino, nitro and 3 to 8 membered cycloalkyl;
    R1、R2、R5、R6、R7、R8、R9、R10、X和Y如权利要求1中所定义。R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined in claim 1 .
  8. 根据权利要求1至7中任一项所述的化合物或其药学上可接受的盐，其为式(II-1)或式(II-2)所示的化合物或其药学上可接受的盐，
    The compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (II-1) or formula (II-2) or a pharmaceutically acceptable salt thereof ,
    其中：加粗的化学键表示化合物存在轴手性；Among them: Bold chemical bonds indicate the presence of axial chirality in the compound;
    R1、R2、R5、R6、R7、R8、R9、R10、R11a、R11b、X和Y如权利要求7中所定义。R 1 , R 2 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , X and Y are as defined in claim 7 .
  9. 根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐，其为式(III)所示的化合物或其药学上可接受的盐，
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, which is a compound represented by formula (III) or a pharmaceutically acceptable salt thereof,
    其中：R11a和R11b相同或不同，且各自独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C1-6羟烷基、氰基、羟基、氨基、硝基和3至8元环烷基；Wherein: R 11a and R 11b are the same or different, and each is independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy , C 1-6 hydroxyalkyl, cyano, hydroxyl, amino, nitro and 3 to 8 membered cycloalkyl;
    R3、R4、R5、R6、R7、R8、R9、R10、X和Y如权利要求1中所定义。R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , X and Y are as defined in claim 1 .
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其为式(III-1)或式(III-2)所示的化合物或其药学上可接受的盐，
    The compound according to claim 9 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (III-1) or formula (III-2) or a pharmaceutically acceptable salt thereof,
    其中：加粗的化学键表示化合物存在轴手性；Among them: Bold chemical bonds indicate the presence of axial chirality in the compound;
    R3、R4、R5、R6、R7、R8、R9、R10、R11a、R11b、X和Y如权利要求9中所定义。R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b , X and Y are as defined in claim 9 .
  11. 根据权利要求1至6中任一项所述的化合物或其药学上可接受的盐，其中选自： The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Selected from:
    G1选自O、NR12a或CR13aR14a；G 1 is selected from O, NR 12a or CR 13a R 14a ;
    G2选自O、NR12b或CR13bR14b；G 2 is selected from O, NR 12b or CR 13b R 14b ;
    R12a和R12b相同或不同，且各自独立地选自H或C1-6烷基； R 12a and R 12b are the same or different, and are each independently selected from H or C 1-6 alkyl;
    R13a、R14a、R13b和R14b相同或不同，且各自独立地选自H、卤素、C1-6烷基或C1-6卤代烷基；R 13a , R 14a , R 13b and R 14b are the same or different, and each is independently selected from H, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    p为0、1、2、3或4；p is 0, 1, 2, 3 or 4;
    q为0、1、2、3或4；条件是p和q不同时为0；q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time;
    j为0、1、2、3或4；j is 0, 1, 2, 3 or 4;
    k为0、1、2、3或4；条件是j和k不同时为0。k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time.
  12. 根据权利要求7或8所述的化合物或其药学上可接受的盐，其中选自： The compound according to claim 7 or 8 or a pharmaceutically acceptable salt thereof, wherein Selected from:
    G1选自O、NR12a或CR13aR14a；G 1 is selected from O, NR 12a or CR 13a R 14a ;
    R12a为H或C1-6烷基；R 12a is H or C 1-6 alkyl;
    R13a和R14a相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13a and R 14a are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
    p为0、1、2、3或4；p is 0, 1, 2, 3 or 4;
    q为0、1、2、3或4；条件是p和q不同时为0。q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time.
  13. 根据权利要求9或10所述的化合物或其药学上可接受的盐，其中选自： The compound according to claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein Selected from:
    G2选自O、NR12b或CR13bR14b；G 2 is selected from O, NR 12b or CR 13b R 14b ;
    R12b为H或C1-6烷基；R 12b is H or C 1-6 alkyl;
    R13b和R14b相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13b and R 14b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
    j为0、1、2、3或4；j is 0, 1, 2, 3 or 4;
    k为0、1、2、3或4；条件是j和k不同时为0。k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time.
  14. 根据权利要求1至6任一项所述的化合物或其药学上可接受的盐，其中选自： The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein Selected from:
  15. 根据权利要求7或8所述的化合物或其药学上可接受的盐，其中选自： The compound according to claim 7 or 8 or a pharmaceutically acceptable salt thereof, wherein Selected from:
  16. 根据权利要求9或10所述的化合物或其药学上可接受的盐，其中选自： The compound according to claim 9 or 10 or a pharmaceutically acceptable salt thereof, wherein Selected from:
  17. 根据权利要求1至8、11和12中任一项所述的化合物或其药学上可接受的盐，其为式(IV)或式(V)所示的化合物或其药学上可接受的盐，
    The compound according to any one of claims 1 to 8, 11 and 12 or a pharmaceutically acceptable salt thereof, which is a compound represented by formula (IV) or formula (V) or a pharmaceutically acceptable salt thereof ,
    其中：in:
    G1选自O、NR12a或CR13aR14a；G 1 is selected from O, NR 12a or CR 13a R 14a ;
    R12a为H或C1-6烷基；R 12a is H or C 1-6 alkyl;
    R13a和R14a相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13a and R 14a are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
    p为0、1、2、3或4；p is 0, 1, 2, 3 or 4;
    q为0、1、2、3或4；条件是p和q不同时为0；q is 0, 1, 2, 3 or 4; the condition is that p and q are not 0 at the same time;
    R5、R6、R7、R8、R9、R10、R11a、R11b和X如权利要求7中所定义。R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and X are as defined in claim 7 .
  18. 根据权利要求1至6、9至11和13中任一项所述的化合物或其药学上可接受的盐，其为式(VI)或式(VII)所示的化合物或其药学上可接受的盐，
    The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, 9 to 11 and 13, which is a compound represented by formula (VI) or formula (VII) or a pharmaceutically acceptable salt thereof of salt,
    其中：in:
    G2选自O、NR12b或CR13bR14b；G 2 is selected from O, NR 12b or CR 13b R 14b ;
    R12b为H或C1-6烷基；R 12b is H or C 1-6 alkyl;
    R13b和R14b相同或不同，且各自独立地选自H、卤素、C1-6烷基和C1-6卤代烷基；R 13b and R 14b are the same or different, and are each independently selected from H, halogen, C 1-6 alkyl and C 1-6 haloalkyl;
    j为0、1、2、3或4；j is 0, 1, 2, 3 or 4;
    k为0、1、2、3或4；条件是j和k不同时为0；k is 0, 1, 2, 3 or 4; the condition is that j and k are not 0 at the same time;
    R5、R6、R7、R8、R9、R10、R11a、R11b和X如权利要求9中所定义。R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11a , R 11b and X are as defined in claim 9 .
  19. 根据权利要求11、12和17中任一项所述的化合物或其药学上可接受的盐，其中选自： The compound according to any one of claims 11, 12 and 17 or a pharmaceutically acceptable salt thereof, wherein Selected from:
  20. 根据权利要求11、13和18中任一项所述的化合物或其药学上可接受的盐，其中选自： The compound according to any one of claims 11, 13 and 18 or a pharmaceutically acceptable salt thereof, wherein Selected from:
  21. 根据权利要求1至20中任一项所述的化合物或其药学上可接受的盐，其中X为N。The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein X is N.
  22. 根据权利要求1至21中任一项所述的化合物或其药学上可接受的盐，其中R5为H或F。The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R5 is H or F.
  23. 根据权利要求1至22中任一项所述的化合物或其药学上可接受的盐，其中R6选自卤素、甲基、乙基、三氟甲基、二氟甲基和CD3；优选地，R6选自Cl、F、甲基、乙基、三氟甲基、二氟甲基和CD3。The compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from halogen, methyl, ethyl, trifluoromethyl, difluoromethyl and CD 3 ; preferably Specifically, R 6 is selected from Cl, F, methyl, ethyl, trifluoromethyl, difluoromethyl and CD 3 .
  24. 根据权利要求1至23中任一项所述的化合物或其药学上可接受的盐，其中R7为Cl。The compound according to any one of claims 1 to 23, or a pharmaceutically acceptable salt thereof, wherein R7 is Cl.
  25. 根据权利要求1至24中任一项所述的化合物或其药学上可接受的盐，其中R8选自H、卤素、C1-3烷基或C1-3卤代烷基；优选地，R8选自甲基、乙基和Cl。The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein R 8 is selected from H, halogen, C 1-3 alkyl or C 1-3 haloalkyl; preferably, R 8 is selected from methyl, ethyl and Cl.
  26. 根据权利要求1至25中任一项所述的化合物或其药学上可接受的盐，其中R9和R10相同或不同， 且各自独立地为H或D。The compound according to any one of claims 1 to 25, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 are the same or different, and are each independently H or D.
  27. 根据权利要求7至26中任一项所述的化合物或其药学上可接受的盐，其中R11a和R11b相同或不同，且各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；优选地，R11a和R11b相同或不同，且各自独立地选自F、Cl、甲基、乙基和三氟甲基。The compound according to any one of claims 7 to 26, or a pharmaceutically acceptable salt thereof, wherein R 11a and R 11b are the same or different, and each is independently selected from halogen, C 1-6 alkyl and C 1 -6 haloalkyl; preferably, R 11a and R 11b are the same or different, and each is independently selected from F, Cl, methyl, ethyl and trifluoromethyl.
  28. 根据权利要求1至27中任一项所述的化合物或其药学上可接受的盐，其中所述的化合物选自以下任一化合物，





















    The compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any of the following compounds,





















    优选地，所述的化合物选自以下任一化合物，







    Preferably, the compound is selected from any of the following compounds,







  29. 一种药物组合物，其包括至少一种治疗有效量的根据权利要求1-28任一项所述的化合物或其药学上可接受的盐，以及一种或多种药学上可接受的赋形剂。A pharmaceutical composition comprising at least a therapeutically effective amount of a compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients agent.
  30. 根据权利要求1-28任一项所述的化合物或其药学上可接受的盐、或权利要求29所述的药物组合物，其在制备用作p38激酶抑制剂的药物中的用途；The compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 29, its use in the preparation of a drug used as a p38 kinase inhibitor;
    优选地，其在制备用于预防和/或治疗p38激酶介导的疾病的药物中的用途；Preferably, its use in the preparation of a medicament for the prevention and/or treatment of p38 kinase-mediated diseases;
    更优选地，p38激酶介导的疾病为与p38 MAPK/MK2通路相关的疾病；More preferably, the p38 kinase-mediated disease is a disease related to the p38 MAPK/MK2 pathway;
    优选地，其在制备用于预防和/或治疗自体免疫疾病、炎症性疾病、心血管类疾病、中枢神经***疾病和癌症的药物中的用途；Preferably, its use in the preparation of medicaments for the prevention and/or treatment of autoimmune diseases, inflammatory diseases, cardiovascular diseases, central nervous system diseases and cancer;
    更优选地，其在制备用于预防和/或治疗关节炎、银屑病、***性红斑狼疮、糖尿病、白血病、淋巴瘤、 动脉粥样硬化和阿尔兹海默症的药物中的用途。 More preferably, it is used for the prevention and/or treatment of arthritis, psoriasis, systemic lupus erythematosus, diabetes, leukemia, lymphoma, Use in drugs for atherosclerosis and Alzheimer's disease.
PCT/CN2023/093248 2022-05-12 2023-05-10 Substituted pyridine or pyrimidine derivative, pharmaceutical composition thereof, preparation method, and use WO2023217184A2 (en)

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