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WO2025247390A1 - Heterobicyclic compounds usable as glp-1r agonists - Google Patents

Heterobicyclic compounds usable as glp-1r agonists

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Publication number
WO2025247390A1
WO2025247390A1 PCT/CN2025/098519 CN2025098519W WO2025247390A1 WO 2025247390 A1 WO2025247390 A1 WO 2025247390A1 CN 2025098519 W CN2025098519 W CN 2025098519W WO 2025247390 A1 WO2025247390 A1 WO 2025247390A1
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Prior art keywords
alkyl
cycloalkyl
halogen
independently selected
optionally substituted
Prior art date
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Pending
Application number
PCT/CN2025/098519
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French (fr)
Chinese (zh)
Inventor
刘世岚
任德成
熊尧
李泽飞
费凡
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Fortvita Biologics Inc
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Fortvita Biologics Inc
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Publication of WO2025247390A1 publication Critical patent/WO2025247390A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • This application relates to heterobicyclic compounds having glucagon-like peptide receptor (GLP-1R) agonist activity, methods for their preparation, pharmaceutical compositions comprising them, and their use as GLP-1R agonists or for the treatment or prevention of GLP-1R-related diseases or disorders.
  • GLP-1R glucagon-like peptide receptor
  • the compounds of this application can be used for weight management, for lowering blood glucose and/or for the treatment or prevention of diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic diseases, cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders or disorders, cancer, etc.
  • fatty liver diseases e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
  • metabolic diseases e.g., cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders or disorders, cancer, etc.
  • GLP-1 Glucagon-like peptide-1
  • GLP-1R GLP-1 receptors
  • GLP-1 receptor agonists are a new class of hypoglycemic drugs developed in recent years. They lower blood sugar by activating GLP-1R, inhibiting glucagon secretion and promoting insulin secretion in a glucose concentration-dependent manner. GLP-1RAs also improve insulin sensitivity, promote the production of liver and muscle glycogen, inhibit liver glycogen output, and increase glucose uptake by adipocytes. These effects help improve the body's sensitivity to insulin, further enhancing the hypoglycemic effect and delaying the progression of diabetes. Furthermore, GLP-1RAs act on the appetite regulation center in the brain, suppressing appetite and delaying gastric emptying, increasing satiety. This helps reduce food intake, thereby reducing glucose intake and further enhancing the hypoglycemic effect. Simultaneously, by reducing appetite, delaying gastric emptying, and increasing satiety, GLP-1RAs also contribute to weight loss.
  • GLP-1RA drugs offer numerous clinical benefits, such as improving dyslipidemia, reducing fatty liver, providing metabolic benefits, lowering blood pressure, providing cardiovascular benefits, providing renal benefits, protecting pancreatic ⁇ -cells, and regulating gastrointestinal function. GLP-1RA drugs can significantly reduce the risk of cardiovascular events, slow the progression of diabetic nephropathy, and improve the long-term prognosis of diabetic patients. GLP-1RA drugs have become an important treatment for diabetes and weight loss.
  • the compounds of this invention possess satisfactory GLP-1R agonist activity and can be used to regulate, particularly to activate, GLP-1R activity, or to treat or prevent GLP-1R-related diseases or disorders.
  • the compounds of this invention are especially satisfactory in lowering blood sugar and reducing weight.
  • the compounds of the present invention exhibit favorable in vivo and in vitro pharmacokinetic properties, such as good solubility and/or absorption, good metabolic stability, improved bioavailability, and reduced side effects (e.g., low risk of hypoglycemia).
  • the compounds of the present invention can be administered at longer intervals, which is convenient for patients and helps improve patient compliance.
  • the compounds of the present invention also possess good physical and/or chemical stability, making them suitable for formulation into various pharmaceutically acceptable preparations.
  • the present invention provides compounds of formula (I) and its subforms or pharmaceutically usable salts, tautomers, stereoisomers, isotope-labeled compounds or solvates.
  • the present invention provides pharmaceutical compositions comprising compounds of formula (I) and its subforms, or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds or solvates, and one or more pharmaceutically acceptable carriers, diluents or excipients.
  • the present invention provides compounds of formula (I) and its subforms, or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates, or pharmaceutical compositions comprising the same, for regulating, in particular activating, GLP-1R activity, or for treating or preventing GLP-1R-related diseases or disorders.
  • the present invention provides a method for regulating, in particular activating, GLP-1R activity or for treating or preventing GLP-1R-related diseases or disorders, the method comprising administering to the individual an effective amount of a compound of formula (I) and its subforms or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound or solvate.
  • the present invention provides the use of compounds of formula (I) and its subforms or pharmaceutically usable salts, tautomers, stereoisomers, isotopically labeled compounds or solvates as pharmaceuticals or in the preparation of pharmaceuticals, said pharmaceuticals being used to regulate, in particular to activate, GLP-1R activity or to treat or prevent GLP-1R-related diseases or disorders.
  • the present invention provides combinations of compounds of formula (I) and its subforms, or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates, with other active agents. These other active agents may have the same or different effects as the compounds of the present invention.
  • the present invention provides a method for preparing compounds of formula (I) and its subforms, or pharmaceutically usable salts, tautomers, stereoisomers, isotope-labeled compounds, or solvates.
  • the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds or solvates thereof.
  • L1 is selected from -CO-, -SO-, -SO2- , -NRa- , and -CRaRb- ;
  • L2 is selected from -R L -NR a -*, -R L -CO-NR a -*, -R L -NR a -CO-NR a -*, -R L -C(S)-NR a -*, -R L -NR a -C(S)-NR a -*, where the asterisk indicates a connection to the N atom of the central ring;
  • Ring A is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted with one or more R3s , each R3 independently selected from halogens, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyls independently selected from halogens and C1-6 alkyls) -RL- , or two of the R3s.
  • 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S
  • said 4- to 6-membered ring optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl;
  • Cycle B is a naphthylene or an 8-10-membered bicyclic heteroarylene, each optionally substituted by one or more R4 groups, each R4 group being independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , (5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein each of the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups is optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy groups;
  • Ring D is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl.
  • Each of the two R1s is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.
  • R2 is independently selected from H, halogen, cyano, OH, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 (C1-6 alkyl), -NR a -S(O) 2- (C1-6 alkyl ), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(O)(
  • R6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl, C ⁇ sub>1-6 ⁇ /sub> haloalkyl, C ⁇ sub>6-10 ⁇ /sub> aryl, or 5-10 heteroaryl;
  • R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;
  • T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;
  • Q is either O or S
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • q can be 0, 1, 2 or 3, preferably 1 or 2.
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof wherein: the ring C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents, each substituent being independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylene group ...
  • 1-6 haloalkanediols COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy)-RL-, (C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl)-C2-4 alkenyl- , ( C3-10 cycloalkyl) -C2-4 alkyne-, ( C3-10 cycloalkyloxy)-RL-, ( 3-10 heterocyclic alkyl) -RL- , (C6-10 aryl) -RL- , ( 5-10 heteroaryl) -RL- , NRsRt- ( CRaRb ) m- , NRaRb - CO- and R6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally substituted
  • the compound of formula (I) has the structure of formula (I-1), such as formula (I-2), formula (I-3), or formula (I-4):
  • the present invention provides compounds of formula (II) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.
  • L1 is selected from -CO-, -SO-, -SO2- , -NRa- , and -CRaRb- ;
  • L2 is selected from -R L -NR a -*, -R L -CO-NR a -*, -R L -NR a -CO-NR a -*, -R L -C(S)-NR a -*, -R L -NR a -C(S)-NR a -*, where the asterisk indicates a connection to the N atom of the central ring;
  • Cycle A is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl , (optionally substituted with one or more C1-6 alkyl groups ) -R L- .
  • Cycle B is a naphthylene or an 8-10-membered bicyclic heteroaryl group, each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups) -RL- , (
  • the ring C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl, 5-10 heteroaryl, NR s R t -(CR a R b ) m - or R 6 ;
  • Ring D is C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl;
  • R1 can be H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl ;
  • R2 is independently selected from H, halogen, cyano, OH, NRaRb , C1-6 alkyl , C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), or -C(O)( C1-6 alkyl), or where , when there are two or more R2 , the two R2 together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, (optionally a C3-10 cyclo
  • R 6 is selected from Wherein R 6a is H or C 1-6 alkyl;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl, C ⁇ sub>1-6 ⁇ /sub> haloalkyl, C ⁇ sub>6-10 ⁇ /sub> aryl, or 5-10 heteroaryl;
  • R and L are each independently valenced or C1-10 alkylene groups
  • T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;
  • Q is either O or S
  • n 0, 1, 2, 3, 4, or 5;
  • n 0, 1, or 2.
  • L1 is -CO-. In some embodiments, L1 is -SO-. In some embodiments, L1 is -SO2- . In some embodiments, L1 is -NRa- , such as -NH- or -N( C1-6 alkyl )-. In some embodiments, L1 is -CRaRb- , such as -CH2- or -CH( C1-6 alkyl)-.
  • L2 is In some implementations, L2 is In some implementations, L2 is In some implementations, L2 is In some implementations, L2 is -RL - NRa- *. In some implementations, L2 is -RL -CO- NRa- *. In some implementations, L2 is -RL- NRa - CO - NRa- *. In some implementations, L2 is -RL-C(S)-NRa-*. In some implementations, L2 is -RL -NRa - C (S) -NRa- * .
  • the asterisk indicates a connection to the N atom of the central ring. It can be understood that when the asterisk is not marked, L2 can be connected to the N atom of the central ring through any end.
  • L2 is Where T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the remainder of the molecule via two different ring carbon atoms, and Q is O or S.
  • T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the remainder of the molecule via two different ring carbon atoms
  • Q is O or S.
  • R1 is independently H, halogen, cyano, hydroxyl, NH2 , NH ( C1-6 alkyl), N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.
  • R1 is independently H, halogen, cyano, hydroxyl, NH2 , NH ( C1-4 alkyl), C1-6 alkyl, C1-6 deuterated alkyl, or C1-6 haloalkyl; or two R1 together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.
  • one of the two R1s is H and the other is cyano, C1-6 alkyl, or C1-6 deuterated alkyl, preferably cyano or C1-6 alkyl; or the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.
  • one of the two R1s is H and the other is cyano, C1-6 alkyl, or C1-6 deuterated alkyl, preferably cyano, C1-4 alkyl, or C1-4 deuterated alkyl, such as cyano, methyl, or CD3 .
  • one of the two R1s is H and the other is cyano or C1-6 alkyl, preferably cyano or C1-4 alkyl.
  • one of the two R1s is H and the other is a C1-6 alkyl, preferably a C1-4 alkyl, such as methyl.
  • the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group, such as cyclopropyl or cyclobutyl.
  • R1 is H. In some embodiments, R1 is a halogen, such as fluorine, chlorine, bromine, or iodine. In some embodiments, R1 is cyano. In some embodiments, R1 is hydroxyl or mercapto. In some embodiments, R1 is NR a R b , such as NH2 , NH ( C1-6 alkyl), or N ( C1-6 alkyl) 2 . In some embodiments, R1 is C1-6 alkyl, preferably C1-4 alkyl, such as methyl . In some embodiments, R1 is C2-6 alkenyl. In some embodiments, R1 is C1-6 haloalkyl.
  • R1 is C1-6 cyanoalkyl. In some embodiments, R1 is C1-6 hydroxyalkyl. In some embodiments, R1 is C1-6 alkoxy. In some embodiments, R1 is C1-6 alkylthio. In some embodiments, R1 is C1-6 haloalkoxy. In some embodiments, R1 is a C3-8 cycloalkyl group. Further, R1 is defined below.
  • ring A is a C6-10 aryl or a 5-10 membered heteroaryl (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each R3 independently selected from halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- and ( C3-10 halocycloalkyl) -RL- , or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with substituents selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 al
  • ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens.
  • R3s each independently selected from halogens, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-
  • ring A is phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, inzozolyl, benzimidazolyl, pyrazolopyridyl, pyrrolopyridyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, or purine, preferably phenyl, pyrazolyl, pyridyl, or benzofuranyl, more preferably phenyl or benzofuranyl, each optionally substituted with one or more R 3 as defined herein.
  • each of the R3s is independently selected from halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- and ( C3-10 halocycloalkyl) -RL- , or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, wherein the 4- to 6-membered ring is optionally substituted with a substituent selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl and C1-6 cyanoalkyl.
  • each of R3 is independently selected from halogens, cyano groups, C1-6 alkyl groups, C1-6 haloalkyl groups, and C3-6 cycloalkyl groups, or two of R3 groups, together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally substituted with one or more halogens or cyano groups, preferably halogens.
  • each of R3 is independently selected from halogens (e.g., F), C1-6 alkyl groups (e.g., methyl), and C1-6 haloalkyl groups (e.g., CF3 ).
  • ring A is a C6-10 aryl or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S, preferably phenyl or a 5-7 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S, more preferably a C6-10 aryl, such as a C6 aryl (i.e., phenyl), optionally substituted with one or more substituents each independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( optionally C3-10 cycloalkyl substituted with one or more C1-6 alkyl)-R L- .
  • ring A is R3a , R3b and R3c are as defined for R3 , and optionally as defined below.
  • ring A is selected from:
  • ring B is an 8-10 membered bicyclic heteroaryl group, such as an 8-10 membered bicyclic heteroaryl group containing one or more heteroatoms independently selected from N, O or S, optionally substituted with one or more R 4 as defined herein.
  • ring B is One bit is connected to L1 , two bits are connected to ring C, and W1 , W2 , W3 , W4 , W5 , W6 , and W7 are each independently C, CH, or N, with at least one of them being N; and R4 is as defined herein. Those skilled in the art will understand that... This indicates that the valence bond can be a single bond or a double bond.
  • ring B is One bit is connected to L1 , two bits are connected to ring C, and W1 , W2 , W3 , W4 , W5 , W6 and W7 are each independently C, CH or N, and at least one of them is N; and R4 is as defined herein.
  • ring B represents Preferred One bit is connected to L1 , two bits are connected to ring C, and W1 , W2 , W3 , W4 , and W5 (if present) are each independently C, CH, or N, with at least one being N; and R4 is as defined herein.
  • W1 is N
  • W3 is N
  • W4 is N
  • W5 is N
  • the rest are each independently C or CH.
  • ring B is One bit is connected to L1 , two bits are connected to ring C, and W1 is C, CH or N, W8 is CH2 , NH, O or S, and R4 is as defined herein.
  • ring B represents Preferred is One bit is connected to L1 , two bits are connected to ring C, and R4 is as defined in this paper.
  • ring B is an 8-10-membered bicyclic heteroaryl group, optionally substituted with one or more substituents each independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups)-RL- , (optionally substituted with one or more
  • ring B is selected from:
  • bit 1 is connected to L1
  • bit 2 is connected to ring C.
  • the cyclic C is a C3-10 cycloalkyl or a 3-10 membered heterocyclic alkyl, preferably a C3-6 cycloalkyl or a 3-6 membered heterocyclic alkyl, more preferably a C3-6 cycloalkyl, each optionally substituted by one or more substituents, each substituent being independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, -CONH2 , -CONH( C1-6 alkyl), -C(
  • the cyclic C is a C3-10 cycloalkyl or a 3-10 membered heterocyclic alkyl, preferably a C3-6 cycloalkyl or a 3-6 membered heterocyclic alkyl, more preferably a C3-6 cycloalkyl, each optionally substituted with one or more substituents, each substituent being independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylene group, C1-6 haloalkylene group, COOH, C1-6 alkoxy-CO-, (C1-6 haloalkoxy) -RL-
  • the cyclic C is a C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, optionally substituted with one or more substituents, each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, (C1-6 haloalkoxy ) -RL- , ( C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl)
  • the ring C is a C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, optionally substituted with one or more substituents, each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl , COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- , and R6, or two of the substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, the ring optionally substituted with
  • the cyclic C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, or 3-10 heterocyclic alkenyl, preferably a C3-6 cycloalkyl or 3-6 heterocyclic alkyl, more preferably a C3-6 cycloalkyl, each optionally substituted by one or more substituents independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl, 5-10 heteroaryl, NR s R t -(CR a R b ) m - or R 6 .
  • ring C represents The variables are defined as described in this paper, and optionally as described below.
  • ring C represents Wherein X is -C(R x1 )(R x2 )-, -NR x1- , -O-, -S-, -SO-, or -SO 2- , wherein R x1 and R x2 are each independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl, or 5-10 heteroaryl.
  • X is -C(R x1 )(R x2 )-, -NR x1- , -O-, -S-, -SO-, or -SO 2- , wherein R x1 and R x2 are each independently selected from H, halogen, or a 5-7 heteroaryl containing one or more heteroatoms independently selected from N, O, or S.
  • ring C is selected from:
  • R6 is defined as in this document, and optionally as defined below.
  • ring D is a C6-10 aryl group or a 5-10 heteroaryl group containing one or more heteroatoms independently selected from N, O, or S, preferably phenyl or a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O, or S, more preferably phenyl.
  • ring D is a phenyl group or a 5-6 heteroaryl group containing one or more N heteroatoms.
  • ring D may be selected from phenyl, pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, preferably phenyl or pyridinyl.
  • R2 ' is selected from H, oxo, halogen, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl) -RL- and (3-10 heterocyclic alkyl) -RL- and C6-10 aryl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from halogen or C1-6 alkoxy, and wherein the cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged; and R2c is H, halogen or C1-6 alkyl.
  • R2 ' is a C1-6 alkyl, C1-6 deuterated alkyl, ( C1-6 alkoxy) -RL- , ( C3-6 cycloalkyl) -RL- , and (3-8 heterocyclic alkyl) -RL- , wherein the cycloalkyl is optionally substituted with one or more halogens; and R2c is H or a halogen.
  • R2a , R2b and R2c are as defined for R2 , and optionally as defined below.
  • R2 is independently selected from -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl) or -C(O)( C1-6 alkyl), preferably -P(O)( C1-6 alkyl)( C1-6 alkyl).
  • the two R2s when there are two or more R2s , the two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring, preferably a 5-6-membered heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-R L- , ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 haloalkylene)-, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 cyanoalkylene)-, and ( C3-10
  • the aromatic or heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 haloalkylene)-, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 cyanoalkylene)-, and ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 hydroxyalkylene)-.
  • a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl optionally substituted with one or more C1-6
  • the aromatic ring or heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, (optionally C3-10 cycloalkyl substituted with one or more C1-6 alkyl) -RL- , (optionally C3-10 cycloalkyl substituted with one or more C1-6 alkyl)-( C1-4 haloalkylene)-.
  • the present invention provides compounds of formula (III) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.
  • W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;
  • T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;
  • Q is either O or S
  • R1 is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms they are attached to form a C3-4 cycloalkyl group.
  • R2a , R2b , and R2c are each independently H, halogen, cyano, OH, NR a , R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NR a -S(O) 2- ( C1-6 alkyl), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycl
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyl atoms independently selected from halogen and C1-6 alkyl) -RL- , or R3a and R3b together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally selected from one or more heteroatoms independently selected from halogen, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 yn
  • R4 is a halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , ( 5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy.
  • R 6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl, C ⁇ sub>1-6 ⁇ /sub> haloalkyl, C ⁇ sub>6-10 ⁇ /sub> aryl, or 5-10 heteroaryl;
  • R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • W1 is N
  • W2 , W3 , W4 , and W5 are C or CH
  • W3 is N
  • W1 , W2 , W4 , and W5 are C or CH
  • W5 is N
  • W1 , W2 , W3 , and W4 are C or CH.
  • the present invention provides compounds of formula (III-1) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.
  • W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;
  • T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;
  • Q is either O or S
  • R1 is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms they are attached to form a C3-4 cycloalkyl group.
  • R2a , R2b , and R2c are each independently H, halogen, cyano, OH, NR a , R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NR a -S(O) 2- ( C1-6 alkyl), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycl
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyl atoms independently selected from halogen and C1-6 alkyl) -RL- , or R3a and R3b together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally selected from one or more heteroatoms independently selected from halogen, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 yn
  • R4 is a halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , ( 5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy.
  • R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl ) -C2-4 alkenyl-, (C (3-10 cycloalkyl)-C 2-4 ynynyl-, (C 3-10 cycl
  • R 6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl, C ⁇ sub>1-6 ⁇ /sub> haloalkyl, C ⁇ sub>6-10 ⁇ /sub> aryl, or 5-10 heteroaryl;
  • R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • W1 is N
  • W2 , W3 , W4 , and W5 are C or CH
  • W3 is N
  • W1 , W2 , W4 , and W5 are C or CH
  • W5 is N
  • W1 , W2 , W3 , and W4 are C or CH.
  • the present invention provides compounds of formula (IV) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.
  • W1 , W2 , W3 , and W4 are each independently C, CH, or N, and at least one of W1 , W2 , W3 , and W4 is N;
  • T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;
  • Q is either O or S
  • R1 is H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, or C1-6 hydroxyalkyl;
  • R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), or -C(O)( C1-6 alkyl), and the other is H, halogen, cyano, OH, NR a R b , or C1-6 alkyl; or R2a and R2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaryl ring, said heteroaryl ring optionally selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, C3-8 cycloalkyl-( C1-4 haloalkylene)-, C3-8 cycloalkyl-( C1-4 cyanoalkylene)-, and
  • R2c can be H, halogen, cyano, hydroxyl, or NR a Rb ;
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, and C3-8 cycloalkyl- ( C1-4 alkylene)-.
  • R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 10-membered heteroaryl, optionally substituted with one or more C1-6 alkyl groups;
  • R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy - CO-, C6-10 aryl, 5-10 heteroaryl, or NRsRt- ( CRaRb ) m- ;
  • R 6 is selected from Wherein R 6a is H or C 1-6 alkyl;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl, C ⁇ sub>1-6 ⁇ /sub> haloalkyl, C ⁇ sub>6-10 ⁇ /sub> aryl, or 5-10 heteroaryl;
  • n 0, 1, 2, 3, 4, 5, or 6;
  • n 0, 1, or 2.
  • W1 is N, and W2 , W3 , and W4 are each independently C or CH. In other embodiments, W3 is N, and W1 , W2 , and W4 are each independently C or CH.
  • the compounds of the present invention each have the following structure:
  • L2 is Where T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different cyclic carbon atoms, and Q is O or S.
  • T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the remainder of the molecule via two different ring carbon atoms, preferably a C2-4 alkenyl group.
  • T is vinylidene (e.g., 1,2-vinylidene), propenyl (e.g., 1,3-propenyl, 1,2-propenylidene), butenyl (e.g., 1,4-butenyl, such as 1,4-butenyl-1-ene or 1,4-butenyl-2-ene), 1,2-cyclopropylidene, 1,3-cyclobutylidene, 1,3-cyclopentylidene, 1,3-cyclohexylidene, or 1,4-cyclohexylidene.
  • vinylidene e.g., 1,2-vinylidene
  • propenyl e.g., 1,3-propenyl, 1,2-propenylidene
  • Q is 0. In other implementations, Q is S.
  • the compounds of formulas (III), (III-1), and (IV) of the present invention each have one of the following formulas:
  • each variable is as defined herein, preferably as defined in formula (III), (III-1) or (IV).
  • R1 is H, a halogen (e.g., fluorine, chlorine, bromine, or iodine), a cyano group, a hydroxyl group, NH2 , NH (C1 -6 alkyl), N (C1 -6 alkyl) 2 , a C1-6 alkyl group, a C1 - 6 haloalkyl group, a C1 -6 cyanoalkyl group, or a C1 -6 hydroxyalkyl group.
  • a halogen e.g., fluorine, chlorine, bromine, or iodine
  • R1 is H, a halogen, a cyano group, a hydroxyl group, NH2 , a C1-6 alkyl group, a C1 -6 haloalkyl group, a C1 -6 cyanoalkyl group, or a C1 -6 hydroxyalkyl group. Even further, R1 is H, a C1-6 alkyl group, or a C1 - 6 haloalkyl group, preferably H or a C1 -6 alkyl group, more preferably a C1 -6 alkyl group.
  • R1 is a halogen, particularly fluorine, chlorine, bromine, or iodine, especially fluorine or chlorine.
  • R1 is NH2 , NH( C1-6 alkyl) or N( C1-6 alkyl) 2 .
  • R1 is NH2 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 or N( CH3 )( CH2CH3 ), preferably NH2, NH( CH3 ) or N ( CH3 ) 2 .
  • R1 is a C1-6 alkyl group, particularly a C1-4 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl.
  • R1 is methyl.
  • R2a , R2b together with the atoms to which they are attached, form a 5-6 member saturated, partially unsaturated, or aromatic heterocycle, said ring optionally being substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C1-6 alkoxy) -RL- , (4-8 member heterocyclic alkyl) -RL- , wherein said C3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic, or bridged; and R2c is H, halogen, or C1-6 alkyl.
  • a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6
  • R2a , R2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, said ring being substituted with ( C3-8 cycloalkyl) -C1-4 alkylene- or ( C3-8 halocycloalkyl) -C1-4 alkylene-, preferably substituted with ( C3-6 cycloalkyl) -C1-4 alkylene- or ( C3-6 halocycloalkyl) -C1-4 alkylene-; and R2c is a halogen, preferably F.
  • R2 ' is selected from H, oxo, halogen, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl) -RL- and (3-10 heterocyclic alkyl) -RL- and C6-10 aryl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from halogen or C1-6 alkoxy, and wherein the cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged; and R2c is H, halogen or C1-6 alkyl.
  • R2 ' is ( C3-8 cycloalkyl) -C1-4 alkylene- or ( C3-8 halocycloalkyl) -C1-4 alkylene-, preferably ( C3-6 cycloalkyl) -C1-4 alkylene- or ( C3-6 halocycloalkyl) -C1-4 alkylene-; and R2c is a halogen, preferably F.
  • R 2a and R 2b together with the carbon atoms to which they are attached, form a 5- or 6-membered heteroaromatic ring containing one, two, or three heteroatoms each independently selected from N, O, or S, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, C3-8 cycloalkyl-( C1-4 haloalkylene)-, C3-8 cycloalkyl-( C1-4 cyanoalkylene)-, and C3-8 cycloalkyl-( C1-4 hydroxyalkylene)-.
  • a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl
  • R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one, two, or three heteroatoms each independently selected from N, O, or S, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-.
  • R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-.
  • R 2a and R 2b are preferably 5- or 6-membered heteroaromatic rings containing one or two heteroatoms each independently selected from N, O or S, and more preferably 5- or 6-membered heteroaromatic rings containing one or two nitrogen heteroatoms.
  • R 2a and R 2b together with the carbon atoms to which they are attached form a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, or a pyrazine ring, preferably a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, or an isothiazole ring, more preferably a pyrazole ring, wherein the ring is optionally substituted with a substituent selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4
  • yes R2aa is selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, C3-8 cycloalkyl-(C1-4 haloalkylene)-, C3-8 cycloalkyl- ( C1-4 cyanoalkylene)-, and C3-8 cycloalkyl-( C1-4 hydroxyalkylene)-.
  • R2aa is selected from C1-6 alkyl , C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-. More preferably, R 2aa is selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-, especially ( C3-8 cycloalkyl-( C1-4 alkylene)-.
  • one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H, halogen, cyano, OH, NH2 , NH( C1-6 alkyl), N( C1-6 alkyl) 2 , or C1-6 alkyl.
  • one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H, NH2 , or NH( C1-6 alkyl).
  • one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H or NH( C1-6 alkyl).
  • one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H or NH( C1-4 alkyl).
  • R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 (C1-6 alkyl), or -C(O)( C1-6 alkyl), and R2b is H, halogen, cyano, OH, NH2 , NH( C1-6 alkyl), N( C1-6 alkyl) 2 , or C1-6 alkyl.
  • R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), and R2b is H, halogen, cyano, OH, NH2 , NH( C1-6 alkyl ), N( C1-6 alkyl) 2 , or C1-6 alkyl.
  • R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), and R2b is H, NH2 , or NH ( C1-6 alkyl).
  • R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), and R2b is H or NH ( C1-6 alkyl).
  • R2a is -P(O)( C1-4 alkyl)( C1-4 alkyl), and R2b is H or NH ( C1-4 alkyl).
  • R2c is H, a halogen, a cyano group, a hydroxyl group, or NH2 .
  • R2c is H, a halogen, or a cyano group. More preferably, R2c is H or a halogen. In some embodiments, R2c is a halogen, such as fluorine. In other embodiments, R2c is H.
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- , and ( C3-10 halocycloalkyl) -RL- , or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally substituted with a substituent selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, and C1-6 cyanoalkyl.
  • R3a , R3b and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, or wherein R3a and R3b together with the atoms to which they are attached form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, said 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens.
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl.
  • R3a is H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl;
  • R3b is halogen;
  • R3c is H or C1-6 alkyl, preferably C1-6 alkyl.
  • R3a is C1-4 alkyl;
  • R3b is halogen, such as fluorine; and R3c is C1-4 alkyl.
  • R3a , R3b , and R3c are each independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups.
  • R3a is a C1-6 alkyl or C1-6 haloalkyl group
  • R3b is a halogen such as fluorine
  • R3c is a C1-6 alkyl group.
  • R3a is a C1-4 alkyl or C1-4 haloalkyl group
  • R3b is a halogen such as fluorine
  • R3c is a C1-4 alkyl group.
  • R 3c is as defined herein, and R 3 ' is independently a halogen, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, or C1-6 hydroxyalkyl, and x is 0, 1, or 2. It is understood that R 3 ', when present, can be attached to any available position on the ring.
  • R 3c is H, halogen, cyano, hydroxyl, NH2 , NH ( C1-4 alkyl), C1-4 alkyl, or C1-4 haloalkyl, more preferably H, halogen, cyano, C1-4 alkyl, or C1-4 haloalkyl, and more preferably H, halogen, or C1-4 alkyl, for example, H.
  • each of R3 ' is independently a halogen, cyano, C1-4 alkyl or C1-4 haloalkyl, preferably a halogen or cyano, more preferably a halogen such as fluorine.
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano , hydroxyl, NH2, NH( C1-6 alkyl), N( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, and C3-8 cycloalkyl-( C1-4 alkylene)-.
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C3-8 cycloalkyl, and C3-8 cycloalkyl-( C1-4 alkylene)-. Furthermore, R3a , R3b and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl and C3-8 cycloalkyl.
  • R3a is H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-; R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl.
  • R3a is H, halogen, cyano, hydroxyl, NH2 , NH( C1-6 alkyl), N( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-; R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl.
  • R3a is selected from H, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-;
  • R3b is halogen; and
  • R3c is H or C1-6 alkyl, preferably C1-6 alkyl.
  • R3a is H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-8 cycloalkyl;
  • R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl.
  • R3a is H, halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R3b is halogen; and R3c is H or C1-4 alkyl, preferably C1-4 alkyl.
  • R4 is each independently selected from C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C3-6 cycloalkyl, and 4-8 membered heterocyclic alkyl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted with one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy.
  • R4 is each independently selected from C1-6 alkoxy, C3-6 cycloalkyl, and 4-8 membered heterocyclic alkyl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted with one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy.
  • R4 is independently selected from C1-6 alkoxy groups, such as methoxy groups.
  • R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 10-membered heteroaryl, preferably a 5- to 7-membered heteroaryl, wherein the heterocyclic alkyl or heteroaryl contains one, two, or three heteroatoms each independently selected from N, O, or S, and the heterocyclic alkyl or heteroaryl is optionally substituted with one or more C1-6 alkyl groups.
  • R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 10-membered heteroaryl, preferably a 5- to 7-membered heteroaryl, wherein the heterocyclic alkyl or heteroaryl contains one or two heteroatoms each independently selected from N, O, or S, and the heterocyclic alkyl or heteroaryl is optionally substituted with one or more C1-6 alkyl groups.
  • R4 is a C3-6 cycloalkyl and a 4-8 heterocyclic alkyl (e.g., a 4-8 heterocyclic alkyl containing one or two heteroatoms each independently selected from N, O or S), wherein the cycloalkyl and heterocyclic alkyl are optionally substituted by one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy.
  • a 4-8 heterocyclic alkyl e.g., a 4-8 heterocyclic alkyl containing one or two heteroatoms each independently selected from N, O or S
  • R4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O, or S (e.g., selected from N or O), preferably a 4- to 8-membered heterocyclic alkyl group containing one or two O heteroatoms, such as aziridine, oxaziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiaranyl, oxazinyl, morpholinyl, or thiomorpholinyl, wherein the heterocyclic alkyl group
  • R4 is a 5-7 membered heteroaryl group containing one or two heteroatoms each independently selected from N, O, or S (e.g., selected from N or O, and also, for example, N), such as pyrroloyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyrazinyl, wherein the heteroaryl group is optionally substituted with one or more, preferably one or two C1-6 alkyl groups.
  • R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 7-membered heteroaryl, the heterocyclic alkyl or heteroaryl containing one or two heteroatoms each independently selected from N and O, and the heterocyclic alkyl or heteroaryl is optionally substituted by one or more, preferably one or two C1-6 alkyl groups.
  • R4 is tetrahydropyranyl, morpholinyl, or pyridyl, each optionally substituted with one or more, preferably one or two, C1-6 alkyl groups.
  • R4 is tetrahydropyranyl, optionally substituted with one or more, preferably one or two, C1-6 alkyl groups.
  • R4 is a cyclohexyl group, optionally substituted with one or more, preferably one or two C1-6 alkoxy groups. In some embodiments, R4 is selected from:
  • R4 is For example
  • R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , ( C1-6 alkoxy)-RL-, ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy ) -RL- , (optionally substituted with halogen or hydroxyl )-RL-, (C3-10 cycloalkyl ) -C2-4 alkenyl-, (C The ring may be formed by two of the following groups together with the atoms to which they are attached
  • R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , ( C1-6 alkoxy)-RL-, ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (optionally C3-10 cycloalkyl substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 ynynyl-, ( C3-10 cycloalkyloxy) -RL- -, (C 6-10
  • R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , ( C1-6 alkoxy)-RL-, ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (optionally C3-10 cycloalkyl substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 ynynyl-, ( C3-10 cycloalkyloxy) -RL- -, (C 6-10
  • R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally being substituted by one or more substituents selected from oxo and 5-7 membered hetero
  • R5a is a C1-6 alkyl or C1-6 alkoxy
  • R5b , R5c and R5d are each independently H or halogen, preferably H.
  • R5a is a C1-6 alkyl group
  • R5b , R5c , and R5d are each independently H or a halogen, preferably H.
  • R5a is a C1-4 alkyl group
  • R5b , R5c , and R5d are each independently H.
  • R5a and R5b together with the atoms they are attached to, form a ring as defined herein.
  • R5a and R5c together with the atoms they are attached to, form a ring as defined herein.
  • R5a , R5b , R5c and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C6-10 aryl, 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl or 5-10 heteroaryl containing one or more heteroatoms each independently selected from N , O or S.
  • R5a , R5b , R5c and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S.
  • R5a , R5b , R5c and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S, or -( CH2 )mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S.
  • R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S, NH2, NH( C1-6 alkyl), N ( C1-6 alkyl) 2 , -( CH2 ) mNH (phenyl), -(CH2) mN ( C1-6 alkyl)(phenyl), -( CH2 ) mNH (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O , or S), or -( CH2 ) mN (C1-6 alkyl)(phenyl)(pheny
  • R5a , R5b , R5c and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, 5-7 heteroaryl containing one or more heteroatoms independently selected from N, O or S, -( CH2 ) mNH (phenyl), -( CH2 ) mN ( C1-6 alkyl) (phenyl), -( CH2 ) mNH (5-7 heteroaryl containing one or more heteroatoms independently selected from N, O or S), or -( CH2 ) mN ( C1-6 alkyl) (5-7 heteroaryl containing one or more heteroatoms independently selected from N, O or S).
  • R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, or -( CH2 ) mN ( C1-6 alkyl) (containing one or more 5- or 7-membered heteroaryl groups, each independently selected from N, O, or S).
  • the 5- or 7-membered heteroaryl group is pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.
  • R5a , R5b , R5c and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, -( CH2 ) mN (C1-6 alkyl )(oxadiazolyl), or -( CH2 ) mN ( C1-6 alkyl)(pyrimidinyl).
  • R5a is H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C6-10 aryl, a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S, or NRsRt- ( CRaRb ) m- , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S; and R5b , R5c , and R5d are each independently H or halogen, preferably H.
  • R5a is H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N, O or S; and R5b , R5c and R5d are each independently H or halogen, preferably H.
  • R5a is H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N , O or S; and R5b , R5c and R5d are each independently H or halogen, preferably H.
  • R 5a is H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S , NH2, NH( C1-6 alkyl), N( C1-6 alkyl) 2 , -( CH2 ) mNH (phenyl), -(CH2) mN ( C1-6 alkyl)(phenyl), -( CH2 ) mNH (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S), or -( CH2 ) mN ( C1-6 alkyl)(phenyl). 1-6 alkyl (containing one or more 5-7 heteroaryl groups,
  • R 5a is H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S, -( CH2 ) mNH (phenyl), -( CH2 ) mN ( C1-6 alkyl) (phenyl), -( CH2 ) mNH (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S), or -( CH2 ) mN ( C1-6 alkyl) (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S); and R 5b , R 5c , and R Each of the 5d elements
  • R5a is H, a halogen, a cyano, a C1-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkylthio, a C1-6 haloalkyl, a C1-6 hydroxyalkyl, COOH, a C1-6 alkoxy-CO-, a phenyl, or -( CH2 ) mN ( C1-6 alkyl) (containing one or more 5-7 membered heteroaryl groups, each independently selected from N, O, or S); and R5b , R5c, and R5d are each independently H or a halogen, preferably H.
  • the 5-7 membered heteroaryl group is pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.
  • R5a is a halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, -( CH2 ) mN ( C1-6 alkyl)(oxadiazolyl), or -(CH2)mN(C1-6 alkyl ) ( pyrimidinyl); and R5b , R5c and R5d are each independently H or a halogen, preferably H.
  • R6 is selected from R 6a is H or C 1-6 alkyl, preferably H.
  • R6 is selected from R 6a is H or C 1-6 alkyl, preferably H.
  • R 6 is selected from: Preferably, selected from in particular
  • R6 is Wherein R 6a is H or C1-6 alkyl. Preferably, R 6 is
  • Rp is independently a halogen, cyano, hydroxyl, NH2 , or C1 -4 alkyl group. In some embodiments, Rp is independently a halogen or cyano group. In some embodiments, n is 0, i.e., Rp is absent. Therefore, in some embodiments, the compounds of formulas (III), (III-1), and (IV) of the present invention can each have the following structure:
  • Ra and Rb are each independently H or C1-6 alkyl. In some embodiments , both Ra and Rb are H. In some embodiments, Ra is H and Rb is C1-6 alkyl. In some embodiments, both Ra and Rb are C1-6 alkyl.
  • R and L are each independently a valence bond; optionally a C1-6 alkylene group substituted with a halogen, cyano, or hydroxyl group; or a C1-4 deuterated alkylene group.
  • R and L are each independently a valence bond, a C1-4 alkylene group, a C1-4 haloalkylene group, or a C1-4 deuterated alkylene group.
  • R and L are each independently a valence bond, methylene, ethylene, halomethylene, haloethylene, or CD3 .
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided.
  • L1 is selected from -CO-, -SO- and -NH-, with -CO- being preferred;
  • L2 is selected from The asterisk indicates a connection to the N atom in the central ring, preferably.
  • Ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano , C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens;
  • R3s each independently selected from halogens, cyano , C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to
  • Cycle B is an 8-10 membered bicyclic heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, optionally substituted by one or more R4 groups, wherein R4 is a 4- to 8 membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C1-6 alkyl groups.
  • the ring C is a C3-6 cycloalkyl group, optionally substituted with one or more substituents, each of which is independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- and R6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, the ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;
  • Ring D is a C6-10 aryl or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O or S, preferably phenyl or a 5-7 heteroaryl containing one or more heteroatoms each independently selected from N, O or S;
  • R1 is independently H, cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;
  • R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl, or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S;
  • R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;
  • T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;
  • Q is either O or S
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • q can be 0, 1, 2 or 3, preferably 1 or 2.
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotope-labeled compound, or solvate thereof is provided, wherein,
  • L1 is selected from -CO-, -SO- and -NH-, with -CO- being preferred;
  • L2 is selected from The asterisk indicates a connection to the N atom in the central ring, preferably.
  • Ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano , C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens;
  • R3s each independently selected from halogens, cyano , C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to
  • Cycle B is an 8-10 membered bicyclic heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, optionally substituted by one or more R4 groups, wherein R4 is a 4- to 8 membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C1-6 alkyl groups.
  • the cyclic C is a C3-6 cycloalkyl group, optionally substituted with one or more substituents, each of which is independently selected from H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH , C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy)-RL-, ( C6-10 aryl)-RL- , NRsRt- ( CRaRb ) m- , and R6 ;
  • Ring D is a C6-10 aryl or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O or S, preferably phenyl or a 5-7 heteroaryl containing one or more heteroatoms each independently selected from N, O or S;
  • R1 is independently cyano, C1-6 alkyl or C1-6 deuterated alkyl, preferably cyano, methyl or CD3 ;
  • C 3-10 cycloalkyl (C 3-10 cycloalkyl) -RL- , (3-10 heterocyclic alkyl ) -RL- and (C 6-10 aryl) -RL- , wherein the C 3-10 cycloalkyl is a monocyclic, bicyclic, spirocyclic or bridged ring;
  • R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl, or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S;
  • R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;
  • T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule via two different ring carbon atoms;
  • Q is either O or S
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • q can be 0, 1, 2 or 3, preferably 1 or 2.
  • W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.
  • a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided, wherein the compound of formula (I) has the structure of formula (I-3):
  • Ring A is R3a , R3b , and R3c are each independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups (preferably, R3a is a C1-6 alkyl or C1-6 haloalkyl group, R3b is a halogen such as fluorine, and R3c is a C1-6 alkyl group), or R3a and R3b, together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, and R3c is H; or
  • Ring A is phenyl or benzofuranyl, each optionally substituted by one or more R3s , each R3 being independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups;
  • Ring B is In this configuration, position 1 is connected to a carbonyl group, position 2 is connected to a ring C, and R4 is a cyclohexyl group optionally substituted with one or two C1-6 alkoxy groups, for example...
  • Ring C is Wherein R 5a is a C1-6 alkyl or C1-6 alkoxy, and R 5b , R 5c , and R 5d are each independently H or a halogen, preferably H; and wherein R 6 is Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • R 2 ' is a C 1-6 alkyl, C 1-6 deuterated alkyl, (C 1-6 alkoxy) -RL- , (C 3-6 cycloalkyl) -RL- , and (3-8 heterocyclic alkyl) -RL- , wherein the cycloalkyl is optionally substituted with one or more halogens; and R 2c is H or a halogen;
  • R1 is a C1-6 alkyl group, preferably methyl
  • R and L are each independently valenced, C1-4 alkylene, or C1-4 deuterated alkylene;
  • n 0 and R p does not exist.
  • a compound of formula (III) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided.
  • W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;
  • T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule via two different ring carbon atoms;
  • Q is either O or S
  • R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;
  • R 2c is H, halogen, or C1-6 alkyl, preferably H or halogen, such as fluorine;
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, wherein the 4- to 6-membered ring is optionally substituted with one or more halogens or cyano, preferably halogens;
  • R 4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C 1-6 alkyl groups;
  • R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy )-RL-, (C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;
  • R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O or S;
  • R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • q can be 0, 1, 2 or 3, preferably 1 or 2.
  • W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.
  • a compound of formula (III-1) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided.
  • W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;
  • T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;
  • Q is either O or S
  • R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;
  • R 2c is H, halogen, or C1-6 alkyl, preferably H or halogen, such as fluorine;
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, wherein the 4- to 6-membered ring is optionally substituted with one or more halogens or cyano, preferably halogens;
  • R 4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C 1-6 alkyl groups;
  • R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy )-RL-, (C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;
  • R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O or S;
  • R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • q can be 0, 1, 2 or 3, preferably 1 or 2.
  • W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.
  • a compound of formula (III) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided, wherein:
  • W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;
  • T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;
  • Q is either O or S
  • R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;
  • R 2c is H, halogen, or C1-6 alkyl, preferably H or halogen, such as fluorine;
  • R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, wherein the 4- to 6-membered ring is optionally substituted with one or more halogens or cyano, preferably halogens;
  • R 4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C 1-6 alkyl groups;
  • R5a , R5b , R5c , and R5d are each independently H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;
  • R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R ⁇ sub>s ⁇ /sub> and R ⁇ sub> t ⁇ /sub> are each independently H, C ⁇ sub>1-6 ⁇ /sub> alkyl or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O or S;
  • R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;
  • n 0, 1, 2, 3, 4 or 5;
  • n 0, 1, or 2;
  • q can be 0, 1, 2 or 3, preferably 1 or 2.
  • W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.
  • the present invention provides compounds of formula (IV) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.
  • W1 , W2 , W3 , and W4 are each independently C, CH, or N, and at least one of W1 , W2 , W3 , and W4 is N;
  • T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;
  • Q can be O or S, preferably O;
  • R1 is a C1-6 alkyl group
  • R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H or NH( C1-6 alkyl);
  • R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)- and C3-8 cycloalkyl-( C1-4 haloalkylene)-.
  • R 2c is H or a halogen
  • R 3a is H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-8 cycloalkyl;
  • R 3b is halogen; and
  • R 3c is H or C1-6 alkyl;
  • R4 is a tetrahydropyranyl group, optionally substituted with one or more, preferably one or two C1-6 alkyl groups;
  • R5a is a halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, or -( CH2 ) mN ( C1-6 alkyl) (containing one or more 5-7 heteroaryl groups, each independently selected from N, O, or S); and R5b , R5c , and R5d are each independently H or a halogen;
  • R 6 is Wherein R 6a is H or C 1-6 alkyl
  • the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof, wherein:
  • W1 is N, and W2 , W3 and W4 are each independently C or CH;
  • T is a C2-4 alkenyl group
  • R1 is a C1-6 alkyl group
  • R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, wherein the heteroaromatic ring is optionally substituted with a C1-6 alkyl group;
  • R2c is a halogen
  • R 3a is a C1-6 alkyl group
  • R 3b is a halogen
  • R 3c is a C1-6 alkyl group.
  • R4 is a tetrahydropyranyl group, optionally substituted with one or more, preferably one or two C1-6 alkyl groups;
  • R 5a is a C1-6 alkyl group
  • R 5b , R 5c and R 5d are each independently H or halogen, preferably H;
  • R 6 is Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof, wherein:
  • W1 is N, and W2 , W3 and W4 are each independently C or CH;
  • T is a C2-4 alkenyl group
  • R1 is a C1-6 alkyl group, preferably a C1-4 alkyl group, such as methyl;
  • R2a and R2b together with the carbon atoms to which they are attached, form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, said ring being substituted with ( C3-8 cycloalkyl) -C1-4 alkylene- or ( C3-8 halocycloalkyl) -C1-4 alkylene-, preferably substituted with ( C3-6 cycloalkyl) -C1-4 alkylene- or ( C3-6 halocycloalkyl) -C1-4 alkylene-; and R2c is a halogen, preferably F;
  • R 3a is a C1-6 alkyl group
  • R 3b is a halogen
  • R 3c is a C1-6 alkyl group.
  • R4 is a tetrahydropyranyl group, optionally substituted with one or more, preferably one or two C1-6 alkyl groups;
  • R 5a is a C1-6 alkyl group
  • R 5b , R 5c and R 5d are each independently H or halogen, preferably H;
  • R 6 is Wherein R 6a is H or C 1-6 alkyl, preferably H;
  • R2 ' is (optionally substituted with one or more halogens) -C1-4 alkylene- , preferably (optionally substituted with one or more halogens such as F) -C1-4 alkylene-, more preferably (optionally substituted with one or more halogens such as fluorine) -C1-4 alkylene-, and R2c is a halogen, preferably F.
  • the present invention provides compounds of the embodiments or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.
  • the compounds of the embodiments are selected from:
  • the present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound or solvate thereof, wherein the compound of formula (I) has the structure of formula (I-1).
  • the compound of formula (I-1) is obtained, and optionally converted into a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate; optionally, the reaction is preferably carried out in a solvent in the presence of a condensing agent and a base.
  • the condensing agent, base, and solvent are as defined herein.
  • the condensing agent is 1-hydroxybenzotriazole (HOBt) and/or 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC).
  • the base is diisopropylethylamine.
  • the solvent is dimethylformamide.
  • the present invention provides a method for preparing a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof, wherein the compound of formula (I) has the structure of formula (I-3):
  • the compound of formula (I-3) is obtained, and optionally converted into a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate; optionally, the reaction is carried out in a solvent in the presence of a condensing agent and a base.
  • the condensing agent, base, and solvent are as defined herein.
  • the condensing agent is 1-hydroxybenzotriazole (HOBt) and/or 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC).
  • the base is diisopropylethylamine.
  • the solvent is dimethylformamide.
  • the compound of formula (A') can be prepared by a method comprising the following steps:
  • PG represents an amino protecting group such as Boc, and other variables are as defined in this paper.
  • the compound of formula (A') is obtained; optionally, the reaction is preferably carried out in the presence of an acid (e.g., p-toluenesulfonic acid) and in a solvent (e.g., m-xylene).
  • an acid e.g., p-toluenesulfonic acid
  • a solvent e.g., m-xylene
  • the reaction can be carried out at elevated temperatures, for example, about 100-200°C, about 120-180°C, about 140-160°C, or 150°C.
  • the reaction time is the time required for the reaction to complete, for example, 1-20 hours, 1-10 hours, 1-5 hours, or 1-2 hours.
  • the compound of formula (A'-5) can be prepared by a method comprising the following steps:
  • PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).
  • PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).
  • methods are provided for preparing compounds of formula (A'-5) or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, or solvates thereof.
  • the method includes:
  • PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).
  • PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).
  • a compound of formula (A'-5) is obtained; optionally, the obtained compound of formula (A'-5) is converted into its pharmaceutically usable salt, stereoisomer, tautomer, isotopically labeled compound or solvate.
  • the chloroformate has the structure of formula (A'-2):
  • RA is any group that does not interfere with the reaction. It can be understood that RA can be located at any available position on the benzene ring.
  • RA is H, nitro, CN, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkenyl, C1-6 haloalkynyl, sulfonate (-SO3H), aldehyde ( -CHO ), or -CO ( C1-6 alkyl).
  • RA is H, nitro, CN, CF3 , CCl3 , sulfonate ( -SO3H ), aldehyde (-CHO), or -CO ( C1-6 alkyl).
  • RA is H or nitro.
  • RA is located at the ortho or para position of the ester group, preferably at the para position.
  • the chloroformate of formula (A'-2) can be phenyl chloroformate or p-nitrobenzene chloroformate.
  • the amount of the chloroformate is about 1 to 10 molar equivalents, preferably about 2 to 4 molar equivalents, and more preferably about 4 molar equivalents.
  • the reaction of the compound of formula (A'-1) with a chloroformate to form the compound of formula (A'-3) is carried out in the presence of a base.
  • the base may be a tertiary amine, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO).
  • the base is diisopropylethylamine (DIPEA).
  • the amount of the base is about 1 to 10 molar equivalents, preferably about 2 to 4 molar equivalents, and more preferably about 4 molar equivalents.
  • the reaction of compound (A'-1) with chloroformate to form compound (A'-3) is carried out in a solvent.
  • the solvent is an aprotic polar solvent, such as acetonitrile.
  • reaction of compound (A'-1) with chloroformate to form compound (A'-3) can be carried out at ambient temperature, for example, about 20-25°C.
  • the reaction time is the time required for the reaction to complete, for example, 5 minutes to 5 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 5-30 minutes, 5-20 minutes, for example, 15 minutes.
  • the in-situ reaction of compound (A'-3) with compound (A'-4) is carried out by adding compound (A'-4) and optionally a base to the reactants of step (a).
  • the in-situ reaction of compound (A'-3) with compound (A'-4) is carried out by mixing compound (A'-4) and a base, such as diisopropylethylamine, in a solvent and then adding it to the reactants of step (a).
  • the base may be a tertiary amine, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO).
  • the base is diisopropylethylamine (DIPEA).
  • the amount of the base is about 0 to 4 equivalents, preferably about 0 to 2 equivalents, and more preferably about 2 equivalents.
  • the solvent is an aprotic polar solvent, such as acetonitrile.
  • the in-situ reaction of compound (A'-3) with compound (A'-4) can be carried out at elevated temperatures, for example, about 40-90°C, for example, 50-60°C, for example, 55°C.
  • the reaction time is the time required for the reaction to complete, for example, 1-20 hours, for example, 1-10 hours, for example, 1-5 hours, for example, 1-2 hours.
  • the amino protecting group can vary depending on its distance from the functional group and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, benzyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenemethoxycarbonyl (Fmoc).
  • Boc benzyloxycarbonyl
  • Fmoc 9-fluorenemethoxycarbonyl
  • a compound of formula (A'-5) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof is provided, wherein:
  • PG indicates an amino protecting group, such as Boc
  • Ring A is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted with one or more R3s , each R3 independently selected from halogens, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyls independently selected from halogens and C1-6 alkyls) -RL- , or two of the R3s.
  • 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S
  • said 4- to 6-membered ring optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl;
  • Ring D is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl.
  • R1 is H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl , C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl;
  • R2 is independently selected from H, halogen, cyano, OH, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 (C1-6 alkyl), -NR a -S(O) 2- (C1-6 alkyl ), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(O)(
  • Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;
  • Ra and Rb are each independently H or C1-6 alkyl
  • R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;
  • n 0, 1, 2, 3, 4, or 5;
  • n 0, 1, or 2.
  • a compound of formula (A'-5) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof is provided, wherein:
  • PG indicates an amino protecting group, such as Boc
  • Ring A is R3a , R3b , and R3c are each independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups (preferably, R3a is a C1-6 alkyl or C1-6 haloalkyl group, R3b is a halogen such as fluorine, and R3c is a C1-6 alkyl group), or R3a and R3b, together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, and R3c is H; or
  • Ring A is phenyl or benzofuranyl, each optionally substituted by one or more R3s , each R3 being independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups;
  • R 2 ' is a C 1-6 alkyl, C 1-6 deuterated alkyl, (C 1-6 alkoxy) -RL- , (C 3-6 cycloalkyl) -RL- , and (3-8 heterocyclic alkyl) -RL- , wherein the cycloalkyl is optionally substituted with one or more halogens; and R 2c is H or a halogen;
  • R1 is a C1-6 alkyl group, preferably methyl
  • R and L are each independently valenced, C1-4 alkylene, or C1-4 deuterated alkylene;
  • n 0 and R p does not exist.
  • Equation (I) or its sub-equations can be applied equally to their respective intermediates, such as Equation A'-1, Equation A'-3, Equation A'-4, Equation A'-5, Equation A' or Equation A, etc., which will not be repeated here.
  • Price key Indicates a single bond or a double bond.
  • halogen or halogenated refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferred halogens are fluorine and chlorine.
  • alkyl alone or as part of other groups refers to a fully saturated straight-chain or branched hydrocarbon group consisting of carbon and hydrogen atoms.
  • C1-6 alkyl refers to an alkyl group having 1-6 carbon atoms.
  • C1-6 alkyl is preferably C1-4 or C1-3 alkyl.
  • Representative examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl and isopropyl), butyl (Bu) (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl, etc.), hexyl, heptyl, octyl, etc.
  • alkylene alone or as part of other groups refers to a fully saturated straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms.
  • Alkylenes are, for example, C1-6 alkylenes, preferably C1-4 alkylenes, and more preferably C1-2 alkylenes. Representative examples include, but are not limited to, methylene, ethylene, propylene, butylene, etc.
  • alkenyl alone or as part of other groups refers to a straight-chain or branched hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one double bond.
  • C2-6 alkenyl refers to an alkenyl group having 2 to 6 carbon atoms.
  • C2-6 alkenyl is preferably C2-4 alkenyl or C2-3 alkenyl.
  • Representative examples include, but are not limited to, vinyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, etc.
  • alkenyl alone or as part of other groups refers to a straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one double bond.
  • C2-6 alkenyl refers to an alkenyl group having 2-6 carbon atoms.
  • C2-6 alkenyl groups are preferably C2-4 or C2-3 alkenyl groups. Representative examples include, but are not limited to, vinylidene, propenyl, allyl, and butenyl groups.
  • alkynyl alone or as part of other groups refers to a straight-chain or branched hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one triple bond.
  • C2-6 alkynyl refers to an alkynyl group having 2-6 carbon atoms.
  • C2-6 alkynyl is preferably C2-4 or C2-3 alkynyl. Representative examples include, but are not limited to, ethynyl, propynyl, propynyl, butynyl, isobutynyl, penynyl, isopentenynyl, hexynyl, heptyynyl, etc.
  • ynynyl alone or as part of other groups refers to a straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one triple bond.
  • C 2-6 ynynyl refers to an ynynyl group having 2-6 carbon atoms.
  • C 2-6 ynynyl is preferably C 2-4 or C 2-3 ynynyl. Representative examples include, but are not limited to, ethynylene, propynylene, and butynylene.
  • haloalkyl refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, such as 1, 2, or 3 hydrogen atoms, are substituted with a halogen. It is understood that when there is more than one halogen substituent, the halogen substituents can be the same or different, and can be located on the same or different carbon atoms.
  • Haloalkyl is preferably a C1-6 haloalkyl, more preferably a C1-4 or C1-3 haloalkyl.
  • Representative examples include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, trichloroethyl, difluorochloroethyl, difluoropropyl, and trifluoropropyl.
  • halogenated alkylene refers to an alkylene group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, such as 1, 2, or 3 hydrogen atoms, are substituted with a halogen. It is understood that when there is more than one halogen substituent, the halogen substituents can be the same or different, and can be located on the same or different carbon atoms.
  • Halogenated alkylenes are preferably C1-4 or C1-3 alkylenes. Representative examples include, but are not limited to, fluoromethylene, chloromethylene, difluoromethylene, dichloromethylene, fluorochloromethylene, trifluoromethylene, trichloromethylene, etc.
  • cyanoalkyl refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, such as 1, 2 , or 3 hydrogen atoms, are replaced by a cyano group.
  • Cyanoalkyl groups are preferably C1-6 cyanoalkyl groups, more preferably C1-4 or C1-3 cyanoalkyl groups. Representative examples include, but are not limited to, cyanomethyl, cyanoethyl, cyanopropyl, etc.
  • cyanoalkylene refers to an alkylene group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or such as 1, 2 , or 3 hydrogen atoms, are replaced by a cyano group.
  • Cyanoalkylene groups are preferably C1-4 or C1-3 cyanoalkylene groups. Representative examples include, but are not limited to, cyanomethylene, cyanoethylene, cyanopropylene, etc.
  • hydroxyalkyl refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or such as 1, 2 , or 3 hydrogen atoms, are replaced by a hydroxyl group.
  • Hydroxyalkyl groups are preferably C1-6 hydroxyalkyl groups, more preferably C1-4 or C1-3 hydroxyalkyl groups. Representative examples include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxypropyl groups.
  • hydroxyalkylene refers to an alkylene group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or such as 1, 2 , or 3 hydrogen atoms, are replaced by a hydroxyl group.
  • Hydroxyalkylene groups are preferably C1-4 or C1-3 hydroxyalkylene groups. Representative examples include, but are not limited to, hydroxymethylene, hydroxyethylene, and hydroxypropylene.
  • alkylidene alone or as part of other groups refers to a fully saturated straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms linked by a double bond at the carbon end.
  • alkylidene refers to an alkylidene as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or for example 1, 2, or 3 hydrogen atoms, are substituted with a halogen. It is understood that when there is more than one halogen substituent, the halogen substituents can be the same or different, and can be located on the same or different carbon atoms.
  • Alkylidenes are, for example, C1-6 alkylidenes, preferably C1-4 alkylidenes. Examples include, but are not limited to, halo-methylidene, halo-ethylidene, halo-propanylidene, halo-butanylidene, etc.
  • alkoxy and alkyloxy are used interchangeably to refer to an alkyl group as defined above, linked by an oxygen bridge.
  • Alkoxy groups are preferably C1-6 alkoxy groups, more preferably C1-4 or C1-3 alkoxy groups. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc.), pentoxy (including n-pentoxy, isopentoxy, neopentoxy, etc.), hexoxy, heptoxy, octoxy, etc.
  • alkathio and “alkylthio” are used interchangeably to refer to an alkyl group as defined above, linked by a sulfur bridge.
  • the alkathio group is preferably a C1-6 alkathio group, more preferably a C1-4 or C1-3 alkathio group.
  • Representative examples include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, etc.), pentylthio (including n-pentylthio, isopentylthio, neopentylthio, etc.), hexylthio, heptylthio, octylthio, etc.
  • cycloalkyl refers to a fully saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, which can be monocyclic, bicyclic, spirocyclic, or bridged.
  • C3-10 cycloalkyl refer to cycloalkyl groups having 3 to 10 cyclic carbon atoms
  • C3-8 cycloalkyl refer to cycloalkyl groups having 3 to 8 cyclic carbon atoms
  • C3-6 cycloalkyl refer to cycloalkyl groups having 3 to 6 cyclic carbon atoms.
  • Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclic [1.1.1]pentyl, spiro[3.3]heptyl, etc.
  • cycloalkenyl refers to a partially unsaturated cyclic hydrocarbon group composed of carbon and hydrogen atoms and containing one or more double bonds. Cycloalkenyl groups are preferably C3-10 cycloalkenyl groups, and more preferably C3-8 cycloalkenyl groups. Representative examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl groups.
  • cycloalkylene refers to a fully saturated divalent cyclic hydrocarbon group consisting of carbon and hydrogen atoms.
  • C3-8 cycloalkylene and C3-6 cycloalkylene refer to cycloalkylene groups having 3 to 8 ring carbon atoms, respectively. Representative examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.
  • the cycloalkylene group can be bonded to other parts of the molecule via the same ring carbon atom or two different ring carbon atoms.
  • aryl refers to an aromatic monocyclic or bicyclic ring with a carbon ring member.
  • C6-10 aryl refers to an aryl group having 6-10 ring carbon atoms. Representative examples include, but are not limited to, phenyl (i.e., C6 aryl) and naphthyl.
  • heterocyclic alkyl refers to a saturated monocyclic or bicyclic group, including spirocyclic groups, having one or more, preferably 1 to 6, for example 1, 2, 3, 4, 5, or 6 heteroatoms, each independently selected from N, O, or S, and with the remaining ring members being carbon.
  • the carbon members of a heterocyclic alkyl group may be replaced by -CO-, and the arbitrary N and S heteroatoms may optionally be oxidized (e.g., in NO, SO, SO2 ) and the arbitrary N heteroatoms may optionally be quaternized (e.g., in [NR] + Cl- , [NR] + OH- ).
  • 3-10-membered heterocyclic alkyl refers to a heterocyclic alkyl group having 3 to 10 ring members. It is preferably a 4-8-membered heterocyclic alkyl, more preferably a 5-6-membered heterocyclic alkyl. Heterocyclic alkyl groups may be attached to the rest of the molecule by carbon atoms or heteroatoms, provided it is chemically feasible.
  • heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, imidazoketyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, piperidinyl, piperidinoneyl, hexahydropyridinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, thiomorpholinyl, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, oxeheptyl, azaheptyl, and oxaazaheptyl.
  • a heterocyclic alkyl group contains only oxygen as a heteroatom, it can be called an "oxeheptyl,
  • heterocyclic alkenyl refers to a non-aromatic monocyclic or bicyclic group, including spirocyclic groups, having one or more, preferably 1 to 6, for example 1, 2, 3, 4, 5, or 6 heteroatoms each independently selected from N, O, or S, and with the remaining ring members being carbon, containing one or more carbon-carbon double bonds.
  • heterocyclic alkenyl refers to a heterocyclic alkenyl group having 3 to 10 ring members.
  • heteroaryl or “heteroary ring” refers to an aromatic cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, and the remaining ring members being carbon. Any N and S heteroatoms of the heteroaryl group may optionally be oxidized (e.g., in NO, SO, SO2 ) and said any N heteroatoms may optionally be quaternized (e.g., in [NR] + Cl ⁇ , [NR] + OH ⁇ ).
  • the heteroaryl is preferably a 5- to 10-membered heteroaryl (heteroary ring), more preferably a 5- to 7-membered heteroaryl (heteroary ring), and most preferably a 5- or 6-heteroaryl (heteroary ring).
  • Representative examples include, but are not limited to: pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, oxadiazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyranyl, thiophene, oxazinyl, oxadiazinyl, indole, isoindole, azaindole (e.g., 7-azaindole, 6-azaindole, 5-azaindole, 4-azaindole), benzofuranyl, isobenzofuranyl, benzothiophene, benzothiazole
  • the compounds include alkyl, indazole, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, cenolinyl, quin
  • Heteroaryl groups can be attached to the rest of the compound via carbon atoms or heteroatoms, as long as it is chemically feasible. Heteroaryl groups (heteroary aromatic rings) can also be fused with other cyclic groups.
  • heteroaryl refers to a divalent aromatic cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, and the remaining ring members being carbon.
  • 8-10-membered bicyclic heteroaryl refers to a divalent aromatic bicyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, and the remaining ring members being carbon.
  • heterocycle refers to a cyclic structure containing one or more, for example, 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, with the remaining ring members being carbon. It can be fully saturated, partially unsaturated (e.g., containing one or more double or triple bonds), or aromatic (satisfying Hückel's rule).
  • the heterocycle is a 3- to 8-membered heterocycle, more preferably a 4- to 8-membered heterocycle, and more preferably a 5- to 6-membered heterocycle.
  • the carbon members of the heterocycle may optionally be replaced by -CO-, and the arbitrary N and S heteroatoms may optionally be oxidized (e.g., in NO, SO, SO2) and the arbitrary N heteroatoms may optionally be quaternized (e.g., in [NR]+Cl-, [NR]+OH-).
  • heterocycles include, but are not limited to: pyrrole, dihydropyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, tetrahydrothiophene 1-oxide, tetrahydrothiophene 1,1-dioxide, pyrazole, dihydropyrazole, pyrazolidine, imidazole, imidazoline, imidazoline, pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyridazine, dihydropyridazine, tetrahydropyridazine, hexahydropyridazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidine, hexahydropyrimidine, pyrazine, dihydropyrazine, tetrahydr
  • cyano refers to CN
  • hydroxyl refers to OH.
  • thiol represents SH.
  • NR a R b indicates NH2 in which two hydrogen atoms are replaced by Ra and Rb , respectively.
  • NH2 indicates an amino group.
  • -NH(C1 -6 alkyl) indicates an amino group substituted with one C1 -6 alkyl group.
  • -N(C1 -6 alkyl)(C1 -6 alkyl) indicates an amino group substituted with two identical or different C1 -6 alkyl groups, such as dimethylamino, (methyl)(ethyl)amino, etc.
  • -PO- represents a phosphoryl group
  • COOH represents a carboxyl group
  • subunit or “sub...group” refers to a divalent group derived by removing two hydrogen atoms from a molecule.
  • divalent or trivalent groups are presented herein as monovalent groups or chemical substances, but those skilled in the art will clearly determine, based on their expertise, that the term refers to the corresponding divalent or trivalent group.
  • naphthalene as defined for ring B refers to a divalent group derived by removing two hydrogen atoms from a naphthalene ring
  • 8-10 membered bicyclic heteroaryl as defined for ring B refers to a divalent group derived by removing two hydrogen atoms from an 8-11 membered bicyclic heteroaryl ring.
  • H mentioned herein includes 1H , 2H (D), and 3H (T), preferably 1H and 2H (D).
  • Carbon in any group mentioned herein includes 12C , 13C , and 14C .
  • a hyphen ("-") not between two letters or symbols indicates the linking site of the group.
  • -NR a R b indicates that the group is linked to the rest of the molecule via a nitrogen atom
  • C3-8 cycloalkyl-( C1-4 alkylene)- indicates that the linking site of the group is on a C1-4 alkylene atom.
  • the "-" may be omitted when the linking site of the group is obvious to those skilled in the art (e.g., for halogens, hydroxyl groups, NR a R b , etc.).
  • any variable appears more than once in a structural formula it is defined independently each time it appears.
  • the halogens can be the same or different, and the halogens can be located on the same or different atoms.
  • substituted by one or more substituents independently selected from A, B, and C indicates the case where the substitute is made by one or more substituents independently selected from A, B, and C. Examples include substitution by one or more A, substitution by one or more B, substitution by one or more C, substitution by one or more A and one or more B, substitution by one or more A and one or more C, substitution by one or more B and one or more C, substitution by one or more A, one or more B, and one or more C, etc.
  • composition of the invention refers to compounds conforming to formula (I) or its sub-forms, such as formulas (II), (III), (IV), (III'), (IV'), (Va) and/or (Vb), or salts thereof, particularly pharmaceutically acceptable salts, as well as tautomers, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotational isomers and trans-isomers), metabolites, prodrugs, and isotopically labeled compounds (particularly deuterated derivatives), polymorphs, solvates and/or hydrates, including those defined in the embodiments and examples.
  • the terms "substance of the invention” or “substance of this application” specifically refer to the compounds of the embodiments or their salts, particularly pharmaceutically acceptable salts, as well as tautomers, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotational isomers and trans-isomers), metabolites, prodrugs, and isotopically labeled compounds (particularly deuterated derivatives), polymorphs, solvates and/or hydrates.
  • formula (I) also includes its sub-formulas, such as formulas (II), (III), (IV), (III’), (IV’), (Va) and/or (Vb).
  • the phrase “medicinal” refers to a substance or composition that, when administered to animals such as humans, does not produce obvious side effects, allergic reactions, or other unwanted reactions.
  • the compounds of this invention can be in the form of salts, such as pharmaceutically acceptable salts.
  • “Pharmaceutically acceptable salts” include acid addition salts and base addition salts.
  • “Pharmaceutical-acceptable acid addition salts” refer to those salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. Acid addition salts can be formed from inorganic or organic acids.
  • Inorganic acid salts include, for example, hydrochlorides, hydrobroms, sulfates, hydrogen sulfates, nitrates, carbonates, phosphates, etc.
  • organic acid salts include, formates, acetates, trifluoroacetates, propionates, glycolates, gluconates, lactates, pyruvates, oxalates, malates, malonates, glutarate, adipates, succinates, fumarates, maleates, tartrates, citrates, aspartate, sine, ascorbate, glutamate, and other similar salts.
  • Salts also include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts; and those derived from non-toxic organic bases: primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Salts can be synthesized from parent compounds using
  • salts are preferred. However, other salts may also be useful, for example, in separation or purification steps, and may be used during preparation, and are therefore included within the scope of this disclosure.
  • the compounds of this invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof.
  • the synthesis of the compounds may employ racemic compounds, diastereomers, or isomers as starting materials or intermediates.
  • a mixture of specific diastereomers can be isolated or enriched with one or more specific diastereomers by chromatographic or crystallographic methods.
  • enantiomer mixtures can be isolated or enriched with enantiomers using the same techniques or other techniques known in the art.
  • the asymmetric carbon or nitrogen atom may each be in an R or S configuration, both of which are within the scope of this invention.
  • all stereoisomers are included as compounds of this invention unless the stereochemistry of any particular chiral atom is specified. Stereochemical definitions and conventions used herein follow those commonly used in the art.
  • stereoisomer refers to compounds that have the same chemical composition but differ in the spatial arrangement of their atoms or groups. Stereoisomers include diastereomers, enantiomers, and conformational isomers.
  • diastereomer refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and biological activity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatographic methods such as HPLC.
  • enantiomer refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.
  • tautomer refers to structural isomers with different energies that can interconvert through low energy barriers.
  • proton tautomers also known as proton shift tautomers
  • Valence tautomers include interconversions via the rearrangement of some bonding electrons.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which is a single enantiomer with an enantiomer excess (%ee) >95%, >98%, or >99%.
  • the single enantiomer is present with an enantiomer excess (%ee) >99%.
  • isotope-labeled compound refers to a compound in which one or more atoms constituting the compound contain an atomic isotope in a non-natural proportion.
  • the compounds of the present invention may contain an atomic isotope in a non-natural proportion on one or more atoms constituting the compound, thereby forming isotopic variations, whether or not they are radioactive, and are intended to be covered within the scope of the present invention.
  • the structural formulas described herein include compounds that differ in the presence of one or more isotope-enriched atoms.
  • isotopes and their pharmaceutically usable salts that can be incorporated into the compounds of this invention include, but are not limited to, isotopes of hydrogen (e.g., 2H , 3H ); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ).
  • isotopes of hydrogen e.g., 2H , 3H
  • Isotope-labeled compounds can be used for the tissue distribution analysis of compounds or substances.
  • Tritium (i.e., 3H ) and carbon-14 (i.e., 14C ) isotopes are useful due to their ease of preparation and detectability. Furthermore, substitution with a heavier isotope, such as deuterium (i.e., 2H ), can provide some therapeutic benefits arising from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement).
  • one or more carbon atoms are replaced with carbons rich in 13C- or 14C .
  • Positron-emitting isotopes such as 15O , 13N , 11C , and 18F can be used in positron emission tomography (PET) studies to detect substrate acceptor occupancy.
  • PET positron emission tomography
  • isotopic variations of the compounds of the present invention can generally be prepared by conventional methods using appropriate isotopic variations with suitable reagents.
  • metabolite refers to a product generated in vivo from the metabolism of a particular compound or its salts. Such products can arise from processes of the administered compound, such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc.
  • the structure of metabolites is determined in a conventional manner, for example by MS, LC/MS, or NMR analysis. Typically, metabolite analysis is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites can be used for diagnostic analysis of therapeutic doses of the compounds of this invention, provided they are not detected in vivo.
  • prodrug refers to a chemically modified active or inactive compound that, after being administered to an individual, undergoes physiological processes in vivo (e.g., hydrolysis, metabolism, etc.) to be converted into the compound of this invention. Techniques for manufacturing and using prodrugs are well known to those skilled in the art.
  • polymorph refers to a crystalline form having the same chemical structure/composition but with different spatial arrangements of the molecules and/or ions that form crystals.
  • the compounds of this invention can be provided as amorphous solids or crystalline solids. The scope of this invention is intended to encompass all such physical forms.
  • solvent refers to an association or complex of one or more solvent molecules with a compound of the present invention.
  • solvents that form solvates include water, isopropanol, ethanol, MeOH, DMSO, EA, acetic acid, and ethanolamine.
  • hydrate refers to a complex in which the solvent molecule is water. Methods of solvation are well known in the art.
  • the compounds of this invention also encompass any N-oxides that may be present, and those skilled in the art can identify stable and viable N-oxides of the compounds of this invention.
  • the compounds of this invention also encompass metabolites of the compounds of this invention, i.e., substances formed in vivo through oxidation, reduction, hydrolysis, amidation, esterification, etc., when the compounds of this invention are administered, which can be identified using techniques known in the art.
  • the term "individual” or “patient” refers to an animal, preferably a mammal.
  • individuals include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), horses, cattle, sheep, cats, dogs, rabbits, and rodents (e.g., mice and rats).
  • primates e.g., humans and non-human primates such as monkeys
  • horses cattle, sheep, cats, dogs, rabbits, and rodents (e.g., mice and rats).
  • rodents e.g., mice and rats.
  • the individual is a person, including children, adolescents, or adults.
  • treatment means (i) treating or preventing a particular disease, symptom, or disorder; (ii) reducing, improving, or eliminating one or more symptoms of a particular disease, symptom, or disorder; and optionally (iii) preventing or delaying the onset of one or more symptoms of a particular disease, symptom, or disorder described herein.
  • treatment means improving at least one bodily parameter, which may not be perceptible to the patient.
  • treatment means regulating a disease or symptom from a physical (e.g., stabilizing perceptible symptoms) or physiological (e.g., stabilizing bodily parameters) or both.
  • prevention refers to the administration of one or more pharmaceutical substances, particularly the compounds of the present invention and/or their pharmaceutically acceptable salts, to an individual with a predisposition to the disease or condition, in order to prevent the individual from contracting the disease.
  • inhibition and “reduction” refer to the reduction or inhibition of a specific patient, symptom, condition, or disease, or a significant reduction in the baseline activity of a biological activity or process.
  • GLP-1R-related disease or disorder refers to any disease or disorder in which GLP-1R receptors (including wild-type or mutant types) play a role. Activation of GLP-1R receptors can have beneficial effects on said disease or disorder, such as reducing or eliminating disease symptoms, alleviating disease severity, and reducing disease incidence.
  • GLP-1R-related diseases or disorders include, but are not limited to, diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic diseases, cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders or disorders, and cancer.
  • fatty liver diseases e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
  • metabolic diseases e.g., cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders or disorders, and cancer.
  • GLP-1R is wild-type GLP-1R. In other implementations, GLP-1R is mutant GLP-1R.
  • diabetes refers to a group of metabolic diseases caused by insufficient insulin secretion or impaired insulin utilization, characterized primarily by persistently elevated blood glucose levels.
  • Diabetes includes type 1 diabetes (insulin-dependent diabetes), type 2 diabetes (non-insulin-dependent diabetes), gestational diabetes, and special types of diabetes.
  • Special types of diabetes a category in the WHO classification of diabetes, refers to diabetes caused by all factors other than type 1, type 2, and gestational diabetes.
  • Special types of diabetes can be further divided into eight categories, including: hereditary defects in pancreatic ⁇ -cell function; hereditary defects in insulin action; pancreatic exocrine disorders; endocrine disorders; drug or chemical-induced; infection-induced; rare immune-mediated diabetes; and diabetes-related genetic syndromes.
  • diabetes complications refers to complications arising from diabetes or hyperglycemia, including ketoacidosis, infectious diseases (such as skin infections, soft tissue infections, biliary tract infections, respiratory infections, and urinary tract infections), microvascular complications (such as nephropathy and retinopathy), neuropathy (such as sensory nerve disorders, motor nerve disorders, and autonomic nerve disorders), and gangrene.
  • infectious diseases such as skin infections, soft tissue infections, biliary tract infections, respiratory infections, and urinary tract infections
  • microvascular complications such as nephropathy and retinopathy
  • neuropathy such as sensory nerve disorders, motor nerve disorders, and autonomic nerve disorders
  • gangrene gangrene.
  • diabetic complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic gangrene.
  • condition requiring blood glucose reduction includes both pathological and non-pathological conditions where lowering blood glucose is beneficial or desirable. These conditions include, but are not limited to, prediabetes, impaired glucose tolerance, impaired glucose metabolism, insulin resistance, hyperglycemia, excessive sugar consumption, and delayed wound healing.
  • weight management refers to maintaining a desired weight or BMI within a healthy range. For example, weight management aims to keep a BMI between 18.5 and 24 kg/ m2 . Specifically, weight management includes weight loss, inducing weight loss, slowing or preventing weight gain, reducing body fat, reducing food intake, delaying gastric emptying, and increasing satiety.
  • an effective dose refers to the amount of medication required to achieve a desired therapeutic or preventative effect at the necessary dosage and for the required duration. It can be determined by the physician or veterinary practitioner involved and will vary depending on factors such as the compound, the state of the disease being treated, the severity of the disease, the individual's age and relevant health conditions, the route and form of administration, and the judgment of the attending physician or veterinary practitioner. Generally, the "preventive effective dose” will be less than the "therapeutic effective dose.”
  • composition refers to a composition suitable for administration to animals, preferably mammals (including humans), comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient.
  • the formulations of this invention can be any formulation applicable in the art, such as tablets, capsules, liquid formulations, etc.
  • pharmaceutical carrier refers to a component in a pharmaceutical preparation other than the active ingredient that is substantially non-toxic to an individual.
  • pharmaceutical carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.
  • processing means the addition or mixing of two or more reagents under appropriate conditions to produce the shown and/or desired product. It should be understood that the reaction producing the shown and/or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the shown and/or desired product.
  • a and/or B includes A alone, B alone, and A+B.
  • the substances of the present invention possess excellent GLP-1R agonist activity. Furthermore, the substances of the present invention exhibit favorable in vivo and in vitro pharmacokinetic properties, such as good solubility and/or absorption, good metabolic stability, improved bioavailability, and reduced side effects (e.g., low risk of hypoglycemia). The substances of the present invention also possess good physical and/or chemical stability, making them suitable for formulation into various pharmaceutically acceptable preparations. Therefore, the substances of the present invention can be used in a variety of applications where GLP-1R agonist activity is advantageous or required, such as as GLP-1R agonists or for the treatment or prevention of GLP-1R-related diseases or disorders.
  • the substances of the present invention can be used for weight management, for lowering blood glucose and/or for the treatment or prevention of diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic diseases, cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders, cancer, etc.
  • fatty liver diseases e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
  • metabolic diseases e.g., cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders, cancer, etc.
  • the substances of the present invention can be used for weight management, particularly for weight loss, inducing weight loss, slowing or preventing weight gain, reducing body fat, reducing food intake, delaying gastric emptying, and increasing satiety.
  • the individual is an individual wishing to lose weight, an overweight individual, or an obese patient.
  • the individual's weight gain may be due to overeating or an unbalanced diet, drug-induced weight gain, hormone-related weight gain, or weight gain after quitting smoking.
  • the weight gain is weight gain prior to reaching obesity, or weight gain in an obese patient.
  • the substances of the present invention can be used to treat or prevent overweight, obesity, or obesity-related diseases or conditions.
  • obesity include, but are not limited to, symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity.
  • symptomatic obesity include, but are not limited to, endocrine obesity (e.g., Cushing's syndrome, insulinoma, type II diabetes with obesity, hypothyroidism, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenobarbital, insulin, sulfonylurea agents, or beta-blocker-induced obesity).
  • endocrine obesity e.g., Cushing's syndrome, insulinoma, type II diabetes with obesity, hypothyroidism, pseudohypoparathyroidism, hypogonadism
  • diseases or conditions associated with obesity include, but are not limited to, reduced glucose tolerance, diabetes, lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatosis (NASH)), coronary artery disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), skeletal or joint disorders (e.g., knee osteoarthritis, hip osteoarthritis, degenerative spondylitis, low back pain), sleep apnea syndrome, obesity-related hypoventilation syndrome (e.g., Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycles, abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome.
  • NASH non-alcoholic steatosis
  • coronary artery disease e.g., myocardial in
  • the substance of the present invention has a good hypoglycemic effect and a low incidence of hypoglycemia, and therefore can be used as a hypoglycemic agent for the treatment or prevention of diabetes, diabetic complications, or situations requiring lower blood sugar.
  • the diabetes, diabetic complications, or situations requiring lower blood sugar include, but are not limited to: type 1 diabetes, type 2 diabetes, gestational diabetes, special types of diabetes (e.g., hereditary defects in pancreatic ⁇ -cell function, hereditary defects in insulin action, pancreatic exocrine disorders, endocrine disorders, drug- or chemical-induced diabetes, infection-induced diabetes, rare immune-mediated diabetes, diabetes-related genetic syndromes), ketoacidosis, metabolic acidosis, diabetic nephropathy, diabetic retinopathy, diabetic uveitis, diabetic cataracts, diabetic neuropathy, diabetic foot, diabetic gangrene, diabetic cardiovascular disease, diabetic cardiomyopathy, diabetic dyslipidemia, diabetic cachexia, prediabetes, impaired glucose tolerance, impaired glucose metabolism, insulin resistance, hyperglycemia, excessive sugar consumption, and delayed wound healing.
  • type 1 diabetes e.g., type 1 diabetes, type 2 diabetes, gestational diabetes, special types of diabetes (e.g., hereditary
  • the substances of the present invention can be used to treat or prevent: idiopathic type 1 diabetes (type 1b), early-onset type 2 diabetes, juvenile-onset atypical diabetes (YOAD), adolescent adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), malnutrition-related diabetes, and hyperosmolar diabetic coma.
  • the substances of the present invention can be used to treat or prevent metabolic diseases, including but not limited to: impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, insulin resistance syndrome, paresthesia caused by hyperinsulinemia/hyperlipidemia/hypercholesterolemia, metabolic syndrome, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or postprandial lipemia), glucagonoma, hyperuricemia, and insulin-related coma endpoints.
  • metabolic diseases including but not limited to: impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, insulin resistance syndrome, paresthesia caused by hyperinsulin
  • liver diseases include, but are not limited to: fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), steatohepatitis such as non-alcoholic steatohepatitis (NASH), alcoholic liver disease, fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, acute fatty liver of pregnancy, hepatic steatosis; liver fibrosis, cirrhosis; autoimmune liver diseases, autoimmune hepatitis, and primary biliary cirrhosis.
  • fatty liver diseases such as non-alcoholic fatty liver disease (NAFLD), steatohepatitis such as non-alcoholic steatohepatitis (NASH), alcoholic liver disease, fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty
  • the substances of the present invention can be used to treat or prevent vascular diseases, including cardiovascular and cerebrovascular diseases and peripheral vascular diseases.
  • vascular diseases include, but are not limited to: hypertension, pulmonary hypertension, atherosclerosis, arteriosclerosis, coronary heart disease (such as myocardial infarction and angina pectoris), coronary artery disease, heart failure (such as congestive heart failure), arrhythmia, left ventricular hypertrophy, angina pectoris, cerebral infarction, stroke (such as hemorrhagic stroke and ischemic stroke), transient ischemic attack, impaired vascular compliance, restenosis, post-angioplasty restenosis, thrombosis, pre-thrombotic state, vascular dysfunction, large vessel complications, abdominal aortic aneurysm, carotid artery disease, chronic venous insufficiency, severe limb ischemia, etc.
  • the substances of the present invention can be used to treat or prevent neurological disorders (e.g., neurodegenerative diseases) or mental disorders.
  • the neurological disorders include, but are not limited to: Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment, dementia, brain insulin resistance, anxiety disorders, traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperkinesia, Down syndrome, myasthenia gravis, neurological trauma, angioamylindrica, brain inflammation, Friedrich's ataxia, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated central nervous system degenerative diseases.
  • AD Alzheimer's disease
  • PD Parkinson's disease
  • cognitive impairment dementia
  • brain insulin resistance anxiety disorders
  • anxiety disorders traumatic brain injury
  • Huntington's disease Huntington's disease
  • tardive dyskinesia hyperkinesia
  • Down syndrome myasthenia gravis
  • neurological trauma angioamylindrica
  • brain inflammation e.g.,
  • the mental disorders include, but are not limited to, drug dependence/addiction, attention deficit hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, or depression.
  • the substances of the present invention can improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and protect dopamine neurons and motor function in Parkinson's disease. Furthermore, the substances of the present invention can improve behavioral responses to addictive drugs, reduce drug dependence, prevent relapse of drug abuse, and alleviate anxiety caused by the lack of a given addictive substance.
  • kidney diseases include, but are not limited to: diabetic nephropathy, chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and end-stage renal disease.
  • the substances of the present invention can be used to treat or prevent gastrointestinal diseases.
  • gastrointestinal diseases include, but are not limited to: ulcers, digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, colitis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), irritable bowel syndrome, steatorrhea, hypogammaglobulinemia-induced sprue, mucositis and diarrhea induced by chemotherapy and/or radiotherapy, gastroesophageal reflux, gastrointestinal inflammation, gastric mucosal damage, small intestinal mucosal damage, and cachexia.
  • the substances of the present invention can be used to treat or prevent autoimmune diseases.
  • autoimmune diseases include, but are not limited to: multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders related to immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease.
  • the substances of the present invention can be used to treat or prevent inflammatory diseases.
  • inflammatory diseases include, but are not limited to: chronic rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease, liver inflammation, pancreatitis, kidney inflammation, intestinal inflammation, and pro-inflammatory states.
  • the substances of the present invention can be used to treat or prevent lung diseases.
  • lung diseases include, but are not limited to: asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the substances of the present invention can be used to treat or prevent diseases or disorders related to the hypothalamus-pituitary-gonadal axis (e.g., the hypothalamus-pituitary-ovarian axis, or the hypothalamus-pituitary-testicular axis), including but not limited to: hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.
  • diseases or disorders related to the hypothalamus-pituitary-gonadal axis e.g., the hypothalamus-pituitary-ovarian axis, or the hypothalamus-pituitary-testicular axis
  • hypogonadism e.g., the hypothalamus-pituitary-ovarian axis, or the hypothalamus-pituitary-testicular axis
  • hypogonadism e.g., the hypothal
  • the substances of the present invention can be used to treat or prevent cancer.
  • cancers include, but are not limited to: pancreatic cancer, gastrointestinal cancer, lung cancer, colon cancer, colorectal cancer, esophageal cancer, tongue cancer, pharyngeal cancer, salivary gland cancer, brain tumors, schwannomas, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, breast cancer, prostate cancer, bladder cancer, urethral cancer, skin cancer, hemangioma, lymphoma, melanoma, thyroid cancer, parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumors, angiofibroma, retinal sarcoma, penile cancer, testicular tumors, Kaposi's sarcoma, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia.
  • the substances of the present invention can also be used for treatment or prevention:
  • Skeletal disorders characterized by altered bone metabolism such as osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and altered bone metabolism due to any cause (e.g., renal failure or hemodialysis, fracture, bone surgery, aging, pregnancy, or polycystic ovary syndrome); joint disorders (e.g., osteoarthritis, secondary osteoarthritis);
  • ⁇ Muscular dystrophy sarcopenia, acute or chronic diarrhea, weakness, testicular dysfunction, respiratory dysfunction, sexual dysfunction (e.g., erectile dysfunction), geriatric syndrome, psoriasis, essential polydipsia, eating disorders, intermittent claudication, premenstrual syndrome, xerostomia, hearing loss, macular degeneration, cataracts, infectious diseases; and
  • the substance or method of the present invention can cause one or more of the following effects: lowering blood glucose, lowering blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing ⁇ -cell mass, regulating gastric acid secretion, regulating gastric emptying, lowering body mass index (BMI), and/or lowering glucagon levels.
  • the substance or method of the present invention can stabilize serum glucose and serum insulin concentrations.
  • a method for regulating serum glucose or insulin levels in an individual is also provided herein, comprising administering an effective amount of the substance of the present invention to the individual.
  • this document provides a method for reducing the risk of major adverse cardiovascular events (MACE) in an individual, the method comprising administering an effective amount of the substance of the present invention to the individual.
  • the reduction is, for example, a reduction of about 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%.
  • the individual is an adult who has or has been diagnosed with type 2 diabetes. In some embodiments, the individual is an adult who has or has been diagnosed with heart disease. In some embodiments, the individual is an adult who has or has been diagnosed with both type 2 diabetes and heart disease.
  • the substances of the present invention can be administered in the form of pharmaceutical compositions via any suitable route, such as, but not limited to, oral administration (in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions, or suspensions), inhalation (e.g., in the form of sprays), rectal administration (e.g., in the form of suppositories), or parenteral administration (e.g., in the form of injections, such as intravenous, intramuscular, subcutaneous, intraperitoneal, intracranial, etc.). Oral, intranasal, and parenteral administration, such as intravenous administration, are particularly preferred.
  • oral administration in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions, or suspensions
  • inhalation e.g., in the form of sprays
  • rectal administration e.g., in the form of suppositories
  • parenteral administration e.g
  • the substances of the present invention can be processed into pharmaceutical compositions, such as tablets, coated tablets, capsules, liquid formulations (e.g., injections, infusions, syrups, emulsions, suspensions, etc.), powders, powder for injection, dispersions, sprays, suppositories, liposomes, etc., using one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • pharmaceutical compositions such as tablets, coated tablets, capsules, liquid formulations (e.g., injections, infusions, syrups, emulsions, suspensions, etc.), powders, powder for injection, dispersions, sprays, suppositories, liposomes, etc., using one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • Pharmaceutically acceptable carriers, diluents, or excipients are well known in the art, and include, for example, fillers, disintegrants, solvents, solubilizers, stabilizers, wetting agents, emulsifiers, preservatives, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, or antioxidants.
  • the substance of the present invention can be administered at any suitable frequency, such as from once to three times daily to once a month, once every two months, or once every three months. Generally, oral administration is preferred for patient convenience and safety.
  • the substance of the present invention can be administered orally once daily, once every two days, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or at longer intervals.
  • the substance of the present invention can be administered orally twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks, with once a week being the most preferred.
  • Dosage can be varied within a wide range and must, of course, be adjusted according to the individual needs of each specific case.
  • the appropriate dosage can be determined by the attending physician at their discretion based on the type and severity of the disease being treated, the individual's health status and medical history, the specific compound and route of administration, and any concomitant medications.
  • the weekly dose for a 70kg adult is typically from about 0.01mg to about 1000mg of the substance of the invention or a corresponding amount of pharmaceutically acceptable salts or esters.
  • the dosage of the substance of the invention may exceed this range as needed.
  • the weekly dose may be administered as a single dose or in divided doses.
  • the substance of the present invention can be used alone or in combination with one or more other active agents or therapies, which may have the same or different pharmacological effects as the substance of the present invention.
  • the substance of the present invention can be administered simultaneously, before, or after the other active agents or therapies.
  • Other representative active agents include, but are not limited to, anti-obesity agents, diabetes treatment agents, diabetes complication treatment agents, hyperlipidemia treatment agents, antihypertensive drugs, diuretics, chemotherapy drugs, immunomodulators, anti-inflammatory drugs, antithrombotic agents, cardiovascular disease treatment agents, liver disease treatment agents, kidney disease treatment agents, eye disease treatment agents, skin disease treatment agents, vascular disease treatment agents, antiviral drugs, osteoporosis treatment agents, vitamins, antidementia drugs, erectile dysfunction drugs, urinary frequency or incontinence treatment agents, NAFLD treatment agents, NASH treatment agents, dysuria treatment agents, antiemetics, analgesics, antiproliferative drugs, and anticancer drugs.
  • anti-obesity agents include, but are not limited to, anti-obesity agents, diabetes treatment agents, diabetes complication treatment agents, hyperlipidemia treatment agents, antihypertensive drugs, diuretics, chemotherapy drugs, immunomodulators, anti-inflammatory drugs, antithrombotic agents, cardiovascular disease treatment
  • Representative treatments include, but are not limited to, dietary therapy (e.g., diet monitoring, diabetes diet therapy), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS), and dietary modifications.
  • dietary therapy e.g., diet monitoring, diabetes diet therapy
  • exercise therapy e.g., physical activity
  • blood glucose monitoring e.g., blood glucose monitoring
  • gastric electrical stimulation e.g., TANTALUS
  • the dosage of the combined active agents will vary depending on factors such as the shared medication, the condition to be treated, the individual's general health condition, and the judgment of the physician or veterinarian.
  • the substances of the present invention can be administered simultaneously, separately, or sequentially with other shared active agents via the same or different routes of administration. They can be contained in the same pharmaceutical composition (fixed composition) or in separate forms, such as in a pillbox. They can be formulated and/or supplied by the same or different manufacturers.
  • the substances of the present invention and other active agents can be (i) before the combined product is sent to a physician (e.g., in the case of a pillbox containing the substances of the present invention and other active agents); (ii) by the physician himself (or under the physician's guidance) before administration; or (iii) by the patient himself, for example, during the sequential administration of the substances of the present invention and other active agents in the combined treatment.
  • a physician e.g., in the case of a pillbox containing the substances of the present invention and other active agents
  • the physician himself or under the physician's guidance
  • the patient himself for example, during the sequential administration of the substances of the present invention and other active agents in the combined treatment.
  • this application provides pharmaceutical compositions comprising the substances of the present invention and one or more other active agents.
  • the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers, diluents, or excipients.
  • this application provides pharmaceutical combination products such as pillboxes containing two or more individual pharmaceutical compositions, at least one of which contains the substance of the present invention.
  • the pillbox includes a device for separately containing the compositions, such as a container, separate bottles, or separate foil pouches.
  • the kit of this application can be used to administer different dosage forms, such as oral and parenteral dosage forms, to administer a single composition at different dose intervals, or to gradually increase a single composition relative to another.
  • the kit of this application typically includes instructions for use.
  • the substances of this invention can be prepared by various methods, including those described in the following flowcharts, the methods given in the examples, or similar methods.
  • suitable reaction conditions are known to those skilled in the art or can be readily determined.
  • the raw materials are generally commercially available or can be readily prepared using methods known in the art or those described herein.
  • the variables in the general formulas have their meanings as defined herein, unless otherwise stated.
  • the raw materials and intermediates in the synthesis reaction process can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography.
  • the materials can be characterized using conventional methods, including physical constants and spectroscopic data.
  • Procedure I illustrates a method for preparing the compounds of the present invention: condensing compound (A) with compound (B) to obtain compound (I-1), wherein the variables are as defined herein.
  • This reaction is preferably carried out in the presence of a condensing agent and a base, in a suitable solvent.
  • Process II illustrates a method for preparing the compound of the present invention: wherein L2 is...
  • Compound (A), i.e., compound (A') is condensed with compound (B) to give compound (I-3), wherein the variables are as defined herein.
  • This reaction is preferably carried out in the presence of a condensing agent and a base, in a suitable solvent.
  • Procedure III illustrates a method for preparing the compounds of the present invention: condensing a compound of formula (A”) with a compound of formula (B’) to obtain a compound of formula (IV), wherein the variables are as defined herein.
  • This reaction is preferably carried out in the presence of a condensing agent and a base, in a suitable solvent.
  • condensing agents for the condensation reactions described herein include, but are not limited to, 1-hydroxybenzotriazole (HOBt), benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazole-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylammonium hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), and dicyclohexylcarbodiimide (DCC).
  • HOBt 1-hydroxybenzotriazole
  • the condensing agent is 1-hydroxybenzotriazole (HOBt) and/or 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC).
  • the condensing agent is 1-hydroxybenzotriazole (HOBt).
  • bases include, but are not limited to: tertiary amines, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.; nitrogen-containing heteroaromatic compounds, such as pyridine, dimethylaminopyridine, methylpyridine, 2,6-dimethylpyridine, pyrazine, pyridazine, etc.
  • the base is a tertiary amine, such as diisopropylethylamine.
  • solvents include, but are not limited to: aprotic polar solvents, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, and 1-methyl-2-pyrrolidone; and ether solvents, such as diethyl ether, tetrahydrofuran (THF), and dioxane.
  • aprotic polar solvents such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, and 1-methyl-2-pyrrolidone
  • ether solvents such as diethyl ether, tetrahydrofuran (THF), and dioxane.
  • the solvent is an aprotic polar solvent, such as DMF.
  • the reaction is carried out at a temperature sufficient for the reaction to proceed.
  • the reaction temperature is 0-80°C, preferably 20-60°C, and more preferably ambient temperature (about 20-25°C).
  • the reaction is carried out for a sufficient time to allow the reaction to complete.
  • the reaction time is from 1 minute to 10 hours, preferably from 30 minutes to 5 hours, such as 4 hours.
  • the obtained compound of formula (I) may be converted into the desired form by methods known to those skilled in the art, such as reacting with an acid or base to form a salt, precipitating from a solvent to obtain a solvate, or heating the solvate under reduced pressure to convert it into a non-solvent.
  • the compounds of the present invention may exist in crystalline or amorphous form.
  • Procedure IV illustrates a method for preparing compound (A'): compound (A'-5) undergoes a ring-closing reaction to yield compound (A').
  • This reaction is preferably carried out in the presence of an acid (e.g., p-toluenesulfonic acid) and in a solvent (e.g., m-xylene).
  • the reaction can be carried out at elevated temperatures, for example, about 100-200°C, about 120-180°C, about 140-160°C, or 150°C.
  • the reaction time is the time required for the reaction to complete, for example, 1-20 hours, 1-10 hours, 1-5 hours, or 1-2 hours.
  • the reaction product of step 3 can optionally be post-treated to obtain a solid of compound (A').
  • Compound (A') can be used to prepare compound (I-3) of the present invention as described in Procedure II.
  • Process V illustrates a method for preparing a compound of formula (A'-5) involving a urea-forming reaction of A'-1 with a chloroformate (e.g., A'-2) to form a bireactive ester intermediate A'-3, which then generates A'-5 in situ.
  • RA can be any group that does not interfere with the reaction, such as those defined herein, and other variables are as defined herein.
  • the reaction of the compound of formula (A'-1) with a chloroformate of formula (A'-2) to form a bireactive ester compound of formula (A'-3) can be carried out in a solvent in the presence of a base.
  • the reaction can be carried out at ambient temperature (e.g., about 20-25°C).
  • the reaction time is the time required for the reaction to complete, for example, 5 minutes to 5 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 5-30 minutes, 5-20 minutes, or, for example, 15 minutes.
  • the reaction product can be used directly in the next step (in situ reaction).
  • the reaction conditions are as described herein.
  • the reaction for the in-situ formation of a urea compound of formula (A'-5) from a compound of formula (A'-3) can be carried out at elevated temperatures, for example, about 40-90°C, for example, 50-60°C, or for example, 55°C.
  • the reaction time is the time required for the reaction to complete, for example, 1-20 hours, for example, 1-10 hours, for example, 1-5 hours, or for example, 1-2 hours.
  • the resulting product can optionally be concentrated and/or purified.
  • the reaction conditions are as described herein.
  • Figure 1 shows the change in the area under the blood glucose-time curve of compound 1 of Example 1 5 h after administration.
  • Figure 2.1 shows the changes in the area under the blood glucose-time curves of compounds 18, 22 and 23 of Examples at 5 h and 48 h after administration.
  • Figure 2.2 shows the changes in the area under the blood glucose-time curves of compounds 24 and 52 at 5 h and 96 h after administration.
  • Figure 3.1 shows the curves of mouse body weight change (0-28 days) after administration of the compound of the example.
  • Figure 3.2 shows the cumulative food intake change curves (0-28 days) after application of the compound of the example.
  • Figure 3.3 shows the PK curves of mice after the last administration of the compound of the example.
  • Step 6 (2S)-3-(4-fluoro-3,5-dimethylbenzamido)-2-methyl-4-oxoperidin-1-carboxylic acid tert-butyl ester (A1-7)
  • Step 7 (S)-2-(4-fluoro-3,5-dimethylphenyl)-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazolium[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-8)
  • Step 8 (S)-3-amino-5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-1-(4-methoxybenzyl)-4-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-3-onthium-2,4,6-trimethylbenzenesulfonate (A1-9)
  • Step 9 (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-10)
  • Step 10 (S)-3-(bis((4-nitrophenoxy)carbonyl)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-11)
  • Step 11 (S)-3-(3-(2,2-dimethoxyethyl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)ureo)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-12)
  • ESI-MS (m/z): [M+H] + 654.5.
  • Step 12 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A1)
  • intermediate A70 was obtained using a similar synthesis method.
  • intermediate A2 was obtained by referring to a synthetic method similar to that of intermediate A1.
  • intermediate A14 was obtained by referring to a synthetic method similar to that of intermediate A2.
  • intermediates A34 and A40 were obtained using substituted boric acid or borate esters and bromoindazole or bromopyridopyrazole as starting materials via a similar synthetic method.
  • intermediate A15 was obtained by referring to a synthetic method similar to that of intermediate A2.
  • intermediates A13, A18–A19, A21–A29, A31–A33, A35, A36, A38, A39 and A42–47 as shown in Table 2 were obtained by similar synthetic methods.
  • intermediate A20 was obtained by referring to a synthetic method similar to that of intermediate A15.
  • Step 1 1-(bicyclo[1.1.1]pent-1-yl)-2-(3,6-dibromo-2-fluorobenzyl)hydrazine (A30-2)
  • Step 2 1-(bicyclo[1.1.1]pent-1-yl)-5-bromo-4-fluoro-1H-indazole (A30-3)
  • intermediate A30 was obtained by referring to a synthetic method similar to that of intermediate A2.
  • intermediate A37 was obtained by referring to a synthetic method similar to that of intermediate A2.
  • N-bromosuccinimide (33.8 g, 189.9 mmol) was added to a solution of compound A49-1 (20.0 g, 126.6 mmol) in concentrated sulfuric acid (100.0 mL).
  • the reaction mixture was heated to 60°C and stirred for 16 hours. After the reaction was complete, the system was cooled, water (500 mL) was added, and the mixture was extracted with ethyl acetate (100 mL ⁇ 3). The organic layers were combined, washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • intermediate A49 was obtained by referring to a synthetic method similar to that of intermediate A1.
  • intermediates A48, A50, A51 and A67 to A69 shown in Table 2, were obtained using different arylformic acids and compounds A1-5 as raw materials and similar synthetic methods.
  • Step 3 (S)-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A52-4)
  • Step 4 (S)-2-bromo-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A52-5)
  • Step 5 (S)-2-(2,6-bis(trifluoromethyl)pyridin-4-yl)-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A52-6)
  • intermediate A52 was obtained by referring to a synthetic method similar to that of intermediate A1.
  • intermediates A53–A58, A65, and A66 were obtained using different arylboronic acids or borate esters and compound A52-5 as starting materials and similar synthetic methods.
  • intermediate A59-3 was synthesized from 4-bromo-3-fluoro-2-methylaniline. Using intermediate A59-3 as a raw material, intermediate A59-4 was obtained by following the synthesis steps of intermediate A1. Intermediate A59-4 was oxidized by a monopersulfate compound to obtain intermediate A59-5, and then cyclized by p-toluenesulfonic acid to obtain intermediate A59.
  • intermediate A60-1 was used as a raw material and methylated in the presence of methylboric acid, copper acetate and pyridine to obtain intermediate A61-1. Then, it was cyclized by p-toluenesulfonic acid to obtain intermediate A61.
  • Step 1 (S,E)-1-(1-cyano-2-phenylvinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B2a-2/B2b-2)
  • Step 2 1-(1-cyano-2-phenylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B2a-3)
  • Step 3 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-((Z)-N'-hydroxymethylamidinyl)-2-phenylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B2a-4)
  • Step 4 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2-phenylcyclopropyl)-N-phenyl-1H-indole-2-carboxamide (B2a-5)
  • Step 5 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2-phenylcyclopropyl)-1H-indole-2-carboxylic acid (B2a)
  • Step 1 (S)-1-(1-cyanovinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (B3-2)
  • Trimethyltin hydroxide (11.6 g, 63.9 mmol) was added to a toluene (50 mL) solution of compound B3-1 (5.0 g, 14.2 mmol), and the reaction mixture was refluxed and stirred overnight. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL ⁇ 3), water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL ⁇ 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid B3-2 (4.5 g). LC-MS: 323.1 ([MH] - ).
  • Step 2 ((S)-1-(1-cyanovinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3-3)
  • Step 3 1-(2,2-dichloro-1-cyanocyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3-4)
  • Step 4 1-(2,2-dichloro-1-((Z)-N'-hydroxyformamidinyl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3-5)
  • Step 5 1-(2,2-dichloro-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3a-6/B3b-6)
  • Step 6 1-(2,2-dichloro-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (B3a/B3b)
  • intermediate B3b was obtained by following the same experimental procedures.
  • Step 1 (S)-1-(1-cyano-2-(dimethylamino)vinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4-2)
  • Step 2 (S)-1-(1-cyano-2-hydroxyvinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4-3)
  • an aqueous hydrochloric acid solution (2N, 40 mL) was added to a tetrahydrofuran solution (140 mL) of compound B4-2 (14.0 g, 35.4 mmol), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with water (50 mL), extracted with ethyl acetate (70 mL ⁇ 3), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 3 (S)-1-(1-cyano-2-methoxyvinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4-4-1/B4-4-2)
  • trimethylsilyldiazomethane (10.2 g, 89.5 mmol) was added to a solution of compound B4-3 (11.0 g, 29.8 mmol) in dichloromethane (110 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (80 mL ⁇ 3). The organic phases were combined, washed with saturated brine (40 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 4 1-(1-cyano-2-methoxycyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4a-5/B4b-5/B4c-5/B4d-5)
  • Step 5 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-((E)-N'-hydroxyformamidinyl)-2-methoxycyclopropyl)-1H-indole-2-carboxylic acid ethyl ester (B4a-6)
  • Step 6 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methoxy-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid ethyl ester (B4a-7)
  • 1,8-diazabicyclo[5.4.0]undec-7-ene (585 mg, 3.8 mmol) and N,N'-carbonyldiimidazole (415 mg, 2.6 mmol) were added to a dimethyl sulfoxide (13 mL) solution of compound B4a-6 (550 mg, 1.3 mmol).
  • the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (25 mL) was added, and the mixture was extracted with ethyl acetate (10 mL ⁇ 3). The organic phases were combined, washed with saturated brine (10 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Step 7 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methoxy-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (B4a)
  • Lithium hydroxide (27 mg, 1.1 mmol) was added to a tetrahydrofuran/methanol/water (7 mL, 3/3/1) mixture of compound B4a-7 (250 mg, 0.55 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL ⁇ 3). The pH of the aqueous phase was adjusted to 6 with citric acid (5.0 mL), and the aqueous phase was extracted with ethyl acetate (15 mL ⁇ 3).
  • Step 2 7-Bromoindoleazine-2-carboxylic acid ethyl ester (B5-3)
  • trimethylchlorosilane (8.6 g, 78.81 mmol) and 1,2-dibromoethane (14.82 g, 78.81 mmol) were added to a solution of zinc powder (46.6 g, 716.42 mmol) in N,N-dimethylformamide (500 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (129.0 g, 537.31 mmol) in N,N-dimethylformamide (130 mL) was added to the mixture, and the mixture was stirred at room temperature for 20 minutes.
  • Step 4 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleazine-2-carboxylic acid ethyl ester (B5a-5)
  • Step 5 3-((1R,2S)-1-cyano-2-methylcyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleazine-2-carboxylic acid ethyl ester (B5a-6)
  • intermediate B5a was obtained by following the same experimental procedures as intermediate B4a.
  • intermediate B5b was obtained by following the same experimental procedures as intermediate B5a.
  • Step 1 (3aR,6aS)-Tetrahydrofurano[3,4-d][1,3,2]dioxathiacyclopentane 2,2-dioxide (B6-2)
  • thionyl chloride (1.7 g, 14.41 mmol) was added dropwise to a solution of compound B6-1 (1.0 g, 9.61 mmol) and triethylamine (3.9 g, 38.42 mmol) in dichloromethane (20 mL) and the mixture was stirred for 1 h. After the reaction was complete, the mixture was quenched with water (20 mL), extracted with dichloromethane (10 mL ⁇ 3), and the organic phases were combined and concentrated under reduced pressure.
  • Step 2 1-(6-cyano-3-oxabicyclo[3.1.0]hex-6-yl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B6-3)
  • Step 3 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-N-phenyl-1H-indole-2-carboxamide (B6-4)
  • Step 4 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1R,5S,6r)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-1H-indole-2-carboxylic acid (B6)
  • Step 1 1-[(1R,5S,6R)-6-cyano-3-thiabicyclo[3.1.0]hex-6-yl]-5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-2)
  • Step 2 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-6-(N'-hydroxyamidinyl)-3-thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-3)
  • Step 3 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-4)
  • N,N'-carbonyldiimidazole 334.9 mg, 2.06 mmol
  • 1,8-diazabicyclo[5.4.0]undec-7-ene 393.1 mg, 2.58 mmol
  • the reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, saturated brine (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL ⁇ 3).
  • Step 4 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-3,3-dioxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3 ⁇ 6 -thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-5)
  • Step 5 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-3,3-dioxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3 ⁇ 6 -thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid (B7)
  • Step 4 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxacyclohexane-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B8-6)
  • Step 5 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxacyclohexane-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B8-7)
  • Step 6 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxacyclohexane-4-yl)-1H-indole-2-carboxylic acid (B8)
  • Example 1 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-3-(3-(4-fluoro)-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1)
  • test compounds refer to the example compounds and control compounds in Table 4 of this invention.
  • Example A Measurement of in vitro cAMP signal activation by a compound
  • cAMP levels were detected using a stable human GLP-1R-expressing CHO-K1 cell line (DiscoverX, Cat#95-0062C2) and the Hithunter cAMP Assay kit (DiscoverX, Cat#90-0075SM2).
  • F12 Gibco, Cat#11765-054
  • FBS fetal bovine serum, Hyclone Cat#SH30406.05
  • 800 ⁇ g/ml G418 Gabco, Cat#10131-027
  • cAMP antibody reagent and working solution a mixture of 19 parts lysis buffer, 5 parts substrate reagent 1, 1 part substrate reagent 2, and 25 parts solution D (enzyme donor-labeled cAMP) and solution A (enzyme acceptor) were added, followed by incubation at room temperature in the dark.
  • Optical signal values were detected using a Spectramax id5 multimodal detection system (Molecular Devices, USA), and the corresponding EC50 values were calculated using GraphPad Prism 9 software.
  • the compounds of this invention exhibit potent h-GLP-1 agonist activity. Specifically, in the experiment stimulating cAMP production in the CHO-K1 cell line with hGLP-1R for 0.5 hours, the EC50 of the generated cAMP is shown in Table 5; in the experiment stimulating cAMP production in the CHO-K1 cell line with hGLP-1R for 2 hours, the EC50 of the generated cAMP is shown in Table 6.
  • mice Male C57BL/6J mice were administered the compound orally via gavage or intravenously, with 3 mice per compound. Animals were sourced from Shanghai Medicilon Biopharmaceutical Co., Ltd. Pharmacokinetic characteristics of the compound after oral (PO) or intravenous (IV) administration were tested using a standard protocol. The IV and PO solvents were 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline. A stock solution of the test compound was prepared and administered to 3 mice via single oral (2 mg/kg) gavage or intravenous (1 mg/kg) administration.
  • mice Male SD rats were administered the compound orally via gavage or intravenously, with 3 rats per compound. Animals were obtained from Shanghai Medicilon Biopharmaceutical Co., Ltd. The pharmacokinetic characteristics of the compound administered orally (PO) or intravenously (IV) in rats were tested using a standard protocol. The IV and PO solvents were 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline. A stock solution of the test compound was prepared and administered orally (2 mg/kg) to 3 mice via gavage at time points of 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration.
  • mice were administered a single intravenous injection (1 mg/kg) at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration.
  • Blood was collected via the jugular vein or other suitable vein, 0.2 mL per time point, anticoagulated with K2-EDTA, and placed on ice after collection. Blood samples were centrifuged within 1 hour after collection to obtain plasma (centrifugation conditions: 6800g, 6 minutes, 2-8°C). The samples to be tested were stored in a -80°C refrigerator before analysis.
  • Example D Pharmacokinetic Analysis of Compounds in Beagle Dog Plasma
  • Three male beagles were administered the compound via oral gavage or intravenous injection, respectively, at a rate of 3 dogs per compound.
  • Animals were sourced from Shanghai Medicilon Biopharmaceutical Co., Ltd.
  • the pharmacokinetic characteristics of the compound in the examples were tested in beagles following oral gavage (PO) or intravenous injection (IV) according to a standard protocol.
  • the solvents for IV and PO were: 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline.
  • test compound After preparing the test compound into a stock solution, three beagle dogs were given a single oral gavage (2 mg/kg) and blood samples were collected at time points of 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Three beagle dogs were also given a single intravenous injection (0.5 mg/kg) and blood samples were collected at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. Blood was collected via forelimb vein or other suitable vein, 1 mL/time point, anticoagulated with K2-EDTA. After collection, the samples were placed on ice. Plasma was obtained by centrifugation within 1 hour of collection (centrifugation conditions: 2200g, 10 minutes, 2-8°C). The test samples were stored at -80°C before analysis.
  • Example F Pharmacokinetic Analysis of the Compounds in Example Example in Mouse Plasma
  • mice Male C57BL/6J mice were administered the compound orally via gavage or intravenously, with 3 mice per compound per dose. Animals were sourced from Shanghai Medicilon Biopharmaceutical Co., Ltd. The pharmacokinetic characteristics of the compound after oral (PO) or intravenous (IV) administration were tested using a standard protocol.
  • IV solvent 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline; PO solvent: 10% PEG400 + 10% propylene glycol (PG) + 80% glycine buffer (100mM glycine, 64mM NaOH, pH 10). After preparing a stock solution of the test compound, each mouse was administered the compound individually.
  • the OGTT test or oral glucose tolerance test, can be used to test the metabolic level of blood glucose in the body and to screen for hypoglycemic drugs.
  • mice Male hGLP1R mice were randomly divided into five groups: a vehicle group (10 mL/kg, solvent: 10% PEG400 + 10% PG + 80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10)), a drug administration group (0.03 mg/kg or 0.1 mg/kg in the vehicle), and an Orforglipron group (0.03 mg/kg in the vehicle) (positive control). Mice were fasted overnight the day before treatment, but provided with ample water during the fasting period. On the day of treatment, mice were weighed using an electronic balance.
  • Blood glucose was measured at 0 h, followed by gavage administration of the treatment (vehicle, the compound described in the examples, or Orforglipron) at a volume of 10 mL/kg, based on body weight. Blood glucose was measured at 5 h, and immediately followed by gavage administration of a 20% glucose solution at a volume of 10 mL/kg, based on body weight. Blood glucose levels were measured and recorded at 15, 30, 60, and 120 min after glucose administration. Animals were fed again after the experiment. GraphPad Prism 10.2.1 was used to plot blood glucose changes over time and the area under the blood glucose-time curve from 0 to 120 min was calculated. The results are shown in Figure 1 and Table 9.
  • Table 9 Difference between the area under the blood glucose-time curve and the solvent group 5 h after administration of the compound in the examples (0.03 mg/kg) for OGTT. Note: The value in parentheses represents the area under the blood glucose-time curve 5 hours after the current orforglipron administration.
  • mice Male hGLP1R mice were randomly divided into five groups: a vehicle group (10 mL/kg, solvent: 10% PEG400 + 10% PG + 80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10)), a drug administration group (0.03 mg/kg or 0.1 mg/kg in the vehicle), and an Orforglipron group (0.03 mg/kg in the vehicle) (positive control). Mice were fasted overnight the day before treatment, but provided with ample water during the fasting period. On the day of treatment, mice were weighed using an electronic balance.
  • Blood glucose was measured at 0 h, followed by gavage administration of the treatment (vehicle, the compound described in the examples, or Orforglipron) at a volume of 10 mL/kg, based on body weight. Blood glucose was measured at 5 h, and immediately followed by gavage administration of a 20% glucose solution at a volume of 10 mL/kg, based on body weight. Blood glucose levels were measured and recorded at 15, 30, 60, and 120 min after glucose administration. After the experiment, the animals were fed again. Mice were fasted overnight the day before the next OGTT experiment, with ample water provided during the fasting period. Blood glucose was measured again at 48 or 96 hours post-treatment.
  • mice Immediately after treatment, mice were administered a 20% glucose solution via gavage at a volume of 10 mL/kg. Blood glucose levels were measured at 15, 30, 60, and 120 minutes post-glucose gavage.
  • GraphPad Prism 10.2.1 was used to plot blood glucose versus time curves, and the area under the blood glucose-time curve from 0 to 120 minutes was calculated. The results are shown in Figures 2.1 and 2.2.
  • the blood glucose AUC of mice in the following groups decreased by 49.63%, 46.20%, 42.61%, and 45.22%, respectively, in the groups treated with Compound 18 (0.03 mg/kg), Compound 22 (0.03 mg/kg), Compound 23 (0.03 mg/kg), and Orforglipron (0.03 mg/kg).
  • Compound 18 at the same dose showed a slightly better hypoglycemic effect than Orforglipron, while Compound 22 and Compound 23 at the same dose showed hypoglycemic effects comparable to Orforglipron.
  • the AUC of blood glucose in mice treated with Compound 18 (0.03 mg/kg), Compound 22 (0.03 mg/kg), Compound 23 (0.03 mg/kg), and Orforglipron (0.03 mg/kg) decreased by 31.05%, 28.08%, 5.91%, and 19.50%, respectively.
  • Compounds 18 and 22 at the same dose showed better hypoglycemic effects than Orforglipron, demonstrating a sustained hypoglycemic effect.
  • the blood glucose AUC of mice in the Compound 24 (0.03 mg/kg), Compound 52 (0.03 mg/kg), and Orforglipron (0.03 mg/kg) groups decreased by 34.93%, 29.91%, and 39.37%, respectively.
  • the hypoglycemic effects of Compound 24 and Compound 52 at 5 h post-administration were comparable to those of Orforglipron.
  • the blood glucose AUC of mice in the Compound 24 (0.03 mg/kg), Compound 52 (0.03 mg/kg), and Orforglipron (0.03 mg/kg) groups decreased by 23.86%, 27.40%, and 14.38%, respectively.
  • the hypoglycemic effects of Compound 24 and Compound 52 were better than those of Orforglipron, demonstrating the long-lasting hypoglycemic effect of the compounds of the present invention.
  • mice Male hGLP1R mice were fed a high-fat diet (D12492) and the experiment began when the average weight of the mice reached 51g. Before grouping, mouse baseline body weight was measured and mice were divided into five groups based on body weight: Vehicle group (solvent: 10% PEG400 + 10% PG + 80% glycine buffer (100mM glycine, 64mM NaOH, pH 10)), Example Compound 1 (Example 1, 1 mg/kg group, Example Compound 1, 5 mg/kg group, Orforglipron, 1 mg/kg group, Orforglipron, 5 mg/kg group). Mouse body weight and food intake were monitored daily. Administration was via gavage at a volume of 10 mL/kg, twice daily for 31 days.
  • Vehicle group solvent: 10% PEG400 + 10% PG + 80% glycine buffer (100mM glycine, 64mM NaOH, pH 10)
  • Example Compound 1 Example 1, 1 mg/kg group, Example Compound 1, 5 mg/kg group, Orforglipron, 1
  • test results showed that, at the same dosage, compound 1 of the example had a stronger appetite-suppressing and weight-reducing effect than Orforglipron.
  • mice OGTT and DIO model weight loss experiments show that, due to the innovative design of the parent nucleus structure, the compounds in the embodiments of the present invention exhibit a more sustained hypoglycemic effect, stronger appetite suppression, and more significant weight loss effect in vivo.

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Abstract

Provided are heterobicyclic compounds having glucagon-like peptide receptor (GLP-1R) agonist activity, preparation methods therefor, pharmaceutical compositions comprising same, and use thereof as GLP-1R agonists or for the treatment or prevention of GLP-1R-related diseases or disorders. The compounds can be used for weight management, for lowering blood sugar, and/or for treating or preventing diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver diseases (such as non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic diseases, cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis-related diseases or disorders, cancer, etc.

Description

可用作GLP-1R激动剂的杂双环化合物Heterocyclic compounds that can be used as GLP-1R agonists 发明领域Invention Field

本申请涉及具有胰高血糖素样肽受体(GLP-1R)激动剂活性的杂双环化合物、它们的制备方法、包含它们的药物组合物以及它们用作GLP-1R激动剂或者用于治疗或预防GLP-1R相关性疾病或紊乱的用途。特别地，本申请的化合物可用于体重管理、用于降血糖和/或用于治疗或预防糖尿病、糖尿病并发症、肥胖症、超重、血脂紊乱、脂肪肝疾病(例如非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH))、代谢性疾病、心血管疾病、神经系统障碍、精神障碍、肾脏疾病、胃肠疾病、自身免疫性疾病、炎性疾病、肺病、下丘脑-垂体-性腺轴相关性疾病或障碍、癌症等。This application relates to heterobicyclic compounds having glucagon-like peptide receptor (GLP-1R) agonist activity, methods for their preparation, pharmaceutical compositions comprising them, and their use as GLP-1R agonists or for the treatment or prevention of GLP-1R-related diseases or disorders. Specifically, the compounds of this application can be used for weight management, for lowering blood glucose and/or for the treatment or prevention of diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic diseases, cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders or disorders, cancer, etc.

发明背景Background of the Invention

胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)是一种由肠道L细胞分泌的肠促胰素，其能以葡萄糖浓度依赖性的方式促进胰岛β细胞分泌胰岛素。GLP-1受体(GLP-1R)广泛分布于中枢神经系统、心血管系统、肌肉、胃肠道等多个器官和组织。Glucagon-like peptide-1 (GLP-1) is an incretin secreted by intestinal L cells that stimulates insulin secretion from pancreatic β cells in a glucose concentration-dependent manner. GLP-1 receptors (GLP-1R) are widely distributed in multiple organs and tissues, including the central nervous system, cardiovascular system, muscles, and gastrointestinal tract.

GLP-1受体激动剂(GLP-1RA)是近年来的一类新型降糖药。其通过激活GLP-1R，以葡萄糖浓度依赖的方式抑制胰高糖素分泌和促进胰岛素分泌，从而发挥降低血糖的作用。GLP-1RA药物还能够改善胰岛素敏感性，促进肝糖原和肌糖原的生成，抑制肝糖原的输出，并增加脂肪细胞对葡萄糖的摄取。这些效应有助于改善机体对胰岛素的敏感性，进一步提高降糖效果和延缓糖尿病的发展。而且，GLP-1RA还作用于大脑的食欲调节中枢，抑制食欲，并且能够延迟胃排空、增加饱腹感。这有助于减少食物摄入，从而减少葡萄糖摄入，进一步发挥降糖作用。同时，通过减少食欲、延迟胃排空和增加饱腹感，GLP-1RA药物也有助于体重减轻。GLP-1 receptor agonists (GLP-1RAs) are a new class of hypoglycemic drugs developed in recent years. They lower blood sugar by activating GLP-1R, inhibiting glucagon secretion and promoting insulin secretion in a glucose concentration-dependent manner. GLP-1RAs also improve insulin sensitivity, promote the production of liver and muscle glycogen, inhibit liver glycogen output, and increase glucose uptake by adipocytes. These effects help improve the body's sensitivity to insulin, further enhancing the hypoglycemic effect and delaying the progression of diabetes. Furthermore, GLP-1RAs act on the appetite regulation center in the brain, suppressing appetite and delaying gastric emptying, increasing satiety. This helps reduce food intake, thereby reducing glucose intake and further enhancing the hypoglycemic effect. Simultaneously, by reducing appetite, delaying gastric emptying, and increasing satiety, GLP-1RAs also contribute to weight loss.

除了降低血糖和减轻体重，GLP-1RA药物还具有诸多临床益处，例如改善血脂紊乱、减轻脂肪肝、代谢获益、降低血压、心血管获益、肾脏获益、对胰岛β细胞的保护、胃肠道功能调节等。GLP-1RA药物可显著减少心血管事件的发生风险，延缓糖尿病性肾病的进展，改善糖尿病患者的远期预后。GLP-1RA药物已经成为糖尿病和减重的重要治疗手段。In addition to lowering blood sugar and reducing weight, GLP-1RA drugs offer numerous clinical benefits, such as improving dyslipidemia, reducing fatty liver, providing metabolic benefits, lowering blood pressure, providing cardiovascular benefits, providing renal benefits, protecting pancreatic β-cells, and regulating gastrointestinal function. GLP-1RA drugs can significantly reduce the risk of cardiovascular events, slow the progression of diabetic nephropathy, and improve the long-term prognosis of diabetic patients. GLP-1RA drugs have become an important treatment for diabetes and weight loss.

首款GLP-1RA药物，Exendin-4(艾塞那肽)，于2005年获批上市用于治疗糖尿病。随后，有多款GLP-1RA药物获批上市，例如诺和诺德的利拉鲁肽(liraglutide)和司美格鲁肽(Semaglutide)以及礼来的度拉糖肽(dulaglutide)和替尔泊肽(tirzepatide)。The first GLP-1RA drug, Exendin-4, was approved for the treatment of diabetes in 2005. Subsequently, several other GLP-1RA drugs were approved for marketing, such as Novo Nordisk's liraglutide and semaglutide, and Eli Lilly's dulaglutide and tirzepatide.

目前，对更多的有效且安全、可带来多种临床获益的GLP-1RA药物存在未被满足的需求。Currently, there is an unmet need for more effective and safe GLP-1RA drugs that can provide multiple clinical benefits.

发明内容Summary of the Invention

发明简述Invention Summary

本发明人出人意料地发现：本发明的化合物具有令人满意的GLP-1R激动活性，可用于调节、特别是激动GLP-1R活性或者用于治疗或预防GLP-1R相关性疾病或紊乱。特别地，本发明的化合物在降低血糖和减轻体重方面的功效是尤其令人满意的。The inventors have unexpectedly discovered that the compounds of this invention possess satisfactory GLP-1R agonist activity and can be used to regulate, particularly to activate, GLP-1R activity, or to treat or prevent GLP-1R-related diseases or disorders. In particular, the compounds of this invention are especially satisfactory in lowering blood sugar and reducing weight.

而且，本发明的化合物还显示出良好的体内和体外药代动力学性质，例如良好的溶解度和/或吸收、良好的代谢稳定性、改善的生物利用度、减少的副作用(例如低血糖的风险低)等。本发明的化合物能够以较长的时间间隔进行施用，这对于患者是便利的，并且有助于改善患者的依从性。本发明的化合物还具有良好的物理和/或化学稳定性，适合制备成符合药用的各种制剂。Furthermore, the compounds of the present invention exhibit favorable in vivo and in vitro pharmacokinetic properties, such as good solubility and/or absorption, good metabolic stability, improved bioavailability, and reduced side effects (e.g., low risk of hypoglycemia). The compounds of the present invention can be administered at longer intervals, which is convenient for patients and helps improve patient compliance. The compounds of the present invention also possess good physical and/or chemical stability, making them suitable for formulation into various pharmaceutically acceptable preparations.

因此，在第一方面，本发明提供了式(I)及其亚式的化合物或可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物。Therefore, in a first aspect, the present invention provides compounds of formula (I) and its subforms or pharmaceutically usable salts, tautomers, stereoisomers, isotope-labeled compounds or solvates.

在第二方面，本发明提供了包含式(I)及其亚式的化合物或可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物以及一种或多种可药用载体、稀释剂或赋形剂的药物组合物，In a second aspect, the present invention provides pharmaceutical compositions comprising compounds of formula (I) and its subforms, or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds or solvates, and one or more pharmaceutically acceptable carriers, diluents or excipients.

在第三方面，本发明提供了用于调节、特别是激活GLP-1R活性或者用于治疗或预防GLP-1R相关性疾病或紊乱的式(I)及其亚式的化合物或可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物或包含其的药物组合物。In a third aspect, the present invention provides compounds of formula (I) and its subforms, or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates, or pharmaceutical compositions comprising the same, for regulating, in particular activating, GLP-1R activity, or for treating or preventing GLP-1R-related diseases or disorders.

在第四方面，本发明提供了调节、特别是激活GLP-1R活性或者治疗或预防GLP-1R相关性疾病或紊乱的方法，该方法包括给所述个体施用有效量的式(I)及其亚式的化合物或可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物。In a fourth aspect, the present invention provides a method for regulating, in particular activating, GLP-1R activity or for treating or preventing GLP-1R-related diseases or disorders, the method comprising administering to the individual an effective amount of a compound of formula (I) and its subforms or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound or solvate.

在第五方面，本发明提供了式(I)及其亚式的化合物或可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物用作药物的用途或在制备药物中的用途，所述药物用于调节、特别是激活GLP-1R活性或者用于治疗或预防GLP-1R相关性疾病或紊乱。In a fifth aspect, the present invention provides the use of compounds of formula (I) and its subforms or pharmaceutically usable salts, tautomers, stereoisomers, isotopically labeled compounds or solvates as pharmaceuticals or in the preparation of pharmaceuticals, said pharmaceuticals being used to regulate, in particular to activate, GLP-1R activity or to treat or prevent GLP-1R-related diseases or disorders.

在第六方面，本发明提供了式(I)及其亚式的化合物或可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物与其它活性剂的组合。所述其它活性剂具有与本发明的化合物相同或不同的功效。In a sixth aspect, the present invention provides combinations of compounds of formula (I) and its subforms, or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates, with other active agents. These other active agents may have the same or different effects as the compounds of the present invention.

在第八方面，本发明提供了式(I)及其亚式的化合物或可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物的制备方法。In an eighth aspect, the present invention provides a method for preparing compounds of formula (I) and its subforms, or pharmaceutically usable salts, tautomers, stereoisomers, isotope-labeled compounds, or solvates.

本发明的上述和其它方面在下文进行了更详细的描述。The above and other aspects of the present invention are described in more detail below.

发明详述Invention Details

在一个方面，本发明提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
In one aspect, the present invention provides compounds of formula (I) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds or solvates thereof.

其中，in,

L1选自-CO-、-SO-、-SO2-、-NRa-和-CRaRb-； L1 is selected from -CO-, -SO-, -SO2- , -NRa- , and -CRaRb- ;

L2选自-RL-NRa-*、-RL-CO-NRa-*、-RL-NRa-CO-NRa-*、-RL-C(S)-NRa-*、-RL-NRa-C(S)-NRa-*，其中星号表示与中心环的N原子连接； L2 is selected from -R L -NR a -*, -R L -CO-NR a -*, -R L -NR a -CO-NR a -*, -R L -C(S)-NR a -*, -R L -NR a -C(S)-NR a -*, where the asterisk indicates a connection to the N atom of the central ring;

环A是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、和(任选被一个或多个独立地选自卤素和C1-6烷基取代的C3-10环烷基)-RL-，或者其中两个R3连同它们所连接的原子一起形成任选地含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基和C1-6羟基烷基的取代基取代；Ring A is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted with one or more R3s , each R3 independently selected from halogens, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyls independently selected from halogens and C1-6 alkyls) -RL- , or two of the R3s. 3 together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, said 4- to 6-membered ring optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl;

环B是亚萘基或8-10元双环亚杂芳基，各自任选被一个或多个R4取代，所述R4各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C3-10环烷基)-RL-、(5-10元杂环烷基)-RL-、(C6-10芳基)-RL-和(5-10元杂芳基)-RL-，其中所述环烷基、杂环烷基、芳基和杂芳基各自任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代；Cycle B is a naphthylene or an 8-10-membered bicyclic heteroarylene, each optionally substituted by one or more R4 groups, each R4 group being independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , (5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein each of the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups is optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy groups;

环C是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个取代基取代；任选地，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、-CONH2、-CONH(C1-6烷基)、-C(＝S)NH2、-C(＝S)NH(C1-6烷基)、-P(Ra)(Rb)(例如-PH2、-PH(C1-6烷基)、-PH(C1-6烷基)(C1-6烷基))、(例如-O-P(＝O)(OH)2、)、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(3-10元杂环烷基氧基)-RL-、(C6-10芳基)-RL-、(C6-10芳基氧基)-RL-、(C6-10芳基-C1-6亚烷基氧基)-RL-(例如苄氧基-RL-)、(5-10元杂芳基)-RL-、(5-10元杂芳基氧基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代；The ring C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents; optionally, each substituent is independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene , COOH, -CONH2 , -CONH( C1-6 alkyl), -C(=S) NH2 -C(＝S)NH(C 1-6 alkyl), -P( Ra )( Rb ) (e.g. -PH 2 , -PH(C 1-6 alkyl), -PH(C 1-6 alkyl)(C 1-6 alkyl)), (For example, -OP(＝O)(OH) 2 , ), C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 alkenyl-, ( C3-10 cycloalkyl)-C2-4 alkyne-, ( C3-10 cycloalkyloxy) -RL- , ( 3-10 heterocyclic alkyl) -RL- , ( 3-10 heterocyclic alkyloxy) -RL- , ( C6-10 aryl)-RL-, (C6-10 aryloxy) -RL- , ( C6-10 aryl- C1-6 alkyleneoxy) -RL- (e.g., benzyloxy - RL- ), ( 5-10 heteroaryl) -RL- , (5-10 heteroaryloxy) -RL- , NRsRt- ( CRaR b ) m- , NR a R b -CO- and R 6 , or two of these substituents together with the atoms to which they are attached, form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl and 5-7 heteroaryl;

环D是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基；Ring D is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl.

两个R1各自独立地是H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C2-6烯基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基；Each of the two R1s is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.

R2各自独立地选自H、卤素、氰基、OH、NRaRb、C1-6烷基、C2-6烯基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6卤代烷氧基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者其中两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2 is independently selected from H, halogen, cyano, OH, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 (C1-6 alkyl), -NR a -S(O) 2- (C1-6 alkyl ), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a )-(C 3-10 cycloalkyl) or -C(=O)-N( Ra )-(C 3-10 cycloalkyl), or where the two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C1-6 alkoxy )-RL-, ( C1-6 alkylthio)-RL-, (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy ) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkyl)-RL-, ( C6-10 aryl) -RL- and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic or bridged ring;

R6是含有一个或多个独立地选自N、O或S的杂原子的5-6元部分不饱和或芳族杂环； R6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或5-10元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, C <sub>1-6 </sub> haloalkyl, C <sub>6-10 </sub> aryl, or 5-10 heteroaryl;

RL各自独立地是价键；任选被卤素、氰基或羟基取代的C1-10亚烷基；或C1-4氘代亚烷基；R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;

T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;

Q为O或S；Q is either O or S;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2.

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，其中：环C是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(C6-10芳基)-RL-、(5-10元杂芳基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代；和其它变量如本文所定义，例如如上文所定义。In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided, wherein: the ring C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents, each substituent being independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylene group ... 1-6 haloalkanediols, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy)-RL-, (C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl)-C2-4 alkenyl- , ( C3-10 cycloalkyl) -C2-4 alkyne-, ( C3-10 cycloalkyloxy)-RL-, ( 3-10 heterocyclic alkyl) -RL- , (C6-10 aryl) -RL- , ( 5-10 heteroaryl) -RL- , NRsRt- ( CRaRb ) m- , NRaRb - CO- and R6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally substituted with one or more oxo groups, halogens, cyano groups, C Substituents of 1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl and 5-7 heteroaryl; and other variables as defined herein, such as those defined above.

在一些实施方案中，式(I)化合物具有式(I-1)、例如式(I-2)、式(I-3)或式(I-4)的结构：
In some embodiments, the compound of formula (I) has the structure of formula (I-1), such as formula (I-2), formula (I-3), or formula (I-4):

其中，各变量如本文所定义。The variables are as defined in this paper.

进一步地，本发明提供了式(II)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
Furthermore, the present invention provides compounds of formula (II) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.

其中，in,

L1选自-CO-、-SO-、-SO2-、-NRa-和-CRaRb-； L1 is selected from -CO-, -SO-, -SO2- , -NRa- , and -CRaRb- ;

L2选自-RL-NRa-*、-RL-CO-NRa-*、-RL-NRa-CO-NRa-*、-RL-C(S)-NRa-*、-RL-NRa-C(S)-NRa-*，其中星号表示与中心环的N原子连接； L2 is selected from -R L -NR a -*, -R L -CO-NR a -*, -R L -NR a -CO-NR a -*, -R L -C(S)-NR a -*, -R L -NR a -C(S)-NR a -*, where the asterisk indicates a connection to the N atom of the central ring;

环A是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-的取代基取代；Cycle A is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl , (optionally substituted with one or more C1-6 alkyl groups ) -R L- .

环B是亚萘基或8-10元双环亚杂芳基，各自任选被一个或多个各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-、(任选被一个或多个C1-6烷基取代的5-10元杂环烷基)-RL-、(任选被一个或多个C1-6烷基取代的C6-10芳基)-RL-、(任选被一个或多个C1-6烷基取代的5-10元杂芳基)-RL-的取代基取代；Cycle B is a naphthylene or an 8-10-membered bicyclic heteroaryl group, each optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups) -RL- .

环C是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基、5-10元杂芳基，各自任选被一个或多个各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、NRsRt-(CRaRb)m-或R6的取代基取代；The ring C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl, 5-10 heteroaryl, NR s R t -(CR a R b ) m - or R 6 ;

环D是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基、5-10元杂芳基；Ring D is C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl;

R1为H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C1-6烷基、C2-6烯基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基； R1 can be H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C1-6 alkyl, C2-6 alkenyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl ;

R2各自独立地选自H、卤素、氰基、OH、NRaRb、C1-6烷基、C2-6烯基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基、-P(O)(C1-6烷基)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、或-C(O)(C1-6烷基)，或者其中当存在两个以上R2时，两个R2与它们所连接的原子一起形成6元芳环或5-6元杂芳环，所述芳环或杂芳环任选被选自C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4卤代亚烷基)-、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4氰基亚烷基)-和(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4羟基亚烷基)-的取代基取代； R2 is independently selected from H, halogen, cyano, OH, NRaRb , C1-6 alkyl , C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), or -C(O)( C1-6 alkyl), or where , when there are two or more R2 , the two R2 together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, (optionally a C3-10 cycloalkyl substituted with one or more C1-6 alkyl) -RL - (optionally substituted with one or more C1-6 alkyl groups)-( C1-4 haloalkylene)-, (optionally substituted with one or more C1-6 alkyl groups)-( C1-4 cyanoalkylene)- and (optionally substituted with one or more C1-6 alkyl groups)-( C1-4 hydroxyalkylene)- substituents;

R6选自其中R6a是H或C1-6烷基；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或5-10元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, C <sub>1-6 </sub> haloalkyl, C <sub>6-10 </sub> aryl, or 5-10 heteroaryl;

RL各自独立地是价键或C1-10亚烷基；R and L are each independently valenced or C1-10 alkylene groups;

T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;

Q为O或S；Q is either O or S;

m是0、1、2、3、4或5；和m is 0, 1, 2, 3, 4, or 5; and

n是0、1或2。n is 0, 1, or 2.

在一些实施方案中，L1是-CO-。在一些实施方案中，L1是-SO-。在一些实施方案中，L1是-SO2-。在一些实施方案中，L1是-NRa-，例如-NH-或-N(C1-6烷基)-。在一些实施方案中，L1是-CRaRb-，例如-CH2-或-CH(C1-6烷基)-。In some embodiments, L1 is -CO-. In some embodiments, L1 is -SO-. In some embodiments, L1 is -SO2- . In some embodiments, L1 is -NRa- , such as -NH- or -N( C1-6 alkyl )-. In some embodiments, L1 is -CRaRb- , such as -CH2- or -CH( C1-6 alkyl)-.

在一些实施方案中，L2是在一些实施方案中，L2是在一些实施方案中，L2是-RL-NRa-*。在一些实施方案中，L2是-RL-CO-NRa-*。在一些实施方案中，L2是-RL-NRa-CO-NRa-*。在一些实施方案中，L2是-RL-C(S)-NRa-*。在一些实施方案中，L2是-RL-NRa-C(S)-NRa-*。星号表示与中心环的N原子连接。可以理解，当未标明星号时，L2可以通过任意端与中心环的N原子连接。In some implementations, L2 is In some implementations, L2 is In some implementations, L2 is -RL - NRa- *. In some implementations, L2 is -RL -CO- NRa- *. In some implementations, L2 is -RL- NRa - CO - NRa- *. In some implementations, L2 is -RL-C(S)-NRa-*. In some implementations, L2 is -RL -NRa - C (S) -NRa- * . The asterisk indicates a connection to the N atom of the central ring. It can be understood that when the asterisk is not marked, L2 can be connected to the N atom of the central ring through any end.

在一些实施方案中，L2是其中T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基，和Q为O或S。变量L2、T和Q进一步如下文所定义。In some implementations, L2 is Where T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the remainder of the molecule via two different ring carbon atoms, and Q is O or S. Variables L2 , T, and Q are further defined below.

R1 R 1

在一些实施方案中，R1各自独立地是H、卤素、氰基、羟基、NH2、NH(C1-6烷基)、N(C1-6烷基)2、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基。In some embodiments, R1 is independently H, halogen, cyano, hydroxyl, NH2 , NH ( C1-6 alkyl), N ( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.

在一些实施方案中，R1各自独立地是H、卤素、氰基、羟基、NH2、NH(C1-4烷基)、C1-6烷基、C1-6氘代烷基或C1-6卤代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基。In some embodiments, R1 is independently H, halogen, cyano, hydroxyl, NH2 , NH ( C1-4 alkyl), C1-6 alkyl, C1-6 deuterated alkyl, or C1-6 haloalkyl; or two R1 together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.

在一些实施方案中，两个R1之一为H且另一个是氰基、C1-6烷基或C1-6氘代烷基，优选氰基或C1-6烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基。In some embodiments, one of the two R1s is H and the other is cyano, C1-6 alkyl, or C1-6 deuterated alkyl, preferably cyano or C1-6 alkyl; or the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group.

在一些实施方案中，两个R1之一为H且另一个是氰基、C1-6烷基或C1-6氘代烷基，优选是氰基、C1-4烷基或C1-4氘代烷基，例如氰基、甲基或CD3。In some embodiments, one of the two R1s is H and the other is cyano, C1-6 alkyl, or C1-6 deuterated alkyl, preferably cyano, C1-4 alkyl, or C1-4 deuterated alkyl, such as cyano, methyl, or CD3 .

在一些实施方案中，两个R1之一为H且另一个是氰基或C1-6烷基，优选是氰基或C1-4烷基。In some embodiments, one of the two R1s is H and the other is cyano or C1-6 alkyl, preferably cyano or C1-4 alkyl.

在一些实施方案中，两个R1之一为H且另一个是C1-6烷基，优选C1-4烷基，例如甲基。In some embodiments, one of the two R1s is H and the other is a C1-6 alkyl, preferably a C1-4 alkyl, such as methyl.

在一些实施方案中，两个R1与它们所连接的碳原子一起形成C3-4环烷基，例如环丙基或环丁基。In some embodiments, the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group, such as cyclopropyl or cyclobutyl.

在一些实施方案中，R1为H。在一些实施方案中，R1为卤素，例如氟、氯、溴或碘。在一些实施方案中，R1为氰基。在一些实施方案中，R1为羟基或巯基。在一些实施方案中，R1为NRaRb，例如NH2、NH(C1-6烷基)或N(C1-6烷基)2。在一些实施方案中，R1为C1-6烷基，优选C1-4烷基，例如甲基。在一些实施方案中，R1为C2-6烯基。在一些实施方案中，R1为C1-6卤代烷基。在一些实施方案中，R1为C1-6氰基烷基。在一些实施方案中，R1为C1-6羟基烷基。在一些实施方案中，R1为C1-6烷氧基。在一些实施方案中，R1为C1-6烷硫基。在一些实施方案中，R1为C1-6卤代烷氧基。在一些实施方案中，R1为C3-8环烷基。进一步地，R1如下文所定义。In some embodiments, R1 is H. In some embodiments, R1 is a halogen, such as fluorine, chlorine, bromine, or iodine. In some embodiments, R1 is cyano. In some embodiments, R1 is hydroxyl or mercapto. In some embodiments, R1 is NR a R b , such as NH2 , NH ( C1-6 alkyl), or N ( C1-6 alkyl) 2 . In some embodiments, R1 is C1-6 alkyl, preferably C1-4 alkyl, such as methyl . In some embodiments, R1 is C2-6 alkenyl. In some embodiments, R1 is C1-6 haloalkyl. In some embodiments, R1 is C1-6 cyanoalkyl. In some embodiments, R1 is C1-6 hydroxyalkyl. In some embodiments, R1 is C1-6 alkoxy. In some embodiments, R1 is C1-6 alkylthio. In some embodiments, R1 is C1-6 haloalkoxy. In some embodiments, R1 is a C3-8 cycloalkyl group. Further, R1 is defined below.

环ARing A

在一些实施方案中，环A是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基(例如单环或双环)，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6氰基烷基、(C3-10环烷基)-RL-和(C3-10卤代环烷基)-RL-，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自卤素、氰基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基和C1-6氰基烷基的取代基取代。In some embodiments, ring A is a C6-10 aryl or a 5-10 membered heteroaryl (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each R3 independently selected from halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- and ( C3-10 halocycloalkyl) -RL- , or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with substituents selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, and C1-6 cyanoalkyl.

在一些实施方案中，环A是苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基(例如单环或双环)，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代。In some embodiments, ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens.

在一些实施方案中，环A是苯基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、吡唑并吡啶基、吡咯并吡啶基、苯并呋喃基、异苯并呋喃基、苯并噻吩基或嘌呤基，优选苯基、吡唑基、吡啶基或苯并呋喃基，更优选苯基或苯并呋喃基，各自任选被一个或多个如本文所定义的R3取代。优选地，R3各自独立地选自卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6氰基烷基、(C3-10环烷基)-RL-和(C3-10卤代环烷基)-RL-，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自卤素、氰基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基和C1-6氰基烷基的取代基取代。更优选地，R3各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代。在一些实施方案中，R3各自独立地选自卤素(例如F)、C1-6烷基(例如甲基)和C1-6卤代烷基(例如CF3)。In some embodiments, ring A is phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, inzozolyl, benzimidazolyl, pyrazolopyridyl, pyrrolopyridyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, or purine, preferably phenyl, pyrazolyl, pyridyl, or benzofuranyl, more preferably phenyl or benzofuranyl, each optionally substituted with one or more R 3 as defined herein. Preferably, each of the R3s is independently selected from halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- and ( C3-10 halocycloalkyl) -RL- , or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, wherein the 4- to 6-membered ring is optionally substituted with a substituent selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl and C1-6 cyanoalkyl. More preferably, each of R3 is independently selected from halogens, cyano groups, C1-6 alkyl groups, C1-6 haloalkyl groups, and C3-6 cycloalkyl groups, or two of R3 groups, together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally substituted with one or more halogens or cyano groups, preferably halogens. In some embodiments, each of R3 is independently selected from halogens (e.g., F), C1-6 alkyl groups (e.g., methyl), and C1-6 haloalkyl groups (e.g., CF3 ).

在一些实施方案中，环A是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基，优选苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基，更优选是C6-10芳基，例如C6芳基(即苯基)，任选被一个或多个各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-的取代基取代。In some embodiments, ring A is a C6-10 aryl or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S, preferably phenyl or a 5-7 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S, more preferably a C6-10 aryl, such as a C6 aryl (i.e., phenyl), optionally substituted with one or more substituents each independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( optionally C3-10 cycloalkyl substituted with one or more C1-6 alkyl)-R L- .

在一些实施方案中，环A是其中R3a、R3b和R3c如对R3所定义，任选地如下文所定义。In some implementations, ring A is R3a , R3b and R3c are as defined for R3 , and optionally as defined below.

在一些实施方案中，环A选自：
In some implementations, ring A is selected from:

环BRing B

在一些实施方案中，环B是8-10元双环亚杂芳基，例如含有一个或多个独立地选自N、O或S的杂原子的8-10元双环亚杂芳基，任选被一个或多个如本文所定义的R4取代。In some embodiments, ring B is an 8-10 membered bicyclic heteroaryl group, such as an 8-10 membered bicyclic heteroaryl group containing one or more heteroatoms independently selected from N, O or S, optionally substituted with one or more R 4 as defined herein.

在一些实施方案中，环B是其中1位与L1连接，2位与环C连接，和其中W1、W2、W3、W4、W5、W6和W7各自独立地是C、CH或N，且其中至少一者是N；和R4如本文所定义。本领域技术人员可以理解，表示该价键可以是单键或双键。In some implementation schemes, ring B is One bit is connected to L1 , two bits are connected to ring C, and W1 , W2 , W3 , W4 , W5 , W6 , and W7 are each independently C, CH, or N, with at least one of them being N; and R4 is as defined herein. Those skilled in the art will understand that... This indicates that the valence bond can be a single bond or a double bond.

在一些实施方案中，环B是其中1位与L1连接，2位与环C连接，和其中W1、W2、W3、W4、W5、W6和W7各自独立地是C、CH或N，且其中至少一者是N；和R4如本文所定义。In some implementation schemes, ring B is One bit is connected to L1 , two bits are connected to ring C, and W1 , W2 , W3 , W4 , W5 , W6 and W7 are each independently C, CH or N, and at least one of them is N; and R4 is as defined herein.

在一些实施方案中，环B表示优选其中1位与L1连接，2位与环C连接，和其中W1、W2、W3、W4和W5(当存在时)各自独立地是C、CH或N，且其中至少一者是N；和R4如本文所定义。任选地，在一些实施方案中，W1为N，且其余各自独立地是C或CH。在另一些实施方案中，W3为N，且其余各自独立地是C或CH。在另一些实施方案中，W5为N，且其余各自独立地是C或CH。In some implementations, ring B represents Preferred One bit is connected to L1 , two bits are connected to ring C, and W1 , W2 , W3 , W4 , and W5 (if present) are each independently C, CH, or N, with at least one being N; and R4 is as defined herein. Optionally, in some embodiments, W1 is N, and the rest are each independently C or CH. In other embodiments, W3 is N, and the rest are each independently C or CH. In still other embodiments, W5 is N, and the rest are each independently C or CH.

在一些实施方案中，环B是其中1位与L1连接，2位与环C连接，和其中W1是C、CH或N，W8是CH2、NH、O或S，和R4如本文所定义。In some implementation schemes, ring B is One bit is connected to L1 , two bits are connected to ring C, and W1 is C, CH or N, W8 is CH2 , NH, O or S, and R4 is as defined herein.

在一些实施方案中，环B表示 优选是其中1位与L1连接，2位与环C连接，和R4如本文所定义。In some implementations, ring B represents Preferred is One bit is connected to L1 , two bits are connected to ring C, and R4 is as defined in this paper.

在一些实施方案中，环B是8-10元双环亚杂芳基，任选被一个或多个各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-、(任选被一个或多个C1-6烷基取代的5-10元杂环烷基)-RL-、(任选被一个或多个C1-6烷基取代的C6-10芳基)-RL-、(任选被一个或多个C1-6烷基取代的5-10元杂芳基)-RL-的取代基取代。In some embodiments, ring B is an 8-10-membered bicyclic heteroaryl group, optionally substituted with one or more substituents each independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups) -RL- , (optionally substituted with one or more C1-6 alkyl groups)-RL-, (optionally substituted with one or more C1-6 alkyl groups) -RL- .

在一些实施方案中，环B选自：
In some implementation schemes, ring B is selected from:

其中，1位与L1连接，2位与环C连接。Of these, bit 1 is connected to L1 , and bit 2 is connected to ring C.

环CRing C

在一些实施方案中，环C是C3-10环烷基或3-10元杂环烷基，优选C3-6环烷基或3-6元杂环烷基，更优选C3-6环烷基，各自任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、-CONH2、-CONH(C1-6烷基)、-C(＝S)NH2、-C(＝S)NH(C1-6烷基)、-P(Ra)(Rb)(例如-PH2、-PH(C1-6烷基)、-PH(C1-6烷基)(C1-6烷基))、(例如-O-P(＝O)(OH)2、)、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(3-10元杂环烷基氧基)-RL-、(C6-10芳基)-RL-、(C6-10芳基氧基)-RL-、(C6-10芳基-C1-6亚烷基氧基)-RL-(例如苄氧基-RL-)、(5-10元杂芳基)-RL-、(5-10元杂芳基氧基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代。In some embodiments, the cyclic C is a C3-10 cycloalkyl or a 3-10 membered heterocyclic alkyl, preferably a C3-6 cycloalkyl or a 3-6 membered heterocyclic alkyl, more preferably a C3-6 cycloalkyl, each optionally substituted by one or more substituents, each substituent being independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, -CONH2 , -CONH( C1-6 alkyl), -C(=S) NH2 , -C(=S)NH( C 1-6 alkyl), -P( Ra )( Rb ) (e.g., -PH2 , -PH( C1-6 alkyl), -PH( C1-6 alkyl)( C1-6 alkyl)), (For example, -OP(＝O)(OH) 2 , ), C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 alkenyl-, ( C3-10 cycloalkyl)-C2-4 alkyne-, ( C3-10 cycloalkyloxy) -RL- , ( 3-10 heterocyclic alkyl) -RL- , ( 3-10 heterocyclic alkyloxy) -RL- , ( C6-10 aryl)-RL-, (C6-10 aryloxy) -RL- , ( C6-10 aryl- C1-6 alkyleneoxy) -RL- (e.g., benzyloxy - RL- ), ( 5-10 heteroaryl) -RL- , (5-10 heteroaryloxy) -RL- , NRsRt- ( CRaR b ) m- , NR a R b -CO- and R 6 , or two of these substituents together with the atoms to which they are attached, form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl and 5-7 heteroaryl.

在一些实施方案中，环C是C3-10环烷基或3-10元杂环烷基，优选C3-6环烷基或3-6元杂环烷基，更优选C3-6环烷基，各自任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(C6-10芳基)-RL-、(5-10元杂芳基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代。In some embodiments, the cyclic C is a C3-10 cycloalkyl or a 3-10 membered heterocyclic alkyl, preferably a C3-6 cycloalkyl or a 3-6 membered heterocyclic alkyl, more preferably a C3-6 cycloalkyl, each optionally substituted with one or more substituents, each substituent being independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylene group, C1-6 haloalkylene group, COOH, C1-6 alkoxy-CO-, (C1-6 haloalkoxy) -RL- , ( C1-6 alkylene group optionally substituted with halogen or hydroxyl ) (3-10 cycloalkyl) -RL- , (C 3-10 cycloalkyl)-C 2-4 alkenyl-, (C 3-10 cycloalkyl)-C 2-4 alkyne-, (C 3-10 cycloalkyloxy)-RL-, (3-10 heterocyclic alkyl) -RL- , (C 6-10 aryl)-RL-, (5-10 heteroaryl) -RL- , NR s R t -(CR a R b ) m- , NR a R b -CO- and R 6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being formed by one or more of oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 heterocyclic alkyl, C Substituents of 6-10 aryl and 5-7 heteroaryl groups.

在一些实施方案中，环C是C3-6环烷基，例如环丙基、环丁基或环戊基，任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基和5-7元杂芳基的取代基取代。In some embodiments, the cyclic C is a C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, optionally substituted with one or more substituents, each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, (C1-6 haloalkoxy ) -RL- , ( C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 ynylene-, (C ( 3-10 cycloalkyloxy) -RL- , ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- and R6 , or two of these substituents together with the atoms to which they are attached, form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano and 5-7 membered heteroaryl.

在一些实施方案中，环C是C3-6环烷基，例如环丙基、环丁基或环戊基，任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代。In some embodiments, the ring C is a C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, optionally substituted with one or more substituents, each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl , COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- , and R6, or two of the substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, the ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups.

在一些实施方案中，环C是C3-10环烷基、C3-10环烯基、3-10元杂环烷基或3-10元杂环烯基，优选是C3-6环烷基或3-6元杂环烷基，更优选是C3-6环烷基，各自任选被一个或多个各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、C3-10环烷基、3-10元杂环烷基、C6-10芳基、5-10元杂芳基、NRsRt-(CRaRb)m-或R6的取代基取代。In some embodiments, the cyclic C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, or 3-10 heterocyclic alkenyl, preferably a C3-6 cycloalkyl or 3-6 heterocyclic alkyl, more preferably a C3-6 cycloalkyl, each optionally substituted by one or more substituents independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl, 5-10 heteroaryl, NR s R t -(CR a R b ) m - or R 6 .

在一些实施方案中，环C表示其中各变量如本文所定义，任选地如下文所定义。In some implementations, ring C represents The variables are defined as described in this paper, and optionally as described below.

在一些实施方案中，环C表示其中X是-C(Rx1)(Rx2)-、-NRx1-、-O-、-S-、-SO-或-SO2-，其中Rx1和Rx2各自独立地选自H、卤素、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基或5-10元杂芳基。优选地，X是-C(Rx1)(Rx2)-、-NRx1-、-O-、-S-、-SO-或-SO2-，其中Rx1和Rx2各自独立地选自H、卤素或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基。In some implementations, ring C represents Wherein X is -C(R x1 )(R x2 )-, -NR x1- , -O-, -S-, -SO-, or -SO 2- , wherein R x1 and R x2 are each independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl, or 5-10 heteroaryl. Preferably, X is -C(R x1 )(R x2 )-, -NR x1- , -O-, -S-, -SO-, or -SO 2- , wherein R x1 and R x2 are each independently selected from H, halogen, or a 5-7 heteroaryl containing one or more heteroatoms independently selected from N, O, or S.

在一些实施方案中，环C选自：
In some implementations, ring C is selected from:

其中R6如本文所定义，任选地如下文所定义。 R6 is defined as in this document, and optionally as defined below.

环D和R2 Ring D and R 2

在一些实施方案中，环D是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基，优选苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基，更优选是苯基。在一些实施方案中，环D是苯基或含有一个或多个N杂原子的5-6元杂芳基。在一些实施方案中，环D可以选自苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基，优选是苯基或吡啶基。In some embodiments, ring D is a C6-10 aryl group or a 5-10 heteroaryl group containing one or more heteroatoms independently selected from N, O, or S, preferably phenyl or a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O, or S, more preferably phenyl. In some embodiments, ring D is a phenyl group or a 5-6 heteroaryl group containing one or more N heteroatoms. In some embodiments, ring D may be selected from phenyl, pyridyl, pyridinyl, pyrimidinyl, pyrazinyl, preferably phenyl or pyridinyl.

在一些实施方案中，R2各自独立地选自H、卤素、氰基、NRaRb、C1-6烷基、C1-6卤代烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者两个R2与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环。In some embodiments, R2 is independently selected from H, halogen, cyano , NRaRb , C1-6 alkyl, C1-6 haloalkyl, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)(C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NRa-S(O) 2- ( C1-6 alkyl), -C (O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl ), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl) or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or two R2 groups. 2. Together with the atoms to which they are attached, they form 5-6 member saturated, partially unsaturated, or aromatic heterocycles, wherein the rings are optionally substituted with substituents selected from: halogen, oxo, (NR a R b ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy)-RL-, ( C1-6 alkylthio) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy) -RL- , ( 3-10 member heterocyclic alkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 haloalkyl) -RL- , and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl is a monocyclic, bicyclic, spirocyclic, or bridged ring.

在一些实施方案中，R2各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环。In some embodiments, R2 is independently selected from H, halogen , NRaRb , C1-6 alkyl, 5-10 membered heteroaryl optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa- S (O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, (C (1-6 alkoxy) -RL- , (C 3-10 cycloalkyl)-RL-, ( 3-10 heterocyclic alkyl) -RL- , and (C 6-10 aryl) -RL- , wherein the C 3-10 cycloalkyl is a monocyclic, bicyclic, spirocyclic, or bridged ring.

在一些实施方案中，可以选自： 优选是 优选是 In some implementation schemes, You can choose from: Preferred is Preferred is

其中，R2’选自H、氧代基、卤素、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(C3-10环烷基)-RL-和(3-10元杂环烷基)-RL-和C6-10芳基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代，和其中所述环烷基是单环、双环、螺环或桥环的；和R2c是H、卤素或C1-6烷基。优选地，R2’是C1-6烷基、C1-6氘代烷基、(C1-6烷氧基)-RL-、(C3-6环烷基)-RL-和(3-8元杂环烷基)-RL-，其中所述环烷基任选被一个或多个卤素取代；和R2c是H或卤素。Wherein, R2 ' is selected from H, oxo, halogen, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl) -RL- and (3-10 heterocyclic alkyl) -RL- and C6-10 aryl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from halogen or C1-6 alkoxy, and wherein the cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged; and R2c is H, halogen or C1-6 alkyl. Preferably, R2 ' is a C1-6 alkyl, C1-6 deuterated alkyl, ( C1-6 alkoxy) -RL- , ( C3-6 cycloalkyl) -RL- , and (3-8 heterocyclic alkyl) -RL- , wherein the cycloalkyl is optionally substituted with one or more halogens; and R2c is H or a halogen.

在一些实施方案中，是其中R2a、R2b和R2c如对R2所定义，任选地如下文所定义。In some implementation schemes, yes R2a , R2b and R2c are as defined for R2 , and optionally as defined below.

在一些实施方案中，可以选自：

In some implementation schemes, You can choose from:

在一些实施方案中，R2各自独立地选自-P(O)(C1-6烷基)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)或-C(O)(C1-6烷基)，优选是-P(O)(C1-6烷基)(C1-6烷基)。In some embodiments, R2 is independently selected from -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl) or -C(O)( C1-6 alkyl), preferably -P(O)( C1-6 alkyl)( C1-6 alkyl).

在一些实施方案中，当存在两个以上R2时，两个R2与它们所连接的原子一起形成6元芳环或5-6元杂芳环、优选5-6元杂芳环，所述芳环或杂芳环任选被选自C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4卤代亚烷基)-、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4氰基亚烷基)-和(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4羟基亚烷基)-的取代基取代。优选地，所述芳环或杂芳环任选被选自C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4卤代亚烷基)-、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4氰基亚烷基)-和(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4羟基亚烷基)-的取代基取代。更优选地，所述芳环或杂芳环任选被选自C1-6烷基、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-RL-、(任选被一个或多个C1-6烷基取代的C3-10环烷基)-(C1-4卤代亚烷基)-的取代基取代。In some embodiments, when there are two or more R2s , the two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6-membered heteroaromatic ring, preferably a 5-6-membered heteroaromatic ring, wherein the aromatic ring or heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-R L- , ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 haloalkylene)-, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 cyanoalkylene)-, and ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 hydroxyalkylene)-. Preferably, the aromatic or heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 haloalkylene)-, ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 cyanoalkylene)-, and ( C3-10 cycloalkyl optionally substituted with one or more C1-6 alkyl)-( C1-4 hydroxyalkylene)-. More preferably, the aromatic ring or heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, (optionally C3-10 cycloalkyl substituted with one or more C1-6 alkyl) -RL- , (optionally C3-10 cycloalkyl substituted with one or more C1-6 alkyl)-( C1-4 haloalkylene)-.

上述各个实施方案及其每个特征以及下文的各个实施方案及其每个特征以及定义可以任意地组合，构成未在说明书中直接记载、但是符合本发明宗旨的实施方案，这些实施方案也囊括在本发明的范围内。The above-described embodiments and their respective features, as well as the embodiments and their respective features and definitions described below, can be arbitrarily combined to constitute embodiments not directly described in the specification but conforming to the spirit of the invention, and these embodiments are also included within the scope of the invention.

因此，在一些实施方案中，本发明提供了式(III)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
Therefore, in some embodiments, the present invention provides compounds of formula (III) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.

其中：in:

W1、W2、W3、W4和W5各自独立地是C、CH或N，其中W1、W2、W3、W4和W5中至少一者是N； W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;

表示单键或双键； Indicates a single bond or a double bond;

T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;

Q为O或S；Q is either O or S;

R1各自独立地是H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C2-6烯基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms they are attached to form a C3-4 cycloalkyl group.

R2a、R2b和R2c各自独立地是H、卤素、氰基、OH、NRaRb、C1-6烷基、C2-6烯基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6卤代烷氧基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2a , R2b , and R2c are each independently H, halogen, cyano, OH, NR a , R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NR a -S(O) 2- ( C1-6 alkyl), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a) R2a , R2b, or R2b together with the atoms they are attached to form a 6- membered aromatic ring or a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from the following : halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, (C1-6 alkoxy)-RL-, (C1-6 alkylthio)-RL-, (C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy ) -RL- , ( optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy)-RL-, ( C6-10 aryl) -RL- and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic or bridged ring;

R3a、R3b和R3c各自独立地选自H、卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、和(任选被一个或多个独立地选自卤素和C1-6烷基取代的C3-10环烷基)-RL-，或者R3a、R3b连同它们所连接的原子一起形成任选地含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基和C1-6羟基烷基的取代基取代； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyl atoms independently selected from halogen and C1-6 alkyl) -RL- , or R3a and R3b together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally selected from one or more heteroatoms independently selected from halogen, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl, C2-6 alkyl, C3-10 cycloalkyl, C3-10 ... Substitution of 1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl groups;

R4为卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C3-10环烷基)-RL-、(5-10元杂环烷基)-RL-、(C6-10芳基)-RL-和(5-10元杂芳基)-RL-，其中所述环烷基、杂环烷基、芳基和杂芳基各自任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代； R4 is a halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , ( 5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy.

R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、-CONH2、-CONH(C1-6烷基)、-C(＝S)NH2、-C(＝S)NH(C1-6烷基)、-P(Ra)(Rb)(例如-PH2、-PH(C1-6烷基)、-PH(C1-6烷基)(C1-6烷基))、(例如-O-P(＝O)(OH)2、)、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(3-10元杂环烷基氧基)-RL-、(C6-10芳基)-RL-、(C6-10芳基氧基)-RL-、(C6-10芳基-C1-6亚烷基氧基)-RL-(例如苄氧基-RL-)、(5-10元杂芳基)-RL-、(5-10元杂芳基氧基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-；或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, -CONH2, -CONH( C1-6 alkyl ) , -C(=S) NH2 , -C(=S)NH( C1-6 alkyl), -P(Ra)( Rb ) (e.g. , -PH2 , -PH( C1-6 alkyl ), -PH(C... 1-6 alkyl)(C 1-6 alkyl) (For example, -OP(＝O)(OH) 2 , ), C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 alkenyl-, ( C3-10 cycloalkyl)-C2-4 alkyne-, ( C3-10 cycloalkyloxy) -RL- , ( 3-10 heterocyclic alkyl) -RL- , ( 3-10 heterocyclic alkyloxy) -RL- , ( C6-10 aryl)-RL-, (C6-10 aryloxy) -RL- , ( C6-10 aryl- C1-6 alkyleneoxy) -RL- (e.g., benzyloxy - RL- ), ( 5-10 heteroaryl) -RL- , (5-10 heteroaryloxy) -RL- , NRsRt- ( CRaR b ) m- , NR a R b -CO-; or two of R 5a , R 5b , R 5c and R 5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 heterocyclic alkyl, C 6-10 aryl and 5-7 heteroaryl;

R6是含有一个或多个独立地选自N、O或S的杂原子的5-6元部分不饱和或芳族杂环；R 6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或5-10元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, C <sub>1-6 </sub> haloalkyl, C <sub>6-10 </sub> aryl, or 5-10 heteroaryl;

RL各自独立地是价键；任选被卤素、氰基或羟基取代的C1-10亚烷基；或C1-4氘代亚烷基；R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。优选地，在一些实施方案中，W1为N，且W2、W3、W4和W5为C或CH；在另一些实施方案中，W3为N，且W1、W2、W4和W5为C或CH；在另一些实施方案中，W5为N，且W1、W2、W3和W4为C或CH。q is 0, 1, 2, or 3, preferably 1 or 2. Preferably, in some embodiments, W1 is N, and W2 , W3 , W4 , and W5 are C or CH; in other embodiments, W3 is N, and W1 , W2 , W4 , and W5 are C or CH; in still other embodiments, W5 is N, and W1 , W2 , W3 , and W4 are C or CH.

在一些实施方案中，本发明提供了式(III-1)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
In some embodiments, the present invention provides compounds of formula (III-1) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.

其中：in:

W1、W2、W3、W4和W5各自独立地是C、CH或N，其中W1、W2、W3、W4和W5中至少一者是N； W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;

T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;

Q为O或S；Q is either O or S;

R1各自独立地是H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C2-6烯基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms they are attached to form a C3-4 cycloalkyl group.

R2a、R2b和R2c各自独立地是H、卤素、氰基、OH、NRaRb、C1-6烷基、C2-6烯基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6卤代烷氧基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2a , R2b , and R2c are each independently H, halogen, cyano, OH, NR a , R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NR a -S(O) 2- ( C1-6 alkyl), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a) R2a , R2b, or R2b together with the atoms they are attached to form a 6- membered aromatic ring or a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from the following : halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, (C1-6 alkoxy)-RL-, (C1-6 alkylthio)-RL-, (C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy ) -RL- , ( optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy)-RL-, ( C6-10 aryl) -RL- and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic or bridged ring;

R3a、R3b和R3c各自独立地选自H、卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、和(任选被一个或多个独立地选自卤素和C1-6烷基取代的C3-10环烷基)-RL-，或者R3a、R3b连同它们所连接的原子一起形成任选地含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基和C1-6羟基烷基的取代基取代； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyl atoms independently selected from halogen and C1-6 alkyl) -RL- , or R3a and R3b together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally selected from one or more heteroatoms independently selected from halogen, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl, C2-6 alkyl, C3-10 cycloalkyl, C3-10 ... Substitution of 1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl groups;

R4为卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C3-10环烷基)-RL-、(5-10元杂环烷基)-RL-、(C6-10芳基)-RL-和(5-10元杂芳基)-RL-，其中所述环烷基、杂环烷基、芳基和杂芳基各自任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代； R4 is a halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , ( 5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy.

R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(C6-10芳基)-RL-、(5-10元杂芳基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-；或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl ) -C2-4 alkenyl-, (C (3-10 cycloalkyl)-C 2-4 ynynyl-, (C 3-10 cycloalkyloxy) -RL- , (3-10 heterocyclic alkyl) -RL- , (C 6-10 aryl)-RL-, (5-10 heteroaryl) -RL- , NR s R t- ( CR a R b ) m- , NR a R b -CO-; or two of R 5a , R 5b , R 5c and R 5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally substituted by one or more substituents selected from oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 heterocyclic alkyl, C 6-10 aryl and 5-7 heteroaryl;

R6是含有一个或多个独立地选自N、O或S的杂原子的5-6元部分不饱和或芳族杂环；R 6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或5-10元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, C <sub>1-6 </sub> haloalkyl, C <sub>6-10 </sub> aryl, or 5-10 heteroaryl;

RL各自独立地是价键；任选被卤素、氰基或羟基取代的C1-10亚烷基；或C1-4氘代亚烷基；R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。优选地，在一些实施方案中，W1为N，且W2、W3、W4和W5为C或CH；在另一些实施方案中，W3为N，且W1、W2、W4和W5为C或CH；在另一些实施方案中，W5为N，且W1、W2、W3和W4为C或CH。q is 0, 1, 2, or 3, preferably 1 or 2. Preferably, in some embodiments, W1 is N, and W2 , W3 , W4 , and W5 are C or CH; in other embodiments, W3 is N, and W1 , W2 , W4 , and W5 are C or CH; in still other embodiments, W5 is N, and W1 , W2 , W3 , and W4 are C or CH.

在一些实施方案中，本发明提供了式(IV)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
In some embodiments, the present invention provides compounds of formula (IV) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.

其中：in:

W1、W2、W3、W4各自独立地是C、CH或N，其中W1、W2、W3、W4中至少一者是N； W1 , W2 , W3 , and W4 are each independently C, CH, or N, and at least one of W1 , W2 , W3 , and W4 is N;

T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms;

Q为O或S；Q is either O or S;

R1为H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C1-6卤代烷基、C1-6氰基烷基或C1-6羟基烷基； R1 is H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, or C1-6 hydroxyalkyl;

R2a和R2b之一为-P(O)(C1-6烷基)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、或-C(O)(C1-6烷基)，且另一个为H、卤素、氰基、OH、NRaRb或C1-6烷基；或者R2a和R2b与它们所连接的碳原子一起形成5或6元杂芳环，所述杂芳环任选被选自C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、C3-8环烷基-(C1-4卤代亚烷基)-、C3-8环烷基-(C1-4氰基亚烷基)-和C3-8环烷基-(C1-4羟基亚烷基)-的取代基取代；One of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), or -C(O)( C1-6 alkyl), and the other is H, halogen, cyano, OH, NR a R b , or C1-6 alkyl; or R2a and R2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaryl ring, said heteroaryl ring optionally selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, C3-8 cycloalkyl-( C1-4 haloalkylene)-, C3-8 cycloalkyl-( C1-4 cyanoalkylene)-, and C3-8 cycloalkyl-(C1-6 alkylene)-. Substitution of 1-4- hydroxyalkylene groups;

R2c为H、卤素、氰基、羟基或NRaRb； R2c can be H, halogen, cyano, hydroxyl, or NR a Rb ;

R3a、R3b和R3c各自独立地选自H、卤素、氰基、羟基、NRaRb、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, and C3-8 cycloalkyl- ( C1-4 alkylene)-.

R4为4至8元杂环烷基或5-10元杂芳基，任选被一个或多个C1-6烷基取代； R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 10-membered heteroaryl, optionally substituted with one or more C1-6 alkyl groups;

R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、C6-10芳基、5-10元杂芳基或NRsRt-(CRaRb)m-； R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy - CO-, C6-10 aryl, 5-10 heteroaryl, or NRsRt- ( CRaRb ) m- ;

R6选自其中R6a是H或C1-6烷基；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或5-10元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, C <sub>1-6 </sub> haloalkyl, C <sub>6-10 </sub> aryl, or 5-10 heteroaryl;

m是0、1、2、3、4、5或6；和m is 0, 1, 2, 3, 4, 5, or 6; and

n是0、1或2。n is 0, 1, or 2.

在一些实施方案中，在式(IV)中，W1为N，且W2、W3和W4各自独立地是C或CH。在另一些实施方案中，W3为N，且W1、W2和W4各自独立地是C或CH。In some embodiments, in formula (IV), W1 is N, and W2 , W3 , and W4 are each independently C or CH. In other embodiments, W3 is N, and W1 , W2 , and W4 are each independently C or CH.

在一些实施方案中，选自 In some implementation schemes, Selected from

在一些实施方案中，本发明的化合物各自具有如下结构：
In some embodiments, the compounds of the present invention each have the following structure:

其中，各变量如本文所定义。The variables are as defined in this paper.

上述各个变量在下文进一步详述。The variables mentioned above are described in further detail below.

L2 L2

在一些实施方案中，L2是其中T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基，和Q为O或S。In some implementations, L2 is Where T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different cyclic carbon atoms, and Q is O or S.

在一些实施方案中，T为C2-4亚烯基或分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基，优选是C2-4亚烯基。例如，T为亚乙烯基(例如1,2-亚乙烯基)、亚丙烯基(例如1,3-亚丙烯基、1,2-亚丙烯基)、亚丁烯基(例如1,4-亚丁烯基，如1,4-亚丁-1-烯基或1,4-亚丁-2-烯基)、1,2-亚环丙基、1,3-亚环丁基、1,3-亚环戊基、1,3-亚环己基、或1,4-亚环己基。In some embodiments, T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the remainder of the molecule via two different ring carbon atoms, preferably a C2-4 alkenyl group. For example, T is vinylidene (e.g., 1,2-vinylidene), propenyl (e.g., 1,3-propenyl, 1,2-propenylidene), butenyl (e.g., 1,4-butenyl, such as 1,4-butenyl-1-ene or 1,4-butenyl-2-ene), 1,2-cyclopropylidene, 1,3-cyclobutylidene, 1,3-cyclopentylidene, 1,3-cyclohexylidene, or 1,4-cyclohexylidene.

在一些实施方案中，Q为O。在另一些实施方案中，Q是S。In some implementations, Q is 0. In other implementations, Q is S.

在一些实施方案中，L2或选自：
In some implementations, L2 or Selected from:

优选地，选自 Preferably, selected from

更优选地，选自最优选是 More preferably, selected from The optimal choice is

在一些实施方案中，L2或选自： In some implementations, L2 or Selected from:

因此，在一些实施方案中，本发明的式(III)、(III-1)和(IV)化合物各自具有下式之一：
Therefore, in some embodiments, the compounds of formulas (III), (III-1), and (IV) of the present invention each have one of the following formulas:

优选具有式(Va)，其中，各变量如本文所定义，优选各自如式(III)、(III-1)或(IV)中所定义。Preferably, it has the formula (Va), wherein each variable is as defined herein, preferably as defined in formula (III), (III-1) or (IV).

R1 R 1

在一些实施方案中，R1是H、卤素(例如氟、氯、溴或碘)、氰基、羟基、NH2、NH(C1-6烷基)、N(C1-6烷基)2、C1-6烷基、C1-6卤代烷基、C1-6氰基烷基或C1-6羟基烷基。进一步地，R1是H、卤素、氰基、羟基、NH2、C1-6烷基、C1-6卤代烷基、C1-6氰基烷基或C1-6羟基烷基。更进一步地，R1是H、C1-6烷基或C1-6卤代烷基，优选是H或C1-6烷基，更优选是C1-6烷基。In some embodiments, R1 is H, a halogen (e.g., fluorine, chlorine, bromine, or iodine), a cyano group, a hydroxyl group, NH₂ , NH (C₁ -6 alkyl), N (C₁ -6 alkyl) ₂ , a C₁-6 alkyl group, a C₁ - 6 haloalkyl group, a C₁ -6 cyanoalkyl group, or a C₁ -6 hydroxyalkyl group. Further, R1 is H, a halogen, a cyano group, a hydroxyl group, NH₂ , a C₁-6 alkyl group, a C₁ -6 haloalkyl group, a C₁ -6 cyanoalkyl group, or a C₁ -6 hydroxyalkyl group. Even further, R1 is H, a C₁-6 alkyl group, or a C₁ - 6 haloalkyl group, preferably H or a C₁ -6 alkyl group, more preferably a C₁ -6 alkyl group.

在一些实施方案中，R1是卤素，特别是氟、氯、溴或碘，更特别是氟或氯。In some implementations, R1 is a halogen, particularly fluorine, chlorine, bromine, or iodine, especially fluorine or chlorine.

在一些实施方案中，R1是NH2、NH(C1-6烷基)或N(C1-6烷基)2。特别地，R1是NH2、NH(CH3)、NH(CH2CH3)、N(CH3)2或N(CH3)(CH2CH3)，优选是NH2、NH(CH3)或N(CH3)2。In some embodiments, R1 is NH2 , NH( C1-6 alkyl) or N( C1-6 alkyl) 2 . In particular, R1 is NH2 , NH( CH3 ), NH( CH2CH3 ), N( CH3 ) 2 or N( CH3 )( CH2CH3 ), preferably NH2, NH( CH3 ) or N ( CH3 ) 2 .

在一些实施方案中，R1是C1-6烷基，特别是C1-4烷基，例如甲基、乙基、丙基、丁基、戊基或己基。优选地，R1是甲基。In some embodiments, R1 is a C1-6 alkyl group, particularly a C1-4 alkyl group, such as methyl, ethyl, propyl, butyl, pentyl, or hexyl. Preferably, R1 is methyl.

R2a、R2b和R2c R2a , R2b and R2c

在一些实施方案中，R2a、R2b和R2c各自独立地是H、卤素、氰基、NRaRb、C1-6烷基、C1-6卤代烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环。In some embodiments, R2a , R2b , and R2c are each independently H, halogen, cyano , NRaRb , C1-6 alkyl, C1-6 haloalkyl, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NRa -S(O) 2- ( C1-6 alkyl), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl) or -C(=O)-N( Ra )-(C 3-10 cycloalkyl), or R2a , R2b together with the atoms they are attached to form a 5-6 member saturated, partially unsaturated or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo , ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (3-10 member heterocyclic alkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 haloalkyl) -RL- and ( C6-10 aryl) -RL- , wherein the C 3-10 Cycloalkyl groups are monocyclic, bicyclic, spirocyclic, or bridged rings.

在一些实施方案中，R2a、R2b和R2c各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环。In some embodiments, R2a , R2b , and R2c are each independently selected from H, halogens, NRaRb , C1-6 alkyl, 5-10 - membered heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa- S (O) 2- (C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl ), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a and R2b together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogens, oxo groups, ( NRaRb ) -RL- , C1-6 alkyl, C 1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , (C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C1-6 alkoxy) -RL- , ( 3-10 heterocyclic alkyl) -RL- and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged ring.

在一些实施方案中，R2a、R2b各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环；和R2c为H、卤素或C1-6烷基，优选H或卤素，例如氟。In some embodiments, R2a and R2b are each independently selected from H, halogens, NRaRb , C1-6 alkyl, 5-10 -membered heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa -S (O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a and R2b together with the atoms to which they are attached form 5-6-membered saturated, partially unsaturated, or aromatic heterocycles, said rings optionally substituted with substituents selected from: halogens, oxo groups, (NRaRb)-RL-, C1-6 alkyl , C1-6 deuterated alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogens or C 1-6 alkoxys) -RL- , (4-8 membered heterocyclic alkyl) -RL- , wherein the C 3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic, or bridged; and R 2c is H, halogen, or C 1-6 alkyl, preferably H or halogen, such as fluorine.

在一些实施方案中，R2a、R2b和R2c各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-7元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-6环烷基)、-S(＝O)(＝NRa)-(C3-6环烷基)或-C(＝O)-N(Ra)-(C3-6烷基)。优选地，R2a和R2b之一是H、卤素、NRaRb或C1-6烷基，且另一个是任选被一个或多个C1-6烷基取代的5-7元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-6环烷基或-C(＝O)-N(Ra)-(C3-6环烷基)；和R2c是H、卤素或C1-6烷基。In some embodiments, R2a , R2b and R2c are each independently selected from H, halogen, NR a R b , C1-6 alkyl, 5-7 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NR a -S(O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-6 cycloalkyl), -S(=O)(=NR a )-( C3-6 cycloalkyl) or -C(=O)-N( Ra )-( C3-6 alkyl). Preferably, one of R2a and R2b is H, a halogen, NR a R b , or a C1-6 alkyl group, and the other is a 5-7 heteroaryl group optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NR a -S(O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a )-( C3-6 cycloalkyl or -C(=O)-N( Ra )-( C3-6 cycloalkyl); and R2c is H, a halogen, or a C1-6 alkyl group.

在一些实施方案中，R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环；和R2c为H、卤素或C1-6烷基。In some embodiments, R2a , R2b, together with the atoms to which they are attached, form a 5-6 member saturated, partially unsaturated, or aromatic heterocycle, said ring optionally being substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C1-6 alkoxy) -RL- , (4-8 member heterocyclic alkyl) -RL- , wherein said C3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic, or bridged; and R2c is H, halogen, or C1-6 alkyl.

在一些实施方案中，R2a、R2b与它们所连接的碳原子一起形成含有一个或两个氮杂原子的5或6元杂芳环，所述环被(C3-8环烷基)-C1-4亚烷基-或(C3-8卤代环烷基)-C1-4亚烷基-取代，优选被(C3-6环烷基)-C1-4亚烷基-或(C3-6卤代环烷基)-C1-4亚烷基-取代,；和R2c为卤素，优选F。In some embodiments, R2a , R2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, said ring being substituted with ( C3-8 cycloalkyl) -C1-4 alkylene- or ( C3-8 halocycloalkyl) -C1-4 alkylene-, preferably substituted with ( C3-6 cycloalkyl) -C1-4 alkylene- or ( C3-6 halocycloalkyl) -C1-4 alkylene-; and R2c is a halogen, preferably F.

在一些实施方案中，可以选自：
In some implementation schemes, You can choose from:

优选，更优选 Preferred, More

其中，R2’选自H、氧代基、卤素、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(C3-10环烷基)-RL-和(3-10元杂环烷基)-RL-和C6-10芳基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代，和其中所述环烷基是单环、双环、螺环或桥环的；和R2c是H、卤素或C1-6烷基。Wherein, R2 ' is selected from H, oxo, halogen, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl) -RL- and (3-10 heterocyclic alkyl) -RL- and C6-10 aryl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from halogen or C1-6 alkoxy, and wherein the cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged; and R2c is H, halogen or C1-6 alkyl.

在一些实施方案中，是其中R2’是(C3-8环烷基)-C1-4亚烷基-或(C3-8卤代环烷基)-C1-4亚烷基-，优选(C3-6环烷基)-C1-4亚烷基-或(C3-6卤代环烷基)-C1-4亚烷基-；和R2c为卤素，优选F。In some implementation schemes, yes Wherein R2 ' is ( C3-8 cycloalkyl) -C1-4 alkylene- or ( C3-8 halocycloalkyl) -C1-4 alkylene-, preferably ( C3-6 cycloalkyl) -C1-4 alkylene- or ( C3-6 halocycloalkyl) -C1-4 alkylene-; and R2c is a halogen, preferably F.

在一些实施方案中，R2a和R2b与它们所连接的碳原子一起形成含有一个、两个或三个各自独立地选自N、O或S的杂原子的5或6元杂芳环，所述杂芳环任选被选自C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、C3-8环烷基-(C1-4卤代亚烷基)-、C3-8环烷基-(C1-4氰基亚烷基)-和C3-8环烷基-(C1-4羟基亚烷基)-的取代基取代。In some embodiments, R 2a and R 2b, together with the carbon atoms to which they are attached, form a 5- or 6-membered heteroaromatic ring containing one, two, or three heteroatoms each independently selected from N, O, or S, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, C3-8 cycloalkyl-( C1-4 haloalkylene)-, C3-8 cycloalkyl-( C1-4 cyanoalkylene)-, and C3-8 cycloalkyl-( C1-4 hydroxyalkylene)-.

进一步地，R2a和R2b与它们所连接的碳原子一起形成含有一个、两个或三个各自独立地选自N、O或S的杂原子的5或6元杂芳环，所述杂芳环任选被选自C1-6烷基、C1-6卤代烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、和C3-8环烷基-(C1-4卤代亚烷基)-的取代基取代。Furthermore, R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one, two, or three heteroatoms each independently selected from N, O, or S, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-.

更进一步地，R2a和R2b与它们所连接的碳原子一起形成含有一个或两个氮杂原子的5或6元杂芳环，所述杂芳环任选被选自C1-6烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、和C3-8环烷基-(C1-4卤代亚烷基)-的取代基取代。Furthermore, R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-.

对于R2a和R2b中定义的5或6元杂芳环，其优选是含有一个或两个各自独立地选自N、O或S的杂原子的5或6元杂芳环，更优选是含有一个或两个氮杂原子的5或6元杂芳环。For the 5- or 6-membered heteroaromatic rings defined in R 2a and R 2b , they are preferably 5- or 6-membered heteroaromatic rings containing one or two heteroatoms each independently selected from N, O or S, and more preferably 5- or 6-membered heteroaromatic rings containing one or two nitrogen heteroatoms.

更进一步地，R2a和R2b与它们所连接的碳原子一起形成吡咯环、呋喃环、噻吩环、吡唑环、咪唑环、噁唑环、异噁唑环、噻唑环、异噻唑环、吡啶环、哒嗪环、嘧啶环或吡嗪环，优选吡唑环、咪唑环、噁唑环、异噁唑环、噻唑环和异噻唑环，更优选吡唑环，所述环任选被选自C1-6烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、和C3-8环烷基-(C1-4卤代亚烷基)-的取代基取代。Furthermore, R 2a and R 2b together with the carbon atoms to which they are attached form a pyrrole ring, a furan ring, a thiophene ring, a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, an isothiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, or a pyrazine ring, preferably a pyrazole ring, an imidazole ring, an oxazole ring, an isoxazole ring, a thiazole ring, or an isothiazole ring, more preferably a pyrazole ring, wherein the ring is optionally substituted with a substituent selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-.

在一些实施方案中，是其中R2aa选自C1-6烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、C3-8环烷基-(C1-4卤代亚烷基)-、C3-8环烷基-(C1-4氰基亚烷基)-和C3-8环烷基-(C1-4羟基亚烷基)-。优选地，R2aa选自C1-6烷基、C1-6卤代烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、和C3-8环烷基-(C1-4卤代亚烷基)-。更优选地，R2aa选自C1-6烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-、和C3-8环烷基-(C1-4卤代亚烷基)-，尤其是(C3-8环烷基-(C1-4亚烷基)-。In some implementation schemes, yes R2aa is selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, C3-8 cycloalkyl-(C1-4 haloalkylene)-, C3-8 cycloalkyl- ( C1-4 cyanoalkylene)-, and C3-8 cycloalkyl-( C1-4 hydroxyalkylene)-. Preferably, R2aa is selected from C1-6 alkyl , C1-6 haloalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-. More preferably, R 2aa is selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-, and C3-8 cycloalkyl-( C1-4 haloalkylene)-, especially ( C3-8 cycloalkyl-( C1-4 alkylene)-.

在一些实施方案中，R2a和R2b之一为-P(O)(C1-6烷基)(C1-6烷基)，且另一个为H、卤素、氰基、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2或C1-6烷基。进一步地，R2a和R2b之一为-P(O)(C1-6烷基)(C1-6烷基)，且另一个为H、NH2或NH(C1-6烷基)。更进一步地，R2a和R2b之一为-P(O)(C1-6烷基)(C1-6烷基)，且另一个为H或NH(C1-6烷基)。更进一步地，R2a和R2b之一为-P(O)(C1-6烷基)(C1-6烷基)，且另一个为H或NH(C1-4烷基)。In some embodiments, one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H, halogen, cyano, OH, NH2 , NH( C1-6 alkyl), N( C1-6 alkyl) 2 , or C1-6 alkyl. Further, one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H, NH2 , or NH( C1-6 alkyl). Even further, one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H or NH( C1-6 alkyl). Still further, one of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H or NH( C1-4 alkyl).

在一些实施方案中，R2a为-P(O)(C1-6烷基)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、或-C(O)(C1-6烷基)，且R2b为H、卤素、氰基、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2或C1-6烷基。进一步地，R2a为-P(O)(C1-6烷基)(C1-6烷基)，且R2b为H、卤素、氰基、OH、NH2、NH(C1-6烷基)、N(C1-6烷基)2或C1-6烷基。更进一步地，R2a为-P(O)(C1-6烷基)(C1-6烷基)，且R2b为H、NH2或NH(C1-6烷基)。更进一步地，R2a为-P(O)(C1-6烷基)(C1-6烷基)，且R2b为H或NH(C1-6烷基)。更进一步地，R2a为-P(O)(C1-4烷基)(C1-4烷基)，且R2b为H或NH(C1-4烷基)In some embodiments, R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 (C1-6 alkyl), or -C(O)( C1-6 alkyl), and R2b is H, halogen, cyano, OH, NH2 , NH( C1-6 alkyl), N( C1-6 alkyl) 2 , or C1-6 alkyl. Further, R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), and R2b is H, halogen, cyano, OH, NH2 , NH( C1-6 alkyl ), N( C1-6 alkyl) 2 , or C1-6 alkyl. Furthermore, R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), and R2b is H, NH2 , or NH ( C1-6 alkyl). Furthermore, R2a is -P(O)( C1-6 alkyl)( C1-6 alkyl), and R2b is H or NH ( C1-6 alkyl). Furthermore, R2a is -P(O)( C1-4 alkyl)( C1-4 alkyl), and R2b is H or NH ( C1-4 alkyl).

在一些实施方案中，R2c为H、卤素、氰基、羟基或NH2。优选地，R2c为H、卤素或氰基。更优选地，R2c为H或卤素。在一些实施方案中，R2c为卤素，例如氟。在另一些实施方案中，R2c为H。In some embodiments, R₂c is H, a halogen, a cyano group, a hydroxyl group, or NH₂ . Preferably, R₂c is H, a halogen, or a cyano group. More preferably, R₂c is H or a halogen. In some embodiments, R₂c is a halogen, such as fluorine. In other embodiments, R₂c is H.

在一些实施方案中，选自：
In some implementation schemes, Selected from:

R3a、R3b和R3c R3a , R3b and R3c

在一些实施方案中，R3a、R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6氰基烷基、(C3-10环烷基)-RL-和(C3-10卤代环烷基)-RL-，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自卤素、氰基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基和C1-6氰基烷基的取代基取代。In some embodiments, R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- , and ( C3-10 halocycloalkyl) -RL- , or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally substituted with a substituent selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, and C1-6 cyanoalkyl.

在一些实施方案中，R3a、R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代。In some embodiments, R3a , R3b and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, or wherein R3a and R3b together with the atoms to which they are attached form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, said 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens.

在一些实施方案中，R3a、R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基。优选地，R3a为H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基；R3b为卤素；和R3c为H或C1-6烷基，优选为C1-6烷基。在一些实施方案中，R3a为C1-4烷基；R3b为卤素，例如氟；和R3c为C1-4烷基。In some embodiments, R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl. Preferably, R3a is H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl. In some embodiments, R3a is C1-4 alkyl; R3b is halogen, such as fluorine; and R3c is C1-4 alkyl.

在一些实施方案中，R3a、R3b和R3c各自独立地选自卤素、C1-6烷基和C1-6卤代烷基。优选地，R3a为C1-6烷基或C1-6卤代烷基，R3b为卤素如氟，和R3c为C1-6烷基。更优选地，R3a为C1-4烷基或C1-4卤代烷基，R3b为卤素如氟，和R3c为C1-4烷基。In some embodiments, R3a , R3b , and R3c are each independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups. Preferably, R3a is a C1-6 alkyl or C1-6 haloalkyl group, R3b is a halogen such as fluorine, and R3c is a C1-6 alkyl group. More preferably, R3a is a C1-4 alkyl or C1-4 haloalkyl group, R3b is a halogen such as fluorine, and R3c is a C1-4 alkyl group.

在一些实施方案中，R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环如本文所定义任选被取代。因此，在一些实施方案中，可以选自： In some embodiments, R3a , R3b, together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring being optionally substituted as defined herein. Thus, in some embodiments, You can choose from:

其中R3c如本文所定义，R3’各自独立地是卤素、氰基、羟基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基或C1-6羟基烷基，和x为0、1或2。可以理解，R3’当存在时可连接于环上任意可用的位置。优选地，R3c是H、卤素、氰基、羟基、NH2、NH(C1-4烷基)、C1-4烷基或C1-4卤代烷基，优选是H、卤素、氰基、C1-4烷基或C1-4卤代烷基，更优选是H、卤素或C1-4烷基，例如是H。另外优选地，R3’各自独立地是卤素、氰基、C1-4烷基或C1-4卤代烷基，优选卤素或氰基，更优选是卤素如氟。Wherein R 3c is as defined herein, and R 3 ' is independently a halogen, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, or C1-6 hydroxyalkyl, and x is 0, 1, or 2. It is understood that R 3 ', when present, can be attached to any available position on the ring. Preferably, R 3c is H, halogen, cyano, hydroxyl, NH₂ , NH ( C1-4 alkyl), C1-4 alkyl, or C1-4 haloalkyl, more preferably H, halogen, cyano, C1-4 alkyl, or C1-4 haloalkyl, and more preferably H, halogen, or C1-4 alkyl, for example, H. In addition, preferably, each of R3 ' is independently a halogen, cyano, C1-4 alkyl or C1-4 haloalkyl, preferably a halogen or cyano, more preferably a halogen such as fluorine.

在一些实施方案中，R3a、R3b和R3c各自独立地选自H、卤素、氰基、羟基、NH2、NH(C1-6烷基)、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C3-8环烷基和C3-8环烷基-(C1-4亚烷基)-。进一步地，R3a、R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C3-8环烷基和C3-8环烷基-(C1-4亚烷基)-。更进一步地，R3a、R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-8环烷基。In some embodiments, R3a , R3b , and R3c are each independently selected from H, halogen, cyano , hydroxyl, NH2, NH( C1-6 alkyl), N( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, and C3-8 cycloalkyl-( C1-4 alkylene)-. Further, R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C3-8 cycloalkyl, and C3-8 cycloalkyl-( C1-4 alkylene)-. Furthermore, R3a , R3b and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl and C3-8 cycloalkyl.

在一些实施方案中，R3a为H、卤素、氰基、羟基、NRaRb、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-；R3b为卤素；和R3c为H或C1-6烷基、优选为C1-6烷基。进一步地，R3a为H、卤素、氰基、羟基、NH2、NH(C1-6烷基)、N(C1-6烷基)2、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-；R3b为卤素；和R3c为H或C1-6烷基，优选为C1-6烷基。更进一步地，R3a选自H、卤素、氰基、C1-6烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-；R3b为卤素；和R3c为H或C1-6烷基，优选为C1-6烷基。更进一步地，R3a为H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-8环烷基；R3b为卤素；和R3c为H或C1-6烷基，优选为C1-6烷基。更进一步地，R3a为H、卤素、氰基、C1-4烷基、C1-4卤代烷基和C3-6环烷基；R3b为卤素；和R3c为H或C1-4烷基，优选为C1-4烷基。In some embodiments, R3a is H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-; R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl. Further, R3a is H, halogen, cyano, hydroxyl, NH2 , NH( C1-6 alkyl), N( C1-6 alkyl) 2 , C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-; R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl. Furthermore, R3a is selected from H, halogen, cyano, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)-; R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl. Further, R3a is H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-8 cycloalkyl; R3b is halogen; and R3c is H or C1-6 alkyl, preferably C1-6 alkyl. Furthermore, R3a is H, halogen, cyano, C1-4 alkyl, C1-4 haloalkyl, and C3-6 cycloalkyl; R3b is halogen; and R3c is H or C1-4 alkyl, preferably C1-4 alkyl.

R4 R 4

在一些实施方案中，R4各自独立地选自C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C3-6环烷基和4-8元杂环烷基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自C1-6烷基或C1-6烷氧基的取代基取代。优选地，R4各自独立地选自C1-6烷氧基、C3-6环烷基和4-8元杂环烷基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自C1-6烷基或C1-6烷氧基的取代基取代。In some embodiments, R4 is each independently selected from C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C3-6 cycloalkyl, and 4-8 membered heterocyclic alkyl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted with one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy. Preferably, R4 is each independently selected from C1-6 alkoxy, C3-6 cycloalkyl, and 4-8 membered heterocyclic alkyl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted with one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy.

在一些实施方案中，R4各自独立地选自C1-6烷氧基，例如甲氧基。In some embodiments, R4 is independently selected from C1-6 alkoxy groups, such as methoxy groups.

在一些实施方案中，R4为4至8元杂环烷基或5-10元杂芳基、优选5-7元杂芳基，所述杂环烷基或杂芳基含有一个、两个或三个各自独立地选自N、O或S的杂原子，并且所述杂环烷基或杂芳基任选被一个或多个C1-6烷基取代。进一步地，R4为4至8元杂环烷基或5-10元杂芳基、优选5-7元杂芳基，所述杂环烷基或杂芳基含有一个或两个各自独立地选自N、O或S的杂原子，并且所述杂环烷基或杂芳基任选被一个或多个C1-6烷基取代。In some embodiments, R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 10-membered heteroaryl, preferably a 5- to 7-membered heteroaryl, wherein the heterocyclic alkyl or heteroaryl contains one, two, or three heteroatoms each independently selected from N, O, or S, and the heterocyclic alkyl or heteroaryl is optionally substituted with one or more C1-6 alkyl groups. Further, R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 10-membered heteroaryl, preferably a 5- to 7-membered heteroaryl, wherein the heterocyclic alkyl or heteroaryl contains one or two heteroatoms each independently selected from N, O, or S, and the heterocyclic alkyl or heteroaryl is optionally substituted with one or more C1-6 alkyl groups.

在一些实施方案中,R4是C3-6环烷基和4-8元杂环烷基(例如含有一个或两个各自独立地选自N、O或S的杂原子的4-8元杂环烷基)，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自C1-6烷基或C1-6烷氧基的取代基取代。In some embodiments, R4 is a C3-6 cycloalkyl and a 4-8 heterocyclic alkyl (e.g., a 4-8 heterocyclic alkyl containing one or two heteroatoms each independently selected from N, O or S), wherein the cycloalkyl and heterocyclic alkyl are optionally substituted by one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy.

在一些实施方案中，R4是含有一个或两个各自独立地选自N、O或S(例如选自N或O)的杂原子的4至8元杂环烷基，优选是含有一个或两个O杂原子的4至8元杂环烷基，例如氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、哌啶基、六氢哒嗪基、六氢嘧啶基、哌嗪基、四氢吡喃基、四氢噻喃基、噁嗪烷基、吗啉基或硫吗啉基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代。In some embodiments, R4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O, or S (e.g., selected from N or O), preferably a 4- to 8-membered heterocyclic alkyl group containing one or two O heteroatoms, such as aziridine, oxaziridine, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, piperidinyl, hexahydropyridinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiaranyl, oxazinyl, morpholinyl, or thiomorpholinyl, wherein the heterocyclic alkyl group is optionally substituted with one or more, preferably one or two C1-6 alkyl groups.

在一些实施方案中，R4为含有一个或两个各自独立地选自N、O或S(例如选自N或O，还例如为N)的杂原子的5-7元杂芳基，例如吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噻唑基、异噻唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基，所述杂芳基任选被一个或多个、优选一个或两个C1-6烷基取代。In some embodiments, R4 is a 5-7 membered heteroaryl group containing one or two heteroatoms each independently selected from N, O, or S (e.g., selected from N or O, and also, for example, N), such as pyrroloyl, furanyl, thiopheneyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, or pyrazinyl, wherein the heteroaryl group is optionally substituted with one or more, preferably one or two C1-6 alkyl groups.

在一些实施方案中，R4为4至8元杂环烷基或5-7元杂芳基，所述杂环烷基或杂芳基含有一个或两个各自独立地选自N和O的杂原子，并且所述杂环烷基或杂芳基任选被一个或多个、优选一个或两个C1-6烷基取代。In some embodiments, R4 is a 4- to 8-membered heterocyclic alkyl or a 5- to 7-membered heteroaryl, the heterocyclic alkyl or heteroaryl containing one or two heteroatoms each independently selected from N and O, and the heterocyclic alkyl or heteroaryl is optionally substituted by one or more, preferably one or two C1-6 alkyl groups.

在一些实施方案中，R4为四氢吡喃基、吗啉基或吡啶基，其各自任选被一个或多个、优选一个或两个C1-6烷基取代。优选地，R4为四氢吡喃基，任选被一个或多个、优选一个或两个C1-6烷基取代。In some embodiments, R4 is tetrahydropyranyl, morpholinyl, or pyridyl, each optionally substituted with one or more, preferably one or two, C1-6 alkyl groups. Preferably, R4 is tetrahydropyranyl, optionally substituted with one or more, preferably one or two, C1-6 alkyl groups.

在一些实施方案中，R4为环己基，任选被一个或多个、优选一个或两个C1-6烷氧基取代。在一些实施方案中，R4选自：
In some embodiments, R4 is a cyclohexyl group, optionally substituted with one or more, preferably one or two C1-6 alkoxy groups. In some embodiments, R4 is selected from:

优选选自更优选 Preferred selection More

在一些实施方案中，R4是例如 In some implementations, R4 is For example

R5a、R5b、R5c和R5d R5a , R5b , R5c and R5d

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、-CONH2、-CONH(C1-6烷基)、-C(＝S)NH2、-C(＝S)NH(C1-6烷基)、-P(Ra)(Rb)(例如-PH2、-PH(C1-6烷基)、-PH(C1-6烷基)(C1-6烷基))、(例如-O-P(＝O)(OH)2、)、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(3-10元杂环烷基氧基)-RL-、(C6-10芳基)-RL-、(C6-10芳基氧基)-RL-、(C6-10芳基-C1-6亚烷基氧基)-RL-(例如苄氧基-RL-)、(5-10元杂芳基)-RL-、(5-10元杂芳基氧基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代。In some embodiments, R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy )-RL-, ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, -CONH2 , -CONH ( C1-6 alkyl), -C(=S)NH2, -C(=S)NH( C1-6 alkyl), -P(Ra) ( Rb ) (e.g., -PH2 , -PH( C1-6 alkyl ), -PH(C... 1-6 alkyl)(C 1-6 alkyl) (For example, -OP(＝O)(OH) 2 , ), C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 alkenyl-, ( C3-10 cycloalkyl)-C2-4 alkyne-, ( C3-10 cycloalkyloxy) -RL- , ( 3-10 heterocyclic alkyl) -RL- , ( 3-10 heterocyclic alkyloxy) -RL- , ( C6-10 aryl)-RL-, (C6-10 aryloxy) -RL- , ( C6-10 aryl- C1-6 alkyleneoxy) -RL- (e.g., benzyloxy - RL- ), ( 5-10 heteroaryl) -RL- , (5-10 heteroaryloxy) -RL- , NRsRt- ( CRaR b ) m- , NR a R b -CO-, or two of R 5a , R 5b , R 5c and R 5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 heterocyclic alkyl, C 6-10 aryl and 5-7 heteroaryl.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(C6-10芳基)-RL-、(5-10元杂芳基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代。In some embodiments, R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , ( C1-6 alkoxy)-RL-, ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy ) -RL- , (optionally substituted with halogen or hydroxyl )-RL-, (C3-10 cycloalkyl ) -C2-4 alkenyl-, (C The ring may be formed by two of the following groups together with the atoms to which they are attached: (3-10 cycloalkyl)-C 2-4 ynynyl-, (C 3-10 cycloalkyloxy) -RL- , (3-10 heterocyclic alkyl) -RL- , (C 6-10 aryl )-RL-, (5-10 heteroaryl)-RL-, NR s R t- (CR a R b ) m- , NR a R b -CO-, or R 5a , R 5b , R 5c and R 5d together with the atoms to which they are attached, forming a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, wherein the ring may be optionally substituted by one or more substituents selected from oxo, halogen, cyano, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, 3-10 heterocyclic alkyl, C 6-10 aryl and 5-7 heteroaryl.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、(C6-10芳基-C1-6亚烷基氧基)-RL-(例如苄氧基-RL-)、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基和5-7元杂芳基的取代基取代。In some embodiments, R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , ( C1-6 alkoxy)-RL-, ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (optionally C3-10 cycloalkyl substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 ynynyl-, ( C3-10 cycloalkyloxy) -RL- -, (C 6-10 aryl) -RL- , (C 6-10 aryl-C 1-6 alkyleneoxy) -RL- (e.g., benzyloxy- RL- ), NR s R t- (CR a R b ) m- , or two of R 5a , R 5b , R 5c and R 5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano and 5-7 membered heteroaryl.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基和5-7元杂芳基的取代基取代。In some embodiments, R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl , ( C1-6 alkoxy)-RL-, ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- , (optionally C3-10 cycloalkyl substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 ynynyl-, ( C3-10 cycloalkyloxy) -RL- -, (C 6-10 aryl) -RL- , NR s R t- (CR a R b ) m- , or two of R 5a , R 5b , R 5c and R 5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano and 5-7 membered heteroaryl.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代。In some embodiments, R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally being substituted by one or more substituents selected from oxo and 5-7 membered heteroaryl groups.

在一些实施方案中，R5a是C1-6烷基或C1-6烷氧基，且R5b、R5c和R5d各自独立地为H或卤素，优选H。In some embodiments, R5a is a C1-6 alkyl or C1-6 alkoxy, and R5b , R5c and R5d are each independently H or halogen, preferably H.

在一些实施方案中，R5a是C1-6烷基，且R5b、R5c和R5d各自独立地为H或卤素，优选H。优选地，R5a是C1-4烷基，且R5b、R5c和R5d各自独立地为H。In some embodiments, R5a is a C1-6 alkyl group, and R5b , R5c , and R5d are each independently H or a halogen, preferably H. Preferably, R5a is a C1-4 alkyl group, and R5b , R5c , and R5d are each independently H.

在一些实施方案中，R5a、R5b连同它们所连接的原子一起形成如本文所定义的环。在另一些实施方案中，R5a、R5c连同它们所连接的原子一起形成如本文所定义的环。In some embodiments, R5a and R5b, together with the atoms they are attached to, form a ring as defined herein. In other embodiments, R5a and R5c , together with the atoms they are attached to, form a ring as defined herein.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、C6-10芳基、含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基、或-(CH2)mNRsRt，其中Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基。In some embodiments, R5a , R5b , R5c and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C6-10 aryl, 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl or 5-10 heteroaryl containing one or more heteroatoms each independently selected from N , O or S.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、或-(CH2)mNRsRt，其中Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基。In some embodiments, R5a , R5b , R5c and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、或-(CH2)mNRsRt，其中Rs和Rt各自独立地是H、C1-6烷基、苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基。In some embodiments, R5a , R5b , R5c and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S, or -( CH2 )mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O or S.

在一些实施方案中，R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、NH2、NH(C1-6烷基)、N(C1-6烷基)2、-(CH2)mNH(苯基)、-(CH2)mN(C1-6烷基)(苯基)、-(CH2)mNH(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)、或-(CH2)mN(C1-6烷基)(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)。In some embodiments, R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S, NH2, NH( C1-6 alkyl), N ( C1-6 alkyl) 2 , -( CH2 ) mNH (phenyl), -(CH2) mN ( C1-6 alkyl)(phenyl), -( CH2 ) mNH (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O , or S), or -( CH2 ) mN (C1-6 alkyl)(phenyl). 1-6 alkyl (containing one or more 5-7 membered heteroaryl groups, each independently selected from N, O or S).

进一步地，R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、-(CH2)mNH(苯基)、-(CH2)mN(C1-6烷基)(苯基)、-(CH2)mNH(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)、或-(CH2)mN(C1-6烷基)(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)。Further, R5a , R5b , R5c and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, 5-7 heteroaryl containing one or more heteroatoms independently selected from N, O or S, -( CH2 ) mNH (phenyl), -( CH2 ) mN ( C1-6 alkyl) (phenyl), -( CH2 ) mNH (5-7 heteroaryl containing one or more heteroatoms independently selected from N, O or S), or -( CH2 ) mN ( C1-6 alkyl) (5-7 heteroaryl containing one or more heteroatoms independently selected from N, O or S).

更进一步地，R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、或-(CH2)mN(C1-6烷基)(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)。优选地，所述5-7元杂芳基是吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基。Furthermore, R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, or -( CH2 ) mN ( C1-6 alkyl) (containing one or more 5- or 7-membered heteroaryl groups, each independently selected from N, O, or S). Preferably, the 5- or 7-membered heteroaryl group is pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

更进一步地，R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、-(CH2)mN(C1-6烷基)(噁二唑基)、或-(CH2)mN(C1-6烷基)(嘧啶基)。Furthermore, R5a , R5b , R5c and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, -( CH2 ) mN (C1-6 alkyl )(oxadiazolyl), or -( CH2 ) mN ( C1-6 alkyl)(pyrimidinyl).

在一些实施方案中，R5a是H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、C6-10芳基、含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基或NRsRt-(CRaRb)m-，其中Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基；且R5b、R5c和R5d各自独立地为H或卤素，优选H。In some embodiments, R5a is H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, C6-10 aryl, a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S, or NRsRt- ( CRaRb ) m- , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O, or S; and R5b , R5c , and R5d are each independently H or halogen, preferably H.

在一些实施方案中，R5a是H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、或-(CH2)mNRsRt，其中Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基；且R5b、R5c和R5d各自独立地为H或卤素，优选H。In some embodiments, R5a is H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, C1-6 haloalkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N, O or S; and R5b , R5c and R5d are each independently H or halogen, preferably H.

在一些实施方案中，R5a是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、或-(CH2)mNRsRt，其中Rs和Rt各自独立地是H、C1-6烷基、苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基；且R5b、R5c和R5d各自独立地为H或卤素，优选H。In some embodiments, R5a is H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, or -( CH2 ) mNRsRt , wherein Rs and Rt are each independently H, C1-6 alkyl, phenyl or a 5-7 heteroaryl group containing one or more heteroatoms each independently selected from N , O or S; and R5b , R5c and R5d are each independently H or halogen, preferably H.

在一些实施方案中，R5a是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、NH2、NH(C1-6烷基)、N(C1-6烷基)2、-(CH2)mNH(苯基)、-(CH2)mN(C1-6烷基)(苯基)、-(CH2)mNH(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)、或-(CH2)mN(C1-6烷基)(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)；且R5b、R5c和R5d各自独立地为H或卤素，优选H。In some embodiments, R 5a is H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S , NH2, NH( C1-6 alkyl), N( C1-6 alkyl) 2 , -( CH2 ) mNH (phenyl), -(CH2) mN ( C1-6 alkyl)(phenyl), -( CH2 ) mNH (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S), or -( CH2 ) mN ( C1-6 alkyl)(phenyl). 1-6 alkyl (containing one or more 5-7 heteroaryl groups, each independently selected from N, O or S); and R 5b , R 5c and R 5d are each independently H or halogen, preferably H.

进一步地，R5a是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基、-(CH2)mNH(苯基)、-(CH2)mN(C1-6烷基)(苯基)、-(CH2)mNH(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)、或-(CH2)mN(C1-6烷基)(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)；且R5b、R5c和R5d各自独立地为H或卤素，优选H。Further, R 5a is H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, phenyl, a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S, -( CH2 ) mNH (phenyl), -( CH2 ) mN ( C1-6 alkyl) (phenyl), -( CH2 ) mNH (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S), or -( CH2 ) mN ( C1-6 alkyl) (a 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S); and R 5b , R 5c , and R Each of the 5d elements is independently H or a halogen, with H being preferred.

更进一步地，R5a是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、苯基、或-(CH2)mN(C1-6烷基)(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)；且R5b、R5c和R5d各自独立地为H或卤素，优选H。优选地，所述5-7元杂芳基是吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噁唑基、噁二唑基、噻唑基、异噻唑基、吡啶基、哒嗪基、嘧啶基或吡嗪基。Furthermore, R5a is H, a halogen, a cyano, a C1-6 alkyl, a C2-6 alkenyl, a C2-6 alkynyl, a C1-6 alkoxy, a C1-6 alkylthio, a C1-6 haloalkyl, a C1-6 hydroxyalkyl, COOH, a C1-6 alkoxy-CO-, a phenyl, or -( CH2 ) mN ( C1-6 alkyl) (containing one or more 5-7 membered heteroaryl groups, each independently selected from N, O, or S); and R5b , R5c, and R5d are each independently H or a halogen, preferably H. Preferably, the 5-7 membered heteroaryl group is pyrroleyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, or pyrazinyl.

特别地，R5a是卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、-(CH2)mN(C1-6烷基)(噁二唑基)、或-(CH2)mN(C1-6烷基)(嘧啶基)；且R5b、R5c和R5d各自独立地为H或卤素，优选H。Specifically, R5a is a halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, -( CH2 ) mN ( C1-6 alkyl)(oxadiazolyl), or -(CH2)mN(C1-6 alkyl ) ( pyrimidinyl); and R5b , R5c and R5d are each independently H or a halogen, preferably H.

在一些实施方案中，选自：
(例如)。In some implementation schemes, Selected from:
(For example ).

R6 R 6

在一些实施方案中，R6选自 其中R6a是H或C1-6烷基，优选H。In some implementations, R6 is selected from R 6a is H or C 1-6 alkyl, preferably H.

在一些实施方案中，R6选自其中R6a是H或C1-6烷基，优选H。In some implementations, R6 is selected from R 6a is H or C 1-6 alkyl, preferably H.

在一些实施方案中，R6选自： 优选地，选自特别是 In some implementations, R 6 is selected from: Preferably, selected from in particular

在一些实施方案中，R6是其中R6a是H或C1-6烷基。优选地，R6是 In some implementations, R6 is Wherein R 6a is H or C1-6 alkyl. Preferably, R 6 is

(Rp ) n (R p ) n

在一些实施方案中，Rp各自独立地是卤素、氰基、羟基、NH2或C1-4烷基。在一些实施方案中，Rp各自独立地是卤素或氰基。在一些实施方案中，n为0，即Rp不存在。因此，在一些实施方案中，本发明的式(III)、(III-1)和(IV)化合物各自可以具有如下结构：
In some embodiments, Rp is independently a halogen, cyano, hydroxyl, NH₂ , or C₁ -4 alkyl group. In some embodiments, Rp is independently a halogen or cyano group. In some embodiments, n is 0, i.e., Rp is absent. Therefore, in some embodiments, the compounds of formulas (III), (III-1), and (IV) of the present invention can each have the following structure:

其中，各变量如本文所定义，例如各自如式(III)、式(III-1)或(IV)中所述。The variables are as defined herein, for example, as described in equation (III), equation (III-1) or (IV).

在一些实施方案中，Ra和Rb各自独立地是H或C1-6烷基。在一些实施方案中，Ra和Rb均为H。在一些实施方案中，Ra为H，且Rb为C1-6烷基。在一些实施方案中，Ra和Rb均为C1-6烷基。In some embodiments, Ra and Rb are each independently H or C1-6 alkyl. In some embodiments , both Ra and Rb are H. In some embodiments, Ra is H and Rb is C1-6 alkyl. In some embodiments, both Ra and Rb are C1-6 alkyl.

在一些实施方案中，RL各自独立地是价键；任选被卤素、氰基或羟基取代的C1-6亚烷基；或C1-4氘代亚烷基。在一些实施方案中，RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基。在一些实施方案中，RL各自独立地是价键、亚甲基、亚乙基、卤代亚甲基、卤代亚乙基或CD3。In some embodiments, R and L are each independently a valence bond; optionally a C1-6 alkylene group substituted with a halogen, cyano, or hydroxyl group; or a C1-4 deuterated alkylene group. In some embodiments, R and L are each independently a valence bond, a C1-4 alkylene group, a C1-4 haloalkylene group, or a C1-4 deuterated alkylene group. In some embodiments, R and L are each independently a valence bond, methylene, ethylene, halomethylene, haloethylene, or CD3 .

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided.

其中，in,

L1选自-CO-、-SO-和-NH-，优选-CO-； L1 is selected from -CO-, -SO- and -NH-, with -CO- being preferred;

L2选自其中星号表示与中心环的N原子连接，优选 L2 is selected from The asterisk indicates a connection to the N atom in the central ring, preferably...

环A是苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基(例如单环或双环)，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代；Ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano , C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens;

环B是含有一个或多个各自独立地选自N、O或S的杂原子的8-10元双环亚杂芳基，任选被一个或多个R4取代，所述R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代；Cycle B is an 8-10 membered bicyclic heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, optionally substituted by one or more R4 groups, wherein R4 is a 4- to 8 membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C1-6 alkyl groups.

环C是C3-6环烷基，任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代；The ring C is a C3-6 cycloalkyl group, optionally substituted with one or more substituents, each of which is independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- and R6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, the ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;

环D是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基，优选苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基；Ring D is a C6-10 aryl or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O or S, preferably phenyl or a 5-7 heteroaryl containing one or more heteroatoms each independently selected from N, O or S;

R1各自独立地是H、氰基、C1-6烷基或C1-6氘代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently H, cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;

R2各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2 is independently selected from H, halogen , NRaRb , C1-6 alkyl, 5-10 membered heteroaryl optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa- S (O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NRa)-( C3-10 cycloalkyl), or -C(= O )-N( Ra )-( C3-10 cycloalkyl), or two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, (C (1-6 alkoxy) -RL- , (C 3-10 cycloalkyl group optionally substituted with one or more substituents independently selected from halogens or C 1-6 alkoxy groups) -RL- , (3-10 heterocyclic alkyl group) -RL- , and (C 6-10 aryl) -RL- , wherein the C 3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic, or bridged ring;

R6选自其中R6a是H或C1-6烷基，优选是H；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S;

RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基；R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;

T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;

Q为O或S；Q is either O or S;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2.

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，其中，In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotope-labeled compound, or solvate thereof is provided, wherein,

L1选自-CO-、-SO-和-NH-，优选-CO-； L1 is selected from -CO-, -SO- and -NH-, with -CO- being preferred;

L2选自其中星号表示与中心环的N原子连接，优选 L2 is selected from The asterisk indicates a connection to the N atom in the central ring, preferably...

环A是苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基(例如单环或双环)，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代；Ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano , C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens;

环B是含有一个或多个各自独立地选自N、O或S的杂原子的8-10元双环亚杂芳基，任选被一个或多个R4取代，所述R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代；Cycle B is an 8-10 membered bicyclic heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, optionally substituted by one or more R4 groups, wherein R4 is a 4- to 8 membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C1-6 alkyl groups.

环C是C3-6环烷基，任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-和R6；The cyclic C is a C3-6 cycloalkyl group, optionally substituted with one or more substituents, each of which is independently selected from H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH , C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy)-RL-, ( C6-10 aryl)-RL- , NRsRt- ( CRaRb ) m- , and R6 ;

环D是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基，优选苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基；Ring D is a C6-10 aryl or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O or S, preferably phenyl or a 5-7 heteroaryl containing one or more heteroatoms each independently selected from N, O or S;

R1各自独立地是氰基、C1-6烷基或C1-6氘代烷基，优选氰基、甲基或CD3； R1 is independently cyano, C1-6 alkyl or C1-6 deuterated alkyl, preferably cyano, methyl or CD3 ;

R2各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2 is independently selected from H, halogen, NR a R b , C1-6 alkyl, 5-10 membered heteroaryl optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, (NR a R b ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , (optionally substituted with one or more independently selected from halogen or C1-6 alkyl groups). (C 3-10 cycloalkyl) -RL- , (3-10 heterocyclic alkyl ) -RL- and (C 6-10 aryl) -RL- , wherein the C 3-10 cycloalkyl is a monocyclic, bicyclic, spirocyclic or bridged ring;

R6选自其中R6a是H或C1-6烷基，优选是H；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S;

RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基；R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;

T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule via two different ring carbon atoms;

Q为O或S；Q is either O or S;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2.

优选地，对于W1、W2、W3、W4和W5而言，在一些实施方案中，W1为N，且其余为C或CH；在另一些实施方案中，W3为N，且其余为C或CH；在另一些实施方案中，W5为N，且其余为C或CH。Preferably, for W1 , W2 , W3 , W4 and W5 , in some embodiments, W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.

在一些实施方案中，提供了式(I)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，其中所述式(I)化合物具有式(I-3)的结构：
In some embodiments, a compound of formula (I) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided, wherein the compound of formula (I) has the structure of formula (I-3):

环A是其中R3a、R3b和R3c各自独立地选自卤素、C1-6烷基和C1-6卤代烷基(优选地，R3a为C1-6烷基或C1-6卤代烷基，R3b为卤素如氟，和R3c为C1-6烷基)，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，和R3c是H；或者Ring A is R3a , R3b , and R3c are each independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups (preferably, R3a is a C1-6 alkyl or C1-6 haloalkyl group, R3b is a halogen such as fluorine, and R3c is a C1-6 alkyl group), or R3a and R3b, together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, and R3c is H; or

环A是苯基或苯并呋喃基，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；Ring A is phenyl or benzofuranyl, each optionally substituted by one or more R3s , each R3 being independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups;

环B是其中1位与羰基连接，2位与环C连接，和其中R4为任选被一个或两个C1-6烷氧基取代的环己基，例如 Ring B is In this configuration, position 1 is connected to a carbonyl group, position 2 is connected to a ring C, and R4 is a cyclohexyl group optionally substituted with one or two C1-6 alkoxy groups, for example...

环C是其中R5a是C1-6烷基或C1-6烷氧基，且R5b、R5c和R5d各自独立地为H或卤素，优选H；和其中R6是其中R6a是H或C1-6烷基，优选H；Ring C is Wherein R 5a is a C1-6 alkyl or C1-6 alkoxy, and R 5b , R 5c , and R 5d are each independently H or a halogen, preferably H; and wherein R 6 is Wherein R 6a is H or C 1-6 alkyl, preferably H;

部分选自其中R2’是C1-6烷基、C1-6氘代烷基、(C1-6烷氧基)-RL-、(C3-6环烷基)-RL-和(3-8元杂环烷基)-RL-，其中所述环烷基任选被一个或多个卤素取代；和R2c是H或卤素；part Selected from Wherein R 2 ' is a C 1-6 alkyl, C 1-6 deuterated alkyl, (C 1-6 alkoxy) -RL- , (C 3-6 cycloalkyl) -RL- , and (3-8 heterocyclic alkyl) -RL- , wherein the cycloalkyl is optionally substituted with one or more halogens; and R 2c is H or a halogen;

R1为C1-6烷基，优选甲基； R1 is a C1-6 alkyl group, preferably methyl;

RL各自独立地是价键、C1-4亚烷基或C1-4氘代亚烷基；R and L are each independently valenced, C1-4 alkylene, or C1-4 deuterated alkylene;

n是0和Rp不存在。n is 0 and R p does not exist.

在一些实施方案中，提供了式(III)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided.

其中：in:

W1、W2、W3、W4和W5各自独立地是C、CH或N，其中W1、W2、W3、W4和W5中至少一者是N； W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;

表示单键或双键； Indicates a single bond or a double bond;

T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule via two different ring carbon atoms;

Q为O或S；Q is either O or S;

R1各自独立地是氰基、C1-6烷基或C1-6氘代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;

R2a、R2b各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2a and R2b are each independently selected from H, halogens, NRaRb , C1-6 alkyl, 5-10 - membered heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa -S(O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a and R2b together with the atoms they are attached to form 5-6-membered saturated, partially unsaturated, or aromatic heterocycles, wherein the rings are optionally substituted with substituents selected from: halogens, oxo groups, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C 1-6 alkoxy) -RL- , (4-8 membered heterocyclic alkyl) -RL- , wherein the C 3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged ring;

R2c为H、卤素或C1-6烷基，优选H或卤素，例如氟；R 2c is H, halogen, or C1-6 alkyl, preferably H or halogen, such as fluorine;

R3a和R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, wherein the 4- to 6-membered ring is optionally substituted with one or more halogens or cyano, preferably halogens;

R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代；R 4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C 1-6 alkyl groups;

R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy )-RL-, (C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;

R6选自其中R6a是H或C1-6烷基，优选是H；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O or S;

RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基；R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2.

优选地，对于W1、W2、W3、W4和W5而言，在一些实施方案中，W1为N，且其余为C或CH；在另一些实施方案中，W3为N，且其余为C或CH；在另一些实施方案中，W5为N，且其余为C或CH。Preferably, for W1 , W2 , W3 , W4 and W5 , in some embodiments, W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.

在一些实施方案中，提供了式(III-1)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
In some embodiments, a compound of formula (III-1) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided.

其中：in:

W1、W2、W3、W4和W5各自独立地是C、CH或N，其中W1、W2、W3、W4和W5中至少一者是N； W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;

T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;

Q为O或S；Q is either O or S;

R1各自独立地是氰基、C1-6烷基或C1-6氘代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;

R2a、R2b各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2a and R2b are each independently selected from H, halogens, NRaRb , C1-6 alkyl, 5-10 - membered heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa -S(O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a and R2b together with the atoms they are attached to form 5-6-membered saturated, partially unsaturated, or aromatic heterocycles, wherein the rings are optionally substituted with substituents selected from: halogens, oxo groups, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C 1-6 alkoxy) -RL- , (4-8 membered heterocyclic alkyl) -RL- , wherein the C 3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged ring;

R2c为H、卤素或C1-6烷基，优选H或卤素，例如氟；R 2c is H, halogen, or C1-6 alkyl, preferably H or halogen, such as fluorine;

R3a和R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, wherein the 4- to 6-membered ring is optionally substituted with one or more halogens or cyano, preferably halogens;

R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代；R 4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C 1-6 alkyl groups;

R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy )-RL-, (C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;

R6选自其中R6a是H或C1-6烷基，优选是H；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O or S;

RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基；R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2.

优选地，对于W1、W2、W3、W4和W5而言，在一些实施方案中，W1为N，且其余为C或CH；在另一些实施方案中，W3为N，且其余为C或CH；在另一些实施方案中，W5为N，且其余为C或CH。Preferably, for W1 , W2 , W3 , W4 and W5 , in some embodiments, W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.

在一些实施方案中，提供了式(III)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，其中：In some embodiments, a compound of formula (III) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof is provided, wherein:

W1、W2、W3、W4和W5各自独立地是C、CH或N，其中W1、W2、W3、W4和W5中至少一者是N； W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N;

T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;

Q为O或S；Q is either O or S;

R1各自独立地是氰基、C1-6烷基或C1-6氘代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group;

R2a、R2b各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2a and R2b are each independently selected from H, halogen, NR a Rb , C1-6 alkyl, 5-10 membered heteroaryl optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a and R2b together with the atoms they are attached to form a 5-6 membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, (NR a Rb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- - ( C3-10 cycloalkyl group optionally substituted with one or more substituents independently selected from halogens or C1-6 alkoxy groups) -RL- , (4-8 membered heterocyclic alkyl group) -RL- , wherein the C3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic or bridged ring;

R2c为H、卤素或C1-6烷基，优选H或卤素，例如氟；R 2c is H, halogen, or C1-6 alkyl, preferably H or halogen, such as fluorine;

R3a和R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, wherein the 4- to 6-membered ring is optionally substituted with one or more halogens or cyano, preferably halogens;

R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代；R 4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C 1-6 alkyl groups;

R5a、R5b、R5c和R5d各自独立地是H、卤素、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently H, halogen, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups;

R6选自其中R6a是H或C1-6烷基，优选是H；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

Rs和Rt各自独立地是H、C1-6烷基或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O or S;

RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基；R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene;

m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5;

n是0、1或2；和n is 0, 1, or 2; and

q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2.

优选地，对于W1、W2、W3、W4和W5而言，在一些实施方案中，W1为N，且其余为C或CH；在另一些实施方案中，W3为N，且其余为C或CH；在另一些实施方案中，W5为N，且其余为C或CH。Preferably, for W1 , W2 , W3 , W4 and W5 , in some embodiments, W1 is N and the rest are C or CH; in other embodiments, W3 is N and the rest are C or CH; in still other embodiments, W5 is N and the rest are C or CH.

在一些实施方案中，本发明提供了式(IV)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，
In some embodiments, the present invention provides compounds of formula (IV) or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof.

其中：in:

W1、W2、W3、W4各自独立地是C、CH或N，其中W1、W2、W3、W4中至少一者是N； W1 , W2 , W3 , and W4 are each independently C, CH, or N, and at least one of W1 , W2 , W3 , and W4 is N;

T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule through two different ring carbon atoms;

Q为O或S，优选为O；Q can be O or S, preferably O;

R1为C1-6烷基； R1 is a C1-6 alkyl group;

R2a和R2b之一为-P(O)(C1-6烷基)(C1-6烷基)，且另一个为H或NH(C1-6烷基)；One of R2a and R2b is -P(O)( C1-6 alkyl)( C1-6 alkyl), and the other is H or NH( C1-6 alkyl);

或者R2a和R2b与它们所连接的碳原子一起形成含有一个或两个氮杂原子的5或6元杂芳环，所述杂芳环任选被选自C1-6烷基、C3-8环烷基、C3-8环烷基-(C1-4亚烷基)-和C3-8环烷基-(C1-4卤代亚烷基)-的取代基取代；Alternatively, R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, wherein the heteroaromatic ring is optionally substituted with a substituent selected from C1-6 alkyl, C3-8 cycloalkyl, C3-8 cycloalkyl-( C1-4 alkylene)- and C3-8 cycloalkyl-( C1-4 haloalkylene)-.

R2c为H或卤素；R 2c is H or a halogen;

R3a为H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-8环烷基；R3b为卤素；和R3c为H或C1-6烷基；R 3a is H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-8 cycloalkyl; R 3b is halogen; and R 3c is H or C1-6 alkyl;

R4为四氢吡喃基，任选被一个或多个、优选一个或两个C1-6烷基取代； R4 is a tetrahydropyranyl group, optionally substituted with one or more, preferably one or two C1-6 alkyl groups;

R5a是卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、或-(CH2)mN(C1-6烷基)(含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基)；且R5b、R5c和R5d各自独立地为H或卤素； R5a is a halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, or -( CH2 ) mN ( C1-6 alkyl) (containing one or more 5-7 heteroaryl groups, each independently selected from N, O, or S); and R5b , R5c , and R5d are each independently H or a halogen;

R6是其中R6a是H或C1-6烷基；和R 6 is Wherein R 6a is H or C 1-6 alkyl; and

n为0，即Rp不存在。When n is 0, Rp does not exist.

在一些实施方案中，本发明提供了式(IV)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，其中：In some embodiments, the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof, wherein:

W1为N，且W2、W3和W4各自独立地是C或CH； W1 is N, and W2 , W3 and W4 are each independently C or CH;

T为C2-4亚烯基；T is a C2-4 alkenyl group;

Q为O；Q is 0;

R1为C1-6烷基； R1 is a C1-6 alkyl group;

R2a和R2b与它们所连接的碳原子一起形成含有一个或两个氮杂原子的5或6元杂芳环，所述杂芳环任选被C1-6烷基取代；R 2a and R 2b together with the carbon atoms to which they are attached form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, wherein the heteroaromatic ring is optionally substituted with a C1-6 alkyl group;

R2c为卤素； R2c is a halogen;

R3a为C1-6烷基；R3b为卤素；和R3c为C1-6烷基；R 3a is a C1-6 alkyl group; R 3b is a halogen; and R 3c is a C1-6 alkyl group.

R4为四氢吡喃基，任选被一个或多个、优选一个或两个C1-6烷基取代； R4 is a tetrahydropyranyl group, optionally substituted with one or more, preferably one or two C1-6 alkyl groups;

R5a是C1-6烷基；且R5b、R5c和R5d各自独立地为H或卤素，优选为H；R 5a is a C1-6 alkyl group; and R 5b , R 5c and R 5d are each independently H or halogen, preferably H;

R6是其中R6a是H或C1-6烷基，优选为H；和R 6 is Wherein R 6a is H or C 1-6 alkyl, preferably H; and

n为0，即Rp不存在。When n is 0, Rp does not exist.

在一些实施方案中，本发明提供了式(IV)化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，其中：In some embodiments, the present invention provides a compound of formula (IV) or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof, wherein:

W1为N，且W2、W3和W4各自独立地是C或CH； W1 is N, and W2 , W3 and W4 are each independently C or CH;

T为C2-4亚烯基；T is a C2-4 alkenyl group;

Q为O；Q is 0;

R1为C1-6烷基，优选C1-4烷基，例如甲基； R1 is a C1-6 alkyl group, preferably a C1-4 alkyl group, such as methyl;

R2a和R2b与它们所连接的碳原子一起形成含有一个或两个氮杂原子的5或6元杂芳环，所述环被(C3-8环烷基)-C1-4亚烷基-或(C3-8卤代环烷基)-C1-4亚烷基-取代，优选被(C3-6环烷基)-C1-4亚烷基-或(C3-6卤代环烷基)-C1-4亚烷基-取代,；和R2c为卤素，优选F； R2a and R2b, together with the carbon atoms to which they are attached, form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, said ring being substituted with ( C3-8 cycloalkyl) -C1-4 alkylene- or ( C3-8 halocycloalkyl) -C1-4 alkylene-, preferably substituted with ( C3-6 cycloalkyl) -C1-4 alkylene- or ( C3-6 halocycloalkyl) -C1-4 alkylene-; and R2c is a halogen, preferably F;

R3a为C1-6烷基；R3b为卤素；和R3c为C1-6烷基；R 3a is a C1-6 alkyl group; R 3b is a halogen; and R 3c is a C1-6 alkyl group.

R4为四氢吡喃基，任选被一个或多个、优选一个或两个C1-6烷基取代； R4 is a tetrahydropyranyl group, optionally substituted with one or more, preferably one or two C1-6 alkyl groups;

R5a是C1-6烷基；且R5b、R5c和R5d各自独立地为H或卤素，优选为H；R 5a is a C1-6 alkyl group; and R 5b , R 5c and R 5d are each independently H or halogen, preferably H;

R6是其中R6a是H或C1-6烷基，优选为H；和R 6 is Wherein R 6a is H or C 1-6 alkyl, preferably H; and

n为0，即Rp不存在。When n is 0, Rp does not exist.

优选地，表示其中R2’是(任选被一个或多个卤素取代的C3-8环烷基)-C1-4亚烷基-，优选是(任选被一个或多个卤素如F取代的C3-6环烷基)-C1-4亚烷基-，更优选是(任选被一个或多个卤素如氟取代的环丙基)-C1-4亚烷基-，和R2c为卤素，优选F。Preferably, express Wherein R2 ' is (optionally substituted with one or more halogens) -C1-4 alkylene- , preferably (optionally substituted with one or more halogens such as F) -C1-4 alkylene-, more preferably (optionally substituted with one or more halogens such as fluorine) -C1-4 alkylene-, and R2c is a halogen, preferably F.

特别地，本发明提供了实施例的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物。优选地，实施例的化合物选自：In particular, the present invention provides compounds of the embodiments or pharmaceutically acceptable salts, tautomers, stereoisomers, isotopically labeled compounds, or solvates thereof. Preferably, the compounds of the embodiments are selected from:

表1.实施例的化合物












Table 1. Compounds from the Examples












在另一方面，本发明还提供了一种制备式(I)化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的方法，其中所述式(I)化合物具有式(I-1)的结构，
In another aspect, the present invention also provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound or solvate thereof, wherein the compound of formula (I) has the structure of formula (I-1).

其中，各变量如本文所定义，该方法包括：The variables are as defined in this paper, and the method includes:

-使式(A)化合物与式(B)化合物反应，
- To react compound (A) with compound (B),

其中各变量如本文所定义，The variables are as defined in this paper.

得到式(I-1)化合物，和任选地将其转化为可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的形式；任选地，该反应优选在缩合剂和碱的存在下、在溶剂中进行。在一些实施方案中，所述缩合剂、碱和溶剂如本文所定义。在一些实施方案中，所述缩合剂是1-羟基苯并三唑(HOBt)和/或1-乙基-(3-二甲氨基丙基)碳二亚胺(EDC)。在一些实施方案中，所述碱是二异丙基乙基胺。在一些实施方案中，所述溶剂是二甲基甲酰胺。The compound of formula (I-1) is obtained, and optionally converted into a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate; optionally, the reaction is preferably carried out in a solvent in the presence of a condensing agent and a base. In some embodiments, the condensing agent, base, and solvent are as defined herein. In some embodiments, the condensing agent is 1-hydroxybenzotriazole (HOBt) and/or 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC). In some embodiments, the base is diisopropylethylamine. In some embodiments, the solvent is dimethylformamide.

在一些实施方案中，本发明提供了一种制备式(I)化合物，或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的方法，其中所述式(I)化合物具有式(I-3)的结构：
In some embodiments, the present invention provides a method for preparing a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof, wherein the compound of formula (I) has the structure of formula (I-3):

其中，各变量如本文所定义，该方法包括：The variables are as defined in this paper, and the method includes:

-使式(A')化合物与式(B)化合物反应，
- To react compound (A') with compound (B),

其中各变量如本文所定义，The variables are as defined in this paper.

得到式(I-3)化合物，和任选地将其转化为可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的形式；任选地，该反应在缩合剂和碱的存在下、在溶剂中进行。在一些实施方案中，所述缩合剂、碱和溶剂如本文所定义。在一些实施方案中，所述缩合剂是1-羟基苯并三唑(HOBt)和/或1-乙基-(3-二甲氨基丙基)碳二亚胺(EDC)。在一些实施方案中，所述碱是二异丙基乙基胺。在一些实施方案中，所述溶剂是二甲基甲酰胺。The compound of formula (I-3) is obtained, and optionally converted into a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate; optionally, the reaction is carried out in a solvent in the presence of a condensing agent and a base. In some embodiments, the condensing agent, base, and solvent are as defined herein. In some embodiments, the condensing agent is 1-hydroxybenzotriazole (HOBt) and/or 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC). In some embodiments, the base is diisopropylethylamine. In some embodiments, the solvent is dimethylformamide.

在一些实施方案中，所述式(A')化合物可通过包括如下步骤的方法制备：In some embodiments, the compound of formula (A') can be prepared by a method comprising the following steps:

-使式(A'-5)化合物发生闭环反应，
- This causes the compound of formula (A'-5) to undergo a ring-closing reaction.

其中，PG表示氨基保护基如Boc，和其它变量如本文所定义，Wherein, PG represents an amino protecting group such as Boc, and other variables are as defined in this paper.

得到式(A')化合物；任选地，该反应优选在酸(例如对甲苯磺酸)的存在下、在溶剂(例如间二甲苯)中进行。The compound of formula (A') is obtained; optionally, the reaction is preferably carried out in the presence of an acid (e.g., p-toluenesulfonic acid) and in a solvent (e.g., m-xylene).

该反应可以在升高温度下、例如约100-200℃、例如约120-180℃、例如约140-160℃、例如150℃下进行。反应时间是使得反应完全的时间，例如1-20小时、例如1-10小时、例如1-5小时、例如1-2小时。在一些实施方案中，式(A'-5)化合物可通过包括如下步骤的方法制备，The reaction can be carried out at elevated temperatures, for example, about 100-200°C, about 120-180°C, about 140-160°C, or 150°C. The reaction time is the time required for the reaction to complete, for example, 1-20 hours, 1-10 hours, 1-5 hours, or 1-2 hours. In some embodiments, the compound of formula (A'-5) can be prepared by a method comprising the following steps:

(a)使式(A'-1)化合物与氯甲酸酯反应，
(a) Reaction of compound (A'-1) with chloroformate,

其中，PG表示氨基保护基如Boc，和其它变量如本文所定义，例如式(A'-5)中所定义，Wherein, PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).

生成式(A'-3)化合物，
Generative (A'-3) compounds,

其中，PG表示氨基保护基如Boc，和其它变量如本文所定义，例如式(A'-5)中所定义，Wherein, PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).

(b)将所得式(A'-3)化合物原位与式(A'-4)化合物反应，
(b) The resulting compound of formula (A'-3) is reacted in situ with the compound of formula (A'-4).

其中，变量如本文所定义，例如如式(A'-5)中所定义，The variables are as defined in this paper, for example, as defined in equation (A'-5).

得到式(A'-5)化合物。The compound of formula (A'-5) was obtained.

因此，在一些实施方案中，提供了制备式(A'-5)化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的方法，
Therefore, in some embodiments, methods are provided for preparing compounds of formula (A'-5) or pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, or solvates thereof.

其中，各变量如本文所定义，The variables are as defined in this paper.

该方法包括：The method includes:

(a)使式(A'-1)化合物与氯甲酸酯反应，
(a) Reaction of compound (A'-1) with chloroformate,

其中，PG表示氨基保护基如Boc，和其它变量如本文所定义，例如式(A'-5)中所定义，Wherein, PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).

生成式(A'-3)化合物，
Generative (A'-3) compounds,

其中，PG表示氨基保护基如Boc，和其它变量如本文所定义，例如式(A'-5)中所定义，Wherein, PG represents an amino protecting group such as Boc, and other variables are as defined herein, for example, as defined in equation (A'-5).

(b)将所得式(A'-3)化合物原位与式(A'-4)化合物反应，
(b) The resulting compound of formula (A'-3) is reacted in situ with the compound of formula (A'-4).

其中，变量如本文所定义，例如式(A'-5)中所定义，The variables are as defined in this paper, for example, as defined in equation (A'-5).

得到式(A'-5)化合物；任选地，将所得式(A'-5)化合物转化为其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的形式。A compound of formula (A'-5) is obtained; optionally, the obtained compound of formula (A'-5) is converted into its pharmaceutically usable salt, stereoisomer, tautomer, isotopically labeled compound or solvate.

在一些实施方案中，所述氯甲酸酯具有式(A'-2)的结构：
In some embodiments, the chloroformate has the structure of formula (A'-2):

其中RA是任意不干扰反应进行的基团。可以理解，RA可以位于苯环上任意可用的位置。Here, RA is any group that does not interfere with the reaction. It can be understood that RA can be located at any available position on the benzene ring.

在一些实施方案中，RA是H、硝基、CN、C1-6烷基、C1-6烯基、C1-6炔基、C1-6卤代烷基、C1-6卤代烯基、C1-6卤代炔基、磺酸酯基(-SO3H)、醛基(-CHO)、-CO(C1-6烷基)。在一些实施方案，RA是H、硝基、CN、CF3、CCl3、磺酸酯基(-SO3H)、醛基(-CHO)、-CO(C1-6烷基)。在一些实施方案中，RA是H或硝基。In some embodiments, RA is H, nitro, CN, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkenyl, C1-6 haloalkynyl, sulfonate (-SO3H), aldehyde ( -CHO ), or -CO ( C1-6 alkyl). In some embodiments, RA is H, nitro, CN, CF3 , CCl3 , sulfonate ( -SO3H ), aldehyde (-CHO), or -CO ( C1-6 alkyl). In some embodiments, RA is H or nitro.

在一些实施方案中，RA位于酯基的邻位或对位，优选位于对位。In some embodiments, RA is located at the ortho or para position of the ester group, preferably at the para position.

优选地，式(A'-2)的氯甲酸酯可以是氯甲酸苯酯或氯甲酸对硝基苯酯。Preferably, the chloroformate of formula (A'-2) can be phenyl chloroformate or p-nitrobenzene chloroformate.

在一些实施方案中，对于1摩尔当量式(A'-1)化合物而言，所述氯甲酸酯的量为约1～10摩尔当量，优选约2～4摩尔当量，更优选约4摩尔当量。In some embodiments, for a 1 molar equivalent (A'-1) compound, the amount of the chloroformate is about 1 to 10 molar equivalents, preferably about 2 to 4 molar equivalents, and more preferably about 4 molar equivalents.

在一些实施方案中，式(A'-1)化合物与氯甲酸酯反应形成式(A'-3)化合物的反应在碱的存在下进行。在一些实施方案中，所述碱可以是叔胺，例如三乙胺、N-甲基吗啉、二异丙基乙胺(DIPEA)、1,8-二氮杂二环十一碳-7-烯(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)。优选地，所述碱是二异丙基乙胺(DIPEA)。在一些实施方案中，对于1摩尔当量式(A'-1)化合物而言，所述碱的量为约1～10摩尔当量，优选约2～4摩尔当量，更优选约4摩尔当量。In some embodiments, the reaction of the compound of formula (A'-1) with a chloroformate to form the compound of formula (A'-3) is carried out in the presence of a base. In some embodiments, the base may be a tertiary amine, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO). Preferably, the base is diisopropylethylamine (DIPEA). In some embodiments, for 1 molar equivalent of the compound of formula (A'-1), the amount of the base is about 1 to 10 molar equivalents, preferably about 2 to 4 molar equivalents, and more preferably about 4 molar equivalents.

在一些实施方案中，式(A'-1)化合物与氯甲酸酯反应形成式(A'-3)化合物的反应在溶剂中进行。在一些实施方案中，所述溶剂是非质子极性溶剂，例如乙腈。In some embodiments, the reaction of compound (A'-1) with chloroformate to form compound (A'-3) is carried out in a solvent. In some embodiments, the solvent is an aprotic polar solvent, such as acetonitrile.

在一些实施方案中，式(A'-1)化合物与氯甲酸酯反应形成式(A'-3)化合物的反应可以在环境温度下进行，例如约20-25℃。反应时间是使得反应完全的时间，例如5分钟至5小时、5分钟至2小时、5分钟至1小时、5-30分钟、5-20分钟，例如15分钟。In some embodiments, the reaction of compound (A'-1) with chloroformate to form compound (A'-3) can be carried out at ambient temperature, for example, about 20-25°C. The reaction time is the time required for the reaction to complete, for example, 5 minutes to 5 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 5-30 minutes, 5-20 minutes, for example, 15 minutes.

在一些实施方案中，式(A'-3)化合物与式(A'-4)化合物的原位反应是通过将式(A'-4)化合物和任选的碱加入到步骤(a)的反应物中来进行的。在一些实施方案中，式(A'-3)化合物与式(A'-4)化合物的原位反应是通过将式(A'-4)化合物和碱例如二异丙基乙胺混合在溶剂中，再加入到步骤(a)的反应物中来进行的。在一些实施方案中，所述碱可以是叔胺，例如三乙胺、N-甲基吗啉、二异丙基乙胺(DIPEA)、1,8-二氮杂二环十一碳-7-烯(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)。优选地，所述碱是二异丙基乙胺(DIPEA)。在一些实施方案中，对于1摩尔当量式(A'-3)化合物而言，所述碱的量为约0～4当量，优选约0～2当量，更优选约2当量。在一些实施方案中，所述溶剂是非质子极性溶剂，例如乙腈。In some embodiments, the in-situ reaction of compound (A'-3) with compound (A'-4) is carried out by adding compound (A'-4) and optionally a base to the reactants of step (a). In some embodiments, the in-situ reaction of compound (A'-3) with compound (A'-4) is carried out by mixing compound (A'-4) and a base, such as diisopropylethylamine, in a solvent and then adding it to the reactants of step (a). In some embodiments, the base may be a tertiary amine, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO). Preferably, the base is diisopropylethylamine (DIPEA). In some embodiments, for a 1 molar equivalent of the (A'-3) compound, the amount of the base is about 0 to 4 equivalents, preferably about 0 to 2 equivalents, and more preferably about 2 equivalents. In some embodiments, the solvent is an aprotic polar solvent, such as acetonitrile.

在一些实施方案中，式(A'-3)化合物与式(A'-4)化合物的原位反应可以在升高温度下、例如约40-90℃、例如50-60℃、例如55℃下进行。反应时间是使得反应完全的时间，例如1-20小时、例如1-10小时、例如1-5小时、例如1-2小时。In some embodiments, the in-situ reaction of compound (A'-3) with compound (A'-4) can be carried out at elevated temperatures, for example, about 40-90°C, for example, 50-60°C, for example, 55°C. The reaction time is the time required for the reaction to complete, for example, 1-20 hours, for example, 1-10 hours, for example, 1-5 hours, for example, 1-2 hours.

氨基保护基可根据远离官能团的性质和制备方法的条件而变化。适宜的氨基保护基包括乙酰基、三氟乙酰基、苄基、苯基磺酰基、叔丁氧羰基(Boc)、苄氧羰基(CBz)和9-芴甲氧羰基(Fmoc)。所述保护的需求由本领域技术人员容易地决定。The amino protecting group can vary depending on its distance from the functional group and the conditions of the preparation method. Suitable amino protecting groups include acetyl, trifluoroacetyl, benzyl, phenylsulfonyl, tert-butoxycarbonyl (Boc), benzyloxycarbonyl (CBz), and 9-fluorenemethoxycarbonyl (Fmoc). The required protection can be readily determined by those skilled in the art.

可以理解，本领域技术人员可以从任意适当的化合物(例如式A'-1、A'-3、A'-5或A')开始并进行随后的步骤，以获得本发明的式(I)或其亚式的化合物。还可以理解，本领域技术人员可以从任意适当的化合物开始，以获得预期的中间体化合物(例如式A'、式A'-5)。It is understood that those skilled in the art can begin with any suitable compound (e.g., formula A'-1, A'-3, A'-5, or A') and proceed with the subsequent steps to obtain a compound of formula (I) or a subform thereof of the present invention. It is also understood that those skilled in the art can begin with any suitable compound to obtain the desired intermediate compound (e.g., formula A', formula A'-5).

在一些实施方案中，提供了式(A'-5)化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中：In some embodiments, a compound of formula (A'-5) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof is provided, wherein:

PG表示氨基保护基如Boc；PG indicates an amino protecting group, such as Boc;

环A是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、和(任选被一个或多个独立地选自卤素和C1-6烷基取代的C3-10环烷基)-RL-，或者其中两个R3连同它们所连接的原子一起形成任选地含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基和C1-6羟基烷基的取代基取代；Ring A is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted with one or more R3s , each R3 independently selected from halogens, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyls independently selected from halogens and C1-6 alkyls) -RL- , or two of the R3s. 3 together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, said 4- to 6-membered ring optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl;

环D是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基；Ring D is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl.

R1是H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C2-6烯基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基； R1 is H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl , C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl;

R2各自独立地选自H、卤素、氰基、OH、NRaRb、C1-6烷基、C2-6烯基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6卤代烷氧基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者其中两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2 is independently selected from H, halogen, cyano, OH, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 (C1-6 alkyl), -NR a -S(O) 2- (C1-6 alkyl ), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a )-(C 3-10 cycloalkyl) or -C(=O)-N( Ra )-(C 3-10 cycloalkyl), or where the two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C1-6 alkoxy )-RL-, ( C1-6 alkylthio)-RL-, (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkyl)-RL-, ( C6-10 aryl) -RL- and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic or bridged ring;

Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present;

Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl;

RL各自独立地是价键；任选被卤素、氰基或羟基取代的C1-10亚烷基；或C1-4氘代亚烷基；R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups;

m是0、1、2、3、4或5；和m is 0, 1, 2, 3, 4, or 5; and

n是0、1或2。n is 0, 1, or 2.

在一些实施方案中，提供了式(A'-5)化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中：In some embodiments, a compound of formula (A'-5) or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof is provided, wherein:

PG表示氨基保护基如Boc；PG indicates an amino protecting group, such as Boc;

环A是其中R3a、R3b和R3c各自独立地选自卤素、C1-6烷基和C1-6卤代烷基(优选地，R3a为C1-6烷基或C1-6卤代烷基，R3b为卤素如氟，和R3c为C1-6烷基)，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，和R3c是H；或者Ring A is R3a , R3b , and R3c are each independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups (preferably, R3a is a C1-6 alkyl or C1-6 haloalkyl group, R3b is a halogen such as fluorine, and R3c is a C1-6 alkyl group), or R3a and R3b, together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, and R3c is H; or

环A是苯基或苯并呋喃基，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、C1-6烷基和C1-6卤代烷基；Ring A is phenyl or benzofuranyl, each optionally substituted by one or more R3s , each R3 being independently selected from halogens, C1-6 alkyl groups, and C1-6 haloalkyl groups;

部分选自其中R2’是C1-6烷基、C1-6氘代烷基、(C1-6烷氧基)-RL-、(C3-6环烷基)-RL-和(3-8元杂环烷基)-RL-，其中所述环烷基任选被一个或多个卤素取代；和R2c是H或卤素；part Selected from Wherein R 2 ' is a C 1-6 alkyl, C 1-6 deuterated alkyl, (C 1-6 alkoxy) -RL- , (C 3-6 cycloalkyl) -RL- , and (3-8 heterocyclic alkyl) -RL- , wherein the cycloalkyl is optionally substituted with one or more halogens; and R 2c is H or a halogen;

R1为C1-6烷基，优选甲基； R1 is a C1-6 alkyl group, preferably methyl;

RL各自独立地是价键、C1-4亚烷基或C1-4氘代亚烷基；R and L are each independently valenced, C1-4 alkylene, or C1-4 deuterated alkylene;

n是0和Rp不存在。n is 0 and R p does not exist.

可以理解，本文对式(I)或其亚式所描述的各个技术方案及变量定义可等同地应用于其各个中间体，例如式A'-1、式A'-3、式A'-4、式A'-5、式A'或式A等，此处不再累述。It is understood that the technical solutions and variable definitions described in Equation (I) or its sub-equations can be applied equally to their respective intermediates, such as Equation A'-1, Equation A'-3, Equation A'-4, Equation A'-5, Equation A' or Equation A, etc., which will not be repeated here.

本文所述的各个方面和实施方案及其每个特征以及下文的定义可以任意地组合，构成未在说明书中直接记载、但是符合本发明宗旨的实施方案，这些实施方案也囊括在本发明的范围内。The various aspects and embodiments described herein, as well as each feature and the definitions herein, can be combined arbitrarily to form embodiments not directly described in the specification but consistent with the spirit of the invention, and these embodiments are also included within the scope of the invention.

定义definition

在本申请中，除非另有说明，否则本申请所用的术语具有下文定义的含义。本申请未明确定义的术语具有本领域技术人员通常理解的一般含义。In this application, unless otherwise stated, the terms used have the meanings defined below. Terms not explicitly defined in this application have the general meanings commonly understood by those skilled in the art.

在本申请中使用的术语“一个”、“一种”、“所述”和类似术语应理解为包括单数和复数，除非上下文另外特别指出或根据上下文明显矛盾。The terms “a,” “an,” “the,” and similar terms used in this application shall be understood to include both the singular and the plural, unless the context otherwise specifically indicates or is obviously contradictory.

价键表示单键或双键。Price key Indicates a single bond or a double bond.

术语“卤素”或“卤代”指氟(F)、氯(Cl)、溴(Br)或碘(I)。优选的卤素是氟和氯。The term "halogen" or "halogenated" refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I). Preferred halogens are fluorine and chlorine.

术语“烷基”单独或作为其它基团一部分表示由碳和氢原子组成的完全饱和的直链或支链烃基团。术语“C1-6烷基”表示具有1-6个碳原子的烷基。C1-6烷基优选是C1-4烷基或C1-3烷基。其代表性实例包括但不限于甲基(Me)、乙基(Et)、丙基(Pr)(包括正丙基和异丙基)、丁基(Bu)(包括正丁基、异丁基、仲丁基和叔丁基)、戊基(包括正戊基、异戊基、新戊基等)、己基、庚基、辛基等。The term "alkyl" alone or as part of other groups refers to a fully saturated straight-chain or branched hydrocarbon group consisting of carbon and hydrogen atoms. The term " C1-6 alkyl" refers to an alkyl group having 1-6 carbon atoms. C1-6 alkyl is preferably C1-4 or C1-3 alkyl. Representative examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (Pr) (including n-propyl and isopropyl), butyl (Bu) (including n-butyl, isobutyl, sec-butyl, and tert-butyl), pentyl (including n-pentyl, isopentyl, neopentyl, etc.), hexyl, heptyl, octyl, etc.

术语“亚烷基”单独或作为其它基团一部分表示由碳和氢原子组成的完全饱和的直链或支链二价烃基团。亚烷基例如是C1-6亚烷基、优选是C1-4亚烷基、更优选是C1-2亚烷基。其代表性实例包括但不限于亚甲基、亚乙基、亚丙基、亚丁基等。The term "alkylene" alone or as part of other groups refers to a fully saturated straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms. Alkylenes are, for example, C1-6 alkylenes, preferably C1-4 alkylenes, and more preferably C1-2 alkylenes. Representative examples include, but are not limited to, methylene, ethylene, propylene, butylene, etc.

术语“烯基”单独或作为其它基团一部分表示由碳原子和氢原子组成的包含至少一条双键的直链或支链烃基团。术语“C2-6烯基”表示具有2-6个碳原子的烯基。C2-6烯基优选是C2-4烯基或C2-3烯基。其代表性实例包括但不限于乙烯基、丙烯基、烯丙基、丁烯基、异丁烯基、戊烯基、异戊烯基、己烯基、庚烯基等。The term "alkenyl" alone or as part of other groups refers to a straight-chain or branched hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one double bond. The term " C2-6 alkenyl" refers to an alkenyl group having 2 to 6 carbon atoms. C2-6 alkenyl is preferably C2-4 alkenyl or C2-3 alkenyl. Representative examples include, but are not limited to, vinyl, propenyl, allyl, butenyl, isobutenyl, pentenyl, isopentenyl, hexenyl, heptenyl, etc.

术语“亚烯基”单独或作为其它基团一部分表示由碳原子和氢原子组成的包含至少一条双键的直链或支链二价烃基团。术语“C2-6亚烯基”表示具有2-6个碳原子的亚烯基。C2-6亚烯基优选是C2-4亚烯基或C2-3亚烯基。其代表性实例包括但不限于亚乙烯基、亚丙烯基、亚烯丙基、亚丁烯基等。The term "alkenyl" alone or as part of other groups refers to a straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one double bond. The term " C2-6 alkenyl" refers to an alkenyl group having 2-6 carbon atoms. C2-6 alkenyl groups are preferably C2-4 or C2-3 alkenyl groups. Representative examples include, but are not limited to, vinylidene, propenyl, allyl, and butenyl groups.

术语“炔基”单独或作为其它基团一部分表示由碳原子和氢原子组成的包含至少一条叁键的直链或支链烃基团。术语“C2-6炔基”表示具有2-6个碳原子的炔基。C2-6炔基优选是C2-4炔基或C2-3炔基。其代表性示例包括但不限于乙炔基、丙炔基、炔丙基、丁炔基、异丁炔基、戊炔基、异戊炔基、己炔基、庚炔基等。The term "alkynyl" alone or as part of other groups refers to a straight-chain or branched hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one triple bond. The term " C2-6 alkynyl" refers to an alkynyl group having 2-6 carbon atoms. C2-6 alkynyl is preferably C2-4 or C2-3 alkynyl. Representative examples include, but are not limited to, ethynyl, propynyl, propynyl, butynyl, isobutynyl, penynyl, isopentenynyl, hexynyl, heptyynyl, etc.

术语“亚炔基”单独或作为其它基团一部分表示由碳原子和氢原子组成的包含至少一条三键的直链或支链二价烃基团。术语“C2-6亚炔基”表示具有2-6个碳原子的亚炔基。C2-6亚炔基优选是C2-4亚炔基或C2-3亚炔基。其代表性实例包括但不限于亚乙炔基、亚丙炔基、亚丁炔基等。The term "ynynyl" alone or as part of other groups refers to a straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms and containing at least one triple bond. The term "C 2-6 ynynyl" refers to an ynynyl group having 2-6 carbon atoms. C 2-6 ynynyl is preferably C 2-4 or C 2-3 ynynyl. Representative examples include, but are not limited to, ethynylene, propynylene, and butynylene.

术语“卤代烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素取代的如本文所定义的烷基。可以理解，当卤素取代基多于一个时，所述卤素取代基可以相同或不同，并且可以位于相同或不同的碳原子上。卤代烷基优选是C1-6卤代烷基，更优选是C1-4卤代烷基或C1-3卤代烷基。其代表性实例包括但不限于氟甲基、氯甲基、二氟甲基、二氯甲基、氟氯甲基、三氟甲基、三氯甲基、二氯氟甲基、二氟乙基、三氟乙基、三氯乙基、二氟氯乙基、二氟丙基和三氟丙基等。The term "haloalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, such as 1, 2, or 3 hydrogen atoms, are substituted with a halogen. It is understood that when there is more than one halogen substituent, the halogen substituents can be the same or different, and can be located on the same or different carbon atoms. Haloalkyl is preferably a C1-6 haloalkyl, more preferably a C1-4 or C1-3 haloalkyl. Representative examples include, but are not limited to, fluoromethyl, chloromethyl, difluoromethyl, dichloromethyl, fluorochloromethyl, trifluoromethyl, trichloromethyl, dichlorofluoromethyl, difluoroethyl, trifluoroethyl, trichloroethyl, difluorochloroethyl, difluoropropyl, and trifluoropropyl.

术语“卤代亚烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素取代的如本文所定义的亚烷基。可以理解，当卤素取代基多于一个时，所述卤素取代基可以相同或不同，并且可以位于相同或不同的碳原子上。卤代亚烷基优选是C1-4卤代亚烷基或C1-3卤代亚烷基。其代表性实例包括但不限于氟亚甲基、氯亚甲基、二氟亚甲基、二氯亚甲基、氟氯亚甲基、三氟亚甲基、三氯亚甲基等。The term "halogenated alkylene" refers to an alkylene group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, such as 1, 2, or 3 hydrogen atoms, are substituted with a halogen. It is understood that when there is more than one halogen substituent, the halogen substituents can be the same or different, and can be located on the same or different carbon atoms. Halogenated alkylenes are preferably C1-4 or C1-3 alkylenes. Representative examples include, but are not limited to, fluoromethylene, chloromethylene, difluoromethylene, dichloromethylene, fluorochloromethylene, trifluoromethylene, trichloromethylene, etc.

术语“氰基烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被氰基替代的如本文所定义的烷基。氰基烷基优选是C1-6氰基烷基，更优选是C1-4氰基烷基或C1-3氰基烷基。其代表性实例包括但不限于氰基甲基、氰基乙基、氰基丙基等。The term "cyanoalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, such as 1, 2 , or 3 hydrogen atoms, are replaced by a cyano group. Cyanoalkyl groups are preferably C1-6 cyanoalkyl groups, more preferably C1-4 or C1-3 cyanoalkyl groups. Representative examples include, but are not limited to, cyanomethyl, cyanoethyl, cyanopropyl, etc.

术语“氰基亚烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被氰基替代的如本文所定义的亚烷基。氰基亚烷基优选是C1-4氰基亚烷基或C1-3氰基亚烷基。其代表性实例包括但不限于氰基亚甲基、氰基亚乙基、氰基亚丙基等。The term "cyanoalkylene" refers to an alkylene group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or such as 1, 2 , or 3 hydrogen atoms, are replaced by a cyano group. Cyanoalkylene groups are preferably C1-4 or C1-3 cyanoalkylene groups. Representative examples include, but are not limited to, cyanomethylene, cyanoethylene, cyanopropylene, etc.

术语“羟基烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被羟基替代的如本文所定义的烷基。羟基烷基优选是C1-6羟基烷基，更优选是C1-4羟基烷基或C1-3羟基烷基。其代表性实例包括但不限于羟甲基、羟乙基、羟丙基等。The term "hydroxyalkyl" refers to an alkyl group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or such as 1, 2 , or 3 hydrogen atoms, are replaced by a hydroxyl group. Hydroxyalkyl groups are preferably C1-6 hydroxyalkyl groups, more preferably C1-4 or C1-3 hydroxyalkyl groups. Representative examples include, but are not limited to, hydroxymethyl, hydroxyethyl, and hydroxypropyl groups.

术语“羟基亚烷基”指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被羟基替代的如本文所定义的亚烷基。羟基亚烷基优选是C1-4羟基亚烷基或C1-3羟基亚烷基。其代表性实例包括但不限于羟基亚甲基、羟基亚乙基、羟基亚丙基等。The term "hydroxyalkylene" refers to an alkylene group as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or such as 1, 2 , or 3 hydrogen atoms, are replaced by a hydroxyl group. Hydroxyalkylene groups are preferably C1-4 or C1-3 hydroxyalkylene groups. Representative examples include, but are not limited to, hydroxymethylene, hydroxyethylene, and hydroxypropylene.

术语“烷亚基”(alkylidene)单独或作为其它基团一部分表示由碳和氢原子组成的完全饱和的直链或支链二价烃基，其经由碳端的一个双键连接。烷亚基例如是C1-6烷亚基、优选C1-4烷亚基。其实例包括但不限于亚甲基(methylidene)(CH2＝)、乙亚基(ethylidene)(CH3CH＝)、丙亚基(propanylidene)((CH3)2C＝)、亚丁基(butanylidene)((CH3CH2)(CH3)C＝)等。The term "alkylidene" alone or as part of other groups refers to a fully saturated straight-chain or branched divalent hydrocarbon group consisting of carbon and hydrogen atoms linked by a double bond at the carbon end. Alkylides are, for example, C1-6 alkylides, preferably C1-4 alkylides. Examples include, but are not limited to, methylidene ( CH2 =), ethylidene ( CH3CH = ), propanylidene (( CH3 ) 2C =), and butanylidene (( CH3CH2 )( CH3 )C=).

术语“卤代烷亚基”(alkylidene)指其中一个或多个氢原子、例如1、2、3、4、5、6或7个氢原子、例如1、2或3个氢原子被卤素取代的如本文所定义的烷亚基。可以理解，当卤素取代基多于一个时，所述卤素取代基可以相同或不同，并且可以位于相同或不同的碳原子上。卤代烷亚基例如是C1-6卤代烷亚基、优选C1-4卤代烷亚基。其实例包括但不限于卤代亚甲基(halo-methylidene)、卤代乙亚基(halo-ethylidene)、卤代丙亚基(halo-propanylidene)、卤代亚丁基(halo-butanylidene)等。The term "alkylidene" refers to an alkylidene as defined herein in which one or more hydrogen atoms, such as 1, 2, 3, 4, 5, 6, or 7 hydrogen atoms, or for example 1, 2, or 3 hydrogen atoms, are substituted with a halogen. It is understood that when there is more than one halogen substituent, the halogen substituents can be the same or different, and can be located on the same or different carbon atoms. Alkylidenes are, for example, C1-6 alkylidenes, preferably C1-4 alkylidenes. Examples include, but are not limited to, halo-methylidene, halo-ethylidene, halo-propanylidene, halo-butanylidene, etc.

术语“烷氧基”或“烷基氧基”可互换使用，表示通过氧桥连接的如上定义的烷基。烷氧基优选是C1-6烷氧基，更优选是C1-4烷氧基或C1-3烷氧基。其代表性实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基、异丙氧基)、丁氧基(包括正丁氧基、仲丁氧基、异丁氧基、叔丁氧基等)、戊氧基(包括正戊氧基、异戊氧基、新戊氧基等)、己氧基、庚氧基、辛氧基等。The terms "alkoxy" and "alkyloxy" are used interchangeably to refer to an alkyl group as defined above, linked by an oxygen bridge. Alkoxy groups are preferably C1-6 alkoxy groups, more preferably C1-4 or C1-3 alkoxy groups. Representative examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, sec-butoxy, isobutoxy, tert-butoxy, etc.), pentoxy (including n-pentoxy, isopentoxy, neopentoxy, etc.), hexoxy, heptoxy, octoxy, etc.

术语“烷硫基”或“烷基硫基”可互换使用，表示通过硫桥连接的如上定义的烷基。烷硫基优选是C1-6烷硫基，更优选是C1-4烷硫基或C1-3烷硫基。其代表性实例包括但不限于甲硫基、乙硫基、丙硫基(包括正丙硫基、异丙硫基)、丁硫基(包括正丁硫基、仲丁硫基、异丁硫基、叔丁硫基等)、戊硫基(包括正戊硫基、异戊硫基、新戊硫基等)、己硫基、庚硫基、辛硫基等。The terms "alkathio" and "alkylthio" are used interchangeably to refer to an alkyl group as defined above, linked by a sulfur bridge. The alkathio group is preferably a C1-6 alkathio group, more preferably a C1-4 or C1-3 alkathio group. Representative examples include, but are not limited to, methylthio, ethylthio, propylthio (including n-propylthio and isopropylthio), butylthio (including n-butylthio, sec-butylthio, isobutylthio, tert-butylthio, etc.), pentylthio (including n-pentylthio, isopentylthio, neopentylthio, etc.), hexylthio, heptylthio, octylthio, etc.

术语“环烷基”表示由碳和氢原子组成的完全饱和的环状烃基团，其可以是单环、双环、螺环或桥环。术语“C3-10环烷基”表示具有3至10个环碳原子的环烷基，术语“C3-8环烷基”表示具有3至8个环碳原子的环烷基，术语“C3-6环烷基”表示具有3至6个环碳原子的环烷基。其代表性实例包括但不限于环丙基、环丁基、环戊基、环己基、双环[1.1.1]戊烷基、螺[3.3]庚烷基等。The term "cycloalkyl" refers to a fully saturated cyclic hydrocarbon group consisting of carbon and hydrogen atoms, which can be monocyclic, bicyclic, spirocyclic, or bridged. The terms " C3-10 cycloalkyl" refer to cycloalkyl groups having 3 to 10 cyclic carbon atoms, " C3-8 cycloalkyl" refer to cycloalkyl groups having 3 to 8 cyclic carbon atoms, and " C3-6 cycloalkyl" refer to cycloalkyl groups having 3 to 6 cyclic carbon atoms. Representative examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclic [1.1.1]pentyl, spiro[3.3]heptyl, etc.

术语“环烯基”表示由碳和氢原子组成的、含有一条或多条双键的部分不饱和的环状烃基团。环烯基优选是C3-10环烯基，更优选是C3-8环烯基。其代表性实例包括但不限于环丙烯基、环丁烯基、环戊烯基、环己烯基、环庚烯基等。The term "cycloalkenyl" refers to a partially unsaturated cyclic hydrocarbon group composed of carbon and hydrogen atoms and containing one or more double bonds. Cycloalkenyl groups are preferably C3-10 cycloalkenyl groups, and more preferably C3-8 cycloalkenyl groups. Representative examples include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl groups.

术语“亚环烷基”表示由碳和氢原子组成的完全饱和的二价环状烃基团。术语“C3-8亚环烷基”表示具有3至8个环碳原子的亚环烷基，术语“C3-6亚环烷基”表示具有3至6个环碳原子的亚环烷基。其代表性实例包括但不限于亚环丙基、亚环丁基、亚环戊基、亚环己基等。所述亚环烷基可以通过相同的环碳原子或两个不同的环碳原子与分子的其它部分键合。The term "cycloalkylene" refers to a fully saturated divalent cyclic hydrocarbon group consisting of carbon and hydrogen atoms. The terms " C3-8 cycloalkylene" and " C3-6 cycloalkylene" refer to cycloalkylene groups having 3 to 8 ring carbon atoms, respectively. Representative examples include, but are not limited to, cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene. The cycloalkylene group can be bonded to other parts of the molecule via the same ring carbon atom or two different ring carbon atoms.

术语“芳基”表示环成员为碳的芳香族单环或双环。术语“C6-10芳基”表示具有6-10个环碳原子的芳基。其代表性实例包括但不限于苯基(即C6芳基)、萘基等。The term "aryl" refers to an aromatic monocyclic or bicyclic ring with a carbon ring member. The term " C6-10 aryl" refers to an aryl group having 6-10 ring carbon atoms. Representative examples include, but are not limited to, phenyl (i.e., C6 aryl) and naphthyl.

术语“杂环烷基”表示具有一个或多个、优选1-6个、例如1、2、3、4、5或6个各自独立地选自N、O或S的杂原子且其余环成员为碳的饱和单环或二环环状基团，包括螺环。杂环烷基的碳成员可以被-CO-代替，并且所述任意N和S杂原子可以任选被氧化(例如在NO、SO、SO2中)和所述任意N杂原子可以任选被季铵化(例如在[NR]+Cl-、[NR]+OH-中)。术语“3-10元杂环烷基”表示具有3至10个环成员的杂环烷基。其优选是4-8元杂环烷基，更优选5-6元杂环烷基。杂环烷基可以通过碳原子或杂原子与分子的其余部分连接，只要化学上可行即可。杂环烷基的代表性实例包括但不限于吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基、咪唑烷基、咪唑酮基、噁唑烷基、异噁唑烷基、噻唑烷基、异噻唑烷基、哌啶基、哌啶酮基、六氢哒嗪基、六氢嘧啶基、哌嗪基、四氢吡喃基、四氢噻喃基、吗啉基、硫吗啉基、硫吗啉1-氧化物、硫吗啉1,1-二氧化物、氧杂环庚烷基、氮杂环庚烷基、氧杂氮杂环庚烷基等。当杂环烷基仅含有氧作为杂原子时，可以称为“氧杂环烷基”。The term "heterocyclic alkyl" refers to a saturated monocyclic or bicyclic group, including spirocyclic groups, having one or more, preferably 1 to 6, for example 1, 2, 3, 4, 5, or 6 heteroatoms, each independently selected from N, O, or S, and with the remaining ring members being carbon. The carbon members of a heterocyclic alkyl group may be replaced by -CO-, and the arbitrary N and S heteroatoms may optionally be oxidized (e.g., in NO, SO, SO₂ ) and the arbitrary N heteroatoms may optionally be quaternized (e.g., in [NR] + Cl- , [NR] + OH- ). The term "3-10-membered heterocyclic alkyl" refers to a heterocyclic alkyl group having 3 to 10 ring members. It is preferably a 4-8-membered heterocyclic alkyl, more preferably a 5-6-membered heterocyclic alkyl. Heterocyclic alkyl groups may be attached to the rest of the molecule by carbon atoms or heteroatoms, provided it is chemically feasible. Representative examples of heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, imidazoketyl, oxazolyl, isoxazolyl, thiazoyl, isothiazolyl, piperidinyl, piperidinoneyl, hexahydropyridinyl, hexahydropyrimidinyl, piperazinyl, tetrahydropyranyl, tetrahydrothiaranyl, morpholinyl, thiomorpholinyl, thiomorpholine 1-oxide, thiomorpholine 1,1-dioxide, oxeheptyl, azaheptyl, and oxaazaheptyl. When a heterocyclic alkyl group contains only oxygen as a heteroatom, it can be called an "oxeheptyl".

术语“杂环烯基”表示具有一个或多个、优选1-6个、例如1、2、3、4、5或6个各自独立地选自N、O或S的杂原子且其余环成员为碳的、包含一条或多条碳碳双键的非芳香族单环或二环环状基团，包括螺环。术语“3-10元杂环烯基”表示具有3至10个环成员的杂环烯基。The term "heterocyclic alkenyl" refers to a non-aromatic monocyclic or bicyclic group, including spirocyclic groups, having one or more, preferably 1 to 6, for example 1, 2, 3, 4, 5, or 6 heteroatoms each independently selected from N, O, or S, and with the remaining ring members being carbon, containing one or more carbon-carbon double bonds. The term "3-10-membered heterocyclic alkenyl" refers to a heterocyclic alkenyl group having 3 to 10 ring members.

术语“杂芳基”或“杂芳环”指具有一个或多个、优选1-6个、更优选1、2、3或4个独立地选自N、O或S的杂原子且其余环成员为碳的芳香族环状基团。杂芳基的任意N和S杂原子可以任选被氧化(例如在NO、SO、SO2中)和所述任意N杂原子可以任选被季铵化(例如在[NR]+Cl-、[NR]+OH-中)。杂芳基(杂芳环)优选是5-10元杂芳基(杂芳环)，更优选5-7元杂芳基(杂芳环)，最优选5-或6-杂芳基(杂芳环)。其代表性实例包括但不限于：吡咯基、呋喃基、噻吩基、吡唑基、咪唑基、噁唑基、异噻唑基、噁二唑基、噻唑基、异噻唑基、三唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吡喃基、噻喃基、噁嗪基、噁二嗪基、吲哚基、异吲哚基、氮杂吲哚基(例如7-氮杂吲哚基、6-氮杂吲哚基、5-氮杂吲哚基、4-氮杂吲哚基)、苯并呋喃基、异苯并呋喃基、苯并噻吩基、苯并噻唑基、吲唑基、苯并咪唑基、苯并噁唑基、喹啉基、异喹啉基、苯并吡喃基、噌啉基、喹唑啉基、喹喔啉基、苯并噁嗪基、苯并三唑基、嘌呤基、中氮茚基、吡咯并吡啶基、吡咯并嘧啶基、吡咯并吡嗪基、咪唑并吡啶基、咪唑并嘧啶基、吡唑并吡啶基、吡唑并哒嗪基、吡唑并嘧啶基、吡唑并吡嗪基、吡啶并吡嗪基、吡啶并嘧啶基、嘧啶并嘧啶基、吡嗪并吡嗪基、酞嗪、萘啶基等。杂芳基(杂芳环)可以通过碳原子或杂原子与化合物的其余部分连接，只要化学上可行即可。杂芳基(杂芳环)也可以与其它环状基团稠合。The term "heteroaryl" or "heteroary ring" refers to an aromatic cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, and the remaining ring members being carbon. Any N and S heteroatoms of the heteroaryl group may optionally be oxidized (e.g., in NO, SO, SO₂ ) and said any N heteroatoms may optionally be quaternized (e.g., in [NR] + Cl⁻ , [NR] + OH⁻ ). The heteroaryl (heteroary ring) is preferably a 5- to 10-membered heteroaryl (heteroary ring), more preferably a 5- to 7-membered heteroaryl (heteroary ring), and most preferably a 5- or 6-heteroaryl (heteroary ring). Representative examples include, but are not limited to: pyrrole, furanyl, thiophene, pyrazolyl, imidazolyl, oxazolyl, isothiazolyl, oxadiazolyl, thiazolyl, isothiazolyl, triazolyl, pyridinyl, pyrazinyl, pyranyl, thiophene, oxazinyl, oxadiazinyl, indole, isoindole, azaindole (e.g., 7-azaindole, 6-azaindole, 5-azaindole, 4-azaindole), benzofuranyl, isobenzofuranyl, benzothiophene, benzothiazole The compounds include alkyl, indazole, benzimidazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, benzopyranyl, cenolinyl, quinazolinyl, quinoxolinyl, benzoxazinyl, benzotriazolyl, purine, indoleyl, pyrrolopyridyl, pyrrolopyrimidinyl, pyrrolopyrazinyl, imidazopyridyl, imidazopyrimidinyl, pyrazolopyridyl, pyrazolopyridyl, pyrazolopyrazinyl, pyridopyrimidinyl, pyrimidopyrimidinyl, pyrazolopyrazinyl, phthalazine, naphthidyl, etc. Heteroaryl groups (heteroary aromatic rings) can be attached to the rest of the compound via carbon atoms or heteroatoms, as long as it is chemically feasible. Heteroaryl groups (heteroary aromatic rings) can also be fused with other cyclic groups.

术语“亚杂芳基”指具有一个或多个、优选1-6个、更优选1、2、3或4个独立地选自N、O或S的杂原子且其余环成员为碳的二价芳香族环状基团。术语“8-10元双环亚杂芳基”指具有一个或多个、优选1-6个、更优选1、2、3或4个独立地选自N、O或S的杂原子且其余环成员为碳的二价芳香族双环基团。The term "heteroaryl" refers to a divalent aromatic cyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, and the remaining ring members being carbon. The term "8-10-membered bicyclic heteroaryl" refers to a divalent aromatic bicyclic group having one or more, preferably 1-6, more preferably 1, 2, 3 or 4 heteroatoms independently selected from N, O or S, and the remaining ring members being carbon.

术语“杂环”指含有一个或多个、例如1、2、3或4个独立地选自N、O或S的杂原子且其余环成员为碳的环状结构，其可以是完全饱和、部分不饱和(例如含有一条或多条双键或三键)或芳族(满足休克尔规则)的。优选地，杂环是3-8元杂环，优选4-8元杂环，更优选5-6元杂环。杂环的碳成员可以任选被-CO-代替，并且所述任意N和S杂原子可以任选被氧化(例如在NO、SO、SO2中)和所述任意N杂原子可以任选被季铵化(例如在[NR]+Cl-、[NR]+OH-中)。杂环的实例包括但不限于：吡咯、二氢吡咯、吡咯烷、呋喃、二氢呋喃、四氢呋喃、噻吩、二氢噻吩、四氢噻吩、四氢噻吩1-氧化物、四氢噻吩1,1-二氧化物、吡唑、二氢吡唑、吡唑烷、咪唑、咪唑啉、咪唑烷、吡啶、二氢吡啶、四氢吡啶、哌啶、哒嗪、二氢哒嗪、四氢哒嗪、六氢哒嗪、嘧啶、二氢嘧啶、四氢嘧啶、六氢嘧啶、吡嗪、二氢吡嗪、四氢吡嗪、哌嗪、吡喃、二氢吡喃、四氢吡喃、噻喃、二氢噻喃和四氢噻喃等。杂环可以与其它环状基团稠合，所述其它环状基团可以是芳族或非芳族的并且可以任选地含有一个或多个选自N、O或S的杂原子，例如在中。The term "heterocycle" refers to a cyclic structure containing one or more, for example, 1, 2, 3, or 4 heteroatoms independently selected from N, O, or S, with the remaining ring members being carbon. It can be fully saturated, partially unsaturated (e.g., containing one or more double or triple bonds), or aromatic (satisfying Hückel's rule). Preferably, the heterocycle is a 3- to 8-membered heterocycle, more preferably a 4- to 8-membered heterocycle, and more preferably a 5- to 6-membered heterocycle. The carbon members of the heterocycle may optionally be replaced by -CO-, and the arbitrary N and S heteroatoms may optionally be oxidized (e.g., in NO, SO, SO2) and the arbitrary N heteroatoms may optionally be quaternized (e.g., in [NR]+Cl-, [NR]+OH-). Examples of heterocycles include, but are not limited to: pyrrole, dihydropyrrole, pyrrolidine, furan, dihydrofuran, tetrahydrofuran, thiophene, dihydrothiophene, tetrahydrothiophene, tetrahydrothiophene 1-oxide, tetrahydrothiophene 1,1-dioxide, pyrazole, dihydropyrazole, pyrazolidine, imidazole, imidazoline, imidazoline, pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyridazine, dihydropyridazine, tetrahydropyridazine, hexahydropyridazine, pyrimidine, dihydropyrimidine, tetrahydropyrimidine, hexahydropyrimidine, pyrazine, dihydropyrazine, tetrahydropyrazine, piperazine, pyran, dihydropyran, tetrahydropyran, thioran, dihydrothioran, and tetrahydrothioran, etc. Heterocycles can be fused with other cyclic groups, which can be aromatic or non-aromatic and may optionally contain one or more heteroatoms selected from N, O, or S, for example in... middle.

术语“氰基”表示CN。The term "cyano" refers to CN.

术语“羟基”表示OH。The term "hydroxyl" refers to OH.

术语“巯基”表示SH。The term "thiol" represents SH.

术语“NRaRb”表示其中两个氢原子分别被Ra和Rb替代的NH2。术语“NH2”表示氨基。术语“-NH(C1-6烷基)”表示被一个C1-6烷基取代的氨基。术语“-N(C1-6烷基)(C1-6烷基)”表示被两个相同或不同的C1-6烷基取代的氨基，例如二甲基氨基、(甲基)(乙基)氨基-等。The term "NR a R b " indicates NH₂ in which two hydrogen atoms are replaced by Ra and Rb , respectively. The term " NH₂ " indicates an amino group. The term "-NH(C₁ -6 alkyl)" indicates an amino group substituted with one C₁ -6 alkyl group. The term "-N(C₁ -6 alkyl)(C₁ -6 alkyl)" indicates an amino group substituted with two identical or different C₁ -6 alkyl groups, such as dimethylamino, (methyl)(ethyl)amino, etc.

术语“-CO-”或“-C(＝O)-”表示羰基。The term "-CO-" or "-C(=O)-" represents a carbonyl group.

术语“-SO-”表示亚磺酰基。The term "-SO-" represents a sulfinyl group.

术语“-SO2-”表示磺酰基。The term "-SO 2 -" indicates a sulfonyl group.

术语“-PO-”表示磷酰基。The term "-PO-" represents a phosphoryl group.

术语“COOH”表示羧基。The term "COOH" represents a carboxyl group.

术语“＝O”表示氧代基。The term "=O" represents an oxy group.

术语“＝S”表示硫代基。The term "=S" represents a thio group.

术语“亚基”或“亚…基”表示从分子上移除两个氢原子而衍生的二价基团。为方便起见，在本文中，一些二价或三价基团以单价基团或化学物质的形式呈现，但是本领域技术人员根据其专业知识可以清楚地确定，该术语表示相应的二价或二价基团。例如，对环B定义的术语“萘”表示从萘环上移除二个氢原子而衍生的二价基团；对环B定义的“8-10元双环杂芳基”表示从8-11元双环杂芳环上移除两个氢原子而衍生的二价基团。The term "subunit" or "sub...group" refers to a divalent group derived by removing two hydrogen atoms from a molecule. For convenience, some divalent or trivalent groups are presented herein as monovalent groups or chemical substances, but those skilled in the art will clearly determine, based on their expertise, that the term refers to the corresponding divalent or trivalent group. For example, the term "naphthalene" as defined for ring B refers to a divalent group derived by removing two hydrogen atoms from a naphthalene ring; and "8-10 membered bicyclic heteroaryl" as defined for ring B refers to a divalent group derived by removing two hydrogen atoms from an 8-11 membered bicyclic heteroaryl ring.

可以理解，本文所述的各元素或者各基团中的元素包括其相应的同位素。例如，本文所述的H包括1H、2H(D)和3H(T)，优选表示1H和2H(D)。本文所述的任意基团中的碳包括12C、13C和14C。It is understood that the elements or groups mentioned herein include their corresponding isotopes. For example, H mentioned herein includes 1H , 2H (D), and 3H (T), preferably 1H and 2H (D). Carbon in any group mentioned herein includes 12C , 13C , and 14C .

不在两个字母或符号之间的短横(“-”)表示该基团的连接位点。例如，-NRaRb表示该基团通过氮原子与分子的其余部分连接，C3-8环烷基-(C1-4亚烷基)-表示该基团的连接点在C1-4亚烷基上。当基团的连接位点对本领域技术人员来说显而易见时(例如对于卤素、羟基、NRaRb等而言)，“-”可以省略。A hyphen ("-") not between two letters or symbols indicates the linking site of the group. For example, -NR a R b indicates that the group is linked to the rest of the molecule via a nitrogen atom, and C3-8 cycloalkyl-( C1-4 alkylene)- indicates that the linking site of the group is on a C1-4 alkylene atom. The "-" may be omitted when the linking site of the group is obvious to those skilled in the art (e.g., for halogens, hydroxyl groups, NR a R b , etc.).

当基团的价键带有波浪线时，表示该基团通过该价键与分子的其余部分连接。When the valence bond of the group has a wavy line When , it indicates that the group is connected to the rest of the molecule through that valence bond.

当取代基的价键穿过环时，例如在中，表示所述取代基位于环上任意可用的位置。When the valence bond of a substituent crosses the ring, for example in In the symbol, it indicates that the substituent is located at any available position on the ring.

结构式或结构片段中的表示存在立体异构体，且表示不对称中心的绝对构型，在本发明所提供的化合物或中间体的命名中通常以R或S表示。当存在于外消旋混合物中时，该实及虚锲形符号表示相对立体化学，而非绝对立体化学。In structural formulas or structural fragments The presence of stereoisomers and the absolute configuration of the asymmetry center are indicated by R or S in the nomenclature of compounds or intermediates provided in this invention. When present in racemic mixtures, the real and imaginary wedge-shaped symbols indicate relative stereochemistry, not absolute stereochemistry.

表述“任选”、“任选的”或“任选地”意指随后描述的事件可以发生或可以不发生，并且该表述包括所述事件发生的情形以及所述事件不发生的情形。例如，“任选被一个或多个取代基取代”包括未被取代的情形以及被一个或多个取代基取代的情形，并且其中所述取代基各自可以相同或不同。“任选的取代基”表明所述取代基可以存在或不存在。本领域技术人员可以理解，对于含有一个或多个取代基的任意基团而言，所述基团不包括任何在空间上不切实际的、化学上不正确的、合成上不可行的和/或内在不稳定的取代模式。The expressions “optional,” “optional,” or “optionally” mean that the event described below may or may not occur, and the expression includes both the scenario where the event occurs and the scenario where the event does not occur. For example, “optionally substituted with one or more substituents” includes both the scenario where the substituent is not substituted and the scenario where it is substituted with one or more substituents, wherein the substituents may be the same or different. “Optional substituents” indicates that the substituents may or may not be present. Those skilled in the art will understand that for any group containing one or more substituents, the group does not include any substitution pattern that is spatially impractical, chemically incorrect, synthetically infeasible, and/or intrinsically unstable.

当任意变量在结构式中出现多于一次时，其在每次出现时是各自独立地定义的。例如，对于表述“任选被一个或多个卤素取代”中被多个卤素取代的情形，所述卤素各自可以相同或不同，并且所述卤素可以位于相同或不同的原子上。When any variable appears more than once in a structural formula, it is defined independently each time it appears. For example, in the case of multiple halogens in the expression "optionally substituted by one or more halogens", the halogens can be the same or different, and the halogens can be located on the same or different atoms.

表述“被一个或多个独立地选自A、B和C的取代基取代”表示被一个或多个各自独立地选自A、B和C的取代基取代的情形，例如被一个或多个A取代，被一个或多个B取代，被一个或多个C取代，被一个或多个A和一个或多个B取代，被一个或多个A和一个或多个C取代，被一个或多个B和一个或多个C取代，被一个或多个A、一个或多个B和一个或多个C取代，等。The expression "substituted by one or more substituents independently selected from A, B, and C" indicates the case where the substitute is made by one or more substituents independently selected from A, B, and C. Examples include substitution by one or more A, substitution by one or more B, substitution by one or more C, substitution by one or more A and one or more B, substitution by one or more A and one or more C, substitution by one or more B and one or more C, substitution by one or more A, one or more B, and one or more C, etc.

取代基和/或变量的组合是允许的，只要这样的组成产生了稳定的化合物。Combinations of substituents and/or variables are permitted, provided that such compositions produce stable compounds.

术语“包含”或“包括”指包括所述的要素、整数或步骤，但是不排除任意其它要素、整数或步骤。在本文中，当使用术语“包含”或“包括”时，除非另有指明，否则也涵盖由所述及的要素、整数或步骤组合的情形。The terms “comprising” or “including” mean that the stated elements, integers, or steps are included, but do not exclude any other elements, integers, or steps. In this document, when the terms “comprising” or “including” are used, unless otherwise specified, they also cover combinations of the stated elements, integers, or steps.

术语“本发明的物质”或“本申请的物质”指符合式(I)或其亚式、例如式(II)、(III)、(IV)、(III’)、(IV’)、(Va)和/或(Vb)的化合物或其盐、特别是可药用盐以及互变异构体、立体异构体(包括非对映异构体、对映异构体和外消旋物)、几何异构体、构象异构体(包括旋转异构体和阻转异构体)、代谢物、前药以及同位素标记化合物(特别是氘代衍生物)、多晶型物、溶剂合物和/或水合物，包括各实施方案以及实施例中定义的那些。在一些实施方案中，术语“本发明的物质”或“本申请的物质”特别指实施例的化合物或其盐、特别是可药用盐以及互变异构体、立体异构体(包括非对映异构体、对映异构体和外消旋物)、几何异构体、构象异构体(包括旋转异构体和阻转异构体)、代谢物、前药以及同位素标记化合物(特别是氘代衍生物)、多晶型物、溶剂合物和/或水合物。The term "substance of the invention" or "substance of this application" refers to compounds conforming to formula (I) or its sub-forms, such as formulas (II), (III), (IV), (III'), (IV'), (Va) and/or (Vb), or salts thereof, particularly pharmaceutically acceptable salts, as well as tautomers, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotational isomers and trans-isomers), metabolites, prodrugs, and isotopically labeled compounds (particularly deuterated derivatives), polymorphs, solvates and/or hydrates, including those defined in the embodiments and examples. In some embodiments, the terms "substance of the invention" or "substance of this application" specifically refer to the compounds of the embodiments or their salts, particularly pharmaceutically acceptable salts, as well as tautomers, stereoisomers (including diastereomers, enantiomers and racemates), geometric isomers, conformational isomers (including rotational isomers and trans-isomers), metabolites, prodrugs, and isotopically labeled compounds (particularly deuterated derivatives), polymorphs, solvates and/or hydrates.

在本文中，式(I)的称谓也包括其亚式，例如式(II)、(III)、(IV)、(III’)、(IV’)、(Va)和/或(Vb)。In this paper, the designation of formula (I) also includes its sub-formulas, such as formulas (II), (III), (IV), (III’), (IV’), (Va) and/or (Vb).

短语“可药用”指当施用于动物如人时不产生明显的副反应、变态反应或其它不想要的反应的物质或组合物。The phrase “medicinal” refers to a substance or composition that, when administered to animals such as humans, does not produce obvious side effects, allergic reactions, or other unwanted reactions.

本发明的化合物可以是盐、例如可药用盐的形式。“可药用盐”包括酸加成盐和碱加成盐。“可药用酸加成盐”指保留游离碱的生物学有效性和性质并且不是生物学或其它方面不期望的那些盐。酸加成盐可以用无机酸或有机酸形成，无机酸盐例如有盐酸盐、氢溴酸盐、硫酸盐、硫酸氢盐、硝酸盐、碳酸盐、磷酸盐等，有机酸盐例如有甲酸盐、乙酸盐、三氟乙酸盐、丙酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、丙酮酸盐、草酸盐、苹果酸盐、丙二酸盐、戊二酸盐、己二酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐、柠檬酸盐、天冬氨酸盐、昔萘酸盐、抗坏血酸盐、谷氨酸盐、邻氨基苯甲酸盐、苯甲酸盐、肉桂酸盐、扁桃酸盐、双羟萘酸盐、苯乙酸盐、甲磺酸盐、乙磺酸盐、乙二磺酸盐、苯磺酸盐、对甲苯磺酸盐、二甲苯磺酸盐、三甲基苯磺酸盐(mesitylate)、羟乙磺酸盐、萘磺酸盐、萘二磺酸盐、樟脑磺酸盐、水杨酸盐、油酸盐、烟酸盐、糖精酸盐(saccharinate)、棕榈酸盐、硬脂酸盐、糠酸盐、马尿酸盐、乳清酸盐和扑酸盐等。盐还包括由无机碱衍生的那些，例如钠、钾、锂、铵、钙、镁、铁、锌、铜、锰、铝盐等；和由无毒有机碱衍生的那些：伯胺、仲胺和叔胺，被取代的胺、包括天然存在的被取代的胺，环胺和碱性离子交换树脂如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、2-二乙基氨基乙醇、氨丁三醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、哈胺(hydrabamine)、胆碱、甜菜碱、乙二胺、葡糖胺、甲基葡糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。盐可以通过常规方法由母体化合物进行合成。The compounds of this invention can be in the form of salts, such as pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" include acid addition salts and base addition salts. "Pharmaceutical-acceptable acid addition salts" refer to those salts that retain the biological effectiveness and properties of the free base and are not biologically or otherwise undesirable. Acid addition salts can be formed from inorganic or organic acids. Inorganic acid salts include, for example, hydrochlorides, hydrobroms, sulfates, hydrogen sulfates, nitrates, carbonates, phosphates, etc., and organic acid salts include, formates, acetates, trifluoroacetates, propionates, glycolates, gluconates, lactates, pyruvates, oxalates, malates, malonates, glutarate, adipates, succinates, fumarates, maleates, tartrates, citrates, aspartate, sine, ascorbate, glutamate, and other similar salts. Aminobenzoate, benzoate, cinnamate, mandelate, dihydroxynaphthalate, phenylacetate, methanesulfonate, ethanesulfonate, ethanedisulfonate, benzenesulfonate, p-toluenesulfonate, xylenesulfonate, trimethylbenzenesulfonate (mesitylate), hydroxyethanesulfonate, naphthalenesulfonate, naphthalenedisulfonate, camphorsulfonate, salicylate, oleate, nicotinate, saccharinate, palmitate, stearate, furoate, hippurate, orotate, and pyruvate, etc. Salts also include those derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts; and those derived from non-toxic organic bases: primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, tromethamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, and polyamine resins. Salts can be synthesized from parent compounds using conventional methods.

可药用盐是优选的。然而，其它盐也可以是有用的，例如在分离或纯化步骤中，其可以在制备期间使用，因此被囊括在本公开的范围内。Pharmaceutically acceptable salts are preferred. However, other salts may also be useful, for example, in separation or purification steps, and may be used during preparation, and are therefore included within the scope of this disclosure.

本发明的化合物可以含有一个或多个不对称碳原子。因此，化合物可以作为非对映异构体、对映异构体或其混合物存在。化合物的合成可以采用外消旋物、非对映异构体或异构体作为原料或作为中间体。可以通过色谱或结晶方法使特定非对映异构化合物的混合物分离或富含一种或多种特定非对映异构体。类似地，采用相同的技术或本领域已知的其它技术可以使对映异构混合物分离或对映异构体富含。非对称碳或氮原子各自可以是R或S构型，这两种构型都在本发明的范围内。在本文所示的结构中，当未指出任意特定手性原子的立体化学时，则所有立体异构体被包括在内作为本发明的化合物。本文使用的立体化学定义和约定遵循本领域的通常约定。The compounds of this invention may contain one or more asymmetric carbon atoms. Therefore, the compounds may exist as diastereomers, enantiomers, or mixtures thereof. The synthesis of the compounds may employ racemic compounds, diastereomers, or isomers as starting materials or intermediates. A mixture of specific diastereomers can be isolated or enriched with one or more specific diastereomers by chromatographic or crystallographic methods. Similarly, enantiomer mixtures can be isolated or enriched with enantiomers using the same techniques or other techniques known in the art. The asymmetric carbon or nitrogen atom may each be in an R or S configuration, both of which are within the scope of this invention. In the structures shown herein, all stereoisomers are included as compounds of this invention unless the stereochemistry of any particular chiral atom is specified. Stereochemical definitions and conventions used herein follow those commonly used in the art.

术语“立体异构体”指具有相同化学组成、但原子或基团在空间上的排列不同的化合物。立体异构体包括非对映异构体、对映异构体、构象异构体等。The term "stereoisomer" refers to compounds that have the same chemical composition but differ in the spatial arrangement of their atoms or groups. Stereoisomers include diastereomers, enantiomers, and conformational isomers.

术语“非对映异构体”指具有两个或更多个手性中心并且其分子不互为镜像的立体异构体。非对映异构体具有不同的物理性质，如熔点、沸点、光谱性质和生物活性。非对映异构体的混合物可通过高分辨分析操作如电泳和色谱法如HPLC来进行分离。The term "diastereomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers possess different physical properties, such as melting point, boiling point, spectral properties, and biological activity. Mixtures of diastereomers can be separated using high-resolution analytical techniques such as electrophoresis and chromatographic methods such as HPLC.

术语“对映异构体”指互为不可重叠的镜像的化合物的两种立体异构体。The term "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

术语“互变异构体”指可通过低能垒互相转化的具有不同能量的结构异构体。例如，质子互变异构体(也称为质子移变互变异构体)包括通过质子迁移的互相转化，例如酮-烯醇异构化和亚胺-烯胺异构化。价键互变异构体包括通过一些成键电子的重组进行的互相转化。The term "tautomer" refers to structural isomers with different energies that can interconvert through low energy barriers. For example, proton tautomers (also known as proton shift tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the rearrangement of some bonding electrons.

在存在手性中心时，本发明的化合物可以以单独的对映异构体或对映体混合物形式存在，本领域技术人员能够确定稳定和可行的本发明化合物的异构体形式。根据一个实施方案，提供了式(I)化合物或其药学上可接受的盐，其是对映体过量(％ee)＞95、＞98％或＞99％的单一对映体。优选地，单一对映异构体以＞99％的对映异构体过量(％ee)存在。In the presence of a chiral center, the compounds of the present invention can exist as individual enantiomers or mixtures of enantiomers, and those skilled in the art can determine stable and viable isomeric forms of the compounds of the present invention. According to one embodiment, a compound of formula (I) or a pharmaceutically acceptable salt thereof is provided, which is a single enantiomer with an enantiomer excess (%ee) >95%, >98%, or >99%. Preferably, the single enantiomer is present with an enantiomer excess (%ee) >99%.

本文所用的术语“同位素标记化合物”指构成该化合物的一个或多个原子上含有非天然比例同位素的化合物。本发明的化合物可在构成化合物的一个或多个原子上包含非天然比例的原子同位素，从而形成同位素变化形式，其无论是否具有放射性，都旨在涵盖在本发明的范围内。除非另外指出，否则文中描述的结构式包括在一个或多个同位素富集原子的存在方面不同的化合物。可以掺入本发明化合物中的同位素及其可药用盐的实例包括但不限于氢的同位素(例如2H、3H)；碳的同位素(例如11C、13C及14C)；氯的同位素(例如36Cl)；氟的同位素(例如18F)；碘的同位素(例如123I及125I)；氮的同位素(例如13N及15N)；氧的同位素(例如15O、17O及18O)；磷的同位素(例如32P)；及硫的同位素(例如35S)。同位素标记的化合物(例如标记了3H和14C的那些)可用于化合物或物质组织分布分析。氚化(即3H)和碳-14(即14C)同位素由于它们易于制备和可检测性而是有用的。而且，用较重的同位素如氘(即2H)替换可以提供一些产生于较高的代谢稳定性的治疗益处(例如体内半衰期增加或剂量需求降低)。在一些实施方案中，在本发明的化合物中，一个或多个碳原子被富含13C-或14C的碳替换。发射正电子的同位素如15O、13N、11C和18F可用于正电子发射断层扫描(PET)研究以检测底物受体占据。应当理解，本发明化合物的同位素变化形式通常可以通过常规方法、使用适合试剂的适当同位素变化形式来制备。As used herein, the term "isotope-labeled compound" refers to a compound in which one or more atoms constituting the compound contain an atomic isotope in a non-natural proportion. The compounds of the present invention may contain an atomic isotope in a non-natural proportion on one or more atoms constituting the compound, thereby forming isotopic variations, whether or not they are radioactive, and are intended to be covered within the scope of the present invention. Unless otherwise indicated, the structural formulas described herein include compounds that differ in the presence of one or more isotope-enriched atoms. Examples of isotopes and their pharmaceutically usable salts that can be incorporated into the compounds of this invention include, but are not limited to, isotopes of hydrogen (e.g., 2H , 3H ); isotopes of carbon (e.g., 11C , 13C , and 14C ); isotopes of chlorine (e.g., 36Cl ); isotopes of fluorine (e.g., 18F ); isotopes of iodine (e.g., 123I and 125I ); isotopes of nitrogen (e.g., 13N and 15N ); isotopes of oxygen (e.g., 15O , 17O , and 18O ); isotopes of phosphorus (e.g., 32P ); and isotopes of sulfur (e.g., 35S ). Isotope-labeled compounds (e.g., those labeled with 3H and 14C ) can be used for the tissue distribution analysis of compounds or substances. Tritium (i.e., 3H ) and carbon-14 (i.e., 14C ) isotopes are useful due to their ease of preparation and detectability. Furthermore, substitution with a heavier isotope, such as deuterium (i.e., 2H ), can provide some therapeutic benefits arising from higher metabolic stability (e.g., increased in vivo half-life or reduced dose requirement). In some embodiments, in the compounds of the present invention, one or more carbon atoms are replaced with carbons rich in 13C- or 14C . Positron-emitting isotopes such as 15O , 13N , 11C , and 18F can be used in positron emission tomography (PET) studies to detect substrate acceptor occupancy. It should be understood that isotopic variations of the compounds of the present invention can generally be prepared by conventional methods using appropriate isotopic variations with suitable reagents.

术语“代谢物”指特定化合物或其盐经体内代谢产生的产物。这类产物可以产生于所施用化合物的例如氧化、还原、水解、酰胺化、脱酰胺化、酯化、脱脂、酶裂解等。代谢物结构以常规方式来确定，例如通过MS、LC/MS或NMR分析。通常，代谢物分析以与本领域技术人员熟知的常规药物代谢研究相同的方式进行。代谢产物可用于本发明的化合物的治疗剂量的诊断分析，只要未在体内发现它们。The term "metabolite" refers to a product generated in vivo from the metabolism of a particular compound or its salts. Such products can arise from processes of the administered compound, such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, defatting, enzymatic cleavage, etc. The structure of metabolites is determined in a conventional manner, for example by MS, LC/MS, or NMR analysis. Typically, metabolite analysis is performed in the same manner as conventional drug metabolism studies well known to those skilled in the art. Metabolites can be used for diagnostic analysis of therapeutic doses of the compounds of this invention, provided they are not detected in vivo.

术语“前药”指被化学修饰的活性或非活性的化合物，其在施用于个体后经过体内生理作用(例如水解、新成代谢等)转化为本发明的化合物。制造和使用前药的技术是本领域技术人员熟知的。The term "prodrug" refers to a chemically modified active or inactive compound that, after being administered to an individual, undergoes physiological processes in vivo (e.g., hydrolysis, metabolism, etc.) to be converted into the compound of this invention. Techniques for manufacturing and using prodrugs are well known to those skilled in the art.

术语“多晶型物”指具有相同的化学结构/组成、但是形成结晶的分子和/或离子的空间排列不同的结晶形式。本发明的化合物可以作为无定型固体或结晶固体来提供。本发明的范围意欲囊括所有这些物理形式。The term "polymorph" refers to a crystalline form having the same chemical structure/composition but with different spatial arrangements of the molecules and/or ions that form crystals. The compounds of this invention can be provided as amorphous solids or crystalline solids. The scope of this invention is intended to encompass all such physical forms.

一些本发明的化合物可以以非溶剂化形式和溶剂化形式、包括水合形式存在。术语“溶剂合物”指一种或多种溶剂分子与本发明的化合物的缔合物或复合物。形成溶剂合物的溶剂的实例包括水、异丙醇、乙醇、MeOH、DMSO、EA、乙酸和乙醇胺。术语“水合物”指其中溶剂分子是水的复合物。溶剂化的方法是本领域公知的。Some compounds of the present invention can exist in non-solventized and solvated forms, including hydrated forms. The term "solvent" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include water, isopropanol, ethanol, MeOH, DMSO, EA, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water. Methods of solvation are well known in the art.

本发明化合物还涵盖可能存在的N-氧化物，本领域技术人员能够确定稳定和可行的本发明化合物的N-氧化物。本发明化合物还涵盖本发明化合物的代谢物，即给药本发明化合物时在体内通过氧化、还原、水解、酰胺化、酯化等形成的物质，其可通过本领域公知的技术进行鉴定。The compounds of this invention also encompass any N-oxides that may be present, and those skilled in the art can identify stable and viable N-oxides of the compounds of this invention. The compounds of this invention also encompass metabolites of the compounds of this invention, i.e., substances formed in vivo through oxidation, reduction, hydrolysis, amidation, esterification, etc., when the compounds of this invention are administered, which can be identified using techniques known in the art.

术语“个体”或“患者”指动物，优选是哺乳动物。个体的实例包括但不限于灵长类(例如人和非人灵长类动物如猴)、马、牛、羊、猫、狗、兔、兔以及啮齿类(例如小鼠和大鼠)。在一些实施方案中，个体是人，包括儿童、青少年或成人。The term "individual" or "patient" refers to an animal, preferably a mammal. Examples of individuals include, but are not limited to, primates (e.g., humans and non-human primates such as monkeys), horses, cattle, sheep, cats, dogs, rabbits, and rodents (e.g., mice and rats). In some embodiments, the individual is a person, including children, adolescents, or adults.

术语“治疗”指(i)治疗或防止特定疾病、病症或障碍、(ii)减弱、改善或消除特定疾病、病症或障碍的一种或多种症状和任选地(iii)防止或延迟本文所述的特定疾病、病症或障碍的一种或多种症状的发作。在一些实施方案中，“治疗”指改善至少一种身体参数，其可能不为患者所察觉。在另一些实施方案中，“治疗”指从身体上(例如稳定可察觉的症状)或生理学上(例如稳定身体的参数)或上述两方面调节疾病或病症。The term "treatment" means (i) treating or preventing a particular disease, symptom, or disorder; (ii) reducing, improving, or eliminating one or more symptoms of a particular disease, symptom, or disorder; and optionally (iii) preventing or delaying the onset of one or more symptoms of a particular disease, symptom, or disorder described herein. In some embodiments, "treatment" means improving at least one bodily parameter, which may not be perceptible to the patient. In other embodiments, "treatment" means regulating a disease or symptom from a physical (e.g., stabilizing perceptible symptoms) or physiological (e.g., stabilizing bodily parameters) or both.

术语“预防”指给具有易患所述疾病或病症的体质的个体施用一种或多种药物物质、特别是本发明的化合物和/或其可药用盐，用以防止个体罹患该疾病。The term "prevention" refers to the administration of one or more pharmaceutical substances, particularly the compounds of the present invention and/or their pharmaceutically acceptable salts, to an individual with a predisposition to the disease or condition, in order to prevent the individual from contracting the disease.

术语“抑制”和“减轻”等指特定的病患、症状或病症或疾病的减轻或抑制，或者生物学活性或过程基线活性的显著降低。The terms “inhibition” and “reduction” refer to the reduction or inhibition of a specific patient, symptom, condition, or disease, or a significant reduction in the baseline activity of a biological activity or process.

术语“GLP-1R相关性疾病或紊乱”指GLP-1R受体(包括野生型或突变型)在其中起作用的任何疾病或紊乱。GLP-1R受体的激活可对所述疾病或紊乱产生有益作用，例如减少或消除疾病症状、减轻疾病严重度、降低疾病发生率等。特别地，GLP-1R相关性疾病或紊乱包括但不限于糖尿病、糖尿病并发症、肥胖症、超重、血脂紊乱、脂肪肝疾病(例如非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH))、代谢性疾病、心血管疾病、神经系统障碍、精神障碍、肾脏疾病、胃肠疾病、自身免疫性疾病、炎性疾病、肺病、下丘脑-垂体-性腺轴相关性疾病或障碍、癌症等。The term "GLP-1R-related disease or disorder" refers to any disease or disorder in which GLP-1R receptors (including wild-type or mutant types) play a role. Activation of GLP-1R receptors can have beneficial effects on said disease or disorder, such as reducing or eliminating disease symptoms, alleviating disease severity, and reducing disease incidence. In particular, GLP-1R-related diseases or disorders include, but are not limited to, diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic diseases, cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders or disorders, and cancer.

在一些实施方案中，GLP-1R是野生型GLP-1R。在其他实施方案中，GLP-1R是突变GLP-1R。In some implementations, GLP-1R is wild-type GLP-1R. In other implementations, GLP-1R is mutant GLP-1R.

术语“糖尿病”以因胰岛素分泌不足或胰岛素利用障碍引起的代谢疾病群，以血液葡萄糖水平长期增高为主要标志。糖尿病包括1型糖尿病(胰岛素依赖型糖尿病)、2型糖尿病(非胰岛素依赖型糖尿病)、妊娠期糖尿病和特殊类型糖尿病。特殊类型糖尿病是WHO糖尿病诊断分型中的一种，指除了1型糖尿病、2型糖尿病、妊娠期糖尿病以外的其它所有病因引起的糖尿病。特殊类型糖尿病可分为8类，包括：胰岛β细胞功能遗传性缺陷；胰岛素作用遗传性缺陷；胰腺外分泌疾病所致；内分泌疾病所致；药物或化学品所致；感染所致；罕见的免疫介导糖尿病所致；以及糖尿病相关的遗传综合征。The term "diabetes" refers to a group of metabolic diseases caused by insufficient insulin secretion or impaired insulin utilization, characterized primarily by persistently elevated blood glucose levels. Diabetes includes type 1 diabetes (insulin-dependent diabetes), type 2 diabetes (non-insulin-dependent diabetes), gestational diabetes, and special types of diabetes. Special types of diabetes, a category in the WHO classification of diabetes, refers to diabetes caused by all factors other than type 1, type 2, and gestational diabetes. Special types of diabetes can be further divided into eight categories, including: hereditary defects in pancreatic β-cell function; hereditary defects in insulin action; pancreatic exocrine disorders; endocrine disorders; drug or chemical-induced; infection-induced; rare immune-mediated diabetes; and diabetes-related genetic syndromes.

术语“糖尿病并发症”是由糖尿病或高血糖引起的并发症，包括酮症酸中毒、感染性疾病(例如皮肤感染、软组织感染、胆道系统感染、呼吸系统感染、尿路感染)、微血管病变(例如肾病变、视网膜病变)、神经病变(例如感觉神经障碍、运动神经障碍、自主神经障碍)和坏疽。特别地，糖尿病并发症包括糖尿病性肾病、糖尿病性视网膜病变、糖尿病性神经病变和糖尿病性坏疽。The term "diabetic complications" refers to complications arising from diabetes or hyperglycemia, including ketoacidosis, infectious diseases (such as skin infections, soft tissue infections, biliary tract infections, respiratory infections, and urinary tract infections), microvascular complications (such as nephropathy and retinopathy), neuropathy (such as sensory nerve disorders, motor nerve disorders, and autonomic nerve disorders), and gangrene. Specifically, diabetic complications include diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, and diabetic gangrene.

术语“需要降低血糖的情况”包括病理性和非病理性的情况，其中降低血糖是有利的或者是期望的。所述需要降低血糖的情况包括但不限于糖尿病前期、葡萄糖耐量受损、葡萄糖代谢受损、胰岛素抵抗、高血糖症、过度嗜糖、伤口愈合迟缓等。The term "conditions requiring blood glucose reduction" includes both pathological and non-pathological conditions where lowering blood glucose is beneficial or desirable. These conditions include, but are not limited to, prediabetes, impaired glucose tolerance, impaired glucose metabolism, insulin resistance, hyperglycemia, excessive sugar consumption, and delayed wound healing.

术语“体重管理”指使体重或BMI处于期望的范围、特别是健康范围内。例如，体重管理使得BMI处于18.5-24kg/m2的范围内。特别地，体重管理包括体重减轻、诱导体重减轻、减缓或预防体重增加、减少体脂肪、减少摄食量、延迟胃排空、增加饱腹感。The term "weight management" refers to maintaining a desired weight or BMI within a healthy range. For example, weight management aims to keep a BMI between 18.5 and 24 kg/ m² . Specifically, weight management includes weight loss, inducing weight loss, slowing or preventing weight gain, reducing body fat, reducing food intake, delaying gastric emptying, and increasing satiety.

术语“有效量”指以需要的剂量并持续需要的时间段有效实现所需治疗效果或预防效果的量。其可以由参与医师或兽医执业者来确定，并且将随着化合物、所治疗的疾病状态、所治疗的疾病的严重程度、个体的年龄和相关健康状况、施用途径和形式、主治医师或兽医执业者的判断等因素而变化。通常，“预防有效量”将小于“治疗有效量”。The term "effective dose" refers to the amount of medication required to achieve a desired therapeutic or preventative effect at the necessary dosage and for the required duration. It can be determined by the physician or veterinary practitioner involved and will vary depending on factors such as the compound, the state of the disease being treated, the severity of the disease, the individual's age and relevant health conditions, the route and form of administration, and the judgment of the attending physician or veterinary practitioner. Generally, the "preventive effective dose" will be less than the "therapeutic effective dose."

术语“药物组合物”指适合于向动物、优选哺乳动物(包括人)施用的包含至少一种活性成分和至少一种非活性成分、例如可药用赋形剂的组合物。本发明的制剂可以是本领域适用的任意制剂，例如片剂、胶囊剂、液体制剂等。The term "pharmaceutical composition" refers to a composition suitable for administration to animals, preferably mammals (including humans), comprising at least one active ingredient and at least one inactive ingredient, such as a pharmaceutically acceptable excipient. The formulations of this invention can be any formulation applicable in the art, such as tablets, capsules, liquid formulations, etc.

术语“可药用载体、稀释剂或赋形剂”指药物制剂中除活性成分以外的成分，其对个体基本上是无毒的。可药用载体的实例包括但不限于粘合剂、崩解剂、润滑剂、溶剂、分散介质、缓冲剂、赋形剂、抗氧化剂、防腐剂或矫味剂等。The term "pharmaceutical carrier, diluent, or excipient" refers to a component in a pharmaceutical preparation other than the active ingredient that is substantially non-toxic to an individual. Examples of pharmaceutical carriers include, but are not limited to, binders, disintegrants, lubricants, solvents, dispersion media, buffers, excipients, antioxidants, preservatives, or flavoring agents.

当涉及化学反应时，“处理”、“接触”和“反应”指在适当的条件下加入或混合两种或更多种试剂，以产生所示的和/或所需的产物。应当理解，产生所示和/或所需产物的反应可能不一定直接来自最初加入的两种试剂的组合，即，在混合物中可能存在生成的一种或多种中间体，这些中间体最终导致了所示和/或所需产物的形成。When referring to chemical reactions, “processing,” “contacting,” and “reaction” mean the addition or mixing of two or more reagents under appropriate conditions to produce the shown and/or desired product. It should be understood that the reaction producing the shown and/or desired product may not necessarily originate directly from the combination of the two initially added reagents; that is, one or more intermediates may be present in the mixture that ultimately lead to the formation of the shown and/or desired product.

表述A“和/或”B包括单独的A、单独的B以及A+B的情形。The statement "A and/or B" includes A alone, B alone, and A+B.

一般而言，术语“约”与数值联合使用时表示该数值±20％、优选±10％、更优选±5％的范围。Generally, when the term "about" is used in conjunction with a numerical value, it indicates a range of ±20%, preferably ±10%, and more preferably ±5% of that value.

功效effect

本发明的物质具有良好的GLP-1R激动活性。而且，本发明的物质还显示出良好的体内和体外药代动力学性质，例如良好的溶解度和/或吸收、良好的代谢稳定性、改善的生物利用度、减少的副作用(例如低血糖的风险低)等。本发明的物质还具有良好的物理和/或化学稳定性，适合制备成符合药用的各种制剂。因此，本发明的物质可用于GLP-1R激动活性有利或者需要GLP-1激动活性的多种应用中，例如用作GLP-1R激动剂或者用于治疗或预防GLP-1R相关性疾病或紊乱。特别地，本发明的物质可用于体重管理、用于降血糖和/或用于治疗或预防糖尿病、糖尿病并发症、肥胖症、超重、血脂紊乱、脂肪肝疾病(例如非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH))、代谢性疾病、心血管疾病、神经系统障碍、精神障碍、肾脏疾病、胃肠疾病、自身免疫性疾病、炎性疾病、肺病、下丘脑-垂体-性腺轴相关性疾病或障碍、癌症等。The substances of the present invention possess excellent GLP-1R agonist activity. Furthermore, the substances of the present invention exhibit favorable in vivo and in vitro pharmacokinetic properties, such as good solubility and/or absorption, good metabolic stability, improved bioavailability, and reduced side effects (e.g., low risk of hypoglycemia). The substances of the present invention also possess good physical and/or chemical stability, making them suitable for formulation into various pharmaceutically acceptable preparations. Therefore, the substances of the present invention can be used in a variety of applications where GLP-1R agonist activity is advantageous or required, such as as GLP-1R agonists or for the treatment or prevention of GLP-1R-related diseases or disorders. In particular, the substances of the present invention can be used for weight management, for lowering blood glucose and/or for the treatment or prevention of diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver diseases (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic diseases, cardiovascular diseases, neurological disorders, mental disorders, kidney diseases, gastrointestinal diseases, autoimmune diseases, inflammatory diseases, lung diseases, hypothalamic-pituitary-gonadal axis disorders, cancer, etc.

在一方面，本发明的物质可用于体重管理，特别是体重减轻、诱导体重减轻、减缓或预防体重增加、减少体脂肪、减少摄食量、延迟胃排空、增加饱腹感。在一些实施方案中，个体是希望减轻体重的个体、超重个体或肥胖症患者。在一些实施方案中，个体的体重增加可以是过度摄食或不平衡饮食导致的体重增加、药物诱发的体重增加、激素相关的体重增加或者停止吸烟之后的体重增加。在一些实施方案中，体重增加是达到肥胖症之前的体重增加，或者是肥胖症患者的体重增加。In one aspect, the substances of the present invention can be used for weight management, particularly for weight loss, inducing weight loss, slowing or preventing weight gain, reducing body fat, reducing food intake, delaying gastric emptying, and increasing satiety. In some embodiments, the individual is an individual wishing to lose weight, an overweight individual, or an obese patient. In some embodiments, the individual's weight gain may be due to overeating or an unbalanced diet, drug-induced weight gain, hormone-related weight gain, or weight gain after quitting smoking. In some embodiments, the weight gain is weight gain prior to reaching obesity, or weight gain in an obese patient.

在一些实施方案中，本发明的物质可用于治疗或预防：超重、肥胖症或与肥胖症相关的疾病或状况。肥胖症的实例包括但不限于症状性肥胖症、单纯性肥胖症、儿童肥胖症、病态肥胖症和腹型肥胖症。症状性肥胖症的实例包括但不限于内分泌性肥胖症(例如库欣综合征(Cushing syndrome)、胰岛素瘤、II型糖尿病伴肥胖症、甲状腺功能减退、假性副甲状腺低能症、性腺功能低下症)、下丘脑性肥胖症、遗传性肥胖症(例如Prader-Willi综合征、Laurence-Moon-Biedl综合征)以及药物诱发性肥胖症(例如类固醇、啡噻嗪、胰岛素、磺酰脲药剂或β-阻断剂诱发性肥胖症)。与肥胖症相关的疾病或状况的实例包括但不限于葡萄糖奶量减低、糖尿病、脂质代谢异常、高脂血症、高血压、心脏衰竭、高尿酸血症、痛风、脂肪肝(包括非酒精性脂肪变性肝炎(NASH))、冠心病(例如心肌梗塞、心绞痛)、脑梗塞(例如脑血栓、暂时性大脑缺血性发作)、骨骼或关节疾病(例如膝骨性关节炎、髋关节炎、变形性脊椎炎、腰痛)、睡眠呼吸中止综合征、肥胖症换气不足综合征(例如Pickwickian综合征)、月经病症(例如异常月经周期、月经量及周期异常、闭经、异常月经症状)、内脏性肥胖综合征以及代谢综合征。In some embodiments, the substances of the present invention can be used to treat or prevent overweight, obesity, or obesity-related diseases or conditions. Examples of obesity include, but are not limited to, symptomatic obesity, simple obesity, childhood obesity, morbid obesity, and abdominal obesity. Examples of symptomatic obesity include, but are not limited to, endocrine obesity (e.g., Cushing's syndrome, insulinoma, type II diabetes with obesity, hypothyroidism, pseudohypoparathyroidism, hypogonadism), hypothalamic obesity, hereditary obesity (e.g., Prader-Willi syndrome, Laurence-Moon-Biedl syndrome), and drug-induced obesity (e.g., steroid, phenobarbital, insulin, sulfonylurea agents, or beta-blocker-induced obesity). Examples of diseases or conditions associated with obesity include, but are not limited to, reduced glucose tolerance, diabetes, lipid metabolism disorders, hyperlipidemia, hypertension, heart failure, hyperuricemia, gout, fatty liver (including non-alcoholic steatosis (NASH)), coronary artery disease (e.g., myocardial infarction, angina pectoris), cerebral infarction (e.g., cerebral thrombosis, transient ischemic attack), skeletal or joint disorders (e.g., knee osteoarthritis, hip osteoarthritis, degenerative spondylitis, low back pain), sleep apnea syndrome, obesity-related hypoventilation syndrome (e.g., Pickwickian syndrome), menstrual disorders (e.g., abnormal menstrual cycles, abnormal menstrual flow and cycle, amenorrhea, abnormal menstrual symptoms), visceral obesity syndrome, and metabolic syndrome.

在另一方面，本发明的物质具有良好的降血糖作用，并且低血糖的发生率低，因此可用作降血糖剂用于治疗或预防糖尿病、糖尿病并发症或需要降低血糖的情况。所述糖尿病、糖尿病并发症或需要降低血糖的情况包括但不限于：1型糖尿病、2型糖尿病、妊娠期糖尿病、特殊类型糖尿病(例如胰岛β细胞功能遗传性缺陷型、胰岛素作用遗传性缺陷型、胰腺外分泌疾病型、内分泌疾病型、药物或化学品所致糖尿病、感染所致糖尿病、罕见免疫介导糖尿病、糖尿病相关遗传综合征)、酮症酸中毒、代谢性酸中毒、糖尿病性肾病、糖尿病性视网膜病变、糖尿病相关葡萄膜炎、糖尿病性白内障、糖尿病性神经病变、糖尿病足、糖尿病性坏疽、糖尿病性心血管病、糖尿病性心肌病、糖尿病性血脂异常、糖尿病性恶病质、糖尿病前期、葡萄糖耐量受损、葡萄糖代谢受损、胰岛素抵抗、高血糖症、过度嗜糖、伤口愈合迟缓。例如，本发明的物质可用于治疗或预防：特发性1型糖尿病(1b型)、早发2型糖尿病、青年发病型非典型糖尿病(YOAD)、青少年的成人发病型糖尿病(MODY)、成人隐匿性自身免疫性糖尿病(LADA)、营养不良相关性糖尿病、高渗压糖尿病性昏迷。On the other hand, the substance of the present invention has a good hypoglycemic effect and a low incidence of hypoglycemia, and therefore can be used as a hypoglycemic agent for the treatment or prevention of diabetes, diabetic complications, or situations requiring lower blood sugar. The diabetes, diabetic complications, or situations requiring lower blood sugar include, but are not limited to: type 1 diabetes, type 2 diabetes, gestational diabetes, special types of diabetes (e.g., hereditary defects in pancreatic β-cell function, hereditary defects in insulin action, pancreatic exocrine disorders, endocrine disorders, drug- or chemical-induced diabetes, infection-induced diabetes, rare immune-mediated diabetes, diabetes-related genetic syndromes), ketoacidosis, metabolic acidosis, diabetic nephropathy, diabetic retinopathy, diabetic uveitis, diabetic cataracts, diabetic neuropathy, diabetic foot, diabetic gangrene, diabetic cardiovascular disease, diabetic cardiomyopathy, diabetic dyslipidemia, diabetic cachexia, prediabetes, impaired glucose tolerance, impaired glucose metabolism, insulin resistance, hyperglycemia, excessive sugar consumption, and delayed wound healing. For example, the substances of the present invention can be used to treat or prevent: idiopathic type 1 diabetes (type 1b), early-onset type 2 diabetes, juvenile-onset atypical diabetes (YOAD), adolescent adult-onset diabetes (MODY), latent autoimmune diabetes in adults (LADA), malnutrition-related diabetes, and hyperosmolar diabetic coma.

在另一方面，本发明的物质可用于治疗或预防代谢性疾病，包括但不限于：空腹葡萄糖受损(IFG)、空腹血糖参数受损(IFG)、高血糖症、胰岛素抵抗(葡萄糖稳态受损)、高胰岛素血症、血液脂肪酸或甘油水平升高、胰岛素抵抗综合征、由高胰岛素血症/高脂血症/高胆固醇血症引起的感觉异常、代谢综合征、伤口愈合受损、瘦素抵抗、葡萄糖不耐受、空腹葡萄糖增加、血脂异常(例如高脂血症、高胆固醇血症、高甘油三酯血症或餐后脂血症)、胰高血糖素瘤、高尿酸血症以及与胰岛素相关的伴随昏迷终点。In another aspect, the substances of the present invention can be used to treat or prevent metabolic diseases, including but not limited to: impaired fasting glucose (IFG), impaired fasting glucose parameters (IFG), hyperglycemia, insulin resistance (impaired glucose homeostasis), hyperinsulinemia, elevated blood fatty acid or glycerol levels, insulin resistance syndrome, paresthesia caused by hyperinsulinemia/hyperlipidemia/hypercholesterolemia, metabolic syndrome, impaired wound healing, leptin resistance, glucose intolerance, increased fasting glucose, dyslipidemia (e.g., hyperlipidemia, hypercholesterolemia, hypertriglyceridemia or postprandial lipemia), glucagonoma, hyperuricemia, and insulin-related coma endpoints.

在另一方面，本发明的物质可用于治疗或预防肝脏疾病。所述肝脏疾病包括但不限于：脂肪肝疾病，例如非酒精性脂肪肝病(NAFLD)、脂肪性肝炎如非酒精性脂肪性肝炎(NASH)、酒精性肝病、肝炎引起的脂肪肝疾病、肥胖症引起的脂肪肝疾病、糖尿病引起的脂肪肝疾病、胰岛素抵抗引起的脂肪肝疾病、高甘油三酯血症引起的脂肪肝疾病、妊娠急性脂肪肝、肝脂肪变性；肝纤维化、肝硬化；自身免疫性肝疾病、自身免疫性肝炎、原发性胆汁性肝硬化。In another aspect, the substances of the present invention can be used to treat or prevent liver diseases. These liver diseases include, but are not limited to: fatty liver diseases, such as non-alcoholic fatty liver disease (NAFLD), steatohepatitis such as non-alcoholic steatohepatitis (NASH), alcoholic liver disease, fatty liver disease caused by hepatitis, fatty liver disease caused by obesity, fatty liver disease caused by diabetes, fatty liver disease caused by insulin resistance, fatty liver disease caused by hypertriglyceridemia, acute fatty liver of pregnancy, hepatic steatosis; liver fibrosis, cirrhosis; autoimmune liver diseases, autoimmune hepatitis, and primary biliary cirrhosis.

在另一方面，本发明的物质可用于治疗或预防血管疾病，包括心脑血管疾病和外周血管疾病。所述血管疾病包括但不限于：高血压、肺性高血压、动脉粥样硬化、动脉硬化、冠心病(如心肌梗塞和心绞痛)、冠状动脉疾病、心脏衰竭(如充血性心力衰竭)、心律失常、左心室肥大、心绞痛、脑梗塞、中风(例如出血性中风和缺血性中风)、短暂性脑缺血发作、血管顺应性受损、血管再狭窄、血管成形术后再狭窄、血栓形成、血栓前状态、血管功能障碍、大血管并发症、腹主动脉瘤、颈动脉疾病、慢性静脉功能不全、严重肢体缺血等。On the other hand, the substances of the present invention can be used to treat or prevent vascular diseases, including cardiovascular and cerebrovascular diseases and peripheral vascular diseases. These vascular diseases include, but are not limited to: hypertension, pulmonary hypertension, atherosclerosis, arteriosclerosis, coronary heart disease (such as myocardial infarction and angina pectoris), coronary artery disease, heart failure (such as congestive heart failure), arrhythmia, left ventricular hypertrophy, angina pectoris, cerebral infarction, stroke (such as hemorrhagic stroke and ischemic stroke), transient ischemic attack, impaired vascular compliance, restenosis, post-angioplasty restenosis, thrombosis, pre-thrombotic state, vascular dysfunction, large vessel complications, abdominal aortic aneurysm, carotid artery disease, chronic venous insufficiency, severe limb ischemia, etc.

在另一方面，本发明的物质可用于治疗或预防神经系统障碍(例如神经变性疾病)或精神障碍。所述神经系统障碍包括但不限于：阿尔茨海默病(AD)、帕金森病(PD)、认知受损、痴呆、脑胰岛素抵抗、焦虑症、创伤性脑损伤、亨廷顿舞蹈病、迟发性运动障碍、运动机能亢进、唐氏综合征、重症肌无力、神经创伤、血管淀粉样变性、脑炎症、Friedrich's共济失调、肌萎缩性侧索硬化(ALS)、青光眼以及凋亡介导的中枢神经系统变性疾病。所述精神障碍包括但不限于药物依赖性/成瘾、注意力不足、多动症(ADHD)、精神分裂症、双相性精神障碍或抑郁症。本发明的物质可通过增强神经元可塑性以及促进细胞分化来改善学习及记忆，并且在帕金森病中保护多巴胺神经元和运动功能。而且，本发明的物质可以改善对成瘾药物的行为反应、减少药物依赖、预防药物滥用复发以及缓解由缺乏给定成瘾物质引起的焦虑。On the other hand, the substances of the present invention can be used to treat or prevent neurological disorders (e.g., neurodegenerative diseases) or mental disorders. The neurological disorders include, but are not limited to: Alzheimer's disease (AD), Parkinson's disease (PD), cognitive impairment, dementia, brain insulin resistance, anxiety disorders, traumatic brain injury, Huntington's disease, tardive dyskinesia, hyperkinesia, Down syndrome, myasthenia gravis, neurological trauma, angioamylindrica, brain inflammation, Friedrich's ataxia, amyotrophic lateral sclerosis (ALS), glaucoma, and apoptosis-mediated central nervous system degenerative diseases. The mental disorders include, but are not limited to, drug dependence/addiction, attention deficit hyperactivity disorder (ADHD), schizophrenia, bipolar disorder, or depression. The substances of the present invention can improve learning and memory by enhancing neuronal plasticity and promoting cell differentiation, and protect dopamine neurons and motor function in Parkinson's disease. Furthermore, the substances of the present invention can improve behavioral responses to addictive drugs, reduce drug dependence, prevent relapse of drug abuse, and alleviate anxiety caused by the lack of a given addictive substance.

在另一方面，本发明的物质可用于治疗或预防肾脏疾病。所述肾脏疾病包括但不限于：糖尿病性肾病、慢性肾衰竭、肾小球肾炎、肾小球硬化、肾病综合征、高血压肾硬化、末期肾脏疾病。In another aspect, the substances of the present invention can be used to treat or prevent kidney diseases. These kidney diseases include, but are not limited to: diabetic nephropathy, chronic renal failure, glomerulonephritis, glomerulosclerosis, nephrotic syndrome, hypertensive nephrosclerosis, and end-stage renal disease.

在另一方面，本发明的物质可用于治疗或预防胃肠疾病。所述胃肠疾病包括但不限于：溃疡、消化障碍、吸收障碍、短肠综合征、盲管综合征(cul-de-sac syndrome)、结肠炎、炎性肠病(克罗恩病和溃疡性结肠炎)、肠易激综合征、脂肪痢、低丙球蛋白血症性口炎性腹泻(hypogammaglobulinemic sprue)、化学疗法和/或放射疗法诱发的黏膜炎和腹泻、胃食道回流、胃肠道炎症、胃粘膜损伤、小肠粘膜损伤和恶病质。In another aspect, the substances of the present invention can be used to treat or prevent gastrointestinal diseases. These gastrointestinal diseases include, but are not limited to: ulcers, digestive disorders, malabsorption, short bowel syndrome, cul-de-sac syndrome, colitis, inflammatory bowel disease (Crohn's disease and ulcerative colitis), irritable bowel syndrome, steatorrhea, hypogammaglobulinemia-induced sprue, mucositis and diarrhea induced by chemotherapy and/or radiotherapy, gastroesophageal reflux, gastrointestinal inflammation, gastric mucosal damage, small intestinal mucosal damage, and cachexia.

在另一方面，本发明的物质可用于治疗或预防自身免疫性疾病。所述自身免疫性疾病包括但不限于：多发性硬化症、实验性自身免疫性脑脊髓炎、与免疫排斥相关的自体免疫障碍、移植物抗宿主病、葡萄膜炎、视神经病变、视神经炎、横贯性脊髓炎、炎性肠病、类风湿性关节炎、僵直性脊椎炎、系统性红斑狼疮、重症肌无力和格雷夫斯病(Gravesdisease)。In another respect, the substances of the present invention can be used to treat or prevent autoimmune diseases. These autoimmune diseases include, but are not limited to: multiple sclerosis, experimental autoimmune encephalomyelitis, autoimmune disorders related to immune rejection, graft-versus-host disease, uveitis, optic neuropathy, optic neuritis, transverse myelitis, inflammatory bowel disease, rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, myasthenia gravis, and Graves' disease.

在另一方面，本发明的物质可用于治疗或预防炎性疾病。所述炎性疾病包括但不限于：慢性类风湿性关节炎、变形性脊椎炎、变形性关节炎、腰痛、痛风、手术后或创伤后炎症、腹胀、神经痛、咽喉炎、膀胱炎、肺炎、胰腺炎、肠炎、炎性肠病、肝脏炎症、胰脏炎症、肾脏炎症、肠炎症、以及促炎性状态。On the other hand, the substances of the present invention can be used to treat or prevent inflammatory diseases. These inflammatory diseases include, but are not limited to: chronic rheumatoid arthritis, degenerative spondylitis, osteoarthritis, low back pain, gout, postoperative or post-traumatic inflammation, abdominal distension, neuralgia, pharyngitis, cystitis, pneumonia, pancreatitis, enteritis, inflammatory bowel disease, liver inflammation, pancreatitis, kidney inflammation, intestinal inflammation, and pro-inflammatory states.

在另一方面，本发明的物质可用于治疗或预防肺病。所述肺病包括但不限于：哮喘、特发性肺纤维化、肺性高血压、阻塞性睡眠呼吸暂停-呼吸不足综合征和慢性阻塞性肺病(COPD)。In another aspect, the substances of the present invention can be used to treat or prevent lung diseases. These lung diseases include, but are not limited to: asthma, idiopathic pulmonary fibrosis, pulmonary hypertension, obstructive sleep apnea-hypopnea syndrome, and chronic obstructive pulmonary disease (COPD).

在另一方面，本发明的物质可用于治疗或预防与下丘脑-垂体-性腺轴(例如下丘脑-垂体-卵巢轴、或下丘脑-垂体-睪丸轴)相关性疾病或障碍，其包括但不限于：性腺机能减退、多囊卵巢综合征、甲状腺功能减退、垂体机能减退、性功能障碍和库欣病(Cushing's disease)。In another respect, the substances of the present invention can be used to treat or prevent diseases or disorders related to the hypothalamus-pituitary-gonadal axis (e.g., the hypothalamus-pituitary-ovarian axis, or the hypothalamus-pituitary-testicular axis), including but not limited to: hypogonadism, polycystic ovary syndrome, hypothyroidism, hypopituitarism, sexual dysfunction, and Cushing's disease.

在另一方面，本发明的物质可用于治疗或预防癌症。所述癌症包括但不限于：胰腺癌、胃肠癌、肺癌、结肠癌、结直肠癌、食道癌、舌癌、咽癌、唾液腺癌、脑肿瘤、神经鞘瘤、肝癌、肾癌、胆管癌、子宫内膜癌、宫颈癌、卵巢癌、乳癌、前列腺癌、膀胱癌、尿道癌、皮肤癌、血管瘤、淋巴瘤、黑色素瘤、甲状腺癌、甲状旁腺癌、鼻腔癌、窦癌、骨肿瘤、血管纤维瘤、视网膜肉瘤、阴茎癌、睾丸肿瘤、卡波西肉瘤、上颌窦肿瘤、纤维组织细胞瘤、平滑肌肉瘤、横纹肌肉瘤和白血病。In another aspect, the substances of the present invention can be used to treat or prevent cancer. These cancers include, but are not limited to: pancreatic cancer, gastrointestinal cancer, lung cancer, colon cancer, colorectal cancer, esophageal cancer, tongue cancer, pharyngeal cancer, salivary gland cancer, brain tumors, schwannomas, liver cancer, kidney cancer, bile duct cancer, endometrial cancer, cervical cancer, ovarian cancer, breast cancer, prostate cancer, bladder cancer, urethral cancer, skin cancer, hemangioma, lymphoma, melanoma, thyroid cancer, parathyroid cancer, nasal cavity cancer, sinus cancer, bone tumors, angiofibroma, retinal sarcoma, penile cancer, testicular tumors, Kaposi's sarcoma, maxillary sinus tumors, fibrous histiocytoma, leiomyosarcoma, rhabdomyosarcoma, and leukemia.

在另一方面，本发明的物质还可用于治疗或预防：On the other hand, the substances of the present invention can also be used for treatment or prevention:

◆内脏脂肪沉积、脂肪细胞功能障碍、内皮细胞功能障碍、皮肤及结缔组织障碍；胆囊障碍；◆ Visceral fat deposition, adipocyte dysfunction, endothelial cell dysfunction, skin and connective tissue disorders; gallbladder disorders;

◆以骨代谢改变为特征的骨骼障碍，例如骨质疏松、骨强度不佳、骨质减少、佩吉特病(Paget's disease)、癌症患者的溶骨性转移、肝病中的骨营养不良以及任意原因(例如肾衰竭或血液透析、骨折、骨手术、老化、怀孕或多囊卵巢综合征)导致的骨代谢改变；关节障碍(例如骨关节炎、继发性骨关节炎)；◆ Skeletal disorders characterized by altered bone metabolism, such as osteoporosis, poor bone strength, osteopenia, Paget's disease, osteolytic metastases in cancer patients, osteodystrophy in liver disease, and altered bone metabolism due to any cause (e.g., renal failure or hemodialysis, fracture, bone surgery, aging, pregnancy, or polycystic ovary syndrome); joint disorders (e.g., osteoarthritis, secondary osteoarthritis);

◆肌营养不良、肌肉减少症、急性或慢性腹泻、虚弱、睪丸功能障碍、呼吸功能障碍、性功能障碍(例如，勃起功能障碍)、老年综合征、银屑病、原发性烦渴、进食障碍、间歇性跛行、经前综合征、口干症、听觉减退、黄斑变性、白内障、感染性疾病；和◆Muscular dystrophy, sarcopenia, acute or chronic diarrhea, weakness, testicular dysfunction, respiratory dysfunction, sexual dysfunction (e.g., erectile dysfunction), geriatric syndrome, psoriasis, essential polydipsia, eating disorders, intermittent claudication, premenstrual syndrome, xerostomia, hearing loss, macular degeneration, cataracts, infectious diseases; and

◆其他与GLP-1R调节、特别是激活相关的疾病或紊乱。◆ Other diseases or disorders related to GLP-1R regulation, especially activation.

在一些实施方案中，本发明的物质或方法可引起如下功效中的一种或多种：降低血糖、降低血液血红蛋白A1c(HbA1c)水平、促进胰岛素合成、刺激胰岛素分泌、增加β细胞质量、调节胃酸分泌、调节胃排空、降低身体质量指数(BMI)和/或降低胰高血糖素水平。在一些实施方案中，本发明的物质或方法可以使血清葡萄糖和血清胰岛素浓度稳定。本文还提供了调节个体的血清葡萄糖或胰岛素水平的方法，该方法包括向所述个体施用有效量的本发明的物质。In some embodiments, the substance or method of the present invention can cause one or more of the following effects: lowering blood glucose, lowering blood hemoglobin A1c (HbA1c) levels, promoting insulin synthesis, stimulating insulin secretion, increasing β-cell mass, regulating gastric acid secretion, regulating gastric emptying, lowering body mass index (BMI), and/or lowering glucagon levels. In some embodiments, the substance or method of the present invention can stabilize serum glucose and serum insulin concentrations. A method for regulating serum glucose or insulin levels in an individual is also provided herein, comprising administering an effective amount of the substance of the present invention to the individual.

在一些实施方案中，本文提供了用于降低个体的主要不良心血管事件(MACE)的风险的方法，该方法包括向所述个体施用有效量的本发明的物质。所述降低例如是降低约至少20％、至少30％、至少40％、至少50％、至少60％、至少70％或至少80％。在一些实施方案中，所述个体是患有或被诊断患有2型糖尿病的成人。在一些实施方案中，所述个体是患有或被诊断患有心脏病的成人。在一些实施方案中，所述患者是患有或被诊断患有2型糖尿病和心脏病的成人。In some embodiments, this document provides a method for reducing the risk of major adverse cardiovascular events (MACE) in an individual, the method comprising administering an effective amount of the substance of the present invention to the individual. The reduction is, for example, a reduction of about 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, or at least 80%. In some embodiments, the individual is an adult who has or has been diagnosed with type 2 diabetes. In some embodiments, the individual is an adult who has or has been diagnosed with heart disease. In some embodiments, the individual is an adult who has or has been diagnosed with both type 2 diabetes and heart disease.

药物组合物和施用Pharmaceutical composition and administration

本发明的物质可以以药物组合物的形式、通过任意适用的途径施用，例如但不限于口服(以片剂、包衣片剂、锭剂、硬和软明胶胶囊、溶液、乳剂或悬浮液的形式)、吸入(例如以喷雾剂形式)、直肠(例如以栓剂形式)或胃肠道外(例如以注射液形式，例如静脉内、肌内、皮下、腹膜内、颅内等)进行施用。特别优选口服、鼻内和肠胃外施用，例如静脉内施用。The substances of the present invention can be administered in the form of pharmaceutical compositions via any suitable route, such as, but not limited to, oral administration (in the form of tablets, coated tablets, lozenges, hard and soft gelatin capsules, solutions, emulsions, or suspensions), inhalation (e.g., in the form of sprays), rectal administration (e.g., in the form of suppositories), or parenteral administration (e.g., in the form of injections, such as intravenous, intramuscular, subcutaneous, intraperitoneal, intracranial, etc.). Oral, intranasal, and parenteral administration, such as intravenous administration, are particularly preferred.

将本发明的物质制备成药物组合物的技术是本领域熟知的。例如，可以使用一种或多种可药用载体、稀释剂或赋形剂将本发明的物质加工成药物组合物的形式，例如片剂、包衣片剂、胶囊剂、液体制剂(例如注射液、输液、糖浆、乳剂、混悬剂等)、散剂、粉针剂、分散体、喷雾剂、栓剂、脂质体等。可药用载体、稀释剂或赋形剂是本领域熟知的，例如填充剂、崩解剂、溶媒、增溶剂、稳定剂、湿润剂、乳化剂、防腐剂、甜味剂、着色剂、矫味剂、用于改变渗透压的盐、缓冲剂、掩蔽剂或抗氧化剂等。Techniques for preparing the substances of the present invention into pharmaceutical compositions are well known in the art. For example, the substances of the present invention can be processed into pharmaceutical compositions, such as tablets, coated tablets, capsules, liquid formulations (e.g., injections, infusions, syrups, emulsions, suspensions, etc.), powders, powder for injection, dispersions, sprays, suppositories, liposomes, etc., using one or more pharmaceutically acceptable carriers, diluents, or excipients. Pharmaceutically acceptable carriers, diluents, or excipients are well known in the art, and include, for example, fillers, disintegrants, solvents, solubilizers, stabilizers, wetting agents, emulsifiers, preservatives, sweeteners, colorants, flavoring agents, salts for altering osmotic pressure, buffers, masking agents, or antioxidants.

本发明的物质可以以任意适宜的给药频率进行施用，例如从每天1-3次到每个月1次或每两个月1次或每三个月1次等。通常，口服给药对于患者的便利性和安全性等而言是优选的。在一些实施方案中，本发明的物质可以以每天1次、每两天1次、每周两次、每周一次、每两周一次、每三周一次、每四周一次、每五周一次、每六周一次或更长的时间间隔口服施用。优选地，本发明的物质可以以每周两次、每周一次、每两周一次、每三周一次或每四周一次的频率进行口服施用，优选每周一次口服施用。The substance of the present invention can be administered at any suitable frequency, such as from once to three times daily to once a month, once every two months, or once every three months. Generally, oral administration is preferred for patient convenience and safety. In some embodiments, the substance of the present invention can be administered orally once daily, once every two days, twice a week, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, or at longer intervals. Preferably, the substance of the present invention can be administered orally twice a week, once a week, once every two weeks, once every three weeks, or once every four weeks, with once a week being the most preferred.

剂量可在宽范围内改变，并且当然必须根据每个具体病例中的个体需要进行调整。适宜剂量的确定可以由主治医师根据所治疗疾病的种类及其严重性、个体的健康状况和既往病史、所施用的具体化合物和施用途径以及共用药物等酌情确定。70kg成人的周剂量典型地为约0.01mg至约1000mg本发明的物质或相应量的可药用盐或酯。根据需要，本发明的物质的用量可以超出该剂量范围。周剂量可作为单剂量或以分次剂量施用。Dosage can be varied within a wide range and must, of course, be adjusted according to the individual needs of each specific case. The appropriate dosage can be determined by the attending physician at their discretion based on the type and severity of the disease being treated, the individual's health status and medical history, the specific compound and route of administration, and any concomitant medications. The weekly dose for a 70kg adult is typically from about 0.01mg to about 1000mg of the substance of the invention or a corresponding amount of pharmaceutically acceptable salts or esters. The dosage of the substance of the invention may exceed this range as needed. The weekly dose may be administered as a single dose or in divided doses.

药物组合Drug combination

本发明的物质可以单独地或与一种或多种其它活性剂或疗法组合使用，所述其它活性剂或疗法可以具有与本发明的物质相同或不同的药理学功效。本发明的物质可以与所述其它活性剂或疗法同时、在其之前或在其之后施用。The substance of the present invention can be used alone or in combination with one or more other active agents or therapies, which may have the same or different pharmacological effects as the substance of the present invention. The substance of the present invention can be administered simultaneously, before, or after the other active agents or therapies.

代表性的其它活性剂包括但不限于抗肥胖剂、糖尿病治疗剂、糖尿病并发症治疗剂、高脂血症治疗剂、抗高血压药、利尿药、化疗药、免疫调节剂、抗炎药物、抗血栓形成剂、心血管疾病治疗剂、肝病治疗剂、肾病治疗剂、眼病治疗剂、皮肤病治疗剂、血管疾病治疗药物、抗病毒药物、骨质疏松治疗剂、维生素、抗痴呆药物、勃起功能障碍药物、尿频或尿失禁治疗药物、NAFLD治疗剂、NASH治疗剂、排尿困难治疗剂、止吐剂、镇痛剂、抗增殖药物、抗癌药。Other representative active agents include, but are not limited to, anti-obesity agents, diabetes treatment agents, diabetes complication treatment agents, hyperlipidemia treatment agents, antihypertensive drugs, diuretics, chemotherapy drugs, immunomodulators, anti-inflammatory drugs, antithrombotic agents, cardiovascular disease treatment agents, liver disease treatment agents, kidney disease treatment agents, eye disease treatment agents, skin disease treatment agents, vascular disease treatment agents, antiviral drugs, osteoporosis treatment agents, vitamins, antidementia drugs, erectile dysfunction drugs, urinary frequency or incontinence treatment agents, NAFLD treatment agents, NASH treatment agents, dysuria treatment agents, antiemetics, analgesics, antiproliferative drugs, and anticancer drugs.

代表性的疗法包括但不限于饮食疗法(例如饮食监测、糖尿病饮食疗法)、运动疗法(例如体能活动)、血糖监测、胃电刺激(例如TANTALUS)和饮食改变。Representative treatments include, but are not limited to, dietary therapy (e.g., diet monitoring, diabetes diet therapy), exercise therapy (e.g., physical activity), blood glucose monitoring, gastric electrical stimulation (e.g., TANTALUS), and dietary modifications.

当本发明的物质与其它活性剂或疗法组合施用时，组合施用的活性剂的剂量将根据共用药物、待治疗病症、个体的一般健康状况、医师或兽医的判断等因素而变化。本发明的物质可以与共用的其它活性剂通过相同或不同的施用途径同时、分别或依次施用。它们可以被包含在同一药物组合物中(固定组合物)，也可以是分开形式、例如药盒形式的组合产品。它们可以由相同或不同的制造商配制和/或供应。而且，本发明的物质和其它活性剂可以(i)在将组合产品发送给医师之前(例如在包含本发明的物质和其它活性剂的药盒的情形中)；(ii)在临施用前由医师自身(或在医师指导下)；或(iii)由患者自身、例如在本发明的物质和其它活性剂的依次施用期间一起加入组合治疗中。When the substances of the present invention are administered in combination with other active agents or therapies, the dosage of the combined active agents will vary depending on factors such as the shared medication, the condition to be treated, the individual's general health condition, and the judgment of the physician or veterinarian. The substances of the present invention can be administered simultaneously, separately, or sequentially with other shared active agents via the same or different routes of administration. They can be contained in the same pharmaceutical composition (fixed composition) or in separate forms, such as in a pillbox. They can be formulated and/or supplied by the same or different manufacturers. Moreover, the substances of the present invention and other active agents can be (i) before the combined product is sent to a physician (e.g., in the case of a pillbox containing the substances of the present invention and other active agents); (ii) by the physician himself (or under the physician's guidance) before administration; or (iii) by the patient himself, for example, during the sequential administration of the substances of the present invention and other active agents in the combined treatment.

在一些实施方案中，本申请提供了包含本发明的物质以及一种或多种其它活性剂的药物组合物。任选地，药物组合物可以包含一种或多种可药用载体、稀释剂或赋形剂。In some embodiments, this application provides pharmaceutical compositions comprising the substances of the present invention and one or more other active agents. Optionally, the pharmaceutical composition may comprise one or more pharmaceutically acceptable carriers, diluents, or excipients.

在一些实施方案中，本申请提供了药物组合产品如药盒，其包含两个或更多个单独的药物组合物，其中至少一个含有本发明的物质。在一些实施方案中，药盒包括用于分别容纳所述组合物的器具，例如容器、分开的瓶或分开的箔袋。In some embodiments, this application provides pharmaceutical combination products such as pillboxes containing two or more individual pharmaceutical compositions, at least one of which contains the substance of the present invention. In some embodiments, the pillbox includes a device for separately containing the compositions, such as a container, separate bottles, or separate foil pouches.

本申请的药盒可用于施用不同的剂型、例如口服和胃肠道外剂型，用于以不同的剂量间隔施用单独的组合物，或用于相对于另一种逐步增加单独的组合物。为了帮助顺应性，本申请的药盒通常包含施用说明书。The kit of this application can be used to administer different dosage forms, such as oral and parenteral dosage forms, to administer a single composition at different dose intervals, or to gradually increase a single composition relative to another. To aid compliance, the kit of this application typically includes instructions for use.

本发明化合物的制备方法Preparation method of the compound of the present invention

本发明的物质可以通过多种方法、包括下文流程中的方法、实施例中给出的方法或与之类似的方法来制备。对于各反应步骤而言，适当的反应条件是本领域技术人员已知的或者可以容易地确定。原料通常可购买获得，或者可以利用本领域公知的方法或本文所述的方法容易地制备。通式中的各变量具有本文定义的含义，另有说明除外。The substances of this invention can be prepared by various methods, including those described in the following flowcharts, the methods given in the examples, or similar methods. For each reaction step, suitable reaction conditions are known to those skilled in the art or can be readily determined. The raw materials are generally commercially available or can be readily prepared using methods known in the art or those described herein. The variables in the general formulas have their meanings as defined herein, unless otherwise stated.

仅为解释目的，以下流程提供了合成本发明化合物的示例性途径。本领域技术人员理解，其它合成途径也是可利用的，并且通过下文所述方法制备的化合物可以根据本申请的内容、利用本领域技术人员熟知的常规化合物进行进一步改变。For illustrative purposes only, the following process provides an exemplary route for synthesizing the compounds of the present invention. Those skilled in the art will understand that other synthetic routes are also available, and that compounds prepared by the methods described below can be further modified based on the content of this application and using conventional compounds well known to those skilled in the art.

在本发明的物质的制备中，基团的保护(例如氨基保护基、羟基保护基)可能是需要的，这可以由本领域技术人员容易地决定。对于保护基的一般描述及其用途，参见T.W.Greene，Protective Groups in Organic Synthesis，John Wiley&Sons，纽约，1991。如果没有特别说明，在制备这些化合物中使用的原料和试剂通常可商购获得，或者可以通过下文的方法、与下文给出的方法类似的方法或本领域已知的方法制得。In the preparation of the substances of this invention, the protection of groups (e.g., amino protecting groups, hydroxyl protecting groups) may be necessary, which can be readily determined by those skilled in the art. For a general description of protecting groups and their uses, see T.W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991. Unless otherwise specified, the raw materials and reagents used in the preparation of these compounds are generally commercially available or can be prepared by the methods described below, similar methods given below, or methods known in the art.

如果需要，合成反应流程中的原料和中间体可以采用常规技术进行分离和纯化，所述技术包括但不限于过滤、蒸馏、结晶、色谱法等。所述材料可以采用包括物理常数和波谱数据在内的常规方法表征。If necessary, the raw materials and intermediates in the synthesis reaction process can be separated and purified using conventional techniques, including but not limited to filtration, distillation, crystallization, and chromatography. The materials can be characterized using conventional methods, including physical constants and spectroscopic data.

流程I
Process I

流程I显示了本发明化合物的一种制备方法：使式(A)化合物与式(B)化合物缩合，得到式(I-1)化合物，其中各变量如本文所定义。该反应优选在缩合剂和碱的存在下、在适当的溶剂中进行。Procedure I illustrates a method for preparing the compounds of the present invention: condensing compound (A) with compound (B) to obtain compound (I-1), wherein the variables are as defined herein. This reaction is preferably carried out in the presence of a condensing agent and a base, in a suitable solvent.

流程II
Process II

流程II显示了本发明化合物的一种制备方法：使其中L2为的式(A)化合物，即式(A')化合物，与式(B)化合物缩合，得到式(I-3)化合物，其中各变量如本文所定义。该反应优选在缩合剂和碱的存在下、在适当的溶剂中进行。Process II illustrates a method for preparing the compound of the present invention: wherein L2 is... Compound (A), i.e., compound (A'), is condensed with compound (B) to give compound (I-3), wherein the variables are as defined herein. This reaction is preferably carried out in the presence of a condensing agent and a base, in a suitable solvent.

流程III
Process III

流程III显示了本发明化合物的一种制备方法：使式(A”)化合物与式(B')化合物缩合，得到式(IV)化合物，其中各变量如本文所定义。该反应优选在缩合剂和碱的存在下、在适当的溶剂中进行。Procedure III illustrates a method for preparing the compounds of the present invention: condensing a compound of formula (A”) with a compound of formula (B’) to obtain a compound of formula (IV), wherein the variables are as defined herein. This reaction is preferably carried out in the presence of a condensing agent and a base, in a suitable solvent.

对于本文所述的缩合反应，缩合剂的实例包括但不限于1-羟基苯并三唑(HOBt)、苯并三唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)、苯并三唑-1-基氧基-三(吡咯烷基)膦鎓六氟磷酸盐(PyBOP)、2-(1H-苯并三唑-1-基)-1,1,3,3-四甲基脲鎓四氟硼酸盐(TBTU)、[二甲基氨基(三唑并[4,5-b]吡啶-3-基氧基)亚甲基]-二甲基铵六氟磷酸盐(HATU)、1-乙基-(3-二甲氨基丙基)碳二亚胺(EDC)、和二环己基碳二亚胺(DCC)。在一些实施方案中，缩合剂是1-羟基苯并三唑(HOBt)和/或1-乙基-(3-二甲氨基丙基)碳二亚胺(EDC)。优选地，缩合剂是1-羟基苯并三唑(HOBt)。Examples of condensing agents for the condensation reactions described herein include, but are not limited to, 1-hydroxybenzotriazole (HOBt), benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), benzotriazole-1-yloxytris(pyrrolidinyl)phosphonium hexafluorophosphate (PyBOP), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethylureon tetrafluoroborate (TBTU), [dimethylamino(triazolo[4,5-b]pyridin-3-yloxy)methylene]-dimethylammonium hexafluorophosphate (HATU), 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC), and dicyclohexylcarbodiimide (DCC). In some embodiments, the condensing agent is 1-hydroxybenzotriazole (HOBt) and/or 1-ethyl-(3-dimethylaminopropyl)carbodiimide (EDC). Preferably, the condensing agent is 1-hydroxybenzotriazole (HOBt).

碱的实例包括但不限于：叔胺，例如三乙胺、N-甲基吗啉、二异丙基乙胺(DIPEA)、1,8-二氮杂二环十一碳-7-烯(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)等；含氮杂芳族化合物，例如吡啶、二甲氨基吡啶、甲基吡啶、2,6-二甲基吡啶、吡嗪、哒嗪等。优选地，所述碱是叔胺，例如二异丙基乙基胺。Examples of bases include, but are not limited to: tertiary amines, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO), etc.; nitrogen-containing heteroaromatic compounds, such as pyridine, dimethylaminopyridine, methylpyridine, 2,6-dimethylpyridine, pyrazine, pyridazine, etc. Preferably, the base is a tertiary amine, such as diisopropylethylamine.

溶剂的实例包括但不限于：非质子极性溶剂，例如二甲亚砜(DMSO)、二甲基甲酰胺(DMF)、二甲基乙酰胺和1-甲基-2-吡咯烷酮；和醚溶剂，例如乙醚、四氢呋喃(THF)和二噁烷。优选地，所述溶剂是非质子极性溶剂，例如DMF。Examples of solvents include, but are not limited to: aprotic polar solvents, such as dimethyl sulfoxide (DMSO), dimethylformamide (DMF), dimethylacetamide, and 1-methyl-2-pyrrolidone; and ether solvents, such as diethyl ether, tetrahydrofuran (THF), and dioxane. Preferably, the solvent is an aprotic polar solvent, such as DMF.

该反应在足以进行反应的温度下进行。例如，反应温度是0-80℃，优选20-60℃，更优选环境温度(约20-25℃)。反应进行足以使反应进行完全的时间。例如，反应时间是1分钟至10小时，优选30分钟至5小时，例如4小时。The reaction is carried out at a temperature sufficient for the reaction to proceed. For example, the reaction temperature is 0-80°C, preferably 20-60°C, and more preferably ambient temperature (about 20-25°C). The reaction is carried out for a sufficient time to allow the reaction to complete. For example, the reaction time is from 1 minute to 10 hours, preferably from 30 minutes to 5 hours, such as 4 hours.

任选地，通过本领域技术人员已知的方法，将所获得的式(I)化合物(包括其亚式化合物或实施例化合物)转化为需要的形式，例如与酸或碱反应形成盐、从溶剂中沉淀获得溶剂合物、将溶剂合物减压加热转化为非溶剂合物等。本发明的化合物可以以晶体或无定型形式存在。Optionally, the obtained compound of formula (I) (including its sub-forms or example compounds) may be converted into the desired form by methods known to those skilled in the art, such as reacting with an acid or base to form a salt, precipitating from a solvent to obtain a solvate, or heating the solvate under reduced pressure to convert it into a non-solvent. The compounds of the present invention may exist in crystalline or amorphous form.

流程IV
Process IV

流程IV显示了一种制备式(A’)化合物的方法：式(A'-5)化合物进行闭环反应，得到式(A')化合物。该反应优选在酸(例如对甲苯磺酸)的存在下、在溶剂(例如间二甲苯)中进行。该反应可以在升高温度下、例如约100-200℃、例如约120-180℃、例如约140-160℃、例如150℃下进行。反应时间是使得反应完全的时间，例如1-20小时、例如1-10小时、例如1-5小时、例如1-2小时。步骤3的反应产物可以任选地进行后处理，得到式(A')化合物的固体。式(A')化合物可以如流程II中所述用于制备本发明的式(I-3)化合物。Procedure IV illustrates a method for preparing compound (A'): compound (A'-5) undergoes a ring-closing reaction to yield compound (A'). This reaction is preferably carried out in the presence of an acid (e.g., p-toluenesulfonic acid) and in a solvent (e.g., m-xylene). The reaction can be carried out at elevated temperatures, for example, about 100-200°C, about 120-180°C, about 140-160°C, or 150°C. The reaction time is the time required for the reaction to complete, for example, 1-20 hours, 1-10 hours, 1-5 hours, or 1-2 hours. The reaction product of step 3 can optionally be post-treated to obtain a solid of compound (A'). Compound (A') can be used to prepare compound (I-3) of the present invention as described in Procedure II.

流程V
Process V

流程V显示了一种制备式(A'-5)化合物的方法，该方法涉及A'-1与氯甲酸酯(例如A'-2)反应形成双活性酯中间态A'-3，进而原位生成A'-5的成脲反应，其中RA可以是任意不干扰反应进行的基团，例如如本文所定义，和其它各变量如本文所定义。式(A'-1)化合物与式(A'-2)的氯甲酸酯反应形成式(A'-3)的双活性酯化合物的反应可以在碱的存在下、在溶剂中进行。该反应可以在环境温度(例如约20-25℃)下进行。反应时间是使得反应完全的时间，例如5分钟至5小时、5分钟至2小时、5分钟至1小时、5-30分钟、5-20分钟，例如15分钟。反应产物可直接用于下一步骤(原位反应)。在一些实施方案中，所述反应条件如本文所述。Process V illustrates a method for preparing a compound of formula (A'-5) involving a urea-forming reaction of A'-1 with a chloroformate (e.g., A'-2) to form a bireactive ester intermediate A'-3, which then generates A'-5 in situ. Here, RA can be any group that does not interfere with the reaction, such as those defined herein, and other variables are as defined herein. The reaction of the compound of formula (A'-1) with a chloroformate of formula (A'-2) to form a bireactive ester compound of formula (A'-3) can be carried out in a solvent in the presence of a base. The reaction can be carried out at ambient temperature (e.g., about 20-25°C). The reaction time is the time required for the reaction to complete, for example, 5 minutes to 5 hours, 5 minutes to 2 hours, 5 minutes to 1 hour, 5-30 minutes, 5-20 minutes, or, for example, 15 minutes. The reaction product can be used directly in the next step (in situ reaction). In some embodiments, the reaction conditions are as described herein.

式(A'-3)化合物原位形成式(A'-5)的脲化合物的反应可以在升高温度下、例如约40-90℃、例如50-60℃、例如55℃下进行。反应时间是使得反应完全的时间，例如1-20小时、例如1-10小时、例如1-5小时、例如1-2小时。所得产物可以任选地进行浓缩和/或纯化。在一些实施方案中，所述反应条件如本文所述。The reaction for the in-situ formation of a urea compound of formula (A'-5) from a compound of formula (A'-3) can be carried out at elevated temperatures, for example, about 40-90°C, for example, 50-60°C, or for example, 55°C. The reaction time is the time required for the reaction to complete, for example, 1-20 hours, for example, 1-10 hours, for example, 1-5 hours, or for example, 1-2 hours. The resulting product can optionally be concentrated and/or purified. In some embodiments, the reaction conditions are as described herein.

附图说明Attached Figure Description

图1显示了实施例化合物1在施用后5h时血糖-时间曲线下面积的变化。Figure 1 shows the change in the area under the blood glucose-time curve of compound 1 of Example 1 5 h after administration.

图2.1显示了实施例化合物18、22和23在施用后5h和48h时血糖-时间曲线下面积的变化。Figure 2.1 shows the changes in the area under the blood glucose-time curves of compounds 18, 22 and 23 of Examples at 5 h and 48 h after administration.

图2.2显示了实施例化合物24和52在施用后5h和96h时血糖-时间曲线下面积的变化。Figure 2.2 shows the changes in the area under the blood glucose-time curves of compounds 24 and 52 at 5 h and 96 h after administration.

图3.1显示了在施用实施例化合物后的小鼠体重变化曲线(0-28天)。Figure 3.1 shows the curves of mouse body weight change (0-28 days) after administration of the compound of the example.

图3.2显示了在施用实施例化合物后的累计摄食量变化曲线(0-28天)。Figure 3.2 shows the cumulative food intake change curves (0-28 days) after application of the compound of the example.

图3.3显示了小鼠在末次施用实施例化合物后的PK曲线。Figure 3.3 shows the PK curves of mice after the last administration of the compound of the example.

实施例Example

提供以下实施例对本发明进行进一步说明。应当理解，其仅仅是为了能够更好地理解本发明，而不以任何方式限定本发明的范围。凡是不背离本发明构思的改变或等同替代均包括在本发明的保护范围之内。The following embodiments are provided to further illustrate the present invention. It should be understood that these are merely for the purpose of better understanding the invention and are not intended to limit the scope of the invention in any way. All changes or equivalent substitutions that do not depart from the inventive concept are included within the scope of protection of the present invention.

在本申请中，当化学名称和结构式不一致时，应当以结构式所示为准，除非根据上下文可以推断化学名称而非结构式是正确的。为简便，在本申请所给出的一些化合物结构式中并非所有氢原子均被明确地标示出来。当化合物中存在空余化合价时，表示存在未标示出的氢原子。In this application, when the chemical name and structural formula are inconsistent, the structural formula shall prevail, unless the chemical name rather than the structural formula can be inferred from the context as correct. For simplicity, not all hydrogen atoms are explicitly labeled in the structural formulas of some compounds given in this application. When a compound has an empty valence, it indicates the presence of unlabeled hydrogen atoms.

下列实施例中未注明具体条件的实验方法时，通常按照这类反应的常规条件，或按照制造厂商所建议的条件。下列实施例中未注明手性中心构型时，意味着可以以单独的对映异构体或对映体混合物形式存在，且本领域技术人员能够确定化合物的稳定和可行的异构体形式。百分比和份数分别是重量百分比和重量份数，液体比为体积比，温度为摄氏度，另有说明除外。下列实施例中，正相柱层析一般是用硅胶柱，反相一般用C18柱，除非特别注明。Unless otherwise specified, experimental methods in the following examples are generally performed under standard conditions for such reactions or as recommended by the manufacturer. The absence of a chiral center configuration in the following examples means that the compound may exist as a single enantiomer or a mixture of enantiomers, and that a person skilled in the art can determine the stable and viable isomeric forms of the compound. Percentages and parts are weight percentages and parts by weight, respectively; liquid ratios are volume ratios; and temperatures are in degrees Celsius, unless otherwise stated. In the following examples, normal-phase column chromatography is generally performed using a silica gel column, and reversed-phase chromatography is generally performed using a C18 column, unless otherwise specified.

以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得、依据现有技术的方法制得或根据与本申请公开的类似的方法制得。除非另有说明，本发明使用的原料都是市售原料，无需进一步纯化可以直接使用。Unless otherwise specified, all experimental materials and reagents used in the following examples are commercially available, prepared using existing methods, or prepared using methods similar to those disclosed in this application. Unless otherwise stated, all raw materials used in this invention are commercially available and can be used directly without further purification.

本申请使用的缩写具有本领域通常理解的含义，除非说明书中另外清楚定义。The abbreviations used in this application have the meanings commonly understood in the art, unless otherwise clearly defined in the specification.

中间体的合成Synthesis of intermediates

中间体A1：1-(4-氟-1-甲基-1H-吲唑-5-基)-3-((S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A1)
 Intermediate A1 : 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A1)

步骤1：(2S)-3-氰基-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(A1-2)Step 1: (2S)-3-cyano-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (A1-2)

将化合物A1-1(44.37g,186.21mmol)溶于乙醇/水(450mL,2/1)的混合溶液中，0℃下，分三批缓慢加入硼氢化钠(3.52g,93.11mmol)，反应混合物缓慢升温至20-25℃下搅拌1小时。反应结束后，减压浓缩除去乙醇，残余物用乙酸乙酯(75mL×3)萃取，合并有机相，用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到棕色液体A1-2(38.41g,85.8％)。ESI-MS(m/z):[M+H]+＝241.3。Compound A1-1 (44.37 g, 186.21 mmol) was dissolved in a mixture of ethanol/water (450 mL, 2/1). Sodium borohydride (3.52 g, 93.11 mmol) was slowly added in three portions at 0 °C. The reaction mixture was slowly heated to 20–25 °C and stirred for 1 hour. After the reaction was complete, the ethanol was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (75 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown liquid, A1-2 (38.41 g, 85.8%). ESI-MS (m/z): [M+H] + = 241.3.

步骤2：(2S)-3-氨基甲酰基-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(A1-3)Step 2: (2S)-3-carbamoyl-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (A1-3)

将化合物A1-2(38.41g,159.84mmol)溶于二甲亚砜(270mL)中，加入碳酸钾(8.84g,63.94mmol)和过氧化氢水溶液(30％,45.30g,399.62mmol)，反应混合物升温至40℃反应14小时。反应结束后，将体系降温，在反应混合物中加水(500mL)，用乙酸乙酯(150mL×3)萃取，合并有机相，用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(乙酸乙酯/正己烷＝1/1)，得到白色固体A1-3(20.93g,50.7％)。ESI-MS(m/z):[M+H]+＝259.4。Compound A1-2 (38.41 g, 159.84 mmol) was dissolved in dimethyl sulfoxide (270 mL), and potassium carbonate (8.84 g, 63.94 mmol) and hydrogen peroxide aqueous solution (30%, 45.30 g, 399.62 mmol) were added. The reaction mixture was heated to 40 °C and reacted for 14 hours. After the reaction was completed, the system was cooled, water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1) to give a white solid A1-3 (20.93 g, 50.7%). ESI-MS (m/z): [M+H] + = 259.4.

步骤3：(4S)-4-甲基-2-氧代六氢噁唑并[4,5-c]吡啶-5(4H)-甲酸叔丁酯(A1-4)Step 3: (4S)-4-methyl-2-oxohexahydrooxazolo[4,5-c]pyridine-5(4H)-carboxylic acid tert-butyl ester (A1-4)

将化合物A1-3(20.93g,81.1mmol)和二乙酸碘苯(31.4g,97.3mmol)溶于乙腈(250mL)中，反应混合物升温至50℃反应3小时。反应结束后，将体系降温，反应液减压浓缩，得到粗品。粗品经硅胶柱层析纯化(乙酸乙酯/正己烷＝1/1)，得到白色固体A1-4(16.76g,80.7％)。ESI-MS(m/z):[M+H]+＝257.4。Compound A1-3 (20.93 g, 81.1 mmol) and diacetic acid iodobenzene (31.4 g, 97.3 mmol) were dissolved in acetonitrile (250 mL), and the reaction mixture was heated to 50 °C and reacted for 3 hours. After the reaction was completed, the system was cooled, and the reaction solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1) to give a white solid A1-4 (16.76 g, 80.7%). ESI-MS (m/z): [M+H] + = 257.4.

步骤4：(2S)-3-氨基-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(A1-5)Step 4: (2S)-3-amino-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (A1-5)

将化合物A1-4(16.76g,65.5mmol)溶于乙醇/水(300mL,2/1)的混合溶液中，加入氢氧化钠(13.1g,327.5mmol)，反应混合物升温至80℃反应2小时。反应结束后，将体系降温，减压浓缩除去乙醇，残余物用乙酸乙酯(75mL×3)萃取，合并有机相，用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到类白色固体A1-5(12.83g,85.1％)。ESI-MS(m/z):[M+H]+＝231.3。Compound A1-4 (16.76 g, 65.5 mmol) was dissolved in a mixture of ethanol/water (300 mL, 2/1), and sodium hydroxide (13.1 g, 327.5 mmol) was added. The reaction mixture was heated to 80 °C and reacted for 2 hours. After the reaction was complete, the system was cooled, and the ethanol was removed by concentration under reduced pressure. The residue was extracted with ethyl acetate (75 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid A1-5 (12.83 g, 85.1%). ESI-MS (m/z): [M+H] + ＝231.3.

步骤5：(2S)-3-(4-氟-3,5-二甲基苯甲酰胺基)-4-羟基-2-甲基哌啶-1-甲酸叔丁酯(A1-6)Step 5: (2S)-3-(4-fluoro-3,5-dimethylbenzamido)-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (A1-6)

将化合物A1-5(12.83g,55.67mmol)、4-氟-3,5-二甲基苯甲酸(9.35g,55.67mmol)、(1-乙基-(3-二甲氨基丙基)碳二亚胺盐酸盐(11.7g,61.24mmol)和1-羟基苯并三唑(8.27g,61.24mmol)溶于二氯甲烷(200mL)中，于20-25℃下反应4小时。反应结束后，减压浓缩得到粗品，粗品经硅胶柱层析纯化(乙酸乙酯/正己烷＝1/1)，得到褐色固体A1-6(15.68g,74.5％)。ESI-MS(m/z):[M+H]+＝381.4。Compound A1-5 (12.83 g, 55.67 mmol), 4-fluoro-3,5-dimethylbenzoic acid (9.35 g, 55.67 mmol), (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (11.7 g, 61.24 mmol), and 1-hydroxybenzotriazole (8.27 g, 61.24 mmol) were dissolved in dichloromethane (200 mL) and reacted at 20–25 °C for 4 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1) to give a brown solid A1-6 (15.68 g, 74.5%). ESI-MS (m/z): [M+H] + = 381.4.

步骤6：(2S)-3-(4-氟-3,5-二甲基苯甲酰胺基)-2-甲基-4-氧代哌啶-1-甲酸叔丁酯(A1-7)Step 6: (2S)-3-(4-fluoro-3,5-dimethylbenzamido)-2-methyl-4-oxoperidin-1-carboxylic acid tert-butyl ester (A1-7)

氮气保护下，将化合物A1-6(15.68g,41.48mmol)和戴斯-马丁试剂(26.38g,62.22mmol)溶于二氯甲烷(250mL)中，于20-25℃下反应12小时。反应结束后，过滤，滤饼用二氯甲烷(10mL×3)洗涤，合并滤液，加水(250mL)，用二氯甲烷(100mL×2)萃取，合并有机相，用饱和食盐水(100mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(乙酸乙酯/正己烷＝1/2)，得到类白色固体A1-7(12.27g,78.3％)。ESI-MS(m/z):[M+H]+＝379.3。Under nitrogen protection, compound A1-6 (15.68 g, 41.48 mmol) and Dys-Martin reagent (26.38 g, 62.22 mmol) were dissolved in dichloromethane (250 mL) and reacted at 20–25 °C for 12 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with dichloromethane (10 mL × 3). The filtrates were combined, water (250 mL) was added, and the mixture was extracted with dichloromethane (100 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/2) to give an off-white solid A1-7 (12.27 g, 78.3%). ESI-MS (m/z): [M+H] + = 379.3.

步骤7：(S)-2-(4-氟-3,5-二甲基苯基)-1-(4-甲氧基苄基)-4-甲基-1,4,6,7-四氢-5H-咪唑[4,5-c]吡啶-5-甲酸叔丁基酯(A1-8)Step 7: (S)-2-(4-fluoro-3,5-dimethylphenyl)-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazolium[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-8)

氮气保护下，将化合物A1-7(12.27g,32.46mmol)、对甲氧基苄胺(6.67g,48.69mmol)和乙酸(974mg,16.23mmol)溶于间二甲苯(150mL)中(用分水器除水)，反应混合物升温至150℃反应6小时。反应结束后，减压浓缩得到粗品，粗品经硅胶柱层析纯化(乙酸乙酯/正己烷＝1/1)，得到类白色固体A1-8(10.15g,65.3％)。ESI-MS(m/z):[M+H]+＝480.4。Under nitrogen protection, compound A1-7 (12.27 g, 32.46 mmol), p-methoxybenzylamine (6.67 g, 48.69 mmol), and acetic acid (974 mg, 16.23 mmol) were dissolved in m-xylene (150 mL) (water was removed using a separator), and the reaction mixture was heated to 150 °C and reacted for 6 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (ethyl acetate/n-hexane = 1/1) to give an off-white solid A1-8 (10.15 g, 65.3%). ESI-MS (m/z): [M+H] + = 480.4.

步骤8：(S)-3-氨基-5-(叔丁氧羰基)-2-(4-氟-3,5-二甲基苯基)-1-(4-甲氧基苄基)-4-甲基-4,5,6,7-四氢-1H-咪唑并[4,5-c]吡啶-3-鎓-2,4,6-三甲基苯磺酸盐(A1-9)Step 8: (S)-3-amino-5-(tert-butoxycarbonyl)-2-(4-fluoro-3,5-dimethylphenyl)-1-(4-methoxybenzyl)-4-methyl-4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine-3-onthium-2,4,6-trimethylbenzenesulfonate (A1-9)

将化合物A1-8(918mg,1.92mmol)和O-(异三甲苯磺酰基)羟胺(1.1g,5.12mmol)溶于二氯甲烷(20mL)中，于20-25℃下反应5小时。反应结束后，减压浓缩得到粗品，粗品经硅胶柱层析纯化(二氯甲烷/甲醇＝95/5)，得到白色固体A1-9(1.14g,85.5％)。ESI-MS(m/z):[M+H]+＝495.3。Compound A1-8 (918 mg, 1.92 mmol) and O-(isotribenzenesulfonyl)hydroxylamine (1.1 g, 5.12 mmol) were dissolved in dichloromethane (20 mL) and reacted at 20–25 °C for 5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol = 95/5) to give a white solid A1-9 (1.14 g, 85.5%). ESI-MS (m/z): [M+H] + = 495.3.

步骤9：(S)-3-氨基-2-(4-氟-3,5-二甲基苯基)-4-甲基-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-甲酸叔丁基酯(A1-10)Step 9: (S)-3-amino-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-10)

将化合物A1-9(1.14g,1.64mmol)和10％钯碳(200mg)溶于甲醇(25mL)中，在氢气氛围下于50℃反应5小时。反应结束后将体系降温，减压浓缩后，加入5％碳酸钾水溶液(25mL)，用二氯甲烷(20mL×3)萃取，合并有机相，用饱和食盐水(15mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到白色固体A1-10(569.0mg,92.5％)。ESI-MS(m/z):[M+H]+＝375.5。Compound A1-9 (1.14 g, 1.64 mmol) and 10% palladium on carbon (200 mg) were dissolved in methanol (25 mL) and reacted at 50 °C for 5 hours under a hydrogen atmosphere. After the reaction was completed, the system was cooled, concentrated under reduced pressure, and then 5% potassium carbonate aqueous solution (25 mL) was added. The mixture was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid A1-10 (569.0 mg, 92.5%). ESI-MS (m/z): [M+H] + ＝375.5.

步骤10：(S)-3-(双((4-硝基苯氧基)羰基)氨基)-2-(4-氟-3,5-二甲基苯基)-4-甲基-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-甲酸叔丁基酯(A1-11)Step 10: (S)-3-(bis((4-nitrophenoxy)carbonyl)amino)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-11)

将化合物A1-10(569.0mg,1.52mmol)、4-硝基苯基氯甲酸酯(610mg,3.04mmol)和二异丙基乙胺(391.4mg,3.04mmol)溶于乙腈(20mL)中，于20℃下反应15分钟，反应液直接用于下一步反应。Compound A1-10 (569.0 mg, 1.52 mmol), 4-nitrophenyl chloroformate (610 mg, 3.04 mmol), and diisopropylethylamine (391.4 mg, 3.04 mmol) were dissolved in acetonitrile (20 mL) and reacted at 20 °C for 15 minutes. The reaction solution was used directly for the next reaction.

步骤11：(S)-3-(3-(2,2-二甲氧基乙基)-3-(4-氟-1-甲基-1H-吲唑-5-基)脲基)-2-(4-氟-3,5-二甲基苯基)-4-甲基-3,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-甲酸叔丁基酯(A1-12)Step 11: (S)-3-(3-(2,2-dimethoxyethyl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)ureo)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-3,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A1-12)

将N-(2,2-二甲氧基乙基)-4-氟-1-甲基-1H-吲唑-5-胺(423mg,1.67mmol)加入到化合物A1-11反应液中，于55℃下反应1小时。反应结束后，减压浓缩得到粗品，粗品经柱层析纯化(正己烷/乙酸乙酯＝1/1)，得到类黄绿色固体A1-12(398.0mg,40.1％)。ESI-MS(m/z):[M+H]+＝654.5。N-(2,2-dimethoxyethyl)-4-fluoro-1-methyl-1H-indazole-5-amine (423 mg, 1.67 mmol) was added to the reaction solution of compound A1-11, and the reaction was carried out at 55 °C for 1 hour. After the reaction was completed, the solution was concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography (n-hexane/ethyl acetate = 1/1) to give a yellowish-green solid A1-12 (398.0 mg, 40.1%). ESI-MS (m/z): [M+H] + = 654.5.

步骤12：1-(4-氟-1-甲基-1H-吲唑-5-基)-3-((S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A1)Step 12: 1-(4-fluoro-1-methyl-1H-indazol-5-yl)-3-((S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A1)

将化合物A1-12(398.0mg,0.61mmol)和对甲苯磺酸(1.05g,6.1mmol)溶于间二甲苯(20mL)中，反应混合物升温至150℃反应2小时。反应结束后体系降温，减压浓缩后，加入5％碳酸钾水溶液(25mL)，用二氯甲烷(20mL×3)萃取，合并有机相，用饱和食盐水(15mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到褐色固体A1(280.0mg,93.9％)。ESI-MS(m/z):[M+H]+＝490.4。Compound A1-12 (398.0 mg, 0.61 mmol) and p-toluenesulfonic acid (1.05 g, 6.1 mmol) were dissolved in m-xylene (20 mL). The reaction mixture was heated to 150 °C and reacted for 2 hours. After the reaction was completed, the system was cooled, concentrated under reduced pressure, and then 5% potassium carbonate aqueous solution (25 mL) was added. The mixture was extracted with dichloromethane (20 mL × 3), the organic phases were combined, washed with saturated brine (15 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown solid A1 (280.0 mg, 93.9%). ESI-MS (m/z): [M+H] + ＝490.4.

参照中间体A1的合成步骤，以类似的合成方法得到表2中所示的中间体A70。Following the same synthesis steps as intermediate A1, intermediate A70, as shown in Table 2, was obtained using a similar synthesis method.

中间体A2：1-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-3-(3-甲基咪唑并[1,5-a]吡啶-7-基)-1,3-二氢-2H-咪唑-2-酮(A2)
 Intermediate A2 : 1-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-3-(3-methylimidazo[1,5-a]pyridin-7-yl)-1,3-dihydro-2H-imidazo-2-one (A2)

步骤1：N-(2,2-二甲氧基乙基)-3-甲基咪唑并[1,5-a]吡啶-7-胺(A2-2)Step 1: N-(2,2-dimethoxyethyl)-3-methylimidazo[1,5-a]pyridine-7-amine (A2-2)

氮气保护下，将2,2-二甲氧基乙烷-1-胺(60.0mg,0.57mmol)、Brettphos G1(7.6mg,0.0095mmol,获自Adamas)和叔丁醇钾(74.3mg，0.66mmol)加入到化合物A2-1(100.5mg,0.47mmol)的二氧六环(2.5mL)溶液中，反应混合物升温至100℃反应5小时。反应结束后，减压浓缩得到粗品，粗品经硅胶柱层析纯化(二氯甲烷/甲醇＝95/5)，得到黄色固体A2-2(85mg,75.9％)。ESI-MS(m/z):[M+H]+＝236.4。Under nitrogen protection, 2,2-dimethoxyethane-1-amine (60.0 mg, 0.57 mmol), Brettphos G1 (7.6 mg, 0.0095 mmol, obtained from Adamas), and potassium tert-butoxide (74.3 mg, 0.66 mmol) were added to a 2.5 mL solution of dioxane (100.5 mg, 0.47 mmol) of compound A2-1. The reaction mixture was heated to 100 °C and reacted for 5 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (dichloromethane/methanol = 95/5) to give a yellow solid A2-2 (85 mg, 75.9%). ESI-MS (m/z): [M+H] + = 236.4.

以化合物A2-2为原料，参照与中间体A1类似的合成方法得到中间体A2。Using compound A2-2 as a starting material, intermediate A2 was obtained by referring to a synthetic method similar to that of intermediate A1.

参照中间体A2的合成步骤，以类似的合成方法得到表2中所示的中间体A3～A12、A16、A17和A41和A62～A64。Following the same synthesis steps as intermediate A2, intermediates A3 to A12, A16, A17, A41, and A62 to A64, as shown in Table 2, were obtained using a similar synthesis method.

中间体A14：1-(1-环丙基-4-氟-1H-吲唑-5-基)-3-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A14)
 Intermediate A14 : 1-(1-cyclopropyl-4-fluoro-1H-indazole-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A14)

步骤1：5-溴-1-环丙基-4-氟-1H-吲唑(A14-2)Step 1: 5-Bromo-1-cyclopropyl-4-fluoro-1H-indazole (A14-2)

氮气保护，室温下，将化合物A14-1(1.60g,7.44mmol)、环丙基硼酸(1.28g,14.88mmol)、醋酸铜(1.35g,7.44mmol)和碳酸钠(1.58g,14.88mmol)溶于二氯乙烷(30mL)中，加入2,2'-联吡啶(1.16g,7.44mmol)，反应混合物升温至60℃搅拌过夜。反应结束后，加水(30mL)，用二氯甲烷(20mL×3)萃取，合并有机相，用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝40/1)，得到黄色油状物A14-2(0.95g,50.0％)。LC-MS:255.0,257.0([M+H]+)；1H NMR(400MHz,CDCl3):δppm 7.98(s,1H),7.46(dd,J＝8.8,6.0Hz,1H),7.28(dd,J＝8.8,0.4Hz,1H),3.64–3.54(m,1H),1.32–1.12(m,4H)。Under nitrogen protection at room temperature, compound A14-1 (1.60 g, 7.44 mmol), cyclopropylboronic acid (1.28 g, 14.88 mmol), copper acetate (1.35 g, 7.44 mmol), and sodium carbonate (1.58 g, 14.88 mmol) were dissolved in dichloroethane (30 mL). 2,2'-Bipyridine (1.16 g, 7.44 mmol) was added, and the reaction mixture was heated to 60 °C and stirred overnight. After the reaction was complete, water (30 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The combined organic phases were washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 40/1) to give a yellow oil, A14-2 (0.95 g, 50.0%). LC-MS: 255.0, 257.0 ([M+H] + ); 1 H NMR (400MHz, CDCl 3 ): δppm 7.98(s,1H),7.46(dd,J＝8.8,6.0Hz,1H),7.28(dd,J＝8.8,0.4Hz,1H),3.64–3.54(m,1H),1.32–1.12(m,4H).

以化合物A14-2为原料，参照与中间体A2类似的合成方法得到中间体A14。Using compound A14-2 as a starting material, intermediate A14 was obtained by referring to a synthetic method similar to that of intermediate A2.

参照中间体A14的合成步骤，以取代硼酸或硼酸酯和溴代吲唑或溴代吡啶并吡唑为起始物料，以类似的合成方法得到表2中所示的中间体A34和A40。Following the synthetic steps of intermediate A14, intermediates A34 and A40, as shown in Table 2, were obtained using substituted boric acid or borate esters and bromoindazole or bromopyridopyrazole as starting materials via a similar synthetic method.

中间体A15：1-(1-(环丙基甲基)-4-氟-1H-吲唑-5-基)-3-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A15)
 Intermediate A15 : 1-(1-(cyclopropylmethyl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A15)

步骤1：5-溴-1-环丙基亚甲基-4-氟-1H-吲唑(A15-2)Step 1: 5-Bromo-1-cyclopropylmethylene-4-fluoro-1H-indazole (A15-2)

室温下，将碳酸铯(6.05g,18.58mmol)和(溴甲基)环丙烷(1.38g,10.22mmol)加入到化合物A15-1(2.0g,9.29mmol)的二甲基甲酰胺(50mL)溶液中，反应混合物升温至70℃搅拌过夜。反应结束后，加水(200mL)，用二氯甲烷(30mL×3)萃取，合并有机层，用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝30/1)，得到白色固体A15-2(0.9g,36.0％)。LC-MS:269.0,271.1([M+H]+).；1H NMR(400MHz,CDCl3):δppm 8.21(s,1H),7.62–7.53(m,2H),4.33(d,J＝6.8Hz,2H),1.31–1.21(m,1H),0.52–0.44(m,2H),0.44–0.36(m,2H).。At room temperature, cesium carbonate (6.05 g, 18.58 mmol) and (bromomethyl)cyclopropane (1.38 g, 10.22 mmol) were added to a dimethylformamide (50 mL) solution of compound A15-1 (2.0 g, 9.29 mmol). The reaction mixture was heated to 70 °C and stirred overnight. After the reaction was complete, water (200 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 3). The organic layers were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30/1) to give a white solid A15-2 (0.9 g, 36.0%). LC-MS: 269.0, 271.1 ([M+H] + ).; 1 H NMR (400MHz, CDCl 3 ): δppm 8.21(s,1H),7.62–7.53(m,2H),4.33(d,J=6.8Hz,2H),1.31–1.21(m,1H),0.52–0.44(m,2H),0.44–0.36(m,2H).

以化合物A15-2为原料，参照与中间体A2类似的合成方法得到中间体A15。Using compound A15-2 as a starting material, intermediate A15 was obtained by referring to a synthetic method similar to that of intermediate A2.

参照中间体A15的合成步骤，以烷基卤代物(Cl,Br,I)或烷基酯(OMs,OTf)和溴代吲唑或溴代吡啶并吡唑为起始物料，以类似的合成方法得到表2中所示的中间体A13、A18～A19、A21～A29、A31～A33、A35、A36、A38、A39和A42～47。Following the synthetic steps of intermediate A15, using alkyl halides (Cl, Br, I) or alkyl esters (OMs, OTf) and bromoinazole or bromopyridopyrazole as starting materials, intermediates A13, A18–A19, A21–A29, A31–A33, A35, A36, A38, A39 and A42–47 as shown in Table 2 were obtained by similar synthetic methods.

中间体A20：1-(4-氟-1-((1-氟环丙基)甲基)-1H-吲唑-5-基)-3-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A20)
 Intermediate A20 : 1-(4-fluoro-1-((1-fluorocyclopropyl)methyl)-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A20)

步骤1：(1-氟环丙基)甲醇(A20-2)Step 1: (1-Fluorocyclopropyl)methanol (A20-2)

在0℃下，向化合物A20-1(5.0g,48.0mmol)的四氢呋喃(50mL)溶液中加入LAH(氢化铝锂,2.7g,72.1mmol)，反应混合物于室温下搅拌2小时。反应结束后，反应混合物垫硅藻土过滤，滤饼用四氢呋喃洗涤(3mL×3)，合并滤液，减压浓缩得到无色液体A20-2(2.5g,57.7％)，无需进一步纯化。At 0 °C, LAH (lithium aluminum hydride, 2.7 g, 72.1 mmol) was added to a tetrahydrofuran (50 mL) solution of compound A20-1 (5.0 g, 48.0 mmol), and the reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction mixture was filtered through a diatomaceous earth filter, and the filter cake was washed with tetrahydrofuran (3 mL × 3). The filtrates were combined and concentrated under reduced pressure to obtain a colorless liquid A20-2 (2.5 g, 57.7%), which did not require further purification.

步骤2：(1-氟环丙基)甲基甲磺酸酯(A20-3)Step 2: (1-Fluorocyclopropyl)methylmethanesulfonate (A20-3)

在0℃下，向化合物A20-2(2.5g,27.75mmol)的二氯甲烷(25mL)溶液中加入三乙胺(5.6g,55.49mmol)和甲磺酸酐(9.7g,55.49mmol)。反应混合物于室温下搅拌1小时。反应结束后，加水(20mL)，用二氯甲烷(10mL×3)萃取，合并有机层，用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到无色液体A20-3(4.0g,85.6％)。1H NMR(400MHz,CDCl3):δppm 4.49(s,1H),4.44(s,1H),3.10(s,3H),1.30–1.18(m,2H),0.91–0.79(m,2H)。At 0 °C, triethylamine (5.6 g, 55.49 mmol) and methanesulfonic anhydride (9.7 g, 55.49 mmol) were added to a solution of compound A20-2 (2.5 g, 27.75 mmol) in dichloromethane (25 mL). The reaction mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with dichloromethane (10 mL × 3). The organic layers were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless liquid A20-3 (4.0 g, 85.6%). ¹H NMR (400 MHz, CDCl₃ ): δppm 4.49 (s, 1H), 4.44 (s, 1H), 3.10 (s, 3H), 1.30–1.18 (m, 2H), 0.91–0.79 (m, 2H).

以化合物A20-3为原料，参照与中间体A15类似的合成方法得到中间体A20。Using compound A20-3 as a starting material, intermediate A20 was obtained by referring to a synthetic method similar to that of intermediate A15.

中间体A30：1-(1-(双环[1.1.1]戊-1-基)-4-氟-1H-吲唑-5-基)-3-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A30)
 Intermediate A30 : 1-(1-(bicyclo[1.1.1]pent-1-yl)-4-fluoro-1H-indazol-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A30)

步骤1：1-(双环[1.1.1]戊-1-基)-2-(3,6-二溴-2-氟苄叉)肼(A30-2)Step 1: 1-(bicyclo[1.1.1]pent-1-yl)-2-(3,6-dibromo-2-fluorobenzyl)hydrazine (A30-2)

室温下，向3,6-二溴-2-氟苯甲醛(600mg,2.13mmol)的乙腈(12mL)溶液中加入双环[1.1.1]戊-1-基肼盐酸盐(134.6mg,2.55mmol)，反应混合物升温至80℃搅拌2小时。反应结束后体系降温，析出固体，过滤，滤饼用乙腈洗涤(1mL×3)，干燥得黄色固体化合物A30-2(500mg,65％)。LC-MS:[M+H]+＝363.2。At room temperature, bicyclo[1.1.1]pentyl-1-ylhydrazine hydrochloride (134.6 mg, 2.55 mmol) was added to a solution of 3,6-dibromo-2-fluorobenzaldehyde (600 mg, 2.13 mmol) in acetonitrile (12 mL). The reaction mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the system was cooled, and a solid precipitated. The solid was filtered, and the filter cake was washed with acetonitrile (1 mL × 3) and dried to give a yellow solid compound A30-2 (500 mg, 65%). LC-MS: [M+H] + = 363.2.

步骤2：1-(双环[1.1.1]戊-1-基)-5-溴-4-氟-1H-吲唑(A30-3)Step 2: 1-(bicyclo[1.1.1]pent-1-yl)-5-bromo-4-fluoro-1H-indazole (A30-3)

室温下，向化合物A30-2(500mg,1.38mmol)的乙腈(20mL)溶液中加入溴化亚铜(109mg,0.760mmol)和1,8-二氮杂二环[5.4.0]十一碳-7-烯(621mg,4.14mmol)，反应混合物升温至50℃搅拌3h。反应结束后，减压浓缩得到粗品，粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝2/1)，得到淡黄色油状化合物A30-3(73mg,19％)。LC-MS:[M+H]+＝281.3。At room temperature, cuprous bromide (109 mg, 0.760 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (621 mg, 4.14 mmol) were added to a 20 mL acetonitrile solution of compound A30-2 (500 mg, 1.38 mmol). The reaction mixture was heated to 50 °C and stirred for 3 h. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give a pale yellow oily compound A30-3 (73 mg, 19%). LC-MS: [M+H] + = 281.3.

以化合物A30-3为原料，参照与中间体A2类似的合成方法得到中间体A30。Using compound A30-3 as a starting material, intermediate A30 was obtained by referring to a synthetic method similar to that of intermediate A2.

中间体A37：1-(1-(叔丁基)-1H-吡唑并[3,4-b]吡啶-5-基)-3-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A37)
 Intermediate A37 : 1-(1-(tert-butyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A37)

步骤1：5-溴-1-(叔丁基)-1H-吡唑并[3,4-b]吡啶(A37-2)Step 1: 5-Bromo-1-(tert-butyl)-1H-pyrazolo[3,4-b]pyridine (A37-2)

在高压釜中，向5-溴-1H-吡唑并[3,4-b]吡啶(3.0g,15.1mmol)的叔丁醇(30mL)溶液中加入浓H2SO4(19.6mg,0.2mmol)。反应混合物升温至150℃搅拌过夜。反应结束后体系降温，减压浓缩除去叔丁醇，残余物加入二氯甲烷(10mL)，依次用饱和碳酸氢钠水溶液(10mL×3)和饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(石油醚)纯化，得到黄色油状物A37-2(420mg,10.9％)。LC-MS:[M+H]+＝254.0；1H NMR(300MHz,DMSO-d6):δ8.58(d,J＝2.4Hz,1H),8.49(d,J＝2.1Hz,1H),8.06(s,1H),1.73(s,9H)。In an autoclave, concentrated H₂SO₄ ( 19.6 mg, 0.2 mmol) was added to a solution of 5-bromo-1H-pyrazolo[3,4-b]pyridine (3.0 g, 15.1 mmol) in tert-butanol (30 mL). The reaction mixture was heated to 150 °C and stirred overnight. After the reaction was complete, the system was cooled, concentrated under reduced pressure to remove tert-butanol, and the residue was added to dichloromethane (10 mL), washed successively with saturated sodium bicarbonate aqueous solution (10 mL × 3) and saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether) to give a yellow oily substance A37-2 (420 mg, 10.9%). LC-MS: [M+H] + =254.0; 1 H NMR (300MHz, DMSO-d 6 ): δ8.58 (d, J = 2.4 Hz, 1H), 8.49 (d, J = 2.1 Hz, 1H), 8.06 (s, 1H), 1.73 (s, 9H).

以化合物A37-2为原料，参照与中间体A2类似的合成方法得到中间体A37。Using compound A37-2 as a starting material, intermediate A37 was obtained by referring to a synthetic method similar to that of intermediate A2.

中间体A49：1-((4S)-2-(3,4-二氟-5-甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-3-(4-氟-1-甲基-1H-吲唑-5-基)-1,3-二氢-2H-咪唑-2-酮(A49)
 Intermediate A49 : 1-((4S)-2-(3,4-difluoro-5-methylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazo-2-one (A49)

步骤1：3-溴-4,5-二氟苯甲酸(A49-2)Step 1: 3-Bromo-4,5-Difluorobenzoic acid (A49-2)

氮气保护，0℃下，将N-溴代丁二酰亚胺(33.8g,189.9mmol)加入到化合物A49-1(20.0g,126.6mmol)的浓硫酸(100.0mL)溶液中，反应混合物升温至60℃搅拌16小时。反应结束后体系降温，加水(500mL)，用乙酸乙酯(100mL×3)萃取，合并有机层，用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到黄色固体A49-2(5.0g,16.6％)。LC-MS:[M-H]-＝235.0。步骤2：3,4-二氟-5-甲基苯甲酸(A49-3)Under nitrogen protection, at 0°C, N-bromosuccinimide (33.8 g, 189.9 mmol) was added to a solution of compound A49-1 (20.0 g, 126.6 mmol) in concentrated sulfuric acid (100.0 mL). The reaction mixture was heated to 60°C and stirred for 16 hours. After the reaction was complete, the system was cooled, water (500 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic layers were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give a yellow solid A49-2 (5.0 g, 16.6%). LC-MS: [MH] - = 235.0. Step 2: 3,4-Difluoro-5-methylbenzoic acid (A49-3)

室温下，将化合物A49-2(5.0g,21.1mmol)和2,4,6-三甲基-1,3,5,2,4,6-三氧杂三硼烷(7.9g,63.3mmol)溶于二氧六环(50mL)中，加入碳酸铯(20.6g,63.3mmol)和Pd(dppf)Cl2(1.5g,2.1mmol)，在氮气保护下，于80℃搅拌2小时。反应结束后体系降温，加水(100mL)，用乙酸乙酯(50mL×3)萃取，合并有机层，用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到黄色固体A49-3(3.5g,96.5％)。LC-MS:[M-H]-＝171.0。Compound A49-2 (5.0 g, 21.1 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxaborane (7.9 g, 63.3 mmol) were dissolved in dioxane (50 mL) at room temperature. Cesium carbonate (20.6 g, 63.3 mmol) and Pd(dppf) Cl₂ (1.5 g, 2.1 mmol) were added, and the mixture was stirred at 80 °C for 2 hours under nitrogen protection. After the reaction was complete, the system was cooled, water (100 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic layers were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give a yellow solid A49-3 (3.5 g, 96.5%). LC-MS: [MH] ⁻ = 171.0.

以化合物A49-3为原料，参照与中间体A1类似的合成方法得到中间体A49。Using compound A49-3 as a starting material, intermediate A49 was obtained by referring to a synthetic method similar to that of intermediate A1.

参照中间体A49的合成步骤，以不同的芳基甲酸和化合物A1-5为原料，以类似的合成方法得到表2中所示的中间体A48、A50、A51和A67～A69。Following the synthetic steps of intermediate A49, intermediates A48, A50, A51 and A67 to A69, shown in Table 2, were obtained using different arylformic acids and compounds A1-5 as raw materials and similar synthetic methods.

中间体A52：1-((4S)-2-(2,6-双(三氟甲基)吡啶-4-基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-3-(4-氟-1-甲基-1H-吲唑-5-基)-1,3-二氢-2H-咪唑-2-酮(A52)
 Intermediate A52 : 1-((4S)-2-(2,6-bis(trifluoromethyl)pyridin-4-yl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-3-(4-fluoro-1-methyl-1H-indazol-5-yl)-1,3-dihydro-2H-imidazo-2-one (A52)

步骤1：(2S)-3-甲酰胺基-4-羟基-2-甲基哌啶-1-羧酸叔丁酯(A52-2)Step 1: (2S)-3-formamido-4-hydroxy-2-methylpiperidine-1-carboxylic acid tert-butyl ester (A52-2)

将化合物A52-1(5g,21.73mmol)溶于甲醇(50mL)的耐压瓶中，加入甲酸甲酯(6.4g,108.47mmol)和甲醇钠(0.94g,17.41mmol),反应混合物升温至50℃搅拌4小时。反应结束后，减压浓缩除去甲醇，残余物加入乙酸乙酯(100mL),依次用水(30mL×2)和饱和食盐水(30mL×2)洗涤，有机相减压浓缩，得到淡黄色固体A52-2(4.6g,82.1％)。Compound A52-1 (5 g, 21.73 mmol) was dissolved in a pressure-resistant flask containing methanol (50 mL). Methyl formate (6.4 g, 108.47 mmol) and sodium methoxide (0.94 g, 17.41 mmol) were added, and the reaction mixture was heated to 50 °C and stirred for 4 hours. After the reaction was completed, the methanol was removed by concentration under reduced pressure. The residue was added to ethyl acetate (100 mL), and washed successively with water (30 mL × 2) and saturated brine (30 mL × 2). The organic phase was concentrated under reduced pressure to give a pale yellow solid A52-2 (4.6 g, 82.1%).

步骤2：(2S)-3-甲酰胺基-2-甲基-4-氧代哌啶-1-羧酸叔丁酯(A52-3)Step 2: (2S)-3-formamido-2-methyl-4-oxoperpiperidine-1-carboxylic acid tert-butyl ester (A52-3)

将化合物A52-2(9.2g,35.65mmol)溶于二氯甲烷(100mL)中，0℃下，加入戴斯-马丁试剂(22.6g,53.3mmol)，反应混合物缓慢升至室温反应4小时。反应结束后，过滤，滤饼用二氯甲烷洗涤(20mL×3)，合并滤液，滤液用1M氢氧化钠水溶液洗涤(30mL×3)。有机相经无水硫酸钠干燥，过滤，浓缩，得淡黄色固体A52-3(5.8g,63.6％)。Compound A52-2 (9.2 g, 35.65 mmol) was dissolved in dichloromethane (100 mL). At 0 °C, Dys-Martin reagent (22.6 g, 53.3 mmol) was added, and the reaction mixture was slowly heated to room temperature for 4 hours. After the reaction was complete, the mixture was filtered, and the filter cake was washed with dichloromethane (20 mL × 3). The filtrates were combined and washed with 1 M sodium hydroxide aqueous solution (30 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give a pale yellow solid A52-3 (5.8 g, 63.6%).

步骤3：(S)-1-(4-甲氧基苄基)-4-甲基-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-甲酸叔丁酯(A52-4)Step 3: (S)-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A52-4)

氮气保护下，将化合物A52-3(5.8g,22.65mmol)、对甲氧基苄胺(4.65g,33.98mmol)和乙酸(0.68g,11.32mmol)溶于间二甲苯(90mL)，反应混合物升温至150℃反应6小时(用分水器除水)。反应结束后，减压浓缩得到粗品，粗品经硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)得到类白色固体A52-4(6g,74.2％)。Under nitrogen protection, compound A52-3 (5.8 g, 22.65 mmol), p-methoxybenzylamine (4.65 g, 33.98 mmol), and acetic acid (0.68 g, 11.32 mmol) were dissolved in m-xylene (90 mL). The reaction mixture was heated to 150 °C and reacted for 6 hours (water was removed using a water separator). After the reaction was completed, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to give a white solid A52-4 (6 g, 74.2%).

步骤4：(S)-2-溴-1-(4-甲氧基苄基)-4-甲基-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-甲酸叔丁酯(A52-5)Step 4: (S)-2-bromo-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A52-5)

将化合物A52-4(500mg,1.4mmol)溶于乙腈(10mL)中，缓慢加入N-溴代丁二酰亚胺(249.2mg,1.4mmol)，于室温反应下2小时。反应结束后，减压浓缩得到粗品，粗品经硅胶柱层析纯化(二氯甲烷/甲醇＝20/1)，得淡黄色固体A52-5(450mg,73.9％)。Compound A52-4 (500 mg, 1.4 mmol) was dissolved in acetonitrile (10 mL), and N-bromosuccinimide (249.2 mg, 1.4 mmol) was slowly added. The reaction was carried out at room temperature for 2 hours. After the reaction was completed, the solution was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (dichloromethane/methanol = 20/1) to give a pale yellow solid A52-5 (450 mg, 73.9%).

步骤5：(S)-2-(2,6-双(三氟甲基)吡啶-4-基)-1-(4-甲氧基苄基)-4-甲基-1,4,6,7-四氢-5H-咪唑并[4,5-c]吡啶-5-甲酸叔丁酯(A52-6)Step 5: (S)-2-(2,6-bis(trifluoromethyl)pyridin-4-yl)-1-(4-methoxybenzyl)-4-methyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (A52-6)

氮气保护下，将磷酸钾(681mg,3.2mg)、CataXium A Pd G2(53.63mg,0.08mmol,获自Adamas)加入到(2,6-双(三氟甲基)吡啶-4-基)硼酸(700mg,1.6mmol)和化合物A52-5(830mg,3.2mmol)的二氧六环/水(18mL,5/1)的混合溶剂中，反应混合物升温至100℃反应6小时。反应结束后，加入乙酸乙酯(30mL)，用饱和食盐水(20mL)洗涤，有机相减压浓缩得粗品。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到浅黄色固体A52-6(700mg,76.5％)。Under nitrogen protection, potassium phosphate (681 mg, 3.2 mg) and CataXium A Pd G2 (53.63 mg, 0.08 mmol, obtained from Adamas) were added to a mixed solvent of dioxane/water (18 mL, 5/1) of (2,6-bis(trifluoromethyl)pyridin-4-yl)boronic acid (700 mg, 1.6 mmol) and compound A52-5 (830 mg, 3.2 mmol). The reaction mixture was heated to 100 °C and reacted for 6 hours. After the reaction was completed, ethyl acetate (30 mL) was added, and the mixture was washed with saturated brine (20 mL). The organic phase was concentrated under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give a pale yellow solid A52-6 (700 mg, 76.5%).

以化合物A52-6为原料，参照与中间体A1类似的合成方法得到中间体A52。Using compound A52-6 as a starting material, intermediate A52 was obtained by referring to a synthetic method similar to that of intermediate A1.

参照中间体A52的合成步骤，以不同的芳基硼酸或硼酸酯和化合物A52-5为原料，以类似的合成方法得到表2中所示的中间体A53～A58、A65和A66。Following the synthetic steps of intermediate A52, intermediates A53–A58, A65, and A66, as shown in Table 2, were obtained using different arylboronic acids or borate esters and compound A52-5 as starting materials and similar synthetic methods.

中间体A59：1-(4-(环丙基磺酰基)-2-氟-3-甲基苯基)-3-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A59)
 Intermediate A59 : 1-(4-(cyclopropylsulfonyl)-2-fluoro-3-methylphenyl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A59)

参照专利WO2024169952 Al，以4-溴-3-氟-2-甲基苯胺为原料合成得到中间体A59-3，以中间体A59-3为原料，参照中间体A1的合成步骤得到中间体A59-4，中间体A59-4经单过硫酸盐化合物氧化得中间体A59-5，再经对甲苯磺酸作用，关环得到中间体A59。Referring to patent WO2024169952 A1, intermediate A59-3 was synthesized from 4-bromo-3-fluoro-2-methylaniline. Using intermediate A59-3 as a raw material, intermediate A59-4 was obtained by following the synthesis steps of intermediate A1. Intermediate A59-4 was oxidized by a monopersulfate compound to obtain intermediate A59-5, and then cyclized by p-toluenesulfonic acid to obtain intermediate A59.

中间体A60：1-(4-(环丙烷磺酰亚胺基)-2-氟-3-甲基苯基)-3-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-1,3-二氢-2H-咪唑-2-酮(A60)
 Intermediate A60 : 1-(4-(cyclopropanesulfonylimide)-2-fluoro-3-methylphenyl)-3-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-1,3-dihydro-2H-imidazo-2-one (A60)

参照专利WO2024169952 Al，以中间体A59-4为原料，在氨基甲酸铵和醋酸碘苯的作用下得到化合物A60-1，再经对甲苯磺酸作用，关环得到中间体A60。Referring to patent WO2024169952 A1, using intermediate A59-4 as raw material, compound A60-1 was obtained under the action of ammonium carbamate and iodobenzene acetate, and then cyclized by p-toluenesulfonic acid to obtain intermediate A60.

中间体A61：1-((4S)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-3-基)-3-(2-氟-3-甲基-4-(N-甲基环丙烷磺酰亚胺基)苯基)-1,3-二氢-2H-咪唑-2-酮(A61)
 Intermediate A61 : 1-((4S)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-3-yl)-3-(2-fluoro-3-methyl-4-(N-methylcyclopropanesulfonylimide)phenyl)-1,3-dihydro-2H-imidazo-2-one (A61)

参照专利WO2024169952 Al，以中间体A60-1为原料，在甲基硼酸、醋酸铜和吡啶的作用下甲基化得到中间体A61-1，再经对甲苯磺酸作用，关环得到中间体A61。Referring to patent WO2024169952 A1, intermediate A60-1 was used as a raw material and methylated in the presence of methylboric acid, copper acetate and pyridine to obtain intermediate A61-1. Then, it was cyclized by p-toluenesulfonic acid to obtain intermediate A61.

表2.中间体A




Table 2. Intermediate A




中间体B2a：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-(1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-2-苯基环丙基)-1H-吲哚-2-羧酸(B2a)
 Intermediate B2a : 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2-phenylcyclopropyl)-1H-indole-2-carboxylic acid (B2a)

步骤1：(S,E)-1-(1-氰基-2-苯基乙烯基)-5-(2,2-二甲基四氢-2H-吡喃-4-基)-N-甲基-N-苯基-1H-吲哚-2-甲酰胺(B2a-2/B2b-2)Step 1: (S,E)-1-(1-cyano-2-phenylvinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B2a-2/B2b-2)

将化合物B2-1(500.0mg,1.24mmol)溶于甲苯(10mL)中，加入四正丁基溴化铵(38.6mg,0.12mmol)和碳酸钾(165.6mg,1.2mmol)，升温至70℃反应过夜。反应结束后，加入乙酸乙酯(30mL)，依次用水(10mL×3)和饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝3/1)，得到黄色固体，再经Prep-HPLC(Waters XBridge Prep C18 OBD,流动相:乙腈/水(5mmol TFA)＝30/100～50/100)纯化，得到黄色B2a-2(150mg,24.6％)和B2b-2(340mg,55.8％)。Compound B2-1 (500.0 mg, 1.24 mmol) was dissolved in toluene (10 mL), and tetrabutylammonium bromide (38.6 mg, 0.12 mmol) and potassium carbonate (165.6 mg, 1.2 mmol) were added. The mixture was heated to 70 °C and reacted overnight. After the reaction was complete, ethyl acetate (30 mL) was added, and the mixture was washed successively with water (10 mL × 3) and saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 3/1) to give a yellow solid, which was then purified by Prep-HPLC (Waters XBridge Prep C18 OBD, mobile phase: acetonitrile/water (5 mmol TFA) = 30/100～50/100) to give yellow B2a-2 (150 mg, 24.6%) and B2b-2 (340 mg, 55.8%).

B2a-2：1H NMR(300MHz,CDCl3):δ7.40–7.27(m,4H),7.24–7.12(m,5H),7.09–6.93(m,4H),5.98(s,1H),3.92–3.72(m,2H),3.46(s,3H),3.00–2.85(m,1H),1.80–1.50(m,4H),1.29(s,3H),1.26(s,3H)。LC-MS:490.2([M+H]+)；B2a-2: 1 H NMR (300MHz, CDCl 3 ): δ7.40–7.27(m,4H),7.24–7.12(m,5H),7.09–6.93(m,4H),5.98(s,1H),3.92–3.72 (m,2H),3.46(s,3H),3.00–2.85(m,1H),1.80–1.50(m,4H),1.29(s,3H),1.26(s,3H). LC-MS: 490.2([M+H] + );

B2b-2：1H NMR(300MHz,CDCl3):δ7.99–7.82(m,2H),7.59–7.45(m,3H),7.51–7.23(m,6H),7.21–7.09(m,2H),6.12(s,1H),3.95–3.69(m,2H),3.50(s,3H),3.11–2.91(m,1H),1.81–1.53(m,4H),1.32(s,3H),1.27(s,3H)。LC-MS:490.2([M+H]+)；B2b-2: 1 H NMR (300MHz, CDCl 3 ): δ7.99–7.82(m,2H),7.59–7.45(m,3H),7.51–7.23(m,6H),7.21–7.09(m,2H),6.12(s,1H),3 .95–3.69(m,2H),3.50(s,3H),3.11–2.91(m,1H),1.81–1.53(m,4H),1.32(s,3H),1.27(s,3H). LC-MS: 490.2([M+H] + );

步骤2：1-(1-氰基-2-苯基环丙基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-N-甲基-N-苯基-1H-吲哚-2-甲酰胺(B2a-3)Step 2: 1-(1-cyano-2-phenylcyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B2a-3)

氮气保护，室温下，将三甲基碘化亚砜(132.0mg,0.62mmol)和化合物B2a-2(150.0mg,0.31mmol)加入到NaH(24.0mg,0.62mmol)的二甲基亚砜(3mL)溶液中，反应混合物于室温下搅拌2小时。反应结束后，0℃下加水(10mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝12/1)，得到白色固体B2a-3(100.0mg,64.8％)。Under nitrogen protection at room temperature, trimethyl sulfoxide (132.0 mg, 0.62 mmol) and compound B2a-2 (150.0 mg, 0.31 mmol) were added to a solution of NaH (24.0 mg, 0.62 mmol) in dimethyl sulfoxide (3 mL). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (10 mL) was added at 0 °C, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 12/1) to give a white solid B2a-3 (100.0 mg, 64.8%).

步骤3：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-(1-((Z)-N'-羟基甲脒基)-2-苯基环丙基)-N-甲基-N-苯基-1H-吲哚-2-甲酰胺(B2a-4)Step 3: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-((Z)-N'-hydroxymethylamidinyl)-2-phenylcyclopropyl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B2a-4)

室温下，将盐酸羟胺(138.0mg,2.00mmol)和碳酸氢钠(251mg,2.40mmol)加入到化合物B2a-3(100.0mg,0.20mmol)的乙醇(4mL)溶液中，反应混合物升温至80℃搅拌2小时。反应结束后，将体系降温，加水(8mL)，用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水(8mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到白色固体B2a-4(80.0mg,75.1％)。At room temperature, hydroxylamine hydrochloride (138.0 mg, 2.00 mmol) and sodium bicarbonate (251 mg, 2.40 mmol) were added to an ethanol (4 mL) solution of compound B2a-3 (100.0 mg, 0.20 mmol). The reaction mixture was heated to 80 °C and stirred for 2 hours. After the reaction was complete, the system was cooled, water (8 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (8 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid B2a-4 (80.0 mg, 75.1%).

步骤4：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-N-甲基-1-(1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-2-苯基环丙基)-N-苯基-1H-吲哚-2-甲酰胺(B2a-5)Step 4: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2-phenylcyclopropyl)-N-phenyl-1H-indole-2-carboxamide (B2a-5)

室温下，将1,8-二氮杂二环[5.4.0]十一碳-7-烯(68.4mg,0.45mmol)和N,N'-羰基二咪唑(48.6mg,0.30mmol)加入到化合物B2a-4(80.0mg,0.15mmol)的二甲基亚砜(4mL)溶液中，于室温下搅拌1小时。反应结束后，加水(8mL)，用乙酸乙酯(20mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经Pre-TLC纯化(石油醚/乙酸乙酯＝1/3)，得到白色固体B2a-5(60.0mg,71.5％)。LC-MS:563.2([M+H]+)。1H NMR(400MHz,CDCl3):δ10.95(brs,1H),7.53(d,J＝8.4Hz,1H),7.43–7.22(m,9H),7.20–7.02(m,4H),5.91(s,1H),3.88–3.68(m,2H),3.59(s,3H),3.01(t,J＝8.0Hz,1H),2.96–2.80(m,1H),2.68(t,J＝7.2Hz,1H),1.82–1.71(m,1H),1.70–1.40(m,4H),1.22(s,3H),1.18(s,3H)。At room temperature, 1,8-diazabicyclo[5.4.0]undec-7-ene (68.4 mg, 0.45 mmol) and N,N'-carbonyldiimidazole (48.6 mg, 0.30 mmol) were added to a dimethyl sulfoxide (4 mL) solution of compound B2a-4 (80.0 mg, 0.15 mmol), and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (8 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Pre-TLC (petroleum ether/ethyl acetate = 1/3) to give a white solid B2a-5 (60.0 mg, 71.5%). LC-MS: 563.2 ([M+H] + ). 1 H NMR (400MHz, CDCl 3 ): δ10.95(brs,1H),7.53(d,J＝8.4Hz,1H),7.43–7.22(m,9H),7.20–7.02(m,4H),5.91(s,1H),3.88–3.68(m,2H),3.59(s,3H),3 .01(t,J＝8.0Hz,1H),2.96–2.80(m,1H),2.68(t,J＝7.2Hz,1H),1.82–1.71(m,1H),1.70–1.40(m,4H),1.22(s,3H),1.18(s,3H).

步骤5：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-(1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-2-苯基环丙基)-1H-吲哚-2-羧酸(B2a)Step 5: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-2-phenylcyclopropyl)-1H-indole-2-carboxylic acid (B2a)

将化合物B2a-5(60.0mg,0.11mmol)溶于2-甲氧基乙醇/水(8mL,3/1)的混合溶液中，加入氢氧化钾(1.2g,22.00mmol)，反应混合物液在180℃微波辐射下反应1.5小时。反应结束后，将体系降温，加水(10mL)，用乙酸乙酯(10mL×3)萃取，水相用2N盐酸水溶液(11mL)调节pH至3，再用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(5mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经Prep-HPLC(Waters XBridge Prep C18 OBD,流动相:乙腈/水(5mmol TFA)＝40/100～50/100)纯化，得到白色固体B2a(20.0mg,39.6％)。Compound B2a-5 (60.0 mg, 0.11 mmol) was dissolved in a mixed solution of 2-methoxyethanol/water (8 mL, 3/1), and potassium hydroxide (1.2 g, 22.00 mmol) was added. The reaction mixture was reacted under microwave irradiation at 180 °C for 1.5 hours. After the reaction was completed, the system was cooled, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The pH of the aqueous phase was adjusted to 3 with 2N hydrochloric acid aqueous solution (11 mL), and then extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Prep-HPLC (Waters XBridge Prep C18 OBD, mobile phase: acetonitrile/water (5 mmol TFA) = 40/100–50/100) to give a white solid B2a (20.0 mg, 39.6%).

以化合物B2b-2为原料，参照与中间体B2a类似的合成方法得到中间体B2b。Intermediate B2b was obtained by using compound B2b-2 as a starting material and following a synthetic method similar to that of intermediate B2a.

中间体B3a/B3b：1-(2,2-二氯-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸(B3a/B3b)
 Intermediate B3a/B3b : 1-(2,2-dichloro-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (B3a/B3b)

步骤1：(S)-1-(1-氰基乙烯基)-5-(2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸(B3-2)Step 1: (S)-1-(1-cyanovinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (B3-2)

将三甲基氢氧化锡(11.6g,63.9mmol)加入到化合物B3-1(5.0g,14.2mmol)的甲苯(50mL)溶液中，反应混合物回流搅拌过夜。反应结束后，过滤，滤饼用乙酸乙酯(10mL×3)洗涤，加水(50mL)，再用乙酸乙酯(40mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩，得到黄色固体B3-2(4.5g)。LC-MS:323.1([M-H]-)。Trimethyltin hydroxide (11.6 g, 63.9 mmol) was added to a toluene (50 mL) solution of compound B3-1 (5.0 g, 14.2 mmol), and the reaction mixture was refluxed and stirred overnight. After the reaction was complete, the mixture was filtered, and the filter cake was washed with ethyl acetate (10 mL × 3), water (50 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give a yellow solid B3-2 (4.5 g). LC-MS: 323.1 ([MH] - ).

步骤2：((S)-1-(1-氰基乙烯基)-5-(2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸叔丁酯(B3-3)Step 2: ((S)-1-(1-cyanovinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3-3)

将化合物B3-2(4.2g,12.9mmol)、4-二甲氨基吡啶(1.6g,12.9mmol)和分子筛(4.2g,100％wt)溶于四氢呋喃(50mL)中，随后加入1-乙基-(3-二甲氨基丙基)碳二亚胺盐酸盐(3.7g,19.4mmol)和叔丁醇(4.8g,64.5mmol)，于室温下搅拌18小时。反应结束后，加水(50mL)，用二氯甲烷(40mL×3)萃取，合并有机相，有机相用饱和食盐水(20mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝15/1)，得到黄色固体B3-3(3.0g,两步收率59.5％)。1H NMR(300MHz,CDCl3):δ7.51(s,1H),7.34–7.27(m,3H),6.38(s,1H),6.08(s,1H),3.94–3.77(m,2H),3.13–2.95(m,1H),1.85–1.65(m,4H),1.63(s,9H),1.34(s,3H),1.29(s,3H)。LC-MS:381.1([M+H]+)。Compound B3-2 (4.2 g, 12.9 mmol), 4-dimethylaminopyridine (1.6 g, 12.9 mmol), and molecular sieve (4.2 g, 100% wt) were dissolved in tetrahydrofuran (50 mL), followed by the addition of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.7 g, 19.4 mmol) and tert-butanol (4.8 g, 64.5 mmol). The mixture was stirred at room temperature for 18 hours. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with dichloromethane (40 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 15/1) to give a yellow solid B3-3 (3.0 g, two-step yield 59.5%). 1 H NMR (300MHz, CDCl 3 ): δ7.51(s,1H),7.34–7.27(m,3H),6.38(s,1H),6.08(s,1H),3.94–3.77(m,2H ),3.13–2.95(m,1H),1.85–1.65(m,4H),1.63(s,9H),1.34(s,3H),1.29(s,3H). LC-MS: 381.1([M+H] + ).

步骤3：1-(2,2-二氯-1-氰基环丙基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸叔丁酯(B3-4)Step 3: 1-(2,2-dichloro-1-cyanocyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3-4)

将化合物B3-3(1.8g,4.7mmol)和四丁基溴化铵(151mg,0.47mmol)溶于氯仿(45mL)中，加入50％氢氧化钠水溶液(4.5mL)，室温下搅拌过夜。反应结束后，加水(10mL)，用二氯甲烷(20mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝5/1)，得到黄色固体B3-4(590.0mg,26.9％)。1H NMR(400MHz,CDCl3):δ7.58–7.55(m,2H),7.32–7.27(m,1H),7.24–7.15(m,1H),3.89–3.79(m,2H),3.11–2.96(m,1H),2.91–2.81(m,1H),2.63(d,J＝8.6Hz,1H),1.83–1.69(m,4H),1.68(s,9H),1.34(s,3H),1.29(s,3H)。LC-MS:480.1([M+NH4 +]+)。Compound B3-3 (1.8 g, 4.7 mmol) and tetrabutylammonium bromide (151 mg, 0.47 mmol) were dissolved in chloroform (45 mL), and 50% sodium hydroxide aqueous solution (4.5 mL) was added. The mixture was stirred overnight at room temperature. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give a yellow solid B3-4 (590.0 mg, 26.9%). 1 H NMR (400MHz, CDCl 3 ): δ7.58–7.55(m,2H),7.32–7.27(m,1H),7.24–7.15(m,1H),3.89–3.79(m,2H),3.11–2.96(m,1H), 2.91–2.81(m,1H),2.63(d,J＝8.6Hz,1H),1.83–1.69(m,4H),1.68(s,9H),1.34(s,3H),1.29(s,3H). LC-MS: 480.1 ([M+NH 4 + ] + ).

步骤4：1-(2,2-二氯-1-((Z)-N'-羟基甲脒基)环丙基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸叔丁酯(B3-5)Step 4: 1-(2,2-dichloro-1-((Z)-N'-hydroxyformamidinyl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3-5)

将盐酸羟胺(885mg,13.0mmol)和碳酸氢钠(1.3g,15.3mmol)加入到化合物B3-4(590mg,1.3mmol)的乙醇(10mL)溶液中，反应混合物升温至50℃搅拌2小时。反应结束后，加水(20mL)，用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到白色固体B3-5(430mg,粗品)。LC-MS:496.1([M+H]+)。Hydroxylamine hydrochloride (885 mg, 13.0 mmol) and sodium bicarbonate (1.3 g, 15.3 mmol) were added to an ethanol solution (10 mL) of compound B3-4 (590 mg, 1.3 mmol). The reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, water (20 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid B3-5 (430 mg, crude product). LC-MS: 496.1 ([M+H] + ).

步骤5：1-(2,2-二氯-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸叔丁酯(B3a-6/B3b-6)Step 5: 1-(2,2-dichloro-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid tert-butyl ester (B3a-6/B3b-6)

室温下，向化合物B3-5(430mg,0.87mmol)的二甲基亚砜(7.0mL)溶液中加入DBU(397mg,2.61mmol)和N,N'-羰基二咪唑(282mg,1.74mmol)，反应混合物升温至50℃下搅拌2小时。反应结束后，加水(8.0mL)，用二氯甲烷/甲醇(20.0mL×3,10/1)萃取，合并有机相，有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经Prep-TLC(二氯甲烷/甲醇＝15/1)纯化，得到黄色固体(200.0mg)，再经SFC(IG3,MeOH,2.0μL,15min，CO2)纯化，得到白色固体B3a-6(40mg,8.8％)和B3b-6(36mg,5.4％)。At room temperature, DBU (397 mg, 2.61 mmol) and N,N'-carbonyldiimidazole (282 mg, 1.74 mmol) were added to a dimethyl sulfoxide (7.0 mL) solution of compound B3-5 (430 mg, 0.87 mmol). The reaction mixture was heated to 50 °C and stirred for 2 hours. After the reaction was complete, water (8.0 mL) was added, and the mixture was extracted with dichloromethane/methanol (20.0 mL × 3, 10/1). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by Prep-TLC (dichloromethane/methanol = 15/1) to obtain a yellow solid (200.0 mg), which was then purified by SFC (IG3, MeOH, 2.0 μL, 15 min, CO2 ) to obtain white solids B3a-6 (40 mg, 8.8%) and B3b-6 (36 mg, 5.4%).

B3a-6:1H NMR(400MHz,CDCl3):δppm 10.24(s,1H),7.50(s,1H),7.40(d,J＝8.8Hz,1H),7.30(dd,J＝8.8Hz,1.3Hz,1H),7.16(s,1H),3.91–3.76(m,2H),3.17(d,J＝8.8Hz,1H),3.08–2.96(m,1H),2.37(d,J＝8.8Hz,1H),1.81–1.70(m,3H),1.68(s,9H),1.66–1.62(m,1H),1.34(s,3H),1.28(s,3H)。LC-MS:520.1([M-H]-)；B3a-6: 1 H NMR (400MHz, CDCl 3 ): δppm 10.24(s,1H),7.50(s,1H),7.40(d,J＝8.8Hz,1H),7.30(dd,J＝8.8Hz,1.3Hz,1H),7.16(s,1H),3.91–3.76(m,2H),3.17(d,J＝8.8 Hz,1H),3.08–2.96(m,1H),2.37(d,J＝8.8Hz,1H),1.81–1.70(m,3H),1.68(s,9H),1.66–1.62(m,1H),1.34(s,3H),1.28(s,3H). LC-MS:520.1([MH] - );

B3b-6:1H NMR(400MHz,CDCl3):δppm 10.24(s,1H),7.50(s,1H),7.40(d,J＝8.8Hz,1H),7.31(dd,J＝8.8Hz,1.2Hz,1H),7.16(s,1H),3.91–3.76(m,2H),3.17(d,J＝8.8Hz,1H),3.08–2.96(m,1H),2.37(d,J＝8.8Hz,1H),1.81–1.70(m,3H),1.68(s,9H),1.66–1.62(m,1H),1.34(s,3H),1.28(s,3H)。LC-MS:520.1([M-H]-)。B3b-6: 1 H NMR (400MHz, CDCl 3 ): δppm 10.24(s,1H),7.50(s,1H),7.40(d,J＝8.8Hz,1H),7.31(dd,J＝8.8Hz,1.2Hz,1H),7.16(s,1H),3.91–3.76(m,2H),3.17(d,J＝8.8 Hz,1H),3.08–2.96(m,1H),2.37(d,J＝8.8Hz,1H),1.81–1.70(m,3H),1.68(s,9H),1.66–1.62(m,1H),1.34(s,3H),1.28(s,3H). LC-MS: 520.1 ([MH] - ).

步骤6：1-(2,2-二氯-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸(B3a/B3b)Step 6: 1-(2,2-dichloro-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid (B3a/B3b)

将三乙胺(14mg,0.154mmol)和三氟甲磺酸三甲基硅酯(86mg,0.385mmol)加入到B3a-6(40mg,0.077mmol)的乙酸乙酯溶液(4mL)中，反应混合物于室温下搅拌过夜。反应结束后，用乙酸乙酯(10mL)稀释混合物，依次用水(5mL×3)和饱和食盐水(5mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到白色固体B3a(33.6mg,94.1％)。LC-MS:483.0([M+NH4 +]+)。Triethylamine (14 mg, 0.154 mmol) and trimethylsilyl trifluoromethanesulfonate (86 mg, 0.385 mmol) were added to an ethyl acetate solution (4 mL) of B3a-6 (40 mg, 0.077 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, the mixture was diluted with ethyl acetate (10 mL), washed successively with water (5 mL × 3) and saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a white solid B3a (33.6 mg, 94.1%). LC-MS: 483.0 ([M+ NH4 + ] + ).

以化合物B3b-6为原料，按照相同的实验步骤，得到中间体B3b。Using compound B3b-6 as a starting material, intermediate B3b was obtained by following the same experimental procedures.

中间体B4a：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-(2-甲氧基-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)-1H-吲哚-2-羧酸(B4a)
 Intermediate B4a : 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methoxy-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (B4a)

步骤1：(S)-1-(1-氰基-2-(二甲氨基)乙烯基)-5-(2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸乙酯(B4-2)Step 1: (S)-1-(1-cyano-2-(dimethylamino)vinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4-2)

将化合物B4-1(17.0g,49.9mmol)溶于叔丁氧基双(二甲胺基)甲烷(40mL)中，反应混合物升温至130℃搅拌2小时。反应结束后，将体系降温，加水(40mL)淬灭，用乙酸乙酯(80mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩，得到棕色油状物B4-2(14.0g,70.9％)。LC-MS:396.2([M+H]+)。Compound B4-1 (17.0 g, 49.9 mmol) was dissolved in tert-butoxybis(dimethylamino)methane (40 mL), and the reaction mixture was heated to 130 °C and stirred for 2 hours. After the reaction was completed, the system was cooled, quenched with water (40 mL), and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give a brown oily substance B4-2 (14.0 g, 70.9%). LC-MS: 396.2 ([M+H] + ).

步骤2：(S)-1-(1-氰基-2-羟基乙烯基)-5-(2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸乙酯(B4-3)Step 2: (S)-1-(1-cyano-2-hydroxyvinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4-3)

在5-10℃下，将盐酸水溶液(2N,40mL)加入到化合物B4-2(14.0g,35.4mmol)的四氢呋喃(140mL)溶液中，反应混合物于室温下搅拌18小时。反应结束后，加水(50mL)淬灭，用乙酸乙酯(70mL×3)萃取，合并有机相，有机相用饱和食盐水(50mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱色谱法纯化(石油醚/乙酸乙酯＝12/1)，得到黄色油状物B4-3(11.0g,84.3％)。1H NMR(300MHz,CDCl3):δ9.10(brs,1H),7.53–7.30(m,3H),7.25–7.15(m,1H),4.45–4.20(m,2H),3.90–3.57(m,2H),3.11–2.87(m,1H),2.02(s,1H),1.84–1.47(m,4H),1.39(t,J＝7.2Hz,3H),1.35–1.10(m,6H)。LC-MS:369.1([M+H]+)。At 5-10°C, an aqueous hydrochloric acid solution (2N, 40 mL) was added to a tetrahydrofuran solution (140 mL) of compound B4-2 (14.0 g, 35.4 mmol), and the reaction mixture was stirred at room temperature for 18 hours. After the reaction was complete, the mixture was quenched with water (50 mL), extracted with ethyl acetate (70 mL × 3), and the organic phases were combined. The organic phases were washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 12/1) to give a yellow oily substance B4-3 (11.0 g, 84.3%). 1 H NMR (300MHz, CDCl 3 ): δ9.10(brs,1H),7.53–7.30(m,3H),7.25–7.15(m,1H),4.45–4.20(m,2H),3.90–3.57(m,2H) ,3.11–2.87(m,1H),2.02(s,1H),1.84–1.47(m,4H),1.39(t,J=7.2Hz,3H),1.35–1.10(m,6H). LC-MS: 369.1 ([M+H] + ).

步骤3：(S)-1-(1-氰基-2-甲氧基乙烯基)-5-(2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸乙酯(B4-4-1/B4-4-2)Step 3: (S)-1-(1-cyano-2-methoxyvinyl)-5-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4-4-1/B4-4-2)

0℃下，将三甲基硅烷化重氮甲烷(10.2g,89.5mmol)加入到化合物B4-3(11.0g,29.8mmol)的二氯甲烷(110mL)溶液中，于室温下搅拌过夜。反应结束后，加水(50mL)，用乙酸乙酯(80mL×3)萃取，合并有机相，有机相用饱和食盐水(40mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝8:1)，得到黄色固体(7.6g,66.5％)。再经SFC分离(柱:Lux Cellulose-3,4.6mm*250mm,5um,流动相:A为CO2,B为MeOH，梯度:B,20％，流速:2.0mL/min,柱温:35℃)纯化，得到黄色固体B4-4-1(4.9g,64.4％,t＝2.583min)和B4-4-2(2.0g,26.3％,t＝4.755min)。At 0 °C, trimethylsilyldiazomethane (10.2 g, 89.5 mmol) was added to a solution of compound B4-3 (11.0 g, 29.8 mmol) in dichloromethane (110 mL), and the mixture was stirred overnight at room temperature. After the reaction was complete, water (50 mL) was added, and the mixture was extracted with ethyl acetate (80 mL × 3). The organic phases were combined, washed with saturated brine (40 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 8:1) to give a yellow solid (7.6 g, 66.5%). Further purification by SFC (column: Lux Cellulose-3, 4.6mm*250mm, 5um; mobile phase: A is CO2 , B is MeOH; gradient: B, 20%; flow rate: 2.0mL/min; column temperature: 35℃) yielded yellow solids B4-4-1 (4.9g, 64.4%, t＝2.583min) and B4-4-2 (2.0g, 26.3%, t＝4.755min).

B4-4-1：1H NMR(400MHz,CDCl3):δ7.51(s,1H),7.35(s,1H),7.31–7.25(m,1H),7.21(d,J＝8.4Hz,1H),7.14(s,1H),4.39(q,J＝7.2Hz,2H),3.93–3.78(m,5H),3.10–2.97(m,1H),1.83–1.61(m,4H),1.41(t,J＝6.8Hz 3H),1.34(s,3H),1.29(s,3H)；B4-4-1: 1 H NMR (400MHz, CDCl 3 ): δ7.51(s,1H),7.35(s,1H),7.31–7.25(m,1H),7.21(d,J＝8.4Hz,1H),7.14(s,1H),4.39( q,J＝7.2Hz,2H),3.93–3.78(m,5H),3.10–2.97(m,1H),1.83–1.61(m,4H),1.41(t,J＝6.8Hz 3H),1.34(s,3H),1.29(s,3H);

B4-4-1：1H NMR(400MHz,CDCl3):δ7.50(s,1H),7.40–7.27(m,3H),7.12(s,1H),4.38(q,J＝7.2Hz,2H),4.03(s,3H),3.93–3.78(m,2H),3.10–2.97(m,1H),1.84–1.60(m,4H),1.41(t,J＝7.2Hz,3H)1.34(s,3H),1.29(s,3H)。B4-4-1: 1 H NMR (400MHz, CDCl 3 ): δ7.50(s,1H),7.40–7.27(m,3H),7.12(s,1H),4.38(q,J＝7.2Hz,2H),4.03(s,3H),3.93–3.7 8(m,2H),3.10–2.97(m,1H),1.84–1.60(m,4H),1.41(t,J＝7.2Hz,3H)1.34(s,3H),1.29(s,3H).

步骤4：1-(1-氰基-2-甲氧基环丙基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1H-吲哚-2-羧酸乙酯(B4a-5/B4b-5/B4c-5/B4d-5)Step 4: 1-(1-cyano-2-methoxycyclopropyl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B4a-5/B4b-5/B4c-5/B4d-5)

将化合物B4-4-1(4.9g,12.8mmol)和50％氢氧化钠水溶液(15mL)加入到三甲基碘化亚砜(7.3g,33.3mmol)的二氯乙烷(60mL)溶液中，于室温下搅拌0.5小时，随后加入苄基三乙基溴化铵(3.8g,14.1mmol)，反应混合物升温至80℃搅拌6小时。反应结束后，将反应体系冷却至0℃，加水(10mL)，用乙酸乙酯(50mL×3)萃取，合并有机相，有机相用饱和食盐水(30mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝20/1)，再经SFC分离纯化(柱:Lux Cellulose-3 4.6mm*250mm,5um,流动相:A为CO2,B为MeOH,梯度:B 20％,流速:2.0mL/min,柱温:35℃)，得到黄色固体B4a-5(730mg,42.9％,t＝2.757min)和B4b-5(670mg,39.4％,t＝4.181min)。B4a-5:1H NMR(400MHz,CDCl3):δ7.78–7.27(m,4H),4.52–4.33(m,2H),4.10–3.69(m,6H),3.10–2.97(m,1H),2.30–2.10(m,1H),1.90–1.70(m,4H),1.69–1.60(m,1H),1.44(t,J＝7.2Hz,3H),1.34(s,3H),1.29(s,3H)。LC-MS:414.2([M+NH4]+)；B4b-5:1H NMR(400MHz,CDCl3):δ7.68–7.45(m,2H),7.36–7.27(m,2H),4.46–4.38(m,2H),3.88–3.75(m,6H),3.08–2.98(m,1H),2.25–2.15(m,1H),1.80–1.70(m,4H),1.67–1.62(m,1H),1.44(t,J＝7.2Hz,3H),1.34(s,3H),1.29(s,3H)。LC-MS:414.2([M+NH4]+)。Compound B4-4-1 (4.9 g, 12.8 mmol) and 50% sodium hydroxide aqueous solution (15 mL) were added to a solution of trimethyl sulfoxide (7.3 g, 33.3 mmol) in dichloroethane (60 mL). The mixture was stirred at room temperature for 0.5 hours, followed by the addition of benzyltriethylammonium bromide (3.8 g, 14.1 mmol). The reaction mixture was heated to 80 °C and stirred for 6 hours. After the reaction was completed, the reaction system was cooled to 0 °C, water (10 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 20/1), followed by SFC separation and purification (column: Lux Cellulose-3 4.6mm*250mm, 5um, mobile phase: A is CO2 , B is MeOH, gradient: B 20%, flow rate: 2.0mL/min, column temperature: 35℃), yielding yellow solids B4a-5 (730mg, 42.9%, t = 2.757min) and B4b-5 (670mg, 39.4%, t = 4.181min). B4a-5: 1 H NMR (400MHz, CDCl 3 ): δ7.78–7.27(m,4H),4.52–4.33(m,2H),4.10–3.69(m,6H),3.10–2.97(m,1H),2.30–2.10(m ,1H),1.90–1.70(m,4H),1.69–1.60(m,1H),1.44(t,J=7.2Hz,3H),1.34(s,3H),1.29(s,3H). LC-MS: 414.2([M+NH 4 ] + ); B4b-5: 1 H NMR (400MHz, CDCl 3 ): δ7.68–7.45(m,2H),7.36–7.27(m,2H),4.46–4.38(m,2H),3.88–3.75(m,6H),3.08–2.98(m,1H),2.2 5–2.15(m,1H),1.80–1.70(m,4H),1.67–1.62(m,1H),1.44(t,J=7.2Hz,3H),1.34(s,3H),1.29(s,3H). LC-MS: 414.2 ([M+NH 4 ] + ).

以化合物B4-4-2(2.0g)为原料，按照相同的实验步骤，得到黄色固体B4c-5(300mg,42.9％)和B4d-5(340mg,39.4％)。B4c-5:1H NMR(400MHz,CDCl3):δ7.70–7.45(m,2H),7.36–7.27(m,2H),4.43(q,J＝7.2Hz,2H),4.10–3.75(m,6H),3.08–2.98(m,1H),2.25–2.15(m,1H),1.80–1.70(m,4H),1.67–1.62(m,1H),1.44(t,J＝7.2Hz,3H),1.34(s,3H),1.29(s,3H)。LC-MS:414.2([M+NH4]+)；B4d-5:1H NMR(400MHz,CDCl3):δ7.70–7.45(m,2H),7.36–7.27(m,2H),4.43(q,J＝7.2Hz,2H),3.88–3.75(m,6H),3.08–2.98(m,1H),2.25–2.15(m,1H),1.80–1.70(m,4H),1.67–1.62(m,1H),1.44(t,J＝7.2Hz,3H),1.34(s,3H),1.29(s,3H)。LC-MS:414.2([M+NH4]+)。Using compound B4-4-2 (2.0 g) as a starting material, and following the same experimental procedure, yellow solids B4c-5 (300 mg, 42.9%) and B4d-5 (340 mg, 39.4%) were obtained. B4c-5: ¹H NMR (400 MHz, CDCl₃ ): δ 7.70–7.45 (m, 2H), 7.36–7.27 (m, 2H), 4.43 (q, J = 7.2 Hz, 2H), 4.10–3.75 (m, 6H), 3.08–2.98 (m, 1H), 2.25–2.15 (m, 1H), 1.80–1.70 (m, 4H), 1.67–1.62 (m, 1H), 1.44 (t, J = 7.2 Hz, 3H), 1.34 (s, 3H), 1.29 (s, 3H). LC-MS: 414.2([M+NH 4 ] + ); B4d-5: 1 H NMR (400MHz, CDCl 3 ): δ7.70–7.45(m,2H),7.36–7.27(m,2H),4.43(q,J＝7.2Hz,2H),3.88–3.75(m,6H),3.08–2.98(m,1H),2 .25–2.15(m,1H),1.80–1.70(m,4H),1.67–1.62(m,1H),1.44(t,J=7.2Hz,3H),1.34(s,3H),1.29(s,3H). LC-MS: 414.2 ([M+NH 4 ] + ).

步骤5：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-(1-((E)-N'-羟基甲脒基)-2-甲氧基环丙基)-1H-吲哚-2-羧酸乙酯(B4a-6)Step 5: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(1-((E)-N'-hydroxyformamidinyl)-2-methoxycyclopropyl)-1H-indole-2-carboxylic acid ethyl ester (B4a-6)

室温下，将盐酸羟胺(1.1g,15.6mmol)和碳酸氢钠(1.6g,18.7mmol)加入到化合物B4a-5(620mg,1.5mmol)的乙醇(15mL)溶液中，反应混合物升温至50℃搅拌1.5小时。反应结束后，加水(15mL)，用乙酸乙酯(30mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。得到黄色油状物B4a-6(550mg,81.9％)。LC-MS:430.2([M+H]+)。At room temperature, hydroxylamine hydrochloride (1.1 g, 15.6 mmol) and sodium bicarbonate (1.6 g, 18.7 mmol) were added to an ethanol (15 mL) solution of compound B4a-5 (620 mg, 1.5 mmol). The reaction mixture was heated to 50 °C and stirred for 1.5 hours. After the reaction was complete, water (15 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. A yellow oil, B4a-6 (550 mg, 81.9%), was obtained. LC-MS: 430.2 ([M+H] + ).

步骤6：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-(2-甲氧基-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)-1H-吲哚-2-羧酸乙酯(B4a-7)Step 6: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methoxy-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid ethyl ester (B4a-7)

将1,8-二氮杂二环[5.4.0]十一碳-7-烯(585mg,3.8mmol)和N,N'-羰基二咪唑(415mg,2.6mmol)加入到化合物B4a-6(550mg,1.3mmol)的二甲基亚砜(13mL)溶液中，反应混合物于室温下搅拌2小时。反应结束后，加水(25mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析纯化(石油醚/乙酸乙酯＝10/1)，得到白色油状物B4a-7(400mg,68.6％)。1H NMR(400MHz,CDCl3):δ7.80–7.70(m,1H),7.70–7.53(m,1H),7.48(s,1H),7.30(dd,J＝8.8Hz,1.2Hz,1H),7.09(s,1H),4.47(q,J＝7.2Hz,2H),3.93–3.78(m,2H),3.77–3.70(m,1H),3.50(s,3H),3.09–2.93(m,1H),2.38–2.27(m,1H),1.82–1.57(m,5H),1.46(d,J＝7.2Hz,3H),1.33(s,3H),1.27(s,3H)。1,8-diazabicyclo[5.4.0]undec-7-ene (585 mg, 3.8 mmol) and N,N'-carbonyldiimidazole (415 mg, 2.6 mmol) were added to a dimethyl sulfoxide (13 mL) solution of compound B4a-6 (550 mg, 1.3 mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, water (25 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 10/1) to give a white oily substance B4a-7 (400 mg, 68.6%). 1 H NMR (400MHz, CDCl 3 ): δ7.80–7.70(m,1H),7.70–7.53(m,1H),7.48(s,1H),7.30(dd,J＝8.8Hz,1.2Hz,1H),7.09(s,1H),4.47(q,J＝7.2Hz,2H),3.93–3.78(m,2H) ,3.77–3.70(m,1H),3.50(s,3H),3.09–2.93(m,1H),2.38–2.27(m,1H ),1.82–1.57(m,5H),1.46(d,J＝7.2Hz,3H),1.33(s,3H),1.27(s,3H).

步骤7：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-(2-甲氧基-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)-1H-吲哚-2-羧酸(B4a)Step 7: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-(2-methoxy-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (B4a)

将氢氧化锂(27mg,1.1mmol)加入到化合物B4a-7(250mg,0.55mmol)的四氢呋喃/甲醇/水(7mL,3/3/1)混合溶液中，反应混合物于室温下搅拌过夜。反应结束后，加水(10mL)，用乙酸乙酯(20mL×3)萃取，水相用柠檬酸(5.0mL)调节pH值至6，水相用乙酸乙酯(15mL×3)萃取，合并有机相，有机相用饱和食盐水(5mL×3)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经通过Pre-TLC(二氯甲烷/甲醇＝8/1)纯化，得到白色固体B4a(132mg,52.3％)。1H NMR(300MHz,DMSO-d6):δppm 13.10–12.00(m,2H),7.57–7.50(m,2H),7.38–7.32(m,1H),7.25–7.16(m,1H),6.74(s,1H),4.31–4.00(m,1H),3.80–3.62(m,2H),3.60–3.40(m,3H),3.10–2.90(m,1H),2.30–2.02(m,1H),1.83–1.35(m,5H),1.30–1.10(m,6H).LC-MS:426.1([M-H]-)。Lithium hydroxide (27 mg, 1.1 mmol) was added to a tetrahydrofuran/methanol/water (7 mL, 3/3/1) mixture of compound B4a-7 (250 mg, 0.55 mmol). The reaction mixture was stirred overnight at room temperature. After the reaction was complete, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The pH of the aqueous phase was adjusted to 6 with citric acid (5.0 mL), and the aqueous phase was extracted with ethyl acetate (15 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by pre-TLC (dichloromethane/methanol = 8/1) to give a white solid B4a (132 mg, 52.3%). 1 H NMR (300MHz, DMSO-d 6 ): δppm 13.10–12.00(m,2H),7.57–7.50(m,2H),7.38–7.32(m,1H),7.25–7.16(m,1H),6.74(s,1H),4.31–4.00(m,1H),3.80–3.62 (m,2H),3.60–3.40(m,3H),3.10–2.90(m,1H),2.30–2.02(m,1H),1.83–1.35(m,5H),1.30–1.10(m,6H).LC-MS:426.1([MH] - ).

以化合物B4b-5/B4c-5/B4d-5分别作为原料，按照相同的实验步骤，分别得到中间体B4b/B4c/B4d。B4b:1H NMR(300MHz,DMSO-d6):δppm 13.10–12.50(brs,1H),12.40–12.00(brs,1H),7.58–7.49(m,2H),7.39–7.31(m,1H),7.28–7.18(m,1H),4.31–4.00(m,1H),3.80–3.62(m,2H),3.60–3.40(m,3H),3.10–2.90(m,1H),2.30–2.02(m,1H),1.78–1.40(m,5H),1.30–1.10(m,6H)。LC-MS:426.1([M-H]-)；B4c：1H NMR(300MHz,DMSO-d6):δppm 13.10–12.05(m,2H),7.58–7.50(m,2H),7.39–7.31(m,1H),7.25–7.18(m,1H),4.30–4.00(m,1H),3.82–3.62(m,2H),3.60–3.43(m,3H),3.10–2.90(m,1H),2.38–2.13(m,1H),1.84–1.40(m,5H),1.27(s,3H),1.18(s,3H)。LC-MS:426.1([M-H]-)；B4d:1H NMR(300MHz,DMSO-d6):δppm 7.60–7.56(m,1H),7.42(s,1H),7.35–7.26(m,1H),7.19–7.16(m,1H),6.74(s,1H),3.88–3.78(m,1H),3.77–3.62(m,2H),3.60–3.40(m,3H),3.10–2.90(m,1H),2.30–2.02(m,1H),1.78–1.40(m,5H),1.30–1.10(m,6H)。LC-MS:426.1([M-H]-)。Using compounds B4b-5/B4c-5/B4d-5 as raw materials, intermediates B4b/B4c/B4d were obtained respectively following the same experimental procedure. B4b: 1 H NMR (300MHz, DMSO-d 6 ): δppm 13.10–12.50(brs,1H),12.40–12.00(brs,1H),7.58–7.49(m,2H),7.39–7.31(m,1H),7.28–7.18(m,1H),4.31–4.00(m, 1H),3.80–3.62(m,2H),3.60–3.40(m,3H),3.10–2.90(m,1H),2.30–2.02(m,1H),1.78–1.40(m,5H),1.30–1.10(m,6H). LC-MS: 426.1 ([MH] - ); B4c: 1 H NMR (300MHz, DMSO-d 6 ): δppm 13.10–12.05(m,2H),7.58–7.50(m,2H),7.39–7.31(m,1H),7.25–7.18(m,1H),4.30–4.00(m,1H),3.82–3.62( m,2H),3.60–3.43(m,3H),3.10–2.90(m,1H),2.38–2.13(m,1H),1.84–1.40(m,5H),1.27(s,3H),1.18(s,3H). LC-MS: 426.1 ([MH] - ); B4d: 1 H NMR (300MHz, DMSO-d 6 ): δppm 7.60–7.56(m,1H),7.42(s,1H),7.35–7.26(m,1H),7.19–7.16(m,1H),6.74(s,1H),3.88–3.78(m,1H),3.77– 3.62(m,2H),3.60–3.40(m,3H),3.10–2.90(m,1H),2.30–2.02(m,1H),1.78–1.40(m,5H),1.30–1.10(m,6H). LC-MS: 426.1 ([MH] - ).

中间体B5a：7-(2,2-二甲基四氢-2H-吡喃-4-基)-3-((1R,2S)-2-甲基-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)吲哚嗪-2-羧酸乙酯(B5a)
 Intermediate B5a : 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-3-((1R,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)indoleazine-2-carboxylic acid ethyl ester (B5a)

步骤1：2-((4-溴吡啶-2-基)(羟基)甲基)丙烯酸乙酯(B5-2)Step 1: Ethyl 2-((4-bromopyridin-2-yl)(hydroxy)methyl)acrylate (B5-2)

室温下，向化合物B5-1(50.0g,268.82mmol)的二氧六环/水(500mL/500mL)溶液中加入丙烯酸乙酯(80.6g,806.45mmol)和1,4-二氮杂二环[2.2.2]辛烷(30.1g,268.82mmol)，反应混合物于室温下搅拌16小时。反应结束后，加入乙酸乙酯/水(2L/1L)，用乙酸乙酯(2L×3)萃取，合并有机相，有机相用饱和食盐水(500mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到黄色油状化合物B5-2(65g,84％)。LC-MS:287.25[M+H]+。At room temperature, ethyl acrylate (80.6 g, 806.45 mmol) and 1,4-diazabicyclo[2.2.2]octane (30.1 g, 268.82 mmol) were added to a dioxane/water (500 mL/500 mL) solution of compound B5-1 (50.0 g, 268.82 mmol). The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, ethyl acetate/water (2 L/1 L) was added, and the mixture was extracted with ethyl acetate (2 L × 3). The organic phases were combined, washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give a yellow oily compound B5-2 (65 g, 84%). LC-MS: 287.25 [M + H] + .

步骤2：7-溴吲哚嗪-2-羧酸乙酯(B5-3)Step 2: 7-Bromoindoleazine-2-carboxylic acid ethyl ester (B5-3)

室温下，将化合物B5-2(65.0g,227.27mmol)溶于乙酸酐(1000mL)中，反应混合物升温至140℃搅拌3小时。反应结束后，将体系降温，加入乙酸乙酯/水(2L/1L)，用乙酸乙酯(2L×3)萃取，合并有机相，有机相用饱和食盐水(500mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到黄色固体化合物B5-3(29.4g,48％)。LC-MS:269.20[M+H]+。Compound B5-2 (65.0 g, 227.27 mmol) was dissolved in acetic anhydride (1000 mL) at room temperature. The reaction mixture was heated to 140 °C and stirred for 3 hours. After the reaction was complete, the system was cooled, and ethyl acetate/water (2 L/1 L) was added. The mixture was extracted with ethyl acetate (2 L × 3), and the organic phases were combined. The organic phases were washed with saturated brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give a yellow solid compound B5-3 (29.4 g, 48%). LC-MS: 269.20 [M + H] + .

步骤3：7-(2,2-二甲基四氢-2H-吡喃-4-基)吲哚嗪-2-羧酸乙酯(B5-4)Step 3: Ethyl 7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleazine-2-carboxylate (B5-4)

在氮气保护下，向锌粉(46.6g，716.42mmol)的N,N-二甲基甲酰胺(500mL)溶液中，加入三甲基氯硅烷(8.6g,78.81mmol)和1,2-二溴乙烷(14.82g,78.81mmol)，于室温下搅拌10分钟。随后，向上述混合物中加入4-碘-2,2-二甲基四氢-2H-吡喃(129.0g,537.31mmol)的N,N-二甲基甲酰胺(130mL)溶液，于室温搅拌下20分钟。随后，在氮气氛围下，加入醋酸钯(4.1g,17.91mmol)、Amphos(9.5g,35.82mmol)和化合物B5-3(48.0g,179.10mmol)，反应混合物于55℃下搅拌3小时。反应结束后，加入乙酸乙酯/水(2L/2L)，用乙酸乙酯(2L×3)萃取，合并有机相，有机相用饱和食盐水(1L×2)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝5/1)纯化，得到黄色油状物化合物B5-4(23.2g,43％)。LC-MS:302.30[M+H]+。Under nitrogen protection, trimethylchlorosilane (8.6 g, 78.81 mmol) and 1,2-dibromoethane (14.82 g, 78.81 mmol) were added to a solution of zinc powder (46.6 g, 716.42 mmol) in N,N-dimethylformamide (500 mL), and the mixture was stirred at room temperature for 10 minutes. Subsequently, a solution of 4-iodo-2,2-dimethyltetrahydro-2H-pyran (129.0 g, 537.31 mmol) in N,N-dimethylformamide (130 mL) was added to the mixture, and the mixture was stirred at room temperature for 20 minutes. Then, under a nitrogen atmosphere, palladium acetate (4.1 g, 17.91 mmol), Amphos (9.5 g, 35.82 mmol), and compound B5-3 (48.0 g, 179.10 mmol) were added, and the reaction mixture was stirred at 55 °C for 3 hours. After the reaction was complete, ethyl acetate/water (2 L/2 L) was added, and the mixture was extracted with ethyl acetate (2 L × 3). The organic phases were combined, washed with saturated brine (1 L × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5/1) to give a yellow oily compound B5-4 (23.2 g, 43%). LC-MS: 302.30 [M + H] + .

步骤4：3-(氰甲基)-7-(2,2-二甲基四氢-2H-吡喃-4-基)吲哚嗪-2-羧酸乙酯(B5a-5)Step 4: 3-(cyanomethyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleazine-2-carboxylic acid ethyl ester (B5a-5)

向化合物B5-4(3.0g,9.97mmol)的二甲基亚砜(30mL)溶液中加入2-溴乙腈(1.3g,10.96mmol)、七水合硫酸亚铁(1.4g,4.98mmol)和碘化钠(1.5g,9.97mmol)。随后，在0℃、氮气保护下，滴加双氧水溶液(35％,5.4mL)，反应混合物在0℃下搅拌20分钟。反应结束后，0℃下将反应混合物倒入饱和碳酸氢钠水溶液中并搅拌10分钟。向上述混合物中加入乙酸乙酯/水(200mL/200mL)，用乙酸乙酯(300mL×3)萃取，合并有机相，有机相用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝2/1)纯化，得到黄色化合物(800mg,35％)。LC-MS:341.20[M+H]+。将黄色固体经SFC拆分得B5a-5和B5b-5。B5a-5:1H NMR(400MHz,Chloroform-d)δ7.79(dt,J＝7.4,1.0Hz,1H),7.20(dd,J＝1.9,0.9Hz,1H),6.79(d,J＝0.9Hz,1H),6.65(dd,J＝7.4,1.9Hz,1H),4.52(s,2H),4.36(q,J＝7.1Hz,2H),3.90–3.75(m,2H),2.92–2.81(m,1H),1.79–1.69(m,2H),1.56(d,J＝12.7Hz,2H),1.39(t,J＝7.1Hz,3H),1.29(d,J＝13.4Hz,6H)；B5b-5:1H NMR(400MHz,Chloroform-d)δ7.79(d,J＝7.4Hz,1H),7.20(d,J＝1.8Hz,1H),6.79(s,1H),6.65(dd,J＝7.4,1.8Hz,1H),4.52(s,2H),4.36(q,J＝7.1Hz,2H),3.89–3.75(m,2H),2.86(ddt,J＝12.4,7.5,3.8Hz,1H),1.78–1.68(m,2H),1.59–1.52(m,2H),1.39(t,J＝7.1Hz,3H),1.29(d,J＝13.4Hz,6H)。To a solution of compound B5-4 (3.0 g, 9.97 mmol) in dimethyl sulfoxide (30 mL), 2-bromoacetonitrile (1.3 g, 10.96 mmol), ferrous sulfate heptahydrate (1.4 g, 4.98 mmol), and sodium iodide (1.5 g, 9.97 mmol) were added. Subsequently, under nitrogen protection at 0 °C, hydrogen peroxide solution (35%, 5.4 mL) was added dropwise, and the reaction mixture was stirred at 0 °C for 20 minutes. After the reaction was complete, the reaction mixture was poured into a saturated sodium bicarbonate aqueous solution at 0 °C and stirred for 10 minutes. Ethyl acetate/water (200 mL/200 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (300 mL × 3). The organic phases were combined, washed with saturated brine (100 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 2/1) to give a yellow compound (800 mg, 35%). LC-MS: 341.20 [M+H] + . The yellow solid was separated into B5a-5 and B5b-5 by SFC. B5a-5: 1 H NMR(400MHz,Chloroform-d)δ7.79(dt,J＝7.4,1.0Hz,1H),7.20(dd,J＝1.9,0.9Hz,1H),6.79(d,J＝0.9Hz,1H),6.65(dd,J＝7.4,1.9Hz,1H),4.52(s,2H),4. 36(q,J＝7.1Hz,2H),3.90–3.75(m,2H),2.92–2.81(m,1H),1.79–1.69(m,2H), 1.56(d,J＝12.7Hz,2H),1.39(t,J＝7.1Hz,3H),1.29(d,J＝13.4Hz,6H); B5b-5: 1 H NMR(400MHz,Chloroform-d)δ7.79(d,J＝7.4Hz,1H),7.20(d,J＝1.8Hz,1H),6.79(s,1H),6.65(dd,J＝7.4,1.8Hz,1H),4.52(s,2H),4.36(q,J＝7.1H z,2H),3.89–3.75(m,2H),2.86(ddt,J＝12.4,7.5,3.8Hz,1H),1.78–1.68 (m,2H),1.59–1.52(m,2H),1.39(t,J＝7.1Hz,3H),1.29(d,J＝13.4Hz,6H).

步骤5：3-((1R,2S)-1-氰基-2-甲基环丙基)-7-(2,2-二甲基四氢-2H-吡喃-4-基)吲哚嗪-2-羧酸乙酯(B5a-6)Step 5: 3-((1R,2S)-1-cyano-2-methylcyclopropyl)-7-(2,2-dimethyltetrahydro-2H-pyran-4-yl)indoleazine-2-carboxylic acid ethyl ester (B5a-6)

在0℃下，向化合物B5a-5(1.7g,5.0mmol)和(S)-4-甲基-1,3,2-二氧硫杂环戊烷-2,2-二氧化物(1.4g,10.0mmol)的四氢呋喃/1,3-二甲基-全氢-2-嘧啶酮(50mL/4.25mL)溶液中加入双(三甲基硅烷基)氨基钾(1M,15.0mL,15.0mmol)，反应混合物于0℃下搅拌2小时。反应结束后，加入2M盐酸水溶液调节pH值至3-4，用乙酸乙酯(100mL×3)萃取，合并有机相，有机相用饱和食盐水(100mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(石油醚/乙酸乙酯＝4/1)纯化，得到黄色固体化合物B5a-6(1.1g，57％)。LC-MS:380.2[M+H]+。At 0 °C, bis(trimethylsilyl)amino potassium (1M, 15.0mL, 15.0mmol) was added to a tetrahydrofuran/1,3-dimethyl-perhydro-2-pyrimidinone (50mL/4.25mL) solution of compound B5a-5 (1.7g, 5.0mmol) and (S)-4-methyl-1,3,2-dioxothiacyclopentane-2,2-dioxide (1.4g, 10.0mmol). The reaction mixture was stirred at 0 °C for 2 hours. After the reaction was complete, the pH was adjusted to 3-4 with 2M hydrochloric acid aqueous solution, and the mixture was extracted with ethyl acetate (100mL × 3). The organic phases were combined, washed with saturated brine (100mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4/1) to give a yellow solid compound B5a-6 (1.1g, 57%). LC-MS: 380.2 [M+H] + .

以化合物B5a-6为原料，按照中间体B4a相同的实验步骤，得到中间体B5a。Using compound B5a-6 as a starting material, intermediate B5a was obtained by following the same experimental procedures as intermediate B4a.

以化合物B5b-5为原料，按照中间体B5a相同的实验步骤，得到中间体B5b。Using compound B5b-5 as a starting material, intermediate B5b was obtained by following the same experimental procedures as intermediate B5a.

中间体B6：5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-((1R,5S,6r)-6-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-3-氧杂双环[3.1.0]己-6-基)-1H-吲哚-2-甲酸(B6)
 Intermediate B6 : 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1R,5S,6r)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-1H-indole-2-carboxylic acid (B6)

步骤1:(3aR,6aS)-四氢呋喃并[3,4-d][1,3,2]二氧杂硫杂环戊烷2,2-二氧化物(B6-2)Step 1: (3aR,6aS)-Tetrahydrofurano[3,4-d][1,3,2]dioxathiacyclopentane 2,2-dioxide (B6-2)

在0℃，向化合物B6-1(1.0g,9.61mmol)和三乙胺(3.9g,38.42mmol)的二氯甲烷(20mL)溶液中滴加亚硫酰氯(1.7g,14.41mmol)并搅拌1h。反应结束后，加水(20mL)淬灭，用二氯甲烷(10mL×3)萃取，合并有机相并减压浓缩。将残余物溶于甲醇(8mL)和水(2mL)，于在0℃加入高碘酸钠(2.5g,11.59mmol)和三氯化钌(40.1mg,0.19mmol)，反应混合物在25℃搅拌2小时。反应结束后，减压浓缩除去溶剂，残余物溶于二氯甲烷(20mL)中，用水(20mL)洗涤，无水硫酸钠干燥，过滤，浓缩得粗品。粗品经硅胶柱层析(乙酸乙酯/石油醚＝1/2)，得到白色固体化合物B6-2(1.1g,69％)。At 0 °C, thionyl chloride (1.7 g, 14.41 mmol) was added dropwise to a solution of compound B6-1 (1.0 g, 9.61 mmol) and triethylamine (3.9 g, 38.42 mmol) in dichloromethane (20 mL) and the mixture was stirred for 1 h. After the reaction was complete, the mixture was quenched with water (20 mL), extracted with dichloromethane (10 mL × 3), and the organic phases were combined and concentrated under reduced pressure. The residue was dissolved in methanol (8 mL) and water (2 mL), and sodium periodate (2.5 g, 11.59 mmol) and ruthenium trichloride (40.1 mg, 0.19 mmol) were added at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. After the reaction was complete, the solvent was removed by concentration under reduced pressure. The residue was dissolved in dichloromethane (20 mL), washed with water (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was subjected to silica gel column chromatography (ethyl acetate/petroleum ether = 1/2) to give a white solid compound B6-2 (1.1 g, 69%).

步骤2:1-(6-氰基-3-氧杂双环[3.1.0]己-6-基)-5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-N-甲基-N-苯基-1H-吲哚-2-甲酰胺(B6-3)Step 2: 1-(6-cyano-3-oxabicyclo[3.1.0]hex-6-yl)-5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-N-phenyl-1H-indole-2-carboxamide (B6-3)

在氮气气氛下、0℃下，向中间体B2-1(211.5mg,0.53mmol)和化合物B6-2(350.0mg,2.11mmol)的四氢呋喃(4mL)溶液中滴加双(三甲基硅烷基)氨基钾的四氢呋喃溶液(1.5mL,1M,1.5mmol)，反应混合物于25℃搅拌2小时。反应结束后，加水(20mL)淬灭，用乙酸乙酯(10mL×3)萃取。合并有机相并减压浓缩，粗品经硅胶柱层析(乙酸乙酯/石油醚＝1/2)，得到黄色固体化合物B6-3(58mg,24％)。LC-MS:[M+H]+＝470.7。Under a nitrogen atmosphere and at 0°C, a tetrahydrofuran solution (1.5 mL, 1 M, 1.5 mmol) of potassium bis(trimethylsilyl)amino in tetrahydrofuran was added dropwise to a tetrahydrofuran solution (4 mL) of intermediate B2-1 (211.5 mg, 0.53 mmol) and compound B6-2 (350.0 mg, 2.11 mmol). The reaction mixture was stirred at 25°C for 2 hours. After the reaction was complete, the mixture was quenched with water (20 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (ethyl acetate/petroleum ether = 1/2) to give a yellow solid compound B6-3 (58 mg, 24%). LC-MS: [M+H] + = 470.7.

步骤3:5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-N-甲基-1-(6-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-3-氧杂双环[3.1.0]己-6-基)-N-苯基-1H-吲哚-2-甲酰胺(B6-4)Step 3: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-methyl-1-(6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-N-phenyl-1H-indole-2-carboxamide (B6-4)

将化合物B6-3(58.0mg,0.12mmol)、羟胺盐酸盐(85.6mg,1.24mmol)和N,N-二异丙基乙胺(159.6mg,1.24mmol)溶于二甲基亚砜(2mL)中，反应混合物升温至60℃并搅拌24小时。反应结束后将体系降温，加入饱和的氯化钠(10mL)淬灭，用乙酸乙酯(5mL×3)萃取，合并有机相，有机相经无水硫酸钠干燥，过滤，浓缩。将残余物溶于二甲基亚砜(2mL)中，加入羰基二咪唑(24.0mg,0.15mmol)和1,8-二氮杂双环十一-7-烯(37.6mg,0.25mmol)，反应混合物于25℃搅拌1小时。反应结束后，加入饱和食盐水(10mL)淬灭，用乙酸乙酯(5mL×3)萃取，合并有机相并减压浓缩，粗品经硅胶柱层析(乙酸乙酯/石油醚＝3/10)纯化，得到棕色固体化合物B6-4(35mg,54％)。LC-MS:[M+H]+＝529.7。Compound B6-3 (58.0 mg, 0.12 mmol), hydroxylamine hydrochloride (85.6 mg, 1.24 mmol), and N,N-diisopropylethylamine (159.6 mg, 1.24 mmol) were dissolved in dimethyl sulfoxide (2 mL). The reaction mixture was heated to 60 °C and stirred for 24 hours. After the reaction was complete, the system was cooled, quenched with saturated sodium chloride (10 mL), and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in dimethyl sulfoxide (2 mL), and carbonyl diimidazole (24.0 mg, 0.15 mmol) and 1,8-diazabicycloundecyl-7-ene (37.6 mg, 0.25 mmol) were added. The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was completed, saturated brine (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate/petroleum ether = 3/10) to give a brown solid compound B6-4 (35 mg, 54%). LC-MS: [M+H] + = 529.7.

步骤4:5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-((1R,5S,6r)-6-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-3-氧杂双环[3.1.0]己-6-基)-1H-吲哚-2-甲酸(B6)Step 4: 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1R,5S,6r)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-oxabicyclo[3.1.0]hex-6-yl)-1H-indole-2-carboxylic acid (B6)

向化合物B6-4(35.0mg,0.66mmol)的2-甲氧基乙醇(2mL)溶液中加入氢氧化钾(392.8mg,7.0mmol)，反应混合物升温至100℃并搅拌7小时。反应结束将体系冷却至0℃，缓慢加入6M盐酸水溶液至pH＝2，用乙酸乙酯(5mL×3)萃取。合并有机相并减压浓缩，粗品经硅胶柱层析(甲醇/二氯甲烷＝1/10)，得到棕色固体化合物B6(18.2mg,52％)。LC-MS:[M+H]+＝440.6。Potassium hydroxide (392.8 mg, 7.0 mmol) was added to a 2 mL solution of compound B6-4 (35.0 mg, 0.66 mmol) in 2-methoxyethanol. The reaction mixture was heated to 100 °C and stirred for 7 hours. After the reaction was complete, the system was cooled to 0 °C, and 6 M hydrochloric acid aqueous solution was slowly added to pH 2. The mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (methanol/dichloromethane = 1/10) to give a brown solid compound B6 (18.2 mg, 52%). LC-MS: [M+H] + = 440.6.

中间体B7：5-[(4S)-2,2-二甲基氧杂环己烷-4-基]-1-[(1R,5S,6R)-3,3-二氧化-6-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-3λ6-硫杂双环[3.1.0]己-6-基]-1H-吲哚-2-甲酸(B7)
 Intermediate B7 : 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-3,3-dioxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3λ 6 -thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid (B7)

步骤1:1-[(1R,5S,6R)-6-氰基-3-硫杂双环[3.1.0]己-6-基]-5-[(4S)-2,2-二甲基氧杂环己烷-4-基]-1H-吲哚-2-甲酸乙酯(B7-2)Step 1: 1-[(1R,5S,6R)-6-cyano-3-thiabicyclo[3.1.0]hex-6-yl]-5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-2)

在氮气气氛、-40℃下，向化合物B4-1(500.0mg,1.47mmol)和化合物B7-1(535.3mg,2.94mmol)的四氢呋喃/1,3-二甲基-全氢-2-嘧啶酮(3mL/3mL)溶液中缓慢加入双(三甲基硅烷基)氨基钾的四氢呋喃溶液(1M,4.41mL)，反应混合物于-40℃搅拌2小时。反应结束后，加水(10mL)淬灭，用乙酸乙酯(5mL×3)萃取。合并有机相并减压浓缩，粗品经硅胶柱层析(石油醚/乙酸乙酯＝80/20)，得到淡黄色固体化合物B7-2(330.0mg,53％)。LC-MS:[M+H]+＝425.0。Under a nitrogen atmosphere and at -40°C, a tetrahydrofuran solution (1M, 4.41mL) of potassium bis(trimethylsilyl)aminoacetate was slowly added to a tetrahydrofuran/1,3-dimethyl-perhydro-2-pyrimidinone (3mL/3mL) solution of compound B4-1 (500.0mg, 1.47mmol) and compound B7-1 (535.3mg, 2.94mmol). The reaction mixture was stirred at -40°C for 2 hours. After the reaction was complete, the mixture was quenched with water (10mL) and extracted with ethyl acetate (5mL × 3). The organic phases were combined and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (petroleum ether/ethyl acetate = 80/20) to give compound B7-2 (330.0mg, 53%) as a pale yellow solid. LC-MS: [M+H] + = 425.0.

步骤2:5-[(4S)-2,2-二甲基氧杂环己烷-4-基]-1-[(1R,5S,6R)-6-(N'-羟基脒基)-3-硫杂双环[3.1.0]己-6-基]-1H-吲哚-2-甲酸乙酯(B7-3)Step 2: 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-6-(N'-hydroxyamidinyl)-3-thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-3)

室温下，向化合物B7-2(441.0mg,1.04mmol)的乙醇(8mL)溶液中加入羟胺盐酸盐(721.8mg,10.39mmol)和N,N-二异丙基乙基胺(1.30g,10.39mmol)，反应混合物于65℃搅拌16小时。反应结束后，将体系降温，减压浓缩除去乙醇。残余物加入饱和食盐水中(10mL)，用乙酸乙酯(5mL×3)萃取。合并有机层，无水硫酸钠干燥，过滤，浓缩，得到浅褐色固体化合物B7-3(472.0mg)。LC-MS:[M+H]+＝458.2。At room temperature, hydroxylamine hydrochloride (721.8 mg, 10.39 mmol) and N,N-diisopropylethylamine (1.30 g, 10.39 mmol) were added to an ethanol (8 mL) solution of compound B7-2 (441.0 mg, 1.04 mmol). The reaction mixture was stirred at 65 °C for 16 hours. After the reaction was complete, the system was cooled and concentrated under reduced pressure to remove ethanol. The residue was added to saturated brine (10 mL) and extracted with ethyl acetate (5 mL × 3). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a light brown solid, compound B7-3 (472.0 mg). LC-MS: [M+H] + = 458.2.

步骤3:5-[(4S)-2,2-二甲基氧杂环己烷-4-基]-1-[(1R,5S,6R)-6-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-3-硫杂双环[3.1.0]己-6-基]-1H-吲哚-2-甲酸乙酯(B7-4)Step 3: 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3-thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-4)

室温下，向化合物B7-3(472.0mg,1.03mmol)的二甲基亚砜(6.00mL)溶液中加入N,N'-羰基二咪唑(334.9mg,2.06mmol)和1,8-二氮杂双环[5.4.0]十一-7-烯(393.1mg,2.58mmol)，反应混合物于25℃搅拌0.5小时。反应结束后，加入饱和食盐水(10mL)淬灭，用乙酸乙酯(5mL×3)萃取。合并有机相，用饱和食盐水(10mL)洗涤，减压浓缩，粗品经硅胶柱层析(二氯甲烷/甲醇＝98/2)纯化，得到白色固体化合物B7-4(346.0mg,69％)。LC-MS:[M+H]+＝484.2。At room temperature, N,N'-carbonyldiimidazole (334.9 mg, 2.06 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (393.1 mg, 2.58 mmol) were added to a dimethyl sulfoxide (6.00 mL) solution of compound B7-3 (472.0 mg, 1.03 mmol). The reaction mixture was stirred at 25 °C for 0.5 h. After the reaction was complete, saturated brine (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (10 mL), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol = 98/2) to give compound B7-4 (346.0 mg, 69%) as a white solid. LC-MS: [M+H] + = 484.2.

步骤4:5-[(4S)-2,2-二甲基氧杂环己烷-4-基]-1-[(1R,5S,6R)-3,3-二氧化-6-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-3λ6-硫杂双环[3.1.0]己-6-基]-1H-吲哚-2-甲酸乙酯(B7-5)Step 4: 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-3,3-dioxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3λ 6 -thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid ethyl ester (B7-5)

在0℃下，向化合物B7-4(346.0mg,0.72mmol)的甲醇/二氯甲烷(3mL/6mL)溶液中加入间氯过氧苯甲酸(435.8mg,2.15mmol)，反应混合物在0℃搅拌0.5小时并在30℃搅拌4小时。反应结束后，加入饱和亚硫酸钠(10mL)淬灭，用乙酸乙酯(5mL×3)萃取。合并有机层，减压浓缩，粗品经硅胶柱层析(二氯甲烷/甲醇＝98/2)纯化，得到黄色固体化合物B7-5(327.0mg,89％)。LC-MS:[M+H]+＝516.0。At 0 °C, m-chloroperoxybenzoic acid (435.8 mg, 2.15 mmol) was added to a methanol/dichloromethane (3 mL/6 mL) solution of compound B7-4 (346.0 mg, 0.72 mmol). The reaction mixture was stirred at 0 °C for 0.5 h and then at 30 °C for 4 h. After the reaction was complete, saturated sodium sulfite (10 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (5 mL × 3). The organic layers were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol = 98/2) to give a yellow solid compound B7-5 (327.0 mg, 89%). LC-MS: [M+H] + = 516.0.

步骤5:5-[(4S)-2,2-二甲基氧杂环己烷-4-基]-1-[(1R,5S,6R)-3,3-二氧化-6-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-3λ6-硫杂双环[3.1.0]己-6-基]-1H-吲哚-2-甲酸(B7)Step 5: 5-[(4S)-2,2-dimethyloxacyclohexane-4-yl]-1-[(1R,5S,6R)-3,3-dioxo-6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-3λ 6 -thiabicyclo[3.1.0]hex-6-yl]-1H-indole-2-carboxylic acid (B7)

向化合物B7-5(327.0mg,0.63mmol)的四氢呋喃/水(5mL/2.5mL)溶液中加入氢氧化锂单水合物(66.5mg,1.59mmol)，反应混合物于40℃搅拌16小时。反应结束后，将体系降温，加入1M盐酸水溶液淬灭至pH＝3，用乙酸乙酯(5mL×3)萃取。合并有机层，减压浓缩，粗品经硅胶柱层析(二氯甲烷/甲醇＝98/5)纯化，得到白色固体化合物B7(105.0mg,34％)。LC-MS:[M-H]-＝486.0。1H NMR(400MHz,CDCl3)δ10.55(s,1H),7.57(d,J＝8.8Hz,2H),7.52(s,1H),7.38(s,1H),7.37(d,J＝8.8Hz,1H),4.07(d,J＝12.8Hz,1H),3.93-3.74(m,3H),3.10(d,J＝15.6Hz,2H),3.05-2.98(m,1H),2.94-2.86(m,1H),2.70-2.62(m,1H),1.73(d,J＝15.6Hz,3H),1.63(t,J＝12.8Hz,1H),1.35(s,3H),1.29(s,3H)。Lithium hydroxide monohydrate (66.5 mg, 1.59 mmol) was added to a tetrahydrofuran/water (5 mL/2.5 mL) solution of compound B7-5 (327.0 mg, 0.63 mmol), and the reaction mixture was stirred at 40 °C for 16 hours. After the reaction was complete, the system was cooled and quenched with 1 M hydrochloric acid aqueous solution to pH 3, and extracted with ethyl acetate (5 mL × 3). The organic layers were combined, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol = 98/5) to give compound B7 (105.0 mg, 34%) as a white solid. LC-MS: [MH] - = 486.0. 1 H NMR (400MHz, CDCl 3 )δ10.55(s,1H),7.57(d,J＝8.8Hz,2H),7.52(s,1H),7.38(s,1H),7.37( d,J＝8.8Hz,1H),4.07(d,J＝12.8Hz,1H),3.93-3.74(m,3H),3.10(d,J＝1 5.6Hz,2H),3.05-2.98(m,1H),2.94-2.86(m,1H),2.70-2.62(m,1H),1. 73(d,J＝15.6Hz,3H),1.63(t,J＝12.8Hz,1H),1.35(s,3H),1.29(s,3H).

中间体B8：1-[(1R,5S,6S)-3-[(叔丁氧基)羰基]-6-(1H-1,2,3,4-四唑-5-基)-3-氮杂双环[3.1.0]己-6-基]-5-(氧杂环己烷-4-基)-1H-吲哚-2-甲酸(B8)
 Intermediate B8 : 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxacyclohexane-4-yl)-1H-indole-2-carboxylic acid (B8)

步骤1:5-(3,6-二氢-2H-吡喃-4-基)-1H-吲哚-2-甲酸乙酯(B8-2)Step 1: Ethyl 5-(3,6-dihydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (B8-2)

在氮气气氛下，将化合物B8-1(8.00g,29.84mmol)、2-(3,4-二氢-2H-吡喃-5-基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(7.50g,35.91mmol)、[1,1’-双(二苯基膦)二茂铁]二氯化钯(2.20g,2.98mmol)和碳酸钾(8.20g,59.68mmol)的1,4-二噁烷/水(160mL/40mL)中的混合物在85℃搅拌3小时。反应结束后，将体系降温，加水(200mL)淬灭，用乙酸乙酯(100mL×3)萃取。合并有机相并减压浓缩，粗品经硅胶柱层析(乙酸乙酯/石油醚＝4/1)，得到黄色固体化合物B8-2(9.6g)。LC-MS:[M+H]+＝271.9。Under a nitrogen atmosphere, a mixture of compound B8-1 (8.00 g, 29.84 mmol), 2-(3,4-dihydro-2H-pyran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (7.50 g, 35.91 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (2.20 g, 2.98 mmol), and potassium carbonate (8.20 g, 59.68 mmol) in 1,4-dioxane/water (160 mL/40 mL) was stirred at 85 °C for 3 hours. After the reaction was complete, the system was cooled, quenched with water (200 mL), and extracted with ethyl acetate (100 mL × 3). The organic phases were combined and concentrated under reduced pressure. The crude product was subjected to silica gel column chromatography (ethyl acetate/petroleum ether = 4/1) to give a yellow solid compound B8-2 (9.6 g). LC-MS:[M+H] + ＝271.9.

步骤2:5-(四氢-2H-吡喃-4-基)-1H-吲哚-2-甲酸乙酯(B8-3)Step 2: Ethyl 5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (B8-3)

在氢气气氛下，将化合物B8-2(9.60g,35.38mmol)和钯碳(0.96g,10wt％)在甲醇/四氢呋喃(30mL/90mL)中的混合物于25℃搅拌16小时。反应结束后，反应混合物经硅藻土过滤，滤液减压浓缩，得到灰色固体化合物B8-3(7.30g)。LC-MS:[M+H]+＝274.0。Under a hydrogen atmosphere, a mixture of compound B8-2 (9.60 g, 35.38 mmol) and palladium on carbon (0.96 g, 10 wt%) in methanol/tetrahydrofuran (30 mL/90 mL) was stirred at 25 °C for 16 hours. After the reaction was complete, the reaction mixture was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to give a gray solid compound B8-3 (7.30 g). LC-MS: [M+H] + = 274.0.

步骤3:1-(氰基甲基)-5-(四氢-2H-吡喃-4-基)-1H-吲哚-2-甲酸乙酯(B8-4)Step 3: Ethyl 1-(cyanomethyl)-5-(tetrahydro-2H-pyran-4-yl)-1H-indole-2-carboxylate (B8-4)

在0℃下，向化合物B8-3(9.00g,33.04mmol)的N,N-二甲基甲酰胺(180mL)溶液中加入氢化钠(2.00g,49.56mmol)，反应混合物于0℃搅拌0.5小时。随后，向上述反应液中加入氯乙腈(5.00g,66.08mmol)，反应混合物升温至75℃搅拌15小时。反应结束后，将体系降温，加水(200mL)淬灭，用乙酸乙酯(150mL×3)萃取。合并有机相，用饱和盐水(100mL)洗涤，无水硫酸钠干燥，过滤，浓缩，粗品用石油醚/乙酸乙酯(30mL/30mL)打浆1小时，过滤，干燥，得到白色固体化合物B8-4(8.30g,80％)。LC-MS:[M+H]+＝313.2。Sodium hydride (2.00 g, 49.56 mmol) was added to a solution of compound B8-3 (9.00 g, 33.04 mmol) in N,N-dimethylformamide (180 mL) at 0 °C, and the reaction mixture was stirred at 0 °C for 0.5 h. Subsequently, chloroacetonitrile (5.00 g, 66.08 mmol) was added to the above reaction solution, and the reaction mixture was heated to 75 °C and stirred for 15 h. After the reaction was completed, the system was cooled, quenched with water (200 mL), and extracted with ethyl acetate (150 mL × 3). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was slurried with petroleum ether/ethyl acetate (30 mL/30 mL) for 1 h, filtered, and dried to give compound B8-4 (8.30 g, 80%) as a white solid. LC-MS: [M+H] + = 313.2.

步骤4 1-[(1R,5S,6S)-3-[(叔丁氧基)羰基]-6-氰基-3-氮杂双环[3.1.0]己-6-基]-5-(氧杂环己烷-4-基)-1H-吲哚-2-甲酸乙酯(B8-6)Step 4: 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-cyano-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxacyclohexane-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B8-6)

在氮气气氛、0℃下，向化合物B8-4(5.00g,16.01mmol)和化合物B8-5(6.40g,24.01mmol)的四氢呋喃(50mL)溶液中，缓慢加入双(三甲基硅烷基)氨基钾的四氢呋喃溶液(1M,43.22mL,43.22mmol)，反应混合物于0℃搅拌0.5小时。反应结束后，加水(200mL)淬灭，用乙酸乙酯(50mL×3)萃取。合并有机相，饱和食盐水(30mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩。粗品经硅胶柱层析(石油醚/乙酸乙酯＝75/25)纯化，得到淡黄色固体化合物B8-6(2.60g,34％)。LC-MS:[M-H]-＝480.6。Under a nitrogen atmosphere and at 0°C, a tetrahydrofuran solution (1M, 43.22mL, 43.22mmol) of potassium bis(trimethylsilyl)aminoacetate was slowly added to a tetrahydrofuran solution (50mL) of compound B8-4 (5.00g, 16.01mmol) and compound B8-5 (6.40g, 24.01mmol). The reaction mixture was stirred at 0°C for 0.5 hours. After the reaction was complete, the mixture was quenched with water (200mL) and extracted with ethyl acetate (50mL × 3). The organic phases were combined, washed with saturated brine (30mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 75/25) to give a pale yellow solid compound B8-6 (2.60g, 34%). LC-MS: [MH] - = 480.6.

步骤5:1-[(1R,5S,6S)-3-[(叔丁氧基)羰基]-6-(1H-1,2,3,4-四唑-5-基)-3-氮杂双环[3.1.0]己-6-基]-5-(氧杂环己烷-4-基)-1H-吲哚-2-甲酸乙酯(B8-7)Step 5: 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxacyclohexane-4-yl)-1H-indole-2-carboxylic acid ethyl ester (B8-7)

在氮气气氛下，将化合物B8-6(500.0mg,1.04mmol)、三甲基硅烷基叠氮(5mL)和四丁基氟化铵(136.3mg,0.52mmol)的N,N-二甲基甲酰胺(2mL)混合物在120℃搅拌16小时。反应结束后，加入饱和氯化铵水溶液(5mL)淬灭，用乙酸乙酯(10mL×3)萃取。合并有机相，用饱和盐水(10mL×2)洗涤，减压浓缩，粗品经硅胶柱层析(二氯甲烷/甲醇＝99/1)纯化，得到黄色固体化合物B8-7(100.0mg,18％)。LC-MS:[M+H]+＝523.3.Under a nitrogen atmosphere, a mixture of compound B8-6 (500.0 mg, 1.04 mmol), trimethylsilyl azide (5 mL), and tetrabutylammonium fluoride (136.3 mg, 0.52 mmol) in N,N-dimethylformamide (2 mL) was stirred at 120 °C for 16 hours. After the reaction was complete, the mixture was quenched with saturated ammonium chloride aqueous solution (5 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were washed with saturated brine (10 mL × 2), concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol = 99/1) to give a yellow solid compound B8-7 (100.0 mg, 18%). LC-MS: [M+H] + = 523.3.

步骤6:1-[(1R,5S,6S)-3-[(叔丁氧基)羰基]-6-(1H-1,2,3,4-四唑-5-基)-3-氮杂双环[3.1.0]己-6-基]-5-(氧杂环己烷-4-基)-1H-吲哚-2-甲酸(B8)Step 6: 1-[(1R,5S,6S)-3-[(tert-butoxy)carbonyl]-6-(1H-1,2,3,4-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-6-yl]-5-(oxacyclohexane-4-yl)-1H-indole-2-carboxylic acid (B8)

向化合物B8-7(0.10g,0.19mmol)的四氢呋喃/乙醇/水(5mL/1mL/1mL)溶液中加入氢氧化锂单水合物(288.0mg,6.85mmol)，反应混合物升温至50℃搅拌3小时。反应结束后，将体系冷却至25℃，加入1M盐酸水溶液酸化至pH＝4，用乙酸乙酯(5mL×3)萃取。合并有机相，无水硫酸钠干燥，过滤，浓缩，得到灰白色固体化合物B8(100.0mg)。LC-MS:[M-H]-＝493.2。1H NMR(400MHz,DMSO-d6)δ7.85(t,J＝7.8Hz,1H),7.49(s,1H),7.40–7.33(m,1H),7.17(d,J＝7.5Hz,1H),3.98–3.93(m,2H),3.92–3.85(m,2H),3.57–3.41(m,4H),2.90–2.77(m,1H),2.76–2.64(m,2H),1.76–1.66(m,4H),1.24(d,J＝8.2Hz,9H)。Lithium hydroxide monohydrate (288.0 mg, 6.85 mmol) was added to a tetrahydrofuran/ethanol/water (5 mL/1 mL/1 mL) solution of compound B8-7 (0.10 g, 0.19 mmol). The reaction mixture was heated to 50 °C and stirred for 3 hours. After the reaction was complete, the system was cooled to 25 °C, acidified to pH 4 with 1 M hydrochloric acid aqueous solution, and extracted with ethyl acetate (5 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to give a grayish-white solid compound B8 (100.0 mg). LC-MS: [MH] - = 493.2. 1 H NMR (400MHz, DMSO-d6) δ7.85(t,J＝7.8Hz,1H),7.49(s,1H),7.40–7.33(m,1H),7.17(d,J＝7.5Hz,1H),3.98–3.93(m,2H) ,3.92–3.85(m,2H),3.57–3.41(m,4H),2.90–2.77(m,1H),2.76–2.64(m,2H),1.76–1.66(m,4H),1.24(d,J＝8.2Hz,9H).

参照以上步骤和专利WO2025026270中实施例的合成方法类似地合成了表3中所示的其它中间体B。Other intermediates B shown in Table 3 were synthesized similarly to the synthesis method in the embodiments of patent WO2025026270, following the steps above.

表3.中间体B


Table 3. Intermediate B


本发明的化合物的合成Synthesis of the compounds of the present invention

实施例1：3-((1S,2S)-1-(5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-2-((4S)-3-(3-(4-氟)-1-甲基-1H-吲唑-5-基)-2-氧代-2,3-二氢-1H-咪唑-1-基)-2-(4-氟-3,5-二甲基苯基)-4-甲基-4,5,6,7-四氢-3H-咪唑并[4,5-c]吡啶-5-羰基)-1H-吲哚-1-基)-2-甲基环丙基)-1,2,4-噁二唑-5(4H)-酮(1)
 Example 1 : 3-((1S,2S)-1-(5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-((4S)-3-(3-(4-fluoro)-1-methyl-1H-indazol-5-yl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl)-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridin-5-carbonyl)-1H-indol-1-yl)-2-methylcyclopropyl)-1,2,4-oxadiazol-5(4H)-one (1)

将化合物A1(280.0mg,0.572mmol)、5-((S)-2,2-二甲基四氢-2H-吡喃-4-基)-1-((1S,2S)-2-甲基-1-(5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)环丙基)-1H-吲哚-2-甲酸(B1,从皓元医药购买,1.05g,6.1mmol)、1-乙基-(3-二甲氨基丙基)碳二亚胺盐酸盐(120.3mg,0.630mmol)、1-羟基苯并三唑(85mg,0.630mmol)和二异丙基乙胺(147.7mg,1.14mmol)溶于N,N-二甲基甲酰胺(2mL)中，在20-25℃反应4小时。反应结束后经反相柱层析纯化(0.1％甲酸水溶液/乙腈,5％-60％)，冷冻干燥后得到白色固体1(250mg,49.5％)。ESI-MS(m/z):[M+H]+＝883.4。Compound A1 (280.0 mg, 0.572 mmol), 5-((S)-2,2-dimethyltetrahydro-2H-pyran-4-yl)-1-((1S,2S)-2-methyl-1-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopropyl)-1H-indole-2-carboxylic acid (B1, purchased from Haoyuan Pharmaceutical, 1.05 g, 6.1 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (120.3 mg, 0.630 mmol), 1-hydroxybenzotriazole (85 mg, 0.630 mmol), and diisopropylethylamine (147.7 mg, 1.14 mmol) were dissolved in N,N-dimethylformamide (2 mL) and reacted at 20-25 °C for 4 hours. After the reaction was completed, the sample was purified by reversed-phase column chromatography (0.1% formic acid aqueous solution/acetonitrile, 5%-60%), and then freeze-dried to give a white solid 1 (250 mg, 49.5%). ESI-MS (m/z): [M+H] + = 883.4.

类似于实施例1的方法，采用适当的中间体(来自表2的中间体A系列和来自表3的中间体B系列)，合成了如下所示的实施例化合物。Similar to the method of Example 1, the compounds of the examples shown below were synthesized using appropriate intermediates (intermediate series A from Table 2 and intermediate series B from Table 3).

表4.实施例的化合物



















Table 4. Compounds from the Examples



















生物学试验Biological experiments

如无特别说明，以下生物学实施例中所用的实验材料、试剂、操作和方法均可从市售渠道获得或基于现有技术容易地获知或制备。待测化合物指本发明中表4的实施例化合物和对照化合物。Unless otherwise specified, the experimental materials, reagents, operations, and methods used in the following biological examples are all available from commercial sources or readily known or prepared based on existing technology. The test compounds refer to the example compounds and control compounds in Table 4 of this invention.

实施例A：化合物体外cAMP信号活化的测量Example A: Measurement of in vitro cAMP signal activation by a compound

根据制造商说明，使用稳定表达人GLP-1R的CHO-K1细胞系(DiscoverX，Cat#95-0062C2)和Hithunter cAMP Assay试剂盒(DiscoverX，Cat#90-0075SM2)检测cAMP水平。将细胞重悬于含10％FBS(胎牛血清,Hyclone Cat#SH30406.05)和800μg/ml G418(Gibco,Cat#10131-027)的F12(Gibco，Cat#11765-054)培养基中，并以2.5×104每孔的密度接种在96孔白板(上海卧宏,Cat#WHB-96-03)中，置于37℃,5％ CO2恒温培养箱培养过夜。使用含有1％ BSA(牛血清白蛋白，Sigma Cat#V900933-100G)的PBS(磷酸盐缓冲液，BBI,Cat#E607008-0500)以3倍梯度稀释化合物或GLP-1肽后处理细胞，37℃孵育30分钟或120分钟后，加入cAMP抗体试剂、工作溶液(混合19份裂解缓冲液、5份底物试剂1、1份底物试剂2、以及25份溶液D(酶供体标记的cAMP)和溶液A(酶受体))后室温避光孵育。使用Spectramax id5多模式检测系统(Molecular Devices,USA)检测光信号数值，并使用GraphPad Prism 9软件拟合计算出相应EC50值。According to the manufacturer's instructions, cAMP levels were detected using a stable human GLP-1R-expressing CHO-K1 cell line (DiscoverX, Cat#95-0062C2) and the Hithunter cAMP Assay kit (DiscoverX, Cat#90-0075SM2). Cells were resuspended in F12 (Gibco, Cat#11765-054) medium containing 10% FBS (fetal bovine serum, Hyclone Cat#SH30406.05) and 800 μg/ml G418 (Gibco, Cat#10131-027), and seeded at a density of 2.5 × 10⁴ cells per well in 96-well white plates (Shanghai Wohong, Cat#WHB-96-03) and incubated overnight at 37°C in a 5% CO₂ incubator. Cells were treated with PBS (phosphate-buffered saline, BBI, Cat#E607008-0500) containing 1% BSA (bovine serum albumin, Sigma Cat#V900933-100G) at a 3-fold serial dilution with either the compound or the GLP-1 peptide. After incubation at 37°C for 30 or 120 minutes, cAMP antibody reagent and working solution (a mixture of 19 parts lysis buffer, 5 parts substrate reagent 1, 1 part substrate reagent 2, and 25 parts solution D (enzyme donor-labeled cAMP) and solution A (enzyme acceptor)) were added, followed by incubation at room temperature in the dark. Optical signal values were detected using a Spectramax id5 multimodal detection system (Molecular Devices, USA), and the corresponding EC50 values were calculated using GraphPad Prism 9 software.

本发明的化合物呈现出有效的h-GLP-1激动活性。其中，化合物刺激hGLP-1R的CHO-K1细胞系0.5小时产生的cAMP的实验中，结果如表5所示生成的cAMP的EC50；化合物刺激hGLP-1R的CHO-K1细胞系2小时产生的cAMP的实验中，结果如表6所示生成的cAMP的EC50。The compounds of this invention exhibit potent h-GLP-1 agonist activity. Specifically, in the experiment stimulating cAMP production in the CHO-K1 cell line with hGLP-1R for 0.5 hours, the EC50 of the generated cAMP is shown in Table 5; in the experiment stimulating cAMP production in the CHO-K1 cell line with hGLP-1R for 2 hours, the EC50 of the generated cAMP is shown in Table 6.

表5.化合物刺激CHO-K1细胞系0.5小时产生的cAMP的EC50


注：检测限为100nM。Table 5. EC50 of cAMP produced in CHO-K1 cell lines after 0.5 hours of compound stimulation.


Note: The detection limit is 100 nM.

表6.化合物刺激CHO-K1细胞系2小时产生的cAMP的EC50
Table 6. EC50 of cAMP produced in CHO-K1 cell lines 2 hours after compound stimulation

实施例B:化合物在小鼠血浆药代动力学分析Example B: Pharmacokinetic Analysis of Compounds in Mouse Plasma

雄性C57BL/6J小鼠，灌胃口服或静脉注射，分别3只小鼠/化合物，动物来自上海美迪西生物医药股份有限公司。以标准方案测试实施例化合物灌胃口服(PO)或静脉注射(IV)后小鼠药代特征，IV和PO溶媒：5％(v/v)DMSO+5％(v/v)Solutol+90％(v/v)生理盐水。待测化合物配成母液，分别给予3只小鼠单次灌胃口服(2mg/kg)或静脉注射(1mg/kg)，按照给药后0.083、0.25、0.5、1、2、4、8、24小时为时间点，经颈静脉或其他合适静脉采血，0.03mL/时间点，K2-EDTA抗凝，采集后放置冰上。血液样本采集后1h内离心得血浆(离心条件：6800g,6分钟,2-8℃)，待测样品在分析前存放于-80℃冰箱内。Male C57BL/6J mice were administered the compound orally via gavage or intravenously, with 3 mice per compound. Animals were sourced from Shanghai Medicilon Biopharmaceutical Co., Ltd. Pharmacokinetic characteristics of the compound after oral (PO) or intravenous (IV) administration were tested using a standard protocol. The IV and PO solvents were 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline. A stock solution of the test compound was prepared and administered to 3 mice via single oral (2 mg/kg) gavage or intravenous (1 mg/kg) administration. Blood was collected via jugular vein or other suitable vein at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration, at a rate of 0.03 mL per time point, anticoagulated with K2-EDTA, and placed on ice after collection. Plasma was obtained by centrifugation within 1 hour of blood collection (centrifugation conditions: 6800g, 6 minutes, 2-8℃). The test samples were stored at -80℃ before analysis.

随后以LC-MS/MS方法分析本发明化合物的血药浓度，运用Phoenix WinNonlin7.0计算药代动力学参数。表7显示了实施例1的化合物的结果。The plasma concentrations of the compounds of this invention were then analyzed by LC-MS/MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. Table 7 shows the results for the compounds of Example 1.

实施例C:化合物在大鼠血浆药代动力学分析Example C: Pharmacokinetic Analysis of Compounds in Rat Plasma

雄性SD大鼠，灌胃口服或静脉注射，分别3只大鼠/化合物，动物来自上海美迪西生物医药股份有限公司。以标准方案测试实施例化合物灌胃口服(PO)或静脉注射(IV)后大鼠药代特征。IV和PO溶媒：5％(v/v)DMSO+5％(v/v)Solutol+90％(v/v)生理盐水。待测化合物配成母液，分别给予3只小鼠单次灌胃口服(2mg/kg)，按照给药后0.25、0.5、1、2、4、6、8、24小时为时间点取血；分别给予3只小鼠单次静脉注射(1mg/kg)，按照给药后0.083、0.25、0.5、1、2、4、8、24小时为时间点取血。取血方式为经颈静脉或其他合适静脉采血，0.2mL/时间点，K2-EDTA抗凝，采集后放置冰上。血液样本采集后1h内离心得血浆(离心条件：6800g,6分钟,2-8℃)，待测样品在分析前存放于-80℃冰箱内。Male SD rats were administered the compound orally via gavage or intravenously, with 3 rats per compound. Animals were obtained from Shanghai Medicilon Biopharmaceutical Co., Ltd. The pharmacokinetic characteristics of the compound administered orally (PO) or intravenously (IV) in rats were tested using a standard protocol. The IV and PO solvents were 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline. A stock solution of the test compound was prepared and administered orally (2 mg/kg) to 3 mice via gavage at time points of 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours post-administration. Alternatively, 3 mice were administered a single intravenous injection (1 mg/kg) at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours post-administration. Blood was collected via the jugular vein or other suitable vein, 0.2 mL per time point, anticoagulated with K2-EDTA, and placed on ice after collection. Blood samples were centrifuged within 1 hour after collection to obtain plasma (centrifugation conditions: 6800g, 6 minutes, 2-8℃). The samples to be tested were stored in a -80℃ refrigerator before analysis.

随后以LC-MS/MS方法分析本发明化合物的血药浓度，运用Phoenix WinNonlin7.0计算药代动力学参数。表7显示了实施例1的化合物的结果。The plasma concentrations of the compounds of this invention were then analyzed by LC-MS/MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. Table 7 shows the results for the compounds of Example 1.

实施例D:化合物在比格犬血浆药代动力学分析Example D: Pharmacokinetic Analysis of Compounds in Beagle Dog Plasma

雄性比格犬，灌胃口服或静脉注射，分别3只比格犬/化合物，动物来自上海美迪西生物医药股份有限公司。以标准方案测试实施例化合物灌胃口服(PO)或静脉注射(IV)后比格犬药代特征。IV和PO溶媒：5％(v/v)DMSO+5％(v/v)Solutol+90％(v/v)生理盐水。待测化合物配成母液后，分别给予3只比格犬单次灌胃口服(2mg/kg)，按照给药后0.25、0.5、1、2、4、6、8、12、24小时为时间点取血；分别给予3只比格犬单次静脉注射(0.5mg/kg)，按照给药后0.083、0.25、0.5、1、2、4、8、12、24小时为时间点取血，取血方式为经前肢静脉或其他合适静脉采血，1mL/时间点，K2-EDTA抗凝，采集后放置冰上，血液样本采集后1h内离心得血浆(离心条件：2200g,10分钟,2-8℃)，待测样本在分析前存放于-80℃冰箱内。Three male beagles were administered the compound via oral gavage or intravenous injection, respectively, at a rate of 3 dogs per compound. Animals were sourced from Shanghai Medicilon Biopharmaceutical Co., Ltd. The pharmacokinetic characteristics of the compound in the examples were tested in beagles following oral gavage (PO) or intravenous injection (IV) according to a standard protocol. The solvents for IV and PO were: 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline. After preparing the test compound into a stock solution, three beagle dogs were given a single oral gavage (2 mg/kg) and blood samples were collected at time points of 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration. Three beagle dogs were also given a single intravenous injection (0.5 mg/kg) and blood samples were collected at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. Blood was collected via forelimb vein or other suitable vein, 1 mL/time point, anticoagulated with K2-EDTA. After collection, the samples were placed on ice. Plasma was obtained by centrifugation within 1 hour of collection (centrifugation conditions: 2200g, 10 minutes, 2-8℃). The test samples were stored at -80℃ before analysis.

随后以LC-MS/MS方法分析本发明化合物的血药浓度，运用Phoenix WinNonlin7.0计算药代动力学参数。表7显示了实施例1的化合物的结果。The plasma concentrations of the compounds of this invention were then analyzed by LC-MS/MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. Table 7 shows the results for the compounds of Example 1.

实施例E:化合物在食蟹猴血浆药代动力学分析Example E: Pharmacokinetic Analysis of Compounds in Cynomolgus Monkey Plasma

雄性食蟹猴，灌胃口服或静脉注射，分别3只食蟹猴/化合物，动物来自上海美迪西生物医药股份有限公司。以标准方案测试实施例化合物灌胃口服(PO)或静脉注射(IV)后食蟹猴药代特征。IV溶媒：5％(v/v)DMSO+5％(v/v)Solutol+90％(v/v)生理盐水，PO溶媒：0.5％CMC-Na，黏度800-1200mPa·s。待测化合物配完母液后，分别给予3只食蟹猴单次灌胃口服(2mg/kg)，按照给药后0.25、0.5、1、2、4、6、8、12、24小时为时间点取血；分别给予3只食蟹猴单次静脉注射(0.5mg/kg)，按照给药后0.083、0.25、0.5、1、2、4、8、12、24小时为时间点取血。取血方式为经前肢静脉或其他合适静脉采血，1mL/时间点，K2-EDTA抗凝，采集后放置冰上，血液样本采集后1h内离心得血浆(离心条件：2200g,10分钟,2-8℃)，待测样本在分析前存放于-80℃冰箱内。Male cynomolgus monkeys were administered the compound orally via gavage or intravenously, with three monkeys per compound. Animals were sourced from Shanghai Medicilon Biopharmaceutical Co., Ltd. The pharmacokinetic characteristics of the compound after oral gavage (PO) or intravenous injection (IV) were tested using a standard protocol. IV solvent: 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline; PO solvent: 0.5% CMC-Na, viscosity 800-1200 mPa·s. After preparing the stock solution of the test compound, three cynomolgus monkeys were administered a single oral gavage (2 mg/kg), with blood samples collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-administration. Three cynomolgus monkeys were also administered a single intravenous injection (0.5 mg/kg), with blood samples collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours post-administration. Blood was collected via the forelimb vein or other suitable vein, 1 mL/time point, anticoagulated with K2-EDTA. After collection, the blood samples were placed on ice and centrifuged within 1 hour to obtain plasma (centrifugation conditions: 2200g, 10 minutes, 2-8℃). The samples to be tested were stored in a -80℃ refrigerator before analysis.

随后以LC-MS/MS方法分析本发明化合物的血药浓度，运用Phoenix WinNonlin7.0计算药代动力学参数。表7显示了实施例1的化合物的结果。The plasma concentrations of the compounds of this invention were then analyzed by LC-MS/MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. Table 7 shows the results for the compounds of Example 1.

表7.实施例化合物1在不同种属的血浆药物动力学分析


注：Vd-表观分布容积；Cl-清除率；F-生物利用度(AUCPO/AUCIV)Table 7. Plasma pharmacokinetic analysis of Compound 1 in different species


Note: Vd - apparent volume of distribution; Cl - clearance rate; F - bioavailability (AUC PO / AUC IV )

实验结果表明，实施例1的化合物表现出良好的药代动力学性质。Experimental results show that the compound in Example 1 exhibits good pharmacokinetic properties.

实施例F：实施例化合物在小鼠血浆药代动力学分析Example F: Pharmacokinetic Analysis of the Compounds in Example Example in Mouse Plasma

雄性C57BL/6J小鼠，灌胃口服或静脉注射，分别3只小鼠/化合物，动物来自上海美迪西生物医药股份有限公司。以标准方案测试实施例化合物灌胃口服(PO)或静脉注射(IV)后小鼠药代特征，IV溶媒：5％(v/v)DMSO+5％(v/v)Solutol+90％(v/v)生理盐水，PO溶媒：10％ PEG400+10％丙二醇(PG)+80％甘氨酸缓冲液(100mM甘氨酸,64mM NaOH,pH 10。待测化合物配成母液后，分别给予3只小鼠单次灌胃口服(2mg/kg)或静脉注射(0.5mg/kg)，按照给药后0.083、0.25、0.5、1、2、4、8、24小时为时间点，经颈静脉或其他合适静脉采血，0.03mL/时间点，K2-EDTA抗凝，采集后放置冰上。血液样本采集后1h内离心得血浆(离心条件：6800g,6分钟,2-8℃)，待测样品在分析前存放于-80℃冰箱内。Male C57BL/6J mice were administered the compound orally via gavage or intravenously, with 3 mice per compound per dose. Animals were sourced from Shanghai Medicilon Biopharmaceutical Co., Ltd. The pharmacokinetic characteristics of the compound after oral (PO) or intravenous (IV) administration were tested using a standard protocol. IV solvent: 5% (v/v) DMSO + 5% (v/v) Solutol + 90% (v/v) physiological saline; PO solvent: 10% PEG400 + 10% propylene glycol (PG) + 80% glycine buffer (100mM glycine, 64mM NaOH, pH 10). After preparing a stock solution of the test compound, each mouse was administered the compound individually. Administer orally (2 mg/kg) orally or intravenously (0.5 mg/kg) once, with blood samples collected via the jugular vein or other suitable vein at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration, at a rate of 0.03 mL/time point. Anticoagulate with K2-EDTA and place on ice after collection. Centrifuge within 1 hour of blood sample collection to obtain plasma (centrifugation conditions: 6800g, 6 minutes, 2-8℃). Store the sample to be analyzed at -80℃ before analysis.

随后以LC-MS/MS方法分析本发明化合物的血药浓度，运用Phoenix WinNonlin7.0计算药代动力学参数。结果见表8。The plasma concentrations of the compounds of this invention were then analyzed by LC-MS/MS, and pharmacokinetic parameters were calculated using Phoenix WinNonlin 7.0. The results are shown in Table 8.

表8.实施例化合物在小鼠血浆药物动力学分析

注：Vd-表观分布容积；Cl-清除率；F-生物利用度(AUCPO/AUCIV)Table 8. Pharmacokinetic analysis of the compounds in the examples in mouse plasma.

Note: Vd - apparent volume of distribution; Cl - clearance rate; F - bioavailability (AUC PO / AUC IV )

实验结果表明，本发明实施例化合物表现出良好的药代动力学性质。Experimental results show that the compounds in the embodiments of the present invention exhibit good pharmacokinetic properties.

实施例G：小鼠单次OGTT实验Example G: Single OGTT Experiment in Mice

OGTT实验是口服葡萄糖耐量实验，可以用于测试血糖在体内的代谢水平，筛选降糖药物。The OGTT test, or oral glucose tolerance test, can be used to test the metabolic level of blood glucose in the body and to screen for hypoglycemic drugs.

将雄性hGLP1R小鼠随机分组，每组5只，分别为：溶媒(Vehicle)组(10mL/kg,溶媒为10％ PEG400+10％ PG+80％甘氨酸缓冲液(100mM甘氨酸,64mM NaOH,pH 10))、给药组(0.03mg/kg或0.1mg/kg，在溶媒中)、Orforglipron组(0.03mg/kg，在溶媒中)(阳性对照)。处置前一天将小鼠禁食过夜，禁食期间提供充足饮水。处置当天电子天平称量小鼠体重，0h时先测量血糖，然后根据体重灌胃处置(溶媒、实施例化合物或Orforglipron)，灌胃体积为10mL/kg；5h时测量血糖后，立刻根据体重给予20％葡萄糖水溶液灌胃，灌胃体积为10mL/kg。在给予葡萄糖后15、30、60、120min测量血糖并记录。实验结束恢复动物喂食。使用GraphPad Prism 10.2.1绘制血糖随时间变化曲线并计算0-120min血糖-时间曲线下面积，结果见图1和表9。Male hGLP1R mice were randomly divided into five groups: a vehicle group (10 mL/kg, solvent: 10% PEG400 + 10% PG + 80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10)), a drug administration group (0.03 mg/kg or 0.1 mg/kg in the vehicle), and an Orforglipron group (0.03 mg/kg in the vehicle) (positive control). Mice were fasted overnight the day before treatment, but provided with ample water during the fasting period. On the day of treatment, mice were weighed using an electronic balance. Blood glucose was measured at 0 h, followed by gavage administration of the treatment (vehicle, the compound described in the examples, or Orforglipron) at a volume of 10 mL/kg, based on body weight. Blood glucose was measured at 5 h, and immediately followed by gavage administration of a 20% glucose solution at a volume of 10 mL/kg, based on body weight. Blood glucose levels were measured and recorded at 15, 30, 60, and 120 min after glucose administration. Animals were fed again after the experiment. GraphPad Prism 10.2.1 was used to plot blood glucose changes over time and the area under the blood glucose-time curve from 0 to 120 min was calculated. The results are shown in Figure 1 and Table 9.

表9.实施例化合物给药(0.03mg/kg)后5h OGTT实验血糖-时间曲线下面积与溶媒组相比的差异

注：括号内为当次orforglipron给药5h后血糖-时间曲线下面积Table 9. Difference between the area under the blood glucose-time curve and the solvent group 5 h after administration of the compound in the examples (0.03 mg/kg) for OGTT.

Note: The value in parentheses represents the area under the blood glucose-time curve 5 hours after the current orforglipron administration.

实施例H.小鼠多次OGTT实验Example H. Multiple OGTT experiments in mice

将雄性hGLP1R小鼠随机分组，每组5只，分别为：溶媒(Vehicle)组(10mL/kg,溶媒为10％ PEG400+10％ PG+80％甘氨酸缓冲液(100mM甘氨酸,64mM NaOH,pH 10))、给药组(0.03mg/kg或0.1mg/kg，在溶媒中)、Orforglipron组(0.03mg/kg，在溶媒中)(阳性对照)。处置前一天将小鼠禁食过夜，禁食期间提供充足饮水。处置当天电子天平称量小鼠体重，0h时先测量血糖，然后根据体重灌胃处置(溶媒、实施例化合物或Orforglipron)，灌胃体积为10mL/kg；5h时测量血糖后，立刻根据体重给予20％葡萄糖水溶液灌胃，灌胃体积为10mL/kg。在给予葡萄糖后15、30、60、120min测量血糖并记录。实验结束恢复动物喂食。再次OGTT实验前一天将小鼠禁食过夜，禁食期间提供充足饮水。处置后48h或96h时再次测量血糖，立即根据体重给予20％葡萄糖水溶液灌胃，灌胃体积为10mL/kg，测量葡萄糖灌胃后15min、30min、60min、120min的血糖。使用GraphPad Prism 10.2.1绘制血糖随时间变化曲线并计算0-120min血糖-时间曲线下面积，结果见图2.1和图2.2。Male hGLP1R mice were randomly divided into five groups: a vehicle group (10 mL/kg, solvent: 10% PEG400 + 10% PG + 80% glycine buffer (100 mM glycine, 64 mM NaOH, pH 10)), a drug administration group (0.03 mg/kg or 0.1 mg/kg in the vehicle), and an Orforglipron group (0.03 mg/kg in the vehicle) (positive control). Mice were fasted overnight the day before treatment, but provided with ample water during the fasting period. On the day of treatment, mice were weighed using an electronic balance. Blood glucose was measured at 0 h, followed by gavage administration of the treatment (vehicle, the compound described in the examples, or Orforglipron) at a volume of 10 mL/kg, based on body weight. Blood glucose was measured at 5 h, and immediately followed by gavage administration of a 20% glucose solution at a volume of 10 mL/kg, based on body weight. Blood glucose levels were measured and recorded at 15, 30, 60, and 120 min after glucose administration. After the experiment, the animals were fed again. Mice were fasted overnight the day before the next OGTT experiment, with ample water provided during the fasting period. Blood glucose was measured again at 48 or 96 hours post-treatment. Immediately after treatment, mice were administered a 20% glucose solution via gavage at a volume of 10 mL/kg. Blood glucose levels were measured at 15, 30, 60, and 120 minutes post-glucose gavage. GraphPad Prism 10.2.1 was used to plot blood glucose versus time curves, and the area under the blood glucose-time curve from 0 to 120 minutes was calculated. The results are shown in Figures 2.1 and 2.2.

如图2.1所示，与Vehicle组相比，在给药后5h，实施例化合物18(Example 18),0.03mg/kg组、实施例化合物22(Example 22),0.03mg/kg组、实施例化合物23(Example 23),0.03mg/kg组、Orforglipron,0.03mg/kg组小鼠血糖AUC分别下降了49.63％、46.20％、42.61％、45.22％。同剂量的实施例化合物18，降糖效果略好于Orforglipron，同剂量的实施例化合物22和实施例化合物23降糖效果与Orforglipron相当。在给药后48h，实施例化合物18,0.03mg/kg组、实施例化合物22,0.03mg/kg组、实施例化合物23,0.03mg/kg组、Orforglipron,0.03mg/kg组小鼠血糖AUC分别下降了31.05％、28.08％、5.91％、19.50％。同剂量的实施例化合物18和实施例化合物22降糖效果好于Orforglipron，显示了持久的降糖效果。As shown in Figure 2.1, compared with the Vehicle group, at 5 h after administration, the blood glucose AUC of mice in the following groups decreased by 49.63%, 46.20%, 42.61%, and 45.22%, respectively, in the groups treated with Compound 18 (0.03 mg/kg), Compound 22 (0.03 mg/kg), Compound 23 (0.03 mg/kg), and Orforglipron (0.03 mg/kg). Compound 18 at the same dose showed a slightly better hypoglycemic effect than Orforglipron, while Compound 22 and Compound 23 at the same dose showed hypoglycemic effects comparable to Orforglipron. At 48 hours post-administration, the AUC of blood glucose in mice treated with Compound 18 (0.03 mg/kg), Compound 22 (0.03 mg/kg), Compound 23 (0.03 mg/kg), and Orforglipron (0.03 mg/kg) decreased by 31.05%, 28.08%, 5.91%, and 19.50%, respectively. Compounds 18 and 22 at the same dose showed better hypoglycemic effects than Orforglipron, demonstrating a sustained hypoglycemic effect.

如图2.2所示，与Vehicle组相比，在给药后5h，实施例化合物24(Example 24,0.03mg/kg组、实施例化合物52(Example 52),0.03mg/kg组、Orforglipron,0.03mg/kg组小鼠血糖AUC分别下降了34.93％、29.91％、39.37％，实施例化合物24和实施例化合物52在给药后5h降糖效果与Orforglipron相当。在给药后96h，实施例化合物24,0.03mg/kg组、实施例化合物52,0.03mg/kg组、Orforglipron,0.03mg/kg组小鼠血糖AUC分别下降了23.86％、27.40％、14.38％，实施例化合物24和实施例化合物52降糖效果好于Orforglipron，显示了本发明化合物降糖的长效性。As shown in Figure 2.2, compared with the Vehicle group, at 5 h post-administration, the blood glucose AUC of mice in the Compound 24 (0.03 mg/kg), Compound 52 (0.03 mg/kg), and Orforglipron (0.03 mg/kg) groups decreased by 34.93%, 29.91%, and 39.37%, respectively. The hypoglycemic effects of Compound 24 and Compound 52 at 5 h post-administration were comparable to those of Orforglipron. At 96 h post-administration, the blood glucose AUC of mice in the Compound 24 (0.03 mg/kg), Compound 52 (0.03 mg/kg), and Orforglipron (0.03 mg/kg) groups decreased by 23.86%, 27.40%, and 14.38%, respectively. The hypoglycemic effects of Compound 24 and Compound 52 were better than those of Orforglipron, demonstrating the long-lasting hypoglycemic effect of the compounds of the present invention.

实施例I.小鼠DIO模型减重实验Example I. Weight Loss Experiment in a Mouse DIO Model

用高脂饲料(D12492)喂养雄性hGLP1R小鼠，当小鼠体重均值达51g时开始试验。分组前测量小鼠体重基线并根据体重分为五组，分别为：溶媒(Vehicle)组(溶媒为10％ PEG400+10％ PG+80％甘氨酸缓冲液(100mM甘氨酸,64mM NaOH,pH 10))、实施例化合物1(Example 1,1mg/kg组、实施例化合物1,5mg/kg组、Orforglipron,1mg/kg组、Orforglipron,5mg/kg组。每天监测小鼠体重和摄食，施用方式为灌胃，施用体积为10mL/kg，每天施用两次，共31天，小鼠体重及摄食量的结果见图3.1和图3.2。末次施用后伴随PK采血，采集时间点为末次施用后0.25h、1h、2h、4h、8h、10h，结果见图3.3和表10。Male hGLP1R mice were fed a high-fat diet (D12492) and the experiment began when the average weight of the mice reached 51g. Before grouping, mouse baseline body weight was measured and mice were divided into five groups based on body weight: Vehicle group (solvent: 10% PEG400 + 10% PG + 80% glycine buffer (100mM glycine, 64mM NaOH, pH 10)), Example Compound 1 (Example 1, 1 mg/kg group, Example Compound 1, 5 mg/kg group, Orforglipron, 1 mg/kg group, Orforglipron, 5 mg/kg group). Mouse body weight and food intake were monitored daily. Administration was via gavage at a volume of 10 mL/kg, twice daily for 31 days. Mouse body weight and food intake results are shown in Figures 3.1 and 3.2. Blood samples were collected from mice after the last administration at 0.25 h, 1 h, 2 h, 4 h, 8 h, and 10 h post-administration. Results are shown in Figure 3.3 and Table 10.

表10.末次PK参数表
Table 10. Parameters of the Last PK Test

试验结果显示同剂量的实施例化合物1比Orforglipron具有更强的抑制食欲和减轻体重药效。The test results showed that, at the same dosage, compound 1 of the example had a stronger appetite-suppressing and weight-reducing effect than Orforglipron.

如图3.1所示，与Vehicle组相比，实施例化合物1,1mg/kg组、实施例化合物1,5mg/kg组、Orforglipron,1mg/kg组、Orforglipron,5mg/kg组小鼠体重分别下降了10.64％、16.69％、9.27％、10.31％，化合物实施例1显示出优于Orforglipron的减重药效并呈现出良好的剂量关系。As shown in Figure 3.1, compared with the Vehicle group, the body weight of mice in the Compound 1 (1 mg/kg), Compound 1 (5 mg/kg), Orforglipron (1 mg/kg), and Orforglipron (5 mg/kg) groups decreased by 10.64%, 16.69%, 9.27%, and 10.31%, respectively. Compound 1 showed superior weight-loss efficacy compared with Orforglipron and exhibited a good dose-response relationship.

如图3.2所示，与Vehicle组相比，实施例化合物1,1mg/kg组、实施例化合物1,5mg/kg组、Orforglipron,1mg/kg组、Orforglipron,5mg/kg组累计摄食量分别降低了16.97％、24.86％、8.32％、14.51％，化合物实施例1显示出远优于Orforglipron的食欲抑制。As shown in Figure 3.2, compared with the Vehicle group, the cumulative food intake of the Compound 1 group (1 mg/kg), Compound 1 group (5 mg/kg), Orforglipron group (1 mg/kg), and Orforglipron group (5 mg/kg) decreased by 16.97%, 24.86%, 8.32%, and 14.51%, respectively. Compound 1 showed a much better appetite suppression effect than Orforglipron.

如图3.3和表10所示，实施例化合物1,1mg/kg组、实施例化合物1,5mg/kg组的Cmax和AUC(last)都与同剂量的Orforglipron相当，表明在同剂量且末次PK暴露量基本相当的情况下，实施例化合物1比Orforglipron具有更强的抑制食欲和减轻体重药效。As shown in Figure 3.3 and Table 10, the Cmax and AUC (last) of Compound 1 in the 1 mg/kg group and Compound 1 in the 5 mg/kg group were comparable to those of Orforglipron at the same dose, indicating that Compound 1 of the example has a stronger appetite suppressant and weight-reducing effect than Orforglipron at the same dose and with essentially the same last PK exposure.

以上小鼠OGTT和DIO模型减重实验表明，本发明实施例的化合物由于创造性的设计母核结构，在体内药效中显示出更持久的降糖效果、更强的食欲抑制以及更显著的减重药效。The above mouse OGTT and DIO model weight loss experiments show that, due to the innovative design of the parent nucleus structure, the compounds in the embodiments of the present invention exhibit a more sustained hypoglycemic effect, stronger appetite suppression, and more significant weight loss effect in vivo.

通过引用将本发明中所提及的所有参考文献均完整合并入本文，就如同每一篇文献均单独列出一样。应理解，在阅读了本发明的公开内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落入本申请所附权利要求书所限定的范围内。All references mentioned in this invention are incorporated herein by reference in their entirety, as if each reference were listed separately. It should be understood that, after reading this disclosure, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims (33)

式(I)化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，
Compound of formula (I) or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound or solvate,
其中，in, L1选自-CO-、-SO-、-SO2-、-NRa-和-CRaRb-； L1 is selected from -CO-, -SO-, -SO2- , -NRa- , and -CRaRb- ; L2选自-RL-NRa-*、-RL-CO-NRa-*、-RL-NRa-CO-NRa-*、-RL-C(S)-NRa-*、-RL-NRa-C(S)-NRa-*，其中星号表示与中心环的N原子连接； L2 is selected from -R L -NR a -*, -R L -CO-NR a -*, -R L -NR a -CO-NR a -*, -R L -C(S)-NR a -*, -R L -NR a -C(S)-NR a -*, where the asterisk indicates a connection to the N atom of the central ring; 环A是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、和(任选被一个或多个独立地选自卤素和C1-6烷基取代的C3-10环烷基)-RL-，或者其中两个R3连同它们所连接的原子一起形成任选地含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基和C1-6羟基烷基的取代基取代；Ring A is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted with one or more R3s , each R3 independently selected from halogens, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyls independently selected from halogens and C1-6 alkyls) -RL- , or two of the R3s. 3 together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, said 4- to 6-membered ring optionally substituted with one or more substituents independently selected from halogen, cyano, hydroxy, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl; 环B是亚萘基或8-10元双环亚杂芳基，各自任选被一个或多个R4取代，所述R4各自独立地选自卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C3-10环烷基)-RL-、(5-10元杂环烷基)-RL-、(C6-10芳基)-RL-和(5-10元杂芳基)-RL-，其中所述环烷基、杂环烷基、芳基和杂芳基各自任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代；Cycle B is a naphthylene or an 8-10-membered bicyclic heteroarylene, each optionally substituted by one or more R4 groups, each R4 group being independently selected from halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , (5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein each of the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups is optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy groups; 环C是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基，各自任选被一个或多个取代基取代；任选地，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(C6-10芳基)-RL-、(5-10元杂芳基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代；The ring C is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl, each optionally substituted by one or more substituents; optionally, each substituent is independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylene group, C1-6 haloalkylene group, COOH, C1-6 alkoxy-CO-, ( C1-6 haloalkoxy) -RL- - (optionally substituted with a halogen or hydroxyl group) -RL- , ( C3-10 cycloalkyl)-C2-4-eneyl-, ( C3-10 cycloalkyl) -C2-4 -ynylene-, ( C3-10 cycloalkyloxy)-RL-, ( 3-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , ( 5-10 heteroaryl)-RL-, NRsRt- ( CRaRb ) m- , NRaRb - CO- and R6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted with one or more of an oxo group, halogen , cyano group, C1-6 alkyl group, C1-6 haloalkyl group, C3-10 cycloalkyl group, 3-10 heterocyclic alkyl group, C Substituent substitution of 6-10 aryl and 5-7 heteroaryl groups; 环D是C3-10环烷基、C3-10环烯基、3-10元杂环烷基、3-10元杂环烯基、C6-10芳基或5-10元杂芳基；Ring D is a C3-10 cycloalkyl, C3-10 cycloalkenyl, 3-10 heterocyclic alkyl, 3-10 heterocyclic alkenyl, C6-10 aryl, or 5-10 heteroaryl. R1各自独立地是H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C2-6烯基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms they are attached to form a C3-4 cycloalkyl group. R2各自独立地选自H、卤素、氰基、OH、NRaRb、C1-6烷基、C2-6烯基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6卤代烷氧基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者其中两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2 is independently selected from H, halogen, cyano, OH, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 (C1-6 alkyl), -NR a -S(O) 2- (C1-6 alkyl ), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a )-(C 3-10 cycloalkyl) or -C(=O)-N( Ra )-(C 3-10 cycloalkyl), or where the two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C1-6 alkoxy )-RL-, ( C1-6 alkylthio)-RL-, (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkoxy ) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl or C1-6 alkyl)-RL-, ( C6-10 aryl) -RL- and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic or bridged ring; R6是含有一个或多个独立地选自N、O或S的杂原子的5-6元部分不饱和或芳族杂环； R6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S; Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present; Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl; Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或5-10元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, C <sub>1-6 </sub> haloalkyl, C <sub>6-10 </sub> aryl, or 5-10 heteroaryl; RL各自独立地是价键；任选被卤素、氰基或羟基取代的C1-10亚烷基；或C1-4氘代亚烷基；R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups; T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms; Q为O或S；Q is either O or S; m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5; n是0、1或2；和n is 0, 1, or 2; and q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2. 根据权利要求1所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中环A是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基(例如单环或双环)，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6氰基烷基、(C3-10环烷基)-RL-和(C3-10卤代环烷基)-RL-，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自卤素、氰基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基和C1-6氰基烷基的取代基取代；The compound of claim 1 or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein ring A is a C6-10 aryl or a 5-10 membered heteroaryl (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each R3 independently selected from halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl , C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- and ( C3-10 halocycloalkyl) -RL- , or wherein two R3s together with the atoms to which they are attached form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C3-10 cycloalkyl ... Substitution of 2-6 ynyl, C1-6 haloalkyl and C1-6 cyanoalkyl groups; 任选地，环A是苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基(例如单环或双环)，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代；Optionally, ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens; 任选地，环A是苯基、吡咯基、吡唑基、咪唑基、三唑基、四唑基、吡啶基、哒嗪基、嘧啶基、吡嗪基、吲哚基、异吲哚基、吲唑基、苯并咪唑基、吡唑并吡啶基、吡咯并吡啶基、苯并呋喃基、异苯并呋喃基、苯并噻吩基或嘌呤基，优选苯基、吡唑基、吡啶基或苯并呋喃基，各自任选被一个或多个R3取代；优选地，R3各自独立地选自卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6氰基烷基、(C3-10环烷基)-RL-和(C3-10卤代环烷基)-RL-，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自卤素、氰基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基和C1-6氰基烷基的取代基取代；更优选地，R3各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代。Optionally, ring A is phenyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl, indolyl, isoydindolyl, indolyl, benzimidazolyl, pyrazolopyridyl, pyrrolopyridyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, or purine, preferably phenyl, pyrazolyl, pyridinyl, or benzofuranyl, each optionally substituted by one or more R3 ; preferably, each R3 is independently selected from halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- and ( C3-10 halocycloalkyl) -RL- , or two of these R3s. The R3s , together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally substituted with a substituent selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, and C1-6 cyanoalkyl; more preferably, each R3 is independently selected from halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two R3s , together with the atoms they are attached to, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中环B是8-10元双环亚杂芳基，例如含有一个或多个独立地选自N、O或S的杂原子的8-10元双环亚杂芳基，任选被一个或多个R4取代，或者环B表示优选其中1位与L1连接，2位与环C连接，和其中W1、W2、W3、W4和W5(当存在时)各自独立地是C、CH或N，且其中至少一者是N，和其中表示单键或双键；和其中The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein ring B is an 8-10 membered bicyclic heteroaryl group, for example, containing one or more heteroatoms independently selected from N, O, or S, optionally substituted with one or more R 4 groups, or ring B represents... Preferred One bit is connected to L1 , two bits are connected to ring C, and W1 , W2 , W3 , W4 , and W5 (if present) are each independently C, CH, or N, with at least one of them being N. Indicates a single or double bond; and among them R4各自独立地选自C1-6烷氧基、C3-6环烷基和4-8元杂环烷基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自C1-6烷基或C1-6烷氧基的取代基取代；R 4 are each independently selected from C 1-6 alkoxy, C 3-6 cycloalkyl and 4-8 heterocyclic alkyl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from C 1-6 alkyl or C 1-6 alkoxy; 优选地，R4各自独立地选自C3-6环烷基和4-8元杂环烷基(例如含有一个或两个各自独立地选自N、O或S的杂原子的4-8元杂环烷基)，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自C1-6烷基或C1-6烷氧基的取代基取代；Preferably, R4 is each independently selected from C3-6 cycloalkyl and 4-8 heterocyclic alkyl (e.g., 4-8 heterocyclic alkyl containing one or two heteroatoms each independently selected from N, O or S), wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy. 更优选地，含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代。More preferably, it contains one or two heteroatoms, each independently selected from N, O or S, of 4 to 8-membered heterocyclic alkyl groups, wherein the heterocyclic alkyl groups are optionally substituted by one or more, preferably one or two C1-6 alkyl groups. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中环C是C3-10环烷基或3-10元杂环烷基，优选C3-6环烷基或3-6元杂环烷基，更优选C3-6环烷基，各自任选被一个或多个取代基取代；任选地，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(C6-10芳基)-RL-、(5-10元杂芳基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代；The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein the ring C is a C3-10 cycloalkyl or a 3-10-membered heterocyclic alkyl, preferably a C3-6 cycloalkyl or a 3-6-membered heterocyclic alkyl, more preferably a C3-6 cycloalkyl, each optionally substituted by one or more substituents; optionally, each substituent is independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylene group, C1-6 haloalkylene group, COOH, C 1-6 alkoxy-CO-, (C 1-6 haloalkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , (C 3-10 cycloalkyl)-C 2-4 alkenyl-, (C 3-10 cycloalkyl)-C 2-4 alkyne-, (C 3-10 cycloalkyloxy) -RL- , (3-10 heterocyclic alkyl) -RL- , (C 6-10 aryl)-RL-, ( 5-10 heteroaryl) -RL- , NRsRt- ( CRaRb ) m- , NRaRb - CO- and R6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally substituted with one or more oxo, halogen, cyano, C 1-6 alkyl, C Substituents of 1-6 haloalkyl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl and 5-7 heteroaryl groups; 任选地，环C是C3-6环烷基，例如环丙基、环丁基或环戊基，任选被一个或多个取代基取代；任选地，所述取代基各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基和5-7元杂芳基的取代基取代；Optionally, the ring C is a C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, optionally substituted with one or more substituents; optionally, each substituent is independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylene group, C1-6 haloalkylene group, COOH, C1-6 alkoxy -CO-, ( C1-6 haloalkoxy) -RL- , ( C3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl)-C 2-4 -ynyl-, (C 3-10 cycloalkyloxy) -RL- , (C 6-10 aryl) -RL- , NR s R t- (CR a R b ) m- and R 6 , or two of these substituents together with the atoms to which they are attached, form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano and 5-7 membered heteroaryl; 任选地，环C是C3-6环烷基，例如环丙基、环丁基或环戊基，任选被一个或多个取代基取代；任选地，所述取代基各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代。Optionally, the ring C is a C3-6 cycloalkyl, such as cyclopropyl, cyclobutyl, or cyclopentyl, optionally substituted with one or more substituents; optionally, each substituent is independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- , and R6, or two of the substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, the ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl . 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中环D是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基，优选是苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基，例如苯基、吡啶基、哒嗪基、嘧啶基、吡嗪基；和The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein ring D is a C6-10 aryl group or a 5-10 heteroaryl group containing one or more heteroatoms independently selected from N, O, or S, preferably phenyl or a 5-7 heteroaryl group containing one or more heteroatoms independently selected from N, O, or S, such as phenyl, pyridinyl, pyridazinyl, pyrimidinyl, or pyrazinyl; and R2各自独立地选自H、卤素、氰基、NRaRb、C1-6烷基、C1-6卤代烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者两个R2与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2 is independently selected from H, halogen, cyano , NRaRb , C1-6 alkyl, C1-6 haloalkyl, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)(C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NRa- S(O) 2- ( C1-6 alkyl), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(＝O)(＝ NRa )-( C3-10 cycloalkyl) or -C(＝O)-N( Ra )-( C3-10 cycloalkyl ), or two R2 groups. 2. Together with the atoms to which they are attached, they form 5-6 member saturated, partially unsaturated, or aromatic heterocycles, wherein the rings are optionally substituted with substituents selected from: halogen, oxo, (NR a R b ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy) -RL- , (3-10 member heterocyclic alkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 haloalkyl) -RL- , and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic, or bridged; 任选地，R2各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环；Optionally, each of R2 is independently selected from H, halogen , NRaRb , C1-6 alkyl, 5-10 membered heteroaryl optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa -S(O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo , ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, (C (1-6 alkoxy) -RL- , (C 3-10 cycloalkyl group optionally substituted with one or more substituents independently selected from halogens or C 1-6 alkoxy groups) -RL- , (3-10 heterocyclic alkyl group) -RL- , and (C 6-10 aryl) -RL- , wherein the C 3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic, or bridged ring; 任选地，选自： 优选 Choose any location Selected from: Preferred 其中，R2’选自H、氧代基、卤素、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(C3-10环烷基)-RL-和(3-10元杂环烷基)-RL-和C6-10芳基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代，和其中所述环烷基是单环、双环、螺环或桥环的；和R2c是H、卤素或C1-6烷基。Wherein, R2 ' is selected from H, oxo, halogen, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl) -RL- and (3-10 heterocyclic alkyl) -RL- and C6-10 aryl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from halogen or C1-6 alkoxy, and wherein the cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged; and R2c is H, halogen or C1-6 alkyl. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中所述化合物为式(III)化合物
The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein the compound is a compound of formula (III)
其中：in: W1、W2、W3、W4和W5各自独立地是C、CH或N，其中W1、W2、W3、W4和W5中至少一者是N； W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N; 表示单键或双键； Indicates a single bond or a double bond; T为C1-4亚烷基、C2-4亚烯基、C2-4亚炔基、或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C1-4 alkylene, C2-4 alkenylene, C2-4 ynynylene, or a C3-6 cycloalkylene bonded to the rest of the molecule via two different ring carbon atoms; Q为O或S；Q is either O or S; R1各自独立地是H、卤素、氰基、羟基、巯基、NRaRb、C1-6烷基、C2-6烯基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷氧基或C3-8环烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently H, halogen, cyano, hydroxyl, mercapto, NR a R b , C1-6 alkyl, C2-6 alkenyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkoxy, or C3-8 cycloalkyl; or two R1s together with the carbon atoms they are attached to form a C3-4 cycloalkyl group. R2a、R2b和R2c各自独立地是H、卤素、氰基、OH、NRaRb、C1-6烷基、C2-6烯基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6卤代烷氧基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-C(O)(C1-6烷基)、-S(O)(C1-6烷基)、-S(O)2(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-C(O)-(C3-10环烷基)、-S(O)-(C3-10环烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(任选被一个或多个独立地选自卤素、C1-6烷基或C1-6卤代烷基的取代基取代的3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2a , R2b , and R2c are each independently H, halogen, cyano, OH, NR a , R b , C1-6 alkyl, C2-6 alkenyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -C(O)( C1-6 alkyl), -S(O)( C1-6 alkyl), -S(O) 2 ( C1-6 alkyl), -NR a -S(O) 2- ( C1-6 alkyl), -C(O)-( C3-10 cycloalkyl), -S(O)-( C3-10 cycloalkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(=NR a) R2a , R2b, or R2b together with the atoms they are attached to form a 6- membered aromatic ring or a 5-6-membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from the following : halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, (C1-6 alkoxy)-RL-, (C1-6 alkylthio)-RL-, (C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy ) -RL- , ( optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy) -RL- , (optionally substituted with one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy)-RL-, ( C6-10 aryl) -RL- and ( C6-10 aryl) -RL- , wherein the C3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic or bridged ring; R3a、R3b和R3c各自独立地选自H、卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、和(任选被一个或多个独立地选自卤素和C1-6烷基取代的C3-10环烷基)-RL-，或者R3a、R3b连同它们所连接的原子一起形成任选地含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个独立地选自卤素、氰基、羟基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基和C1-6羟基烷基的取代基取代； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and (optionally substituted with one or more C3-10 cycloalkyl atoms independently selected from halogen and C1-6 alkyl) -RL- , or R3a and R3b together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, said 4- to 6-membered ring optionally selected from one or more heteroatoms independently selected from halogen, cyano, hydroxyl, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 alkyl, C2-6 alkyl, C3-10 cycloalkyl, C3-10 ... Substitution of 1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl and C1-6 hydroxyalkyl groups; R4为卤素、氰基、羟基、NRaRb、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、(C3-10环烷基)-RL-、(5-10元杂环烷基)-RL-、(C6-10芳基)-RL-和(5-10元杂芳基)-RL-，其中所述环烷基、杂环烷基、芳基和杂芳基各自任选被一个或多个独立地选自卤素、C1-6烷基或C1-6烷氧基的取代基取代； R4 is a halogen, cyano, hydroxyl, NR a R b , C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, ( C3-10 cycloalkyl) -RL- , ( 5-10 heterocyclic alkyl) -RL- , ( C6-10 aryl) -RL- , and (5-10 heteroaryl) -RL- , wherein the cycloalkyl, heterocyclic alkyl, aryl, and heteroaryl groups are each optionally substituted by one or more substituents independently selected from halogen, C1-6 alkyl, or C1-6 alkoxy. R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6氰基烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、-CONH2、-CONH(C1-6烷基)、-C(＝S)NH2、-C(＝S)NH(C1-6烷基)、-P(Ra)(Rb)(例如-PH2、-PH(C1-6烷基)、-PH(C1-6烷基)(C1-6烷基))、(例如-O-P(＝O)(OH)2、)、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚烯基-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(3-10元杂环烷基)-RL-、(3-10元杂环烷基氧基)-RL-、(C6-10芳基)-RL-、(C6-10芳基氧基)-RL-、(5-10元杂芳基)-RL-、(5-10元杂芳基氧基)-RL-、NRsRt-(CRaRb)m-、NRaRb-CO-；或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基、C1-6烷基、C1-6卤代烷基、C3-10环烷基、3-10元杂环烷基、C6-10芳基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, -CONH2, -CONH ( C1-6 alkyl ) , -C(=S) NH2 , -C(=S)NH( C1-6 alkyl), -P(Ra)( Rb ) (e.g., -PH2 , -PH( C1-6 alkyl ), -PH(C... 1-6 alkyl)(C 1-6 alkyl) (For example, -OP(＝O)(OH) 2 , ), C 1-6 alkoxy-CO-, (C 1-6 haloalkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with halogen or hydroxyl) -RL- , (C 3-10 cycloalkyl)-C 2-4 alkenyl-, (C 3-10 cycloalkyl)-C 2-4 alkyne-, (C 3-10 cycloalkyloxy) -RL- , (3-10 heterocyclic alkyl) -RL- , (3-10 heterocyclic alkyloxy) -RL- , (C 6-10 aryl) -RL- , (C 6-10 aryloxy) -RL- , (5-10 heteroaryl)-RL-, (5-10 heteroaryloxy)-RL-, NR s R t- (CR a R b ) m- , NR a R b -CO-; or R 5a , R 5b , R The two of 5c and R 5d , together with the atoms they are attached to, form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, C3-10 cycloalkyl, 3-10 heterocyclic alkyl, C6-10 aryl and 5-7 heteroaryl; R6是含有一个或多个独立地选自N、O或S的杂原子的5-6元部分不饱和或芳族杂环； R6 is a 5- or 6-membered partially unsaturated or aromatic heterocycle containing one or more heteroatoms independently selected from N, O, or S; Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present; Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl; Rs和Rt各自独立地是H、C1-6烷基、C1-6卤代烷基、C6-10芳基或5-10元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, C <sub>1-6 </sub> haloalkyl, C <sub>6-10 </sub> aryl, or 5-10 heteroaryl; RL各自独立地是价键；任选被卤素、氰基或羟基取代的C1-10亚烷基；或C1-4氘代亚烷基；R and L are each independently valence bonds; C1-10 alkylene groups optionally substituted with halogen, cyano or hydroxyl groups; or C1-4 deuterated alkylene groups; m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5; n是0、1或2；和n is 0, 1, or 2; and q是0、1、2或3，优选为1或2；q can be 0, 1, 2 or 3, preferably 1 or 2; 优选地，W1为N，且W2、W3、W4和W5为C或CH；或者，W3为N，且W1、W2、W4和W5为C或CH；或者，W5为N，且W1、W2、W3和W4为C或CH。Preferably, W1 is N, and W2 , W3 , W4 and W5 are C or CH; or, W3 is N, and W1 , W2 , W4 and W5 are C or CH; or, W5 is N, and W1 , W2 , W3 and W4 are C or CH. 根据权利要求6所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中T为C2-4亚烯基或分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基，和Q为O或S，优选为O。The compound according to claim 6 or its pharmaceutically usable salt, stereoisomer, tautomer, isotopically labeled compound or solvate, wherein T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the remainder of the molecule by two different cyclic carbon atoms, and Q is O or S, preferably O. 根据权利要求6所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中所述化合物具有下式之一：
The compound according to claim 6, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof, wherein the compound has one of the following formulas:
其中各变量如权利要求6中所定义。Each of the variables is defined as described in claim 6. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中：R1各自独立地是H、卤素、氰基、羟基、NH2、NH(C1-4烷基)、C1-6烷基、C1-6氘代烷基或C1-6卤代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基；The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein: R1 is each independently H, halogen, cyano, hydroxyl, NH2 , NH ( C1-4 alkyl), C1-6 alkyl, C1-6 deuterated alkyl, or C1-6 haloalkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group; 任选地，R1各自独立地是氰基、C1-6烷基或C1-6氘代烷基，优选氰基或C1-6烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基；Optionally, each R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl, preferably cyano or C1-6 alkyl; or the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group. 任选地，p为1，且R1是氰基、C1-6烷基或C1-6氘代烷基，优选是氰基、C1-4烷基或C1-4氘代烷基；Optionally, p is 1, and R1 is cyano, C1-6 alkyl, or C1-6 deuterated alkyl, preferably cyano, C1-4 alkyl, or C1-4 deuterated alkyl; 任选地，p为2，且两个R1与它们所连接的碳原子一起形成C3-4环烷基。Optionally, p is 2, and the two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中：R2a、R2b各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环；The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein: R2a and R2b are each independently selected from H, halogen, NRaRb , C1-6 alkyl, 5-10 heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa- S (O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl) or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a , R 2b, together with the atoms to which they are attached, form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from the following: halogen, oxo, (NR a R b ) -RL- , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C 1-6 alkoxy) -RL- , (3-10 membered heterocyclic alkyl) -RL- , and (C 6-10 aryl) -RL- , wherein the C 3-10 cycloalkyl is a monocyclic, bicyclic, spirocyclic, or bridged ring; 任选地，R2a、R2b各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环；和R2c为H、卤素或C1-6烷基，优选H或卤素，例如氟；Optionally, R2a and R2b are each independently selected from H, halogens, NRaRb , C1-6 alkyl, 5-10 - membered heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa- S(O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a and R2b together with the atoms to which they are attached form 5-6-membered saturated, partially unsaturated, or aromatic heterocycles, said rings optionally substituted with substituents selected from: halogens, oxo groups, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogens or C 1-6 alkoxys) -RL- , (4-8 membered heterocyclic alkyl) -RL- , wherein the C 3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged; and R 2c is H, halogen or C 1-6 alkyl, preferably H or halogen, such as fluorine; 任选地，R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环；和R2c为H、卤素或C1-6烷基；Optionally, R2a and R2b, together with the atoms to which they are attached, form a 5-6 member saturated, partially unsaturated, or aromatic heterocycle, said ring being optionally substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C1-6 alkoxy) -RL- , (4-8 member heterocyclic alkyl) -RL- , wherein said C3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic, or bridged; and R2c is H, halogen, or C1-6 alkyl; 任选地，选自：
Choose any location Selected from:
优选，更优选 Preferred, More 其中，R2’选自H、氧代基、卤素、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(C3-10环烷基)-RL-和(3-10元杂环烷基)-RL-和C6-10芳基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代，和其中所述环烷基是单环、双环、螺环或桥环的；和R2c是H、卤素或C1-6烷基。Wherein, R2 ' is selected from H, oxo, halogen, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, ( C1-6 alkoxy) -RL- , ( C3-10 cycloalkyl) -RL- and (3-10 heterocyclic alkyl) -RL- and C6-10 aryl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from halogen or C1-6 alkoxy, and wherein the cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged; and R2c is H, halogen or C1-6 alkyl. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中R3a、R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基、C1-6氰基烷基、(C3-10环烷基)-RL-和(C3-10卤代环烷基)-RL-，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自卤素、氰基、氧代基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6卤代烷基和C1-6氰基烷基的取代基取代；The compound according to any one of the preceding claims or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound or solvate, wherein R3a , R3b and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl, C1-6 cyanoalkyl, ( C3-10 cycloalkyl) -RL- and ( C3-10 halocycloalkyl) -RL- , or wherein R3a and R3b together with the atoms to which they are attached form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O or S, said 4- to 6-membered ring optionally substituted with a substituent selected from halogen, cyano, oxo, C1-6 alkyl, C2-6 alkenyl, C2-6 ynyl, C1-6 haloalkyl and C1-6 cyanoalkyl; 任选地，R3a、R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代；Optionally, R3a , R3b and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl and C3-6 cycloalkyl, or wherein R3a and R3b together with the atoms to which they are attached form a 4 to 6 membered ring optionally containing one or more heteroatoms independently selected from N, O or S, said 4 to 6 membered ring optionally substituted with one or more halogens or cyano, preferably halogens; 任选地，R3a为H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基；R3b为卤素；和R3c为H或C1-6烷基；Optionally, R 3a is H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl; R 3b is halogen; and R 3c is H or C1-6 alkyl; 任选地，R3a为C1-4烷基；R3b为卤素，例如氟；和R3c为C1-4烷基。Optionally, R 3a is a C1-4 alkyl group; R 3b is a halogen, such as fluorine; and R 3c is a C1-4 alkyl group. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中R4各自独立地选自C3-6环烷基和4-8元杂环烷基(例如含有一个或两个各自独立地选自N、O或S的杂原子的4-8元杂环烷基)，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自C1-6烷基或C1-6烷氧基的取代基取代；The compound according to any one of the preceding claims or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound or solvate, wherein each of R 4 is independently selected from C 3-6 cycloalkyl and 4-8 heterocyclic alkyl (e.g., 4-8 heterocyclic alkyl containing one or two heteroatoms independently selected from N, O or S), wherein the cycloalkyl and heterocyclic alkyl are optionally substituted by one or more substituents independently selected from C 1-6 alkyl or C 1-6 alkoxy; 优选地，R4各自独立地选自C1-6烷氧基、C3-6环烷基和4-8元杂环烷基，其中所述环烷基和杂环烷基各自任选被一个或多个独立地选自C1-6烷基或C1-6烷氧基的取代基取代；Preferably, each of R4 is independently selected from C1-6 alkoxy, C3-6 cycloalkyl, and 4-8 membered heterocyclic alkyl, wherein the cycloalkyl and heterocyclic alkyl are each optionally substituted by one or more substituents independently selected from C1-6 alkyl or C1-6 alkoxy; 任选地，R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，优选是含有一个或两个O杂原子的4至8元杂环烷基，例如四氢吡喃基、吗啉基或吡啶基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代。Optionally, R4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, preferably a 4- to 8-membered heterocyclic alkyl group containing one or two O heteroatoms, such as tetrahydropyranyl, morpholinyl or pyridinyl, wherein the heterocyclic alkyl group is optionally substituted with one or more, preferably one or two C1-6 alkyl groups. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中：The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein: R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、羟基、C1-6烷基、C2-6烯基、C2-6炔基、(C1-6烷氧基)-RL-、(C1-6烷硫基)-RL-、C1-6烷氧基-C1-6烷氧基-、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、C1-6烷亚基、C1-6卤代烷亚基、COOH、C1-6烷氧基-CO-、(C1-6卤代烷氧基)-RL-、(任选被卤素或羟基取代的C3-10环烷基)-RL-、(C3-10环烷基)-C2-4亚炔基-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、(C6-10芳基氧基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基、卤素、氰基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently selected from H, halogen, cyano, hydroxyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, ( C1-6 alkoxy) -RL- , ( C1-6 alkylthio) -RL- , C1-6 alkoxy- C1-6 alkoxy-, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, C1-6 alkylidene, C1-6 haloalkylidene, COOH, C1-6 alkoxy-CO-, (C1-6 haloalkoxy ) -RL- , (optionally C3-10 cycloalkyl substituted with halogen or hydroxyl) -RL- , ( C3-10 cycloalkyl) -C2-4 ynylene-, ( C3-10 cycloalkyloxy) -RL- , (C (6-10 aryl) -RL- , (C 6-10 aryloxy) -RL- , NR s R t- (CR a R b ) m- , or two of R 5a , R 5b , R 5c and R 5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo, halogen, cyano and 5-7 membered heteroaryl; 任选地，R5a、R5b、R5c和R5d各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代；Optionally, R5a , R5b , R5c and R5d are each independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy)-RL-, (C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, said ring optionally being substituted by one or more substituents selected from oxo and 5-7 membered heteroaryl; 任选地，R5a是C1-6烷基，且R5b、R5c和R5d各自独立地为H或卤素，优选H；Optionally, R 5a is a C1-6 alkyl group, and R 5b , R 5c and R 5d are each independently H or halogen, preferably H; 任选地，R5a是C1-4烷基，且R5b、R5c和R5d各自独立地为H。Optionally, R5a is a C1-4 alkyl group, and R5b , R5c and R5d are each independently H. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中R6选自 其中R6a是H或C1-6烷基，优选H：The compound according to any one of the preceding claims, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein R6 is selected from... Wherein R 6a is H or C 1-6 alkyl, preferably H: 任选地，R6选自优选是其中R6a是H或C1-6烷基，优选H。Optionally, R 6 is selected from Preferred is R 6a is H or C 1-6 alkyl, preferably H. 根据前述权利要求任一项所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基。The compound according to any one of the preceding claims or its pharmaceutically usable salt, stereoisomer, tautomer, isotopically labeled compound or solvate, wherein R and L are each independently valence, C1-4 alkylene, C1-4 haloalkylene or C1-4 deuteralkylene. 根据权利要求1所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中所述化合物具有式(I)，
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof, wherein the compound has formula (I),
其中in L1选自-CO-、-SO-和-NH-，优选-CO-； L1 is selected from -CO-, -SO- and -NH-, with -CO- being preferred; L2选自其中星号表示与中心环的N原子连接，优选 L2 is selected from The asterisk indicates a connection to the N atom in the central ring, preferably... 环A是苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基(例如单环或双环)，各自任选被一个或多个R3取代，所述R3各自独立地选自卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中两个R3连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代；Ring A is a phenyl or a 5-10 membered heteroaryl group (e.g., monocyclic or bicyclic) containing one or more heteroatoms each independently selected from N, O, or S, each optionally substituted with one or more R3s , each independently selected from halogens, cyano , C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or two of the R3s together with the atoms they are attached to form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, the 4- to 6-membered ring optionally substituted with one or more halogens or cyano, preferably halogens; 环B是含有一个或多个各自独立地选自N、O或S的杂原子的8-10元双环亚杂芳基，任选被一个或多个R4取代，所述R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代；Cycle B is an 8-10 membered bicyclic heteroaryl group containing one or more heteroatoms each independently selected from N, O or S, optionally substituted by one or more R4 groups, wherein R4 is a 4- to 8 membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C1-6 alkyl groups. 环C是C3-6环烷基，任选被一个或多个取代基取代，所述取代基各自独立地选自H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-和R6，或者其中两个取代基连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代；The ring C is a C3-6 cycloalkyl group, optionally substituted with one or more substituents, each of which is independently selected from H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy) -RL- , ( C6-10 aryl) -RL- , NRsRt- ( CRaRb ) m- and R6 , or two of these substituents together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O or S, the ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups; 环D是C6-10芳基或含有一个或多个各自独立地选自N、O或S的杂原子的5-10元杂芳基，优选苯基或含有一个或多个各自独立地选自N、O或S的杂原子的5-7元杂芳基；Ring D is a C6-10 aryl or a 5-10 heteroaryl containing one or more heteroatoms each independently selected from N, O or S, preferably phenyl or a 5-7 heteroaryl containing one or more heteroatoms each independently selected from N, O or S; R1各自独立地是氰基、C1-6烷基或C1-6氘代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group; R2各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者两个R2与它们所连接的原子一起形成6元芳环或者5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(3-10元杂环烷基)-RL-和(C6-10芳基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2 is independently selected from H, halogen , NRaRb , C1-6 alkyl, 5-10 membered heteroaryl optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa- S (O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or two R2s together with the atoms they are attached to form a 6-membered aromatic ring or a 5-6 membered saturated, partially unsaturated, or aromatic heterocycle, wherein the ring is optionally substituted with a substituent selected from: halogen, oxo, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C1-6 haloalkyl, (C (1-6 alkoxy) -RL- , (C 3-10 cycloalkyl group optionally substituted with one or more substituents independently selected from halogens or C 1-6 alkoxy groups) -RL- , (3-10 heterocyclic alkyl group) -RL- , and (C 6-10 aryl) -RL- , wherein the C 3-10 cycloalkyl group is a monocyclic, bicyclic, spirocyclic, or bridged ring; R6选自其中R6a是H或C1-6烷基，优选是H；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H; Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present; Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl; Rs和Rt各自独立地是H、C1-6烷基或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S; RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基；R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene; T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule via two different ring carbon atoms; Q为O或S；Q is either O or S; m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5; n是0、1或2；和n is 0, 1, or 2; and q是0、1、2或3，优选为1或2。q can be 0, 1, 2 or 3, preferably 1 or 2. 根据权利要求1所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中所述化合物具有式(III)，
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof, wherein the compound has formula (III),
其中：in: W1、W2、W3、W4和W5各自独立地是C、CH或N，其中W1、W2、W3、W4和W5中至少一者是N； W1 , W2 , W3 , W4 and W5 are each independently C, CH or N, of which at least one of W1 , W2 , W3 , W4 and W5 is N; 表示单键或双键； Indicates a single bond or a double bond; T为C2-4亚烯基或者分别通过两个不同的环碳原子与分子其余部分键合的C3-6亚环烷基；T is a C2-4 alkenyl group or a C3-6 cycloalkyl group bonded to the rest of the molecule via two different ring carbon atoms; Q为O或S；Q is either O or S; R1各自独立地是氰基、C1-6烷基或C1-6氘代烷基；或者两个R1与它们所连接的碳原子一起形成C3-4环烷基； R1 is independently a cyano, C1-6 alkyl, or C1-6 deuterated alkyl; or two R1s together with the carbon atoms to which they are attached form a C3-4 cycloalkyl group; R2a、R2b各自独立地选自H、卤素、NRaRb、C1-6烷基、任选被一个或多个C1-6烷基取代的5-10元杂芳基、-P(O)(C1-6烷基)(C1-6烷基)、-NRa-S(O)2-(C1-6烷基)、-S(O)2-(C3-10环烷基)、-S(＝O)(＝NRa)-(C3-10环烷基)或-C(＝O)-N(Ra)-(C3-10环烷基)，或者R2a、R2b与它们所连接的原子一起形成5-6元饱和、部分不饱和或芳族杂环，所述环任选被选自如下的取代基取代：卤素、氧代基、(NRaRb)-RL-、C1-6烷基、C1-6氘代烷基、C1-6卤代烷基、(C1-6烷氧基)-RL-、(任选被一个或多个独立地选自卤素或C1-6烷氧基的取代基取代的C3-10环烷基)-RL-、(4-8元杂环烷基)-RL-，其中所述C3-10环烷基是单环、双环、螺环或桥环； R2a and R2b are each independently selected from H, halogens, NRaRb , C1-6 alkyl, 5-10 - membered heteroaryl groups optionally substituted with one or more C1-6 alkyl groups, -P(O)( C1-6 alkyl)( C1-6 alkyl), -NRa -S(O) 2- ( C1-6 alkyl), -S(O) 2- ( C3-10 cycloalkyl), -S(=O)(= NRa )-( C3-10 cycloalkyl), or -C(=O)-N( Ra )-( C3-10 cycloalkyl), or R2a and R2b together with the atoms they are attached to form 5-6-membered saturated, partially unsaturated, or aromatic heterocycles, wherein the rings are optionally substituted with substituents selected from: halogens, oxo groups, ( NRaRb ) -RL- , C1-6 alkyl, C1-6 deuterated alkyl, C 1-6 haloalkyl, (C 1-6 alkoxy) -RL- , (C 3-10 cycloalkyl optionally substituted with one or more substituents independently selected from halogen or C 1-6 alkoxy) -RL- , (4-8 membered heterocyclic alkyl) -RL- , wherein the C 3-10 cycloalkyl is monocyclic, bicyclic, spirocyclic or bridged ring; R2c为H、卤素或C1-6烷基，优选H或卤素，例如氟；R 2c is H, halogen, or C1-6 alkyl, preferably H or halogen, such as fluorine; R3a和R3b和R3c各自独立地选自H、卤素、氰基、C1-6烷基、C1-6卤代烷基和C3-6环烷基，或者其中R3a、R3b连同它们所连接的原子一起形成任选含有一个或多个独立地选自N、O或S的杂原子的4至6元环，所述4至6元环任选被选自一个或多个卤素或氰基、优选卤素取代； R3a , R3b , and R3c are each independently selected from H, halogen, cyano, C1-6 alkyl, C1-6 haloalkyl, and C3-6 cycloalkyl, or wherein R3a and R3b, together with the atoms to which they are attached, form a 4- to 6-membered ring optionally containing one or more heteroatoms independently selected from N, O, or S, wherein the 4- to 6-membered ring is optionally substituted with one or more halogens or cyano, preferably halogens; R4是含有一个或两个各自独立地选自N、O或S的杂原子的4至8元杂环烷基，所述杂环烷基任选被一个或多个、优选一个或两个C1-6烷基取代；R 4 is a 4- to 8-membered heterocyclic alkyl group containing one or two heteroatoms each independently selected from N, O or S, wherein the heterocyclic alkyl group is optionally substituted by one or more, preferably one or two C 1-6 alkyl groups; R5a、R5b、R5c和R5d各自独立地是H、卤素、氰基、C1-6烷基、C2-6烯基、C2-6炔基、C1-6烷氧基、C1-6烷硫基、C1-6氘代烷基、C1-6卤代烷基、C1-6羟基烷基、COOH、C1-6烷氧基-CO-、(C3-10环烷基氧基)-RL-、(C6-10芳基)-RL-、NRsRt-(CRaRb)m-，或者R5a、R5b、R5c和R5d中的两个连同它们所连接的原子一起形成任选地含有一个或多个选自N、O或S的杂原子的3-7元环，所述环任选被一个或多个选自氧代基和5-7元杂芳基的取代基取代； R5a , R5b , R5c , and R5d are each independently H, halogen, cyano, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 deuterated alkyl, C1-6 haloalkyl, C1-6 hydroxyalkyl, COOH, C1-6 alkoxy-CO-, ( C3-10 cycloalkyloxy )-RL-, (C6-10 aryl ) -RL- , NRsRt- ( CRaRb ) m- , or two of R5a , R5b , R5c , and R5d together with the atoms they are attached to form a 3-7 membered ring optionally containing one or more heteroatoms selected from N, O, or S, said ring optionally substituted with one or more substituents selected from oxo and 5-7 membered heteroaryl groups; R6选自其中R6a是H或C1-6烷基，优选是H；R 6 is selected from Wherein R 6a is H or C 1-6 alkyl, preferably H; Rp各自独立地是卤素、氰基、羟基、NH2或C1-6烷基，或者不存在； Rp are each independently a halogen, cyano, hydroxyl, NH2 or C1-6 alkyl, or not present; Ra和Rb各自独立地是H或C1-6烷基； Ra and Rb are each independently H or C1-6 alkyl; Rs和Rt各自独立地是H、C1-6烷基或含有一个或多个独立地选自N、O或S的杂原子的5-7元杂芳基；R <sub>s</sub> and R<sub>t</sub> are each independently H, C <sub>1-6 </sub> alkyl, or 5-7 membered heteroaryl containing one or more heteroatoms independently selected from N, O, or S; RL各自独立地是价键、C1-4亚烷基、C1-4卤代亚烷基或C1-4氘代亚烷基；R and L are each independently valence bonded, C1-4 alkylene, C1-4 haloalkylene, or C1-4 deuteralkylene; m是0、1、2、3、4或5；m is 0, 1, 2, 3, 4 or 5; n是0、1或2；和n is 0, 1, or 2; and q是0、1、2或3，优选为1或2；q can be 0, 1, 2 or 3, preferably 1 or 2; 优选地，对于W1、W2、W3、W4和W5而言，W1为N，且其余为C或CH；或者，W3为N，且其余为C或CH；或者，W5为N，且其余为C或CH。Preferably, for W1 , W2 , W3 , W4 and W5 , W1 is N and the rest are C or CH; or, W3 is N and the rest are C or CH; or, W5 is N and the rest are C or CH. 根据权利要求1所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中所述化合物具有式(IV)，
The compound according to claim 1, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof, wherein the compound has formula (IV),
其中：in: W1为N，且W2、W3和W4各自独立地是C或CH； W1 is N, and W2 , W3 and W4 are each independently C or CH; T为C2-4亚烯基；T is a C2-4 alkenyl group; Q为O；Q is 0; R1为C1-6烷基，优选C1-4烷基，例如甲基； R1 is a C1-6 alkyl group, preferably a C1-4 alkyl group, such as methyl; R2a和R2b与它们所连接的碳原子一起形成含有一个或两个氮杂原子的5或6元杂芳环，所述环被(C3-8环烷基)-C1-4亚烷基-或(C3-8卤代环烷基)-C1-4亚烷基-取代，优选被(C3-6环烷基)-C1-4亚烷基-或(C3-6卤代环烷基)-C1-4亚烷基-取代,；和R2c为卤素，优选F； R2a and R2b, together with the carbon atoms to which they are attached, form a 5- or 6-membered heteroaromatic ring containing one or two nitrogen heteroatoms, said ring being substituted with ( C3-8 cycloalkyl) -C1-4 alkylene- or ( C3-8 halocycloalkyl) -C1-4 alkylene-, preferably substituted with ( C3-6 cycloalkyl) -C1-4 alkylene- or ( C3-6 halocycloalkyl) -C1-4 alkylene-; and R2c is a halogen, preferably F; R3a为C1-6烷基；R3b为卤素；和R3c为C1-6烷基；R 3a is a C1-6 alkyl group; R 3b is a halogen; and R 3c is a C1-6 alkyl group. R4为四氢吡喃基，任选被一个或多个、优选一个或两个C1-6烷基取代； R4 is a tetrahydropyranyl group, optionally substituted with one or more, preferably one or two C1-6 alkyl groups; R5a是C1-6烷基；且R5b、R5c和R5d各自独立地为H或卤素，优选为H；R 5a is a C1-6 alkyl group; and R 5b , R 5c and R 5d are each independently H or halogen, preferably H; R6是其中R6a是H或C1-6烷基，优选为H；和R 6 is Wherein R 6a is H or C 1-6 alkyl, preferably H; and n为0，即Rp不存在；n is 0, meaning R p does not exist; 优选地，表示其中R2’是(任选被一个或多个卤素取代的C3-8环烷基)-C1-4亚烷基-，优选是(任选被一个或多个卤素如F取代的C3-6环烷基)-C1-4亚烷基-，更优选是(任选被一个或多个卤素如氟取代的环丙基)-C1-4亚烷基-，和R2c为卤素，优选F。Preferably, express Wherein R2 ' is (optionally substituted with one or more halogens) -C1-4 alkylene- , preferably (optionally substituted with one or more halogens such as F) -C1-4 alkylene-, more preferably (optionally substituted with one or more halogens such as fluorine) -C1-4 alkylene-, and R2c is a halogen, preferably F. 根据权利要求1所述的化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物，其中所述化合物选自：











The compound according to claim 1, or its pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate, wherein the compound is selected from:











药物组合物，包含权利要求1-19任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物以及一种或多种可药用的载体、稀释剂或赋形剂。A pharmaceutical composition comprising a compound of any one of claims 1-19 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound or solvate thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients. 用作GLP-1R激动剂或者用于治疗或预防GLP-1R相关性疾病或紊乱的权利要求1-19任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物。The compound of any one of claims 1-19, or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof, used as a GLP-1R agonist or for the treatment or prevention of GLP-1R-related diseases or disorders. 根据权利要求21的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物，其用于体重管理、用于降血糖和/或用于治疗或预防糖尿病、糖尿病并发症、肥胖症、超重、血脂紊乱、脂肪肝疾病(例如非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH))、代谢性疾病、心血管疾病、神经系统障碍、精神障碍、肾脏疾病、胃肠疾病、自身免疫性疾病、炎性疾病、肺病、下丘脑-垂体-性腺轴相关性疾病或障碍、癌症。The compound of claim 21 or its pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound or solvate, for use in weight management, for lowering blood glucose and/or for treating or preventing diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver disease (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic disease, cardiovascular disease, neurological disorder, mental disorder, kidney disease, gastrointestinal disease, autoimmune disease, inflammatory disease, lung disease, hypothalamic-pituitary-gonadal axis disorders or disorders, and cancer. 在个体中用于治疗或预防GLP-1R相关性疾病或紊乱的方法，该方法包括给所述个体施用有效量的权利要求1-19任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物。A method for treating or preventing GLP-1R-related diseases or disorders in an individual, the method comprising administering to the individual an effective amount of a compound of any one of claims 1-19 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound, or solvate thereof. 根据权利要求23的方法，其中所述方法用于体重管理、用于降血糖和/或用于治疗或预防糖尿病、糖尿病并发症、肥胖症、超重、血脂紊乱、脂肪肝疾病(例如非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH))、代谢性疾病、心血管疾病、神经系统障碍、精神障碍、肾脏疾病、胃肠疾病、自身免疫性疾病、炎性疾病、肺病、下丘脑-垂体-性腺轴相关性疾病或障碍、癌症。The method of claim 23, wherein the method is used for weight management, for lowering blood glucose and/or for treating or preventing diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver disease (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic disease, cardiovascular disease, neurological disorder, mental disorder, kidney disease, gastrointestinal disease, autoimmune disease, inflammatory disease, lung disease, hypothalamic-pituitary-gonadal axis disorders or disorders, and cancer. 权利要求1-19任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物的用途，用作药剂或用于制备药剂，所述药剂用作GLP-1R激动剂或者用于治疗或预防GLP-1R相关性疾病或紊乱。The use of the compound of any one of claims 1-19 or its pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound or solvate, as a pharmaceutical agent or for the preparation of a pharmaceutical agent, said pharmaceutical agent as a GLP-1R agonist or for the treatment or prevention of GLP-1R-related diseases or disorders. 根据权利要求25的用途，其中所述药剂用于体重管理、用于降血糖和/或用于治疗或预防糖尿病、糖尿病并发症、肥胖症、超重、血脂紊乱、脂肪肝疾病(例如非酒精性脂肪肝病(NAFLD)和非酒精性脂肪性肝炎(NASH))、代谢性疾病、心血管疾病、神经系统障碍、精神障碍、肾脏疾病、胃肠疾病、自身免疫性疾病、炎性疾病、肺病、下丘脑-垂体-性腺轴相关性疾病或障碍、癌症。According to the use of claim 25, the agent is used for weight management, for lowering blood sugar and/or for treating or preventing diabetes, diabetic complications, obesity, overweight, dyslipidemia, fatty liver disease (e.g., non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)), metabolic disease, cardiovascular disease, neurological disorder, mental disorder, kidney disease, gastrointestinal disease, autoimmune disease, inflammatory disease, lung disease, hypothalamic-pituitary-gonadal axis disorders or disorders, and cancer. 根据权利要求21的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物、根据权利要求23的方法或根据权利要求25的用途，其中所述体重管理是体重减轻，和/或所述糖尿病是1型或2型糖尿病。The compound of claim 21 or its pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound or solvate, the method of claim 23 or the use of claim 25, wherein the weight management is weight loss, and/or the diabetes is type 1 or type 2 diabetes. 药物组合产品，包含权利要求1-19任一项的化合物或其可药用的盐、互变异构体、立体异构体、同位素标记化合物或溶剂合物或权利要求20的药物组合物与一种或多种其它活性剂。A pharmaceutical combination product comprising a compound of any one of claims 1-19 or a pharmaceutically acceptable salt, tautomer, stereoisomer, isotopically labeled compound or solvate thereof, or a pharmaceutical composition of claim 20, and one or more other active agents. 制备式(A'-5)化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的方法，
Methods for preparing compounds of formula (A'-5) or their pharmaceutically acceptable salts, stereoisomers, tautomers, isotopically labeled compounds, or solvates.
其中，PG表示氨基保护基如Boc，和其它变量如前述权利要求中任一项所定义，Wherein, PG represents an amino protecting group such as Boc, and other variables are as defined in any of the preceding claims. 该方法包括：The method includes: (a)使式(A'-1)化合物与氯甲酸酯反应，
(a) Reaction of compound (A'-1) with chloroformate,
其中，PG表示氨基保护基如Boc，和其它变量如式(A'-5)中所定义，Where PG represents an amino protecting group such as Boc, and other variables are as defined in equation (A'-5). 生成式(A'-3)化合物，
Generative (A'-3) compounds,
其中，PG表示氨基保护基如Boc，和其它变量如式(A'-5)中所定义；Where PG represents an amino protecting group such as Boc, and other variables are as defined in equation (A'-5); (b)将所得式(A'-3)化合物原位与式(A'-4)化合物反应，
(b) The resulting compound of formula (A'-3) is reacted in situ with the compound of formula (A'-4).
其中，变量如式(A'-5)中所定义，The variables are defined as shown in equation (A'-5). 得到式(A'-5)化合物；任选地，将所得式(A'-5)化合物转化为其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的形式。A compound of formula (A'-5) is obtained; optionally, the obtained compound of formula (A'-5) is converted into its pharmaceutically usable salt, stereoisomer, tautomer, isotopically labeled compound or solvate. 制备权利要求1-19任一项所述的式(I)化合物或其可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的方法，其中所述式(I)化合物具有式(I-3)的结构：
A method for preparing a compound of formula (I) according to any one of claims 1-19, or a pharmaceutically acceptable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate thereof, wherein the compound of formula (I) has the structure of formula (I-3):
其中，各变量如式(I)中所定义，该方法包括：The variables are defined in equation (I), and the method includes: -使式(A')化合物与式(B)化合物反应，
- To react compound (A') with compound (B),
其中各变量如式(I-3)中定义，The variables are defined as shown in equation (I-3). 得到式(I-3)化合物，和任选地将其转化为可药用的盐、立体异构体、互变异构体、同位素标记化合物或溶剂合物的形式；任选地，该反应在缩合剂和碱的存在下、在溶剂中进行；The compound of formula (I-3) is obtained, and optionally converted into a pharmaceutically usable salt, stereoisomer, tautomer, isotopically labeled compound, or solvate; optionally, the reaction is carried out in a solvent in the presence of a condensing agent and a base. -任选地，所述式(A')化合物通过包括如下步骤的方法制备：使式(A'-5)化合物发生闭环反应，
- Optionally, the compound of formula (A') is prepared by a method comprising the steps of: causing the compound of formula (A'-5) to undergo a ring-closing reaction,
其中，PG表示氨基保护基如Boc，和其它变量如式(I-3)中所定义，Where PG represents an amino protecting group such as Boc, and other variables are as defined in equation (I-3). 得到式(A')化合物；任选地，该反应在酸(例如对甲苯磺酸)的存在下、在溶剂(例如间二甲苯)中进行；The reaction yields a compound of formula (A'); optionally, the reaction is carried out in the presence of an acid (e.g., p-toluenesulfonic acid) and in a solvent (e.g., m-xylene); -任选地，所述式(A'-5)化合物通过权利要求29所述的方法获得。- Optionally, the compound of formula (A'-5) is obtained by the method of claim 29. 根据权利要求29或30所述的方法，其中所述氯甲酸酯具有式(A'-2)的结构：
According to the method of claim 29 or 30, the chloroformate has the structure of formula (A'-2):
其中RA是任意不干扰反应进行的基团；优选地，RA是H、硝基、CN、C1-6烷基、C1-6烯基、C1-6炔基、C1-6卤代烷基、C1-6卤代烯基、C1-6卤代炔基、磺酸酯基(-SO3H)、醛基(-CHO)、-CO(C1-6烷基)；更优选地，RA是H、硝基、CN、CF3、CCl3、磺酸酯基(-SO3H)、醛基(-CHO)、-CO(C1-6烷基)；例如，RA是H或硝基；Wherein, RA is any group that does not interfere with the reaction; preferably, RA is H, nitro, CN, C1-6 alkyl, C1-6 alkenyl, C1-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkenyl, C1-6 haloalkynyl, sulfonate ( -SO3H ), aldehyde (-CHO), -CO (C1-6 alkyl); more preferably, RA is H, nitro, CN, CF3 , CCl3 , sulfonate ( -SO3H ), aldehyde (-CHO), -CO ( C1-6 alkyl ); for example, RA is H or nitro; 任选地，RA位于酯基的邻位或对位，优选位于对位；Optionally, RA is located at the ortho or para position of the ester group, preferably at the para position; 任选地，所述氯甲酸酯是氯甲酸苯酯或氯甲酸对硝基苯酯；Optionally, the chloroformate is phenyl chloroformate or p-nitrobenzene chloroformate; 任选地，对于1摩尔当量式(A'-1)化合物而言，所述碱的量为约1～10摩尔当量，优选2～4摩尔当量，更优选约4摩尔当量。Optionally, for a 1 molar equivalent (A'-1) compound, the amount of the base is about 1 to 10 molar equivalents, preferably 2 to 4 molar equivalents, and more preferably about 4 molar equivalents. 根据权利要求29-31任一项所述的方法，其中，步骤(a)的反应在碱的存在下进行；The method according to any one of claims 29-31, wherein the reaction in step (a) is carried out in the presence of a base; 任选地，所述碱是叔胺，例如三乙胺、N-甲基吗啉、二异丙基乙胺(DIPEA)、1,8-二氮杂二环十一碳-7-烯(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)；更优选地，所述碱是二异丙基乙胺(DIPEA)；Optionally, the base is a tertiary amine, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO); more preferably, the base is diisopropylethylamine (DIPEA); 任选地，对于1摩尔当量式(A'-1)化合物而言，所述碱的量为约1～10摩尔当量，优选约2～4摩尔当量，更优选约4摩尔当量；Optionally, for a 1 molar equivalent (A'-1) compound, the amount of the base is about 1 to 10 molar equivalents, preferably about 2 to 4 molar equivalents, and more preferably about 4 molar equivalents; 任选地，步骤(a)的反应在溶剂、例如非质子极性溶剂、例如乙腈中进行；Optionally, the reaction in step (a) is carried out in a solvent, such as an aprotic polar solvent, such as acetonitrile; 任选地，步骤(a)的在环境温度、例如约20-25℃下进行。Optionally, step (a) is performed at an ambient temperature, for example, about 20-25°C. 根据权利要求29-32任一项所述的方法，其中，步骤(b)的原位反应是通过将式(A'-4)化合物和任选的碱加入到步骤(a)的反应物中来进行的；任选地，步骤(b)的原位反应是通过将式(A'-4)化合物和碱例如二异丙基乙胺混合在溶剂中，再加入到步骤(a)的反应物中来进行的；The method according to any one of claims 29-32, wherein the in-situ reaction of step (b) is carried out by adding the compound of formula (A'-4) and optionally a base to the reactants of step (a); optionally, the in-situ reaction of step (b) is carried out by mixing the compound of formula (A'-4) and a base, such as diisopropylethylamine, in a solvent and then adding it to the reactants of step (a); 任选地，所述碱是叔胺，例如三乙胺、N-甲基吗啉、二异丙基乙胺(DIPEA)、1,8-二氮杂二环十一碳-7-烯(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)；优选地，所述碱是二异丙基乙胺(DIPEA)；Optionally, the base is a tertiary amine, such as triethylamine, N-methylmorpholine, diisopropylethylamine (DIPEA), 1,8-diazabicycloundec-7-ene (DBU), or 1,4-diazabicyclo[2.2.2]octane (DABCO); preferably, the base is diisopropylethylamine (DIPEA). 任选地，对于1摩尔当量式(A'-3)化合物而言，所述碱的量为约0～4当量，优选约0～2当量，更优选约2当量；Optionally, for a 1 molar equivalent of the compound of formula (A'-3), the amount of the base is about 0 to 4 equivalents, preferably about 0 to 2 equivalents, and more preferably about 2 equivalents; 任选地，步骤(b)的反应在升高温度下、例如约40-90℃、例如50-60℃、例如55℃下进行。Optionally, the reaction in step (b) is carried out at elevated temperatures, for example, about 40-90°C, for example, 50-60°C, for example, 55°C.
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CN116390926A (en) * 2020-07-20 2023-07-04 上海诚益生物科技有限公司 Tetrahydropyrazolo-pyrazinyl-dihydroimidazolone or tetrahydropyrazolo-pyridyl-dihydroimidazolone compounds and methods of use thereof

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WO2011080755A1 (en) * 2009-12-29 2011-07-07 Advinus Therapeutics Private Limited Fused nitrogen heterocyclic compounds, process of preparation and uses thereof
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