WO2023088493A1 - Composé furopyridone et utilisation associée - Google Patents

Composé furopyridone et utilisation associée Download PDF

Info

Publication number
WO2023088493A1
WO2023088493A1 PCT/CN2022/142283 CN2022142283W WO2023088493A1 WO 2023088493 A1 WO2023088493 A1 WO 2023088493A1 CN 2022142283 W CN2022142283 W CN 2022142283W WO 2023088493 A1 WO2023088493 A1 WO 2023088493A1
Authority
WO
WIPO (PCT)
Prior art keywords
phenyl
methyl
pyridin
difluorophenoxy
dihydrofuro
Prior art date
Application number
PCT/CN2022/142283
Other languages
English (en)
Chinese (zh)
Inventor
许�永
李俊骅
张岩
张�成
庄晓曦
Original Assignee
中国科学院广州生物医药与健康研究院
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 中国科学院广州生物医药与健康研究院 filed Critical 中国科学院广州生物医药与健康研究院
Publication of WO2023088493A1 publication Critical patent/WO2023088493A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4355—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/16—Masculine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/64—One oxygen atom attached in position 2 or 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the application belongs to the technical field of compound synthesis, and relates to a furopyridone compound and its application, in particular to a furopyridone compound as a bromodomain inhibitor and its application.
  • Epigenetic regulation mainly includes DNA chemical modification (such as methylation of cytosine) and histone modification (such as acetylation, methylation, phosphorylation and ubiquitination). These epigenetic regulatory modes collectively determine the activation and silencing of genes in response to physiological processes and external environmental stimuli.
  • the acetylation of histones especially the acetylation of lysine, is regarded as a sign of gene transcription activation, which plays an important role in normal life processes and diseases.
  • Bromodomains (BRDs) are readers that specifically recognize lysine acetylation sites, mediate signal transduction and regulate gene networks by forming transcriptional complexes.
  • bromodomains are found in 46 proteins in the human body.
  • the BET (bromodomain and extra-terminal domain) family includes BRD2, BRD3, BRD4 and BRDT. Structurally, they all have two tandem BD bromodomains and an outer terminal domain (ET). Numbering from the N-terminus of BET family proteins, the tandem BD bromodomains are usually labeled bromodomain 1 (BD1) and bromodomain 2 (BD2).
  • BET family proteins participate in many DNA-centered life processes by recruiting transcriptional regulatory complexes to acetylated histones. When BET family protein dysfunction occurs, it leads to the occurrence of various human diseases. Studies have confirmed that drugs targeting the bromodomain of BET can be used to treat diseases such as cancer, inflammation, diabetes, cardiovascular disease, and anti-male fertility. At the same time, studies have found that the BD1 and BD2 bromodomains of the BET family can play different transcriptional regulatory functions by recognizing different acetylated lysines. The development of selective BET family BD1 or BD2 inhibitors will help to further understand the respective functions of the tandem bromodomains, and may help reduce the toxic side effects during drug treatment.
  • the application provides a furopyridone compound and its application, especially a furopyridone compound as a bromodomain inhibitor and its application.
  • This application takes BET protein as the target, and develops a novel furopyridone compound, which can selectively inhibit the binding of BET family bromodomain and acetylated lysine. It is used to treat BET-related diseases such as cancer and inflammation.
  • the application provides a furopyridone compound
  • the furopyridone compound has the structure shown in the following formula I:
  • R 1 is C1 ⁇ C4 alkyl or deuterated C1 ⁇ C4 alkyl
  • R 2 is selected from C1 ⁇ C6 alkoxy, -(R a ) 2 OH, -(R b ) 2 OCR c , -CH 2 S(O) 2 R d , -NHS(O) 2 R e , -NHC (O)R f or -S(O) 2 NR g R h ;
  • R a , R b , R c , R d , R e , R f , R g and Rh are each independently selected from H, C1-C10 alkyl;
  • R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;
  • R 8 is selected from unsubstituted or substituted C6-C15 aryl, unsubstituted or substituted C3-C15 heteroaryl by R j ;
  • the R i is selected from hydrogen, C1 ⁇ C10 alkyl, C1 ⁇ C10 alkoxy or -O(C1 ⁇ C5 alkyl)OH;
  • the R j and R k are independently selected from hydrogen, C1 ⁇ C10 alkyl, C1 ⁇ C6 cycloalkyl, C1 ⁇ C10 alkoxy, oxygen-containing 5 or 6-membered saturated ring, sulfur-containing 5- or 6-membered saturated ring Or a nitrogen-containing 5- or 6-membered saturated ring.
  • the C1-C4 alkyl group may be C1, C2, C3 or C4 alkyl group, which may be a straight-chain alkyl group or a branched-chain alkyl group, such as methyl, ethyl, normal Propyl, n-butyl, isopropyl, etc.
  • the same C1 ⁇ C10 alkyl group can be C1, C2, C3, C4, C5, C6, C7, C8, C9 or C10 alkyl group
  • the same C1 ⁇ C6 alkyl group can be C1, C2, C3, C4 , C5 or C6 alkyl.
  • the C1-C6 alkoxy group may be C1, C2, C3, C4, C5 or C6 alkoxy group, such as methoxy, ethoxy, butoxy or hexyloxy, etc. .
  • the C6-C15 aryl group can be C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 aryl group
  • the C3-C15 heteroaryl group can be C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14 or C15 heteroaryl.
  • the heteroatom in the heteroaryl group is preferably at least one of oxygen, nitrogen, and sulfur atoms; the heteroatom in the heterocycloalkyl group is preferably at least one of oxygen, nitrogen, and sulfur atoms.
  • said R 8 is unsubstituted or substituted by R i phenyl, unsubstituted or substituted by R j C3-C8 nitrogen-containing heteroaryl.
  • the furopyridone compound has the structure shown in formula II;
  • R 1 is C1 ⁇ C4 alkyl or deuterated C1 ⁇ C4 alkyl
  • R 2 is selected from C1 ⁇ C6 alkoxy, -(R a ) 2 OH, -(R b ) 2 OCR c , -CH 2 S(O) 2 R d , -NHS(O) 2 R e , -NHC (O)R f or -S(O) 2 NR g R h ;
  • R a , R b , R c , R d , R e , R f , R g and Rh are each independently selected from H, C1-C10 alkyl;
  • R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;
  • R 9 , R 10 , R 11 , R 12 and R 13 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy or -O(C1-C6 alkyl)OH.
  • the furopyridone compound has the structure shown in formula III:
  • R 1 is C1 ⁇ C4 alkyl or deuterated C1 ⁇ C4 alkyl
  • R 2 is selected from C1 ⁇ C6 alkoxy, -(R a ) 2 OH, -(R b ) 2 OCR c , -CH 2 S(O) 2 R d , -NHS(O) 2 R e , -NHC (O)R f or -S(O) 2 NR g R h ;
  • R a , R b , R c , R d , R e , R f , R g and Rh are each independently selected from H, C1-C10 alkyl;
  • R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;
  • R 13 is selected from hydrogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 cycloalkyl, C1 ⁇ C6 alkoxy or a 5- or 6-membered saturated ring containing heteroatoms, and the heteroatoms are oxygen, nitrogen, sulfur atoms at least one.
  • the furopyridone compound has the structure shown in formula IV:
  • R 2 is selected from -(R a ) 2 OH, -(R b ) 2 OCR c , -CH 2 S(O) 2 R d , -NHS(O) 2 R e , -NHC(O)R f or -S(O) 2 NR g R h ;
  • R a , R b , R c , R d , R e , R f , R g and Rh are each independently selected from H, C1-C6 alkyl;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;
  • the R 10 , R 11 and R 12 are each independently selected from hydrogen, C1-C6 alkyl, C1-C6 alkoxy, and -O(C1-C5 alkyl)OH.
  • the furopyridone compound has the structure shown in formula V:
  • R 2 is selected from -(R a ) 2 OH, -(R b ) 2 OCR c , -CH 2 S(O) 2 R d , -NHS(O) 2 R e , -NHC(O)R f or -S(O) 2 NR g R h ;
  • R a , R b , R c , R d , R e , R f , R g and Rh are each independently selected from H, C1-C6 alkyl;
  • R 3 , R 4 and R 5 are each independently selected from H, halogen, C1-C6 alkyl, C1-C6 alkoxy;
  • R 13 is selected from hydrogen, C1-C6 alkyl, C1-C6 cycloalkyl or oxygen-containing 5- or 6-membered saturated ring.
  • said R is selected from
  • the R is selected from
  • R3 , R4 , R5 , R6 and R7 are each independently selected from H, F, methyl, ethyl, methoxy, ethoxy or butoxy.
  • the furopyridone compound described in the present application is any one of the following compounds:
  • the present application provides a pharmaceutically acceptable salt of the above-mentioned furopyridone compound.
  • the pharmaceutically acceptable salt is a salt of a basic compound prepared by reacting the furopyridone compound with an appropriate inorganic or organic acid in an appropriate solvent or a combination of multiple solvents.
  • salts of acidic compounds are formed by reaction with an appropriate inorganic or organic base.
  • the pharmaceutically acceptable salt of the compound of the present application includes the compound obtained by the compound of the present application and inorganic acid (such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid) or organic acid (such as acetic acid, propionic acid, succinic acid) , glycolic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanil Acid, 2-acetoxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid) the conventional no poisonous salt.
  • inorganic acid such as hydrochloric acid, hydrobro
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 are defined by the compound of formula (I);
  • X is selected from -B(OH) 2 , pinacol boronic acid ester or neopentyl glycol borate.
  • Step a The raw material 1 can be reacted under reflux at a suitable temperature such as 130° C. for a suitable period of time such as 7 hours in the presence of Ac 2 O.
  • Step b In the presence of a suitable base such as Cs 2 CO 3 , K 2 CO 3 or NaH, in a suitable solvent such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), In tetrahydrofuran (THF), react for a period of time (for example, 2-5 hours or overnight) at a suitable temperature such as ice bath or room temperature.
  • a suitable base such as Cs 2 CO 3 , K 2 CO 3 or NaH
  • a suitable solvent such as N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), In tetrahydrofuran (THF)
  • Step c Add N - iodosuccinimide ( NIS ) or I 2 Treat for a period of time (eg 2-5 hours or overnight).
  • Step d In the presence of a suitable palladium catalyst such as PdCl 2 (dppf) CH 2 Cl 2 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4 Next, add a suitable phosphine ligand such as BINAP, and a suitable base such as Cs 2 CO 3 , K 2 CO 3 or K 3 PO 4 , in a suitable solvent such as THF, dioxane, toluene, and a suitable The temperature is such as 40-80° C., and the reaction is performed for a period of time, such as 5 hours or overnight.
  • a suitable palladium catalyst such as PdCl 2 (dppf) CH 2 Cl 2 , PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4
  • Step e first carry out step e-1, and when there is a protecting group, carry out step e-2 or e-3 after completing step e-1:
  • Step e-1 in a suitable palladium catalyst such as PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4 , and an additional catalyst such as cuprous iodide, and In the presence of a suitable base such as diethylamine, triethylamine or K2CO3 , in a suitable solvent such as THF, dioxane or DMF , at a suitable temperature such as 80-90 ° C, react for a period of time such as 5-7 days.
  • a suitable palladium catalyst such as PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4
  • an additional catalyst such as cuprous iodide
  • Step e-2 when there is a silyl ether protecting group: after completing reaction e-1, add TBAF, Cs 2 CO 3 , K 2 CO 3 in DMF, DMSO, THF or dioxane solvent, and A suitable temperature is room temperature, and the reaction is carried out for a period of time, such as 3-6 hours or overnight.
  • Step e-3 when there is an acetyl protecting group: after the e-1 reaction is completed, the aqueous solution of KOH, NaOH, Cs 2 CO 3 , K 2 CO 3 can be added in DMSO, DMF, MeOH, THF solvent, in A suitable temperature is room temperature, for a period of time such as 4-6 hours.
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are defined by the compound of formula (I).
  • Step a In a suitable palladium catalyst such as PdCl 2 (PPh 3 ) 2 , Pd 2 (dba) 3 , Pd(OAc) 2 or Pd(PPh 3 ) 4 , and an additional catalyst such as cuprous iodide, and in a suitable In the presence of a base such as diethylamine, triethylamine or K2CO3 , in a suitable solvent such as THF, dioxane or DMF , at a suitable temperature such as 80-90 ° C, react for a period of time such as overnight .
  • a base such as diethylamine, triethylamine or K2CO3
  • a suitable solvent such as THF, dioxane or DMF
  • Step b first carry out step b-1, and when there is a protecting group, carry out step b-2 or b-3 after completing step b-1:
  • Step b-1 In a suitable solvent such as CH 3 CN or DMF, in the presence of a suitable base such as diethylamine or triethylamine, at a suitable temperature such as 60-90°C, react for a period of time such as 5- 7 days.
  • a suitable solvent such as CH 3 CN or DMF
  • a suitable base such as diethylamine or triethylamine
  • Step b-2 when there is a silyl ether protecting group: after completing the reaction b-1, you can add TBAF, Cs 2 CO 3 , K 2 CO 3 in DMF, DMSO, THF or dioxane solvent, in A suitable temperature is room temperature, and the reaction is carried out for a period of time, such as 3-6 hours or overnight.
  • Step b-3 when there is an acetyl protecting group: after the b-1 reaction is completed, the aqueous solution of KOH, NaOH, Cs 2 CO 3 , K 2 CO 3 can be added in DMSO, DMF, MeOH, THF solvent, in A suitable temperature is room temperature, for a period of time such as 4-6 hours.
  • the present application provides a bromodomain protein inhibitor, the bromodomain protein inhibitor comprising at least one of the above-mentioned furopyridone compounds.
  • the bromodomain protein inhibitor is an inhibitor that selectively inhibits BET family bromodomain 2 (BD2).
  • BD2 BET family bromodomain 2
  • the present application provides a pharmaceutical composition, the pharmaceutical composition comprising at least one of the above-mentioned furopyridone compounds or a pharmaceutically acceptable compound of the above-mentioned furopyridone compounds. acceptable salts, and at least one pharmaceutically acceptable carrier and/or at least one other therapeutically active agent.
  • the other therapeutically active agents include HDAC inhibitors, CDK6 inhibitors, CDK9 inhibitors, CXCR1/2 inhibitors, PI3K inhibitors, AKT inhibitors, PARP inhibitors, MEK inhibitors, and the like.
  • the medicine prepared by the BET protein inhibitor described in the present application, and the pharmaceutical composition can be applied to various routes of administration, and the typical but non-limiting examples of the route of administration are: oral, buccal, inhalation, sublingual, rectal , vaginal, intracisternal or intrathecal, through lumbar puncture, transurethral, transdermal or parenteral (including intravenous, intramuscular, subcutaneous, intradermal, intraperitoneal, intrathecal, surgical implantation), etc.
  • the pharmaceutical composition described in this application can be prepared by combining the compound of this application with suitable pharmaceutically acceptable auxiliary materials, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules , powder, granule, ointment, emulsion, suspension, suppository, injection, inhalant, gel, microsphere or aerosol, etc.
  • composition described in this application can be produced by methods well known in the art, such as conventional mixing, dissolving, granulating, sugar-coated pills, pulverizing, emulsifying, freeze-drying and the like.
  • compositions for oral administration may be solid, gel or liquid.
  • solid formulations include, but are not limited to, tablets, capsules, granules, and bulk powders. These preparations may optionally contain binders, diluents, disintegrants, lubricants, glidants, sweeteners, flavoring agents and the like.
  • binders include, but are not limited to, microcrystalline cellulose, dextrose solution, acacia mucilage, gelatin solution, sucrose, and starch paste;
  • examples of lubricants include, but are not limited to, talc, starch, magnesium stearate, calcium stearate , stearic acid;
  • examples of diluents include but not limited to lactose, sucrose, starch, mannitol, dicalcium phosphate;
  • examples of glidants include but not limited to silicon dioxide; Sodium carboxymethylcellulose, sodium starch glycolate, alginic acid, corn starch, potato starch, methylcellulose, agar, and carboxymethylcellulose.
  • composition described in this application is administered parenterally, generally by injection, including subcutaneous, intramuscular or intravenous injection.
  • injectables can be prepared in any conventional form, such as liquid solutions or suspensions, solid forms suitable for solution in or suspension in liquid prior to injection, or emulsions.
  • pharmaceutically acceptable carriers that can be used in the injections of this application include but are not limited to aqueous carriers, non-aqueous carriers, antimicrobial agents, isotonic agents, buffers, antioxidants, suspending and dispersing agents, emulsifying agents, chelating agents and other pharmaceutically acceptable substances.
  • aqueous vehicles include Sodium Chloride Injection, Ringer's Injection, Isotonic Dextrose Injection, Sterile Water Injection, Dextrose and Lactated Ringer's Injection;
  • non-aqueous vehicles include fixed oils of vegetable origin, Cottonseed oil, corn oil, sesame oil, and peanut oil;
  • antimicrobial agents include m-cresol, benzyl alcohol, chlorobutanol, and benzalkonium chloride, etc.;
  • isotonic agents include sodium chloride and dextrose; buffers include phosphate and Citrate.
  • the pharmaceutical composition described in the present application can also be prepared as sterile freeze-dried powder injection, the compound is dissolved in sodium phosphate buffer solution, which contains glucose or other suitable excipients, and then the compound is dissolved under standard conditions known to those skilled in the art. Sterile filtration of the solution followed by lyophilization affords the desired formulation.
  • the present application provides the above-mentioned furopyridone compounds or pharmaceutically acceptable salts thereof or the bromodomain protein inhibitor or the pharmaceutical composition in the preparation of diseases mediated by BET proteins Or the application in the medicine of disease.
  • the disease or condition includes but is not limited to cancer, inflammation, autoimmune disease, non-alcoholic fatty liver disease, cardiovascular disease, diabetic pulmonary fibrosis, myelofibrosis or chronic obstructive pulmonary disease.
  • the cancer is selected from solid tumors or hematological tumors.
  • said solid tumor is selected from breast cancer or prostate cancer.
  • the hematological tumor is selected from acute myeloid leukemia, multiple myeloma or diffuse large B-cell lymphoma.
  • the present application provides the above-mentioned furopyridone compounds or pharmaceutically acceptable salts thereof or the bromodomain protein inhibitor or the pharmaceutical composition in the preparation by inhibiting BET protein bromodomain
  • drugs for antiviral, antibacterial or antiparasitic treatment or male contraceptive drugs are used.
  • the furopyridone compounds of the present application can selectively inhibit the binding of BET family bromodomains and acetylated lysine, and can be used as bromodomain inhibitors to treat BET-related diseases such as cancer and inflammation.
  • FIG. 1 is a diagram of the TSA experimental measurement results in the present application.
  • reaction vials were closed with rubber stoppers to allow addition of substrate and reagents by syringe; glassware was heated dry before use .
  • the solvents used for NMR data include CDCl 3 , DMSO-d6, etc., based on tetramethylsilane (0.00ppm) or residual solvent peaks (CDCl 3 : 7.26ppm, DMSO-d6: 2.50ppm).
  • s singlet
  • d doublet
  • t triplet
  • q quartet
  • m multiplet
  • br br
  • dd double doublet
  • dt double triplet
  • td triple doublet
  • the coupling constant given is in Hertz (Hz).
  • Step 2 Synthesis of tert-butyl(2-(4-iodo-2,6-dimethylphenoxy)ethoxy)dimethylsilane
  • Step 3 Synthesis of tert-butyl(2-(2,6-dimethyl4-((trimethylsilyl)ethynyl)phenoxy)ethoxy)dimethylsilane
  • Step 4 Synthesis of tert-butyl(2-(4-ethynyl-2,6-dimethylphenoxy)ethoxy)dimethylsilyl
  • Step 3 4-(2,4-Difluorophenoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline
  • Step 4 5-(5-Amino-2-(2,4-difluorophenoxy)phenyl)-3-iodo-4-methoxy-1-methylpyridin-2(1H)-one
  • Step 5 N-(4-(2,4-difluorophenoxy)-3-(5-iodo-4-methoxy-1-methyl-6-oxo-1,6-dihydropyridine- 3-yl)phenyl)ethylsulfonamide
  • Step 6 N-(3-(2-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3,5-dimethylphenyl)-5-methanol Base-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)-4-(2,4-difluorophenoxy)phenyl)ethylsulfonamide
  • the reactant was pre-dried, sealed and dried to obtain the compound N-(4-(2,4-difluorophenoxy)-3-(5-iodo-4-methoxy-1-methyl-6- Oxygen-1,6-dihydropyridin-3-yl)phenyl)ethylsulfonamide (576.35, 200mg, 0.347mmol, 1eq), CuI (190.45, 15mg, 0.0788mmol, 0.22eq), PdCl 2 (PPh 3 ) 2 (701.9, 28mg, 0.0399mmol, 0.11eq), the oil pump is strictly ventilated.
  • Step 7 N-(4-(2,4-difluorophenoxy)-3-(2-(4-(2-hydroxyethoxy)-3,5-dimethylbenzene)-5-methanol Base-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)phenyl)ethylsulfonamide
  • Example 21 4-(4-fluoro-2,6-dimethylphenoxy)-3-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl) -5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)benzenesulfonamide
  • trimethyl borate (103.91, 17mL, 152.478mmol, 1.2eq, 0.932g/mL) was added by needle, slowly added dropwise to the reaction system, stirred at -78°C for 3h after the dropwise addition, and then warmed to room temperature and stirred for 4h.
  • Step 4 4-(4-Fluoro-2,6-dimethylphenoxy)-3-iodobenzenesulfonamide
  • Step 5 3-(5,5-Dimethyl-1,3,2-dioxaborolan-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy)benzenesulfonate Amide
  • Step 6 4-(4-Fluoro-2,6-dimethylphenoxy)-3-(5-iodo-4-methoxy-1-methyl-6-oxo-1,6-dihydro Pyridin-3-yl)benzenesulfonamide
  • Step 7 3-(2-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3,5-dimethylphenyl)-5-methyl-4 -Oxygen-4,5-dihydrofuro[3,2-c]pyridin-7-yl)-4-(4-fluoro-2,6-dimethylphenoxy)benzenesulfonamide
  • Step 8 4-(4-Fluoro-2,6-dimethylphenoxy)-3-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)- 5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)benzenesulfonamide
  • Step 6 2-(2-(2,4-Difluorophenoxy)-5-((thymphenyl)methyl)phenyl)-5,5-dimethyl-1,3,2-di Oxyborane
  • Step 7 5-(2-(2,4-Difluorophenoxy)-5-((thysulfonyl)methyl)phenyl)-3-iodo-4-methoxy-1-methylpyridine -2(1H)-one
  • the needle was added to the reaction system, the oil bath was refluxed at 60°C for 24 hours, filtered with diatomaceous earth, dissolved in ethyl acetate, extracted with water and saturated NaCl aqueous solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation.
  • Step 8 2-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3,5-dimethylphenyl)-7-(2-(2,4 -Difluorophenoxy)-5-((methylsulfonyl)methyl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Step 9 7-(2-(2,4-Difluorophenoxy)-5-((thymphenyl)methyl)phenyl)-2-(4-(2-hydroxyethoxy)-3 , 5-Dimethylphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Example 24 7-(2-(2,4-difluorophenoxy)-5-((isopropylsulfone)methyl)phenyl)-2-(4-(2-hydroxyethoxy) )-3,5-dimethylphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Example 25 7-(5-((tert-butylsulfone)methyl)-2-(2,4-difluorophenoxy)phenyl)2-(4-(2-hydroxyethoxy) -3,5-Dimethylphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Step 1 ((3-Bromo-4-(2,4-difluorophenoxy)phenyl)oxy)(tert-butyl)dimethylsilane
  • Step 2 tert-butyl((4-(2,4-difluorophenoxy)-3-(5,5-dimethyl-1,3,2-dioxaborolan-2-yl)phenyl )oxy)dimethylsilane
  • Step 3 5-(5-(((tert-Butyldimethylsilyl)oxy)methyl)-2-(2,4-difluorophenoxy)phenyl)-3-iodo-4- Methoxy-1-methylpyridin-2(1H)-one
  • Step 4 2-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3,5-dimethylphenyl)-7-(5-(((tert- Butyldimethylsilyl)oxy)methyl)-2-(2,4-difluorophenoxy)phenyl)-5-methylfuro[3,2-c]pyridine-4(5H) -ketone
  • Step 4 7-(2-(2,4-Difluorophenoxy)-5-(hydroxymethyl)phenyl)-2-(4-(2-hydroxyethoxy)-3,5-di Methylphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Example 27 7-(2-(2,4-difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4-(2-hydroxyethoxy) -3,5-Dimethylphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Step 3 2-(4-(2,4-difluorophenoxy)-3-(5,5-dimethyl-1,3,2-dioxabor-2-yl)phenyl)propane- 2-ol
  • Step 4 5-(2-(2,4-Difluorophenoxy)-5-(2-hydroxypropan-2-olyl)phenyl)-3-iodo-4-methoxy-1-methanol ylpyridin-2(1H)-one
  • Step 5 2-(4-(2,4-Difluorophenoxy)-3-(5-iodo-4-methoxy-1-methyl-6-oxo-1,6-dihydropyridine- 3-yl)phenyl)propan-2-ol acetate
  • Step 6 2-(3-(2-(4-(2-((tert-Butyldimethylsilyl)oxy)ethoxy)-3,5-dimethylphenyl)-5-methoxy Base-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)-4-(2,4-difluorophenoxy)phenyl)propan-2-ol acetic acid ester
  • the reactant was pre-drained, sealed and dried, and the compound 2-(4-(2,4-difluorophenoxy)-3-(5-iodo-4-methoxy-1-methyl-6- Oxy-1,6-dihydropyridin-3-yl)phenyl)propan-2-ol acetate (569.34, 295mg, 0.518mmol, 1eq), CuI (190.45, 19mg, 0.0998mmol, 0.2eq), PdCl 2 (PPh 3 ) 2 (701.9, 36mg, 0.0513mmol, 0.1eq), the oil pump is strictly ventilated.
  • Step 7 2-(4-(2,4-Difluorophenoxy)-3-(2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5- Methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)phenyl)propan-2-ol acetate
  • Step 8 7-(2-(2,4-Difluorophenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(4-(2-hydroxyethoxy)- 3,5-Dimethylphenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Example 28 N-(3-(2-(1H-imidazol-5-yl)-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl )-4-(2,4-difluorophenoxy)phenyl)ethanesulfonamide
  • the reactant was pre-dried, sealed and dried to obtain the compound N-(4-(2,4-difluorophenoxy)-3-(5-iodo-4-methoxy-1-methyl-6- Oxygen-1,6-dihydropyridin-3-yl)phenyl)ethylsulfonamide (576.35, 250mg, 0.434mmol, 1eq), CuI (190.45, 16mg, 0.0840mmol, 0.2eq), PdCl 2 (PPh 3 ) 2 (701.9, 30mg, 0.0427mmol, 0.1eq), the oil pump is strictly ventilated.
  • Methyl magnesium bromide Take the compound methyl-3-bromo-4-(4-fluoro-2,6-dimethylphenoxy)benzoate (353.19, 39.3g, 111mmol, 1eq) in a dry three-necked flask After ventilation, 450 mL of dry THF was added, and after strict ventilation, the temperature was cooled in an ice bath, and finally 3M methylmagnesium bromide (200 mL, 600 mmol, 5.4 eq) was taken, and slowly added to the reaction system through a dropping funnel. Stir in ice bath for 2.5h.
  • Step 3 2-(3-(5,5-Dimethyl-1,3,2-dioxaborolan-2-yl)-4-(4-fluoro-2,6-dimethylphenoxy ) phenyl) propan-2-ol
  • Step 4 5-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-3-iodo-4-methoxy -1-Methylpyridin-2(1H)-one
  • Step 5 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(5-iodo-4-methoxy-1-methyl-6-oxo-1,6 -Dihydropyridin-3-yl)phenyl)propan-2-ylacetate
  • Step 6 2-(3-(2-(2-Ethyl-1H-imidazol-5-yl)-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c]pyridine -7-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-yl acetate
  • Step 7 2-(2-Ethyl-1H-imidazol-5-yl)-7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropane- 2-yl)phenyl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Example 36 2-(4-(4-fluoro-2,6-dimethylphenoxy)-3-(2-(2-isopropyl-1H-imidazol-5-yl)-5-methanol Base-4-oxo-4,5-dihydrofuro[3,2-c]pyridin-7-yl)phenyl)propan-2-yl acetate
  • Example 37 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-2-(2-isopropyl -1H-imidazol-5-yl)-5-methylfuro[3,2-c]pyridin-4(5H)-one
  • Example 38 2-(3-(2-(2-Cyclopropyl-1H-imidazol-5-yl)-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c ]pyridin-7-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-yl acetate
  • Example 41 2-(3-(2-(2-cyclopentyl-1H-imidazol-5-yl)-5-methyl-4-oxo-4,5-dihydrofuro[3,2-c ]pyridin-7-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-yl acetate
  • Example 43 2-(3-(2-(2-cyclohexyl-1H-imidazol-5-yl)-5-methyl-4-oxo-4,5-dihydrofuran[3,2-c] Pyridin-7-yl)-4-(4-fluoro-2,6-dimethylphenoxy)phenyl)propan-2-yl acetate
  • Example 45 2-(4-(4-fluoro-2,6-dimethylphenoxy)-2-(5-methyl-4-oxo-2-(2-(tetrahydrofuran-3-yl) -1H-imidazol-5-yl)-4,5-dihydrofuro[3,2-c]pyridin-7-yl)phenyl)propan-2-yl acetate
  • Example 48 7-(2-(4-fluoro-2,6-dimethylphenoxy)-5-(2-hydroxypropan-2-yl)phenyl)-5-methyl-2-( 2-(tetrahydro-2hydro-pyran-4-yl)-1H-imidazol-5-yl)furo[3,2-c]pyridin-4(5H)-one
  • the inhibitory IC50 value of the compound on the enzymatic binding reaction of the BET bromodomain was determined by the homogeneous time-resolved fluorescence (HTRF) method.
  • the C-terminal biotinylated bH4KAc4 polypeptide sequence is: SEQ ID NO: 1: H-SGRGK(Ac)GGK(Ac)GLGK(Ac)GGAK(Ac)RHRK-Biotin-OH.
  • Eu 3+ cryptate-lable anti-His antibody was purchased from Thermo Fisher; Streptavidin-XL-665 was purchased from PerkinElmer; 384-well plate was purchased from PerkinElmer.
  • Reaction buffer 20 mM HEPES, 150 mM NaCl, 5 mM DTT, 0.005% Tween 20 and 100 ⁇ g/mL BSA, pH adjusted to 7.5. All bromodomain proteins used were His-tagged.
  • TSA assay Thermal Stability Shift Assay was used to measure the ability to stabilize the protein after binding to the protein.
  • the experimental results are presented by ⁇ T m (°C). The larger the ⁇ T m value, the stronger the ability of the compound to stabilize the protein after binding, and the stronger the protein binding ability.
  • JQ1 is a known high-efficiency BET bromodomain inhibitor, and the ordinate is 23 representative bromodomain proteins, (wherein the BET family includes BRD4, BRD3, BRD2, BRDT, Each member includes BD1, BD2); the value in the figure represents the binding strength of the compound and the protein, and the larger the value, the stronger the binding. It can be seen from Figure 1 that compounds 39, 40, 42, and 44 have strong BET BD2 binding activity, high BD2 selectivity, and good bromodomain selectivity, and have no binding to other bromodomain proteins active.
  • the Kd value of the compound's enzyme-binding reaction to the bromodomain of the BET family was carried out using a biolayer interferometry (BLI) method.
  • Purified His6-tagged bromodomain protein was biotinylated using a biotinylation kit (G-MM-IGT, Genemore). Briefly, protein and biotinylation reagent were mixed in a 1:1 molar ratio at room temperature. The reaction mixture was incubated at room temperature for 1 hour and then dialyzed using a 10KMWCO dialysis cassette (Thermo Fisher Scientific) to remove unreacted biotinylation reagent. BLI experiments were performed using ForteBio's OctetR8 instrument.
  • the detection buffer is composed of 25mM HEPES, 100mM sodium chloride, 0.02% Tween-20, 1mg/mL BSA and 1% DMSO, and the pH is adjusted to 7.5.
  • Biotinylated BET family proteins were bound to super streptavidin (SSA) biosensors (ForteBio) by immersing the sensors in protein solution. All BET family proteins reached an average saturation response level of 10-15 nm within 10 min. The sensor is then washed for 10 min in assay buffer to eliminate non-specifically bound proteins and establish a stable baseline before beginning the association-dissociation cycle with the test compound.
  • the DMSO blank control was carried out synchronously.
  • the collected raw kinetic data were processed in the data analysis software provided by the manufacturer.
  • the double control subtraction method was used to subtract the DMSO control and the blank control of the biosensor uncoupled protein.
  • the resulting data were analyzed using a 1:1 binding model from which K on and K off values were derived and Kd values were then calculated.
  • the Cell Titer-Glo reagent was used to determine the ability of the compound to inhibit the proliferation of cancer cells.
  • the MV4-11, MOLM-13, Kasumi-1, LNCaP, 22Rv1, HT-29 and HFL-1 cells used were suspended in RPMI1640 medium containing 10% FBS and cultured at 37°C in a 5% CO2 incubator. After recovery, various cells were subcultured for at least two generations before use. When used, cells are seeded in 384-well plates at 500-1000 cells per well.
  • Adherent cells Each well contains 20 ⁇ L of medium, placed in a cell culture incubator for 12 hours, and then 10 ⁇ L of the compound is added to each well at each concentration to make three replicate wells; the suspension cells are not cultured for 12 hours while inoculating the cells. Hours, the test compound can be added directly.
  • MOLM-13 Kasumi-1 and HT-29 cells
  • the compounds were incubated with cells for 72 hours before testing; for LNCaP and 22Rv1 cells, compounds were incubated with cells for 96 hours before testing; for MV-411 cells, compounds were tested with Cells were incubated for 120 hours before testing.
  • test results of the above-mentioned embodiment numbers 42 and 1 are shown in Table 4, wherein the cell types are as follows: leukemia cells: MV4-11, MOLM-13, Kasumi-1; colorectal cancer cells: HT-29; prostate cancer cells: LNCaP , 22Rv1; human normal lung fibroblasts: HFL-1.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Endocrinology (AREA)
  • Epidemiology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Reproductive Health (AREA)
  • Emergency Medicine (AREA)
  • Hematology (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Virology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un composé furopyridone et une utilisation associée. Le composé furopyridone selon la présente invention peut inhiber sélectivement la combinaison entre un bromodomaine de la famille BET et la lysine acétylée, peut être utilisé en tant qu'inhibiteur de bromodomaine, et est utilisé pour traiter des affections associées aux BET telles que le cancer et l'inflammation.
PCT/CN2022/142283 2021-11-16 2022-12-27 Composé furopyridone et utilisation associée WO2023088493A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111356757.0A CN116135858A (zh) 2021-11-16 2021-11-16 一种呋喃并吡啶酮类化合物及其应用
CN202111356757.0 2021-11-16

Publications (1)

Publication Number Publication Date
WO2023088493A1 true WO2023088493A1 (fr) 2023-05-25

Family

ID=86333011

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/142283 WO2023088493A1 (fr) 2021-11-16 2022-12-27 Composé furopyridone et utilisation associée

Country Status (2)

Country Link
CN (1) CN116135858A (fr)
WO (1) WO2023088493A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN118141943A (zh) * 2024-03-14 2024-06-07 上海市第十人民医院 一种淀粉碘纳米材料及其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105189515A (zh) * 2013-03-14 2015-12-23 葛兰素史克知识产权第二有限公司 作为溴结构域抑制剂的呋喃并吡啶类
US20210002293A1 (en) * 2019-07-02 2021-01-07 Nuvation Bio Inc. Heterocyclic compounds as bet inhibitors
CN113226322A (zh) * 2018-10-30 2021-08-06 诺维逊生物股份有限公司 作为bet抑制剂的杂环化合物
WO2021222466A1 (fr) * 2020-04-29 2021-11-04 Nuvation Bio Inc. Composés hétérocycliques en tant qu'inhibiteurs de bet

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2930305T3 (es) * 2013-10-18 2022-12-09 Celgene Quanticel Res Inc Inhibidores del bromodominio

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105189515A (zh) * 2013-03-14 2015-12-23 葛兰素史克知识产权第二有限公司 作为溴结构域抑制剂的呋喃并吡啶类
CN113226322A (zh) * 2018-10-30 2021-08-06 诺维逊生物股份有限公司 作为bet抑制剂的杂环化合物
US20210002293A1 (en) * 2019-07-02 2021-01-07 Nuvation Bio Inc. Heterocyclic compounds as bet inhibitors
WO2021222466A1 (fr) * 2020-04-29 2021-11-04 Nuvation Bio Inc. Composés hétérocycliques en tant qu'inhibiteurs de bet

Also Published As

Publication number Publication date
CN116135858A (zh) 2023-05-19

Similar Documents

Publication Publication Date Title
KR102548191B1 (ko) 표적 단백질 분해 화합물, 이의 항종양 응용, 이의 중간체 및 중간체의 응용
EP2978759B1 (fr) Dérivés de benzimidazolone en tant qu'inhibiteurs de bromodomaine
JP2021500330A (ja) Ｐａｄ阻害剤としてのイミダゾ−ピリジン化合物
CN112424185B (zh) 含苯环的化合物、其制备方法及应用
JP2023514782A (ja) 芳香族化合物および抗腫瘍薬物の調製におけるその使用
KR20210089195A (ko) 비페닐계 화합물, 이의 중간체, 제조 방법, 약학 조성물 및 용도
CN111647000A (zh) 吡嗪类衍生物及其在抑制shp2中的应用
WO2018137644A1 (fr) Inhibiteur de lsd1, son procédé de préparation et son application
WO2023011513A1 (fr) Inhibiteur de shp2, composition pharmaceutique le comprenant et son application
CN111433196A (zh) 新颖缓激肽b2受体拮抗剂及其用途
WO2023246656A1 (fr) Chimère ciblant la protéolyse sos1, composition, préparation et utilisation associées
CN110041253B (zh) 吡啶类n-氧化衍生物及其制备方法和应用
JP7278273B2 (ja) アクチビン受容体様キナーゼの阻害剤としての置換ピロロピリジン
KR20220018475A (ko) Ep300 또는 cbp 조절 및 이의 표시를 위한 응축 아진
WO2023088493A1 (fr) Composé furopyridone et utilisation associée
BR112019021049A2 (pt) Macrociclos de peptídeos antibacterianos e uso dos mesmos
CN109836385B (zh) 四氢喹啉类n-氧化衍生物及其制备方法和应用
WO2021129841A1 (fr) Composé utilisé comme inhibiteur de kinase ret et son application
WO2020200284A1 (fr) Procédé de préparation de composé tricyclique et son utilisation dans le domaine de la médecine
CN114907387B (zh) 嘧啶并吡咯类kras抑制剂及其制备方法与应用
TW202345806A (zh) 噻唑并〔５，４－ｂ〕吡啶ｍａｌｔ－１抑制劑
CN105712992B (zh) 作为cMet抑制剂的化合物及其制备方法和用途
CN111747927B (zh) 作为免疫调节剂的化合物及其应用
CN112839931B (zh) 1,2,3,4-四氢喹喔啉衍生物及其制备方法和应用
WO2022063333A1 (fr) Composé de pyrimidine carboxamide et son utilisation

Legal Events

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

Ref document number: 22895022

Country of ref document: EP

Kind code of ref document: A1