WO2023227118A1 - 3c-like protease inhibitor - Google Patents

3c-like protease inhibitor Download PDF

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Publication number
WO2023227118A1
WO2023227118A1 PCT/CN2023/096597 CN2023096597W WO2023227118A1 WO 2023227118 A1 WO2023227118 A1 WO 2023227118A1 CN 2023096597 W CN2023096597 W CN 2023096597W WO 2023227118 A1 WO2023227118 A1 WO 2023227118A1
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Prior art keywords
alkylene
halogen
alkyl
haloalkyl
compound
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PCT/CN2023/096597
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French (fr)
Chinese (zh)
Inventor
张宏波
杨琪
张伟
孙静
石磊
丁康
王虎庭
许庆博
黄博
赵金存
陈新文
彭伟
Original Assignee
广州国家实验室
北京望石智慧科技有限公司
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Publication of WO2023227118A1 publication Critical patent/WO2023227118A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • the present invention relates to a new class of 3C-like protease inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof .
  • the present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in treating or preventing diseases caused by viral infections.
  • 2019-nCoV The new coronavirus discovered in December 2019 was initially named 2019-nCoV.
  • the World Health Organization (WHO) renamed it COVID-19.
  • WHO World Health Organization
  • 2019-nCoV The virus was named SARS-CoV-2.
  • SARS-CoV-2 can cause severe acute respiratory (SARI) symptoms, including fever, dyspnea, fatigue, and pneumonia.
  • RNA viruses the maximum genome length of coronaviruses ranges from approximately 26 to 32 kb.
  • Mpro main protease
  • 3Cpro picornavirus 3C protease
  • 3CLpro 3C-like protease
  • 3CLpro The function of 3CLpro is to hydrolyze and cleave the expressed peptide chain at the appropriate site, preparing the peptide chain to form a three-dimensional and four-dimensional structure to form the enzyme required for virus proliferation.
  • the enzyme does not change during the catalytic process, but the activation energy of the hydrolysis reaction is reduced, thereby accelerating the rate of the hydrolysis reaction.
  • the sulfhydryl group on cysteine plays a key role in the entire catalytic hydrolysis process, see Thanigaimalai et al.
  • WO2021/250648A1 discloses a compound currently known as Nirmatrelvir (PF-07321332). As one of the active ingredients of Paxlovid, it can be used in combination with ritonavir to reduce the risk of COVID-19. Risk of death and hospitalization from the virus SARS-CoV-2.
  • WO2021/205290A1 also discloses compounds with similar structures, which treat diseases caused by SARS-CoV-2 through a pathway mediated by 3C-like protease inhibitors.
  • Parovide also inhibits the CYP3A4 enzyme, which may interfere with the enzyme's metabolism of other drugs, change the half-life and clearance rate, reduce efficacy, or produce adverse reactions. situation.
  • CYP3A4 enzyme that inhibits the oxidative metabolism of terfenadine by CYP3A4
  • the concentration of the latter in the patient's body increases abnormally, causing cardiac QT wave prolongation and arrhythmia.
  • the compounds disclosed in WO2021/205290A1 also face the problem of being ineffective when administered orally. Therefore, the need to develop new 3C-like protease inhibitors is increasingly urgent.
  • the present invention uses 3C-like protease as a target and develops a new class of small molecule inhibitors, which can be used to treat or prevent viral infections.
  • the compound of the present invention targets 3C-like protease, has excellent inhibitory activity against 3C-like protease with P132H mutation, and can significantly inhibit the proliferation of SARS-CoV-2.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof Object:
  • Y is N or CR 7 ;
  • R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is selected from chemical bond, C 1-6 alkylene, -NH-, -O- or -S-;
  • R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
  • R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 Metaheteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, - NH-3-8-membered heterocyclyl, -NH-3-8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 Cycloalkyl, -
  • two R 1s on the same carbon atom together form oxo or sulfo;
  • L 2 is selected from chemical bond or C 1-6 alkylene
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
  • R 2s is selected from H, D, halogen, CN, -L 2a -R' or
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from H, NH 2 , CN, C 0-6 alkylene-C(O)R a , C 0-6 alkylene-C(O)OR a , C 1-6 alkylene-OC (O)-R a , C 0-6 alkylene-NHC(O)R a , C 0-6 alkylene-C(O)NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OR a , C 2-6 alkenyl or C 2- 6 alkynyl;
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
  • R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group , 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cyclo
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
  • Y is N or CR 7 ;
  • R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is selected from chemical bond or C 1-6 alkylene group, -NH-, -O- or -S-;
  • R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
  • R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclic group Aryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH- 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl base
  • L 2 is selected from chemical bond or C 1-6 alkylene
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
  • R 2s is selected from H, D, halogen, CN, -L 2a -R' or
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
  • R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group, 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH - 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycl
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.
  • the present invention provides a pharmaceutical composition containing a compound of the present invention and a pharmaceutically acceptable excipient, which also contains other therapeutic agents, for example, selected from: Remdesivir (Remdesivir or GS-5734), Lopinavir, Molnupiravir, Ritonavir, chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine, or alpha-interferon.
  • a pharmaceutically acceptable excipient which also contains other therapeutic agents, for example, selected from: Remdesivir (Remdesivir or GS-5734), Lopinavir, Molnupiravir, Ritonavir, chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine, or alpha-interferon.
  • the present invention provides the use of a compound of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and/or preventing diseases caused by viral infection.
  • the invention provides a method of treating and/or preventing diseases caused by viral infection in a subject, comprising administering to the subject a compound of the invention or a pharmaceutical composition of the invention.
  • the invention provides a compound of the invention or a pharmaceutical composition of the invention for treating and/or preventing diseases caused by viral infection.
  • the compounds or pharmaceutical compositions of the invention are used to inhibit viral proliferation
  • a compound or pharmaceutical composition of the invention inhibits the activity of viral 3CL protease.
  • the 3CL protease has a P132H mutation.
  • the virus is a coronavirus, preferably an alphacoronavirus and/or a betacoronavirus, more preferably SARS-CoV-2.
  • the present invention is used to treat and/or prevent the following diseases caused by viral infections: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, olfactory disorder, taste disorder and its complications. disease, or a combination thereof.
  • C 1-6 alkyl includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5, C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
  • C 1-10 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, and C 1-2 alkyl are preferred.
  • C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-pentyl (C 5 ) and n-hexyl (C 6 ).
  • C 1-6 alkyl also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • Alkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).
  • C 2-6 alkenyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl groups include: vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc.
  • C 2-6 alkenyl also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • Alkenyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 2-6 alkynyl refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl groups include, but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-Butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), etc.
  • C 2-6 alkynyl also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution.
  • An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 alkylene refers to a divalent group formed by removing another hydrogen of C 1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred.
  • the unsubstituted alkylene group includes, but is not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), ethylene Base (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,etc.
  • alkylene groups substituted by one or more alkyl (methyl) include, but are not limited to: substituted methylene (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, - CH 2 CH 2 C(CH 3 ) 2 -), etc.
  • C 2-6 alkynylene refers to a divalent group formed by removing the other hydrogen of the C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene is particularly preferred. Exemplary alkynylene groups include, but are not limited to: ethynylene (-C ⁇ C-), substituted or unsubstituted propynylene (-C ⁇ CCH 2 -), and the like.
  • C 0-6 alkylene means a chemical bond and the above-mentioned “C 1-6 alkylene”
  • C 0-4 alkylene means a chemical bond and the above-mentioned “C 1-4 alkylene”
  • C “0-3 alkylene” refers to a chemical bond as well as the above-mentioned "C 1-3 alkylene”.
  • C 1-10 alkoxy refers to OC 1-10 alkyl. In some embodiments, C 1-6 alkyl is preferred. In other embodiments, C 1-4 alkoxy is preferred, for example, methoxy, ethoxy, etc.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-10 haloalkyl refers to the above-mentioned “C 1-10 alkyl” which is substituted by one or more halogen groups.
  • C 1-6 haloalkyl is preferred, C 1-4 haloalkyl is particularly preferred, C 1-3 haloalkyl is more preferred, and C 1-2 haloalkyl is more preferred.
  • haloalkyl groups include, but are not limited to: -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc.
  • Haloalkyl groups may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • C 1-6 haloalkoxy refers to OC 1-6 haloalkyl. In some embodiments, C 1-4 haloalkoxy is preferred, for example, halomethoxy, haloethoxy, and the like.
  • C 3-10 cycloalkyl and “C 3-10 cycloalkenyl” refer to non-aromatic cyclic hydrocarbon groups having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1, 2 or 3 double or triple bonds.
  • C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, with C 5-7 cycloalkyl and C 5-6 cycloalkyl being more preferred base.
  • Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues as indicated The number of carbons in a cycloalkyl system. Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which the substituents on any non-adjacent carbon atoms are connected to form a bridged ring, which together form a polycyclic alkane sharing two or more carbon atoms.
  • Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which substituents on the same carbon atom are connected to form a ring, and together form a polycyclic alkane sharing one carbon atom.
  • Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene group (C 7 ), cycloheptadienyl (C 7 ), cycloheptadienyl (C 7 ), etc.
  • ring Alkyl groups may be optional
  • C 3-10 cycloalkylene refers to a divalent group formed by removing another hydrogen of C 3-10 cycloalkyl, and may be substituted or unsubstituted.
  • C 5-10 cycloalkylene, C 5-7 cycloalkylene, C 3-7 cycloalkylene, C 3-6 cycloalkylene, and C 3-4 cycloalkylene is particularly preferred, and cyclopropylene is particularly preferred.
  • 3-14 membered heterocyclyl refers to a saturated or unsaturated group of 3 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 7 ring heteroatoms, wherein each heteroatom is independently selected from Nitrogen, oxygen, sulfur, boron, phosphorus and silicon, optionally containing 1, 2 or 3 double or triple bonds.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-10 membered is preferred Heterocyclyl, which is a 5 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3 to 7 membered heterocyclyl is preferred, which is a 5 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms.
  • a 3- to 7-membered non-aromatic ring system with 1 to 4 ring heteroatoms preferably a 5-7-membered heterocyclic group, which is a 5- to 7-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms;
  • Preferred are 3-6-membered heterocyclyl groups, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms;
  • a 4- to 6-membered non-aromatic ring system with 3 ring heteroatoms more preferably a 5-6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms. More preferred is a 5-membered heterocyclyl group, which is a 5-membered non-aromatic ring system heterocyclyl group having ring carbon atoms and 1 to 3 ring heteroatoms. It also includes wherein the above-mentioned heterocyclyl ring is fused with one or more cycloalkyl groups.
  • Heterocyclyl also includes the above-mentioned heterocyclyl rings, in which the substituents on any non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, which together form a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes the above-mentioned heterocyclyl rings, in which substituents on the same carbon atom are connected to form a ring and together form a polycyclic heteroalkane sharing one carbon atom.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxirinyl, and thiorenyl.
  • Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl.
  • Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, 2,5-dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, di Hydropyrrolyl and pyrrolyl-2,5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: pyrazolidinyl, dioxolyl, oxasulfuranyl, dithiolyl (disulfuranyl) and oxazolidin-2-one.
  • Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl.
  • Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl).
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl, oxpanyl, and thipanyl.
  • the base ring fused 5-membered heterocyclyl includes, but is not limited to: indolyl, isoindolyl, dihydrobenzofuranyl , dihydrobenzothienyl, benzoxazolinone, etc.
  • Exemplary 6-membered heterocyclyl fused to a C6 aryl ring include, but are not limited to: tetrahydroquinolyl, tetrahydroisoquinolyl, etc.
  • Heterocyclyl also includes the above-mentioned heterocyclyl sharing one or two atoms with a cycloalkyl, heterocyclyl, aryl or heteroaryl to form a bridged ring or spiro ring. As long as the valency allows, the shared atoms can be carbon or Nitrogen atom. Heterocyclyl also includes the above-mentioned heterocyclyl and heterocyclyl groups may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
  • C 6-20 aryl refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having a cyclic arrangement) having 6-20 ring carbon atoms and zero heteroatoms. Shared 6 or 10 ⁇ electrons) group.
  • C 6-10 aryl groups are preferred.
  • an aryl group has six ring carbon atoms ("C 6 aryl”; e.g., phenyl).
  • an aryl group has ten ring carbon atoms ("C 10 aryl”; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl).
  • Aryl also includes ring systems in which the aryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system.
  • Aryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • 3-20 membered heteroaryl refers to a 3-20 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-8 ring heteroatoms (e.g., having a 6 or 10 ⁇ electrons), in which each heteroatom is independently selected from nitrogen, oxygen and sulfur.
  • the point of attachment may be a carbon or nitrogen atom as long as the valency permits.
  • Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings.
  • Heteroaryl also includes ring systems in which the heteroaryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom Number continues to represent the number of carbon atoms in the heteroaryl ring system.
  • 5-14 membered heteroaryl groups are particularly preferred, which are 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-6 ring heteroatoms.
  • 5-10 membered heteroaryl groups are particularly preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms.
  • 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-3 ring heteroatoms.
  • Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl.
  • Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl.
  • Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl.
  • Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl.
  • Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl or pyridonyl.
  • Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl.
  • Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively.
  • Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepantrienyl, oxetapyltrienyl, and thioheptantrienyl.
  • Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzopyrazolyl, benzothienyl, isobenzothiophene base, benzofuranyl, benzisofuranyl, benzimidazolyl, Benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanazinyl and purinyl.
  • Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pyridinyl, quinolinyl, isoquinolinyl, quinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl .
  • Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the divalent groups formed by removing another hydrogen from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups defined above are collectively referred to as "subunits".
  • Ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl are collectively referred to as "cyclic groups”.
  • Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc. are defined herein as optionally substituted groups.
  • Each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa groups are combined to form heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups group replacement;
  • Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or Two Rcc groups combine to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups substituted;
  • Each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;
  • Each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff groups combine to form a heterocyclyl or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;
  • coronavirus includes, but is not limited to, the following viruses: HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and/or SARSCoV-2.
  • coronavirus is an alphacoronavirus and/or a betacoronavirus, more preferably a betacoronavirus.
  • the alphacoronavirus is selected from HCoV-229E and HCoV-NL63, preferably HCoV-229E.
  • the betacoronavirus is selected from HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, more preferably SARS-CoV- 2.
  • treatment refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition.
  • noun “treat” refers to the action of the verb treat, as just defined.
  • the term "pharmaceutically acceptable salts” means those carboxylate salts and amino acid addition salts of the compounds of the present invention which are suitable for contact with patient tissue within the scope of reliable medical judgment and will not produce undue toxicity, Irritation effects, allergic reactions, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the invention.
  • Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines.
  • metals used as cations are sodium, potassium, magnesium, calcium, etc.
  • suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
  • Base addition salts of acidic compounds may be prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base to form the salt.
  • the free acid can be regenerated by contacting the salt form with the acid and isolating the free acid in the usual manner.
  • the free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention the salts are nevertheless equivalent to their respective free acids.
  • the salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salt, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc.
  • Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate Acid, borate, benzoate, lactate, Phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurate sulfonate and isethionate, etc.
  • Salts may also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like.
  • Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate Lenate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylbenzoate Acid, citrate, lactate, maleate, tartrate, methanesulfonate, etc.
  • Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19 , incorporated by reference).
  • Subjects for administration include, but are not limited to: humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs.
  • the subject is a human.
  • the subject is a non-human animal.
  • the terms "human,” “patient,” and “human” are used interchangeably herein. "Subject”.
  • treatment includes an action in a subject suffering from a specific disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a condition ("therapeutic treatment”), and also includes effects that occur before a subject begins to suffer from a specific disease, disorder or condition ("preventive treatment").
  • an "effective amount" of a compound is an amount sufficient to elicit a target biological response.
  • the effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age health conditions and symptoms.
  • the effective amount includes a therapeutically effective amount and a preventive effective amount.
  • a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition The amount to delay or minimize.
  • a therapeutically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition.
  • the term "therapeutically effective amount” may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
  • a prophylactically effective amount of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of a disorder or condition.
  • a prophylactically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in preventing a disease, disorder, or condition.
  • the term “prophylactically effective amount” may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
  • Combination and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent.
  • the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or with other therapeutic agents in a single unit dosage form.
  • compounds of the present invention refer to the following formulas (I), (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII), (VIII'), (IX), (IX'), (X), ( Compounds such as Polymorphs, hydrates or solvates.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
  • Y is N or CR 7 ;
  • R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is selected from chemical bond, C 1-6 alkylene, -NH-, -O- or -S-;
  • R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
  • R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 Metaheteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, - NH-3-8-membered heterocyclyl, -NH-3-8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 Cycloalkyl, -
  • two R 1s on the same carbon atom together form oxo or sulfo;
  • L 2 is selected from chemical bond or C 1-6 alkylene
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
  • R 2s is selected from H, D, halogen, CN, -L 2a -R' or
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from H, NH 2 , CN, C 0-6 alkylene-C(O)R a , C 0-6 alkylene-C(O)OR a , C 1-6 alkylene-OC (O)-R a , C 0-6 alkylene-NHC(O)R a , C 0-6 alkylene-C(O)NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OR a , C 2-6 alkenyl or C 2- 6 alkynyl;
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
  • R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group , 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cyclo
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvates:
  • Y is N or CR 7 ;
  • R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is selected from chemical bond or C 1-6 alkylene group, -NH-, -O- or -S-;
  • R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
  • R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclic group Aryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH- 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl base
  • L 2 is selected from chemical bond or C 1-6 alkylene
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
  • R 2s is selected from H, D, halogen, CN, -L 2a -R' or
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
  • R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group, 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH - 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycl
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • Y is N or CR 7 or CR 7 R 8 ;
  • Y is CR7 , such as CH; in another embodiment, Y is CR7R8 , such as CH2 ; in another embodiment, Y is N.
  • Said Y may be optionally substituted with D, up to complete deuteration.
  • R 7 is H; in another embodiment, R 7 is C 1-6 alkyl; in another embodiment, R 7 is C 1-6 haloalkyl.
  • R 8 is H; in another embodiment, R 8 is C 1-6 alkyl; in another embodiment, R 8 is C 1-6 haloalkyl.
  • the R 7 and R 8 may be optionally substituted with D until fully deuterated.
  • L 1 is a chemical bond; in another embodiment, L 1 is C 1-6 alkylene; in another embodiment, L 1 is -NH-; in another embodiment, L 1 is -O-; in another embodiment, L 1 is -S-.
  • the L 1 may optionally be substituted by D until fully deuterated.
  • R 1 is C 1-6 alkyl; in another embodiment, R 1 is C 1-6 haloalkyl; in another embodiment, R 1 is C 1-6 alkoxy , such as C 1-4 alkoxy; in another embodiment, R 1 is C 1-6 haloalkoxy, such as C 1-4 haloalkoxy; in another embodiment, R 1 is C 3- 10 cycloalkyl; in another embodiment, R 1 is 3-10 membered heterocyclyl; in another embodiment, R 1 is C 6-20 aryl, such as C 6-10 aryl; in another In one embodiment, R 1 is a 5-20-membered heteroaryl group, such as a 5-10-membered heteroaryl group, or a 5-6-membered heteroaryl group.
  • R 1 is OCH 3 ; in another specific embodiment, R 1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is O another specific embodiment, R1 is OCH 3 ; in another specific embodiment, R 1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is OCH 3 ; in another specific embodiment, R 1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment
  • R 1 is unsubstituted; in another embodiment, R 1 is optionally substituted with 1, 2 or 3, 4 or 5 independently selected R 1s .
  • Said R1 may be optionally substituted by D, up to complete deuteration.
  • R 1s is H; in another embodiment, R 1s is deuterium; in another embodiment, R 1s is CN; in another embodiment, R 1s is NO 2 ; in another In one embodiment, R 1s is NH 2 ; in another embodiment, R 1s is OH; in another embodiment, R 1s is halogen, such as F; in another embodiment, R 1s is C 1 -6 alkyl, such as C 1-4 alkyl; in another embodiment, R 1s is C 1-6 haloalkyl, preferably C 1-4 haloalkyl, such as CH 3 ; in another embodiment, R 1s is C 1-6 alkoxy, preferably C 1-4 alkoxy, such as OCH 3 ; in another embodiment, R 1s is C 1-6 haloalkoxy, preferably C 1-4 haloalkyl Oxygen; in another embodiment, R 1s is C 2-6 alkenyl; in another embodiment, R 1s is halogenated C 2-6 alkenyl; in another embodiment, R 1s
  • two R 1s on the same carbon atom together form oxo or thio.
  • the R 1s may be optionally substituted with D until fully deuterated.
  • L 2 is a chemical bond; in another embodiment, L 2 is C 1-6 alkylene, preferably C 1-4 alkylene, such as -CH 2 -;
  • the L2 may optionally be substituted with D until fully deuterated.
  • R 2 is C 3-10 cycloalkyl; in another embodiment, R 2 is 3-10 membered heterocyclyl; in another embodiment, R 2 is C 6-10 aromatic group, preferably a C 6-10 aryl group, more preferably a phenyl group; in another embodiment, R 2 is a 5-10 membered heteroaryl group.
  • R 2 is unsubstituted; in another embodiment, R 2 is optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s .
  • the R2 may optionally be substituted with D, up to complete deuteration.
  • R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen; in another embodiment, R 2s is CN; in another In an embodiment, R 2s is -L 2a -R'; in another embodiment, R 2s is
  • the R 2s may be optionally substituted with D until fully deuterated.
  • R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a is In another embodiment, R 2a is -L 2a -R'.
  • R 2b is H; in another embodiment, R 2b is D; in another embodiment, R 2b is In another embodiment, R 2b is -L 2a -R'.
  • the R 2a and R 2b may be optionally substituted with D until fully deuterated.
  • L 2a is a chemical bond; in another embodiment, L 2a is -C 1-6 alkylene; in another embodiment, L 2a is -C 0-6 alkylene-OC 0-6 alkylene-; in another embodiment, L 2a is -C 0-6 alkylene-SC 0-6 alkylene-; in another embodiment, L 2a is -C 0- 6 alkylene-C(O)-C 0-6 alkylene-; in another embodiment, L 2a is -C 0-6 alkylene-C(O)OC 0-6 alkylene- ;In another embodiment, L 2a is -C 0-6 alkylene-NH-C 0-6 alkylene-; In another embodiment, L 2a is -C 0-6 alkylene- C(O)NH-C 0-6 alkylene-; in another embodiment, L 2a is -C 0-6 alkylene-NHC(O)-C 0-6 alkylene- or -C 2-6 alkenylene-.
  • L 2a is a chemical bond; in another specific embodiment, L 2a is -O-; in another specific embodiment, L 2a is -S-; in another specific embodiment In an embodiment, L 2a is -C 1-6 alkylene-; in another specific embodiment, L 2a is -C 1-6 alkylene-O-; in another specific embodiment, L 2a is -OC 1-6 alkylene-; in another specific embodiment, L 2a is -C(O)-; in another specific embodiment, L 2a is -C(O)O -; In another specific embodiment, L 2a is -NH-; In another specific embodiment, L 2a is -C(O)NH-; In another specific embodiment, L 2a is -NHC(O)-; In another specific embodiment, L 2a is C 2-6 alkenylene.
  • the L 2a is unsubstituted; in another embodiment, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#s.
  • the L 2a may be optionally substituted by D until fully deuterated.
  • R# is H; in another embodiment, R # is halogen; in another embodiment, R# is C 1-6 alkyl, such as C 1-4 alkyl; in another In one embodiment, R# is C 1-6 haloalkyl, such as C 1-4 haloalkyl; in another embodiment, R# is C 1-6 alkoxy, such as C 1-4 alkoxy; In another embodiment, R# is C 1-6 haloalkoxy, such as C 1-4 haloalkoxy; in another embodiment, R# is C 2-6 alkenyl; in another embodiment , R# is C 2-6 alkynyl.
  • the R# may optionally be substituted with D, up to complete deuteration.
  • Ring A is C 3-10 cycloalkyl; in another embodiment, Ring A is C 5-10 cycloalkyl; in another embodiment, Ring A is C 5-8 cycloalkyl Alkyl; in another embodiment, Ring A is C 3-8 cycloalkyl; in another embodiment, Ring A is C 3-6 cycloalkyl; in another embodiment, Ring A is C 5-6 cycloalkyl; in another embodiment, ring A is a 3-10 membered heterocyclyl; in another embodiment, ring A is a 4-10 membered heterocyclyl, such as a 3-8 membered heterocyclyl group, another example is a 4-7 membered heterocyclyl group; in another embodiment, ring A is a 5-6 membered heterocyclyl group; in another embodiment, ring A is a C 6-10 aryl group; in another In an embodiment, Ring A is phenyl; in another embodiment, Ring A is a 5-10 membered heteroaryl; in another embodiment, Ring A is phenyl
  • Ring A is Where, Q 1 is CH or N.
  • Ring A is Among them, Q 2 is selected from S or NH, and Q 3 is selected from CH or N.
  • Ring A is Among them, one of Q 4 , Q 5 and Q 6 is N, and the other two are CH.
  • Ring A is In another specific embodiment, Ring A is a 5-membered heteroaryl group, such as one containing 1-2 heteroatoms selected from S or N.
  • X 2a is CR; in another embodiment, X 2a is N.
  • X 2b is CR; in another embodiment, X 2b is N.
  • R is H; in another embodiment, R is halogen; in another embodiment, R is CN; in another embodiment, R is OR a ; in another embodiment , R is NR b R c ; in another embodiment, R is C 1-10 alkyl; in another embodiment, R is C 1-6 alkyl; in another embodiment, R is C 1-10 alkoxy; in another embodiment, R is C 1-6 alkoxy; in another embodiment, R is C 1-10 haloalkyl; in another embodiment, R is C 1-6 haloalkyl; in another embodiment, R is C 1-10 haloalkoxy; in another embodiment, R is C 1-6 haloalkoxy; in another embodiment, R is C (O)R a ; in another embodiment, R is C(O)OR a ; in another embodiment, R is NHC(O)R a ; in another embodiment, R is C(O )NH-R a ; In another embodiment, R is Boc; In another embodiment, R is C 2-6 alkenyl
  • R is independently selected from H; in another specific embodiment, R is halogen, such as F or Cl; in another embodiment, R is CN; in another embodiment, R is OH; in another embodiment, R is NH 2 ; in another embodiment, R is C 1-6 haloalkyl, preferably C 1-4 haloalkyl, such as CF 3 ; in another embodiment , R is C 1-6 alkoxy; in another embodiment, R is C 1-6 haloalkoxy, preferably C 1-4 haloalkoxy, such as OCF 3 ; in another embodiment, R for Boc.
  • m is 0; in another embodiment, m is 1; in another embodiment, m is 2; in another embodiment, m is 3; in another embodiment, m is 4; in another embodiment, m is 5.
  • R' is H; in another embodiment, R' is NH 2 ; in another embodiment, R' is CN; in another embodiment, R' is C(O) Ra ; in another embodiment, R' is C(O)OR a ; in another embodiment, R' is NHC(O)R a , preferably NHC(O)-C 1-6 haloalkyl , such as NHC(O)-CF 3 ; in another embodiment, R' is C(O)NH- R a , preferably C(O)NH-C 1-6 haloalkyl, such as C(O)NH-CF 3 ; in another embodiment, R' is C 0-6 alkylene-C(O) R a ; in another embodiment, R' is C 0-6 alkylene-C(O)OR a ; in another embodiment, R' is C 1-6 alkylene-OC(O) -R a ; in another embodiment, R' is C 0-6 alkylene-NHC(O)R a ;
  • R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is in another embodiment, R' is in another embodiment, R' is in another embodiment, R' is in another embodiment, R' is in another embodiment, R' is in another embodiment, R' is in another embodiment, R' is
  • Said R' may be optionally substituted by D, up to complete deuteration.
  • R 2c is halogen, preferably F.
  • R 2d is halogen, preferably Cl; in another embodiment, R 2d is CN.
  • R" is H; in another embodiment, R" is halogen, such as F or Cl; in another embodiment, R" is C 1-6 haloalkyl; in another embodiment Among them, R′′ is a C 1-6 haloalkoxy group, preferably a C 1-4 haloalkoxy group, such as OCF 3 .
  • Said R" may be optionally substituted by D, up to complete deuteration.
  • L 3 is -NR b -, such as -NH-; in another embodiment, L 3 is -CR a R b -, such as -CH 2 -.
  • the L 3 and L 3 ' may be optionally substituted with D until fully deuterated.
  • R 3 is C 6-14 aryl, preferably C 6-10 aryl; in another embodiment, R 3 is 5-14 heteroaryl, such as 5-10 heteroaryl; In another embodiment, R 3 is C 3-8 cycloalkyl; in another embodiment, R 3 is 3-14 membered heterocyclyl.
  • R 3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is
  • the R 3 is unsubstituted; in another embodiment, the R 3 is optionally substituted with 1, 2, 3, 4 or 5 independently selected R 3s .
  • the R3 may optionally be substituted with D until fully deuterated.
  • R 3s is H; in another embodiment, R 3s is deuterium; in another embodiment, R 3s is halogen; in another embodiment, R 3s is CN; in another In one embodiment, R 3s is NO 2 ; in another embodiment, R 3s is NH 2 ; in another embodiment, R 3s is C 1-6 alkyl, preferably C 1-4 alkyl; in In another embodiment, R 3s is C 1-6 alkoxy, preferably C 1-4 alkoxy; in another embodiment, R 3s is C 2-6 alkenyl; in another embodiment , R 3s is C 2-6 alkynyl; in another embodiment, R 3s is halogenated C 1-6 alkyl; in another embodiment, R 3s is halogenated C 1-6 alkoxy; In another embodiment, R 3s is haloC 2-6 alkenyl; in another embodiment, R 3s is haloC 2-6 alkynyl; in another embodiment, R 3s is C 6 -10 aryl; in another embodiment, R 3s
  • the R 3s may be optionally substituted with D until fully deuterated.
  • R 3a is halogen, preferably Cl.
  • R 3f is C 1-6 alkyl, preferably C 1-4 alkyl, such as CH 3 .
  • the R 3s may be optionally substituted with D until fully deuterated.
  • R a is H; in another embodiment, R a is C 1-6 alkyl; in another embodiment, R a is C 1-6 haloalkyl; in another embodiment In, R a is C 2-6 alkenyl; in another embodiment, R a is C 2-6 alkynyl.
  • R b is H; in another embodiment, R b is C 1-6 alkyl; in another embodiment, R b is C 1-6 haloalkyl; in another embodiment In, R b is C 2-6 alkenyl; in another embodiment, R b is C 2-6 alkynyl.
  • R c is H; in another embodiment, R c is C 1-6 alkyl; in another embodiment, R c is C 1-6 haloalkyl; in another embodiment In, R c is C 2-6 alkenyl; in another embodiment, R c is C 2-6 alkynyl.
  • R a , R b and R c may be optionally substituted with D until fully deuterated.
  • any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments.
  • any technical solution of R 1 or any combination thereof can be combined with any technical solution of Y, L 1 , L 2 , R 2 , L 3 and R 3 or any combination thereof.
  • the present invention is intended to include combinations of all these technical solutions, and due to space limitations, they will not be listed one by one.
  • the invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
  • Y is N or CR 7 ;
  • R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • L 1 is selected from chemical bond or C 1-6 alkylene group, -NH-, -O- or -S-;
  • R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
  • R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclic group Aryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH- 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl base
  • L 2 is selected from chemical bond or C 1-6 alkylene
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
  • R 2s is selected from H, D, halogen, CN, -L 2a -R' or
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
  • R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group, 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH - 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycl
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, which is the structure of formula (I'):
  • Y' is NR 7 or CR 7 R 8 ;
  • R 7 and R 8 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate of formula (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), Structure of (VI'), (VII), (VII'), (VIII) or (VIII'):
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
  • R 2c is halogen, preferably F
  • R 2d is halogen or CN, preferably Cl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-6 alkyl, preferably CH 3 ;
  • the invention provides compounds of formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 1 is selected from chemical bond or C 1-6 alkylene
  • R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 1, 4 or 5 R 1s are substituted;
  • R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# replace;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2c is halogen, preferably F
  • R 2d is halogen or CN, preferably Cl;
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and the R 3 is optionally substituted by 1, 2, 3, 4 or 5 R 3s ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the invention provides compounds of the above formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 1 is selected from chemical bond or C 1-6 alkylene
  • R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 1, 4 or 5 R 1s are substituted;
  • R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# replace;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2c is halogen, preferably F
  • R 2d is halogen or CN, preferably Cl;
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and the R 3 is optionally substituted by 1, 2, 3, 4 or 5 R 3s ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, which is the structure of formula (III) or (III'):
  • R 2a is selected from or -L 2a -R';
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene- or C 2-6 alkenylene, L 2a is optionally selected from halogen, C 1- 6 alkyl or C 1-6 haloalkyl substituent substitution;
  • Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • Each R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C( O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl, or the same
  • n 0, 1, 2, 3, 4 or 5;
  • R' is selected from NH 2 , CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O) -C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl;
  • R 2c is selected from halogen
  • R 2d is selected from halogen or CN
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (III) or (III'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2a is selected from or -L 2a -R';
  • L 2a is selected from chemical bonds, -O-, -S-, -C 1-6 alkylene-, -C 1-6 alkylene-O-, -OC 1-6 alkylene-, -C(O )-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)- or C 2-6 alkenylene, L 2a is optionally replaced by 1, 2 or Substituted with 3 substituents independently selected from halogen or C 1-6 alkyl;
  • Ring A is selected from C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n 0, 1, 2, 3 or 4;
  • R' is selected from NH 2 , CN, C 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl;
  • R 2c is selected from halogen
  • R 2d is selected from halogen or CN
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (III) or (III'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2a is selected from or -L 2a -R';
  • R' is selected from CN, NHC(O)-CF 3 or CF 3 ;
  • R 2c is selected from F or Cl, preferably F;
  • R 2d is selected from F, Cl or CN, preferably Cl.
  • the invention provides compounds of formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 2a is selected from -O-, -S- or -C 2-6 alkenylene-;
  • Ring A is selected from C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2c is halogen, preferably F
  • R 2d is selected from halogen or CN, preferably Cl.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is selected from -O- or -C 2-6 alkenylene-;
  • Ring A is selected from C 5-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2c is halogen, preferably F
  • R 2d is selected from halogen or CN, preferably Cl.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is selected from -O- or -C 2-4 alkenylene-;
  • Ring A is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl;
  • n 0, 1, 2 or 3;
  • R 2c is halogen, preferably F
  • R 2d is selected from halogen or CN, preferably Cl.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2c is selected from F or Cl, preferably F;
  • R 2d is selected from F, Cl or CN, preferably Cl.
  • the invention provides compounds of formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 2a is C 2-6 alkenylene
  • Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl
  • R is selected from H, halogen or C 1-6 haloalkyl
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2c is halogen, preferably F
  • R 2d is halogen, preferably Cl
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • Ring A is selected from phenyl or 5-6 membered heteroaryl, and the 5-membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from S or N;
  • R is selected from H or halogen, preferably H or F;
  • n 0, 1, 2 or 3;
  • R 2c is halogen, preferably F
  • R 2d is halogen, preferably Cl.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2c is F
  • R 2d is Cl or F, preferably Cl.
  • the invention provides compounds of formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 2a is -O- or -S-;
  • Ring A is selected from or 5-membered heteroaryl
  • X 2a and X 2b are independently selected from CR or N;
  • Each R is independently selected from H, halogen, CN, OH, NH 2 , C 1-6 alkoxy or C 1-6 haloalkoxy, preferably H, F, Cl, CN, OCF 3 ;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is -O-
  • Ring A is selected from or 5-membered heteroaryl
  • X 2a and X 2b are independently selected from CR or N;
  • Each R is independently selected from H, halogen, CN or C 1-6 haloalkoxy;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is -O-
  • Ring A is selected from Or a 5-membered heteroaryl group, the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;
  • X 2a and X 2b are independently selected from CR or N;
  • Each R is independently selected from H, halogen, CN or C 1-4 haloalkoxy, preferably H, F, Cl, CN or OCF 3 ;
  • n 0, 1, 2 or 3;
  • the invention provides compounds of formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • R 2b is or -L 2a -R'
  • L 2a is -C 1-6 alkylene-, -C 2-6 alkenylene-, -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene- SC 0-6 alkylene-;
  • Ring A is C 6-10 aryl or 5-10 membered heteroaryl
  • Each R is independently selected from H, halogen, NH 2 , OH, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
  • R' is selected from C(O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl base;
  • R 2c is halogen
  • R 2d is selected from halogen or CN
  • n 0, 1, 2, 3, 4 or 5;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2b is or -L 2a -R'
  • L 2a is selected from -O-, -S-, -C 1-4 alkylene-, -C 1-4 alkylene-O-, -OC 1-4 alkylene-, -C 1-4 alkylene Alkyl-S- or -SC 1-4 alkylene-;
  • Ring A is a phenyl group or a 5-6-membered heteroaryl group, and the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;
  • Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, Cl, CN, CF 3 or OCF 3 ;
  • R' is selected from NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl, preferably NHC(O)CF 3 ;
  • R 2c is halogen
  • R 2d is selected from halogen or CN
  • n 0, 1, 2 or 3;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2b is or -L 2a -R'
  • L 2a is -O-, -S-, -CH 2 -, -CH 2 -O-, -CH 2 -CH 2 -O- or -O-CH 2 -;
  • R' is NHC(O)CF 3 ;
  • R 2c is F
  • R 2d is selected from F, Cl or CN, preferably Cl.
  • the invention provides compounds of formula (VI) or (VI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 2a is -O- or -S-;
  • Ring A is C 6-10 aryl or 5-10 membered heteroaryl
  • Each R is independently selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
  • n 0, 1, 2, 3, 4 or 5;
  • R 2c is halogen
  • R 2d is selected from halogen or CN
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (VI) or (VI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is -O-
  • Ring A is phenyl
  • Each R is independently selected from H, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, Cl, CF 3 or OCF 3 ;
  • n 0, 1, 2 or 3;
  • R 2c is halogen, preferably F
  • R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides the above-mentioned compound of formula (VII) or (VII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate:
  • L 2a is O or S
  • R is selected from H or halogen
  • R is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy.
  • the present invention provides the above-mentioned compound of formula (VII) or (VII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is selected from -O-;
  • R is selected from H or halogen, preferably H, F or Cl;
  • R is selected from H, halogen or C 1-4 haloalkoxy, preferably H, F, Cl or OCF 3 .
  • the invention provides compounds of formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 1 is selected from chemical bond or C 1-6 alkylene
  • R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 , 4 or 5 independently selected R 1s substitutions;
  • R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • L 2a is selected from chemical bond, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene-, -C 0-6 alkylene -C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0-6 alkylene-NH-C 0 -6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC(O)-C 0-6 alkylene Alkyl-or-C 2-6 alkenylene-, the L 2a is optionally substituted by 1, 2, 3, 4 or 5 independently selected R#;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • Ring A is selected from C 3-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 haloalkyl, C 1-6 haloalkoxy or Boc, preferably H, F, Cl, CN, CF 3 , OCF 3 or Boc;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2c is halogen, preferably F
  • R 2d is halogen, preferably Cl
  • L 3 is -NR b - or -CR a R b -;
  • R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and said R 3 is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 3s ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the invention provides compounds of the above formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 1 is selected from chemical bond or C 1-4 alkylene
  • R 1 is selected from C 1-4 alkoxy or 5-6 membered heteroaryl, and R 1 is optionally substituted by 1, 2 or 3 independently selected R 1s ;
  • R 1s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, preferably F, CH 3 or OCH 3 ;
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • L 2a is selected from chemical bonds, -O-, -S-, -C 1-4 alkylene-O-, -OC 1-4 alkylene-, -C(O)O-, -NH-, -C (O)NH-, -NHC(O)-, -C(O)- or C 2-4 alkenylene, the L 2a is optionally substituted by 1, 2 or 3 independently selected R# ;
  • R# is selected from H, C 1-4 alkyl or C 1-4 haloalkyl
  • Ring A is selected from C 3-6 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy or Boc, preferably H, F, Cl, CN, CF 3 , OCF 3 or Boc;
  • n 0, 1, 2 or 3;
  • R' is selected from C 1-4 alkyl or C 1-4 haloalkyl
  • R 2c is halogen, preferably F
  • R 2d is halogen, preferably Cl
  • L 3 is -NH-
  • R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and said R 3 is optionally substituted by 1, 2 or 3 independently selected R 3s ;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the invention provides compounds of the above formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 1 is selected from chemical bonds or -CH 2 -;
  • R 1 is selected from OCH 3 ,
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • R' is selected from CHF 2 or CF 3 ;
  • R 2c is selected from F
  • R 2d is selected from F or Cl
  • L 3 is -NH-
  • R 3 is selected from
  • L 1 is selected from chemical bonds or -CH 2 -;
  • R 1 is selected from OCH 3 ,
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • R' is selected from CHF 2 or CF 3 ;
  • R 2c is selected from F
  • R 2d is selected from F or Cl
  • L 3 is -NH-
  • R 3 is selected from
  • the invention provides compounds of formula (VIII) or (VIII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 2a is O or S
  • R 1s is selected from halogen or C 1-6 haloalkoxy
  • R is selected from halogen, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-6 alkyl, preferably CH 3 .
  • the present invention provides the above-mentioned compound of formula (VIII) or (VIII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is O
  • R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3 ;
  • R is selected from halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably F, CN, CF 3 or OCF 3 ;
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-4 alkyl, preferably CH 3 .
  • the present invention provides compounds of the above formula (VIII) or (VIII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate:
  • L 2a is O or S
  • R 1s is selected from halogen or C 1-6 haloalkoxy
  • R is selected from halogen or CN
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-6 alkyl, preferably CH 3 ;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides the above-mentioned compound of formula (VIII) or (VIII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is O
  • R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3 ;
  • R is selected from halogen or CN, preferably F or CN;
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-4 alkyl, preferably CH 3 .
  • the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate of formula (IV), (IV'), (V), (V'), (IX), (IX'), (X), (X'), (XI), Structure of (XI'), (XII) or (XII'):
  • R 2a and R 2b are or -L 2a -R', the other is H or D;
  • L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
  • R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 2c is halogen, preferably F
  • R 2d is halogen or CN, preferably Cl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-6 alkyl, preferably CH 3 ;
  • the invention provides compounds of formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl
  • R is selected from H, halogen, CN, OR a , NR b R c , C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2d is selected from halogen
  • R 2c is selected from halogen
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from phenyl or 5-6 membered heteroaryl
  • R is selected from H, halogen, CN, OH, NH 2 , C(O)NH 2 or C 1-4 haloalkyl, preferably H, F, Cl, CN, OH, NH 2 , C(O)NH 2 or CF 3 ;
  • n is selected from 1, 2 or 3;
  • R 2d is selected from halogen, preferably Cl or F;
  • R 2c is selected from halogen, preferably F.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is -S- or -O-;
  • R 2d is selected from halogen, preferably Cl or F;
  • R 2c is selected from halogen, preferably F.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl
  • R is selected from H, halogen, CN, NH 2 , C 1-6 alkyl or C 1-6 haloalkyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2d is selected from halogen, preferably Cl;
  • R 2c is selected from halogen, preferably F;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from phenyl or 5-6 membered heteroaryl
  • R is selected from H, halogen, CN, NH 2 or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 or CF 3 ;
  • n is selected from 1, 2 or 3;
  • R 2d is selected from halogen, preferably Cl;
  • R 2c is selected from halogen, preferably F.
  • the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • L 2a is -S- or -O-, preferably -S-;
  • R 2d is selected from halogen, preferably Cl;
  • R 2c is selected from halogen, preferably F.
  • the invention provides compounds of formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • R 2b is selected from or -L 2a -R';
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 6-10 membered heteroaryl;
  • R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
  • R 2d is selected from halogen
  • R 2c is selected from halogen
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2b is selected from or -L 2a -R';
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • R is selected from H, halogen, NH 2 , CN, OH or C 1-4 haloalkyl, preferably H, F, NH 2 , CN, OH or CF 3 ;
  • n is selected from 1, 2 or 3;
  • R' is C 1-4 alkylene-OC 1-4 alkyl
  • R 2d is selected from halogen, preferably Cl;
  • R 2c is selected from halogen, preferably F.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2b is selected from or -L 2a -R';
  • L 2a is selected from -S- or -O-;
  • R 2d is selected from halogen, preferably Cl;
  • R 2c is selected from halogen, preferably F.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2b is selected from or -L 2a -R';
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 6-10 membered heteroaryl;
  • R is selected from H, halogen, C 0-6 alkylene-NH 2 , C 0-6 alkylene-CN or C 0-6 alkylene-OH;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
  • R 2d is selected from halogen
  • R 2c is selected from halogen
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2b is selected from or -L 2a -R';
  • L 2a is selected from -S- or -O-;
  • Ring A is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
  • R is selected from H, halogen, NH 2 , CN or OH, preferably H, F, NH 2 , CN or OH;
  • n is selected from 1, 2 or 3;
  • R' is C 1-4 alkylene-OC 1-4 alkyl
  • R 2d is selected from halogen, preferably Cl;
  • R 2c is selected from halogen, preferably F.
  • the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 2b is selected from or -L 2a -R';
  • L 2a is selected from -S- or -O-;
  • R 2d is selected from halogen, preferably Cl;
  • R 2c is selected from halogen, preferably F.
  • the invention provides compounds of formula (IX) or (IX'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
  • Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl
  • R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy C 2-6 Alkenyl or C 2-6 alkynyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F;
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-6 alkyl, preferably CH 3 ;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (IX) or (IX'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
  • Ring A is selected from phenyl or 5-6 membered heteroaryl
  • R is selected from H, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 , OH, CH 3 or CF 3 ;
  • n is selected from 1, 2 or 3;
  • R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F;
  • R 3a is halogen, preferably Cl
  • R 3f is C 1-4 alkyl, preferably CH 3 .
  • the present invention provides compounds of the above formula (IX) or (IX'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is selected from H, F, CH 3 or OCH 3 ;
  • L 2a is -S- or -S-CH 2 -;
  • R 2d is selected from Cl or CN
  • R 2c is selected from H or F
  • R 3a is Cl
  • R 3f is CH 3 .
  • the invention provides compounds of formula (X) or (X'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • R 1S is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • L 2a is -S- or -O-;
  • Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the 5-10 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
  • R is selected from H, halogen, CN, NR b R c , OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (X) or (X'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy
  • L 2a is -S- or -O-;
  • Ring A is selected from phenyl or 5-6-membered heteroaryl, and the 5-6-membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
  • R is selected from H, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 , OH, CH 3 or CF 3 ;
  • n is selected from 1, 2 or 3;
  • R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F.
  • the present invention provides compounds of the above formula (X) or (X'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is selected from CH 3 or OCH 3 ;
  • L 2a is -S- or -O-, preferably -S-;
  • R 2d is selected from Cl or CN
  • R 2c is selected from H or F.
  • the invention provides compounds of formula (XI) or (XI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2b is selected from or -L 2a -R';
  • L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
  • R 2d is selected from halogen or CN
  • R 2c is selected from H or halogen
  • R 3a is halogen
  • R 3f is C 1-6 alkyl
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (XI) or (XI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is CH 3 ;
  • R 2b is selected from or -L 2a -R';
  • L 2a is -S-
  • R' is selected from
  • R 2d is selected from F, Cl or CN
  • R 2c is selected from H or F
  • R 3a is Cl
  • R 3f is CH 3 .
  • the invention provides compounds of formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
  • R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy
  • R 2b is selected from or -L 2a -R';
  • L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
  • Ring A is selected from 3-8 membered heterocyclyl, Or a 5-membered heteroaryl group, the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from N, O or S;
  • Q 1 is CH or N
  • R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
  • R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy
  • R 2b is selected from or -L 2a -R';
  • L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
  • Ring A is selected from 3-6 membered heterocyclyl
  • Q 1 is CN or N
  • Q 2 is selected from S or NH
  • Q 3 is selected from CH or N;
  • Q 4 , Q 5 and Q 6 is N, and the other two are CH;
  • R is selected from H, halogen, OH, CN, NR b R c , C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, OH, CN, NH 2 , NHCH 3 , CF 3 or CH 3 ;
  • n is selected from 1, 2 or 3;
  • R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
  • R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F;
  • R a , R b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
  • the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is CH 3 ;
  • R 2b is selected from or -L 2a -R';
  • L 2a is -S-
  • R' is selected from
  • R 2d is selected from F, Cl or CN
  • R 2c is selected from H or F.
  • the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy
  • R 2b is selected from or -L 2a -R';
  • L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
  • Ring A is selected from phenyl, thienyl, pyrazolyl or thiazolyl;
  • R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • n is selected from 0, 1, 2, 3, 4 or 5;
  • R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NH 2 or C 1-6 alkylene-OR a ;
  • R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F;
  • R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • Each group defined therein may optionally be substituted by D, up to complete deuteration.
  • the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy
  • R 2b is selected from or -L 2a -R';
  • L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
  • Ring A is selected from phenyl, thienyl,
  • R is selected from H, halogen, CN, NR b R c , C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, CN, NH 2 , NHCH 3 , CF 3 or CH 3 ;
  • R b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
  • n is selected from 1, 2 or 3;
  • R' is selected from C 1-4 alkylene-NHC(O)-C 1-4 haloalkyl, C 1-4 alkylene-C(O)NH 2 or C 1-4 alkylene-OC 1- 4 alkyl;
  • R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
  • R 2c is selected from H or halogen, preferably H or F, more preferably F.
  • the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
  • R 1S is CH 3 ;
  • R 2b is selected from or -L 2a -R';
  • L 2a is -S-
  • R' is selected from
  • R 2d is selected from F, Cl or CN
  • R 2c is selected from H or F.
  • the invention provides compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof Object, wherein said compound is selected from the following:
  • the invention provides compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof Object, wherein said compound is selected from the following:
  • the present invention also relates to the following technical solutions:
  • Ring A represents a 5- to 20-membered heteroaryl group or a C 6-20 aryl group
  • R 1 is each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl, Halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8-membered heterocyclyl, 3 to 8-membered heteroaryl, -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8-membered heterocyclyl, -NH-3 to 8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl, -OC 6-10 aryl, -O -3 to 8-membered hetero
  • L 1 represents a single bond, -CH 2 -, -NH-, -O- or -S-,
  • n is an integer from 0 to 10
  • R 2 represents H, C 1-6 alkyl, halogen or deuterated C 1-6 alkyl
  • R 3 is each independently selected from H, C 1-6 alkyl, halogen, cyano, nitro or amino,
  • n is an integer from 0 to 3.
  • ring A, R 1 , R 2 , R 3 , n and m are as defined in formula (PI).
  • ring A, R 1 and n are as defined in formula (PI).
  • ring A represents a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group, a 9- or 10-membered heteroaryl group Fused heteroaryl groups, such as thiazolyl, pyrazolyl, pyridyl, isoquinolinyl, pyrazolopyridyl, pyrrolopyridyl.
  • R 1 , R 2 , R 3 , n and m are as defined in formula (PI).
  • Ring B represents a 5- to 20-membered heteroaryl group or a C 6-20 aryl group
  • L 2 represents a single bond, -CH 2 -, -NH-, -O- or -S-,
  • R 4 is each independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl base, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8-membered heterocyclyl, 3 to 8-membered heteroaryl, -NH (C 1-6 Alkyl), -N(C 1-6 alkyl) 2 , -NH - C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8-membered heterocyclyl, -NH -3 to 8-membered heteroaryl, -OC 1-6 alkyl , -OC 2-6 alkenyl, -OC 2-6 alkynyl , -OC 3-8 cycloalkyl, -OC 6-10 aryl, -O
  • L 3 represents -(CH 2 ) p -O-, -O-(CH 2 ) q -, -(CH 2 ) r -NH-, -NH-(CH 2 ) s -, -(CH 2 ) t - S-or-S-(CH 2 ) t -,
  • o, p, q, r, s, t and u are each independently an integer from 0 to 3,
  • E represents the following group that is unsubstituted or optionally substituted by one, two or more R 5 : C 1-6 alkylcarbonyl, 5 to 20 membered heteroaryl or C 6-20 aryl,
  • R 5 each independently represents H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl, halogen Substituted C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heteroaryl, -NH (C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8-membered heterocyclyl, -NH-3 to 8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl , -OC 3-8 cycloalkyl, -OC 6-10 aryl, -O- 3 to 8-member
  • R 6 represents H, C 1-6 alkyl, halogen or deuterated C 1-6 alkyl.
  • ring B is a 5- or 6-membered heteroaryl group
  • R 4 , R 6 , o, L 3 and E are as defined in formula (P-II).
  • composition which contains a therapeutically effective amount of a compound of formula (P-I) or a compound of formula (P-II) or a salt or ester thereof according to any one of technical schemes 1-14, and their stereoisomers Conforms or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites and optionally at least one physiologically/pharmaceutically acceptable excipient.
  • additional active ingredients include remdesivir, lopinavir, monupivir, rituximab Navir, chloroquine, hydroxychloroquine and/or alpha-interferon.
  • the medicine is an RNA-dependent RNA polymerase inhibitor, a 3CLpro protease inhibitor, a CYP3A4 inhibitor agent or host-targeted antiviral drug; more preferably, the drug optionally contains an additional active ingredient, wherein the additional active ingredient includes remdesivir, lopinavir, monupivir, rivir, Tonavir, chloroquine, hydroxychloroquine and/or alpha-interferon; more preferably, the medicament is used to prevent or treat a disease, condition, syndrome and/or disorder selected from the group below, or to alleviate a disease, condition, syndrome and/or disorder selected from the group below Group of symptoms
  • a method for treating or preventing diseases, conditions, syndromes and/or disorders caused by SARS-CoV-2 coronavirus infection which method includes administering a formula according to any one of technical solutions 1 to 14 to an individual in need
  • the compounds of the present invention may contain one or more asymmetric centers and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms.
  • the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, Includes racemic mixtures and mixtures enriched in one or more stereoisomers.
  • the isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers may be separated by asymmetric synthesis preparation.
  • HPLC high pressure liquid chromatography
  • Tautomers are functional group isomers produced by the rapid movement of an atom in a molecule between two positions.
  • a tautomer is a special functional group isomer.
  • a pair of tautomers can interact with each other. conversion, but usually one of the more stable isomers is its main form of existence. The most important examples are the enol and keto tautomers.
  • formula (I) of the present invention the compounds represented when Y is N and X is NH, and formulas (I'), (II), (II'), (III), (III'), ( Compounds represented by IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII) and (VIII') include the following interactions Variants:
  • the compound represented when Y is CH and X is NH includes the following tautomers:
  • Example 1 of the present invention contains the following tautomers:
  • solvate refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding.
  • solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc.
  • Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolating, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid.
  • “Solvate” includes both solution solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methoxides.
  • hydrate refers to a compound combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined.
  • a hydrate of a compound may be represented, for example, by the general formula R.xH2O , where R is the compound and x is a number greater than zero.
  • a given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1), for example, hemihydrate (R ⁇ 0.5H 2 O) and polyhydrates (x is a number greater than 1, for example, dihydrate (R ⁇ 2H 2 O) and hexahydrate (R ⁇ 6H 2 O).
  • the compounds of the invention may be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention.
  • polymorph refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
  • the present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I), except that one or more atoms are surrounded by atoms having an atomic mass or mass number different from that common in nature. replaced.
  • isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl.
  • the isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by replacing non-isotopes with readily available isotope-labeled reagents when performing the following processes and/or the processes disclosed in the Examples and Preparation Examples. Labeled reagents.
  • prodrugs are also included within the context of the present invention.
  • the term "prodrug” as used herein refers to a compound that is converted in the body to its active form having a medical effect, for example, by hydrolysis in the blood.
  • Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each introduced This article serves as a reference.
  • a prodrug is any covalently bonded compound of the invention that releases the parent compound in the body when administered to a patient.
  • Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved by conventional manipulations or in vivo to yield the parent compound.
  • Prodrugs include, for example, compounds of the invention in which a hydroxyl, amino or thiol group is bonded to any group which, when administered When administered to patients, it can be cleaved to form hydroxyl, amino or sulfhydryl groups.
  • prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxyl, thiol and amino functionality of compounds of formula (I).
  • esters such as methyl ester, ethyl ester, etc. can be used.
  • the ester itself may be reactive and/or hydrolyzable under human body conditions.
  • Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily break down in the human body to release the parent acid or salt thereof.
  • the present invention also provides pharmaceutical preparations, comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the invention.
  • the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient.
  • the pharmaceutical compositions comprise an effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention.
  • the pharmaceutical compositions comprise a prophylactically effective amount of a compound of the invention.
  • compositions of the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds with which they are formulated.
  • Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin) protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols, and
  • Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions (especially injections (subcutaneous, intravenous solution for intramuscular administration) and infusion (injection)), elixir, syrup, cachet, emulsion, inhalation or dispersible powder.
  • the content of one or more pharmaceutically active compounds should range from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight of the composition as a whole, ie an amount sufficient to achieve the dosage ranges specified below. If necessary, the specified dose may be administered several times per day.
  • kits eg, pharmaceutical packaging.
  • Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packaging or other) containing the compounds of the invention, other therapeutic agents. suitable container).
  • provided kits may also optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents.
  • the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
  • parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal membrane drug administration, intralesional drug administration, and intracranial injection or infusion techniques.
  • an effective amount of a compound provided herein is administered.
  • the amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
  • a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice of and under the supervision of a physician, at dosage levels as described above.
  • Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or those who have been determined by genetic testing or screening to be particularly susceptible to developing the condition.
  • compositions provided herein can also be administered over a long period of time ("chronic administration").
  • Long-term administration refers to the administration of a compound or pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may be continued indefinitely, For example, the remainder of the subject's life.
  • chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.
  • a pharmaceutical composition may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to an effective level.
  • the bolus dose depends on the target systemic levels of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, whereas a bolus dose delivered directly into the vein (e.g., via an IV drip) ) can be delivered more quickly, allowing the concentration of active ingredients in the blood to quickly increase to effective levels.
  • the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
  • Oral compositions may take the form of bulk liquid solutions or suspensions, or bulk powders. More typically, however, the compositions are provided in unit dosage form to facilitate precise dosing.
  • dosage unit form refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient.
  • Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions.
  • the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.
  • a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses.
  • each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
  • a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
  • Injectable dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially from 24 to 96 hours. To achieve adequate steady state levels, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.
  • Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like.
  • Solid forms may include, for example, any of the following components, or compounds of similar nature: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricant, for example, magnesium stearate; glidant, for example, colloidal silicon dioxide; sweetener, for example, sucrose or saccharin; or flavoring agent, for example, mint, water Methyl glycolate or orange flavoring.
  • binders for example, microcrystalline cellulose, tragacanth, or gelatin
  • excipients for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch
  • Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As stated previously, in such compositions the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
  • Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredients.
  • the active ingredients When formulated as an ointment, the active ingredients are typically combined with a paraffin or water-miscible ointment base.
  • the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base.
  • Such transdermal formulations are well known in the art and often include other ingredients for promoting stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by this invention.
  • transdermal administration may be achieved using reservoir or porous membrane types, or a variety of solid matrix patches.
  • compositions for oral administration, injection or topical administration are merely representative.
  • Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which article is incorporated by reference.
  • the compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system.
  • sustained release materials can be found in Remington's Pharmaceutical Sciences.
  • the invention also relates to pharmaceutically acceptable formulations of the compounds of the invention.
  • the formulation includes water.
  • the formulation contains a cyclodextrin derivative.
  • the most common cyclodextrins are ⁇ -, ⁇ - and ⁇ -cyclodextrins consisting of 6, 7 and 8 ⁇ -1,4-linked glucose units respectively, optionally including a or multiple substituents including, but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions.
  • the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, for example, US 5,376,645.
  • the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
  • 3C-like protease inhibitors For diseases caused by viral infections, the development of 3C-like protease inhibitors can provide therapeutic benefits for a large number of patients.
  • the compounds in the present invention exert therapeutic effects by negatively regulating the activity of 3C-like protease in viruses, especially viruses with P132H mutation in the 3C-like protease.
  • the 3C-like protease inhibitors of the present invention can treat various diseases caused by viral infections and their complications.
  • these compounds can be used to treat the following diseases caused by viral infections: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, smell disorder, taste disorder and its complications, etc.
  • these compounds can be used for the above-mentioned diseases or symptoms caused by SARS-CoV-2 infection.
  • the 3C-like protease inhibitor of the present invention can be combined with other drugs to treat cancer, and contains at least one target drug/viral activity modulator, including Remdesivir (Remdesivir or GS-5734), Lopinavir (Lopinavir) ), Molnupiravir, Ritonavir, chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine and/or alpha-interferon, etc.
  • Remdesivir Remdesivir or GS-5734
  • Lopinavir Lopinavir
  • Molnupiravir Ritonavir
  • chloroquine Chloroquine or Sigma-C6628
  • hydroxychloroquine and/or alpha-interferon etc.

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Abstract

Provided in the present invention is a 3C-like protease inhibitor as shown in formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof. Also provided in the present invention are a preparation method of the compound, a pharmaceutical composition containing the compound, and an effect of the compound in treating or preventing diseases caused by virus infection.

Description

3C样蛋白酶抑制剂3C-like protease inhibitor
本申请要求提交于2022年5月27日的中国申请202210600337.0、以及提交于2023年1月20日的中国申请202310077572.9的优先权，将它们以其整体引入本文作为参考。This application claims priority to Chinese application 202210600337.0, filed on May 27, 2022, and Chinese application 202310077572.9, filed on January 20, 2023, which are incorporated herein by reference in their entirety.
技术领域Technical field
本发明涉及一类新的3C样蛋白酶抑制剂，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。本发明还涉及所述化合物的制备方法、包含所述化合物的药物组合物，以及所述化合物在治疗或预防病毒感染导致的疾病中的作用。The present invention relates to a new class of 3C-like protease inhibitors, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof . The present invention also relates to methods for preparing the compounds, pharmaceutical compositions containing the compounds, and the effects of the compounds in treating or preventing diseases caused by viral infections.
背景技术Background technique
2019年12月发现的新型冠状病毒一开始被命名为2019-nCoV，世界卫生组织(WHO)将其改称为COVID-19，之后国际病毒分类委员会根据系统学、分类学和惯例，正式将新型冠状病毒命名为SARS-CoV-2。SARS-CoV-2可引起严重急性呼吸道(SARI)症状，包括发烧、呼吸困难、乏力和肺炎等。The new coronavirus discovered in December 2019 was initially named 2019-nCoV. The World Health Organization (WHO) renamed it COVID-19. Later, the International Committee on Classification of Viruses officially classified the new coronavirus as 2019-nCoV based on systematics, taxonomy and convention. The virus was named SARS-CoV-2. SARS-CoV-2 can cause severe acute respiratory (SARI) symptoms, including fever, dyspnea, fatigue, and pneumonia.
在所有已知的RNA病毒中，冠状病毒的最大基因组长度在约26到32kb之间。除编码结构蛋白外，冠状病毒基因组的大部分也被转录并翻译成多肽，该多肽编码病毒复制和基因表达所必需的蛋白质。约306aa长的主要蛋白酶(Mpro)是冠状病毒复制的关键酶，也由该多肽编码，并负责将该多肽加工为功能蛋白。Mpro具有与微小RNA病毒3C蛋白酶(3Cpro)相似的切割位点特异性，因此也称为3C样蛋白酶(3CLpro)。研究表明，不同的冠状病毒的3CLpro在序列和3D结构方面都高度保守。这些特征及其功能重要性使3CLpro成为抗冠状病毒药物设计的靶标。Among all known RNA viruses, the maximum genome length of coronaviruses ranges from approximately 26 to 32 kb. In addition to encoding structural proteins, much of the coronavirus genome is transcribed and translated into polypeptides that encode proteins necessary for viral replication and gene expression. The approximately 306 aa long main protease (Mpro) is a key enzyme for coronavirus replication and is also encoded by this polypeptide and is responsible for processing this polypeptide into functional proteins. Mpro has a similar cleavage site specificity to picornavirus 3C protease (3Cpro), so it is also called 3C-like protease (3CLpro). Research shows that 3CLpro of different coronaviruses is highly conserved in both sequence and 3D structure. These characteristics and their functional importance make 3CLpro a target for anti-coronavirus drug design.
3CLpro的作用是在适当位点水解切割经表达的肽链，为肽链形成三维四维结构做准备，以形成病毒增殖所需要的酶。在催化过程中酶没有发生改变，但降低了水解反应的活化能，由此加快水解反应的速率，其中，半胱氨酸上的巯基在整个催化水解过程中起关键性作用，参见Thanigaimalai et.al,An Overview of Severe Acute Respiratory Syndrome-Coronavirus(SARS-CoV)3CL Protease Inhibitors:Peptidomimetics and Small Molecule Chemotherapy,Journal of Medicinal Chemistry,59(14):6595-6628。The function of 3CLpro is to hydrolyze and cleave the expressed peptide chain at the appropriate site, preparing the peptide chain to form a three-dimensional and four-dimensional structure to form the enzyme required for virus proliferation. The enzyme does not change during the catalytic process, but the activation energy of the hydrolysis reaction is reduced, thereby accelerating the rate of the hydrolysis reaction. Among them, the sulfhydryl group on cysteine plays a key role in the entire catalytic hydrolysis process, see Thanigaimalai et al. al, An Overview of Severe Acute Respiratory Syndrome-Coronavirus (SARS-CoV) 3CL Protease Inhibitors: Peptidomimetics and Small Molecule Chemotherapy, Journal of Medicinal Chemistry, 59(14):6595-6628.
现有技术中存在关于3CLpro抑制剂的公开文献。例如WO2021/250648A1中公开了目前被称为Nirmatrelvir的化合物(PF-07321332)，其作为帕罗韦德(Paxlovid)的活性成分之一，与其中的利托那韦联用，能够降低由新型冠状病毒SARS-CoV-2导致的死亡和住院风险。There are published documents on 3CLpro inhibitors in the prior art. For example, WO2021/250648A1 discloses a compound currently known as Nirmatrelvir (PF-07321332). As one of the active ingredients of Paxlovid, it can be used in combination with ritonavir to reduce the risk of COVID-19. Risk of death and hospitalization from the virus SARS-CoV-2.
此外，WO2021/205290A1也公开了类似结构的化合物，其通过3C样蛋白酶抑制剂所介导的途径治疗SARS-CoV-2导致的疾病。In addition, WO2021/205290A1 also discloses compounds with similar structures, which treat diseases caused by SARS-CoV-2 through a pathway mediated by 3C-like protease inhibitors.
然而现有技术的化合物均存在不利之处，例如帕罗韦德同时还抑制CYP3A4酶，从而导致可能出现干扰该酶对其他药物的代谢，使半衰期和清除率发生改变，疗效降低或产生不良反应的情形。例如， 患者同时服用帕罗韦德和特非那定时，因帕罗韦德抑制CYP3A4对特非那定的氧化代谢，致使后者在患者体内浓度异常增高，引起心脏的QT波延长和心率失常。而WO2021/205290A1所公开的化合物还面对通过口服给药时无效的问题。因此，研发新的3C样蛋白酶抑制剂的需求日渐迫切。However, existing compounds have disadvantages. For example, Parovide also inhibits the CYP3A4 enzyme, which may interfere with the enzyme's metabolism of other drugs, change the half-life and clearance rate, reduce efficacy, or produce adverse reactions. situation. For example, When patients take parovide and terfenadine at the same time, because parovide inhibits the oxidative metabolism of terfenadine by CYP3A4, the concentration of the latter in the patient's body increases abnormally, causing cardiac QT wave prolongation and arrhythmia. The compounds disclosed in WO2021/205290A1 also face the problem of being ineffective when administered orally. Therefore, the need to develop new 3C-like protease inhibitors is increasingly urgent.
发明内容Contents of the invention
本发明以3C样蛋白酶作为靶点，研发了一类新的小分子抑制剂，可用于治疗或预防病毒感染。The present invention uses 3C-like protease as a target and develops a new class of small molecule inhibitors, which can be used to treat or prevent viral infections.
本发明化合物靶向3C样蛋白酶，对具有P132H突变的3C样蛋白酶具有优异的抑制活性，能够显著抑制SARS-CoV-2的增殖。The compound of the present invention targets 3C-like protease, has excellent inhibitory activity against 3C-like protease with P132H mutation, and can significantly inhibit the proliferation of SARS-CoV-2.
在一个方面，本发明提供了式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof Object:
其中：in:
其中，in,
Y为N或CR7；Y is N or CR 7 ;
R7选自H、C1-6烷基或C1-6卤代烷基；R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L1选自化学键、C1-6亚烷基、-NH-、-O-或-S-；L 1 is selected from chemical bond, C 1-6 alkylene, -NH-, -O- or -S-;
R1选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基、3-10元杂环基、C6-20芳基或5-20元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；所述R1优选为C6-10芳基或5-10元杂芳基；R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
R1s选自H、氘、CN、NO2、NH2、OH、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、卤代C2-6烯基、C2-6炔基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基或-O-3-8元杂芳基；R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 Metaheteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, - NH-3-8-membered heterocyclyl, -NH-3-8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 aryl, -O-3-8-membered heterocyclyl or -O-3-8-membered heteroaryl;
或者，同一个碳原子上的两个R1s一起形成氧代或硫代；Alternatively, two R 1s on the same carbon atom together form oxo or sulfo;
L2选自化学键或C1-6亚烷基；L 2 is selected from chemical bond or C 1-6 alkylene;
R2选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，优选为C6-10芳基，更优选为苯基，所述R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代； R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
R2s选自H、D、卤素、CN、-L2a-R’或 R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a为-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-10烷基、C1-10烷氧基、C1-10卤代烷基、C1- 10卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6烯基或C2-6炔基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , Boc, C 2-6 alkenyl or C 2-6 alkynyl, or the same Two R's on a carbon atom together form C=O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自H、NH2、CN、C0-6亚烷基-C(O)Ra、C0-6亚烷基-C(O)ORa、C1-6亚烷基-OC(O)-Ra、C0-6亚烷基-NHC(O)Ra、C0-6亚烷基-C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C2-6烯基或C2- 6炔基；R' is selected from H, NH 2 , CN, C 0-6 alkylene-C(O)R a , C 0-6 alkylene-C(O)OR a , C 1-6 alkylene-OC (O)-R a , C 0-6 alkylene-NHC(O)R a , C 0-6 alkylene-C(O)NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OR a , C 2-6 alkenyl or C 2- 6 alkynyl;
L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
R3选自C6-14芳基或5-14杂芳基、C3-8环烷基、3至14元杂环基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
R3s选自H、氘、卤素、CN、NO2、NH2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤代C1- 6烷基、卤代C1-6烷氧基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基、-O-3-8元杂芳基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group , 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基、C2-6烯基或C2-6炔基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在另一个方面，本发明提供了式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In another aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
其中：in:
Y为N或CR7；Y is N or CR 7 ;
R7选自H、C1-6烷基或C1-6卤代烷基；R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L1选自化学键或C1-6亚烷基，-NH-、-O-或-S-；L 1 is selected from chemical bond or C 1-6 alkylene group, -NH-, -O- or -S-;
R1选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基、3-10元杂环基、C6-20芳基或5-20元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；所述R1优选为C6-10芳基或5-10元杂芳基；R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
R1s选自H、氘、CN、NO2、NH2、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、卤代C2-6烯基、C2-6炔基、卤代C2-6炔基、C6-10芳基、3至8元杂环基、3至8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基或-O-3-8元杂芳基；R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclic group Aryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH- 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl base, -OC 6-10 aryl group, -O-3-8 membered heterocyclyl group or -O-3-8 membered heteroaryl group;
L2选自化学键或C1-6亚烷基；L 2 is selected from chemical bond or C 1-6 alkylene;
R2选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，优选为C6-10芳基，更优选为苯基，所述R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代；R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
R2s选自H、D、卤素、CN、-L2a-R’或 R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a优选-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-10烷基、C1-10烷氧基、C1-10卤代烷基、C1-10卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6烯基或C2-6炔基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , Boc, C 2-6 alkenyl or C 2-6 alkynyl, or the same Two R's on a carbon atom together form C=O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
L3为-NRb-或-CRaRb-； L 3 is -NR b - or -CR a R b -;
R3选自C6-14芳基或5-14杂芳基、C3-8环烷基、3至14元杂环基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
R3s选自H、氘、卤素、CN、NO2、NH2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1- 6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基、-O-3-8元杂芳基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group, 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH - 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基、C2-6烯基或C2-6炔基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在另一个方面，本发明提供了一种药物组合物，所述药物组合物含有本发明化合物，和任选地药学上可接受的赋形剂，例如载体、佐剂或媒介物。In another aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, and optionally a pharmaceutically acceptable excipient, such as a carrier, adjuvant or vehicle.
在另一个方面，本发明提供了含有本发明化合物和药学上可接受的赋形剂的药物组合物，其还含有其它治疗剂，例如选自：瑞德西韦(Remdesivir或GS-5734)、洛匹那韦(Lopinavir)、莫努匹韦(Molnupiravir)、利托那韦(Ritonavir)、氯喹(Chloroquine或Sigma-C6628)、羟氯喹或α-干扰素。In another aspect, the present invention provides a pharmaceutical composition containing a compound of the present invention and a pharmaceutically acceptable excipient, which also contains other therapeutic agents, for example, selected from: Remdesivir (Remdesivir or GS-5734), Lopinavir, Molnupiravir, Ritonavir, chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine, or alpha-interferon.
在另一个方面，本发明提供了本发明化合物或本发明药物组合物在制备用于治疗和/或预防病毒感染导致的疾病的药物中的用途。In another aspect, the present invention provides the use of a compound of the present invention or a pharmaceutical composition of the present invention in the preparation of a medicament for treating and/or preventing diseases caused by viral infection.
在另一个方面，本发明提供了在受试者中治疗和/或预防病毒感染导致的疾病的方法，包括向所述受试者给药本发明化合物或本发明药物组合物。In another aspect, the invention provides a method of treating and/or preventing diseases caused by viral infection in a subject, comprising administering to the subject a compound of the invention or a pharmaceutical composition of the invention.
在另一个方面，本发明提供了本发明化合物或本发明药物组合物，其用于治疗和/或预防病毒感染导致的疾病。In another aspect, the invention provides a compound of the invention or a pharmaceutical composition of the invention for treating and/or preventing diseases caused by viral infection.
在具体实施方案中，本发明化合物或药物组合物用于抑制病毒增殖；In specific embodiments, the compounds or pharmaceutical compositions of the invention are used to inhibit viral proliferation;
在另一具体实施方案中，本发明化合物或药物组合物抑制病毒3CL蛋白酶的活性。In another specific embodiment, a compound or pharmaceutical composition of the invention inhibits the activity of viral 3CL protease.
在另一具体实施方案中，所述3CL蛋白酶具有P132H突变。In another specific embodiment, the 3CL protease has a P132H mutation.
在另一具体实施方案中，所述病毒为冠状病毒，优选为α冠状病毒和/或β冠状病毒，更优选为SARS-CoV-2。In another specific embodiment, the virus is a coronavirus, preferably an alphacoronavirus and/or a betacoronavirus, more preferably SARS-CoV-2.
在另一具体实施方案中，本发明用于治疗和/或预防以下病毒感染导致的疾病：发热、恶心、呕吐、头痛、呼吸困难、乏力、呼吸道感染、肺炎、嗅觉障碍、味觉障碍及其并发症，或其组合。In another specific embodiment, the present invention is used to treat and/or prevent the following diseases caused by viral infections: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, olfactory disorder, taste disorder and its complications. disease, or a combination thereof.
定义definition
化学定义 chemical definition
下面更详细地描述具体官能团和化学术语的定义。Definitions of specific functional groups and chemical terms are described in more detail below.
当列出数值范围时，既定包括每个值和在所述范围内的子范围。例如“C1-6烷基”包括C1、C2、C3、C4、C5、C6、C1-6、C1-5、C1-4、C1-3、C1-2、C2-6、C2-5、C2-4、C2-3、C3-6、C3-5、C3-4、C4-6、C4-5和C5-6烷基。When numerical ranges are listed, each value and subrange within the stated range is intended to be included. For example, "C 1-6 alkyl" includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1-6 , C 1-5 , C 1-4 , C 1-3 , C 1 -2 , C 2-6 , C 2-5 , C 2-4 , C 2-3 , C 3-6 , C 3-5, C 3-4 , C 4-6 , C 4-5 and C 5 -6 alkyl.
“C1-10烷基”是指具有1至10个碳原子的直链或支链饱和烃基团。在一些实施方案中，C1-6烷基、C1-4烷基、C1-3烷基和C1-2烷基是优选的。C1-6烷基的例子包括：甲基(C1)、乙基(C2)、正丙基(C3)、异丙基(C3)、正丁基(C4)、叔丁基(C4)、仲丁基(C4)、异丁基(C4)、正戊基(C5)、3-戊基(C5)、戊基(C5)、新戊基(C5)、3-甲基-2-丁基(C5)、叔戊基(C5)和正己基(C6)。术语“C1-6烷基”还包括杂烷基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。常规烷基缩写包括：Me(-CH3)、Et(-CH2CH3)、iPr(-CH(CH3)2)、nPr(-CH2CH2CH3)、n-Bu(-CH2CH2CH2CH3)或i-Bu(-CH2CH(CH3)2)。"C 1-10 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 10 carbon atoms. In some embodiments, C 1-6 alkyl, C 1-4 alkyl, C 1-3 alkyl, and C 1-2 alkyl are preferred. Examples of C 1-6 alkyl groups include: methyl (C 1 ), ethyl (C 2 ), n-propyl (C 3 ), isopropyl (C 3 ), n-butyl (C 4 ), tert-butyl base (C 4 ), sec-butyl (C 4 ), isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentyl (C 5 ), pentyl (C 5 ), neopentyl ( C 5 ), 3-methyl-2-butyl (C 5 ), tert-pentyl (C 5 ) and n-hexyl (C 6 ). The term "C 1-6 alkyl" also includes heteroalkyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Alkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent. Conventional alkyl abbreviations include: Me(-CH 3 ), Et(-CH 2 CH 3 ), iPr(-CH(CH 3 ) 2 ), nPr(-CH 2 CH 2 CH 3 ), n-Bu(-CH 2 CH 2 CH 2 CH 3 ) or i-Bu(-CH 2 CH(CH 3 ) 2 ).
“C2-6烯基”是指具有2至6个碳原子和至少一个碳碳双键的直链或支链烃基团。在一些实施方案中，C2-4烯基是优选的。C2-6烯基的例子包括：乙烯基(C2)、1-丙烯基(C3)、2-丙烯基(C3)、1-丁烯基(C4)、2-丁烯基(C4)、丁二烯基(C4)、戊烯基(C5)、戊二烯基(C5)、己烯基(C6)，等等。术语“C2-6烯基”还包括杂烯基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。烯基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"C 2-6 alkenyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms and at least one carbon-carbon double bond. In some embodiments, C 2-4 alkenyl is preferred. Examples of C 2-6 alkenyl groups include: vinyl (C 2 ), 1-propenyl (C 3 ), 2-propenyl (C 3 ), 1-butenyl (C 4 ), 2-butenyl (C 4 ), butadienyl (C 4 ), pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), etc. The term "C 2-6 alkenyl" also includes heteroalkenyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. Alkenyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C2-6炔基”是指具有2至6个碳原子、至少一个碳-碳叁键以及任选地一个或多个碳-碳双键的直链或支链烃基团。在一些实施方案中，C2-4炔基是优选的。C2-6炔基的例子包括但不限于：乙炔基(C2)、1-丙炔基(C3)、2-丙炔基(C3)、1-丁炔基(C4)、2-丁炔基(C4)，戊炔基(C5)、己炔基(C6)，等等。术语“C2- 6炔基”还包括杂炔基，其中一或多个(例如，1、2、3或4个)碳原子被杂原子(例如，氧、硫、氮、硼、硅、磷)替代。炔基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"C 2-6 alkynyl" refers to a straight or branched chain hydrocarbon group having 2 to 6 carbon atoms, at least one carbon-carbon triple bond, and optionally one or more carbon-carbon double bonds. In some embodiments, C 2-4 alkynyl is preferred. Examples of C 2-6 alkynyl groups include, but are not limited to: ethynyl (C 2 ), 1-propynyl (C 3 ), 2-propynyl (C 3 ), 1-butynyl (C 4 ), 2-Butynyl (C 4 ), pentynyl (C 5 ), hexynyl (C 6 ), etc. The term "C 2-6 alkynyl" also includes heteroalkynyl groups in which one or more (e.g., 1, 2, 3, or 4) carbon atoms are replaced by heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, Phosphorus) substitution. An alkynyl group may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C1-6亚烷基”是指除去C1-6烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C1-4亚烷基、C2-4亚烷基和C1-3亚烷基是优选的。未取代的所述亚烷基包括但不限于：亚甲基(-CH2-)、亚乙基(-CH2CH2-)、亚丙基(-CH2CH2CH2-)、亚丁基(-CH2CH2CH2CH2-)、亚戊基(-CH2CH2CH2CH2CH2-)、亚己基(-CH2CH2CH2CH2CH2CH2-)，等等。示例性的取代的所述亚烷基，例如，被一个或多个烷基(甲基)取代的所述亚烷基，包括但不限于：取代的亚甲基(-CH(CH3)-、-C(CH3)2-)、取代的亚乙基(-CH(CH3)CH2-、-CH2CH(CH3)-、-C(CH3)2CH2-、-CH2C(CH3)2-)、取代的亚丙基(-CH(CH3)CH2CH2-、-CH2CH(CH3)CH2-、-CH2CH2CH(CH3)-、-C(CH3)2CH2CH2-、-CH2C(CH3)2CH2-、- CH2CH2C(CH3)2-)，等等。"C 1-6 alkylene" refers to a divalent group formed by removing another hydrogen of C 1-6 alkyl, and may be substituted or unsubstituted. In some embodiments, C 1-4 alkylene, C 2-4 alkylene, and C 1-3 alkylene are preferred. The unsubstituted alkylene group includes, but is not limited to: methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (-CH 2 CH 2 CH 2 -), ethylene Base (-CH 2 CH 2 CH 2 CH 2 -), pentylene (-CH 2 CH 2 CH 2 CH 2 CH 2 -), hexylene (-CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -) ,etc. Exemplary substituted alkylene groups, for example, the alkylene groups substituted by one or more alkyl (methyl) include, but are not limited to: substituted methylene (-CH(CH 3 )- , -C(CH 3 ) 2 -), substituted ethylene (-CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -C(CH 3 ) 2 CH 2 -, -CH 2 C(CH 3 ) 2- ), substituted propylene (-CH(CH 3 )CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH 2 CH 2 CH(CH 3 ) -, -C(CH 3 ) 2 CH 2 CH 2 -, -CH 2 C(CH 3 ) 2 CH 2 -, - CH 2 CH 2 C(CH 3 ) 2 -), etc.
“C2-6亚烯基”是指除去C2-6烯基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C2-4亚烯基是特别优选的。示例性的未取代的所述亚烯基包括但不限于：亚乙烯基(-CH＝CH-)和亚丙烯基(例如，-CH＝CHCH2-、-CH2-CH＝CH-)。示例性的取代的所述亚烯基，例如，被一个或多个烷基(甲基)取代的亚烯基，包括但不限于：取代的亚乙基(-C(CH3)＝CH-、-CH＝C(CH3)-)、取代的亚丙烯基(-C(CH3)＝CHCH2-、-CH＝C(CH3)CH2-、-CH＝CHCH(CH3)-、-CH＝CHC(CH3)2-、-CH(CH3)-CH＝CH-、-C(CH3)2-CH＝CH-、-CH2-C(CH3)＝CH-、-CH2-CH＝C(CH3)-)，等等。"C 2-6 alkenylene" refers to a divalent group formed by removing the other hydrogen of the C 2-6 alkenyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkenylene is particularly preferred. Exemplary unsubstituted alkenylene groups include, but are not limited to: vinylene (-CH=CH-) and propenylene (eg, -CH= CHCH2- , -CH2 -CH=CH-). Exemplary substituted alkenylene groups, such as alkenylene groups substituted by one or more alkyl (methyl) groups, include but are not limited to: substituted ethylene (-C(CH 3 )=CH- , -CH＝C(CH 3 )-), substituted propenylene (-C(CH 3 )＝CHCH 2 -, -CH＝C(CH 3 )CH 2 -, -CH＝CHCH(CH 3 )- , -CH＝CHC(CH 3 ) 2 -, -CH(CH 3 )-CH＝CH-, -C(CH 3 ) 2 -CH＝CH-, -CH 2 -C(CH 3 )＝CH-, -CH 2 -CH=C(CH 3 )-), etc.
“C2-6亚炔基”是指除去C2-6炔基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C2-4亚炔基是特别优选的。示例性的所述亚炔基包括但不限于：亚乙炔基(-C≡C-)、取代或未取代的亚丙炔基(-C≡CCH2-)，等等。"C 2-6 alkynylene" refers to a divalent group formed by removing the other hydrogen of the C 2-6 alkynyl group, and may be substituted or unsubstituted. In some embodiments, C 2-4 alkynylene is particularly preferred. Exemplary alkynylene groups include, but are not limited to: ethynylene (-C≡C-), substituted or unsubstituted propynylene (-C≡CCH 2 -), and the like.
“C0-6亚烷基”是指化学键以及上述“C1-6亚烷基”，“C0-4亚烷基”是指化学键以及上述“C1-4亚烷基”，“C0-3亚烷基”是指化学键以及上述“C1-3亚烷基”。"C 0-6 alkylene" means a chemical bond and the above-mentioned "C 1-6 alkylene", "C 0-4 alkylene" means a chemical bond and the above-mentioned "C 1-4 alkylene", "C "0-3 alkylene" refers to a chemical bond as well as the above-mentioned "C 1-3 alkylene".
“C1-10烷氧基”是指O-C1-10烷基。在一些实施方案中，C1-6烷基是优选的。在另一些实施方案中，C1-4烷氧基是优选的，例如，甲氧基、乙氧基等。"C 1-10 alkoxy" refers to OC 1-10 alkyl. In some embodiments, C 1-6 alkyl is preferred. In other embodiments, C 1-4 alkoxy is preferred, for example, methoxy, ethoxy, etc.
“卤代”或“卤素”是指氟(F)、氯(Cl)、溴(Br)和碘(I)。"Halo" or "halogen" refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
因此，“C1-10卤代烷基”是指上述“C1-10烷基”，其被一个或多个卤素基团取代。在一些实施方案中，C1-6卤代烷基是优选的，C1-4卤代烷基是特别优选的，更优选C1-3卤代烷基，更优选C1-2卤代烷基。示例性的所述卤代烷基包括但不限于：-CF3、-CH2F、-CHF2、-CHFCH2F、-CH2CHF2、-CF2CF3、-CCl3、-CH2Cl、-CHCl2、2,2,2-三氟-1,1-二甲基-乙基，等等。卤代烷基基团可以在任何可用的连接点上被取代，例如，1至5个取代基、1至3个取代基或1个取代基。Therefore, "C 1-10 haloalkyl" refers to the above-mentioned "C 1-10 alkyl" which is substituted by one or more halogen groups. In some embodiments, C 1-6 haloalkyl is preferred, C 1-4 haloalkyl is particularly preferred, C 1-3 haloalkyl is more preferred, and C 1-2 haloalkyl is more preferred. Exemplary haloalkyl groups include, but are not limited to: -CF 3 , -CH 2 F, -CHF 2 , -CHFCH 2 F, -CH 2 CHF 2 , -CF 2 CF 3 , -CCl 3 , -CH 2 Cl , -CHCl 2 , 2,2,2-trifluoro-1,1-dimethyl-ethyl, etc. Haloalkyl groups may be substituted at any available point of attachment, for example, 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C1-6卤代烷氧基”是指O-C1-6卤代烷基。在一些实施方案中，C1-4卤代烷氧基是优选的，例如，卤代甲氧基、卤代乙氧基等。"C 1-6 haloalkoxy" refers to OC 1-6 haloalkyl. In some embodiments, C 1-4 haloalkoxy is preferred, for example, halomethoxy, haloethoxy, and the like.
“C3-10环烷基”和“C3-10环烯基”是指具有3至10个环碳原子和零个杂原子的非芳香环烃基团，其中任选地含有1、2或3个双键或叁键。在一些实施方案中，C5-10环烷基、C3-7环烷基和C3-6环烷基是特别优选的，更优选C5-7环烷基和C5-6环烷基。环烷基还包括其中上述环烷基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在环烷基环上，且在这样的情况中，碳的数目继续表示环烷基体系中的碳的数目。环烷基还包括其中上述环烷基环，其中任意不相邻的碳原子上的取代基相连形成桥环，一起形成共用两个或两个以上碳原子的多环烷烃。环烷基还包括其中上述环烷基环，其中同一碳原子上的取代基相连成环，一起形成共用一个碳原子的多环烷烃。示例性的所述环烷基包括但不限于：环丙基(C3)、环丙烯基(C3)、环丁基(C4)、环丁烯基(C4)、环戊基(C5)、环戊烯基(C5)、环己基(C6)、环己烯基(C6)、环已二烯基(C6)、环庚基(C7)、环庚烯基(C7)、环庚二烯基(C7)、环庚三烯基(C7)，等等。环 烷基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"C 3-10 cycloalkyl" and "C 3-10 cycloalkenyl" refer to non-aromatic cyclic hydrocarbon groups having 3 to 10 ring carbon atoms and zero heteroatoms, optionally containing 1, 2 or 3 double or triple bonds. In some embodiments, C 5-10 cycloalkyl, C 3-7 cycloalkyl and C 3-6 cycloalkyl are particularly preferred, with C 5-7 cycloalkyl and C 5-6 cycloalkyl being more preferred base. Cycloalkyl also includes ring systems in which the above-described cycloalkyl ring is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the cycloalkyl ring, and in such cases the number of carbons continues as indicated The number of carbons in a cycloalkyl system. Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which the substituents on any non-adjacent carbon atoms are connected to form a bridged ring, which together form a polycyclic alkane sharing two or more carbon atoms. Cycloalkyl also includes the above-mentioned cycloalkyl rings, in which substituents on the same carbon atom are connected to form a ring, and together form a polycyclic alkane sharing one carbon atom. Exemplary cycloalkyl groups include, but are not limited to: cyclopropyl (C 3 ), cyclopropenyl (C 3 ), cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl ( C 5 ), cyclopentenyl (C 5 ), cyclohexyl (C 6 ), cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), cycloheptyl (C 7 ), cycloheptene group (C 7 ), cycloheptadienyl (C 7 ), cycloheptadienyl (C 7 ), etc. ring Alkyl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“C3-10亚环烷基”是指除去C3-10环烷基的另一个氢而形成的二价基团，并且可以是取代或未取代的。在一些实施方案中，C5-10亚环烷基、C5-7亚环烷基、C3-7亚环烷基、C3-6亚环烷基和C3-4亚环烷基是特别优选的，尤其优选亚环丙基。"C 3-10 cycloalkylene" refers to a divalent group formed by removing another hydrogen of C 3-10 cycloalkyl, and may be substituted or unsubstituted. In some embodiments, C 5-10 cycloalkylene, C 5-7 cycloalkylene, C 3-7 cycloalkylene, C 3-6 cycloalkylene, and C 3-4 cycloalkylene is particularly preferred, and cyclopropylene is particularly preferred.
“3-14元杂环基”是指具有环碳原子和1至7个环杂原子的3至14元非芳香环系的饱和或不饱和基团，其中，每个杂原子独立地选自氮、氧、硫、硼、磷和硅，其中任选地含有1、2或3个双键或叁键。在包含一个或多个氮原子的杂环基中，只要化合价允许，连接点可为碳或氮原子。在一些实施方案中，优选3-10元杂环基，其为具有环碳原子和1至5个环杂原子的3至10元非芳香环系；在一些实施方案中，优选5-10元杂环基，其为具有环碳原子和1至5个环杂原子的5至10元非芳香环系；在一些实施方案中，优选3-7元杂环基，其为具有环碳原子和1至4个环杂原子的3至7元非芳香环系；优选5-7元杂环基，其为具有环碳原子和1至3个环杂原子的5至7元非芳香环系；优选3-6元杂环基，其为具有环碳原子和1至3个环杂原子的3至6元非芳香环系；优选4-6元杂环基，其为具有环碳原子和1至3个环杂原子的4至6元非芳香环系；更优选5-6元杂环基，其为具有环碳原子和1至3个环杂原子的5至6元非芳香环系。更优选5元杂环基，其为具有环碳原子和1至3个环杂原子的5元非芳香环系杂环基还包括其中上述杂环基环与一个或多个环烷基稠合的环体系，其中连接点在杂环基环上，或其中上述杂环基环与一个或多个芳基或杂芳基稠合的环体系，其中连接点在杂环基环上；且在这样的情况下，环成员的数目继续表示在杂环基环体系中环成员的数目。杂环基还包括其中上述杂环基环，其中任意不相邻的碳或氮原子上的取代基相连形成桥环，一起形成共用两个或两个以上碳或氮原子的多环杂烷烃。杂环基还包括其中上述杂环基环，其中同一碳原子上的取代基相连成环，一起形成共用一个碳原子的多环杂烷烃。示例性的包含一个杂原子的3元杂环基包括但不限于：氮杂环丙烷基、氧杂环丙烷基、硫杂环丙烷基(thiorenyl)。示例性的含有一个杂原子的4元杂环基包括但不限于：氮杂环丁烷基、氧杂环丁烷基和硫杂环丁烷基。示例性的含有一个杂原子的5元杂环基包括但不限于：四氢呋喃基、二氢呋喃基、2,5-二氢呋喃基、四氢噻吩基、二氢噻吩基、吡咯烷基、二氢吡咯基和吡咯基-2,5-二酮。示例性的包含两个杂原子的5元杂环基包括但不限于：吡唑烷基、二氧杂环戊烷基、氧硫杂环戊烷基(oxasulfuranyl)、二硫杂环戊烷基(disulfuranyl)和噁唑烷-2-酮。示例性的包含三个杂原子的5元杂环基包括但不限于：三唑啉基、噁二唑啉基和噻二唑啉基。示例性的包含一个杂原子的6元杂环基包括但不限于：哌啶基、四氢吡喃基、二氢吡啶基和硫杂环己烷基(thianyl)。示例性的包含两个杂原子的6元杂环基包括但不限于：哌嗪基、吗啉基、二硫杂环己烷基、二噁烷基。示例性的包含三个杂原子的6元杂环基包括但不限于：六氢三嗪基(triazinanyl)。示例性的含有一个杂原子的7元杂环基包括但不限于：氮杂环庚烷基、氧杂环庚烷基和硫杂环庚烷基。示例性的与C6芳 基环稠合的5元杂环基(在本文中也称作5,6-双环杂环基)包括但不限于：二氢吲哚基、异二氢吲哚基、二氢苯并呋喃基、二氢苯并噻吩基、苯并噁唑啉酮基，等等。示例性的与C6芳基环稠合的6元杂环基(本文还指的是6,6-双环杂环基)包括但不限于：四氢喹啉基、四氢异喹啉基，等等。杂环基还包括上述杂环基与一个环烷基、杂环基、芳基或杂芳基共享一个或两个原子，形成桥环或螺环，只要化合价允许，共享的原子可为碳或氮原子。杂环基还包括上述杂环基与杂环基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"3-14 membered heterocyclyl" refers to a saturated or unsaturated group of 3 to 14 membered non-aromatic ring system having ring carbon atoms and 1 to 7 ring heteroatoms, wherein each heteroatom is independently selected from Nitrogen, oxygen, sulfur, boron, phosphorus and silicon, optionally containing 1, 2 or 3 double or triple bonds. In heterocyclyl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valency permits. In some embodiments, 3-10 membered heterocyclyl is preferred, which is a 3-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 5-10 membered is preferred Heterocyclyl, which is a 5 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3 to 7 membered heterocyclyl is preferred, which is a 5 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms. A 3- to 7-membered non-aromatic ring system with 1 to 4 ring heteroatoms; preferably a 5-7-membered heterocyclic group, which is a 5- to 7-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; Preferred are 3-6-membered heterocyclyl groups, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms; preferred are 4-6-membered heterocyclyl groups, which are 3- to 6-membered non-aromatic ring systems having ring carbon atoms and 1 to 3 ring heteroatoms. to a 4- to 6-membered non-aromatic ring system with 3 ring heteroatoms; more preferably a 5-6-membered heterocyclyl, which is a 5- to 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms. More preferred is a 5-membered heterocyclyl group, which is a 5-membered non-aromatic ring system heterocyclyl group having ring carbon atoms and 1 to 3 ring heteroatoms. It also includes wherein the above-mentioned heterocyclyl ring is fused with one or more cycloalkyl groups. and in In such cases, the number of ring members continues to represent the number of ring members in the heterocyclyl ring system. Heterocyclyl also includes the above-mentioned heterocyclyl rings, in which the substituents on any non-adjacent carbon or nitrogen atoms are connected to form a bridged ring, which together form a polycyclic heteroalkane sharing two or more carbon or nitrogen atoms. Heterocyclyl also includes the above-mentioned heterocyclyl rings, in which substituents on the same carbon atom are connected to form a ring and together form a polycyclic heteroalkane sharing one carbon atom. Exemplary 3-membered heterocyclyl groups containing one heteroatom include, but are not limited to: aziridinyl, oxirinyl, and thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azetidinyl, oxetanyl, and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, but are not limited to: tetrahydrofuryl, dihydrofuryl, 2,5-dihydrofuryl, tetrahydrothienyl, dihydrothienyl, pyrrolidinyl, di Hydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: pyrazolidinyl, dioxolyl, oxasulfuranyl, dithiolyl (disulfuranyl) and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, but are not limited to: piperidinyl, tetrahydropyranyl, dihydropyridyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, but are not limited to: piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, but are not limited to: hexahydrotriazinyl (triazinanyl). Exemplary 7-membered heterocyclyl groups containing one heteroatom include, but are not limited to: azepanyl, oxpanyl, and thipanyl. Exemplary with C 6 aromatic The base ring fused 5-membered heterocyclyl (also referred to as 5,6-bicyclic heterocyclyl herein) includes, but is not limited to: indolyl, isoindolyl, dihydrobenzofuranyl , dihydrobenzothienyl, benzoxazolinone, etc. Exemplary 6-membered heterocyclyl fused to a C6 aryl ring (also referred to herein as 6,6-bicyclic heterocyclyl) include, but are not limited to: tetrahydroquinolyl, tetrahydroisoquinolyl, etc. Heterocyclyl also includes the above-mentioned heterocyclyl sharing one or two atoms with a cycloalkyl, heterocyclyl, aryl or heteroaryl to form a bridged ring or spiro ring. As long as the valency allows, the shared atoms can be carbon or Nitrogen atom. Heterocyclyl also includes the above-mentioned heterocyclyl and heterocyclyl groups may be optionally substituted by one or more substituents, for example, by 1 to 5 substituents, 1 to 3 substituents or 1 substituent.
“C6-20芳基”是指具有6-20个环碳原子和零个杂原子的单环或多环的(例如，双环)4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团。在一些实施方案中，C6-10芳基是优选的。在一些实施方案中，芳基具有六个环碳原子(“C6芳基”；例如，苯基)。在一些实施方案中，芳基具有十个环碳原子(“C10芳基”；例如，萘基，例如，1-萘基和2-萘基)。芳基还包括其中上述芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述芳基环上，在这种情况下，碳原子的数目继续表示所述芳基环系统中的碳原子数目。芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"C 6-20 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system (e.g., having a cyclic arrangement) having 6-20 ring carbon atoms and zero heteroatoms. Shared 6 or 10 π electrons) group. In some embodiments, C 6-10 aryl groups are preferred. In some embodiments, an aryl group has six ring carbon atoms ("C 6 aryl"; e.g., phenyl). In some embodiments, an aryl group has ten ring carbon atoms ("C 10 aryl"; eg, naphthyl, eg, 1-naphthyl and 2-naphthyl). Aryl also includes ring systems in which the aryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on said aryl ring, in which case the number of carbon atoms continues to indicate The number of carbon atoms in the aryl ring system. Aryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
“3-20元杂芳基”是指具有环碳原子和1-8个环杂原子的3-20元单环或双环的4n+2芳族环体系(例如，具有以环状排列共享的6或10个π电子)的基团，其中每个杂原子独立地选自氮、氧和硫。在含有一个或多个氮原子的杂芳基中，只要化合价允许，连接点可以是碳或氮原子。杂芳基双环系统在一个或两个环中可以包括一个或多个杂原子。杂芳基还包括其中上述杂芳基环与一个或多个环烷基或杂环基稠合的环系统，而且连接点在所述杂芳基环上，在这种情况下，碳原子的数目继续表示所述杂芳基环系统中的碳原子数目。在一些实施方案中，5-14元杂芳基是特别优选的，其为具有环碳原子和1-6个环杂原子的5-14元单环或双环的4n+2芳族环体系。在一些实施方案中，5-10元杂芳基是特别优选的，其为具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系。在一些实施方案中，5-6元杂芳基是特别优选的，其为具有环碳原子和1-3个环杂原子的5-6元单环或双环的4n+2芳族环体系。示例性的含有一个杂原子的5元杂芳基包括但不限于：吡咯基、呋喃基和噻吩基。示例性的含有两个杂原子的5元杂芳基包括但不限于：咪唑基、吡唑基、噁唑基、异噁唑基、噻唑基和异噻唑基。示例性的含有三个杂原子的5元杂芳基包括但不限于：三唑基、噁二唑基(例如，1,2,4-噁二唑基)和噻二唑基。示例性的含有四个杂原子的5元杂芳基包括但不限于：四唑基。示例性的含有一个杂原子的6元杂芳基包括但不限于：吡啶基或吡啶酮基。示例性的含有两个杂原子的6元杂芳基包括但不限于：哒嗪基、嘧啶基和吡嗪基。示例性的含有三个或四个杂原子的6元杂芳基分别包括但不限于：三嗪基和四嗪基。示例性的含有一个杂原子的7元杂芳基包括但不限于：氮杂环庚三烯基、氧杂环庚三烯基和硫杂环庚三烯基。示例性的5,6-双环杂芳基包括但不限于：吲哚基、异吲哚基、吲唑基、苯并三唑基、苯并吡唑基、苯并噻吩基、异苯并噻吩基、苯并呋喃基、苯并异呋喃基、苯并咪唑基、 苯并噁唑基、苯并异噁唑基、苯并噁二唑基、苯并噻唑基、苯并异噻唑基、苯并噻二唑基、茚嗪基和嘌呤基。示例性的6,6-双环杂芳基包括但不限于：萘啶基、喋啶基、喹啉基、异喹啉基、噌琳基、喹喔啉基、酞嗪基和喹唑啉基。杂芳基基团可以被一或多个取代基任选取代，例如，被1至5个取代基、1至3个取代基或1个取代基取代。"3-20 membered heteroaryl" refers to a 3-20 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-8 ring heteroatoms (e.g., having a 6 or 10 π electrons), in which each heteroatom is independently selected from nitrogen, oxygen and sulfur. In heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom as long as the valency permits. Heteroaryl bicyclic systems may include one or more heteroatoms in one or both rings. Heteroaryl also includes ring systems in which the heteroaryl ring described above is fused to one or more cycloalkyl or heterocyclyl groups, and the point of attachment is on the heteroaryl ring, in which case the carbon atom Number continues to represent the number of carbon atoms in the heteroaryl ring system. In some embodiments, 5-14 membered heteroaryl groups are particularly preferred, which are 5-14 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-6 ring heteroatoms. In some embodiments, 5-10 membered heteroaryl groups are particularly preferred, which are 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 ring heteroatoms. In some embodiments, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-3 ring heteroatoms. Exemplary 5-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyrrolyl, furyl, and thienyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, but are not limited to: imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, but are not limited to: triazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl), and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, but are not limited to: tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, but are not limited to: pyridyl or pyridonyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, but are not limited to: pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, but are not limited to, triazinyl and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, but are not limited to: azepantrienyl, oxetapyltrienyl, and thioheptantrienyl. Exemplary 5,6-bicyclic heteroaryl groups include, but are not limited to: indolyl, isoindolyl, indazolyl, benzotriazolyl, benzopyrazolyl, benzothienyl, isobenzothiophene base, benzofuranyl, benzisofuranyl, benzimidazolyl, Benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indanazinyl and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, but are not limited to: naphthyridinyl, pyridinyl, quinolinyl, isoquinolinyl, quinolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl . Heteroaryl groups may be optionally substituted with one or more substituents, for example, with 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
上文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等基团除去另一个氢而形成的二价基团统称为“亚基”。环烷基、杂环基、芳基和杂芳基等成环的基团统称为“环基”。The divalent groups formed by removing another hydrogen from the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups defined above are collectively referred to as "subunits". Ring-forming groups such as cycloalkyl, heterocyclyl, aryl and heteroaryl are collectively referred to as "cyclic groups".
本文定义的烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基等为任选取代的基团。Alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, etc. are defined herein as optionally substituted groups.
示例性的碳原子上的取代基包括但不局限于：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORaa、-ON(Rbb)2、-N(Rbb)2、-N(Rbb)3 +X-、-N(ORcc)Rbb、-SH、-SRaa、-SSRcc、-C(＝O)Raa、-CO2H、-CHO、-C(ORcc)2、-CO2Raa、-OC(＝O)Raa、-OCO2Raa、-C(＝O)N(Rbb)2、-OC(＝O)N(Rbb)2、-NRbbC(＝O)Raa、-NRbbCO2Raa、-NRbbC(＝O)N(Rbb)2、-C(＝NRbb)Raa、-C(＝NRbb)ORaa、-OC(＝NRbb)Raa、-OC(＝NRbb)ORaa、-C(＝NRbb)N(Rbb)2、-OC(＝NRbb)N(Rbb)2、-NRbbC(＝NRbb)N(Rbb)2、-C(＝O)NRbbSO2Raa、-NRbbSO2Raa、-SO2N(Rbb)2、-SO2Raa、-SO2ORaa、-OSO2Raa、-S(＝O)Raa、-OS(＝O)Raa、-Si(Raa)3、-OSi(Raa)3、-C(＝S)N(Rbb)2、-C(＝O)SRaa、-C(＝S)SRaa、-SC(＝S)SRaa、-SC(＝O)SRaa、-OC(＝O)SRaa、-SC(＝O)ORaa、-SC(＝O)Raa、-P(＝O)2Raa、-OP(＝O)2Raa、-P(＝O)(Raa)2、-OP(＝O)(Raa)2、-OP(＝O)(ORcc)2、-P(＝O)2N(Rbb)2、-OP(＝O)2N(Rbb)2、-P(＝O)(NRbb)2、-OP(＝O)(NRbb)2、-NRbbP(＝O)(ORcc)2、-NRbbP(＝O)(NRbb)2、-P(Rcc)2、-P(Rcc)3、-OP(Rcc)2、-OP(Rcc)3、-B(Raa)2、-B(ORcc)2、-BRaa(ORcc)、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；Exemplary substituents on carbon atoms include, but are not limited to: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR aa , -ON(R bb ) 2 , -N(R bb ) 2 , -N(R bb ) 3 + X - , -N(OR cc )R bb , -SH, -SR aa , -SSR cc , -C(＝O)R aa , -CO 2 H, -CHO, -C(OR cc ) 2 , -CO 2 R aa , -OC(=O)R aa , -OCO 2 R aa , -C(=O)N(R bb ) 2 , -OC(=O)N(R bb ) 2 , -NR bb C(=O)R aa , -NR bb CO 2 R aa , -NR bb C(=O)N(R bb ) 2 , -C (=NR bb )R aa , -C(=NR bb )OR aa , -OC(=NR bb )R aa , -OC(=NR bb )OR aa , -C(=NR bb )N(R bb ) 2 , -OC(=NR bb )N(R bb ) 2 , -NR bb C(=NR bb )N(R bb ) 2 , -C(=O)NR bb SO 2 R aa , -NR bb SO 2 R aa , -SO 2 N(R bb ) 2 , -SO 2 R aa , -SO 2 OR aa , -OSO 2 R aa , -S(=O)R aa , -OS(=O)R aa ,- Si(R aa ) 3 , -OSi(R aa ) 3 , -C(=S)N(R bb ) 2 , -C(=O)SR aa , -C(=S)SR aa , -SC(= S)SR aa , -SC(=O)SR aa , -OC(=O)SR aa , -SC(=O)OR aa , -SC(=O)R aa , -P(=O) 2 R aa , -OP(＝O) 2 R aa , -P(＝O)(R aa ) 2 , -OP(＝O)(R aa ) 2 , -OP(＝O)(OR cc ) 2 , -P( ＝O) 2 N(R bb ) 2 , -OP(＝O) 2 N(R bb ) 2 , -P(＝O)(NR bb ) 2 , -OP(＝O)(NR bb ) 2 ,- NR bb P(＝O)(OR cc ) 2 , -NR bb P(＝O)(NR bb ) 2 , -P(R cc ) 2 , -P(R cc ) 3 , -OP(R cc ) 2 , -OP(R cc ) 3 , -B(R aa ) 2 , -B(OR cc ) 2 , -BR aa (OR cc ), alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, hetero Cyclyl, aryl and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups substituted;
或者在碳原子上的两个偕氢被基团＝O、＝S、＝NN(Rbb)2、＝NNRbbC(＝O)Raa、＝NNRbbC(＝O)ORaa、＝NNRbbS(＝O)2Raa、＝NRbb或＝NORcc取代；Or two bihydrogen groups on carbon atoms =O, =S, =NN(R bb ) 2 , =NNR bb C(=O)R aa , =NNR bb C(=O)OR aa , = NNR bb S(=O) 2 R aa , =NR bb or =NOR cc substituted;
Raa的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Raa基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；Each R aa is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R aa groups are combined to form heterocyclyl or Heteroaryl rings, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl group is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups group replacement;
Rbb的每个独立地选自：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、-C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rbb基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；Each of R bb is independently selected from: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , -C(=O)N(R cc ) 2. -CO 2 R aa , -SO 2 R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C(=O)SR cc , -C(=S)SR cc , -P(=O ) 2 R aa , -P(=O)(R aa ) 2 , -P(=O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkene radical, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R bb groups combined to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkyne Base, cycloalkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R dd groups;
Rcc的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者 两个Rcc基团结合以形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代；Each of Rcc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or Two Rcc groups combine to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd groups substituted;
Rdd的每个独立地选自：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-ORee、-ON(Rff)2、-N(Rff)2,、-N(Rff)3 +X-、-N(ORee)Rff、-SH、-SRee、-SSRee、-C(＝O)Ree、-CO2H、-CO2Ree、-OC(＝O)Ree、-OCO2Ree、-C(＝O)N(Rff)2、-OC(＝O)N(Rff)2、-NRffC(＝O)Ree、-NRffCO2Ree、-NRffC(＝O)N(Rff)2、-C(＝NRff)ORee、-OC(＝NRff)Ree、-OC(＝NRff)ORee、-C(＝NRff)N(Rff)2、-OC(＝NRff)N(Rff)2、-NRffC(＝NRff)N(Rff)2、-NRffSO2Ree、-SO2N(Rff)2、-SO2Ree、-SO2ORee、-OSO2Ree、-S(＝O)Ree、-Si(Ree)3、-OSi(Ree)3、-C(＝S)N(Rff)2、-C(＝O)SRee、-C(＝S)SRee、-SC(＝S)SRee、-P(＝O)2Ree、-P(＝O)(Ree)2、-OP(＝O)(Ree)2、-OP(＝O)(ORee)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基、杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代，或者两个偕Rdd取代基可结合以形成＝O或＝S；Each of R dd is independently selected from: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OR ee , -ON(R ff ) 2 , -N ( R ff ) 2 , -N ( R ff ) 3 + H, -CO 2 R ee , -OC(=O)R ee , -OCO 2 R ee , -C(=O)N(R ff ) 2 , -OC(=O)N(R ff ) 2 , - NR ff C(=O)R ee , -NR ff CO 2 R ee , -NR ff C(=O)N(R ff ) 2 , -C(=NR ff )OR ee , -OC(=NR ff ) R ee , -OC(=NR ff )OR ee , -C(=NR ff )N(R ff ) 2 , -OC(=NR ff )N(R ff ) 2 , -NR ff C(=NR ff ) N(R ff ) 2 , -NR ff SO 2 R ee , -SO 2 N(R ff ) 2 , -SO 2 R ee , -SO 2 OR ee , -OSO 2 R ee , -S(＝O)R ee , -Si(R ee ) 3 , -OSi(R ee ) 3 , -C(=S)N(R ff ) 2 , -C(=O)SR ee , -C(=S)SR ee , - SC(=S)SR ee , -P(=O) 2 R ee , -P(=O)(R ee ) 2 , -OP(=O)(R ee ) 2 , -OP(=O)(OR ee ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle Aryl, aryl and heteroaryl groups are independently substituted with 0, 1, 2, 3, 4 or 5 R gg groups, or two geminal R dd substituents may be combined to form =O or =S;
Ree的每个独立地选自烷基、卤代烷基、烯基、炔基、环烷基、芳基、杂环基和杂芳基，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代；Each R ee is independently selected from alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl, and heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl Alkyl, heterocyclyl, aryl and heteroaryl are independently substituted by 0, 1, 2, 3, 4 or 5 R gg groups;
Rff的每个独立地选自氢、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者两个Rff基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rgg基团取代；Each R ff is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R ff groups combine to form a heterocyclyl or a heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R gg group substitution;
Rgg的每个独立地是：卤素、-CN、-NO2、-N3、-SO2H、-SO3H、-OH、-OC1-6烷基、-ON(C1-6烷基)2、-N(C1-6烷基)2、-N(C1-6烷基)3 +X-、-NH(C1-6烷基)2 +X-、-NH2(C1-6烷基)+X-、-NH3 +X-、-N(OC1-6烷基)(C1-6烷基)、-N(OH)(C1-6烷基)、-NH(OH)、-SH、-SC1-6烷基、-SS(C1-6烷基)、-C(＝O)(C1-6烷基)、-CO2H、-CO2(C1-6烷基)、-OC(＝O)(C1-6烷基)、-OCO2(C1-6烷基)、-C(＝O)NH2、-C(＝O)N(C1-6烷基)2、-OC(＝O)NH(C1-6烷基)、-NHC(＝O)(C1-6烷基)、-N(C1-6烷基)C(＝O)(C1-6烷基)、-NHCO2(C1-6烷基)、-NHC(＝O)N(C1-6烷基)2、-NHC(＝O)NH(C1-6烷基)、-NHC(＝O)NH2、-C(＝NH)O(C1-6烷基)、-OC(＝NH)(C1- 6烷基)、-OC(＝NH)OC1-6烷基、-C(＝NH)N(C1-6烷基)2、-C(＝NH)NH(C1-6烷基)、-C(＝NH)NH2、-OC(＝NH)N(C1-6烷基)2、-OC(NH)NH(C1-6烷基)、-OC(NH)NH2、-NHC(NH)N(C1-6烷基)2、-NHC(＝NH)NH2、-NHSO2(C1-6烷基)、-SO2N(C1-6烷基)2、-SO2NH(C1-6烷基)、-SO2NH2、-SO2C1-6烷基、-SO2OC1-6烷基、-OSO2C1-6烷基、-SOC1-6烷基、-Si(C1-6烷基)3、-OSi(C1-6烷基)3、-C(＝S)N(C1-6烷基)2、C(＝S)NH(C1-6烷基)、C(＝S)NH2、-C(＝O)S(C1-6烷基)、-C(＝S)SC1-6烷基、-SC(＝S)SC1-6烷基、-P(＝O)2(C1-6烷基)、-P(＝O)(C1- 6烷基)2、-OP(＝O)(C1-6烷基)2、-OP(＝O)(OC1-6烷基)2、C1-6烷基、C1-6卤代烷基、C2-C6烯基、C2-C6炔基、C3-C7环烷基、C6-C10芳基、C3-C7杂环基、C5-C10杂芳基；或者两个偕Rgg取代基可结合形成＝O或＝S；其中，X-为反离子。Each of R gg is independently: halogen, -CN, -NO 2 , -N 3 , -SO 2 H, -SO 3 H, -OH, -OC 1-6 alkyl, -ON(C 1-6 Alkyl) 2 , -N(C 1-6 alkyl) 2 , -N(C 1-6 alkyl) 3 + X - , -NH(C 1-6 alkyl) 2 + X - , -NH 2 ( C 1-6 alkyl ) + _ _ _ ), -NH(OH), -SH, -SC 1-6 alkyl, -SS (C 1-6 alkyl), -C (=O) (C 1-6 alkyl), -CO 2 H, -CO 2 (C 1-6 alkyl), -OC (=O) (C 1-6 alkyl), -OCO 2 (C 1-6 alkyl), -C (=O)NH 2 , -C (=O)N(C 1-6 alkyl) 2 , -OC(=O)NH(C 1-6 alkyl), -NHC(=O)(C 1-6 alkyl), -N(C 1-6 alkyl)C(=O)(C 1-6 alkyl), -NHCO 2 (C 1-6 alkyl), -NHC(=O)N(C 1-6 alkyl) 2 , - NHC(=O)NH(C 1-6 alkyl), -NHC(=O)NH 2 , -C(=NH)O(C 1-6 alkyl), -OC(=NH)(C 1- 6 alkyl), -OC(=NH)OC 1-6 alkyl, -C(=NH)N(C 1-6 alkyl) 2 , -C(=NH)NH(C 1-6 alkyl) , -C(=NH)NH 2 , -OC(=NH)N(C 1-6 alkyl) 2 , -OC(NH)NH(C 1-6 alkyl), -OC(NH)NH 2 , -NHC(NH)N(C 1-6 alkyl) 2 , -NHC(=NH)NH 2 , -NHSO 2 (C 1-6 alkyl), -SO 2 N(C 1-6 alkyl) 2 , -SO 2 NH (C 1-6 alkyl), -SO 2 NH 2 , -SO 2 C 1-6 alkyl, -SO 2 OC 1-6 alkyl, -OSO 2 C 1-6 alkyl, -SOC 1-6 alkyl, -Si(C 1-6 alkyl) 3 , -OSi(C 1-6 alkyl) 3 , -C(=S)N(C 1-6 alkyl) 2 , C (=S)NH(C 1-6 alkyl), C(=S)NH 2 , -C(=O)S(C 1-6 alkyl), -C(=S)SC 1-6 alkyl , -SC(=S)SC 1-6 alkyl, -P(=O ) 2 (C 1-6 alkyl), -P(=O)(C 1-6 alkyl) 2 , -OP(= O)(C 1-6 alkyl) 2 , -OP(=O)(OC 1-6 alkyl) 2 , C 1-6 alkyl, C 1-6 haloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 6 -C 10 aryl, C 3 -C 7 heterocyclyl, C 5 -C 10 heteroaryl; or two R gg substituted The radicals may combine to form =O or =S; where X - is the counterion.
示例性的氮原子上取代基包括但不局限于：氢、-OH、-ORaa、-N(Rcc)2、-CN、-C(＝O)Raa、- C(＝O)N(Rcc)2、-CO2Raa、-SO2Raa、-C(＝NRbb)Raa、-C(＝NRcc)ORaa、-C(＝NRcc)N(Rcc)2、-SO2N(Rcc)2、-SO2Rcc、-SO2ORcc、-SORaa、-C(＝S)N(Rcc)2、-C(＝O)SRcc、-C(＝S)SRcc、-P(＝O)2Raa、-P(＝O)(Raa)2、-P(＝O)2N(Rcc)2、-P(＝O)(NRcc)2、烷基、卤代烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基，或者连接至氮原子的两个Rcc基团结合形成杂环基或杂芳基环，其中，每个烷基、烯基、炔基、环烷基、杂环基、芳基和杂芳基独立地被0、1、2、3、4或5个Rdd基团取代，且其中Raa、Rbb、Rcc和Rdd如上所述。Exemplary substituents on the nitrogen atom include, but are not limited to: hydrogen, -OH, -OR aa , -N(R cc ) 2 , -CN, -C(=O)R aa , - C(=O)N(R cc ) 2 , -CO 2 R aa , -SO 2 R aa , -C(=NR bb )R aa , -C(=NR cc )OR aa , -C(=NR cc )N(R cc ) 2 , -SO 2 N(R cc ) 2 , -SO 2 R cc , -SO 2 OR cc , -SOR aa , -C(=S)N(R cc ) 2 , -C( ＝O)SR cc , -C(＝S)SR cc , -P(＝O) 2 R aa , -P(＝O)(R aa ) 2 , -P(＝O) 2 N(R cc ) 2 , -P(=O)(NR cc ) 2 , alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, or two R cc attached to a nitrogen atom The groups combine to form a heterocyclyl or heteroaryl ring, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3 , 4 or 5 R dd groups are substituted, and wherein R aa , R bb , R cc and R dd are as described above.
其它定义Other definitions
术语“冠状病毒”包括但不限于下列病毒：HCoV-229E、HCoV-NL63、HCoV-HKU1、HCoV-OC43、SARS-CoV、MERS-CoV和/或SARSCoV-2。The term "coronavirus" includes, but is not limited to, the following viruses: HCoV-229E, HCoV-NL63, HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and/or SARSCoV-2.
在一个实施方案中，术语“冠状病毒”为α冠状病毒和/或β冠状病毒、更优选β冠状病毒。In one embodiment, the term "coronavirus" is an alphacoronavirus and/or a betacoronavirus, more preferably a betacoronavirus.
在一个实施方案中，α冠状病毒选自HCoV-229E和HCoV-NL63，优选HCoV-229E。In one embodiment, the alphacoronavirus is selected from HCoV-229E and HCoV-NL63, preferably HCoV-229E.
在一个实施方案中，β冠状病毒选自HCoV-HKU1、HCoV-OC43、SARS-CoV、MERS-CoV和SARS-CoV-2，优选HCoV-OC43或SARS-CoV-2，更优选SARS-CoV-2。In one embodiment, the betacoronavirus is selected from HCoV-HKU1, HCoV-OC43, SARS-CoV, MERS-CoV and SARS-CoV-2, preferably HCoV-OC43 or SARS-CoV-2, more preferably SARS-CoV- 2.
本文所用的术语“治疗”涉及逆转、减轻、抑制该术语适用的障碍或病症的进展或者预防之，或者这类障碍或病症的一种或多种症状。本文所用的名词“治疗”涉及动词治疗的动作，后者是如刚才所定义的。As used herein, the term "treatment" refers to reversing, alleviating, inhibiting the progression of, or preventing the disorder or condition to which the term applies, or one or more symptoms of such disorder or condition. As used herein, the noun "treat" refers to the action of the verb treat, as just defined.
本文所用的术语“药学上可接受的盐”表示本发明化合物的那些羧酸盐、氨基酸加成盐，它们在可靠的医学判断范围内适用于与患者组织接触，不会产生不恰当的毒性、刺激作用、变态反应等，与合理的益处/风险比相称，就它们的预期应用而言是有效的，包括(可能的话)本发明化合物的两性离子形式。As used herein, the term "pharmaceutically acceptable salts" means those carboxylate salts and amino acid addition salts of the compounds of the present invention which are suitable for contact with patient tissue within the scope of reliable medical judgment and will not produce undue toxicity, Irritation effects, allergic reactions, etc., commensurate with a reasonable benefit/risk ratio, are effective for their intended use, including (where possible) zwitterionic forms of the compounds of the invention.
药学上可接受的碱加成盐是与金属或胺生成的，例如碱金属与碱土金属氢氧化物或有机胺。用作阳离子的金属的实例有钠、钾、镁、钙等。适合的胺的实例有N,N'-二苄基乙二胺、氯普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因。Pharmaceutically acceptable base addition salts are formed with metals or amines, such as alkali metal and alkaline earth metal hydroxides or organic amines. Examples of metals used as cations are sodium, potassium, magnesium, calcium, etc. Examples of suitable amines are N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine and procaine.
酸性化合物的碱加成盐可以这样制备，按照常规方式使游离酸形式与足量所需的碱接触，生成盐。按照常规方式使盐形式与酸接触，再分离游离酸，可以使游离酸再生。游离酸形式在某些物理性质上多少不同于它们各自的盐形式，例如在极性溶剂中的溶解度，但是出于本发明的目的，盐还是等价于它们各自的游离酸。Base addition salts of acidic compounds may be prepared in conventional manner by contacting the free acid form with a sufficient amount of the desired base to form the salt. The free acid can be regenerated by contacting the salt form with the acid and isolating the free acid in the usual manner. The free acid forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of this invention the salts are nevertheless equivalent to their respective free acids.
盐可以是从无机酸制备的硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、硝酸盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物，酸例如盐酸、硝酸、硫酸、氢溴酸、氢碘酸、磷酸等。代表性盐包括：氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、硝酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、月桂酸盐、硼酸盐、苯甲酸盐、乳酸盐、 磷酸盐、甲苯磺酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、萘甲酸盐、甲磺酸盐、葡庚糖酸盐、乳糖酸盐、月桂基磺酸盐和羟乙磺酸盐等。盐也可以是从有机酸制备的，例如脂肪族一元与二元羧酸、苯基取代的烷酸、羟基烷酸、烷二酸、芳香族酸、脂肪族与芳香族磺酸等。代表性盐包括乙酸盐、丙酸盐、辛酸盐、异丁酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、扁桃酸盐、苯甲酸盐、氯苯甲酸盆、甲基苯甲酸盐、二硝基苯甲酸盐、萘甲酸盐、苯磺酸盐、甲苯磺酸盐、苯乙酸盐、柠檬酸盐、乳酸盐、马来酸盐、酒石酸盐、甲磺酸盐等。药学上可接受的盐可以包括基于碱金属与碱土金属的阳离子，例如钠、锂、钾、钙、镁等，以及无毒的铵、季铵和胺阳离子，包括但不限于铵、四甲基铵、四乙基铵、甲胺、二甲胺、三甲胺、三乙胺、乙胺等。还涵盖氨基酸的盐，例如精氨酸盐、葡糖酸盐、半乳糖醛酸盐等(例如参见Berge S.M.et al.，"Pharmaceutical Salts,”J.Pharm.Sci.，1977；66:1-19，引入此作为参考)。The salts may be sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates prepared from inorganic acids Salt, chloride, bromide, iodide, acids such as hydrochloric acid, nitric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, etc. Representative salts include: hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate Acid, borate, benzoate, lactate, Phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthoate, mesylate, glucoheptonate, lactobionate, laurate sulfonate and isethionate, etc. Salts may also be prepared from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like. Representative salts include acetate, propionate, octanoate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malonate Lenate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, naphthoate, benzenesulfonate, toluenesulfonate, phenylbenzoate Acid, citrate, lactate, maleate, tartrate, methanesulfonate, etc. Pharmaceutically acceptable salts may include alkali and alkaline earth metal based cations such as sodium, lithium, potassium, calcium, magnesium, etc., as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethyl Ammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, etc. Also contemplated are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge SM et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66:1-19 , incorporated by reference).
给药的“受试者”包括但不限于：人(即，任何年龄组的男性或女性，例如，儿科受试者(例如，婴儿、儿童、青少年)或成人受试者(例如，年轻的成人、中年的成人或年长的成人)和/或非人的动物，例如，哺乳动物，例如，灵长类(例如，食蟹猴、恒河猴)、牛、猪、马、绵羊、山羊、啮齿动物、猫和/或狗。在一些实施方案中，受试者是人。在一些实施方案中，受试者是非人动物。本文可互换使用术语“人”、“患者”和“受试者”。"Subjects" for administration include, but are not limited to: humans (i.e., males or females of any age group, e.g., pediatric subjects (e.g., infants, children, adolescents) or adult subjects (e.g., young Adults, middle-aged adults or older adults) and/or non-human animals, e.g., mammals, e.g., primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and/or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal. The terms "human," "patient," and "human" are used interchangeably herein. "Subject".
“疾病”、“障碍”和“病症”在本文中可互换地使用。"Disease," "disorder," and "condition" are used interchangeably herein.
除非另作说明，否则，本文使用的术语“治疗”包括受试者患有具体疾病、障碍或病症时所发生的作用，它降低疾病、障碍或病症的严重程度，或延迟或减缓疾病、障碍或病症的发展(“治疗性治疗”)，还包括在受试者开始患有具体疾病、障碍或病症之前发生的作用(“预防性治疗”)。Unless otherwise indicated, the term "treatment" or "treatment" as used herein includes an action in a subject suffering from a specific disease, disorder or condition that reduces the severity of the disease, disorder or condition, or delays or slows down the disease, disorder or the development of a condition ("therapeutic treatment"), and also includes effects that occur before a subject begins to suffer from a specific disease, disorder or condition ("preventive treatment").
通常，化合物的“有效量”是指足以引起目标生物反应的数量。正如本领域普通技术人员所理解的那样，本发明化合物的有效量可以根据下列因素而改变：例如，生物学目标、化合物的药代动力学、所治疗的疾病、给药模式以及受试者的年龄健康情况和症状。有效量包括治疗有效量和预防有效量。Generally, an "effective amount" of a compound is an amount sufficient to elicit a target biological response. As will be understood by those of ordinary skill in the art, the effective amount of a compound of the present invention may vary depending on factors such as, for example, the biological target, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the condition of the subject. Age health conditions and symptoms. The effective amount includes a therapeutically effective amount and a preventive effective amount.
除非另作说明，否则，本文使用的化合物的“治疗有效量”是在治疗疾病、障碍或病症的过程中足以提供治疗益处的量，或使与疾病、障碍或病症有关的一或多种症状延迟或最小化的量。化合物的治疗有效量是指单独使用或与其它疗法联用时，治疗剂的量，它在治疗疾病、障碍或病症的过程中提供治疗益处。术语“治疗有效量”可以包括改善总体治疗、降低或避免疾病或病症的症状或病因、或增强其它治疗剂的治疗效果的量。Unless otherwise specified, a "therapeutically effective amount" of a compound as used herein is an amount sufficient to provide a therapeutic benefit in treating a disease, disorder, or condition, or to cause one or more symptoms associated with the disease, disorder, or condition The amount to delay or minimize. A therapeutically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" may include an amount that improves overall treatment, reduces or avoids symptoms or causes of a disease or disorder, or enhances the therapeutic effect of other therapeutic agents.
除非另作说明，否则，本文使用的化合物的“预防有效量”是足以预防疾病、障碍或病症的量，或足以预防与疾病、障碍或病症有关的一或多种症状的量，或防止疾病、障碍或病症复发的量。化合物的预防有效量是指单独使用或与其它药剂联用时，治疗剂的量，它在预防疾病、障碍或病症的过程中提供预防益处。术语“预防有效量”可以包括改善总体预防的量，或增强其它预防药剂的预防效果的量。 Unless otherwise stated, a "prophylactically effective amount" of a compound as used herein is an amount sufficient to prevent a disease, disorder or condition, or to prevent one or more symptoms associated with a disease, disorder or condition, or to prevent a disease , the amount of recurrence of a disorder or condition. A prophylactically effective amount of a compound is that amount of therapeutic agent that, when used alone or in combination with other agents, provides a prophylactic benefit in preventing a disease, disorder, or condition. The term "prophylactically effective amount" may include an amount that improves overall prophylaxis, or an amount that enhances the prophylactic effect of other prophylactic agents.
“组合”以及相关术语是指同时或依次给药本发明化合物和其它治疗剂。例如，本发明化合物可以与其它治疗剂以分开的单位剂型同时或依次给药，或与其它治疗剂一起在单一单位剂型中同时给药。"Combination" and related terms refer to the simultaneous or sequential administration of a compound of the invention and another therapeutic agent. For example, the compounds of the present invention may be administered simultaneously or sequentially with other therapeutic agents in separate unit dosage forms, or with other therapeutic agents in a single unit dosage form.
具体实施方案Specific implementation plan
本文中，“本发明化合物”指的是以下的式(I)、(I’)、(II)、(II’)、(III)、(III’)、(IV)、(IV’)、(V)、(V’)、(VI)、(VI’)、(VII)、(VII’)、(VIII)、(VIII’)、(IX)、(IX’)、(X)、(X’)、(XI)、(XI’)、(XII)或(XII’)等化合物、其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物。Herein, "compounds of the present invention" refer to the following formulas (I), (I'), (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII), (VIII'), (IX), (IX'), (X), ( Compounds such as Polymorphs, hydrates or solvates.
本文中，化合物使用标准的命名法命名。具有非对称中心的化合物，应该明白(除非另有说明)所有的光学异构体及其混合物均包含在内。此外，除非另有规定，本发明所包括的所有异构体化合物与碳碳双键可能以Z和E的形式出现。在不同的互变异构形式存在的化合物，一个所述化合物并不局限于任何特定的互变异构体，而是旨在涵盖所有的互变异构形式。In this article, compounds are named using standard nomenclature. For compounds having asymmetric centers, it should be understood that (unless otherwise stated) all optical isomers and mixtures thereof are included. Furthermore, unless otherwise specified, all isomeric compounds encompassed by the present invention with carbon-carbon double bonds may appear in the Z and E forms. Compounds exist in different tautomeric forms, and a said compound is not limited to any particular tautomeric form, but is intended to encompass all tautomeric forms.
在一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In one embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound:
其中，in,
Y为N或CR7；Y is N or CR 7 ;
R7选自H、C1-6烷基或C1-6卤代烷基；R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L1选自化学键、C1-6亚烷基、-NH-、-O-或-S-；L 1 is selected from chemical bond, C 1-6 alkylene, -NH-, -O- or -S-;
R1选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基、3-10元杂环基、C6-20芳基或5-20元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；所述R1优选为C6-10芳基或5-10元杂芳基；R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
R1s选自H、氘、CN、NO2、NH2、OH、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、卤代C2-6烯基、C2-6炔基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基或-O-3-8元杂芳基；R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 Metaheteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, - NH-3-8-membered heterocyclyl, -NH-3-8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 aryl, -O-3-8-membered heterocyclyl or -O-3-8-membered heteroaryl;
或者，同一个碳原子上的两个R1s一起形成氧代或硫代； Alternatively, two R 1s on the same carbon atom together form oxo or sulfo;
L2选自化学键或C1-6亚烷基；L 2 is selected from chemical bond or C 1-6 alkylene;
R2选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，优选为C6-10芳基，更优选为苯基，所述R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代；R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
R2s选自H、D、卤素、CN、-L2a-R’或 R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a为-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-10烷基、C1-10烷氧基、C1-10卤代烷基、C1-10卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6烯基或C2-6炔基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , Boc, C 2-6 alkenyl or C 2-6 alkynyl, or the same Two R's on a carbon atom together form C=O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自H、NH2、CN、C0-6亚烷基-C(O)Ra、C0-6亚烷基-C(O)ORa、C1-6亚烷基-OC(O)-Ra、C0-6亚烷基-NHC(O)Ra、C0-6亚烷基-C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C2-6烯基或C2- 6炔基；R' is selected from H, NH 2 , CN, C 0-6 alkylene-C(O)R a , C 0-6 alkylene-C(O)OR a , C 1-6 alkylene-OC (O)-R a , C 0-6 alkylene-NHC(O)R a , C 0-6 alkylene-C(O)NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OR a , C 2-6 alkenyl or C 2- 6 alkynyl;
L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
R3选自C6-14芳基或5-14杂芳基、C3-8环烷基、3至14元杂环基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
R3s选自H、氘、卤素、CN、NO2、NH2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤代C1- 6烷基、卤代C1-6烷氧基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基、-O-3-8元杂芳基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group , 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基、C2-6烯基或C2-6炔基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在另一个实施方案中，本发明涉及式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In another embodiment, the present invention relates to a compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvates:
其中：in:
Y为N或CR7；Y is N or CR 7 ;
R7选自H、C1-6烷基或C1-6卤代烷基；R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L1选自化学键或C1-6亚烷基，-NH-、-O-或-S-；L 1 is selected from chemical bond or C 1-6 alkylene group, -NH-, -O- or -S-;
R1选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基、3-10元杂环基、C6-20芳基或5-20元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；所述R1优选为C6-10芳基或5-10元杂芳基；R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
R1s选自H、氘、CN、NO2、NH2、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、卤代C2-6烯基、C2-6炔基、卤代C2-6炔基、C6-10芳基、3至8元杂环基、3至8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基或-O-3-8元杂芳基；R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclic group Aryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH- 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl base, -OC 6-10 aryl group, -O-3-8 membered heterocyclyl group or -O-3-8 membered heteroaryl group;
L2选自化学键或C1-6亚烷基；L 2 is selected from chemical bond or C 1-6 alkylene;
R2选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，优选为C6-10芳基，更优选为苯基，所述R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代；R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
R2s选自H、D、卤素、CN、-L2a-R’或 R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a优选-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基； Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-10烷基、C1-10烷氧基、C1-10卤代烷基、C1-10卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6烯基或C2-6炔基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , Boc, C 2-6 alkenyl or C 2-6 alkynyl, or the same Two R's on a carbon atom together form C=O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
R3选自C6-14芳基或5-14杂芳基、C3-8环烷基、3至14元杂环基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
R3s选自H、氘、卤素、CN、NO2、NH2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1- 6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基、-O-3-8元杂芳基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group, 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH - 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基、C2-6烯基或C2-6炔基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
YY
Y为N或CR7或CR7R8；Y is N or CR 7 or CR 7 R 8 ;
在一个实施方式中，Y为CR7，例如CH；在另一个实施方式中，Y为CR7R8，例如CH2；在另一个实施方式中，Y为N。In one embodiment, Y is CR7 , such as CH; in another embodiment, Y is CR7R8 , such as CH2 ; in another embodiment, Y is N.
所述Y可任选地被D取代，直至完全氘代。Said Y may be optionally substituted with D, up to complete deuteration.
R7和R8 R 7 and R 8
在一个实施方式中，R7为H；在另一个实施方式中，R7为C1-6烷基；在另一个实施方式中，R7为C1-6卤代烷基。In one embodiment, R 7 is H; in another embodiment, R 7 is C 1-6 alkyl; in another embodiment, R 7 is C 1-6 haloalkyl.
在一个实施方式中，R8为H；在另一个实施方式中，R8为C1-6烷基；在另一个实施方式中，R8为C1-6卤代烷基。In one embodiment, R 8 is H; in another embodiment, R 8 is C 1-6 alkyl; in another embodiment, R 8 is C 1-6 haloalkyl.
所述R7和R8可任选地被D取代，直至完全氘代。The R 7 and R 8 may be optionally substituted with D until fully deuterated.
L1 L 1
在一个实施方式中，L1为化学键；在另一个实施方式中，L1为C1-6亚烷基；在另一个实施方式中，L1为-NH-；在另一个实施方式中，L1为-O-；在另一个实施方式中，L1为-S-。In one embodiment, L 1 is a chemical bond; in another embodiment, L 1 is C 1-6 alkylene; in another embodiment, L 1 is -NH-; in another embodiment, L 1 is -O-; in another embodiment, L 1 is -S-.
所述L1可任选地被D取代，直至完全氘代。The L 1 may optionally be substituted by D until fully deuterated.
R1 R 1
在一个实施方式中，R1为C1-6烷基；在另一个实施方式中，R1为C1-6卤代烷基；在另一个实施方式中，R1为C1-6烷氧基，例如C1-4烷氧基；在另一个实施方式中，R1为C1-6卤代烷氧基，例如C1-4卤代烷氧基；在另一个实施方式中，R1为C3-10环烷基；在另一个实施方式中，R1为3-10元杂环基；在另一个实施方式中，R1为C6-20芳基，例如C6-10芳基；在另一个实施方式中，R1为5-20元杂芳基，例如5-10元杂芳基，又如5-6元杂芳基。In one embodiment, R 1 is C 1-6 alkyl; in another embodiment, R 1 is C 1-6 haloalkyl; in another embodiment, R 1 is C 1-6 alkoxy , such as C 1-4 alkoxy; in another embodiment, R 1 is C 1-6 haloalkoxy, such as C 1-4 haloalkoxy; in another embodiment, R 1 is C 3- 10 cycloalkyl; in another embodiment, R 1 is 3-10 membered heterocyclyl; in another embodiment, R 1 is C 6-20 aryl, such as C 6-10 aryl; in another In one embodiment, R 1 is a 5-20-membered heteroaryl group, such as a 5-10-membered heteroaryl group, or a 5-6-membered heteroaryl group.
在一个具体的实施方式中，R1为OCH3；在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为在另一个具体的实施方式中，R1为 In a specific embodiment, R 1 is OCH 3 ; in another specific embodiment, R 1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is In another specific embodiment, R1 is
在一个实施方式中，R1未被取代；在另一个实施方案中，R1任选地被1个、2个或3个、4个或5个独立选择的R1s取代。In one embodiment, R 1 is unsubstituted; in another embodiment, R 1 is optionally substituted with 1, 2 or 3, 4 or 5 independently selected R 1s .
所述R1可任选地被D取代，直至完全氘代。 Said R1 may be optionally substituted by D, up to complete deuteration.
R1s R 1s
在一个实施方式中，R1s为H；在另一个实施方式中，R1s为氘；在另一个实施方式中，R1s为CN；在另一个实施方式中，R1s为NO2；在另一个实施方式中，R1s为NH2；在另一个实施方式中，R1s为OH；在另一个实施方式中，R1s为卤素，例如F；在另一个实施方式中，R1s为C1-6烷基，例如C1-4烷基；在另一个实施方式中，R1s为C1-6卤代烷基，优选为C1-4卤代烷基，例如CH3；在另一个实施方式中，R1s为C1-6烷氧基，优选为C1-4烷氧基，例如OCH3；在另一个实施方式中，R1s为C1-6卤代烷氧基，优选为C1-4卤代烷氧基；在另一个实施方式中，R1s为C2-6烯基；在另一个实施方式中，R1s为卤代C2-6烯基；在另一个实施方式中，R1s为C2-6炔基；在另一个实施方式中，R1s为卤代C2-6炔基；在另一个实施方式中，R1s为C6-10芳基；在另一个实施方式中，R1s为3至8元杂环基；在另一个实施方式中，R1s为3至8元杂芳基；在另一个实施方式中，R1s为-NH(C1-6烷基)；在另一个实施方式中，R1s为-N(C1-6烷基)2；在另一个实施方式中，R1s为-NH-C3-8环烷基；在另一个实施方式中，R1s为-NH-C6- 10芳基；在另一个实施方式中，R1s为-NH-3-8元杂环基；在另一个实施方式中，R1s为-NH-3-8元杂芳基；在另一个实施方式中，R1s为-O-C1-6烷基；在另一个实施方式中，R1s为-O-C2-6烯基；在另一个实施方式中，R1s为-O-C2-6炔基；在另一个实施方式中，R1s为-O-C3-8环烷基；在另一个实施方式中，R1s为-O-C6-10芳基；在另一个实施方式中，R1s为-O-3-8元杂环基；在另一个实施方式中，R1s为-O-3-8元杂芳基。In one embodiment, R 1s is H; in another embodiment, R 1s is deuterium; in another embodiment, R 1s is CN; in another embodiment, R 1s is NO 2 ; in another In one embodiment, R 1s is NH 2 ; in another embodiment, R 1s is OH; in another embodiment, R 1s is halogen, such as F; in another embodiment, R 1s is C 1 -6 alkyl, such as C 1-4 alkyl; in another embodiment, R 1s is C 1-6 haloalkyl, preferably C 1-4 haloalkyl, such as CH 3 ; in another embodiment, R 1s is C 1-6 alkoxy, preferably C 1-4 alkoxy, such as OCH 3 ; in another embodiment, R 1s is C 1-6 haloalkoxy, preferably C 1-4 haloalkyl Oxygen; in another embodiment, R 1s is C 2-6 alkenyl; in another embodiment, R 1s is halogenated C 2-6 alkenyl; in another embodiment, R 1s is C 2-6 alkynyl; in another embodiment, R 1s is halogenated C 2-6 alkynyl; in another embodiment, R 1s is C 6-10 aryl; in another embodiment, R 1s is a 3- to 8-membered heterocyclyl group; in another embodiment, R 1s is a 3- to 8-membered heteroaryl group; in another embodiment, R 1s is -NH (C 1-6 alkyl); in In another embodiment, R 1s is -N(C 1-6 alkyl) 2 ; in another embodiment, R 1s is -NH-C 3-8 cycloalkyl; in another embodiment, R 1s is -NH-C 6-10 aryl; in another embodiment, R 1s is -NH-3-8-membered heterocyclyl; in another embodiment , R 1s is -NH-3-8-membered Heteroaryl; in another embodiment, R 1s is -OC 1-6 alkyl; in another embodiment, R 1s is -OC 2-6 alkenyl; in another embodiment, R 1s is -OC 2-6 alkynyl; in another embodiment, R 1s is -OC 3-8 cycloalkyl; in another embodiment, R 1s is -OC 6-10 aryl; in another embodiment , R 1s is -O-3-8-membered heterocyclyl; in another embodiment, R 1s is -O-3-8-membered heteroaryl.
在一个实施方式中，同一个碳原子上的两个R1s一起形成氧代或硫代。In one embodiment, two R 1s on the same carbon atom together form oxo or thio.
所述R1s可任选地被D取代，直至完全氘代。The R 1s may be optionally substituted with D until fully deuterated.
L2 L 2
在一个实施方式中，L2为化学键；在另一个实施方式中，L2为C1-6亚烷基，优选为C1-4亚烷基，例如-CH2-；In one embodiment, L 2 is a chemical bond; in another embodiment, L 2 is C 1-6 alkylene, preferably C 1-4 alkylene, such as -CH 2 -;
所述L2可任选地被D取代，直至完全氘代。The L2 may optionally be substituted with D until fully deuterated.
R2 R 2
在一个实施方式中，R2为C3-10环烷基；在另一个实施方式中，R2为3-10元杂环基；在另一个实施方式中，R2为C6-10芳基，优选为C6-10芳基，更优选为苯基；在另一个实施方式中，R2为5-10元杂芳基。In one embodiment, R 2 is C 3-10 cycloalkyl; in another embodiment, R 2 is 3-10 membered heterocyclyl; in another embodiment, R 2 is C 6-10 aromatic group, preferably a C 6-10 aryl group, more preferably a phenyl group; in another embodiment, R 2 is a 5-10 membered heteroaryl group.
在一个实施方式中，R2未被取代；在另一个实施方案中，R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代。In one embodiment, R 2 is unsubstituted; in another embodiment, R 2 is optionally substituted with 1, 2, 3, 4 or 5 independently selected R 2s .
所述R2可任选地被D取代，直至完全氘代。 The R2 may optionally be substituted with D, up to complete deuteration.
R2s R 2s
在一个实施方式中，R2s为H；在另一个实施方式中，R2s为D；在另一个实施方式中，R2s为卤素；在另一个实施方式中，R2s为CN；在另一个实施方式中，R2s为-L2a-R’；在另一个实施方式中，R2s为 In one embodiment, R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen; in another embodiment, R 2s is CN; in another In an embodiment, R 2s is -L 2a -R'; in another embodiment, R 2s is
所述R2s可任选地被D取代，直至完全氘代。The R 2s may be optionally substituted with D until fully deuterated.
R2a和R2b R 2a and R 2b
在一个实施方式中，R2a为H；在另一个实施方式中，R2a为D；在另一个实施方式中，R2a为在另一个实施方式中，R2a为-L2a-R’。In one embodiment, R 2a is H; in another embodiment, R 2a is D; in another embodiment, R 2a is In another embodiment, R 2a is -L 2a -R'.
在一个实施方式中，R2b为H；在另一个实施方式中，R2b为D；在另一个实施方式中，R2b为在另一个实施方式中，R2b为-L2a-R’。In one embodiment, R 2b is H; in another embodiment, R 2b is D; in another embodiment, R 2b is In another embodiment, R 2b is -L 2a -R'.
所述R2a和R2b可任选地被D取代，直至完全氘代。The R 2a and R 2b may be optionally substituted with D until fully deuterated.
L2a L 2a
在一个实施方式中，L2a为化学键；在另一个实施方式中，L2a为-C1-6亚烷基；在另一个实施方式中，L2a为-C0-6亚烷基-O-C0-6亚烷基-；在另一个实施方式中，L2a为-C0-6亚烷基-S-C0-6亚烷基-；在另一个实施方式中，L2a为-C0-6亚烷基-C(O)-C0-6亚烷基-；在另一个实施方式中，L2a为-C0-6亚烷基-C(O)O-C0-6亚烷基-；在另一个实施方式中，L2a为-C0-6亚烷基-NH-C0-6亚烷基-；在另一个实施方式中，L2a为-C0-6亚烷基-C(O)NH-C0-6亚烷基-；在另一个实施方式中，L2a为-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-。In one embodiment, L 2a is a chemical bond; in another embodiment, L 2a is -C 1-6 alkylene; in another embodiment, L 2a is -C 0-6 alkylene-OC 0-6 alkylene-; in another embodiment, L 2a is -C 0-6 alkylene-SC 0-6 alkylene-; in another embodiment, L 2a is -C 0- 6 alkylene-C(O)-C 0-6 alkylene-; in another embodiment, L 2a is -C 0-6 alkylene-C(O)OC 0-6 alkylene- ;In another embodiment, L 2a is -C 0-6 alkylene-NH-C 0-6 alkylene-; In another embodiment, L 2a is -C 0-6 alkylene- C(O)NH-C 0-6 alkylene-; in another embodiment, L 2a is -C 0-6 alkylene-NHC(O)-C 0-6 alkylene- or -C 2-6 alkenylene-.
在一个具体的实施方式中，L2a为化学键；在另一个具体的实施方式中，L2a为-O-；在另一个具体的实施方式中，L2a为-S-；在另一个具体的实施方式中，L2a为-C1-6亚烷基-；在另一个具体的实施方式中，L2a为-C1-6亚烷基-O-；在另一个具体的实施方式中，L2a为-O-C1-6亚烷基-；在另一个具体的实施方式中，L2a为-C(O)-；在另一个具体的实施方式中，L2a为-C(O)O-；在另一个具体的实施方式中，L2a为-NH-；在另一个具体的实施方式中，L2a为-C(O)NH-；在另一个具体的实施方式中，L2a为-NHC(O)-；在另一个具体的实施方式中，L2a为C2-6亚烯基。In a specific embodiment, L 2a is a chemical bond; in another specific embodiment, L 2a is -O-; in another specific embodiment, L 2a is -S-; in another specific embodiment In an embodiment, L 2a is -C 1-6 alkylene-; in another specific embodiment, L 2a is -C 1-6 alkylene-O-; in another specific embodiment, L 2a is -OC 1-6 alkylene-; in another specific embodiment, L 2a is -C(O)-; in another specific embodiment, L 2a is -C(O)O -; In another specific embodiment, L 2a is -NH-; In another specific embodiment, L 2a is -C(O)NH-; In another specific embodiment, L 2a is -NHC(O)-; In another specific embodiment, L 2a is C 2-6 alkenylene.
在一个更具体的实施方式中，L2a为化学键；在另一个更具体的实施方式中，L2a为-O-；在另一 个更具体的实施方式中，L2a为-S-；在另一个更具体的实施方式中，L2a为-CH2-；在另一个更具体的实施方式中，L2a为-CH2-O-；在另一个更具体的实施方式中，L2a为-CH2-CH2-O-；在另一个更具体的实施方式中，L2a为-O-CH2-；在另一个更具体的实施方式中，L2a为-C(O)-；在另一个更具体的实施方式中，L2a为-C(O)O-；在另一个更具体的实施方式中，L2a为-NH-；在另一个更具体的实施方式中，L2a为-C(O)NH-；在另一个更具体的实施方式中，L2a为-NH-C(O)-或-CH＝CH-；在另一个更具体的实施方式中，上述L2a任选地被CH3取代。In a more specific embodiment, L 2a is a chemical bond; in another more specific embodiment, L 2a is -O-; in another In a more specific embodiment, L 2a is -S-; in another more specific embodiment, L 2a is -CH 2 -; in another more specific embodiment, L 2a is -CH 2 - O-; in another more specific embodiment, L 2a is -CH 2 -CH 2 -O-; in another more specific embodiment, L 2a is -O-CH 2 -; in another more specific embodiment In a specific embodiment, L 2a is -C(O)-; in another more specific embodiment, L 2a is -C(O)O-; in another more specific embodiment, L 2a is -NH-; In another more specific embodiment, L 2a is -C(O)NH-; In another more specific embodiment, L 2a is -NH-C(O)- or -CH= CH-; In another more specific embodiment, the above-mentioned L 2a is optionally substituted by CH 3 .
在一个实施方式中，所述L2a未被取代；在另一个实施方式中，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代。In one embodiment, the L 2a is unsubstituted; in another embodiment, the L 2a is optionally substituted with 1, 2, 3, 4 or 5 independently selected R#s.
所述L2a可任选地被D取代，直至完全氘代。The L 2a may be optionally substituted by D until fully deuterated.
R#R#
在一个实施方式中，R#为H；在另一个实施方式中，R#为卤素；在另一个实施方式中，R#为C1- 6烷基，例如C1-4烷基；在另一个实施方式中，R#为C1-6卤代烷基，例如C1-4卤代烷基；在另一个实施方式中，R#为C1-6烷氧基，例如C1-4烷氧基；在另一个实施方式中，R#为C1-6卤代烷氧基，例如C1-4卤代烷氧基；在另一个实施方式中，R#为C2-6烯基；在另一个实施方式中，R#为C2-6炔基。In one embodiment, R# is H; in another embodiment, R # is halogen; in another embodiment, R# is C 1-6 alkyl, such as C 1-4 alkyl; in another In one embodiment, R# is C 1-6 haloalkyl, such as C 1-4 haloalkyl; in another embodiment, R# is C 1-6 alkoxy, such as C 1-4 alkoxy; In another embodiment, R# is C 1-6 haloalkoxy, such as C 1-4 haloalkoxy; in another embodiment, R# is C 2-6 alkenyl; in another embodiment , R# is C 2-6 alkynyl.
所述R#可任选地被D取代，直至完全氘代。The R# may optionally be substituted with D, up to complete deuteration.
环A、R和mRings A, R and m
在一个实施方式中，环A为C3-10环烷基；在另一个实施方式中，环A为C5-10环烷基；在另一个实施方式中，环A为C5-8环烷基；在另一个实施方式中，环A为C3-8环烷基；在另一个实施方式中，环A为C3-6环烷基；在另一个实施方式中，环A为C5-6环烷基；在另一个实施方式中，环A为3-10元杂环基；在另一个实施方式中，环A为4-10元杂环基，例如3-8元杂环基，又如4-7元杂环基；在另一个实施方式中，环A为5-6元杂环基；在另一个实施方式中，环A为C6-10芳基；在另一个实施方式中，环A为苯基；在另一个实施方式中，环A为5-10元杂芳基；在另一个实施方式中，环A为5-6元杂芳基，例如，所述5-6元杂芳基为含有1-2个选自S或N的杂原子的杂芳基；在另一个实施方式中，环A为5-6元杂芳基，例如，所述5-6元杂芳基为含有1-2个选自O、S或N的杂原子的杂芳基；在另一个实施方式中，环A为5元杂芳基，例如，所述5元杂芳基为含有1-2个选自N、O或S的杂原子的杂芳基。In one embodiment, Ring A is C 3-10 cycloalkyl; in another embodiment, Ring A is C 5-10 cycloalkyl; in another embodiment, Ring A is C 5-8 cycloalkyl Alkyl; in another embodiment, Ring A is C 3-8 cycloalkyl; in another embodiment, Ring A is C 3-6 cycloalkyl; in another embodiment, Ring A is C 5-6 cycloalkyl; in another embodiment, ring A is a 3-10 membered heterocyclyl; in another embodiment, ring A is a 4-10 membered heterocyclyl, such as a 3-8 membered heterocyclyl group, another example is a 4-7 membered heterocyclyl group; in another embodiment, ring A is a 5-6 membered heterocyclyl group; in another embodiment, ring A is a C 6-10 aryl group; in another In an embodiment, Ring A is phenyl; in another embodiment, Ring A is a 5-10 membered heteroaryl; in another embodiment, Ring A is a 5-6 membered heteroaryl, for example, as described A 5-6 membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N; in another embodiment, ring A is a 5-6 membered heteroaryl group, for example, the 5- A 6-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from O, S or N; in another embodiment, Ring A is a 5-membered heteroaryl group, for example, the 5-membered heteroaryl group The radical is a heteroaryl group containing 1-2 heteroatoms selected from N, O or S.
在一个具体的实施方式中，环A为其中，Q1为CH或N。In a specific embodiment, Ring A is Where, Q 1 is CH or N.
在一个具体的实施方式中，环A为其中，Q2选自S或NH，Q3选自CH或N。 In a specific embodiment, Ring A is Among them, Q 2 is selected from S or NH, and Q 3 is selected from CH or N.
在一个具体的实施方式中，环A为其中，Q4、Q5和Q6中的一个为N，另外两个为CH。In a specific embodiment, Ring A is Among them, one of Q 4 , Q 5 and Q 6 is N, and the other two are CH.
在一个具体的实施方式中，环A为在另一个具体的实施方式中，环A为5元杂芳基，例如含有1-2个选自S或N的杂原子的杂芳基。In a specific embodiment, Ring A is In another specific embodiment, Ring A is a 5-membered heteroaryl group, such as one containing 1-2 heteroatoms selected from S or N.
在一个实施方式中，X2a为CR；在另一个实施方式中，X2a为N。In one embodiment, X 2a is CR; in another embodiment, X 2a is N.
在一个实施方式中，X2b为CR；在另一个实施方式中，X2b为N。In one embodiment, X 2b is CR; in another embodiment, X 2b is N.
在一个实施方式中，R为H；在另一个实施方式中，R为卤素；在另一个实施方式中，R为CN；在另一个实施方式中，R为ORa；在另一个实施方式中，R为NRbRc；在另一个实施方式中，R为C1- 10烷基；在另一个实施方式中，R为C1-6烷基；在另一个实施方式中，R为C1-10烷氧基；在另一个实施方式中，R为C1-6烷氧基；在另一个实施方式中，R为C1-10卤代烷基；在另一个实施方式中，R为C1-6卤代烷基；在另一个实施方式中，R为C1-10卤代烷氧基；在另一个实施方式中，R为C1-6卤代烷氧基；在另一个实施方式中，R为C(O)Ra；在另一个实施方式中，R为C(O)ORa；在另一个实施方式中，R为NHC(O)Ra；在另一个实施方式中，R为C(O)NH-Ra；在另一个实施方式中，R为Boc；在另一个实施方式中，R为C2-6烯基；在另一个实施方式中，R为C2-6炔基；在另一个实施方式中，同一个碳原子上的两个R一起形成C＝O或C＝S。In one embodiment, R is H; in another embodiment, R is halogen; in another embodiment, R is CN; in another embodiment, R is OR a ; in another embodiment , R is NR b R c ; in another embodiment, R is C 1-10 alkyl; in another embodiment, R is C 1-6 alkyl; in another embodiment, R is C 1-10 alkoxy; in another embodiment, R is C 1-6 alkoxy; in another embodiment, R is C 1-10 haloalkyl; in another embodiment, R is C 1-6 haloalkyl; in another embodiment, R is C 1-10 haloalkoxy; in another embodiment, R is C 1-6 haloalkoxy; in another embodiment, R is C (O)R a ; in another embodiment, R is C(O)OR a ; in another embodiment, R is NHC(O)R a ; in another embodiment, R is C(O )NH-R a ; In another embodiment, R is Boc; In another embodiment, R is C 2-6 alkenyl; In another embodiment, R is C 2-6 alkynyl; in In another embodiment, two R's on the same carbon atom together form C=O or C=S.
在一个实施方式中，R独立地选自H；在另一个具体的实施方式中，R为卤素，例如F或Cl；在另一个实施方式中，R为CN；在另一个实施方式中，R为OH；在另一个实施方式中，R为NH2；在另一个实施方式中，R为C1-6卤代烷基，优选为C1-4卤代烷基，例如CF3；在另一个实施方式中，R为C1-6烷氧基；在另一个实施方式中，R为C1-6卤代烷氧基，优选为C1-4卤代烷氧基，例如OCF3；在另一个实施方式中，R为Boc。In one embodiment, R is independently selected from H; in another specific embodiment, R is halogen, such as F or Cl; in another embodiment, R is CN; in another embodiment, R is OH; in another embodiment, R is NH 2 ; in another embodiment, R is C 1-6 haloalkyl, preferably C 1-4 haloalkyl, such as CF 3 ; in another embodiment , R is C 1-6 alkoxy; in another embodiment, R is C 1-6 haloalkoxy, preferably C 1-4 haloalkoxy, such as OCF 3 ; in another embodiment, R for Boc.
在一个实施方式中，m为0；在另一个实施方式中，m为1；在另一个实施方式中，m为2；在另一个实施方式中，m为3；在另一个实施方式中，m为4；在另一个实施方式中，m为5。In one embodiment, m is 0; in another embodiment, m is 1; in another embodiment, m is 2; in another embodiment, m is 3; in another embodiment, m is 4; in another embodiment, m is 5.
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上述环A、R和m等可任选地被D取代，直至完全氘代。The above-mentioned rings A, R, m, etc. may be optionally substituted by D until completely deuterated.
R’R’
在一个实施方式中，R’为H；在另一个实施方式中，R’为NH2；在另一个实施方式中，R’为CN；在另一个实施方式中，R’为C(O)Ra；在另一个实施方式中，R’为C(O)ORa；在另一个实施方式中，R’为NHC(O)Ra，优选为NHC(O)-C1-6卤代烷基，例如NHC(O)-CF3；在另一个实施方式中，R’为C(O)NH- Ra，优选为C(O)NH-C1-6卤代烷基，例如C(O)NH-CF3；在另一个实施方式中，R’为C0-6亚烷基-C(O)Ra；在另一个实施方式中，R’为C0-6亚烷基-C(O)ORa；在另一个实施方式中，R’为C1-6亚烷基-OC(O)-Ra；在另一个实施方式中，R’为C0-6亚烷基-NHC(O)Ra；在另一个实施方式中，R’为C0-6亚烷基-C(O)NRbRc；在另一个实施方式中，R’为C1-6烷基；在另一个实施方式中，R’为C1-6卤代烷基，优选为C1-4卤代烷基，例如CHF2或CF3；在另一个实施方式中，R’为C1-6烷氧基；在另一个实施方式中，R’为C1-6卤代烷氧基；在另一个实施方式中，R’为C2-6烯基；在另一个实施方式中，R’为C2-6炔基。In one embodiment, R' is H; in another embodiment, R' is NH 2 ; in another embodiment, R' is CN; in another embodiment, R' is C(O) Ra ; in another embodiment, R' is C(O)OR a ; in another embodiment, R' is NHC(O)R a , preferably NHC(O)-C 1-6 haloalkyl , such as NHC(O)-CF 3 ; in another embodiment, R' is C(O)NH- R a , preferably C(O)NH-C 1-6 haloalkyl, such as C(O)NH-CF 3 ; in another embodiment, R' is C 0-6 alkylene-C(O) R a ; in another embodiment, R' is C 0-6 alkylene-C(O)OR a ; in another embodiment, R' is C 1-6 alkylene-OC(O) -R a ; in another embodiment, R' is C 0-6 alkylene-NHC(O)R a ; in another embodiment, R' is C 0-6 alkylene-C(O )NR b R c ; In another embodiment, R' is C 1-6 alkyl; in another embodiment, R' is C 1-6 haloalkyl, preferably C 1-4 haloalkyl, for example CHF 2 or CF 3 ; in another embodiment, R' is C 1-6 alkoxy; in another embodiment, R' is C 1-6 haloalkoxy; in another embodiment, R ' is C 2-6 alkenyl; in another embodiment, R' is C 2-6 alkynyl.
在一个实施方式中，R’为在另一个实施方式中，R’为在另一个实施方式中，R’为在另一个实施方式中，R’为在另一个实施方式中，R’为在另一个实施方式中，R’为在另一个实施方式中，R’为 In one embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is In another embodiment, R' is
所述R’可任选地被D取代，直至完全氘代。Said R' may be optionally substituted by D, up to complete deuteration.
R2c和R2d R 2c and R 2d
在一个实施方式中，R2c为卤素，优选为F。In one embodiment, R 2c is halogen, preferably F.
在一个实施方式中，R2d为卤素，优选为Cl；在另一个实施方式中，R2d为CN。In one embodiment, R 2d is halogen, preferably Cl; in another embodiment, R 2d is CN.
R”R"
在一个实施方式中，R”为H；在另一个实施方式中，R”为卤素，例如F或Cl；在另一个实施方式中，R”为C1-6卤代烷基；在另一个实施方式中，R”为C1-6卤代烷氧基，优选为C1-4卤代烷氧基，例如OCF3。In one embodiment, R" is H; in another embodiment, R" is halogen, such as F or Cl; in another embodiment, R" is C 1-6 haloalkyl; in another embodiment Among them, R″ is a C 1-6 haloalkoxy group, preferably a C 1-4 haloalkoxy group, such as OCF 3 .
所述R”可任选地被D取代，直至完全氘代。Said R" may be optionally substituted by D, up to complete deuteration.
L3和L3’L 3 and L 3 '
在一个实施方式中，L3为-NRb-，例如-NH-；在另一个实施方式中，L3为-CRaRb-，例如-CH2-。In one embodiment, L 3 is -NR b -, such as -NH-; in another embodiment, L 3 is -CR a R b -, such as -CH 2 -.
在一个实施方式中，L3’为-N＝；在另一个实施方式中，L3’为-CRa＝，例如-CH＝。In one embodiment, L 3 ' is -N=; in another embodiment, L 3 ' is -CR a =, such as -CH=.
所述L3和L3’可任选地被D取代，直至完全氘代。The L 3 and L 3 ' may be optionally substituted with D until fully deuterated.
R3 R 3
在一个实施方式中，R3为C6-14芳基，优选为C6-10芳基；在另一个实施方式中，R3为5-14杂芳基，例如5-10杂芳基；在另一个实施方式中，R3为C3-8环烷基；在另一个实施方式中，R3为3-14元杂环基。In one embodiment, R 3 is C 6-14 aryl, preferably C 6-10 aryl; in another embodiment, R 3 is 5-14 heteroaryl, such as 5-10 heteroaryl; In another embodiment, R 3 is C 3-8 cycloalkyl; in another embodiment, R 3 is 3-14 membered heterocyclyl.
在一个具体的实施方式中，R3为在另一个具体的实施方式中，R3为在另一个具体的实施方式中，R3为在另一个具体的实施方式中，R3为 In a specific embodiment, R 3 is In another specific embodiment, R3 is In another specific embodiment, R3 is In another specific embodiment, R3 is
在一个实施方式中，所述R3未被取代；在另一个实施方式中，所述R3任选地被1个、2个、3个、4个或5个独立选择的R3s取代。In one embodiment, the R 3 is unsubstituted; in another embodiment, the R 3 is optionally substituted with 1, 2, 3, 4 or 5 independently selected R 3s .
所述R3可任选地被D取代，直至完全氘代。The R3 may optionally be substituted with D until fully deuterated.
R3s R 3s
在一个实施方式中，R3s为H；在另一个实施方式中，R3s为氘；在另一个实施方式中，R3s为卤素；在另一个实施方式中，R3s为CN；在另一个实施方式中，R3s为NO2；在另一个实施方式中，R3s为NH2；在另一个实施方式中，R3s为C1-6烷基，优选为C1-4烷基；在另一个实施方式中，R3s为C1-6烷氧基，优选为C1-4烷氧基；在另一个实施方式中，R3s为C2-6烯基；在另一个实施方式中，R3s为C2-6炔基；在另一个实施方式中，R3s为卤代C1-6烷基；在另一个实施方式中，R3s为卤代C1-6烷氧基；在另一个实施方式中，R3s为卤代C2-6烯基；在另一个实施方式中，R3s为卤代C2-6炔基；在另一个实施方式中，R3s为C6-10芳基；在另一个实施方式中，R3s为3-8元杂环基；在另一个实施方式中，R3s为3-8元杂芳基；在另一个实施方式中，R3s为-NH(C1-6烷基)；在另一个实施方式中，R3s为-N(C1-6烷基)2；在另一个实施方式中，R3s为-NH-C3-8环烷基；在另一个实施方式中，R3s为-NH-C6-10芳基；在另一个实施方式中，R3s为-NH-3-8元杂环基；在另一个实施方式中，R3s为-NH-3-8元杂芳基；在另一个实施方式中，R3s为-O-C1-6烷基；在另一个实施方式中，R3s为-O-C2-6烯基；在另一个实施方式中，R3s为-O-C2-6炔基；在另一个实施方式中，R3s为-O-C3-8环烷基；在另一个实施方式中，R3s为-O-C6-10芳基；在另一个实施方式中，R3s为-O-3-8元杂环基；在另一个实施方式中，R3s为-O-3-8元杂芳基；在另一个实施方式中，同一个碳原子上的两个R3s一起形成C＝O；在另一个实施方式中，同一个碳原子上的两个R3s一起形成C＝S。In one embodiment, R 3s is H; in another embodiment, R 3s is deuterium; in another embodiment, R 3s is halogen; in another embodiment, R 3s is CN; in another In one embodiment, R 3s is NO 2 ; in another embodiment, R 3s is NH 2 ; in another embodiment, R 3s is C 1-6 alkyl, preferably C 1-4 alkyl; in In another embodiment, R 3s is C 1-6 alkoxy, preferably C 1-4 alkoxy; in another embodiment, R 3s is C 2-6 alkenyl; in another embodiment , R 3s is C 2-6 alkynyl; in another embodiment, R 3s is halogenated C 1-6 alkyl; in another embodiment, R 3s is halogenated C 1-6 alkoxy; In another embodiment, R 3s is haloC 2-6 alkenyl; in another embodiment, R 3s is haloC 2-6 alkynyl; in another embodiment, R 3s is C 6 -10 aryl; in another embodiment, R 3s is a 3-8 membered heterocyclyl; in another embodiment, R 3s is a 3-8 membered heteroaryl; in another embodiment, R 3s is -NH(C 1-6 alkyl); in another embodiment, R 3s is -N(C 1-6 alkyl) 2 ; in another embodiment, R 3s is -NH-C 3- 8 cycloalkyl; in another embodiment, R 3s is -NH-C 6-10 aryl; in another embodiment, R 3s is -NH-3-8 membered heterocyclyl; in another embodiment In another embodiment, R 3s is -NH-3-8-membered heteroaryl; in another embodiment, R 3s is -OC 1-6 alkyl; in another embodiment, R 3s is -OC 2-6 Alkenyl; in another embodiment, R 3s is -OC 2-6 alkynyl; in another embodiment, R 3s is -OC 3-8 cycloalkyl; in another embodiment, R 3s is -OC 6-10 aryl; in another embodiment, R 3s is -O-3-8-membered heterocyclyl; in another embodiment, R 3s is -O-3-8-membered heteroaryl; In another embodiment, two R 3s on the same carbon atom together form C=O; in another embodiment, two R 3s on the same carbon atom together form C=S.
所述R3s可任选地被D取代，直至完全氘代。The R 3s may be optionally substituted with D until fully deuterated.
R3a和R3f R 3a and R 3f
在一个实施方式中，R3a为卤素，优选为Cl。In one embodiment, R 3a is halogen, preferably Cl.
在一个实施方式中，R3f为C1-6烷基，优选为C1-4烷基，例如CH3。In one embodiment, R 3f is C 1-6 alkyl, preferably C 1-4 alkyl, such as CH 3 .
所述R3s可任选地被D取代，直至完全氘代。The R 3s may be optionally substituted with D until fully deuterated.
Ra、Rb和Rc R a , R b and R c
在一个实施方式中，Ra为H；在另一个实施方式中，Ra为C1-6烷基；在另一个实施方式中，Ra为C1-6卤代烷基；在另一个实施方式中，Ra为C2-6烯基；在另一个实施方式中，Ra为C2-6炔基。In one embodiment, R a is H; in another embodiment, R a is C 1-6 alkyl; in another embodiment, R a is C 1-6 haloalkyl; in another embodiment In, R a is C 2-6 alkenyl; in another embodiment, R a is C 2-6 alkynyl.
在一个实施方式中，Rb为H；在另一个实施方式中，Rb为C1-6烷基；在另一个实施方式中，Rb为C1-6卤代烷基；在另一个实施方式中，Rb为C2-6烯基；在另一个实施方式中，Rb为C2-6炔基。In one embodiment, R b is H; in another embodiment, R b is C 1-6 alkyl; in another embodiment, R b is C 1-6 haloalkyl; in another embodiment In, R b is C 2-6 alkenyl; in another embodiment, R b is C 2-6 alkynyl.
在一个实施方式中，Rc为H；在另一个实施方式中，Rc为C1-6烷基；在另一个实施方式中，Rc为C1-6卤代烷基；在另一个实施方式中，Rc为C2-6烯基；在另一个实施方式中，Rc为C2-6炔基。In one embodiment, R c is H; in another embodiment, R c is C 1-6 alkyl; in another embodiment, R c is C 1-6 haloalkyl; in another embodiment In, R c is C 2-6 alkenyl; in another embodiment, R c is C 2-6 alkynyl.
所述Ra、Rb和Rc可任选地被D取代，直至完全氘代。The R a , R b and R c may be optionally substituted with D until fully deuterated.
以上任一具体实施方案中的任一技术方案或其任意组合，可以与其它具体实施方案中的任一技术方案或其任意组合进行组合。例如，R1的任一技术方案或其任意组合，可以与Y、L1、L2、R2、L3和R3等的任一技术方案或其任意组合进行组合。本发明旨在包括所有这些技术方案的组合，限于篇幅，不再一一列出。Any technical solution or any combination thereof in any of the above specific embodiments may be combined with any technical solution or any combination thereof in other specific embodiments. For example, any technical solution of R 1 or any combination thereof can be combined with any technical solution of Y, L 1 , L 2 , R 2 , L 3 and R 3 or any combination thereof. The present invention is intended to include combinations of all these technical solutions, and due to space limitations, they will not be listed one by one.
在更具体的实施方案中，本发明提供了式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates thereof substance or solvate:
其中：in:
Y为N或CR7；Y is N or CR 7 ;
R7选自H、C1-6烷基或C1-6卤代烷基；R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L1选自化学键或C1-6亚烷基，-NH-、-O-或-S-；L 1 is selected from chemical bond or C 1-6 alkylene group, -NH-, -O- or -S-;
R1选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基、3-10元杂环基、C6-20芳基或5-20元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；所述R1优选为C6-10芳基或5-10元杂芳基； R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
R1s选自H、氘、CN、NO2、NH2、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、卤代C2-6烯基、C2-6炔基、卤代C2-6炔基、C6-10芳基、3至8元杂环基、3至8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基或-O-3-8元杂芳基；R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heterocyclic group Aryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH- 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl base, -OC 6-10 aryl group, -O-3-8 membered heterocyclyl group or -O-3-8 membered heteroaryl group;
L2选自化学键或C1-6亚烷基；L 2 is selected from chemical bond or C 1-6 alkylene;
R2选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，优选为C6-10芳基，更优选为苯基，所述R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代；R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
R2s选自H、D、卤素、CN、-L2a-R’或 R 2s is selected from H, D, halogen, CN, -L 2a -R' or
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a优选-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-10烷基、C1-10烷氧基、C1-10卤代烷基、C1-10卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6烯基或C2-6炔基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , Boc, C 2-6 alkenyl or C 2-6 alkynyl, or the same Two R's on a carbon atom together form C=O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
R3选自C6-14芳基或5-14杂芳基、C3-8环烷基、3至14元杂环基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
R3s选自H、氘、卤素、CN、NO2、NH2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1- 6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基、-O-3-8元杂芳基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S； R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group, 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH - 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基、C2-6烯基或C2-6炔基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(I’)的结构：
In a more specific embodiment, the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, which is the structure of formula (I'):
其中：in:
Y’为NR7或CR7R8；Y' is NR 7 or CR 7 R 8 ;
R7和R8独立地选自H、C1-6烷基或C1-6卤代烷基；R 7 and R 8 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
L3’为-N＝或-CRa＝；L 3 ' is -N= or -CR a =;
其他各基团如上文所定义。Each other group is as defined above.
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(II)、(II’)、(III)、(III’)、(IV)、(IV’)、(V)、(V’)、(VI)、(VI’)、(VII)、(VII’)、(VIII)或(VIII’)的结构：


In a more specific embodiment, the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate of formula (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), Structure of (VI'), (VII), (VII'), (VIII) or (VIII'):


其中，in,
R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a优选-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
R”选自H、卤素、C1-6卤代烷基或C1-6卤代烷氧基；R” is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
其他各基团如上文所定义。Each other group is as defined above.
在更具体的实施方案中，本发明提供了式(II)或(II’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中：in:
L1选自化学键或C1-6亚烷基；L 1 is selected from chemical bond or C 1-6 alkylene;
R1选自C1-6烷氧基、C1-6卤代烷氧基、C6-10芳基或5-10元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 1, 4 or 5 R 1s are substituted;
R1s选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# replace;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
L3’为-N＝或-CRa＝；L 3 ' is -N= or -CR a =;
R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and the R 3 is optionally substituted by 1, 2, 3, 4 or 5 R 3s ;
R3s选自卤素、C1-6烷基或C1-6烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S； R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(II)或(II’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the invention provides compounds of the above formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L1选自化学键或C1-6亚烷基；L 1 is selected from chemical bond or C 1-6 alkylene;
R1选自C1-6烷氧基、C1-6卤代烷氧基、C6-10芳基或5-10元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 1, 4 or 5 R 1s are substituted;
R1s选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# replace;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
L3’为-N＝或-CRa＝；L 3 ' is -N= or -CR a =;
R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and the R 3 is optionally substituted by 1, 2, 3, 4 or 5 R 3s ;
R3s选自卤素、C1-6烷基或C1-6烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。 Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III)或(III’)的结构：
In a more specific embodiment, the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, which is the structure of formula (III) or (III'):
其中：in:
R2a选自或-L2a-R’；R 2a is selected from or -L 2a -R';
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或C2-6亚烯基，L2a任选地被1个、2个、3个、4个或5个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene- or C 2-6 alkenylene, L 2a is optionally selected from halogen, C 1- 6 alkyl or C 1-6 haloalkyl substituent substitution;
环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、OH、NH2、CN、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)-C1-6卤代烷基、C(O)O-C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C( O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl, or the same Two R's on a carbon atom together form C=O or C=S;
m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
R’选自NH2、CN、C1-6烷基、C1-6卤代烷基、C(O)-C1-6卤代烷基、C(O)O-C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基；R' is selected from NH 2 , CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O) -C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl;
R2c选自卤素；R 2c is selected from halogen;
R2d选自卤素或CN；R 2d is selected from halogen or CN;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(III)或(III’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (III) or (III'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2a选自或-L2a-R’； R 2a is selected from or -L 2a -R';
L2a选自化学键、-O-、-S-、-C1-6亚烷基-、-C1-6亚烷基-O-、-O-C1-6亚烷基-、-C(O)-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-或C2-6亚烯基，L2a任选地被1个、2个或3个独立地选自卤素或C1-6烷基的取代基取代；L 2a is selected from chemical bonds, -O-, -S-, -C 1-6 alkylene-, -C 1-6 alkylene-O-, -OC 1-6 alkylene-, -C(O )-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)- or C 2-6 alkenylene, L 2a is optionally replaced by 1, 2 or Substituted with 3 substituents independently selected from halogen or C 1-6 alkyl;
环A选自C3-8环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、OH、NH2、CN、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或NHC(O)-C1-6卤代烷基，或者，同一个碳原子上的两个R一起形成C＝O；Each R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or NHC ( O)-C 1-6 haloalkyl, or two R on the same carbon atom together form C=O;
m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
R’选自NH2、CN、C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基；R' is selected from NH 2 , CN, C 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl;
R2c选自卤素；R 2c is selected from halogen;
R2d选自卤素或CN；R 2d is selected from halogen or CN;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(III)或(III’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (III) or (III'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2a选自或-L2a-R’；R 2a is selected from or -L 2a -R';
L2a选自化学键、-O-、-S-、-CH2-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)-、-C(O)O-、-NH-、-C(O)NH-、-NH-C(O)-或-CH＝CH-，所述L2a任选地被CH3取代；L 2a is selected from chemical bonds, -O-, -S-, -CH 2 -, -CH 2 -O-, -CH 2 -CH 2 -O-, -O-CH 2 -, -C(O)-, -C(O)O-, -NH-, -C(O)NH-, -NH-C(O)- or -CH=CH-, the L 2a is optionally substituted by CH 3 ;
选自
Selected from
R’选自CN、NHC(O)-CF3或CF3；R' is selected from CN, NHC(O)-CF 3 or CF 3 ;
R2c选自F或Cl，优选为F；R 2c is selected from F or Cl, preferably F;
R2d选自F、Cl或CN，优选为Cl。R 2d is selected from F, Cl or CN, preferably Cl.
在更具体的实施方案中，本发明提供了式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中：in:
L2a选自-O-、-S-或-C2-6亚烯基-；L 2a is selected from -O-, -S- or -C 2-6 alkenylene-;
环A选自C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、OH、NH2、-C(O)-C1-6卤代烷基、-C(O)O-C1-6卤代烷基、-NHC(O)-C1-6卤代烷基、-C(O)NH-C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OH, NH 2 , -C(O)-C 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -NHC(O)-C 1-6 haloalkyl, -C(O)NH-C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; or, two R on the same carbon atom together form C =O or C=S;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d选自卤素或CN，优选为Cl。 R 2d is selected from halogen or CN, preferably Cl.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a选自-O-或-C2-6亚烯基-；L 2a is selected from -O- or -C 2-6 alkenylene-;
环A选自C5-8环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 5-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、OH、NH2、-NHC(O)-C1-6卤代烷基、-C(O)NH-C1-6卤代烷氧基、C1-6烷氧基或C1-6卤代烷氧基；或者，同一个碳原子上的两个R一起形成C＝O；Each R is independently selected from H, halogen, CN, OH, NH 2 , -NHC(O)-C 1-6 haloalkyl, -C(O)NH-C 1-6 haloalkoxy, C 1-6 Alkoxy or C 1-6 haloalkoxy; or, two R on the same carbon atom together form C=O;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d选自卤素或CN，优选为Cl。R 2d is selected from halogen or CN, preferably Cl.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a选自-O-或-C2-4亚烯基-；L 2a is selected from -O- or -C 2-4 alkenylene-;
环A选自C5-6环烷基、5-6元杂环基、苯基或5-10元杂芳基；Ring A is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、-NHC(O)-C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基，优选为H、F、Cl、CN、OCH3、OCF3或-NHC(O)-CF3；或者，同一个碳原子上的两个R一起形成C＝O；Each R is independently selected from H, halogen, CN, -NHC(O)-C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, preferably H, F, Cl, CN, OCH 3 , OCF 3 or -NHC(O)-CF 3 ; or, two R on the same carbon atom together form C=O;
m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d选自卤素或CN，优选为Cl。R 2d is selected from halogen or CN, preferably Cl.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a选自-O-、-CH＝CH-；L 2a is selected from -O-, -CH=CH-;
选自 Selected from
R2c选自F或Cl，优选为F；R 2c is selected from F or Cl, preferably F;
R2d选自F、Cl或CN，优选为Cl。R 2d is selected from F, Cl or CN, preferably Cl.
在更具体的实施方案中，本发明提供了式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中：in:
L2a为C2-6亚烯基；L 2a is C 2-6 alkenylene;
环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R选自H、卤素或C1-6卤代烷基；R is selected from H, halogen or C 1-6 haloalkyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d为卤素，优选为Cl；R 2d is halogen, preferably Cl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a为C2-4亚烯基，优选为-CH＝CH-；L 2a is C 2-4 alkenylene, preferably -CH=CH-;
环A选自苯基或5-6元杂芳基，所述5元杂芳基为含有1-2个选自S或N的杂原子的杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl, and the 5-membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from S or N;
R选自H或卤素，优选为H或F； R is selected from H or halogen, preferably H or F;
m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d为卤素，优选为Cl。R 2d is halogen, preferably Cl.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a为C2-4烯基，优选为-CH＝CH-；L 2a is C 2-4 alkenyl, preferably -CH=CH-;
选自 Selected from
R2c为F；R 2c is F;
R2d为Cl或F，优选为Cl。R 2d is Cl or F, preferably Cl.
在更具体的实施方案中，本发明提供了式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中：in:
L2a为-O-或-S-；L 2a is -O- or -S-;
环A选自或5元杂芳基；Ring A is selected from or 5-membered heteroaryl;
X2a和X2b独立地选自CR或N；X 2a and X 2b are independently selected from CR or N;
每个R独立地选自H、卤素、CN、OH、NH2、C1-6烷氧基或C1-6卤代烷氧基，优选为H、F、Cl、CN、OCF3；Each R is independently selected from H, halogen, CN, OH, NH 2 , C 1-6 alkoxy or C 1-6 haloalkoxy, preferably H, F, Cl, CN, OCF 3 ;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
其中各基团定义可任选地被D取代，直至完全氘代。 Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a为-O-；L 2a is -O-;
环A选自或5元杂芳基；Ring A is selected from or 5-membered heteroaryl;
X2a和X2b独立地选自CR或N；X 2a and X 2b are independently selected from CR or N;
每个R独立地选自H、卤素、CN或C1-6卤代烷氧基；Each R is independently selected from H, halogen, CN or C 1-6 haloalkoxy;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a为-O-；L 2a is -O-;
环A选自或5元杂芳基，所述5元杂芳基为含有1-2个选自S或N的杂原子的杂芳基；Ring A is selected from Or a 5-membered heteroaryl group, the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;
X2a和X2b独立地选自CR或N；X 2a and X 2b are independently selected from CR or N;
每个R独立地选自H、卤素、CN或C1-4卤代烷氧基，优选为H、F、Cl、CN或OCF3；Each R is independently selected from H, halogen, CN or C 1-4 haloalkoxy, preferably H, F, Cl, CN or OCF 3 ;
m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
优选地，Preferably,
选自 Selected from
在更具体的实施方案中，本发明提供了式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
R2b为或-L2a-R’；R 2b is or -L 2a -R';
L2a为-C1-6亚烷基-、-C2-6亚烯基-、-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 1-6 alkylene-, -C 2-6 alkenylene-, -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene- SC 0-6 alkylene-;
环A为C6-10芳基或5-10元杂芳基；Ring A is C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、NH2、OH、CN、C1-6卤代烷基或C1-6卤代烷氧基；Each R is independently selected from H, halogen, NH 2 , OH, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
R’选自C(O)-C1-6卤代烷基、C(O)O-C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基；R' is selected from C(O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl base;
R2c为卤素；R 2c is halogen;
R2d选自卤素或CN；R 2d is selected from halogen or CN;
m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2b为或-L2a-R’；R 2b is or -L 2a -R';
L2a选自-O-、-S-、-C1-4亚烷基-、-C1-4亚烷基-O-、-O-C1-4亚烷基-、-C1-4亚烷基-S-或-S-C1-4亚烷基-；L 2a is selected from -O-, -S-, -C 1-4 alkylene-, -C 1-4 alkylene-O-, -OC 1-4 alkylene-, -C 1-4 alkylene Alkyl-S- or -SC 1-4 alkylene-;
环A为苯基或5-6元杂芳基，所述5元杂芳基为含有1-2个选自S或N的杂原子的杂芳基；Ring A is a phenyl group or a 5-6-membered heteroaryl group, and the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;
每个R独立地选自H、卤素、CN、C1-4卤代烷基或C1-4卤代烷氧基，优选为H、F、Cl、CN、CF3或OCF3；Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, Cl, CN, CF 3 or OCF 3 ;
R’选自NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基，优选为NHC(O)CF3；R' is selected from NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl, preferably NHC(O)CF 3 ;
R2c为卤素； R 2c is halogen;
R2d选自卤素或CN；R 2d is selected from halogen or CN;
m为0、1、2或3；m is 0, 1, 2 or 3;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2b为或-L2a-R’；R 2b is or -L 2a -R';
L2a为-O-、-S-、-CH2-、-CH2-O-、-CH2-CH2-O-或-O-CH2-；L 2a is -O-, -S-, -CH 2 -, -CH 2 -O-, -CH 2 -CH 2 -O- or -O-CH 2 -;
选自 Selected from
R’为NHC(O)CF3；R' is NHC(O)CF 3 ;
R2c为F；R 2c is F;
R2d选自F、Cl或CN，优选为Cl。R 2d is selected from F, Cl or CN, preferably Cl.
在更具体的实施方案中，本发明提供了式(VI)或(VI’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In more specific embodiments, the invention provides compounds of formula (VI) or (VI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
L2a为-O-或-S-；L 2a is -O- or -S-;
环A为C6-10芳基或5-10元杂芳基；Ring A is C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、C1-6卤代烷基或C1-6卤代烷氧基；Each R is independently selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
R2c为卤素；R 2c is halogen;
R2d选自卤素或CN；R 2d is selected from halogen or CN;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VI)或(VI’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (VI) or (VI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a为-O-；L 2a is -O-;
环A为苯基；Ring A is phenyl;
每个R独立地选自H、卤素、C1-4卤代烷基或C1-4卤代烷氧基，优选为H、F、Cl、CF3或OCF3；Each R is independently selected from H, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, Cl, CF 3 or OCF 3 ;
m为0、1、2或3；m is 0, 1, 2 or 3;
优选地，选自 Preferably, Selected from
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VII)或(VII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VII) or (VII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate:
其中，in,
L2a为O或S；L 2a is O or S;
R选自H或卤素；R is selected from H or halogen;
R”选自H、卤素、C1-6卤代烷基或C1-6卤代烷氧基。R” is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy.
在更具体的实施方案中，本发明提供了上述式(VII)或(VII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VII) or (VII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate, wherein:
L2a选自-O-；L 2a is selected from -O-;
R选自H或卤素，优选为H、F或Cl；R is selected from H or halogen, preferably H, F or Cl;
R”选自H、卤素或C1-4卤代烷氧基，优选为H、F、Cl或OCF3。R” is selected from H, halogen or C 1-4 haloalkoxy, preferably H, F, Cl or OCF 3 .
在更具体的实施方案中，本发明提供了式(II)或(II’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
L1选自化学键或C1-6亚烷基；L 1 is selected from chemical bond or C 1-6 alkylene;
R1选自C1-6烷氧基、C1-6卤代烷氧基、C6-10芳基或5-10元杂芳基，所述R1任选地被1个、2个3个、4个或5个独立选择的R1s取代； R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 , 4 or 5 independently selected R 1s substitutions;
R1s选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；L 2a is selected from chemical bond, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene-, -C 0-6 alkylene -C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0-6 alkylene-NH-C 0 -6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC(O)-C 0-6 alkylene Alkyl-or-C 2-6 alkenylene-, the L 2a is optionally substituted by 1, 2, 3, 4 or 5 independently selected R#;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
环A选自C3-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6卤代烷基、C1-6卤代烷氧基或Boc，优选为H、F、Cl、CN、CF3、OCF3或Boc；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 haloalkyl, C 1-6 haloalkoxy or Boc, preferably H, F, Cl, CN, CF 3 , OCF 3 or Boc;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d为卤素，优选为Cl；R 2d is halogen, preferably Cl;
L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个、3个、4个或5个独立选择的R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and said R 3 is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 3s ;
R3s选自H、卤素、C1-6烷基或C1-6烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form C=O or C=S;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(II)或(II’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the invention provides compounds of the above formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L1选自化学键或C1-4亚烷基；L 1 is selected from chemical bond or C 1-4 alkylene;
R1选自C1-4烷氧基或5-6元杂芳基，所述R1任选地被1个、2个或3个独立选择的R1s取代；R 1 is selected from C 1-4 alkoxy or 5-6 membered heteroaryl, and R 1 is optionally substituted by 1, 2 or 3 independently selected R 1s ;
R1s选自H、卤素、C1-4烷基或C1-4烷氧基，优选为F、CH3或OCH3；R 1s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, preferably F, CH 3 or OCH 3 ;
R2a和R2b之一为或-L2a-R’，另一个为H或D； One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-O-、-S-、-C1-4亚烷基-O-、-O-C1-4亚烷基-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)-或C2-4亚烯基，所述L2a任选地被1个、2个或3个独立选择的R#取代；L 2a is selected from chemical bonds, -O-, -S-, -C 1-4 alkylene-O-, -OC 1-4 alkylene-, -C(O)O-, -NH-, -C (O)NH-, -NHC(O)-, -C(O)- or C 2-4 alkenylene, the L 2a is optionally substituted by 1, 2 or 3 independently selected R# ;
R#选自H、C1-4烷基或C1-4卤代烷基；R# is selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
环A选自C3-6环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-6 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、C1-4卤代烷基、C1-4卤代烷氧基或Boc，优选为H、F、Cl、CN、CF3、OCF3或Boc；Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy or Boc, preferably H, F, Cl, CN, CF 3 , OCF 3 or Boc;
m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
R’选自C1-4烷基或C1-4卤代烷基；R' is selected from C 1-4 alkyl or C 1-4 haloalkyl;
R2c为卤素，优选为F；R 2c is halogen, preferably F;
R2d为卤素，优选为Cl；R 2d is halogen, preferably Cl;
L3为-NH-；L 3 is -NH-;
R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个或3个独立选择的R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and said R 3 is optionally substituted by 1, 2 or 3 independently selected R 3s ;
R3s选自H、卤素、C1-4烷基或C1-4烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O；R 3s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, or two R 3s on the same carbon atom together form C=O;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(II)或(II’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the invention provides compounds of the above formula (II) or (II'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L1选自化学键或-CH2-；L 1 is selected from chemical bonds or -CH 2 -;
R1选自OCH3、 R 1 is selected from OCH 3 ,
R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)-或-CH＝CH-，所述L2a任选地被CH3取代；L 2a is selected from chemical bonds, -O-, -S-, -CH 2 -O-, -CH 2 -CH 2 -O-, -O-CH 2 -, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, the L 2a is optionally substituted by CH 3 ;
选自 Selected from
R’选自CHF2或CF3；R' is selected from CHF 2 or CF 3 ;
R2c选自F；R 2c is selected from F;
R2d选自F或Cl；R 2d is selected from F or Cl;
L3为-NH-；L 3 is -NH-;
R3选自 R 3 is selected from
L1选自化学键或-CH2-；L 1 is selected from chemical bonds or -CH 2 -;
R1选自OCH3、 R 1 is selected from OCH 3 ,
R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)-或-CH＝CH-，所述L2a任选地被CH3取代； L 2a is selected from chemical bonds, -O-, -S-, -CH 2 -O-, -CH 2 -CH 2 -O-, -O-CH 2 -, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, the L 2a is optionally substituted by CH 3 ;
选自 Selected from
R’选自CHF2或CF3；R' is selected from CHF 2 or CF 3 ;
R2c选自F；R 2c is selected from F;
R2d选自F或Cl；R 2d is selected from F or Cl;
L3为-NH-；L 3 is -NH-;
R3选自 R 3 is selected from
在更具体的实施方案中，本发明提供了式(VIII)或(VIII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In more specific embodiments, the invention provides compounds of formula (VIII) or (VIII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中：in:
L2a为O或S；L 2a is O or S;
R1s选自卤素或C1-6卤代烷氧基；R 1s is selected from halogen or C 1-6 haloalkoxy;
R选自卤素、CN、C1-6卤代烷基或C1-6卤代烷氧基；R is selected from halogen, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-6烷基，优选为CH3。R 3f is C 1-6 alkyl, preferably CH 3 .
在更具体的实施方案中，本发明提供了上述式(VIII)或(VIII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VIII) or (VIII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate, wherein:
L2a为O；L 2a is O;
R1s选自卤素或C1-4卤代烷氧基，优选为F或OCH3；R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3 ;
R选自卤素、CN、C1-4卤代烷基或C1-4卤代烷氧基，优选为F、CN、CF3或OCF3；R is selected from halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably F, CN, CF 3 or OCF 3 ;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-4烷基，优选为CH3。R 3f is C 1-4 alkyl, preferably CH 3 .
在更具体的实施方案中，本发明提供了上述式(VIII)或(VIII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the present invention provides compounds of the above formula (VIII) or (VIII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate:
其中：in:
L2a为O或S；L 2a is O or S;
R1s选自卤素或C1-6卤代烷氧基；R 1s is selected from halogen or C 1-6 haloalkoxy;
R选自卤素或CN；R is selected from halogen or CN;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(VIII)或(VIII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides the above-mentioned compound of formula (VIII) or (VIII'), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, or prodrug thereof , polymorph, hydrate or solvate, wherein:
L2a为O；L 2a is O;
R1s选自卤素或C1-4卤代烷氧基，优选为F或OCH3；R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3 ;
R选自卤素或CN，优选为F或CN；R is selected from halogen or CN, preferably F or CN;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-4烷基，优选为CH3。R 3f is C 1-4 alkyl, preferably CH 3 .
在更具体的实施方案中，本发明提供了上述式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IV)、(IV’)、(V)、(V’)、(IX)、(IX’)、(X)、(X’)、(XI)、(XI’)、(XII)或(XII’)的结构：

In a more specific embodiment, the present invention provides the above-mentioned compound of formula (I), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate of formula (IV), (IV'), (V), (V'), (IX), (IX'), (X), (X'), (XI), Structure of (XI'), (XII) or (XII'):

R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a优选-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
R2c为卤素，优选为F； R 2c is halogen, preferably F;
R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
其他各基团如前述所定义。Each other group is as defined above.
在更具体的实施方案中，本发明提供了式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R选自H、卤素、CN、ORa、NRbRc、C(O)NRbRc、C1-6烷基或C1-6卤代烷基；R is selected from H, halogen, CN, OR a , NR b R c , C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R2d选自卤素；R 2d is selected from halogen;
R2c选自卤素；R 2c is selected from halogen;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自苯基或5-6元杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl;
R选自H、卤素、CN、OH、NH2、C(O)NH2或C1-4卤代烷基，优选为H、F、Cl、CN、OH、NH2、C(O)NH2或CF3；R is selected from H, halogen, CN, OH, NH 2 , C(O)NH 2 or C 1-4 haloalkyl, preferably H, F, Cl, CN, OH, NH 2 , C(O)NH 2 or CF 3 ;
m选自1、2或3；m is selected from 1, 2 or 3;
R2d选自卤素，优选为Cl或F； R 2d is selected from halogen, preferably Cl or F;
R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a为-S-或-O-；L 2a is -S- or -O-;
选自 Selected from
R2d选自卤素，优选为Cl或F；R 2d is selected from halogen, preferably Cl or F;
R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R选自H、卤素、CN、NH2、C1-6烷基或C1-6卤代烷基；R is selected from H, halogen, CN, NH 2 , C 1-6 alkyl or C 1-6 haloalkyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
R2c选自卤素，优选为F；R 2c is selected from halogen, preferably F;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自苯基或5-6元杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl;
R选自H、卤素、CN、NH2或C1-4卤代烷基，优选为H、F、Cl、CN、NH2或CF3；R is selected from H, halogen, CN, NH 2 or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 or CF 3 ;
m选自1、2或3；m is selected from 1, 2 or 3;
R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
R2c选自卤素，优选为F。 R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了上述式(IV)或(IV’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IV) or (IV'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
L2a为-S-或-O-，优选为-S-；L 2a is -S- or -O-, preferably -S-;
选自 Selected from
R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或6-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 6-10 membered heteroaryl;
R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自C0-6亚烷基-OC1-6烷基或C0-6亚烷基-OC1-6卤代烷基；R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
R2d选自卤素；R 2d is selected from halogen;
R2c选自卤素；R 2c is selected from halogen;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。 Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自4-7元杂环基、苯基或5-6元杂芳基；Ring A is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
R选自H、卤素、NH2、CN、OH或C1-4卤代烷基，优选为H、F、NH2、CN、OH或CF3；R is selected from H, halogen, NH 2 , CN, OH or C 1-4 haloalkyl, preferably H, F, NH 2 , CN, OH or CF 3 ;
m选自1、2或3；m is selected from 1, 2 or 3;
R’为C1-4亚烷基-OC1-4烷基；R' is C 1-4 alkylene-OC 1-4 alkyl;
R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
选自 Selected from
R’为 R' is
R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2b选自或-L2a-R’； R 2b is selected from or -L 2a -R';
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或6-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 6-10 membered heteroaryl;
R选自H、卤素、C0-6亚烷基-NH2、C0-6亚烷基-CN或C0-6亚烷基-OH；R is selected from H, halogen, C 0-6 alkylene-NH 2 , C 0-6 alkylene-CN or C 0-6 alkylene-OH;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自C0-6亚烷基-OC1-6烷基或C0-6亚烷基-OC1-6卤代烷基；R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
R2d选自卤素；R 2d is selected from halogen;
R2c选自卤素；R 2c is selected from halogen;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
环A选自4-7元杂环基、苯基或5-6元杂芳基；Ring A is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
R选自H、卤素、NH2、CN或OH，优选为H、F、NH2、CN或OH；R is selected from H, halogen, NH 2 , CN or OH, preferably H, F, NH 2 , CN or OH;
m选自1、2或3；m is selected from 1, 2 or 3;
R’为C1-4亚烷基-OC1-4烷基；R' is C 1-4 alkylene-OC 1-4 alkyl;
R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了上述式(V)或(V’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (V) or (V'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
选自 Selected from
R’为 R' is
R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
在更具体的实施方案中，本发明提供了式(IX)或(IX’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In more specific embodiments, the invention provides compounds of formula (IX) or (IX'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
R1S选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基C2- 6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy C 2-6 Alkenyl or C 2-6 alkynyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(IX)或(IX’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IX) or (IX'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S选自H、卤素、C1-4烷基或C1-4烷氧基；R 1S is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy;
L2a为-O-C0-4亚烷基-或-S-C0-4亚烷基-；L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
环A选自苯基或5-6元杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl;
R选自H、卤素、CN、NH2、OH、C1-4烷基或C1-4卤代烷基，优选为H、F、Cl、CN、NH2、OH、CH3或CF3； R is selected from H, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 , OH, CH 3 or CF 3 ;
m选自1、2或3；m is selected from 1, 2 or 3;
R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
R3f为C1-4烷基，优选为CH3。R 3f is C 1-4 alkyl, preferably CH 3 .
在更具体的实施方案中，本发明提供了上述式(IX)或(IX’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (IX) or (IX'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S选自H、F、CH3或OCH3；R 1S is selected from H, F, CH 3 or OCH 3 ;
L2a为-S-或-S-CH2-；L 2a is -S- or -S-CH 2 -;
选自 Selected from
R2d选自Cl或CN；R 2d is selected from Cl or CN;
R2c选自H或F；R 2c is selected from H or F;
R3a为Cl；R 3a is Cl;
R3f为CH3。R 3f is CH 3 .
在更具体的实施方案中，本发明提供了式(X)或(X’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In more specific embodiments, the invention provides compounds of formula (X) or (X'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中， in,
R1S选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1S is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
L2a为-S-或-O-；L 2a is -S- or -O-;
环A选自C6-10芳基或5-10元杂芳基，所述5-10元杂芳基为含有1-2个选自O、S或N的杂原子的杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the 5-10 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
R选自H、卤素、CN、NRbRc、ORa、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, NR b R c , OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(X)或(X’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (X) or (X'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S选自C1-4烷基或C1-4烷氧基；R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
L2a为-S-或-O-；L 2a is -S- or -O-;
环A选自苯基或5-6元杂芳基，所述5-6元杂芳基为含有1-2个选自O、S或N的杂原子的杂芳基；Ring A is selected from phenyl or 5-6-membered heteroaryl, and the 5-6-membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
R选自H、卤素、CN、NH2、OH、C1-4烷基或C1-4卤代烷基，优选为H、F、Cl、CN、NH2、OH、CH3或CF3；R is selected from H, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 , OH, CH 3 or CF 3 ;
m选自1、2或3；m is selected from 1, 2 or 3;
R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F。R 2c is selected from H or halogen, preferably H or F, more preferably F.
在更具体的实施方案中，本发明提供了上述式(X)或(X’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (X) or (X'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S选自CH3或OCH3；R 1S is selected from CH 3 or OCH 3 ;
L2a为-S-或-O-，优选为-S-； L 2a is -S- or -O-, preferably -S-;
选自 Selected from
R2d选自Cl或CN；R 2d is selected from Cl or CN;
R2c选自H或F。R 2c is selected from H or F.
在更具体的实施方案中，本发明提供了式(XI)或(XI’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (XI) or (XI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
R1S选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)-Ra、C1-6亚烷基-OC(O)-Ra、C1-6亚烷基-C(O)O-Ra、C1-6亚烷基-C(O)NRbRc或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
R2d选自卤素或CN；R 2d is selected from halogen or CN;
R2c选自H或卤素；R 2c is selected from H or halogen;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基； R 3f is C 1-6 alkyl;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(XI)或(XI’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (XI) or (XI'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S为CH3；R 1S is CH 3 ;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-S-；L 2a is -S-;
选自 Selected from
R’选自 R' is selected from
R2d选自F、Cl或CN；R 2d is selected from F, Cl or CN;
R2c选自H或F；R 2c is selected from H or F;
R3a为Cl；R 3a is Cl;
R3f为CH3。R 3f is CH 3 .
在更具体的实施方案中，本发明提供了式(XII)或(XII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
In a more specific embodiment, the invention provides compounds of formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs thereof, Polymorph, hydrate or solvate:
其中，in,
R1S选自C1-6烷基或C1-6烷氧基；R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
环A选自3-8元杂环基、或5元杂芳基，所述5元杂芳基为含有1-2个选自N、O或S的杂原子的杂芳基；Ring A is selected from 3-8 membered heterocyclyl, Or a 5-membered heteroaryl group, the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from N, O or S;
Q1为CH或N；Q 1 is CH or N;
R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)-Ra、C1-6亚烷基-OC(O)-Ra、C1-6亚烷基-C(O)O-Ra、C1-6亚烷基-C(O)NRbRc或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(XII)或(XII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S选自C1-4烷基或C1-4烷氧基；R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-O-C0-4亚烷基-或-S-C0-4亚烷基-；L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
环A选自3-6元杂环基、 Ring A is selected from 3-6 membered heterocyclyl,
Q1为CN或N；Q 1 is CN or N;
Q2选自S或NH； Q 2 is selected from S or NH;
Q3选自CH或N；Q 3 is selected from CH or N;
Q4、Q5和Q6中的一个为N，另外两个为CH；One of Q 4 , Q 5 and Q 6 is N, and the other two are CH;
R选自H、卤素、OH、CN、NRbRc、C1-4烷基或C1-4卤代烷基，优选为H、F、OH、CN、NH2、NHCH3、CF3或CH3；R is selected from H, halogen, OH, CN, NR b R c , C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, OH, CN, NH 2 , NHCH 3 , CF 3 or CH 3 ;
m选自1、2或3；m is selected from 1, 2 or 3;
R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)NRbRc或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
Ra、Rb和Rc独立地选自H、C1-4烷基或C1-4卤代烷基。R a , R b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(XII)或(XII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S为CH3；R 1S is CH 3 ;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-S-；L 2a is -S-;
选自 Selected from
R’选自 R' is selected from
R2d选自F、Cl或CN；R 2d is selected from F, Cl or CN;
R2c选自H或F。R 2c is selected from H or F.
在更具体的实施方案中，本发明提供了上述式(XII)或(XII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中： In a more specific embodiment, the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S选自C1-6烷基或C1-6烷氧基；R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
环A选自苯基、噻吩基、吡唑基或噻唑基；Ring A is selected from phenyl, thienyl, pyrazolyl or thiazolyl;
R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)-Ra、C1-6亚烷基-OC(O)-Ra、C1-6亚烷基-C(O)O-Ra、C1-6亚烷基-C(O)NH2或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NH 2 or C 1-6 alkylene-OR a ;
R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(XII)或(XII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：In a more specific embodiment, the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S选自C1-4烷基或C1-4烷氧基；R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-O-C0-4亚烷基-或-S-C0-4亚烷基-；L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
环A选自苯基、噻吩基、 Ring A is selected from phenyl, thienyl,
R选自H、卤素、CN、NRbRc、C1-4烷基或C1-4卤代烷基，优选为H、F、CN、NH2、NHCH3、CF3或CH3；R is selected from H, halogen, CN, NR b R c , C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, CN, NH 2 , NHCH 3 , CF 3 or CH 3 ;
Rb和Rc独立地选自H、C1-4烷基或C1-4卤代烷基；R b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
m选自1、2或3；m is selected from 1, 2 or 3;
R’选自C1-4亚烷基-NHC(O)-C1-4卤代烷基、C1-4亚烷基-C(O)NH2或C1-4亚烷基-O-C1-4烷基；R' is selected from C 1-4 alkylene-NHC(O)-C 1-4 haloalkyl, C 1-4 alkylene-C(O)NH 2 or C 1-4 alkylene-OC 1- 4 alkyl;
R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
R2c选自H或卤素，优选为H或F，更优选为F。R 2c is selected from H or halogen, preferably H or F, more preferably F.
在更具体的实施方案中，本发明提供了上述式(XII)或(XII’)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中： In a more specific embodiment, the present invention provides compounds of the above formula (XII) or (XII'), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, and prodrugs thereof , polymorph, hydrate or solvate, wherein:
R1S为CH3；R 1S is CH 3 ;
R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
L2a为-S-；L 2a is -S-;
选自 Selected from
R’选自 R' is selected from
R2d选自F、Cl或CN；R 2d is selected from F, Cl or CN;
R2c选自H或F。R 2c is selected from H or F.
在更具体的实施方案中，本发明提供了化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，所述化合物选自以下：













In more specific embodiments, the invention provides compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof Object, wherein said compound is selected from the following:













在更具体的实施方案中，本发明提供了化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，所述化合物选自以下：




In more specific embodiments, the invention provides compounds, or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof Object, wherein said compound is selected from the following:




具体地，本发明还涉及以下技术方案：Specifically, the present invention also relates to the following technical solutions:
1.式(P-I)的化合物或其生理学上/药学上可接受的盐或酯，它们的立体异构体或互变异构体、消旋体、氮氧化物、溶剂合物、同位素标记物、前药或代谢产物：
1. Compounds of formula (PI) or their physiologically/pharmaceutically acceptable salts or esters, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, and isotopic markers , prodrugs or metabolites:
其中，in,
环A表示5至20元杂芳基或C6-20芳基，Ring A represents a 5- to 20-membered heteroaryl group or a C 6-20 aryl group,
R1各自彼此独立地选自H、C1-6烷基、C2-6烯基、C2-6炔基、卤素、氰基、硝基、氨基、卤代C1-6烷基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3至8元杂环基、3至8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3至8元杂环基、-NH-3至8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3至8元杂环基、-O-3至8元杂芳基，R 1 is each independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl, Halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8-membered heterocyclyl, 3 to 8-membered heteroaryl, -NH(C 1-6 alkyl ), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8-membered heterocyclyl, -NH-3 to 8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl, -OC 6-10 aryl, -O -3 to 8-membered heterocyclyl, -O-3 to 8-membered heteroaryl,
L1表示单键、-CH2-、-NH-、-O-或-S-，L 1 represents a single bond, -CH 2 -, -NH-, -O- or -S-,
n为0至10的整数，n is an integer from 0 to 10,
R2表示H、C1-6烷基、卤素或氘代C1-6烷基，R 2 represents H, C 1-6 alkyl, halogen or deuterated C 1-6 alkyl,
R3各自彼此独立地选自H、C1-6烷基、卤素、氰基、硝基或氨基，R 3 is each independently selected from H, C 1-6 alkyl, halogen, cyano, nitro or amino,
m为0至3的整数。m is an integer from 0 to 3.
2.根据技术方案1所述的式(P-I)的化合物，其具有如下的式(P-IA)的结构：
2. The compound of formula (PI) according to technical scheme 1, which has the structure of the following formula (P-IA):
其中，环A、R1、R2、R3、n和m如式(P-I)中所定义。Wherein, ring A, R 1 , R 2 , R 3 , n and m are as defined in formula (PI).
3.根据技术方案1所述的式(P-I)的化合物，其具有如下的式(P-IB)的结构：
3. The compound of formula (PI) according to technical scheme 1, which has the structure of the following formula (P-IB):
其中，环A、R1和n如式(P-I)中所定义。Wherein, ring A, R 1 and n are as defined in formula (PI).
4.根据技术方案1至3中任一项所述的式(P-I)的化合物，其中，环A表示5至10元杂芳基，优选5元或6元杂芳基、9元或10元稠合杂芳基，例如噻唑基、吡唑基、吡啶基、异喹啉基、吡唑并吡啶基、吡咯并吡啶基。4. The compound of formula (P-I) according to any one of technical schemes 1 to 3, wherein ring A represents a 5- to 10-membered heteroaryl group, preferably a 5- or 6-membered heteroaryl group, a 9- or 10-membered heteroaryl group Fused heteroaryl groups, such as thiazolyl, pyrazolyl, pyridyl, isoquinolinyl, pyrazolopyridyl, pyrrolopyridyl.
5.根据技术方案1至4中任一项所述的式(P-I)的化合物，其中，表示下述基团：
5. The compound of formula (PI) according to any one of technical schemes 1 to 4, wherein, Represents the following groups:
6.根据技术方案1至6中任一项所述的式(P-I)的化合物，其中，式(P-I)的化合物具有如下的式(P-IC)、(P-ID)或(P-IE)的结构：
6. The compound of formula (PI) according to any one of technical schemes 1 to 6, wherein the compound of formula (PI) has the following formula (P-IC), (P-ID) or (P-IE )Structure:
其中，R1、R2、R3、n和m如式(P-I)中所定义。Among them, R 1 , R 2 , R 3 , n and m are as defined in formula (PI).
7.式(P-II)的化合物或其生理学上/药学上可接受的盐或酯，它们的立体异构体或互变异构体、消旋体、氮氧化物、溶剂合物、同位素标记物、前药或代谢产物：
7. Compounds of formula (P-II) or their physiologically/pharmaceutically acceptable salts or esters, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, and isotopes Markers, prodrugs or metabolites:
其中，in,
环B表示5至20元杂芳基或C6-20芳基， Ring B represents a 5- to 20-membered heteroaryl group or a C 6-20 aryl group,
L2表示单键、-CH2-、-NH-、-O-或-S-，L 2 represents a single bond, -CH 2 -, -NH-, -O- or -S-,
R4各自彼此独立地选自H、氘、C1-6烷基、C2-6烯基、C2-6炔基、卤素、氰基、硝基、氨基、卤代C1- 6烷基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3至8元杂环基、3至8元杂芳基、-NH(C1-6烷基)、-N(C1- 6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3至8元杂环基、-NH-3至8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3至8元杂环基、-O-3至8元杂芳基，R 4 is each independently selected from H, deuterium, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl base, halogenated C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8-membered heterocyclyl, 3 to 8-membered heteroaryl, -NH (C 1-6 Alkyl), -N(C 1-6 alkyl) 2 , -NH - C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8-membered heterocyclyl, -NH -3 to 8-membered heteroaryl, -OC 1-6 alkyl , -OC 2-6 alkenyl, -OC 2-6 alkynyl , -OC 3-8 cycloalkyl, -OC 6-10 aryl, -O-3 to 8-membered heterocyclyl, -O-3 to 8-membered heteroaryl,
L3表示-(CH2)p-O-、-O-(CH2)q-、-(CH2)r-NH-、-NH-(CH2)s-、-(CH2)t-S-或-S-(CH2)t-，L 3 represents -(CH 2 ) p -O-, -O-(CH 2 ) q -, -(CH 2 ) r -NH-, -NH-(CH 2 ) s -, -(CH 2 ) t - S-or-S-(CH 2 ) t -,
o、p、q、r、s、t和u各自彼此独立地为0至3的整数，o, p, q, r, s, t and u are each independently an integer from 0 to 3,
E表示未取代的或任选地被一个、两个或更多个R5取代的下述基团：C1-6烷基羰基、5至20元杂芳基或C6-20芳基，E represents the following group that is unsubstituted or optionally substituted by one, two or more R 5 : C 1-6 alkylcarbonyl, 5 to 20 membered heteroaryl or C 6-20 aryl,
R5各自彼此独立地表示H、C1-6烷基、C2-6烯基、C2-6炔基、卤素、氰基、硝基、氨基、卤代C1-6烷基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3至8元杂环基、3至8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3至8元杂环基、-NH-3至8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3至8元杂环基、-O-3至8元杂芳基。R 5 each independently represents H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, cyano, nitro, amino, halogenated C 1-6 alkyl, halogen Substituted C 2-6 alkenyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3 to 8 membered heterocyclyl, 3 to 8 membered heteroaryl, -NH (C 1-6 alkyl) , -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH-3 to 8-membered heterocyclyl, -NH-3 to 8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl , -OC 3-8 cycloalkyl, -OC 6-10 aryl, -O- 3 to 8-membered heterocyclyl, -O-3 to 8-membered heteroaryl.
R6表示H、C1-6烷基、卤素或氘代C1-6烷基。R 6 represents H, C 1-6 alkyl, halogen or deuterated C 1-6 alkyl.
8.根据技术方案7所述的式(P-II)的化合物，其具有如下式(P-IIA)的结构：
8. The compound of formula (P-II) according to technical scheme 7, which has the structure of the following formula (P-IIA):
其中，环B为5元或6元杂芳基，R4、R6、o、L3和E如式(P-II)中所定义。Among them, ring B is a 5- or 6-membered heteroaryl group, and R 4 , R 6 , o, L 3 and E are as defined in formula (P-II).
9.根据技术方案7或8所述的式(P-II)的化合物，其中，环B为吡啶基或三唑基，更优选吡啶-2-基、吡啶-3-基、吡啶-4-基、1H-1,2,4-三唑-3-基或1H-1,2,4-三唑-5-基。9. The compound of formula (P-II) according to technical scheme 7 or 8, wherein ring B is pyridyl or triazolyl, more preferably pyridin-2-yl, pyridin-3-yl, pyridin-4- base, 1H-1,2,4-triazol-3-yl or 1H-1,2,4-triazol-5-yl.
10.根据技术方案7至9中任一项所述的式(P-II)的化合物，其具有如下式(P-IIB)或(P-IIC)的结构：
10. The compound of formula (P-II) according to any one of technical schemes 7 to 9, which has the structure of the following formula (P-IIB) or (P-IIC):
11.根据技术方案7至10中任一项所述的式(P-II)的化合物，其中，L3表示-(CH2)-O-、-O-(CH2)-、-(CH2)-NH-、-NH-(CH2)-、-(CH2)-S-或-S-(CH2)-。11. The compound of formula (P-II) according to any one of technical schemes 7 to 10, wherein L 3 represents -(CH 2 )-O-, -O-(CH 2 )-, -(CH 2 )-NH-, -NH-(CH 2 )-, -(CH 2 )-S- or -S-(CH 2 )-.
12.根据技术方案7至11中任一项所述的式(P-II)的化合物，其中，E表示未取代的或任选地被一个、两个或更多个R4取代的下述基团：C1-6烷基羰基、5至10元杂芳基或C6-12芳基，优选C1-3烷基羰基、5至10元杂芳基或苯基，其中R4各自彼此独立地表示卤素、氰基、卤代C1-6烷基或-N(C1-6烷基)2。12. The compound of formula (P-II) according to any one of technical schemes 7 to 11, wherein E represents the following that is unsubstituted or optionally substituted by one, two or more R 4 Group: C 1-6 alkylcarbonyl, 5 to 10 membered heteroaryl or C 6-12 aryl, preferably C 1-3 alkylcarbonyl, 5 to 10 membered heteroaryl or phenyl, wherein R 4 each Each independently represents halogen, cyano, halogenated C 1-6 alkyl or -N(C 1-6 alkyl) 2 .
13.根据技术方案7至12中任一项所述的式(P-II)的化合物，其中，E-L3-表示苄氧基、2-氯苄氧基、3-氯苄氧基、4-氯苄氧基、3-氰基苄氧基、2-氟苄氧基、3-氟苄氧基、4-氟苄氧基、3,4-氟苄氧基、3-氯-4-氟苄氧基、2-氟-3-氯苄氧基、3-氰基苄氧基、噻唑-5-基甲氧基、4-三氟甲基噻唑-5-基甲氧基、5-氰基噻唑-2-基甲氧基、5-二甲氨基噻唑-2-基甲氧基、三氟乙酰氨基甲基、吡啶-2-基甲氧基、吡啶-3-基甲氧基、1,2,4-三唑并[1,5-a]吡啶-7-基甲氧基、1H-苯并[d]咪唑-6-基甲氧基、苯氧基甲基或苯氧基。13. The compound of formula (P-II) according to any one of technical schemes 7 to 12, wherein EL 3 - represents benzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy, 4- Chlorobenzyloxy, 3-cyanobenzyloxy, 2-fluorobenzyloxy, 3-fluorobenzyloxy, 4-fluorobenzyloxy, 3,4-fluorobenzyloxy, 3-chloro-4-fluoro Benzyloxy, 2-fluoro-3-chlorobenzyloxy, 3-cyanobenzyloxy, thiazol-5-ylmethoxy, 4-trifluoromethylthiazol-5-ylmethoxy, 5-cyano Thiazol-2-ylmethoxy, 5-dimethylaminothiazol-2-ylmethoxy, trifluoroacetylaminomethyl, pyridin-2-ylmethoxy, pyridin-3-ylmethoxy, 1 ,2,4-triazolo[1,5-a]pyridin-7-ylmethoxy, 1H-benzo[d]imidazol-6-ylmethoxy, phenoxymethyl or phenoxy.
14.根据技术方案1至13中任一项所述的式(P-I)的化合物或式(P-II)的化合物，其具有如下结构：


14. The compound of formula (PI) or the compound of formula (P-II) according to any one of technical schemes 1 to 13, which has the following structure:


15.药物组合物，其包含治疗有效量的根据技术方案1-14中任一项所述的式(P-I)的化合物或式(P-II)的化合物或其盐或酯，它们的立体异构体或互变异构体、消旋体、氮氧化物、溶剂合物、同位素标记物、前药或代谢产物和任选的至少一种生理学上/药学上可接受的辅料。15. Pharmaceutical composition, which contains a therapeutically effective amount of a compound of formula (P-I) or a compound of formula (P-II) or a salt or ester thereof according to any one of technical schemes 1-14, and their stereoisomers Conforms or tautomers, racemates, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites and optionally at least one physiologically/pharmaceutically acceptable excipient.
16.根据技术方案15所述的药物组合物，其任选地包含另外的活性成分；优选地，所述另外的活性成分包括瑞德西韦、洛匹那韦、莫努匹韦、利托那韦、氯喹、羟氯喹和/或α-干扰素。16. The pharmaceutical composition according to technical solution 15, optionally comprising additional active ingredients; preferably, the additional active ingredients include remdesivir, lopinavir, monupivir, rituximab Navir, chloroquine, hydroxychloroquine and/or alpha-interferon.
17.根据技术方案1-14中任一项所述的式(P-I)的化合物或式(P-II)的化合物或其盐或酯，它们的立体异构体或互变异构体、消旋体、氮氧化物、溶剂合物、同位素标记物、前药或代谢产物在制备药物中的用途；优选地，所述药物是RNA依赖性RNA聚合酶抑制剂、3CLpro蛋白酶抑制剂、CYP3A4抑制剂或靶向宿主的抗病毒药物；更优选地，所述药物任选地包含另外的活性成分，其中所述另外的活性成分包括瑞德西韦、洛匹那韦、莫努匹韦、利托那韦、氯喹、羟氯喹和/或α-干扰素；更优选地，所述药物用于预防或治疗选自下组的疾病、病症、症候群和/或紊乱，或者用于缓解选自下组的疾病、病症、症候群和/或紊乱的症状：由SARS-CoV-2冠状病毒感染引起的发热、恶心、呕吐、头痛、呼吸困难、乏力、呼吸道感染、肺炎、嗅觉味觉出现障碍及其并发症，或其组合。17. The compound of formula (P-I) or the compound of formula (P-II) or its salt or ester according to any one of technical schemes 1-14, their stereoisomers or tautomers, elimination The use of spinners, nitrogen oxides, solvates, isotope labels, prodrugs or metabolites in the preparation of medicines; preferably, the medicine is an RNA-dependent RNA polymerase inhibitor, a 3CLpro protease inhibitor, a CYP3A4 inhibitor agent or host-targeted antiviral drug; more preferably, the drug optionally contains an additional active ingredient, wherein the additional active ingredient includes remdesivir, lopinavir, monupivir, rivir, Tonavir, chloroquine, hydroxychloroquine and/or alpha-interferon; more preferably, the medicament is used to prevent or treat a disease, condition, syndrome and/or disorder selected from the group below, or to alleviate a disease, condition, syndrome and/or disorder selected from the group below Group of symptoms of diseases, conditions, syndromes and/or disorders: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory infections, pneumonia, disorders of smell and taste and their complications caused by SARS-CoV-2 coronavirus infection disease, or a combination thereof.
18.用于治疗或预防由SARS-CoV-2冠状病毒感染引起的疾病、病症、症候群和/或紊乱的方法，该方法包括对有需要的个体给予根据技术方案1至14任一项的式(P-I)的化合物或式(P-II)的化合物或其盐或酯，它们的立体异构体或互变异构体、消旋体、氮氧化物、溶剂合物、同位素标记物、前药或代谢产物或根据技术方案15或16所述的药物组合物。18. A method for treating or preventing diseases, conditions, syndromes and/or disorders caused by SARS-CoV-2 coronavirus infection, which method includes administering a formula according to any one of technical solutions 1 to 14 to an individual in need The compound of (P-I) or the compound of formula (P-II) or its salt or ester, their stereoisomers or tautomers, racemates, nitrogen oxides, solvates, isotope labels, precursors Drug or metabolite or pharmaceutical composition according to technical solution 15 or 16.
本发明化合物可包括一个或多个不对称中心，且因此可以存在多种立体异构体形式，例如，对映异构体和/或非对映异构体形式。例如，本发明化合物可为单独的对映异构体、非对映异构体或几何异构体(例如顺式和反式异构体)，或者可为立体异构体的混合物的形式，包括外消旋体混合物和富含一种或多种立体异构体的混合物。异构体可通过本领域技术人员已知的方法从混合物中分离，所述方法包括：手性高压液相色谱法(HPLC)以及手性盐的形成和结晶；或者优选的异构体可通过不对称合成来 制备。The compounds of the present invention may contain one or more asymmetric centers and thus may exist in multiple stereoisomeric forms, for example, enantiomeric and/or diastereomeric forms. For example, the compounds of the present invention may be individual enantiomers, diastereomers, or geometric isomers (e.g., cis and trans isomers), or may be in the form of mixtures of stereoisomers, Includes racemic mixtures and mixtures enriched in one or more stereoisomers. The isomers may be separated from the mixture by methods known to those skilled in the art, including chiral high pressure liquid chromatography (HPLC) and the formation and crystallization of chiral salts; or the preferred isomers may be separated by asymmetric synthesis preparation.
本发明化合物可以互变异构体形式存在。互变异构体为因分子中某一原子在两个位置迅速移动而产生的官能团异构体，互变异构体是一种特殊的官能团异构体，一对互变异构体可以互相转换，但通常以比较稳定的一种异构体为其主要的存在形式。最主要的例子为烯醇式和酮式互变异构体。The compounds of the present invention may exist in tautomeric forms. Tautomers are functional group isomers produced by the rapid movement of an atom in a molecule between two positions. A tautomer is a special functional group isomer. A pair of tautomers can interact with each other. conversion, but usually one of the more stable isomers is its main form of existence. The most important examples are the enol and keto tautomers.
例如，在本发明式(I)中，当Y为N且X为NH时表示的化合物，以及式(I’)、(II)、(II’)、(III)、(III’)、(IV)、(IV’)、(V)、(V’)、(VI)、(VI’)、(VII)、(VII’)、(VIII)和(VIII’)表示的化合物，包含如下互变异构体：
For example, in formula (I) of the present invention, the compounds represented when Y is N and X is NH, and formulas (I'), (II), (II'), (III), (III'), ( Compounds represented by IV), (IV'), (V), (V'), (VI), (VI'), (VII), (VII'), (VIII) and (VIII') include the following interactions Variants:
例如，在本发明式(I)中，当Y为CH且X为NH时表示的化合物，包含如下互变异构体：
For example, in formula (I) of the present invention, the compound represented when Y is CH and X is NH includes the following tautomers:
例如，本发明实施例1化合物包含如下互变异构体：
For example, the compound of Example 1 of the present invention contains the following tautomers:
本领域技术人员将理解，有机化合物可以与溶剂形成复合物，其在该溶剂中发生反应或从该溶剂中沉淀或结晶出来。这些复合物称为“溶剂合物”。当溶剂是水时，复合物称为“水合物”。本发明涵盖了本发明化合物的所有溶剂合物。Those skilled in the art will understand that organic compounds can form complexes with solvents, react in the solvent, or precipitate or crystallize out of the solvent. These complexes are called "solvates". When the solvent is water, the complex is called a "hydrate." This invention encompasses all solvates of the compounds of the invention.
术语“溶剂合物”是指通常由溶剂分解反应形成的与溶剂相结合的化合物或其盐的形式。这个物理缔合可包括氢键键合。常规溶剂包括水、甲醇、乙醇、乙酸、DMSO、THF、乙醚等。本文所述的化合物可制备成，例如，结晶形式，且可被溶剂化。合适的溶剂合物包括药学上可接受的溶剂合物且进一步包括化学计量的溶剂合物和非化学计量的溶剂合物。在一些情况下，所述溶剂合物将能够分离，例如，当一或多个溶剂分子掺入结晶固体的晶格中时。“溶剂合物”包括溶液状态的溶剂合物和可分离的溶剂合物。代表性的溶剂合物包括水合物、乙醇合物和甲醇合物。 The term "solvate" refers to a form of a compound or a salt thereof that is combined with a solvent, usually formed by a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, ether, etc. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include stoichiometric and non-stoichiometric solvates. In some cases, the solvate will be capable of isolating, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid. "Solvate" includes both solution solvates and isolable solvates. Representative solvates include hydrates, ethanolates, and methoxides.
术语“水合物”是指与水相结合的化合物。通常，包含在化合物的水合物中的水分子数与该水合物中该化合物分子数的比率确定。因此，化合物的水合物可用例如通式R·x H2O代表，其中R是该化合物，和x是大于0的数。给定化合物可形成超过一种水合物类型，包括，例如，单水合物(x为1)、低级水合物(x是大于0且小于1的数，例如，半水合物(R·0.5H2O)和多水合物(x为大于1的数，例如，二水合物(R·2H2O)和六水合物(R·6H2O)。The term "hydrate" refers to a compound combined with water. Typically, the ratio of the number of water molecules contained in a hydrate of a compound to the number of molecules of the compound in the hydrate is determined. Thus, a hydrate of a compound may be represented, for example, by the general formula R.xH2O , where R is the compound and x is a number greater than zero. A given compound may form more than one hydrate type, including, for example, monohydrate (x is 1), lower hydrate (x is a number greater than 0 and less than 1), for example, hemihydrate (R·0.5H 2 O) and polyhydrates (x is a number greater than 1, for example, dihydrate (R·2H 2 O) and hexahydrate (R·6H 2 O).
本发明化合物可以是无定形或结晶形式(多晶型)。此外，本发明化合物可以以一种或多种结晶形式存在。因此，本发明在其范围内包括本发明化合物的所有无定形或结晶形式。术语“多晶型物”是指特定晶体堆积排列的化合物的结晶形式(或其盐、水合物或溶剂合物)。所有的多晶型物具有相同的元素组成。不同的结晶形式通常具有不同的X射线衍射图、红外光谱、熔点、密度、硬度、晶体形状、光电性质、稳定性和溶解度。重结晶溶剂、结晶速率、贮存温度和其他因素可导致一种结晶形式占优。化合物的各种多晶型物可在不同的条件下通过结晶制备。The compounds of the invention may be in amorphous or crystalline forms (polymorphs). Furthermore, the compounds of the present invention may exist in one or more crystalline forms. Accordingly, the present invention includes within its scope all amorphous or crystalline forms of the compounds of the invention. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate or solvate thereof) in a specific crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms often have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shape, optoelectronic properties, stability and solubility. Recrystallization solvent, crystallization rate, storage temperature, and other factors can lead to the dominance of one crystalline form. Various polymorphs of the compounds can be prepared by crystallization under different conditions.
本发明还包括同位素标记的化合物(同位素变体)，它们等同于式(I)所述的那些，但一个或多个原子被原子质量或质量数不同于自然界常见的原子质量或质量数的原子所代替。可以引入本发明化合物中的同位素的实例包括氢、碳、氮、氧、磷、硫、氟和氯的同位素，分别例如2H、3H、13C、11C、14C、15N、18O、17O、31P、32P、35S、18F和36Cl。含有上述同位素和/或其它原子的其它同位素的本发明化合物、其前体药物和所述化合物或所述前体药物的药学上可接受的盐都属于本发明的范围。某些同位素标记的本发明化合物、例如引入放射性同位素(例如3H和14C)的那些可用于药物和/或底物组织分布测定。氚、即3H和碳-14、即14C同位素是特别优选的，因为它们容易制备和检测。进而，被更重的同位素取代，例如氘、即2H，由于代谢稳定性更高可以提供治疗上的益处，例如延长体内半衰期或减少剂量需求，因而在有些情况下可能是优选的。同位素标记的本发明式(I)化合物及其前体药物一般可以这样制备，在进行下述流程和/或实施例与制备例所公开的工艺时，用容易得到的同位素标记的试剂代替非同位素标记的试剂。The present invention also includes isotopically labeled compounds (isotopic variants) which are identical to those described in formula (I), except that one or more atoms are surrounded by atoms having an atomic mass or mass number different from that common in nature. replaced. Examples of isotopes that may be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as 2 H, 3 H, 13 C, 11 C, 14 C, 15 N, 18 respectively. O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 Cl. Compounds of the invention containing the above-mentioned isotopes and/or other isotopes of other atoms, prodrugs thereof and pharmaceutically acceptable salts of the compounds or prodrugs are within the scope of the present invention. Certain isotopically labeled compounds of the present invention, such as those incorporating radioactive isotopes (eg, 3 H and 14 C), may be used in drug and/or substrate tissue distribution assays. Tritium, ie 3 H, and carbon-14, ie 14 C isotopes are particularly preferred because they are easy to prepare and detect. Furthermore, substitution with heavier isotopes, such as deuterium, i.e. 2 H, may be preferred in some cases as greater metabolic stability may provide therapeutic benefits, such as increased half-life in vivo or reduced dosage requirements. The isotope-labeled compounds of formula (I) of the present invention and their prodrugs can generally be prepared by replacing non-isotopes with readily available isotope-labeled reagents when performing the following processes and/or the processes disclosed in the Examples and Preparation Examples. Labeled reagents.
此外，前药也包括在本发明的上下文内。本文所用的术语“前药”是指在体内通过例如在血液中水解转变成其具有医学效应的活性形式的化合物。药学上可接受的前药描述于T.Higuchi和V.Stella，Prodrugs as Novel Delivery Systems，A.C.S.Symposium Series的Vol.14，Edward B.Roche，ed.，Bioreversible Carriers in Drug Design，American Pharmaceutical Association and Pergamon Press，1987，以及D.Fleisher、S.Ramon和H.Barbra“Improved oral drug delivery：solubility limitations overcome by the use of prodrugs”，Advanced Drug Delivery Reviews(1996)19(2)115-130，每篇引入本文作为参考。Furthermore, prodrugs are also included within the context of the present invention. The term "prodrug" as used herein refers to a compound that is converted in the body to its active form having a medical effect, for example, by hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, and D. Fleisher, S. Ramon and H. Barbra "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs", Advanced Drug Delivery Reviews (1996) 19 (2) 115-130, each introduced This article serves as a reference.
前药为任何共价键合的本发明化合物，当将这种前药给予患者时，其在体内释放母体化合物。通常通过修饰官能团来制备前药，修饰是以使得该修饰可以通过常规操作或在体内裂解产生母体化合物的方式进行的。前药包括，例如，其中羟基、氨基或巯基与任意基团键合的本发明化合物，当将其给 予患者时，可以裂解形成羟基、氨基或巯基。因此，前药的代表性实例包括(但不限于)式(I)化合物的羟基、巯基和氨基官能团的乙酸酯/酰胺、甲酸酯/酰胺和苯甲酸酯/酰胺衍生物。另外，在羧酸(-COOH)的情况下，可以使用酯，例如甲酯、乙酯等。酯本身可以是有活性的和/或可以在人体体内条件下水解。合适的药学上可接受的体内可水解的酯基包括容易在人体中分解而释放母体酸或其盐的那些基团。A prodrug is any covalently bonded compound of the invention that releases the parent compound in the body when administered to a patient. Prodrugs are typically prepared by modifying functional groups in a manner such that the modification can be cleaved by conventional manipulations or in vivo to yield the parent compound. Prodrugs include, for example, compounds of the invention in which a hydroxyl, amino or thiol group is bonded to any group which, when administered When administered to patients, it can be cleaved to form hydroxyl, amino or sulfhydryl groups. Accordingly, representative examples of prodrugs include, but are not limited to, acetate/amide, formate/amide and benzoate/amide derivatives of the hydroxyl, thiol and amino functionality of compounds of formula (I). In addition, in the case of carboxylic acid (-COOH), esters such as methyl ester, ethyl ester, etc. can be used. The ester itself may be reactive and/or hydrolyzable under human body conditions. Suitable pharmaceutically acceptable in vivo hydrolyzable ester groups include those that readily break down in the human body to release the parent acid or salt thereof.
本发明还提供药物制剂，包含治疗有效量的式(I)化合物或其治疗学上可接受的盐和其药学上可接受的载体、稀释剂或赋形剂。所有这些形式都属于本发明。The present invention also provides pharmaceutical preparations, comprising a therapeutically effective amount of a compound of formula (I) or a therapeutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or excipient thereof. All these forms belong to the invention.
药物组合物和试剂盒Pharmaceutical compositions and kits
在另一方面，本发明提供了药物组合物，其包含本发明化合物(还称为“活性组分”)和药学上可接受的赋形剂。在一些实施方案中，所述药物组合物包含有效量的本发明化合物。在一些实施方案中，所述药物组合物包含治疗有效量的本发明化合物。在一些实施方案中，所述药物组合物包含预防有效量的本发明化合物。In another aspect, the invention provides pharmaceutical compositions comprising a compound of the invention (also referred to as an "active ingredient") and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions comprise an effective amount of a compound of the invention. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound of the invention. In some embodiments, the pharmaceutical compositions comprise a prophylactically effective amount of a compound of the invention.
用于本发明的药学上可接受的赋形剂是指不会破坏一起调配的化合物的药理学活性的无毒载剂、佐剂或媒剂。可以用于本发明组合物中的药学上可接受的载剂、佐剂或媒剂包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(如人类血清白蛋白)、缓冲物质(如磷酸盐)、甘氨酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(如硫酸鱼精蛋白)、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、硅胶、三硅酸镁、聚乙烯吡咯烷酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、聚乙二醇以及羊毛脂。Pharmaceutically acceptable excipients for use in the present invention refer to non-toxic carriers, adjuvants or vehicles that do not destroy the pharmacological activity of the compounds with which they are formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the present invention include, but are not limited to, ion exchangers, aluminum oxide, aluminum stearate, lecithin, serum proteins (such as human serum albumin) protein), buffer substances (such as phosphate), glycine, sorbic acid, potassium sorbate, partial glyceride mixture of saturated vegetable fatty acids, water, salt or electrolyte (such as protamine sulfate), disodium hydrogen phosphate, potassium hydrogen phosphate , sodium chloride, zinc salt, silica gel, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene- Block polymers, polyethylene glycols, and lanolin.
用于给予本发明化合物的合适制剂将对于本领域普通技术人员而言是显而易见的，并且包括例如片剂、丸剂、胶囊、栓剂、锭剂、糖锭剂、溶液(特别是注射(皮下、静脉内、肌内)和输注(注射剂)用溶液)、酏剂、糖浆、扁囊剂、乳液、吸入剂或可分散粉剂。一种或多种药物活性化合物的含量的范围应该是作为整体的组合物的0.1至90wt％、优选0.5至50wt％，即，其量足以实现以下指定的剂量范围。如有必要，指定的剂量可每天给药若干次。Suitable formulations for administering the compounds of the invention will be apparent to those of ordinary skill in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, lozenges, solutions (especially injections (subcutaneous, intravenous solution for intramuscular administration) and infusion (injection)), elixir, syrup, cachet, emulsion, inhalation or dispersible powder. The content of one or more pharmaceutically active compounds should range from 0.1 to 90% by weight, preferably from 0.5 to 50% by weight of the composition as a whole, ie an amount sufficient to achieve the dosage ranges specified below. If necessary, the specified dose may be administered several times per day.
本发明还包括试剂盒(例如，药物包装)。所提供的试剂盒可以包括本发明化合物、其它治疗剂，以及含有本发明化合物、其它治疗剂的第一和第二容器(例如，小瓶、安瓿瓶、瓶、注射器和/或可分散包装或其它合适的容器)。在一些实施方案中，提供的试剂盒还可以任选包括第三容器，其含有用于稀释或悬浮本发明化合物和/或其它治疗剂的药用赋形剂。在一些实施方案中，提供在第一容器和第二容器中的本发明化合物和其它治疗剂组合形成一个单位剂型。The present invention also includes kits (eg, pharmaceutical packaging). Kits provided may include a compound of the invention, other therapeutic agents, and first and second containers (e.g., vials, ampoules, bottles, syringes, and/or dispersible packaging or other) containing the compounds of the invention, other therapeutic agents. suitable container). In some embodiments, provided kits may also optionally include a third container containing pharmaceutical excipients for diluting or suspending the compounds of the invention and/or other therapeutic agents. In some embodiments, the compound of the invention and the other therapeutic agent provided in the first container and the second container are combined to form a unit dosage form.
给药Give medication
本发明提供的药物组合物可以通过许多途径给药，包括但不限于：口服给药、肠胃外给药、吸入 给药、局部给药、直肠给药、鼻腔给药、口腔给药、阴道给药、通过植入剂给药或其它给药方式。例如，本文使用的肠胃外给药包括皮下给药、皮内给药、静脉内给药、肌肉内给药、关节内给药、动脉内给药、滑膜腔内给药、胸骨内给药、脑脊髓膜内给药、病灶内给药、和颅内的注射或输液技术。The pharmaceutical composition provided by the invention can be administered through many routes, including but not limited to: oral administration, parenteral administration, inhalation Administration, topical, rectal, nasal, oral, vaginal, via implant or other means of administration. For example, parenteral administration as used herein includes subcutaneous administration, intradermal administration, intravenous administration, intramuscular administration, intraarticular administration, intraarterial administration, intrasynovial administration, intrasternal administration , intracerebrospinal membrane drug administration, intralesional drug administration, and intracranial injection or infusion techniques.
通常，给予有效量的本文所提供的化合物。按照有关情况，包括所治疗的病症、选择的给药途径、实际给予的化合物、个体患者的年龄、体重和响应、患者症状的严重程度，等等，可以由医生确定实际上给予的化合物的量。Typically, an effective amount of a compound provided herein is administered. The amount of compound actually administered can be determined by the physician depending on the circumstances, including the condition being treated, the route of administration chosen, the compound actually administered, the age, weight and response of the individual patient, the severity of the patient's symptoms, etc. .
当用于预防本发明所述病症时，给予处于形成所述病症危险之中的受试者本文所提供的化合物，典型地基于医生的建议并在医生监督下给药，剂量水平如上所述。处于形成具体病症的危险之中的受试者，通常包括具有所述病症的家族史的受试者，或通过遗传试验或筛选确定尤其对形成所述病症敏感的那些受试者。When used to prevent a condition described herein, a compound provided herein is administered to a subject at risk of developing the condition, typically on the advice of and under the supervision of a physician, at dosage levels as described above. Subjects at risk of developing a particular condition generally include subjects with a family history of the condition or those who have been determined by genetic testing or screening to be particularly susceptible to developing the condition.
还可以长期给予本文所提供的药物组合物(“长期给药”)。长期给药是指在长时间内给予化合物或其药物组合物，例如，3个月、6个月、1年、2年、3年、5年等等，或者可无限期地持续给药，例如，受试者的余生。在一些实施方案中，长期给药意欲在长时间内在血液中提供所述化合物的恒定水平，例如，在治疗窗内。The pharmaceutical compositions provided herein can also be administered over a long period of time ("chronic administration"). Long-term administration refers to the administration of a compound or pharmaceutical composition thereof over a long period of time, for example, 3 months, 6 months, 1 year, 2 years, 3 years, 5 years, etc., or administration may be continued indefinitely, For example, the remainder of the subject's life. In some embodiments, chronic administration is intended to provide a constant level of the compound in the blood over an extended period of time, eg, within a therapeutic window.
可以使用各种给药方法，进一步递送本发明的药物组合物。例如，在一些实施方案中，可以推注给药药物组合物，例如，为了使化合物在血液中的浓度提高至有效水平。推注剂量取决于通过身体的活性组分的目标全身性水平，例如，肌内或皮下的推注剂量使活性组分缓慢释放，而直接递送至静脉的推注(例如，通过IV静脉滴注)能够更加快速地递送，使得活性组分在血液中的浓度快速升高至有效水平。在其它实施方案中，可以以持续输液形式给予药物组合物，例如，通过IV静脉滴注，从而在受试者身体中提供稳态浓度的活性组分。此外，在其它实施方案中，可以首先给予推注剂量的药物组合物，而后持续输液。Various methods of administration may be used to further deliver the pharmaceutical compositions of the present invention. For example, in some embodiments, a pharmaceutical composition may be administered as a bolus injection, eg, in order to increase the concentration of the compound in the blood to an effective level. The bolus dose depends on the target systemic levels of the active ingredient through the body, e.g., an intramuscular or subcutaneous bolus dose provides a slow release of the active ingredient, whereas a bolus dose delivered directly into the vein (e.g., via an IV drip) ) can be delivered more quickly, allowing the concentration of active ingredients in the blood to quickly increase to effective levels. In other embodiments, the pharmaceutical composition may be administered as a continuous infusion, for example, by IV infusion, thereby providing a steady-state concentration of the active ingredient in the subject's body. Additionally, in other embodiments, a bolus dose of the pharmaceutical composition may be administered first, followed by a continuous infusion.
口服组合物可以采用散装液体溶液或混悬剂或散装粉剂形式。然而，更通常，为了便于精确地剂量给药，以单位剂量形式提供所述组合物。术语“单位剂型”是指适合作为人类患者及其它哺乳动物的单元剂量的物理离散单位，每个单位包含预定数量的、适于产生所需要的治疗效果的活性物质与合适药学赋形剂。典型的单位剂量形式包括液体组合物的预装填的、预先测量的安瓿或注射器，或者在固体组合物情况下的丸剂、片剂、胶囊剂等。在这种组合物中，所述化合物通常为较少的组分(约0.1至约50重量％，或优选约1至约40重量％)，剩余部分为对于形成所需给药形式有用的各种载体或赋形剂以及加工助剂。Oral compositions may take the form of bulk liquid solutions or suspensions, or bulk powders. More typically, however, the compositions are provided in unit dosage form to facilitate precise dosing. The term "dosage unit form" refers to physically discrete units suitable as unitary dosages for human patients and other mammals, each unit containing a predetermined quantity of active material suitable to produce the desired therapeutic effect in association with a suitable pharmaceutical excipient. Typical unit dosage forms include prefilled, premeasured ampoules or syringes for liquid compositions, or pills, tablets, capsules, and the like in the case of solid compositions. In such compositions, the compound will generally be a minor component (from about 0.1 to about 50% by weight, or preferably from about 1 to about 40% by weight), with the remainder being various components useful in forming the desired administration form. carriers or excipients and processing aids.
对于口服剂量，代表性的方案是，每天一个至五个口服剂量，尤其是两个至四个口服剂量，典型地是三个口服剂量。使用这些剂量给药模式，每个剂量提供大约0.01至大约20mg/kg的本发明化合物，优选的剂量各自提供大约0.1至大约10mg/kg，尤其是大约1至大约5mg/kg。 For oral dosing, a typical regimen is one to five oral doses per day, especially two to four oral doses, typically three oral doses. Using these dosing modes, each dose provides from about 0.01 to about 20 mg/kg of a compound of the invention, with preferred doses each providing from about 0.1 to about 10 mg/kg, especially from about 1 to about 5 mg/kg.
为了提供与使用注射剂量类似的血液水平，或比使用注射剂量更低的血液水平，通常选择透皮剂量，数量为大约0.01至大约20％重量，优选大约0.1至大约20％重量，优选大约0.1至大约10％重量，且更优选大约0.5至大约15％重量。In order to provide similar blood levels, or lower blood levels than with injectable doses, a transdermal dose is generally selected in an amount of about 0.01 to about 20% by weight, preferably about 0.1 to about 20% by weight, preferably about 0.1 to about 10% by weight, and more preferably from about 0.5 to about 15% by weight.
从大约1至大约120小时，尤其是24至96小时，注射剂量水平在大约0.1mg/kg/小时至至少10mg/kg/小时的范围。为了获得足够的稳定状态水平，还可以给予大约0.1mg/kg至大约10mg/kg或更多的预载推注。对于40至80kg的人类患者来说，最大总剂量不能超过大约2g/天。Injectable dose levels range from about 0.1 mg/kg/hour to at least 10 mg/kg/hour from about 1 to about 120 hours, especially from 24 to 96 hours. To achieve adequate steady state levels, a preload bolus of about 0.1 mg/kg to about 10 mg/kg or more may also be given. For human patients weighing 40 to 80 kg, the maximum total dose should not exceed approximately 2 g/day.
适于口服给药的液体形式可包括合适的水性或非水载体以及缓冲剂、悬浮剂和分散剂、着色剂、调味剂，等等。固体形式可包括，例如，任何下列组份，或具有类似性质的化合物：粘合剂，例如，微晶纤维素、黄蓍胶或明胶；赋形剂，例如，淀粉或乳糖，崩解剂，例如，褐藻酸、Primogel或玉米淀粉；润滑剂，例如，硬脂酸镁；助流剂，例如，胶体二氧化硅；甜味剂，例如，蔗糖或糖精；或调味剂，例如，薄荷、水杨酸甲酯或橙味调味剂。Liquid forms suitable for oral administration may include suitable aqueous or non-aqueous carriers as well as buffering agents, suspending and dispersing agents, coloring agents, flavoring agents, and the like. Solid forms may include, for example, any of the following components, or compounds of similar nature: binders, for example, microcrystalline cellulose, tragacanth, or gelatin; excipients, for example, starch or lactose, disintegrants, For example, alginic acid, Primogel or corn starch; lubricant, for example, magnesium stearate; glidant, for example, colloidal silicon dioxide; sweetener, for example, sucrose or saccharin; or flavoring agent, for example, mint, water Methyl glycolate or orange flavoring.
可注射的组合物典型地基于可注射用的无菌盐水或磷酸盐缓冲盐水，或本领域中已知的其它可注射的赋形剂。如前所述，在这种组合物中，活性化合物典型地为较少的组分，经常为约0.05至10％重量，剩余部分为可注射的赋形剂等。Injectable compositions are typically based on injectable sterile saline or phosphate buffered saline, or other injectable excipients known in the art. As stated previously, in such compositions the active compound is typically a minor component, often about 0.05 to 10% by weight, with the remainder being injectable excipients and the like.
典型地将透皮组合物配制为含有活性组分的局部软膏剂或乳膏剂。当配制为软膏剂时，活性组分典型地与石蜡或可与水混溶的软膏基质组合。或者，活性组分可与例如水包油型乳膏基质一起配制为乳膏剂。这种透皮制剂是本领域中公知的，且通常包括用于提升活性组分或制剂的稳定的皮肤渗透的其它组份。所有这种已知的透皮制剂和组份包括在本发明提供的范围内。Transdermal compositions are typically formulated as topical ointments or creams containing the active ingredients. When formulated as an ointment, the active ingredients are typically combined with a paraffin or water-miscible ointment base. Alternatively, the active ingredient may be formulated as a cream with, for example, an oil-in-water cream base. Such transdermal formulations are well known in the art and often include other ingredients for promoting stable skin penetration of the active ingredient or formulation. All such known transdermal formulations and components are included within the scope provided by this invention.
本发明化合物还可通过经皮装置给予。因此，经皮给药可使用贮存器(reservoir)或多孔膜类型、或者多种固体基质的贴剂实现。The compounds of the present invention may also be administered via transdermal devices. Thus, transdermal administration may be achieved using reservoir or porous membrane types, or a variety of solid matrix patches.
用于口服给予、注射或局部给予的组合物的上述组份仅仅是代表性的。其它材料以及加工技术等阐述于Remington's Pharmaceutical Sciences,17th edition,1985,Mack Publishing Company,Easton,Pennsylvania的第8部分中，本文以引用的方式引入该文献。The foregoing components of compositions for oral administration, injection or topical administration are merely representative. Other materials and processing techniques are described in Part 8 of Remington's Pharmaceutical Sciences, 17th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which article is incorporated by reference.
本发明化合物还可以以持续释放形式给予，或从持续释放给药系统中给予。代表性的持续释放材料的描述可在Remington's Pharmaceutical Sciences中找到。The compounds of the present invention may also be administered in sustained release form or from a sustained release drug delivery system. Descriptions of representative sustained release materials can be found in Remington's Pharmaceutical Sciences.
本发明还涉及本发明化合物的药学上可接受的制剂。在一个实施方案中，所述制剂包含水。在另一个实施方案中，所述制剂包含环糊精衍生物。最常见的环糊精为分别由6、7和8个α-1,4-连接的葡萄糖单元组成的α-、β-和γ-环糊精，其在连接的糖部分上任选包括一个或多个取代基，其包括但不限于：甲基化的、羟基烷基化的、酰化的和磺烷基醚取代。在一些实施方案中，所述环糊精为磺烷基醚β-环糊精，例如，磺丁基醚β-环糊精，也称作Captisol。参见，例如，U.S.5,376,645。在一些实施方案中，所述制剂包括六丙基-β-环糊精(例如，在水中，10-50％)。 The invention also relates to pharmaceutically acceptable formulations of the compounds of the invention. In one embodiment, the formulation includes water. In another embodiment, the formulation contains a cyclodextrin derivative. The most common cyclodextrins are α-, β- and γ-cyclodextrins consisting of 6, 7 and 8 α-1,4-linked glucose units respectively, optionally including a or multiple substituents including, but not limited to: methylated, hydroxyalkylated, acylated, and sulfoalkyl ether substitutions. In some embodiments, the cyclodextrin is a sulfoalkyl ether beta-cyclodextrin, for example, sulfobutyl ether beta-cyclodextrin, also known as Captisol. See, for example, US 5,376,645. In some embodiments, the formulation includes hexapropyl-beta-cyclodextrin (eg, in water, 10-50%).
适应症Indications
对于被病毒感染导致的疾病，开发3C样蛋白酶抑制剂可以为大量的肿病人提供治疗获益。本发明中的化合物通过负调节病毒内3C样蛋白酶的活性发挥治疗作用，尤其是3C样蛋白酶具有P132H突变的病毒。For diseases caused by viral infections, the development of 3C-like protease inhibitors can provide therapeutic benefits for a large number of patients. The compounds in the present invention exert therapeutic effects by negatively regulating the activity of 3C-like protease in viruses, especially viruses with P132H mutation in the 3C-like protease.
在一些实施方案中，本发明的3C样蛋白酶抑制剂可以治疗由病毒感染导致的多种疾病及其并发症。In some embodiments, the 3C-like protease inhibitors of the present invention can treat various diseases caused by viral infections and their complications.
更具体地说，这些化合物可用于治疗病毒感染导致的如下疾病：发热、恶心、呕吐、头痛、呼吸困难、乏力、呼吸道感染、肺炎、嗅觉障碍、味觉障碍及其并发症等。More specifically, these compounds can be used to treat the following diseases caused by viral infections: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract infection, pneumonia, smell disorder, taste disorder and its complications, etc.
更具体地说，这些化合物可用于SARS-CoV-2感染导致的上述疾病或症状。More specifically, these compounds can be used for the above-mentioned diseases or symptoms caused by SARS-CoV-2 infection.
联合用药Combination medication
本发明所述的3C样蛋白酶抑制剂可以与其他药物联合治疗癌症，至少包含一种靶点药物/病毒活性调节剂，包括瑞德西韦(Remdesivir或GS-5734)、洛匹那韦(Lopinavir)、莫努匹韦(Molnupiravir)、利托那韦(Ritonavir)、氯喹(Chloroquine或Sigma-C6628)、羟氯喹和/或α-干扰素等。The 3C-like protease inhibitor of the present invention can be combined with other drugs to treat cancer, and contains at least one target drug/viral activity modulator, including Remdesivir (Remdesivir or GS-5734), Lopinavir (Lopinavir) ), Molnupiravir, Ritonavir, chloroquine (Chloroquine or Sigma-C6628), hydroxychloroquine and/or alpha-interferon, etc.
实施例Example
下文将结合具体实施例对本公开的化合物和制备方法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发明，而不应被解释为对本发明保护范围的限制。凡基于本发明的内容所实现的技术方案均涵盖在本发明旨在保护的范围内。The compounds and preparation methods of the present disclosure will be described in further detail below with reference to specific examples. It should be understood that the following examples are only illustrative and explain the present invention and should not be construed as limiting the scope of the present invention. All technical solutions implemented based on the content of the present invention are covered by the scope of protection intended by the present invention.
除非另外指明，否则下述实施例中所使用的实验方法均为本领域常规方法；下述实施例中所使用的试剂、原料、仪器、设备等，均可从商业途径获得。Unless otherwise specified, the experimental methods used in the following examples are routine methods in the art; the reagents, raw materials, instruments, equipment, etc. used in the following examples can all be obtained from commercial sources.
实施例1的合成
Synthesis of Example 1
1.中间体1-2的合成1.Synthesis of intermediate 1-2
室温下将1-1(1g，5.32mmol)溶解到乙腈(20mL)中，并加入间氯苄溴(1.02g，5.94mmol)和碳酸钾(2.05g,14.85mmol)在70℃搅拌16小时。反应完成后加入水(100mL)和乙酸乙酯(300mL)进行萃取，有机相用饱和氯化钠水溶液(3x 100mL)洗涤，无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚：乙酸乙酯＝10:1)得淡黄色油状物1-2(1.1g，产率：66.1％)。Dissolve 1-1 (1g, 5.32mmol) in acetonitrile (20mL) at room temperature, add m-chlorobenzyl bromide (1.02g, 5.94mmol) and potassium carbonate (2.05g, 14.85mmol) and stir at 70°C for 16 hours. After the reaction is completed, water (100 mL) and ethyl acetate (300 mL) are added for extraction. The organic phase is washed with saturated sodium chloride aqueous solution (3x 100 mL) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain light yellow oil 1-2 (1.1g, yield: 66.1%).
LCMS(ESI)m/z:313.1[M+H]+。LCMS(ESI)m/z:313.1[M+H] + .
2.中间体1-3的合成2.Synthesis of intermediates 1-3
冰浴下向1-2(1.1g，3.53mmol)的四氢呋喃(10mL)溶液中加入氢化铝锂(0.59g，7.54mmol)。冰水浴下搅拌2小时，然后于冰水浴下加入15％氢氧化钠溶液产生固体颗粒，过滤并旋干滤液得白色固体1-3(0.80g，产率：79.9％)。To a solution of 1-2 (1.1 g, 3.53 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.59 g, 7.54 mmol) under ice bath. Stir in an ice-water bath for 2 hours, then add 15% sodium hydroxide solution in an ice-water bath to produce solid particles, filter and spin the filtrate to obtain white solid 1-3 (0.80g, yield: 79.9%).
LCMS(ESI)m/z:285.1[M+H]+。LCMS(ESI)m/z:285.1[M+H] + .
3.中间体1-4的合成3.Synthesis of intermediates 1-4
冰浴下向1-3(0.8g，2.82mmol)的二氯甲烷(10mL)溶液中加入三苯基膦(1.26g，4.80mmol)和N-溴代丁二酰亚胺(0.85g，4.80mmol)。在0℃下搅拌30分钟。反应完成后，加入水(50mL)和二氯甲烷(100mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚：乙酸乙酯＝10:1)得黄色固体1-4(0.8g，产率：82.1％)。To a solution of 1-3 (0.8g, 2.82mmol) in dichloromethane (10mL) under ice bath, triphenylphosphine (1.26g, 4.80mmol) and N-bromosuccinimide (0.85g, 4.80 mmol). Stir at 0°C for 30 minutes. After the reaction was completed, water (50 mL) and dichloromethane (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain yellow solid 1-4 (0.8g, yield: 82.1%).
LCMS(ESI)m/z:346.9[M+H]+。LCMS(ESI)m/z:346.9[M+H] + .
4.中间体1-6的合成4.Synthesis of intermediates 1-6
常温下向1-4(300mg，0.87mmol)的乙腈(10mL)溶液中加入碳酸钾(379mg，2.88mmol)和化合物1-5(241.8mg，1.06mmol)，混合溶液在室温下搅拌16小时。加入水(10mL)和二氯甲烷(150mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚：乙酸乙酯＝3:1)得淡黄色油状 物1-6(396mg，产率：91.9％)。Potassium carbonate (379 mg, 2.88 mmol) and compound 1-5 (241.8 mg, 1.06 mmol) were added to a solution of 1-4 (300 mg, 0.87 mmol) in acetonitrile (10 mL) at room temperature, and the mixed solution was stirred at room temperature for 16 hours. Water (10 mL) and dichloromethane (150 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 3:1) to obtain a light yellow oil. Compound 1-6 (396 mg, yield: 91.9%).
LCMS(ESI)m/z:496.1[M+H]+。LCMS(ESI)m/z:496.1[M+H] + .
5.中间体1-7的合成5.Synthesis of intermediates 1-7
常温下将1-6(400mg，0.81mmol)加入二氯甲烷/三氟乙酸＝1/1(6mL)溶液中，混合溶液在室温下搅拌2小时。在冰浴下用碳酸钠溶液将反应液调至pH＝7。混合溶液加入二氯甲烷(100mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚：乙酸乙酯＝1:1)得淡黄色油状物1-7(301mg，产率：84.4％)。1-6 (400 mg, 0.81 mmol) was added to a dichloromethane/trifluoroacetic acid = 1/1 (6 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH=7 with sodium carbonate solution under ice bath. Dichloromethane (100 mL) was added to the mixed solution for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain light yellow oil 1-7 (301 mg, yield: 84.4%).
LCMS(ESI)m/z:440.1[M+H]+。LCMS(ESI)m/z:440.1[M+H] + .
6.中间体1-9的合成6.Synthesis of intermediates 1-9
常温下向1-7(300mg，0.68mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入碳酸钾(295mg，2.13mmol)和1-8(139.5mg，1.07mmol)，在70℃下搅拌2小时。反应完成后加入水(100mL)和乙酸乙酯(300mL)进行萃取，有机相用饱和氯化钠水溶液(3x 100mL)洗涤，无水硫酸钠干燥。粗品用柱层析提纯(硅胶，二氯甲烷：甲醇＝10:1)得白色固体1-9(250mg，产率：68.8％)。To a solution of 1-7 (300 mg, 0.68 mmol) in N,N-dimethylformamide (10 mL), potassium carbonate (295 mg, 2.13 mmol) and 1-8 (139.5 mg, 1.07 mmol) were added at room temperature. Stir for 2 hours at ℃. After the reaction is completed, water (100 mL) and ethyl acetate (300 mL) are added for extraction. The organic phase is washed with saturated sodium chloride aqueous solution (3x 100 mL) and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, dichloromethane: methanol = 10:1) to obtain white solid 1-9 (250 mg, yield: 68.8%).
LCMS(ESI)m/z:535.1[M+H]+。LCMS(ESI)m/z:535.1[M+H] + .
7.化合物1的合成7. Synthesis of Compound 1
冰浴下向1-9(200mg，0.37mmol)的四氢呋喃(7mL)溶液中加入1-10(111mg，0.62mmol)，再加入双(三甲基硅基)氨基锂(1.2mL)，在-15℃下搅拌2小时。加入水(50mL)和乙酸乙酯(100mL)进行萃取，有机相用无水硫酸钠干燥。粗品由高压制备色谱纯化得到白色固体化合物1(7.2mg，产率：2.97％)。To a solution of 1-9 (200 mg, 0.37 mmol) in tetrahydrofuran (7 mL), 1-10 (111 mg, 0.62 mmol) was added under ice bath, and then lithium bis(trimethylsilyl)amide (1.2 mL) was added. Stir for 2 hours at 15°C. Water (50 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high-pressure preparative chromatography to obtain compound 1 as a white solid (7.2 mg, yield: 2.97%).
LCMS(ESI)m/z:654.1[M+H]+。LCMS(ESI)m/z:654.1[M+H] + .
1HNMR(400MHz,DMSO-d6)δ8.28(s,1H),8.16(s,1H),7.68–7.60(m,1H),7.45–7.30(m,4H),7.24–7.18(m,2H),5.28(s,2H),5.09(s,2H),5.04(s,2H),4.17(s,3H),3.84(s,3H). 1 HNMR(400MHz, DMSO-d 6 )δ8.28(s,1H),8.16(s,1H),7.68–7.60(m,1H),7.45–7.30(m,4H),7.24–7.18(m, 2H),5.28(s,2H),5.09(s,2H),5.04(s,2H),4.17(s,3H),3.84(s,3H).
以上述同样方法合成如下表A的化合物。The compounds in Table A below were synthesized in the same manner as above.
表A














Table A














实施例86化合物86的合成
Example 86 Synthesis of Compound 86
中间体86-2的合成Synthesis of intermediate 86-2
常温下向1-1(2.00g，10.6mmol)的二氯甲烷(20mL)溶液中加入4-二甲氨基吡啶(2.60g，21.3mmol)、86-1(4.46g，31.9mmol)和醋酸铜(3.86g，21.3mmol)。混合溶液在25℃并且氧气流通下搅拌16小时。反应完成后，过滤，滤液减压浓缩。粗品用柱层析(硅胶，二氯甲烷:甲醇＝30:1)提纯得黄色油状化合物86-2(401mg，产率：15.8％)。To a solution of 1-1 (2.00g, 10.6mmol) in dichloromethane (20mL), 4-dimethylaminopyridine (2.60g, 21.3mmol), 86-1 (4.46g, 31.9mmol) and copper acetate were added at room temperature. (3.86g, 21.3mmol). The mixed solution was stirred for 16 hours at 25°C with oxygen flow. After the reaction was completed, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=30:1) to obtain yellow oily compound 86-2 (401 mg, yield: 15.8%).
LCMS(ESI)m/z:283.1[M+H]+。LCMS(ESI)m/z:283.1[M+H] + .
中间体86-3的合成Synthesis of intermediate 86-3
冰浴下向86-2(626mg，2.22mmol)的四氢呋喃(7mL)溶液中加入四氢铝锂(210mg，5.55mmol)。氮气保护，混合溶液在0℃下搅拌1小时。反应完成后，在0℃下依次加水(0.21mL)，15％氢氧化钠水溶液(0.21mL)，水(0.63mL)淬灭，混合溶液过滤，滤液减压浓缩得到淡黄色油状化合物86-3(390mg，产率：58.8％)。To a solution of 86-2 (626 mg, 2.22 mmol) in tetrahydrofuran (7 mL) was added lithium aluminum tetrahydrhydride (210 mg, 5.55 mmol) under ice bath. Under nitrogen protection, the mixed solution was stirred at 0°C for 1 hour. After the reaction was completed, water (0.21 mL), 15% sodium hydroxide aqueous solution (0.21 mL), and water (0.63 mL) were added successively at 0°C to quench the mixture. The mixed solution was filtered, and the filtrate was concentrated under reduced pressure to obtain light yellow oily compound 86-3. (390 mg, yield: 58.8%).
GCMS(ESI)m/z:254.1[M]+。GCMS(ESI)m/z:254.1[M] + .
中间体86-4的合成Synthesis of intermediate 86-4
冰浴下向86-3(390mg，1.53mmol)的二氯甲烷(4mL)溶液中加入三苯基膦(604mg,2.30mmol)和四溴化碳(763mg，2.30mmol)。氮气保护，混合溶液在0℃下搅拌1小时。反应完成后，混合溶液加入水(40mL)和二氯甲烷(40mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品用柱层析(硅胶，石油醚:乙酸乙酯＝20:1)提纯得淡黄色油状化合物86-4(324mg，产率：63.3％)。To a solution of 86-3 (390 mg, 1.53 mmol) in dichloromethane (4 mL) was added triphenylphosphine (604 mg, 2.30 mmol) and carbon tetrabromide (763 mg, 2.30 mmol) under ice bath. Under nitrogen protection, the mixed solution was stirred at 0°C for 1 hour. After the reaction is completed, add water (40 mL) and dichloromethane (40 mL*3) to the mixed solution for extraction. The combined organic phases are dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 20:1) to obtain light yellow oily compound 86-4 (324 mg, yield: 63.3%).
GCMS(ESI)m/z:316.0[M]+。GCMS(ESI)m/z:316.0[M] + .
中间体86-5的合成Synthesis of intermediate 86-5
常温下向86-4(180mg，0.785mmol)的乙腈(2mL)溶液中加入碳酸钾(217mg，1.57mmol)和2-5(324mg，1.02mmol)，混合溶液在80℃下搅拌4小时。反应完成后，混合溶液加入乙酸乙酯(100mL)，依次用水(40mL)和饱和氯化钠溶液(40mL)洗涤，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品用柱层析(硅胶，石油醚:乙酸乙酯＝5:1)提纯得淡黄色油状化合物86-5(400mg，产率： 93.0％)。To a solution of 86-4 (180 mg, 0.785 mmol) in acetonitrile (2 mL), potassium carbonate (217 mg, 1.57 mmol) and 2-5 (324 mg, 1.02 mmol) were added at room temperature, and the mixed solution was stirred at 80°C for 4 hours. After the reaction was completed, ethyl acetate (100 mL) was added to the mixed solution, washed with water (40 mL) and saturated sodium chloride solution (40 mL) in sequence, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 5:1) to obtain light yellow oily compound 86-5 (400 mg, yield: 93.0%).
LCMS(ESI)m/z:466.1[M+H]+。LCMS(ESI)m/z:466.1[M+H] + .
中间体86-6的合成Synthesis of intermediate 86-6
常温下将86-5(400mg，0.860mmol)加入二氯甲烷/三氟乙酸＝1/1(8mL)溶液中，混合溶液在30℃下搅拌1小时。反应完成后，反应液减压浓缩得到白色固体86-6(346mg，产率：93.4％)。86-5 (400 mg, 0.860 mmol) was added to the dichloromethane/trifluoroacetic acid = 1/1 (8 mL) solution at room temperature, and the mixed solution was stirred at 30°C for 1 hour. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain white solid 86-6 (346 mg, yield: 93.4%).
LCMS(ESI)m/z:410.1[M+H]+。LCMS(ESI)m/z:410.1[M+H] + .
中间体86-7的合成Synthesis of intermediate 86-7
常温下向86-6(346mg，0.845mmol)的N,N-二甲基甲酰胺(4mL)溶液中加入1-8(170mg，1.01mmol)和碳酸钾(350mg，2.54mmol)，混合溶液在80℃下搅拌4小时。反应完成后，反应液过滤，滤液减压浓缩。粗品用柱层析(硅胶，二氯甲烷:甲醇＝30:1)提纯得淡黄色油状化合物86-7(259mg，产率：57.9％)。To a solution of 86-6 (346 mg, 0.845 mmol) in N,N-dimethylformamide (4 mL), 1-8 (170 mg, 1.01 mmol) and potassium carbonate (350 mg, 2.54 mmol) were added at room temperature, and the mixed solution was Stir at 80°C for 4 hours. After the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=30:1) to obtain light yellow oily compound 86-7 (259 mg, yield: 57.9%).
LCMS(ESI)m/z:505.1[M+H]+。LCMS(ESI)m/z:505.1[M+H] + .
化合物86的合成Synthesis of Compound 86
冰浴下向86-7(260mg，0.515mmol)的四氢呋喃(2.5mL)溶液中加入1-10(112mg,0.618mmol)，混合溶液在氮气保护下加入双(三甲基硅基)氨基锂(1.5mL)。0℃下搅拌2小时。反应完成后，混合溶液加入水(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品由高压制备色谱(色谱柱:-Gemini-C18 150x 21.2mm，5μm。流动相:ACN--H2O(0.1％FA)。梯度:40-60)纯化得到白色固体化合物86(44.8mg，产率：13.2％)。To a solution of 86-7 (260 mg, 0.515 mmol) in tetrahydrofuran (2.5 mL), 1-10 (112 mg, 0.618 mmol) was added under ice bath, and the mixed solution was added with lithium bis(trimethylsilyl)amide ( 1.5mL). Stir at 0°C for 2 hours. After the reaction was completed, the mixed solution was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (column: -Gemini-C18 150x 21.2mm, 5 μm. Mobile phase: ACN--H 2 O (0.1% FA). Gradient: 40-60) to obtain white solid compound 86 (44.8 mg, Yield: 13.2%).
LCMS(ESI)m/z:624.1[M+H]+。LCMS(ESI)m/z:624.1[M+H] + .
1H NMR(400MHz,CD3OD)δ8.40–8.30(m,1H),8.26–8.04(s,1H),7.84–7.66(m,1H),7.62–7.50(m,1H),7.45–7.09(m,2H),7.02–6.72(m,4H),5.30(s,2H),5.05(s,2H),4.20(s,3H),3.90(s,3H). 1 H NMR (400MHz, CD 3 OD) δ8.40–8.30(m,1H),8.26–8.04(s,1H),7.84–7.66(m,1H),7.62–7.50(m,1H),7.45– 7.09(m,2H),7.02–6.72(m,4H),5.30(s,2H),5.05(s,2H),4.20(s,3H),3.90(s,3H).
以上述同样方法合成如下表B的化合物。The compounds in Table B below were synthesized in the same manner as above.
表B





Table B





实施例115化合物115的合成
Example 115 Synthesis of Compound 115
中间体115-3的合成Synthesis of intermediate 115-3
室温下将BINAP(0.99g，1.59mol)，碳酸铯(7.8g，23.9mol)，醋酸钯(0.36g，1.59mol)加入115-1(2.0g，7.97mol)和115-2(1.13g，15.9mol)的甲苯溶液中，反应液加热到100度，反应16小时，反应完成后冷却到室温过滤旋干，粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝2:1)得淡黄色油状物115-3(398mg，产率：20.8％)。BINAP (0.99g, 1.59mol), cesium carbonate (7.8g, 23.9mol), and palladium acetate (0.36g, 1.59mol) were added to 115-1 (2.0g, 7.97mol) and 115-2 (1.13g, 15.9 mol) of toluene solution, the reaction solution was heated to 100 degrees and reacted for 16 hours. After the reaction was completed, it was cooled to room temperature, filtered and spin-dried. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain Light yellow oil 115-3 (398 mg, yield: 20.8%).
LCMS(ESI)m/z:241.9[M+H]+。LCMS(ESI)m/z:241.9[M+H] + .
中间体115-4的合成Synthesis of intermediate 115-4
冰浴下向115-3(0.40g，1.66mol)的四氢呋喃(10mL)溶液中加入氢化铝锂(0.13g，3.31mol)。冰水浴下搅拌2小时，然后于冰水浴下加入15％氢氧化钠溶液产生固体颗粒，过滤并旋干滤液得淡黄色油状物115-4(303mg，产率：84.9％)。To a solution of 115-3 (0.40 g, 1.66 mol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (0.13 g, 3.31 mol) under ice bath. Stir in an ice-water bath for 2 hours, then add 15% sodium hydroxide solution in an ice-water bath to produce solid particles, filter and spin the filtrate to obtain light yellow oil 115-4 (303 mg, yield: 84.9%).
LCMS(ESI)m/z:213.9[M+H]+。LCMS(ESI)m/z:213.9[M+H] + .
中间体115-5的合成Synthesis of intermediate 115-5
冰浴下向115-4(270mg，1.3mmol)的二氯甲烷(6mL)溶液中加入氯化亚砜(452mg，3.8mmol)。室温搅拌2小时，反应完成后，旋干得淡黄色油状物115-5(291mg，产率：98.9％)。To a solution of 115-4 (270 mg, 1.3 mmol) in dichloromethane (6 mL) was added thionyl chloride (452 mg, 3.8 mmol) under ice bath. Stir at room temperature for 2 hours. After the reaction is completed, spin dry to obtain light yellow oil 115-5 (291 mg, yield: 98.9%).
中间体115-6的合成 Synthesis of intermediate 115-6
常温下向1-5(290mg，1.25mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入碳酸钾(519mg，1.95mmol)和化合物115-5(344mg，1.5mmol)，混合溶液在室温下搅拌16小时。加入水(50mL)和乙酸乙酯(150mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝1:1)得淡黄色油状物115-6(248mg，产率：47.0％)。To a solution of 1-5 (290 mg, 1.25 mmol) in N,N-dimethylformamide (10 mL), potassium carbonate (519 mg, 1.95 mmol) and compound 115-5 (344 mg, 1.5 mmol) were added at room temperature, and the solution was mixed. Stir at room temperature for 16 hours. Water (50 mL) and ethyl acetate (150 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain light yellow oil 115-6 (248 mg, yield: 47.0%).
LCMS(ESI)m/z:424.8[M+H]+。LCMS(ESI)m/z:424.8[M+H] + .
中间体115-7的合成Synthesis of intermediate 115-7
常温下将115-6(250mg，0.59mmol)加入二氯甲烷/三氟乙酸＝1/1(10mL)溶液中，混合溶液在室温下搅拌2小时。在冰浴下用碳酸钠溶液将反应液调至pH＝7。混合溶液加入二氯甲烷(100mL)进行萃取，有机相用无水硫酸钠干燥。粗品减压浓缩得到淡黄色固体115-7(171mg，粗产品)。115-6 (250 mg, 0.59 mmol) was added to the dichloromethane/trifluoroacetic acid = 1/1 (10 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction solution was adjusted to pH=7 with sodium carbonate solution under ice bath. Dichloromethane (100 mL) was added to the mixed solution for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to obtain light yellow solid 115-7 (171 mg, crude product).
LCMS(ESI)m/z:368.8[M+H]+。LCMS(ESI)m/z:368.8[M+H] + .
中间体115-8的合成Synthesis of intermediate 115-8
常温下向115-7(80mg，0.21mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入碳酸钾(90mg，0.65mmol)和3-9(42mg，0.32mmol)，在60℃下搅拌16小时。加入水(10mL)和二氯甲烷(10mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝1:1)得棕色油状物115-8(20mg，产率：19.8％)。To a solution of 115-7 (80 mg, 0.21 mmol) in N,N-dimethylformamide (10 mL), potassium carbonate (90 mg, 0.65 mmol) and 3-9 (42 mg, 0.32 mmol) were added at room temperature. Stir for 16 hours. Water (10 mL) and dichloromethane (10 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain brown oil 115-8 (20 mg, yield: 19.8%).
LCMS(ESI)m/z:464[M+H]+。LCMS(ESI)m/z:464[M+H] + .
化合物115的合成Synthesis of Compound 115
冰浴下向115-8(20mg，0.04mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入1-10(11mg，0.06mmol)，再加入双(三甲基硅基)氨基锂(0.1mL)。0℃下搅拌2小时。加入水(10mL)和乙酸乙酯(100mL)进行萃取，有机相用无水硫酸钠干燥。粗品由高压制备色谱纯化得到白色固体化合物115(1.1mg，产率：4.41％)。Add 1-10 (11 mg, 0.06 mmol) to a solution of 115-8 (20 mg, 0.04 mmol) in N,N-dimethylformamide (5 mL) under ice bath, and then add bis(trimethylsilyl)amino group Lithium (0.1 mL). Stir at 0°C for 2 hours. Water (10 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high-pressure preparative chromatography to obtain compound 115 as a white solid (1.1 mg, yield: 4.41%).
LCMS(ESI)m/z:582.7[M+H]+。LCMS(ESI)m/z:582.7[M+H] + .
1H NMR(400MHz,CD3OD)δ8.28(s,1H),8.16(s,1H),7.64(d,J＝17.0Hz,2H),7.60–7.48(m,1H),7.26(dd,J＝12.2,7.4Hz,1H),5.20(s,2H),5.03(s,2H),4.12(s,3H),3.78(s,3H),3.07(m,4H)1.71(m,4H). 1 H NMR (400MHz, CD 3 OD) δ8.28 (s, 1H), 8.16 (s, 1H), 7.64 (d, J = 17.0Hz, 2H), 7.60–7.48 (m, 1H), 7.26 (dd ,J＝12.2,7.4Hz,1H),5.20(s,2H),5.03(s,2H),4.12(s,3H),3.78(s,3H),3.07(m,4H)1.71(m,4H ).
以上述同样方法合成如下表C的化合物。The compounds in Table C below were synthesized in the same manner as above.
表C


Table C


实施例125化合物125的合成
Example 125 Synthesis of Compound 125
中间体125-2的合成Synthesis of intermediate 125-2
在-78℃下将125-1(3.0g，0.01mol)溶解到无水甲苯(100mL)溶液中。加入二异丁基氢化铝的正己烷溶液(13mL，0.013mol)搅拌30分钟。该混合溶液在25℃下搅拌16小时反应完成后，加入饱和氯化铵溶液(100mL)淬灭,混合液体用乙酸乙酯(500mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝4:1)得淡黄色油状物125-2(2.7g，产率：98.3％)。Dissolve 125-1 (3.0 g, 0.01 mol) into anhydrous toluene (100 mL) solution at -78°C. A solution of diisobutylaluminum hydride in n-hexane (13 mL, 0.013 mol) was added and stirred for 30 minutes. The mixed solution was stirred at 25°C for 16 hours. After the reaction was completed, saturated ammonium chloride solution (100 mL) was added to quench the mixture. The mixed solution was extracted with ethyl acetate (500 mL), and the organic phase was dried with anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=4:1) to obtain light yellow oil 125-2 (2.7g, yield: 98.3%).
LCMS(ESI)m/z:269.0[M-H]+。LCMS(ESI)m/z:269.0[MH] + .
中间体125-3的合成 Synthesis of intermediate 125-3
冰浴下向125-2(2.7g，0.01mol)的二氯甲烷(100mL)溶液中加入三苯基膦(4.0g，0.015mol)和四溴化碳(4.0g，0.012mol)。在0℃搅拌30分钟。反应完成后，反应液直接加压浓缩得到粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝10:1)得淡黄色油状物125-3(3.0g，产率：89％)。To a solution of 125-2 (2.7g, 0.01mol) in dichloromethane (100mL) was added triphenylphosphine (4.0g, 0.015mol) and carbon tetrabromide (4.0g, 0.012mol) under ice bath. Stir at 0°C for 30 minutes. After the reaction was completed, the reaction solution was directly concentrated under pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain light yellow oil 125-3 (3.0 g, yield: 89%).
1H NMR(400MHz,CDCl3)δ7.65(dd,J＝9.3,7.7Hz,1H),7.33(dd,J＝10.6,7.9Hz,1H),4.51(s,2H). 1 H NMR (400MHz, CDCl3) δ7.65 (dd, J=9.3, 7.7Hz, 1H), 7.33 (dd, J=10.6, 7.9Hz, 1H), 4.51 (s, 2H).
中间体125-4的合成Synthesis of intermediate 125-4
常温下向125-3(3.0g，0.009mol)的乙腈(100mL)溶液中加入碳酸钾(3.74g，0.027mol)和化合物1-5(2.1g，0.009mol)，混合溶液在80℃下搅拌16小时。加入水(10mL)和二氯甲烷(200mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝1:1)得淡黄色油状固体125-4(3.8g，产率：87％)。To a solution of 125-3 (3.0g, 0.009mol) in acetonitrile (100mL), potassium carbonate (3.74g, 0.027mol) and compound 1-5 (2.1g, 0.009mol) were added at room temperature, and the mixed solution was stirred at 80°C. 16 hours. Water (10 mL) and dichloromethane (200 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate=1:1) to obtain light yellow oily solid 125-4 (3.8g, yield: 87%).
LCMS(ESI)m/z:504.0[M+Na]+。LCMS(ESI)m/z:504.0[M+Na] + .
中间体125-5的合成Synthesis of intermediate 125-5
冰盐浴下向125-4(3.8g，0.008mol)的四氢呋喃(150mL)溶液中加入化合物1-10(1.44g，0.008mol)，再加入双(三甲基硅基)氨基锂(16mL)。混合溶液在冰盐浴下搅拌反应2小时。反应完毕后，向反应液中加入饱和氯化铵溶液(50mL)进行淬灭，之后用乙酸乙酯(400mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝1:1)得白色固体125-5(4.3g，产率：90％)。Add compound 1-10 (1.44g, 0.008mol) to a solution of 125-4 (3.8g, 0.008mol) in tetrahydrofuran (150mL) under an ice-salt bath, and then add lithium bis(trimethylsilyl)amide (16mL) . The mixed solution was stirred and reacted in an ice-salt bath for 2 hours. After the reaction was completed, saturated ammonium chloride solution (50 mL) was added to the reaction solution for quenching, and then extracted with ethyl acetate (400 mL). The organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain white solid 125-5 (4.3 g, yield: 90%).
LCMS(ESI)m/z:601.0[M+H]+。LCMS(ESI)m/z:601.0[M+H] + .
中间体125-7的合成Synthesis of intermediate 125-7
常温下将125-5(1.0g，1.66mmol)加入N,N-二甲基甲酰胺(20mL)溶液中，依次加入化合物125-6(867mg，8.3mmol)、三乙胺(505mg，5.0mmol)、醋酸钯(37mg，0.16mmol)和三(邻甲基苯基)膦(51mg，0.16mmol)，加入完毕后，混合物使用氮气保护。并将混合溶液在80℃下搅拌12小时。加入水(60mL)和乙酸乙酯(200mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝1:1)得棕色油状物125-7(590mg，产率：55％)。Add 125-5 (1.0g, 1.66mmol) to a solution of N,N-dimethylformamide (20mL) at room temperature, followed by the addition of compound 125-6 (867mg, 8.3mmol) and triethylamine (505mg, 5.0mmol). ), palladium acetate (37 mg, 0.16 mmol) and tris(o-methylphenyl)phosphine (51 mg, 0.16 mmol). After the addition is completed, the mixture is protected with nitrogen. And the mixed solution was stirred at 80°C for 12 hours. Water (60 mL) and ethyl acetate (200 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:1) to obtain brown oil 125-7 (590 mg, yield: 55%).
LCMS(ESI)m/z:577.2[M+H]+。LCMS(ESI)m/z:577.2[M+H] + .
中间体125-8的合成Synthesis of intermediate 125-8
常温下将125-7(590mg，1.0mmol)加入二氯甲烷/三氟乙酸＝3/1(6mL)溶液中，混合溶液在室温下搅拌2小时。反应完毕后，将反应液减压浓缩得到淡黄色固体125-8(241mg，粗产品)。125-7 (590 mg, 1.0 mmol) was added to a dichloromethane/trifluoroacetic acid = 3/1 (6 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain light yellow solid 125-8 (241 mg, crude product).
LCMS(ESI)m/z:521.2[M+H]+。LCMS(ESI)m/z:521.2[M+H] + .
化合物125的合成Synthesis of Compound 125
常温下向125-8(240mg，0.46mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入化合物1-8(116 mg，0.69mmol)，再加入碳酸铯(450mg，1.38mmol)和碘化钠(138mg，0.92mmol)。混合物在80℃下搅拌3小时。加入水(10mL)和乙酸乙酯(500mL)进行萃取，有机相用无水硫酸钠干燥。粗品由高压制备色谱纯化得到白色固体化合物125(73mg，产率：25％)。To a solution of 125-8 (240 mg, 0.46 mmol) in N,N-dimethylformamide (10 mL) at room temperature was added compound 1-8 (116 mg, 0.69mmol), and then add cesium carbonate (450mg, 1.38mmol) and sodium iodide (138mg, 0.92mmol). The mixture was stirred at 80°C for 3 hours. Water (10 mL) and ethyl acetate (500 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high-pressure preparative chromatography to obtain compound 125 as a white solid (73 mg, yield: 25%).
LCMS(ESI)m/z:616.2[M+Na]+。LCMS(ESI)m/z:616.2[M+Na] + .
1H NMR(400MHz,DMSO-d6)δ8.24(s,1H),8.10(s,1H),7.66(s,1H),7.58–7.35(m,5H),7.33–7.13(m,4H),7.01(d,J＝14.4Hz,1H),5.40(s,2H),5.04(s,2H),4.14(s,3H),3.80(s,3H). 1 H NMR (400MHz, DMSO-d 6 ) δ8.24(s,1H),8.10(s,1H),7.66(s,1H),7.58–7.35(m,5H),7.33–7.13(m,4H) ),7.01(d,J=14.4Hz,1H),5.40(s,2H),5.04(s,2H),4.14(s,3H),3.80(s,3H).
以上述同样方法合成如下表D的化合物。The compounds in Table D below were synthesized in the same manner as above.
表D


Form D


实施例141化合物141的合成
Example 141 Synthesis of Compound 141
参照实施例1合成中间体141-1.Intermediate 141-1 was synthesized with reference to Example 1.
中间体141-3的合成Synthesis of intermediate 141-3
常温下向141-1(150mg，0.34mmol)的N,N-二甲基甲酰胺(2mL)溶液中加入三乙胺(173mg，1.71mmol)，141-2(209mg，1.71mmol)，醋酸铜(124mg，0.682mmol)和分子筛(380mg)。混合溶液在60℃并且氧气流通下搅拌16小时。反应完成后，过滤，滤液减压浓缩。粗品用柱层析(硅胶，二氯甲烷:甲醇＝30:1)提纯得黄色油状化合物141-3(141mg，产率：75.5％)。To a solution of 141-1 (150 mg, 0.34 mmol) in N,N-dimethylformamide (2 mL), triethylamine (173 mg, 1.71 mmol), 141-2 (209 mg, 1.71 mmol), and copper acetate were added at room temperature. (124 mg, 0.682 mmol) and molecular sieve (380 mg). The mixed solution was stirred at 60° C. with oxygen flow for 16 hours. After the reaction was completed, it was filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=30:1) to obtain yellow oily compound 141-3 (141 mg, yield: 75.5%).
LCMS(ESI)m/z:517.1[M+H]+。LCMS(ESI)m/z:517.1[M+H] + .
化合物141的合成Synthesis of Compound 141
冰浴下向141-3(140mg，0.271mmol)的四氢呋喃(2mL)溶液中加入1-10(59.0mg,0.325mmol)，混合溶液在氮气保护下加入双(三甲基硅基)氨基锂(0.5mL)。0℃下搅拌2小时。反应完成后，混合溶液加入水(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品由高压制备色谱(色谱柱:-Gemini-C18 150x 21.2mm，5μm。流动相:ACN--H2O(0.1％FA)。梯度:40-60)纯化得到白色固体化合物141(36.2mg，产率：20.2％)。Add 1-10 (59.0 mg, 0.325 mmol) to a solution of 141-3 (140 mg, 0.271 mmol) in tetrahydrofuran (2 mL) under ice bath, and add lithium bis(trimethylsilyl)amide (lithium bis(trimethylsilyl)amide) to the mixed solution under nitrogen protection. 0.5mL). Stir at 0°C for 2 hours. After the reaction was completed, the mixed solution was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (chromatographic column: -Gemini-C18 150x 21.2mm, 5μm. Mobile phase: ACN--H 2 O (0.1% FA). Gradient: 40-60) to obtain white solid compound 141 (36.2mg, Yield: 20.2%).
LCMS(ESI)m/z:636.1[M+H]+。LCMS(ESI)m/z:636.1[M+H] + .
1H NMR(400MHz,CD3OD)δ8.73–8.65(m,2H),8.20(s,1H),8.18–8.14(m,1H),7.81–7.75(m,1H),7.67(s,1H),7.54–7.46(m,3H),7.35–7.31(m,1H),7.23–7.10(m,3H),5.32(s,2H),5.23(s,2H),4.18(s,3H). 1 H NMR (400MHz, CD 3 OD) δ8.73–8.65(m,2H),8.20(s,1H),8.18–8.14(m,1H),7.81–7.75(m,1H),7.67(s, 1H),7.54–7.46(m,3H),7.35–7.31(m,1H),7.23–7.10(m,3H),5.32(s,2H),5.23(s,2H),4.18(s,3H) .
以上述同样方法合成如下表E的化合物。The compounds in Table E below were synthesized in the same manner as above.
表E




Table E




实施例168化合物168的合成
Example 168 Synthesis of Compound 168
参照实施例1合成中间体168-1.Intermediate 168-1 was synthesized with reference to Example 1.
中间体168-2的合成Synthesis of intermediate 168-2
盐冰浴下向168-1(20mg,0.044mmol)和1-10(12mg,0.066mmol)的N,N-二甲基甲酰胺(3mL)溶 液中加入双(三甲基硅基)氨基锂(0.08mL,0.088mmol)。-20℃下搅拌1小时。加入饱和氯化钠溶液(10mL)和乙酸乙酯(50mL)进行萃取，有机相用无水硫酸钠干燥。粗品由薄板层析纯化得到棕色固体168-2(28mg，产率：100％)。Dissolve 168-1 (20 mg, 0.044 mmol) and 1-10 (12 mg, 0.066 mmol) in N,N-dimethylformamide (3 mL) under an ice-salt bath. Lithium bis(trimethylsilyl)amide (0.08 mL, 0.088 mmol) was added to the solution. Stir at -20°C for 1 hour. Saturated sodium chloride solution (10 mL) and ethyl acetate (50 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by thin plate chromatography to obtain 168-2 as a brown solid (28 mg, yield: 100%).
LCMS(ESI)m/z:574.0[M+H]+。LCMS(ESI)m/z:574.0[M+H] + .
中间体168-3的合成Synthesis of intermediate 168-3
常温下将168-2(28mg，0.048mmol)加入二氯甲烷/三氟乙酸＝1/1(4mL)溶液中，混合溶液在室温下搅拌2小时。反应液减压浓缩得到淡黄色固体168-3(30mg，粗产品)。168-2 (28 mg, 0.048 mmol) was added to the dichloromethane/trifluoroacetic acid = 1/1 (4 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain light yellow solid 168-3 (30 mg, crude product).
LCMS(ESI)m/z:518.0[M+H]+。LCMS(ESI)m/z:518.0[M+H] + .
化合物168的合成Synthesis of compound 168
常温下向168-3(140mg，0.27mmol)和141-2(49mg，0.405mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入醋酸铜(97mg，0.54mmol)，三乙胺(136mg，1.351mmol)和4A分子筛(140mg)，在60℃下搅拌16小时。加入水(20mL)和乙酸乙酯(50mL)进行萃取，有机相用无水硫酸钠干燥。粗品用高压制备色谱纯化得白色固体化合物168(3mg，产率：1.8％)。To a solution of 168-3 (140 mg, 0.27 mmol) and 141-2 (49 mg, 0.405 mmol) in N,N-dimethylformamide (10 mL) at room temperature, copper acetate (97 mg, 0.54 mmol) and triethylamine were added (136 mg, 1.351 mmol) and 4A molecular sieve (140 mg), stirred at 60°C for 16 hours. Water (20 mL) and ethyl acetate (50 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high-pressure preparative chromatography to obtain compound 168 as a white solid (3 mg, yield: 1.8%).
LCMS(ESI)m/z:595.0[M+H]+。LCMS(ESI)m/z:595.0[M+H] + .
1H NMR(400MHz,CD3OD)δ8.71(d,J＝17.0Hz,2H),8.19-8.16(m,2H),7.78-7.75(m,2H),7.53-7.48(m,2H),6.72(dd,J＝12.6,7.7Hz,1H),5.20(s,2H),4.18(s,3H),3.85–3.75(m,2H),3.41(td,J＝11.6,2.1Hz,3H),1.85(d,J＝11.7Hz,2H),1.42–1.22(m,2H). 1 H NMR (400MHz, CD 3 OD) δ8.71 (d, J = 17.0Hz, 2H), 8.19-8.16 (m, 2H), 7.78-7.75 (m, 2H), 7.53-7.48 (m, 2H) ,6.72(dd,J＝12.6,7.7Hz,1H),5.20(s,2H),4.18(s,3H),3.85–3.75(m,2H),3.41(td,J＝11.6,2.1Hz,3H ),1.85(d,J＝11.7Hz,2H),1.42–1.22(m,2H).
以上述同样方法合成如下表F的化合物。The compounds in Table F below were synthesized in the same manner as above.
表F

Table F

实施例176化合物176的合成
Example 176 Synthesis of Compound 176
参照实施例1合成中间体176-1.Intermediate 176-1 was synthesized with reference to Example 1.
中间体176-3的合成Synthesis of intermediate 176-3
常温下向176-1(200mg，0.47mmol)的N,N-二甲基甲酰胺(6mL)溶液中加入乙酸铜(170mg，0.94mmol)，176-2(359mg，2.35mmol)，三乙胺(238mg，2.35mmol)和4A分子筛(600mg)，在60℃下搅拌16小时。加入饱和氯化钠溶液(50mL)和乙酸乙酯(200mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，二氯甲烷:甲醇＝20:1)得棕色油状物176-3(151mg，产率：30.0％)。To a solution of 176-1 (200 mg, 0.47 mmol) in N,N-dimethylformamide (6 mL), copper acetate (170 mg, 0.94 mmol), 176-2 (359 mg, 2.35 mmol), and triethylamine were added at room temperature. (238 mg, 2.35 mmol) and 4A molecular sieve (600 mg), stirred at 60°C for 16 hours. Saturated sodium chloride solution (50 mL) and ethyl acetate (200 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=20:1) to obtain brown oil 176-3 (151 mg, yield: 30.0%).
LCMS(ESI)m/z:533.0[M+H]+。LCMS(ESI)m/z:533.0[M+H] + .
化合物176的合成 Synthesis of compound 176
冰浴下向176-3(150mg，0.28mmol)的四氢呋喃(3mL)溶液中加入1-10(71mg，0.39mmol)，再加入叔丁醇钾(0.5mL)。-78℃下搅拌1小时。加入饱和氯化钠溶液(10mL)和乙酸乙酯(100mL)进行萃取，有机相用无水硫酸钠干燥。粗品由高压制备色谱纯化得到浅棕色固体化合物176(14.7mg，产率：7.9％)。To a solution of 176-3 (150 mg, 0.28 mmol) in tetrahydrofuran (3 mL) was added 1-10 (71 mg, 0.39 mmol) under ice bath, and then potassium tert-butoxide (0.5 mL) was added. Stir at -78°C for 1 hour. Saturated sodium chloride solution (10 mL) and ethyl acetate (100 mL) were added for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by high-pressure preparative chromatography to obtain light brown solid compound 176 (14.7 mg, yield: 7.9%).
LCMS(ESI)m/z:652.0[M+H]+。LCMS(ESI)m/z:652.0[M+H] + .
1H NMR(400MHz,CD3OD)δ8.40(s,1H),8.23(d,J＝6.4Hz,2H),7.83–7.72(m,2H),7.68(s,1H),7.53(s,1H),7.15(d,J＝6.2Hz,4H),6.69(d,J＝10.2Hz,1H),5.45(s,2H),4.22(s,3H),3.95(s,3H). 1 H NMR (400MHz, CD 3 OD) δ8.40 (s, 1H), 8.23 (d, J = 6.4Hz, 2H), 7.83–7.72 (m, 2H), 7.68 (s, 1H), 7.53 (s ,1H),7.15(d,J＝6.2Hz,4H),6.69(d,J＝10.2Hz,1H),5.45(s,2H),4.22(s,3H),3.95(s,3H).
以上述同样方法合成如下表G的化合物。The compounds in Table G below were synthesized in the same manner as above.
表G




Form G




实施例201化合物201的合成
Example 201 Synthesis of Compound 201
参照实施例125合成中间体201-1Synthesize intermediate 201-1 with reference to Example 125
化合物201-3的合成Synthesis of Compound 201-3
室温下将201-1(88.0mg，0.20mmol)，醋酸铜(108.6mg，0.60mmol)，三乙胺(201.7，1.99mmol)，DMF(5mL)，201-2(98.3mg，0.70mmol)混合，于氧气环境下60℃下搅拌16小时。加入水(10mL)，乙酸乙酯(10mL*5)进行萃取，合并有机相，用饱和食盐水洗涤(10mL*3)。分出有机相，粗品用柱层析提纯(硅胶，乙酸乙酯)得淡黄色油状物201-3(202mg，粗产品)。Mix 201-1 (88.0 mg, 0.20 mmol), copper acetate (108.6 mg, 0.60 mmol), triethylamine (201.7, 1.99 mmol), DMF (5 mL), and 201-2 (98.3 mg, 0.70 mmol) at room temperature. , stirred at 60°C for 16 hours in an oxygen environment. Add water (10 mL), extract with ethyl acetate (10 mL*5), combine the organic phases, and wash with saturated brine (10 mL*3). The organic phase was separated, and the crude product was purified by column chromatography (silica gel, ethyl acetate) to obtain light yellow oil 201-3 (202 mg, crude product).
LCMS(ESI)m/z:537.0/539.0[M+H]+。LCMS(ESI)m/z:537.0/539.0[M+H] + .
中间体201-4的合成Synthesis of intermediate 201-4
常温下将201-3(300mg，0.56mmol)，1-10(112mg，0.61mmol)加入四氢呋喃(15mL)溶液中，氮气保护下降温至-60℃,然后加入叔丁醇钾(0.16mL，1.12mmol)，混合溶液在-60℃下搅拌1个小时。加入饱和氯化铵水溶液(10mL)淬灭,乙酸乙酯萃取(10mL*5)，合并有机相，饱和食盐水洗涤(10mL*3)，分出有机相，减压浓缩，所得物柱层析纯化(硅胶，二氯甲烷：甲醇＝20：1)，得到201-4(229mg，黄色油状物，室温静置后变为固体，产率：62.1％)。Add 201-3 (300mg, 0.56mmol) and 1-10 (112mg, 0.61mmol) into the tetrahydrofuran (15mL) solution at room temperature, lower the temperature to -60°C under nitrogen protection, and then add potassium tert-butoxide (0.16mL, 1.12 mmol), the mixed solution was stirred at -60°C for 1 hour. Add saturated aqueous ammonium chloride solution (10mL) to quench, extract with ethyl acetate (10mL*5), combine the organic phases, wash with saturated brine (10mL*3), separate the organic phase, concentrate under reduced pressure, and the resultant is column chromatographed. Purification (silica gel, methylene chloride:methanol=20:1) gave 201-4 (229 mg, yellow oil, which turned into a solid after standing at room temperature, yield: 62.1%).
LCMS(ESI)m/z:656.0/658.0[M+H]+。LCMS(ESI)m/z:656.0/658.0[M+H] + .
中间体201-5的合成Synthesis of intermediate 201-5
冰水浴下将201-4(600mg，0.92mmol)，加入二氯甲烷(20mL)中，随后加入DIPEA(238mg，1.84mmol)，氮气保护下缓慢加入MOMBr(138mg，1.1mmol)，加毕，室温反应1小时,减压浓缩，所得物柱层析纯化(二氯甲烷：甲醇＝20：1)，得到201-5(340mg，黄色油状物，室温静置后变为固体，产率：26.5％)。Add 201-4 (600 mg, 0.92 mmol) to methylene chloride (20 mL) in an ice water bath, then add DIPEA (238 mg, 1.84 mmol), slowly add MOMBr (138 mg, 1.1 mmol) under nitrogen protection, complete the addition, room temperature React for 1 hour, concentrate under reduced pressure, and the resultant is purified by column chromatography (dichloromethane: methanol = 20:1) to obtain 201-5 (340 mg, yellow oily substance, which becomes solid after standing at room temperature, yield: 26.5% ).
LCMS(ESI)m/z:696.0/698.0[M+H]+。 LCMS(ESI)m/z:696.0/698.0[M+H] + .
化合物201的合成Synthesis of Compound 201
室温下将201-5(50mg，0.072mmol),乙醇/水(3mL/2mL)，CuI(6.84mg，0.04mmol)，L-脯氨酸(8.27g，0.07mmol)，K3PO4(30.5mg，0.14mmol)混合溶液在氮气保护下于80℃搅拌16小时。冷至室温，减压除去溶剂，所得残余物由高压制备色谱纯化得到淡黄色固体化合物201(2mg，产率：3.9％)。201-5 (50mg, 0.072mmol), ethanol/water (3mL/2mL), CuI (6.84mg, 0.04mmol), L-proline (8.27g, 0.07mmol), K 3 PO 4 (30.5 mg, 0.14 mmol) mixed solution was stirred at 80°C for 16 hours under nitrogen protection. Cool to room temperature, remove the solvent under reduced pressure, and the resulting residue is purified by high-pressure preparative chromatography to obtain light yellow solid compound 201 (2 mg, yield: 3.9%).
LCMS(ESI)m/z:652.1/654.1[M+H]+。LCMS(ESI)m/z:652.1/654.1[M+H] + .
1H NMR(400MHz,MeOD)δ8.61(d,J＝18.7Hz,2H),8.19(d,J＝23.2Hz,4H),7.84(d,J＝8.4Hz,2H),7.73(s,1H),7.68(d,J＝7.3Hz,2H),7.53(s,1H),5.24(s,2H),4.20(s,3H),2.51(s,3H)。 1 H NMR (400MHz, MeOD) δ8.61 (d, J = 18.7Hz, 2H), 8.19 (d, J = 23.2Hz, 4H), 7.84 (d, J = 8.4Hz, 2H), 7.73 (s, 1H), 7.68 (d, J = 7.3Hz, 2H), 7.53 (s, 1H), 5.24 (s, 2H), 4.20 (s, 3H), 2.51 (s, 3H).
以上述同样方法合成如下表H的化合物。The compounds in Table H below were synthesized in the same manner as above.
表H




















Table H




















实施例239化合物239的合成

Example 239 Synthesis of Compound 239

中间体239-3的合成Synthesis of intermediate 239-3
室温下向239-1(750mg，4.67mmol)的1，4-二氧六环(8mL)溶液中加入239-2(1.19g，5.14mmol)、N,N-二甲基甘氨酸(241mg，2.34mmol)、碘化亚铜(445mg，2.34mmol)和碳酸铯(3.04g，9.34mmol)。氮气保护，混合溶液在110℃下搅拌48小时。加水(100mL)淬灭，乙酸乙酯(50mL*3)萃取，合并有机相用无水硫酸钠干燥。过滤，滤液减压浓缩。粗品用柱层析(硅胶，石油醚:乙酸乙酯＝50:1)提纯得黄色油状化合物239-3(420mg，产率：29.1％)。To a solution of 239-1 (750 mg, 4.67 mmol) in 1,4-dioxane (8 mL) was added 239-2 (1.19 g, 5.14 mmol) and N, N-dimethylglycine (241 mg, 2.34 mmol), copper iodide (445 mg, 2.34 mmol) and cesium carbonate (3.04 g, 9.34 mmol). Under nitrogen protection, the mixed solution was stirred at 110°C for 48 hours. Add water (100 mL) to quench, extract with ethyl acetate (50 mL*3), and dry the combined organic phases over anhydrous sodium sulfate. Filter, and the filtrate is concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 50:1) to obtain compound 239-3 (420 mg, yield: 29.1%) as a yellow oil.
GCMS(ESI)m/z:310.0[M]+。GCMS(ESI)m/z:310.0[M] + .
中间体239-4的合成Synthesis of Intermediate 239-4
冰浴下向239-3(410mg，1.32mmol)的四氯化碳(5mL)溶液中加入偶氮二异丁腈(21.6mg,0.132mmol)和N-溴化丁二酰亚胺(235mg，1.32mmol)。混合溶液在80℃下搅拌16小时。混合溶液加入水(40mL)和二氯甲烷(40mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品用柱层析(硅胶，石油醚:乙酸乙酯＝10:1)提纯得黄色油状化合物239-4(450mg，产率：87.7％)。To a solution of 239-3 (410 mg, 1.32 mmol) in carbon tetrachloride (5 mL), azobisisobutyronitrile (21.6 mg, 0.132 mmol) and N-bromosuccinimide (235 mg, 1.32mmol). The mixed solution was stirred at 80°C for 16 hours. Add water (40 mL) and dichloromethane (40 mL*3) to the mixed solution for extraction. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain compound 239-4 (450 mg, yield: 87.7%) as a yellow oil.
LCMS(ESI)m/z:388.9[M+H]+。LCMS(ESI)m/z:388.9[M+H] + .
中间体239-6的合成Synthesis of intermediate 239-6
常温下向239-4(230mg，0.591mmol)的乙腈(3mL)溶液中加入碳酸钾(245mg，1.77mmol)和239-5(120mg，0.591mmol)，混合溶液在80℃下搅拌4小时。混合溶液加入乙酸乙酯(50mL)，依次用水(20mL)和饱和氯化钠溶液(20mL)洗涤，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品用柱层析(硅胶，石油醚:乙酸乙酯＝10:1)提纯得黄色油状化合物239-6(97.0mg，产率：32.0％)。Potassium carbonate (245 mg, 1.77 mmol) and 239-5 (120 mg, 0.591 mmol) were added to a solution of 239-4 (230 mg, 0.591 mmol) in acetonitrile (3 mL) at room temperature, and the mixed solution was stirred at 80°C for 4 hours. Ethyl acetate (50 mL) was added to the mixed solution, washed with water (20 mL) and saturated sodium chloride solution (20 mL) in sequence, the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 10:1) to obtain compound 239-6 (97.0 mg, yield: 32.0%) as a yellow oil.
LCMS(ESI)m/z:512.0[M+H]+。LCMS(ESI)m/z:512.0[M+H] + .
化合物239的合成Synthesis of compound 239
零下40℃向239-6(97.0mg，0.189mmol)的四氢呋喃(3mL)溶液中加入1-10(34.3mg,0.189mmol)，混合溶液在氮气保护下加入叔丁醇钾(0.57mL)。零下40℃下搅拌2小时。混合溶液加入水(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品由高压制备色谱(色谱柱:-Gemini-C18 150x 21.2mm，5μm。流动项:ACN--H2O(0.1％FA)。梯度:40-70)纯化得到白色固体化合物240(14.2mg，产率：11.9％)。To a solution of 239-6 (97.0 mg, 0.189 mmol) in tetrahydrofuran (3 mL) was added 1-10 (34.3 mg, 0.189 mmol) at minus 40°C, and potassium tert-butoxide (0.57 mL) was added to the mixed solution under nitrogen protection. Stir at minus 40°C for 2 hours. The mixed solution was quenched by adding water (10 mL), extracted with ethyl acetate (10 mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (column: -Gemini-C18 150x 21.2mm, 5 μm. Flow term: ACN--H 2 O (0.1% FA). Gradient: 40-70) to obtain white solid compound 240 (14.2 mg, Yield: 11.9%).
LCMS(ESI)m/z:631.0[M+H]+。 LCMS(ESI)m/z:631.0[M+H] + .
1H NMR(400MHz,CD3OD)δ8.44(s,1H),8.07(s,1H),7.96(s,1H),7.52(d,J＝8.0Hz,1H),7.42(s,1H),7.21(d,J＝4.0Hz,1H),6.86(d,J＝12.0Hz,1H),4.65(s,1H),4.47(s,1H),4.28(s,3H),3.95(s,3H). 1 H NMR (400MHz, CD 3 OD) δ8.44(s,1H),8.07(s,1H),7.96(s,1H),7.52(d,J＝8.0Hz,1H),7.42(s,1H ),7.21(d,J＝4.0Hz,1H),6.86(d,J＝12.0Hz,1H),4.65(s,1H),4.47(s,1H),4.28(s,3H),3.95(s ,3H).
表H
Table H
生物学实施例Biological Examples
1.酶学活性测定1. Enzymatic activity determination
测定体系(120uL)：蛋白酶(108uL)：(150nM)WT或P132HAssay system (120uL): Protease (108uL): (150nM) WT or P132H
底物(10uL终浓度：20uM)Substrate (10uL final concentration: 20uM)
小分子(2uL；3倍梯度稀释)Small molecules (2uL; 3-fold gradient dilution)
底物：荧光底物MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2；主蛋白酶通用引物反应Buffer：50mM Tris pH 7.4,1mM EDTA,0.01％tritonX-100孵育30min后酶标仪检测；Substrate: Fluorescent substrate MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2; Main protease universal primer reaction Buffer: 50mM Tris pH 7.4, 1mM EDTA, 0.01% tritonX-100, incubate for 30 minutes and then detect with a microplate reader;
酶标仪检测：激发320nm；发射405nm；Microplate reader detection: excitation 320nm; emission 405nm;
使用不同药物浓度对酶初反应速率与对照组酶初反应速率的比值确定代表性化合物对主蛋白酶的抑制率，再使用GraphPad Prism非线性拟合曲线计算IC50值。Use the ratio of the initial reaction rate of the enzyme at different drug concentrations to the initial reaction rate of the enzyme in the control group to determine the inhibitory rate of the representative compound on the main protease, and then use GraphPad Prism nonlinear fitting curve to calculate the IC 50 value.
公式一：抑制率(％)＝(RFU 100％酶活性对照-RFU样品)/(RFU100％酶活性对照-RFU空白对照)×100％Formula 1: Inhibition rate (%) = (RFU 100% enzyme activity control - RFU sample) / (RFU 100% enzyme activity control - RFU blank control) × 100%
公式二：抑制率(％)＝(NC初速度V0-样品初速度V0)/NC初速度×100；Formula 2: Inhibition rate (%) = (NC initial velocity V0 - sample initial velocity V0)/NC initial velocity × 100;
NC为加DMSO对照，酶活定为100％NC is the control with DMSO added, and the enzyme activity is determined as 100%.
初速度计算＝Slope(200s内RFU：时间s)Initial velocity calculation = Slope (RFU within 200s: time s)
公式二优化：抑制率(％)＝(NC初速度V0-(样品初速度V0-无蛋白的小分子对照V0)/NC初速度V0×100用来消除V0(斜率)为负值的问题。Formula 2 Optimization: Inhibition rate (%) = (NC initial velocity V0 - (sample initial velocity V0 - protein-free small molecule control V0)/NC initial velocity V0 × 100 is used to eliminate the problem that V0 (slope) is a negative value.
2、抗SARS-COV-22. Anti-SARS-COV-2
(一)实验材料(1) Experimental materials
细胞系：非洲绿猴肾细胞Vero E6(ATCC，CRL-1586),人结直肠腺癌细胞Caco-2(ATCC,HTB-37) 和人肺腺癌细胞Calu-3(ATCC,HTB-55)。Cell lines: African green monkey kidney cells Vero E6 (ATCC, CRL-1586), human colorectal adenocarcinoma cells Caco-2 (ATCC, HTB-37) and human lung adenocarcinoma cell Calu-3 (ATCC, HTB-55).
病毒株：2019-nCoV-WIV04(IVCAS 6.7512)Virus strain: 2019-nCoV-WIV04(IVCAS 6.7512)
感染剂量：MOI＝0.01Infectious dose: MOI=0.01
(二)实验方法(2) Experimental methods
1)将100μL含2×104细胞接种至96孔板中，放置于37℃恒温恒湿培养箱过夜培养；1) Inoculate 100 μL of 2 × 10 4 cells into a 96-well plate and place it in a 37°C constant temperature and humidity incubator for overnight culture;
2)细胞贴壁20小时后吸弃培养液，每孔分别加入100μL含指定浓度测试化合物+CP-100356的培养液。每种测试化合物设置8个稀释度，每个稀释度设置3～4个复孔，同时设置DMSO处理组和正常细胞组。除正常细胞组外，其它孔加入含0.01MOI病毒完全培养液，37℃恒温恒湿培养箱孵育72小时。2) After the cells have adhered for 20 hours, aspirate the culture medium and add 100 μL of culture medium containing the specified concentration of test compound + CP-100356 to each well. Set up 8 dilutions for each test compound, set up 3 to 4 duplicate wells for each dilution, and set up a DMSO-treated group and a normal cell group at the same time. Except for the normal cell group, complete virus culture medium containing 0.01 MOI was added to other wells and incubated in a 37°C constant temperature and humidity incubator for 72 hours.
3)在感染后72小时使用全视野细胞扫描仪记录细胞病变率，抑制率＝(1－测试化合物组的病变率)×100％。3) Use a full-field cell scanner to record the cell lesion rate 72 hours after infection, and the inhibition rate = (1 - the lesion rate of the test compound group) × 100%.
4)根据抑制率结果，进行四参数拟合计算EC50。4) Based on the inhibition rate results, perform four-parameter fitting to calculate EC 50 .
本发明代表性化合物的测试结果如表1所示。The test results of representative compounds of the present invention are shown in Table 1.
表1





















































Table 1





















































实施例A1Example A1
6-((6-氯-2-甲基-2H-吲唑-5-基)氨基)-3-(吡啶-3-基)-1-(2,4,5-三氟苄基)-1,3,5-三嗪-2,4(1H,3H)-二酮)的合成
6-((6-chloro-2-methyl-2H-indazol-5-yl)amino)-3-(pyridin-3-yl)-1-(2,4,5-trifluorobenzyl)- Synthesis of 1,3,5-triazine-2,4(1H,3H)-dione)
中间体1-2的合成Synthesis of intermediate 1-2
冰浴下将亚硝酸钠(4.44g，0.06mol)的水溶液(10mL)加入到中间体1-1(10g，0.05mol)的冰醋酸(100mL)溶液中并混合。将混合溶液在室温下搅拌6个小时，然后将反应混合物浓缩并向其中加入乙酸乙酯(200mL)稀释，用饱和碳酸氢钠溶液(100mL*2)洗涤，分离出有机相并用无水硫酸钠干燥，过滤。滤液减压浓缩得棕色固体状中间体1-2(10g)，直接用于下一步反应。An aqueous solution (10 mL) of sodium nitrite (4.44 g, 0.06 mol) was added to a solution of intermediate 1-1 (10 g, 0.05 mol) in glacial acetic acid (100 mL) under ice bath and mixed. The mixed solution was stirred at room temperature for 6 hours, then the reaction mixture was concentrated and diluted with ethyl acetate (200mL), washed with saturated sodium bicarbonate solution (100mL*2), the organic phase was separated and washed with anhydrous sodium sulfate Dry and filter. The filtrate was concentrated under reduced pressure to obtain brown solid intermediate 1-2 (10 g), which was directly used in the next reaction.
LCMS(ESI)m/z:198.0[M+H]+。LCMS(ESI)m/z:198.0[M+H] + .
中间体1-3的合成Synthesis of intermediates 1-3
室温下向中间体1-2(10g，0.05mol)的乙酸乙酯(200mL)溶液中加入三甲基氧鎓四氟硼酸盐(11.34g，0.08mol)。室温搅拌过夜，将反应混合物用水(200mL)和饱和氯化钠溶液(200mL)洗涤，分离出有机相并用无水硫酸钠干燥，过滤。滤液减压浓缩，粗品柱层析纯化(二氧化硅，石油醚:乙酸乙酯＝4:1)得黄色固体状中间体1-3(4.93g，产率46.1％)。To a solution of intermediate 1-2 (10 g, 0.05 mol) in ethyl acetate (200 mL) was added trimethyloxonium tetrafluoroborate (11.34 g, 0.08 mol) at room temperature. Stir at room temperature overnight, wash the reaction mixture with water (200 mL) and saturated sodium chloride solution (200 mL), separate the organic phase, dry over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 4:1) to obtain yellow solid intermediate 1-3 (4.93 g, yield 46.1%).
LCMS(ESI)m/z:212.0[M+H]+。LCMS(ESI)m/z:212.0[M+H] + .
中间体1-4的合成Synthesis of intermediates 1-4
室温下将饱和氯化铵溶液(100mL)和还原铁粉(3.91g，0.07mol)加入中间体1-3(4.93g，0.02mol)的无水乙醇(100mL)溶液中。80℃搅拌过夜。冷却后过滤，滤液减压浓缩，加入乙酸乙酯(100mL)稀释。用水(100mL*2)洗涤，分离出有机相并用无水硫酸钠干燥，过滤。滤液减压浓缩，粗品经柱层析纯化(二氧化硅，石油醚:乙酸乙酯＝1:1)得棕色固体状中间体1-4(3.4g，产率80.9％)。Saturated ammonium chloride solution (100 mL) and reduced iron powder (3.91 g, 0.07 mol) were added to a solution of intermediate 1-3 (4.93 g, 0.02 mol) in absolute ethanol (100 mL) at room temperature. Stir overnight at 80°C. After cooling, filter, and the filtrate was concentrated under reduced pressure, and diluted with ethyl acetate (100 mL). Wash with water (100mL*2), separate the organic phase, dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 1:1) to obtain brown solid intermediate 1-4 (3.4 g, yield 80.9%).
LCMS(ESI)m/z:182.2[M+H]+。LCMS(ESI)m/z:182.2[M+H] + .
中间体1-6的合成 Synthesis of intermediates 1-6
0℃下向中间体1-5(10.0g，0.054mol)的N,N-二甲基甲酰胺(60mL)溶液中加入2-异氰酸-2-甲基丙烷(5.62g，0.057mol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(10.52g，0.069mol)。室温搅拌5小时，0℃下加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(10.52g，0.069mol)和N,N-羰基二咪唑(10.51g，0.065mol)。室温搅拌24小时。用1N HCl调pH至3-4，用乙酸乙酯萃取(200mL*3)，合并有机相，用饱和氯化钠溶液(100mL)洗涤，分离出有机相并且用无水硫酸钠干燥，过滤。滤液减压浓缩，粗品经柱层析纯化(二氧化硅，二氯甲烷:乙酸乙酯＝5:1)得白色固体状中间体1-6(5.23g,产率45.1％)。To a solution of intermediate 1-5 (10.0 g, 0.054 mol) in N,N-dimethylformamide (60 mL) was added 2-isocyanato-2-methylpropane (5.62 g, 0.057 mol) at 0°C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52g, 0.069mol). Stir at room temperature for 5 hours, then add 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52g, 0.069mol) and N,N-carbonyldiimidazole (10.51g, 0.065mol) at 0°C. ). Stir at room temperature for 24 hours. Adjust the pH to 3-4 with 1N HCl, extract with ethyl acetate (200mL*3), combine the organic phases, wash with saturated sodium chloride solution (100mL), separate the organic phase, dry with anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, dichloromethane:ethyl acetate=5:1) to obtain white solid intermediate 1-6 (5.23g, yield 45.1%).
LCMS(ESI)m/z:252.0[M+Na]+。LCMS(ESI)m/z:252.0[M+Na] + .
中间体1-7的合成Synthesis of intermediates 1-7
将1-(溴甲基)-2,4,5-三氟甲苯(8.46g,37.6mmol)加入1-6(5.75g,25.0mmol)，碳酸钾(6.93g,50.0mmol)和乙腈(30mL)混合物中，85℃搅拌16小时。冷却，加入水(100mL)，乙酸乙酯萃取(200mL*3)，合并有机相并用饱和食盐水(100mL)洗涤，经无水硫酸钠干燥，过滤并减压浓缩滤液，粗品经柱层析纯化(二氧化硅，石油醚:乙酸乙酯＝2:1)得白色固体状中间体1-7(8.6g,产率:89％)。Add 1-(bromomethyl)-2,4,5-trifluorotoluene (8.46g, 37.6mmol), 1-6 (5.75g, 25.0mmol), potassium carbonate (6.93g, 50.0mmol) and acetonitrile (30mL ) mixture, stir at 85°C for 16 hours. Cool, add water (100mL), extract with ethyl acetate (200mL*3), combine the organic phases and wash with saturated brine (100mL), dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure, the crude product is purified by column chromatography (Silica, petroleum ether: ethyl acetate = 2:1) White solid intermediate 1-7 (8.6 g, yield: 89%) was obtained.
LCMS(ESI)m/z:318.0[M+H-56]+。LCMS(ESI)m/z:318.0[M+H-56] + .
中间体1-8的合成Synthesis of intermediates 1-8
将中间体1-7(6.7g,17.9mmol)溶于二氯甲烷和三氟乙酸(30/30mL)中，室温搅拌6小时。减压浓缩得白色固体1-8(7.8g)，直接用于下一步反应。Intermediate 1-7 (6.7g, 17.9mmol) was dissolved in dichloromethane and trifluoroacetic acid (30/30mL), and stirred at room temperature for 6 hours. Concentrate under reduced pressure to obtain white solid 1-8 (7.8g), which was directly used in the next reaction.
LCMS(ESI)m/z:318.0[M+H]+。LCMS(ESI)m/z:318.0[M+H] + .
中间体1-9的合成Synthesis of intermediates 1-9
将中间体1-8(160mg,0.5mmol)，吡啶-3-基硼烷二醇(93mg,0.75mmol),醋酸铜(92mg,0.5mmol)，4-二甲氨基吡啶(247mg,2.0mmol),吡啶(100mg,1.2mmol)和二氧六环(10mL)的混合物在氧气球保护下在100℃搅拌16小时。冷却，加入水(30mL)，用乙酸乙酯萃取(3*30mL)，合并有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥，过滤并减压浓缩，粗品经柱层析纯化(二氧化硅，二氯甲烷：甲醇＝20:1)得白色固体状中间体1-9(120mg，产率：40％)。Combine intermediate 1-8 (160mg, 0.5mmol), pyridin-3-ylboranediol (93mg, 0.75mmol), copper acetate (92mg, 0.5mmol), 4-dimethylaminopyridine (247mg, 2.0mmol) , a mixture of pyridine (100 mg, 1.2 mmol) and dioxane (10 mL) was stirred at 100°C for 16 hours under the protection of an oxygen sphere. Cool, add water (30mL), extract with ethyl acetate (3*30mL), wash the combined organic phases with saturated brine (30mL), dry over anhydrous sodium sulfate, filter and concentrate under reduced pressure, and the crude product is purified by column chromatography ( Silica, dichloromethane: methanol = 20:1) to obtain white solid intermediate 1-9 (120 mg, yield: 40%).
LCMS(ESI)m/z:395.0[M+H]+。LCMS(ESI)m/z:395.0[M+H] + .
化合物1(6-((6-氯-2-甲基-2H-吲唑-5-基)氨基)-3-(吡啶-3-基)-1-(2,4,5-三氟苄基)-1,3,5-三嗪-2,4(1H,3H)-二酮)的合成Compound 1(6-((6-chloro-2-methyl-2H-indazol-5-yl)amino)-3-(pyridin-3-yl)-1-(2,4,5-trifluorobenzyl Synthesis of 1,3,5-triazine-2,4(1H,3H)-dione)
0℃下，向中间体1-9(120mg,0.3mmol)的四氢呋喃(20mL)溶液中依次加入六甲基二硅基胺基锂(0.6mmol,0.6mL,1.0M in THF)和中间体1-4(67mg,0.37mmol)。保持0℃搅拌2小时。饱和氯化铵溶液(30mL)淬灭，乙酸乙酯(3*30mL)萃取，合并有机相用饱和食盐水(30mL)洗涤，用无水硫酸钠干燥，过滤并减压浓缩滤液，粗品经高压制备色谱纯化(Gemini-C18 150x 21.2mm，5μm，乙腈-水(0.1％甲酸)，梯度：30％-60％)得白色固体1(14.5mg,产率:9％)。 To a solution of intermediate 1-9 (120 mg, 0.3 mmol) in tetrahydrofuran (20 mL) at 0°C, lithium hexamethyldisilazide (0.6 mmol, 0.6 mL, 1.0 M in THF) and intermediate 1 were added in sequence. -4(67mg,0.37mmol). Keep stirring at 0°C for 2 hours. Quench with saturated ammonium chloride solution (30 mL), extract with ethyl acetate (3*30 mL), wash the combined organic phases with saturated brine (30 mL), dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure, and the crude product is treated with high pressure Preparative chromatography purification (Gemini-C18 150x 21.2 mm, 5 μm, acetonitrile-water (0.1% formic acid), gradient: 30%-60%) gave a white solid 1 (14.5 mg, yield: 9%).
LCMS(ESI)m/z:513.9[M+H]+。LCMS(ESI)m/z:513.9[M+H] + .
1H NMR(400MHz,DMSO-d6,DCl in D2O)δ9.17(d,J＝2.0Hz,1H),9.05(d,J＝5.5Hz,1H),8.77–8.74(m,1H),8.54(s,1H),8.32-8.27(m,1H),7.88–7.82(m,2H),7.64–7.56(m,2H),5.34(s,2H),4.21(s,3H)。 1 H NMR (400MHz, DMSO-d6, DCl in D 2 O) δ9.17 (d, J = 2.0Hz, 1H), 9.05 (d, J = 5.5Hz, 1H), 8.77–8.74 (m, 1H) ,8.54(s,1H),8.32-8.27(m,1H),7.88–7.82(m,2H),7.64–7.56(m,2H),5.34(s,2H),4.21(s,3H).
参考上述实施例A1的方法合成如下表A1的化合物。The compounds in Table A1 below were synthesized with reference to the method of Example A1 above.
表A1


Table A1


实施例A2Example A2
(E)-1-(2-(苄氧基)-4,5-二氟苄基)-6-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-3-((1-甲基-1H-1,2,4-三唑-3-基)甲基)-1,3,5-三嗪-2,4-二酮的合成
(E)-1-(2-(benzyloxy)-4,5-difluorobenzyl)-6-((6-chloro-2-methyl-2H-indazol-5-yl)imino) Synthesis of -3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1,3,5-triazine-2,4-dione
中间体2-2的合成Synthesis of intermediate 2-2
0℃下向中间体2-1(10.0g，0.054mol)的N,N-二甲基甲酰胺(60mL)溶液中加入2-异氰酸-2-甲基丙烷(5.62g，0.057mol)和1,8-二氮杂双环[5.4.0]十一碳-7-烯(10.52g，0.069mol)。室温搅拌5小时，0℃下加入1,8-二氮杂双环[5.4.0]十一碳-7-烯(10.52g，0.069mol)和N,N-羰基二咪唑(10.51g，0.065mol)。室温搅拌24小时。用1N HCl调pH至3-4，用乙酸乙酯萃取(200mL*3)，合并有机相，用饱和氯化钠溶液(100mL)洗涤，有机相经无水硫酸钠干燥，过滤。滤液减压浓缩，粗品经柱层析纯化(二氧化硅，二氯甲烷:乙酸乙酯＝5:1)得白色固体状中间体2-2(5.23g,产率45.1％)。To a solution of intermediate 2-1 (10.0g, 0.054mol) in N,N-dimethylformamide (60mL) was added 2-isocyanato-2-methylpropane (5.62g, 0.057mol) at 0°C. and 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52g, 0.069mol). Stir at room temperature for 5 hours, then add 1,8-diazabicyclo[5.4.0]undec-7-ene (10.52g, 0.069mol) and N,N-carbonyldiimidazole (10.51g, 0.065mol) at 0°C. ). Stir at room temperature for 24 hours. Adjust the pH to 3-4 with 1N HCl, extract with ethyl acetate (200mL*3), combine the organic phases, wash with saturated sodium chloride solution (100mL), dry the organic phase over anhydrous sodium sulfate, and filter. The filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, dichloromethane:ethyl acetate=5:1) to obtain white solid intermediate 2-2 (5.23g, yield 45.1%).
LCMS(ESI)m/z:252.0[M+Na]+。LCMS(ESI)m/z:252.0[M+Na] + .
中间体2-4的合成Synthesis of intermediate 2-4
0℃下，向中间体2-3(10g,0.0884mol)的二氯甲烷(100mL)溶液中滴加氯化亚砜(15.8g,0.133mol)。滴毕，室温搅拌24小时。将混合物减压浓缩得白色固体状中间体2-4(14g)。直接用于下一步反应。Thionyl chloride (15.8g, 0.133mol) was added dropwise to a solution of intermediate 2-3 (10g, 0.0884mol) in dichloromethane (100mL) at 0°C. After the dropping is completed, stir at room temperature for 24 hours. The mixture was concentrated under reduced pressure to obtain intermediate 2-4 (14 g) as a white solid. used directly for the next reaction.
LCMS(ESI)m/z:131.9[M+H]+。 LCMS(ESI)m/z:131.9[M+H] + .
中间体2-6的合成Synthesis of intermediate 2-6
冰浴下将氢氧化钠(34g,085mol)加入中间体2-5(30g，0.17mol)的1,3-二甲基-2-咪唑啉酮(500mL)溶液中。混合溶液在120℃下搅拌16小时。冷却至室温，将半固体溶于水，冰浴下用盐酸调pH至2，过滤得白色固体状中间体2-6(32g，产率：97.0％)。Sodium hydroxide (34g, 085mol) was added to a solution of intermediate 2-5 (30g, 0.17mol) in 1,3-dimethyl-2-imidazolinone (500mL) under ice bath. The mixed solution was stirred at 120°C for 16 hours. Cool to room temperature, dissolve the semi-solid in water, adjust the pH to 2 with hydrochloric acid in an ice bath, and filter to obtain white solid intermediate 2-6 (32 g, yield: 97.0%).
LCMS(ESI)m/z:173.1[M-H]-。LCMS(ESI)m/z:173.1[MH] - .
中间体2-7的合成Synthesis of intermediate 2-7
冰浴下向中间体2-6(32g，0.18mol)的甲醇(300mL)溶液中加入浓硫酸(50mL)。将混合溶液在70℃下回流16小时，减压浓缩，向其中加入水(100mL)，过滤。滤饼干燥得白色固体状中间体2-7(18g,产率：49.4％)。Concentrated sulfuric acid (50 mL) was added to a solution of intermediate 2-6 (32 g, 0.18 mol) in methanol (300 mL) under ice bath. The mixed solution was refluxed at 70° C. for 16 hours, concentrated under reduced pressure, water (100 mL) was added, and filtered. The filter cake was dried to obtain white solid intermediate 2-7 (18g, yield: 49.4%).
1H NMR(400MHz,DMSO-d6)δ10.63(s,1H),7.79-7.66(m,1H),7.15-7.03(m,1H),3.89(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ10.63(s,1H),7.79-7.66(m,1H),7.15-7.03(m,1H),3.89(s,3H).
中间体2-8的合成Synthesis of intermediate 2-8
常温下向中间体2-7(2g，0.01mol)的N,N-二甲基甲酰胺(20mL)溶液中加入碳酸钾(4.4g，0.03mol)和溴化苄(2.18g，0.013mol)。将混合溶液在70℃下搅拌16小时，然后冷却至室温。反应液依次用水(20mL)和饱和氯化钠溶液(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体状中间体2-8(2.4g)，直接用于下一步反应。To a solution of intermediate 2-7 (2g, 0.01mol) in N,N-dimethylformamide (20mL), potassium carbonate (4.4g, 0.03mol) and benzyl bromide (2.18g, 0.013mol) were added at room temperature. . The mixed solution was stirred at 70°C for 16 hours and then cooled to room temperature. The reaction solution was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain white solid intermediate 2-8 (2.4 g), which was directly used Next reaction.
1H NMR(400MHz,DMSO-d6)δ7.73(dd,J＝10.8,9.4Hz,1H),7.62-7.23(m,6H),5.17(s,2H),3.77(dd,J＝6.4,1.0Hz,3H)。 1 H NMR (400MHz, DMSO-d6) δ7.73 (dd, J＝10.8, 9.4Hz, 1H), 7.62-7.23 (m, 6H), 5.17 (s, 2H), 3.77 (dd, J＝6.4, 1.0Hz,3H).
中间体2-9的合成Synthesis of intermediate 2-9
冰浴下向中间体2-8(2.4g，8.6mmol)的四氢呋喃(30mL)溶液中加入四氢铝锂(820mg，21.5mmol)。缓慢升至室温搅拌16小时。混合溶液用水(30mL)淬灭，用乙酸乙酯(50mL*3)萃取，分离出有机相并用无水硫酸钠干燥。过滤，滤液减压浓缩得白色固体状中间体2-9(1.8g)，直接用于下一步反应。Lithium aluminum tetrahydrogen (820 mg, 21.5 mmol) was added to a solution of intermediate 2-8 (2.4 g, 8.6 mmol) in tetrahydrofuran (30 mL) under ice bath. Slowly raise to room temperature and stir for 16 hours. The mixed solution was quenched with water (30 mL), extracted with ethyl acetate (50 mL*3), and the organic phase was separated and dried over anhydrous sodium sulfate. Filter, and the filtrate is concentrated under reduced pressure to obtain white solid intermediate 2-9 (1.8g), which is directly used in the next reaction.
LCMS(ESI)m/z:273.0[M+Na]+。LCMS(ESI)m/z:273.0[M+Na] + .
中间体2-10的合成Synthesis of intermediate 2-10
冰浴下向中间体2-9(500mg，2mmol)的二氯甲烷(10mL)溶液中加入三苯基膦(786mg,3mmol)和N-溴代丁二酰亚胺(534mg，3mmol)。混合溶液0℃下搅拌30分钟。混合溶液加入水(10mL)，二氯甲烷(10mL*3)萃取，合并有机相并用无水硫酸钠干燥。过滤，滤液减压浓缩，粗品经柱层析纯化(二氧化硅，石油醚:乙酸乙酯＝20:1)得白色固体状中间体2-14(600mg，产率：96.1％)。To a solution of intermediate 2-9 (500 mg, 2 mmol) in dichloromethane (10 mL) was added triphenylphosphine (786 mg, 3 mmol) and N-bromosuccinimide (534 mg, 3 mmol) under ice bath. The mixed solution was stirred at 0°C for 30 minutes. Water (10 mL) was added to the mixed solution, and extracted with dichloromethane (10 mL*3). The organic phases were combined and dried over anhydrous sodium sulfate. Filtration, the filtrate was concentrated under reduced pressure, and the crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 20:1) to obtain white solid intermediate 2-14 (600 mg, yield: 96.1%).
1H NMR(400MHz,DMSO-d6)δ7.56(dd,J＝10.9,9.4Hz,1H),7.52-7.43(m,2H),7.43-7.21(m,4H),5.17(s,2H),4.60(s,2H)。 1 H NMR (400MHz, DMSO-d6) δ7.56 (dd, J＝10.9, 9.4Hz, 1H), 7.52-7.43 (m, 2H), 7.43-7.21 (m, 4H), 5.17 (s, 2H) ,4.60(s,2H).
中间体2-11的合成Synthesis of intermediate 2-11
常温下向中间体2-2(528mg，2.31mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入碳酸钾(796mg， 5.76mmol)和中间体2-10(600mg，1.92mmol)，混合溶液室温下搅拌16小时。混合溶液依次用水(20mL)和饱和氯化钠溶液(20mL)洗涤，分离出有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体2-11(700mg)，直接用于下一步反应。To a solution of intermediate 2-2 (528 mg, 2.31 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (796 mg, 5.76mmol) and intermediate 2-10 (600mg, 1.92mmol), and the mixed solution was stirred at room temperature for 16 hours. The mixed solution was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in sequence. The organic phase was separated and dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid 2-11 (700 mg), which was used directly in the next step. reaction.
LCMS(ESI)m/z:461.8[M+H]+。LCMS(ESI)m/z:461.8[M+H] + .
中间体2-12的合成Synthesis of intermediate 2-12
常温下将中间体2-11(600mg，1.3mmol)加入二氯甲烷/三氟乙酸＝1/1(6mL)中，混合溶液在室温下搅拌16小时。冰浴下用碳酸钠溶液将反应液调pH至7。二氯甲烷(10mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体2-12(500mg)，直接用于下一步反应。Intermediate 2-11 (600 mg, 1.3 mmol) was added to dichloromethane/trifluoroacetic acid = 1/1 (6 mL) at room temperature, and the mixed solution was stirred at room temperature for 16 hours. Adjust the pH of the reaction solution to 7 with sodium carbonate solution under ice bath. Extract with dichloromethane (10 mL*3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain white solid 2-12 (500 mg), which is directly used in the next step of the reaction.
LCMS(ESI)m/z:406.0[M+H]+。LCMS(ESI)m/z:406.0[M+H] + .
中间体2-13的合成Synthesis of intermediate 2-13
常温下向中间体2-12(250mg，0.62mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入碳酸钾(426mg，3.08mmol)和2-4(97mg，0.74mmol)。混合溶液在50℃下搅拌16小时。冷却至室温，混合溶液加入乙酸乙酯(50mL)，依次用水(10mL)和饱和氯化钠溶液(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品用柱层析纯化(二氧化硅，石油醚:乙酸乙酯＝2:1)得白色固体2-13(100mg，产率：32.5％)。To a solution of intermediate 2-12 (250 mg, 0.62 mmol) in N,N-dimethylformamide (5 mL) was added potassium carbonate (426 mg, 3.08 mmol) and 2-4 (97 mg, 0.74 mmol) at room temperature. The mixed solution was stirred at 50°C for 16 hours. Cool to room temperature, add ethyl acetate (50 mL) to the mixed solution, wash with water (10 mL) and saturated sodium chloride solution (20 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and use column layer for the crude product Analysis and purification (silica, petroleum ether: ethyl acetate = 2:1) gave white solid 2-13 (100 mg, yield: 32.5%).
LCMS(ESI)m/z:501.2[M+H]+。LCMS(ESI)m/z:501.2[M+H] + .
化合物A21的合成Synthesis of Compound A21
冰浴下向中间体2-13(100mg，0.2mmol)和1-4(45mg，0.24mmol)的四氢呋喃(5mL)溶液中加入双(三甲基硅基)氨基锂(2mL)。0℃下搅拌2小时。混合溶液加入水(10mL)淬灭，乙酸乙酯(10mL*3)萃取，合并有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经高压液相制备色谱纯化(色谱柱:-Gemini-C18 150x 21.2mm，5μm。流动相:ACN-H2O(0.1％FA)。梯度:40-55)得白色固体状化合物21(19.3mg，产率：14.9％)。To a solution of intermediates 2-13 (100 mg, 0.2 mmol) and 1-4 (45 mg, 0.24 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (2 mL) under ice bath. Stir at 0°C for 2 hours. The mixed solution was quenched by adding water (10mL), extracted with ethyl acetate (10mL*3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was purified by high-pressure liquid phase preparative chromatography (chromatography column: - Gemini-C18 150x 21.2 mm, 5 μm. Mobile phase: ACN-H 2 O (0.1% FA). Gradient: 40-55) to obtain compound 21 (19.3 mg, yield: 14.9%) as a white solid.
LCMS(ESI)m/z:620.0[M+H]+。LCMS(ESI)m/z:620.0[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.24(s,1H),7.66(s,1H),7.54-7.16(m,8H),5.26-5.11(m,4H),4.88(s,2H),4.13(s,3H),3.78(s,3H)。 1 H NMR(400MHz,DMSO-d6)δ8.33(s,1H),8.24(s,1H),7.66(s,1H),7.54-7.16(m,8H),5.26-5.11(m,4H) ,4.88(s,2H),4.13(s,3H),3.78(s,3H).
实施例A3Example A3
6-((6-氯-2-甲基-2H-吲唑-5-基)氨基)-1-(3-((3-氯苄基)氧基)-4,5-二氟苄基)-3-((1-甲基-1H-1,2,4-三唑-3-基)甲基)-1,3,5-三嗪-2,4(1H,3H)-二酮的合成
6-((6-chloro-2-methyl-2H-indazol-5-yl)amino)-1-(3-((3-chlorobenzyl)oxy)-4,5-difluorobenzyl )-3-((1-methyl-1H-1,2,4-triazol-3-yl)methyl)-1,3,5-triazine-2,4(1H,3H)-dione Synthesis
中间体3-2的合成Synthesis of intermediate 3-2
常温下向中间体3-1(600mg，2.97mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入碳酸钾(1.2g，8.91mol)和3-氯苄基溴(727mg，3.56mol)。混合溶液在70℃下搅拌16小时。冷却至室温，混合溶液依次用水(20mL)和饱和氯化钠溶液(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体状中间体3-2(700mg)，直接用于下一步反应。To a solution of intermediate 3-1 (600 mg, 2.97 mmol) in N,N-dimethylformamide (10 mL) was added potassium carbonate (1.2 g, 8.91 mol) and 3-chlorobenzyl bromide (727 mg, 3.56 mol). The mixed solution was stirred at 70°C for 16 hours. Cool to room temperature, wash the mixed solution with water (20 mL) and saturated sodium chloride solution (20 mL) in sequence, dry the organic phase with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain white solid intermediate 3-2 (700 mg). used directly for the next reaction.
中间体3-3的合成Synthesis of intermediate 3-3
冰浴下向3-2(500mg，1.53mmol)的四氢呋喃(10mL)溶液中加入四氢铝锂(174mg，4.6mmol)。混合溶液缓慢升至室温并搅拌16小时。用水(20mL)淬灭，乙酸乙酯(20mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体状中间体3-3(400mg)，直接用于下一步反应。To a solution of 3-2 (500 mg, 1.53 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum tetrahydrogen (174 mg, 4.6 mmol) under ice bath. The mixed solution was slowly warmed to room temperature and stirred for 16 hours. Quench with water (20 mL), extract with ethyl acetate (20 mL*3), combine the organic phases and dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain white solid intermediate 3-3 (400 mg), which is used directly in the next step One step reaction.
中间体3-4的合成Synthesis of intermediate 3-4
冰浴下向3-3(200mg，0.7mmol)的二氯甲烷(6mL)溶液中加入三苯基膦(276mg，1.05mmol)和N-溴代丁二酰亚胺(188mg，1.05mmol)。混合溶液0℃下搅拌30分钟。加入水(20mL)，二氯甲烷(20mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体状中间体3-4(220mg)。To a solution of 3-3 (200 mg, 0.7 mmol) in dichloromethane (6 mL) was added triphenylphosphine (276 mg, 1.05 mmol) and N-bromosuccinimide (188 mg, 1.05 mmol) under ice bath. The mixed solution was stirred at 0°C for 30 minutes. Add water (20 mL), extract with dichloromethane (20 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain white solid intermediate 3-4 (220 mg).
1H NMR(400MHz,DMSO-d6)δ7.56(s,1H),7.55-7.26(m,4H),7.26-7.12(m,1H),5.24(d,J＝12.2Hz,2H),4.66(s,2H). 1 H NMR (400MHz, DMSO-d6) δ7.56 (s, 1H), 7.55-7.26 (m, 4H), 7.26-7.12 (m, 1H), 5.24 (d, J = 12.2Hz, 2H), 4.66 (s,2H).
中间体3-5的合成 Synthesis of intermediate 3-5
常温下向2-2(182mg，0.79mmol)的N,N-二甲基甲酰胺(10mL)溶液中加入碳酸钾(263mg，1.91mmol)和中间体3-4(220mg，0.63mmol)，混合溶液在室温下搅拌16小时。混合溶液依次用水(20mL)和饱和氯化钠溶液(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体状中间体3-5(230mg)，直接用于下一步反应。To a solution of 2-2 (182 mg, 0.79 mmol) in N,N-dimethylformamide (10 mL), potassium carbonate (263 mg, 1.91 mmol) and intermediate 3-4 (220 mg, 0.63 mmol) were added at room temperature, and mixed The solution was stirred at room temperature for 16 hours. The mixed solution was washed with water (20 mL) and saturated sodium chloride solution (20 mL) in sequence. The organic phase was dried with anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to obtain white solid intermediate 3-5 (230 mg), which was used directly in the following step. One step reaction.
LCMS(ESI)m/z:496.1[M+H]+。LCMS(ESI)m/z:496.1[M+H] + .
中间体3-6的合成Synthesis of intermediate 3-6
常温下将3-5(230mg，0.46mmol)加入二氯甲烷/三氟乙酸＝1/1(6mL)中，并于室温下搅拌16小时。冰浴下用碳酸钠溶液将反应液pH调至7，二氯甲烷(20mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩得白色固体状中间体3-6(180mg)，直接用于下一步反应。Add 3-5 (230 mg, 0.46 mmol) to dichloromethane/trifluoroacetic acid = 1/1 (6 mL) at room temperature, and stir at room temperature for 16 hours. Adjust the pH of the reaction solution to 7 with sodium carbonate solution under ice bath, extract with dichloromethane (20mL*3), combine the organic phases and dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain white solid intermediate 3-6 (180mg), used directly in the next reaction.
LCMS(ESI)m/z:440.0[M+H]+。LCMS(ESI)m/z:440.0[M+H] + .
中间体3-7的合成Synthesis of intermediate 3-7
冰浴下向3-6(180mg，0.41mmol)的N,N-二甲基甲酰胺(5mL)溶液中加入碳酸钾(283mg，2.05mmol)和中间体2-4(70mg，0.54mmol)，混合溶液在50℃下搅拌16小时。向混合溶液加入乙酸乙酯(50mL),依次用水(10mL)和饱和氯化钠溶液(20mL)洗涤，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品用柱层析纯化(二氧化硅，石油醚：乙酸乙酯＝2:1)得白色固体状中间体3-7(130mg，产率：53.4％)。To a solution of 3-6 (180 mg, 0.41 mmol) in N,N-dimethylformamide (5 mL), potassium carbonate (283 mg, 2.05 mmol) and intermediate 2-4 (70 mg, 0.54 mmol) were added under ice bath. The mixed solution was stirred at 50°C for 16 hours. Ethyl acetate (50 mL) was added to the mixed solution, washed with water (10 mL) and saturated sodium chloride solution (20 mL) in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (silica, petroleum ether: ethyl acetate = 2:1) to obtain white solid intermediate 3-7 (130 mg, yield: 53.4%).
LCMS(ESI)m/z:535.0[M+H]+。LCMS(ESI)m/z:535.0[M+H] + .
化合物A22的合成Synthesis of Compound A22
冰浴下向中间体3-7(100mg，0.18mmol)和中间体1-4(41mg，0.22mmol)的四氢呋喃(5mL)溶液中加入双(三甲基硅基)氨基锂(2mL)。0℃下搅拌2小时。加入水(10mL)，乙酸乙酯(10mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经高压液相制备色谱纯化(色谱柱:-Gemini-C18 150x 21.2mm，5μm。流动相:ACN-H2O(0.1％FA)。梯度:55-65)得白色固体状化合物22(16mg，产率：13％)。To a solution of intermediate 3-7 (100 mg, 0.18 mmol) and intermediate 1-4 (41 mg, 0.22 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (2 mL) under ice bath. Stir at 0°C for 2 hours. Add water (10 mL), extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by high-pressure liquid chromatography (chromatographic column: -Gemini-C18 150x 21.2mm, 5 μm. Mobile phase: ACN-H 2 O (0.1% FA). Gradient: 55-65) to obtain compound 22 (16 mg) as a white solid , yield: 13%).
LCMS(ESI)m/z:653.9[M+H]+。LCMS(ESI)m/z:653.9[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.33–8.19(m,3H),7.70(s,1H),7.41(s,1H),7.17(d,J＝6.8Hz,1H),7.11–7.06(m,1H),5.21(s,4H),4.91(s,2H),4.14(s,3H),3.78(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.33–8.19(m,3H),7.70(s,1H),7.41(s,1H),7.17(d,J＝6.8Hz,1H),7.11–7.06 (m,1H),5.21(s,4H),4.91(s,2H),4.14(s,3H),3.78(s,3H).
参考上述实施例A2和A3的方法合成如下表B的化合物。The compounds in Table B below were synthesized with reference to the methods of Examples A2 and A3 above.
表A2





Table A2





实施例A4化合物61((E)-1-(2-(苄氧基)-4,5-二氟苄基)-6-((6-氯-2-甲基-2H-吲唑-5-基)亚氨基)-3-(吡啶-2-基)-1,3,5-三嗪-2,4-二酮)的合成
Example A4 Compound 61 ((E)-1-(2-(benzyloxy)-4,5-difluorobenzyl)-6-((6-chloro-2-methyl-2H-indazole-5) Synthesis of -yl)imino)-3-(pyridin-2-yl)-1,3,5-triazine-2,4-dione)
中间体4-1的合成Synthesis of intermediate 4-1
将中间体2-12(380mg,0.93mmol)，吡啶-3-基硼烷二醇(230mg,1.87mmol),醋酸铜(560mg,2.8mmol)，4-二甲氨基吡啶(11.4mg,0.09mmol),吡啶(370mg,4.68mmol)，分子筛(380mg)和二氧六环(10mL)的混合物在氧气球保护下在100℃搅拌16小时。冷却，加入水(30mL)，用乙酸乙酯萃取(3*30mL)，合并有机相并用饱和食盐水(30mL)洗涤，用无水硫酸钠干燥，过滤并减压浓缩滤液，粗品经柱层析纯化(二氧化硅，石油醚：乙酸乙酯＝1:1)得白色固体状中间体4-1(200mg，产率：44.2％)。Intermediate 2-12 (380mg, 0.93mmol), pyridin-3-ylboranediol (230mg, 1.87mmol), copper acetate (560mg, 2.8mmol), 4-dimethylaminopyridine (11.4mg, 0.09mmol) ), a mixture of pyridine (370 mg, 4.68 mmol), molecular sieve (380 mg) and dioxane (10 mL) was stirred at 100°C for 16 hours under the protection of an oxygen sphere. Cool, add water (30mL), extract with ethyl acetate (3*30mL), combine the organic phases and wash with saturated brine (30mL), dry over anhydrous sodium sulfate, filter and concentrate the filtrate under reduced pressure, the crude product is subjected to column chromatography Purification (silica, petroleum ether: ethyl acetate = 1:1) yielded white solid intermediate 4-1 (200 mg, yield: 44.2%).
LCMS(ESI)m/z:483.1[M+H]+。LCMS(ESI)m/z:483.1[M+H] + .
化合物A61的合成Synthesis of Compound A61
冰浴下向中间体4-1(200mg，0.36mmol)和中间体1-4(90mg，0.49mmol)的四氢呋喃(5mL)溶液中加入双(三甲基硅基)氨基锂(2mL)。0℃下搅拌2小时。加入水(10mL)，用乙酸乙酯(10mL*3)萃取，合并有机相并用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经高压液相制备色谱纯化(色谱柱:-Gemini-C18 150x 21.2mm，5μm。流动相:ACN-H2O(0.1％FA)。梯度:40-55)得粉色固体状化合物61(38.8mg，产率：14.9％)。To a solution of intermediate 4-1 (200 mg, 0.36 mmol) and intermediate 1-4 (90 mg, 0.49 mmol) in tetrahydrofuran (5 mL) was added lithium bis(trimethylsilyl)amide (2 mL) under ice bath. Stir at 0°C for 2 hours. Add water (10 mL), extract with ethyl acetate (10 mL*3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The crude product was purified by high-pressure liquid chromatography (chromatographic column: -Gemini-C18 150x 21.2mm, 5 μm. Mobile phase: ACN-H 2 O (0.1% FA). Gradient: 40-55) to obtain compound 61 as a pink solid (38.8 mg, yield: 14.9%).
LCMS(ESI)m/z:602.1[M+H]+。LCMS(ESI)m/z:602.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ8.59(s,2H),8.32(s,1H),7.90(d,J＝8.0Hz,1H),7.61–7.54(m,4H),7.43(d,J＝7.2Hz,2H),7.35–7.23(m,4H),5.15(s,4H),4.12(s,3H)。 1 H NMR (400MHz, DMSO-d6) δ8.59 (s, 2H), 8.32 (s, 1H), 7.90 (d, J = 8.0Hz, 1H), 7.61–7.54 (m, 4H), 7.43 (d ,J＝7.2Hz,2H),7.35–7.23(m,4H),5.15(s,4H),4.12(s,3H).
生物学实施例ABiological Example A
hERG钾离子通道的安全性评估Safety assessment of hERG potassium channels
稳定表达hERG离子通道的HEK293细胞株购自Invitrogen公司。该细胞株被培养消化，接种在玻片上以备后续的手动膜片钳的实验。The HEK293 cell line stably expressing hERG ion channel was purchased from Invitrogen. The cell line was cultured, digested, and seeded on glass slides for subsequent manual patch-clamp experiments.
待测化合物用DMSO溶解并配制成终浓度为10mM的储备液。将储备液以DMSO为溶剂以1:3比例梯度稀释成其他三个中间浓度溶液，浓度分别为(mM)：3.33，1.11和0.37。实验开始前，用细胞外液将待测化合物梯度中间溶液再次按1：1000的比例稀释成一系列浓度的工作溶液，其终浓度分别为(M)：10，3.33，1.11和0.37，而30M工作液由10mM储液稀释333.33倍而成。DMSO在工 作溶液中的含量为0.1-0.3％(体积比)。5个不同浓度梯度30，10，3.33，1.11和0.37M的工作溶液用于测定化合物对hERG通道的潜在抑制作用并用以拟合量效曲线和计算IC50。The compound to be tested was dissolved in DMSO and prepared into a stock solution with a final concentration of 10mM. The stock solution was gradiently diluted with DMSO as the solvent at a ratio of 1:3 into three other intermediate concentration solutions, with concentrations (mM): 3.33, 1.11 and 0.37. Before starting the experiment, use extracellular fluid to dilute the intermediate solution of the gradient of the compound to be tested into a series of working solutions with a ratio of 1:1000. The final concentrations are (M): 10, 3.33, 1.11 and 0.37, while the 30M working solution The solution was diluted 333.33 times from the 10mM stock solution. DMSO is working The content in the solution is 0.1-0.3% (volume ratio). Five working solutions with different concentration gradients of 30, 10, 3.33, 1.11 and 0.37M were used to determine the potential inhibitory effect of the compound on hERG channels and to fit the dose-effect curve and calculate IC 50 .
将培养皿中载有HEK293细胞的小玻片放置于显微操作台的灌流槽中。在Olympus IX51，IX71或IX73倒置显微镜下将合适的细胞调置于视野中央，使用×10倍物镜找到玻璃电极的尖端，并置于视野的中央。然后使用微操纵器下移电极，同时调整粗准焦螺旋，使电极慢慢接近细胞。当快接近细胞时，转换为×40倍物镜进行观察，通过微操纵器微调档，使电极逐渐接近细胞的表面。给予负压，使电极尖与细胞膜之间形成电阻高于1G的封接。在电压钳模式下对瞬时电容电流Cfast进行补偿。然后重复给予短促的负压进行破膜，最终形成全细胞记录模式。在膜电位钳制于-60mV的条件下，对缓慢电容电流Cslow，细胞膜电容(Cm)和输入膜电阻(Ra)分别进行补偿。细胞稳定后，将钳制电压改为-90mV，采样频率设置为20kHz，过滤频率为10kHz。漏电流的检测条件为钳制电压转为-80mV，时程500ms。Place the small slide containing HEK293 cells in the culture dish into the perfusion tank of the microscope operating table. Place the appropriate cells in the center of the field of view under an Olympus IX51, IX71 or IX73 inverted microscope, use a ×10x objective lens to find the tip of the glass electrode, and place it in the center of the field of view. Then use the micromanipulator to move the electrode downward, and at the same time adjust the coarse focus screw to make the electrode slowly approach the cells. When approaching the cell, switch to the ×40 objective lens for observation, and fine-tune the gears with the micromanipulator so that the electrode gradually approaches the surface of the cell. Apply negative pressure to form a seal with a resistance higher than 1G between the electrode tip and the cell membrane. Compensates for the instantaneous capacitive current Cfast in voltage clamp mode. Then, short periods of negative pressure are applied repeatedly to rupture the membrane, and finally a whole-cell recording mode is formed. Under the condition that the membrane potential is clamped at -60mV, the slow capacitive current Cslow, cell membrane capacitance (Cm) and input membrane resistance (Ra) are compensated respectively. After the cells stabilize, change the clamping voltage to -90mV, set the sampling frequency to 20kHz, and the filtering frequency to 10kHz. The detection conditions for leakage current are that the clamping voltage changes to -80mV and the time duration is 500ms.
hERG电流测试方法如下：施加4.8秒去极化命令电压将膜电位从-80mV去极化至+30mV，然后瞬间施加5.2秒的复极化电压使膜电位降至-50mV以去除通道失活，从而得以观察到hERG尾电流。尾电流的峰值为hERG电流的大小。The hERG current test method is as follows: apply a depolarization command voltage for 4.8 seconds to depolarize the membrane potential from -80mV to +30mV, and then instantaneously apply a repolarization voltage for 5.2 seconds to reduce the membrane potential to -50mV to remove channel inactivation. This allowed the observation of hERG tail currents. The peak value of the tail current is the magnitude of the hERG current.
用于检测待测化合物的hERG电流在给药前均被持续记录120秒以评估受试细胞产生hERG电流的稳定性。只有在评价标准接受范围以内的稳定细胞才能进入后续化合物检测。The hERG current used to detect the test compound was continuously recorded for 120 seconds before administration to evaluate the stability of the hERG current generated by the test cells. Only stable cells within the acceptance range of the evaluation criteria can enter subsequent compound testing.
待测化合物对hERG电流抑制作用的测试：首先将在含0.1％DMSO的细胞外液中测定得到的hERG电流作为检测基线。在hERG电流保持稳定至少5分钟后将含有待测化合物的溶液从低浓度到高浓度依次灌注于细胞周围。每次灌流结束后等待约5分钟以使化合物充分作用于细胞并同步记录hERG电流。待记录电流趋于稳定后记录最后5个hERG电流值，并取其平均值作为其最终在特定浓度下的电流值。在测试完化合物后，加入150nM多菲莱德至同一个细胞上，将其电流完全抑制，作为该细胞的阳性对照。同时，阳性化合物多菲莱德在测试药实验结束前后用同一膜片钳系统进行同步检测，以确保整个检测系统的可靠性和灵敏性。Test of the inhibitory effect of the compound to be tested on hERG current: First, the hERG current measured in extracellular fluid containing 0.1% DMSO was used as the detection baseline. After the hERG current remains stable for at least 5 minutes, the solution containing the compound to be tested is perfused around the cells sequentially from low concentration to high concentration. Wait about 5 minutes after each perfusion to allow the compound to fully act on the cells and to record hERG current simultaneously. After the recorded current stabilizes, record the last 5 hERG current values, and take their average value as the final current value at a specific concentration. After testing the compound, 150 nM Dophilide was added to the same cell to completely inhibit its current and serve as a positive control for the cell. At the same time, the positive compound Dophilide was detected simultaneously using the same patch clamp system before and after the test drug experiment was completed to ensure the reliability and sensitivity of the entire detection system.
灌注空白溶剂或化合物梯度溶液后，稳定得到的5个连续电流值，求取平均值，分别作为“尾电流大小空白”和“尾电流大小化合物”。After instilling the blank solvent or compound gradient solution, the five continuous current values obtained are stabilized and averaged, which are regarded as "tail current size blank " and "tail current size compound " respectively.
电流抑制百分率通过以下公式进行计算。
The current suppression percentage is calculated using the following formula.
量效曲线通过Graphpad Prism 8.0软件进行拟合并计算IC50值。The dose-response curve was fitted by Graphpad Prism 8.0 software and the IC 50 value was calculated.
表A3
Table A3
口服后雄性CD1小鼠体内的药代动力学实验Pharmacokinetic experiments in male CD1 mice after oral administration
雄性CD1小鼠在给药前禁食过夜，自由饮水，给药4小时后给予饲料。给药剂量10mg/kg，体积10mL/kg，采用口服给药。样品以5％DMSO/95％“10％HP-β-CD in water”配制。Male CD1 mice were fasted overnight before administration and had free access to water, and were given feed 4 hours after administration. The dosage is 10 mg/kg, the volume is 10 mL/kg, and it is administered orally. The sample was prepared with 5% DMSO/95% "10% HP-β-CD in water".
采用足背静脉取血，时间点为0.25、0.5、1、2、4、8和24小时。每次取血30μL，置于含有EDTA-K2的抗凝管中颠倒数次充分混匀。全血样品在4℃，4000g条件下离心5分钟分离血浆。血浆样品分装至干净的聚乙烯微量离心管中，然后置于-75±15℃冰箱保存直至分析。Blood was collected from the dorsal foot vein at 0.25, 0.5, 1, 2, 4, 8 and 24 hours. Take 30 μL of blood each time, place it in an anticoagulant tube containing EDTA-K2, and mix thoroughly by inverting several times. Whole blood samples were centrifuged at 4°C and 4000g for 5 minutes to separate plasma. Plasma samples were aliquoted into clean polyethylene microcentrifuge tubes and stored in a -75 ± 15°C refrigerator until analysis.
应用LC-MS/MS检测方法，对血浆测定结果，将用WinNonlin 8.3(PhoenixTM)或其它类似软件进行药代动力学参数计算。Using the LC-MS/MS detection method, WinNonlin 8.3 (PhoenixTM) or other similar software will be used to calculate pharmacokinetic parameters for plasma measurement results.
表A4本公开的代表性化合物的口服(10mg/kg)药代动力学参数
Table A4 Oral (10 mg/kg) pharmacokinetic parameters of representative compounds of the present disclosure

Claims (68)

  1. 式(I)化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
    Compounds of formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, hydrates or solvates thereof:
    其中，in,
    Y为N或CR7；Y is N or CR 7 ;
    R7选自H、C1-6烷基或C1-6卤代烷基；R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    L1选自化学键、C1-6亚烷基、-NH-、-O-或-S-；L 1 is selected from chemical bond, C 1-6 alkylene, -NH-, -O- or -S-;
    R1选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基、3-10元杂环基、C6-20芳基或5-20元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；所述R1优选为C6-10芳基或5-10元杂芳基；R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
    R1s选自H、氘、CN、NO2、NH2、OH、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、卤代C2-6烯基、C2-6炔基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基或-O-3-8元杂芳基；R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , OH, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 Metaheteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, - NH-3-8-membered heterocyclyl, -NH-3-8-membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 Cycloalkyl, -OC 6-10 aryl, -O-3-8-membered heterocyclyl or -O-3-8-membered heteroaryl;
    或者，同一个碳原子上的两个R1s一起形成氧代或硫代；Alternatively, two R 1s on the same carbon atom together form oxo or sulfo;
    L2选自化学键或C1-6亚烷基；L 2 is selected from chemical bond or C 1-6 alkylene;
    R2选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，优选为C6-10芳基，更优选为苯基，所述R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代；R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
    R2s选自H、D、卤素、CN、-L2a-R’或 R 2s is selected from H, D, halogen, CN, -L 2a -R' or
    L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a为-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
    环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基； Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-10烷基、C1-10烷氧基、C1-10卤代烷基、C1- 10卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6烯基或C2-6炔基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , Boc, C 2-6 alkenyl or C 2-6 alkynyl, or the same Two R's on a carbon atom together form C=O or C=S;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自H、NH2、CN、C0-6亚烷基-C(O)Ra、C0-6亚烷基-C(O)ORa、C1-6亚烷基-OC(O)-Ra、C0-6亚烷基-NHC(O)Ra、C0-6亚烷基-C(O)NRbRc、C1-6烷基、C1-6卤代烷基、C1-6亚烷基-ORa、C2-6烯基或C2-6炔基；R' is selected from H, NH 2 , CN, C 0-6 alkylene-C(O)R a , C 0-6 alkylene-C(O)OR a , C 1-6 alkylene-OC (O)-R a , C 0-6 alkylene-NHC(O)R a , C 0-6 alkylene-C(O)NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 1-6 alkylene-OR a , C 2-6 alkenyl or C 2-6 alkynyl;
    L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
    R3选自C6-14芳基或5-14杂芳基、C3-8环烷基、3至14元杂环基，所述R3任选地被1个、2R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, said R 3 is optionally replaced by 1, 2
    个、3个、4个或5个R3s取代；Replaced by one, three, four or five R 3s ;
    R3s选自H、氘、卤素、CN、NO2、NH2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤代C1- 6烷基、卤代C1-6烷氧基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基、-O-3-8元杂芳基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group , 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH-3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form C=O or C=S;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基、C2-6烯基或C2-6炔基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  2. 权利要求1的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物：
    The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof:
    其中：in:
    Y为N或CR7；Y is N or CR 7 ;
    R7选自H、C1-6烷基或C1-6卤代烷基；R 7 is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    L1选自化学键、C1-6亚烷基、-NH-、-O-或-S-；L 1 is selected from chemical bond, C 1-6 alkylene, -NH-, -O- or -S-;
    R1选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基、3-10元杂环基、C6-20芳基或5-20元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；所述R1优选为C6-10芳基或5-10元杂芳基；R 1 is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-20 aryl or 5-20 membered heteroaryl, the R 1 is optionally substituted by 1, 2 or 3, 4 or 5 R 1s ; the R 1 is preferably C 6- 10 aryl or 5-10 membered heteroaryl;
    R1s选自H、氘、CN、NO2、NH2、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基、卤代C2-6烯基、C2-6炔基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1- 6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O- C1-6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基或-O-3-8元杂芳基；R 1s is selected from H, deuterium, CN, NO 2 , NH 2 , halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2 -6 alkenyl, halogenated C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 2-6 alkynyl, C 6-10 aryl, 3-8 membered heterocyclyl, 3-8 membered hetero Aryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl, -NH- 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -O- C 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3-8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl or -O-3-8 membered heteroaryl;
    L2选自化学键或C1-6亚烷基；L 2 is selected from chemical bond or C 1-6 alkylene;
    R2选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，优选为C6-10芳基，更优选为苯基，所述R2任选地被1个、2个、3个、4个或5个独立选择的R2s取代；R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, preferably C 6-10 aryl, more preferably phenyl, The R 2s are optionally replaced by 1, 2, 3, 4 or 5 independently selected R 2s ;
    R2s选自H、D、卤素、CN、-L2a-R’或 R 2s is selected from H, D, halogen, CN, -L 2a -R' or
    L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a为-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkyne base;
    环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-10烷基、C1-10烷氧基、C1-10卤代烷基、C1-10卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、Boc、C2-6烯基或C2-6炔基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-10 alkyl, C 1-10 alkoxy, C 1-10 haloalkyl, C 1-10 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , Boc, C 2-6 alkenyl or C 2-6 alkynyl, or the same Two R's on a carbon atom together form C=O or C=S;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C2-6烯基或C2-6炔基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 2-6 alkenyl or C 2-6 alkynyl;
    L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
    R3选自C6-14芳基或5-14杂芳基、C3-8环烷基、3至14元杂环基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-14 aryl or 5-14 heteroaryl, C 3-8 cycloalkyl, 3 to 14 membered heterocyclyl, and the R 3 is optionally replaced by 1, 2, or 3 , 4 or 5 R 3s replaced;
    R3s选自H、氘、卤素、CN、NO2、NH2、C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基、卤代C1-6烷基、卤代C1-6烷氧基、卤代C2-6烯基、卤代C2-6炔基、C6-10芳基、3-8元杂环基、3-8元杂芳基、-NH(C1-6烷基)、-N(C1-6烷基)2、-NH-C3-8环烷基、-NH-C6-10芳基、-NH-3-8元杂环基、-NH-3-8元杂芳基、-O-C1- 6烷基、-O-C2-6烯基、-O-C2-6炔基、-O-C3-8环烷基、-O-C6-10芳基、-O-3-8元杂环基、-O-3-8元杂芳基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, deuterium, halogen, CN, NO 2 , NH 2 , C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy group, halogenated C 2-6 alkenyl group, halogenated C 2-6 alkynyl group, C 6-10 aryl group, 3-8 membered heterocyclic group, 3 -8-membered heteroaryl, -NH(C 1-6 alkyl), -N(C 1-6 alkyl) 2 , -NH-C 3-8 cycloalkyl, -NH-C 6-10 aryl , -NH - 3-8 membered heterocyclyl, -NH-3-8 membered heteroaryl, -OC 1-6 alkyl, -OC 2-6 alkenyl, -OC 2-6 alkynyl, -OC 3 -8 cycloalkyl, -OC 6-10 aryl, -O-3-8 membered heterocyclyl, -O-3-8 membered heteroaryl, or two R 3s on the same carbon atom together form C=O or C=S;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基、C2-6烯基或C2-6炔基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    其中各基团定义可任选地被D取代，直至完全氘代。 Each group defined therein may optionally be substituted by D, up to complete deuteration.
  3. 权利要求1或2的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(I’)的结构：
    The compound of claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of the formula ( The structure of I'):
    其中：in:
    Y’为NR7或CR7R8；Y' is NR 7 or CR 7 R 8 ;
    R7和R8独立地选自H、C1-6烷基或C1-6卤代烷基；R 7 and R 8 are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    L3’为-N＝或-CRa＝；L 3 ' is -N= or -CR a =;
    其他各基团如权利要求1中所定义。Each other group is as defined in claim 1.
  4. 权利要求1-3中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(II)、(II’)、(III)、(III’)、(IV)、(IV’)、(V)、(V’)、(VI)、(VI’)、(VII)、(VII’)、(VIII)或(VIII’)的结构：

    The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, It is formula (II), (II'), (III), (III'), (IV), (IV'), (V), (V'), (VI), (VI'), (VII ), (VII'), (VIII) or (VIII') structure:

    其中， in,
    R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a优选-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
    R”选自H、卤素、C1-6卤代烷基或C1-6卤代烷氧基；R” is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
    其他各基团如权利要求1-3中任一项所定义。Each other group is as defined in any one of claims 1-3.
  5. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(II)或(II’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is formula (II) Or the structure of (II'):
    其中：in:
    L1选自化学键或C1-6亚烷基；L 1 is selected from chemical bond or C 1-6 alkylene;
    R1选自C1-6烷氧基、C1-6卤代烷氧基、C6-10芳基或5-10元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代； R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 1, 4 or 5 R 1s are substituted;
    R1s选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# replace;
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
    L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
    L3’为-N＝或-CRa＝；L 3 ' is -N= or -CR a =;
    R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and the R 3 is optionally substituted by 1, 2, 3, 4 or 5 R 3s ;
    R3s选自卤素、C1-6烷基或C1-6烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form C=O or C=S;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  6. 权利要求5的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L1选自化学键或C1-6亚烷基；L 1 is selected from chemical bond or C 1-6 alkylene;
    R1选自C1-6烷氧基、C1-6卤代烷氧基、C6-10芳基或5-10元杂芳基，所述R1任选地被1个、2个或3个、4个或5个R1s取代；R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 1, 4 or 5 R 1s are substituted;
    R1s选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2a和R2b之一为或-L2a-R’，另一个为H或D； One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# replace;
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自H、NH2、CN、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R' is selected from H, NH 2 , CN, C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a , C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
    L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
    L3’为-N＝或-CRa＝；L 3 ' is -N= or -CR a =;
    R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个、3个、4个或5个R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and the R 3 is optionally substituted by 1, 2, 3, 4 or 5 R 3s ;
    R3s选自卤素、C1-6烷基或C1-6烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form C=O or C=S;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  7. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(III)或(III’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (III) Or the structure of (III'):
    其中：in:
    R2a选自或-L2a-R’； R 2a is selected from or -L 2a -R';
    L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或C2-6亚烯基，L2a任选地被1个、2个、3个、4个或5个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene- or C 2-6 alkenylene, L 2a is optionally selected from halogen, C 1- 6 alkyl or C 1-6 haloalkyl substituent substitution;
    环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、OH、NH2、CN、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)-C1-6卤代烷基、C(O)O-C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C( O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl, or the same Two R's on a carbon atom together form C=O or C=S;
    m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
    R’选自NH2、CN、C1-6烷基、C1-6卤代烷基、C(O)-C1-6卤代烷基、C(O)O-C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基；R' is selected from NH 2 , CN, C 1-6 alkyl, C 1-6 haloalkyl, C(O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O) -C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl;
    R2c选自卤素；R 2c is selected from halogen;
    R2d选自卤素或CN；R 2d is selected from halogen or CN;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  8. 权利要求7的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2a选自或-L2a-R’；R 2a is selected from or -L 2a -R';
    L2a选自化学键、-O-、-S-、-C1-6亚烷基-、-C1-6亚烷基-O-、-O-C1-6亚烷基-、-C(O)-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-或C2-6亚烯基，L2a任选地被1个、2个或3个独立地选自卤素或C1-6烷基的取代基取代；L 2a is selected from chemical bonds, -O-, -S-, -C 1-6 alkylene-, -C 1-6 alkylene-O-, -OC 1-6 alkylene-, -C(O )-, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)- or C 2-6 alkenylene, L 2a is optionally replaced by 1, 2 or Substituted with 3 substituents independently selected from halogen or C 1-6 alkyl;
    环A选自C3-8环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-8 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、OH、NH2、CN、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基或NHC(O)-C1-6卤代烷基，或者，同一个碳原子上的两个R一起形成C＝O；Each R is independently selected from H, halogen, OH, NH 2 , CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy or NHC ( O)-C 1-6 haloalkyl, or two R on the same carbon atom together form C=O;
    m为0、1、2、3或4；m is 0, 1, 2, 3 or 4;
    R’选自NH2、CN、C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基；R' is selected from NH 2 , CN, C 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl;
    R2c选自卤素；R 2c is selected from halogen;
    R2d选自卤素或CN；R 2d is selected from halogen or CN;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  9. 权利要求8的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中： The compound of claim 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2a选自或-L2a-R’；R 2a is selected from or -L 2a -R';
    L2a选自化学键、-O-、-S-、-CH2-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)-、-C(O)O-、-NH-、-C(O)NH-、-NH-C(O)-或-CH＝CH-，所述L2a任选地被CH3取代；L 2a is selected from chemical bonds, -O-, -S-, -CH 2 -, -CH 2 -O-, -CH 2 -CH 2 -O-, -O-CH 2 -, -C(O)-, -C(O)O-, -NH-, -C(O)NH-, -NH-C(O)- or -CH=CH-, the L 2a is optionally substituted by CH 3 ;
    选自 Selected from
    R’选自CN、NHC(O)-CF3或CF3；R' is selected from CN, NHC(O)-CF 3 or CF 3 ;
    R2c选自F或Cl，优选为F；R 2c is selected from F or Cl, preferably F;
    R2d选自F、Cl或CN，优选为Cl。R 2d is selected from F, Cl or CN, preferably Cl.
  10. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IV)或(IV’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (IV) Or the structure of (IV'):
    其中：in:
    L2a选自-O-、-S-或-C2-6亚烯基-；L 2a is selected from -O-, -S- or -C 2-6 alkenylene-;
    环A选自C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、OH、NH2、-C(O)-C1-6卤代烷基、-C(O)O-C1-6卤代烷基、-NHC(O)-C1-6卤代烷基、-C(O)NH-C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OH, NH 2 , -C(O)-C 1-6 haloalkyl, -C(O)OC 1-6 haloalkyl, -NHC(O)-C 1-6 haloalkyl, -C(O)NH-C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; or, two R on the same carbon atom together form C =O or C=S;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d选自卤素或CN，优选为Cl。R 2d is selected from halogen or CN, preferably Cl.
  11. 权利要求10的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a选自-O-或-C2-6亚烯基-；L 2a is selected from -O- or -C 2-6 alkenylene-;
    环A选自C5-8环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 5-8 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、OH、NH2、-NHC(O)-C1-6卤代烷基、-C(O)NH-C1-6卤代烷氧基、C1-6烷氧基或C1-6卤代烷氧基；或者，同一个碳原子上的两个R一起形成C＝O；Each R is independently selected from H, halogen, CN, OH, NH 2 , -NHC(O)-C 1-6 haloalkyl, -C(O)NH-C 1-6 haloalkoxy, C 1-6 Alkoxy or C 1-6 haloalkoxy; or, two R on the same carbon atom together form C=O;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d选自卤素或CN，优选为Cl。R 2d is selected from halogen or CN, preferably Cl.
  12. 权利要求11的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a选自-O-或-C2-4亚烯基-；L 2a is selected from -O- or -C 2-4 alkenylene-;
    环A选自C5-6环烷基、5-6元杂环基、苯基或5-10元杂芳基；Ring A is selected from C 5-6 cycloalkyl, 5-6 membered heterocyclyl, phenyl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、-NHC(O)-C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基，优选为H、F、Cl、CN、OCH3、OCF3或-NHC(O)-CF3；或者，同一个碳原子上的两个R一起形成C＝O；Each R is independently selected from H, halogen, CN, -NHC(O)-C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy, preferably H, F, Cl, CN, OCH 3 , OCF 3 or -NHC(O)-CF 3 ; or, two R on the same carbon atom together form C=O;
    m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
    R2c为卤素，优选为F； R 2c is halogen, preferably F;
    R2d选自卤素或CN，优选为Cl。R 2d is selected from halogen or CN, preferably Cl.
  13. 权利要求12的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a选自-O-、-CH＝CH-；L 2a is selected from -O-, -CH=CH-;
    选自 Selected from
    R2c选自F或Cl，优选为F；R 2c is selected from F or Cl, preferably F;
    R2d选自F、Cl或CN，优选为Cl。R 2d is selected from F, Cl or CN, preferably Cl.
  14. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IV)或(IV’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (IV) Or the structure of (IV'):
    其中：in:
    L2a为C2-6亚烯基；L 2a is C 2-6 alkenylene;
    环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    R选自H、卤素或C1-6卤代烷基； R is selected from H, halogen or C 1-6 haloalkyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素，优选为Cl；R 2d is halogen, preferably Cl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  15. 权利要求14的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为C2-4亚烯基，优选为-CH＝CH-；L 2a is C 2-4 alkenylene, preferably -CH=CH-;
    环A选自苯基或5-6元杂芳基，所述5元杂芳基为含有1-2个选自S或N的杂原子的杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl, and the 5-membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from S or N;
    R选自H或卤素，优选为H或F；R is selected from H or halogen, preferably H or F;
    m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素，优选为Cl。R 2d is halogen, preferably Cl.
  16. 权利要求15的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为C2-4烯基，优选为-CH＝CH-；L 2a is C 2-4 alkenyl, preferably -CH=CH-;
    选自优选地，选自 Selected from Preferably, Selected from
    R2c为F；R 2c is F;
    R2d为Cl或F，优选为Cl。R 2d is Cl or F, preferably Cl.
  17. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(V)或(V’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (V) Or the structure of (V'):
    其中： in:
    L2a为-O-或-S-；L 2a is -O- or -S-;
    环A选自或5元杂芳基；Ring A is selected from or 5-membered heteroaryl;
    X2a和X2b独立地选自CR或N；X 2a and X 2b are independently selected from CR or N;
    每个R独立地选自H、卤素、CN、OH、NH2、C1-6烷氧基或C1-6卤代烷氧基，优选为H、卤素、CN、OH或NH2，更优选为H、F、Cl或CN；Each R is independently selected from H, halogen, CN, OH, NH 2 , C 1-6 alkoxy or C 1-6 haloalkoxy, preferably H, halogen, CN, OH or NH 2 , more preferably H, F, Cl or CN;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  18. 权利要求17的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为-O-；L 2a is -O-;
    环A选自或5元杂芳基；Ring A is selected from or 5-membered heteroaryl;
    X2a和X2b独立地选自CR或N；X 2a and X 2b are independently selected from CR or N;
    每个R独立地选自H、卤素、CN或C1-6卤代烷氧基，优选为H、卤素或CN；Each R is independently selected from H, halogen, CN or C 1-6 haloalkoxy, preferably H, halogen or CN;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  19. 权利要求18的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为-O-；L 2a is -O-;
    环A选自或5元杂芳基，所述5元杂芳基为含有1-2个选自S或N的杂原子的杂芳基；Ring A is selected from Or a 5-membered heteroaryl group, the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;
    X2a和X2b独立地选自CR或N；X 2a and X 2b are independently selected from CR or N;
    每个R独立地选自H、卤素、CN或C1-4卤代烷氧基，优选为H、卤素或CN，更优选为H、F、Cl或CN；Each R is independently selected from H, halogen, CN or C 1-4 haloalkoxy, preferably H, halogen or CN, more preferably H, F, Cl or CN;
    m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
    优选地， Preferably,
    选自 优选为 Selected from Preferably
  20. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(V)或(V’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (V) Or the structure of (V'):
    其中，in,
    R2b为或-L2a-R’；R 2b is or -L 2a -R';
    L2a为-C1-6亚烷基-、-C2-6亚烯基-、-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 1-6 alkylene-, -C 2-6 alkenylene-, -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene- SC 0-6 alkylene-;
    环A为C6-10芳基或5-10元杂芳基；Ring A is C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、NH2、OH、CN、C1-6卤代烷基或C1-6卤代烷氧基；Each R is independently selected from H, halogen, NH 2 , OH, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
    R’选自C(O)-C1-6卤代烷基、C(O)O-C1-6卤代烷基、NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基；R' is selected from C(O)-C 1-6 haloalkyl, C(O)OC 1-6 haloalkyl, NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl base;
    R2c为卤素； R 2c is halogen;
    R2d选自卤素或CN；R 2d is selected from halogen or CN;
    m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  21. 权利要求20的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2b为或-L2a-R’；R 2b is or -L 2a -R';
    L2a选自-O-、-S-、-C1-4亚烷基-、-C1-4亚烷基-O-、-O-C1-4亚烷基-、-C1-4亚烷基-S-或-S-C1-4亚烷基-；L 2a is selected from -O-, -S-, -C 1-4 alkylene-, -C 1-4 alkylene-O-, -OC 1-4 alkylene-, -C 1-4 alkylene Alkyl-S- or -SC 1-4 alkylene-;
    环A为苯基或5-6元杂芳基，所述5元杂芳基为含有1-2个选自S或N的杂原子的杂芳基；Ring A is a phenyl group or a 5-6-membered heteroaryl group, and the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from S or N;
    每个R独立地选自H、卤素、CN、C1-4卤代烷基或C1-4卤代烷氧基，优选为H、F、Cl、CN、CF3或OCF3；Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, Cl, CN, CF 3 or OCF 3 ;
    R’选自NHC(O)-C1-6卤代烷基或C(O)NH-C1-6卤代烷基，优选为NHC(O)CF3；R' is selected from NHC(O)-C 1-6 haloalkyl or C(O)NH-C 1-6 haloalkyl, preferably NHC(O)CF 3 ;
    R2c为卤素；R 2c is halogen;
    R2d选自卤素或CN；R 2d is selected from halogen or CN;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  22. 权利要求21的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2b为或-L2a-R’；R 2b is or -L 2a -R';
    L2a为-O-、-S-、-CH2-、-CH2-O-、-CH2-CH2-O-或-O-CH2-；L 2a is -O-, -S-, -CH 2 -, -CH 2 -O-, -CH 2 -CH 2 -O- or -O-CH 2 -;
    选自 Selected from
    R’为NHC(O)CF3；R' is NHC(O)CF 3 ;
    R2c为F；R 2c is F;
    R2d选自F、Cl或CN，优选为Cl。R 2d is selected from F, Cl or CN, preferably Cl.
  23. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(VI)或(VI’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is formula (VI) Or the structure of (VI'):
    其中，in,
    L2a为-O-或-S-；L 2a is -O- or -S-;
    环A为C6-10芳基或5-10元杂芳基；Ring A is C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、C1-6卤代烷基或C1-6卤代烷氧基；Each R is independently selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy;
    m为0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;
    R2c为卤素；R 2c is halogen;
    R2d选自卤素或CN；R 2d is selected from halogen or CN;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  24. 权利要求23的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为-O-；L 2a is -O-;
    环A为苯基；Ring A is phenyl;
    每个R独立地选自H、卤素、C1-4卤代烷基或C1-4卤代烷氧基，优选为H、F、Cl、CF3或OCF3；Each R is independently selected from H, halogen, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably H, F, Cl, CF 3 or OCF 3 ;
    m为0、1、2或3；m is 0, 1, 2 or 3;
    优选地，选自 Preferably, Selected from
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  25. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(VII)或(VII’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is formula (VII) Or the structure of (VII'):
    其中，in,
    L2a为O或S；L 2a is O or S;
    R选自H或卤素；R is selected from H or halogen;
    R”选自H、卤素、C1-6卤代烷基或C1-6卤代烷氧基。R” is selected from H, halogen, C 1-6 haloalkyl or C 1-6 haloalkoxy.
  26. 权利要求25的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a选自-O-；L 2a is selected from -O-;
    R选自H或卤素，优选为H、F或Cl；R is selected from H or halogen, preferably H, F or Cl;
    R”选自H、卤素或C1-4卤代烷氧基，优选为H、F、Cl或OCF3。R” is selected from H, halogen or C 1-4 haloalkoxy, preferably H, F, Cl or OCF 3 .
  27. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(II)或(II’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is formula (II) Or the structure of (II'):
    其中，in,
    L1选自化学键或C1-6亚烷基；L 1 is selected from chemical bond or C 1-6 alkylene;
    R1选自C1-6烷氧基、C1-6卤代烷氧基、C6-10芳基或5-10元杂芳基，所述R1任选地被1个、2个3个、4个或5个独立选择的R1s取代；R 1 is selected from C 1-6 alkoxy, C 1-6 haloalkoxy, C 6-10 aryl or 5-10 membered heteroaryl, and R 1 is optionally replaced by 1, 2 or 3 , 4 or 5 independently selected R 1s substitutions;
    R1s选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1s is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0- 6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；L 2a is selected from chemical bond, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene-, -C 0-6 alkylene -C(O)-C 0- 6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0-6 alkylene-NH-C 0 -6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC(O)-C 0-6 alkylene Alkyl-or-C 2-6 alkenylene-, the L 2a is optionally substituted by 1, 2, 3, 4 or 5 independently selected R#;
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    环A选自C3-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6卤代烷基、C1-6卤代烷氧基或Boc，优选为H、F、Cl、CN、CF3、OCF3或Boc；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 haloalkyl, C 1-6 haloalkoxy or Boc, preferably H, F, Cl, CN, CF 3 , OCF 3 or Boc;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R' is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素，优选为Cl；R 2d is halogen, preferably Cl;
    L3为-NRb-或-CRaRb-；L 3 is -NR b - or -CR a R b -;
    R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个、3个、4个或5个独立选择的R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and said R 3 is optionally substituted by 1, 2, 3, 4 or 5 independently selected R 3s ;
    R3s选自H、卤素、C1-6烷基或C1-6烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O或C＝S；R 3s is selected from H, halogen, C 1-6 alkyl or C 1-6 alkoxy, or two R 3s on the same carbon atom together form C=O or C=S;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  28. 权利要求27的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L1选自化学键或C1-4亚烷基；L 1 is selected from chemical bond or C 1-4 alkylene;
    R1选自C1-4烷氧基或5-6元杂芳基，所述R1任选地被1个、2个或3个独立选择的R1s取代；R 1 is selected from C 1-4 alkoxy or 5-6 membered heteroaryl, and said R 1 is optionally substituted by 1, 2 or 3 independently selected R 1s ;
    R1s选自H、卤素、C1-4烷基或C1-4烷氧基，优选为F、CH3或OCH3； R 1s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, preferably F, CH 3 or OCH 3 ;
    R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-O-、-S-、-C1-4亚烷基-O-、-O-C1-4亚烷基-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)-或C2-4亚烯基，所述L2a任选地被1个、2个或3个独立选择的R#取代；L 2a is selected from chemical bond, -O-, -S-, -C 1-4 alkylene-O-, -OC 1-4 alkylene-, -C(O)O-, -NH-, -C (O)NH-, -NHC(O)-, -C(O)- or C 2-4 alkenylene, the L 2a is optionally substituted by 1, 2 or 3 independently selected R# ;
    R#选自H、C1-4烷基或C1-4卤代烷基；R# is selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
    环A选自C3-6环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-6 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、C1-4卤代烷基、C1-4卤代烷氧基或Boc，优选为H、F、Cl、CN、CF3、OCF3或Boc；Each R is independently selected from H, halogen, CN, C 1-4 haloalkyl, C 1-4 haloalkoxy or Boc, preferably H, F, Cl, CN, CF 3 , OCF 3 or Boc;
    m选自0、1、2或3；m is selected from 0, 1, 2 or 3;
    R’选自C1-4烷基或C1-4卤代烷基；R' is selected from C 1-4 alkyl or C 1-4 haloalkyl;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素，优选为Cl；R 2d is halogen, preferably Cl;
    L3为-NH-；L 3 is -NH-;
    R3选自C6-10芳基或5-10杂芳基，所述R3任选地被1个、2个或3个独立选择的R3s取代；R 3 is selected from C 6-10 aryl or 5-10 heteroaryl, and said R 3 is optionally substituted by 1, 2 or 3 independently selected R 3s ;
    R3s选自H、卤素、C1-4烷基或C1-4烷氧基，或者，同一个碳原子上的两个R3s一起形成C＝O；R 3s is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy, or two R 3s on the same carbon atom together form C=O;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  29. 权利要求28的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L1选自化学键或-CH2-；L 1 is selected from chemical bonds or -CH 2 -;
    R1选自OCH3、 R 1 is selected from OCH 3 ,
    R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、-C(O)-或-CH＝CH-，所述L2a任选地被CH3取代； L 2a is selected from chemical bonds, -O-, -S-, -CH 2 -O-, -CH 2 -CH 2 -O-, -O-CH 2 -, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, the L 2a is optionally substituted by CH 3 ;
    选自 Selected from
    R’选自CHF2或CF3；R' is selected from CHF 2 or CF 3 ;
    R2c选自F；R 2c is selected from F;
    R2d选自F或Cl；R 2d is selected from F or Cl;
    L3为-NH-；L 3 is -NH-;
    R3选自 R 3 is selected from
    L1选自化学键或-CH2-；L 1 is selected from chemical bonds or -CH 2 -;
    R1选自OCH3、 R 1 is selected from OCH 3 ,
    R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-O-、-S-、-CH2-O-、-CH2-CH2-O-、-O-CH2-、-C(O)O-、-NH-、-C(O)NH-、-NHC(O)-、 -C(O)-或-CH＝CH-，所述L2a任选地被CH3取代；L 2a is selected from chemical bonds, -O-, -S-, -CH 2 -O-, -CH 2 -CH 2 -O-, -O-CH 2 -, -C(O)O-, -NH-, -C(O)NH-, -NHC(O)-, -C(O)- or -CH=CH-, the L 2a is optionally substituted by CH 3 ;
    选自 Selected from
    R’选自CHF2或CF3；R' is selected from CHF 2 or CF 3 ;
    R2c选自F；R 2c is selected from F;
    R2d选自F或Cl；R 2d is selected from F or Cl;
    L3为-NH-；L 3 is -NH-;
    R3选自 R 3 is selected from
  30. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(VIII)或(VIII’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is formula (VIII) Or the structure of (VIII'):
    其中：in:
    L2a为O或S；L 2a is O or S;
    R1s选自卤素或C1-6卤代烷氧基；R 1s is selected from halogen or C 1-6 haloalkoxy;
    R选自卤素、CN、C1-6卤代烷基或C1-6卤代烷氧基；R is selected from halogen, CN, C 1-6 haloalkyl or C 1-6 haloalkoxy;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-6烷基，优选为CH3。R 3f is C 1-6 alkyl, preferably CH 3 .
  31. 权利要求30的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为O；L 2a is O;
    R1s选自卤素或C1-4卤代烷氧基，优选为F或OCH3；R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3 ;
    R选自卤素、CN、C1-4卤代烷基或C1-4卤代烷氧基，优选为F、CN、CF3或OCF3；R is selected from halogen, CN, C 1-4 haloalkyl or C 1-4 haloalkoxy, preferably F, CN, CF 3 or OCF 3 ;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-4烷基，优选为CH3。R 3f is C 1-4 alkyl, preferably CH 3 .
  32. 权利要求4的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(VIII)或(VIII’)的结构：
    The compound of claim 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is formula (VIII) Or the structure of (VIII'):
    其中： in:
    L2a为O或S；L 2a is O or S;
    R1s选自卤素或C1-6卤代烷氧基；R 1s is selected from halogen or C 1-6 haloalkoxy;
    R选自卤素或CN；R is selected from halogen or CN;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  33. 权利要求32的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 32, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为O；L 2a is O;
    R1s选自卤素或C1-4卤代烷氧基，优选为F或OCH3；R 1s is selected from halogen or C 1-4 haloalkoxy, preferably F or OCH 3 ;
    R选自卤素或CN，优选为F或CN；R is selected from halogen or CN, preferably F or CN;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-4烷基，优选为CH3。R 3f is C 1-4 alkyl, preferably CH 3 .
  34. 权利要求1-3中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IV)、(IV’)、(V)、(V’)、(IX)、(IX’)、(X)、(X’)、(XI)、(XI’)、(XII)或(XII’)的结构：

    The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, It is formula (IV), (IV'), (V), (V'), (IX), (IX'), (X), (X'), (XI), (XI'), (XII ) or (XII') structure:

    R2a和R2b之一为或-L2a-R’，另一个为H或D；One of R 2a and R 2b is or -L 2a -R', the other is H or D;
    L2a选自化学键、-C1-6亚烷基、-C0-6亚烷基-O-C0-6亚烷基-、-C0-6亚烷基-S-C0-6亚烷基-、-C0-6亚烷基-C(O)-C0-6亚烷基-、-C0-6亚烷基-C(O)O-C0-6亚烷基-、-C0-6亚烷基-NH-C0-6亚烷基-、-C0-6亚烷基-C(O)NH-C0-6亚烷基-、-C0-6亚烷基-NHC(O)-C0-6亚烷基-或-C2-6亚烯基-，所述L2a任选地被1个、2个、3个、4个或5个独立选择的R#取代；所述L2a优选为-O-或-S-；优选地，所述L2a为-O-；优选地，所述L2a优选-S-；L 2a is selected from chemical bond, -C 1-6 alkylene, -C 0-6 alkylene-OC 0-6 alkylene-, -C 0-6 alkylene-SC 0-6 alkylene- , -C 0-6 alkylene-C(O)-C 0-6 alkylene-, -C 0-6 alkylene-C(O)OC 0-6 alkylene-, -C 0- 6 -alkylene-NH-C 0-6 alkylene-, -C 0-6 alkylene-C(O)NH-C 0-6 alkylene-, -C 0-6 alkylene-NHC (O)-C 0-6 alkylene-or-C 2-6 alkenylene-, the L 2a is optionally selected by 1, 2, 3, 4 or 5 independently selected R# Substitution; the L 2a is preferably -O- or -S-; preferably, the L 2a is -O-; preferably, the L 2a is -S-;
    R#选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R# is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    环A选自C3-10环烷基、4-10元杂环基、C6-10芳基或5-10元杂芳基； Ring A is selected from C 3-10 cycloalkyl, 4-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    每个R独立地选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6烷氧基、C1-6卤代烷基、C1-6卤代烷氧基、C(O)Ra、C(O)ORa、NHC(O)Ra、C(O)NH-Ra或Boc，或者，同一个碳原子上的两个R一起形成C＝O或C＝S；Each R is independently selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy , C(O)R a , C(O)OR a , NHC(O)R a , C(O)NH-R a or Boc, or two R on the same carbon atom together form C=O or C=S;
    R2c为卤素，优选为F；R 2c is halogen, preferably F;
    R2d为卤素或CN，优选为Cl；R 2d is halogen or CN, preferably Cl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
    其他各基团如权利要求1-3中任一项所定义。Each other group is as defined in any one of claims 1-3.
  35. 权利要求34的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IV)或(IV’)的结构：
    The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (IV) Or the structure of (IV'):
    其中，in,
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    R选自H、卤素、CN、ORa、NRbRc、C(O)NRbRc、C1-6烷基或C1-6卤代烷基；R is selected from H, halogen, CN, OR a , NR b R c , C(O)NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R2d选自卤素；R 2d is selected from halogen;
    R2c选自卤素；R 2c is selected from halogen;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  36. 权利要求35的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自苯基或5-6元杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl;
    R选自H、卤素、CN、OH、NH2、C(O)NH2或C1-4卤代烷基，优选为H、F、Cl、CN、OH、NH2、C(O)NH2或CF3； R is selected from H, halogen, CN, OH, NH 2 , C(O)NH 2 or C 1-4 haloalkyl, preferably H, F, Cl, CN, OH, NH 2 , C(O)NH 2 or CF 3 ;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R2d选自卤素，优选为Cl或F；R 2d is selected from halogen, preferably Cl or F;
    R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
  37. 权利要求35或36的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 35 or 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为-S-或-O-；L 2a is -S- or -O-;
    选自 Selected from
    R2d选自卤素，优选为Cl或F；R 2d is selected from halogen, preferably Cl or F;
    R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
  38. 权利要求35的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    R选自H、卤素、CN、NH2、C1-6烷基或C1-6卤代烷基；R is selected from H, halogen, CN, NH 2 , C 1-6 alkyl or C 1-6 haloalkyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
    R2c选自卤素，优选为F；R 2c is selected from halogen, preferably F;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  39. 权利要求38的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自苯基或5-6元杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl;
    R选自H、卤素、CN、NH2或C1-4卤代烷基，优选为H、F、Cl、CN、NH2或CF3；R is selected from H, halogen, CN, NH 2 or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 or CF 3 ;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
    R2c选自卤素，优选为F。 R 2c is selected from halogen, preferably F.
  40. 权利要求38或39的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 38 or 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    L2a为-S-或-O-，优选为-S-；L 2a is -S- or -O-, preferably -S-;
    选自 Selected from
    R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
    R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
  41. 权利要求34的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(V)或(V’)的结构：
    The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (V) Or the structure of (V'):
    其中，in,
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或6-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 6-10 membered heteroaryl;
    R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自C0-6亚烷基-OC1-6烷基或C0-6亚烷基-OC1-6卤代烷基；R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
    R2d选自卤素；R 2d is selected from halogen;
    R2c选自卤素；R 2c is selected from halogen;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  42. 权利要求41的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中： The compound of claim 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自4-7元杂环基、苯基或5-6元杂芳基；Ring A is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
    R选自H、卤素、NH2、CN、OH或C1-4卤代烷基，优选为H、F、NH2、CN、OH或CF3；R is selected from H, halogen, NH 2 , CN, OH or C 1-4 haloalkyl, preferably H, F, NH 2 , CN, OH or CF 3 ;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R’为C1-4亚烷基-OC1-4烷基；R' is C 1-4 alkylene-OC 1-4 alkyl;
    R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
    R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
  43. 权利要求41或42的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 41 or 42, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    选自 Selected from
    R’为 R' is
    R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
    R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
  44. 权利要求41的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 41, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或6-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 6-10 membered heteroaryl;
    R选自H、卤素、C0-6亚烷基-NH2、C0-6亚烷基-CN或C0-6亚烷基-OH；R is selected from H, halogen, C 0-6 alkylene-NH 2 , C 0-6 alkylene-CN or C 0-6 alkylene-OH;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自C0-6亚烷基-OC1-6烷基或C0-6亚烷基-OC1-6卤代烷基；R' is selected from C 0-6 alkylene-OC 1-6 alkyl or C 0-6 alkylene-OC 1-6 haloalkyl;
    R2d选自卤素； R 2d is selected from halogen;
    R2c选自卤素；R 2c is selected from halogen;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  45. 权利要求46的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 46, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    环A选自4-7元杂环基、苯基或5-6元杂芳基；Ring A is selected from 4-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl;
    R选自H、卤素、NH2、CN或OH，优选为H、F、NH2、CN或OH；R is selected from H, halogen, NH 2 , CN or OH, preferably H, F, NH 2 , CN or OH;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R’为C1-4亚烷基-OC1-4烷基；R' is C 1-4 alkylene-OC 1-4 alkyl;
    R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
    R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
  46. 权利要求44或45的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 44 or 45, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a选自-S-或-O-；L 2a is selected from -S- or -O-;
    选自 Selected from
    R’为 R' is
    R2d选自卤素，优选为Cl；R 2d is selected from halogen, preferably Cl;
    R2c选自卤素，优选为F。R 2c is selected from halogen, preferably F.
  47. 权利要求34的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(IX)或(IX’)的结构：
    The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (IX) Or the structure of (IX'):
    其中，in,
    R1S选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
    环A选自C6-10芳基或5-10元杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl;
    R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基C2- 6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy C 2-6 Alkenyl or C 2-6 alkynyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-6烷基，优选为CH3；R 3f is C 1-6 alkyl, preferably CH 3 ;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  48. 权利要求47的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S选自H、卤素、C1-4烷基或C1-4烷氧基；R 1S is selected from H, halogen, C 1-4 alkyl or C 1-4 alkoxy;
    L2a为-O-C0-4亚烷基-或-S-C0-4亚烷基-；L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
    环A选自苯基或5-6元杂芳基；Ring A is selected from phenyl or 5-6 membered heteroaryl;
    R选自H、卤素、CN、NH2、OH、C1-4烷基或C1-4卤代烷基，优选为H、F、Cl、CN、NH2、OH、CH3或CF3；R is selected from H, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 , OH, CH 3 or CF 3 ;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
    R3a为卤素，优选为Cl；R 3a is halogen, preferably Cl;
    R3f为C1-4烷基，优选为CH3。 R 3f is C 1-4 alkyl, preferably CH 3 .
  49. 权利要求48的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 48, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S选自H、F、CH3或OCH3；R 1S is selected from H, F, CH 3 or OCH 3 ;
    L2a为-S-或-S-CH2-；L 2a is -S- or -S-CH 2 -;
    选自 Selected from
    R2d选自Cl或CN；R 2d is selected from Cl or CN;
    R2c选自H或F；R 2c is selected from H or F;
    R3a为Cl；R 3a is Cl;
    R3f为CH3。R 3f is CH 3 .
  50. 权利要求34的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(X)或(X’)的结构：
    The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (X) Or the structure of (X'):
    其中，in,
    R1S选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1S is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    L2a为-S-或-O-；L 2a is -S- or -O-;
    环A选自C6-10芳基或5-10元杂芳基，所述5-10元杂芳基为含有1-2个选自O、S或N的杂原子的杂芳基；Ring A is selected from C 6-10 aryl or 5-10 membered heteroaryl, and the 5-10 membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
    R选自H、卤素、CN、NRbRc、ORa、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基； R is selected from H, halogen, CN, NR b R c , OR a , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  51. 权利要求50的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 50, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S选自C1-4烷基或C1-4烷氧基；R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
    L2a为-S-或-O-；L 2a is -S- or -O-;
    环A选自苯基或5-6元杂芳基，所述5-6元杂芳基为含有1-2个选自O、S或N的杂原子的杂芳基；Ring A is selected from phenyl or 5-6-membered heteroaryl, and the 5-6-membered heteroaryl is a heteroaryl containing 1-2 heteroatoms selected from O, S or N;
    R选自H、卤素、CN、NH2、OH、C1-4烷基或C1-4卤代烷基，优选为H、F、Cl、CN、NH2、OH、CH3或CF3；R is selected from H, halogen, CN, NH 2 , OH, C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, Cl, CN, NH 2 , OH, CH 3 or CF 3 ;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R2d选自卤素或CN，优选为Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F。R 2c is selected from H or halogen, preferably H or F, more preferably F.
  52. 权利要求50或51的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 50 or 51, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S选自CH3或OCH3；R 1S is selected from CH 3 or OCH 3 ;
    L2a为-S-或-O-，优选为-S-；L 2a is -S- or -O-, preferably -S-;
    选自 Selected from
    R2d选自Cl或CN；R 2d is selected from Cl or CN;
    R2c选自H或F。 R 2c is selected from H or F.
  53. 权利要求34的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(XI)或(XI’)的结构：
    The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (XI) Or the structure of (XI'):
    其中，in,
    R1S选自H、卤素、C1-6烷基、C1-6卤代烷基、C1-6烷氧基或C1-6卤代烷氧基；R 1S is selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
    环A选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)-Ra、C1-6亚烷基-OC(O)-Ra、C1-6亚烷基-C(O)O-Ra、C1-6亚烷基-C(O)NRbRc或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
    R2d选自卤素或CN；R 2d is selected from halogen or CN;
    R2c选自H或卤素；R 2c is selected from H or halogen;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基；R 3f is C 1-6 alkyl;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  54. 权利要求53的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 53, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S为CH3；R 1S is CH 3 ;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-S-； L 2a is -S-;
    选自 Selected from
    R’选自 R' is selected from
    R2d选自F、Cl或CN；R 2d is selected from F, Cl or CN;
    R2c选自H或F；R 2c is selected from H or F;
    R3a为Cl；R 3a is Cl;
    R3f为CH3。R 3f is CH 3 .
  55. 权利要求34的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其为式(XII)或(XII’)的结构：
    The compound of claim 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, which is of formula (XII) Or the structure of (XII'):
    其中，in,
    R1S选自C1-6烷基或C1-6烷氧基；R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
    环A选自3-8元杂环基、或5元杂芳基，所述5元杂芳基为含有1-2个选自N、O或S的杂原子的杂芳基；Ring A is selected from 3-8 membered heterocyclyl, Or a 5-membered heteroaryl group, the 5-membered heteroaryl group is a heteroaryl group containing 1-2 heteroatoms selected from N, O or S;
    Q1为CH或N； Q 1 is CH or N;
    R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)-Ra、C1-6亚烷基-OC(O)-Ra、C1-6亚烷基-C(O)O-Ra、C1-6亚烷基-C(O)NRbRc或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
    R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  56. 权利要求55的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 55, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S选自C1-4烷基或C1-4烷氧基；R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-O-C0-4亚烷基-或-S-C0-4亚烷基-；L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
    环A选自3-6元杂环基、 Ring A is selected from 3-6 membered heterocyclyl,
    Q1为CH或N；Q 1 is CH or N;
    Q2选自S或NH；Q 2 is selected from S or NH;
    Q3选自CH或N；Q 3 is selected from CH or N;
    Q4、Q5和Q6中的一个为N，另外两个为CH；One of Q 4 , Q 5 and Q 6 is N, and the other two are CH;
    R选自H、卤素、OH、CN、NRbRc、C1-4烷基或C1-4卤代烷基，优选为H、F、OH、CN、NH2、NHCH3、CF3或CH3；R is selected from H, halogen, OH, CN, NR b R c , C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, OH, CN, NH 2 , NHCH 3 , CF 3 or CH 3 ;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)NRbRc或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)NR b R c or C 1-6 alkylene-OR a ;
    R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
    Ra、Rb和Rc独立地选自H、C1-4烷基或C1-4卤代烷基。R a , R b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl.
  57. 权利要求55或56的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 55 or 56, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S为CH3； R 1S is CH 3 ;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-S-；L 2a is -S-;
    选自 Selected from
    R’选自 R' is selected from
    R2d选自F、Cl或CN；R 2d is selected from F, Cl or CN;
    R2c选自H或F。R 2c is selected from H or F.
  58. 权利要求55的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 55, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S选自C1-6烷基或C1-6烷氧基；R 1S is selected from C 1-6 alkyl or C 1-6 alkoxy;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-C0-6亚烷基-O-C0-6亚烷基-或-C0-6亚烷基-S-C0-6亚烷基-；L 2a is -C 0-6 alkylene-OC 0-6 alkylene- or -C 0-6 alkylene-SC 0-6 alkylene-;
    环A选自苯基、噻吩基、吡唑基或噻唑基；Ring A is selected from phenyl, thienyl, pyrazolyl or thiazolyl;
    R选自H、卤素、CN、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基；R is selected from H, halogen, CN, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    m选自0、1、2、3、4或5；m is selected from 0, 1, 2, 3, 4 or 5;
    R’选自C1-6亚烷基-NHC(O)-Ra、C1-6亚烷基-C(O)-Ra、C1-6亚烷基-OC(O)-Ra、C1-6亚烷基-C(O)O-Ra、C1-6亚烷基-C(O)NH2或C1-6亚烷基-ORa；R' is selected from C 1-6 alkylene-NHC(O)-R a , C 1-6 alkylene-C(O)-R a , C 1-6 alkylene-OC(O)-R a , C 1-6 alkylene-C(O)OR a , C 1-6 alkylene-C(O)NH 2 or C 1-6 alkylene-OR a ;
    R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F；R 2c is selected from H or halogen, preferably H or F, more preferably F;
    Ra、Rb和Rc独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中各基团定义可任选地被D取代，直至完全氘代。Each group defined therein may optionally be substituted by D, up to complete deuteration.
  59. 权利要求58的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中： The compound of claim 58, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S选自C1-4烷基或C1-4烷氧基；R 1S is selected from C 1-4 alkyl or C 1-4 alkoxy;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-O-C0-4亚烷基-或-S-C0-4亚烷基-；L 2a is -OC 0-4 alkylene- or -SC 0-4 alkylene-;
    环A选自苯基、噻吩基、 Ring A is selected from phenyl, thienyl,
    R选自H、卤素、CN、NRbRc、C1-4烷基或C1-4卤代烷基，优选为H、F、CN、NH2、NHCH3、CF3或CH3；R is selected from H, halogen, CN, NR b R c , C 1-4 alkyl or C 1-4 haloalkyl, preferably H, F, CN, NH 2 , NHCH 3 , CF 3 or CH 3 ;
    Rb和Rc独立地选自H、C1-4烷基或C1-4卤代烷基；R b and R c are independently selected from H, C 1-4 alkyl or C 1-4 haloalkyl;
    m选自1、2或3；m is selected from 1, 2 or 3;
    R’选自C1-4亚烷基-NHC(O)-C1-4卤代烷基、C1-4亚烷基-C(O)NH2或C1-4亚烷基-O-C1-4烷基；R' is selected from C 1-4 alkylene-NHC(O)-C 1-4 haloalkyl, C 1-4 alkylene-C(O)NH 2 or C 1-4 alkylene-OC 1- 4 alkyl;
    R2d选自卤素或CN，优选为F、Cl或CN，更优选为Cl；R 2d is selected from halogen or CN, preferably F, Cl or CN, more preferably Cl;
    R2c选自H或卤素，优选为H或F，更优选为F。R 2c is selected from H or halogen, preferably H or F, more preferably F.
  60. 权利要求58或59的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中：The compound of claim 58 or 59, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein:
    R1S为CH3；R 1S is CH 3 ;
    R2b选自或-L2a-R’；R 2b is selected from or -L 2a -R';
    L2a为-S-；L 2a is -S-;
    选自 Selected from
    R’选自 R' is selected from
    R2d选自F、Cl或CN；R 2d is selected from F, Cl or CN;
    R2c选自H或F。R 2c is selected from H or F.
  61. 权利要求1的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，所述化合物选自以下：












    The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from Since:












  62. 权利要求1的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，其中，所述化合物选自以下：




    The compound of claim 1, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein the compound is selected from Since:




  63. 药物组合物，其包含权利要求1-62中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，和药学上可接受的载体、佐剂或媒介物，任选地其它治疗剂；Pharmaceutical compositions comprising a compound according to any one of claims 1 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate thereof compounds or solvates, and a pharmaceutically acceptable carrier, adjuvant or vehicle, optionally other therapeutic agents;
    优选地，所述其它治疗剂选自：瑞德西韦(Remdesivir或GS-5734)、洛匹那韦(Lopinavir)、莫努匹韦(Molnupiravir)、利托那韦(Ritonavir)、氯喹(Chloroquine或Sigma-C6628)、羟氯喹或α-干扰素。 Preferably, the other therapeutic agent is selected from: Remdesivir (Remdesivir or GS-5734), Lopinavir, Molnupiravir, Ritonavir, Chloroquine or Sigma-C6628), hydroxychloroquine or alpha-interferon.
  64. 权利要求1-62中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，或权利要求63的药物组合物在制备用于治疗或预防病毒感染导致的疾病的药物中的用途。The compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, Or the use of the pharmaceutical composition of claim 63 in the preparation of medicaments for treating or preventing diseases caused by viral infections.
  65. 一种在受试者中治疗或预防病毒感染导致的疾病的方法，包括向所述受试者给药权利要求1-62中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，或权利要求63的药物组合物。A method for treating or preventing diseases caused by viral infection in a subject, comprising administering to the subject a compound according to any one of claims 1-62, or a pharmaceutically acceptable salt or isotope change thereof. isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, or the pharmaceutical composition of claim 63.
  66. 权利要求1-62中任一项的化合物，或其药学上可接受的盐、同位素变体、互变异构体、立体异构体、前药、多晶型、水合物或溶剂合物，或权利要求63的药物组合物，其用于治疗或预防病毒感染导致的疾病。The compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, Or the pharmaceutical composition of claim 63, which is used to treat or prevent diseases caused by viral infection.
  67. 权利要求64的用途或权利要求65的方法或权利要求66的化合物或药物组合物的用途，其中，所述化合物或药物组合物抑制病毒增殖；The use of claim 64 or the method of claim 65 or the use of a compound or pharmaceutical composition of claim 66, wherein the compound or pharmaceutical composition inhibits viral proliferation;
    优选地，所述化合物或药物组合物抑制病毒3CL蛋白酶的活性；Preferably, the compound or pharmaceutical composition inhibits the activity of viral 3CL protease;
    优选地，所述3CL蛋白酶具有P132H突变；Preferably, the 3CL protease has a P132H mutation;
    优选地，所述病毒为冠状病毒，优选为α冠状病毒和/或β冠状病毒，更优选为SARS-CoV-2。Preferably, the virus is a coronavirus, preferably alphacoronavirus and/or betacoronavirus, more preferably SARS-CoV-2.
  68. 权利要求64的用途或权利要求65的方法或权利要求66的化合物或药物组合物的用途，其中，所述病毒感染导致的疾病选自：发热、恶心、呕吐、头痛、呼吸困难、乏力、呼吸道感染、肺炎、嗅觉障碍、味觉障碍及其并发症，或其组合。 The use of claim 64 or the method of claim 65 or the compound or pharmaceutical composition of claim 66, wherein the disease caused by the viral infection is selected from: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract Infection, pneumonia, anosmia, taste disorder, their complications, or combinations thereof.
PCT/CN2023/096597 2022-05-27 2023-05-26 3c-like protease inhibitor WO2023227118A1 (en)

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