WO2023227117A1 - 3c-like protease inhibitor - Google Patents

3c-like protease inhibitor Download PDF

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Publication number
WO2023227117A1
WO2023227117A1 PCT/CN2023/096587 CN2023096587W WO2023227117A1 WO 2023227117 A1 WO2023227117 A1 WO 2023227117A1 CN 2023096587 W CN2023096587 W CN 2023096587W WO 2023227117 A1 WO2023227117 A1 WO 2023227117A1
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alkyl
haloalkyl
halogen
cycloalkyl
membered heterocyclyl
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PCT/CN2023/096587
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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
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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 WO2023227117A1 publication Critical patent/WO2023227117A1/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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

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. For example, when a patient takes 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 arrhythmias. .
  • 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
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 1s is -C(O)NR 1b R 1c or
  • L 1a is selected from chemical bond, O, S or NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a 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 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
  • R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • n 3 is 0, 1, 2 or 3;
  • L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
  • R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 0, 1 or 2;
  • R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
  • R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
  • R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
  • R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R 3s or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
  • R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
  • Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
  • each of the above defined groups is optionally deuterated until completely deuterated;
  • 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 1-6 alkyl refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, 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 ).
  • 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 ), hexyne base (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 1-6 alkoxy refers to -OC 1-6 alkyl. In some embodiments, C 1-4 alkyl is preferred. In other embodiments, C 1-3 alkoxy is preferred, for example, methoxy, ethoxy, etc.
  • Halo or "halogen” refers to fluorine (F), chlorine (Cl), bromine (Br) and iodine (I).
  • C 1-6 haloalkyl refers to the above-mentioned “C 1-6 alkyl” which is substituted by one or more halogen groups.
  • C 1-4 haloalkyl is particularly preferred, more preferably C 1-3 haloalkyl, more preferably C 1-2 haloalkyl.
  • 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.
  • C 1-4 haloalkoxy is preferred, for example, halomethoxy (eg, OCH 2 F, OCHF 2 or OCF 3 ), haloethoxy, and the like.
  • C 3-10 cycloalkyl refers to a non-aromatic cyclic hydrocarbon group 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, more C 5-7 cycloalkyl and C 5-6 cycloalkyl are preferred.
  • 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.
  • a cycloalkyl group may
  • 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.
  • 3-10 membered heterocyclyl refers to a saturated or unsaturated group of 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 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.
  • 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered is preferred Heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably 5-7-membered heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms.
  • 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 5-membered heterocyclyl fused to a C6 aryl ring include, but are 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 6-10 aryl refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having a Shared 6 or 10 ⁇ electrons) group.
  • 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.
  • 5-10 membered heteroaryl refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 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.
  • 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 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, benzofuryl, benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzene Thiadiazolyl, indazinyl 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 R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocycle or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;
  • 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, Methanesulfonate, glucoheptonate, lactobionate, lauryl 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 covered are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge S.M. 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 human.
  • the subject is a non-human animal.
  • the terms "person,”"patient,” and “subject” are used interchangeably herein.
  • 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.
  • the "compounds of the present invention” refer to compounds of the following formula (I), formula (II), formula (III-1), formula (III-2) and formula (III-3), which pharmaceutically acceptable Accepted salts, isotopic variants, tautomers, stereoisomers, prodrugs, 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
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 1s is -C(O)NR 1b R 1c or
  • L 1a is selected from chemical bond, O, S or NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a 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 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
  • R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • n 3 is 0, 1, 2 or 3;
  • L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
  • R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 0, 1 or 2;
  • R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
  • R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
  • R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
  • R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R 3s or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
  • R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
  • Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
  • each of the above defined groups is optionally deuterated until completely deuterated;
  • Y is CR7 , such as CH; in another embodiment, Y is N.
  • R 7 is H; in another embodiment, R 7 is C 1-6 alkyl; in another embodiment, R 7 is C 1-6 haloalkyl.
  • Ring A is C 3-10 cycloalkyl; in another embodiment, Ring A is 3-10 membered heterocyclyl; in another embodiment, Ring A is C 6-10 aromatic group, such as phenyl; in another embodiment, ring A is a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group, such as pyridyl, such as thiazolyl, such as For example
  • ring A is a C 6-10 aryl group or a 5-10 membered heteroaryl group; in another more specific embodiment, ring A is a phenyl group or a 5-6 membered heteroaryl group; In another more specific embodiment, Ring A is a 5-6 membered heteroaryl; in another more specific embodiment, Ring A is pyridyl or thiazolyl; in another more specific embodiment, Ring A is pyridyl; in another more specific embodiment, Ring A is In a more specific embodiment, Ring A is
  • Ring A and R 1s consist of In another specific embodiment, Ring A and R 1s consist of
  • R 1s is For example For example More specifically, e.g. For example For example For example, For example For example, For example For example, For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For
  • R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is not
  • R 1s is selected from Preferably Preferably
  • R 1s is selected from: Preferably selected from: Preferably, for Preferably, for Preferably, for Preferably, for
  • R 1s is selected from: Preferably: Preferably Preferably, for
  • R 1s is selected from: Preferably Preferably Preferably Preferably, for
  • L 1a is O; in another embodiment, L 1a is S; in another embodiment, L 1a is NR 5a , such as NH, such as NMe; in another embodiment, L 1a is a chemical bond.
  • L 1a is selected from O, S, NH or NMe; in another more specific embodiment, L 1a is selected from O, S or NH; in another more specific embodiment , L 1a is O or NH; in another more specific embodiment, L 1a is O or S; in another more specific embodiment, L 1a is selected from O, S, NR 5a .
  • L 1b is a chemical bond; in another embodiment, L 1b is O; in another embodiment, L 1b is S; in another embodiment, L 1b is NR 5b , such as NH , such as NMe.
  • L 1b is selected from O, S or NR 5b ; in another more specific embodiment, L 1b is selected from O or NR 5b ; in another more specific embodiment, L 1b is selected from O, S or NMe; in another more specific embodiment, L 1b is selected from O or S; in another more specific embodiment, L 1b is selected from O or NMe; in another more specific embodiment In the embodiment of , L 1b is selected from O, S or NR 5b .
  • R 1a is C 1-6 alkyl, such as Me; in another embodiment, R 1a is C 1-6 haloalkyl; in another embodiment, R 1a is C 3-10 Cycloalkyl, such as C 3-7 cycloalkyl, such as C 3-5 cycloalkyl, such as cyclopropyl; in another embodiment, R 1a is 3-10 membered heterocyclyl, such as 3-7 membered Heterocyclyl, such as 3-5 membered heterocyclyl, such as 4-6 membered heterocyclyl, such as Such as 4-5 membered heterocyclyl, for example For example For example, a 5-membered heterocyclyl group, such as For example In another embodiment, R 1a is a C 6-10 aryl group, such as phenyl; in another embodiment, R 1a is a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group, such as For example For example For example For example For example For example For example For example For
  • R 1a is unsubstituted; in another embodiment, R 1a is substituted with 1 R 1as ; in another embodiment, R 1a is substituted with 2 R 1as ; in another embodiment , R 1a is replaced by 3 R 1as .
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific implementation In this way, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1a is selected from From C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl group, C 1-6 haloalkyl or C 3-5 cycloalkyl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment In an embodiment, R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific implementation
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl , 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another In a more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alk
  • R 1as is H; in another embodiment, R 1as is D; in another embodiment, R 1as is halogen, such as F; in another embodiment, R 1as is cyano. ; In another embodiment, R 1as is C 1-6 alkyl, such as Me; In another embodiment, R 1as is C 1-6 haloalkyl; In another embodiment, R 1as is -L 1c -OR a , preferably OR a ; in another embodiment, R 1as is -L 1c -SR a , preferably SR a ; in another embodiment, R 1as is -L 1c -NR b R c , preferably NR b R c , such as NH 2 , such as -NHCH 3 , such as -NH(CH 3 ) 2 ; in another embodiment, R 1as is C 3-10 cycloalkyl, such as C 3-7 ring Alkyl; in another embodiment, R 1as is a
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl group, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, C 1- 6 alkyl or C 1-6 haloalkyl; in another more specific embodiment
  • R 1as is independently selected from H, D, halogen, cyano, OR a , NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 Alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3 -7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; In another more specific embodiment, R 1as is independently selected from H, D, halogen, OR a ,
  • n 1 is 0; in another embodiment, n 1 is 1; in another embodiment, n 1 is 2; in another embodiment, n 1 is 3; in another In one embodiment, n 1 is 4; in another embodiment, n 1 is 5; in another embodiment, n 1 is 6.
  • n2 is 0; in another embodiment, n2 is 1; in another embodiment, n2 is 2; in another embodiment, n2 is 3; in another In one embodiment, n 2 is 4; in another embodiment, n 2 is 5; in another embodiment, n 2 is 6.
  • n 1 is selected from 0, 1, 2 or 3; in another more specific embodiment, n 1 is selected from 0, 1 or 2; in another more specific embodiment , n 1 is selected from 1, 2 or 3.
  • n 2 is selected from 0, 1, 2 or 3; in another more specific embodiment, n 2 is selected from 0 or 1; in another more specific embodiment, n 2 is 0, 1 or 2.
  • R 5a is H; in another embodiment, R 5a is C 1-6 alkyl, such as C 1-3 alkyl, such as Me; in another embodiment, R 5a is C 1-6 haloalkyl, such as C 1-3 haloalkyl.
  • R 5b is H; in another embodiment, R 5b is C 1-6 alkyl, such as C 1-3 alkyl, such as Me; in another embodiment, R 5b is C 1-6 haloalkyl, such as C 1-3 haloalkyl.
  • R 5a is H or Me.
  • R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-3 alkyl or C 1-3 haloalkyl.
  • R 1b is H; in another embodiment, R 1b is C 1-6 alkyl, such as Me; in another embodiment, R 1b is C 1-6 haloalkyl.
  • R 1c is H; in another embodiment, R 1c is C 1-6 alkyl, such as Me; in another embodiment, R 1c is C 1-6 haloalkyl; in another In one embodiment, R 1c is C 3-10 cycloalkyl; in another embodiment, R 1c is 3-10 membered heterocyclyl; in another embodiment, R 1c is C 6-10 aryl ; In another embodiment, R 1c is 5-10 membered heteroaryl.
  • R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment In an embodiment, R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 1c is selected from C 1-6 alkyl or C 1-6 Haloalkyl.
  • R' 1s is H; in another embodiment, R' 1s is D; in another embodiment, R' 1s is halogen; in another embodiment, R' 1s is cyanide group; in another embodiment, R' 1s is -L 1d -OR a , preferably OR a ; in another embodiment, R' 1s is -L 1d -SR a , preferably SR a ; in another embodiment In one embodiment, R' 1s is -L 1d -NR b R c , preferably NR b R c ; in another embodiment, R' 1s is C 1-6 alkyl; in another embodiment, R' 1s is C 1-6 haloalkyl; in another embodiment, R' 1s is C 3-10 cycloalkyl; in another embodiment, R' 1s is 3-10 membered heterocyclyl.
  • R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; In another more specific embodiment, R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
  • n 3 is 0; in another embodiment, n 3 is 1; in another embodiment, n 3 is 2; in another embodiment, n 3 is 3.
  • n 3 is 0 or 1; in another more specific embodiment, n 3 is 0.
  • L 2 is -(CR 4a R 4b ) m1 -, such as CR 4a R 4b , such as methylene; in another embodiment, L 2 is O; in another embodiment, L 2 is S; in another embodiment, L 2 is NR 4c .
  • R 4a is H; in another embodiment, R 4a is D; in another embodiment, R 4a is C 1-6 alkyl; in another embodiment, R 4a is C 1-6 haloalkyl.
  • R 4b is H; in another embodiment, R 4b is D; in another embodiment, R 4b is C 1-6 alkyl; in another embodiment, R 4b is C 1-6 haloalkyl.
  • m 1 is 0; in another embodiment, m 1 is 1; in another embodiment, m 1 is 2.
  • R 4c is H; in another embodiment, R 4c is C 1-6 alkyl; in another embodiment, R 4c is C 1-6 haloalkyl.
  • 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, such as phenyl; in another embodiment, R 2 is a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group.
  • R 2 is unsubstituted; in another embodiment, R 2 is substituted with 1 R 2s ; in another embodiment, R 2 is substituted with 2 R 2s ; in another embodiment , R 2 is replaced by 3 R 2s ; in another embodiment, R 2 is replaced by 4 R 2s ; in another embodiment, R 2 is replaced by 5 R 2s ; in another embodiment, R 2 for For example
  • R 2 for example For example
  • For example For example
  • R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 2 is phenyl or 5-6 membered heteroaryl; in another more specific embodiment, R 2 is selected from In another more specific embodiment, R is selected from In another more specific embodiment, R is selected from In another more specific embodiment, R is selected from
  • R 2 is optionally substituted with 1, 2, 3 or 4 R 2s ; in another more specific embodiment, R 2 is optionally substituted with 2 or 3 R 2s .
  • R 2s is H; in another embodiment, R 2s is D; in another embodiment, R 2s is halogen, such as F, such as Cl; in another embodiment, R 2s is cyano; in another embodiment, R 2s is -L 2a -OR a , preferably OR a ; in another embodiment, R 2s is -L 2a -SR a , preferably SR a ; in another embodiment In one embodiment, R 2s is -L 2a -NR b R c , preferably NR b R c ; in another embodiment, R 2s is C 1-6 alkyl, such as Me; in another embodiment , R 2s is C 1-6 haloalkyl; in another embodiment, R 2s is C 3-10 cycloalkyl; in another embodiment, R 2s is 3-10 membered heterocyclyl; in another In one embodiment, R 2s is C 1-6 alkoxy, such as OMe; in another embodiment, R 2s is C 1-6 halo
  • R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered Heterocyclyl; in another more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2s is independently selected from H, F, Cl , CN, Me , CHF 2 or CF 3 ; in another more specific embodiment, R 2s is independently selected from H, F, Cl, CN or Me.
  • R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or In another more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1- 4 haloalkoxy.
  • R 2s is independently R 2a , R 2b , R 2c or R 2d .
  • R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; in In another more specific embodiment, R 2a is selected from H, D, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; in In another more specific embodiment, R 2a is selected from halogen, C 1-4 alkyl or C 1-4 alkoxy; in another more specific embodiment, R 2a is selected from H, F, Me, CF 3 , OMe or OCHF 2 ; in another more specific embodiment, R 2a is selected from F, Me or OMe; in another more specific embodiment, R 2a is selected from H, D, halogen, C 1 -6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2a is selected from H, D, halogen, C 1-4
  • R 2b is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2b is selected from H, D Or halogen; in another more specific embodiment, R 2b is selected from H or F; in another more specific embodiment, R 2b is selected from H, D, halogen, C 1-4 alkyl or C 1 -4 haloalkyl; in another more specific embodiment, R 2b is selected from H, F or Me; in another more specific embodiment, R 2b is selected from H or D; preferably in another more specific embodiment In an embodiment, R 2b is H; in another more specific embodiment, R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl; in another more specific embodiment , R 2b is selected from H or Me.
  • R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2c is selected from H, D Or halogen; in another more specific embodiment, R 2c is selected from H, F or Cl; in another more specific embodiment, R 2c is selected from H or F; in another more specific embodiment, R 2c is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl; in another more specific embodiment, R 2c is selected from H, F or Cl; in another more specific embodiment In an embodiment, R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2c is halogen; in another more specific embodiment, R 2c is F.
  • R 2d is selected from H, D, halogen or cyano; in another more specific embodiment, R 2d is halogen or cyano; in another more specific embodiment in, R 2d is F, Cl or CN; in another more specific embodiment In, R 2d is Cl or CN; in another more specific embodiment, R 2d is F or CN.
  • L 3 is a chemical bond; in another embodiment, L 3 is CR 6a R 6b ; in another embodiment, L 3 is O; in another embodiment, L 3 is S; In another embodiment, L3 is NR6c , such as NH.
  • R 6a is H; in another embodiment, R 6a is D; in another embodiment, R 6a is C 1-6 alkyl; in another embodiment, R 6a is C 1-6 haloalkyl.
  • R 6b is H; in another embodiment, R 6b is D; in another embodiment, R 6b is C 1-6 alkyl; in another embodiment, R 6b is C 1-6 haloalkyl.
  • R 6c is H; in another embodiment, R 6c is C 1-6 alkyl; in another embodiment, R 6c is C 1-6 haloalkyl.
  • R 3 is C 3-10 cycloalkyl; in another embodiment, R 3 is 3-10 membered heterocyclyl; in another embodiment, R 3 is C 6-10 aromatic group, such as phenyl, such as For example In another embodiment, R3 is 5-10 membered heteroaryl, such as For example
  • R 3 is unsubstituted; in another embodiment, R 3 is substituted with 1 R 3s ; in another embodiment, R 3 is substituted with 2 R 3s ; in another embodiment , R 3 is substituted with 3 R 3s ; in another embodiment, R 3 is substituted with 4 R 3s ; in another embodiment, R 3 is substituted with 5 R 3s .
  • R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 3 is selected from
  • R 3s is H; in another embodiment, R 3s is D; in another embodiment, R 3s is halogen, such as Cl; in another embodiment, R 3s is cyano. ; In another embodiment, R 3s is -L 3a -OR a , preferably OR a , such as OMe; in another embodiment, R 3s is -L 3a -SR a , preferably SR a ; in another embodiment In one embodiment, R 3s is -L 3a -NR b R c , preferably NR b R c ; in another embodiment, R 3s is C 1-6 alkyl; in another embodiment, R 3s is C 1-6 haloalkyl; in another embodiment, R 3s is C 3-10 cycloalkyl; in another embodiment, R 3s is 3-10 membered heterocyclyl; in another embodiment , two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl group, such as C
  • the ring group formed by two adjacent R 3s and the atoms to which they are connected is unsubstituted; in another embodiment, the ring group formed by two adjacent R 3s and the atoms to which they are connected together is unsubstituted.
  • the group is replaced by 1 R 3ss ; in another embodiment, the ring group formed by two adjacent R 3s and the atoms they are connected to is replaced by 2 R 3ss ; in another embodiment, two adjacent R 3ss
  • the ring group formed by the R 3s and the atoms to which they are connected is replaced by 3 R 3ss .
  • R 3s is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3- 10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3s is selected from H, D, halogen, OR a , SR a , NR b R c , C 1-6 alkyl Or C 1-6 haloalkyl; in another more specific embodiment, R 3s is selected from H, D, halogen, OR a , C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment In an embodiment, R 3s is selected from H, D, Cl, OMe or Me; in another more specific embodiment, R 3s is Cl or Me.
  • two adjacent R 3s and the atoms to which they are connected together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; In another more specific embodiment, two adjacent R 3s and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group; in another more specific embodiment, Two adjacent R 3s and the atoms to which they are connected together form pyrazolyl or dihydrofuranyl; in another more specific embodiment, two adjacent R 3s and the atoms to which they are connected together form
  • R 3ss is H; in another embodiment, R 3ss is D; in another embodiment, R 3ss is halogen; in another embodiment, R 3ss is cyano; in another In one embodiment, R 3ss is -L 3b -OR a , preferably OR a ; in another embodiment, R 3ss is -L 3b -SR a , preferably SR a ; in another embodiment, R 3ss is -L 3b -NR b R c , preferably NR b R c ; in another embodiment, R 3ss is C 1-6 alkyl, such as Me; in another embodiment, R 3ss is C 1-6 haloalkyl base; on another In one embodiment, R 3ss is C 3-10 cycloalkyl; in another embodiment, R 3ss is 3-10 membered heterocyclyl; in another embodiment, R 3ss is C 3-10 aryl; In another embodiment, R 3ss is 3-10 membered heteroaryl
  • R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3ss is independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ; In another more specific embodiment, R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
  • L 1c , L 1d , L 2a , L 3a and L 3b are independently chemical bonds; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently C 1-6 alkylene, such as C 1-3 alkylene; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently C 2-6 alkenylene; in another In one embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently C 2-6 alkynylene; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b is independently unsubstituted; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkyny
  • each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from a chemical bond or a C 1-6 alkylene group, which is optionally selected from 1, 2 or 3 H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl group substitution.
  • Ra , Rb , and Rc are independently H; in another embodiment, Ra , Rb, and Rc are independently C 1-6 alkyl, such as Me; in another In one embodiment, R a , R b and R c are independently C 1-6 haloalkyl; in another embodiment, R a , R b and R c are independently C 3-10 cycloalkyl, such as C 3-7 cycloalkyl; in another embodiment, R a , R b and R c are independently 3-10 membered heterocyclyl, such as 3-7 membered heterocyclyl; in another embodiment, R a , R b and R c are independently C 6-10 aryl; in another embodiment, Ra , R b and R c are independently 5-10 membered heteroaryl; in another embodiment, R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclyl group, for example, a 3-7 membered heterocyclyl
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered Heterocyclyl; in another more specific embodiment, R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl Or 3-7 membered heterocyclyl; in another more specific embodiment, R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; in another In a more specific embodiment, R b , R c and the atoms to which they are connected together Forms 3-7 membered heterocyclyl.
  • 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 ring A or any combination thereof can be combined with Y, R 7 , R 1s , L 1a , L 1b , R 1a , R 1as , n 1 , n 2 , R 5a , R 5b , R 1b , R 1c , R' 1s , n 3 , L 2 , R 4a , R 4b , m 1 , R 4c , R 2 , R 2s , L 3 , R 6a , R 6b , R 6c , R 3 , R 3s , Any technical solutions of R 3ss , L 1c , L 1d , L 2a , L 3a , L 3b , R a , R b and R c or any combination thereof are combined.
  • the present invention is intended to include combinations of all these technical solutions,
  • 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
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 1s is -C(O)NR 1b R 1c or
  • L 1a is selected from chemical bond, O, S or NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a 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 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
  • R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • n 3 is 0, 1, 2 or 3;
  • L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
  • R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 0, 1 or 2;
  • R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
  • R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
  • R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
  • R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R 3s or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
  • R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
  • Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
  • each of the above defined groups is optionally deuterated until completely deuterated;
  • 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
  • Ring A is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • R 1s is or -C(O)NR 1b R 1c ;
  • L 1a is selected from O, S or NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally substituted with 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
  • n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
  • R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • n 3 is 0, 1, 2 or 3;
  • L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
  • R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 0, 1 or 2;
  • R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
  • R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
  • R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
  • R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R 3s or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
  • R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
  • Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
  • each of the above defined groups is optionally deuterated until completely deuterated;
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein Y is N.
  • 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, wherein ring A is a C 6-10 aryl group or a 5-10 membered heteroaryl group; preferably a phenyl group or a 5-6 membered heteroaryl group; preferably a 5-6 membered heteroaryl group, Preferably it is pyridyl or thiazolyl; preferably it is pyridyl; preferably it is More preferably
  • 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, wherein R 1s is selected from Preferably selected from Preferably selected from Preferably selected from More preferably not
  • 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, wherein L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH; preferably O or NH; preferably O or S; preferably O; preferably S.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, where L 1b is a chemical bond.
  • L 1b is selected from O, S or NR 5b ; preferably selected from O or NR 5b ; preferably selected from O, S or NMe; preferably selected from O or S; preferably selected from O or NMe; preferably O.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from C 1-6 Alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl Or 3-5 membered heterocyclyl; preferably selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl; preferably selected from C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from Me, Preferably selected from Me, Me is preferred.
  • R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably 3-7 membered heterocyclic group; preferably a 4-5-membered heterocyclic group; preferably a 5-membered heterocyclic group; preferably selected from Preferably
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3 -10-membered heterocyclyl; preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7-membered heterocyclyl; preferably Selected from H, D, halogen, cyano
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein n 1 is selected from 0, 1, 2 or 3; preferably selected from 0, 1 or 2; preferably selected from 1, 2 or 3; preferably 0; preferably 1; preferably 2 .
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein n 2 is selected from 0, 1, 2 or 3; preferably selected from 0 or 1; preferably 0.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 5a is H or Me; preferably H.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 1b is H;
  • R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from H, C 1-6 alkyl Or C 1-6 haloalkyl; preferably C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; Preferably selected from H, D, halogen, 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, wherein n 3 is 0 or 1; preferably 0.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, n 3 is 1, 2 or 3; preferably 0 or 1; preferably 0.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein L 2 is -(CR 4a R 4b ) m1 -; preferably it is methylene.
  • m 1 is 1.
  • R 4a and R 4b are H.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably phenyl.
  • R 2 is optionally substituted with 1, 2, 3 or 4 R 2s .
  • R 2 is optionally substituted by 2 or 3 R 2s .
  • R 2 is selected from Preferably selected from Preferably selected from
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl; preferably selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl; preferably Selected from H, F, Cl, CN, Me, CHF 2 or CF 3 ; preferably selected from H, F, Cl, CN or Me.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein L 3 is NR 6c ; preferably NH.
  • R 6a and R 6b are H.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl; preferably
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 3s is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3- 10- cycloalkyl or 3-10-membered heterocyclyl; preferably selected from H, D, halogen, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, OR a , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, Cl, OMe or Me; preferably Cl or Me.
  • R 3s is selected from H, D, halogen, cyano, OR
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, in which two adjacent R 3s and the atoms they are connected together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; It is preferred to form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group; it is preferred to form a pyrazolyl or dihydrofuranyl group; it is preferred to form Preferably form
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocycle Group; preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein each of L 1c , L 1d , L 2a , L 3a and L 3b Independently selected from chemical bonds or C 1-6 alkylene, optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ; Preferably selected from chemical bonds or C 1-3 alkylene groups.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl; preferably selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, C 1-6 alkyl Or C 1-6 haloalkyl; preferably C 1-6 alkyl or C 1-6 haloalkyl;
  • R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclyl group; preferably, a 3-7 membered heterocyclyl group is formed.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, which has the following structural formula:
  • n 2 is 1, 2, 3 or 4;
  • X 1 is CR 3b or N
  • X 2 is CR 3c or N
  • X 1 is C(O) and X 2 is NH;
  • R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R 3b is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl;
  • R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3b and R 3c and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1 , 2 or 3 R 3ss replacement;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl , C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2d is selected from H, D, halogen or cyano
  • R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
  • Ring A is C 6-10 aryl or 5-10 membered heteroaryl
  • R 1s is or -C(O)NR 1b R 1c ;
  • L 1a is selected from O, S or NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 1b is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 3 is 0, 1, 2 or 3;
  • R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • n 2 is 1, 2, 3 or 4;
  • X 1 is CR 3b or N
  • X 2 is CR 3c or N
  • X 1 is C(O) and X 2 is NH;
  • R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R 3b is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl;
  • R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3b and R 3c and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1 , 2 or 3 R 3ss replacement;
  • R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; or R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclic group;
  • each of the above defined groups is optionally deuterated until completely deuterated;
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • Ring A is phenyl or 5-6 membered heteroaryl
  • R 1s is or -C(O)NHR 1c ; preferably
  • L 1a is selected from O, S or NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • n 1 and n 2 are independently selected from 0, 1, 2 or 3;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H;
  • R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 3 is 0 or 1;
  • R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 2 is 1, 2, 3 or 4;
  • X 1 is CR 3b
  • X 2 is CR 3c ;
  • X 1 is C(O) and X 2 is NH;
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3b is selected from OR a , SR a or NR b R c ; preferably OR a or SR a ;
  • R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3b and R 3c and the atoms to which they are connected together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
  • R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; or R b , R c and the atoms to which they are connected together form a 3-7 membered heterocyclyl group.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • Ring A is a 5-6 membered heteroaryl group, preferably pyridyl or thiazolyl;
  • R 1s is or -C(O)NHR 1c ; preferably
  • L 1a is selected from O, S, NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 is selected from 0, 1 or 2;
  • n 2 is selected from 0 or 1;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H; preferably R 5b is C 1-6 alkyl or C 1-6 haloalkyl, preferably for Me;
  • R 1c is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • n 3 is 0;
  • R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl;
  • n 2 is 2 or 3;
  • X 1 is CR 3b
  • X 2 is CR 3c ;
  • X 1 is C(O) and X 2 is NH;
  • R 3a is halogen
  • R 3b is OR a ;
  • R 3c , R 3d and R 3e are independently H or D;
  • R 3b and R 3c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, preferably a pyrazolyl group or a dihydrofuranyl group, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
  • R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • R 1s is Or C(O)NHCH 3 ; preferably
  • L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH;
  • L 1b is selected from O, S or NMe
  • R 1a is selected from Me
  • n 1 is selected from 0, 1 or 2;
  • n 2 is selected from 0 or 1;
  • n 3 is 0;
  • R 2s is independently selected from H, F, Cl, CN, Me, CHF 2 or CF 3 , preferably selected from H, F, Cl, CN or Me;
  • n 2 is 2 or 3;
  • X 1 is CR 3b
  • X 2 is CR 3c ;
  • X 1 is C(O) and X 2 is NH;
  • R 3a is Cl
  • R 3b is OMe
  • R 3c , R 3d and R 3e are H
  • R 1s is selected from
  • Ring A and the substituents thereon together form:
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • L 1a is selected from O, S or NR 5a ;
  • L 1b is selected from O, S or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • n 1 is selected from 1, 2, 3, 4, 5 or 6;
  • n 2 is selected from 0, 1, 2, 3, 4, 5 or 6;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
  • R 2d is selected from H, D, halogen or cyano
  • R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S; preferably O; preferably S;
  • L 1b is selected from O, S or NR 5b ; preferably O or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, D, halogen , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 is selected from 1, 2 or 3; preferably 2;
  • n 2 is selected from 0, 1, 2 or 3; preferably 0 or 1;
  • R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably C 1-3 alkyl or C 1-3 haloalkyl;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • R 2a is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2b is H
  • R 2c is selected from H, D or halogen
  • R 2d is selected from halogen or cyano
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt or isotopic modification thereof. isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • L 1a is selected from O or S
  • L 1b is selected from O or S
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
  • n 1 is 2;
  • n 2 is 0 or 1;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S; preferably O;
  • L 1b is O
  • R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl
  • n 1 is 2;
  • n 2 is 0;
  • R 2a , R 2c and R 2d are independently halogen
  • R 2b is H or D
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S; preferably O;
  • L 1b is selected from O or NMe; preferably O;
  • R 1a is selected from Me, Preferably Me;
  • n 1 is 2;
  • n 2 is 0 or 1; preferably 0;
  • R 2a is selected from F or Me; preferably F;
  • R 2b is H
  • R 2c is selected from H or F; more preferably, it is F;
  • R 2d is selected from F, Cl or CN; preferably F or Cl;
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides the compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • L 1a is selected from O, S or NR 5a ;
  • R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • n 1 is selected from 1, 2, 3, 4, 5 or 6;
  • R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
  • R 2d is selected from H, D, halogen or cyano
  • R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S; preferably O; preferably S;
  • R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 is selected from 1, 2 or 3;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S; preferably O;
  • R 1a is a 3-7-membered heterocyclyl group, preferably a 4-5-membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me;
  • n 1 1;
  • R 2a , R 2c and R 2d are independently halogen
  • R 2b is H or D
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S; preferably O;
  • R 1a is selected from
  • n 1 1;
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O, S or NR 5a ;
  • R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
  • R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
  • R 2d is selected from H, D, halogen or cyano
  • R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O, S or NH; preferably O or NH; preferably S;
  • R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the above-mentioned compound of formula (III-3), or a pharmaceutically acceptable salt or isotopic modification thereof. isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • L 1a is selected from O, S or NH; preferably O or NH;
  • R 1a is a 4-6 membered heterocyclyl group, preferably a 5-membered heterocyclyl group, preferably a tetrahydrofuranyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2b is selected from H, D or halogen
  • R 2c is halogen
  • R 2d is selected from halogen or cyano
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom of R 1a and L 1a is a chiral carbon atom, it is for
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O, S or NH; preferably O or NH;
  • R 1a is selected from Preferably More preferably
  • R 2a is H, F, Cl or Me
  • R 2b is H or F
  • R 2c is F or Cl; preferably F;
  • R 2d is F, Cl or CN
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
  • Ring A is phenyl or 5-6 membered heteroaryl
  • R 1s is -C(O)NHR 1c or
  • L 1a is selected from chemical bond, O, S or NR 5a ;
  • L 1b is selected from chemical bond, O, S or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, Phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, cyano, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered hetero Ring group;
  • n 1 and n 2 are independently selected from 0, 1, 2 or 3;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H;
  • R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 3 is 0 or 1;
  • R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or
  • n 2 is 1, 2, 3 or 4;
  • X 1 is CR 3b
  • X 2 is CR 3c ;
  • X 1 is C(O) and X 2 is NH;
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3b is selected from OR a , SR a or NR b R c ; preferably OR a or SR a ;
  • R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3b and R 3c and the atoms to which they are connected together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
  • R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • each of the above defined groups is optionally deuterated until completely deuterated;
  • the present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
  • Ring A is a 5-6 membered heteroaryl group, preferably pyridyl or thiazolyl, preferably pyridyl, preferably
  • R 1s is Preferably
  • L 1a is selected from O, S, NR 5a ;
  • L 1b is selected from chemical bond, O or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 is selected from 0, 1 or 2;
  • n 2 is selected from 0, 1 or 2;
  • R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H; preferably R 5b is C 1-3 alkyl or C 1-3 haloalkyl;
  • n 3 is 0;
  • R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;
  • n 2 is 2 or 3;
  • X 1 is CR 3b
  • X 2 is CR 3c ;
  • X 1 is C(O) and X 2 is NH;
  • R 3a is halogen
  • R 3b is OR a ; preferably OMe;
  • R 3c , R 3d and R 3e are independently H or D;
  • R 3b and R 3c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 3ss ; preferably, it forms
  • R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • L 1a is selected from O or S
  • L 1b is selected from O, S or NR 5b ;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, It is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, D , halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • n 1 is selected from 1, 2 or 3;
  • n 2 is selected from 0, 1, 2 or 3;
  • R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
  • R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from H, D, halogen or cyano; preferably halogen or cyano;
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S
  • L 1b is O or NR 5b ; preferably O;
  • R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl or 3-5 membered heterocyclyl; Preferably it is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-5 cycloalkyl; preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
  • n 1 is 2;
  • n 2 is 0, 1 or 2;
  • R 5b is C 1-3 alkyl or C 1-3 haloalkyl, preferably Me;
  • R 2a is selected from H, D, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; preferably halogen, C 1-4 alkyl or C 1-4 alkoxy;
  • R 2b is H, D or halogen
  • R 2c is selected from H, D or halogen
  • R 2d is halogen or CN
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O or S; preferably O;
  • L 1b is selected from O or NMe; preferably O;
  • R 1a is selected from Me, OMe, cyclopropyl or Preferably it is Me, OMe or cyclopropyl; Preferably it is Me or cyclopropyl;
  • n 1 is 2;
  • n 2 is 0, 1 or 2; preferably 0 or 1;
  • R 2a is selected from H, F, Me, CF 3 , OMe or OCHF 2 ; preferably F, Me or OMe;
  • R 2b is H or F
  • R 2c is selected from H, F or Cl; more preferably H or F;
  • R 2d is selected from F, Cl or CN; preferably Cl or CN;
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • L 1a is selected from O, S or NR 5a ;
  • R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 5a is selected from H, C 1-3 alkyl or C 1-3 haloalkyl; preferably R 5a is H;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O, S or NH;
  • R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, F, Me, NH 2 , -NHCH 3 or -NH ( CH 3 ) 2 ; preferably selected from H, F, Me, NH 2 or -NHCH 3 ;
  • R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
  • R 2b is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
  • R 2c is H, D or halogen
  • R 2d is halogen or cyano
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl
  • R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom of R 1a and L 1a is a chiral carbon atom, it is for
  • the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • L 1a is selected from O, S or NH;
  • R 1a is selected from Preferably selected from: Preferably, for
  • R 2a is H, F, Cl or Me
  • R 2b is H, F or Me
  • R 2c is H, F or Cl
  • R 2d is F, Cl or CN
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides the compound of the above formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of the above formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 4-6 A membered heterocyclyl optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl, preferably selected from H, D or NR b R c ; preferably selected from H, NH 2 or -N(CH 3 ) 2 ; preferably selected from H or NH 2 ;
  • R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
  • R 2b is selected from H, D or halogen
  • R 2c is halogen
  • R 2d is selected from halogen or cyano
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl
  • R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably H.
  • the present invention provides the compound of the above formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom of R 1a and O is a chiral carbon atom, it is for
  • the present invention provides the compound of formula (IV-1) above, or a pharmaceutically acceptable salt or isotopic modification thereof. isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • L 1a is selected from O, S or NH; preferably O or NH;
  • R 2a is H, F, Cl or Me; preferably H, Cl or Me;
  • R 2b is H or F; preferably H;
  • R 2c is F
  • R 2d is F, Cl or CN; preferably Cl or CN;
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides the compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • R 1a is a 4-6 membered heterocyclyl group, preferably a 5-membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl; preferably selected from H, D or halogen;
  • R 2b is selected from H or D
  • R 2c is halogen
  • R 2d is selected from halogen or cyano
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom between R 1a and NH is a chiral carbon atom, it is for
  • the present invention provides the compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • R 2a is H, F, Cl or Me; preferably H or F;
  • R 2b is H
  • R 2c is F
  • R 2d is F, Cl or CN; preferably F or CN;
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides the compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
  • R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 2d is selected from halogen or cyano
  • R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
  • R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl
  • R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
  • each of the above defined groups is optionally deuterated, up to complete deuteration.
  • the present invention provides the compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotope change thereof isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
  • R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl radical, which is optionally substituted by 1, 2 or 3 R 1as ;
  • R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, F, Me, NH 2 or NHCH 3 ; preferably H, F or Me;
  • R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
  • R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl
  • R 2c is selected from H, D or halogen
  • R 2d is selected from halogen or cyano
  • R 3a is halogen
  • R 3f is C 1-6 alkyl or C 1-6 haloalkyl
  • R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  • the present invention provides the compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom between R 1a and S is a chiral carbon atom, it is for
  • the present invention provides the compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
  • R 2a is H, F or Me
  • R 2b is H or Me
  • R 2c is H, F or Cl
  • R 2d is Cl or CN
  • R 3a is Cl
  • R 3f is Me.
  • the present invention provides compounds of the above formula (I), or pharmaceutically acceptable salts, isotopic variants, tautomers, stereoisomers, prodrugs, polymorphs, Hydrate or solvate, wherein the compound is selected from the following:
  • 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 Prepared by asymmetric synthesis.
  • 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.
  • 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)).
  • monohydrate x is 1
  • lower hydrate x is a number greater than 0 and less than 1
  • hemihydrate R ⁇ 0.5H 2 O
  • 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.
  • Isotopically labeled compounds of formula (I) of the present invention and their prodrugs are generally It can be prepared by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents when performing the processes disclosed in the following schemes and/or examples and preparation examples.
  • 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 that can be cleaved to form a hydroxyl, amino or thiol group when administered to a patient.
  • 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).
  • 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. carrier or form agents 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 to 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.
  • the crude product was purified by high-pressure preparative chromatography ((Column: -Gemini-C18 150x 21.2mm, 5 ⁇ m. Flow term: ACN--H 2 O (0.1% FA). Gradient: 35-45)) to obtain white solid compound 1 ((( 49.3mg, yield: 35.2%)).
  • reaction solution was cooled to room temperature, petroleum ether ((500 mL)) was added, and the resulting solution was stirred at room temperature for 1 hour, then filtered through diatomaceous earth, the filter cake was washed with petroleum ether, and the resulting filtrate was concentrated to dryness.
  • reaction solution was cooled to room temperature, petroleum ether (500 mL) was added, and the resulting solution was stirred at room temperature for 1 hour, then filtered through diatomaceous earth, the filter cake was washed with petroleum ether, and the filtrate was concentrated to dryness.
  • the crude product was purified by high performance liquid chromatography (column: Gemini-C18 150x21.2mm, 5 ⁇ m. Mobile item: ACN--H 2 O (0.1% FA)) to obtain light yellow solid compound 32 (0.474g, yield: 15.0 %).
  • the crude product was purified by high performance liquid chromatography (column: -Gemini-C18 150x21.2mm, 5 ⁇ m. Mobile item: ACN--H 2 O (0.1% FA)) to obtain light yellow solid compound 35 (0.434g, yield: 14.0 %).
  • Reaction Buffer 50mM Tris pH 7.4, 1mM EDTA, 0.01% tritonX-100
  • Microplate reader detection excitation 320nm; emission 405nm
  • Inhibition rate (%) (RFU 100% enzyme activity control - RFU sample) / (RFU 100% enzyme activity control - RFU blank control) ⁇ 100%
  • Inhibition rate (%) (NC initial velocity V 0 - sample initial velocity V 0 )/NC initial velocity ⁇ 100
  • NC is a control with DMSO added, and the enzyme activity is determined as 100%.
  • Inhibition rate (%) (NC initial velocity V 0 - (sample initial velocity V 0 - protein-free small molecule control V 0 )/NC initial velocity V 0 ⁇ 100 is used to eliminate V 0 (slope) as Problem with negative values.

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05月27日的中国申请202210600337.0、以及提交于2023年01月19日的中国申请202310082317.3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 202310082317.3, filed on January 19, 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***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 a patient takes 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 arrhythmias. . 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,
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;
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;
R1s为-C(O)NR1bR1c或 R 1s is -C(O)NR 1b R 1c or
L1a选自化学键、O、S或NR5a；L 1a is selected from chemical bond, O, S or NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a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、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R1as取代；R 1a 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 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、-L1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1b选自H、C1-6烷基或C1-6卤代烷基；R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
R’1s独立地选自H、D、卤素、氰基、-L1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
L2选自-(CR4aR4b)m1-、O、S或NR4c；L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
R4a和R4b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m1为0、1或2；m 1 is 0, 1 or 2;
R4c选自H、C1-6烷基或C1-6卤代烷基； R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
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，其任选地被1、2、3、4或5个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, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
R2s独立地选自H、D、卤素、氰基、-L2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基；R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
L3选自化学键、CR6aR6b、O、S或NR6c；L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
R6a和R6b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R6c选自H、C1-6烷基或C1-6卤代烷基；R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R3选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2、3、4或5个R3s取代；R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
R3s独立地选自H、D、卤素、氰基、-L3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
或者两个相邻的R3s以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
R3ss独立地选自H、D、卤素、氰基、-L3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C3-10芳基或3-10元杂芳基；R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
L1c、L1d、L2a、L3a和L3b各自独立地选自化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基或5-10元杂芳基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
条件是，当环A为吡啶基，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基；且所述化合物不为如下结构：
The condition is that when ring A is pyridyl, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group; and the compound does not have the following structure:
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.
“C1-6烷基”是指具有1至6个碳原子的直链或支链饱和烃基团。在一些实施方案中，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 1-6 alkyl" refers to a straight or branched chain saturated hydrocarbon group having 1 to 6 carbon atoms. In some embodiments, 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 ), hexyne base (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".
“C1-6烷氧基”是指-O-C1-6烷基。在一些实施方案中，C1-4烷基是优选的。在另一些实施方案中，C1-3烷氧基是优选的，例如，甲氧基、乙氧基等。"C 1-6 alkoxy" refers to -OC 1-6 alkyl. In some embodiments, C 1-4 alkyl is preferred. In other embodiments, C 1-3 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，“C1-6卤代烷基”是指上述“C1-6烷基”，其被一个或多个卤素基团取代。在一些实施方案中，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 1-6 haloalkyl" refers to the above-mentioned "C 1-6 alkyl" which is substituted by one or more halogen groups. In some embodiments, C 1-4 haloalkyl is particularly preferred, more preferably C 1-3 haloalkyl, more preferably C 1-2 haloalkyl. 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(例如OCH2F、OCHF2或OCF3)、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 (eg, OCH 2 F, OCHF 2 or OCF 3 ), haloethoxy, and the like.
“C3-10环烷基”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" refers to a non-aromatic cyclic hydrocarbon group 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, more C 5-7 cycloalkyl and C 5-6 cycloalkyl are preferred. 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. A cycloalkyl group 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.
“3-10元杂环基”是指具有环碳原子和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：***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。"3-10 membered heterocyclyl" refers to a saturated or unsaturated group of 3 to 10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 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, 5-10 membered heterocyclyl is preferred, which is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1 to 5 ring heteroatoms; in some embodiments, 3-7 membered is preferred Heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms; preferably 5-7-membered heterocyclyl, which is a 3- to 7-membered non-aromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms. 5 to 7 membered non-aromatic ring system of atoms; preferably 3 to 6 membered heterocyclyl, which is a 3 to 6 membered nonaromatic ring system having ring carbon atoms and 1 to 3 ring heteroatoms; preferably 4 to 6 membered heterocyclyl Cyclic group, which is a 4- to 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms; more preferably, a 5-6-membered heterocyclyl group, which is a 4- to 6-membered non-aromatic ring system with ring carbon atoms and 1 to 3 ring heteroatoms. A 5- to 6-membered nonaromatic ring system of atoms. 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. Show 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 5-membered heterocyclyl fused to a C6 aryl ring (also referred to herein as 5,6-bicyclic heterocyclyl) include, but are 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.
“C6-10芳基”是指具有6-10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，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***，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***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 6-10 aryl" refers to a monocyclic or polycyclic (e.g., bicyclic) 4n+2 aromatic ring system having 6-10 ring carbon atoms and zero heteroatoms (e.g., having a Shared 6 or 10 π electrons) group. 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.
“5-10元杂芳基”是指具有环碳原子和1-4个环杂原子的5-10元单环或双环的4n+2芳族环体系(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***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***，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***中的碳原子数目。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1-4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：***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***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。 "5-10 membered heteroaryl" refers to a 5-10 membered monocyclic or bicyclic 4n+2 aromatic ring system having ring carbon atoms and 1-4 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, 5-6 membered heteroaryl groups are particularly preferred, which are 5-6 membered monocyclic or bicyclic 4n+2 aromatic ring systems having ring carbon atoms and 1-4 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, benzofuryl, benzisofuryl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzene Thiadiazolyl, indazinyl 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 R cc is independently selected from hydrogen, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, or two R cc groups are combined to form a heterocycle or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R dd group substitution;
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, where each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, 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 combine 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 groups connected to the nitrogen atom combine to form a heterocycle or heteroaryl ring, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl is independently replaced by 0, 1, 2, 3, 4 or 5 R The dd group is 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、***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, Methanesulfonate, glucoheptonate, lactobionate, lauryl 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 covered are salts of amino acids, such as arginates, gluconates, galacturonates, etc. (see, for example, Berge S.M. 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 human. In some embodiments, the subject is a non-human animal. The terms "person,""patient," and "subject" are used interchangeably herein.
“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.
具体实施方式Detailed ways
本文中，“本发明化合物”指的是以下的式(I)、式(II)、式(III-1)、式(III-2)和式(III-3)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。As used herein, the "compounds of the present invention" refer to compounds of the following formula (I), formula (II), formula (III-1), formula (III-2) and formula (III-3), which pharmaceutically acceptable Accepted salts, isotopic variants, tautomers, stereoisomers, prodrugs, 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;
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;
R1s为-C(O)NR1bR1c或 R 1s is -C(O)NR 1b R 1c or
L1a选自化学键、O、S或NR5a；L 1a is selected from chemical bond, O, S or NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a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、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R1as取代；R 1a 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 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、-L1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1b选自H、C1-6烷基或C1-6卤代烷基；R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
R’1s独立地选自H、D、卤素、氰基、-L1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
L2选自-(CR4aR4b)m1-、O、S或NR4c；L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
R4a和R4b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m1为0、1或2；m 1 is 0, 1 or 2;
R4c选自H、C1-6烷基或C1-6卤代烷基；R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
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，其任选地被1、2、3、4或5个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, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
R2s独立地选自H、D、卤素、氰基、-L2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基；R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
L3选自化学键、CR6aR6b、O、S或NR6c；L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
R6a和R6b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R6c选自H、C1-6烷基或C1-6卤代烷基；R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R3选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2、3、4或5个R3s取代；R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
R3s独立地选自H、D、卤素、氰基、-L3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
或者两个相邻的R3s以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代； Or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
R3ss独立地选自H、D、卤素、氰基、-L3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C3-10芳基或3-10元杂芳基；R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
L1c、L1d、L2a、L3a和L3b各自独立地选自化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基或5-10元杂芳基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
条件是，当环A为吡啶基，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基；且所述化合物不为如下结构：
The condition is that when ring A is pyridyl, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group; and the compound does not have the following structure:
YY
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N。In one embodiment, Y is CR7 , such as CH; in another embodiment, Y is N.
R7 R 7
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.
环ARing A
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3-10元杂环基；在另一个实施方式中，环A为C6-10芳基，例如苯基；在另一个实施方式中，环A为5-10元杂芳基，例如5-6元杂芳基，例如吡啶基，例如噻唑基，例如例如 In one embodiment, Ring A is C 3-10 cycloalkyl; in another embodiment, Ring A is 3-10 membered heterocyclyl; in another embodiment, Ring A is C 6-10 aromatic group, such as phenyl; in another embodiment, ring A is a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group, such as pyridyl, such as thiazolyl, such as For example
在一个具体的实施方式中，环A为C6-10芳基或5-10元杂芳基；在另一个更具体的实施方式中，环A为苯基或5-6元杂芳基；在另一个更具体的实施方式中，环A为5-6元杂芳基；在另一个更具体的实施方式中，环A为吡啶基或噻唑基；在另一个更具体的实施方式中，环A为吡啶基；在另一个更具体的实施方式中，环A为在一个更具体的实施方式中，环A为 In a specific embodiment, ring A is a C 6-10 aryl group or a 5-10 membered heteroaryl group; in another more specific embodiment, ring A is a phenyl group or a 5-6 membered heteroaryl group; In another more specific embodiment, Ring A is a 5-6 membered heteroaryl; in another more specific embodiment, Ring A is pyridyl or thiazolyl; in another more specific embodiment, Ring A is pyridyl; in another more specific embodiment, Ring A is In a more specific embodiment, Ring A is
在一个具体的实施方式中，环A和R1s组成在另一个具体的实施方式中，环A和R1s组成 In a specific embodiment, Ring A and R 1s consist of In another specific embodiment, Ring A and R 1s consist of
R1s R 1s
在一个实施方式中，R1s为例如例如更具体地，例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如 例如例如例如在另一个实施方式中，R1s为C(O)NR1bR1c，例如C(O)NHCH3；在另一个实施方式中，R1s为例如 In one embodiment, R 1s is For example For example More specifically, e.g. For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example In another embodiment, R 1s is C(O)NR 1b R 1c , such as C(O)NHCH 3 ; in another embodiment, R 1s is For example
在一个更具体的实施方案中，R1s选自 在另一个更具体的实施方式中，R1s选自 在另一个更具体的实施方式中，R1s选自 在另一个更具体的实施方式中，R1s选自 在另一个更具体的实施方式中，R1s选自 在另一个更具体的实施方式中，R1s选自 在另一个更具体的实施方式中，R1s不为 In a more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is selected from In another more specific embodiment, R 1s is not
在一个更具体的实施方案中，R1s选自 优选为优选为 In a more specific embodiment, R 1s is selected from Preferably Preferably
在一个更具体的实施方案中，R1s选自： 优选选自： 优选地，为优选地，为优选地，为 In a more specific embodiment, R 1s is selected from: Preferably selected from: Preferably, for Preferably, for Preferably, for
在一个更具体的实施方案中，R1s选自：优选为：优选为优选地，为 In a more specific embodiment, R 1s is selected from: Preferably: Preferably Preferably, for
在一个更具体的实施方案中，R1s选自： 优选为 优选为 优选为 优选地，为 In a more specific embodiment, R 1s is selected from: Preferably Preferably Preferably Preferably, for
L1a L 1a
在一个实施方式中，L1a为O；在另一个实施方式中，L1a为S；在另一个实施方式中，L1a为NR5a，例如NH，例如NMe；在另一个实施方式中，L1a为化学键。In one embodiment, L 1a is O; in another embodiment, L 1a is S; in another embodiment, L 1a is NR 5a , such as NH, such as NMe; in another embodiment, L 1a is a chemical bond.
在一个更具体的实施方式中，L1a选自O、S、NH或NMe；在另一个更具体的实施方式中，L1a选自O、S或NH；在另一个更具体的实施方式中，L1a为O或NH；在另一个更具体的实施方式中，L1a为O或S；在另一个更具体的实施方式中，L1a选自O、S、NR5a。In a more specific embodiment, L 1a is selected from O, S, NH or NMe; in another more specific embodiment, L 1a is selected from O, S or NH; in another more specific embodiment , L 1a is O or NH; in another more specific embodiment, L 1a is O or S; in another more specific embodiment, L 1a is selected from O, S, NR 5a .
L1b L 1b
在一个实施方式中，L1b为化学键；在另一个实施方式中，L1b为O；在另一个实施方式中，L1b为S；在另一个实施方式中，L1b为NR5b，例如NH，例如NMe。In one embodiment, L 1b is a chemical bond; in another embodiment, L 1b is O; in another embodiment, L 1b is S; in another embodiment, L 1b is NR 5b , such as NH , such as NMe.
在一个更具体的实施方式中，L1b选自O、S或NR5b；在另一个更具体的实施方式中，L1b选自O或NR5b；在另一个更具体的实施方式中，L1b选自O、S或NMe；在另一个更具体的实施方式中，L1b选自O或S；在另一个更具体的实施方式中，L1b选自O或NMe；在另一个更具体的实施方式中，L1b选自O、S或NR5b。In a more specific embodiment, L 1b is selected from O, S or NR 5b ; in another more specific embodiment, L 1b is selected from O or NR 5b ; in another more specific embodiment, L 1b is selected from O, S or NMe; in another more specific embodiment, L 1b is selected from O or S; in another more specific embodiment, L 1b is selected from O or NMe; in another more specific embodiment In the embodiment of , L 1b is selected from O, S or NR 5b .
R1a R 1a
在一个实施方式中，R1a为C1-6烷基，例如Me；在另一个实施方式中，R1a为C1-6卤代烷基；在另一个实施方式中，R1a为C3-10环烷基，例如C3-7环烷基，例如C3-5环烷基，例如环丙基；在另一个实施方式中，R1a为3-10元杂环基，例如3-7元杂环基，例如3-5元杂环基，例如4-6元杂环基，例 如4-5元杂环基，例如例如例如例如5元杂环基，例如例如例如在另一个实施方式中，R1a为C6-10芳基，例如苯基；在另一个实施方式中，R1a为5-10元杂芳基，例如5-6元杂芳基，例如例如例如例如例如例如例如例如例如例如例如例如例如在另一个实施方式中，R1a为C1-6烷氧基，例如OMe；在另一个实施方式中，R1a为C1-6卤代烷氧基，例如OCHF2，例如OCF3。In one embodiment, R 1a is C 1-6 alkyl, such as Me; in another embodiment, R 1a is C 1-6 haloalkyl; in another embodiment, R 1a is C 3-10 Cycloalkyl, such as C 3-7 cycloalkyl, such as C 3-5 cycloalkyl, such as cyclopropyl; in another embodiment, R 1a is 3-10 membered heterocyclyl, such as 3-7 membered Heterocyclyl, such as 3-5 membered heterocyclyl, such as 4-6 membered heterocyclyl, such as Such as 4-5 membered heterocyclyl, for example For example For example For example, a 5-membered heterocyclyl group, such as For example For example In another embodiment, R 1a is a C 6-10 aryl group, such as phenyl; in another embodiment, R 1a is a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group, such as For example For example For example For example For example For example For example For example For example For example For example For example In another embodiment, R 1a is C 1-6 alkoxy, such as OMe; in another embodiment, R 1a is C 1-6 haloalkoxy, such as OCHF 2 , such as OCF 3 .
在一个实施方式中，R1a未被取代；在另一个实施方式中，R1a被1个R1as取代；在另一个实施方式中，R1a被2个R1as取代；在另一个实施方式中，R1a被3个R1as取代。In one embodiment, R 1a is unsubstituted; in another embodiment, R 1a is substituted with 1 R 1as ; in another embodiment, R 1a is substituted with 2 R 1as ; in another embodiment , R 1a is replaced by 3 R 1as .
在一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C3-5环烷基或3-5元杂环基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基或C3-5环烷基；在另一个更具体的实施方式中，R1a选自C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R1a选自C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R1a选自C3-7环烷基或3-7元杂环基。In a more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific implementation In this way, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1a is selected from From C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl group, C 1-6 haloalkyl or C 3-5 cycloalkyl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment In an embodiment, R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1a is selected from C 3-7 cycloalkyl or 3-7 Heterocyclic group.
在一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基或5-6元杂芳基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-5环烷基或3-5元杂环基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C3-5环烷基；在另一个更具体的实施方式中，R1a选自C1-6烷基、C1-6卤代烷基或C3-5环烷基；在另一个更具体的实施方式中，R1a选自Me、OMe、环丙基或在另一个更具体的实施方式中，R1a选自Me、OMe或环丙基；在另一个更具体的实施方式中，R1a为Me或环丙基；在另一个更具体的实施方式中，R1a选自C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基；在另一个更具体的实施方式中，R1a选自C3-7环烷基、3-7元杂环基或5-6元杂芳基；在另一个 更具体的实施方式中，R1a选自3-7元杂环基或5-6元杂芳基；在另一个更具体的实施方式中，R1a选自 在另一个更具体的实施方式中，R1a选自： 在另一个更具体的实施方式中，R1a选自C3-6环烷基、4-6元杂环基或5-6元杂芳基。In a more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl , 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1 -6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a Selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another In a more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl or 3-5 membered heterocyclyl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-5 cycloalkyl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl; in another more specific embodiment, R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl; in another more specific embodiment In specific embodiments, R 1a is selected from Me, OMe, cyclopropyl or In another more specific embodiment, R 1a is selected from Me, OMe or cyclopropyl; in another more specific embodiment, R 1a is Me or cyclopropyl; in another more specific embodiment , R 1a is selected from C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a is selected from C 3-7 Cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl; in another In a more specific embodiment, R 1a is selected from 3-7 membered heterocyclyl or 5-6 membered heteroaryl; in another more specific embodiment, R 1a is selected from In another more specific embodiment, R 1a is selected from: In another more specific embodiment, R 1a is selected from C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl.
在一个更具体的实施方式中，选自：优选为：优选为优选地，为在一个更具体的实施方式中，选自：优选为 In a more specific implementation, Selected from: Preferably: Preferably Preferably, for In a more specific implementation, Selected from: Preferably
在一个更具体的实施方式中，选自： 优选为 优选为 优选为 优选地，为 In a more specific implementation, Selected from: Preferably Preferably Preferably Preferably, for
R1as R 1as
在一个实施方式中，R1as为H；在另一个实施方式中，R1as为D；在另一个实施方式中，R1as为卤素，例如F；在另一个实施方式中，R1as为氰基；在另一个实施方式中，R1as为C1-6烷基，例如Me；在另一个实施方式中，R1as为C1-6卤代烷基；在另一个实施方式中，R1as为-L1c-ORa，优选为ORa；在另一个实施方式中，R1as为-L1c-SRa，优选为SRa；在另一个实施方式中，R1as为-L1c-NRbRc，优选为NRbRc，例如NH2，例如-NHCH3，例如-NH(CH3)2；在另一个实施方式中，R1as为C3-10环烷基，例如C3-7环烷基；在另一个实施方式中，R1as为3-10元杂环基，例如3-7元杂环基；在另一个实施方式中，R1as为C6-10芳基；在另一个实施方式中，R1as为5-10元杂芳基。In one embodiment, R 1as is H; in another embodiment, R 1as is D; in another embodiment, R 1as is halogen, such as F; in another embodiment, R 1as is cyano. ; In another embodiment, R 1as is C 1-6 alkyl, such as Me; In another embodiment, R 1as is C 1-6 haloalkyl; In another embodiment, R 1as is -L 1c -OR a , preferably OR a ; in another embodiment, R 1as is -L 1c -SR a , preferably SR a ; in another embodiment, R 1as is -L 1c -NR b R c , preferably NR b R c , such as NH 2 , such as -NHCH 3 , such as -NH(CH 3 ) 2 ; in another embodiment, R 1as is C 3-10 cycloalkyl, such as C 3-7 ring Alkyl; in another embodiment, R 1as is a 3-10 membered heterocyclyl group, such as a 3-7 membered heterocyclyl group; in another embodiment, R 1as is a C 6-10 aryl group; in another In embodiments, R 1as is a 5-10 membered heteroaryl group.
在一个更具体的实施方式中，R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、ORa、SRa、NRbRc、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；在另一个更具体的实施方式中，R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R1as独立地选自H、D、C1-6烷基或C1-6卤代烷基。In a more specific embodiment, R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1- 6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl group, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, C 1- 6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 1as is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
在一个更具体的实施方式中，R1as独立地选自H、D、卤素、氰基、ORa、NRbRc、C1-6烷基、C1-6 卤代烷基、C3-7环烷基或3-7元杂环基；在另一个更具体的实施方式中，R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R1as独立地选自H、D、卤素、CN、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；在另一个更具体的实施方式中，R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R1as独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R1as独立地选自H、F、Me、NH2、-NHCH3或-NH(CH3)2；在另一个更具体的实施方式中，R1as独立地选自H、F、Me、NH2或-NHCH3；在另一个更具体的实施方式中，R1as独立地选自H、D或NRbRc；优选选自H、NH2或-N(CH3)2；在另一个更具体的实施方式中，R1as独立地选自H或NH2；在另一个更具体的实施方式中，R1as独立地选自H、F、Me、NH2或NHCH3；在另一个更具体的实施方式中，R1as独立地为H、F或Me。In a more specific embodiment, R 1as is independently selected from H, D, halogen, cyano, OR a , NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 Alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3 -7 cycloalkyl or 3-7 membered heterocyclyl; in another more specific embodiment, R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; In another more specific embodiment, R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment In an embodiment, R 1as is independently selected from H, F, Me, NH 2 , -NHCH 3 or -NH(CH 3 ) 2 ; in another more specific embodiment, R 1as is independently selected from H, F , Me, NH 2 or -NHCH 3 ; in another more specific embodiment, R 1as is independently selected from H, D or NR b R c ; preferably selected from H, NH 2 or -N(CH 3 ) 2 ; In another more specific embodiment, R 1as is independently selected from H or NH 2 ; In another more specific embodiment, R 1as is independently selected from H, F, Me, NH 2 or NHCH 3 ; In another more specific embodiment, R 1as is independently H, F, or Me.
n1和n2 n 1 and n 2
在一个实施方式中，n1为0；在另一个实施方式中，n1为1；在另一个实施方式中，n1为2；在另一个实施方式中，n1为3；在另一个实施方式中，n1为4；在另一个实施方式中，n1为5；在另一个实施方式中，n1为6。In one embodiment, n 1 is 0; in another embodiment, n 1 is 1; in another embodiment, n 1 is 2; in another embodiment, n 1 is 3; in another In one embodiment, n 1 is 4; in another embodiment, n 1 is 5; in another embodiment, n 1 is 6.
在一个实施方式中，n2为0；在另一个实施方式中，n2为1；在另一个实施方式中，n2为2；在另一个实施方式中，n2为3；在另一个实施方式中，n2为4；在另一个实施方式中，n2为5；在另一个实施方式中，n2为6。In one embodiment, n2 is 0; in another embodiment, n2 is 1; in another embodiment, n2 is 2; in another embodiment, n2 is 3; in another In one embodiment, n 2 is 4; in another embodiment, n 2 is 5; in another embodiment, n 2 is 6.
在一个更具体的实施方式中，n1选自0、1、2或3；在另一个更具体的实施方式中，n1选自0、1或2；在另一个更具体的实施方式中，n1选自1、2或3。In a more specific embodiment, n 1 is selected from 0, 1, 2 or 3; in another more specific embodiment, n 1 is selected from 0, 1 or 2; in another more specific embodiment , n 1 is selected from 1, 2 or 3.
在一个更具体的实施方式中，n2选自0、1、2或3；在另一个更具体的实施方式中，n2选自0或1；在另一个更具体的实施方式中，n2为0、1或2。In a more specific embodiment, n 2 is selected from 0, 1, 2 or 3; in another more specific embodiment, n 2 is selected from 0 or 1; in another more specific embodiment, n 2 is 0, 1 or 2.
R5a和R5b R 5a and R 5b
在一个实施方式中，R5a为H；在另一个实施方式中，R5a为C1-6烷基，例如C1-3烷基，例如Me；在另一个实施方式中，R5a为C1-6卤代烷基，例如C1-3卤代烷基。In one embodiment, R 5a is H; in another embodiment, R 5a is C 1-6 alkyl, such as C 1-3 alkyl, such as Me; in another embodiment, R 5a is C 1-6 haloalkyl, such as C 1-3 haloalkyl.
在一个实施方式中，R5b为H；在另一个实施方式中，R5b为C1-6烷基，例如C1-3烷基，例如Me；在另一个实施方式中，R5b为C1-6卤代烷基，例如C1-3卤代烷基。In one embodiment, R 5b is H; in another embodiment, R 5b is C 1-6 alkyl, such as C 1-3 alkyl, such as Me; in another embodiment, R 5b is C 1-6 haloalkyl, such as C 1-3 haloalkyl.
在一个更具体的实施方式中，R5a为H或Me。In a more specific embodiment, R 5a is H or Me.
在一个更具体的实施方式中，R5b选自C1-6烷基或C1-6卤代烷基，优选为C1-3烷基或C1-3卤代烷基。In a more specific embodiment, R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-3 alkyl or C 1-3 haloalkyl.
R1b和R1c R 1b and R 1c
在一个实施方式中，R1b为H；在另一个实施方式中，R1b为C1-6烷基，例如Me；在另一个实施方式中，R1b为C1-6卤代烷基。 In one embodiment, R 1b is H; in another embodiment, R 1b is C 1-6 alkyl, such as Me; in another embodiment, R 1b is C 1-6 haloalkyl.
在一个实施方式中，R1c为H；在另一个实施方式中，R1c为C1-6烷基，例如Me；在另一个实施方式中，R1c为C1-6卤代烷基；在另一个实施方式中，R1c为C3-10环烷基；在另一个实施方式中，R1c为3-10元杂环基；在另一个实施方式中，R1c为C6-10芳基；在另一个实施方式中，R1c为5-10元杂芳基。In one embodiment, R 1c is H; in another embodiment, R 1c is C 1-6 alkyl, such as Me; in another embodiment, R 1c is C 1-6 haloalkyl; in another In one embodiment, R 1c is C 3-10 cycloalkyl; in another embodiment, R 1c is 3-10 membered heterocyclyl; in another embodiment, R 1c is C 6-10 aryl ; In another embodiment, R 1c is 5-10 membered heteroaryl.
在一个更具体的实施方式中，R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R1c选自H、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R1c选自C1-6烷基或C1-6卤代烷基。In a more specific embodiment, R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment In an embodiment, R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 1c is selected from C 1-6 alkyl or C 1-6 Haloalkyl.
R’1s R' 1s
在一个实施方式中，R’1s为H；在另一个实施方式中，R’1s为D；在另一个实施方式中，R’1s为卤素；在另一个实施方式中，R’1s为氰基；在另一个实施方式中，R’1s为-L1d-ORa，优选为ORa；在另一个实施方式中，R’1s为-L1d-SRa，优选为SRa；在另一个实施方式中，R’1s为-L1d-NRbRc，优选为NRbRc；在另一个实施方式中，R’1s为C1-6烷基；在另一个实施方式中，R’1s为C1-6卤代烷基；在另一个实施方式中，R’1s为C3-10环烷基；在另一个实施方式中，R’1s为3-10元杂环基。In one embodiment, R' 1s is H; in another embodiment, R' 1s is D; in another embodiment, R' 1s is halogen; in another embodiment, R' 1s is cyanide group; in another embodiment, R' 1s is -L 1d -OR a , preferably OR a ; in another embodiment, R' 1s is -L 1d -SR a , preferably SR a ; in another embodiment In one embodiment, R' 1s is -L 1d -NR b R c , preferably NR b R c ; in another embodiment, R' 1s is C 1-6 alkyl; in another embodiment, R' 1s is C 1-6 haloalkyl; in another embodiment, R' 1s is C 3-10 cycloalkyl; in another embodiment, R' 1s is 3-10 membered heterocyclyl.
在一个更具体的实施方式中，R’1s独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R’1s独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基。In a more specific embodiment, R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; In another more specific embodiment, R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
n3 n 3
在一个实施方式中，n3为0；在另一个实施方式中，n3为1；在另一个实施方式中，n3为2；在另一个实施方式中，n3为3。In one embodiment, n 3 is 0; in another embodiment, n 3 is 1; in another embodiment, n 3 is 2; in another embodiment, n 3 is 3.
在一个更具体的实施方式中，n3为0或1；在另一个更具体的实施方式中，n3为0。In a more specific embodiment, n 3 is 0 or 1; in another more specific embodiment, n 3 is 0.
L2 L 2
在一个实施方式中，L2为-(CR4aR4b)m1-，例如CR4aR4b，例如亚甲基；在另一个实施方式中，L2为O；在另一个实施方式中，L2为S；在另一个实施方式中，L2为NR4c。In one embodiment, L 2 is -(CR 4a R 4b ) m1 -, such as CR 4a R 4b , such as methylene; in another embodiment, L 2 is O; in another embodiment, L 2 is S; in another embodiment, L 2 is NR 4c .
R4a和R4b R 4a and R 4b
在一个实施方式中，R4a为H；在另一个实施方式中，R4a为D；在另一个实施方式中，R4a为C1-6烷基；在另一个实施方式中，R4a为C1-6卤代烷基。In one embodiment, R 4a is H; in another embodiment, R 4a is D; in another embodiment, R 4a is C 1-6 alkyl; in another embodiment, R 4a is C 1-6 haloalkyl.
在一个实施方式中，R4b为H；在另一个实施方式中，R4b为D；在另一个实施方式中，R4b为C1-6烷基；在另一个实施方式中，R4b为C1-6卤代烷基。In one embodiment, R 4b is H; in another embodiment, R 4b is D; in another embodiment, R 4b is C 1-6 alkyl; in another embodiment, R 4b is C 1-6 haloalkyl.
m1 m 1
在一个实施方式中，m1为0；在另一个实施方式中，m1为1；在另一个实施方式中，m1为2。 In one embodiment, m 1 is 0; in another embodiment, m 1 is 1; in another embodiment, m 1 is 2.
R4c R 4c
在一个实施方式中，R4c为H；在另一个实施方式中，R4c为C1-6烷基；在另一个实施方式中，R4c为C1-6卤代烷基。In one embodiment, R 4c is H; in another embodiment, R 4c is C 1-6 alkyl; in another embodiment, R 4c is C 1-6 haloalkyl.
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，例如苯基；在另一个实施方式中，R2为5-10元杂芳基，例如5-6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, such as phenyl; in another embodiment, R 2 is a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group.
在一个实施方式中，R2未被取代；在另一个实施方式中，R2被1个R2s取代；在另一个实施方式中，R2被2个R2s取代；在另一个实施方式中，R2被3个R2s取代；在另一个实施方式中，R2被4个R2s取代；在另一个实施方式中，R2被5个R2s取代；在另一个实施方式中，R2为例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如例如 In one embodiment, R 2 is unsubstituted; in another embodiment, R 2 is substituted with 1 R 2s ; in another embodiment, R 2 is substituted with 2 R 2s ; in another embodiment , R 2 is replaced by 3 R 2s ; in another embodiment, R 2 is replaced by 4 R 2s ; in another embodiment, R 2 is replaced by 5 R 2s ; in another embodiment, R 2 for For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example For example
在一个更具体的实施方式中，R2选自C6-10芳基或5-10元杂芳基；在另一个更具体的实施方式中， R2为苯基或5-6元杂芳基；在另一个更具体的实施方式中，R2选自 在另一个更具体的实施方式中，R2选自 在另一个更具体的实施方式中，R2选自 In a more specific embodiment, R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 2 is phenyl or 5-6 membered heteroaryl; in another more specific embodiment, R 2 is selected from In another more specific embodiment, R is selected from In another more specific embodiment, R is selected from
在一个更具体的实施方式中，R2任选地被1、2、3或4个R2s取代；在另一个更具体的实施方式中，R2任选地被2或3个R2s取代。In a more specific embodiment, R 2 is optionally substituted with 1, 2, 3 or 4 R 2s ; in another more specific embodiment, R 2 is optionally substituted with 2 or 3 R 2s .
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，例如F，例如Cl；在另一个实施方式中，R2s为氰基；在另一个实施方式中，R2s为-L2a-ORa，优选为ORa；在另一个实施方式中，R2s为-L2a-SRa，优选为SRa；在另一个实施方式中，R2s为-L2a-NRbRc，优选为NRbRc；在另一个实施方式中，R2s为C1-6烷基，例如Me；在另一个实施方式中，R2s为C1-6卤代烷基；在另一个实施方式中，R2s为C3-10环烷基；在另一个实施方式中，R2s为3-10元杂环基；在另一个实施方式中，R2s为C1-6烷氧基，例如OMe；在另一个实施方式中，R2s为C1-6卤代烷氧基， 例如OCHF2，例如OCF3；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, such as F, such as Cl; in another embodiment, R 2s is cyano; in another embodiment, R 2s is -L 2a -OR a , preferably OR a ; in another embodiment, R 2s is -L 2a -SR a , preferably SR a ; in another embodiment In one embodiment, R 2s is -L 2a -NR b R c , preferably NR b R c ; in another embodiment, R 2s is C 1-6 alkyl, such as Me; in another embodiment , R 2s is C 1-6 haloalkyl; in another embodiment, R 2s is C 3-10 cycloalkyl; in another embodiment, R 2s is 3-10 membered heterocyclyl; in another In one embodiment, R 2s is C 1-6 alkoxy, such as OMe; in another embodiment, R 2s is C 1-6 haloalkoxy, For example, OCHF 2 , such as OCF 3 ; in another embodiment, R 2s is
在一个更具体的实施方式中，R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R2s独立地选自H、D、卤素、氰基、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R2s独立地选自H、D、卤素、氰基或C1-6烷基；在另一个更具体的实施方式中，R2s独立地选自H、F、Cl、CN、Me、CHF2或CF3；在另一个更具体的实施方式中，R2s独立地选自H、F、Cl、CN或Me。In a more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered Heterocyclyl; in another more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment In another more specific embodiment , R 2s is independently selected from H, F, Cl , CN, Me , CHF 2 or CF 3 ; in another more specific embodiment, R 2s is independently selected from H, F, Cl, CN or Me.
在一个更具体的实施方式中，R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或在另一个更具体的实施方式中，R2s独立地选自H、D、卤素、氰基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基。In a more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or In another more specific embodiment, R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, or C 1- 4 haloalkoxy.
在一个更具体的实施方式中，R2s独立地为R2a、R2b、R2c或R2d。In a more specific embodiment, R 2s is independently R 2a , R 2b , R 2c or R 2d .
在一个更具体的实施方式中，R2a选自H、D、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；在另一个更具体的实施方式中，R2a选自H、D、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基；在另一个更具体的实施方式中，R2a选自卤素、C1-4烷基或C1-4烷氧基；在另一个更具体的实施方式中，R2a选自H、F、Me、CF3、OMe或OCHF2；在另一个更具体的实施方式中，R2a选自F、Me或OMe；在另一个更具体的实施方式中，R2a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；在另一个更具体的实施方式中，R2a选自H、F、Cl或Me；在另一个更具体的实施方式中，R2a选自H、Cl或Me；优选选自H、D或卤素；在另一个更具体的实施方式中，R2a选自H或F；在另一个更具体的实施方式中，R2a选自H、F或Me。In a more specific embodiment, R 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy; in In another more specific embodiment, R 2a is selected from H, D, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; in In another more specific embodiment, R 2a is selected from halogen, C 1-4 alkyl or C 1-4 alkoxy; in another more specific embodiment, R 2a is selected from H, F, Me, CF 3 , OMe or OCHF 2 ; in another more specific embodiment, R 2a is selected from F, Me or OMe; in another more specific embodiment, R 2a is selected from H, D, halogen, C 1 -6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl; in another more specific embodiment In a specific embodiment, R 2a is selected from H, F, Cl or Me; in another more specific embodiment, R 2a is selected from H, Cl or Me; preferably selected from H, D or halogen; in another In a more specific embodiment, R 2a is selected from H or F; in another more specific embodiment, R 2a is selected from H, F or Me.
在一个更具体的实施方式中，R2b选自H、D、卤素、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R2b选自H、D或卤素；在另一个更具体的实施方式中，R2b选自H或F；在另一个更具体的实施方式中，R2b选自H、D、卤素、C1-4烷基或C1-4卤代烷基；在另一个更具体的实施方式中，R2b选自H、F或Me；在另一个更具体的实施方式中，R2b选自H或D；优在另一个更具体的实施方式中，R2b为H；在另一个更具体的实施方式中，R2b选自H、D、C1-4烷基或C1-4卤代烷基；在另一个更具体的实施方式中，R2b选自H或Me。In a more specific embodiment, R 2b is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2b is selected from H, D Or halogen; in another more specific embodiment, R 2b is selected from H or F; in another more specific embodiment, R 2b is selected from H, D, halogen, C 1-4 alkyl or C 1 -4 haloalkyl; in another more specific embodiment, R 2b is selected from H, F or Me; in another more specific embodiment, R 2b is selected from H or D; preferably in another more specific embodiment In an embodiment, R 2b is H; in another more specific embodiment, R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl; in another more specific embodiment , R 2b is selected from H or Me.
在一个更具体的实施方式中，R2c选自H、D、卤素、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R2c选自H、D或卤素；在另一个更具体的实施方式中，R2c选自H、F或Cl；在另一个更具体的实施方式中，R2c选自H或F；在另一个更具体的实施方式中，R2c选自H、D、卤素、C1-4烷基或C1-4卤代烷基；在另一个更具体的实施方式中，R2c选自H、F或Cl；在另一个更具体的实施方式中，R2c选自卤素、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R2c为卤素；在另一个更具体的实施方式中，R2c为F。In a more specific embodiment, R 2c is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2c is selected from H, D Or halogen; in another more specific embodiment, R 2c is selected from H, F or Cl; in another more specific embodiment, R 2c is selected from H or F; in another more specific embodiment , R 2c is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl; in another more specific embodiment, R 2c is selected from H, F or Cl; in another more specific embodiment In an embodiment, R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment, R 2c is halogen; in another more specific embodiment, R 2c is F.
在一个更具体的实施方式中，R2d选自选自H、D、卤素或氰基；在另一个更具体的实施方式中，R2d为卤素或氰基；在另一个更具体的实施方式中，R2d为F、Cl或CN；在另一个更具体的实施方式 中，R2d为Cl或CN；在另一个更具体的实施方式中，R2d为F或CN。In a more specific embodiment, R 2d is selected from H, D, halogen or cyano; in another more specific embodiment, R 2d is halogen or cyano; in another more specific embodiment in, R 2d is F, Cl or CN; in another more specific embodiment In, R 2d is Cl or CN; in another more specific embodiment, R 2d is F or CN.
L3 L 3
在一个实施方式中，L3为化学键；在另一个实施方式中，L3为CR6aR6b；在另一个实施方式中，L3为O；在另一个实施方式中，L3为S；在另一个实施方式中，L3为NR6c，例如NH。In one embodiment, L 3 is a chemical bond; in another embodiment, L 3 is CR 6a R 6b ; in another embodiment, L 3 is O; in another embodiment, L 3 is S; In another embodiment, L3 is NR6c , such as NH.
R6a和R6b R 6a and R 6b
在一个实施方式中，R6a为H；在另一个实施方式中，R6a为D；在另一个实施方式中，R6a为C1-6烷基；在另一个实施方式中，R6a为C1-6卤代烷基。In one embodiment, R 6a is H; in another embodiment, R 6a is D; in another embodiment, R 6a is C 1-6 alkyl; in another embodiment, R 6a is C 1-6 haloalkyl.
在一个实施方式中，R6b为H；在另一个实施方式中，R6b为D；在另一个实施方式中，R6b为C1-6烷基；在另一个实施方式中，R6b为C1-6卤代烷基。In one embodiment, R 6b is H; in another embodiment, R 6b is D; in another embodiment, R 6b is C 1-6 alkyl; in another embodiment, R 6b is C 1-6 haloalkyl.
R6c R 6c
在一个实施方式中，R6c为H；在另一个实施方式中，R6c为C1-6烷基；在另一个实施方式中，R6c为C1-6卤代烷基。In one embodiment, R 6c is H; in another embodiment, R 6c is C 1-6 alkyl; in another embodiment, R 6c is C 1-6 haloalkyl.
R3 R 3
在一个实施方式中，R3为C3-10环烷基；在另一个实施方式中，R3为3-10元杂环基；在另一个实施方式中，R3为C6-10芳基，例如苯基，例如例如在另一个实施方式中，R3为5-10元杂芳基，例如例如 In one embodiment, R 3 is C 3-10 cycloalkyl; in another embodiment, R 3 is 3-10 membered heterocyclyl; in another embodiment, R 3 is C 6-10 aromatic group, such as phenyl, such as For example In another embodiment, R3 is 5-10 membered heteroaryl, such as For example
在一个实施方式中，R3未被取代；在另一个实施方式中，R3被1个R3s取代；在另一个实施方式中，R3被2个R3s取代；在另一个实施方式中，R3被3个R3s取代；在另一个实施方式中，R3被4个R3s取代；在另一个实施方式中，R3被5个R3s取代。In one embodiment, R 3 is unsubstituted; in another embodiment, R 3 is substituted with 1 R 3s ; in another embodiment, R 3 is substituted with 2 R 3s ; in another embodiment , R 3 is substituted with 3 R 3s ; in another embodiment, R 3 is substituted with 4 R 3s ; in another embodiment, R 3 is substituted with 5 R 3s .
在一个更具体的实施方式中，R3选自C6-10芳基或5-10元杂芳基；在另一个更具体的实施方式中，R3选自 In a more specific embodiment, R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl; in another more specific embodiment, R 3 is selected from
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D；在另一个实施方式中，R3s为卤素，例如Cl；在另一个实施方式中，R3s为氰基；在另一个实施方式中，R3s为-L3a-ORa，优选为ORa，例如OMe；在另一个实施方式中，R3s为-L3a-SRa，优选为SRa；在另一个实施方式中，R3s为-L3a-NRbRc，优选为NRbRc；在另一个实施方式中，R3s为C1-6烷基；在另一个实施方式中，R3s为C1-6卤代烷基；在另一个实施方式中，R3s为C3-10环烷基；在另一个实施方式中，R3s为3-10元杂环基；在另一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成C5-10环烷基，例如C5-7环烷基；在另一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成5-10元杂环基，例如5-7元杂环基，例如二氢呋喃基例如；在另一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成C6-10芳基，例如苯基；在另一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成5-10元杂芳基，例如5-6元杂芳基，例如吡唑基，例如 In one embodiment, R 3s is H; in another embodiment, R 3s is D; in another embodiment, R 3s is halogen, such as Cl; in another embodiment, R 3s is cyano. ; In another embodiment, R 3s is -L 3a -OR a , preferably OR a , such as OMe; in another embodiment, R 3s is -L 3a -SR a , preferably SR a ; in another embodiment In one embodiment, R 3s is -L 3a -NR b R c , preferably NR b R c ; in another embodiment, R 3s is C 1-6 alkyl; in another embodiment, R 3s is C 1-6 haloalkyl; in another embodiment, R 3s is C 3-10 cycloalkyl; in another embodiment, R 3s is 3-10 membered heterocyclyl; in another embodiment , two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl group, such as C 5-7 cycloalkyl; in another embodiment, two adjacent R 3s and the atoms to which they are connected form The atoms together form a 5-10 membered heterocyclyl group, such as a 5-7 membered heterocyclyl group, such as a dihydrofuranyl group For example; in another embodiment, two adjacent R 3s and the atoms to which they are connected together form a C 6-10 aryl group, such as phenyl; in another embodiment, two adjacent R 3s and their connected The connected atoms together form a 5-10 membered heteroaryl group, such as a 5-6 membered heteroaryl group, such as pyrazolyl, e.g.
在一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成的环基未被取代；在另一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成的环基被1个R3ss取代；在另一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成的环基被2个R3ss取代；在另一个实施方式中，两个相邻的R3s以及它们连接的原子共同形成的环基被3个R3ss取代。In one embodiment, the ring group formed by two adjacent R 3s and the atoms to which they are connected is unsubstituted; in another embodiment, the ring group formed by two adjacent R 3s and the atoms to which they are connected together is unsubstituted. The group is replaced by 1 R 3ss ; in another embodiment, the ring group formed by two adjacent R 3s and the atoms they are connected to is replaced by 2 R 3ss ; in another embodiment, two adjacent R 3ss The ring group formed by the R 3s and the atoms to which they are connected is replaced by 3 R 3ss .
在一个更具体的实施方式中，R3s选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R3s选自H、D、卤素、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R3s选自H、D、卤素、ORa、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R3s选自H、D、Cl、OMe或Me；在另一个更具体的实施方式中，R3s为Cl或Me。In a more specific embodiment, R 3s is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3- 10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3s is selected from H, D, halogen, OR a , SR a , NR b R c , C 1-6 alkyl Or C 1-6 haloalkyl; in another more specific embodiment, R 3s is selected from H, D, halogen, OR a , C 1-6 alkyl or C 1-6 haloalkyl; in another more specific embodiment In an embodiment, R 3s is selected from H, D, Cl, OMe or Me; in another more specific embodiment, R 3s is Cl or Me.
在一个更具体的实施方式中，两个相邻的R3s以及它们连接的原子共同形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基；在另一个更具体的实施方式中，两个相邻的R3s以及它们连接的原子共同形成5-7元杂环基或5-6元杂芳基；在另一个更具体的实施方式中，两个相邻的R3s以及它们连接的原子共同形成吡唑基或二氢呋喃基；在另一个更具体的实施方式中，两个相邻的R3s以及它们连接的原子共同形成 In a more specific embodiment, two adjacent R 3s and the atoms to which they are connected together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; In another more specific embodiment, two adjacent R 3s and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group; in another more specific embodiment, Two adjacent R 3s and the atoms to which they are connected together form pyrazolyl or dihydrofuranyl; in another more specific embodiment, two adjacent R 3s and the atoms to which they are connected together form
R3ss R 3ss
在一个实施方式中，R3ss为H；在另一个实施方式中，R3ss为D；在另一个实施方式中，R3ss为卤素；在另一个实施方式中，R3ss为氰基；在另一个实施方式中，R3ss为-L3b-ORa，优选ORa；在另一个实施方式中，R3ss为-L3b-SRa，优选SRa；在另一个实施方式中，R3ss为-L3b-NRbRc，优选NRbRc；在另一个实施方式中，R3ss为C1-6烷基，例如Me；在另一个实施方式中，R3ss为C1-6卤代烷基；在另一个 实施方式中，R3ss为C3-10环烷基；在另一个实施方式中，R3ss为3-10元杂环基；在另一个实施方式中，R3ss为C3-10芳基；在另一个实施方式中，R3ss为3-10元杂芳基；In one embodiment, R 3ss is H; in another embodiment, R 3ss is D; in another embodiment, R 3ss is halogen; in another embodiment, R 3ss is cyano; in another In one embodiment, R 3ss is -L 3b -OR a , preferably OR a ; in another embodiment, R 3ss is -L 3b -SR a , preferably SR a ; in another embodiment, R 3ss is -L 3b -NR b R c , preferably NR b R c ; in another embodiment, R 3ss is C 1-6 alkyl, such as Me; in another embodiment, R 3ss is C 1-6 haloalkyl base; on another In one embodiment, R 3ss is C 3-10 cycloalkyl; in another embodiment, R 3ss is 3-10 membered heterocyclyl; in another embodiment, R 3ss is C 3-10 aryl; In another embodiment, R 3ss is 3-10 membered heteroaryl;
在一个更具体的实施方式中，R3ss独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R3ss独立地选自H、D、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，R3ss独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，R3ss独立地选自H、D、C1-6烷基或C1-6卤代烷基。In a more specific embodiment, R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3ss is independently selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; in another more specific embodiment, R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ; In another more specific embodiment, R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl.
L1c、L1d、L2a、L3a和L3b L 1c , L 1d , L 2a , L 3a and L 3b
在一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地为化学键；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地为C1-6亚烷基，例如C1-3亚烷基；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地为C2-6亚烯基；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地为C2-6亚炔基；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地为未被取代；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地被1个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地被2个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地被3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地被1个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地被2个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代；在另一个实施方式中，L1c、L1d、L2a、L3a和L3b独立地被3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代。In one embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently chemical bonds; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently C 1-6 alkylene, such as C 1-3 alkylene; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently C 2-6 alkenylene; in another In one embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently C 2-6 alkynylene; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b is independently unsubstituted; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl groups are substituted; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently substituted by 2 Substituted with a group selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently 3 selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkyne group; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently selected from H, D, halogen, C 1-6 alkyl or C 1- 6 haloalkyl groups substituted; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently substituted by 2 selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl groups substituted; in another embodiment, L 1c , L 1d , L 2a , L 3a and L 3b are independently substituted by 3 selected from H, D, halogen, C 1-6 alkyl Or substituted with a C 1-6 haloalkyl group.
在一个更具体的实施方式中，L1c、L1d、L2a、L3a和L3b各自独立地选自化学键或C1-6亚烷基，其任选被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代。In a more specific embodiment, each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from a chemical bond or a C 1-6 alkylene group, which is optionally selected from 1, 2 or 3 H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl group substitution.
Ra、Rb和Rc R a , R b and R c
在一个实施方式中，Ra、Rb和Rc独立地为H；在另一个实施方式中，Ra、Rb和Rc独立地为C1-6烷基，例如Me；在另一个实施方式中，Ra、Rb和Rc独立地为C1-6卤代烷基；在另一个实施方式中，Ra、Rb和Rc独立地为C3-10环烷基，例如C3-7环烷基；在另一个实施方式中，Ra、Rb和Rc独立地为3-10元杂环基，例如3-7元杂环基；在另一个实施方式中，Ra、Rb和Rc独立地为C6-10芳基；在另一个实施方式中，Ra、Rb和Rc独立地为5-10元杂芳基；在另一个实施方式中，Rb、Rc以及他们连接的原子一起形成3-10元杂环基，例如形成3-7元杂环基。In one embodiment, Ra , Rb , and Rc are independently H; in another embodiment, Ra , Rb, and Rc are independently C 1-6 alkyl, such as Me; in another In one embodiment, R a , R b and R c are independently C 1-6 haloalkyl; in another embodiment, R a , R b and R c are independently C 3-10 cycloalkyl, such as C 3-7 cycloalkyl; in another embodiment, R a , R b and R c are independently 3-10 membered heterocyclyl, such as 3-7 membered heterocyclyl; in another embodiment, R a , R b and R c are independently C 6-10 aryl; in another embodiment, Ra , R b and R c are independently 5-10 membered heteroaryl; in another embodiment, R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclyl group, for example, a 3-7 membered heterocyclyl group.
在一个更具体的实施方式中，Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；在另一个更具体的实施方式中，Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；在另一个更具体的实施方式中，Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；在另一个更具体的实施方式中，Rb、Rc以及他们连接的原子一起 形成3-7元杂环基。In a more specific embodiment, R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered Heterocyclyl; in another more specific embodiment, R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl Or 3-7 membered heterocyclyl; in another more specific embodiment, R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; in another In a more specific embodiment, R b , R c and the atoms to which they are connected together Forms 3-7 membered heterocyclyl.
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，环A的任一技术方案或其任意组合，可以与Y、R7、R1s、L1a、L1b、R1a、R1as、n1、n2、R5a、R5b、R1b、R1c、R’1s、n3、L2、R4a、R4b、m1、R4c、R2、R2s、L3、R6a、R6b、R6c、R3、R3s、R3ss、L1c、L1d、L2a、L3a、L3b、Ra、Rb和Rc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 ring A or any combination thereof can be combined with Y, R 7 , R 1s , L 1a , L 1b , R 1a , R 1as , n 1 , n 2 , R 5a , R 5b , R 1b , R 1c , R' 1s , n 3 , L 2 , R 4a , R 4b , m 1 , R 4c , R 2 , R 2s , L 3 , R 6a , R 6b , R 6c , R 3 , R 3s , Any technical solutions of R 3ss , L 1c , L 1d , L 2a , L 3a , L 3b , R a , R b and R c or any combination thereof are combined. 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;
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;
R1s为-C(O)NR1bR1c或 R 1s is -C(O)NR 1b R 1c or
L1a选自化学键、O、S或NR5a；L 1a is selected from chemical bond, O, S or NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a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、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R1as取代；R 1a 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 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、-L1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1b选自H、C1-6烷基或C1-6卤代烷基；R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
R’1s独立地选自H、D、卤素、氰基、-L1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
L2选自-(CR4aR4b)m1-、O、S或NR4c； L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
R4a和R4b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m1为0、1或2；m 1 is 0, 1 or 2;
R4c选自H、C1-6烷基或C1-6卤代烷基；R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
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，其任选地被1、2、3、4或5个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, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
R2s独立地选自H、D、卤素、氰基、-L2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基；R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
L3选自化学键、CR6aR6b、O、S或NR6c；L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
R6a和R6b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R6c选自H、C1-6烷基或C1-6卤代烷基；R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R3选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2、3、4或5个R3s取代；R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
R3s独立地选自H、D、卤素、氰基、-L3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
或者两个相邻的R3s以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
R3ss独立地选自H、D、卤素、氰基、-L3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C3-10芳基或3-10元杂芳基；R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
L1c、L1d、L2a、L3a和L3b各自独立地选自化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基或5-10元杂芳基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
条件是，当环A为吡啶基，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基；且所述化合物不为如下结构：
The condition is that when ring A is a pyridyl group, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group; and the compound does not have the following structure:
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;
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;
R1s为或-C(O)NR1bR1c；R 1s is or -C(O)NR 1b R 1c ;
L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally substituted with 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、-L1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1b选自H、C1-6烷基或C1-6卤代烷基；R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
R’1s独立地选自H、D、卤素、氰基、-L1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
L2选自-(CR4aR4b)m1-、O、S或NR4c；L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
R4a和R4b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
m1为0、1或2；m 1 is 0, 1 or 2;
R4c选自H、C1-6烷基或C1-6卤代烷基；R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
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，其任选地被1、2、3、4或5个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, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
R2s独立地选自H、D、卤素、氰基、-L2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
L3选自化学键、CR6aR6b、O、S或NR6c；L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
R6a和R6b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
R6c选自H、C1-6烷基或C1-6卤代烷基； R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R3选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2、3、4或5个R3s取代；R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
R3s独立地选自H、D、卤素、氰基、-L3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
或者两个相邻的R3s以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
R3ss独立地选自H、D、卤素、氰基、-L3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C3-10芳基或3-10元杂芳基；R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
L1c、L1d、L2a、L3a和L3b各自独立地选自化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基或5-10元杂芳基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
条件是，当环A为吡啶基，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基；且所述化合物不为如下结构：
The condition is that when ring A is pyridyl, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group; and the compound does not have the following structure:
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，其中，Y为N。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, wherein Y is N.
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，其中，环A为C6-10芳基或5-10元杂芳基；优选为苯基或5-6元杂芳基；优选为5-6元杂芳基，优选为吡啶基或噻唑基；优选为吡啶基；优选为更优选为 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, wherein ring A is a C 6-10 aryl group or a 5-10 membered heteroaryl group; preferably a phenyl group or a 5-6 membered heteroaryl group; preferably a 5-6 membered heteroaryl group, Preferably it is pyridyl or thiazolyl; preferably it is pyridyl; preferably it is More preferably
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，其中，R1s选自 优选选自 优选选自 优选选自 更优选不为 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, wherein R 1s is selected from Preferably selected from Preferably selected from Preferably selected from More preferably not
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，其中，L1a选自O、S、NH或NMe；优选选自O、S或NH；优选为O或NH；优选为O或S；优选为O；优选为S。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, wherein L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH; preferably O or NH; preferably O or S; preferably O; preferably S.
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，其中，L1b为化学键。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, where L 1b is a chemical bond.
优选地，L1b选自O、S或NR5b；优选选自O或NR5b；优选选自O、S或NMe；优选选自O或S；优选选自O或NMe；优选为O。Preferably, L 1b is selected from O, S or NR 5b ; preferably selected from O or NR 5b ; preferably selected from O, S or NMe; preferably selected from O or S; preferably selected from O or NMe; preferably O.
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，其中，R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自C1-6烷基、C1-6卤代烷基、C3-5环烷基或3-5元杂环基；优选选自C1-6烷基、C1-6卤代烷基或 C3-5环烷基；优选选自C1-6烷基或C1-6卤代烷基；优选选自Me、 优选选自Me、优选为Me。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, wherein R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from C 1-6 Alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl Or 3-5 membered heterocyclyl; preferably selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl; preferably selected from C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from Me, Preferably selected from Me, Me is preferred.
优选地，R1a选自C3-10环烷基或3-10元杂环基；优选选自C3-7环烷基或3-7元杂环基；优选为3-7元杂环基；优选为4-5元杂环基；优选为5元杂环基；优选选自 优选为 Preferably, R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably 3-7 membered heterocyclic group; preferably a 4-5-membered heterocyclic group; preferably a 5-membered heterocyclic group; preferably selected from Preferably
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，其中，R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、ORa、SRa、NRbRc、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；优选选自H、D、C1-6烷基或C1-6卤代烷基；优选为Me。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, wherein R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3 -10-membered heterocyclyl; preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7-membered heterocyclyl; preferably Selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
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，其中，n1选自0、1、2或3；优选选自0、1或2；优选选自1、2或3；优选为0；优选为1；优选为2。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, wherein n 1 is selected from 0, 1, 2 or 3; preferably selected from 0, 1 or 2; preferably selected from 1, 2 or 3; preferably 0; preferably 1; preferably 2 .
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，其中，n2选自0、1、2或3；优选选自0或1；优选为0。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, wherein n 2 is selected from 0, 1, 2 or 3; preferably selected from 0 or 1; preferably 0.
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，其中，R5a为H或Me；优选为H。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, wherein R 5a is H or Me; preferably H.
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，其中，R5b选自C1-6烷基或C1-6卤代烷基；优选为Me。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, wherein R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
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，其中，R1b为H；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, wherein R 1b is H;
优选地，R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、C1-6烷基或C1-6卤代烷基；优选为C1-6烷基或C1-6卤代烷基；优选为Me。Preferably, R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from H, C 1-6 alkyl Or C 1-6 haloalkyl; preferably C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
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，其中，R’1s独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基。 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, wherein R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; Preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
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，其中，n3为0或1；优选为0。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, wherein n 3 is 0 or 1; preferably 0.
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，n3为1、2或3；优选为0或1；优选为0。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, n 3 is 1, 2 or 3; preferably 0 or 1; preferably 0.
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，其中，L2为-(CR4aR4b)m1-；优选为亚甲基。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, wherein L 2 is -(CR 4a R 4b ) m1 -; preferably it is methylene.
优选地，m1为1。Preferably, m 1 is 1.
优选地，R4a和R4b为H。Preferably, R 4a and R 4b are H.
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，其中R2选自C6-10芳基或5-10元杂芳基；优选为苯基或5-6元杂芳基；优选为苯基。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, wherein R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably phenyl.
优选地，R2任选地被1、2、3或4个R2s取代。Preferably, R 2 is optionally substituted with 1, 2, 3 or 4 R 2s .
优选地，R2任选地被2或3个R2s取代。Preferably, R 2 is optionally substituted by 2 or 3 R 2s .
优选地，R2选自 优选选自 优选选自 Preferably, R 2 is selected from Preferably selected from Preferably selected from
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，其中，R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、氰基、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、氰基或C1-6烷基；优选选自H、F、Cl、CN、Me、CHF2或CF3；优选选自H、F、Cl、CN或Me。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, wherein R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl; preferably selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl; preferably Selected from H, F, Cl, CN, Me, CHF 2 or CF 3 ; preferably selected from H, F, Cl, CN or Me.
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，其中，L3为NR6c；优选为NH。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, wherein L 3 is NR 6c ; preferably NH.
优选地，R6a和R6b为H。Preferably, R 6a and R 6b are H.
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，其中，R3选自C6-10芳基或5-10元杂芳基；优选为 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, wherein R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl; preferably
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，其中，R3s选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、ORa、C1-6烷基或C1-6卤代烷基；优选选自H、D、Cl、OMe或Me；优选为Cl或Me。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, wherein R 3s is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3- 10- cycloalkyl or 3-10-membered heterocyclyl; preferably selected from H, D, halogen, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, OR a , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, Cl, OMe or Me; preferably Cl or Me.
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，其中，两个相邻的R3s以及它们连接的原子共同形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基；优选形成5-7元杂环基或5-6元杂芳基；优选形成吡唑基或二氢呋喃基；优选形成优选形成 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, in which two adjacent R 3s and the atoms they are connected together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl; It is preferred to form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group; it is preferred to form a pyrazolyl or dihydrofuranyl group; it is preferred to form Preferably form
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，其中，R3ss独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；优选选自H、D、C1-6烷基或C1-6卤代烷基；优选为Me。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, wherein R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocycle Group; preferably selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
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，其中，L1c、L1d、L2a、L3a和L3b各自 独立地选自化学键或C1-6亚烷基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代；优选选自化学键或C1-3亚烷基。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, wherein each of L 1c , L 1d , L 2a , L 3a and L 3b Independently selected from chemical bonds or C 1-6 alkylene, optionally substituted by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl ; Preferably selected from chemical bonds or C 1-3 alkylene groups.
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，其中，Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、C1-6烷基或C1-6卤代烷基；优选为C1-6烷基或C1-6卤代烷基；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, wherein R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl; preferably selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, C 1-6 alkyl Or C 1-6 haloalkyl; preferably C 1-6 alkyl or C 1-6 haloalkyl;
或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基；优选形成3-7元杂环基。Or R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclyl group; preferably, a 3-7 membered heterocyclyl group is formed.
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，其具有以下结构式：

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 has the following structural formula:

其中，in,
m2为1、2、3或4；m 2 is 1, 2, 3 or 4;
X1为CR3b或N，X2为CR3c或N；X 1 is CR 3b or N, X 2 is CR 3c or N;
或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
R3b选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3b is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl;
R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
或者R3b与R3c以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1 , 2 or 3 R 3ss replacement;
R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C1-6烷氧基或C1-6卤代烷氧基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl , C 1-6 alkoxy or C 1-6 haloalkoxy;
R2d选自H、D、卤素或氰基；R 2d is selected from H, D, halogen or cyano;
R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
其余各基团如本发明所定义。The remaining groups are as defined in the present invention.
在更具体的实施方案中，本发明提供了上述式(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 present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
其中，in,
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;
R1s为或-C(O)NR1bR1c；R 1s is or -C(O)NR 1b R 1c ;
L1a选自O、S或NR5a； L 1a is selected from O, S or NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、ORa、SRa、NRbRc、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1b独立地选自H、C1-6烷基或C1-6卤代烷基；R 1b is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
R’1s独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
m2为1、2、3或4；m 2 is 1, 2, 3 or 4;
X1为CR3b或N，X2为CR3c或N；X 1 is CR 3b or N, X 2 is CR 3c or N;
或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
R3b选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3b is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl;
R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
或者R3b与R3c以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1 , 2 or 3 R 3ss replacement;
R3ss独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; or R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclic group;
其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
条件是，当环A为吡啶基时，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基，且所述化合物不为如下结构：
The condition is that when ring A is a pyridyl group, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group, and the compound does not have the following structure:
在更具体的实施方案中，本发明提供了上述式(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 present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
环A为苯基或5-6元杂芳基；Ring A is phenyl or 5-6 membered heteroaryl;
R1s为或-C(O)NHR1c；优选为 R 1s is or -C(O)NHR 1c ; preferably
L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
n1和n2独立地选自0、1、2或3；n 1 and n 2 are independently selected from 0, 1, 2 or 3;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H;
R1c选自H、C1-6烷基或C1-6卤代烷基；R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R’1s独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n3为0或1；n 3 is 0 or 1;
R2s独立地选自H、D、卤素、氰基、C1-6烷基或C1-6卤代烷基；R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
m2为1、2、3或4；m 2 is 1, 2, 3 or 4;
X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3b选自ORa、SRa或NRbRc；优选为ORa或SRa；R 3b is selected from OR a , SR a or NR b R c ; preferably OR a or SR a ;
R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
或者R3b与R3c以及它们连接的原子共同形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
R3ss独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；或者Rb、Rc以及他们连接的原子一起形成3-7元杂环基。R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; or R b , R c and the atoms to which they are connected together form a 3-7 membered heterocyclyl group.
在更具体的实施方案中，本发明提供了上述式(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 present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
环A为5-6元杂芳基，优选为吡啶基或噻唑基；Ring A is a 5-6 membered heteroaryl group, preferably pyridyl or thiazolyl;
R1s为或-C(O)NHR1c；优选为 R 1s is or -C(O)NHR 1c ; preferably
L1a选自O、S、NR5a；L 1a is selected from O, S, NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C3-5环烷基或3-5元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基； R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n1选自0、1或2；n 1 is selected from 0, 1 or 2;
n2选自0或1；n 2 is selected from 0 or 1;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H；优选R5b为C1-6烷基或C1-6卤代烷基，优选为Me；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H; preferably R 5b is C 1-6 alkyl or C 1-6 haloalkyl, preferably for Me;
R1c选自C1-6烷基或C1-6卤代烷基；R 1c is selected from C 1-6 alkyl or C 1-6 haloalkyl;
n3为0；n 3 is 0;
R2s独立地选自H、D、卤素、氰基、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、氰基或C1-6烷基；R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl;
m2为2或3；m 2 is 2 or 3;
X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
R3a为卤素；R 3a is halogen;
R3b为ORa；R 3b is OR a ;
R3c、R3d和R3e独立地为H或D；R 3c , R 3d and R 3e are independently H or D;
或者R3b与R3c以及它们连接的原子共同形成5-7元杂环基或5-6元杂芳基，优选形成吡唑基或二氢呋喃基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, preferably a pyrazolyl group or a dihydrofuranyl group, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
R3ss独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
Ra选自H、C1-6烷基或C1-6卤代烷基，优选为C1-6烷基或C1-6卤代烷基。R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(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 present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
环A为 Ring A is
R1s为或C(O)NHCH3；优选为 R 1s is Or C(O)NHCH 3 ; preferably
L1a选自O、S、NH或NMe；优选选自O、S或NH；L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH;
L1b选自O、S或NMe；L 1b is selected from O, S or NMe;
R1a选自Me、 R 1a is selected from Me,
n1选自0、1或2；n 1 is selected from 0, 1 or 2;
n2选自0或1；n 2 is selected from 0 or 1;
n3为0；n 3 is 0;
R2s独立地选自H、F、Cl、CN、Me、CHF2或CF3，优选选自H、F、Cl、CN或Me；R 2s is independently selected from H, F, Cl, CN, Me, CHF 2 or CF 3 , preferably selected from H, F, Cl, CN or Me;
m2为2或3；m 2 is 2 or 3;
X1为CR3b，X2为CR3c； X 1 is CR 3b , X 2 is CR 3c ;
或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
R3a为Cl；R 3a is Cl;
R3b为OMe；R 3b is OMe;
R3c、R3d和R3e为H；R 3c , R 3d and R 3e are H;
或者R3b与R3c以及它们连接的原子共同形成 Or R 3b together with R 3c and the atoms to which they are connected form
优选地，R1s选自 Preferably, R 1s is selected from
优选地，环A及其上的取代基共同形成： Preferably, Ring A and the substituents thereon together form:
优选地，选自 Preferably, Selected from
优选地，选自 Preferably, Selected from
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
其中，in,
L1a选自O、S或NR5a； L 1a is selected from O, S or NR 5a ;
L1b选自O、S或NR5b；L 1b is selected from O, S or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
n1选自1、2、3、4、5或6；n 1 is selected from 1, 2, 3, 4, 5 or 6;
n2选自0、1、2、3、4、5或6；n 2 is selected from 0, 1, 2, 3, 4, 5 or 6;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
R2d选自H、D、卤素或氰基；R 2d is selected from H, D, halogen or cyano;
R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；优选为O；优选为S；L 1a is selected from O or S; preferably O; preferably S;
L1b选自O、S或NR5b；优选为O或NR5b；L 1b is selected from O, S or NR 5b ; preferably O or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, D, halogen , C 1-6 alkyl or C 1-6 haloalkyl;
n1选自1、2或3；优选为2；n 1 is selected from 1, 2 or 3; preferably 2;
n2选自0、1、2或3；优选为0或1；n 2 is selected from 0, 1, 2 or 3; preferably 0 or 1;
R5b选自H、C1-6烷基或C1-6卤代烷基；优选为C1-3烷基或C1-3卤代烷基；R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably C 1-3 alkyl or C 1-3 haloalkyl;
R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基。R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
优选地，Preferably,
R2a选自卤素、C1-6烷基或C1-6卤代烷基；R 2a is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2b为H；R 2b is H;
R2c选自H、D或卤素；R 2c is selected from H, D or halogen;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt or isotopic modification thereof. isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
L1a选自O或S；L 1a is selected from O or S;
L1b选自O或S；L 1b is selected from O or S;
R1a选自C1-6烷基、C1-6卤代烷基或C3-5环烷基；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
n1为2；n 1 is 2;
n2为0或1；n 2 is 0 or 1;
R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基。R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
L1b为O；L 1b is O;
R1a选自C1-6烷基或C1-6卤代烷基；R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl;
n1为2；n 1 is 2;
n2为0；n 2 is 0;
R2a、R2c和R2d独立地为卤素；R 2a , R 2c and R 2d are independently halogen;
R2b为H或D；R 2b is H or D;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
L1b选自O或NMe；优选为O；L 1b is selected from O or NMe; preferably O;
R1a选自Me、优选为Me；R 1a is selected from Me, Preferably Me;
n1为2；n 1 is 2;
n2为0或1；优选0；n 2 is 0 or 1; preferably 0;
R2a选自F或Me；优选为F；R 2a is selected from F or Me; preferably F;
R2b为H；R 2b is H;
R2c选自H或F；更优选为F；R 2c is selected from H or F; more preferably, it is F;
R2d选自F、Cl或CN；优选为F或Cl；R 2d is selected from F, Cl or CN; preferably F or Cl;
R3a为Cl；R 3a is Cl;
R3f为Me。 R 3f is Me.
优选地，选自：优选为 Preferably, Selected from: Preferably
优选地，选自：优选为 Preferably, Selected from: Preferably
在更具体的实施方案中，本发明提供了上述式(III-2)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 compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
其中，in,
L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
R1a选自C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
n1选自1、2、3、4、5或6；n 1 is selected from 1, 2, 3, 4, 5 or 6;
R5a选自H、C1-6烷基或C1-6卤代烷基；R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
R2d选自H、D、卤素或氰基；R 2d is selected from H, D, halogen or cyano;
R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基； R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(III-2)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 compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；优选为O；优选为S；L 1a is selected from O or S; preferably O; preferably S;
R1a为C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n1选自1、2或3；n 1 is selected from 1, 2 or 3;
R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基。R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-2)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 compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
R1a为3-7元杂环基，优选为4-5元杂环基，其任选地被1、2或3个R1as取代；R 1a is a 3-7-membered heterocyclyl group, preferably a 4-5-membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as选自H、D、C1-6烷基或C1-6卤代烷基；优选为Me；R 1as is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me;
n1为1；n 1 is 1;
R2a、R2c和R2d独立地为卤素；R 2a , R 2c and R 2d are independently halogen;
R2b为H或D；R 2b is H or D;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-2)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 compound of formula (III-2) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
R1a选自 R 1a is selected from
n1为1；n 1 is 1;
为 for
R3a为Cl；R 3a is Cl;
R3f为Me。 R 3f is Me.
优选地，选自： Preferably, Selected from:
在更具体的实施方案中，本发明提供了上述式(III-3)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 compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
其中，in,
L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
R1a选自C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
R5a选自H、C1-6烷基或C1-6卤代烷基；R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
R2d选自H、D、卤素或氰基；R 2d is selected from H, D, halogen or cyano;
R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(III-3)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 compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O、S或NH；优选为O或NH；优选为S；L 1a is selected from O, S or NH; preferably O or NH; preferably S;
R1a为C3-7环烷基或3-7元杂环基，优选为3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基。R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-3)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 (III-3), or a pharmaceutically acceptable salt or isotopic modification thereof. isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
L1a选自O、S或NH；优选为O或NH；L 1a is selected from O, S or NH; preferably O or NH;
R1a为4-6元杂环基，优选为5元杂环基，优选为四氢呋喃基，其任选地被1、2或3个R1as取代；R 1a is a 4-6 membered heterocyclyl group, preferably a 5-membered heterocyclyl group, preferably a tetrahydrofuranyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2b选自H、D或卤素；R 2b is selected from H, D or halogen;
R2c为卤素；R 2c is halogen;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-3)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，当R1a与L1a的连接原子为手性碳原子时，为为 In a more specific embodiment, the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom of R 1a and L 1a is a chiral carbon atom, it is for
在更具体的实施方案中，本发明提供了上述式(III-3)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 compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O、S或NH；优选为O或NH；L 1a is selected from O, S or NH; preferably O or NH;
R1a选自优选为更优选为 R 1a is selected from Preferably More preferably
R2a为H、F、Cl或Me；R 2a is H, F, Cl or Me;
R2b为H或F；R 2b is H or F;
R2c为F或Cl；优选为F；R 2c is F or Cl; preferably F;
R2d为F、Cl或CN；R 2d is F, Cl or CN;
R3a为Cl；R 3a is Cl;
R3f为Me。R 3f is Me.
优选地，选自：优选不为更优选为 Preferably, Selected from: Prefer not to More preferably
优选地，选自： 优选选自 Preferably, Selected from: Preferably selected from
在更具体的实施方案中，本发明提供了上述式(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 present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate,
其中，in,
环A为苯基或5-6元杂芳基；Ring A is phenyl or 5-6 membered heteroaryl;
R1s为-C(O)NHR1c或 R 1s is -C(O)NHR 1c or
L1a选自化学键、O、S或NR5a；L 1a is selected from chemical bond, O, S or NR 5a ;
L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, Phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、氰基、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 1as is independently selected from H, D, halogen, cyano, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered hetero Ring group;
n1和n2独立地选自0、1、2或3；n 1 and n 2 are independently selected from 0, 1, 2 or 3;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H;
R1c选自H、C1-6烷基或C1-6卤代烷基；R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R’1s独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n3为0或1；n 3 is 0 or 1;
R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或 R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or
m2为1、2、3或4； m 2 is 1, 2, 3 or 4;
X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3b选自ORa、SRa或NRbRc；优选为ORa或SRa；R 3b is selected from OR a , SR a or NR b R c ; preferably OR a or SR a ;
R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
或者R3b与R3c以及它们连接的原子共同形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
R3ss独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
条件是，当环A为吡啶基时，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基，且所述化合物不为如下结构：
The condition is that when ring A is a pyridyl group, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group, and the compound does not have the following structure:
在更具体的实施方案中，本发明提供了上述式(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 present invention provides the compound of formula (II) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, Hydrate or solvate, wherein,
环A为5-6元杂芳基，优选为吡啶基或噻唑基，优选为吡啶基，优选为 Ring A is a 5-6 membered heteroaryl group, preferably pyridyl or thiazolyl, preferably pyridyl, preferably
R1s为优选为 R 1s is Preferably
L1a选自O、S、NR5a；L 1a is selected from O, S, NR 5a ;
L1b选自化学键、O或NR5b；L 1b is selected from chemical bond, O or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
n1选自0、1或2；n 1 is selected from 0, 1 or 2;
n2选自0、1或2；n 2 is selected from 0, 1 or 2;
R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H；优选R5b为C1-3烷基或C1-3卤代烷基； R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H; preferably R 5b is C 1-3 alkyl or C 1-3 haloalkyl;
n3为0；n 3 is 0;
R2s独立地选自H、D、卤素、氰基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基；R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;
m2为2或3；m 2 is 2 or 3;
X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
R3a为卤素；R 3a is halogen;
R3b为ORa；优选为OMe；R 3b is OR a ; preferably OMe;
R3c、R3d和R3e独立地为H或D；R 3c , R 3d and R 3e are independently H or D;
或者R3b与R3c以及它们连接的原子共同形成5-7元杂环基或5-6元杂芳基，其任选地被1、2或3个R3ss取代；优选形成 Or R 3b and R 3c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 3ss ; preferably, it forms
R3ss独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基。R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，选自 优选优选 In a more specific embodiment, Selected from preferred preferred
在更具体的实施方案中，当L1b为化学键时，R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基。In a more specific embodiment, when L 1b is a chemical bond, R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, or 5-6 membered heteroaryl.
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
其中，in,
L1a选自O或S； L 1a is selected from O or S;
L1b选自O、S或NR5b；L 1b is selected from O, S or NR 5b ;
R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, It is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、CN、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, D , halogen, C 1-6 alkyl or C 1-6 haloalkyl;
n1选自1、2或3；n 1 is selected from 1, 2 or 3;
n2选自0、1、2或3；n 2 is selected from 0, 1, 2 or 3;
R5b选自H、C1-6烷基或C1-6卤代烷基；R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
R2a选自H、D、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 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自选自H、D、卤素或氰基；优选为卤素或氰基；R 2d is selected from H, D, halogen or cyano; preferably halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；L 1a is selected from O or S;
L1b为O或NR5b；优选为O；L 1b is O or NR 5b ; preferably O;
R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-5环烷基或3-5元杂环基；优选为C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C3-5环烷基；优选为C1-6烷基、C1-6卤代烷基或C3-5环烷基；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl or 3-5 membered heterocyclyl; Preferably it is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-5 cycloalkyl; preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
n1为2；n 1 is 2;
n2为0、1或2；n 2 is 0, 1 or 2;
R5b为C1-3烷基或C1-3卤代烷基，优选为Me；R 5b is C 1-3 alkyl or C 1-3 haloalkyl, preferably Me;
R2a选自H、D、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基；优选为卤素、C1-4烷基或C1-4烷氧基；R 2a is selected from H, D, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; preferably halogen, C 1-4 alkyl or C 1-4 alkoxy;
R2b为H、D或卤素；R 2b is H, D or halogen;
R2c选自H、D或卤素；R 2c is selected from H, D or halogen;
R2d为卤素或CN；R 2d is halogen or CN;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-1)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 compound of formula (III-1) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
L1b选自O或NMe；优选为O； L 1b is selected from O or NMe; preferably O;
R1a选自Me、OMe、环丙基或优选为Me、OMe或环丙基；优选为Me或环丙基；R 1a is selected from Me, OMe, cyclopropyl or Preferably it is Me, OMe or cyclopropyl; Preferably it is Me or cyclopropyl;
n1为2；n 1 is 2;
n2为0、1或2；优选0或1；n 2 is 0, 1 or 2; preferably 0 or 1;
R2a选自H、F、Me、CF3、OMe或OCHF2；优选为F、Me或OMe；R 2a is selected from H, F, Me, CF 3 , OMe or OCHF 2 ; preferably F, Me or OMe;
R2b为H或F；R 2b is H or F;
R2c选自H、F或Cl；更优选为H或F；R 2c is selected from H, F or Cl; more preferably H or F;
R2d选自F、Cl或CN；优选为Cl或CN；R 2d is selected from F, Cl or CN; preferably Cl or CN;
R3a为Cl；R 3a is Cl;
R3f为Me。R 3f is Me.
在更具体的实施方案中，选自： 优选为优选为 In a more specific embodiment, Selected from: Preferably Preferably
在更具体的实施方案中，选自： 优选为 In a more specific embodiment, Selected from: Preferably
在更具体的实施方案中，本发明提供了上述式(III-3)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 compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
其中，in,
L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
R1a为C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
R5a选自H、C1-3烷基或C1-3卤代烷基；优选R5a为H；R 5a is selected from H, C 1-3 alkyl or C 1-3 haloalkyl; preferably R 5a is H;
R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(III-3)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 compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O、S或NH；L 1a is selected from O, S or NH;
R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、F、Me、NH2、-NHCH3或-NH(CH3)2；优选选自H、F、Me、NH2或-NHCH3；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, F, Me, NH 2 , -NHCH 3 or -NH ( CH 3 ) 2 ; preferably selected from H, F, Me, NH 2 or -NHCH 3 ;
R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R2b选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2b is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R2c为H、D或卤素；R 2c is H, D or halogen;
R2d为卤素或氰基；R 2d is halogen or cyano;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基；R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基。R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(III-3)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，当R1a与L1a的连接原子为手性碳原子时，为为 In a more specific embodiment, the present invention provides the compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom of R 1a and L 1a is a chiral carbon atom, it is for
在更具体的实施方案中，本发明提供了上述式(III-3)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 compound of formula (III-3) above, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
L1a选自O、S或NH；L 1a is selected from O, S or NH;
R1a选自 优选选自： 优选地，为 R 1a is selected from Preferably selected from: Preferably, for
R2a为H、F、Cl或Me；R 2a is H, F, Cl or Me;
R2b为H、F或Me；R 2b is H, F or Me;
R2c为H、F或Cl；R 2c is H, F or Cl;
R2d为F、Cl或CN；R 2d is F, Cl or CN;
R3a为Cl；R 3a is Cl;
R3f为Me。R 3f is Me.
在更具体的实施方案中，选自： 优选选自： In a more specific embodiment, Selected from: Preferably selected from:
在更具体的实施方案中，为 In a more specific embodiment, for
在更具体的实施方案中，为 In a more specific embodiment, for
在更具体的实施方案中，为 In a more specific embodiment, for
在更具体的实施方案中，选自： In a more specific embodiment, Selected from:
在更具体的实施方案中，本发明提供了上述式(IV-1)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 compound of the above formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
其中，in,
R1a为C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
R2a和R2b独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2c选自卤素、C1-6烷基或C1-6卤代烷基；R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(IV-1)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 compound of the above formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基，优选为3-7元杂环基或5-6元杂芳基，优选为4-6元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 4-6 A membered heterocyclyl optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基，优选选自H、D或NRbRc；优选选自H、NH2或-N(CH3)2；优选选自H或NH2；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl, preferably selected from H, D or NR b R c ; preferably selected from H, NH 2 or -N(CH 3 ) 2 ; preferably selected from H or NH 2 ;
R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R2b选自H、D或卤素；R 2b is selected from H, D or halogen;
R2c为卤素；R 2c is halogen;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基；R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基，优选为H。R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably H.
在更具体的实施方案中，本发明提供了上述式(IV-1)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，当R1a与O的连接原子为手性碳原子时，为为 In a more specific embodiment, the present invention provides the compound of the above formula (IV-1), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom of R 1a and O is a chiral carbon atom, it is for
在更具体的实施方案中，本发明提供了上述式(IV-1)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 compound of formula (IV-1) above, or a pharmaceutically acceptable salt or isotopic modification thereof. isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
L1a选自O、S或NH；优选为O或NH；L 1a is selected from O, S or NH; preferably O or NH;
选自：优选为：优选为优选地，为 Selected from: Preferably: Preferably Preferably, for
R2a为H、F、Cl或Me；优选为H、Cl或Me；R 2a is H, F, Cl or Me; preferably H, Cl or Me;
R2b为H或F；优选为H；R 2b is H or F; preferably H;
R2c为F；R 2c is F;
R2d为F、Cl或CN；优选为Cl或CN；R 2d is F, Cl or CN; preferably Cl or CN;
R3a为Cl；R 3a is Cl;
R3f为Me。R 3f is Me.
在更具体的实施方案中，选自： 优选选自优选选自 In a more specific embodiment, Selected from: Preferably selected from Preferably selected from
在更具体的实施方案中，本发明提供了上述式(IV-2)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 compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
其中，in,
R1a为C3-7环烷基或3-7元杂环基，优选为3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2a和R2b独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2c选自卤素、C1-6烷基或C1-6卤代烷基；R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(IV-2)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 compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
R1a为4-6元杂环基，优选为5元杂环基，其任选地被1、2或3个R1as取代；R 1a is a 4-6 membered heterocyclyl group, preferably a 5-membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；优选选自H、D或卤素；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl; preferably selected from H, D or halogen;
R2b选自H或D；R 2b is selected from H or D;
R2c为卤素；R 2c is halogen;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(IV-2)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，当R1a与NH的连接原子为手性碳原子时，为为 In a more specific embodiment, the present invention provides the compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom between R 1a and NH is a chiral carbon atom, it is for
在更具体的实施方案中，本发明提供了上述式(IV-2)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 compound of the above formula (IV-2), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
选自：优选为 Selected from: Preferably
R2a为H、F、Cl或Me；优选为H或F；R 2a is H, F, Cl or Me; preferably H or F;
R2b为H；R 2b is H;
R2c为F；R 2c is F;
R2d为F、Cl或CN；优选为F或CN；R 2d is F, Cl or CN; preferably F or CN;
R3a为Cl；R 3a is Cl;
R3f为Me。R 3f is Me.
在更具体的实施方案中，选自： 优选选自 优选为 In a more specific embodiment, Selected from: Preferably selected from Preferably
在更具体的实施方案中，本发明提供了上述式(IV-3)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 compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate,
其中，in,
R1a为C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
在更具体的实施方案中，本发明提供了上述式(IV-3)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 compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotope change thereof isomer, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate, wherein,
R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基，优选C3-6环烷基、4-6元杂环基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl radical, which is optionally substituted by 1, 2 or 3 R 1as ;
R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、F、Me、NH2或NHCH3；优选为H、F或Me；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, F, Me, NH 2 or NHCH 3 ; preferably H, F or Me;
R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
R2b选自H、D、C1-4烷基或C1-4卤代烷基；R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl;
R2c选自H、D或卤素；R 2c is selected from H, D or halogen;
R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
R3a为卤素；R 3a is halogen;
R3f为C1-6烷基或C1-6卤代烷基；R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基。R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
在更具体的实施方案中，本发明提供了上述式(IV-3)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，当R1a与S的连接原子为手性碳原子时，为为 In a more specific embodiment, the present invention provides the compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein when the connecting atom between R 1a and S is a chiral carbon atom, it is for
在更具体的实施方案中，本发明提供了上述式(IV-3)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 compound of the above formula (IV-3), or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph thereof form, hydrate or solvate, wherein,
选自： 优选为 优选为 优选为优选地，为 Selected from: Preferably Preferably Preferably Preferably, for
R2a为H、F或Me；R 2a is H, F or Me;
R2b为H或Me；R 2b is H or Me;
R2c为H、F或Cl；R 2c is H, F or Cl;
R2d为Cl或CN；R 2d is Cl or CN;
R3a为Cl；R 3a is Cl;
R3f为Me。R 3f is Me.
在更具体的实施方案中，选自： 优选为优选为 In a more specific embodiment, Selected from: Preferably Preferably
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，其中，所述化合物选自以下：








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, wherein the compound is selected from the following:








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 Prepared by asymmetric synthesis.
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(II)、(III-1)、(III-2)、(III-3)、(IV-1)、(IV-2)和(IV-3)等表示的化合物，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 (II), (III-1), (III-2), (III-3), (IV Compounds represented by -1), (IV-2) and (IV-3) include the following tautomers:
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、***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. Isotopically labeled compounds of formula (I) of the present invention and their prodrugs are generally It can be prepared by substituting readily available isotope-labeled reagents for non-isotope-labeled reagents when performing the processes disclosed in the following schemes and/or examples and preparation examples.
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 that can be cleaved to form a hydroxyl, amino or thiol group when administered to a patient. 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、***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 present invention can be administered through many routes, including but not limited to: oral administration, parenteral administration, inhalation administration, topical administration, rectal administration, nasal administration, buccal administration, vaginal administration drugs, administered via implants or other methods 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. carrier or form agents 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***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 to 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
Example 1
中间体1-3的合成Synthesis of intermediates 1-3
将1-(溴甲基)-2,4,5-三氟甲苯(8.46g,37.6mmol)加入1-1(5.73g,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)， 合并有机相用饱和食盐水(100mL)洗涤,无水硫酸钠干燥，过滤并减压浓缩，粗品经柱层析纯化(硅胶，石油醚:乙酸乙酯＝2:1)得白色固体1-3(8.3g,产率:89％)。Add 1-(bromomethyl)-2,4,5-trifluorotoluene (8.46g, 37.6mmol) to 1-1 (5.73g, 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), The combined organic phases were washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 2:1) to obtain white solid 1-3 (8.3g, yield: 89%).
LCMS(ESI)m/z:318.0[M+H-56]+。LCMS(ESI)m/z:318.0[M+H-56] + .
中间体1-4的合成Synthesis of intermediates 1-4
1-3(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1-4，直接用于下一步反应。1-3 (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 1-4, 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1-6的合成Synthesis of intermediates 1-6
常温下向1-4((250mg，0.79mmol))的N,N-二甲基甲酰胺((5mL))溶液中加入三乙胺((398mg，3.94mmol))，1-5((362mg，2.37mmol))，醋酸铜((242mg，1.35mmol))和分子筛((300mg))。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1-6((120mg，产率：42.1％))。To a solution of 1-4((250mg, 0.79mmol)) in N,N-dimethylformamide ((5mL)), triethylamine ((398mg, 3.94mmol)) was added at room temperature, 1-5((362mg , 2.37mmol)), copper acetate ((242mg, 1.35mmol)) and molecular sieve ((300mg)). 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 compound 1-6 ((120 mg, yield: 42.1%)) as a yellow oil.
LCMS(ESI)m/z:425.1[M+H]+。LCMS(ESI)m/z:425.1[M+H] + .
化合物1的合成Synthesis of Compound 1
冰浴下向1-6((110mg，0.26mmol))的四氢呋喃((2mL))溶液中加入1-7((56.7mg，0.31mmol))，氮气保护，0℃下加入双(三甲基硅基)氨基锂(0.65mL)并搅拌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。流动项:ACN--H2O(0.1％FA)。梯度:35-45))纯化得到白色固体化合物1((49.3mg，产率：35.2％))。Add 1-7 ((56.7mg, 0.31mmol)) to a solution of 1-6 ((110mg, 0.26mmol)) in tetrahydrofuran ((2mL)) under ice bath, under nitrogen protection, add bis(trimethyl) at 0°C Silica)lithium amide (0.65 mL) and stirred 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. Flow term: ACN--H 2 O (0.1% FA). Gradient: 35-45)) to obtain white solid compound 1 ((( 49.3mg, yield: 35.2%)).
LCMS(ESI)m/z:544.1[M+H]+。LCMS(ESI)m/z:544.1[M+H] + .
1H NMR(400MHz,CD3OD)δ8.30(d,J＝2.6Hz,1H),8.18(s,2H),7.75(s,1H),7.66(d,J＝9.6Hz,1H),7.55(s,1H),7.23(s,2H),5.39(s,2H),4.21(s,3H),3.91(s,3H). 1 H NMR (400MHz, CD 3 OD) δ8.30(d,J＝2.6Hz,1H),8.18(s,2H),7.75(s,1H),7.66(d,J＝9.6Hz,1H), 7.55(s,1H),7.23(s,2H),5.39(s,2H),4.21(s,3H),3.91(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15化合物15的合成
Example 15 Synthesis of Compound 15
中间体15-6c的合成Synthesis of intermediate 15-6c
冰浴下将三苯基膦((11.3g，43.1mmol))溶解到四氢呋喃((100mL))溶液中，并加入偶氮二甲酸二异丙酯((8.71g，43.1mmol))，冰浴下搅拌15分钟至大量白色固体析出。随后冰浴下加入15-6a((5.0g，28.7mmol))，并于此温度下搅拌15分钟。再加入15-6b((2.53g，28.7mmol))，该混合溶液在氮气保护下于20℃搅拌16个小时。反应完成后，加入水((200mL))，用乙酸乙酯((200mL x 2))进行萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗品。粗品用柱层析提纯((硅胶石油醚:乙酸乙酯＝1:2))得黄色油状物15-6c((6.46g，产率：92.3％))。Dissolve triphenylphosphine ((11.3g, 43.1mmol)) into tetrahydrofuran ((100mL)) solution under ice bath, and add diisopropyl azodicarboxylate ((8.71g, 43.1mmol)), and keep in ice bath Stir for 15 minutes until a large amount of white solid precipitates. Then 15-6a ((5.0g, 28.7mmol)) was added under ice bath and stirred at this temperature for 15 minutes. Then 15-6b ((2.53g, 28.7mmol)) was added, and the mixed solution was stirred at 20° C. for 16 hours under nitrogen protection. After the reaction is completed, add water ((200mL)), extract with ethyl acetate ((200mL x 2)), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was purified by column chromatography ((silica gel petroleum ether: ethyl acetate = 1:2)) to obtain yellow oil 15-6c ((6.46g, yield: 92.3%)).
LCMS(ESI)m/z:244.0[M+H]+。LCMS(ESI)m/z:244.0[M+H] + .
中间体15-6的合成Synthesis of intermediate 15-6
常温下将中间体15-6c((6.4g,26.2mmol))溶解到1，4-二氧六环((100mL))溶液中，并加入联硼酸频那醇酯((9.98g,39.3mmol))，醋酸钾((7.71g,78.6mmol))和1,1-双(二苯基膦)二荗铁二氯化钯((1.92g,2.62mmol))，该混合溶液在氮气保护下于80℃下搅拌16小时。反应完全后，反应液冷却至室温，加入石油醚((500mL))，所得溶液于室温搅拌1小时，随后通过硅藻土进行过滤，滤饼用石油醚洗涤，所得滤液浓缩至干。所得粗品用反相柱层析提纯((C18，水((0.1％三氟乙酸)):乙腈＝5:95～15/85))得黄色固体15-6((3.8g，产率：69.9％))。Dissolve intermediate 15-6c ((6.4g, 26.2mmol)) into 1,4-dioxane ((100mL)) solution at room temperature, and add pinacol diborate ((9.98g, 39.3mmol) )), potassium acetate ((7.71g, 78.6mmol)) and 1,1-bis(diphenylphosphine)diphenyliron palladium dichloride ((1.92g, 2.62mmol)), this mixed solution was under nitrogen protection Stir at 80°C for 16 hours. After the reaction was completed, the reaction solution was cooled to room temperature, petroleum ether ((500 mL)) was added, and the resulting solution was stirred at room temperature for 1 hour, then filtered through diatomaceous earth, the filter cake was washed with petroleum ether, and the resulting filtrate was concentrated to dryness. The obtained crude product was purified by reverse-phase column chromatography ((C18, water ((0.1% trifluoroacetic acid)): acetonitrile=5:95~15/85)) to obtain yellow solid 15-6 ((3.8g, yield: 69.9 %)).
LCMS(ESI)m/z:210.1[M+H]+。 LCMS(ESI)m/z:210.1[M+H] + .
中间体15-2的合成Synthesis of intermediate 15-2
常温下将中间体15-1((5.0g,26.0mmol))溶解到四氢呋喃(50mL)溶液中，并加入硼烷的四氢呋喃溶液(1M,52mL,52.0mmol)，该混合溶液在60℃下搅拌3个小时。反应完全后，反应液冷却至室温后，于冰浴下缓慢滴加甲醇(50mL)，所得混合溶液60℃下搅拌1个小时，减压浓缩得到粗品。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝5:1)得黄色油状物2-2(4.4g，产率：94.6％)。Dissolve intermediate 15-1 ((5.0g, 26.0mmol)) into a tetrahydrofuran (50mL) solution at room temperature, add a borane solution in tetrahydrofuran (1M, 52mL, 52.0mmol), and stir the mixed solution at 60°C. 3 hours. After the reaction was completed, the reaction solution was cooled to room temperature, and methanol (50 mL) was slowly added dropwise in an ice bath. The resulting mixed solution was stirred at 60° C. for 1 hour, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 5:1) to obtain yellow oil 2-2 (4.4 g, yield: 94.6%).
LCMS(ESI)m/z:161.4[M-18+H]+。LCMS(ESI)m/z:161.4[M-18+H] + .
中间体15-3的合成Synthesis of intermediate 15-3
冰浴下向15-2(4.4g,24.6mmol)的二氯甲烷(50mL)溶液中加入三苯基膦(9.68g，36.9mmol)和四溴化碳(8.97g，27.1mmol)，该混合溶液在20℃下搅拌4个小时。加入水(50mL)进行萃取，二氯甲烷(50mL x 2)萃取两次，合并有机相，用无水硫酸钠干燥，减压浓缩得到粗品。粗品用柱层析提纯(石油醚:乙酸乙酯＝10:1)得淡黄色油状物15-3(5.6g，产率：94.3％)。To a solution of 15-2 (4.4g, 24.6mmol) in dichloromethane (50mL), triphenylphosphine (9.68g, 36.9mmol) and carbon tetrabromide (8.97g, 27.1mmol) were added under ice bath, and the mixture was The solution was stirred at 20°C for 4 hours. Add water (50mL) for extraction, and extract twice with dichloromethane (50mL x 2). Combine the organic phases, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 10:1) to obtain light yellow oil 15-3 (5.6 g, yield: 94.3%).
1H NMR(400MHz,CDCl3)δ7.50–7.43(m,1H),6.96–6.90(m,1H),4.42(d,J＝0.9Hz,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.50–7.43 (m, 1H), 6.96–6.90 (m, 1H), 4.42 (d, J = 0.9Hz, 2H).
中间体15-4的合成Synthesis of intermediate 15-4
常温下向15-3(5.6g，23.2mmol)的乙腈(60mL)溶液中加入碳酸钾(6.41g，46.4mmol)和化合物1-1(3.99g，17.4mmol)，该混合溶液在80℃下搅拌16个小时。反应完全后，减压浓缩得到粗品。粗品用柱层析提纯(石油醚:乙酸乙酯＝1:1)得淡黄色固体15-4(5.4g，产率：79.7％)。Potassium carbonate (6.41g, 46.4mmol) and compound 1-1 (3.99g, 17.4mmol) were added to a solution of 15-3 (5.6g, 23.2mmol) in acetonitrile (60mL) at room temperature. The mixed solution was heated at 80°C. Stir for 16 hours. After the reaction is complete, concentrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain light yellow solid 15-4 (5.4 g, yield: 79.7%).
LCMS(ESI)m/z:412.1[M+Na]+。LCMS(ESI)m/z:412.1[M+Na] + .
中间体15-5的合成Synthesis of intermediate 15-5
常温下将15-4(7.2g，18.5mmol)加入二氯甲烷/三氟乙酸＝1/1(30mL)溶液中，混合溶液在20℃下搅拌3个小时。反应完全后，减压浓缩得到淡黄色固体15-5(6.15g，粗产品)。15-4 (7.2g, 18.5mmol) was added to the dichloromethane/trifluoroacetic acid = 1/1 (30mL) solution at room temperature, and the mixed solution was stirred at 20°C for 3 hours. After the reaction was completed, it was concentrated under reduced pressure to obtain light yellow solid 15-5 (6.15 g, crude product).
LCMS(ESI)m/z:334.0[M+H]+。LCMS(ESI)m/z:334.0[M+H] + .
中间体15-7的合成Synthesis of intermediate 15-7
常温下向15-6(2.0g，6.0mmol)的N,N-二甲基甲酰胺(50mL)中化合物15-6(3.76g，18.0mmol)，随后加入三乙胺(3.04g，30.0mmol)，醋酸铜(2.18g，12.0mmol)和4A分子筛(13.2g，30.0mmol)，混合溶液在氧气氛围下于60℃搅拌16小时。反应完全后，向反应溶液中加入乙酸乙酯(250mL)和水(250mL)，析出大量固体，通过硅藻土进行过滤，滤饼用乙酸乙酯洗涤，所得滤液分出有机相，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤两次，无水硫酸钠干燥，减压浓缩得到粗品。粗品用柱层析提纯(二氯甲烷:甲醇＝10:1)得淡黄色固体15-7(2.4g，产率：79.7％)。Compound 15-6 (3.76g, 18.0mmol) was added to 15-6 (2.0g, 6.0mmol) in N,N-dimethylformamide (50mL) at room temperature, and then triethylamine (3.04g, 30.0mmol) was added ), copper acetate (2.18g, 12.0mmol) and 4A molecular sieve (13.2g, 30.0mmol), the mixed solution was stirred at 60°C for 16 hours under an oxygen atmosphere. After the reaction is complete, add ethyl acetate (250 mL) and water (250 mL) to the reaction solution, precipitate a large amount of solid, filter it through diatomaceous earth, wash the filter cake with ethyl acetate, separate the organic phase from the filtrate, and use Extract with ethyl acetate, combine the organic phases, wash twice with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (dichloromethane: methanol = 10:1) to obtain light yellow solid 15-7 (2.4 g, yield: 79.7%).
LCMS(ESI)m/z:497.0[M+H]+。LCMS(ESI)m/z:497.0[M+H] + .
化合物15的合成Synthesis of compound 15
常温下将15-7(2.5g，5.0mmol)和化合物1-7(0.95g，5.25mmol)溶解到四氢呋喃(25mL)溶液中，氮气保护下降温至-60℃,随后向反应液中滴加叔丁醇钾的四氢呋喃溶液(8.3mL，15.0mmol，1.8M)。所得溶液于此温度下搅拌1小时。反应完全后，加入饱和食盐水(50mL)淬灭，所得溶液用乙酸乙酯(50mL x 2)进行萃取，有机相用无水硫酸钠干燥，减压浓缩得到粗品。粗品由高效液相制备色谱纯化得到淡黄色固体化合物15(0.4914g，产率：16.0％)。 Dissolve 15-7 (2.5g, 5.0mmol) and compound 1-7 (0.95g, 5.25mmol) into tetrahydrofuran (25mL) solution at room temperature, cool to -60°C under nitrogen protection, and then add dropwise to the reaction solution Potassium tert-butoxide in tetrahydrofuran (8.3 mL, 15.0 mmol, 1.8 M). The resulting solution was stirred at this temperature for 1 hour. After the reaction was complete, saturated brine (50 mL) was added to quench the reaction. The resulting solution was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a crude product. The crude product was purified by high-performance liquid chromatography to obtain compound 15 as a light yellow solid (0.4914 g, yield: 16.0%).
LCMS(ESI)m/z:615.9[M+H]+。LCMS(ESI)m/z:615.9[M+H] + .
1H NMR(400MHz,CD3OD)δ8.33(s,1H),8.25(s,1H),8.18(s,1H),7.81(t,J＝7.8Hz,1H),7.71(s,1H),7.69–7.67(m,1H),7.45(br,1H),7.18(t,J＝9.5Hz,1H),5.35(s,2H),5.11(d,J＝1.4Hz,1H),4.18(s,3H),3.95(d,J＝3.1Hz,3H),3.87-3.83(m,1H),2.32-2.23(m,1H),2.16–2.09(m,1H). 1 H NMR (400MHz, CD 3 OD) δ8.33(s,1H),8.25(s,1H),8.18(s,1H),7.81(t,J＝7.8Hz,1H),7.71(s,1H ),7.69–7.67(m,1H),7.45(br,1H),7.18(t,J＝9.5Hz,1H),5.35(s,2H),5.11(d,J＝1.4Hz,1H),4.18 (s,3H),3.95(d,J=3.1Hz,3H),3.87-3.83(m,1H),2.32-2.23(m,1H),2.16–2.09(m,1H).
以上述同样方法合成如下表B的化合物Use the same method as above to synthesize the compounds in Table B below.
表B


Table B


实施例27化合物27的合成
Example 27 Synthesis of Compound 27
中间体27-2c的合成Synthesis of intermediate 27-2c
常温下向27-1a(1.00g，5.68mmol)的N-甲基吡咯烷酮(10mL)溶液中加入27-2b(1.54g，12.5mmol)，混合溶液在微波反应器中200℃下搅拌4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＝20:1)提纯得淡黄色油状化合物27-2c(1.20g，产率：86.9％)。To a solution of 27-1a (1.00g, 5.68mmol) in N-methylpyrrolidone (10mL) was added 27-2b (1.54g, 12.5mmol) at room temperature, and the mixed solution was stirred in a microwave reactor at 200°C for 4 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 = 20:1) to obtain light yellow oily compound 27-2c (1.20 g, yield: 86.9%).
LCMS(ESI)m/z:241.0[M+H]+。LCMS(ESI)m/z:241.0[M+H] + .
中间体27-2d的合成Synthesis of intermediate 27-2d
常温下向27-2c(3.48g，14.4mmol)的四氢呋喃(35mL)溶液中加入三乙胺(4.37g，43.2mmol)，二碳酸二叔丁酯(7.86g，36mmol)和4-二甲氨基吡啶(0.18g，1.44mmol)。氮气保护，混合溶液在65℃下搅拌16小时。反应完成后，反应液减压浓缩得粗品，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27-2d(1.41g，产率：28.5％)。 To a solution of 27-2c (3.48g, 14.4mmol) in tetrahydrofuran (35mL), triethylamine (4.37g, 43.2mmol), di-tert-butyl dicarbonate (7.86g, 36mmol) and 4-dimethylamino were added at room temperature. Pyridine (0.18g, 1.44mmol). Under nitrogen protection, the mixed solution was stirred at 65°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 20:1) to obtain light yellow oily compound 27-2d (1.41g, yield: 28.5%) .
LCMS(ESI)m/z:343.1[M+H]+。LCMS(ESI)m/z:343.1[M+H] + .
中间体27-2的合成Synthesis of intermediate 27-2
-78℃下向27-2d(1.00g，2.91mmol)和异丙醇频哪醇硼酸酯(2.16g，11.6mmol)的四氢呋喃(10mL)溶液中滴加正丁基锂(4.8mL,11.6mmol)。氮气保护，混合溶液在-78℃下搅拌2个小时。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(二氯甲烷:甲醇＝20:1)提纯得淡黄色固状化合物27-2(0.76g，产率：85.0％)。To a solution of 27-2d (1.00g, 2.91mmol) and isopropyl pinacol borate (2.16g, 11.6mmol) in tetrahydrofuran (10mL) at -78°C, n-butyllithium (4.8mL, 11.6 mmol). Under nitrogen protection, the mixed solution was stirred at -78°C for 2 hours. 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 (dichloromethane:methanol=20:1) to obtain light yellow solid compound 27-2 (0.76g, yield: 85.0%).
LCMS(ESI)m/z:309.1[M+H]+。LCMS(ESI)m/z:309.1[M+H] + .
中间体27-3的合成Synthesis of intermediate 27-3
常温下向27-1(250mg，0.75mmol)的N,N-二甲基甲酰胺(3mL)溶液中加入27-2(278mg，0.90mmol)，醋酸铜(272mg，1.50mmol)和三乙胺(379mg，3.75mmol)，混合溶液用氧气保护在室温下搅拌16小时。反应完成后，混合溶液依次用水(10mL)和饱和氯化钠溶液(20mL)洗涤，有机相用无水硫酸钠干燥。粗品用柱层析提纯(硅胶，二氯甲烷:甲醇＝10:1)得黄色油状27-3(179mg，产率：40.2％)。To a solution of 27-1 (250 mg, 0.75 mmol) in N,N-dimethylformamide (3 mL), 27-2 (278 mg, 0.90 mmol), copper acetate (272 mg, 1.50 mmol) and triethylamine were added at room temperature. (379 mg, 3.75 mmol), the mixed solution was stirred at room temperature for 16 hours under the protection of oxygen. After the reaction was completed, the mixed solution was washed with water (10 mL) and saturated sodium chloride solution (20 mL) in sequence, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, dichloromethane:methanol=10:1) to obtain 27-3 (179 mg, yield: 40.2%) as a yellow oil.
LCMS(ESI)m/z:596.0[M+H]+。LCMS(ESI)m/z:596.0[M+H] + .
中间体27-4的合成Synthesis of intermediate 27-4
-40℃下向27-3-(200mg，0.36mmol)的四氢呋喃(2mL)溶液中加入1-7(73.0mg,0.40mmol)，混合溶液在氮气保护下加入叔丁醇钾溶液(1mL)。-40℃下搅拌2个小时。反应完成后，混合溶液依次加入水(10mL)和乙酸乙酯(10mL)进行萃取，有机相用无水硫酸钠干燥。粗品用柱层析提纯(二氯甲烷:甲醇＝10:1)得黄色油状27-4(96.6mg，产率：37.5％)。To a solution of 27-3-(200 mg, 0.36 mmol) in tetrahydrofuran (2 mL) was added 1-7 (73.0 mg, 0.40 mmol) at -40°C, and potassium tert-butoxide solution (1 mL) was added to the mixed solution under nitrogen protection. Stir at -40°C for 2 hours. After the reaction was completed, water (10 mL) and ethyl acetate (10 mL) were added to the mixed solution in sequence for extraction, and the organic phase was dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (dichloromethane:methanol=10:1) to obtain 27-4 as a yellow oil (96.6 mg, yield: 37.5%).
LCMS(ESI)m/z:715.0[M+H]+。LCMS(ESI)m/z:715.0[M+H] + .
化合物27的合成Synthesis of compound 27
常温下将27-4-(100mg，0.15mmol)加入二氯甲烷/三氟乙酸＝1/1(2mL)溶液中，混合溶液在室温下搅拌2个小时。反应完成后，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(10mL)进行萃取，有机相用无水硫酸钠干燥后减压浓缩。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:30-50)纯化得到白色固体化合物27(SWD0309)(27.1mg，产率：29.4％)。27-4-(100 mg, 0.15 mmol) was added to the dichloromethane/trifluoroacetic acid = 1/1 (2 mL) solution at room temperature, and the mixed solution was stirred at room temperature for 2 hours. After the reaction is completed, the reaction solution is adjusted to pH=7 with sodium carbonate solution in an ice bath. Dichloromethane (10 mL) was added to the mixed solution for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by high-pressure preparative chromatography (Column: -Gemini-C18 150x 21.2mm, 5μm. Flow term: ACN--H 2 O (0.1% FA). Gradient: 30-50) to obtain white solid compound 27 (SWD0309) ( 27.1 mg, yield: 29.4%).
LCMS(ESI)m/z:615.0[M+H]+。LCMS(ESI)m/z:615.0[M+H] + .
1H NMR(400MHz,CD3OD)δ8.23(s,2H),8.03(d,J＝15.6Hz,2H),7.85(s,1H),7.76(s,1H),7.53(s,1H),7.24(s,1H),5.40(s,2H),4.23(s,3H),4.15(s,1H),3.98-3.94(m,2H),3.90-3.85(m,1H),3.75-3.72(m,1H),2.37-2.28(m,1H),1.94-1.91(m,1H). 1 H NMR (400MHz, CD 3 OD) δ8.23 (s, 2H), 8.03 (d, J = 15.6Hz, 2H), 7.85 (s, 1H), 7.76 (s, 1H), 7.53 (s, 1H ),7.24(s,1H),5.40(s,2H),4.23(s,3H),4.15(s,1H),3.98-3.94(m,2H),3.90-3.85(m,1H),3.75- 3.72(m,1H),2.37-2.28(m,1H),1.94-1.91(m,1H).
以上述同样方法合成如下表C的化合物Use the same method as above to synthesize the compounds in Table C below.
表C


Table C


实施例32化合物32的合成
Example 32 Synthesis of Compound 32
中间体32-2c的合成Synthesis of intermediate 32-2c
冰浴下将三苯基膦(11.3g，43.1mmol)溶解到四氢呋喃(100mL)溶液中，并加入偶氮二甲酸二异丙酯(8.71g，43.1mmol)，冰浴下搅拌15分钟至大量白色固体析出。随后冰浴下加入32-2a(5.45g，28.7mmol)，并于此温度下搅拌15分钟。再加入32-2b(2.53g，28.7mmol)，该混合溶液在氮气保护下于20℃搅拌16个小时。反应完成后，加入水(200mL)，用乙酸乙酯(200mL x 2)进行萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得到粗品。粗品用柱层析提纯(硅胶，石油醚:乙酸乙酯＝1:2)得黄色油状物32-2c(6.9g，产率：92.3％)。Dissolve triphenylphosphine (11.3g, 43.1mmol) in tetrahydrofuran (100mL) solution under ice bath, add diisopropyl azodicarboxylate (8.71g, 43.1mmol), and stir for 15 minutes under ice bath until sufficient A white solid precipitated. Then 32-2a (5.45g, 28.7mmol) was added under ice bath, and stirred at this temperature for 15 minutes. Then 32-2b (2.53g, 28.7mmol) was added, and the mixed solution was stirred at 20°C for 16 hours under nitrogen protection. After the reaction is completed, add water (200mL), extract with ethyl acetate (200mL x 2), combine the organic phases, wash with saturated brine, dry over anhydrous sodium sulfate, and concentrate under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (silica gel, petroleum ether: ethyl acetate = 1:2) to obtain yellow oil 32-2c (6.9 g, yield: 92.3%).
LCMS(ESI)m/z:260.0[M+H]+。LCMS(ESI)m/z:260.0[M+H] + .
中间体32-2的合成Synthesis of intermediate 32-2
常温下将中间体32-1c(6.8g,26.2mmol)溶解到1，4-二氧六环(100mL)溶液中，并加入联硼酸频那醇酯(9.98g,39.3mmol)，醋酸钾(7.71g,78.6mmol)和1,1-双(二苯基膦)二荗铁二氯化钯(1.92g,2.62mmol)，该混合溶液在氮气保护下于80℃下搅拌16小时。反应完全后，反应液冷却至室温，加入石油醚(500mL)，所得溶液于室温搅拌1小时，随后通过硅藻土进行过滤，滤饼用石油醚洗涤，所得滤液浓缩至干。所得粗品用反相柱层析提纯(C18，水(0.1％三氟乙酸):乙腈＝5:95～15/85)得黄色固体32-2(4.12g，产率：69.9％)。Dissolve intermediate 32-1c (6.8g, 26.2mmol) into 1,4-dioxane (100mL) solution at room temperature, and add pinacol diborate (9.98g, 39.3mmol), potassium acetate ( 7.71g, 78.6mmol) and 1,1-bis(diphenylphosphine)diphenyliron palladium dichloride (1.92g, 2.62mmol). The mixed solution was stirred at 80°C for 16 hours under nitrogen protection. After the reaction was completed, the reaction solution was cooled to room temperature, petroleum ether (500 mL) was added, and the resulting solution was stirred at room temperature for 1 hour, then filtered through diatomaceous earth, the filter cake was washed with petroleum ether, and the filtrate was concentrated to dryness. The obtained crude product was purified by reverse-phase column chromatography (C18, water (0.1% trifluoroacetic acid): acetonitrile = 5:95~15/85) to obtain yellow solid 32-2 (4.12g, yield: 69.9%).
LCMS(ESI)m/z:226.1[M+H]+。LCMS(ESI)m/z:226.1[M+H] + .
中间体32-3的合成Synthesis of intermediate 32-3
常温下向32-1(0.2g，0.6mmol)的N,N-二甲基甲酰胺(5mL)中加入化合物32-2(0.405g，1.8mmol)、三乙胺(0.304g，3.0mmol)、醋酸铜(0.218g，1.2mmol)和4A分子筛(1.32g，3.0mmol)，混 合溶液在氧气氛围下于60℃搅拌16小时。向反应溶液中加入乙酸乙酯(25mL)和水(25mL)，过滤，滤饼用乙酸乙酯洗涤，所得滤液分出有机相，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品用柱层析提纯(二氯甲烷:甲醇＝10:1)得淡黄色固体4-32-3(0.25g，产率：80％)。To 32-1 (0.2g, 0.6mmol) in N,N-dimethylformamide (5mL), compound 32-2 (0.405g, 1.8mmol) and triethylamine (0.304g, 3.0mmol) were added at room temperature. , copper acetate (0.218g, 1.2mmol) and 4A molecular sieve (1.32g, 3.0mmol), mixed The combined solution was stirred at 60°C for 16 hours under an oxygen atmosphere. Add ethyl acetate (25 mL) and water (25 mL) to the reaction solution, filter, wash the filter cake with ethyl acetate, separate the organic phase from the filtrate, extract the aqueous phase with ethyl acetate, combine the organic phases, and use saturated brine Wash twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography (dichloromethane:methanol=10:1) to obtain light yellow solid 4-32-3 (0.25g, yield: 80%).
LCMS(ESI)m/z:513.1[M+H]+。LCMS(ESI)m/z:513.1[M+H] + .
化合物32的合成Synthesis of compound 32
常温下将32-3(2.5g，5.0mmol)和化合物1-7(0.95g，5.25mmol)溶解到四氢呋喃(25mL)溶液中，氮气保护下降温至-60℃,随后向反应液中滴加叔丁醇钾的四氢呋喃溶液(8.3mL，15.0mmol，1.8M)。所得溶液于此温度下搅拌1小时。加入饱和食盐水(50mL)淬灭，乙酸乙酯(50mL x 2)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品由高效液相制备色谱(色谱柱:-Gemini-C18 150x21.2mm，5μm。流动项:ACN--H2O(0.1％FA)纯化得到淡黄色固体化合物32(0.474g，产率：15.0％)。Dissolve 32-3 (2.5g, 5.0mmol) and compound 1-7 (0.95g, 5.25mmol) into tetrahydrofuran (25mL) solution at room temperature, cool to -60°C under nitrogen protection, and then add dropwise to the reaction solution Potassium tert-butoxide in tetrahydrofuran (8.3 mL, 15.0 mmol, 1.8 M). The resulting solution was stirred at this temperature for 1 hour. Saturated brine (50 mL) was added to quench, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: Gemini-C18 150x21.2mm, 5 μm. Mobile item: ACN--H 2 O (0.1% FA)) to obtain light yellow solid compound 32 (0.474g, yield: 15.0 %).
LCMS(ESI)m/z:632.1[M+H]+。LCMS(ESI)m/z:632.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.26(s,0.56H),9.73(s,0.44H),8.57(d,J＝16.5Hz,1H),8.47(s,1H),8.33(d,J＝50.2Hz,1H),8.09–7.68(m,3.5H),7.59(dt,J＝40.5,9.5Hz,1H),7.13(s,0.5H),5.25(d,J＝31.6Hz,2H),4.34–3.94(m,5H),3.89–3.70(m,2H),3.59–3.51(m,1H),2.43–2.31(m,1H),1.86–1.73(m,1H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.26 (s, 0.56H), 9.73 (s, 0.44H), 8.57 (d, J = 16.5Hz, 1H), 8.47 (s, 1H), 8.33 ( d,J＝50.2Hz,1H),8.09–7.68(m,3.5H),7.59(dt,J＝40.5,9.5Hz,1H),7.13(s,0.5H),5.25(d,J＝31.6Hz ,2H),4.34–3.94(m,5H),3.89–3.70(m,2H),3.59–3.51(m,1H),2.43–2.31(m,1H),1.86–1.73(m,1H).
以上述同样方法合成如下表D的化合物Use the same method as above to synthesize the compounds in Table D below.
表D


Form D


实施例35化合物35的合成
Example 35 Synthesis of Compound 35
参照实施例32合成中间体35-2.Intermediate 35-2 was synthesized with reference to Example 32.
LCMS(ESI)m/z:213.1[M+H]+。LCMS(ESI)m/z:213.1[M+H] + .
中间体32-3的合成Synthesis of intermediate 32-3
常温下向35-1(0.2g，0.6mmol)的N,N-二甲基甲酰胺(5mL)中加入化合物35-2(0.383g，1.8mmol)、三乙胺(0.304g，3.0mmol)、醋酸铜(0.218g，1.2mmol)和4A分子筛(1.32g，3.0mmol)，混合溶液在氧气氛围下于60℃搅拌16小时。向反应溶液中加入乙酸乙酯(25mL)和水(25mL)，过滤，滤饼用乙酸乙酯洗涤，所得滤液分出有机相，水相用乙酸乙酯萃取，合并有机相，用饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品用柱层析提纯(二氯甲烷:甲醇＝10:1)得淡黄色固体35-3(0.25g，产率：82％)。To 35-1 (0.2g, 0.6mmol) in N,N-dimethylformamide (5mL), compound 35-2 (0.383g, 1.8mmol) and triethylamine (0.304g, 3.0mmol) were added at room temperature. , copper acetate (0.218g, 1.2mmol) and 4A molecular sieve (1.32g, 3.0mmol), the mixed solution was stirred at 60°C for 16 hours under an oxygen atmosphere. Add ethyl acetate (25 mL) and water (25 mL) to the reaction solution, filter, wash the filter cake with ethyl acetate, separate the organic phase from the filtrate, extract the aqueous phase with ethyl acetate, combine the organic phases, and use saturated brine Wash twice, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain crude product. The crude product was purified by column chromatography (dichloromethane:methanol=10:1) to obtain light yellow solid 35-3 (0.25g, yield: 82%).
LCMS(ESI)m/z:513.1[M+H]+。LCMS(ESI)m/z:513.1[M+H] + .
化合物35的合成Synthesis of compound 35
常温下将35-3(2.5g，5.0mmol)和化合物1-7(0.95g，5.25mmol)溶解到四氢呋喃(25mL)溶液中，氮气保护下降温至-60℃,随后向反应液中滴加叔丁醇钾的四氢呋喃溶液(8.3mL，15.0mmol，1.8M)。所得溶液于此温度下搅拌1小时。加入饱和食盐水(50mL)淬灭，乙酸乙酯(50mL x 2)萃取，有机相用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品。粗品由高效液相制备色谱(色谱柱:-Gemini-C18 150x21.2mm，5μm。流动项:ACN--H2O(0.1％FA)纯化得到淡黄色固体化合物35(0.434g，产率：14.0％)。Dissolve 35-3 (2.5g, 5.0mmol) and compound 1-7 (0.95g, 5.25mmol) into tetrahydrofuran (25mL) solution at room temperature, cool to -60°C under nitrogen protection, and then add dropwise to the reaction solution Potassium tert-butoxide in tetrahydrofuran (8.3 mL, 15.0 mmol, 1.8 M). The resulting solution was stirred at this temperature for 1 hour. Saturated brine (50 mL) was added to quench, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by high performance liquid chromatography (column: -Gemini-C18 150x21.2mm, 5 μm. Mobile item: ACN--H 2 O (0.1% FA)) to obtain light yellow solid compound 35 (0.434g, yield: 14.0 %).
LCMS(ESI)m/z:620.1[M+H]+。LCMS(ESI)m/z:620.1[M+H] + .
1H NMR(400MHz,DMSO-d6)δ11.25(s,1H),8.58-8.52(m,1H),8.47-8.42(m,1H),8.26(s,1H),7.97-7.79(m,2H),7.87-7.51(m,3H),5.24-5.21(m,2H),4.16-4.13(m,3H),3.58-3.52(m,2H),3.28–3.17(m,5H). 1 H NMR (400MHz, DMSO-d 6 ) δ11.25(s,1H),8.58-8.52(m,1H),8.47-8.42(m,1H),8.26(s,1H),7.97-7.79(m ,2H),7.87-7.51(m,3H),5.24-5.21(m,2H),4.16-4.13(m,3H),3.58-3.52(m,2H),3.28–3.17(m,5H).
以上述同样方法合成如下表E的化合物Use the same method as above to synthesize the compounds in Table E below.
表E

Table E

实验例1Experimental example 1
1、抗SARS-Cov-2的生化IC50测试方法1. Biochemical IC 50 test method for anti-SARS-Cov-2
测定体系(120ul)：Measurement system (120ul):
蛋白酶(108ul)：(150nM)WT或P132HProtease (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substrate
荧光底物MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2；主蛋白酶通用引物Fluorescent substrate MCA-AVLQ↓SGFR-Lys(Dnp)-Lys-NH2; universal primer for main protease
反应Buffer：50mM Tris pH 7.4,1mM EDTA,0.01％tritonX-100Reaction Buffer: 50mM Tris pH 7.4, 1mM EDTA, 0.01% tritonX-100
孵育30min后酶标仪检测After incubation for 30 minutes, microplate reader detection
酶标仪检测：激发320nm；发射405nmMicroplate 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，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.
再使用GraphPad Prism非线性拟合曲线计算IC50值。Then use GraphPad Prism nonlinear fitting curve to calculate the IC50 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×100Formula 2: Inhibition rate (%) = (NC initial velocity V 0 - sample initial velocity V 0 )/NC initial velocity × 100
NC为加DMSO对照，酶活定为100％。NC is a 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 V 0 - (sample initial velocity V 0 - protein-free small molecule control V 0 )/NC initial velocity V 0 ×100 is used to eliminate V 0 (slope) as Problem with negative values.
2、抗SARS-Cov-2的细胞EC50测试方法2. Anti-SARS-Cov-2 cell EC 50 test method
(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 cells 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. The inhibition rate = (1-lesion in the test compound group rate)×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 .
测试结果见表1。The test results are shown in Table 1.
表1







Table 1







Claims (74)

  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;
    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;
    R1s为-C(O)NR1bR1c或 R 1s is -C(O)NR 1b R 1c or
    L1a选自化学键、O、S或NR5a；L 1a is selected from chemical bond, O, S or NR 5a ;
    L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
    R1a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、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R1as取代；R 1a 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 6-10 aryl or 5-10 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、-L1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R1b选自H、C1-6烷基或C1-6卤代烷基；R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
    R’1s独立地选自H、D、卤素、氰基、-L1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
    L2选自-(CR4aR4b)m1-、O、S或NR4c；L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
    R4a和R4b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    m1为0、1或2；m 1 is 0, 1 or 2;
    R4c选自H、C1-6烷基或C1-6卤代烷基；R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    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，其任选地被1、2、3、4或5个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, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
    R2s独立地选自H、D、卤素、氰基、-L2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-10环烷基或3-10元杂环基；R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    L3选自化学键、CR6aR6b、O、S或NR6c；L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
    R6a和R6b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R6c选自H、C1-6烷基或C1-6卤代烷基；R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R3选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2、3、4或5个R3s取代；R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
    R3s独立地选自H、D、卤素、氰基、-L3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    或者两个相邻的R3s以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or two adjacent R 3s and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally Replaced by 1, 2 or 3 R 3ss ;
    R3ss独立地选自H、D、卤素、氰基、-L3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C3-10芳基或3-10元杂芳基；R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
    L1c、L1d、L2a、L3a和L3b各自独立地选自化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基或5-10元杂芳基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
    其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
    条件是，当环A为吡啶基，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基；且所述化合物不为如下结构：
    The condition is that when ring A is pyridyl, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group; and the compound does not have the following structure:
  2. 权利要求1的式(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：
    The compound of formula (I) according to 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;
    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;
    R1s为或-C(O)NR1bR1c；R 1s is or -C(O)NR 1b R 1c ;
    L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
    L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which optionally substituted with 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、-L1c-ORa、-L1c-SRa、-L1c-NRbRc、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, -L 1c -OR a , -L 1c -SR a , -L 1c -NR b R c , C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl;
    n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R1b选自H、C1-6烷基或C1-6卤代烷基；R 1b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl ;
    R’1s独立地选自H、D、卤素、氰基、-L1d-ORa、-L1d-SRa、-L1d-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R' 1s is independently selected from H, D, halogen, cyano, -L 1d -OR a , -L 1d -SR a , -L 1d -NR b R c , C 1-6 alkyl, C 1-6 Haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
    L2选自-(CR4aR4b)m1-、O、S或NR4c；L 2 is selected from -(CR 4a R 4b ) m1 -, O, S or NR 4c ;
    R4a和R4b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 4a and R 4b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    m1为0、1或2；m 1 is 0, 1 or 2;
    R4c选自H、C1-6烷基或C1-6卤代烷基；R 4c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    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，其任选地被1、2、3、4或5个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, which is optionally replaced by 1, 2, 3, 4 or 5 R 2s substitution;
    R2s独立地选自H、D、卤素、氰基、-L2a-ORa、-L2a-SRa、-L2a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 2s is independently selected from H, D, halogen, cyano, -L 2a -OR a , -L 2a -SR a , -L 2a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    L3选自化学键、CR6aR6b、O、S或NR6c；L 3 is selected from chemical bond, CR 6a R 6b , O, S or NR 6c ;
    R6a和R6b各自独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 6a and R 6b are each independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    R6c选自H、C1-6烷基或C1-6卤代烷基；R 6c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R3选自C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2、3、4或5个R3s取代；R 3 is selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1, 2, 3, 4 or 5 R 3s replaced;
    R3s独立地选自H、D、卤素、氰基、-L3a-ORa、-L3a-SRa、-L3a-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3s is independently selected from H, D, halogen, cyano, -L 3a -OR a , -L 3a -SR a , -L 3a -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    或者两个相邻的R3s以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10 元杂芳基，其任选地被1、2或3个R3ss取代；Or two adjacent R 3s and the atoms they are connected together form C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 Metaheteroaryl, which is optionally substituted by 1, 2 or 3 R 3ss ;
    R3ss独立地选自H、D、卤素、氰基、-L3b-ORa、-L3b-SRa、-L3b-NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C3-10芳基或3-10元杂芳基；R 3ss is independently selected from H, D, halogen, cyano, -L 3b -OR a , -L 3b -SR a , -L 3b -NR b R c , C 1-6 alkyl, C 1-6 haloalkyl base, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 3-10 aryl or 3-10 membered heteroaryl;
    L1c、L1d、L2a、L3a和L3b各自独立地选自化学键、C1-6亚烷基、C2-6亚烯基或C2-6亚炔基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C2-6烯基或C2-6炔基的基团取代；Each of L 1c , L 1d , L 2a , L 3a and L 3b is independently selected from chemical bond, C 1-6 alkylene, C 2-6 alkenylene or C 2-6 alkynylene, which is optionally replaced by 1, 2 or 3 groups selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl or C 2-6 alkynyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环基、C6-10芳基或5-10元杂芳基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基或5-10元杂芳基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 membered heterocyclyl, C 6-10 aromatic group or a 5-10-membered heteroaryl group; or R b , R c and the atoms they are connected together form a 3-10-membered heterocyclyl group or a 5-10-membered heteroaryl group;
    其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
    条件是，当环A为吡啶基，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基；且所述化合物不为如下结构：
    The condition is that when ring A is pyridyl, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group; and the compound does not have the following structure:
  3. 权利要求1或2的式(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，其中，Y为N。A compound of formula (I) according to claim 1 or 2, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, Among them, Y is N.
  4. 权利要求1-3任一项的式(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，其中，环A为C6-10芳基或5-10元杂芳基；优选为苯基或5-6元杂芳基；优选为5-6元杂芳基，优选为吡啶基或噻唑基；优选为吡啶基；优选为 更优选为 The compound of formula (I) according to any one of claims 1 to 3, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound, wherein ring A is C 6-10 aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably 5-6 membered heteroaryl, preferably pyridyl Or thiazolyl; preferably pyridyl; preferably More preferably
  5. 权利要求1-4任一项的式(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，其中，R1s选自优选选自 优选选自 优选选自 更优选不为 The compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R 1s is selected from Preferably selected from Preferably selected from Preferably selected from More preferably not
  6. 权利要求1-5任一项的式(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，其中，L1a选自O、S、NH或NMe；优选选自O、S或NH；优选为O或NH；优选为O或S；优选为O；优选为S。The compound of formula (I) according to any one of claims 1 to 5, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound, wherein L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH; preferably O or NH; preferably O or S; preferably O; preferably S.
  7. 权利要求1-6任一项的式(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，其中，L1b为化学键；The compound of formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound, where L 1b is a chemical bond;
    优选地，L1b选自O、S或NR5b；优选选自O或NR5b；优选选自O、S或NMe；优选选自O或S；优选选自O或NMe；优选为O。Preferably, L 1b is selected from O, S or NR 5b ; preferably selected from O or NR 5b ; preferably selected from O, S or NMe; preferably selected from O or S; preferably selected from O or NMe; preferably O.
  8. 权利要求1-7任一项的式(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，其中，R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自C1-6烷基、C1-6卤代烷基、C3-5环烷基或3-5元杂环基；优选选自C1-6烷基、C1-6卤代烷基或C3-5环烷基；优选选自C1-6烷基或C1-6卤代烷基；优选选自Me、 优选选自Me、优选为Me；The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound, wherein R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 One-membered heterocyclyl; preferably selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl; preferably selected from C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from Me, Preferably selected from Me, Preferably Me;
    优选地，R1a选自C3-10环烷基或3-10元杂环基；优选选自C3-7环烷基或3-7元杂环基；优选为 3-7元杂环基；优选为4-5元杂环基；优选为5元杂环基；优选选自 优选为 Preferably, R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably 3-7 membered heterocyclyl; preferably 4-5 membered heterocyclyl; preferably 5-membered heterocyclyl; preferably selected from Preferably
  9. 权利要求1-8任一项的式(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，其中，R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、ORa、SRa、NRbRc、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；优选选自H、D、C1-6烷基或C1-6卤代烷基；优选为Me。The compound of formula (I) according to any one of claims 1 to 8, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 ring Alkyl or 3-10 membered heterocyclyl; preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl Ring group; preferably selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, D. Halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
  10. 权利要求1-9任一项的式(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，其中，n1选自0、1、2或3；优选选自0、1或2；优选选自1、2或3；优选为0；优选为1；优选为2。The compound of formula (I) according to any one of claims 1 to 9, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein n 1 is selected from 0, 1, 2 or 3; preferably selected from 0, 1 or 2; preferably selected from 1, 2 or 3; preferably 0; preferably 1; preferably 2.
  11. 权利要求1-10中任一项的式(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，其中，n2选自0、1、2或3；优选选自0或1；优选为0。The compound of formula (I) according to any one of claims 1 to 10, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or Solvate, wherein n 2 is selected from 0, 1, 2 or 3; preferably selected from 0 or 1; preferably 0.
  12. 权利要求1-11任一项的式(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，其中，R5a为H或Me；优选为H。The compound of formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R 5a is H or Me; preferably H.
  13. 权利要求1-12任一项的式(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，其中，R5b选自C1-6烷基或C1-6卤代烷基；优选为Me。The compound of formula (I) according to any one of claims 1 to 12, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound, wherein R 5b is selected from C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
  14. 权利要求1-13任一项的式(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，其中，R1b为H；The compound of formula (I) according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R 1b is H;
    优选地，R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、C1-6烷基或C1-6卤代烷基；优选为C1-6烷基或C1-6卤代烷基；优选为Me。Preferably, R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably selected from H, C 1-6 alkyl Or C 1-6 haloalkyl; preferably C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
  15. 权利要求1-14任一项的式(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，其中，R’1s独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基。The compound of formula (I) according to any one of claims 1 to 14, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H , D, halogen, C 1-6 alkyl or C 1-6 haloalkyl.
  16. 权利要求1-15任一项的式(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，其中，n3为0或1；优选为0。The compound of formula (I) according to any one of claims 1 to 15, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein n 3 is 0 or 1; preferably 0.
  17. 权利要求1-16任一项的式(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，n3为1、2或3；优选为0或1；优选为0。The compound of formula (I) according to any one of claims 1 to 16, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, n 3 is 1, 2 or 3; preferably 0 or 1; preferably 0.
  18. 权利要求1-17任一项的式(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，其中，L2为-(CR4aR4b)m1-；优选为亚甲基；The compound of formula (I) according to any one of claims 1 to 17, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound, wherein L 2 is -(CR 4a R 4b ) m1 -; preferably methylene;
    优选地，m1为1； Preferably, m 1 is 1;
    优选地，R4a和R4b为H。Preferably, R 4a and R 4b are H.
  19. 权利要求1-18任一项的式(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，其中R2选自C6-10芳基或5-10元杂芳基；优选为苯基或5-6元杂芳基；优选为苯基；The compound of formula (I) according to any one of claims 1 to 18, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound, wherein R 2 is selected from C 6-10 aryl or 5-10 membered heteroaryl; preferably phenyl or 5-6 membered heteroaryl; preferably phenyl;
    优选地，R2任选地被1、2、3或4个R2s取代；Preferably, R 2 is optionally substituted by 1, 2, 3 or 4 R 2s ;
    优选地，R2任选地被2或3个R2s取代；Preferably, R 2 is optionally substituted by 2 or 3 R 2s ;
    优选地，R2选自 优选选自 优选选自 Preferably, R 2 is selected from Preferably selected from Preferably selected from
  20. 权利要求1-19任一项的式(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，其中，R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、氰基、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、氰基或C1-6烷基；优选选自H、F、Cl、CN、Me、CHF2或CF3；优选选自H、F、Cl、CN或Me。The compound of formula (I) according to any one of claims 1 to 19, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; Preferably selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl; preferably selected from H, F, Cl, CN, Me, CHF 2 or CF 3 ; preferably selected from H, F, Cl, CN or Me.
  21. 权利要求1-20任一项的式(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，其中，L3为NR6c；优选为NH；The compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound, wherein L 3 is NR 6c ; preferably NH;
    优选地，R6a和R6b为H。Preferably, R 6a and R 6b are H.
  22. 权利要求1-21任一项的式(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，其中，R3选自C6-10芳基或5-10元杂芳基；优选为 The compound of formula (I) according to any one of claims 1 to 21, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound, wherein R 3 is selected from C 6-10 aryl or 5-10 membered heteroaryl; preferably
  23. 权利要求1-22任一项的式(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，其中，R3s选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、ORa、C1-6烷基或C1-6卤代烷基；优选选自H、D、Cl、OMe或Me；优选为Cl或Me。The compound of formula (I) according to any one of claims 1 to 22, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compound, wherein R 3s is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl Or 3-10 membered heterocyclyl; preferably selected from H, D, halogen, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, Halogen, OR a , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, Cl, OMe or Me; preferably Cl or Me.
  24. 权利要求1-23任一项的式(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，其中，两个相邻的R3s以及它们连接的原子共同形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基；优选形成5-7元杂环基或5-6元杂芳基；优选形成吡唑基或二氢呋喃基；优选形成优选形成 The compound of formula (I) according to any one of claims 1 to 23, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein two adjacent R 3s and the atoms to which they are connected together form a C 5-7 cycloalkyl group, a 5-7 membered heterocyclyl group, a phenyl group or a 5-6 membered heteroaryl group; preferably, a 5- 7-membered heterocyclyl or 5-6-membered heteroaryl; preferably forming pyrazolyl or dihydrofuranyl; preferably forming Preferably form
  25. 权利要求1-24任一项的式(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，其中，R3ss独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；优选选自H、D、C1-6烷基或C1-6卤代烷基；优选为Me。The compound of formula (I) according to any one of claims 1 to 24, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 ring Alkyl or 3-10 membered heterocyclyl; preferably selected from H, D, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; preferably From H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me.
  26. 权利要求1-25任一项的式(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，其中，L1c、L1d、L2a、L3a和L3b各自独立地选自化学键或C1-6亚烷基，其任选地被1、2或3个选自H、D、卤素、C1-6烷基或C1-6卤代烷基的基团取代；优选选自化学键或C1-3亚烷基。The compound of formula (I) according to any one of claims 1 to 25, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein L 1c , L 1d , L 2a , L 3a and L 3b are each independently selected from chemical bonds or C 1-6 alkylene groups, which are optionally replaced by 1, 2 or 3 selected from H, D , halogen, C 1-6 alkyl or C 1-6 haloalkyl group substitution; preferably selected from chemical bonds or C 1-3 alkylene.
  27. 权利要求1-26任一项的式(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，其中，Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；优选选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、C1-6烷基或C1-6卤代烷基；优选为C1-6烷基或C1-6卤代烷基；The compound of formula (I) according to any one of claims 1 to 26, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof Compounds, wherein R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; Preferably selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, C 1-6 alkyl or C 1- 6 haloalkyl; preferably C 1-6 alkyl or C 1-6 haloalkyl;
    或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基；优选形成3-7元杂环基。Or R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclyl group; preferably, a 3-7 membered heterocyclyl group is formed.
  28. 权利要求1-27任一项的式(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，其具有以下结构式：
    The compound of formula (I) according to any one of claims 1 to 27, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound, which has the following structural formula:
    其中，in,
    m2为1、2、3或4；m 2 is 1, 2, 3 or 4;
    X1为CR3b或N，X2为CR3c或N；X 1 is CR 3b or N, X 2 is CR 3c or N;
    或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
    R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基； R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    R3b选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3b is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl;
    R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    或者R3b与R3c以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1 , 2 or 3 R 3ss replacement;
    R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基、3-7元杂环基、C1-6烷氧基或C1-6卤代烷氧基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl, 3-7 membered heterocyclyl , C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2d选自H、D、卤素或氰基；R 2d is selected from H, D, halogen or cyano;
    R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    其余各基团如权利要求1-27所定义。The remaining groups are as defined in claims 1-27.
  29. 权利要求28的式(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，
    The compound of formula (II) according to claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    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;
    R1s为或-C(O)NR1bR1c；R 1s is or -C(O)NR 1b R 1c ;
    L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
    L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、ORa、SRa、NRbRc、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, OR a , SR a , NR b R c , C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
    n1和n2独立地选自0、1、2、3、4、5或6；n 1 and n 2 are independently selected from 0, 1, 2, 3, 4, 5 or 6;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R1b独立地选自H、C1-6烷基或C1-6卤代烷基；R 1b is independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R1c选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1c is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    R’1s独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基或C1-6卤代烷基；R' 1s is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
    n3为0、1、2或3；n 3 is 0, 1, 2 or 3;
    R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基； R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    m2为1、2、3或4；m 2 is 1, 2, 3 or 4;
    X1为CR3b或N，X2为CR3c或N；X 1 is CR 3b or N, X 2 is CR 3c or N;
    或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
    R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    R3b选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3b is selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 yuan Heterocyclyl;
    R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    或者R3b与R3c以及它们连接的原子共同形成C5-10环烷基、5-10元杂环基、C6-10芳基或5-10元杂芳基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a C 5-10 cycloalkyl, 5-10 membered heterocyclyl, C 6-10 aryl or 5-10 membered heteroaryl, which is optionally replaced by 1 , 2 or 3 R 3ss replacement;
    R3ss独立地选自H、D、卤素、氰基、ORa、SRa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 3ss is independently selected from H, D, halogen, cyano, OR a , SR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3- 10-membered heterocyclyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；或者Rb、Rc以及他们连接的原子一起形成3-10元杂环基；R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl; or R b , R c and the atoms to which they are connected together form a 3-10 membered heterocyclic group;
    其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
    条件是，当环A为吡啶基时，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基，且所述化合物不为如下结构：
    The condition is that when ring A is a pyridyl group, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group, and the compound does not have the following structure:
  30. 权利要求29的式(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，The compound of formula (II) of claim 29, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    环A为苯基或5-6元杂芳基；Ring A is phenyl or 5-6 membered heteroaryl;
    R1s为或-C(O)NHR1c；优选为 R 1s is or -C(O)NHR 1c ; preferably
    L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
    L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    n1和n2独立地选自0、1、2或3；n 1 and n 2 are independently selected from 0, 1, 2 or 3;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H； R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H;
    R1c选自H、C1-6烷基或C1-6卤代烷基；R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R’1s独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n3为0或1；n 3 is 0 or 1;
    R2s独立地选自H、D、卤素、氰基、C1-6烷基或C1-6卤代烷基；R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl;
    m2为1、2、3或4；m 2 is 1, 2, 3 or 4;
    X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
    或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3b选自ORa、SRa或NRbRc；优选为ORa或SRa；R 3b is selected from OR a , SR a or NR b R c ; preferably OR a or SR a ;
    R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    或者R3b与R3c以及它们连接的原子共同形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
    R3ss独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；或者Rb、Rc以及他们连接的原子一起形成3-7元杂环基。R a , R b and R c are each independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; or R b , R c and the atoms to which they are connected together form a 3-7 membered heterocyclyl group.
  31. 权利要求29或30的式(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，The compound of formula (II) according to claim 29 or 30, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    环A为5-6元杂芳基，优选为吡啶基或噻唑基；Ring A is a 5-6 membered heteroaryl group, preferably pyridyl or thiazolyl;
    R1s为或-C(O)NHR1c；优选为 R 1s is or -C(O)NHR 1c ; preferably
    L1a选自O、S、NR5a；L 1a is selected from O, S, NR 5a ;
    L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C3-5环烷基或3-5元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-5 cycloalkyl or 3-5 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n1选自0、1或2；n 1 is selected from 0, 1 or 2;
    n2选自0或1；n 2 is selected from 0 or 1;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H；优选R5b为C1-6烷基或C1-6卤代烷基，优选为Me；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H; preferably R 5b is C 1-6 alkyl or C 1-6 haloalkyl, preferably for Me;
    R1c选自C1-6烷基或C1-6卤代烷基；R 1c is selected from C 1-6 alkyl or C 1-6 haloalkyl;
    n3为0；n 3 is 0;
    R2s独立地选自H、D、卤素、氰基、C1-6烷基或C1-6卤代烷基；优选选自H、D、卤素、氰基或C1-6烷基；R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, D, halogen, cyano or C 1-6 alkyl;
    m2为2或3；m 2 is 2 or 3;
    X1为CR3b，X2为CR3c； X 1 is CR 3b , X 2 is CR 3c ;
    或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
    R3a为卤素；R 3a is halogen;
    R3b为ORa；R 3b is OR a ;
    R3c、R3d和R3e独立地为H或D；R 3c , R 3d and R 3e are independently H or D;
    或者R3b与R3c以及它们连接的原子共同形成5-7元杂环基或5-6元杂芳基，优选形成吡唑基或二氢呋喃基，其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, preferably a pyrazolyl group or a dihydrofuranyl group, which is optionally replaced by 1, 2 or 3 R 3ss replaced;
    R3ss独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    Ra选自H、C1-6烷基或C1-6卤代烷基，优选为C1-6烷基或C1-6卤代烷基。R a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably C 1-6 alkyl or C 1-6 haloalkyl.
  32. 权利要求29-31任一项的式(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，The compound of formula (II) according to any one of claims 29 to 31, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvent thereof compound, among which,
    环A为 Ring A is
    R1s为或C(O)NHCH3；优选为 R 1s is Or C(O)NHCH 3 ; preferably
    L1a选自O、S、NH或NMe；优选选自O、S或NH；L 1a is selected from O, S, NH or NMe; preferably selected from O, S or NH;
    L1b选自O、S或NMe；L 1b is selected from O, S or NMe;
    R1a选自Me、 R 1a is selected from Me,
    n1选自0、1或2；n 1 is selected from 0, 1 or 2;
    n2选自0或1；n 2 is selected from 0 or 1;
    n3为0；n 3 is 0;
    R2s独立地选自H、F、Cl、CN、Me、CHF2或CF3，优选选自H、F、Cl、CN或Me；R 2s is independently selected from H, F, Cl, CN, Me, CHF 2 or CF 3 , preferably selected from H, F, Cl, CN or Me;
    m2为2或3；m 2 is 2 or 3;
    X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
    或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
    R3a为Cl；R 3a is Cl;
    R3b为OMe；R 3b is OMe;
    R3c、R3d和R3e为H；R 3c , R 3d and R 3e are H;
    或者R3b与R3c以及它们连接的原子共同形成 Or R 3b together with R 3c and the atoms to which they are connected form
    优选地，R1s选自 Preferably, R 1s is selected from
    优选地，环A及其上的取代基共同形成： Preferably, Ring A and the substituents thereon together form:
    优选地，选自 Preferably, Selected from
    优选地，选自 Preferably, Selected from
  33. 权利要求28的式(III-1)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 formula (III-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
    L1b选自O、S或NR5b；L 1b is selected from O, S or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    n1选自1、2、3、4、5或6；n 1 is selected from 1, 2, 3, 4, 5 or 6;
    n2选自0、1、2、3、4、5或6；n 2 is selected from 0, 1, 2, 3, 4, 5 or 6;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
    R2d选自H、D、卤素或氰基； R 2d is selected from H, D, halogen or cyano;
    R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  34. 权利要求33的式(III-1)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 formula (III-1) of claim 33, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    L1a选自O或S；优选为O；优选为S；L 1a is selected from O or S; preferably O; preferably S;
    L1b选自O、S或NR5b；优选为O或NR5b；L 1b is selected from O, S or NR 5b ; preferably O or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, D, halogen , C 1-6 alkyl or C 1-6 haloalkyl;
    n1选自1、2或3；优选为2；n 1 is selected from 1, 2 or 3; preferably 2;
    n2选自0、1、2或3；优选为0或1；n 2 is selected from 0, 1, 2 or 3; preferably 0 or 1;
    R5b选自H、C1-6烷基或C1-6卤代烷基；优选为C1-3烷基或C1-3卤代烷基；R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably C 1-3 alkyl or C 1-3 haloalkyl;
    R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    优选地，Preferably,
    R2a选自卤素、C1-6烷基或C1-6卤代烷基；R 2a is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2b为H；R 2b is H;
    R2c选自H、D或卤素；R 2c is selected from H, D or halogen;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  35. 权利要求33或34的式(III-1)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 formula (III-1) according to claim 33 or 34, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof things, among which,
    L1a选自O或S；L 1a is selected from O or S;
    L1b选自O或S；L 1b is selected from O or S;
    R1a选自C1-6烷基、C1-6卤代烷基或C3-5环烷基；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
    n1为2；n 1 is 2;
    n2为0或1；n 2 is 0 or 1;
    R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基； R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基。R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  36. 权利要求33-35任一项的式(III-1)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 formula (III-1) according to any one of claims 33 to 35, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
    L1b为O；L 1b is O;
    R1a选自C1-6烷基或C1-6卤代烷基；R 1a is selected from C 1-6 alkyl or C 1-6 haloalkyl;
    n1为2；n 1 is 2;
    n2为0；n 2 is 0;
    R2a、R2c和R2d独立地为卤素；R 2a , R 2c and R 2d are independently halogen;
    R2b为H或D；R 2b is H or D;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  37. 权利要求33-36任一项的式(III-1)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 formula (III-1) according to any one of claims 33 to 36, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
    L1b选自O或NMe；优选为O；L 1b is selected from O or NMe; preferably O;
    R1a选自Me、优选为Me；R 1a is selected from Me, Preferably Me;
    n1为2；n 1 is 2;
    n2为0或1；优选0；n 2 is 0 or 1; preferably 0;
    R2a选自F或Me；优选为F；R 2a is selected from F or Me; preferably F;
    R2b为H；R 2b is H;
    R2c选自H或F；更优选为F；R 2c is selected from H or F; more preferably, it is F;
    R2d选自F、Cl或CN；优选为F或Cl；R 2d is selected from F, Cl or CN; preferably F or Cl;
    R3a为Cl；R 3a is Cl;
    R3f为Me；R 3f is Me;
    优选地，选自：优选为 Preferably, Selected from: Preferably
    优选地，选自：优选为 Preferably, Selected from: Preferably
  38. 权利要求28的式(III-2)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 formula (III-2) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
    R1a选自C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    n1选自1、2、3、4、5或6；n 1 is selected from 1, 2, 3, 4, 5 or 6;
    R5a选自H、C1-6烷基或C1-6卤代烷基；R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
    R2d选自H、D、卤素或氰基；R 2d is selected from H, D, halogen or cyano;
    R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  39. 权利要求38的式(III-2)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 formula (III-2) of claim 38, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    L1a选自O或S；优选为O；优选为S；L 1a is selected from O or S; preferably O; preferably S;
    R1a为C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n1选自1、2或3；n 1 is selected from 1, 2 or 3;
    R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基； R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基。R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  40. 权利要求38或39的式(III-2)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 formula (III-2) according to claim 38 or 39, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof things, among them,
    L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
    R1a为3-7元杂环基，优选为4-5元杂环基，其任选地被1、2或3个R1as取代；R 1a is a 3-7-membered heterocyclyl group, preferably a 4-5-membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as选自H、D、C1-6烷基或C1-6卤代烷基；优选为Me；R 1as is selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl; preferably Me;
    n1为1；n 1 is 1;
    R2a、R2c和R2d独立地为卤素；R 2a , R 2c and R 2d are independently halogen;
    R2b为H或D；R 2b is H or D;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  41. 权利要求38-40任一项的式(III-2)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 formula (III-2) according to any one of claims 38 to 40, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
    R1a选自 R 1a is selected from
    n1为1；n 1 is 1;
    为 for
    R3a为Cl；R 3a is Cl;
    R3f为Me；R 3f is Me;
    优选地，选自： Preferably, Selected from:
  42. 权利要求28的式(III-3)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 formula (III-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    其中，in,
    L1a选自O、S或NR5a；L 1a is selected from O, S or NR 5a ;
    R1a选自C3-10环烷基或3-10元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 3-10 cycloalkyl or 3-10 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基或3-10元杂环基；R 1as is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl or 3-10 membered heterocyclyl;
    R5a选自H、C1-6烷基或C1-6卤代烷基；R 5a is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a、R2b和R2c独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl ;
    R2d选自H、D、卤素或氰基；R 2d is selected from H, D, halogen or cyano;
    R3a选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3a is selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    R3f选自H、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 3f is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  43. 权利要求42的式(III-3)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 formula (III-3) of claim 42, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    L1a选自O、S或NH；优选为O或NH；优选为S；L 1a is selected from O, S or NH; preferably O or NH; preferably S;
    R1a为C3-7环烷基或3-7元杂环基，优选为3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基。R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  44. 权利要求42或43的式(III-3)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 formula (III-3) according to claim 42 or 43, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof things, among them,
    L1a选自O、S或NH；优选为O或NH；L 1a is selected from O, S or NH; preferably O or NH;
    R1a为4-6元杂环基，优选为5元杂环基，优选为四氢呋喃基，其任选地被1、2或3个R1as取代；R 1a is a 4-6 membered heterocyclyl group, preferably a 5-membered heterocyclyl group, preferably a tetrahydrofuranyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2b选自H、D或卤素； R 2b is selected from H, D or halogen;
    R2c为卤素；R 2c is halogen;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  45. 权利要求42-44任一项的式(III-3)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，当R1a与L1a的连接原子为手性碳原子时，为为 The compound of formula (III-3) according to any one of claims 42 to 44, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof Or a solvate, where, when the connecting atom of R 1a and L 1a is a chiral carbon atom, it is for
  46. 权利要求44-45任一项的式(III-3)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 formula (III-3) according to any one of claims 44 to 45, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    L1a选自O、S或NH；优选为O或NH；L 1a is selected from O, S or NH; preferably O or NH;
    R1a选自优选为更优选为 R 1a is selected from Preferably More preferably
    R2a为H、F、Cl或Me；R 2a is H, F, Cl or Me;
    R2b为H或F；R 2b is H or F;
    R2c为F或Cl；优选为F；R 2c is F or Cl; preferably F;
    R2d为F、Cl或CN；R 2d is F, Cl or CN;
    R3a为Cl；R 3a is Cl;
    R3f为Me；R 3f is Me;
    优选地，选自：优选不为更优选为 Preferably, Selected from: Prefer not to More preferably
    优选地，选自： 优选选自 Preferably, Selected from: Preferably selected from
  47. 权利要求28的式(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，
    The compound of formula (II) according to claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    环A为苯基或5-6元杂芳基；Ring A is phenyl or 5-6 membered heteroaryl;
    R1s为-C(O)NHR1c或 R 1s is -C(O)NHR 1c or
    L1a选自化学键、O、S或NR5a；L 1a is selected from chemical bond, O, S or NR 5a ;
    L1b选自化学键、O、S或NR5b；L 1b is selected from chemical bond, O, S or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl, Phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、氰基、ORa、NRbRc、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；R 1as is independently selected from H, D, halogen, cyano, OR a , NR b R c , C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered hetero Ring group;
    n1和n2独立地选自0、1、2或3；n 1 and n 2 are independently selected from 0, 1, 2 or 3;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H;
    R1c选自H、C1-6烷基或C1-6卤代烷基；R 1c is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R’1s独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R' 1s is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n3为0或1；n 3 is 0 or 1;
    R2s独立地选自H、D、卤素、氰基、C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或 R 2s is independently selected from H, D, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or
    m2为1、2、3或4；m 2 is 1, 2, 3 or 4;
    X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
    或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3b选自ORa、SRa或NRbRc；优选为ORa或SRa；R 3b is selected from OR a , SR a or NR b R c ; preferably OR a or SR a ;
    R3c、R3d和R3e独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3c , R 3d and R 3e are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    或者R3b与R3c以及它们连接的原子共同形成C5-7环烷基、5-7元杂环基、苯基或5-6元杂芳基， 其任选地被1、2或3个R3ss取代；Or R 3b and R 3c and the atoms they are connected together form C 5-7 cycloalkyl, 5-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, It is optionally replaced by 1, 2 or 3 R 3ss ;
    R3ss独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代；wherein each of the above defined groups is optionally deuterated until completely deuterated;
    条件是，当环A为吡啶基时，L1a为NH，L1b为化学键时，R1a不为C1-6烷基或C1-6卤代烷基，且所述化合物不为如下结构：
    The condition is that when ring A is a pyridyl group, L 1a is NH, and L 1b is a chemical bond, R 1a is not a C 1-6 alkyl group or a C 1-6 haloalkyl group, and the compound does not have the following structure:
  48. 权利要求47的式(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，The compound of formula (II) of claim 47, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, wherein,
    环A为5-6元杂芳基，优选为吡啶基或噻唑基，优选为吡啶基，优选为 Ring A is a 5-6 membered heteroaryl group, preferably pyridyl or thiazolyl, preferably pyridyl, preferably
    R1s为优选为 R 1s is Preferably
    L1a选自O、S、NR5a；L 1a is selected from O, S, NR 5a ;
    L1b选自化学键、O或NR5b；L 1b is selected from chemical bond, O or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基、3-7元杂环基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
    n1选自0、1或2；n 1 is selected from 0, 1 or 2;
    n2选自0、1或2；n 2 is selected from 0, 1 or 2;
    R5a和R5b独立地选自H、C1-6烷基或C1-6卤代烷基；优选R5a为H；优选R5b为C1-3烷基或C1-3卤代烷基；R 5a and R 5b are independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl; preferably R 5a is H; preferably R 5b is C 1-3 alkyl or C 1-3 haloalkyl;
    n3为0；n 3 is 0;
    R2s独立地选自H、D、卤素、氰基、C1-4烷基、C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基；R 2s is independently selected from H, D, halogen, cyano, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy;
    m2为2或3；m 2 is 2 or 3;
    X1为CR3b，X2为CR3c；X 1 is CR 3b , X 2 is CR 3c ;
    或者X1为C(O)，X2为NH；Or X 1 is C(O) and X 2 is NH;
    R3a为卤素； R 3a is halogen;
    R3b为ORa；优选为OMe；R 3b is OR a ; preferably OMe;
    R3c、R3d和R3e独立地为H或D；R 3c , R 3d and R 3e are independently H or D;
    或者R3b与R3c以及它们连接的原子共同形成5-7元杂环基或5-6元杂芳基，其任选地被1、2或3个R3ss取代；优选形成 Or R 3b and R 3c and the atoms to which they are connected together form a 5-7 membered heterocyclyl group or a 5-6 membered heteroaryl group, which is optionally substituted by 1, 2 or 3 R 3ss ; preferably, it forms
    R3ss独立地选自H、D、C1-6烷基或C1-6卤代烷基；R 3ss is independently selected from H, D, C 1-6 alkyl or C 1-6 haloalkyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    优选地，选自优选优选 Preferably, Selected from preferred preferred
    优选地，当L1b为化学键时，R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基。Preferably, when L 1b is a chemical bond, R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl.
  49. 权利要求28的式(III-1)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 formula (III-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    L1a选自O或S；L 1a is selected from O or S;
    L1b选自O、S或NR5b；L 1b is selected from O, S or NR 5b ;
    R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-7环烷基或3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-7 cycloalkyl or 3-7 membered heterocyclyl, It is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、CN、C1-6烷基、C1-6卤代烷基、C3-7环烷基或3-7元杂环基；优选选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 3-7 cycloalkyl or 3-7 membered heterocyclyl; preferably selected from H, D , halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    n1选自1、2或3； n 1 is selected from 1, 2 or 3;
    n2选自0、1、2或3；n 2 is selected from 0, 1, 2 or 3;
    R5b选自H、C1-6烷基或C1-6卤代烷基；R 5b is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a选自H、D、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 2a is selected from H, D, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy or C 1-6 haloalkoxy;
    R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自选自H、D、卤素或氰基；优选为卤素或氰基；R 2d is selected from H, D, halogen or cyano; preferably halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  50. 权利要求49的式(III-1)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 formula (III-1) of claim 49, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    L1a选自O或S；L 1a is selected from O or S;
    L1b为O或NR5b；优选为O；L 1b is O or NR 5b ; preferably O;
    R1a选自C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基、C3-5环烷基或3-5元杂环基；优选为C1-6烷基、C1-6卤代烷基、C1-6烷氧基、C1-6卤代烷氧基或C3-5环烷基；优选为C1-6烷基、C1-6卤代烷基或C3-5环烷基；R 1a is selected from C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 3-5 cycloalkyl or 3-5 membered heterocyclyl; Preferably it is C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy or C 3-5 cycloalkyl; preferably C 1-6 alkyl, C 1-6 haloalkyl or C 3-5 cycloalkyl;
    n1为2；n 1 is 2;
    n2为0、1或2；n 2 is 0, 1 or 2;
    R5b为C1-3烷基或C1-3卤代烷基，优选为Me；R 5b is C 1-3 alkyl or C 1-3 haloalkyl, preferably Me;
    R2a选自H、D、卤素、C1-4烷基、C1-4卤代烷基、C1-4烷氧基或C1-4卤代烷氧基；优选为卤素、C1-4烷基或C1-4烷氧基；R 2a is selected from H, D, halogen, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy or C 1-4 haloalkoxy; preferably halogen, C 1-4 alkyl or C 1-4 alkoxy;
    R2b为H、D或卤素；R 2b is H, D or halogen;
    R2c选自H、D或卤素；R 2c is selected from H, D or halogen;
    R2d为卤素或CN；R 2d is halogen or CN;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  51. 权利要求49或50的式(III-1)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 formula (III-1) according to claim 49 or 50, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof things, among them,
    L1a选自O或S；优选为O；L 1a is selected from O or S; preferably O;
    L1b选自O或NMe；优选为O；L 1b is selected from O or NMe; preferably O;
    R1a选自Me、OMe、环丙基或优选为Me、OMe或环丙基；优选为Me或环丙基；R 1a is selected from Me, OMe, cyclopropyl or Preferably it is Me, OMe or cyclopropyl; Preferably it is Me or cyclopropyl;
    n1为2；n 1 is 2;
    n2为0、1或2；优选0或1；n 2 is 0, 1 or 2; preferably 0 or 1;
    R2a选自H、F、Me、CF3、OMe或OCHF2；优选为F、Me或OMe；R 2a is selected from H, F, Me, CF 3 , OMe or OCHF 2 ; preferably F, Me or OMe;
    R2b为H或F； R 2b is H or F;
    R2c选自H、F或Cl；更优选为H或F；R 2c is selected from H, F or Cl; more preferably H or F;
    R2d选自F、Cl或CN；优选为Cl或CN；R 2d is selected from F, Cl or CN; preferably Cl or CN;
    R3a为Cl；R 3a is Cl;
    R3f为Me；R 3f is Me;
    优选地，选自： 优选为优选为 Preferably, Selected from: Preferably Preferably
    优选地，选自： 优选为 Preferably, Selected from: Preferably
  52. 权利要求28的式(III-3)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 formula (III-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    L1a选自O、S或NR5a； L 1a is selected from O, S or NR 5a ;
    R1a为C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
    R5a选自H、C1-3烷基或C1-3卤代烷基；优选R5a为H；R 5a is selected from H, C 1-3 alkyl or C 1-3 haloalkyl; preferably R 5a is H;
    R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  53. 权利要求52的式(III-3)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 formula (III-3) of claim 52, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    L1a选自O、S或NH；L 1a is selected from O, S or NH;
    R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、F、Me、NH2、-NHCH3或-NH(CH3)2；优选选自H、F、Me、NH2或-NHCH3；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, F, Me, NH 2 , -NHCH 3 or -NH ( CH 3 ) 2 ; preferably selected from H, F, Me, NH 2 or -NHCH 3 ;
    R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R2b选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2b is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R2c为H、D或卤素；R 2c is H, D or halogen;
    R2d为卤素或氰基；R 2d is halogen or cyano;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基；R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
    Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基。R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  54. 权利要求52或53的式(III-3)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，当R1a与L1a的连接原子为手性碳原子时，为为 The compound of formula (III-3) according to claim 52 or 53, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof thing, where, when the connecting atom of R 1a and L 1a is a chiral carbon atom, it is for
  55. 权利要求52-54任一项的式(III-3)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 formula (III-3) according to any one of claims 52 to 54, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    L1a选自O、S或NH；L 1a is selected from O, S or NH;
    R1a选自 优选选自： 优选地，为 R 1a is selected from Preferably selected from: Preferably, for
    R2a为H、F、Cl或Me；R 2a is H, F, Cl or Me;
    R2b为H、F或Me；R 2b is H, F or Me;
    R2c为H、F或Cl；R 2c is H, F or Cl;
    R2d为F、Cl或CN；R 2d is F, Cl or CN;
    R3a为Cl；R 3a is Cl;
    R3f为Me；R 3f is Me;
    优选地，选自： 优选选自： 优选地，为优选地，为优选地，为 Preferably, Selected from: Preferably selected from: Preferably, for Preferably, for Preferably, for
    优选地，选自： Preferably, Selected from:
  56. 权利要求28的式(IV-1)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 formula (IV-1) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    R1a为C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
    R2a和R2b独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2c选自卤素、C1-6烷基或C1-6卤代烷基；R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基； R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  57. 权利要求56的式(IV-1)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 formula (IV-1) of claim 56, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基，优选为3-7元杂环基或5-6元杂芳基，优选为4-6元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably 4-6 A membered heterocyclyl optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基，优选选自H、D或NRbRc；优选选自H、NH2或-N(CH3)2；优选选自H或NH2；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl, preferably selected from H, D or NR b R c ; preferably selected from H, NH 2 or -N(CH 3 ) 2 ; preferably selected from H or NH 2 ;
    R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R2b选自H、D或卤素；R 2b is selected from H, D or halogen;
    R2c为卤素；R 2c is halogen;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基；R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
    Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基，优选为H。R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl, preferably H.
  58. 权利要求56或57的式(IV-1)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，当R1a与O的连接原子为手性碳原子时，为为 The compound of formula (IV-1) according to claim 56 or 57, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof thing, where, when the connecting atom between R 1a and O is a chiral carbon atom, it is for
  59. 权利要求56-58任一项的式(IV-1)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 formula (IV-1) according to any one of claims 56 to 58, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    L1a选自O、S或NH；优选为O或NH；L 1a is selected from O, S or NH; preferably O or NH;
    选自：优选为：优选为优选地，为 Selected from: Preferably: Preferably Preferably, for
    R2a为H、F、Cl或Me；优选为H、Cl或Me；R 2a is H, F, Cl or Me; preferably H, Cl or Me;
    R2b为H或F；优选为H；R 2b is H or F; preferably H;
    R2c为F；R 2c is F;
    R2d为F、Cl或CN；优选为Cl或CN；R 2d is F, Cl or CN; preferably Cl or CN;
    R3a为Cl；R 3a is Cl;
    R3f为Me； R 3f is Me;
    优选地，选自： 优选选自 优选选自 Preferably, Selected from: Preferably selected from Preferably selected from
  60. 权利要求28的式(IV-2)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 formula (IV-2) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    R1a为C3-7环烷基或3-7元杂环基，优选为3-7元杂环基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl or 3-7 membered heterocyclyl, preferably 3-7 membered heterocyclyl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a和R2b独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a and R 2b are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2c选自卤素、C1-6烷基或C1-6卤代烷基；R 2c is selected from halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  61. 权利要求60的式(IV-2)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 formula (IV-2) of claim 60, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    R1a为4-6元杂环基，优选为5元杂环基，其任选地被1、2或3个R1as取代；R 1a is a 4-6 membered heterocyclyl group, preferably a 5-membered heterocyclyl group, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基； R 1as is independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；优选选自H、D或卤素；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl; preferably selected from H, D or halogen;
    R2b选自H或D；R 2b is selected from H or D;
    R2c为卤素；R 2c is halogen;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基。R 3f is C 1-6 alkyl or C 1-6 haloalkyl.
  62. 权利要求60或61的式(IV-2)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，当R1a与NH的连接原子为手性碳原子时，为为 The compound of formula (IV-2) according to claim 60 or 61, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof thing, where, when the connecting atom between R 1a and NH is a chiral carbon atom, it is for
  63. 权利要求60-62任一项的式(IV-2)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 formula (IV-2) according to any one of claims 60 to 62, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    选自：优选为 Selected from: Preferably
    R2a为H、F、Cl或Me；优选为H或F；R 2a is H, F, Cl or Me; preferably H or F;
    R2b为H；R 2b is H;
    R2c为F；R 2c is F;
    R2d为F、Cl或CN；优选为F或CN；R 2d is F, Cl or CN; preferably F or CN;
    R3a为Cl；R 3a is Cl;
    R3f为Me；R 3f is Me;
    优选地，选自： 优选选自优选为 Preferably, Selected from: Preferably selected from Preferably
  64. 权利要求28的式(IV-3)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 formula (IV-3) of claim 28, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof,
    其中，in,
    R1a为C3-7环烷基、3-7元杂环基、苯基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl, phenyl or 5-6 membered heteroaryl, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、ORa、NRbRc、C1-6烷基或C1-6卤代烷基；R 1as is independently selected from H, D, halogen, OR a , NR b R c , C 1-6 alkyl or C 1-6 haloalkyl;
    R2a、R2b和R2c独立地选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 2a , R 2b and R 2c are independently selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a选自H、D、卤素、C1-6烷基或C1-6卤代烷基；R 3a is selected from H, D, halogen, C 1-6 alkyl or C 1-6 haloalkyl;
    R3f选自H、C1-6烷基或C1-6卤代烷基；R 3f is selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    Ra、Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基；R a , R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl;
    其中上述各个基团定义任选地被氘代，直至完全氘代。Wherein each of the above defined groups is optionally deuterated, up to complete deuteration.
  65. 权利要求64的式(IV-3)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 formula (IV-3) of claim 64, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, in,
    R1a为C3-7环烷基、3-7元杂环基或5-6元杂芳基，优选C3-6环烷基、4-6元杂环基或5-6元杂芳基，其任选地被1、2或3个R1as取代；R 1a is C 3-7 cycloalkyl, 3-7 membered heterocyclyl or 5-6 membered heteroaryl, preferably C 3-6 cycloalkyl, 4-6 membered heterocyclyl or 5-6 membered heteroaryl radical, which is optionally substituted by 1, 2 or 3 R 1as ;
    R1as独立地选自H、D、卤素、NRbRc、C1-6烷基或C1-6卤代烷基；优选选自H、F、Me、NH2或NHCH3；优选为H、F或Me；R 1as is independently selected from H, D, halogen, NR b R c , C 1-6 alkyl or C 1-6 haloalkyl; preferably selected from H, F, Me, NH 2 or NHCH 3 ; preferably H, F or Me;
    R2a选自H、D、卤素、C1-4烷基或C1-4卤代烷基；R 2a is selected from H, D, halogen, C 1-4 alkyl or C 1-4 haloalkyl;
    R2b选自H、D、C1-4烷基或C1-4卤代烷基；R 2b is selected from H, D, C 1-4 alkyl or C 1-4 haloalkyl;
    R2c选自H、D或卤素；R 2c is selected from H, D or halogen;
    R2d选自卤素或氰基；R 2d is selected from halogen or cyano;
    R3a为卤素；R 3a is halogen;
    R3f为C1-6烷基或C1-6卤代烷基；R 3f is C 1-6 alkyl or C 1-6 haloalkyl;
    Rb和Rc各自独立地选自H、C1-6烷基或C1-6卤代烷基。R b and R c are each independently selected from H, C 1-6 alkyl or C 1-6 haloalkyl.
  66. 权利要求64或65的式(IV-3)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，当R1a与S的连接原子为手性碳原子时，为为 The compound of formula (IV-3) according to claim 64 or 65, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof thing, where, when the connecting atom between R 1a and S is a chiral carbon atom, it is for
  67. 权利要求64-66任一项的式(IV-3)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 formula (IV-3) according to any one of claims 64 to 66, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, or hydrate thereof or solvate, where,
    选自： 优选为 优选为 优选为优选地，为 Selected from: Preferably Preferably Preferably Preferably, for
    R2a为H、F或Me；R 2a is H, F or Me;
    R2b为H或Me；R 2b is H or Me;
    R2c为H、F或Cl；R 2c is H, F or Cl;
    R2d为Cl或CN；R 2d is Cl or CN;
    R3a为Cl；R 3a is Cl;
    R3f为Me；R 3f is Me;
    优选地，选自： 优选为优选为 Preferably, Selected from: Preferably Preferably
  68. 权利要求1的式(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，其中，所述化合物选自以下：







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







  69. 药物组合物，其包含权利要求1-68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 68, 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.
  70. 权利要求1-68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69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 68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, Or the use of the pharmaceutical composition of claim 69 in the preparation of medicaments for treating or preventing diseases caused by viral infections.
  71. 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 1-68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69的药物组合物。A method of treating or preventing a disease caused by a viral infection in a subject, comprising administering to the subject claims The compound of any one of 1-68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, or the rights thereof A pharmaceutical composition as claimed in claim 69.
  72. 权利要求1-68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69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 68, or a pharmaceutically acceptable salt, isotopic variant, tautomer, stereoisomer, prodrug, polymorph, hydrate or solvate thereof, Or the pharmaceutical composition of claim 69, which is used to treat or prevent diseases caused by viral infection.
  73. 权利要求70的用途或权利要求71的方法或权利要求72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 70 or the method of claim 71 or the use of a compound or pharmaceutical composition of claim 72, 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.
  74. 权利要求70的用途或权利要求71的方法或权利要求72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 70 or the method of claim 71 or the compound or pharmaceutical composition of claim 72, wherein the disease caused by the viral infection is selected from: fever, nausea, vomiting, headache, dyspnea, fatigue, respiratory tract disease Infection, pneumonia, anosmia, taste disorder, their complications, or combinations thereof.
PCT/CN2023/096587 2022-05-27 2023-05-26 3c-like protease inhibitor WO2023227117A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395571A (en) * 2009-02-13 2012-03-28 盐野义制药株式会社 Novel triazine derivative and pharmaceutical composition containing same
WO2013089212A1 (en) * 2011-12-15 2013-06-20 塩野義製薬株式会社 Substituted triazine derivative and pharmaceutical composition containing same
CN115038696A (en) * 2021-04-14 2022-09-09 盐野义制药株式会社 Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395571A (en) * 2009-02-13 2012-03-28 盐野义制药株式会社 Novel triazine derivative and pharmaceutical composition containing same
WO2013089212A1 (en) * 2011-12-15 2013-06-20 塩野義製薬株式会社 Substituted triazine derivative and pharmaceutical composition containing same
CN115038696A (en) * 2021-04-14 2022-09-09 盐野义制药株式会社 Triazine derivatives having virus proliferation inhibitory activity and pharmaceutical composition containing the same

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