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WO2021160132A1 - Composé hétérocyclique, son procédé de préparation et son utilisation - Google Patents

Composé hétérocyclique, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2021160132A1
WO2021160132A1 PCT/CN2021/076311 CN2021076311W WO2021160132A1 WO 2021160132 A1 WO2021160132 A1 WO 2021160132A1 CN 2021076311 W CN2021076311 W CN 2021076311W WO 2021160132 A1 WO2021160132 A1 WO 2021160132A1
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group
membered
formula
compound represented
substituents
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Chinese (zh)
Inventor
栾林波
野国中
唐春兰
陈永凯
王朝东
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Shanghai Meiyue Biotech Development Co Ltd
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Shanghai Meiyue Biotech Development Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • C07—ORGANIC CHEMISTRY
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    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D517/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms
    • C07D517/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having selenium, tellurium, or halogen atoms as ring hetero atoms in which the condensed system contains two hetero rings
    • C07D517/04—Ortho-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the invention relates to a heterocyclic compound and its preparation method and application.
  • PU.1 (Spleen focus forming virus (SFFV)proviral integration oncogene, SPI-1) is a member of the conservative DNA-binding protein ETS (E26transformation-specific) transcriptional regulatory factor family. Because its DNA binding region recognizes the consensus sequence GAGGAA, This area is also called ETS binding area or PU.1box.
  • ETS E26transformation-specific transcriptional regulatory factor family.
  • PU.1box ETS binding area
  • PU.1 is mainly involved in the regulation of intercellular signals, but also involved in the downstream signal transduction of plasma membrane proteins, and many nuclear proteins regulated by PU.1 are themselves important transcription factors.
  • PU.1 can regulate downstream gene networks at multiple levels, and its functions can be roughly divided into three categories: (1) regulating the expression of antibodies, receptors and complement, (2) regulating the proliferation and differentiation of immune cells, and (3) regulating inflammation-related Expression of cytokines and effector enzymes. Recent studies have shown that PU.1 plays an important role in multiple pathological processes.
  • PU.1 plays an important role in regulating the formation and development of fibrosis.
  • fibrotic diseases such as systemic sclerosis
  • excessive activation of connective tissue cells leads to tissue hardening and scarring in the affected organs.
  • these diseases can affect all organ systems in the body and often lead to the destruction and damage of organ functions.
  • Connective tissue cells play a key role in normal wound healing in healthy individuals; however, if the activation of connective tissue cells cannot be turned off or is over-activated, fibrotic diseases will occur.
  • a large amount of matrix is deposited, which causes the affected tissues and organs to form scars and further suffer functional damage.
  • PU.1 is activated in a variety of connective tissues during the pathological process, and then PU.1 binds to the DNA in connective tissue cells to reprogram them, leading to long-term deposition of scar tissue components.
  • PU.1 plays a central role in the factor network that controls this process.
  • In vivo experiments in mice have shown that inhibiting PU.1 can not only prevent the development of fibrosis in various tissues and organs of mice, including skin, lungs, and liver, but also induce the regression of existing fibrosis.
  • PU.1 plays an important role in inflammatory diseases.
  • allelic knockout that PU.1 plays a key role in regulating the differentiation of myeloid cells, especially macrophages and neutrophils; it is believed that PU.1 is the central link in the inflammatory response and has a critical role in immunity. The regulation of function is very important (GenesDev, 2011, 25(2), 101-106).
  • PU.1 can activate many important inflammation-related cytokines and some receptors; for example, it participates in the activation of IL-1b gene.
  • PU.1 can also promote the secretion of IL-9 by T lymphocytes; IL-9 is not only an important lymphocyte growth factor, but also related to the body's allergic inflammatory response. In addition, PU.1 is also involved in regulating the expression of other important inflammatory factors including TNF- ⁇ , IL-18 and IL-12 (Biochem Biophys Res Commun., 2009, 388(1), 102-106; Blood, 2011 , 118(19), 5255-5266).
  • PU.1 can directly affect cell migration and homing by regulating related cytokines, receptors and binding factors.
  • cytokines include chemokines CCL3, CCL5, CXCL9 and related receptors such as CXCR1.
  • PU.1 as an important transcription factor, is also involved in the pathogenesis of Alzheimer's disease (AD). Chromatin immunoprecipitation analysis experiments proved that PU.1 is abundantly present in central nervous system microglia and blood bone marrow cells, and as the expression of PU.1 changes, the expression of AD-related pathogenic genes also Significant changes (NatNeurosci., 2017, 20(8): 1052-1061).
  • PRRs participate in the identification of pathogenic microorganisms, the activation of immune function and the bactericidal effect, and are the initial link of the body's antibacterial immunity.
  • PU.1 participates in the expression regulation of a variety of PRRs, including dectin-1 receptor, Mannose Receptor (MR), Toll-like receptor (TLR) 4, TLR9 and TLR4 costimulatory factors The expression regulation of MD-2 (LY96), etc. (J Biol Chem., 2009, 284(39), 26261-26272). This indicates that PU.1 may be a potential target for diseases related to these targets.
  • PU.1 is involved in regulating the levels of related cytokines and receptors of lymphoid and myeloid cells, enabling immune cells to proliferate and differentiate normally and maintain immune homeostasis. It plays an important role in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
  • ALL acute lymphoblastic leukemia
  • AML acute myeloid leukemia
  • the invention provides a heterocyclic compound and a preparation method and application thereof.
  • the compound of the present invention has the activity of inhibiting PU.1, can inhibit the PU.1-dependent transcription activity based on hepatocytes and inhibit the development of fibrosis.
  • the present invention provides a heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • R 1a , R 1b , R 1c , R 1d , R 1e and R 1f are independently H, halogen or C 1 -C 4 alkyl;
  • R 2a , R 2b , R 2c and R 2d are independently H, OH, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
  • R 2a and R 2b , R 2c and R 2d are connected respectively, and connected to it Together to form a 5-6 membered heterocycloalkenyl group, in the 5-6 membered heterocycloalkenyl group, except In addition to the two Ns, it also includes 0 or 1 heteroatoms selected from N, O or S, and the rest are carbon;
  • X is Ring A and ring B are connected in parallel; ring C and Parallel connection;
  • Ring A is a phenyl group or a 5-6 membered heteroaryl group; in the 5-6 membered heteroaryl group, the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1 to 3.
  • the phenyl group and the 5-6 membered heteroaryl group are optionally substituted by one or more substituents R 3a , and the R 3a is independently selected from the following substituents: halogen or C 1 -C 4 alkyl; when there are multiple substituents, they are the same or different;
  • Ring B is a 5-6 membered heteroaryl group, a 5-6 membered heterocycloalkenyl group, a C 4 -C 6 cycloalkyl group or a 5-6 membered heterocycloalkyl group; the 5-6 membered heteroaryl group, the In the 5-6 membered heterocycloalkenyl group and the 5-6 membered heterocycloalkyl group, the heteroatom is selected from one or more of N, O, S, Se and Te, and the number of heteroatoms is 1.
  • the 5-6 membered heteroaryl group is optionally substituted by one or more substituents R 3b , and the R 3b is independently selected from the following substituents: halogen or C 1 -C 4 alkyl;
  • Ring C is phenyl, 5-6 membered heteroaryl, 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl or 5-10 membered heterocycloalkyl; said 5-6 membered heteroaryl and In the 5-10 membered heterocycloalkyl group, the heteroatoms are selected from one or more of N, O and S, and the number of heteroatoms is 1 to 3; the phenyl group and the 5- The 6-membered heteroaryl group is optionally substituted by one or more substituents R 3d , and said R 3d is independently selected from the following substituents: halogen or C 1 -C 4 alkyl; said 5-10 membered cycloalkane Group, 5-10 membered cycloalkenyl group and 5-10 membered heterocycloalkyl group are optionally substituted by one or more substituents R 3e , and said R 3e is independently selected from the following substituents: halogen, C 1 -C 4
  • Z 3 is N(R h ), O, S, Se or Te;
  • R f , R g and R h are independently H or C 1 -C 4 alkyl
  • R 1a , R 1b , R 1c , R 1d , R 1e and R 1f are independently H;
  • R 2a , R 2b , R 2c and R 2d are independently H, OH, C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl;
  • Ring A is phenyl or 6-membered heteroaryl
  • Ring B is a 5-6 membered heteroaryl group, a 5-6 membered heterocycloalkenyl group, a C 4 -C 6 cycloalkyl group or a 5-6 membered heterocycloalkyl group; the 5-6 membered heterocycloalkenyl group is any Optionally substituted by one or more substituents R 3c ;
  • Ring C is a phenyl group, a 5-10 membered cycloalkyl group, a 5-10 membered cycloalkenyl group or a 5-10 membered heterocycloalkyl group; the phenyl group is optionally substituted by one or more substituents R 3d ;
  • the 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl and 5-10 membered heterocycloalkyl are optionally substituted by one or more substituents R 3e ;
  • Z 3 is NH, O, S or Se.
  • R 1a , R 1b , R 1c , R 1d , R 1e and R 1f are independently H;
  • R 2a , R 2b , R 2c and R 2d are independently H;
  • Ring A is phenyl or 6-membered heteroaryl
  • Ring B is a 5-6 membered heteroaryl group or a 5-6 membered heterocycloalkenyl group; the 5-6 membered heterocycloalkenyl group is optionally substituted by one or more substituents R 3c ;
  • Ring C is a phenyl group, a 5-10 membered cycloalkyl group, a 5-10 membered cycloalkenyl group or a 5-10 membered heterocycloalkyl group; the phenyl group is optionally substituted by one or more substituents R 3d ;
  • the 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl and 5-10 membered heterocycloalkyl are optionally substituted by one or more substituents R 3e ;
  • Z 1 is N (R f ), O or S;
  • Z 2 is O, S or Se;
  • Z 3 is N (R h ), O, S or Se.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when R 2a , R 2b , When R 2c and R 2d are independently C 1 -C 4 alkyl, the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl or tert-butyl; for example isopropyl.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when R 2a , R 2b , When R 2c and R 2d are independently C 3 -C 6 cycloalkyl, the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; for example, cyclopropyl.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when R 2a and R 2b , R 2c and R 2d are connected independently, and connected to it When a 5-6 membered heterocycloalkenyl group is formed together, the 5-6 membered heterocycloalkenyl group is
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when ring A is a 6-membered hetero
  • the heteroatom is selected from N, and the number of heteroatoms is 1 to 2; for example (E.g ), (E.g )or (E.g ).
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when B is 5-6 yuan
  • the 5-6 membered heteroaryl is (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g )or (E.g ).
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when B is 5-6 yuan
  • B is 5-6 yuan
  • the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1 to 2; for example, (E.g ), (E.g ), (E.g ).
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when B is C 4 -C In the case of 6 cycloalkyl, the C 4 -C 6 cycloalkyl is cyclobutyl, cyclopentyl or cyclohexyl, such as cyclohexyl.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when B is 5-6 yuan
  • the heteroatom in the 5-6 membered heterocycloalkyl, the heteroatom is selected from one or more of N, O, S and Se, and the number of heteroatoms is 1 to 2; for example, (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g )or (E.g ).
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when ring C is 5-10
  • the 5-10 membered cycloalkyl group is a cyclopentyl group or a cyclohexyl group, for example, a cyclohexyl group.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when ring C is 5-10 In the case of a membered cycloalkenyl group, the 5-10 membered cycloalkenyl group is a 5-10 membered bridged cycloalkenyl group, for example (a side and And ring connection).
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when ring C is 5-10
  • the 5-10 membered heterocycloalkyl group is a 5-6 membered heterocycloalkyl group, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms 1 to 2; for example (a side and And ring connection).
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when R 3d is halogen, the halogen is fluorine, chlorine, bromine or iodine, such as fluorine or chlorine.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when R 3e is C 1-
  • the C 1 -C 4 alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; for example, methyl .
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when R f , R g and When R h is independently a C 1 -C 4 alkyl group, the C 1 -C 4 alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl Or tert-butyl; for example, methyl.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), R 1a , R 1b , R 1c , R 1d , R 1e and R 1f are independently H.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), and The same or different, preferably the same.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), R 2a , R 2b , R 2c and R 2d are independently H (i.e. for ).
  • certain groups in the compound represented by formula I are defined as follows (the undefined groups are the same as those described in any of the schemes of this application), and X is Among them, ring A is phenyl or 6-membered heteroaryl; ring B is 5-6 membered heteroaryl, 5-6 membered heterocycloalkenyl, C 4 -C 6 cycloalkyl or 5-6 membered heterocycloalkane base;
  • ring B is a 5-6 membered heteroaryl group or a 5-6 membered heterocycloalkenyl group; the 5-6 membered heterocycloalkenyl group is optionally substituted by one or more substituents R 3c .
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when X is When the said Selected from:
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), R f is H or C 1 -C 4 alkyl.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when X is Hour, Selected from:
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when X is Hour, for:
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), and Z 3 is N(R h ), O, S or Se; Ring C is a phenyl group, a 5-10 membered cycloalkyl group, a 5-10 membered cycloalkenyl group or a 5-10 membered heterocycloalkyl group; the phenyl group may be optionally substituted by one or more One substituent R 3d is substituted; the 5-10 membered cycloalkyl, 5-10 membered cycloalkenyl and 5-10 membered heterocycloalkyl are optionally substituted by one or more substituents R 3e .
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), Z 3 is N(R h ), O, S, or Se.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), and ring C is phenyl, 5 -10 membered cycloalkyl, 5-10 membered cycloalkenyl or 5-10 membered heterocycloalkyl.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), and R h is H.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), and R 3d is halogen.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when X is Hour, for:
  • X is Hour
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), Including its tautomers Or its mixture.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when X is Hour, and Are tautomers between each other; for example, and Between each other are tautomers.
  • certain groups in the compound represented by formula I are defined as follows (undefined groups are the same as those described in any of the schemes of this application), when X is When the said It can be a tautomer or a mixture of the following groups:
  • heterocyclic compound represented by formula I is selected from the following compounds:
  • the pharmaceutically acceptable salt of the heterocyclic compound represented by formula I is selected from the following compounds:
  • the heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof may have one or more chiral carbon atoms, so optically pure isomers, such as pure enantiomers, can be separated. Isomers, or racemates, or mixed isomers.
  • the pure single isomer can be obtained by separation methods in the art, such as chiral crystallization into a salt, or chiral preparation column separation.
  • the heterocyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof may exist in a crystalline or amorphous form.
  • crystal form means that the ions or molecules are arranged strictly and periodically in a three-dimensional space in a certain way, and have the regularity of periodic recurrence at a certain distance; due to the above-mentioned periodic arrangement, there may be multiple Crystal form, that is, polymorphism.
  • amorphous means that the ions or molecules present in a disorderly distribution state, that is, there is no periodic arrangement between the ions and molecules.
  • the heterocyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof, if there are stereoisomers can be used as a single stereoisomer or a mixture thereof (such as a racemate).
  • stereoisomer refers to cis-trans isomers or optical isomers.
  • stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.).
  • asymmetric synthesis methods or chiral separation methods including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.
  • chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • the heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof may exist in the form of a single tautomer or a mixture thereof, It preferably exists in the form of relatively stable tautomers.
  • the present invention also includes isotopically labeled heterocyclic compounds of formula I according to the present invention or pharmaceutically acceptable salts thereof, in which one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. replace.
  • isotopes that can be incorporated into the compounds of the present invention include, but are not limited to, isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, sulfur and chlorine (e.g. 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 35 S and 36 Cl).
  • Isotopically labeled compounds of the present invention can be used for the determination of the tissue distribution of compounds and their prodrugs and metabolites; preferred isotopes for such determinations include 3 H and 14 C.
  • preferred isotopes for such determinations include 3 H and 14 C.
  • substitution with heavier isotopes such as deuterium (2H or D) can provide increased metabolic stability, which provides therapeutic advantages such as increased in vivo half-life or reduced dosage requirements.
  • the isotopically-labeled compounds of the present invention can generally be prepared according to the methods described herein by substituting isotopically-labeled reagents for non-isotopically-labeled reagents.
  • the heterocyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof can be synthesized by a method similar to a method known in the chemical field, and its steps and conditions can be referred to the steps and conditions of similar reactions in the art. Conditions, especially the synthesis according to the instructions in this article.
  • the starting materials are usually from commercial sources, such as Aldrich or can be easily prepared using methods known to those skilled in the art (obtained through SciFinder, Reaxys online databases).
  • the heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof can also be obtained by preparing the heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof. Using conventional methods in the art, peripheral modification can be used to obtain other heterocyclic compounds represented by formula I or pharmaceutically acceptable salts thereof.
  • the necessary raw materials or reagents for preparing the heterocyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof can be obtained commercially, or prepared by synthetic methods known in the art.
  • the compound of the present invention can be prepared as the free base or the salt formed by adding an acid by the method described in the following experimental part.
  • the term pharmaceutically acceptable salt refers to a pharmaceutically acceptable salt as defined herein, and has all the pharmacological activities of the parent compound.
  • the pharmaceutically acceptable salt can be prepared by adding the corresponding acid in a suitable organic solvent of the organic base, and processing according to a conventional method.
  • salt formation examples include: salt formation with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; and salts formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, Ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, malonic acid, almonds Acid, methanesulfonic acid, mucofuroic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid or trimethylacetic acid.
  • inorganic acids such
  • the present invention also provides a method for preparing the heterocyclic compound represented by formula I as described above, when R 1a and R 1d are the same, R 1b and R 1e are the same, R 1c and R 1f are the same, and R 2a and R are the same.
  • R 1a and R 1d are the same
  • R 1b and R 1e are the same
  • R 1c and R 1f are the same
  • R 2a and R are the same.
  • R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 2a , R 2b , R 2c , R 2d and X are as defined above.
  • the conditions and operations of the addition reaction shown can be the conventional conditions and operations in this type of reaction in the art; in the present invention, the following are preferred:
  • the solvent can be an alcohol solvent (for example, ethanol).
  • the amount of the solvent does not need to affect the reaction.
  • the molar volume ratio of the compound represented by formula II to the solvent is 0.01-0.1 mol/L (for example, 0.05 mol/L).
  • the molar ratio of the compound represented by formula II to the compound represented by formula III is 2-2.2 (for example, 2-2.1).
  • the molar ratio of the benzoquinone to the compound represented by formula II is 1-1.2 (for example, 1-1.1).
  • the addition reaction is preferably carried out under gas protection; the gas can be argon and/or nitrogen.
  • the temperature of the addition reaction may be 60°C-90°C (for example, 78°C-80°C).
  • the progress of the addition reaction can be detected by conventional monitoring methods in the art (for example, TLC, HPLC, or NMR). Generally, the end of the reaction is when the compound represented by formula II disappears or no longer reacts.
  • the reaction time can be 1-48 hours, for example 12-30 hours.
  • the preparation method may also include post-treatment; the post-treatment may include the following steps: after the addition reaction is completed, an organic solvent is added to precipitate a solid to obtain the heterocyclic compound represented by formula I That's it.
  • the present invention also provides a pharmaceutical composition, which comprises the heterocyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • the heterocyclic compound represented by Formula I or a pharmaceutically acceptable salt thereof may be a therapeutically effective amount.
  • the present invention also provides an application of the above heterocyclic compound as shown in formula I or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition or compound 80 or a salt thereof as shown below in the preparation of a PU.1 inhibitor ;
  • the present invention also provides a heterocyclic compound as shown in formula I or a pharmaceutically acceptable salt thereof, the above-mentioned pharmaceutical composition or compound 80 or a salt thereof as shown below in the preparation of prevention and/or treatment and PU. 1
  • the diseases related to PU.1 are preferably one or more of tumors, fibrotic diseases, inflammatory diseases, autoimmune diseases, infectious diseases, intestinal endotoxemia and neurodegenerative diseases;
  • the present invention also provides an application of the above heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, the above pharmaceutical composition, or compound 80 or a salt thereof as shown below in the preparation of medicines.
  • the drug is preferably one or more drugs for preventing and/or treating tumors, fibrotic diseases, inflammatory diseases, autoimmune diseases, infectious diseases, intestinal endotoxemia and neurodegenerative diseases ;
  • the present invention also provides a method for treating one or more of tumors, fibrotic diseases, inflammatory diseases and autoimmune diseases, infectious diseases, intestinal endotoxemia and neurodegenerative diseases, which Including administering to the patient a therapeutically effective amount of the above heterocyclic compound represented by formula I or a pharmaceutically acceptable salt thereof, the above pharmaceutical composition or the compound 80 shown below or a salt thereof;
  • the above-mentioned tumors include but are not limited to: lung cancer, colon cancer, rectal cancer, breast cancer, prostate cancer, liver cancer, pancreatic cancer, brain cancer, kidney cancer, ovarian cancer, stomach cancer, skin cancer, bone cancer, glioma, glue Plasmoblastoma, hepatocellular carcinoma, papillary renal cancer, head and neck cancer, leukemia, lymphoma, myeloma, multiple myeloma and other solid tumors and hematological tumors; especially acute lymphocytic leukemia and acute myeloid leukemia and bone cancer .
  • fibrotic diseases include but are not limited to: systemic sclerosis (cutaneous scleroderma and diffuse cutaneous scleroderma) ⁇ systemic sclerosis (I ⁇ m ⁇ ted cutaneous scleroderma and d ⁇ ffuse cutaneous scleroderma) ⁇ , pulmonary fibrosis, renal Fibrosis, hepatic cirrhosis, non-alcoholic steatohepatitis (NASH), alcoholic steatohepatitis, non-alcoholic fatty liver disease, NAFLO ), renal fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, vascular sclerosis, chronic graft-versus host disease , Crohn's disease, colitis ulcerosa, collagenous colitis, arthritis, myelofibrosis, ureteral disease (Oupuytren's disease), kidney origin Nephrogenic systemic fibrosis, atherosclerosis, restenosis, cardiac fibrosis,
  • autoimmune diseases and inflammatory diseases include but are not limited to: rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, psoriasis, perfusion injury after ischemia, contact dermatitis, inflammatory bowel Disease (inflammatory bowel disease), giant cell arteritis (giant cell arteritis), chronic inflammatory lung disease (rheumatoid arthritis), eczema, asthma (asthma), psoriasis, ulcerative colitis, acute respiratory distress syndrome, silver Squamous arthritis, infectious arthritis, progressive chronic arthritis, deformed arthritis, femoral arthritis, traumatic arthritis, gouty arthritis, Reiter's syndrome, polychondritis, acute synovium Inflammation and spondylitis, glomerulonephritis, hemolytic anemia, aplastic anemia, idiopathic thrombocytopenia, neutropenia, ulcerative colitis, Crohn's disease, graft
  • the "compounds" of the present invention may include all possible stereoisomers, geometric isomers, tautomers and isotopic isomers.
  • stereoisomer refers to cis-trans isomers or optical isomers. These stereoisomers can be separated, purified and enriched by asymmetric synthesis methods or chiral separation methods (including but not limited to thin layer chromatography, rotation chromatography, column chromatography, gas chromatography, high pressure liquid chromatography, etc.), and can also be obtained by It can be obtained by chiral resolution by forming bonds with other chiral compounds (chemical bonding, etc.) or salting (physical bonding, etc.).
  • single stereoisomer means that the mass content of one stereoisomer of the compound of the present invention relative to all stereoisomers of the compound is not less than 95%.
  • the “compounds” of the present invention can exist in the form of single tautomers or their mixtures, preferably in the form of relatively stable tautomers.
  • the tautomeric form is derived from the exchange of a single bond with an adjacent double bond and together with the migration of a proton.
  • the atoms in the "compounds” of the present invention may exist in the form of their natural abundance or non-natural abundance. Taking the hydrogen atom as an example, the form of its natural abundance means that about 99.995% of it is protium and about 0.015% is deuterium; the form of its unnatural abundance means that about 95% of it is deuterium. That is, one or more of the atoms in the terms “compound”, “pharmaceutically acceptable salt”, “solvate” and “solvate of pharmaceutically acceptable salt” may be in unnatural abundance. Atom that exists in form.
  • pharmaceutically acceptable means that salts, solvents, excipients, etc. are generally non-toxic, safe, and suitable for use by patients.
  • the "patient” is preferably a mammal, more preferably a human.
  • pharmaceutically acceptable salt refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid.
  • the acid addition can be obtained by contacting the neutral form of the compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent.
  • the pharmaceutically acceptable acids include inorganic acids, and the inorganic acids include but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate Root, phosphorous acid, sulfuric acid, hydrogen sulfate, etc.
  • the pharmaceutically acceptable acids include organic acids, including but not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , Tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluconic acid, sugar acid, formic acid, ethanesulfonic acid, pamoic acid (i.e.
  • Treatment means any treatment of diseases in mammals, including: (1) preventing diseases, that is, the symptoms that cause clinical diseases do not develop; (2) inhibiting diseases, that is, preventing the development of clinical symptoms; (3) alleviating diseases, That is to cause the disappearance of clinical symptoms.
  • Effective amount means that when the compound is administered to a patient in need of treatment, the amount is sufficient to (i) treat a related disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease or condition, or (iii) Delay the onset of one or more symptoms of a particular disease or condition described herein.
  • the amount corresponding to the amount of the heterocyclic compound represented by formula I or its pharmaceutically acceptable salt or the pharmaceutical composition as described above will be based on, for example, the specific compound, the disease condition and its severity, and the need for treatment The patient's characteristics (for example, weight) and other factors vary, but nonetheless can still be routinely determined by those skilled in the art.
  • prevention in the present invention refers to the reduction of the risk of acquiring or developing a disease or disorder.
  • the "pharmaceutical composition” in the present invention refers to a preparation of one or more compounds of the present invention or their salts and a carrier generally accepted in the art for delivering biologically active compounds to organisms (such as humans).
  • the purpose of the pharmaceutical composition is to facilitate administration and delivery to organisms.
  • pharmaceutically acceptable carrier refers to a substance that is co-administered with the active ingredient and facilitates the administration of the active ingredient, including but not limited to those acceptable for use in humans or animals approved by the State Food and Drug Administration (such as livestock) any glidant, sweetener, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersant, disintegrant, suspending agent, stabilizer , Isotonic agent, solvent or emulsifier. Examples include, but are not limited to, calcium carbonate, calcium phosphate, various sugars and various starches, cellulose derivatives, gelatin, vegetable oils, and polyethylene glycols.
  • the pharmaceutical composition of the present invention can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders, granules, ointments, emulsions, suspensions, solutions, suppositories, injections, Inhalants, gels, microspheres and aerosols, etc.
  • the pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing method, dissolution method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • the administration route of the compound of the present invention or its pharmaceutically acceptable salt or its pharmaceutical composition includes but not limited to oral, rectal, transmucosal, enteral administration, or topical, transdermal, inhalation, parenteral , Sublingual, intravaginal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, and intravenous administration.
  • the preferred route of administration is oral administration.
  • the pharmaceutical composition can be formulated by mixing the active compound with a pharmaceutically acceptable carrier well known in the art.
  • a pharmaceutically acceptable carrier well known in the art.
  • These carriers enable the compound of the present invention to be formulated into tablets, pills, lozenges, sugar coatings, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • tablets can be obtained by combining the active ingredient with one or more solid carriers, granulating the resulting mixture if necessary, and adding a small amount of excipients if necessary Processed into mixtures or granules to form tablets or tablet cores.
  • the tablet core can be combined with coating materials that are optionally suitable for enteric dissolution, and processed into a coating preparation form that is more conducive to absorption by organisms (such as humans).
  • C 1 -C 6 alkyl refers to alkyl groups having a total of 5 or 6 carbon atoms as defined below.
  • the total number of carbon atoms in the simplified notation does not include the carbons that may be present in the substituents of the group.
  • the numerical range defined in the substituents such as 0 to 4, 1-4, 1 to 3, etc., indicates an integer within the range, for example, 1-6 is 1, 2, 3, 4, 5, 6.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, including deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable .
  • substituted means that one or more hydrogen atoms in a given structure are replaced by a specific substituent. Further, when the group is substituted by one or more of the substituents, the substituents are independent of each other, that is, the one or more substituents may be different from each other or the same of. Unless otherwise indicated, a substituent group can be substituted at each substitutable position of the substituted group. When more than one position in the given structural formula can be substituted by one or more substituents selected from specific groups, then the substituents can be substituted at each position with the same or different substitutions.
  • C 1 ⁇ C 6 alkyl or “C 1 ⁇ C 6 alkyl” particularly refers to independently disclosed methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 Alkyl;
  • C 1-4 alkyl specifically refers to independently disclosed methyl, ethyl, C 3 alkyl (ie propyl, including n-propyl and isopropyl), C 4 alkyl (ie butyl, Including n-butyl, isobutyl, sec-butyl and tert-butyl).
  • halogen refers to fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.
  • alkyl refers to a linear or branched saturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms.
  • C 1 -C 20 alkyl preferably C 1 -C 6 alkyl, such as methyl, ethyl, propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl) , Sec-butyl or tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl), n-hexyl, 2-methylhexyl, etc.
  • cycloalkyl refers to a saturated monocyclic or polycyclic carbocyclic substituent composed only of carbon atoms and hydrogen atoms, and which can be connected to the rest of the molecule through a single bond via any suitable carbon atom; In the case of multiple rings, it may be a combined ring system, a bridged ring connection, or a spiro ring connection (that is, two geminal hydrogens on the carbon atom are replaced by an alkylene group), a bridged ring system, or a spiro ring system.
  • a typical monocyclic cycloalkyl group such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkenyl refers to a monocyclic or polycyclic carbocyclic substituent containing an unsaturated double bond, and it can be connected to the rest of the molecule through a single bond via any suitable carbon atom; when it is polycyclic, it can be It is a fused ring system, a bridged ring system, or a spiro ring system in which the two geminal hydrogens on the carbon atom are replaced by an alkylene group, which is a fused ring connection, a bridged ring connection, or a spiro ring connection.
  • a typical bridged cycloalkenyl group such as
  • heterocycloalkyl refers to a saturated cyclic group with heteroatoms, containing one or more heteroatoms independently selected from the group consisting of N, O, S, Se and Te, and the rest are stable 3 carbon atoms.
  • a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or more cyclic ring system, which may include and Cyclic (fused), bridged (bridged) or spiro ring systems (e.g. bicyclic systems ("bicyclic heterocycloalkyl").
  • the heterocycloalkyl bicyclic ring system can be in one Or include one or more heteroatoms in both rings; and are saturated.
  • Exemplary 3-membered heterocyclyl groups include, but are not limited to, aziridinyl, oxiranyl, and thiolanyl , Or its stereoisomers;
  • exemplary 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, propylene oxide, thietane, or its isomers and Stereoisomers;
  • exemplary 5-membered heterocyclyl groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidine Group, imidazolidinyl, pyrazolidinyl, dioxolane, oxathiofuranyl, dithio
  • Exemplary 6-membered heterocyclyl groups include, but are not limited to, piperidinyl, tetrahydropyranyl, cyclopentyl sulfide, morpholinyl, thiomorpholinyl, dithianyl, dioxanyl, piperazinyl, triazinyl , Or its isomers and stereoisomers;
  • exemplary 7-membered heterocyclyl groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl, And diazacycloheptyl, or its isomers and stereoisomers.
  • heterocycloalkyl is a 5-6 membered heterocycloalkyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, or 3. .
  • heterocycloalkenyl refers to a cyclic group with heteroatoms and unsaturated double bonds, containing one or more heteroatoms independently selected from N, O, S, Se and Te, and the rest are composed of carbon
  • a heterocycloalkenyl group may be monocyclic ("monocyclic heterocycloalkenyl"), or a bicyclic, tricyclic or more cyclic ring system, which may include and Cyclic (fused), bridged (bridged) or spiro ring systems (e.g., bicyclic systems ("bicyclic heterocycloalkenyl").
  • the heterocycloalkenyl bicyclic ring system can be in one Or two rings include one or more heteroatoms; and at least one ring contains unsaturated double bonds. In a certain scheme, it typically contains one or more independently selected from N, O, S, Se and Te heteroatom of 5-6 membered monocyclic heterocyclic group, for example In a certain scheme, "heterocycloalkenyl” is a 5-6 membered heterocycloalkenyl, wherein the heteroatom is selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, or 3. .
  • aryl refers to a full-carbon aromatic group with a fully conjugated ⁇ -electron system, which can be a single ring or a condensed ring, usually having 6-14 carbon atoms, preferably 6-12 carbon atoms, most It preferably has 6 carbon atoms.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to an aromatic group containing heteroatoms, which can be a single ring or a condensed ring, preferably containing 1-4 5-12 membered heteroaromatic groups independently selected from N, O, S, Se and Te Groups, including but not limited to pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl, iso Quinolinyl, triazolyl, tetrahydropyrrolyl, selenophene (selenophene, for example ) Tellurophene (tellurophene, for example ).
  • a 5-6 membered monocyclic heteroaryl group containing one or more heteroatoms independently selected from N, O, S, Se and Te for example (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g ), (E.g )or (E.g ).
  • the "heteroaryl group” is a 5-6 membered heteroaryl group, wherein the heteroatom is selected from one or more of N, O, and S, and the number of heteroatoms is 1, 2, or 3.
  • part refers to specific fragments or functional groups in a molecule.
  • the chemical moiety is generally considered to be a chemical entity embedded or attached to a molecule.
  • substituents When the listed substituents do not indicate through which atom they are connected to the compounds included in the general formula of the chemical structure but are not specifically mentioned, such substituents may be bonded through any of its atoms. Combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking substituents are described.
  • the Markush variables listed for the group should be understood as the linking group.
  • the Markush group definition of the variable lists “alkyl” or “aryl” it should be understood that the “alkyl” or “aryl” respectively represents the attached Alkylene group or arylene group.
  • alkyl group when an alkyl group is clearly expressed as a linking group, then the alkyl group represents a linked alkylene group, for example, the group "halo-C 1 -C 6 alkane
  • the C 1 -C 6 alkyl group in "radical” should be understood as a C 1 -C 6 alkylene group.
  • the present invention adopts traditional methods of mass spectrometry and elemental analysis, and the steps and conditions can refer to the conventional operating steps and conditions in the art.
  • the present invention adopts standard nomenclature and standard laboratory procedures and techniques of analytical chemistry, synthetic organic chemistry and optics. In some cases, standard techniques are used for chemical synthesis, chemical analysis, and performance testing of light-emitting devices.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive and progressive effect of the present invention is that the compound provided by the present invention has the activity of inhibiting PU.1, can inhibit the PU.1-dependent transcription activity based on hepatocytes and inhibit the development of fibrosis.
  • the raw material 4-nitrile-2-nitroaniline (5.0g, 31.0mmol) was added to anhydrous dioxane (75mL) and anhydrous methanol (25mL); the temperature of the system was reduced to 0°C, at this temperature Fill the system with hydrochloric acid gas down until the system is saturated. Then the filling of hydrochloric acid gas was stopped, and the reaction was naturally raised to room temperature and stirred at room temperature for 5 days. After the reaction, the temperature of the reaction system was lowered to 0-5°C, filtered under the protection of dry nitrogen, and the filter cake was washed with a small amount of anhydrous ether several times, and then collected to obtain a yellow solid.
  • the raw material 3-hydroxy-4-iodo-benzoic acid methyl ester (10g, 35.9mmol), raw material 1 triethyl orthoformate (5.7ml, 40.0mmol), triphenylphosphine palladium acetate (538mg , 0.72mmol), cuprous iodide (273mg, 1.4mmol) and piperidine (3.94ml, 40.0mmol) were added to dimethylformamide (50mL), the reaction was heated to 45 °C and carried out for 6 hours, and then The reaction temperature was lowered to room temperature and reacted overnight.
  • reaction solution was diluted with 250 mL of ethyl acetate and washed with 50% saturated 1:1 sodium chloride/sodium bicarbonate (4 ⁇ 100 mL).
  • the organic phase was dried with anhydrous sodium sulfate, filtered, and the crude intermediate 1 was concentrated.
  • the raw material 6-bromo-2-methyl-benzo[b]thiophene (691mg, 3.05mmol) was dissolved in anhydrous tetrahydrofuran (2mL), and the solution was then slowly added dropwise to isopropyl bromide at -25°C In tetrahydrofuran (1M, 3.35 mL). After the dropwise addition, the reaction was continued to stir at -25°C for 30 minutes, and then anhydrous nitrogen, nitrogen-dimethylformamide (0.3 mL, 3.91 mmol) was added dropwise to the reaction. The reaction was naturally warmed to room temperature, and the reaction was over after about 1 hour.
  • the reaction was quenched by adding 1 mL of saturated aqueous ammonium chloride solution, 10 mL of ethyl acetate was added, and the organic phase was separated. The aqueous phase was extracted twice with ethyl acetate (2 mL) and used Drying with anhydrous sodium sulfate, filtering and concentration under reduced pressure to obtain crude intermediate 1.
  • n-butyl selenium lithium (9.2 mL, 1.05 mmol) (reference for the preparation method of n-butyl selenium lithium: Tetrahedron 74(2018) 3748-3754) was slowly added dropwise to Intermediate 2 (2.1g, 8.73mmol) ) In anhydrous tetrahydrofuran (30 mL) solution, the reaction was carried out at this temperature for 0.5 hours.
  • reaction solution was directly concentrated, and the phases were separated in ethyl acetate (40 mL) and water (5 mL).
  • the aqueous phase was extracted twice with ethyl acetate (5 mL), and the organic phases were combined and washed with saturated brine (4 mL) , Drying, filtering, and concentrating under reduced pressure to obtain crude intermediate 6.
  • the raw material 6-bromo-2-methylbenzo[d]oxazole (538mg, 2.54mmol) was dissolved in anhydrous tetrahydrofuran (1mL), and the solution was then slowly added dropwise to isopropyl bromide at -25°C In tetrahydrofuran (1M, 2.79 mL). After the dropwise addition, the reaction was continued to stir at -25°C for 30 minutes, and anhydrous N,N-dimethylformamide (0.24 mL, 3.05 mmol) was added dropwise to the reaction. The reaction was naturally warmed to room temperature, and the reaction was completed after about 1 hour, and the reaction was quenched by adding 1 mL of saturated aqueous ammonium chloride solution.
  • SPR detection uses a 4-channel Biacore T200 optical biosensing system (GE).
  • GE 4-channel Biacore T200 optical biosensing system
  • the 5'end biotin-labeled hairpin structure DNA is immobilized on the CM4 chip.
  • the PU.1 protein solution was injected at a constant concentration of 100nM to saturate the DNA binding site, and then different concentrations of the compound were added to the protein solution.
  • the experiment used Na 2 HPO 4 (PH7.4, Containing 0.05% P20, 400 mM sodium chloride and 1 mM ethylene diamine tetraacetic acid) at 25 °C suction filtration, the analysis in the steady state binding state uses different concentrations of compounds as the mobile phase injected and passed through the solidified DNA surface, the flow rate is 30 ⁇ L/min. To alter protein signal corresponding compound concentration was plotted, a protein concentration of compound inhibiting the signal corresponding to 50% as IC 50.
  • the ⁇ B site issuance structure is as follows:
  • the biological data of the compounds of the present invention in inhibiting PU.1 are as follows:
  • the compounds of the present invention can effectively bind to hairpin DNA at concentrations below 10 ⁇ M in vitro, thereby inhibiting PU.1. Most of the compounds have IC 50 lower than 100 nM, and some compounds have IC 50 lower than 10 nM.
  • the full-length plasmid expressing PU.1 was cloned at the NheI/BamHI site of pcNDA3.1(+).
  • the CMV promoter of the commercial green fluorescent protein (EGFP) reporter gene plasmid was replaced by a synthetic enhancing element combinator of the liver tandem repeat ⁇ B site, separated by the spiral part, connected by the smallest TATA box promoter.
  • PU.1 expression and EGFR reporter plasmids were named pcDNA-FL-PU.1 and p ⁇ B 5-EGFP, respectively.
  • HEK293 cells were cultured in RPM1 1680 medium containing 10% fetal bovine serum, and the culture condition was 5% CO 2 .
  • mice Male C57 mice aged 6-8 weeks, blank group, model group (vehicle administration group), and administration group. Each group has 6 animals. The first day is the initial administration of bleomycin, and the blank group is not given the injection. The injection is administered to mice at a concentration of 4mg/kg and 1mg/ml every day for 3 Zhou, the model was simultaneously given the test compound. No test compound was given to the blank group and model group (vehicle group). The mice were sacrificed on the 22nd day, and lung tissues were taken and fixed with paraformaldehyde. After alcohol gradient dehydration, xylene was transparent, it was embedded in paraffin, stained with 0.1% Sirius red, and observed with an optical microscope at 100 times.

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Abstract

La présente invention concerne un composé hétérocyclique, son procédé de préparation et son utilisation. La présente invention concerne un composé hétérocyclique tel que représenté dans la formule I ou un sel pharmaceutiquement acceptable de celui-ci. Le composé a une activité d'inhibition de PU.1 et peut inhiber l'activité transcriptionnelle dépendante de PU.1 basée sur l'hépatocyte et inhiber le développement de fibrose.
PCT/CN2021/076311 2020-02-14 2021-02-09 Composé hétérocyclique, son procédé de préparation et son utilisation Ceased WO2021160132A1 (fr)

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