WO2023274397A1 - Cdk2 inhibitor, preparation method therefor and use thereof - Google Patents

Cdk2 inhibitor, preparation method therefor and use thereof Download PDF

Info

Publication number
WO2023274397A1
WO2023274397A1 PCT/CN2022/103293 CN2022103293W WO2023274397A1 WO 2023274397 A1 WO2023274397 A1 WO 2023274397A1 CN 2022103293 W CN2022103293 W CN 2022103293W WO 2023274397 A1 WO2023274397 A1 WO 2023274397A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
halogen
cycloalkyl
alkoxy
cyano
Prior art date
Application number
PCT/CN2022/103293
Other languages
French (fr)
Chinese (zh)
Inventor
李云飞
刘浩淼
张瑱
庞夏明
胡逸民
李志亚
吴杰
Original Assignee
上海拓界生物医药科技有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 上海拓界生物医药科技有限公司 filed Critical 上海拓界生物医药科技有限公司
Publication of WO2023274397A1 publication Critical patent/WO2023274397A1/en

Links

Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
    • C07D473/32—Nitrogen atom
    • C07D473/34—Nitrogen atom attached in position 6, e.g. adenine

Definitions

  • the disclosure belongs to the field of medicine and relates to a CDK2 inhibitor.
  • Cyclin-dependent kinases are members of the serine/threonine kinase subfamily, and each CDK/cyclin complex is responsible for a specific phase transition or progression within the cell cycle, which plays an important role in regulating eukaryotic cell division and important role in proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits called cyclins. At least 16 mammalian cell cyclins have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312).
  • Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important regulators of cell cycle progression.
  • Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation and apoptosis (Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).
  • CDK2 Overexpression of CDK2 is associated with abnormal regulation of the cell cycle.
  • the cyclin E/CDK2 complex plays an important role in regulating the G1/S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and promotes S phase entry. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that allow DNA replication and inactivation of E2F to complete S phase (Nat.Rev.Drug.Discov.2015; 14( 2): 130-146).
  • Cyclin E is overexpressed in various cancers, especially breast cancer, lung cancer, leukemia, and lymphoma (Guo Cuiping et al., Regulation of Cyclin E and Malignant Tumors, International Journal of Oncology, 2012,39(005):337 -340), the amplification or overexpression of cyclin E is also associated with poor prognosis in ovarian, gastric, endometrial and other cancers.
  • CDK2 cyclin A/E
  • CDK2 also binds cyclin A for progression through S phase and participates in DNA repair.
  • major companies have identified and discovered a series of selective CDK 2 inhibitors for the treatment of cancer and other diseases, such as Seliciclib, Dinaciclib, etc., but in order to achieve better cancer treatment effects, better meet Market demand still requires the development of a new generation of selective CDK2 inhibitors with high efficiency and low toxicity.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • -L 1 - is selected from bond, C 1-6 alkylene, -O- and -NH-, and said C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkane Substituents of oxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;
  • R1 is Wherein ring A and ring B are each independently selected from aryl, heteroaryl and heterocycloalkyl, ring A and ring B together form a ring structure, the A ring is optionally substituted by one or more Z, The B ring is optionally substituted with one or more Z 2 ;
  • R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally each independently selected from one or more halogen, alkyl, alkoxy, cyano, amino, Substituent substitution of nitro, hydroxyl, hydroxyalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R 2 and R 3 together form a 3-8 membered ring, the 3-8 The membered ring is optionally substituted by one or more Z3;
  • R 4 is -L 2 -R 7 ;
  • R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Oxo , carboxyl and carboxylate substituent substitution;
  • R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more Z ;
  • -L 2 - is selected from bond, C 1-6 alkylene, -O- and -NH-, the C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkoxy , haloalkyl, haloalkoxy, halogen, cyano, amino and nitro substituents;
  • R is an alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group, most preferably a methyl group;
  • R 9 and R 10 are each independently selected from hydrogen, alkyl and cycloalkyl, preferably selected from hydrogen, C 1-6 alkyl and 3-7 membered cycloalkyl, more preferably selected from hydrogen, C 1-3 alkane and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;
  • Each X is independently selected from O, S and NH, preferably from O;
  • the aryl groups are each independently optionally replaced by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkyla
  • Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl , nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, Carboxyl and carboxylate substituents are substituted.
  • the -L 1 - is selected from a bond, C 1-6 alkylene, -O- and -NH-, preferably selected from a bond, C 1-3 alkylene, -O- and -NH -, more preferably selected from a bond, C 1-2 alkylene, -O- and -NH-, particularly preferably selected from a bond, C 1-2 alkylene and -O-, most preferably O.
  • the -L 2 - is a bond or a C 1-6 alkylene group, preferably a bond or a C 1-3 alkylene group.
  • the R 7 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, Preferably C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl Base, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrimidyl Azolyl, thiazolyl and oxazolyl, most preferably selected from isopropyl, Cyclopropyl,
  • the R 5 is selected from hydrogen, C 1-6 alkyl and halogen, preferably hydrogen or C 1-3 alkyl.
  • the compound of formula I is wherein -L 1 -, R 1 , R 2 , R 3 , R 6 and Z 4 are as defined above.
  • the R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro and oxo, preferably selected from hydrogen, halogen and C 1-6 6 alkyl, more preferably hydrogen.
  • the compound of formula I is wherein -L 1 -, R 1 , R 6 and Z 4 are as defined above.
  • the compound of formula I is wherein R 1 , R 6 and Z 4 are as defined above.
  • the compound of formula I is wherein R 1 is as defined above.
  • the ring A and ring B are each independently selected from 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from 5-6 membered heterocyclic Alkyl, 6-10 membered aryl and 5-6 membered heteroaryl;
  • the ring A and ring B are each independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine Base, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrrolyl, tetrahydropyrrolyl, dihydropyrrolyl, triazolyl and piperidinyl, the A ring is optionally replaced by one or more Z is substituted, and the B ring is optionally substituted with one or more Z.
  • the Z is selected from halogen, cyano, hydroxyl, nitro , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 6 hydroxyalkyl; In some embodiments, the Z is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy ; In some embodiments, Said Z is selected from halogen, oxo and C 1-6 alkyl ; in some embodiments, said Z is selected from fluorine, chlorine, bromine, oxo, methyl, ethyl, propyl and iso Propyl.
  • the Z 2 is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 6 hydroxyalkyl
  • the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl are optionally selected from cyano, alkyl , alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkyloxy substituents, optionally,
  • the substituent is selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy
  • the substituent is selected from cyano, C 1-3 alkyl, C 1-3 alkoxy
  • the Z is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C
  • the 1-6 alkoxy groups are each independently optionally replaced by one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, hetero Aryl, heterocycloalkyl and heterocycloalkyloxy are substituted by substituents, optionally, the substituents are selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 alkane Oxygen, C 1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy
  • the Z is selected from halogen, hydroxyl, oxo, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy
  • Each is independently optionally selected from one or more groups selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkane and heterocycloalkyloxy substituents
  • the substituents are selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy , halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1- 3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyan
  • said Z is selected from fluorine, chlorine, bromine, oxo, hydroxyl, methyl, ethyl, propyl, isopropyl and methoxy; said methyl, ethyl, propyl , isopropyl and methoxy are each independently optionally replaced by one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl , heteroaryl, heterocycloalkyl and heterocycloalkyloxy substituents, optionally, the substituents are selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 3 alkoxy, C 1-3 deuterated alkoxy, heterocyclo
  • the Z 2 is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 6 hydroxyalkyl; In some embodiments, the Z is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy; In some embodiments, Said Z is selected from halogen, hydroxyl, oxo, C 1-6 alkyl and C 1-6 alkoxy ; in some embodiments, said Z is selected from fluorine, chlorine, bromine, oxo, Hydroxy, methyl, ethyl, propyl, isopropyl and methoxy; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are optionally selected from one or more of alkyl, alkoxy, Halogen, mercapto, hydroxyl, nitro, cyano,
  • the R 1 is selected from wherein Z2 is as defined above.
  • the R 1 is selected from wherein Z2 is as defined above.
  • the present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein,
  • -L 1 - is selected from bond, C 1-6 alkylene, -O- and -NH-, and said C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkane Substituents of oxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;
  • R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally selected from one or more of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Substituents of alkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl ; or R and R together form a 3-8 membered ring optionally replaced by One or more Z3 substitutions ;
  • R 4 is -L 2 -R 7 ;
  • R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Oxo , carboxyl and carboxylate substituent substitution;
  • R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more Z ;
  • -L 2 - is selected from bond, C 1-6 alkylene, -O- and -NH-, the alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkoxy, haloalkyl, Substituents of haloalkoxy, halogen, cyano, amino and nitro;
  • R is an alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group, most preferably a methyl group;
  • R 9 and R 10 are each independently selected from hydrogen, alkyl, cycloalkyl, preferably selected from hydrogen, C 1-6 alkyl and 3-7 membered cycloalkyl, more preferably selected from hydrogen, C 1-3 alkane and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;
  • Each X is independently selected from O, S and NH, preferably O;
  • the aryl groups are each independently optionally replaced by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkyla
  • Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more of deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto , hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo Substituent substitution of group, carboxyl group and carboxylate group;
  • n are each independently selected from 0, 1 or 2.
  • the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, which is a compound represented by formula II, wherein, R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and Z 2 are as defined in the compound shown in formula I,
  • the present disclosure provides a compound represented by formula II, wherein L 1 is -O-.
  • the present disclosure provides the compound shown in formula II, wherein, the R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro and Oxo is preferably selected from hydrogen, halogen and C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula II, wherein the R 2 and R 3 are each independently hydrogen.
  • the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl; said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxy and haloalkyl.
  • the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl; said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl.
  • the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, Methyl, ethyl, propyl, isopropyl, cyano, hydroxy and haloalkyl.
  • the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, Methyl, ethyl, propyl and isopropyl.
  • the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine Base, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, Propyl, isopropyl, cyano, hydroxy and haloalkyl.
  • the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine Base, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, Propyl and Isopropyl.
  • the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from isopropyl, Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 , said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, Chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxy, and haloalkyl.
  • the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from isopropyl, Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 , said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, Chlorine, bromine, methyl, ethyl, propyl, and isopropyl.
  • the present disclosure provides a compound represented by formula II, wherein the R 5 is selected from hydrogen, C 1-6 alkyl and halogen, and optionally, the R 5 is hydrogen or C 1- 3 alkyl.
  • the present disclosure provides a compound represented by formula II, wherein L 1 is -O-, R 2 and R 3 are each independently hydrogen, and R 5 is hydrogen.
  • the R 6 is H or The X is -O-, the R 9 and R 10 are each independently selected from hydrogen, alkyl and cycloalkyl, optionally, R 9 and R 10 are each independently selected from hydrogen, C1-6 alkyl and 3-7 membered cycloalkyl, optional, R 9 and R 10 are each independently selected from hydrogen, C 1-3 alkyl and cyclopropyl, optional, R 9 and R 10 are each independently hydrogen methyl or ethyl.
  • R 6 is H.
  • R is selected from
  • the present disclosure provides a compound represented by formula II , wherein the Z is selected from cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from one or more of alkyl, alkoxy , deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl and heterocycloalkyloxy substituents.
  • the present disclosure provides a compound represented by formula II , wherein the Z is selected from cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from cyano, C 1- Substituents of 6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy.
  • the present disclosure provides a compound represented by formula II , wherein the Z is selected from cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from one or more of cyano, methyl, Substituents of ethyl, methoxy, monodeuteromethoxy, dideuteriomethoxy, trideuteromethoxy, 3 to 7 membered cycloalkyl and 3 to 7 membered heterocycloalkyl.
  • the present disclosure provides the compound shown in formula II, wherein, said Z 2 is selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; the alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from one or more of cyano, methyl, ethyl, methoxy, a deuterium Substituents of methoxy, dideuteriomethoxy, trideuteriomethoxy, 3 to 7-membered cycloalkyl and 3 to 7-membered heterocycloalkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -COOR' and -CONR'(R"); the alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl are optionally selected from one or more of halogen, mercapto, hydroxyl, -NR'(R"), -SOR', -SO 2 R', -SO(NH)R' and -S(NH)R' are substituted by substituents;
  • Each R' or R" is independently selected from hydrogen, hydroxy and alkyl optionally substituted with one or more substituents selected from deuterium, halo, mercapto, hydroxy and cyano.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, mercapto and -NR'(R"), each R' or R" As defined in the compound shown in claim formula IG.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each R' or R" is independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each R' or R" is independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more deuteriums.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more hydroxyl groups.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more mercapto groups.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3-7 membered cycloalkyl is substituted by one or more -NR'(R"), and the R' or R" are independently hydrogen.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7-membered cycloalkyl is substituted by one or more -NR'(R"), and the R' or R" are independently hydrogen or C 1-6 alkyl, The C 1-6 alkyl is optionally substituted with one or more deuteriums.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7-membered cycloalkyl is substituted by one or more -NR'(R"), the R' or R" are independently hydrogen or methyl, and the methyl Optionally substituted with one, two or three deuteriums.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more halogens.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more hydroxyl groups.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more cyano groups.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more alkoxy groups.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more C 1-6 alkoxy groups.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-6 alkyl group is Substituted by one or more C 1-3 alkoxy groups.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently a C 1-3 alkyl group, and the one or more fluorine substituted .
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally substituted with one or more substituents selected from -SOR', -SO2R ', -SO(NH)R' and -S(NH)R';
  • Each R' or R" is independently a C 1-6 alkyl group optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally replaced by one or more SOR';
  • R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is Optionally substituted by one or more SOR', R' is C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more SO 2 R';
  • R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is Optionally substituted by one or more -SO 2 R';R' is C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more -SO(NH)R';
  • R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is Optionally substituted by one or more -SO(NH)R';R' is C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more -S(NH)R';
  • R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl, cyano.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more -S(NH)R';
  • R' is C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently -COOR', and said R' is independently selected from hydrogen, hydroxyl and C 1-6 alkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently -COOR', and the R' is hydrogen.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently -CONR'(R"), and said R' or R" independently selected from hydrogen or C 1-6 alkyl optionally substituted with one or more deuteriums.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently -CONR'(R"), and said R' or R" independently hydrogen or methyl optionally substituted with one, two or three deuteriums.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein L 1 is -O-.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkane A group, a cyano group, a hydroxyl group, a nitro group and an oxo group are preferably selected from hydrogen, halogen and C 1-6 alkyl, more preferably hydrogen.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 Selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C 1-4 alkyl , C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl yl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl,
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, Isopropyl, cyano, hydroxy and haloalkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and Isopropyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said R 5 is selected from hydrogen, C 1-6 alkyl and halogen.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein, wherein, said R 5 is hydrogen or C 1-3 alkyl.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein L 1 is -O-, R 2 and R 3 are each independently hydrogen, and R 5 is hydrogen.
  • the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
  • the present disclosure provides a compound of formula IG or a pharmaceutically acceptable salt thereof, wherein Z is selected from halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy , haloalkyl and hydroxyalkyl.
  • the present disclosure provides a compound represented by formula IG or a pharmaceutically acceptable salt thereof, wherein Z is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl and C 1-6 hydroxyalkyl.
  • the present disclosure provides a compound represented by formula IG or a pharmaceutically acceptable salt thereof, wherein Z 1 is halogen.
  • the present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein n is 0.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula III or a compound represented by formula IV or a pharmaceutically acceptable salt thereof,
  • R 4 , R 5 , X, R 9 , R 10 and Z 2 are as defined in the compound shown in formula I or the compound shown in formula II.
  • the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula V or a compound represented by formula VI or a pharmaceutically acceptable salt thereof,
  • R 4 , R 5 , X, R 9 , R 10 and Z 2 are respectively as defined in the compound shown in formula I or the compound shown in formula II.
  • the R 1 is selected from
  • the R 1 is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl, preferably selected from fluorine, chlorine, bromine, methyl, Ethyl, Propyl and Isopropyl.
  • said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl, preferably selected from fluorine, chlorine, bromine, methyl, Ethyl, Propyl and Isopropyl.
  • the R' or R" are independently hydrogen or hydroxyl.
  • the present disclosure also provides a series of compounds selected from:
  • the present disclosure also provides a series of compounds selected from:
  • the present disclosure also provides isotope substitutions of the above-mentioned compounds, and in some embodiments, the isotope substitutions are deuterium atom substitutions.
  • the present disclosure provides a deuterated version of the following compound,
  • the present disclosure also provides a preparation method of the compound or a pharmaceutically acceptable salt thereof in the first or second aspect.
  • the reagent for basic conditions is an organic base or an inorganic base
  • the organic base is selected from triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamide lithium, bistrimethyl Lithium silylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide
  • the inorganic base is selected from sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, acetic acid Potassium, Cesium Carbonate, Sodium Hydroxide and Lithium Hydroxide;
  • LG 3 is phenoxy or 4-nitrophenoxy.
  • the following steps are included: the step of removing the protecting group PG from the compound represented by formula X under acidic conditions,
  • R 2 , R 3 , R 4 , R 5 , L 1 and Z 2 are as defined in claim 1
  • R 6 is hydrogen
  • PG is an amino protecting group, which can be selected from tert-butyl, acetyl, trifluoro Acetyl, Trityl, Benzyl and Formyl.
  • the present disclosure also provides a compound represented by formula X,
  • R 2 , R 3 , R 4 , R 5 , L 1 and Z 2 are as defined in the compound shown in formula I, II, III, IV, V or IV, and PG is an amino protecting group, which can be selected from tert-butyl acetyl, trifluoroacetyl, trityl, benzyl and formyl.
  • the present disclosure also provides a compound represented by formula XI,
  • X is selected from halogen
  • R is selected from alkyl, deuterated alkyl, heterocycloalkyl and cycloalkyl.
  • the present disclosure also provides a pharmaceutical composition, which comprises the compound or pharmaceutically acceptable salt thereof as described in the first or second aspect, and at least one pharmaceutically acceptable carrier, diluent or excipient agent.
  • the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
  • the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
  • the present disclosure also provides a method for preventing and/or treating a patient suffering from a cyclin-dependent kinase-related disease, by administering to the patient a therapeutically effective amount of the compound described in the present disclosure or its A pharmaceutically acceptable salt or the aforementioned pharmaceutical composition.
  • the present disclosure also provides a method for preventing and/or treating a patient suffering from a cell cycle protein-related disease, by administering to the patient a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt or the aforementioned pharmaceutical composition.
  • the cyclin-dependent kinase-associated disease or cyclin-associated disease is preferably a cell proliferative disease, cancer or immune disease.
  • the cyclin-dependent kinase-associated disease or cyclin-associated disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer , colorectal, lung, kidney, skin, glioblastoma, neuroblastoma, and sarcoma.
  • the cancer is selected from cancers in which cyclin E1 and/or cyclin E2 are amplified.
  • the present disclosure also provides a method for preventing and/or treating a patient suffering from cancer, by administering to the patient a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition,
  • Said cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma Cell tumors and sarcomas.
  • the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases related to cyclin-dependent kinases.
  • the cyclin-dependent kinase is CDK2
  • the disease associated with the cyclin-dependent kinase is selected from cell proliferative diseases, cancer or immune diseases.
  • the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of cyclin-related diseases .
  • the cyclin is selected from cyclin E, such as cyclin E1, cyclin E2.
  • the cyclin-associated disease is selected from cell proliferative disease, cancer or immune disease.
  • the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for treating cancer.
  • the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer Carcinoma, glioblastoma, neuroblastoma, and sarcoma.
  • the cancer is selected from cancers in which cyclin E1 and/or cyclin E2 are amplified.
  • the pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts.
  • the disclosed compounds have a good inhibitory effect on cyclin-dependent kinases, and the IC50 value of the inhibitory activity of CDK2/cyclin E is between 0.01 and 1000nM, and the inhibitory activity of some compounds on CDK2/cyclin E
  • the IC 50 value of the inhibitory activity of some compounds on CDK2/cyclin E is in the range of 0.01 to 300nM, and the IC 50 value of the inhibitory activity of some compounds on CDK2/cyclin E is in the range of 0.01
  • the inhibitory activity of some compounds on CDK2/cyclin E has IC50 values from 0.01 to 100nM up to 200nM, and the inhibitory activity of some compounds on CDK2/cyclin E has IC50 values ⁇ 100nM.
  • Some embodiments provide compounds that achieve ⁇ 50 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve ⁇ 20 nM inhibitory activity against CDK2/cyclin E. Still other embodiments provide compounds that achieve ⁇ 10 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve ⁇ 5 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve ⁇ 1 nM inhibitory activity against CDK2/cyclin E.
  • the disclosed compound also has good inhibitory effect on CDK2/cyclin A.
  • Some embodiments provide compounds that achieve ⁇ 500 nM inhibitory activity against CDK2/cyclin E.
  • Other embodiments provide compounds that achieve ⁇ 200 nM inhibitory activity against CDK2/cyclin E.
  • Other embodiments provide compounds that achieve ⁇ 150 nM inhibitory activity against CDK2/cyclin E.
  • Still other embodiments provide compounds that achieve ⁇ 100 nM inhibitory activity against CDK2/cyclin E.
  • Other embodiments provide compounds that achieve ⁇ 50 nM inhibitory activity against CDK2/cyclin E.
  • Other embodiments provide compounds that achieve ⁇ 20 nM inhibitory activity against CDK2/cyclin E.
  • Still other embodiments provide compounds that achieve ⁇ 10 nM inhibitory activity against CDK2/cyclin E.
  • the compounds of the present disclosure have weak inhibitory activity on other kinases such as CDK4, CDK5, CDK7, CDK9 or GSK3 ⁇ , and have CDK2-specific selection.
  • the disclosed compounds may exist in particular geometric or stereoisomeric forms.
  • This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
  • tautomer or tautomeric form refers to structural isomers of different energies that can interconvert via a low energy barrier.
  • proton tautomers also known as prototropic tautomers
  • interconversions via migration of a proton such as keto-enol and imine-enamine, lactam-lactam, pyrazole base isomerization.
  • Compounds of the present disclosure may be asymmetric, eg, possess one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers.
  • Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature.
  • isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
  • deuterium when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation).
  • exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium.
  • the present disclosure also includes various deuterated forms of compounds of formula I. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom.
  • deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula I, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane Tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • C 1-6 alkyl optionally substituted by halogen or cyano means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
  • the bond Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond can be or both Two configurations.
  • the bond configuration is not specified, i.e. the key The configuration of can be E type or Z type, or contain both E and Z configurations.
  • pharmaceutical composition means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as a physiologically acceptable carrier and excipient.
  • the purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
  • pharmaceutically acceptable excipient or “pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration for use in humans or livestock animals. excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifier.
  • an effective amount encompasses an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition.
  • An effective amount also means an amount sufficient to allow or facilitate diagnosis.
  • Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects.
  • An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
  • alkyl refers to a saturated aliphatic hydrocarbon group, which is a linear or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms.
  • Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylp
  • alkyl groups containing 1 to 6 carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, etc.
  • Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkyloxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • alkylene means what remains of an alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms.
  • Alkylene groups containing 1 to 6 carbon atoms non-limiting examples include methylene (-CH 2 -), ethylene (such as -CH 2 CH 2 - or -CH(CH 3 )-), ethylene Propyl (eg -CH 2 CH 2 CH 2 - or -CH(CH 2 CH 3 )-), butylene (eg -CH 2 CH 2 CH 2 CH 2 -).
  • an alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 7 carbon atoms.
  • monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.
  • multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings.
  • Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • the cycloalkyl ring may be fused to an aryl or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo Heptyl, etc.
  • Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio Substituted by group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • heterocycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen or A heteroatom of S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • m is an integer from 0 to 2
  • it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms.
  • Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperrolyl, Pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc.
  • Multicyclic heterocycloalkyls include spiro, fused and bridged heterocycloalkyls.
  • Non-limiting examples of "heterocycloalkyl" include:
  • heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
  • Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkane Thio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated pi-electron system, such as benzene base and naphthyl.
  • the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
  • Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, hetero Cycloalkylthio, oxo, carboxyl or carboxylate substituted.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • the heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered.
  • Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl, Wait.
  • the heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
  • Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio Substituted by group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • spiro refers to a compound in which two rings share one atom.
  • spirocycloalkyl refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl.
  • spirocarbocycle refers to the ring system in a spirocycloalkyl.
  • Non-limiting examples of spirocycloalkyl groups include:
  • spiroheterocycloalkyl refers to a polycyclic heterocycloalkyl group that shares one atom (called a spiro atom) between a 5- to 20-membered monocyclic ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) heteroatoms of m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • Spiroheterocycloalkyl is divided into single spiroheterocycloalkyl, double spiroheterocycloalkyl or polyspiroheterocycloalkyl according to the number of spiro atoms shared between rings, preferably single spiroheterocycloalkyl and double spiroheterocycloalkyl Spiroheterocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocycloalkyl group.
  • Spiroheterocycle refers to the ring system in a spiroheterocycloalkyl.
  • Non-limiting examples of spiroheterocycloalkyl include:
  • fused ring and “joined ring” are used interchangeably and refer to a compound in which two or more rings are fused by sharing two adjacent atoms.
  • fused cycloalkyl refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups.
  • fused carbocycle refers to the ring system in a fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:
  • fused heterocycloalkyl refers to a 5 to 20 membered polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), The remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • fused heterocycle refers to the ring system in a fused heterocycloalkyl group.
  • fused heterocycloalkyl include:
  • fused heteroaryl may contain 5-14 ring atoms (including at least one heteroatom), which is formed by connecting two or more ring structures with two adjacent atoms.
  • Aromatic condensed ring structure, including carbon atoms, nitrogen atoms and sulfur atoms can be oxo, preferably "5-12 membered fused heteroaryl", “7-12 membered fused heteroaryl”, “9-12 membered Fused heteroaryl” etc., such as benzofuryl, benzoisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazole, indazolyl, benzotri Azolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinolinyl Azolinyl
  • Fused heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, carboxyl group or carboxylate group.
  • bridged ring refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
  • bridged cycloalkyl refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated ⁇ -electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged cycloalkyl groups include:
  • bridged heterocycloalkyl refers to a 5 to 14 membered, polycyclic heterocycloalkyl group of 5 to 14 membered, any two rings sharing two atoms not directly attached, which may contain one or more double bonds, but none of the rings has A fully conjugated ⁇ -electron system wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon.
  • it is 6 to 14 yuan, more preferably 7 to 10 yuan.
  • bridged heterocycloalkyl groups preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • bridged heterocycloalkyl groups include:
  • alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
  • alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
  • Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate substituted.
  • the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl,
  • hydroxyl refers to a -OH group.
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
  • heterocycloalkyloxy refers to heterocycloalkyl-O-, wherein heterocycloalkyl is as defined above.
  • heterocycloalkylthio refers to heterocycloalkyl-S-, wherein heterocycloalkyl is as defined above.
  • a carbon atom is linked to an oxygen atom by a double bond, where a ketone or aldehyde group is formed.
  • amino refers to -NH2 .
  • cyano refers to -CN.
  • nitro refers to -NO2 .
  • substituted means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
  • Substituted by one or more means that it can be substituted by single or multiple substituents. When substituted by a plurality of substituents, it may be a plurality of the same substituents, or one or a combination of a plurality of different substituents.
  • NMR nuclear magnetic resonance
  • MS mass spectroscopy
  • MS was determined by Shimadzu 2010Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
  • HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200LC high pressure liquid chromatography (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).
  • Chiralpak IC-3 100 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 150 ⁇ 4.6mm I.D., 3um, Chiralpak AD-3 50 ⁇ 4.6mm I.D., 3um, Chiralpak AS-3 150 ⁇ 4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OD-3 150 ⁇ 4.6mm I.D., 3um, Chiralcel OD-3 100 ⁇ 4.6mm I.D., 3 ⁇ m, ChiralCel OJ-H 150 ⁇ 4.6mm I.D., 5um, Chiralcel OJ-3 150 ⁇ 4.6mm I.D., 3um column;
  • the thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate.
  • the specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ⁇ 0.5mm.
  • the chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
  • the CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
  • the known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
  • the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
  • the argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
  • the hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
  • the pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
  • the hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
  • the solution refers to an aqueous solution.
  • reaction temperature is room temperature, which is 20°C to 30°C.
  • the monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent
  • TLC thin-layer chromatography
  • the ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
  • 2-chloro-3-fluoropyridine (12.6g, 75.7mmol) was dissolved in 40mL of anhydrous tetrahydrofuran, and n-butyllithium (35.8mL, 2.5N solution in tetrahydrofuran) was slowly added dropwise to maintain the internal temperature at Stirring was continued for 1 hour at -55°C, and compound 1B (8.5g, 63.8mmol) dissolved in 40mL of anhydrous THF was slowly added dropwise to the reaction solution, and stirring was continued at -65°C for 1 hour after the addition was complete.
  • compound 1D (0.9g, 4.6mmol) was dissolved in 5mL of N,N-dimethylformamide, cooled to 0-5°C in an ice bath, cesium carbonate (4.45g, 13.6mmol) was added, and stirred at constant temperature for 20 Minutes later, methyl iodide (0.71g, 5mmol) was added dropwise. After the addition, it was slowly raised to room temperature for 2 hours. After the reaction was complete, it was quenched with 50mL of water, followed by extraction with ethyl acetate (30mL ⁇ 3), and the organic phases were combined.
  • compound 1H-pyrazole-3-carboxylic acid 2A (3.0g, 26.8mmol), O-(7-nitrobenzotriazole)-N,N,N,N-tetramethylurea Hexafluorophosphate (12.2g, 32.1mmol), N,N-diisopropylethylamine (6.9g, 53.6mmol) and 2,2-dimethoxyethane-1-amine 2B (3.4g, 32.1 mmol) was dissolved in N,N-dimethylformamide (20 mL). The reaction was carried out at room temperature for 12 hours.
  • Dissolve compound 3D (1.2g, 7.7mmol) in 10mL of methanol, add 2mL of water, add lithium hydroxide (368mg, 15.4mmol), react at room temperature for 5 hours, adjust the pH to 1. Extract with ethyl acetate, combine the organic phases, wash the organic phases, dry, and concentrate under reduced pressure. The residue is purified by C-18 reverse phase chromatography to obtain the title compound 3E (850 mg, yield 83.6%).
  • reaction solution was quenched with saturated ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL*3).
  • the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product of the title compound 4B (35 mg).
  • the reaction solution was diluted with 300 mL of ethyl acetate, washed with 300 mL of water, the organic phase was separated, and washed twice with 300 mL of saturated aqueous sodium chloride solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. Concentration gave the crude product of the title compound, which was separated and purified by silica gel chromatography with petroleum ether/ethyl acetate as the eluent to obtain the title compound 10B (6.1 g, yield: 54%).
  • methyl magnesium bromide (0.9 mL, 1.773 mmol, 3M) was added dropwise to a solution of compound 10D (0.2 g, 0.886 mmol) in tetrahydrofuran (10 mL), and slowly returned to room temperature, reaction 2 Hour.
  • Test Example 1 Detection of cyclin-dependent kinase activity of the disclosed compounds.
  • Compound dilutions were transferred to each well of the assay plate using an Echo 550 (784075, Greiner). Seal the assay plate and centrifuge the assay plate at 1000g for 1 min; prepare 2x enzyme in 1x kinase buffer ((40mM Tris-HCl, pH 7.4, 20mM MgCl2, 0.1mg/ml BSA, 50uM DTT) by dissolving 2.5 ⁇ l of 2x enzyme Add to 384-well assay plate, centrifuge the plate at 1000g for 30s, and let it stand at room temperature for 10 minutes. Prepare 2x substrate and ATP mix in 1x kinase buffer, add 2.5 ⁇ l 2x substrate and ATP mix to start the reaction.
  • 1x kinase buffer ((40mM Tris-HCl, pH 7.4, 20mM MgCl2, 0.1mg/ml BSA, 50uM DTT)
  • the luminescent signal of each well was read on an Envision 2104 plate reader.
  • Percent inhibition 100 - (cmpd signal - Ave_PC signal) / (Ave_VC signal - Ave_PC signal) x 100. cmpd signal: compound signal; Ave_PC signal: average signal of positive control; Ave_VC signal: average signal of vehicle group.
  • Test Example 2 Test of the Inhibitory Activity of the Compounds of the Disclosure on Ovarian Cancer Cells (OVCAR3)
  • Ovarian cancer cells OVCAR3 (derived from ATCC) were cultured in RPMI 1640 medium with 10% FBS in a cell culture incubator with 37% and 5% CO 2 . On the first day, cells were plated in 96-well plates at a concentration of 2500 cells/well and incubated overnight in an incubator. Compound treatment was performed on the second day, the highest concentration of compound treatment was 10 ⁇ M, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.1%. After the cells continued to be cultured in the incubator for 7 days, the cell viability was tested using the Celltiter Glo detection kit (Promega), and the test method was consistent with the operation method provided by the kit. Data were processed and IC50 calculated using GraphPad Prism 8.
  • X log value of compound concentration
  • Y % inhibition.

Abstract

Disclosed are a cyclin-dependent kinase 2 (CDK2) inhibitor as shown in formula I, a preparation method therefor and use thereof. The compound of formula I can be used as a CDK inhibitor for preventing and/or treating diseases associated with CDK or cyclin such as cell proliferative diseases, cancer, or immune diseases.

Description

CDK2抑制剂及其制备方法和用途CDK2 inhibitor and its preparation method and use 技术领域technical field
本公开属于医药领域，涉及一种CDK2抑制剂。The disclosure belongs to the field of medicine and relates to a CDK2 inhibitor.
背景技术Background technique
细胞周期蛋白-依赖性激酶(CDK)是丝氨酸/苏氨酸激酶亚家族的成员，每个CDK/细胞周期蛋白复合物负责细胞周期内特定期的转换或进展，其在调节真核细胞***和增殖中发挥重要作用。细胞周期蛋白-依赖性激酶催化单元被称为细胞周期蛋白的调节亚基激活。已经鉴定出至少16种哺乳动物细胞周期蛋白(Annu.Rev.Pharmacol.Toxicol.(1999)39:295-312)。细胞周期蛋白B/CDK1、细胞周期蛋白A/CDK2、细胞周期蛋白E/CDK2、细胞周期蛋白D/CDK4、细胞周期蛋白D/CDK6和可能的其他heterodynes是细胞周期进展的重要调节因子。细胞周期蛋白/CDK heterodynes的其他功能包括转录调节、DNA修复、分化和凋亡(Annu.Rev.Cell.Dev.Biol.(1997)13:261-291)。Cyclin-dependent kinases (CDKs) are members of the serine/threonine kinase subfamily, and each CDK/cyclin complex is responsible for a specific phase transition or progression within the cell cycle, which plays an important role in regulating eukaryotic cell division and important role in proliferation. Cyclin-dependent kinase catalytic units are activated by regulatory subunits called cyclins. At least 16 mammalian cell cyclins have been identified (Annu. Rev. Pharmacol. Toxicol. (1999) 39:295-312). Cyclin B/CDK1, cyclin A/CDK2, cyclin E/CDK2, cyclin D/CDK4, cyclin D/CDK6 and possibly other heterodynes are important regulators of cell cycle progression. Other functions of cyclin/CDK heterodynes include transcriptional regulation, DNA repair, differentiation and apoptosis (Annu. Rev. Cell. Dev. Biol. (1997) 13:261-291).
近年来，乳腺癌治疗领域最大的进展无疑是CDK4/6单用或联合内分泌治疗在激素受体阳性晚期乳腺癌，如帕博西尼(palbociclib)、瑞博西尼(ribociclib)和玻玛西尼(abemaciclib)已被批准与芳香酶抑制剂组合用于治疗绝经后妇女的激素受体(HR)-阳性、人类表皮生长因子受体2(HER2)-阴性晚期或转移性乳腺癌，并且帕博西尼和玻玛西尼(abemaciclib)已被批准与氟维司群组合用于在内分泌疗法后疾病进展后治疗绝经后妇女的激素受体(HR)-阳性、人类表皮生长因子受体2(HER2)-阴性晚期或转移性乳腺癌(Nature Reviews(2016)13:417-430、J Clin Oncol 2017,35,2875-2884)。尽管CDK4/6抑制剂在***受体ER阳性转移性乳腺癌中显示出显著的临床功效，但与其他激酶一样，它们的作用可能随着时间的推移被原发性或获得性抗性的发展限制。In recent years, the greatest progress in the field of breast cancer treatment is undoubtedly the CDK4/6 monotherapy or combined with endocrine therapy in hormone receptor positive advanced breast cancer, such as palbociclib, ribociclib and bomaciclib Abemaciclib has been approved in combination with an aromatase inhibitor for the treatment of postmenopausal women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer, and Bociclib and abemaciclib have been approved in combination with fulvestrant for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 in postmenopausal women after disease progression on endocrine therapy (HER2)-negative advanced or metastatic breast cancer (Nature Reviews (2016) 13:417-430, J Clin Oncol 2017, 35, 2875-2884). Although CDK4/6 inhibitors have shown remarkable clinical efficacy in estrogen receptor ER-positive metastatic breast cancer, like other kinases, their effects may be over time controlled by primary or acquired resistance. development restrictions.
CDK2的过表达与细胞周期的异常调节有关。细胞周期蛋白E/CDK2复合物在调节G1/S转换、组蛋白生物合成和中心体复制中起重要作用。细胞周期蛋白D/Cdk4/6和细胞周期蛋白E/Cdk2对Rb的进行性磷酸化释放G1转录因子E2F，并促进S期进入。在早期S期期间细胞周期蛋白A/CDK2的激活促进内源性底物的磷酸化，其允许DNA复制和E2F的失活，以完成S期(Nat.Rev.Drug.Discov.2015；14(2):130-146)。细胞周期蛋白E在多种癌症中过度表达，特别是乳腺癌、肺癌、白血病、淋巴瘤(郭翠萍等，细胞周期蛋白E的调控与恶性肿瘤，国际肿瘤学杂志,2012,39(005):337-340)，细胞周期蛋白E的扩增或过表达也与卵巢癌、胃癌、子宫内膜癌和其他癌症的不良预后有关。Overexpression of CDK2 is associated with abnormal regulation of the cell cycle. The cyclin E/CDK2 complex plays an important role in regulating the G1/S transition, histone biosynthesis and centrosome duplication. Progressive phosphorylation of Rb by cyclin D/Cdk4/6 and cyclin E/Cdk2 releases the G1 transcription factor E2F and promotes S phase entry. Activation of cyclin A/CDK2 during early S phase promotes phosphorylation of endogenous substrates that allow DNA replication and inactivation of E2F to complete S phase (Nat.Rev.Drug.Discov.2015; 14( 2): 130-146). Cyclin E is overexpressed in various cancers, especially breast cancer, lung cancer, leukemia, and lymphoma (Guo Cuiping et al., Regulation of Cyclin E and Malignant Tumors, International Journal of Oncology, 2012,39(005):337 -340), the amplification or overexpression of cyclin E is also associated with poor prognosis in ovarian, gastric, endometrial and other cancers.
研究表明，抑制CDK2激酶会诱导肿瘤细胞调亡，但对于正常细胞只会造成较小的损伤。CDK激酶的单体形式是无活性的，而细胞周期蛋白A/E与 CDK2结合并促发磷酸化的结合激活CDK2。CDK2还可结合细胞周期蛋白A用于S期的整个进展并参与DNA修复。近几年各大公司分别鉴定发现了一系列选择性抑制CDK 2的抑制剂，用于治疗癌症等疾病，如Seliciclib、Dinaciclib等，但是为了达到更好的癌症治疗效果的目的，更好的满足市场需求，仍需要开发出新一代的高效低毒的选择性CDK2抑制剂。Studies have shown that inhibition of CDK2 kinase induces tumor cell apoptosis, but causes only minor damage to normal cells. The monomeric form of the CDK kinase is inactive, whereas the binding of cyclin A/E to CDK2 and triggering phosphorylation activates CDK2. CDK2 also binds cyclin A for progression through S phase and participates in DNA repair. In recent years, major companies have identified and discovered a series of selective CDK 2 inhibitors for the treatment of cancer and other diseases, such as Seliciclib, Dinaciclib, etc., but in order to achieve better cancer treatment effects, better meet Market demand still requires the development of a new generation of selective CDK2 inhibitors with high efficiency and low toxicity.
发明内容Contents of the invention
第一方面，本公开提供式I所示的化合物或其可药用的盐，In a first aspect, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022103293-appb-000001
Figure PCTCN2022103293-appb-000001
其中，-L 1-选自键、C 1-6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取代基取代； Wherein, -L 1 - is selected from bond, C 1-6 alkylene, -O- and -NH-, and said C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkane Substituents of oxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;
R 1为
Figure PCTCN2022103293-appb-000002
其中环A和环B各自独立地选自芳基、杂芳基和杂环烷基，环A和环B一起形成并环结构，所述A环任选地被一个或多个Z 1取代，所述B环任选地被一个或多个Z 2取代； R1 is
Figure PCTCN2022103293-appb-000002
Wherein ring A and ring B are each independently selected from aryl, heteroaryl and heterocycloalkyl, ring A and ring B together form a ring structure, the A ring is optionally substituted by one or more Z, The B ring is optionally substituted with one or more Z 2 ;
R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基、氧代基、环烷基、杂环烷基、芳基和杂芳基，其中所述C 1-6烷基、环烷基、杂环烷基、芳基或杂芳基任选各自独立地被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环烷基、芳基和杂芳基的取代基取代；或R 2和R 3一起形成3-8元环，所述3-8元环任选地被一个或多个Z 3取代； R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally each independently selected from one or more halogen, alkyl, alkoxy, cyano, amino, Substituent substitution of nitro, hydroxyl, hydroxyalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R 2 and R 3 together form a 3-8 membered ring, the 3-8 The membered ring is optionally substituted by one or more Z3;
R 4为-L 2-R 7； R 4 is -L 2 -R 7 ;
R 5选自氢、烷基和卤素，其中所述烷基任选被一个或多个选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Oxo , carboxyl and carboxylate substituent substitution;
R 7选自氢、烷基、环烷基、杂环烷基、芳基和杂芳基，任选地被一个或多个Z 4取代； R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more Z ;
-L 2-选自键、C 1-6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取 代基取代； -L 2 -is selected from bond, C 1-6 alkylene, -O- and -NH-, the C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkoxy , haloalkyl, haloalkoxy, halogen, cyano, amino and nitro substituents;
R 6选自H、R 8-(C＝O)-和
Figure PCTCN2022103293-appb-000003
R 6 is selected from H, R 8 -(C=O)- and
Figure PCTCN2022103293-appb-000003
R 8为烷基，优选为C 1-6烷基，更优选为C 1-3烷基，最优选为甲基； R is an alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group, most preferably a methyl group;
R 9和R 10各自独立地选自氢、烷基和环烷基，优选选自氢、C 1-6烷基和3-7元环烷基，更优选选自氢、C 1-3烷基和环丙基，最优选选自氢、甲基和乙基； R 9 and R 10 are each independently selected from hydrogen, alkyl and cycloalkyl, preferably selected from hydrogen, C 1-6 alkyl and 3-7 membered cycloalkyl, more preferably selected from hydrogen, C 1-3 alkane and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;
每个X选自独立地O、S和NH，优选自O；Each X is independently selected from O, S and NH, preferably from O;
Z 1、Z 2、Z 3和Z 4各自独立地选自卤素、氰基、羟基、硝基、氧代基、烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-SR'、-SOR'、-SO 2R'、-SO 2NR'(R”)、-NR'(R”)、-COR'、-COOR'、-CONR'(R”)和-(P＝O)R'(R”)；所述烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、烯基、炔基、烷氧基、氘代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic Alkyl, aryl, heteroaryl, -SR', -SOR ', -SO2R ', -SO2NR'(R"), -NR'(R"), -COR', -COOR', -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and hetero The aryl groups are each independently optionally replaced by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, Cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylic acid substituent substitution of ester group;
每个R'或R”独立地选自氢、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基或杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代。Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl , nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, Carboxyl and carboxylate substituents are substituted.
一些实施方案中，所述的Z 1、Z 2、Z 3和Z 4各自独立地选自卤素、氰基、羟基、硝基、氧代基、烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-SR'、-SOR'、-SO 2R'、-SO 2NR'(R”)、-NR'(R”)、-COR'、-COOR'、-CONR'(R”)和-(P＝O)R'(R”)；所述烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代。一些实施方案中，所述-L 1-选自键、C 1-6亚烷基、-O-和-NH-，优选选自键、C 1-3亚烷基、-O-和-NH-，更优选选自键、C 1-2亚烷基、-O-和-NH-，特别优选选自键、C 1-2亚烷基和-O-，最优选为O。 In some embodiments, said Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkane radical, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, -SR', -SOR', -SO 2 R', -SO 2 NR'(R"), -NR'(R"), -COR', -COOR', -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, hetero Cycloalkyl, aryl and heteroaryl are each independently optionally selected from the group consisting of one or more alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitr group, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl and Carboxylate substituent substitution. In some embodiments, the -L 1 - is selected from a bond, C 1-6 alkylene, -O- and -NH-, preferably selected from a bond, C 1-3 alkylene, -O- and -NH -, more preferably selected from a bond, C 1-2 alkylene, -O- and -NH-, particularly preferably selected from a bond, C 1-2 alkylene and -O-, most preferably O.
一些实施方案中，所述-L 2-为键或C 1-6亚烷基，优选为键或C 1-3亚烷基。 In some embodiments, the -L 2 - is a bond or a C 1-6 alkylene group, preferably a bond or a C 1-3 alkylene group.
一些实施方案中，所述R 7选自C 1-6烷基、C 3-7环烷基、3-7元杂环烷基、6-12元芳基、5-12元杂芳基，优选为C 1-4烷基、C 3-5环烷基、6-10元芳基和5-6元杂芳基，更优选选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、苯基、萘基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪 唑基、吡唑基、噻唑基和噁唑基，最优选选自异丙基、
Figure PCTCN2022103293-appb-000004
环丙基、苯基和吡啶基；所述R 7任选地被一个或多个Z 4取代。 In some embodiments, the R 7 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl, 5-12 membered heteroaryl, Preferably C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl Base, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrimidyl Azolyl, thiazolyl and oxazolyl, most preferably selected from isopropyl,
Figure PCTCN2022103293-appb-000004
Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 .
一些实施方案中，所述R 5选自氢、C 1-6烷基和卤素，优选为氢或C 1-3烷基。 In some embodiments, the R 5 is selected from hydrogen, C 1-6 alkyl and halogen, preferably hydrogen or C 1-3 alkyl.
一些实施方案中，所述式I化合物为
Figure PCTCN2022103293-appb-000005
Figure PCTCN2022103293-appb-000006
Figure PCTCN2022103293-appb-000007
其中-L 1-、R 1、R 2、R 3、R 6和Z 4如上述所定义。 In some embodiments, the compound of formula I is
Figure PCTCN2022103293-appb-000005
Figure PCTCN2022103293-appb-000006
Figure PCTCN2022103293-appb-000007
wherein -L 1 -, R 1 , R 2 , R 3 , R 6 and Z 4 are as defined above.
一些实施方案中，所述R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基和氧代基，优选选自氢、卤素和C 1-6烷基，更优选为氢。 In some embodiments, the R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro and oxo, preferably selected from hydrogen, halogen and C 1-6 6 alkyl, more preferably hydrogen.
一些实施方案中，所述式I化合物为
Figure PCTCN2022103293-appb-000008
Figure PCTCN2022103293-appb-000009
Figure PCTCN2022103293-appb-000010
其中-L 1-、R 1、R 6和Z 4如上述所定义。 In some embodiments, the compound of formula I is
Figure PCTCN2022103293-appb-000008
Figure PCTCN2022103293-appb-000009
Figure PCTCN2022103293-appb-000010
wherein -L 1 -, R 1 , R 6 and Z 4 are as defined above.
一些实施方案中，所述式I化合物为
Figure PCTCN2022103293-appb-000011
Figure PCTCN2022103293-appb-000012
Figure PCTCN2022103293-appb-000013
其中R 1、R 6和Z 4如上述所定义。 In some embodiments, the compound of formula I is
Figure PCTCN2022103293-appb-000011
Figure PCTCN2022103293-appb-000012
Figure PCTCN2022103293-appb-000013
wherein R 1 , R 6 and Z 4 are as defined above.
一些实施方案中，所述式I化合物为
Figure PCTCN2022103293-appb-000014
Figure PCTCN2022103293-appb-000015
Figure PCTCN2022103293-appb-000016
Figure PCTCN2022103293-appb-000017
其中R 1如上述所定义。 In some embodiments, the compound of formula I is
Figure PCTCN2022103293-appb-000014
Figure PCTCN2022103293-appb-000015
Figure PCTCN2022103293-appb-000016
Figure PCTCN2022103293-appb-000017
wherein R 1 is as defined above.
一些实施方案中，所述环A和环B各自独立地选自3-7元杂环烷基、6-12元芳基和5-12元杂芳基，优选选自5-6元杂环烷基、6-10元芳基和5-6元杂芳基；一些实施方案中，所述环A和环B各自独立地选自苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、噁唑基、吡咯基、四氢吡咯基、二氢吡咯基、三氮唑基和哌啶基，所述A环任选地被一个或多个Z 1取代，所述B环任选地被一个或多个Z 2取代。 In some embodiments, the ring A and ring B are each independently selected from 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from 5-6 membered heterocyclic Alkyl, 6-10 membered aryl and 5-6 membered heteroaryl; In some embodiments, the ring A and ring B are each independently selected from phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine Base, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrrolyl, tetrahydropyrrolyl, dihydropyrrolyl, triazolyl and piperidinyl, the A ring is optionally replaced by one or more Z is substituted, and the B ring is optionally substituted with one or more Z.
一些实施方案中，所述Z 1选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基；一些实施方案中，所述Z 1选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基和C 1-6烷氧基；一些实施方案中，所述Z 1选自卤素、氧代基和C 1-6烷基；一些实施方案中，所述Z 1选自氟、氯、溴、氧代基、甲基、乙基、丙基和异丙基。 In some embodiments, the Z is selected from halogen, cyano, hydroxyl, nitro , oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 6 hydroxyalkyl; In some embodiments, the Z is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy ; In some embodiments, Said Z is selected from halogen, oxo and C 1-6 alkyl ; in some embodiments, said Z is selected from fluorine, chlorine, bromine, oxo, methyl, ethyl, propyl and iso Propyl.
一些实施方案中，所述Z 2选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基，所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基任选被一个或多个选自氰基、烷基、烷氧基、氘代烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基、杂环烷基和杂环烷基氧基的取代基取代，可选地，所述取代基选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6氘代烷氧基、卤素、杂芳基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、C 1-3烷基、C 1-3烷氧基、C 1-3氘代烷氧基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、甲基、乙基、甲氧基、氘代甲氧基、乙氧基和四氢呋喃基氧基。 In some embodiments, the Z 2 is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 6 hydroxyalkyl, the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl are optionally selected from cyano, alkyl , alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl, and heterocycloalkyloxy substituents, optionally, The substituent is selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy Optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy Optionally, the substituent is selected from cyano, methyl, ethyl, methoxy, deuterated methoxy, ethoxy and tetrahydrofuranyloxy.
一些实施方案中，所述Z 2选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基和C 1-6烷氧基各自独立地任选被一个或多个选自氰基、烷基、烷氧基、氘代烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基、杂环烷基和杂环烷基氧基的取代基取代，可选地，所述取代基选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6氘代烷氧基、卤素、杂芳基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、C 1-3烷基、C 1-3烷氧基、C 1-3氘代烷氧基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、甲基、乙基、甲氧基、氘代 甲氧基、乙氧基和四氢呋喃基氧基。 In some embodiments, the Z is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C The 1-6 alkoxy groups are each independently optionally replaced by one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, hetero Aryl, heterocycloalkyl and heterocycloalkyloxy are substituted by substituents, optionally, the substituents are selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1- 6 deuterated alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 alkane Oxygen, C 1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, methyl, ethyl, methoxy, deuterated Methoxy, ethoxy and tetrahydrofuryloxy.
一些实施方案中，所述Z 2选自卤素、羟基、氧代基、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基和C 1-6烷氧基各自独立地任选被一个或多个选自氰基、烷基、烷氧基、氘代烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基、杂环烷基和杂环烷基氧基的取代基取代，可选地，所述取代基选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6氘代烷氧基、卤素、杂芳基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、C 1-3烷基、C 1-3烷氧基、C 1-3氘代烷氧基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、甲基、乙基、甲氧基、氘代甲氧基、乙氧基和四氢呋喃基氧基。 In some embodiments, the Z is selected from halogen, hydroxyl, oxo, C 1-6 alkyl and C 1-6 alkoxy, and the C 1-6 alkyl and C 1-6 alkoxy Each is independently optionally selected from one or more groups selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkane and heterocycloalkyloxy substituents, optionally, the substituents are selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy , halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 alkoxy, C 1- 3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, methyl, ethyl, methoxy, deuterated methoxy, ethoxy group and tetrahydrofuryloxy group.
一些实施方案中，所述Z 2选自氟、氯、溴、氧代基、羟基、甲基、乙基、丙基、异丙基和甲氧基；所述甲基、乙基、丙基、异丙基和甲氧基各自独立地任选被一个或多个选自氰基、烷基、烷氧基、氘代烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基、杂环烷基和杂环烷基氧基的取代基取代，可选地，所述取代基选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6氘代烷氧基、卤素、杂芳基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、C 1-3烷基、C 1-3烷氧基、C 1-3氘代烷氧基、杂环烷基和杂环烷基氧基，可选地，所述取代基选自氰基、甲基、乙基、甲氧基、氘代甲氧基、乙氧基和四氢呋喃基氧基。 In some embodiments, said Z is selected from fluorine, chlorine, bromine, oxo, hydroxyl, methyl, ethyl, propyl, isopropyl and methoxy; said methyl, ethyl, propyl , isopropyl and methoxy are each independently optionally replaced by one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl , heteroaryl, heterocycloalkyl and heterocycloalkyloxy substituents, optionally, the substituents are selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, C 1-3 alkyl, C 1-3 3 alkoxy, C 1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, optionally, the substituent is selected from cyano, methyl, ethyl, methoxy, Deuterated methoxy, ethoxy and tetrahydrofuryloxy.
一些实施方案中，所述Z 2选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基；一些实施方案中，所述Z 2选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基和C 1-6烷氧基；一些实施方案中，所述Z 2选自卤素、羟基、氧代基、C 1-6烷基和C 1-6烷氧基；一些实施方案中，所述Z 2选自氟、氯、溴、氧代基、羟基、甲基、乙基、丙基、异丙基和甲氧基；所述烷基、烷氧基、卤代烷基和羟烷基任选被一个或多个选自烷基、烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基和杂环烷基的取代基取代；一些实施方案中，所述取代基选自C 1-6烷基、C 1-6烷氧基、卤素、杂芳基和杂环烷基；一选自C 1-3烷基、C 1-3烷氧基和杂环烷基；一些实施方案中，所述取代基选自甲基、乙基、甲氧基、乙氧基和四氢呋喃基。 In some embodiments, the Z 2 is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 6 hydroxyalkyl; In some embodiments, the Z is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy; In some embodiments, Said Z is selected from halogen, hydroxyl, oxo, C 1-6 alkyl and C 1-6 alkoxy ; in some embodiments, said Z is selected from fluorine, chlorine, bromine, oxo, Hydroxy, methyl, ethyl, propyl, isopropyl and methoxy; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are optionally selected from one or more of alkyl, alkoxy, Halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, and heterocycloalkyl are substituted by substituents; in some embodiments, the substituents are selected from C 1-6 alkyl, C 1-6 Alkoxy, halogen, heteroaryl and heterocycloalkyl; one is selected from C 1-3 alkyl, C 1-3 alkoxy and heterocycloalkyl; in some embodiments, the substituent is selected from methyl group, ethyl, methoxy, ethoxy and tetrahydrofuryl.
一些实施方案中，所述R 1选自
Figure PCTCN2022103293-appb-000018
Figure PCTCN2022103293-appb-000019
Figure PCTCN2022103293-appb-000020
其中Z 2如上述所定义。 In some embodiments, the R 1 is selected from
Figure PCTCN2022103293-appb-000018
Figure PCTCN2022103293-appb-000019
Figure PCTCN2022103293-appb-000020
wherein Z2 is as defined above.
一些实施方案中，所述R 1选自
Figure PCTCN2022103293-appb-000021
Figure PCTCN2022103293-appb-000022
Figure PCTCN2022103293-appb-000023
其中Z 2如上述所定义。 In some embodiments, the R 1 is selected from
Figure PCTCN2022103293-appb-000021
Figure PCTCN2022103293-appb-000022
Figure PCTCN2022103293-appb-000023
wherein Z2 is as defined above.
本公开提供一种式I-G所示化合物或其可药用的盐，其中，The present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein,
Figure PCTCN2022103293-appb-000024
Figure PCTCN2022103293-appb-000024
其中，-L 1-选自键、C 1-6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取代基取代； Wherein, -L 1 - is selected from bond, C 1-6 alkylene, -O- and -NH-, and said C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkane Substituents of oxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;
R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基、氧代基、环烷基、杂环烷基、芳基和杂芳基，其中所述的烷基、环烷基、杂环烷基、芳基或杂芳基任选被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环烷基、芳基和杂芳基的取代基取代；或R 2和R 3一起形成3-8元环，所述3-8元环任选地被一个或多个Z 3取代； R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally selected from one or more of halogen, alkyl, alkoxy, cyano, amino, nitro, hydroxyl, hydroxyl Substituents of alkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl ; or R and R together form a 3-8 membered ring optionally replaced by One or more Z3 substitutions ;
R 4为-L 2-R 7； R 4 is -L 2 -R 7 ;
R 5选自氢、烷基和卤素，其中所述烷基任选被一个或多个选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Oxo , carboxyl and carboxylate substituent substitution;
R 7选自氢、烷基、环烷基、杂环烷基、芳基和杂芳基，任选地被一个或多个Z 4取代； R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more Z ;
-L 2-选自键、C 1-6亚烷基、-O-和-NH-，所述亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取代基取代； -L 2 -is selected from bond, C 1-6 alkylene, -O- and -NH-, the alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkoxy, haloalkyl, Substituents of haloalkoxy, halogen, cyano, amino and nitro;
R 6选自H、R 8-(C＝O)-和
Figure PCTCN2022103293-appb-000025
R 6 is selected from H, R 8 -(C=O)- and
Figure PCTCN2022103293-appb-000025
R 8为烷基，优选为C 1-6烷基，更优选为C 1-3烷基，最优选为甲基； R is an alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group, most preferably a methyl group;
R 9和R 10各自独立地选自氢、烷基、环烷基，优选选自氢、C 1-6烷基和3-7元 环烷基，更优选选自氢、C 1-3烷基和环丙基，最优选选自氢、甲基和乙基； R 9 and R 10 are each independently selected from hydrogen, alkyl, cycloalkyl, preferably selected from hydrogen, C 1-6 alkyl and 3-7 membered cycloalkyl, more preferably selected from hydrogen, C 1-3 alkane and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;
每个X独立地选自O、S和NH，优选为O；Each X is independently selected from O, S and NH, preferably O;
Z 1、Z 2、Z 3和Z 4各自独立地选自卤素、氰基、羟基、硝基、氧代基、烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-SR'、-SOR'、-SO 2R'、-SO 2NR'(R”)、-NR'(R”)、-COR'、-COOR'、-CONR'(R”)和-(P＝O)R'(R”)；所述烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、烯基、炔基、烷氧基、氘代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、-NR'(R”)、-SOR'、-SO 2R'、-SO(NH)R'、-S(NH)R'、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic Alkyl, aryl, heteroaryl, -SR', -SOR ', -SO2R ', -SO2NR'(R"), -NR'(R"), -COR', -COOR', -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and hetero The aryl groups are each independently optionally replaced by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, -NR'(R"), -SOR', -SO 2 R', -SO(NH)R', -S(NH)R', cyano, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl and carboxylate substituents;
每个R'或R”独立地选自氢、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自氘、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代；Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more of deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto , hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo Substituent substitution of group, carboxyl group and carboxylate group;
m和n各自独立地选自0、1或2。m and n are each independently selected from 0, 1 or 2.
一些实施方案中，本公开提供的式I所示的化合物或其可药用的盐，其为式II所示化合物，其中，R 2、R 3、R 4、R 5、R 6、L 1和Z 2如式I所示的化合物中所定义， In some embodiments, the present disclosure provides a compound represented by formula I or a pharmaceutically acceptable salt thereof, which is a compound represented by formula II, wherein, R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and Z 2 are as defined in the compound shown in formula I,
Figure PCTCN2022103293-appb-000026
Figure PCTCN2022103293-appb-000026
可选的实施方案中，本公开提供的式II所示化合物，其中，L 1为-O-。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein L 1 is -O-.
可选的实施方案中，本公开提供的式II所示化合物，其中，所述R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基和氧代基，优选选自氢、卤素和C 1-6烷基。 In an optional embodiment, the present disclosure provides the compound shown in formula II, wherein, the R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro and Oxo is preferably selected from hydrogen, halogen and C 1-6 alkyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，所述R 2和R 3各自独立地为氢。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein the R 2 and R 3 are each independently hydrogen.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自C 1-6烷基、C 3-7环烷基、3-7元杂环烷基、6-12元芳基和5-12元杂芳基；所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl; said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxy and haloalkyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自C 1-6烷基、C 3-7环烷基、3-7元杂环烷基、6-12元芳基和5-12元杂芳基；所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、 乙基、丙基和异丙基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl; said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自C 1-4烷基、C 3-5环烷基、6-10元芳基和5-6元杂芳基，所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, Methyl, ethyl, propyl, isopropyl, cyano, hydroxy and haloalkyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自C 1-4烷基、C 3-5环烷基、6-10元芳基和5-6元杂芳基，所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、乙基、丙基和异丙基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, Methyl, ethyl, propyl and isopropyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、苯基、萘基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基和噁唑基，所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine Base, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, Propyl, isopropyl, cyano, hydroxy and haloalkyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、苯基、萘基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基和噁唑基，所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、乙基、丙基和异丙基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein, R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from methyl, ethyl, propyl , isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazine Base, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, chlorine, bromine, methyl, ethyl, Propyl and Isopropyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自异丙基、
Figure PCTCN2022103293-appb-000027
环丙基、苯基和吡啶基；所述R 7任选地被一个或多个Z 4取代，所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from isopropyl,
Figure PCTCN2022103293-appb-000027
Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 , said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, Chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxy, and haloalkyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自异丙基、
Figure PCTCN2022103293-appb-000028
环丙基、苯基和吡啶基；所述R 7任选地被一个或多个Z 4取代，所述R 7任选地被一个或多个Z 4取代，所述Z 4选自氟、氯、溴、甲基、乙基、丙基和异丙基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from isopropyl,
Figure PCTCN2022103293-appb-000028
Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 , said R 7 is optionally substituted by one or more Z 4 , said Z 4 is selected from fluorine, Chlorine, bromine, methyl, ethyl, propyl, and isopropyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，所述R 5选自氢、C 1-6烷基和卤素，可选的，所述R 5为氢或C 1-3烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein the R 5 is selected from hydrogen, C 1-6 alkyl and halogen, and optionally, the R 5 is hydrogen or C 1- 3 alkyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，L 1为-O-，R 2和R 3各自独立地为氢，R 5为氢。 In an optional embodiment, the present disclosure provides a compound represented by formula II, wherein L 1 is -O-, R 2 and R 3 are each independently hydrogen, and R 5 is hydrogen.
可选的实施方案中，所述R 6为H或
Figure PCTCN2022103293-appb-000029
所述X为-O-，所述R 9和R 10各自独立地选自氢、烷基和环烷基，可选的，R 9和R 10各自独立地选自氢、C1-6 烷基和3-7元环烷基，可选的，R 9和R 10各自独立地选自氢、C 1-3烷基和环丙基，可选的，R 9和R 10各自独立地为氢甲基或乙基。 In an optional embodiment, the R 6 is H or
Figure PCTCN2022103293-appb-000029
The X is -O-, the R 9 and R 10 are each independently selected from hydrogen, alkyl and cycloalkyl, optionally, R 9 and R 10 are each independently selected from hydrogen, C1-6 alkyl and 3-7 membered cycloalkyl, optional, R 9 and R 10 are each independently selected from hydrogen, C 1-3 alkyl and cyclopropyl, optional, R 9 and R 10 are each independently hydrogen methyl or ethyl.
可选的实施方案中，R 6为H。 In an alternative embodiment, R 6 is H.
可选的实施方案中，其中，R 6为
Figure PCTCN2022103293-appb-000030
In an optional embodiment, wherein, R 6 is
Figure PCTCN2022103293-appb-000030
可选的实施方案中，R 6选自
Figure PCTCN2022103293-appb-000031
Figure PCTCN2022103293-appb-000032
 In an optional embodiment, R is selected from
Figure PCTCN2022103293-appb-000031
Figure PCTCN2022103293-appb-000032
可选的实施方案中，本公开提供的式II所示化合物，其中，所述Z 2选自氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基；所述烷基、烷氧基、卤代烷基和羟烷基各自独立地任选被一个或多个选自烷基、烷氧基、氘代烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基、杂环烷基和杂环烷基氧基的取代基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula II , wherein the Z is selected from cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from one or more of alkyl, alkoxy , deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl and heterocycloalkyloxy substituents.
可选的实施方案中，本公开提供的式II所示化合物，其中，所述Z 2选自氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基；所述烷基、烷氧基、卤代烷基和羟烷基各自独立地任选被一个或多个选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6氘代烷氧基、杂环烷基和杂环烷基氧基的取代基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula II , wherein the Z is selected from cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from cyano, C 1- Substituents of 6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy.
可选的实施方案中，本公开提供的式II所示化合物，其中，所述Z 2选自氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基；所述烷基、烷氧基、卤代烷基和羟烷基各自独立地任选被一个或多个选自氰基、甲基、乙基、甲氧基、一氘代甲氧基、二氘代甲氧基、三氘代甲氧基、3至7元环烷基和3至7元杂环烷基的取代基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula II , wherein the Z is selected from cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy group, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; said alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from one or more of cyano, methyl, Substituents of ethyl, methoxy, monodeuteromethoxy, dideuteriomethoxy, trideuteromethoxy, 3 to 7 membered cycloalkyl and 3 to 7 membered heterocycloalkyl.
可选的实施方案中，本公开提供的式II所示化合物，其中，所述Z 2选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基；所述烷基、烷氧基、卤代烷基和羟烷基各自独立地任选被一个或多个选自氰基、甲基、乙基、甲氧基、一氘代甲氧基、二氘代甲氧基、三氘代甲氧基、3至7元环烷基和3至7元杂环烷基的取代基取代。 In an optional embodiment, the present disclosure provides the compound shown in formula II, wherein, said Z 2 is selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; the alkyl, alkoxy, haloalkyl and hydroxyalkyl are each independently optionally selected from one or more of cyano, methyl, ethyl, methoxy, a deuterium Substituents of methoxy, dideuteriomethoxy, trideuteriomethoxy, 3 to 7-membered cycloalkyl and 3 to 7-membered heterocycloalkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地选自烷基、卤代烷基、羟烷基、环烷基、-COOR'和-CONR'(R”)；所述烷基、卤代烷基、羟烷基、环烷基任选被一个或多个选自卤素、巯基、羟基、-NR'(R”)、-SOR'、-SO 2R'、-SO(NH)R'和-S(NH)R'的取代基取代； In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -COOR' and -CONR'(R"); the alkyl, haloalkyl, hydroxyalkyl, and cycloalkyl are optionally selected from one or more of halogen, mercapto, hydroxyl, -NR'(R"), -SOR', -SO 2 R', -SO(NH)R' and -S(NH)R' are substituted by substituents;
每个R'或R”独立地选自氢、羟基和烷基，所述烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代。Each R' or R" is independently selected from hydrogen, hydroxy and alkyl optionally substituted with one or more substituents selected from deuterium, halo, mercapto, hydroxy and cyano.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述C 1-6烷基或3至7元环 烷基任选被一个或多个选自卤素、羟基、巯基和-NR'(R”)的取代基取代，每个R'或R”如权利要求式I-G所示化合物中定义。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7 membered cycloalkyl is optionally substituted by one or more substituents selected from halogen, hydroxyl, mercapto and -NR'(R"), each R' or R" As defined in the compound shown in claim formula IG.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，每个R'或R”独立地为氢或C 1-6烷基，所述C 1-6烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each R' or R" is independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，每个R'或R”独立地为氢或C 1-6烷基，所述C 1-6烷基任选被一个或多个氘取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each R' or R" is independently hydrogen or C 1-6 alkyl, said C 1-6 alkyl is optionally substituted with one or more deuteriums.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述的C 1-6烷基或3至7元环烷基被一个或多个羟基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more hydroxyl groups.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述的C 1-6烷基或3至7元环烷基被一个或多个巯基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7 membered cycloalkyl is substituted by one or more mercapto groups.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述的C 1-6烷基或3至7元环烷基被一个或多个-NR'(R”)取代，所述R'或R”独立地为氢。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3-7 membered cycloalkyl is substituted by one or more -NR'(R"), and the R' or R" are independently hydrogen.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述的C 1-6烷基或3至7元环烷基被一个或多个-NR'(R”)取代，所述R'或R”独立地为氢或C 1-6烷基，所述C 1-6烷基任选被一个或多个氘取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7-membered cycloalkyl is substituted by one or more -NR'(R"), and the R' or R" are independently hydrogen or C 1-6 alkyl, The C 1-6 alkyl is optionally substituted with one or more deuteriums.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述的C 1-6烷基或3至7元环烷基被一个或多个-NR'(R”)取代，所述R'或R”独立地为氢或甲基，所述甲基任选被一个、两个或三个氘取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently C 1-6 alkyl or 3 to 7-membered cycloalkyl, The C 1-6 alkyl or 3 to 7-membered cycloalkyl is substituted by one or more -NR'(R"), the R' or R" are independently hydrogen or methyl, and the methyl Optionally substituted with one, two or three deuteriums.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基，所述C 1-6烷基被一个或多个卤素取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more halogens.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基，所述C 1-6烷基被一个或多个羟基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more hydroxyl groups.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基，所述C 1-6烷基被一个或多个氰基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more cyano groups.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基，所述C 1-6烷基被一个或多个烷氧基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more alkoxy groups.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基，所述C 1-6烷基被一个或多个C 1-6烷氧基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is Substituted by one or more C 1-6 alkoxy groups.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐， 其中，Z 2各自独立地为C 1-3烷基，所述C 1-6烷基被一个或多个C 1-3烷氧基取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-6 alkyl group is Substituted by one or more C 1-3 alkoxy groups.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述一个或多个氟取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently a C 1-3 alkyl group, and the one or more fluorine substituted .
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基，所述C 1-6烷基任选被一个或多个选自-SOR'、-SO 2R'、-SO(NH)R'和-S(NH)R'的取代基取代； In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-6 alkyl group, and the C 1-6 alkyl group is optionally substituted with one or more substituents selected from -SOR', -SO2R ', -SO(NH)R' and -S(NH)R';
每个R'或R”独立地为C 1-6烷基，所述烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代。 Each R' or R" is independently a C 1-6 alkyl group optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个SOR'取代； In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally replaced by one or more SOR';
R'选自C 1-6烷基，所述烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代。 R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个SOR'取代，R'为C 1-3烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is Optionally substituted by one or more SOR', R' is C 1-3 alkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个SO 2R'取代； In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more SO 2 R';
R'选自C 1-6烷基，所述烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代。 R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个-SO 2R'取代；R'为C 1-3烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is Optionally substituted by one or more -SO 2 R';R' is C 1-3 alkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个-SO(NH)R'取代； In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more -SO(NH)R';
R'选自C 1-6烷基，所述烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代。 R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个-SO(NH)R'取代；R'为C 1-3烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is Optionally substituted by one or more -SO(NH)R';R' is C 1-3 alkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个-S(NH)R'取代； In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more -S(NH)R';
R'选自C 1-6烷基，所述烷基任选被一个或多个选自氘、卤素、巯基、羟基、氰基的取代基取代。 R' is selected from C 1-6 alkyl optionally substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl, cyano.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为C 1-3烷基，所述C 1-3烷基任选被一个或多个-S(NH)R'取代； In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently a C 1-3 alkyl group, and the C 1-3 alkyl group is optionally substituted by one or more -S(NH)R';
R'为C 1-3烷基。 R' is C 1-3 alkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为-COOR'，所述R'独立地选自氢、羟基和C 1-6烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently -COOR', and said R' is independently selected from hydrogen, hydroxyl and C 1-6 alkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为-COOR'，所述R'为氢。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein each of Z 2 is independently -COOR', and the R' is hydrogen.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为-CONR'(R”)，所述R'或R”独立地选自氢或C 1-6烷基，所述C 1-6烷基任选被一个或多个氘取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently -CONR'(R"), and said R' or R" independently selected from hydrogen or C 1-6 alkyl optionally substituted with one or more deuteriums.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，Z 2各自独立地为-CONR'(R”)，所述R'或R”独立地为氢或甲基，所述甲基任选被一个、两个或三个氘取代。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein Z 2 are each independently -CONR'(R"), and said R' or R" independently hydrogen or methyl optionally substituted with one, two or three deuteriums.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，L 1为-O-。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein L 1 is -O-.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，所述R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基和氧代基，优选选自氢、卤素和C 1-6烷基，更优选为氢。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkane A group, a cyano group, a hydroxyl group, a nitro group and an oxo group are preferably selected from hydrogen, halogen and C 1-6 alkyl, more preferably hydrogen.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自C 1-6烷基、C 3-7环烷基、3-7元杂环烷基、6-12元芳基和5-12元杂芳基，优选选自C 1-4烷基、C 3-5环烷基、6-10元芳基和5-6元杂芳基，更优选选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、苯基、萘基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基和噁唑基，最优选选自异丙基、
Figure PCTCN2022103293-appb-000033
环丙基、苯基和吡啶基；所述R 7任选地被一个或多个Z 4取代，所述Z4如式I-G所示化合物中定义。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 Selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C 1-4 alkyl , C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl yl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and oxazole group, most preferably selected from isopropyl,
Figure PCTCN2022103293-appb-000033
Cyclopropyl, phenyl and pyridyl; the R 7 is optionally substituted by one or more Z 4 , and the Z 4 is as defined in the compound shown in formula IG.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, Isopropyl, cyano, hydroxy and haloalkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，所述Z 4选自氟、氯、溴、甲基、乙基、丙基和异丙基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and Isopropyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，所述R 5选自氢、C 1-6烷基和卤素。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein said R 5 is selected from hydrogen, C 1-6 alkyl and halogen.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，所其中，所述R 5为氢或C 1-3烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein, wherein, said R 5 is hydrogen or C 1-3 alkyl.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，L 1为-O-，R 2和R 3各自独立地为氢，R 5为氢。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein L 1 is -O-, R 2 and R 3 are each independently hydrogen, and R 5 is hydrogen.
可选的实施方案中，本公开提供的式I-G或式II所示化合物或其可药用的盐，其中，R 6为H。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or formula II or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
可选的实施方案中，本公开提供的式I-G所示化合物或其可药用的盐，其中，Z 1选自卤素、氰基、羟基、硝基、氧代基、烷基、烷氧基、卤代烷基和羟烷基。 In an optional embodiment, the present disclosure provides a compound of formula IG or a pharmaceutically acceptable salt thereof, wherein Z is selected from halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy , haloalkyl and hydroxyalkyl.
可选的实施方案中，本公开提供的式I-G所示化合物或其可药用的盐，其中，Z 1选自卤素、氰基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or a pharmaceutically acceptable salt thereof, wherein Z is selected from halogen, cyano, C 1-6 alkyl, C 1-6 alkoxy , C 1-6 haloalkyl and C 1-6 hydroxyalkyl.
可选的实施方案中，本公开提供的式I-G所示化合物或其可药用的盐，其中，Z 1为卤素。 In an optional embodiment, the present disclosure provides a compound represented by formula IG or a pharmaceutically acceptable salt thereof, wherein Z 1 is halogen.
可选的实施方案中，本公开提供的式I-G所示化合物或其可药用的盐，其中，n为0。In an optional embodiment, the present disclosure provides a compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein n is 0.
可选的实施方案中，本公开提供的式I所示化合物或其可药用的盐，其为式III所示化合物或式IV所示化合物或其可药用的盐，
Figure PCTCN2022103293-appb-000034
Figure PCTCN2022103293-appb-000035
In an optional embodiment, the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula III or a compound represented by formula IV or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022103293-appb-000034
Figure PCTCN2022103293-appb-000035
其中，R 4、R 5、X、R 9、R 10和Z 2如式I所示化合物或式II所示化合物中定义。 Wherein, R 4 , R 5 , X, R 9 , R 10 and Z 2 are as defined in the compound shown in formula I or the compound shown in formula II.
可选的实施方案中，本公开提供的式I所示化合物或其可药用的盐，其为式V所示化合物或式VI所示化合物或其可药用的盐，In an optional embodiment, the compound represented by formula I or a pharmaceutically acceptable salt thereof provided by the present disclosure is a compound represented by formula V or a compound represented by formula VI or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022103293-appb-000036
Figure PCTCN2022103293-appb-000036
其中，R 4、R 5、X、R 9、R 10和Z 2分别如式I所示化合物或式II所示化合物中定义。 Wherein, R 4 , R 5 , X, R 9 , R 10 and Z 2 are respectively as defined in the compound shown in formula I or the compound shown in formula II.
一些实施方案中，所述R 1选自
Figure PCTCN2022103293-appb-000037
Figure PCTCN2022103293-appb-000038
Figure PCTCN2022103293-appb-000039
In some embodiments, the R 1 is selected from
Figure PCTCN2022103293-appb-000037
Figure PCTCN2022103293-appb-000038
Figure PCTCN2022103293-appb-000039
一些实施方案中，所述R 1为
Figure PCTCN2022103293-appb-000040
Figure PCTCN2022103293-appb-000041
Figure PCTCN2022103293-appb-000042
In some embodiments, the R 1 is
Figure PCTCN2022103293-appb-000040
Figure PCTCN2022103293-appb-000041
Figure PCTCN2022103293-appb-000042
一些实施方案中，所述Z 3选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基，优选选自氟、氯、溴、甲基、乙基、丙基和异丙基。 In some embodiments, said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl, preferably selected from fluorine, chlorine, bromine, methyl, Ethyl, Propyl and Isopropyl.
一些实施方案中，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基，优选选自氟、氯、溴、甲基、乙基、丙基和异丙基。 In some embodiments, said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl, preferably selected from fluorine, chlorine, bromine, methyl, Ethyl, Propyl and Isopropyl.
一些实施方案中，所述R'或R”独立地为氢或羟基。In some embodiments, the R' or R" are independently hydrogen or hydroxyl.
第二方面，本公开还提供一系列化合物，选自：In a second aspect, the present disclosure also provides a series of compounds selected from:
Figure PCTCN2022103293-appb-000043
Figure PCTCN2022103293-appb-000043
Figure PCTCN2022103293-appb-000044
Figure PCTCN2022103293-appb-000044
Figure PCTCN2022103293-appb-000045
Figure PCTCN2022103293-appb-000045
Figure PCTCN2022103293-appb-000046
Figure PCTCN2022103293-appb-000046
Figure PCTCN2022103293-appb-000047
Figure PCTCN2022103293-appb-000047
Figure PCTCN2022103293-appb-000048
Figure PCTCN2022103293-appb-000048
Figure PCTCN2022103293-appb-000049
Figure PCTCN2022103293-appb-000049
Figure PCTCN2022103293-appb-000050
Figure PCTCN2022103293-appb-000050
Figure PCTCN2022103293-appb-000051
Figure PCTCN2022103293-appb-000051
Figure PCTCN2022103293-appb-000052
或其可药用的盐。
Figure PCTCN2022103293-appb-000052
or a pharmaceutically acceptable salt thereof.
本公开还提供一系列化合物，选自：The present disclosure also provides a series of compounds selected from:
Figure PCTCN2022103293-appb-000053
Figure PCTCN2022103293-appb-000053
Figure PCTCN2022103293-appb-000054
Figure PCTCN2022103293-appb-000054
Figure PCTCN2022103293-appb-000055
Figure PCTCN2022103293-appb-000055
Figure PCTCN2022103293-appb-000056
Figure PCTCN2022103293-appb-000056
Figure PCTCN2022103293-appb-000057
Figure PCTCN2022103293-appb-000057
Figure PCTCN2022103293-appb-000058
Figure PCTCN2022103293-appb-000058
Figure PCTCN2022103293-appb-000059
Figure PCTCN2022103293-appb-000059
Figure PCTCN2022103293-appb-000060
Figure PCTCN2022103293-appb-000060
Figure PCTCN2022103293-appb-000061
Figure PCTCN2022103293-appb-000061
本公开提供的化合物不为：
Figure PCTCN2022103293-appb-000062
Figure PCTCN2022103293-appb-000063
Compounds provided by this disclosure are not:
Figure PCTCN2022103293-appb-000062
Figure PCTCN2022103293-appb-000063
本公开还提供上述的化合物的同位素取代物，一些实施方案中，所述的同位素取代物为氘原子取代物。The present disclosure also provides isotope substitutions of the above-mentioned compounds, and in some embodiments, the isotope substitutions are deuterium atom substitutions.
可选的实施方案中，本公开提供一种下列化合物的氘代物，In an alternative embodiment, the present disclosure provides a deuterated version of the following compound,
Figure PCTCN2022103293-appb-000064
Figure PCTCN2022103293-appb-000064
第三方面，本公开还提供第一或第二方面所述化合物或其可药用的盐的制备方法。In the third aspect, the present disclosure also provides a preparation method of the compound or a pharmaceutically acceptable salt thereof in the first or second aspect.
一些实施方案中，包括如下步骤：In some embodiments, the following steps are included:
Figure PCTCN2022103293-appb-000065
其中，
Figure PCTCN2022103293-appb-000065
in,
式I-5所示化合物与式I-6所示化合物在碱性条件下，经取代反应，得到式I所示化合物；The compound shown in formula I-5 and the compound shown in formula I-6 are subjected to substitution reaction under basic conditions to obtain the compound shown in formula I;
碱性条件的试剂为有机碱或无机碱，所述的有机碱选自三乙胺、N,N-二异丙基乙胺、正丁基锂、二异丙基氨基锂、双三甲基硅基胺基锂、醋酸钾、叔丁醇钠和叔丁醇钾；所述的无机碱选自氢化钠、磷酸钾、碳酸钠、碳酸钾、甲醇钠、乙醇钠、叔丁醇钠、醋酸钾、碳酸铯、氢氧化钠和氢氧化锂；The reagent for basic conditions is an organic base or an inorganic base, and the organic base is selected from triethylamine, N,N-diisopropylethylamine, n-butyllithium, diisopropylamide lithium, bistrimethyl Lithium silylamide, potassium acetate, sodium tert-butoxide and potassium tert-butoxide; the inorganic base is selected from sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, sodium methylate, sodium ethylate, sodium tert-butoxide, acetic acid Potassium, Cesium Carbonate, Sodium Hydroxide and Lithium Hydroxide;
LG 3为苯氧基或4-硝基苯氧基。 LG 3 is phenoxy or 4-nitrophenoxy.
一些实施方案中，包括以下步骤：式X所示化合物在酸性条件下脱除保护基PG的步骤，In some embodiments, the following steps are included: the step of removing the protecting group PG from the compound represented by formula X under acidic conditions,
Figure PCTCN2022103293-appb-000066
Figure PCTCN2022103293-appb-000066
其中，R 2、R 3、R 4、R 5、L 1和Z 2如权利要求1中所定义，R 6为氢，PG为氨基保护基，可选自叔丁基、乙酰基、三氟乙酰基、三苯甲基、苄基和甲酰基。 Among them, R 2 , R 3 , R 4 , R 5 , L 1 and Z 2 are as defined in claim 1, R 6 is hydrogen, PG is an amino protecting group, which can be selected from tert-butyl, acetyl, trifluoro Acetyl, Trityl, Benzyl and Formyl.
本公开还提供一种式X所示的化合物，The present disclosure also provides a compound represented by formula X,
Figure PCTCN2022103293-appb-000067
Figure PCTCN2022103293-appb-000067
其中，R 2、R 3、R 4、R 5、、L 1和Z 2如式I、II、III、IV、V或IV所示化合物中定义，PG为氨基保护基，可选自叔丁基、乙酰基、三氟乙酰基、三苯甲基、苄基和甲酰基。 Wherein, R 2 , R 3 , R 4 , R 5 , L 1 and Z 2 are as defined in the compound shown in formula I, II, III, IV, V or IV, and PG is an amino protecting group, which can be selected from tert-butyl acetyl, trifluoroacetyl, trityl, benzyl and formyl.
本公开还提供一种式XI所示的化合物，The present disclosure also provides a compound represented by formula XI,
Figure PCTCN2022103293-appb-000068
Figure PCTCN2022103293-appb-000068
其中，X选自卤素，R选自烷基、氘代烷基、杂环烷基和环烷基。Wherein, X is selected from halogen, and R is selected from alkyl, deuterated alkyl, heterocycloalkyl and cycloalkyl.
第四方面，本公开还提供一种药物组合物，其包含第一或第二方面所述的化 合物或其可药用的盐，和至少一种药学上可接受的载体、稀释剂或者赋形剂。在一些实施方案中，所述的药物组合物的单位剂量为0.001mg-1000mg。In the fourth aspect, the present disclosure also provides a pharmaceutical composition, which comprises the compound or pharmaceutically acceptable salt thereof as described in the first or second aspect, and at least one pharmaceutically acceptable carrier, diluent or excipient agent. In some embodiments, the unit dose of the pharmaceutical composition is 0.001 mg-1000 mg.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01-99.99％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.1-99.9％的前述化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有1％-99％的化合物或其可药用的盐。在某些实施方案中，所述的药物组合物含有2％-98％的化合物或其可药用的盐。In certain embodiments, the pharmaceutical composition contains 0.01-99.99% of the aforementioned compound or a pharmaceutically acceptable salt thereof, based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1-99.9% of the aforementioned compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 1%-99% of the compound or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition contains 2%-98% of the compound or a pharmaceutically acceptable salt thereof.
在某些实施方案中，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.1％-99.9％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有0.5％-99.5％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有1％-99％的药学上可接受的赋形剂。在某些实施方案中，所述的药物组合物含有2％-98％的药学上可接受的赋形剂。In certain embodiments, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable excipients.
第五方面，本公开还提供一种预防和/或治疗患有与细胞周期蛋白依赖性激酶相关疾病的患者的方法，其通过向所述患者施用治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物。In a fifth aspect, the present disclosure also provides a method for preventing and/or treating a patient suffering from a cyclin-dependent kinase-related disease, by administering to the patient a therapeutically effective amount of the compound described in the present disclosure or its A pharmaceutically acceptable salt or the aforementioned pharmaceutical composition.
另一方面，本公开还提供一种预防和/或治疗患有与细胞周期蛋白相关疾病的患者的方法，其通过向所述患者施用治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物。In another aspect, the present disclosure also provides a method for preventing and/or treating a patient suffering from a cell cycle protein-related disease, by administering to the patient a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt or the aforementioned pharmaceutical composition.
在一些实施方案中，所述与细胞周期蛋白依赖性激酶相关疾病或与细胞周期蛋白相关疾病优选为细胞增殖性疾病、癌症或免疫性疾病。In some embodiments, the cyclin-dependent kinase-associated disease or cyclin-associated disease is preferably a cell proliferative disease, cancer or immune disease.
在一些实施方案中，所述与细胞周期蛋白依赖性激酶相关疾病或与细胞周期蛋白相关疾病选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌、胰腺癌、结直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤和肉瘤。In some embodiments, the cyclin-dependent kinase-associated disease or cyclin-associated disease is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer , colorectal, lung, kidney, skin, glioblastoma, neuroblastoma, and sarcoma.
一些具体的实施方案中，所述的癌症选自细胞周期蛋白E1和/或细胞周期蛋白E2扩增的癌症。In some specific embodiments, the cancer is selected from cancers in which cyclin E1 and/or cyclin E2 are amplified.
本公开还提供一种预防和/或治疗患有癌症的患者的方法，其通过向所述患者施用治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物，所述的癌症选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌、胰腺癌、结直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤和肉瘤。The present disclosure also provides a method for preventing and/or treating a patient suffering from cancer, by administering to the patient a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition, Said cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer, glioblastoma, neuroblastoma Cell tumors and sarcomas.
本公开提供了治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物在制备用于预防和/或治疗与细胞周期蛋白依赖性激酶相关疾病的药物中的用途。The present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for preventing and/or treating diseases related to cyclin-dependent kinases.
一些具体的实施方案中，细胞周期蛋白依赖性激酶为CDK2，与细胞周期蛋白 依赖性激酶相关疾病选自细胞增殖性疾病、癌症或免疫性疾病。In some specific embodiments, the cyclin-dependent kinase is CDK2, and the disease associated with the cyclin-dependent kinase is selected from cell proliferative diseases, cancer or immune diseases.
另一方面，本公开提供了治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物在制备用于预防和/或治疗与细胞周期蛋白相关疾病的药物中的用途。In another aspect, the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for the prevention and/or treatment of cyclin-related diseases .
一些具体的实施方案中，细胞周期蛋白选自细胞周期蛋白E，例如细胞周期蛋白E1、细胞周期蛋白E2。与细胞周期蛋白相关疾病选自细胞增殖性疾病、癌症或免疫性疾病。In some specific embodiments, the cyclin is selected from cyclin E, such as cyclin E1, cyclin E2. The cyclin-associated disease is selected from cell proliferative disease, cancer or immune disease.
在一些实施方案中，本公开提供了治疗有效量的本公开所述的化合物或其可药用的盐或前述药物组合物在制备治疗癌症的药物中的用途。In some embodiments, the present disclosure provides the use of a therapeutically effective amount of the compound described in the present disclosure or a pharmaceutically acceptable salt thereof or the aforementioned pharmaceutical composition in the preparation of a medicament for treating cancer.
一些具体的实施方案中，所述的癌症选自选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌、胰腺癌、结直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤和肉瘤。In some specific embodiments, the cancer is selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, kidney cancer, skin cancer Carcinoma, glioblastoma, neuroblastoma, and sarcoma.
一些具体的实施方案中，所述的癌症选自细胞周期蛋白E1和/或细胞周期蛋白E2扩增的癌症。本公开中所述化合物可药用盐选自无机盐或有机盐，本公开所述化合物可与酸性或碱性物质反应成相应盐。本公开化合物对细胞周期蛋白-依赖性激酶具有很好的抑制作用，对CDK2/细胞周期蛋白E的抑制活性的IC 50值在0.01至1000nM，某些化合物对CDK2/细胞周期蛋白E的抑制活性的IC 50值在0.01至500nM，某些化合物对CDK2/细胞周期蛋白E的抑制活性的IC 50值在0.01至300nM，某些化合物对CDK2/细胞周期蛋白E的抑制活性的IC 50值在0.01至200nM，某些化合物对CDK2/细胞周期蛋白E的抑制活性的IC 50值在0.01至100nM，某些化合物对CDK2/细胞周期蛋白E的抑制活性的IC50值<100nM。 In some specific embodiments, the cancer is selected from cancers in which cyclin E1 and/or cyclin E2 are amplified. The pharmaceutically acceptable salts of the compounds described in the present disclosure are selected from inorganic salts or organic salts, and the compounds described in the present disclosure can react with acidic or basic substances to form corresponding salts. The disclosed compounds have a good inhibitory effect on cyclin-dependent kinases, and the IC50 value of the inhibitory activity of CDK2/cyclin E is between 0.01 and 1000nM, and the inhibitory activity of some compounds on CDK2/cyclin E The IC 50 value of the inhibitory activity of some compounds on CDK2/cyclin E is in the range of 0.01 to 300nM, and the IC 50 value of the inhibitory activity of some compounds on CDK2/cyclin E is in the range of 0.01 The inhibitory activity of some compounds on CDK2/cyclin E has IC50 values from 0.01 to 100nM up to 200nM, and the inhibitory activity of some compounds on CDK2/cyclin E has IC50 values <100nM.
一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<50nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<20nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<10nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<5nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<1nM。Some embodiments provide compounds that achieve <50 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <20 nM inhibitory activity against CDK2/cyclin E. Still other embodiments provide compounds that achieve <10 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <5 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <1 nM inhibitory activity against CDK2/cyclin E.
另一方面，本公开化合物对CDK2/细胞周期蛋白A也有较好的抑制效果。一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<500nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<200nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<150nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<100nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<50nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<20nM。另一些实施方案提供的化合物对CDK2/细胞周期蛋白E抑制活性达到<10nM。On the other hand, the disclosed compound also has good inhibitory effect on CDK2/cyclin A. Some embodiments provide compounds that achieve <500 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <200 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <150 nM inhibitory activity against CDK2/cyclin E. Still other embodiments provide compounds that achieve <100 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <50 nM inhibitory activity against CDK2/cyclin E. Other embodiments provide compounds that achieve <20 nM inhibitory activity against CDK2/cyclin E. Still other embodiments provide compounds that achieve <10 nM inhibitory activity against CDK2/cyclin E.
在另一些实施方案中，本公开化合物对其他激酶如CDK4、CDK5、CDK7、CDK9或GSK3β抑制活性偏弱，具有CDK2特异性选择。In other embodiments, the compounds of the present disclosure have weak inhibitory activity on other kinases such as CDK4, CDK5, CDK7, CDK9 or GSK3β, and have CDK2-specific selection.
另一方面，本公开化合物可以存在特定的几何或立体异构体形式。本公开设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本公开的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本公开的范围之内。On the other hand, the disclosed compounds may exist in particular geometric or stereoisomeric forms. This disclosure contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of this disclosure. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this disclosure.
另外，本公开的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本公开的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺、内酰胺-内酰亚胺、吡唑基异构化。In addition, the compounds and intermediates of the present disclosure may also exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that can interconvert via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine, lactam-lactam, pyrazole base isomerization.
吡唑基平衡实例是在如下所示的E和F之间：An example of a pyrazolyl equilibrium is between E and F as shown below:
Figure PCTCN2022103293-appb-000069
Figure PCTCN2022103293-appb-000069
具体到本公开：Specific to this disclosure:
Figure PCTCN2022103293-appb-000070
Figure PCTCN2022103293-appb-000070
所有的互变异构形式在本发明的范围内。化合物的命名不排除任何互变异构体。All tautomeric forms are within the scope of the invention. The naming of compounds does not exclude any tautomers.
本公开化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本公开的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。Compounds of the present disclosure may be asymmetric, eg, possess one or more stereoisomers. Unless otherwise stated, all stereoisomers are included, such as enantiomers and diastereomers. Compounds of the present disclosure containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or reagents.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本公开某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present disclosure is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
本公开还包括一些与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本公开化合物。可结合到本公开化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。 The present disclosure also includes certain isotopically labeled compounds of the disclosure that are identical to those described herein, but wherein one or more atoms are replaced by an atom of an atomic mass or mass number different from that normally found in nature. Examples of isotopes that can be incorporated into compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl, etc.
除另有说明，当一个位置被特别地指定为氘(D)时，该位置应理解为具有大于氘的天然丰度(其为0.015％)至少1000倍的丰度的氘(即，至少10％的氘掺入)。示例中化合物的具有大于氘的天然丰度可以是至少1000倍的丰度的氘、至少2000倍的丰度的氘、至少3000倍的丰度的氘、至少4000倍的丰度的氘、至少5000倍的丰度的氘、至少6000倍的丰度的氘或更高丰度的氘。本公开还包括各种氘化形式的式I化合物。与碳原子连接的各个可用的氢原子可独立地被氘原子替换。本领域技术人员能够参考相关文献合成氘化形式的式I化合物。在制备氘代形式的式I化合物时可使用市售的氘代起始物质，或它们可使用常规技术采用氘代试剂合成，氘代试剂包括但不限于氘代硼烷、三氘代硼烷四氢呋喃溶液、氘代氢化锂铝、氘代碘乙烷和氘代碘甲烷等。Unless otherwise stated, when a position is specifically designated as deuterium (D), the position is understood to have an abundance of deuterium (i.e., at least 10 % deuterium incorporation). Exemplary compounds having a natural abundance greater than deuterium can be at least 1000 times more abundant deuterium, at least 2000 times more abundant deuterium, at least 3000 times more abundant deuterium, at least 4000 times more abundant deuterium, at least 5000 times more abundant deuterium, at least 6000 times more abundant deuterium, or more abundant deuterium. The present disclosure also includes various deuterated forms of compounds of formula I. Each available hydrogen atom attached to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can refer to the relevant literature to synthesize the deuterated form of the compound of formula I. Commercially available deuterated starting materials can be used in the preparation of deuterated forms of compounds of formula I, or they can be synthesized using conventional techniques using deuterated reagents, including but not limited to deuterated borane, trideuterated borane Tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
“任选地”或“任选”是指意味着随后所描述的事件或环境可以但不必发生，该说明包括该事件或环境发生或不发生的场合。例如“任选的被卤素或者氰基取代的C 1-6烷基”是指卤素或者氰基可以但不必须存在，该说明包括烷基被卤素或者氰基取代的情形和烷基不被卤素和氰基取代的情形。 "Optionally" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where the event or circumstance occurs or does not occur. For example, "C 1-6 alkyl optionally substituted by halogen or cyano" means that halogen or cyano may but not necessarily exist, and this description includes the case where the alkyl is substituted by halogen or cyano and the alkyl is not substituted by halogen And the case of cyano substitution.
本发明所述化合物的化学结构中，键
Figure PCTCN2022103293-appb-000071
表示未指定构型，即如果化学结构中存在手性异构体，键
Figure PCTCN2022103293-appb-000072
可以为
Figure PCTCN2022103293-appb-000073
或者同时包含
Figure PCTCN2022103293-appb-000074
两种构型。虽然为简便起见将全部上述结构式画成某些异构体形式，但是本发明可以包括所有的异构体，如互变异构体、旋转异构体、几何异构体、非对映异构体、外消旋体和对映异构体。本公开所述化合物的化学结构中，键
Figure PCTCN2022103293-appb-000075
并未指定构型，即键
Figure PCTCN2022103293-appb-000076
的构型可以为E型或Z型，或者同时包含E和Z两种构型。 In the chemical structure of the compound of the present invention, the bond
Figure PCTCN2022103293-appb-000071
Indicates unassigned configuration, i.e. if chiral isomers exist in the chemical structure, the bond
Figure PCTCN2022103293-appb-000072
can be
Figure PCTCN2022103293-appb-000073
or both
Figure PCTCN2022103293-appb-000074
Two configurations. Although all of the above formulas are drawn as certain isomeric forms for simplicity, the present invention may include all isomers such as tautomers, rotamers, geometric isomers, diastereoisomers body, racemate and enantiomer. In the chemical structures of the compounds described in this disclosure, the bond
Figure PCTCN2022103293-appb-000075
configuration is not specified, i.e. the key
Figure PCTCN2022103293-appb-000076
The configuration of can be E type or Z type, or contain both E and Z configurations.
术语解释：Explanation of terms:
术语“药物组合物”表示含有一种或多种本文所述化合物或其生理学上可药用的盐或前体药物与其他化学组分的混合物，以及其他组分例如生理学可药用的载体和赋形剂。药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。The term "pharmaceutical composition" means a mixture containing one or more compounds described herein, or a physiologically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as a physiologically acceptable carrier and excipient. The purpose of the pharmaceutical composition is to promote the administration to the organism, facilitate the absorption of the active ingredient and thus exert biological activity.
术语“可药用赋形剂”或“药学上可接受的赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、赋形剂、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。The term "pharmaceutically acceptable excipient" or "pharmaceutically acceptable excipient" includes, but is not limited to, any adjuvant, carrier, excipient that has been approved by the U.S. Food and Drug Administration for use in humans or livestock animals. excipients, glidants, sweeteners, diluents, preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents or emulsifier.
术语“有效量”或“有效治疗量”包含足以改善或预防医学病症的症状或病症的 量。有效量还意指足以允许或促进诊断的量。用于特定患者或兽医学受试者的有效量可依据以下因素而变化：如待治疗的病症、患者的总体健康情况、给药的方法途径和剂量以及副作用严重性。有效量可以是避免显著副作用或毒性作用的最大剂量或给药方案。The term "effective amount" or "therapeutically effective amount" encompasses an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount also means an amount sufficient to allow or facilitate diagnosis. Effective amounts for a particular patient or veterinary subject may vary depending on factors such as the condition being treated, the general health of the patient, the method, route and dosage of administration, and the severity of side effects. An effective amount may be the maximum dose or dosing regimen that avoids significant side effects or toxic effects.
术语“烷基”指饱和脂肪族烃基团，其为包含1至20个碳原子的直链或支链基团，优选含有1至12个碳原子的烷基。非限制性实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基、正庚基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、正辛基、2,3-二甲基己基、2,4-二甲基己基、2,5-二甲基己基、2,2-二甲基己基、3,3-二甲基己基、4,4-二甲基己基、2-乙基己基、3-乙基己基、4-乙基己基、2-甲基-2-乙基戊基、2-甲基-3-乙基戊基、正壬基、2-甲基-2-乙基己基、2-甲基-3-乙基己基、2,2-二乙基戊基、正癸基、3,3-二乙基己基、2,2-二乙基己基，及其各种支链异构体等。更优选的是含有1至6个碳原子的烷基，非限制性实施例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、正己基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、2,3-二甲基丁基等。烷基可以是取代的或非取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，所述取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基。The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a linear or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl ylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl 2,2-diethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers. More preferred are alkyl groups containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -Methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted, and when substituted, substituents may be substituted at any available point of attachment, said substituents being preferably one or more of the following groups independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxy group, heterocycloalkyloxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
术语“亚烷基”表示烷烃分子中去除2个氢原子后余下的部分，包括1至20个碳原子的直链和支链亚基团。含有1至6个碳原子的亚烷基，非限制性实施例包括亚甲基(-CH 2-)、亚乙基(如-CH 2CH 2-或-CH(CH 3)-)、亚丙基(如-CH 2CH 2CH 2-或-CH(CH 2CH 3)-)、亚丁基(如-CH 2CH 2CH 2CH 2-)。如无特殊说明，亚烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基所取代。 The term "alkylene" means what remains of an alkane molecule after removal of 2 hydrogen atoms, including straight and branched chain subgroups of 1 to 20 carbon atoms. Alkylene groups containing 1 to 6 carbon atoms, non-limiting examples include methylene (-CH 2 -), ethylene (such as -CH 2 CH 2 - or -CH(CH 3 )-), ethylene Propyl (eg -CH 2 CH 2 CH 2 - or -CH(CH 2 CH 3 )-), butylene (eg -CH 2 CH 2 CH 2 CH 2 -). Unless otherwise specified, an alkylene group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from alkyl radical, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkane Oxygen, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“环烷基”或“碳环”指饱和或部分不饱和单环或多环环状烃取代基，环烷基 环包含3至20个碳原子，优选包含3至7个碳原子。单环环烷基的非限制性实例包括环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基等；多环环烷基包括螺环、稠环和桥环的环烷基。环烷基可以是取代的或未取代的，当被取代时，取代基可以在任何可使用的连接点上被取代，优选一个或多个以下基团，独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基所取代。The term "cycloalkyl" or "carbocycle" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing 3 to 20 carbon atoms, preferably containing 3 to 7 carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, etc.; multicyclic cycloalkyls include spiro Cycloalkyl rings, fused rings and bridged rings. Cycloalkyl groups may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from alkyl, alkenyl, Alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycle Alkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
所述环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为环烷基，非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基所取代。The cycloalkyl ring may be fused to an aryl or heteroaryl ring where the ring bonded to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzo Heptyl, etc. Cycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio Substituted by group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
术语“杂环烷基”(Heterocycloalkyl)指饱和或部分不饱和单环或多环环状烃取代基，其包含3至20个环原子，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，但不包括-O-O-、-O-S-或-S-S-的环部分，其余环原子为碳。优选包含3至12个环原子，其中1～4个是杂原子；更优选包含3至7个环原子。单环杂环烷基的非限制性实例包括吡咯烷基、咪唑烷基、四氢呋喃基、四氢噻吩基、二氢咪唑基、二氢呋喃基、二氢吡唑基、二氢吡咯基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环烷基包括螺环、稠环和桥环的杂环烷基。“杂环烷基”非限制性实例包括： The term "heterocycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising 3 to 20 ring atoms, one or more of which are selected from nitrogen, oxygen or A heteroatom of S(O) m (where m is an integer from 0 to 2), excluding ring portions of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. Preferably it contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably it contains 3 to 7 ring atoms. Non-limiting examples of monocyclic heterocycloalkyl include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperrolyl, Pyridyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc. Multicyclic heterocycloalkyls include spiro, fused and bridged heterocycloalkyls. Non-limiting examples of "heterocycloalkyl" include:
Figure PCTCN2022103293-appb-000077
Figure PCTCN2022103293-appb-000077
Figure PCTCN2022103293-appb-000078
等等。
Figure PCTCN2022103293-appb-000078
wait.
所述杂环烷基环可以稠合于芳基或杂芳基环上，其中与母体结构连接在一起的环为杂环烷基，其非限制性实例包括：The heterocycloalkyl ring may be fused to an aryl or heteroaryl ring, wherein the ring bonded to the parent structure is a heterocycloalkyl, non-limiting examples of which include:
Figure PCTCN2022103293-appb-000079
等。
Figure PCTCN2022103293-appb-000079
Wait.
杂环烷基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基所取代。Heterocycloalkyl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkane Thio, heterocycloalkylthio, oxo, carboxyl or carboxylate.
术语“芳基”指具有共轭的π电子体系的6至14元全碳单环或稠合多环(也就是共享毗邻碳原子对的环)基团，优选为6至12元，例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为芳基环，其非限制性实例包括：The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) group, preferably 6 to 12 membered, having a conjugated pi-electron system, such as benzene base and naphthyl. The aryl ring may be fused to a heteroaryl, heterocycloalkyl or cycloalkyl ring, where the ring bonded to the parent structure is an aryl ring, non-limiting examples of which include:
Figure PCTCN2022103293-appb-000080
Figure PCTCN2022103293-appb-000080
芳基可以是取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基所取代。Aryl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, hetero Cycloalkylthio, oxo, carboxyl or carboxylate substituted.
术语“杂芳基”指包含1至4个杂原子、5至14个环原子的杂芳族体系，其中杂原子选自氧、硫和氮。杂芳基优选为6至12元，更优选为5元或6元。例如。其非限制性实例包括：咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基(oxazolyl)、异噁唑基(isoxazolyl)、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基、***基、吲唑基、苯并咪唑基、
Figure PCTCN2022103293-appb-000081
等。 The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4 heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. The heteroaryl group is preferably 6 to 12 membered, more preferably 5 or 6 membered. E.g. Non-limiting examples thereof include: imidazolyl, furyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, isoxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl , Thiadiazole, pyrazinyl, triazolyl, indazolyl, benzimidazolyl,
Figure PCTCN2022103293-appb-000081
Wait.
所述杂芳基环可以稠合于芳基、杂环烷基或环烷基环上，其中与母体结构连接在一起的环为杂芳基环，其非限制性实例包括：The heteroaryl ring may be fused to an aryl, heterocycloalkyl or cycloalkyl ring, wherein the ring bonded to the parent structure is a heteroaryl ring, non-limiting examples of which include:
Figure PCTCN2022103293-appb-000082
Figure PCTCN2022103293-appb-000082
杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多 个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基所取代。Heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio Substituted by group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
术语“螺环”指两环共用一个原子的化合物。The term "spiro" refers to a compound in which two rings share one atom.
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基，优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。“螺碳环”指的是螺环烷基中的环系。螺环烷基的非限制性实例包括：The term "spirocycloalkyl" refers to a polycyclic group of 5 to 20 membered monocyclic rings sharing one carbon atom (called a spiro atom), which may contain one or more double bonds, but none of the rings has complete conjugation The π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of spiro atoms shared between the rings, the spirocycloalkyl group can be divided into single spirocycloalkyl, double spirocycloalkyl or polyspirocycloalkyl, preferably single spirocycloalkyl and double spirocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospirocycloalkyl group. "Spirocarbocycle" refers to the ring system in a spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:
Figure PCTCN2022103293-appb-000083
Figure PCTCN2022103293-appb-000083
术语“螺杂环烷基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环烷基团，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环烷基分为单螺杂环烷基、双螺杂环烷基或多螺杂环烷基，优选为单螺杂环烷基和双螺杂环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环烷基。“螺杂环”指的是螺杂环烷基中的环系。螺杂环烷基的非限制性实例包括： The term "spiroheterocycloalkyl" refers to a polycyclic heterocycloalkyl group that shares one atom (called a spiro atom) between a 5- to 20-membered monocyclic ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O) heteroatoms of m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated pi-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. Spiroheterocycloalkyl is divided into single spiroheterocycloalkyl, double spiroheterocycloalkyl or polyspiroheterocycloalkyl according to the number of spiro atoms shared between rings, preferably single spiroheterocycloalkyl and double spiroheterocycloalkyl Spiroheterocycloalkyl. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monospiroheterocycloalkyl group. "Spiroheterocycle" refers to the ring system in a spiroheterocycloalkyl. Non-limiting examples of spiroheterocycloalkyl include:
Figure PCTCN2022103293-appb-000084
Figure PCTCN2022103293-appb-000084
术语“稠环”与“并环”可互换使用，指两个或两个以上环通过共用两个相邻的原子稠合而成的化合物。The terms "fused ring" and "joined ring" are used interchangeably and refer to a compound in which two or more rings are fused by sharing two adjacent atoms.
术语“稠环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团，其中一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环烷基。“稠碳环”指的是稠环烷基中的环系。稠环烷基的非限制性实例包括：The term "fused cycloalkyl" refers to a 5 to 20 membered all-carbon polycyclic group in which each ring of the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyl groups, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicycloalkyl groups. "Fused carbocycle" refers to the ring system in a fused cycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:
Figure PCTCN2022103293-appb-000085
Figure PCTCN2022103293-appb-000085
术语“稠杂环烷基”指5至20元，***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环烷基团，一个或多个环可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环烷基，优选为双环或三环，更优选为5元/5元或5元/6元双环稠杂环烷基。“稠杂环”指的是稠杂环烷基中的环系。稠杂环烷基的非限制性实例包括： The term "fused heterocycloalkyl" refers to a 5 to 20 membered polycyclic heterocycloalkyl group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), The remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic condensed heterocycloalkane base. "Fused heterocycle" refers to the ring system in a fused heterocycloalkyl group. Non-limiting examples of fused heterocycloalkyl include:
Figure PCTCN2022103293-appb-000086
Figure PCTCN2022103293-appb-000086
术语“稠杂芳基”可以是含有5-14个环原子(其中至少含有一个杂原子)由两个或两个以上环状结构彼此共用两个相邻的原子连接起来形成的不饱和的具有芳香性的稠环结构，同时包括碳原子、氮原子和硫原子可以被氧代，优选"5-12元稠杂芳基"、"7-12元稠杂芳基"、"9-12元稠杂芳基"等，例如苯并呋喃基、苯并异呋喃基、苯并噻吩基、吲哚基、异吲哚、苯并噁唑基、苯并咪唑基、吲唑基、苯并***基、喹啉基、2-喹啉酮、4-喹啉酮、1-异喹啉酮、异喹啉基、吖啶基、菲啶基、苯并哒嗪基、酞嗪基、喹唑啉基、喹喔啉基、酚嗪基、喋啶基、嘌呤基、萘啶基、吩嗪、吩噻嗪等。“稠杂芳环”指的是稠杂芳基中的环系。The term "fused heteroaryl" may contain 5-14 ring atoms (including at least one heteroatom), which is formed by connecting two or more ring structures with two adjacent atoms. Aromatic condensed ring structure, including carbon atoms, nitrogen atoms and sulfur atoms can be oxo, preferably "5-12 membered fused heteroaryl", "7-12 membered fused heteroaryl", "9-12 membered Fused heteroaryl" etc., such as benzofuryl, benzoisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazole, indazolyl, benzotri Azolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinolinyl Azolinyl, quinoxalinyl, phenazinyl, pteridyl, purinyl, naphthyridyl, phenazine, phenothiazine, etc. "Fused heteroaryl ring" refers to a ring system in a fused heteroaryl group.
稠杂芳基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、羧基或羧酸酯基。术语“桥环”指两个或两个以上环状结构彼此共用两个非相邻的环原子所形成的结构。Fused heteroaryl groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio group, heterocycloalkylthio group, carboxyl group or carboxylate group. The term "bridged ring" refers to a structure formed by two or more ring structures sharing two non-adjacent ring atoms with each other.
术语“桥环烷基”指5至20元，任意两个环共用两个不直接连接的碳原子的全碳多环基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基，优选为双环、三环或四环，更有选为双环或三环。 桥环烷基的非限制性实例包括：The term "bridged cycloalkyl" refers to a 5 to 20 membered, all-carbon polycyclic group having any two rings sharing two carbon atoms not directly attached, which may contain one or more double bonds, but none of the rings has a complete Conjugated π-electron systems. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:
Figure PCTCN2022103293-appb-000087
Figure PCTCN2022103293-appb-000087
术语“桥杂环烷基”指5至14元，任意两个环共用两个不直接连接的原子的多环杂环烷基团，其可以含有一个或多个双键，但没有一个环具有完全共轭的π电子***，其中一个或多个环原子为选自氮、氧或S(O) m(其中m是整数0至2)的杂原子，其余环原子为碳。优选为6至14元，更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环烷基，优选为双环、三环或四环，更有选为双环或三环。桥杂环烷基的非限制性实例包括： The term "bridged heterocycloalkyl" refers to a 5 to 14 membered, polycyclic heterocycloalkyl group of 5 to 14 membered, any two rings sharing two atoms not directly attached, which may contain one or more double bonds, but none of the rings has A fully conjugated π-electron system wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2) and the remaining ring atoms are carbon. Preferably it is 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocycloalkyl groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocycloalkyl groups include:
Figure PCTCN2022103293-appb-000088
Figure PCTCN2022103293-appb-000088
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基)，其中烷基的定义如上所述。烷氧基的非限制性实例包括：甲氧基、乙氧基、丙氧基、丁氧基、环丙氧基、环丁氧基、环戊氧基、环己氧基。烷氧基可以是任选取代的或非取代的，当被取代时，取代基优选为一个或多个以下基团，其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、羧基或羧酸酯基所取代。The term "alkoxy" refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. Alkoxy may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkoxy Thio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , Heterocycloalkylthio, oxo, carboxyl or carboxylate substituted.
术语“羟基”指-OH基团。The term "hydroxyl" refers to a -OH group.
术语“卤素”指氟、氯、溴或碘。The term "halogen" refers to fluorine, chlorine, bromine or iodine.
术语“卤代烷基”指被卤素取代的烷基，其中烷基如上所定义。The term "haloalkyl" refers to an alkyl group substituted with a halogen, wherein alkyl is as defined above.
术语“杂环烷基氧基”指杂环烷基-O-，其中杂环烷基如上所定义。The term "heterocycloalkyloxy" refers to heterocycloalkyl-O-, wherein heterocycloalkyl is as defined above.
术语“杂环烷基硫基”指杂环烷基-S-，其中杂环烷基如上所定义。The term "heterocycloalkylthio" refers to heterocycloalkyl-S-, wherein heterocycloalkyl is as defined above.
术语“氧代”指＝O基团。例如，碳原子与氧原子通过双键连接，其中形成酮或醛基。The term "oxo" refers to the =O group. For example, a carbon atom is linked to an oxygen atom by a double bond, where a ketone or aldehyde group is formed.
术语“氨基”指-NH 2。 The term "amino" refers to -NH2 .
术语“氰基”指-CN。The term "cyano" refers to -CN.
术语“硝基”指-NO 2。 The term "nitro" refers to -NO2 .
术语“羧基”指-C(O)OH。The term "carboxy" refers to -C(O)OH.
术语“取代的”指基团中的一个或多个氢原子，优选为最多5个，更优选为1～3个氢原子彼此独立地被相应数目的取代基取代。不言而喻，取代基仅处在它们的可能的化学位置，本领域技术人员能够在不付出过多努力的情况下确定(通过实验或理论)可能或不可能的取代。The term "substituted" means that one or more hydrogen atoms in a group, preferably up to 5, more preferably 1 to 3 hydrogen atoms are independently substituted by the corresponding number of substituents. It goes without saying that substituents are only in their possible chemical positions and that a person skilled in the art can determine (by experiment or theory) possible or impossible substitutions without undue effort.
“被一个或多个……取代”是指可以被单个或多个取代基取代。当被多个取代基取代时，可以是复数个相同取代基，也可以是一个或复数个不同取代基的组合。"Substituted by one or more" means that it can be substituted by single or multiple substituents. When substituted by a plurality of substituents, it may be a plurality of the same substituents, or one or a combination of a plurality of different substituents.
具体实施方式detailed description
以下结合实施例进一步描述本公开，但这些实施例并非限制着本公开的范围。The present disclosure is further described below in conjunction with examples, but these examples do not limit the scope of the present disclosure.
本公开实施例中未注明具体条件的实验方法，通常按照常规条件，或按照原料或商品制造厂商所建议的条件。未注明具体来源的试剂，为市场购买的常规试剂。The experimental methods in the embodiments of the present disclosure that do not indicate specific conditions are generally in accordance with conventional conditions, or in accordance with the conditions suggested by the raw material or commodity manufacturers. Reagents without specific sources indicated are conventional reagents purchased in the market.
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10 -6(ppm)的单位给出。NMR的测定是用Bruker AVANCE-400核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d 6)，氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，内标为四甲基硅烷(TMS)。 Compound structures were determined by nuclear magnetic resonance (NMR) or/and mass spectroscopy (MS). NMR shifts (δ) are given in units of 10 -6 (ppm). The determination of NMR is to use Bruker AVANCE-400 nuclear magnetic instrument, and the determination solvent is deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard is four Methylsilane (TMS).
MS的测定用Shimadzu 2010Mass Spectrometer或Agilent 6110A MSD质谱仪。MS was determined by Shimadzu 2010Mass Spectrometer or Agilent 6110A MSD mass spectrometer.
HPLC的测定使用Shimadzu LC-20A systems、Shimadzu LC-2010HT series或安捷伦Agilent 1200LC高压液相色谱仪(Ultimate XB-C18 3.0*150mm色谱柱或Xtimate C18 2.1*30mm色谱柱)。The determination of HPLC uses Shimadzu LC-20A systems, Shimadzu LC-2010HT series or Agilent Agilent 1200LC high pressure liquid chromatography (Ultimate XB-C18 3.0*150mm column or Xtimate C18 2.1*30mm column).
手性HPLC分析测定使用Chiralpak IC-3 100×4.6mm I.D.,3um、Chiralpak AD-3 150×4.6mm I.D.,3um、Chiralpak AD-3 50×4.6mm I.D.,3um、Chiralpak AS-3 150×4.6mm I.D.,3um、Chiralpak AS-3 100×4.6mm I.D.,3μm、ChiralCel OD-3 150×4.6mm I.D.,3um、Chiralcel OD-3 100×4.6mm I.D.,3μm、ChiralCel OJ-H 150×4.6mm I.D.,5um、Chiralcel OJ-3 150×4.6mm I.D.,3um色谱柱；Chiralpak IC-3 100×4.6mm I.D., 3um, Chiralpak AD-3 150×4.6mm I.D., 3um, Chiralpak AD-3 50×4.6mm I.D., 3um, Chiralpak AS-3 150×4.6mm were used for chiral HPLC analysis and determination I.D., 3um, Chiralpak AS-3 100×4.6mm I.D., 3μm, ChiralCel OD-3 150×4.6mm I.D., 3um, Chiralcel OD-3 100×4.6mm I.D., 3μm, ChiralCel OJ-H 150×4.6mm I.D., 5um, Chiralcel OJ-3 150×4.6mm I.D., 3um column;
薄层层析硅胶板使用烟台黄海HSGF254或青岛GF254硅胶板，薄层色谱法(TLC)使用的硅胶板采用的规格是0.15mm～0.2mm，薄层层析分离纯化产品采用的规格是0.4mm～0.5mm。The thin-layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate. The specification of the silica gel plate used in thin-layer chromatography (TLC) is 0.15mm-0.2mm, and the specification of thin-layer chromatography separation and purification products is 0.4mm. ~0.5mm.
柱层析一般使用烟台黄海硅胶100～200目、200～300目或300～400目硅胶为载体。Column chromatography generally uses Yantai Huanghai silica gel 100-200 mesh, 200-300 mesh or 300-400 mesh silica gel as the carrier.
手性制备柱使用DAICEL CHIRALPAK IC(250mm*30mm,10um)或Phenomenex-Amylose-1(250mm*30mm,5um)。The chiral preparative column uses DAICEL CHIRALPAK IC (250mm*30mm, 10um) or Phenomenex-Amylose-1 (250mm*30mm, 5um).
CombiFlash快速制备仪使用Combiflash Rf150(TELEDYNE ISCO)。The CombiFlash rapid preparation instrument uses Combiflash Rf150 (TELEDYNE ISCO).
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH & Co.KG，Acros Organics，Aldrich Chemical Company，韶远化 学科技(Accela ChemBio Inc)、达瑞化学品等公司。The known starting materials of the present disclosure can be adopted or synthesized according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc), Darui Chemicals and other companies.
实施例中无特殊说明，反应能够均在氩气氛或氮气氛下进行。Unless otherwise specified in the examples, the reactions can all be carried out under an argon atmosphere or a nitrogen atmosphere.
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。The argon atmosphere or nitrogen atmosphere means that the reaction bottle is connected to an argon or nitrogen balloon with a volume of about 1 L.
氢气氛是指反应瓶连接一个约1L容积的氢气气球。The hydrogen atmosphere means that the reaction bottle is connected to a hydrogen balloon with a capacity of about 1L.
加压氢化反应使用Parr 3916EKX型氢化仪和清蓝QL-500型氢气发生器或HC2-SS型氢化仪。The pressurized hydrogenation reaction uses Parr 3916EKX hydrogenation instrument and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenation instrument.
氢化反应通常抽真空，充入氢气，反复操作3次。The hydrogenation reaction is usually vacuumized and filled with hydrogen, and the operation is repeated 3 times.
微波反应使用CEM Discover-S 908860型微波反应器。For the microwave reaction, a CEM Discover-S 908860 microwave reactor was used.
实施例中无特殊说明，溶液是指水溶液。Unless otherwise specified in the examples, the solution refers to an aqueous solution.
实施例中无特殊说明，反应的温度为室温，为20℃～30℃。Unless otherwise specified in the examples, the reaction temperature is room temperature, which is 20°C to 30°C.
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。The monitoring of the reaction progress in the embodiment adopts thin-layer chromatography (TLC), the developing agent used in reaction, the eluent system of the eluent system of the column chromatography that purification compound adopts and the developing agent system of thin-layer chromatography, the volume of solvent The ratio is adjusted according to the polarity of the compound, and it can also be adjusted by adding a small amount of basic or acidic reagents such as triethylamine and acetic acid.
实施例1Example 1
顺式3-(5-((3-(甲氧基甲基)-1-甲基-1H-吡唑并[3,4-c]吡啶-7-基)氨基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯1cis 3-(5-((3-(methoxymethyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)amino)-1H-pyrazole- 3-yl) cyclopentyl isopropyl carbamate 1
Figure PCTCN2022103293-appb-000089
Figure PCTCN2022103293-appb-000089
第一步first step
N-2-二甲氧基-N-甲基乙酰胺1BN-2-Dimethoxy-N-methylacetamide 1B
室温下，依次将化合物1A(13.5g,0.12mol)、甲氧基胺盐酸盐(13.4g,0.14mol)、溶于100mL无水二氯甲烷中，在0-5℃滴加三乙胺(37.8g,0.37mol)。滴毕后缓慢升至室温，反应过夜，待反应完全后，加入150mL水淬灭反应，二氯甲烷萃取(50mL×3)，合并有机相，用饱和氯化钠溶液洗涤(50mL)，无水硫酸钠干燥，过滤，收集滤液，减压浓缩柱层析得标题化合物1B(12g，产率：72％)。At room temperature, sequentially dissolve compound 1A (13.5g, 0.12mol), methoxylamine hydrochloride (13.4g, 0.14mol) in 100mL of anhydrous dichloromethane, and add triethylamine dropwise at 0-5°C (37.8 g, 0.37 mol). After dripping, it was slowly raised to room temperature and reacted overnight. After the reaction was complete, 150 mL of water was added to quench the reaction, extracted with dichloromethane (50 mL×3), the organic phases were combined, washed with saturated sodium chloride solution (50 mL), and anhydrous Dry over sodium sulfate, filter, collect the filtrate, concentrate under reduced pressure and perform column chromatography to obtain the title compound 1B (12 g, yield: 72%).
第二步second step
1-(2-氯-3-氟吡啶-4-基)-2-甲氧基乙烷-1-酮1C1-(2-Chloro-3-fluoropyridin-4-yl)-2-methoxyethan-1-one 1C
-65℃，将2-氯-3-氟吡啶(12.6g,75.7mmol)溶于40mL无水四氢呋喃中，缓慢滴加正丁基锂(35.8mL,2.5N的四氢呋喃溶液)，维持内温在-55℃下，继续搅拌1小时，然后将化合物1B(8.5g,63.8mmol)溶于40mL无水四氢呋喃中缓慢滴加入反应液中，待加完后继续在-65℃下搅拌1小时。用100mL饱和氯化铵溶液淬灭，用乙酸乙酯萃取(50mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥，过滤，收集滤液，减压浓缩柱层析得标题化合物1C(6.0g，产率：46％)。LCMS(ESI)m/z 204.1[M+H] +。 -65°C, 2-chloro-3-fluoropyridine (12.6g, 75.7mmol) was dissolved in 40mL of anhydrous tetrahydrofuran, and n-butyllithium (35.8mL, 2.5N solution in tetrahydrofuran) was slowly added dropwise to maintain the internal temperature at Stirring was continued for 1 hour at -55°C, and compound 1B (8.5g, 63.8mmol) dissolved in 40mL of anhydrous THF was slowly added dropwise to the reaction solution, and stirring was continued at -65°C for 1 hour after the addition was complete. Quenched with 100 mL of saturated ammonium chloride solution, extracted with ethyl acetate (50 mL×3), combined the organic phases, washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, collected the filtrate, and reduced pressure Concentration column chromatography gave the title compound 1C (6.0 g, yield: 46%). LCMS (ESI) m/z 204.1 [M+H] + .
第三步third step
7-氯-3-(甲氧基甲基)-1H-吡唑[3,4-c]吡啶1D7-Chloro-3-(methoxymethyl)-1H-pyrazol[3,4-c]pyridine 1D
室温下，依次将化合物1C(3.0g,14.7mmol)、碳酸氢钠(1.24g,14.7mmol)、水合肼(0.79mL,16.2mmol)、溶于18mL二氧六环和3mL乙醇中，封管升温至70℃，继续搅拌15小时。待反应完全后，过滤，旋干滤液柱层析得标题化合物1D(2g，产率：68％)。LCMS(ESI)m/z 198.1[M+H] +。 At room temperature, sequentially dissolve compound 1C (3.0g, 14.7mmol), sodium bicarbonate (1.24g, 14.7mmol), hydrazine hydrate (0.79mL, 16.2mmol) in 18mL dioxane and 3mL ethanol, seal the tube The temperature was raised to 70°C and stirring was continued for 15 hours. After the reaction was complete, filter and spin the filtrate to obtain the title compound 1D (2 g, yield: 68%) by column chromatography. LCMS (ESI) m/z 198.1 [M+H] + .
第四步the fourth step
7-氯-3-(甲氧基甲基)-1-甲基-1H-吡唑[3,4-c]吡啶1E7-Chloro-3-(methoxymethyl)-1-methyl-1H-pyrazolo[3,4-c]pyridine 1E
室温，将化合物1D(0.9g,4.6mmol)溶于5mL的N,N-二甲基甲酰胺中，冰浴降温至0-5℃，加入碳酸铯(4.45g,13.6mmol)，恒温搅拌20分钟后滴加碘甲烷(0.71g,5mmol)，加完后缓慢升至室温反应2小时，待反应完全后，用50mL水淬灭，接着用乙酸乙酯萃取(30mL×3)，合并有机相，用饱和氯化钠溶液洗涤(100mL)，无水硫酸钠干燥，过滤，收集滤液，减压浓缩柱层析得标题化合物1E(0.30g，产率：31％)。LCMS(ESI)m/z 212.1[M+H] +。 At room temperature, compound 1D (0.9g, 4.6mmol) was dissolved in 5mL of N,N-dimethylformamide, cooled to 0-5°C in an ice bath, cesium carbonate (4.45g, 13.6mmol) was added, and stirred at constant temperature for 20 Minutes later, methyl iodide (0.71g, 5mmol) was added dropwise. After the addition, it was slowly raised to room temperature for 2 hours. After the reaction was complete, it was quenched with 50mL of water, followed by extraction with ethyl acetate (30mL×3), and the organic phases were combined. , was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and concentrated under reduced pressure by column chromatography to obtain the title compound 1E (0.30 g, yield: 31%). LCMS (ESI) m/z 212.1 [M+H] + .
第五步the fifth step
顺式3-(1-(叔丁基)-5-((3-(甲氧基甲基)-1-甲基-1H-吡唑[3,4-c]吡啶-7-基)氨基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯1Fcis 3-(1-(tert-butyl)-5-((3-(methoxymethyl)-1-methyl-1H-pyrazol[3,4-c]pyridin-7-yl)amino )-1H-pyrazol-3-yl)cyclopentyl isopropyl carbamate 1F
氮气氛下，化合物1E(100mg，0.47mmol)、顺式3-(5-氨基-1-(叔丁基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯1-INT(0.15g，0.47mmol，采用专利申请“WO2020/157652A2”公开的方法制备而得)、叔丁醇钠(0.9g，0.94mmol)、XPhos(9mg，0.02mmol，4mol％)、Pd(dba) 2(5.4mg，0.01mmol，2mol％)和甲苯(2mL)的混合物100℃持续19小时。反应液浓缩用硅胶层析纯化得到标题化合物1F(130mg，产率：56％)。 Under nitrogen atmosphere, compound 1E (100mg, 0.47mmol), cis 3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentylisopropylcarbamate 1 -INT (0.15g, 0.47mmol, prepared by the method disclosed in the patent application "WO2020/157652A2"), sodium tert-butoxide (0.9g, 0.94mmol), XPhos (9mg, 0.02mmol, 4mol%), Pd ( A mixture of dba) 2 (5.4 mg, 0.01 mmol, 2 mol%) and toluene (2 mL) was maintained at 100° C. for 19 hours. The reaction solution was concentrated and purified by silica gel chromatography to obtain the title compound 1F (130 mg, yield: 56%).
MS(ESI)m/z 484.6[M+H] +。 MS (ESI) m/z 484.6 [M+H] + .
第六步step six
顺式3-(5-((3-(甲氧基甲基)-1-甲基-1H-吡唑并[3,4-c]吡啶-7-基)氨基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯1cis 3-(5-((3-(methoxymethyl)-1-methyl-1H-pyrazolo[3,4-c]pyridin-7-yl)amino)-1H-pyrazole- 3-yl) cyclopentyl isopropyl carbamate 1
氮气氛下，将化合物1F(60mg,0.12mmol)溶于2mL甲酸中，75℃条件下加热反应20小时，反应液冷却至室温，减压浓缩后残余物用饱和碳酸氢钠溶液调至pH＝7，用乙酸乙酯萃取(15mL×3)，合并有机相，用饱和氯化钠溶液洗涤(20mL)，无水硫酸钠干燥，过滤，收集滤液，减压浓缩后残余物用硅胶柱层析得到标题化合物1(2mg)，其为一对对映异构体。Under a nitrogen atmosphere, compound 1F (60 mg, 0.12 mmol) was dissolved in 2 mL of formic acid, heated at 75°C for 20 hours, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was adjusted to pH = 7. Extract with ethyl acetate (15mL×3), combine the organic phases, wash with saturated sodium chloride solution (20mL), dry over anhydrous sodium sulfate, filter, collect the filtrate, concentrate under reduced pressure and the residue is subjected to silica gel column chromatography The title compound 1 (2 mg) was obtained as a pair of enantiomers.
MS(ESI)m/z 428.5[M+H] +。 MS (ESI) m/z 428.5 [M+H] + .
实施例2Example 2
(1R,3S)-3-(3-(吡唑并[1,5-a]吡嗪-4-基氨基)-1H-吡唑-5-基)环戊基异丙基氨基甲酸酯2(1R,3S)-3-(3-(Pyrazolo[1,5-a]pyrazin-4-ylamino)-1H-pyrazol-5-yl)cyclopentylisopropylcarbamate 2
Figure PCTCN2022103293-appb-000090
Figure PCTCN2022103293-appb-000090
第一步first step
N-(2,2-二甲氧基乙基)-1H-吡唑-5-甲酰胺2CN-(2,2-dimethoxyethyl)-1H-pyrazole-5-carboxamide 2C
氮气氛下，依次将化合物1H-吡唑-3-羧酸2A(3.0g，26.8mmol)、O-(7-氮苯并三氮唑)-N,N,N,N-四甲基脲六氟磷酸酯(12.2g，32.1mmol)、N,N-二异丙基乙胺(6.9g，53.6mmol)和2,2-二甲氧基乙烷-1-胺2B(3.4g,32.1mmol)溶于N,N-二甲基甲酰胺(20mL)中。室温下反应12小时。反应液加入100ml水，用乙酸乙酯萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后残余物用硅胶正相色谱法纯化得到标题化合物2C(2.6g,产率48.8％)。Under nitrogen atmosphere, compound 1H-pyrazole-3-carboxylic acid 2A (3.0g, 26.8mmol), O-(7-nitrobenzotriazole)-N,N,N,N-tetramethylurea Hexafluorophosphate (12.2g, 32.1mmol), N,N-diisopropylethylamine (6.9g, 53.6mmol) and 2,2-dimethoxyethane-1-amine 2B (3.4g, 32.1 mmol) was dissolved in N,N-dimethylformamide (20 mL). The reaction was carried out at room temperature for 12 hours. 100ml of water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed, dried, concentrated under reduced pressure, and the residue was purified by silica gel normal phase chromatography to obtain the title compound 2C (2.6 g, yield 48.8%).
第二步second step
7-羟基-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮2D7-Hydroxy-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 2D
将化合物2C(2.6g,13.1mmol)加入到4mL二氯甲烷中，加入三氟乙酸(4mL)。在室温下反应3小时，反应液减压浓缩后得到标题化合物2D(2.0g,产率100％)。Compound 2C (2.6 g, 13.1 mmol) was added to 4 mL of dichloromethane, and trifluoroacetic acid (4 mL) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure to obtain the title compound 2D (2.0 g, yield 100%).
第三步third step
吡唑并[1,5-a]吡嗪-4(5H)-酮2EPyrazolo[1,5-a]pyrazin-4(5H)-one 2E
氮气氛下，将多聚磷酸(10mL)加入到化合物2D(2.0g,13.1mmol)中，在140℃ 条件下反应3小时。加入水(50ml),用氨水将pH调至10，用二氯甲烷萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后残余物中加入一滴浓盐酸，用100ml的石油醚乙酸乙酯(3:1)溶液打浆，过滤，滤饼干燥后得到标题化合物2E(1.1g,产率56.8％)。Under nitrogen atmosphere, polyphosphoric acid (10 mL) was added to compound 2D (2.0 g, 13.1 mmol), and reacted at 140° C. for 3 hours. Add water (50ml), adjust the pH to 10 with ammonia water, extract with dichloromethane, combine the organic phases, wash the organic phases, dry, concentrate under reduced pressure, add a drop of concentrated hydrochloric acid to the residue, and use 100ml of petroleum ether ethyl acetate The ester (3:1) solution was beaten, filtered, and the filter cake was dried to obtain the title compound 2E (1.1 g, yield 56.8%).
第四步the fourth step
4-氯吡唑并[1,5-a]吡嗪2F4-Chloropyrazolo[1,5-a]pyrazine 2F
将化合物2E(700mg，5.2mmol)、N,N-二异丙基乙胺(669mg，5.2mmol)加入到反应瓶中，加入三氯氧磷(5mL),在100℃条件下反应2小时。反应液降至室温，将反应液倒入冰水(25ml)中，用二氯甲烷萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后残余物用硅胶正相色谱法纯化得到标题化合物2F(260mg,产率32.7％)。Add compound 2E (700mg, 5.2mmol), N,N-diisopropylethylamine (669mg, 5.2mmol) into the reaction flask, add phosphorus oxychloride (5mL), and react at 100°C for 2 hours. The reaction solution was lowered to room temperature, the reaction solution was poured into ice water (25ml), extracted with dichloromethane, the organic phases were combined, the organic phase was washed, dried, concentrated under reduced pressure, and the residue was purified by silica gel normal phase chromatography to obtain the title Compound 2F (260 mg, yield 32.7%).
MS(ESI)m/z 154.4[M+H] +。 MS (ESI) m/z 154.4 [M+H] + .
第五步the fifth step
(1R,3S)-3-(1-(叔-丁基)-5-(吡唑并[1,5-a]吡嗪-4-基氨基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯2H(1R,3S)-3-(1-(tert-butyl)-5-(pyrazolo[1,5-a]pyrazin-4-ylamino)-1H-pyrazol-3-yl)ring Amyl isopropyl carbamate 2H
氮气氛下，依次将化合物2F(40mg，0.26mmol)、(1R,3S)-3-(5-氨基-1-(叔-丁基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯2G(80.3mg，0.26mmol，采用专利申请“WO 2020/157652A2”公开的方法制备而得)、三(二亚苄基丙酮)二钯(23.8mg，0.03mmol)和4,5-双二苯基膦-9,9-二甲基氧杂蒽(34.7mg，0.06mmol)溶于1,4-二氧六环(3mL)中。加入碳酸钾(71.9mg，0.52mmol)，70℃条件下反应3小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物2H(53mg,产率47.7％)。Under nitrogen atmosphere, compound 2F (40mg, 0.26mmol), (1R,3S)-3-(5-amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyliso Propylcarbamate 2G (80.3mg, 0.26mmol, prepared by the method disclosed in patent application "WO 2020/157652A2"), tris(dibenzylideneacetone)dipalladium (23.8mg, 0.03mmol) and 4 , 5-bisdiphenylphosphine-9,9-dimethylxanthene (34.7 mg, 0.06 mmol) was dissolved in 1,4-dioxane (3 mL). Potassium carbonate (71.9mg, 0.52mmol) was added and reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected, concentrated under reduced pressure, and the residue was purified by C-18 reverse phase chromatography to obtain the title compound 2H (53 mg, yield 47.7%).
MS(ESI)m/z 426.4[M+H] +。 MS (ESI) m/z 426.4 [M+H] + .
第六步step six
(1R,3S)-3-(3-(吡唑并[1,5-a]吡嗪-4-基氨基)-1H-吡唑-5-基)环戊基异丙基氨基甲酸酯2(1R,3S)-3-(3-(Pyrazolo[1,5-a]pyrazin-4-ylamino)-1H-pyrazol-5-yl)cyclopentylisopropylcarbamate 2
将化合物2H(53mg,0.12mmol)溶于3mL甲酸中，在80℃条件下反应18小时。冷却至室温，反应液直接用C-18反相色谱法纯化得到标题化合物2(10mg,产率21.7％)。Compound 2H (53 mg, 0.12 mmol) was dissolved in 3 mL of formic acid and reacted at 80° C. for 18 hours. After cooling to room temperature, the reaction solution was directly purified by C-18 reverse phase chromatography to obtain the title compound 2 (10 mg, yield 21.7%).
MS(ESI)m/z 370.4[M+H] +。 MS (ESI) m/z 370.4 [M+H] + .
实施例3Example 3
(1R,3S)-3-(3-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙基氨基甲酸酯3(1R,3S)-3-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl isopropyl carbamate 3
Figure PCTCN2022103293-appb-000091
Figure PCTCN2022103293-appb-000091
第一步first step
乙基-5-甲氧基-2,4-二羰基戊酸酯3CEthyl-5-methoxy-2,4-dicarbonylpentanoate 3C
氮气氛下，将1-甲氧基丙烷-2-酮3A(2.5g，28.4mmol)溶于乙醇(20mL)中。降温至0℃，在0℃下分批加入叔丁醇钾(3.2g，28.4mmol)，在0℃下搅拌半小时，加入草酸二乙酯3B(4.2g，28.4mmol)，室温下反应18小时。用稀盐酸(1mol/l)将pH调至4，用二氯甲烷萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后得到标题化合物3C(2.1g,产率39.6％)。1-Methoxypropan-2-one 3A (2.5 g, 28.4 mmol) was dissolved in ethanol (20 mL) under nitrogen atmosphere. Cool down to 0°C, add potassium tert-butoxide (3.2g, 28.4mmol) in batches at 0°C, stir at 0°C for half an hour, add diethyl oxalate 3B (4.2g, 28.4mmol), react at room temperature for 18 Hour. The pH was adjusted to 4 with dilute hydrochloric acid (1 mol/l), extracted with dichloromethane, the organic phases were combined, washed, dried, and concentrated under reduced pressure to obtain the title compound 3C (2.1 g, yield 39.6%).
第二步second step
乙基-3-(甲氧基甲基)-1H-吡唑-5-羧酸酯3DEthyl-3-(methoxymethyl)-1H-pyrazole-5-carboxylate 3D
将化合物3C(2.1g,11.2mmol)加入到15mL乙醇中，加入水合肼(50％wt,0.7g,11.2mmol)。在70℃下反应1小时，降温至室温，加入水(50ml),用乙酸乙酯萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后得到标题化合物3D(1.2g,产率58.4％)。Compound 3C (2.1 g, 11.2 mmol) was added into 15 mL of ethanol, and hydrazine hydrate (50% wt, 0.7 g, 11.2 mmol) was added. React at 70°C for 1 hour, cool down to room temperature, add water (50ml), extract with ethyl acetate, combine the organic phases, wash the organic phases, dry, and concentrate under reduced pressure to obtain the title compound 3D (1.2g, yield 58.4 %).
MS(ESI)m/z 185.5[M+H] +。 MS (ESI) m/z 185.5 [M+H] + .
第三步third step
3-(甲氧基甲基)-1H-吡唑-5-羧酸3E3-(Methoxymethyl)-1H-pyrazole-5-carboxylic acid 3E
将化合物3D(1.2g,7.7mmol)溶于10mL甲醇中，加入2mL水，加入氢氧化锂(368mg,15.4mmol)，在室温下反应5小时，用稀盐酸(1mol/L)将pH调至1，用乙酸乙酯萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后残余物用C-18反相色谱法纯化得到标题化合物3E(850mg,产率83.6％)。Dissolve compound 3D (1.2g, 7.7mmol) in 10mL of methanol, add 2mL of water, add lithium hydroxide (368mg, 15.4mmol), react at room temperature for 5 hours, adjust the pH to 1. Extract with ethyl acetate, combine the organic phases, wash the organic phases, dry, and concentrate under reduced pressure. The residue is purified by C-18 reverse phase chromatography to obtain the title compound 3E (850 mg, yield 83.6%).
MS(ESI)m/z 157.1[M+H] +。 MS (ESI) m/z 157.1 [M+H] + .
第四步the fourth step
N-(2,2-二甲氧基乙基)-3-(甲氧基甲基)-1H-吡唑-5-甲酰胺3FN-(2,2-dimethoxyethyl)-3-(methoxymethyl)-1H-pyrazole-5-carboxamide 3F
将化合物3E(750mg，4.8mmol)、1-丙基磷酸酐(50％wt,3.4g，5.3mmol)、N,N-二异丙基乙胺(1.2g，9.6mmol)、2,2-二甲氧基乙烷-1-胺2B(555mg,5.3mmol)溶于N,N-二甲基甲酰胺(15mL)中。室温下反应12小时。反应液加入100ml水，用乙酸乙酯萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后得到标题化合物3F(1.1g,产率100％)。Compound 3E (750mg, 4.8mmol), 1-propylphosphoric anhydride (50%wt, 3.4g, 5.3mmol), N,N-diisopropylethylamine (1.2g, 9.6mmol), 2,2- Dimethoxyethane-1-amine 2B (555 mg, 5.3 mmol) was dissolved in N,N-dimethylformamide (15 mL). The reaction was carried out at room temperature for 12 hours. 100ml of water was added to the reaction solution, extracted with ethyl acetate, the organic phases were combined, washed, dried, and concentrated under reduced pressure to obtain the title compound 3F (1.1 g, yield 100%).
MS(ESI)m/z 242.2[M-H] -。 MS (ESI) m/z 242.2 [MH] - .
第五步the fifth step
7-羟基-2-(甲氧基甲基)-6,7-二氢吡唑并[1,5-a]吡嗪-4(5H)-酮3G7-Hydroxy-2-(methoxymethyl)-6,7-dihydropyrazolo[1,5-a]pyrazin-4(5H)-one 3G
将化合物3F(1.1g,5.6mmol)加入到4mL二氯甲烷中，加入三氟乙酸(4mL)。在室温下反应3小时，反应液减压浓缩后得到标题化合物3G(1.2g,产率100％)。Compound 3F (1.1 g, 5.6 mmol) was added to 4 mL of dichloromethane, and trifluoroacetic acid (4 mL) was added. After reacting at room temperature for 3 hours, the reaction solution was concentrated under reduced pressure to obtain the title compound 3G (1.2 g, yield 100%).
第六步step six
2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4(5H)-酮3H2-(Methoxymethyl)pyrazolo[1,5-a]pyrazin-4(5H)-one 3H
将甲磺酸(8mL)加入到化合物3G(1.2g,6.1mmol)中，在室温下反应3天。反应液直接用C-18反相色谱法纯化得到标题化合物3H(430mg,产率39.4％)。Methanesulfonic acid (8 mL) was added to compound 3G (1.2 g, 6.1 mmol) and reacted at room temperature for 3 days. The reaction solution was directly purified by C-18 reverse phase chromatography to obtain the title compound 3H (430 mg, yield 39.4%).
MS(ESI)m/z 180.2[M+H] +。 MS (ESI) m/z 180.2 [M+H] + .
第七步step seven
4-氯-2-(甲氧基甲基)吡唑并[1,5-a]吡嗪3I4-Chloro-2-(methoxymethyl)pyrazolo[1,5-a]pyrazine 3I
将化合物3H(110mg，0.6mmol)、N,N-二异丙基乙胺(72mg，0.6mmol)加入到反应瓶中，加入三氯氧磷(3mL),在100℃条件下反应2小时。反应液降至室温，将反应液倒入冰水(20ml)中，用二氯甲烷萃取，合并有机相，将有机相洗涤，干燥，减压浓缩后残余物用硅胶正相色谱法纯化得到标题化合物3I(86mg,产率71.1％)。Add compound 3H (110mg, 0.6mmol), N,N-diisopropylethylamine (72mg, 0.6mmol) into the reaction flask, add phosphorus oxychloride (3mL), and react at 100°C for 2 hours. The reaction solution was cooled to room temperature, the reaction solution was poured into ice water (20ml), extracted with dichloromethane, the organic phases were combined, the organic phase was washed, dried, concentrated under reduced pressure, and the residue was purified by silica gel normal phase chromatography to obtain the title Compound 3I (86 mg, yield 71.1%).
MS(ESI)m/z 198.1[M+H] +。 MS (ESI) m/z 198.1 [M+H] + .
第八步eighth step
(1R,3S)-3-(1-(叔-丁基)-5-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯3J(1R,3S)-3-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino) -1H-pyrazol-3-yl)cyclopentyl isopropyl carbamate 3J
氮气氛下，依次将化合物3I(60mg，0.3mmol)、化合物2G(93.8mg，0.3mmol，采用专利申请“WO 2020/157652A2”公开的方法制备而得)、三(二亚苄基丙酮)二钯(27.5mg，0.03mmol)、4,5-双二苯基膦-9,9-二甲基氧杂蒽(34.7mg，0.06mmol)溶于1,4-二氧六环(3mL)中。加入碳酸钾(82.9mg，0.6mmol)，70℃条件下反应3小时。反应液冷却至室温，过滤，收集滤液，减压浓缩后得到标题化合物粗品3J(52mg,产率36.4％)Under a nitrogen atmosphere, compound 3I (60 mg, 0.3 mmol), compound 2G (93.8 mg, 0.3 mmol, prepared by the method disclosed in the patent application "WO 2020/157652A2"), tris(dibenzylideneacetone) di Palladium (27.5 mg, 0.03 mmol), 4,5-bisdiphenylphosphine-9,9-dimethylxanthene (34.7 mg, 0.06 mmol) in 1,4-dioxane (3 mL) . Potassium carbonate (82.9mg, 0.6mmol) was added and reacted at 70°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product 3J of the title compound (52mg, yield 36.4%)
MS(ESI)m/z 470.5[M+H] +。 MS (ESI) m/z 470.5 [M+H] + .
第九步Ninth step
(1R,3S)-3-(3-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙基氨基甲酸酯3(1R,3S)-3-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl isopropyl carbamate 3
将化合物3J(52mg,0.11mmol)溶于3mL甲酸中，在80℃条件下反应18小时。冷却至室温，反应液直接用C-18反相色谱法纯化得到标题化合物3(12.6mg,产率27.5％)。Compound 3J (52 mg, 0.11 mmol) was dissolved in 3 mL of formic acid and reacted at 80°C for 18 hours. After cooling to room temperature, the reaction solution was directly purified by C-18 reverse phase chromatography to obtain the title compound 3 (12.6 mg, yield 27.5%).
MS(ESI)m/z 414.4[M+H] +。 MS (ESI) m/z 414.4 [M+H] + .
1H NMR:(400MHz,DMSO-d 6)δ＝ppm 10.02(s,1H),8.02-8.00(d,J＝4.8Hz,1H),7.38-7.37(d,J＝4.8Hz,1H),7.28(s,1H),6.96-6.94(d,J＝7.2,Hz,1H),6.58(s,1H),5.01(s,1H),4.55(s,2H),3.60-3.54(m,1H),3.32(s,3H),3.10-3.06(m,1H),2.05-2.03(m,1H),1.91-1.90(m,1H),1.75-1.50(m,3H),1.50-1.45(m,1H),1.03-1.02(d,J＝6.0Hz,6H)。 1H NMR: (400MHz,DMSO-d 6 )δ=ppm 10.02(s,1H),8.02-8.00(d,J=4.8Hz,1H),7.38-7.37(d,J=4.8Hz,1H),7.28 (s,1H),6.96-6.94(d,J＝7.2,Hz,1H),6.58(s,1H),5.01(s,1H),4.55(s,2H),3.60-3.54(m,1H) ,3.32(s,3H),3.10-3.06(m,1H),2.05-2.03(m,1H),1.91-1.90(m,1H),1.75-1.50(m,3H),1.50-1.45(m, 1H), 1.03-1.02 (d, J=6.0Hz, 6H).
实施例4Example 4
(1R,3S)-3-(3-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯4(1R,3S)-3-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl (1-methylcyclopropyl) carbamate 4
Figure PCTCN2022103293-appb-000092
Figure PCTCN2022103293-appb-000092
第一步first step
(1R,3S)-3-(1-(叔丁基)-5-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基(1-甲基环丙基)氨基甲酸酯(1R,3S)-3-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)- 1H-pyrazol-3-yl)cyclopentyl(1-methylcyclopropyl)carbamate
氮气下，将(1R,3S)-3-(5-氨基-1-(叔丁基)-1H-吡唑-3-基)环戊(1-甲基环丙基)氨基甲酸酯4A(81.1mg，0.253mmol,采用专利申请“WO 2020/157652A2”公开的方法制备而得)溶于四氢呋喃(2mL)中。冰浴下加入NaHMDS(0.278mL，0.557mmol,2M)，室温搅拌0.5小时。在反应液中加入化合物3I(50mg，0.253mmol)，反应液在60℃氮气下搅拌1小时。反应液使用饱和氯化铵淬灭(20mL)，乙酸乙酯(15mL*3)萃取。有机相使用饱和食盐水洗涤(30mL)洗涤，无水硫酸钠干燥，过滤，收集滤液，减压浓缩后得到标题化合物粗品4B(35mg)。Under nitrogen, (1R,3S)-3-(5-Amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopenta(1-methylcyclopropyl)carbamate 4A (81.1mg, 0.253mmol, prepared by the method disclosed in the patent application "WO 2020/157652A2") was dissolved in tetrahydrofuran (2mL). NaHMDS (0.278 mL, 0.557 mmol, 2M) was added under ice-cooling, and stirred at room temperature for 0.5 hours. Compound 3I (50 mg, 0.253 mmol) was added to the reaction solution, and the reaction solution was stirred at 60°C under nitrogen for 1 hour. The reaction solution was quenched with saturated ammonium chloride (20 mL), and extracted with ethyl acetate (15 mL*3). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was collected and concentrated under reduced pressure to obtain the crude product of the title compound 4B (35 mg).
MS(ESI)m/z 482.4[M+H] +。 MS (ESI) m/z 482.4 [M+H] + .
第二步second step
(1R,3S)-3-(3-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基(1-甲基环丙基)氨基甲酸酯(1R,3S)-3-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl (1-methylcyclopropyl) carbamate
将化合物4B(35mg,0.073mmol)溶于2mL甲酸中，在80℃条件下反应2小时。冷却至室温，反应液浓缩，反相C-18柱层析纯化得到标题化合物4(15mg,产率48.5％)。Compound 4B (35 mg, 0.073 mmol) was dissolved in 2 mL of formic acid and reacted at 80° C. for 2 hours. After cooling to room temperature, the reaction solution was concentrated and purified by reverse phase C-18 column chromatography to obtain the title compound 4 (15 mg, yield 48.5%).
MS(ESI)m/z 426.3[M+H] +。 MS (ESI) m/z 426.3 [M+H] + .
实施例5Example 5
(1R,3S)-3-(5-((2-((甲氧基-d3)甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯5(1R,3S)-3-(5-((2-((methoxy-d3)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole -3-yl) cyclopentyl isopropyl carbamate 5
Figure PCTCN2022103293-appb-000093
Figure PCTCN2022103293-appb-000093
第一步first step
(1R,3S)-3-(5-((2-(溴甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基异丙氨基甲酸酯5A(1R,3S)-3-(5-((2-(Bromomethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)ring Amyl isopropyl carbamate 5A
氮气下，将化合物3(100mg，0.242mmol)溶于二氯甲烷(0.2mL)中，加入三溴化硼(0.73mL，0.726mmol,1M)，室温下反应过夜。使用甲醇淬灭反应液，减压浓缩，粗品使用反相柱层析得到标题化合物5A(85mg,产率87.9％)。Under nitrogen, compound 3 (100 mg, 0.242 mmol) was dissolved in dichloromethane (0.2 mL), and boron tribromide (0.73 mL, 0.726 mmol, 1M) was added to react overnight at room temperature. The reaction solution was quenched with methanol, concentrated under reduced pressure, and the crude product was subjected to reverse-phase column chromatography to obtain the title compound 5A (85 mg, yield 87.9%).
MS(ESI)m/z 462.3,464.3[M+H] + MS(ESI)m/z 462.3,464.3[M+H] +
第二步second step
(1R,3S)-3-(5-((2-((甲氧基-d3)甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基异丙氨基甲酸酯5(1R,3S)-3-(5-((2-((methoxy-d3)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole -3-yl) cyclopentyl isopropyl carbamate 5
将化合物5A(40mg,0.087mmol)加入到2mL氘代甲醇中，加入碳酸钾(18mg,0.131mmol)。在室温下反应2小时。将反应液浓缩。粗品使用反相柱层析得到标题化合物5(20mg,产率55％)。Compound 5A (40 mg, 0.087 mmol) was added to 2 mL of deuterated methanol, and potassium carbonate (18 mg, 0.131 mmol) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated. The crude product was obtained by reverse-phase column chromatography to obtain the title compound 5 (20 mg, yield 55%).
MS(ESI)m/z 417.4[M+H] +。 MS (ESI) m/z 417.4 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ＝12.12(s,1H),9.98(s,1H),8.01(d,J＝4.7Hz,1H),7.37(d,J＝4.7Hz,1H),7.27(s,1H),6.96(d,J＝7.8Hz,1H),6.58(s,1H),5.01(s,1H),4.55(s,2H),3.58(h,J＝6.7Hz,1H),3.08(t,J＝9.0Hz,1H),2.11–1.54(m,6H),1.03(d,J＝4.0Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ=12.12(s,1H),9.98(s,1H),8.01(d,J=4.7Hz,1H),7.37(d,J=4.7Hz,1H) ,7.27(s,1H),6.96(d,J=7.8Hz,1H),6.58(s,1H),5.01(s,1H),4.55(s,2H),3.58(h,J=6.7Hz, 1H), 3.08(t, J=9.0Hz, 1H), 2.11–1.54(m, 6H), 1.03(d, J=4.0Hz, 6H).
实施例6Example 6
(1R,3S)-3-(5-((2-(吗啉甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊 基异丙氨基甲酸酯6(1R,3S)-3-(5-((2-(morpholinomethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl) Cyclopentyl isopropyl carbamate 6
Figure PCTCN2022103293-appb-000094
Figure PCTCN2022103293-appb-000094
将化合物5A(10mg,0.022mmol)加入到1mL二甲基亚砜中，加入吗啉(18mg,0.043mmol)。在室温下反应2小时。将反应液浓缩。粗品使用反相柱层析得到标题化合物6(3mg,产率30％)。Compound 5A (10 mg, 0.022 mmol) was added to 1 mL of dimethylsulfoxide, and morpholine (18 mg, 0.043 mmol) was added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated. The crude product was subjected to reverse-phase column chromatography to obtain the title compound 6 (3 mg, yield 30%).
MS(ESI)m/z 469.6[M+H] +。 MS (ESI) m/z 469.6 [M+H] + .
实施例7Example 7
(1R,3S)-3-(5-((2-(氰甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基异丙氨基甲酸酯7(1R,3S)-3-(5-((2-(cyanomethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)ring Amyl isopropyl carbamate 7
Figure PCTCN2022103293-appb-000095
Figure PCTCN2022103293-appb-000095
将化合物5A(10mg,0.022mmol)加入到1mL四氢呋喃中，加入三甲基氰硅烷(6mg,0.066mmol)和四丁基氟化铵(0.066mL,0.066mmol,1M)。在室温下反应2小时。将反应液浓缩。粗品使用反相柱层析得到标题化合物7(2mg,产率22％)。Compound 5A (10 mg, 0.022 mmol) was added to 1 mL of tetrahydrofuran, and trimethylsilyl cyanide (6 mg, 0.066 mmol) and tetrabutylammonium fluoride (0.066 mL, 0.066 mmol, 1 M) were added. The reaction was carried out at room temperature for 2 hours. The reaction solution was concentrated. The crude product was subjected to reverse-phase column chromatography to obtain the title compound 7 (2 mg, yield 22%).
MS(ESI)m/z 409.8[M+H] +。 MS (ESI) m/z 409.8 [M+H] + .
实施例8Example 8
(1R,3S)-3-(5-((2-(羟甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基异丙氨基甲酸酯8(1R,3S)-3-(5-((2-(Hydroxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-3-yl)ring Amyl isopropyl carbamate 8
Figure PCTCN2022103293-appb-000096
Figure PCTCN2022103293-appb-000096
Figure PCTCN2022103293-appb-000097
Figure PCTCN2022103293-appb-000097
向化合物3(400mg，0.968mmol)的二氯甲烷(8mL)浑浊液中逐滴加入三氯化硼的二氯甲烷溶液(1mol/L,6mL)。在室温下反应3小时。将反应液倒入50mL冰水中，抽滤得白色固体，将白色固体用C-18反相色谱法纯化得到标题化合物8(200mg，产率：52％)。To the cloudy solution of compound 3 (400 mg, 0.968 mmol) in dichloromethane (8 mL) was added dropwise a solution of boron trichloride in dichloromethane (1 mol/L, 6 mL). The reaction was carried out at room temperature for 3 hours. The reaction solution was poured into 50 mL of ice water, and a white solid was obtained by suction filtration. The white solid was purified by C-18 reverse phase chromatography to obtain the title compound 8 (200 mg, yield: 52%).
MS(ESI)m/z 400.4[M+H] +。 MS (ESI) m/z 400.4 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ＝10.18(bs,1H),8.42(s,2H),7.98(d,J＝4.0Hz,1H),7.35(d,J＝4.0Hz,1H),7.27(s,1H),7.69(d,J＝8.0Hz,1H),6.57(s,1H),5.04-5.02(m,1H),4.62(s,2H),3.63-3.54(m,1H),3.15-3.06(m,1H),2.07-1.62(m,6H),1.05-1.02(m,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ=10.18(bs,1H),8.42(s,2H),7.98(d,J=4.0Hz,1H),7.35(d,J=4.0Hz,1H) ,7.27(s,1H),7.69(d,J=8.0Hz,1H),6.57(s,1H),5.04-5.02(m,1H),4.62(s,2H),3.63-3.54(m,1H ), 3.15-3.06 (m, 1H), 2.07-1.62 (m, 6H), 1.05-1.02 (m, 6H).
实施例9Example 9
(1R,3S)-3-(3-((2-((甲磺酰基)甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙氨基甲酸酯9(1R,3S)-3-(3-((2-((methylsulfonyl)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5 -yl) cyclopentyl isopropyl carbamate 9
Figure PCTCN2022103293-appb-000098
Figure PCTCN2022103293-appb-000098
第一步first step
(1R,3S)-3-(3-((2-((甲硫基)甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙氨基甲酸酯9A(1R,3S)-3-(3-((2-((methylthio)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5 -yl) cyclopentyl isopropyl carbamate 9A
将化合物5A(780mg，1.866mmol)溶于6mL二甲基亚砜中。加入甲硫醇钠(261mg，3.733mmol)。在室温下反应1小时。将反应液倒入50mL水中，水相用乙酸乙酯萃取(50mL×2)，分离有机相，合并有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到标题化合物9A(650mg，产率：81％)。Compound 5A (780 mg, 1.866 mmol) was dissolved in 6 mL of dimethylsulfoxide. Sodium methylthiolate (261 mg, 3.733 mmol) was added. React at room temperature for 1 hour. The reaction solution was poured into 50 mL of water, the aqueous phase was extracted with ethyl acetate (50 mL × 2), the organic phase was separated, the organic phase was combined, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 9A (650 mg , yield: 81%).
MS(ESI)m/z 430.20[M+H] +。 MS (ESI) m/z 430.20 [M+H] + .
第二步second step
(1R,3S)-3-(3-((2-((甲磺酰基)甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙氨基甲酸酯9(1R,3S)-3-(3-((2-((methylsulfonyl)methyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole-5 -yl) cyclopentyl isopropyl carbamate 9
将化合物9A(540mg，1.257mmol)溶于5mL二氯甲烷中。加入间氯过氧苯甲酸(433.8mg,2.514mmol),在室温下反应16小时。向反应液中加入水(40mL), 然后用二氯甲烷(50mL×3)萃取,合并有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩，将粗品用HPLC制备纯化，冻干得到标题化合物9(120mg，产率：19.03％)。Compound 9A (540 mg, 1.257 mmol) was dissolved in 5 mL of dichloromethane. Add m-chloroperoxybenzoic acid (433.8 mg, 2.514 mmol) and react at room temperature for 16 hours. Add water (40mL) to the reaction solution, then extract with dichloromethane (50mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, collect the filtrate, concentrate the filtrate under reduced pressure, prepare and purify the crude product by HPLC, freeze Drying gave the title compound 9 (120 mg, yield: 19.03%).
MS(ESI)m/z＝462.3[M+H] +。 MS (ESI) m/z = 462.3 [M+H] + .
实施例10Example 10
(1R,3S)-3-(3-((2-(1-羟乙基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙氨基甲酸酯10(1R,3S)-3-(3-((2-(1-Hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl isopropyl carbamate 10
Figure PCTCN2022103293-appb-000099
Figure PCTCN2022103293-appb-000099
第一步first step
1-(2,2-二甲氧基乙基)-1H-吡唑-3,5-二羧酸二乙酯10BDiethyl 1-(2,2-dimethoxyethyl)-1H-pyrazole-3,5-dicarboxylate 10B
将1H-吡唑-3,5-二甲酸二乙酯10A(8g,37.699mmol)溶于N,N-二甲基甲酰胺(100mL)中，加入2-溴-1,1-二甲氧基乙烷10A-1(7.65g,45.238mmol)，碳酸铯(24.57g,75.397mmol)，100℃下反应16小时。反应结束后，将反应液用300mL乙酸乙酯稀释，用300mL水洗涤，分离有机相，并用饱和氯化钠水溶液300mL洗涤2次，收集有机相，无水硫酸钠干燥，过滤，收集滤液，滤液浓缩得到标题化合物粗品，将粗品通过硅胶色谱法以石油醚/乙酸乙酯为洗脱液，分离纯化得到标题化合物10B(6.1g，产率：54％)。1H-Diethyl pyrazole-3,5-dicarboxylate 10A (8 g, 37.699 mmol) was dissolved in N,N-dimethylformamide (100 mL), and 2-bromo-1,1-dimethoxy Ethyl ethane 10A-1 (7.65g, 45.238mmol), cesium carbonate (24.57g, 75.397mmol), react at 100°C for 16 hours. After the reaction, the reaction solution was diluted with 300 mL of ethyl acetate, washed with 300 mL of water, the organic phase was separated, and washed twice with 300 mL of saturated aqueous sodium chloride solution, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was collected. Concentration gave the crude product of the title compound, which was separated and purified by silica gel chromatography with petroleum ether/ethyl acetate as the eluent to obtain the title compound 10B (6.1 g, yield: 54%).
MS(ESI)m/z 269.1[M-31] +。 MS (ESI) m/z 269.1 [M-31] + .
第二步second step
4-羟基吡唑并[1,5-a]吡嗪-2-羧酸乙酯10C4-Hydroxypyrazolo[1,5-a]pyrazine-2-carboxylic acid ethyl ester 10C
将化合物10B(2g,6.66mmol)，醋酸铵(10.27g,133.196mmol)，醋酸(6mL)置于25mL微波管中，150℃下微波照射2小时，反应结束后，将反应液通过反相 色谱法分离纯化，冻干得到标题化合物10C(320mg,产率：23％)。Compound 10B (2g, 6.66mmol), ammonium acetate (10.27g, 133.196mmol), and acetic acid (6mL) were placed in a 25mL microwave tube and irradiated with microwaves at 150°C for 2 hours. After the reaction, the reaction solution was passed through reverse-phase chromatography. Separation and purification by lyophilization method to obtain the title compound 10C (320 mg, yield: 23%).
MS(ESI)m/z 208.1[M+H] +。 MS (ESI) m/z 208.1 [M+H] + .
第三步third step
4-氯吡唑并[1,5-a]吡嗪-2-羧酸乙酯10DEthyl 4-chloropyrazolo[1,5-a]pyrazine-2-carboxylate 10D
将化合物10C(800mg,3.861mmol)置于100mL圆底烧瓶中，加入三氯氧磷(6mL)，100℃下反应1小时。反应结束后，减压浓缩得到标题化合物粗品，将粗品通过硅胶色谱法以石油醚/乙酸乙酯为洗脱液，分离得到标题化合物10D(450mg,产率：52％)。Compound 10C (800 mg, 3.861 mmol) was placed in a 100 mL round bottom flask, phosphorus oxychloride (6 mL) was added, and reacted at 100° C. for 1 hour. After the reaction, the crude product was concentrated under reduced pressure to obtain the crude product of the title compound, which was separated by silica gel chromatography with petroleum ether/ethyl acetate as the eluent to obtain the title compound 10D (450 mg, yield: 52%).
MS(ESI)m/z 226.1[M+H] +。 MS (ESI) m/z 226.1 [M+H] + .
第四步the fourth step
4-氯吡唑并[1,5-a]吡嗪-2-乙烷-1-酮10E4-Chloropyrazolo[1,5-a]pyrazin-2-ethan-1-one 10E
在-60℃，氮气氛下，向化合物10D(0.2g,0.886mmol)的四氢呋喃(10mL)溶液中逐滴加入甲基溴化镁(0.9mL,1.773mmol,3M)，缓慢恢复室温，反应2小时。反应结束后，向反应液中加入饱和氯化铵水溶液(10mL)，乙酸乙酯(50mL)萃取，收集有机相，无水硫酸钠干燥，过滤，浓缩得到标题化合物粗品，将粗品通过硅胶色谱法以石油醚/乙酸乙酯为洗脱液，得到标题化合物10E(60mg,产率：35％).At -60°C, under a nitrogen atmosphere, methyl magnesium bromide (0.9 mL, 1.773 mmol, 3M) was added dropwise to a solution of compound 10D (0.2 g, 0.886 mmol) in tetrahydrofuran (10 mL), and slowly returned to room temperature, reaction 2 Hour. After the reaction, add saturated ammonium chloride aqueous solution (10mL) to the reaction solution, extract with ethyl acetate (50mL), collect the organic phase, dry over anhydrous sodium sulfate, filter, concentrate to obtain the crude product of the title compound, and pass the crude product through silica gel chromatography Using petroleum ether/ethyl acetate as the eluent, the title compound 10E (60 mg, yield: 35%) was obtained.
MS(ESI)m/z 196.1[M+H] +。 MS (ESI) m/z 196.1 [M+H] + .
第五步the fifth step
(1R,3S)-3-(5-((2-乙酰基吡唑并[1,5-a]吡嗪-4-基)氨基)-1-(叔丁基)-1H-吡唑-3-基)环戊基异丙氨基甲酸酯10F(1R,3S)-3-(5-((2-Acetylpyrazolo[1,5-a]pyrazin-4-yl)amino)-1-(tert-butyl)-1H-pyrazole- 3-yl) cyclopentyl isopropyl carbamate 10F
在-60℃，氮气氛下，向化合物2G(95mg，0.307mmol)的四氢呋喃(10mL)溶液逐滴加入双(三甲基硅基)氨基钠(1.22mL，1.227mmol)，在此温度下搅拌0.5小时，相同温度下逐滴加入化合物10E(60mg,0.307mmol),缓慢恢复室温，搅拌1小时。反应结束后，向反应液中加入5mL水，乙酸乙酯(20mL×3)萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩得到标题化合物10F粗品(90mg，产率：63％)。At -60°C, under a nitrogen atmosphere, to a solution of compound 2G (95 mg, 0.307 mmol) in tetrahydrofuran (10 mL) was added dropwise bis(trimethylsilyl) sodium amide (1.22 mL, 1.227 mmol), and stirred at this temperature For 0.5 hours, compound 10E (60 mg, 0.307 mmol) was added dropwise at the same temperature, slowly returned to room temperature, and stirred for 1 hour. After the reaction, 5 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product of the title compound 10F (90 mg, yield: 63%).
MS(ESI)m/z 468.1[M+H] +。 MS (ESI) m/z 468.1 [M+H] + .
第六步step six
(1R,3S)-3-(1-(叔丁基)-5-((2-(1-羟基乙基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基异丙基氨基甲酸酯10G(1R,3S)-3-(1-(tert-butyl)-5-((2-(1-hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)- 1H-pyrazol-3-yl)cyclopentyl isopropyl carbamate 10G
在0摄氏度下，向化合物10F(20mg，0.043mmol)的甲醇(3mL)溶液中缓慢加入硼氢化钠(7mg，0.215mmol),室温下反应1小时。反应结束后，将反应液浓缩，乙酸乙酯(15mL)稀释，用水(10mL)洗涤，收集有机相，无水硫酸钠干燥，过滤，收集滤液，滤液减压浓缩得到标题化合物10G粗品(11mg,产率：54％)。Sodium borohydride (7 mg, 0.215 mmol) was slowly added to a solution of compound 10F (20 mg, 0.043 mmol) in methanol (3 mL) at 0°C, and reacted at room temperature for 1 hour. After the reaction, the reaction solution was concentrated, diluted with ethyl acetate (15mL), washed with water (10mL), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated under reduced pressure to obtain the title compound 10G crude product (11mg, Yield: 54%).
MS(ESI)m/z 470.1[M+H] +。 MS (ESI) m/z 470.1 [M+H] + .
第七步step seven
(1R,3S)-3-(3-((2-(1-羟乙基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙 氨基甲酸酯10(1R,3S)-3-(3-((2-(1-Hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl isopropyl carbamate 10
将化合物10G(11mg，0.023mmol)的甲酸(2mL)溶液升温至100℃搅拌反应1小时，反应结束后，冷却至室温。向反应液中加入四氢呋喃(5mL)和水(1mL)，再加入氢氧化锂(10mg，0.227mmol)，将反应液升温至75℃搅拌反应16小时。反应结束后，采用HPLC制备分离纯化，冻干得到标题化合物10(3.9mg，产率：40％，该化合物为一对异构体)。A solution of compound 10G (11 mg, 0.023 mmol) in formic acid (2 mL) was heated to 100° C. and stirred for 1 hour. After the reaction was completed, it was cooled to room temperature. Tetrahydrofuran (5 mL) and water (1 mL) were added to the reaction liquid, and then lithium hydroxide (10 mg, 0.227 mmol) was added, and the reaction liquid was heated to 75° C. and stirred for 16 hours. After the reaction, the preparation was separated and purified by HPLC, and lyophilized to obtain the title compound 10 (3.9 mg, yield: 40%, the compound was a pair of isomers).
MS(ESI)m/z 414.1[M+H] +。 MS (ESI) m/z 414.1 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ＝9.89(s,1H),7.95(d,J＝4.8Hz,1H),7.30(d,J＝4.8Hz,1H),7.21(s,1H),6.93(d,J＝7.8Hz,1H),6.52(s,1H),5.30(s,1H),4.98(s,1H),4.85(d,J＝6.7Hz,1H),3.54(q,J＝6.7Hz,1H),3.06(d,J＝9.8Hz,1H),1.98(d,J＝20.8Hz,1H),1.86(d,J＝13.8Hz,1H),1.80-1.53(m,4H),1.41(d,J＝6.5Hz,3H),0.99(d,J＝6.6Hz,6H)。 1 H NMR (400MHz, DMSO-d 6 )δ=9.89(s,1H),7.95(d,J=4.8Hz,1H),7.30(d,J=4.8Hz,1H),7.21(s,1H) ,6.93(d,J=7.8Hz,1H),6.52(s,1H),5.30(s,1H),4.98(s,1H),4.85(d,J=6.7Hz,1H),3.54(q, J＝6.7Hz, 1H), 3.06(d, J＝9.8Hz, 1H), 1.98(d, J＝20.8Hz, 1H), 1.86(d, J＝13.8Hz, 1H), 1.80-1.53(m, 4H), 1.41 (d, J=6.5Hz, 3H), 0.99 (d, J=6.6Hz, 6H).
化合物10通过如下方法拆分得到一对异构体(保留时间为1.776min和2.073min)。Compound 10 was resolved by the following method to obtain a pair of isomers (retention time of 1.776min and 2.073min).
方法如下：Methods as below:
柱：CHIRALPAK IG-3(50*4.6mm I.D.,3μm)；Column: CHIRALPAK IG-3 (50*4.6mm I.D., 3μm);
条件：CO 2条件下，B为40％EtOH(0.1％IPAm)；在0.2-1.2min，梯度从5％的B升到50％的B，保持一分钟。 Conditions: under CO 2 , B was 40% EtOH (0.1% IPAm); at 0.2-1.2 min, the gradient was raised from 5% B to 50% B and maintained for one minute.
流速：3.4mL/min；Flow rate: 3.4mL/min;
ABPR：1800psi；ABPR: 1800psi;
温度:35℃。Temperature: 35°C.
实施例11Example 11
(1R,3S)-3-(3-((2-(2-羟基丙-2-基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙氨基甲酸酯11(1R,3S)-3-(3-((2-(2-Hydroxypropan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole- 5-yl) cyclopentyl isopropyl carbamate 11
Figure PCTCN2022103293-appb-000100
Figure PCTCN2022103293-appb-000100
第一步first step
(1R,3S)-3-(3-((2-乙酰基吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙氨基甲酸酯11A(1R,3S)-3-(3-((2-Acetylpyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl)cyclopentyliso Propyl carbamate 11A
将化合物10F(20mg,0.043mmol)置于25mL圆底烧瓶中，加入甲酸(2mL)，升温至100℃，在100℃下搅拌1小时。反应结束后，将反应液通过反相色谱(乙腈/水为洗脱液)分离纯化，冻干得到标题化合物11A(12mg，产率：68％)。Compound 10F (20 mg, 0.043 mmol) was placed in a 25 mL round bottom flask, formic acid (2 mL) was added, the temperature was raised to 100° C., and stirred at 100° C. for 1 hour. After the reaction, the reaction solution was separated and purified by reverse phase chromatography (acetonitrile/water as the eluent), and lyophilized to obtain the title compound 11A (12 mg, yield: 68%).
MS(ESI)m/z 412.1[M+H] +。 MS (ESI) m/z 412.1 [M+H] + .
第二步second step
(1R,3S)-3-(3-((2-(2-羟基丙-2-基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基异丙氨基甲酸酯11(1R,3S)-3-(3-((2-(2-Hydroxypropan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole- 5-yl) cyclopentyl isopropyl carbamate 11
在-60摄氏度，氮气氛下，向化合物11A(12mg,0.029mmol)的四氢呋喃(3mL)溶液中，逐滴加入甲基溴化镁(0.1mL,0.292mmol,3M)，缓慢恢复室温搅拌2小时。反应结束后，通过HPLC制备纯化，冻干得到标题化合物11(1.2mg,产率：8.5％)。MS(ESI)m/z 428.1[M+H] +。 At -60 degrees Celsius, under a nitrogen atmosphere, to a solution of compound 11A (12 mg, 0.029 mmol) in tetrahydrofuran (3 mL), methylmagnesium bromide (0.1 mL, 0.292 mmol, 3M) was added dropwise, and slowly returned to room temperature and stirred for 2 hours . After the reaction, it was purified by HPLC and lyophilized to obtain the title compound 11 (1.2 mg, yield: 8.5%). MS (ESI) m/z 428.1 [M+H] + .
实施例12Example 12
(1R,3S)-3-(3-((2-(羟甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基((S)-仲丁基)氨基甲酸酯12(1R,3S)-3-(3-((2-(Hydroxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl)ring Pentyl ((S)-sec-butyl) carbamate 12
Figure PCTCN2022103293-appb-000101
Figure PCTCN2022103293-appb-000101
第一步first step
(1R,3S)-3-(1-(叔丁基)-5-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-3-基)环戊基((S)-仲丁基)氨基甲酸酯12B(1R,3S)-3-(1-(tert-butyl)-5-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)- 1H-pyrazol-3-yl)cyclopentyl((S)-sec-butyl)carbamate 12B
将(1R,3S)-3-(5-氨基-1-(叔丁基)-1H-吡唑-3-基)环戊基((S)-仲丁基)氨基甲酸酯12A(20.0mg，0.10mmol，根据WO2020157652报道的方法合成得到)溶于四氢呋喃(1mL)中，-60℃，氮气氛下，逐滴加入二(三甲基硅基)氨基钠(0.20mL，0.40mmol，4eq，2N)，在-60℃反应30分钟。-60℃下加入化合物3I(32.6mg，0.10mmol)的四氢呋喃(1mL)溶液，缓慢恢复室温反应1小时。反应结束后加水淬灭，用乙酸乙酯(20mL)萃取三次，合并有机相用饱和食盐水(20mL)洗涤一次，硫酸镁干燥，过滤，收集滤液，滤液浓缩得到标题化合物12B(30mg，粗品)。(1R,3S)-3-(5-Amino-1-(tert-butyl)-1H-pyrazol-3-yl)cyclopentyl ((S)-sec-butyl)carbamate 12A (20.0 mg, 0.10mmol, synthesized according to the method reported in WO2020157652) was dissolved in tetrahydrofuran (1mL), at -60°C, under a nitrogen atmosphere, sodium bis(trimethylsilyl)amide (0.20mL, 0.40mmol, 4eq , 2N), react at -60°C for 30 minutes. A solution of compound 3I (32.6 mg, 0.10 mmol) in tetrahydrofuran (1 mL) was added at -60°C, and the reaction was slowly returned to room temperature for 1 hour. After the reaction was completed, it was quenched with water, extracted three times with ethyl acetate (20 mL), the combined organic phase was washed once with saturated brine (20 mL), dried over magnesium sulfate, filtered, the filtrate was collected, and the filtrate was concentrated to obtain the title compound 12B (30 mg, crude product) .
MS(ESI)m/z 484.5[M+H] +。 MS (ESI) m/z 484.5 [M+H] + .
第二步second step
(1R,3S)-3-(3-((2-(甲氧基甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基((S)-仲丁基)氨基甲酸酯12C(1R,3S)-3-(3-((2-(methoxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl ((S)-sec-butyl) carbamate 12C
将化合物12B(30mg，0.06mmol)加到甲酸(1mL)中，在100℃下反应3h。反应结束后,使用反相色谱法(以乙腈/水为洗脱剂)分离纯化，得到标题化合物12C(18mg,产率：67.87％)。Compound 12B (30 mg, 0.06 mmol) was added into formic acid (1 mL), and reacted at 100° C. for 3 h. After the reaction, it was separated and purified by reverse phase chromatography (acetonitrile/water as eluent) to obtain the title compound 12C (18 mg, yield: 67.87%).
MS(ESI)m/z 428.4[M+H] +。 MS (ESI) m/z 428.4 [M+H] + .
第三步third step
(1R,3S)-3-(3-((2-(羟甲基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基((S)-仲丁基)氨基甲酸酯12(1R,3S)-3-(3-((2-(Hydroxymethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl)ring Pentyl ((S)-sec-butyl) carbamate 12
在0℃下，将化合物12C(16mg,0.037mmol)加到三氯化硼的二氯甲烷(0.4mL)中，在20℃下反应2h。反应结束后，加水淬灭，用二氯甲烷萃取三次水相，合并有机相用饱和食盐水洗涤一次，硫酸镁干燥，过滤，收集滤液，滤液减压浓缩，残留物通过HPLC制备分离纯化，冻干得到标题化合物12(1.5mg，产率：9.69％)。Compound 12C (16mg, 0.037mmol) was added to boron trichloride in dichloromethane (0.4mL) at 0°C, and reacted at 20°C for 2h. After the reaction was completed, add water to quench, extract the aqueous phase three times with dichloromethane, wash the combined organic phase once with saturated brine, dry over magnesium sulfate, filter, collect the filtrate, concentrate the filtrate under reduced pressure, and prepare the residue for separation and purification by HPLC. Drying gave the title compound 12 (1.5 mg, yield: 9.69%).
MS(ESI)m/z 414.4[M+H] +。 MS (ESI) m/z 414.4 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ＝12.09(s,1H),9.92(s,1H),7.98(d,J＝4.8Hz,1H),7.34(d,J＝4.8Hz,1H),7.24(s,1H),6.89(d,J＝8.0Hz,1H),6.63(s,1H),5.33-5.29(m,1H),5.01(s,1H),4.61(d,J＝5.6Hz,2H),3.11-3.09(m,1H),2.08-1.96(m,2H),1.92-1.88(m,1H),1.77-1.65(m,3H),1.37-1.24(m,3H),1.01(d,J＝6.4Hz,3H),0.86(t,J＝7.2,7.6Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ=12.09(s,1H),9.92(s,1H),7.98(d,J=4.8Hz,1H),7.34(d,J=4.8Hz,1H) ,7.24(s,1H),6.89(d,J=8.0Hz,1H),6.63(s,1H),5.33-5.29(m,1H),5.01(s,1H),4.61(d,J=5.6 Hz,2H),3.11-3.09(m,1H),2.08-1.96(m,2H),1.92-1.88(m,1H),1.77-1.65(m,3H),1.37-1.24(m,3H), 1.01 (d, J = 6.4Hz, 3H), 0.86 (t, J = 7.2, 7.6Hz, 3H).
实施例13Example 13
(1R,3S)-3-(3-((2-(1-羟乙基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基((S)-仲丁基)氨基甲酸酯13(1R,3S)-3-(3-((2-(1-Hydroxyethyl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazol-5-yl ) cyclopentyl ((S)-sec-butyl) carbamate 13
Figure PCTCN2022103293-appb-000102
Figure PCTCN2022103293-appb-000102
从化合物12A出发，按照实施例10的类似的合成步骤合成得到化合物13。Starting from compound 12A, compound 13 was synthesized according to the similar synthesis steps of Example 10.
MS(ESI)m/z 428.2[M+H] +。 MS (ESI) m/z 428.2 [M+H] + .
1H NMR(400MHz,DMSO-d 6)δ＝12.10(s,1H),9.91(s,1H),7.98(d,J＝4.8Hz,1H),7.33(d,J＝4.8Hz,1H),7.24(s,1H),6.89(d,J＝8.4Hz,1H),6.56(s,1H),5.31(d,J＝4.8Hz,1H),5.03-4.98(m,1H),4.90-4.86(m,1H),3.42-3.35(m,1H),3.10-3.06(m,1H),2.07-2.01(m,1H),1.93-1.87(m,1H),1.80-1.61(m,4H),1.44(d,J＝6.4Hz,3H),1.37-1.31(m,2H),1.01(d,J＝6.4Hz,3H),0.79(t,J＝7.2,7.6Hz,3H)。 1 H NMR (400MHz, DMSO-d 6 )δ=12.10(s,1H),9.91(s,1H),7.98(d,J=4.8Hz,1H),7.33(d,J=4.8Hz,1H) ,7.24(s,1H),6.89(d,J=8.4Hz,1H),6.56(s,1H),5.31(d,J=4.8Hz,1H),5.03-4.98(m,1H),4.90- 4.86(m,1H),3.42-3.35(m,1H),3.10-3.06(m,1H),2.07-2.01(m,1H),1.93-1.87(m,1H),1.80-1.61(m,4H ), 1.44 (d, J=6.4Hz, 3H), 1.37-1.31 (m, 2H), 1.01 (d, J=6.4Hz, 3H), 0.79 (t, J=7.2, 7.6Hz, 3H).
实施例14Example 14
(1R,3S)-3-(3-((2-(2-羟基丙-2-基)吡唑并[1,5-a]吡嗪-4-基)氨基)-1H-吡唑-5-基)环戊基((S)-仲丁基)氨基甲酸酯14(1R,3S)-3-(3-((2-(2-Hydroxypropan-2-yl)pyrazolo[1,5-a]pyrazin-4-yl)amino)-1H-pyrazole- 5-yl)cyclopentyl ((S)-sec-butyl)carbamate 14
Figure PCTCN2022103293-appb-000103
Figure PCTCN2022103293-appb-000103
从化合物12A出发，按照实施例11的类似的合成步骤合成得到化合物14。Starting from compound 12A, compound 14 was synthesized according to the similar synthesis steps of Example 11.
MS(ESI)m/z 442.2[M+H] +。 MS (ESI) m/z 442.2 [M+H] + .
生物学评价biological evaluation
以下结合测试例进一步描述解释本公开，但这些实施例并非意味着限制本公开的范围。The following further describes and explains the present disclosure in combination with test examples, but these examples are not meant to limit the scope of the present disclosure.
测试例1.本公开化合物对细胞周期蛋白-依赖性激酶活性检测。Test Example 1. Detection of cyclin-dependent kinase activity of the disclosed compounds.
1.实验材料及仪器1. Experimental materials and instruments
仪器名称equipment name 设备厂家Equipment manufacturers 型号model
振荡器oscillator ThermoThermo 4625-1 CECN/THZ Q4625-1 CECN/THZ Q
离心机centrifuge EppendorfEppendorf 5810R5810R
Envision 2104多标记读板器Envision 2104 Multilabel Plate Reader PerkinElmerPerkinElmer Oct-4Oct-4
EchoEcho EppendorfEppendorf 5810R5810R
离心机centrifuge LabcyteLabcyte 550550
试剂名称Reagent name 厂商manufacturers 货号Item No.
ADP-Glo激酶检测试剂盒ADP-Glo Kinase Assay Kit PromegaPromega V9102V9102
CDK1/细胞周期蛋白BCDK1/Cyclin B proqinaseproqinase 0134-0135-10134-0135-1
CDK2/细胞周期蛋白ECDK2/cyclin E CarnaCarna 04-16504-165
组蛋白H1蛋白(CDK1,CDK2底物)Histone H1 protein (CDK1, CDK2 substrate) SignalChemSignalChem H10-54NH10-54N
CDK9/细胞周期蛋白T1CDK9/cyclin T1 BiortusBiortus BP480BP480
PDKtide(CDK9底物)PDKtide (CDK9 substrate) SignalChemSignalChem P10-58P10-58
ATPATP PromegaPromega V910BV910B
DMSODMSO SigmaSigma D8418D8418
96-孔板96-well plates NuncNunc 249944249944
384-孔板384-well plate GreinerGreiner 784075784075
PHA-793887PHA-793887 SelleckchemSelleckchem S1487S1487
2.实验步骤2. Experimental steps
使用Echo 550将化合物稀释液转移到测定板的每个孔中(784075，Greiner)。密封测定板，以1000g离心测定板1分钟；在1x激酶缓冲液((40mM Tris-HCl,pH7.4,20mM MgCl2,0.1mg/ml BSA,50uM DTT)中准备2x酶，将2.5μl 2x酶加入384孔测定板，将板在1000g下离心30s，在室温放置10分钟。在1x激酶缓冲液中制备2x底物和ATP混合物，加入2.5μl 2x底物和ATP混合物开始反应。将板以1000g离心30秒，密封测定板，室温反应1小时。加入4μl ADP-Glo试剂，在室温下孵育40分钟，再加入8μl激酶检测试剂，在室温下孵育40分钟。Compound dilutions were transferred to each well of the assay plate using an Echo 550 (784075, Greiner). Seal the assay plate and centrifuge the assay plate at 1000g for 1 min; prepare 2x enzyme in 1x kinase buffer ((40mM Tris-HCl, pH 7.4, 20mM MgCl2, 0.1mg/ml BSA, 50uM DTT) by dissolving 2.5 μl of 2x enzyme Add to 384-well assay plate, centrifuge the plate at 1000g for 30s, and let it stand at room temperature for 10 minutes. Prepare 2x substrate and ATP mix in 1x kinase buffer, add 2.5μl 2x substrate and ATP mix to start the reaction. Centrifuge the plate at 1000g Centrifuge for 30 seconds, seal the assay plate, and react at room temperature for 1 hour. Add 4 μl ADP-Glo reagent, incubate at room temperature for 40 minutes, then add 8 μl kinase detection reagent, and incubate at room temperature for 40 minutes.
在Envision 2104读板器上读取每个孔发光信号。The luminescent signal of each well was read on an Envision 2104 plate reader.
抑制百分率计算如下：抑制百分率＝100-(cmpd信号-Ave_PC信号)/(Ave_VC信号-Ave_PC信号)×100。cmpd信号：化合物信号；Ave_PC信号：阳性对照信号平均值；Ave_VC信号：载体组信号平均值。Percent inhibition was calculated as follows: Percent inhibition = 100 - (cmpd signal - Ave_PC signal) / (Ave_VC signal - Ave_PC signal) x 100. cmpd signal: compound signal; Ave_PC signal: average signal of positive control; Ave_VC signal: average signal of vehicle group.
使用GraphPad 8.0通过将抑制百分率值和化合物浓度的对数拟合为非线性回归(剂量响应–可变斜率)来计算IC 50。Y＝底部+(顶部-底部)/(1+10^((LogIC50-X)*斜率))，其中X：抑制剂浓度的对数；Y：％抑制。 IC50s were calculated using GraphPad 8.0 by fitting the percent inhibition values and the logarithm of the compound concentration to a non-linear regression (dose response - variable slope). Y=bottom+(top-bottom)/(1+10^((LogIC50-X)*slope)), where X: logarithm of inhibitor concentration; Y: % inhibition.
测得的IC 50值见表1。 See Table 1 for the measured IC50 values.
表1.本公开化合物对CDK1/B、CDK2/细胞周期蛋白E的IC 50值 Table 1. IC 50 values of compounds of the present disclosure against CDK1/B, CDK2/cyclin E
Figure PCTCN2022103293-appb-000104
Figure PCTCN2022103293-appb-000104
Figure PCTCN2022103293-appb-000105
Figure PCTCN2022103293-appb-000105
注：PHA-793887CAS 718630-59-2。Note: PHA-793887CAS 718630-59-2.
根据WO20200157652A的实施例192，合成得到化合物EX192-P1和EX192-P2。According to Example 192 of WO20200157652A, compounds EX192-P1 and EX192-P2 were synthesized.
Figure PCTCN2022103293-appb-000106
Figure PCTCN2022103293-appb-000106
测试例2.本公开化合物对卵巢癌细胞(OVCAR3)抑制活性测试Test Example 2. Test of the Inhibitory Activity of the Compounds of the Disclosure on Ovarian Cancer Cells (OVCAR3)
实验材料和仪器Experimental Materials and Instruments
Figure PCTCN2022103293-appb-000107
Figure PCTCN2022103293-appb-000107
实验步骤Experimental procedure
卵巢癌细胞OVCAR3(来源于ATCC)使用10％FBS的RPMI 1640培养基在37％，5％CO 2的细胞培养箱中培养。第一天，细胞铺板在96-孔板中，铺板细胞浓度为2500个细胞/孔，在培养箱中培养过夜。第二天进行化合物处理，化合物处理最高浓度为10μM,3倍稀释，9个浓度,DMSO的终浓度为0.1％。细胞继续在培养箱中培养7天后，使用Celltiter Glo检测试剂盒(Promega)测试细胞活力，测试方法与试剂盒提供的操作方法保持一致。使用GraphPad Prism 8处理数据并计算IC 50。 Ovarian cancer cells OVCAR3 (derived from ATCC) were cultured in RPMI 1640 medium with 10% FBS in a cell culture incubator with 37% and 5% CO 2 . On the first day, cells were plated in 96-well plates at a concentration of 2500 cells/well and incubated overnight in an incubator. Compound treatment was performed on the second day, the highest concentration of compound treatment was 10 μM, 3-fold dilution, 9 concentrations, and the final concentration of DMSO was 0.1%. After the cells continued to be cultured in the incubator for 7 days, the cell viability was tested using the Celltiter Glo detection kit (Promega), and the test method was consistent with the operation method provided by the kit. Data were processed and IC50 calculated using GraphPad Prism 8.
计算公式Y＝底部+(顶部-底部)/(1+10^((LogIC50-X)*斜率))。Calculation formula Y=bottom+(top-bottom)/(1+10^((LogIC50-X)*slope)).
X:化合物浓度的对数值；Y:％抑制。X: log value of compound concentration; Y: % inhibition.
表2.本公开化合物的对OVCAR3的IC 50(nM) Table 2. IC 50 (nM) for OVCAR3 of Compounds of the Disclosure
Figure PCTCN2022103293-appb-000108
Figure PCTCN2022103293-appb-000108
Figure PCTCN2022103293-appb-000109
Figure PCTCN2022103293-appb-000109

Claims (35)

  1. 一种式I所示的化合物或其可药用的盐，A compound represented by formula I or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022103293-appb-100001
    Figure PCTCN2022103293-appb-100001
    其中，-L 1-选自键、C 1-6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取代基取代； Wherein, -L 1 - is selected from bond, C 1-6 alkylene, -O- and -NH-, and said C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkane Substituents of oxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;
    R 1为
    Figure PCTCN2022103293-appb-100002
    其中环A和环B各自独立地选自芳基、杂芳基和杂环烷基，环A和环B一起形成并环结构，所述A环任选地被一个或多个Z 1取代，所述B环任选地被一个或多个Z 2取代；     R1 is
    Figure PCTCN2022103293-appb-100002
    Wherein ring A and ring B are each independently selected from aryl, heteroaryl and heterocycloalkyl, ring A and ring B together form a ring structure, the A ring is optionally substituted by one or more Z, The B ring is optionally substituted with one or more Z 2 ;
    R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基、氧代基、环烷基、杂环烷基、芳基和杂芳基，其中所述C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环烷基、芳基和杂芳基的取代基取代；或R 2和R 3一起形成3-8元环，所述3-8元环任选地被一个或多个Z 3取代； R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, cyano, amino, Substituent substitution of nitro, hydroxyl, hydroxyalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R 2 and R 3 together form a 3-8 membered ring, the 3-8 The membered ring is optionally substituted by one or more Z3;
    R 4为-L 2-R 7； R 4 is -L 2 -R 7 ;
    R 5选自氢、烷基和卤素，其中所述烷基任选被一个或多个选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Oxo , carboxyl and carboxylate substituent substitution;
    R 7选自氢、烷基、环烷基、杂环烷基、芳基和杂芳基，任选地被一个或多个Z 4取代； R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more Z ;
    -L 2-选自键、C 1-6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取代基取代； -L 2 -is selected from bond, C 1-6 alkylene, -O- and -NH-, the C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkoxy , haloalkyl, haloalkoxy, halogen, cyano, amino and nitro substituents;
    R 6选自H、R 8-(C＝O)-和
    Figure PCTCN2022103293-appb-100003
    R 6 is selected from H, R 8 -(C=O)- and
    Figure PCTCN2022103293-appb-100003
    R 8为烷基，优选为C 1-6烷基，更优选为C 1-3烷基，最优选为甲基； R is an alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group, most preferably a methyl group;
    R 9和R 10各自独立地选自氢、烷基和环烷基，优选选自氢、C 1-6烷基和3-7元 环烷基，更优选选自氢、C 1-3烷基和环丙基，最优选选自氢、甲基和乙基； R 9 and R 10 are each independently selected from hydrogen, alkyl and cycloalkyl, preferably selected from hydrogen, C 1-6 alkyl and 3-7 membered cycloalkyl, more preferably selected from hydrogen, C 1-3 alkane and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;
    每个X独立地选自O、S和NH，优选为O；Each X is independently selected from O, S and NH, preferably O;
    Z 1、Z 2、Z 3和Z 4各自独立地选自卤素、氰基、羟基、硝基、氧代基、烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-SR'、-SOR'、-SO 2R'、-SO 2NR'(R”)、-NR'(R”)、-COR'、-COOR'、-CONR'(R”)和-(P＝O)R'(R”)；所述烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、烯基、炔基、烷氧基、氘代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic Alkyl, aryl, heteroaryl, -SR', -SOR ', -SO2R ', -SO2NR'(R"), -NR'(R"), -COR', -COOR', -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and hetero The aryl groups are each independently optionally replaced by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, Cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl, and carboxylic acid substituent substitution of ester group;
    每个R'或R”独立地选自氢、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代。Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more groups selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl , nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, Carboxyl and carboxylate substituents are substituted.
  2. 根据权利要求1所述的化合物或其可药用的盐，所述-L 1-选自键、C 1-6亚烷基、-O-和-NH-，优选选自键、C 1-3亚烷基、-O-和-NH-，更优选选自键、C 1-2亚烷基、-O-和-NH-，特别优选选自键、C 1-2亚烷基和-O-，最优选为-O-。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, said -L 1 - is selected from a bond, C 1-6 alkylene, -O- and -NH-, preferably selected from a bond, C 1- 3 alkylene, -O- and -NH-, more preferably selected from bond, C 1-2 alkylene, -O- and -NH-, particularly preferably selected from bond, C 1-2 alkylene and - O-, most preferably -O-.
  3. 根据权利要求1或2所述的化合物或其可药用的盐，所述-L 2-为键或C 1-6亚烷基，优选为键或C 1-3亚烷基。 The compound or the pharmaceutically acceptable salt thereof according to claim 1 or 2, said -L 2 - is a bond or a C 1-6 alkylene group, preferably a bond or a C 1-3 alkylene group.
  4. 根据权利要求1-3中任一项所述的化合物或其可药用的盐，所述R 7选自C 1-6烷基、C 3-7环烷基、3-7元杂环烷基、6-12元芳基和5-12元杂芳基，优选选自C 1-4烷基、C 3-5环烷基、6-10元芳基和5-6元杂芳基，更优选选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、苯基、萘基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基和噁唑基，最优选选自异丙基、
    Figure PCTCN2022103293-appb-100004
    环丙基、苯基和吡啶基；所述R 7任选地被一个或多个Z 4取代。     The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-3, said R is selected from C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkane Base, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, More preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, Pyridyl, pyrimidyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, most preferably selected from isopropyl,
    Figure PCTCN2022103293-appb-100004
    Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 .
  5. 根据权利要求1-4中任一项所述的化合物或其可药用的盐，所述R 5选自氢、C 1-6烷基和卤素，优选为氢或C 1-3烷基。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-4, said R 5 is selected from hydrogen, C 1-6 alkyl and halogen, preferably hydrogen or C 1-3 alkyl.
  6. 根据权利要求1-5中任一项所述的化合物或其可药用的盐，其为式I-1、I-2、 I-3、I-4或I-5所示化合物或其可药用的盐，The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-5, which is a compound shown in formula I-1, I-2, I-3, I-4 or I-5 or its medicinal salt,
    Figure PCTCN2022103293-appb-100005
    Figure PCTCN2022103293-appb-100006
    其中-L 1-、R 1、R 2、R 3、R 6和Z 4如权利要求1-5任一项中所定义。
    Figure PCTCN2022103293-appb-100005
    Figure PCTCN2022103293-appb-100006
    wherein -L 1 -, R 1 , R 2 , R 3 , R 6 and Z 4 are as defined in any one of claims 1-5.
  7. 根据权利要求1-6中任一项所述的化合物或其可药用的盐，所述R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基和氧代基，优选选自氢、卤素和C 1-6烷基，更优选为氢。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-6, said R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, Nitro and oxo are preferably selected from hydrogen, halogen and C 1-6 alkyl, more preferably hydrogen.
  8. 根据权利要求1-7中任一项所述的化合物或其可药用的盐，所述环A和环B各自独立地选自3-7元杂环烷基、6-12元芳基和5-12元杂芳基，优选选自5-6元杂环烷基、6-10元芳基和5-6元杂芳基，更优选选自苯基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基、噁唑基、吡咯基、四氢吡咯基、二氢吡咯基、三氮唑基和哌啶基，所述A环任选地被一个或多个Z 1取代，所述B环任选地被一个或多个Z 2取代；所述Z 1选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基，优选选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基和C 1-6烷氧基，更优选选自卤素、氧代基和C 1-6烷基，最优选选自氟、氯、溴、氧代基、甲基、乙基、丙基和异丙基；所述Z 2选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基，优选选自卤素、氰基、羟基、硝基、氧代基、C 1-6烷基和C 1-6烷氧基，更优选选自卤素、羟基、氧代基、C 1-6烷基和C 1-6烷氧基，最优选选自氟、氯、溴、氧代基、羟基、甲基、乙基、丙基、异丙基和甲氧基；所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基各自独立地任选被一个或多个选自氰基、烷基、烷氧基、氘代烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基、杂环烷基和杂环烷基氧基的取代基取代，所述取代基优选选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6氘代烷氧基、卤素、杂芳基、杂环烷基和杂环烷基氧基，更优选选自氰基、C 1-3 烷基、C 1-3烷氧基、C 1-3氘代烷氧基、杂环烷基和杂环烷基氧基，最优选选自氰基、甲基、乙基、甲氧基、氘代甲氧基、乙氧基和四氢呋喃基氧基。 According to the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-7, said ring A and ring B are each independently selected from 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from 5-6 membered heterocycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from phenyl, pyridyl, pyrimidinyl, pyridazine Base, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, pyrrolyl, tetrahydropyrrolyl, dihydropyrrolyl, triazolyl and piperidinyl, the A ring is optionally One or more Z 1 are substituted, and the B ring is optionally substituted by one or more Z 2 ; the Z 1 is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, preferably selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl and C 1 -6 alkoxy, more preferably selected from halogen, oxo and C 1-6 alkyl, most preferably selected from fluorine, chlorine, bromine, oxo, methyl, ethyl, propyl and isopropyl; Said Z is selected from halogen, cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl, Preferably selected from halogen, cyano, hydroxy, nitro, oxo, C 1-6 alkyl and C 1-6 alkoxy, more preferably selected from halogen, hydroxy, oxo, C 1-6 alkyl and C 1-6 alkoxy, most preferably selected from fluorine, chlorine, bromine, oxo, hydroxy, methyl, ethyl, propyl, isopropyl and methoxy; said C 1-6 alkyl , C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl are each independently optionally replaced by one or more selected from cyano, alkyl, alkoxy, deuterated alkoxy , halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkyl and heterocycloalkyloxy substituents are preferably selected from cyano, C 1-6 Alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, halogen, heteroaryl, heterocycloalkyl and heterocycloalkyloxy, more preferably selected from cyano, C 1-3 Alkyl, C 1-3 alkoxy, C 1-3 deuterated alkoxy, heterocycloalkyl and heterocycloalkyloxy, most preferably selected from cyano, methyl, ethyl, methoxy, Deuterated methoxy, ethoxy and tetrahydrofuryloxy.
  9. 根据权利要求1-8中任一项所述的化合物或其可药用的盐，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基，优选选自氟、氯、溴、甲基、乙基、丙基和异丙基。 According to the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-8, said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, Hydroxy and haloalkyl are preferably selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl.
  10. 一种式I-G所示化合物或其可药用的盐，其中，A compound represented by formula I-G or a pharmaceutically acceptable salt thereof, wherein,
    Figure PCTCN2022103293-appb-100007
    Figure PCTCN2022103293-appb-100007
    其中，-L 1-选自键、C 1-6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取代基取代； Wherein, -L 1 - is selected from bond, C 1-6 alkylene, -O- and -NH-, and said C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkane Substituents of oxy, haloalkyl, haloalkoxy, halogen, cyano, amino and nitro;
    R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基、氧代基、环烷基、杂环烷基、芳基和杂芳基，其中所述C 1-6烷基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自卤素、烷基、烷氧基、氰基、氨基、硝基、羟基、羟烷基、羧基、环烷基、杂环烷基、芳基和杂芳基的取代基取代；或R 2和R 3一起形成3-8元环，所述3-8元环任选地被一个或多个Z 3取代； R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, hydroxyl, nitro, oxo, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein The C 1-6 alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more of halogen, alkyl, alkoxy, cyano, amino, Substituent substitution of nitro, hydroxyl, hydroxyalkyl, carboxyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl; or R 2 and R 3 together form a 3-8 membered ring, the 3-8 The membered ring is optionally substituted by one or more Z3;
    R 4为-L 2-R 7； R 4 is -L 2 -R 7 ;
    R 5选自氢、烷基和卤素，其中所述烷基任选被一个或多个选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； R is selected from hydrogen, alkyl and halogen, wherein the alkyl is optionally replaced by one or more selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, Hydroxy, Nitro, Cyano, Cycloalkyl, Heterocycloalkyl, Aryl, Heteroaryl, Cycloalkoxy, Heterocycloalkyloxy, Cycloalkylthio, Heterocycloalkylthio, Oxo , carboxyl and carboxylate substituent substitution;
    R 7选自氢、烷基、环烷基、杂环烷基、芳基和杂芳基，任选地被一个或多个Z 4取代； R is selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, optionally substituted by one or more Z ;
    -L 2-选自键、C 1-6亚烷基、-O-和-NH-，所述C 1-6亚烷基任选被一个或多个选自羟基、烷基、烷氧基、卤代烷基、卤代烷氧基、卤素、氰基、氨基和硝基的取代基取代； -L 2 -is selected from bond, C 1-6 alkylene, -O- and -NH-, the C 1-6 alkylene is optionally replaced by one or more selected from hydroxyl, alkyl, alkoxy , haloalkyl, haloalkoxy, halogen, cyano, amino and nitro substituents;
    R 6选自H、R 8-(C＝O)-和
    Figure PCTCN2022103293-appb-100008
    R 6 is selected from H, R 8 -(C=O)- and
    Figure PCTCN2022103293-appb-100008
    R 8为烷基，优选为C 1-6烷基，更优选为C 1-3烷基，最优选为甲基； R is an alkyl group, preferably a C 1-6 alkyl group, more preferably a C 1-3 alkyl group, most preferably a methyl group;
    R 9和R 10各自独立地选自氢、烷基和环烷基，优选选自氢、C 1-6烷基和3-7元环烷基，更优选选自氢、C 1-3烷基和环丙基，最优选选自氢、甲基和乙基； R 9 and R 10 are each independently selected from hydrogen, alkyl and cycloalkyl, preferably selected from hydrogen, C 1-6 alkyl and 3-7 membered cycloalkyl, more preferably selected from hydrogen, C 1-3 alkane and cyclopropyl, most preferably selected from hydrogen, methyl and ethyl;
    每个X独立地选自O、S和NH，优选为O；Each X is independently selected from O, S and NH, preferably O;
    Z 1、Z 2、Z 3和Z 4各自独立地选自卤素、氰基、羟基、硝基、氧代基、烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基、杂芳基、-SR'、-SOR'、-SO 2R'、-SO 2NR'(R”)、-NR'(R”)、-COR'、-COOR'、-CONR'(R”)和-(P＝O)R'(R”)；所述烷基、烷氧基、卤代烷基、羟烷基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自烷基、烯基、炔基、烷氧基、氘代烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、-NR'(R”)、-SOR'、-SO 2R'、-SO(NH)R'、-S(NH)R'、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代； Z 1 , Z 2 , Z 3 and Z 4 are each independently selected from halogen, cyano, hydroxyl, nitro, oxo, alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclic Alkyl, aryl, heteroaryl, -SR', -SOR ', -SO2R ', -SO2NR'(R"), -NR'(R"), -COR', -COOR', -CONR'(R") and -(P=O)R'(R"); the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocycloalkyl, aryl and hetero The aryl groups are each independently optionally replaced by one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, alkoxy, deuterated alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, -NR'(R"), -SOR', -SO 2 R', -SO(NH)R', -S(NH)R', cyano, cycloalkyl, heterocycloalkyl, aryl, hetero Aryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo, carboxyl and carboxylate substituents;
    每个R'或R”独立地选自氢、羟基、烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基，所述烷基、烷氧基、环烷基、杂环烷基、芳基和杂芳基各自独立地任选被一个或多个选自氘、烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷基氧基、环烷硫基、杂环烷硫基、氧代基、羧基和羧酸酯基的取代基取代；Each R' or R" is independently selected from hydrogen, hydroxy, alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, the alkyl, alkoxy, cycloalkyl , heterocycloalkyl, aryl and heteroaryl are each independently optionally selected from one or more of deuterium, alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto , hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkyloxy, cycloalkylthio, heterocycloalkylthio, oxo Substituent substitution of group, carboxyl group and carboxylate group;
    m和n各自独立地选自0、1和2。m and n are each independently selected from 0, 1 and 2.
  11. 根据权利要求1-10中任一项所述的化合物或其可药用的盐，其为式II所示化合物或其可药用的盐，The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-10, which is a compound represented by formula II or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022103293-appb-100009
    Figure PCTCN2022103293-appb-100009
    其中，R 2、R 3、R 4、R 5、R 6、L 1和Z 2如权利要求1或9中所定义。 Wherein, R 2 , R 3 , R 4 , R 5 , R 6 , L 1 and Z 2 are as defined in claim 1 or 9.
  12. 根据权利要求10或11所述的化合物或其可药用的盐，其中，L 1为-O-。 The compound or pharmaceutically acceptable salt thereof according to claim 10 or 11, wherein L 1 is -O-.
  13. 根据权利要求10-12中任一项所述的化合物或其可药用的盐，其中，所述R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基和氧代基，优选选自氢、卤素和C 1-6烷基，更优选为氢。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10-12, wherein, said R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl, cyano, Hydroxy, nitro and oxo are preferably selected from hydrogen, halogen and C 1-6 alkyl, more preferably hydrogen.
  14. 根据权利要求10-13中任一项所述的化合物或其可药用的盐，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自C 1-6烷基、C 3-7环烷基、3-7元杂环烷基、6-12元芳基和5-12元杂芳基，优选选自C 1-4烷基、C 3-5环烷基、6-10元芳基和5-6元杂芳基，更优选选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、苯基、萘基、吡啶基、嘧啶基、哒嗪基、吡嗪基、 咪唑基、吡唑基、噻唑基和噁唑基，最优选选自异丙基、
    Figure PCTCN2022103293-appb-100010
    环丙基、苯基和吡啶基；所述R 7任选地被一个或多个Z 4取代，所述Z 4如权利要求1中定义。     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10-13, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; the R 7 is selected from C 1- 6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C 1-4 alkyl, C 3-5 Cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl , cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl, most preferably from isopropyl,
    Figure PCTCN2022103293-appb-100010
    Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 , said Z 4 being as defined in claim 1.
  15. 根据权利要求14所述的化合物或其可药用的盐，其中，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基，优选选自氟、氯、溴、甲基、乙基、丙基和异丙基。 The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl , preferably selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl.
  16. 根据权利要求10-15中任一项所述的化合物或其可药用的盐，其中所述R 5选自氢、C 1-6烷基和卤素，优选为氢、C 1-3烷基。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 10-15, wherein said R is selected from hydrogen, C 1-6 alkyl and halogen, preferably hydrogen, C 1-3 alkyl .
  17. 根据权利要求10-16中任一项所述的化合物或其可药用的盐，其中L 1为-O-，R 2和R 3各自独立地为氢，R 5为氢。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10-16, wherein L 1 is -O-, R 2 and R 3 are each independently hydrogen, and R 5 is hydrogen.
  18. 根据权利要求10-17中任一项所述的化合物或其可药用的盐，其中，R 6为H。 The compound according to any one of claims 10-17, or a pharmaceutically acceptable salt thereof, wherein R 6 is H.
  19. 根据权利要求10-18中任一项所述的化合物或其可药用的盐，其中，所述Z 2选自氰基、羟基、硝基、氧代基、C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6卤代烷基和C 1-6羟烷基各自独立地任选被一个或多个选自烷基、烷氧基、氘代烷氧基、卤素、巯基、羟基、硝基、氰基、芳基、杂芳基、杂环烷基和杂环烷基氧基的取代基取代，所述取代基优选选自氰基、C 1-6烷基、C 1-6烷氧基、C 1-6氘代烷氧基、杂环烷基和杂环烷基氧基，更优选选自氰基、甲基、乙基、甲氧基、一氘代甲氧基、二氘代甲氧基、三氘代甲氧基、3至7元环烷基和3至7元杂环烷基。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 10-18, wherein said Z is selected from cyano, hydroxyl, nitro, oxo, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 hydroxyalkyl; said C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl and C 1-6 The hydroxyalkyl groups are each independently optionally selected from the group consisting of alkyl, alkoxy, deuterated alkoxy, halogen, mercapto, hydroxyl, nitro, cyano, aryl, heteroaryl, heterocycloalkane Substituent group and heterocycloalkyloxy group, said substituent is preferably selected from cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 deuterated alkoxy, heterocycle Alkyl and heterocycloalkyloxy, more preferably selected from cyano, methyl, ethyl, methoxy, a deuteriomethoxy, diduteriomethoxy, trideuteriomethoxy, 3 to 7-membered cycloalkyl and 3 to 7-membered heterocycloalkyl.
  20. 根据权利要求10或11所述的化合物或其可药用的盐，其中，Z 2各自独立地选自烷基、卤代烷基、羟烷基、环烷基、-COOR'和-CONR'(R”)；所述烷基、卤代烷基、羟烷基和环烷基各自独立地任选被一个或多个选自卤素、巯基、羟基、-NR'(R”)、-SOR'、-SO 2R'、-SO(NH)R'和-S(NH)R'的取代基取代； The compound or pharmaceutically acceptable salt thereof according to claim 10 or 11 , wherein Z2 is each independently selected from alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, -COOR' and -CONR' (R ”); The alkyl, haloalkyl, hydroxyalkyl and cycloalkyl are each independently optionally selected from one or more of halogen, mercapto, hydroxyl, -NR'(R"), -SOR', -SO Substituents of 2 R', -SO(NH)R' and -S(NH)R';
    每个R'或R”独立地选自氢、羟基和烷基，所述烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代；Each R' or R" is independently selected from hydrogen, hydroxy and alkyl optionally substituted with one or more substituents selected from deuterium, halogen, mercapto, hydroxy and cyano;
    优选地，所述Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述C 1-6烷基或3至7元环烷基任选被一个或多个选自卤素、羟基、巯基和-NR'(R”)的取代基取代，所述每个R'或R”独立地为氢或C 1-6烷基，所述C 1-6烷基任选被一个或多个选自氘、卤素、巯基、羟基和氰基的取代基取代，优选地，所述C 1-6烷基任选被一个或多个氘取代。 Preferably, said Z 2 are each independently C 1-6 alkyl or 3 to 7 membered cycloalkyl, and said C 1-6 alkyl or 3 to 7 membered cycloalkyl is optionally selected from one or more Substituents from halogen, hydroxy, mercapto and -NR'(R"), each R' or R" is independently hydrogen or C 1-6 alkyl, the C 1-6 alkyl is optionally Substituted by one or more substituents selected from deuterium, halogen, mercapto, hydroxyl and cyano, preferably, the C 1-6 alkyl is optionally substituted by one or more deuteriums.
  21. 根据权利要求20所述的化合物或其可药用的盐，其中，Z 2各自独立地为C 1-6烷基或3至7元环烷基，所述C 1-6烷基和3至7元环烷基被一个或多个羟基取代。 The compound according to claim 20 or a pharmaceutically acceptable salt thereof, wherein, Z 2 are each independently C 1-6 alkyl or 3 to 7 membered cycloalkyl, the C 1-6 alkyl and 3 to 7 membered cycloalkyl A 7-membered cycloalkyl group is substituted with one or more hydroxyl groups.
  22. 根据权利要求10-11和20中任一项所述的式I-G所示化合物或其可药用的盐，其中，L 1为-O-。 The compound represented by formula IG or a pharmaceutically acceptable salt thereof according to any one of claims 10-11 and 20, wherein L 1 is -O-.
  23. 根据权利要求10-11和20-22中任一项所述的化合物或其可药用的盐，其中，所述R 2和R 3各自独立地选自氢、卤素、C 1-6烷基、氰基、羟基、硝基和氧代基，优选选自氢、卤素和C 1-6烷基，更优选为氢。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 10-11 and 20-22, wherein, said R 2 and R 3 are each independently selected from hydrogen, halogen, C 1-6 alkyl , cyano, hydroxyl, nitro and oxo, preferably selected from hydrogen, halogen and C 1-6 alkyl, more preferably hydrogen.
  24. 根据权利要求10-11和20-23中任一项所述的化合物或其可药用的盐，其中，R 4为-L 2-R 7；-L 2-为键；所述R 7选自C 1-6烷基、C 3-7环烷基、3-7元杂环烷基、6-12元芳基和5-12元杂芳基，优选选自C 1-4烷基、C 3-5环烷基、6-10元芳基和5-6元杂芳基，更优选选自甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、环丙基、环丁基、环戊基、苯基、萘基、吡啶基、嘧啶基、哒嗪基、吡嗪基、咪唑基、吡唑基、噻唑基和噁唑基，最优选选自异丙基、
    Figure PCTCN2022103293-appb-100011
    环丙基、苯基和吡啶基；所述R 7任选地被一个或多个Z 4取代，所述Z 4如权利要求9中定义。     The compound or pharmaceutically acceptable salt thereof according to any one of claims 10-11 and 20-23, wherein R 4 is -L 2 -R 7 ; -L 2 - is a bond; and the R 7 is selected from From C 1-6 alkyl, C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, 6-12 membered aryl and 5-12 membered heteroaryl, preferably selected from C 1-4 alkyl, C 3-5 cycloalkyl, 6-10 membered aryl and 5-6 membered heteroaryl, more preferably selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl , tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, naphthyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, thiazolyl and oxazolyl , most preferably selected from isopropyl,
    Figure PCTCN2022103293-appb-100011
    Cyclopropyl, phenyl and pyridyl; said R 7 is optionally substituted by one or more Z 4 , said Z 4 being as defined in claim 9.
  25. 根据权利要求24所述的化合物或其可药用的盐，其中，所述Z 4选自氟、氯、溴、甲基、乙基、丙基、异丙基、氰基、羟基和卤代烷基，优选选自氟、氯、溴、甲基、乙基、丙基和异丙基。 The compound or pharmaceutically acceptable salt thereof according to claim 24 , wherein, said Z is selected from fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, cyano, hydroxyl and haloalkyl , preferably selected from fluorine, chlorine, bromine, methyl, ethyl, propyl and isopropyl.
  26. 根据权利要求10-11和20-25中任一项所述的化合物或其可药用的盐，其中所述R 5选自氢、C 1-6烷基和卤素，优选为氢、C 1-3烷基。 The compound or pharmaceutically acceptable salt thereof according to any one of claims 10-11 and 20-25, wherein said R is selected from hydrogen, C 1-6 alkyl and halogen, preferably hydrogen, C 1 -3 alkyl.
  27. 根据权利要求10-11和20-26中任一项所述的化合物或其可药用的盐，其中L 1为-O-，R 2和R 3各自独立地为氢，R 5为氢。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 10-11 and 20-26, wherein L 1 is -O-, R 2 and R 3 are each independently hydrogen, and R 5 is hydrogen.
  28. 根据权利要求1-27中任一项所述的化合物或其可药用的盐，其中所述化合物选自：The compound or pharmaceutically acceptable salt thereof according to any one of claims 1-27, wherein the compound is selected from:
    Figure PCTCN2022103293-appb-100012
    Figure PCTCN2022103293-appb-100012
    Figure PCTCN2022103293-appb-100013
    Figure PCTCN2022103293-appb-100013
    Figure PCTCN2022103293-appb-100014
    Figure PCTCN2022103293-appb-100014
    Figure PCTCN2022103293-appb-100015
    Figure PCTCN2022103293-appb-100015
    Figure PCTCN2022103293-appb-100016
    Figure PCTCN2022103293-appb-100016
    Figure PCTCN2022103293-appb-100017
    Figure PCTCN2022103293-appb-100017
    Figure PCTCN2022103293-appb-100018
    Figure PCTCN2022103293-appb-100018
    Figure PCTCN2022103293-appb-100019
    Figure PCTCN2022103293-appb-100019
    Figure PCTCN2022103293-appb-100020
    Figure PCTCN2022103293-appb-100020
    Figure PCTCN2022103293-appb-100021
    Figure PCTCN2022103293-appb-100021
    Figure PCTCN2022103293-appb-100022
    Figure PCTCN2022103293-appb-100022
    Figure PCTCN2022103293-appb-100023
    Figure PCTCN2022103293-appb-100023
    Figure PCTCN2022103293-appb-100024
    Figure PCTCN2022103293-appb-100024
    Figure PCTCN2022103293-appb-100025
    Figure PCTCN2022103293-appb-100025
    Figure PCTCN2022103293-appb-100026
    Figure PCTCN2022103293-appb-100026
    Figure PCTCN2022103293-appb-100027
    Figure PCTCN2022103293-appb-100027
    Figure PCTCN2022103293-appb-100028
    Figure PCTCN2022103293-appb-100028
  29. 一种根据权利要求1-28中任一项所述的化合物或其可药用的盐的同位素取代物，优选地，所述同位素取代物为氘原子取代物。An isotopic substitution of the compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, preferably, the isotopic substitution is a deuterium atom substitution.
  30. 一种药物组合物，包括至少一种治疗有效量的根据权利要求1-28中任一项所述的化合物或其可药用的盐或根据权利要求29所述的同位素取代物以及药学上可接受的赋形剂。A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-28 or an isotope substitution according to claim 29 and a pharmaceutically acceptable Accepted excipients.
  31. 一种药物组合物，包括至少一种治疗有效量的根据权利要求1-28中任一项所述的化合物或其可药用的盐或根据权利要求29所述的同位素取代物以及药学上可接受的赋形剂，基于组合物的总重量，所述的药物组合物含有0.01％-99.99％的药学上可接受的赋形剂。A pharmaceutical composition comprising at least one therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1-28 or an isotope substitution according to claim 29 and a pharmaceutically acceptable Acceptable excipients, based on the total weight of the composition, the pharmaceutical composition contains 0.01%-99.99% of pharmaceutically acceptable excipients.
  32. 根据权利要求1-28中任一项所述的化合物或其可药用的盐、根据权利要求29所述的同位素取代物或根据权利要求30或31任一项所述的药物组合物在制备用于预防和/或治疗与细胞周期蛋白依赖性激酶相关疾病的药物中的用途，所述细胞周期蛋白依赖性激酶优选为CDK2，所述与细胞周期蛋白依赖性激酶相关疾病 优选为细胞增殖性疾病、癌症或免疫性疾病。The compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, the isotope substitution according to claim 29 or the pharmaceutical composition according to any one of claims 30 or 31 are being prepared Use in medicines for the prevention and/or treatment of cyclin-dependent kinase-related diseases, preferably CDK2, and preferably cell proliferation Disease, cancer or immune disease.
  33. 根据权利要求1-28中任一项所述的化合物或其可药用的盐、根据权利要求29所述的同位素取代物或根据权利要30或31任一项所述的药物组合物在制备用于预防和/或治疗与细胞周期蛋白相关疾病的药物中的用途，所述细胞周期蛋白优选为细胞周期蛋白E，更优选为细胞周期蛋白E1或细胞周期蛋白E2，所述与细胞周期蛋白相关疾病优选为细胞增殖性疾病、癌症或免疫性疾病。The compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, the isotope substitution according to claim 29 or the pharmaceutical composition according to any one of claims 30 or 31 are being prepared Use in drugs for the prevention and/or treatment of diseases associated with cell cyclins, the cyclins are preferably cyclin E, more preferably cyclin E1 or cyclin E2, the cyclins associated with cell cyclins The relevant disease is preferably a cell proliferative disease, cancer or an immune disease.
  34. 根据权利要求1-28中任一项所述的化合物或其可药用的盐、根据权利要求29所述的同位素取代物或根据权利要求30或31任一项所述的药物组合物在制备用于预防和/或治疗癌症的药物中的用途，所述癌症选自乳腺癌、卵巢癌、***癌、黑色素瘤、脑瘤、食道癌、胃癌、肝癌、胰腺癌、结直肠癌、肺癌、肾癌、皮肤癌、成胶质细胞瘤、神经母细胞瘤和肉瘤。The compound according to any one of claims 1-28 or a pharmaceutically acceptable salt thereof, the isotope substitution according to claim 29 or the pharmaceutical composition according to any one of claims 30 or 31 are being prepared Use in a medicament for the prevention and/or treatment of cancer selected from breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer, lung cancer, Kidney cancer, skin cancer, glioblastoma, neuroblastoma, and sarcoma.
  35. 一种式II所示化合物或其可药用的盐的制备方法，其包括式III所示化合物在酸性条件下脱除保护基PG的步骤，A preparation method of a compound represented by formula II or a pharmaceutically acceptable salt thereof, which comprises the step of removing the protecting group PG from the compound represented by formula III under acidic conditions,
    Figure PCTCN2022103293-appb-100029
    Figure PCTCN2022103293-appb-100029
    其中，R 2、R 3、R 4、R 5、L 1和Z 2如权利要求10-28中所定义，R 6为氢，PG为氨基保护基，优选选自叔丁基、乙酰基、三氟乙酰基、三苯甲基、苄基和甲酰基，最优选为叔丁基。 Among them, R 2 , R 3 , R 4 , R 5 , L 1 and Z 2 are as defined in claims 10-28, R 6 is hydrogen, PG is an amino protecting group, preferably selected from tert-butyl, acetyl, Trifluoroacetyl, trityl, benzyl and formyl, most preferably t-butyl.
PCT/CN2022/103293 2021-07-01 2022-07-01 Cdk2 inhibitor, preparation method therefor and use thereof WO2023274397A1 (en)

Applications Claiming Priority (12)

Application Number Priority Date Filing Date Title
CN202110750499 2021-07-01
CN202110750499.8 2021-07-01
CN202110903770 2021-08-06
CN202110903770.7 2021-08-06
CN202111260223 2021-10-28
CN202111260223.8 2021-10-28
CN202111586611.5 2021-12-23
CN202111586611 2021-12-23
CN202210037396 2022-01-13
CN202210037396.1 2022-01-13
CN202210572267 2022-05-24
CN202210572267.2 2022-05-24

Publications (1)

Publication Number Publication Date
WO2023274397A1 true WO2023274397A1 (en) 2023-01-05

Family

ID=84690466

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/103293 WO2023274397A1 (en) 2021-07-01 2022-07-01 Cdk2 inhibitor, preparation method therefor and use thereof

Country Status (2)

Country Link
TW (1) TW202317564A (en)
WO (1) WO2023274397A1 (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023160572A1 (en) * 2022-02-24 2023-08-31 楚浦创制（武汉）医药科技有限公司 Pyrazole derivative, pharmaceutical composition, and use
WO2023208143A1 (en) * 2022-04-28 2023-11-02 正大天晴药业集团股份有限公司 Pyrazole-substituted cyclopentanol ester derivative and use thereof
WO2024051727A1 (en) * 2022-09-09 2024-03-14 楚浦创制（武汉）医药科技有限公司 Pyrazole derivative, pharmaceutical composition, and use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1518543A (en) * 2000-08-31 2004-08-04 �Ʒ� Pyrazole derivatives and their use as protein kinase inhibitors
WO2005051919A1 (en) * 2003-11-26 2005-06-09 Pfizer Products Inc. Aminopyrazole derivatives as gsk-3 inhibitors
WO2020157652A2 (en) * 2019-01-31 2020-08-06 Pfizer Inc. Cdk2 inhibitors
WO2022135365A1 (en) * 2020-12-22 2022-06-30 Anrui Biomedical Technology (Guangzhou) Co., Ltd. Disubstituted cyclopentane kinase inhibitors
WO2022174031A1 (en) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Cdk inhibitors and methods of use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1518543A (en) * 2000-08-31 2004-08-04 �Ʒ� Pyrazole derivatives and their use as protein kinase inhibitors
WO2005051919A1 (en) * 2003-11-26 2005-06-09 Pfizer Products Inc. Aminopyrazole derivatives as gsk-3 inhibitors
WO2020157652A2 (en) * 2019-01-31 2020-08-06 Pfizer Inc. Cdk2 inhibitors
WO2022135365A1 (en) * 2020-12-22 2022-06-30 Anrui Biomedical Technology (Guangzhou) Co., Ltd. Disubstituted cyclopentane kinase inhibitors
WO2022174031A1 (en) * 2021-02-12 2022-08-18 Relay Therapeutics, Inc. Cdk inhibitors and methods of use thereof

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023160572A1 (en) * 2022-02-24 2023-08-31 楚浦创制（武汉）医药科技有限公司 Pyrazole derivative, pharmaceutical composition, and use
WO2023208143A1 (en) * 2022-04-28 2023-11-02 正大天晴药业集团股份有限公司 Pyrazole-substituted cyclopentanol ester derivative and use thereof
WO2024051727A1 (en) * 2022-09-09 2024-03-14 楚浦创制（武汉）医药科技有限公司 Pyrazole derivative, pharmaceutical composition, and use

Also Published As

Publication number Publication date
TW202317564A (en) 2023-05-01

Similar Documents

Publication Publication Date Title
TWI772386B (en) Heteroaryl fused [4,3-c]pyrimidin-5-amine derivative, a preparation method therefor, and a pharmaceutical use thereof
AU2018278311B2 (en) IRE1 small molecule inhibitors
WO2020108590A1 (en) Pyrimidine and five-membered nitrogen heterocycle derivative, preparation method therefor, and medical uses thereof
WO2023274397A1 (en) Cdk2 inhibitor, preparation method therefor and use thereof
CN112552294B (en) Piperazine heterocyclic derivative-containing inhibitor, preparation method and application thereof
WO2012019427A1 (en) Phthalazinone ketone derivative, preparation method thereof, and pharmaceutical use thereof
WO2020063792A1 (en) Indole macrocyclic derivative, preparation method therefor and application thereof in medicine
JP7237017B2 (en) Compounds used as autophagy modulators, and methods for their preparation and use
WO2020200069A1 (en) Pyrroloheterocyclic derivative, preparation method therefor, and application thereof in medicine
BR112021000857A2 (en) ADDITIONAL REPLACED DERIVATIVES OF QUINOXALIN TRIAZOLE
JP6967302B2 (en) Azaaryl derivative, its manufacturing method and pharmaceutical application
WO2023083201A1 (en) Aminopyrazole derivative, and preparation method therefor and use thereof
WO2022135442A1 (en) Cdk2 inhibitor and preparation method therefor
WO2022184049A1 (en) Plk4 inhibitor and use thereof
WO2020221209A1 (en) Cd73 inhibitor, preparation method therefor and application thereof
WO2017185959A1 (en) Fused imidazole derivatives having ido/tdo inhibiting activity, and preparation method and use therefor
CN115677682B (en) Spiro PLK4 inhibitor and application thereof
CN108779100B (en) 3, 4-dipyridyl pyrazole derivatives, preparation method and medical application thereof
WO2020082921A1 (en) Nitrogen heteroaryl amide derivative, preparation method therefor, and application thereof
TW201835079A (en) 6-pyrazol-[1,2,4]triazolo[4,3-a]pyridine-3-carboxamide derivatives, a preparation method thereof and pharmaceutical use thereof
CN112574212B (en) Pyrimido five-membered nitrogen heterocyclic derivative, preparation method and medical application thereof
WO2023109540A1 (en) Heterocyclic compound with akt kinase inhibitory activity, preparation method therefor and medical use thereof
WO2022199676A1 (en) Fused tetracyclic compound, preparation method therefor and application thereof in medicine
WO2023051302A1 (en) Heterocyclic compound having cyclin-dependent kinase inhibitory activity, preparation method therefor and medical use thereof
TW202246271A (en) Aza-aryl compound as well as preparation method and application thereof

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22832209

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE