WO2023227117A1 - Inhibiteur de protéase de type 3c - Google Patents

Inhibiteur de protéase de type 3c 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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English (en)
Chinese (zh)
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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/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—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.

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Abstract

La présente invention concerne un inhibiteur de protéase de type 3C tel que représenté dans la formule (I), ou un sel, un variant isotopique, un tautomère, un stéréoisomère, un promédicament, un polymorphe, un hydrate ou un solvate pharmaceutiquement acceptables de celui-ci. La présente invention concerne également un procédé de préparation du composé, une composition pharmaceutique contenant le composé, et un effet du composé dans le traitement ou la prévention de maladies provoquées par une infection virale.
PCT/CN2023/096587 2022-05-27 2023-05-26 Inhibiteur de protéase de type 3c WO2023227117A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12091420B2 (en) 2022-08-05 2024-09-17 Gilead Sciences, Inc. SARS-COV2 main protease inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395571A (zh) * 2009-02-13 2012-03-28 盐野义制药株式会社 新型三嗪衍生物及含有该三嗪衍生物的药物组合物
WO2013089212A1 (fr) * 2011-12-15 2013-06-20 塩野義製薬株式会社 Dérivé de triazine substituée et composition pharmaceutique le contenant
CN115038696A (zh) * 2021-04-14 2022-09-09 盐野义制药株式会社 具有病毒增殖抑制作用的三嗪衍生物及含有其的药物组合物

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102395571A (zh) * 2009-02-13 2012-03-28 盐野义制药株式会社 新型三嗪衍生物及含有该三嗪衍生物的药物组合物
WO2013089212A1 (fr) * 2011-12-15 2013-06-20 塩野義製薬株式会社 Dérivé de triazine substituée et composition pharmaceutique le contenant
CN115038696A (zh) * 2021-04-14 2022-09-09 盐野义制药株式会社 具有病毒增殖抑制作用的三嗪衍生物及含有其的药物组合物

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12091420B2 (en) 2022-08-05 2024-09-17 Gilead Sciences, Inc. SARS-COV2 main protease inhibitors

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