WO2023125845A1 - Composé bicyclique hétéroaromatique et son application antivirale - Google Patents

Composé bicyclique hétéroaromatique et son application antivirale Download PDF

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WO2023125845A1
WO2023125845A1 PCT/CN2022/143565 CN2022143565W WO2023125845A1 WO 2023125845 A1 WO2023125845 A1 WO 2023125845A1 CN 2022143565 W CN2022143565 W CN 2022143565W WO 2023125845 A1 WO2023125845 A1 WO 2023125845A1
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alkyl
compound
halogen
substituted
cycloalkyl
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彭程
宋国伟
赖小刚
刘奉友
高广林
李中洋
张绍云
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苏州爱科百发生物医药技术有限公司
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Publication of WO2023125845A1 publication Critical patent/WO2023125845A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention belongs to the field of compounds, in particular to an aromatic heterobicyclic compound, in particular to an aromatic heterobicyclic compound and a mixture or composition containing an aromatic heterobicyclic compound, especially as a drug for preventing and treating RSV virus infection Aryl heterobicyclic compounds and mixtures or compositions containing aromatic heterobicyclic compounds.
  • Respiratory syncytial virus is an important pathogen that causes lower respiratory tract infection in infants, the elderly and immunocompromised patients. According to reports, the number of RSV infections among children under the age of 5 in the world reaches 33 million every year, and the death toll is about 160,000. After RSV infection, continuous immunity cannot be obtained, and reinfection may occur. Therefore, the reinfection rate of RSV is high. More than 96% of children under the age of 2 have been infected with RSV at least once, and 70% of them have hospitalized infection and concurrent bronchiolitis, pneumonia and asthma. , the elderly often lead to obstructive pulmonary disease with cardiopulmonary complications. RSV causes huge economic losses every year and seriously threatens human health.
  • Palivizumab is a monoclonal antibody that can effectively act on the F protein of RSV and prevent the virus from entering cells. It can produce better effects after intramuscular injection, and basically will not cause toxic side effects in children. However, due to the high price, many countries have not yet started to apply it. Since 2014, the United States only recommends the use of premature infants under 29 weeks within 12 months of birth, premature infants under 32 weeks with chronic lung disease, and infants with congenital heart disease, while 29 weeks within 6 months after birth Premature infants at ⁇ 31 weeks, and premature infants at 32-34 weeks with risk factors within 3 months after birth, are no longer routinely recommended to use palivizumab to prevent acute lower respiratory tract infection caused by RSV infection.
  • new RSV inhibitors can be divided into nucleotide synthesis inhibitors, fusion inhibitors and non-fusion non-nucleotide synthesis inhibitors. Except for palivizumab, these antiviral drugs are in different stages of clinical research.
  • Nucleotide synthesis inhibitors are nucleoside analogs containing a base or a ribose-like part of the base, which can be encapsulated by viral polymerases to terminate the polymerization of nucleotides and inhibit viral replication.
  • Drugs under development include: ALS-8176 (Lumicitabine, discontinued) and GS-5734 (remdesivir); preventing the fusion of viruses and host cells through drugs is a commonly used antiviral strategy.
  • RSV fusion inhibitors are a relatively concentrated field of research, and the main drugs include: AK-0529, GS-5806, VP-14637, JNJ-53718678 and BTA-C585.
  • Non-fusion non-nucleotide synthesis inhibitors are also under study, specifically including nuclear protein inhibitors (RSV604), small interfering RNA (siRNA) technology drugs (ALN-RSV01), antibody drugs (Palivizumab, approved for marketing ), REGN2222 (full human monoclonal antibody against F protein), MEDI8897 (modified Fc recombinant human IgG1 monoclonal antibody) and ALX-0171 (nanobody trimer), etc.
  • RSV604 nuclear protein inhibitors
  • siRNA small interfering RNA
  • AN-RSV01 antibody drugs
  • REGN2222 full human monoclonal antibody against F protein
  • MEDI8897 modified Fc recombinant human IgG1 monoclonal antibody
  • ALX-0171 nanobody trimer
  • RSV is widely prevalent in the world, RSV drugs are scarce on the market, and small molecule antiviral drugs have many advantages such as low production cost, ability to penetrate the cell membrane to target intracellular targets, and can be taken orally. Therefore, there is an urgent need to develop suitable for Small molecule antiviral drugs for different populations such as newborns, children, pregnant women and the elderly.
  • the present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:
  • X 1 , X 2 , X 3 , X 4 and X 5 are selected from combinations of b-1 to b-7 groups:
  • X 6 , X 7 and X 8 are each independently selected from CR 6' and N;
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 5 is selected from substituted or unsubstituted -NR 7 R 8 , -NR 7 -(CO)-heterocycloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl; One or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 ,- (CO)-NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 -(CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 - Substituents
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl and C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • R 6 and R 6' are each independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy and at least one halogen substituted C 1-6 alkyl;
  • Ring A is selected from groups A-1 to A-3, specifically as follows:
  • R i is selected from halogen, C 1-3 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • o is an integer of 0-4;
  • p is an integer of 0-2;
  • q is an integer of 0-3.
  • the aromatic heterobicyclic compounds provided by the present disclosure have high inhibitory activity against RSV, excellent drug efficacy, in vitro/in vivo pharmacokinetic properties and safety, and have high clinical application prospects.
  • FIG. 1 Effect of test substances on RSV titers in the model.
  • RSV titers in mouse lung tissues were determined by the plaque method. Error bars show standard error.
  • the present disclosure provides a compound represented by general formula I or its stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts:
  • X 1 , X 2 , X 3 , X 4 and X 5 are selected from combinations of b-1 to b-7 groups:
  • X 6 , X 7 and X 8 are each independently selected from CR 6' and N;
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 5 is selected from substituted or unsubstituted -NR 7 R 8 , -NR 7 -(CO)-heterocycloalkyl, C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl; One or more selected from deuterium, halogen, amino, hydroxyl, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 ,- (CO)-NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 -(CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 - Substituents
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl and C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • R 6 and R 6' are each independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy and at least one halogen substituted C 1-6 alkyl;
  • Ring A is selected from groups A-1 to A-3, specifically as follows:
  • R i is selected from halogen, C 1-3 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • o is an integer of 0-4;
  • p is an integer of 0-2;
  • q is an integer of 0-3.
  • the R 1 is selected from C 1-3 alkyl and C 3-6 cycloalkyl.
  • said R 1 is selected from methyl, ethyl, propyl, isopropyl.
  • said R 1 is selected from methyl.
  • each of R 2 and R 2′ is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyl substituted by at least one halogen.
  • each of said R 2 and R 2' is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl.
  • each of said R2 and R2 ' is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.
  • said R2 and R2 ' are each independently selected from hydrogen, fluorine.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • said R is selected from substituted or unsubstituted C 3-7 cycloalkyl and 3-7 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from N, O and S.
  • said R is selected from substituted or unsubstituted C 3-5 cycloalkyl and 5-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from N and O.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl.
  • the R 5 is selected from substituted or unsubstituted cyclopropyl and pyrrolidinyl.
  • the substitution in R is by one or more selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH , Substituents of -(CO)-NR 7 R 8 are substituted.
  • substitution in R 5 is substituted with one or more substituents selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R6 and R6' is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen.
  • said R 6 and R 6' are each independently selected from hydrogen, deuterium, halogen.
  • each of said R 6 and R 6′ is independently selected from hydrogen.
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • the R i is selected from halogen, C 1-6 alkyl, C 1-3 alkoxy.
  • said R i is selected from halogen.
  • the o is selected from an integer of 0-2.
  • said o is selected from 0 and 1.
  • said o is selected from 0.
  • the p is selected from 0 and 1.
  • said p is selected from zero.
  • said q is selected from 0 and 1.
  • said q is selected from zero.
  • the compound of formula I is a compound of formula I-1:
  • X 1 , X 2 , X 3 , X 4 and X 5 are selected from combinations of b-1 to b-7 groups:
  • X 6 , X 7 and X 8 are each independently selected from CR 6' and N;
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from the group consisting of halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen-substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 9 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and -(CO)-NR 7 R 8 ;
  • R 10 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and at least one halogen substituted C 1-6 alkyl;
  • R 11 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • n is an integer of 1-3;
  • R 6 and R 6' are each independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy and at least one halogen substituted C 1-6 alkyl;
  • Ring A is selected from groups A-1 to A-3, specifically as follows:
  • R i is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • o is an integer of 0-4;
  • p is an integer of 0-2;
  • q is an integer of 0-3.
  • the R 1 is selected from C 1-3 alkyl and C 3-6 cycloalkyl.
  • said R 1 is selected from methyl, ethyl, propyl, isopropyl.
  • said R 1 is selected from methyl.
  • each of R 2 and R 2′ is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyl substituted by at least one halogen.
  • each of said R 2 and R 2' is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl.
  • each of said R2 and R2 ' is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.
  • said R2 and R2 ' are each independently selected from hydrogen, fluorine.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • each of R6 and R6' is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen.
  • said R 6 and R 6' are each independently selected from hydrogen, deuterium, halogen.
  • each of said R 6 and R 6′ is independently selected from hydrogen.
  • said R9 is selected from hydrogen, deuterium, fluorine.
  • said R9 is selected from hydrogen.
  • said R 10 is selected from hydrogen, deuterium, fluorine.
  • said R 10 is selected from hydrogen.
  • the R 11 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 11 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said n is selected from 1.
  • the R i is selected from halogen, C 1-6 alkyl, C 1-3 alkoxy.
  • said R i is selected from halogen.
  • the o is selected from an integer of 0-2.
  • said o is selected from 0 and 1.
  • said o is selected from 0.
  • the p is selected from 0 and 1.
  • said p is selected from zero.
  • said q is selected from 0 and 1.
  • said q is selected from zero.
  • the compound of formula I is a compound of formula I-2:
  • X 1 , X 2 , X 3 , X 4 and X 5 are selected from combinations of b-1 to b-7 groups:
  • X 6 , X 7 and X 8 are each independently selected from CR 6' and N;
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 12 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 13 is selected from hydrogen, deuterium, C 1-6 alkyl, hydroxyl, halogen and C 1-6 alkoxy;
  • R 14 is selected from hydrogen, deuterium and halogen
  • R 15 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 16 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • R 17 is selected from hydrogen, deuterium and C 1-6 alkyl
  • n is an integer of 1-3;
  • R 6 and R 6' are each independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy and at least one halogen substituted C 1-6 alkyl;
  • Ring A is selected from groups A-1 to A-3, specifically as follows:
  • R i is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • o is an integer of 0-4;
  • p is an integer of 0-2;
  • q is an integer of 0-3.
  • the R 1 is selected from C 1-3 alkyl and C 3-6 cycloalkyl.
  • said R 1 is selected from methyl, ethyl, propyl, isopropyl.
  • said R 1 is selected from methyl.
  • each of R 2 and R 2′ is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyl substituted by at least one halogen.
  • each of said R 2 and R 2' is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl.
  • each of said R2 and R2 ' is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.
  • said R2 and R2 ' are each independently selected from hydrogen, fluorine.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • each of R6 and R6' is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen.
  • said R 6 and R 6' are each independently selected from hydrogen, deuterium, halogen.
  • each of said R 6 and R 6′ is independently selected from hydrogen.
  • said R 12 is selected from hydrogen, deuterium.
  • said R 12 is selected from hydrogen.
  • said R 13 is selected from hydrogen, deuterium, hydroxyl.
  • said R 13 is selected from hydrogen, hydroxyl.
  • said R 14 is selected from hydrogen, deuterium.
  • said R 14 is selected from hydrogen.
  • said R 15 is selected from hydrogen, deuterium.
  • said R 15 is selected from hydrogen.
  • said R 16 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 16 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said R 17 is selected from hydrogen, deuterium.
  • said R 17 is selected from hydrogen.
  • said m is selected from 1.
  • the R i is selected from halogen, C 1-6 alkyl, C 1-3 alkoxy.
  • said R i is selected from halogen.
  • the o is selected from an integer of 0-2.
  • said o is selected from 0 and 1.
  • said o is selected from 0.
  • the p is selected from 0 and 1.
  • said p is selected from zero.
  • said q is selected from 0 and 1.
  • said q is selected from zero.
  • the compound of formula I is a compound of formula I-3:
  • X 1 , X 2 , X 3 , X 4 and X 5 are selected from combinations of b-1 to b-7 groups:
  • X 6 , X 7 and X 8 are each independently selected from CR 6' and N;
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 9 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and -(CO)-NR 7 R 8 ;
  • R 10 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and at least one halogen substituted C 1-6 alkyl;
  • R 11 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • n is an integer of 1-3;
  • R 6 and R 6' are each independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy and at least one halogen substituted C 1-6 alkyl;
  • R i is halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl or C 1-6 alkoxy;
  • o is an integer of 0-4.
  • the R 1 is selected from C 1-3 alkyl and C 3-6 cycloalkyl.
  • said R 1 is selected from methyl, ethyl, propyl, isopropyl.
  • said R 1 is selected from methyl.
  • each of R 2 and R 2′ is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyl substituted by at least one halogen.
  • each of said R 2 and R 2' is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl.
  • each of said R2 and R2 ' is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.
  • said R2 and R2' are each independently selected from hydrogen, fluorine.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • each of R6 and R6' is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen.
  • said R 6 and R 6' are each independently selected from hydrogen, deuterium, halogen.
  • each of said R 6 and R 6′ is independently selected from hydrogen.
  • said R9 is selected from hydrogen, deuterium, fluorine.
  • said R9 is selected from hydrogen.
  • said R 10 is selected from hydrogen, deuterium, fluorine.
  • said R 10 is selected from hydrogen.
  • the R 11 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 11 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said n is selected from 1.
  • the R i is selected from halogen, C 1-6 alkyl, C 1-3 alkoxy.
  • said R i is selected from halogen.
  • the o is selected from an integer of 0-2.
  • said o is selected from 0 and 1.
  • said o is selected from 0.
  • the compound of formula I is a compound of formula I-4:
  • X 1 , X 2 , X 3 , X 4 and X 5 are selected from combinations of b-1 to b-7 groups:
  • X 6 , X 7 and X 8 are each independently selected from CR 6' or N;
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 12 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 13 is selected from hydrogen, deuterium, C 1-6 alkyl, hydroxyl, halogen and C 1-6 alkoxy;
  • R 14 is selected from hydrogen, deuterium and halogen
  • R 15 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 16 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • R 17 is selected from hydrogen, deuterium and C 1-6 alkyl
  • n is an integer of 1-3;
  • R 6 and R 6' are each independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen, C 1-6 alkyl, C 1-6 alkoxy and at least one halogen substituted C 1-6 alkyl;
  • R i is halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl or C 1-6 alkoxy;
  • o is an integer of 0-4.
  • the R 1 is selected from C 1-3 alkyl and C 3-6 cycloalkyl.
  • said R 1 is selected from methyl, ethyl, propyl, isopropyl.
  • said R 1 is selected from methyl.
  • each of R 2 and R 2′ is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyl substituted by at least one halogen.
  • each of said R 2 and R 2' is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl.
  • each of said R2 and R2 ' is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.
  • said R2 and R2' are each independently selected from hydrogen, fluorine.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • each of R6 and R6' is independently selected from hydrogen, deuterium, hydroxyl, cyano, halogen.
  • said R 6 and R 6' are each independently selected from hydrogen, deuterium, halogen.
  • each of said R 6 and R 6′ is independently selected from hydrogen.
  • said R 12 is selected from hydrogen, deuterium.
  • said R 12 is selected from hydrogen.
  • said R 13 is selected from hydrogen, deuterium, hydroxyl.
  • said R 13 is selected from hydrogen, hydroxyl.
  • said R 14 is selected from hydrogen, deuterium.
  • said R 14 is selected from hydrogen.
  • said R 15 is selected from hydrogen, deuterium.
  • said R 15 is selected from hydrogen.
  • said R 16 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 16 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said R 17 is selected from hydrogen, deuterium.
  • said R 17 is selected from hydrogen.
  • said m is selected from 1.
  • the R i is selected from halogen, C 1-6 alkyl, C 1-3 alkoxy.
  • said R i is selected from halogen.
  • the o is selected from an integer of 0-2.
  • said o is selected from 0 and 1.
  • said o is selected from 0.
  • the compound of formula I is a compound of formula I-5:
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 9 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and -(CO)-NR 7 R 8 ;
  • R 10 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and at least one halogen substituted C 1-6 alkyl;
  • R 11 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • n is an integer of 1-3;
  • R i is halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl or C 1-6 alkoxy;
  • o is an integer of 0-4.
  • the R 1 is selected from C 1-3 alkyl and C 3-6 cycloalkyl.
  • said R 1 is selected from methyl, ethyl, propyl, isopropyl.
  • said R 1 is selected from methyl.
  • each of R 2 and R 2′ is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyl substituted by at least one halogen.
  • each of said R 2 and R 2' is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl.
  • each of said R2 and R2 ' is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.
  • said R2 and R2 ' are each independently selected from hydrogen, fluorine.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • said R9 is selected from hydrogen, deuterium, fluorine.
  • said R9 is selected from hydrogen.
  • said R 10 is selected from hydrogen, deuterium, fluorine.
  • said R 10 is selected from hydrogen.
  • the R 11 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 11 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said n is selected from 1.
  • the R i is selected from halogen, C 1-6 alkyl, C 1-3 alkoxy.
  • said R i is selected from halogen.
  • the o is selected from an integer of 0-2.
  • said o is selected from 0 and 1.
  • said o is selected from 0.
  • the compound of formula I is a compound of formula I-6:
  • R 1 is selected from C 1-6 alkyl and C 3-7 cycloalkyl
  • R 2 and R 2' are each independently selected from hydrogen, deuterium, halogen, C 1-6 alkyl, C 1-6 alkyl and C 3-7 cycloalkyl substituted by at least one halogen;
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 12 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 13 is selected from hydrogen, deuterium, C 1-6 alkyl, hydroxyl, halogen and C 1-6 alkoxy;
  • R 14 is selected from hydrogen, deuterium and halogen
  • R 15 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 16 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • R 17 is selected from hydrogen, deuterium and C 1-6 alkyl
  • n is an integer of 1-3;
  • R i is halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl or C 1-6 alkoxy;
  • o is an integer of 0-4.
  • the R 1 is selected from C 1-3 alkyl and C 3-6 cycloalkyl.
  • said R 1 is selected from methyl, ethyl, propyl, isopropyl.
  • said R 1 is selected from methyl.
  • each of R 2 and R 2′ is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl, C 1-3 alkyl substituted by at least one halogen.
  • each of said R 2 and R 2' is independently selected from hydrogen, deuterium, halogen, C 1-3 alkyl.
  • each of said R2 and R2 ' is independently selected from hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl.
  • said R2 and R2 ' are each independently selected from hydrogen, fluorine.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • said R 12 is selected from hydrogen, deuterium.
  • said R 12 is selected from hydrogen.
  • said R 13 is selected from hydrogen, deuterium, hydroxyl.
  • said R 13 is selected from hydrogen, hydroxyl.
  • said R 14 is selected from hydrogen, deuterium.
  • said R 14 is selected from hydrogen.
  • said R 15 is selected from hydrogen, deuterium.
  • said R 15 is selected from hydrogen.
  • said R 16 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 16 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said R 17 is selected from hydrogen, deuterium.
  • said R 17 is selected from hydrogen.
  • said m is selected from 1.
  • the R i is selected from halogen, C 1-6 alkyl, C 1-3 alkoxy.
  • said R i is selected from halogen.
  • the o is selected from an integer of 0-2.
  • said o is selected from 0 and 1.
  • said o is selected from 0.
  • the compound of formula I is a compound of formula I-7:
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 9 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and -(CO)-NR 7 R 8 ;
  • R 10 is selected from hydrogen, deuterium, fluorine, C 1-6 alkyl and at least one halogen substituted C 1-6 alkyl;
  • R 11 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • n is an integer of 1-3.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • said R9 is selected from hydrogen, deuterium, fluorine.
  • said R9 is selected from hydrogen.
  • said R 10 is selected from hydrogen, deuterium, fluorine.
  • said R 10 is selected from hydrogen.
  • the R 11 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 11 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said n is selected from 1.
  • the compound of formula I is a compound of formula I-8:
  • R 3 is selected from halogen, C 1-6 alkyl, C 1-6 alkyl substituted by at least one halogen, C 3-7 cycloalkyl and C 1-6 alkoxy;
  • R is selected from substituted or unsubstituted C 1-6 alkyl, C 3-7 cycloalkyl, (C 1-6 alkyl) 2 amino, 3-7 membered heterocycloalkyl, aryl, heteroaryl ;
  • the substitution is substituted by one or more substituents selected from halogen, hydroxyl, cyano, C 1-6 alkyl, at least one halogen substituted C 1-6 alkyl and C 1-6 alkoxy ;
  • R 12 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 13 is selected from hydrogen, deuterium, C 1-6 alkyl, hydroxyl, halogen and C 1-6 alkoxy;
  • R 14 is selected from hydrogen, deuterium and halogen
  • R 15 is selected from hydrogen, deuterium, C 1-6 alkyl and hydroxy-C 1-6 alkyl;
  • R 16 is selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 , -(CO)- NR 7 -SO 2 -R 8 , -NR 7 R 8 , -NR 7 -(CO)-C 1-6 alkyl, -NR 7 -(CO)-C 3-7 cycloalkyl, -NR 7 - (CO)-OR 8 , -NR 7 -(CO)-NR 7 R 8 , -NR 7 -SO 2 -R 8 , -NR 7 -SO 2 -NR 7 R 8 , -SO 2 -NR 7 R 8 and -SO 2 -NR 7 -(CO)-R 8 ;
  • R 7 and R 8 are each independently selected from hydrogen, deuterium, cyano, C 1-6 alkyl, C 2-6 alkenyl, hydroxyl-C 1-6 alkyl, at least one halogen substituted C 1- 6 alkyl, C 3-7 cycloalkyl, C 1-6 alkyl-C 3-7 cycloalkyl, C 3-7 cycloalkyl substituted by hydroxyl or cyano;
  • R 17 is selected from hydrogen, deuterium and C 1-6 alkyl
  • n is an integer of 1-3.
  • said R 3 is selected from halogen, C 1-3 alkyl.
  • said R is selected from fluoro, chloro, methyl, ethyl, propyl, isopropyl.
  • said R3 is selected from fluoro.
  • the R 4 is selected from substituted or unsubstituted C 3-7 cycloalkyl, 3-7 membered heterocycloalkyl, C 6-10 aryl, 5-10 membered heteroaryl.
  • said R is selected from substituted or unsubstituted C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, said heterocycloalkyl contains 1-2 heteroatoms, so The heteroatoms are selected from O, S and N, and 5-6 membered heteroaryls, the heteroaryls contain 1-2 heteroatoms, and the heteroatoms are selected from O, S and N.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl , Morpholinyl, pyridyl, furyl, thienyl, pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl.
  • said R is selected from substituted or unsubstituted cyclopropyl, cyclobutyl, azetidinyl, pyrrolidinyl, morpholinyl, pyridyl, pyrimidinyl, pyrazinyl, Imidazolyl, pyrazolyl, thiazolyl.
  • the substitution in R is one or more selected from halogen, C 1-3 alkyl, C 1-3 alkyl and C 1-3 alkoxy substituted by at least one halogen of substituents.
  • the substitution in R is one or more selected from fluorine, chlorine, methyl, ethyl, propyl, isopropyl, fluoromethyl, difluoromethyl, trifluoro
  • the substituents of methyl, fluoroethyl, methoxy, and ethoxy are substituted.
  • substitution in R 4 is substituted by one or more substituents selected from fluorine, methyl, difluoromethyl, fluoroethyl, and methoxy.
  • said R 12 is selected from hydrogen, deuterium.
  • said R 12 is selected from hydrogen.
  • said R 13 is selected from hydrogen, deuterium, hydroxyl.
  • said R 13 is selected from hydrogen, hydroxyl.
  • said R 14 is selected from hydrogen, deuterium.
  • said R 14 is selected from hydrogen.
  • said R 15 is selected from hydrogen, deuterium.
  • said R 15 is selected from hydrogen.
  • said R 16 is selected from halogen, hydroxyl, cyano, C 1-3 alkyl, C 1-3 alkoxy, -(CO)-OH, -(CO)-NR 7 R 8 .
  • the R 16 is selected from hydroxyl, cyano, -(CO)-OH, -(CO)-NR 7 R 8 .
  • each of R and R is independently selected from hydrogen, deuterium, C 1-3 alkyl, hydroxy-C 1-3 alkyl, at least one halogen-substituted C 1-3 alkyl .
  • each of R and R is independently selected from hydrogen, methyl, hydroxyethyl, difluoroethyl.
  • said R 17 is selected from hydrogen, deuterium.
  • said R 17 is selected from hydrogen.
  • said m is selected from 1.
  • the compound of general formula I is any of the following:
  • the compound of general formula I is any of the following:
  • the present disclosure also provides a preparation method of the compound shown in formula I, specifically as follows:
  • X is halogen, preferably among Cl, Br and I.
  • Other groups are as shown in claim 1.
  • Step 1 Compound I-A undergoes a condensation reaction with Compound I-B to obtain Compound I-C;
  • Step 2 preparing boronate compound I-D from compound I-C;
  • the present disclosure also provides another preparation method of the compound shown in formula I, specifically as follows:
  • X is halogen, preferably among Cl, Br and I.
  • Other groups are as shown in claim 1.
  • Step 1 Compound I-A' undergoes a condensation reaction with Compound I-B to obtain Compound I-C';
  • Step 2 Compound I-C' undergoes a substitution or coupling reaction to obtain a compound of formula I.
  • the present disclosure also provides a pharmaceutical composition, comprising at least one of the aforementioned compounds or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts, and pharmaceutically acceptable acceptable carrier, diluent or excipient.
  • 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 based on the total weight of the composition. In some embodiments, the pharmaceutical composition contains 0.1%-99.9% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 0.5%-99.5% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 1%-99% of the aforementioned compounds. In some embodiments, the pharmaceutical composition contains 2%-98% of the aforementioned compounds.
  • the pharmaceutical composition contains 0.01%-99.99% of a pharmaceutically acceptable carrier, diluent or excipient based on the total weight of the composition. In certain embodiments, the pharmaceutical composition contains 0.1%-99.9% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 0.5%-99.5% of a pharmaceutically acceptable carrier, diluent or excipient. In certain embodiments, the pharmaceutical composition contains 1%-99% of pharmaceutically acceptable carriers, diluents or excipients. In certain embodiments, the pharmaceutical composition contains 2%-98% of pharmaceutically acceptable carriers, diluents or excipients.
  • All of the compounds involved in the present disclosure, mixtures, compositions, and the like including the compounds of the present invention can be administered to a living body through any route of administration.
  • the route of administration can be oral administration, intravenous injection, intramuscular injection, subcutaneous injection, rectal administration, vaginal administration, sublingual administration, nasal cavity inhalation, oral inhalation, eye drops, and local or systemic transdermal administration.
  • All the compounds involved in the present disclosure and the mixtures, compositions, etc. containing the compounds of the present invention can be formulated into a single dose, which contains the active compound of the present invention, as well as carriers, excipients, etc., and the dosage forms can be tablets, capsules , injections, granules, powders, suppositories, pills, creams, pastes, gels, powders, oral solutions, inhalants, suspensions, dry suspensions, patches, lotions, etc.
  • These dosage forms may contain ingredients commonly used in pharmaceutical preparations, such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH regulators, antioxidants, bacteriostats, isotonic regulators, Anti-sticking agent, etc.
  • ingredients commonly used in pharmaceutical preparations such as diluents, absorbents, wetting agents, binders, disintegrants, colorants, pH regulators, antioxidants, bacteriostats, isotonic regulators, Anti-sticking agent, etc.
  • Suitable formulations of the above-mentioned various dosage forms can be obtained from public sources, such as Remington: The Science and Practice of Pharmacy, 21st edition, Lippincott Williams & Wilkins published in 2006 and Rowe, Raymond C. Handbook of Pharmaceutical Excipients, Chicago, Pharmaceutical Press in 2005 Published in 2010. Therefore, those skilled in the art can easily prepare.
  • the dosage of the compound of the present invention can be 0.01 to 500 mg/kg per day , the preferred daily dose is 1-100 mg/kg, which can be administered in single or multiple doses.
  • the present disclosure also provides the compounds described in the present disclosure or their stereoisomers, solvates, hydrates, prodrugs, stable isotope derivatives and pharmaceutically acceptable salts or the aforementioned compositions in the preparation of preventive and/or therapeutic The use in the medicine of RSV virus infection disease.
  • the present disclosure also provides a method for preventing and/or treating RSV virus-infected diseases, which comprises the following steps: injecting a therapeutically effective amount of the aforementioned compound or its stereoisomer, solvate, hydrate, prodrug, stabilized
  • injecting a therapeutically effective amount of the aforementioned compound or its stereoisomer, solvate, hydrate, prodrug, stabilized The isotope derivatives and pharmaceutically acceptable salts, or pharmaceutical compositions are administered to patients in need.
  • C 1-6 alkyl alone or in combination means a saturated linear or branched alkyl group containing 1-6, especially 1-4 carbon atoms, including methyl, ethyl, propyl, Isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2- Butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2 -Pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3 ,-Dimethyl-2-butyl and so on.
  • C 1-6 alkyl is any one of methyl, ethyl, isopropyl and tert-butyl.
  • 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, heterocycloalkoxy group, cycloalkylthio group, heterocycloalkylthio group, oxo group, carboxyl group or carboxylate group.
  • C 2-6 alkenyl refers to a C 2-6 alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein “C 2-6 alkyl” means containing 2-6 alone or in combination, especially It is a saturated linear or branched alkyl group with 2-4 carbon atoms, including ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2- Pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl , 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2 -methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,
  • the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkane
  • substituents in yloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl are substituents in yloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.
  • C 3-7 cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, which represents a saturated cycloalkyl group having 3 to 7, especially 3-6 carbon atoms, including Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, etc.
  • Particular “C 3-7 cycloalkyl” is cyclopropyl, cyclopentyl, cyclohexyl and the like.
  • C 3-5 cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic ring hydrocarbon substituent, which represents a saturated cycloalkyl group with 3 to 5 carbon atoms, including cyclopropyl, cyclobutyl , cyclopentyl, etc.
  • C 1-6 alkoxy alone or in combination, denotes the group C 1-6 alkyl-O-, wherein “C 1-6 alkyl” denotes as defined above.
  • heterocycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) non-aromatic cyclic group composed of carbon atoms and heteroatoms such as nitrogen, oxygen or sulfur, which can be It is a monocyclic or bicyclic group.
  • the number of heteroatoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or sulfur atoms in the heterocycloalkyl group can be optionally oxidized.
  • the hydrogen atoms on the "heterocycloalkyl” are independently optionally substituted with one or more substituents described herein.
  • Heterocycloalkyl can be attached to the parent molecule through any ring atom in the ring.
  • 3-7 membered heterocycloalkyl refers to a monocyclic heterocycloalkyl group containing 3-7 carbon atoms and heteroatoms; for example, aziridinyl, azetidinyl, oxetanyl, pyrrole Alkyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.
  • 5-6 membered heterocycloalkyl refers to a monocyclic heterocycloalkyl group containing 5-6 carbon atoms and heteroatoms; for example, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, morpholine thiomorpholinyl, tetrahydropyranyl, 1,1-dioxothiomorpholinyl.
  • aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic (a fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated ⁇ -electron system, preferably 6 to 10 membered , such as phenyl and naphthyl.
  • the aryl ring includes an aryl ring as described above fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein 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, they may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, haloalkane one of radical, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxyl, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl or multiple substituents.
  • heteroaryl refers to a heteroaromatic system comprising 1 to 4 (eg 1, 2, 3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen.
  • Heteroaryl is preferably 5 to 10 membered (eg 5, 6, 7, 8, 9 or 10 membered), more preferably 5 or 6 membered, eg furyl, thienyl, pyridyl, pyrrolyl, N-alkyl Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc.
  • the heteroaryl ring includes a heteroaryl as described above fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include :
  • Heteroaryl may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably the substituents are independently optionally selected from halogen, alkyl, alkoxy, One of haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl or multiple substituents.
  • amino alone or in combination denotes a primary (-NH 2 ), secondary (-NH-) or tertiary amino group
  • halogen alone or in combination denotes fluorine, chlorine, bromine or iodine. Especially fluorine, chlorine or bromine.
  • cyano alone or in combination refers to the group -CN.
  • hydroxy alone or in combination refers to the group -OH.
  • 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. For example, an amino or hydroxyl group with free hydrogen may be unstable when bonded to a carbon atom with an unsaturated (eg, ethylenic) bond.
  • the bond configuration is not specified, i.e. the key can be or both and Two configurations.
  • key represents a single configuration, for or
  • the bond If the configuration is not specified, it can be Z configuration or E configuration, or both configurations.
  • stereoisomer refers to compounds that have the same chemical structure, but differ in the way the atoms or groups are arranged in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric (cis/trans) isomers, atropisomers, and the like.
  • isotopically derivative refers to compounds that differ in structure only by the presence of one or more isotopically enriched atoms.
  • hydrogen is replaced by "deuterium” or “tritium”
  • fluorine is replaced by 18 F-fluorine label ( 18 F isotope), or 11 C-, 13 C-, or 14 C-enriched
  • carbon 11 C-, 13 C-, or 14 C-carbon labels; 11 C-, 13 C-, or 14 C-isotopes
  • Such compounds are useful, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies.
  • the various deuterated forms of the compounds of the present disclosure mean that 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.
  • deuterated starting materials can be used in the preparation of deuterated forms of the compounds, or they can be synthesized using conventional techniques using deuterated reagents including but not limited to deuterated borane, trideuterioborane in tetrahydrofuran , deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.
  • Deuterated compounds generally retain comparable activity to undeuterated compounds, and can achieve better metabolic stability when deuterated at certain sites, thereby gaining certain therapeutic advantages.
  • pharmaceutically acceptable salt means that the compounds of the present invention exist in the form of their pharmaceutically acceptable salts, including acid addition salts and base addition salts.
  • Pharmaceutically acceptable salts are described in pharmaceutically salts by SM Berge in J. Pharmaceutical Sciences (Vol. 66: 1-19, 1977).
  • the pharmaceutically acceptable non-toxic acid addition salt means the salt formed by the compound in the present invention and organic or inorganic acid
  • organic or inorganic acid includes but not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydrogen iodide Acid, phosphoric acid, nitric acid, perchloric acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc.
  • Non-toxic base addition salts refer to salts formed by the compounds of the present invention with organic or inorganic bases, including but not limited to alkali metal salts such as lithium, sodium or potassium salts; alkaline earth metal salts such as calcium or magnesium salts; organic base salts, such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed by organic bases containing N groups.
  • alkali metal salts such as lithium, sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • organic base salts such as ammonium salts or N + (C 1-6 alkyl) 4 salts formed by organic bases containing N groups.
  • solvate refers to a physical association of a compound of the present disclosure with one or more, preferably 1-3, solvent molecules, whether organic or inorganic. This physical association includes hydrogen bonding. In some cases, for example, when one or more, preferably 1-3, solvent molecules are incorporated in the crystal lattice of a crystalline solid, solvates will be isolated. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.
  • prodrug refers to a compound that can be transformed in vivo under physiological conditions, for example by hydrolysis in blood, to yield the active prodrug.
  • pharmaceutical composition means a mixture containing one or more compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiologically/pharmaceutically acceptable Carriers and Excipients.
  • 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.
  • Oxalyl chloride oxalyl chloride
  • PBS Phosphate Buffered Saline
  • the chromatographic column is filled with silica gel.
  • the silica gel 300-400 mesh
  • the preparative chromatographic plate is produced by Yantai Jiangyou Silica Gel Development Co., Ltd.
  • the chromatographic column used by ISCO is produced by Changzhou Santai Technology Co., Ltd.
  • the LC-MS liquid mass spectrometry chromatograph uses ACQUITY Arc from Waters Company equipped with QDa Detector. A Waters XBridge C18 chromatographic column (specification 2.1 ⁇ 50mm, 3.5 ⁇ m) was used. Mass Spectrometry (MS) using an ESI source indicates only the molecular weight M of the parent molecule, usually reported as [M+H] + .
  • the injection volume was determined by the sample concentration; the flow rate was: 1.2 mL/min; the HPLC peaks were recorded and read by UV-Vis wavelengths at 220 nm and 254 nm.
  • the mobile phases were 0.01% formic acid in ultrapure water (mobile phase A) and 0.01% formic acid in acetonitrile (mobile phase B). Gradient elution conditions are shown in Table 1 and Table 2 below:
  • the NMR spectrum is obtained using a Varian 400MHz nuclear magnetic resonance spectrometer , usually using CDCl 3 and DMSO-d 6 as solvents, and reporting chemical shifts in ppm.
  • the various peaks are described as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz.
  • Example 1 Intermediate A ((1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid ethyl ester) and intermediate B ((1R,2R)-2- Preparation of (4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid ethyl ester))
  • Step 1 Preparation of ethyl (2E)-3-(4-bromo-3-fluorophenyl)prop-2-enoate (compound A-2)
  • Step 2 Preparation of ethyl trans-(1S,2S)/(1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylate (Compound A-3)
  • Step 3 Preparation of trans-(1S,2S)/(1R,2R)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid (compound A-4)
  • Step 4 trans-(1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid (Intermediate A) and trans-(1R,2R)-2- Preparation of (4-bromo-3-fluorophenyl)cyclopropane-1-carboxylic acid (Intermediate B)
  • Step 5 Preparation of ethyl (1S,2S)-2-(4-bromo-3-fluorophenyl)cyclopropane-1-carboxylate (Intermediate A)
  • Step 1 Preparation of (R)-(1-phenylethyl)glycine ethyl ester (compound C-3)
  • Step 2 Preparation of (R)-N-(1-phenylethyl)-N-(2,2,2-trifluoroacetyl)glycine ethyl ester (compound C-4)
  • Step 3 Preparation of (R)-N-(1-phenylethyl)-N-(2,2,2-trifluoroacetyl)glycine (compound C-5)
  • Step 4 (R)-1-methyl-2-(2,2,2-trifluoroacetyl)-2,3-dihydroisoquinolin-4(1H)-one (C-6) preparation
  • reaction solution was added to ice water to quench, diluted with ethyl acetate (300 mL), washed with water (100 mL) and saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was The product was purified by column chromatography to obtain brown oil (R)-1-methyl-2-(2,2,2-trifluoroacetyl)-2,3-dihydroisoquinoline-4(1H)- Ketone (compound C-6, 1.7 g).
  • Step 7 Isolation of (1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (Intermediate C and Intermediate D)
  • the liquid phase conditions are: Waters HPLC-ACQUITY Arc equipped with 2998PDA detector; Shield RP 18 3.5um, 4.6*150mm column.
  • Step 3 Preparation of ethyl 2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carboxylate (compound 3-5)
  • Step 4 Preparation of 2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazolo[1,5-a]pyrimidine-5-carboxylic acid (compound 3-6)
  • Step 5 (S)-7-cyclopropyl-2-(2-fluoro-4-(3-(methoxycarbonyl)pyrrolidin-1-yl)phenyl)pyrazolo[1,5- a] Preparation of pyrimidine-5-carboxylic acid (compound 3-7)
  • Step 6 (S)-1-(4-(7-cyclopropyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydro Preparation of isoquinoline-2-carbonyl)pyrazol[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)pyrrolidine-3-carboxylic acid methyl ester (compound 3-9)
  • Step 7 (S)-1-(4-(7-cyclopropyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydro Preparation of isoquinoline-2-carbonyl)pyrazol[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)pyrrolidine-3-carboxylic acid (compound 1)
  • Step 1 Preparation of ethyl 4-cyclopropyl-2-hydroxy-4-oxobutyl-2-enoate (compound E-3)
  • Step 2 Preparation of ethyl 2-bromo-7-cyclopropylpyrazol[1,5-a]pyrimidine-5-carboxylate (compound E-5)
  • Step 1 (2-Bromo-7-cyclopropylpyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1-methyl-3,4 -Preparation of dihydroisoquinoline-2(1H)-yl)methanone (compound 6-2)
  • reaction solution was added to water (50 mL), diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by column chromatography to obtain brown oil compound (2-bromo-7-cyclopropylpyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4- Fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 6-2, 550 mg).
  • Step 2 (7-cyclopropyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl)pyrazol[1,5-a ]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 6-3) preparation of
  • compound 6-2 (300mg, 0.70mmol), pinacol diboronate (213mg, 0.84mmol), potassium acetate (206mg, 2.10mmol) in 1,4-dioxane solution (5mL) [1,1'-Bis(diphenylphosphino)ferrocene]palladium dichloride (51 mg, 0.07 mmol) was added. The mixture was heated to 85°C and stirred for 3 hours.
  • Step 3 (1S,2S)-2-(4-(7-cyclopropyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4- Synthesis of ethyl tetrahydroisoquinoline-2-carbonyl)pyrazol[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)cyclopropane-1-carboxylate (compound 6-4)
  • compound 6-3 250 mg, 0.52 mmol
  • (1S, 2S)-2-(4-bromo-3-fluorophenyl) cyclopropane-1-carboxylic acid ethyl ester (Intermediate A) ( 166mg, 0.58mmol), potassium carbonate (218mg, 1.57mmol) in 1,4-dioxane solution (5mL) and water (1mL) were added [1,1'-bis(diphenylphosphino) di Ferrocene]palladium dichloride (40 mg, 0.05 mmol). The mixture was heated to 100°C and stirred for 3 hours.
  • Step 4 (1S,2S)-2-(4-(7-cyclopropyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4- Preparation of tetrahydroisoquinoline-2-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)cyclopropane-1-carboxylic acid (compound 2)
  • Example 8 (1S,2S)-2-(4-(7-cyclopropyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4- Preparation of tetrahydroisoquinoline-2-carbonyl)pyrazol[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)cyclopropane-1-carboxamide (Compound 4)
  • the mixture was stirred at 25°C for 2 hours.
  • the reaction solution was added to water (50 mL), diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • Example 9 (7-cyclopropyl-2-(4-((3R,4R/4S)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)pyrazol[1, Preparation of 5-a]pyrimidin-5-yl)((1R)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5)
  • Step 1 (2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4- Preparation of fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 9-1)
  • reaction solution was added to water (50 mL), diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product.
  • the crude product was purified by column chromatography to obtain yellow solid (2-(4-bromo-2-fluorophenyl)-7-cyclopropylpyrazol[1,5-a]pyrimidin-5-yl)((1R ,4R/4S)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 9-1, 300mg).
  • Step 2 (7-cyclopropyl-2-(4-((3R,4R)-3,4-dihydroxypyrrolidin-1-yl)-2-fluorophenyl)pyrazol[1,5- a] pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 5) preparation
  • Example 12 (1S,2S)-2-(4-(7-cyclopropyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4- Preparation of tetrahydroisoquinoline-2-carbonyl)pyrazol[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)-N-methylcyclopropane-1-carboxamide (Compound 8)
  • Example 14 (3S)-1-(4-(7-cyclopropyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydro Preparation of isoquinoline-2-carbonyl)pyrazol[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)pyrrolidine-3-carbonitrile (compound 10)
  • Step 1 Preparation of methyl 7-(azetidin-1-yl)-2-bromopyrazolo[1,5-a]pyrimidine-5-carboxylate (compound 14-2)
  • Step 2 Preparation of (7-(azetidin-1-yl)-2-bromopyrazolo[1,5-a]pyrimidine-5-carboxylic acid (14-3)
  • Step 3 (7-(azetidin-1-yl)-2-bromopyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro- Preparation of 1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 14-4)
  • Step 4 (7-(azetidin-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl) Pyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl) Preparation of Methanone (Compound 14-5)
  • Step 6 (1S,2S)-2-(4-(7-(azetidin-1-yl)-5-((1R,4R/4S)-4-fluoro-1-methyl- 1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrazolyl[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)cyclopropane-1-carboxylic acid (compound 11)
  • Step 2 (3S)-1-(4-(7-(azetidin-1-yl)-5-((1R,4R/4S)-4-fluoro-1-methyl-1, 2,3,4-tetrahydroisoquinoline-2-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)pyrrolidine-3-carboxylic acid (compound 12) preparation of
  • Step 2 ((1R,4R/4S)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(2-(4,4,5,5 -Tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-7-(thiazol-2-yl)pyrazol[1,5-a]pyrimidin-5-yl)methanone (compound 16 -3)
  • compound 16 -3 ((1R,4R/4S)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)(2-(4,4,5,5 -Tetramethyl-1,3,2-dioxybenzaldehyde-2-yl)-7-(thiazol-2-yl)pyrazol[1,5-a]pyrimidin-5-yl)methanone
  • Step 3 Preparation of (1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetra Hydroisoquinoline-2-carbonyl)-7-(thiazol-2-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 16- 4) Synthesis of
  • Step 4 Preparation of (1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetra Preparation of Hydroisoquinoline-2-carbonyl)-7-(thiazol-2-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid (compound 13)
  • Step 1 Preparation of ethyl 2,4-dioxy-4-(pyridin-2-yl)butanoate (compound 17-2)
  • Step 2 ethyl 2-(4-bromo-2-fluorophenyl)-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (compound 17-4 ) preparation
  • Step 3 2-(4-bromo-2-fluorophenyl)-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid potassium salt (compound 17-5 ) preparation
  • Step 4 (2-(4-bromo-2-fluorophenyl)-7-(pyridin-2-yl)pyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S )-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 17-6)
  • HATU 120 mg, 0.32 mmol
  • potassium 2-(4-bromo-2-fluorophenyl)-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylate salt 95mg, 0.21mmol
  • (1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline 38mg, 0.23mmol
  • DIPEA 82mg, 0.63 mmol
  • Step 5 (S)-1-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquine Phenyl-2-carbonyl)-7-(pyridin-2-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid methyl ester (compound 17-7) preparation of
  • reaction mixture was stirred at 100 °C for 5 h.
  • the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc and filtered.
  • the filtrate was washed with brine, dried over anhydrous Na2SO4 , filtered and evaporated to dryness .
  • Step 6 (3S)-1-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquine Preparation of phylloline-2-carbonyl)-7-(pyridin-2-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-3-carboxylic acid (compound 14)
  • Lithium hydroxide monohydrate (9mg, 0.22mmol) was added to methyl(S)-1-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl -1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(pyridin-2-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)pyrrolidine-
  • 3-carboxylate 27 mg, 0.04 mmol
  • THF 1 mL
  • H2O 0.3 mL
  • Step 1 Preparation of methyl 2-bromo-7-hydroxypyrazol[1,5-a]pyrimidine-5-carboxylate (compound 18-3)
  • Step 2 Preparation of methyl 2-bromo-7-chloropyrazolo[1,5-a]pyrimidine-5-carboxylate (compound 18-4)
  • Step 3 Preparation of methyl 2-bromo-7-(pyrrolidin-1-yl)pyrazol[1,5-a]pyrimidine-5-carboxylate (compound 18-5)
  • Step 4 Preparation of 2-bromo-7-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid potassium salt (compound 18-6)
  • Step 5 ((2-bromo-7-(pyrrolidin-1-yl)pyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1- Preparation of methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 18-7)
  • HATU 230 mg, 0.61 mmol
  • 2-bromo-7-(pyrrolidin-1-yl)pyrazol[1,5-a]pyrimidine-5-carboxylic acid potassium salt 141 mg, 0.40 mmol
  • (1R ,,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline 100 mg, 0.61 mmol
  • DIPEA 157 mg, 1.21 mmol
  • Step 6 (5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(pyrrolidine- Preparation of 1-yl)pyrazol[1,5-a]pyrimidin-2-yl)boronic acid (compound 18-8)
  • Step 7 1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroiso Quinoline-2-carbonyl)-7-(pyrrolidin-1-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylate (compound 18-9) preparation of
  • reaction mixture was stirred at 100 °C for 3 h.
  • the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc and filtered.
  • the filtrate was washed with brine, dried over anhydrous Na2SO4 , filtered and evaporated to dryness .
  • Step 8 (1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydro
  • Lithium hydroxide monohydrate (29mg, 0.70mmol) was added to ethyl(1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1- Methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(pyrrolidin-1-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)
  • a solution of cyclopropane-1-carboxylate 80 mg, 0.14 mmol
  • THF 2 mL
  • H2O 0.3 mL
  • Step 1 Preparation of ethyl 2,4-dioxy-4-(pyridin-2-yl)butanoate (compound 19-2)
  • Step 2 Preparation of ethyl 2-bromo-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylate (compound 19-4)
  • Step 3 Preparation of 2-bromo-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid potassium salt (compound 19-5)
  • Step 4 (2-Bromo-7-(pyridin-2-yl)pyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1-methyl Preparation of -3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 19-6)
  • HATU (192 mg, 0.50 mmol) was added to 2-bromo-7-(pyridin-2-yl)pyrazolo[1,5-a]pyrimidine-5-carboxylic acid potassium salt (120 mg, 0.34 mmol), (1R )-a mixture of 4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline (83 mg, 0.50 mmol) and DIPEA (130 mg, 1.01 mmol) in DMF (2 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was poured into water and the aqueous phase was extracted with EtOAc.
  • Step 5 (5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(pyridine-2 Preparation of -yl)pyrazol[1,5-a]pyrimidin-2-yl)boronic acid (compound 19-7)
  • Step 6 (1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)-7-(pyridin-2-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid ethyl ester (compound 19-8 ) preparation
  • reaction mixture was stirred at 100 °C for 3 h.
  • the reaction mixture was poured into water and the aqueous phase was extracted with EtOAc and filtered.
  • the filtrate was washed with brine, dried over anhydrous Na2SO4 , filtered and evaporated to dryness .
  • Step 7 (1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydro
  • Lithium hydroxide monohydrate (21 mg, 0.51 mmol) was added to ethyl(1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1- Methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)-7-(pyridin-2-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl) ring
  • propane-1-carboxylate 60 mg, 0.10 mmol
  • THF 1 mL
  • H2O 0.3 mL
  • Step 1 Preparation of ethyl 4-cyclobutyl-2,4-dioxobutyrate (compound 20-2)
  • Step 2 Preparation of ethyl 2-bromo-7-cyclobutylpyrazolo[1,5-a]pyrimidine-5-carboxylate (compound 20-3)
  • Step 4 (2-bromo-7-cyclobutylpyrazolo[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1-methyl-3, Preparation of 4-dihydroisoquinolin-2(1H)-yl)methanone (compound 20-5)
  • Step 5 (7-cyclobutyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)pyridine
  • Azolo[1,5-a]pyrimidin-2-yl)boronic acid (Compound 20-6)
  • Step 6 (1S,2S)-2-(4-(7-cyclobutyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4- Preparation of ethyl tetrahydroisoquinoline-2-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)cyclopropane-1-carboxylate (compound 20-7)
  • Step 7 ((1S,2S)-2-(4-(7-cyclobutyl-5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4 - Preparation of tetrahydroisoquinoline-2-carbonyl)pyrazolo[1,5-a]pyrimidin-2-yl)-3-fluorophenyl)cyclopropane-1-carboxylic acid (compound 17)
  • Step 1 Preparation of methyl 2-bromo-7-(1H-pyrazol-1-yl)pyrazol[1,5-a]pyrimidine-5-carboxylate (compound 21-1)
  • Step 2 Preparation of lithium salt of 2-bromo-7-(1H-pyrazol-1-yl)pyrazol[1,5-a]pyrimidine-5-carboxylate (21-2)
  • Step 3 (2-bromo-7-(1H-pyrazol-1-yl)pyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1 Synthesis of -methyl-3,4-dihydroisoquinolin-2(1H)-yl)methanone (compound 21-3)
  • Step 4 ((7-(1H-pyrazol-1-yl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxobenzofuran-2-yl) Pyrazol[1,5-a]pyrimidin-5-yl)((1R,4R/4S)-4-fluoro-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl) Preparation of methyl ketone (compound 21-4)
  • Step 6 (1S,2S)-2-(3-fluoro-4-(5-((1R,4R/4S)-4-fluoro-1-methyl-1,2,3,4-tetrahydro Isoquinoline-2-carbonyl)-7-(1H-pyrazol-1-yl)pyrazol[1,5-a]pyrimidin-2-yl)phenyl)cyclopropane-1-carboxylic acid (compound 18) preparation of

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Abstract

L'invention concerne un composé anti-VRS tel que représenté dans la formule (I), et son procédé de préparation ainsi qu'une application de celui-ci. Le composé représenté dans la formule (I) a une activité inhibitrice très élevée sur le VRS, a une excellente efficacité, d'excellentes propriétés pharmacocinétiques in vitro/in vivo et une excellente sécurité, et a de grandes perspectives pour une application clinique.
PCT/CN2022/143565 2021-12-30 2022-12-29 Composé bicyclique hétéroaromatique et son application antivirale WO2023125845A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011163518A1 (fr) * 2010-06-24 2011-12-29 Gilead Sciences, Inc. Pyrazolo[1,5-a]pyrimidines en tant qu'agents antiviraux
WO2017196970A1 (fr) * 2016-05-10 2017-11-16 Georgia State University Research Foundation, Inc. Dérivés hétérocycliques pour le traitement de rsv
CN107531715A (zh) * 2015-04-28 2018-01-02 爱尔兰詹森科学公司 Rsv抗病毒吡唑并‑以及三唑并‑嘧啶化合物
WO2021147947A1 (fr) * 2020-01-22 2021-07-29 苏州爱科百发生物医药技术有限公司 Synthèse et utilisation d'une classe d'inhibiteurs du virus respiratoire syncytial

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011163518A1 (fr) * 2010-06-24 2011-12-29 Gilead Sciences, Inc. Pyrazolo[1,5-a]pyrimidines en tant qu'agents antiviraux
CN107531715A (zh) * 2015-04-28 2018-01-02 爱尔兰詹森科学公司 Rsv抗病毒吡唑并‑以及三唑并‑嘧啶化合物
WO2017196970A1 (fr) * 2016-05-10 2017-11-16 Georgia State University Research Foundation, Inc. Dérivés hétérocycliques pour le traitement de rsv
WO2021147947A1 (fr) * 2020-01-22 2021-07-29 苏州爱科百发生物医药技术有限公司 Synthèse et utilisation d'une classe d'inhibiteurs du virus respiratoire syncytial

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