WO2022166761A1 - Thienopyrimidine derivative - Google Patents

Thienopyrimidine derivative Download PDF

Info

Publication number
WO2022166761A1
WO2022166761A1 PCT/CN2022/074327 CN2022074327W WO2022166761A1 WO 2022166761 A1 WO2022166761 A1 WO 2022166761A1 CN 2022074327 W CN2022074327 W CN 2022074327W WO 2022166761 A1 WO2022166761 A1 WO 2022166761A1
Authority
WO
WIPO (PCT)
Prior art keywords
membered
heterocyclic group
atom
nitrogen
oxygen
Prior art date
Application number
PCT/CN2022/074327
Other languages
French (fr)
Chinese (zh)
Inventor
张寅生
刘保民
黄雨
陈正帮
朱炎
盖阔
Original Assignee
正大天晴药业集团股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 正大天晴药业集团股份有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to CN202280012196.9A priority Critical patent/CN116745299A/en
Publication of WO2022166761A1 publication Critical patent/WO2022166761A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present application belongs to the field of medicinal chemistry, and relates to thienopyrimidine derivatives, in particular to a compound of formula I or a pharmaceutically acceptable salt thereof, a method for preparing the same, a pharmaceutical composition containing the compound, and its use in the treatment of individuals by acetyl-CoA carboxyl Use in the medicament of acylase (ACC)-mediated diseases.
  • thienopyrimidine derivatives in particular to a compound of formula I or a pharmaceutically acceptable salt thereof, a method for preparing the same, a pharmaceutical composition containing the compound, and its use in the treatment of individuals by acetyl-CoA carboxyl Use in the medicament of acylase (ACC)-mediated diseases.
  • ACC acylase
  • Acetyl-CoA carboxylase is the rate-limiting enzyme for fatty acid synthesis and is mainly distributed in hepatocytes and adipocytes. It uses biotin as a coenzyme to catalyze acetyl-CoA to generate malonyl-CoA, which provides a substrate for fatty acid synthesis.
  • the activity of ACC is not only regulated by a variety of factors, insulin, glucagon, thyroid hormone, etc. also have certain regulatory effects on ACC.
  • people's understanding of ACC was mainly limited to fatty acid synthesis.
  • studies have found that ACC is widely involved in the occurrence and development of metabolic diseases such as obesity, non-alcoholic steatohepatitis, and diabetes. Therefore, ACC is expected to become a treatment for various metabolic diseases. potential target of action.
  • Obesity, non-alcoholic steatohepatitis, diabetes and other metabolic diseases are intractable diseases that have been plaguing people for a long time, and there is no clinically effective therapeutic drug so far.
  • people's living standards people eat a variety of high-fat foods, leading to increasingly serious obesity, and obesity brings a series of metabolic syndromes, such as non-alcoholic steatohepatitis, diabetes, hyperuricemia, hypertension, stroke and atherosclerosis, so the development of drugs to treat these diseases is of great significance.
  • the present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof,
  • R 1 and R 2 are independently selected from hydrogen or C 1-6 alkyl, which may be optionally substituted with a group selected from hydroxy, -OC 1-6 alkyl, amino, halogen, cyano and nitro;
  • R 4 is selected from hydrogen, -R', -O-R';R' is independently selected from the following groups optionally substituted by R: C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8-membered cycloalkenyl, 6-10-membered aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl;
  • A is selected from -OC 1-6 alkylene optionally substituted by R, or a chemical bond;
  • L is selected from a chemical bond, or a divalent group optionally substituted by R selected from a 3-10-membered cycloalkyl group, a 6-10-membered aryl group, a 3-10-membered heterocyclic group, and a 5-10-membered heteroaryl group;
  • Z is selected from -COOR 3 ;
  • R 3 is selected from hydrogen, or optionally R-substituted C 1-6 alkyl, phenyl C 1-6 alkyl, silyl;
  • One of A and L is a chemical bond
  • R is independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, silyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-5 alkenyl, C 2-5 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano C 1-6 alkyl, hydroxy C 1-6 alkyl, phenyl C 1-6 alkyl , 3-8 membered cycloalkyl, phenyl, phenyl C 1-6 alkyl, halophenyl, cyanophenyl, with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-8 membered heterocyclyl, 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • the sites of attachment of A and Z to L are different.
  • R 1 and R 2 are independently selected from methyl, ethyl.
  • R is selected from hydrogen, -O-R', wherein R' is independently selected from a group optionally substituted by R: C 1-6 alkyl, 3-8 membered ring Alkyl, 5-8 membered cycloalkenyl, 6-10 membered aryl, 4-10 membered heterocyclyl with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1, 2, 5-8 membered heteroaryl with 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • R is selected from hydrogen, -O-R', wherein R' is selected from a group optionally substituted with R: -C 1-4 alkyl, 5, 6, 7 or 8 membered cycloalkyl, 5, 6, 7, 8, 9 or 10 membered heterocyclyl with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1 or 2 independently selected from nitrogen 5-6 membered heteroaryl with heteroatoms of , oxygen and sulfur.
  • R is selected from hydrogen, -O-R', wherein R' is selected from a saturated 5- optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur 8-membered heterocyclyl.
  • R4 is selected from hydrogen, -O-R', wherein R' is selected from unsaturated 5 optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur -8-membered heterocyclyl.
  • R is selected from hydrogen, -O-R', wherein R' is selected from saturated 5-8 membered heterocyclyl with 1 nitrogen atom optionally substituted with R, Unsaturated 5-8 membered heterocyclic group, saturated 5-8 membered heterocyclic group with 1 oxygen atom, unsaturated 5-8 membered heterocyclic group with 1 oxygen atom, saturated 5-membered heterocyclic group with 1 sulfur atom 8-membered heterocyclic group, unsaturated 5-8-membered heterocyclic group with 1 sulfur atom, 5-6-membered saturated heterocyclic group with 2 nitrogen atoms, 5-6-membered unsaturated heterocyclic group with 2 nitrogen atoms Ring group, 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 2 oxygen atoms 5-6 membered saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group with 2 oxygen atom, 2 oxygen
  • R4 is selected from hydrogen, -O-R', wherein R' is selected from 5-6 membered saturated heterocyclyl optionally substituted by R with 1 nitrogen atom, with 1 oxygen atom 5-6 membered saturated heterocyclic group, 5-6 membered saturated heterocyclic group having 1 sulfur atom.
  • R is selected from hydrogen, or a group optionally substituted with R: methoxy, ethoxy,
  • R 4 is
  • R 3 is selected from hydrogen, or optionally R-substituted C 1-4 alkyl, phenyl C 1-4 alkyl, C 1-6 silyl;
  • R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, methylphenyl, ethylphenyl, trimethyl Silyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
  • R3 is selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, tert-butyldiphenylsilyl.
  • A is selected from -OC 1-6 alkylene optionally substituted with R.
  • A is selected from the following groups: -O-CH2-, -O- CH ( CH3 )-, -O-CH2CH2-, -O - CH ( CH2CH3 ) - , -O-CH(CH 3 )CH 2 -, -O-CH 2 CH(CH 3 )-, -OC(CH 3 ) 2 -, -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH2CH2CH2- , -O-CH2CH( CH3 )CH2-, -O - CH ( CH3 ) CH2CH2-, -O - CH2CH2CH ( CH3 ) -, -O-CH 2 C(CH 3 ) 2 -, -OC(CH 3 ) 2 CH 2 -, -O-CH 2 CH(CH 2 CH 3 )-, -O-CH(CH 2 CH 3 )CH 2 -, -O- CH ( CH2CH3 )-, -O- CH ( CH
  • A is selected from the following groups: -O-CH2-, -O- CH ( CH3 )-, -O-CH2CH2-, -O - CH ( CH2CH3 ) - , -O- CH ( CH3 )CH2-, -O-CH2CH( CH3 )-, -OC( CH3 ) 2- , -O - CH2CH2CH2- .
  • A is -OC( CH3 ) 2- .
  • L is selected from 3-10 membered cycloalkyl, phenyl, 3- with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally substituted with R 8-membered heterocyclyl, divalent group of 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  • L is selected from a divalent group of 3-8 membered cycloalkyl optionally substituted with R.
  • L is selected from a saturated 3-8 membered heterocyclyl divalent group optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • L is selected from an unsaturated 3-8 membered heterocyclyl divalent group optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • L is selected from saturated 3-8 membered heterocyclyl with 1 nitrogen atom, unsaturated 3-8 membered heterocyclyl with 1 nitrogen atom, optionally substituted with R, with 1 A saturated 3-8-membered heterocyclic group with 1 oxygen atom, an unsaturated 3-8-membered heterocyclic group with 1 oxygen atom, a saturated 3-8-membered heterocyclic group with 1 sulfur atom, a saturated 3-8-membered heterocyclic group with 1 sulfur atom Unsaturated 3-8 membered heterocyclic group, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 1 nitrogen atom and 1 oxygen 5-6 membered saturated heterocyclic group of atoms, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered saturated heterocyclic group with 2 oxygen atoms, 2 5-6 membered unsaturated heterocyclic group with oxygen atoms, 2
  • L is selected from a divalent group of 5-6 membered heteroaryl optionally substituted with R having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • L is selected from 4-6 membered heteroaryl with 1 nitrogen atom, 5-6 membered heteroaryl with 1 oxygen atom, optionally substituted with R, with 1 sulfur atom 5-6-membered heteroaryl group, 5-6-membered heteroaryl group with 2 nitrogen atoms, divalent group of 5-6-membered heteroaryl group with 3 nitrogen atoms.
  • L is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[1.1.1]pentyl, optionally substituted with R, Bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, Bicyclo[3.3.1]nonyl, bicyclo[4.2.2]decyl, bicyclo[3.3.2]decyl, phenyl, epoxy, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2 ,5-dihydrofuranyl, furanyl, tetrahydropyranyl, pyrrolyl, 2,3-di
  • L is selected from a group optionally substituted with R:
  • L is selected from a divalent group optionally substituted with R selected from cyclobutyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl.
  • L is selected from groups optionally substituted with R
  • R is selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, cyano C 1-4 alkyl, hydroxy C 1-4 alkyl, phenyl C 1-3 alkyl, 3-6 membered cycloalkyl, phenyl, phenyl C 1-3 Alkyl, halophenyl, cyanophenyl.
  • R is selected from saturated 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is selected from unsaturated 3-8 membered heterocyclyl groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is selected from saturated 3-8 membered heterocyclyl having 1 nitrogen atom, unsaturated 3-8 membered heterocyclyl having 1 nitrogen atom, saturated 3-8 membered heterocyclyl having 1 oxygen atom Member heterocyclic group, unsaturated 3-8 membered heterocyclic group with 1 oxygen atom, saturated 3-8 membered heterocyclic group with 1 sulfur atom, unsaturated 3-8 membered heterocyclic group with 1 sulfur atom base, 4-8 membered saturated heterocyclic group with 2 nitrogen atoms, 4-8 membered unsaturated heterocyclic group with 2 nitrogen atoms, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom Ring group, 4-8-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 4-8-membered saturated heterocyclic group having 2 oxygen atoms, 4-8-membered non-saturated heterocyclic group having 2 oxygen atoms Saturated heterocyclic group, 4-8 membered saturated heterocyclyl having 1
  • R is selected from 4-6 membered saturated heterocyclyl having 1 nitrogen atom, 4-6 membered unsaturated heterocyclyl having 1 nitrogen atom, 4-6 membered having 1 oxygen atom Saturated heterocyclic group, 4-6 membered unsaturated heterocyclic group with 1 oxygen atom, 4-6 membered saturated heterocyclic group with 1 sulfur atom, 4-6 membered unsaturated heterocyclic group with 1 sulfur atom base, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom Ring group, 5-6-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 5-6-membered saturated heterocyclic group having 2 oxygen atoms, 5-6-membered non-saturated heterocyclic group having 2 oxygen atoms Saturated heterocyclic group, 5-6 membered saturated heterocyclic group with
  • R is selected from 5-6 membered heteroaryl groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
  • R is selected from 4-6 membered heteroaryl with 1 nitrogen atom, 5-6 membered heteroaryl with 1 oxygen atom, 5-6 membered heteroaryl with 1 sulfur atom , 5-6-membered heteroaryl with 2 nitrogen atoms, 5-6-membered heteroaryl with 3 nitrogen atoms.
  • R is selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, benzyl , methylphenyl, ethylphenyl, furanyl, pyranyl, pyrrolidinyl, pyridyl, piperidinyl, piperazinyl, pyrimidinyl, thienyl, trimethylsilyl, triethylsilyl , Triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
  • R is selected from hydrogen, methyl, ethyl, tert-butyl, methoxy, ethoxy, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-Butyldiphenylsilyl.
  • the compound of formula I of the present application is selected from a compound of formula II, or a pharmaceutically acceptable salt thereof,
  • a compound of formula I of the present application is selected from a compound of formula III, or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula II-A or a pharmaceutically acceptable salt thereof,
  • a compound of formula I of the present application is selected from a compound of formula II-B, or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application is selected from a compound of formula III-A, or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula III-A-1 to III-A-6 or a pharmaceutically acceptable salt thereof,
  • R 1 , R' and R are as defined above.
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula III-B or a pharmaceutically acceptable salt thereof,
  • a compound of formula I of the present application is selected from a compound of formula IV, or a pharmaceutically acceptable salt thereof,
  • a compound of formula I of the present application is selected from a compound of formula IV-A, or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula IV-A-1 to IV-A-6 or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula IV-B or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application is selected from a compound of formula V, or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application is selected from compounds of formula V-A, or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula V-A-1 to V-A-6 or a pharmaceutically acceptable salt thereof,
  • a compound of formula I of the present application is selected from a compound of formula V-B, or a pharmaceutically acceptable salt thereof,
  • the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
  • the present application relates to pharmaceutical compositions comprising a compound of formula I of the present application or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical compositions of the present application further include pharmaceutically acceptable excipients.
  • the present application relates to a method of treating a disease mediated by acetyl-CoA carboxylase (ACC) in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of formula I or a pharmacy an acceptable salt thereof, or a pharmaceutical composition thereof.
  • ACC acetyl-CoA carboxylase
  • the present application relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.
  • ACC acetyl-CoA carboxylase
  • the present application relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.
  • ACC acetyl-CoA carboxylase
  • the present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.
  • ACC acetyl-CoA carboxylase
  • diseases mediated by acetyl-CoA carboxylase include, but are not limited to, insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease Steatohepatitis, lung cancer, pancreatic cancer.
  • the compound of the present invention can inhibit ACC1 enzyme and ACC2 enzyme with high activity, has good inhibitory effect on ACC-mediated diseases such as lung cancer and pancreatic cancer, has good metabolic stability in vivo and good pharmacokinetic absorption.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable.
  • an ethyl group “optionally” substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
  • Cmn in this context is that the moiety has an integer number of carbon atoms in the given range.
  • C1-6 means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
  • any variable eg, R
  • its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a chemical bond.
  • substituents When a substituent's bond is cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring.
  • structural unit Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • hydroxyl refers to the -OH group.
  • cyano refers to the -CN group.
  • amino refers to the -NH2 group.
  • nitro refers to the -NO 2 group.
  • alkyl refers to a hydrocarbon group of the general formula CnH2n+1 .
  • the alkyl group can be straight or branched.
  • C1-6 alkyl refers to an alkyl group containing 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).
  • alkyl portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio ie, alkyl
  • silyl refers to a silyl group substituted with an alkyl group, which may be straight or branched chain.
  • silyl groups can also be further substituted with phenyl groups, such as tert-butyldiphenylsilyl.
  • alkylene refers to a straight-chain or straight-chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the remainder through two points of attachment.
  • Non-limiting examples of this term include -CH2- , -CH( CH3 )-, -CH2CH2- , -CH( CH2CH3 ) - , -CH2CH( CH3 ) -, -CH 2 CH 2 CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH 2 - , -CH 2 C(CH 3 ) 2 -.
  • alkoxy refers to -O-alkyl
  • alkylamino refers to -NH-alkyl
  • dialkylamino refers to -N(alkyl) 2 .
  • alkylsulfonyl refers to -SO2 -alkyl.
  • alkylthio refers to -S-alkyl.
  • alkenyl refers to a straight or branched chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms having at least one double bond.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
  • alkynyl refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond.
  • alkynyl groups include, but are not limited to, ethynyl (-C ⁇ CH), 1-propynyl (-C ⁇ C- CH3 ), 2-propynyl ( -CH2 -C ⁇ CH), 1,3-Butadiynyl (-C ⁇ CC ⁇ CH) and the like.
  • cycloalkyl refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 3- to 10-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to Adamantyl etc.
  • cycloalkenyl refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 5- to 8-membered ring.
  • Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
  • heterocyclyl refers to fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic, eg, having 1 or 2 double bonds), and may exist as a monocyclic, bridged or spirocyclic ring non-aromatic ring.
  • the heterocycle is typically one containing 1, 2, 3 or 4 heteroatoms independently selected from sulfur S(O) n (wherein n is 0, 1 or 2), oxygen and/or nitrogen ( 3, 4, 5, 6, 7, 8, 9, 10 membered rings with 1 or 2 heteroatoms) are preferred.
  • saturated 3-membered heterocyclyl groups include, but are not limited to, oxiranyl, oxiranyl, azithryl, and non-limiting examples of saturated 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, Examples of oxetanyl, thibutanyl, saturated 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl , thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of saturated 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazine base, 1,4-thioxanyl, 1,4
  • Non-limiting examples of partially unsaturated heterocyclyl groups include, but are not limited to Wait.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetralin, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring.
  • Preferred heteroaryl groups have a single 4 to 8 membered ring, especially 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • Non-limiting examples of heteroaryl groups include, but are not limited to Wait.
  • treating means administering a compound or formulation described herein to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned .
  • composition refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
  • tautomer or "tautomeric form” refers to structural isomers of different energies that are interconvertible via a low energy barrier.
  • proton tautomers also known as proton tautomers
  • proton tautomers include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations.
  • a specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogens.
  • Valence tautomers include interconversions through recombination of some of the bonding electrons.
  • the present application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature.
  • isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like.
  • isotopically-labeled compounds of the present application are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred for their ease of preparation and detectability.
  • Positron emitting isotopes such as15O , 13N , 11C and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy.
  • Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • substitution with heavier isotopes such as deuterium (ie 2H ) may provide certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, where the deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
  • the compounds of the present application may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers.
  • the compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Exemplary stereoisomeric compounds are shown below, but are not limited thereto.
  • the pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
  • Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
  • the pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
  • Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to give tablets or icing core.
  • Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application.
  • the compounds of general formula IV of the present application can be prepared by the following routes, including the following steps:
  • the compound of formula G can be prepared by removing the R 3 group according to conventional methods in the art to obtain the compound of formula IV.
  • A, L, R 1 , R 3 and R are as defined above, X is F, Cl, Br, I; C* is R configuration, S configuration or racemate.
  • X is Br.
  • the compound of formula F in step 5) is combined with (R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethane -1-ol reaction.
  • the compound of general formula IV of the present application can also be prepared by the following route, including the following steps:
  • the compound of formula G can be prepared by removing the R 3 group according to conventional methods in the art to obtain the compound of formula IV.
  • A, L, R 1 , R 3 and R are as defined above, X is F, Cl, Br, I; C* is R configuration, S configuration or racemate.
  • X is Br.
  • the compound of formula H is (R)-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran. This application uses the following acronyms:
  • Cbz stands for benzyloxycarbonyl; TMS stands for trimethylsilyl; TES stands for triethylsilyl; TIPS stands for triisopropylsilyl; TBS stands for tert-butyldimethylsilyl; TBDPS stands for tert-butyldiphenyl silyl; MS for methanesulfonyl; DCM for dichloromethane; PE for petroleum ether; DMF for N,N-dimethylformamide; EtOAc for ethyl acetate; i-PrOH for isopropanol; EtOH for ethanol ; MeOH is methanol; THF is tetrahydrofuran.
  • Step 1 Synthesis of methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate
  • Step 3 Synthesis of ethyl 2-(3-(3-(methoxycarbonyl)bicyclo[1.1.1]pent-1-yl)ureido)-4-methylthiophene-3-carboxylate
  • Ethyl 2-amino-4-methylthiophene-3-carboxylate (12 g, 64.8 mmol) was dissolved in dichloromethane (120 mL), to which was added N,N-carbonyldiimidazole (11.55 g in portions at 0°C) , 71.3 mmol), reacted at room temperature for 12 hours, followed by adding triethylamine (9.93 mL, 71.3 mmol) and 3-aminobicyclo[1.1.1]pentane-1-carboxylate methyl ester hydrochloride (12.66 g, 71.3 mmol) ) for 2 hours at room temperature.
  • N-bromosuccinimide (9.47 g, 53.2 mmol) was added in three portions to 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[ 2,3]-d]pyrimidin-3(2H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (16.3 g, 53.2 mmol) in dichloromethane (380 mL), 0 °C
  • reaction solution was adjusted to acidity with 1N hydrochloric acid solution, ethyl acetate (100 mL) was added, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration and concentration to obtain 2.652 g of the title compound.
  • Step Eight 3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine- Synthesis of 3(2H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid tert-butyldiphenylsilyl ester
  • Step 9 (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)bicyclo [1.1.1] Synthesis of pentane-1-carboxylic acid tert-butyldiphenylsilyl ester (compound of formula I-9)
  • the compound of formula I-9 (0.1 g, 0.097 mmol), tetrabutylammonium fluoride (1 mL, 1 mmol) and tetrahydrofuran (0.5 mL) were mixed and reacted at room temperature for 1 hour.
  • Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration, and the obtained crude product was separated and purified by column chromatography (dichloromethane:methanol 40:1) to obtain 0.025 g of the compound of formula I-1.
  • Step 1 Synthesis of (1S,3S)-3-hydroxycyclobutane-1-carboxylic acid tert-butyl ester
  • tert-butyl 3-oxocyclobutane-1-carboxylate 45 g, 264 mmol
  • tetrahydrofuran 432 mL
  • methanol 54 mL
  • sodium borohydride 5.00 g, 132 mmol
  • 20% potassium carbonate solution 500 mL
  • ethyl acetate 500 mL
  • the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration and concentration to obtain 44.96 g of the title compound.
  • Step 2 Synthesis of ((1R,3R)-3-(1,3-dioxoisoindolin-2-yl)cyclobutane-1-carboxylic acid tert-butyl ester
  • Step 3 Synthesis of (1R,3R)-3-aminocyclobutane-1-carboxylic acid tert-butyl ester hydrochloride
  • Step 4 Synthesis of 2-(3-((1R,3R)-3-(tert-butoxycarbonyl)cyclobutyl)ureido)-4-methylthiophene-3-carboxylic acid ethyl ester
  • Ethyl 2-amino-4-methylthiophene-3-carboxylate 14 g, 76 mmol was dissolved in dichloromethane (140 mL), and N,N-carbonyldiimidazole (13.76 g, 83 mmol) was added in portions at 0°C. ), reacted at room temperature for 12 hours, and added triethylamine (1.59 mL, 83 mmol) and (1R, 3R)-3-aminocyclobutane-1-carboxylate tert-butyl ester hydrochloride (17.27 g, 83 mmol) successively to it , and react at room temperature for 2 hours.
  • Step six (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine-3(2H) -Synthesis of tert-butyl)cyclobutane-1-carboxylate
  • Step 7 (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine-3(2H) -Synthesis of cyclobutane-1-carboxylic acid
  • Trifluoroacetic acid (45 ml, 584 mmol) was slowly added to (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno at 0°C
  • a solution of [2,3-d]pyrimidin-3(2H)-yl)cyclobutane-1-carboxylate tert-butyl ester (18 g, 43.3 mmol) in dichloromethane (225 mL)
  • the reaction solution was poured into ice water (1500 mL) and filtered with suction to obtain 13.5 g of the title compound.
  • Step 8 (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine-3-(2H) -Synthesis of methyl)cyclobutane-1-carboxylate
  • reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added to the residue, stirred for 30 minutes, suction filtered, the filter cake was washed with water, and dried to obtain 4.1 g of the title compound.
  • Step 9 (1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3 Synthesis of -d]pyrimidin-3-(2H)-yl)cyclobutane-1-carboxylic acid methyl ester
  • Step eleven (1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2 Synthesis of ,3-d]pyrimidin-3-(2H)-yl)cyclobutane-1-carboxylic acid tert-butyldiphenylsilyl ester
  • Step 1 Synthesis of 2-(3-(4-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylic acid ethyl ester
  • Ethyl 2-amino-4-methylthiophene-3-carboxylate (10 g, 54 mmol) was dissolved in dichloromethane (70 mL), cooled in an ice-water bath, and N,N-carbonyldiimidazole (9.63 g, 59.4 mmol), remove the ice bath after the addition, and react at room temperature overnight.
  • Triethylamine (8.25 ml, 59.4 mmol
  • 4-aminobenzoic acid ethyl ester (9.81 g, 59.4 mmol) were sequentially added to the reaction solution, and the reaction was carried out at room temperature overnight.
  • Step 2 Synthesis of ethyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
  • Step 3 (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Synthesis of ethyl methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
  • Step 4 (R)-4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid ethyl ester
  • Step 5 (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzene Synthesis of ethyl formate (compound of formula I-10)
  • Step 1 Synthesis of 2-(3-(3-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylic acid ethyl ester
  • Ethyl 2-amino-4-methylthiophene-3-carboxylate (15 g, 81 mmol) was mixed with dichloromethane (140 mL), cooled in an ice-water bath, carbonyldiimidazole (14.44 g, 89 mmol) was added in batches, and the addition was completed. The ice bath was removed and the reaction was carried out at room temperature overnight. Triethylamine (12.42 mL, 89 mmol) and 3-aminobenzoic acid ethyl ester (14.71 g, 89 mmol) were sequentially added to the reaction solution, and the reaction was carried out at room temperature overnight.
  • Step 2 Synthesis of ethyl 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
  • Step 3 (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Synthesis of ethyl methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
  • Step 4 (R)-3-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid ethyl ester
  • Step 5 (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzene Synthesis of ethyl formate (compound of formula I-11)
  • Step 1 Synthesis of ethyl 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate
  • Ethyl 2-amino-4-methylthiophene-3-carboxylate (60.2 g, 325 mmol) was mixed with ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate solution (500 mL), to which was added phenyl chloroformate (61.1 g, 390 mmol), and reacted at room temperature for 17 h.
  • Ethyl acetate (1 L) was added to the reaction solution until the solid was completely dissolved, the aqueous phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL ⁇ 2).
  • the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated.
  • the obtained crude product was slurried with petroleum ether, filtered with suction, and the filter cake was dried to obtain 88.3 g of the title compound.
  • Step 2 Synthesis of methyl 4-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate
  • Step 3 Methyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate / Synthesis of ethyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
  • Step 4 (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate/(R)-4-( 1-(2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo - Synthesis of ethyl 1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
  • Step 5 (R)-4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester/(R) -4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl - Synthesis of methyl 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
  • Succinimide (0.871 g, 4.89 mmol) was reacted at 0°C for 1 hour.
  • Step 6 (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine -Methyl 2-carboxylate (compound of formula I-12)/(R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d ] Synthesis of pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester (compound of formula I-13
  • the compound of formula I-12, a mixture of compounds of formula I-13 (250 mg), methanol (1.5 mL), and an aqueous solution (0.5 mL) of lithium hydroxide hydrate (49.7 mg, 1.185 mmol) were mixed and reacted at room temperature for 2 hours.
  • Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6.
  • Step 1 Synthesis of methyl 6-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate
  • 6-Aminopyridine-2-carboxylic acid methyl ester (10 g, 65.7 mmol), 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (24.08 g, 79 mmol), trimethylate Ethylamine (12.83 mL, 92 mmol) was mixed with toluene (100 mL), and the mixture was heated to 110°C for 12 hours.
  • the reaction solution was cooled to room temperature, filtered with suction, the filter cake was slurried with petroleum ether and ethyl acetate, filtered with suction, and the filter cake was dried to obtain 16.6 g of the title compound.
  • Step 2 Methyl 6-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate /Synthesis of ethyl 6-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
  • Step 3 (R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester/(R)-6-( 1-(2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo - Synthesis of ethyl 1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
  • Step 4 (R)-6-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester/(R) -6-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl - Synthesis of ethyl 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
  • Step 5 (R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine -Methyl 2-carboxylate (compound of formula I-14)/(R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d ] Synthesis of pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester (compound of formula I-15
  • the compound of formula I-14, a mixture of compounds of formula I-15 (300 mg), methanol (5 mL), and an aqueous solution (1.5 mL) of lithium hydroxide hydrate (64 mg, 1.526 mmol) were mixed and reacted at room temperature for 2 hours.
  • Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6.
  • Step 1 Synthesis of methyl 5-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)nicotinate
  • Step 2 Methyl 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate/3- Synthesis of ethyl (5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
  • the obtained crude product was purified by slurrying with dichloromethane and methanol, suction filtered, and the filter cake was dried to obtain 3.1 g of the title compound (a mixture of methyl ester and ethyl ester, the ratio of the two being 3:2).
  • Step 3 (R)-5-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid methyl ester/(R)-5-(1-( 2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1, Synthesis of 4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid ethyl ester
  • Step 4 (R)-5-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid methyl ester/(R)-5- (6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2, Synthesis of 4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid ethyl ester
  • Step 5 (R)-5-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotine Methyl acid (compound of formula I-16)/(R)-5-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy yl)ethyl)-5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine- Synthesis of 3(2H)-yl)nicotinic acid ethyl ester (compound of formula I-17)
  • Step 1 Synthesis of tert-butyl 2-((1,3-dioxoisoindol-2-yl)oxy)-2-methylpropanoate
  • Step 2 Synthesis of 2-(aminooxy)-2-methylpropionic acid tert-butyl ester
  • the filter cake was washed with dichloromethane (30ml), the filtrate was concentrated, the residue was diluted with ethyl acetate (50ml), washed with water (50ml) and saturated brine (50ml) successively, dried over anhydrous sodium sulfate, suction After filtration, the filtrate was concentrated to obtain 3.4 g of the title compound.
  • Step 3 Synthesis of ethyl 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate
  • reaction liquid was separated, the aqueous phase was washed with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the residual solid was slurried with petroleum ether (10 mL) to obtain The title compound 1.25 g.
  • Step 7 2-((6-Bromo-5-methyl-2,4-dioxy-1,4-dihydrothiophen[2,3-d]pyrimidin-3(2H)-yl)oxy) Synthesis of -2-methylpropionic acid benzyl ester
  • reaction solution was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain 6.25 g of the title compound, which was used directly in the next step. one-step reaction.
  • Step 8 (R)-2-((6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl yl)-5-methyl-2,4-dioxy-1,4-dihydrothiophene[2,3-d]pyrimidin-3(2H)-yl)oxy)-2-methylpropionic acid benzyl Synthesis of Esters
  • Step 9 (R)-2-((1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Synthesis of benzyl oxy)-2-methylpropanoate (compound of formula I-18)
  • the compound of formula I-18 (0.3 g, 0.464 mmol) was mixed with lithium hydroxide (0.012 g, 0.510 mmol), tetrahydrofuran (6 mL) and water (3 mL), and the mixture was reacted at room temperature overnight.
  • ACC1 enzyme was diluted to 8.25ng/ ⁇ L with 1x concentration of enzyme buffer (30mM HEPES, 2mM MgCl 2 , 1mM DTT, 2mM sodium citrate), 1.8 ⁇ L was added to each well, and 1.8 ⁇ L of 1x concentration was added to blank control wells. Enzyme buffer, centrifuge, and react at room temperature for 60 minutes.
  • ACC2 enzyme was diluted to 5.4ng/ ⁇ L with 1x concentration of enzyme buffer (30mM HEPES, 2mM MgCl 2 , 1mM DTT, 2mM sodium citrate), 1.8 ⁇ L was added to each well, and 1.8 ⁇ L of 1x concentration was added to blank control wells. Enzyme buffer, centrifuge, and react at room temperature for 60 minutes.
  • A549 adenocarcinoma human alveolar basal epithelial cell line
  • NCI-H460 large cell lung cancer cell line
  • the density of ⁇ 10 4 cells/mL was inoculated into a 96-well plate, 100 ⁇ L per well, and placed in a cell incubator at 37°C with a saturated humidity of 5% CO 2 for overnight incubation.
  • the nanoliter dispenser was used for compound addition and testing.
  • the final concentrations of the compounds were 10000.0, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, and 4.6 nM, respectively, and two replicate wells were set for each concentration.
  • the groups with and without palmitic acid were set.
  • the cells without compound were used as negative control, and the blank group without cells was used as blank control.
  • the cells were placed in a cell culture incubator containing 5% CO 2 saturated humidity at 37° C. for 6 days, and after 6 days of culture, 10 ⁇ L of CCK-8 was added to each well, and the culture was continued for 2-4 h.
  • Measure the absorbance value A of each well at 450nm of the microplate reader, and calculate the inhibition rate according to the following formula: inhibition rate (%) (average A value of negative control group - average A value of experimental group)/(average A value of negative control group) -The average A value of the blank control group) ⁇ 100%, and the IC 50 was calculated from the obtained data.
  • liver microsome body temperature incubation sample mix PBS buffer (pH 7.4), liver microsome solution (0.5mg/mL), test compound and NADPH+MgCl 2 solution, incubate at 37°C and 300rpm for 60min.

Abstract

The present invention relates to a thienopyrimidine derivative, in particular to a compound, as represented by formula I, or a pharmaceutically acceptable salt thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and the use thereof in the preparation of a drug for treating acetyl-CoA carboxylase (ACC)-mediated diseases in individuals, such as insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, lung cancer and pancreatic cancer.

Description

噻吩并嘧啶衍生物Thienopyrimidine Derivatives 技术领域technical field
本申请属于药物化学领域，涉及噻吩并嘧啶衍生物，具体涉及式I化合物或其药学上可接受的盐、其制备方法、含有该化合物的药物组合物、以及其在治疗个体由乙酰辅酶A羧化酶(ACC)介导疾病的药物中的用途。The present application belongs to the field of medicinal chemistry, and relates to thienopyrimidine derivatives, in particular to a compound of formula I or a pharmaceutically acceptable salt thereof, a method for preparing the same, a pharmaceutical composition containing the compound, and its use in the treatment of individuals by acetyl-CoA carboxyl Use in the medicament of acylase (ACC)-mediated diseases.
背景技术Background technique
乙酰辅酶A羧化酶(ACC)是脂肪酸合成的限速酶，主要分布于肝细胞和脂肪细胞。它以生物素为辅酶，催化乙酰辅酶A生成丙二酰辅酶A，为脂肪酸的合成提供底物。ACC的活性除了受到多种因子调节之外，胰岛素、胰高血糖素、甲状腺激素等也对ACC有一定的调控作用。起初，人们对ACC的认识主要局限在脂肪酸合成，近年来研究发现，ACC广泛参与肥胖、非酒精性脂肪性肝炎、糖尿病等代谢性疾病的发生、发展，因此ACC有望成为多种代谢性疾病治疗的潜在作用靶点。Acetyl-CoA carboxylase (ACC) is the rate-limiting enzyme for fatty acid synthesis and is mainly distributed in hepatocytes and adipocytes. It uses biotin as a coenzyme to catalyze acetyl-CoA to generate malonyl-CoA, which provides a substrate for fatty acid synthesis. The activity of ACC is not only regulated by a variety of factors, insulin, glucagon, thyroid hormone, etc. also have certain regulatory effects on ACC. At first, people's understanding of ACC was mainly limited to fatty acid synthesis. In recent years, studies have found that ACC is widely involved in the occurrence and development of metabolic diseases such as obesity, non-alcoholic steatohepatitis, and diabetes. Therefore, ACC is expected to become a treatment for various metabolic diseases. potential target of action.
肥胖、非酒精性脂肪肝炎以及糖尿病等代谢性疾病是一直困扰着人们的疑难杂症，临床上至今没有疗效较好的治疗药物。随着人们生活水平的提高，人们进食各种高脂肪的食品导致肥胖现象日趋严重，并且肥胖带来一系列代谢综合征，如非酒精性脂肪肝炎、糖尿病、高尿酸血症、高血压、中风和动脉粥样硬化等，因此开发治疗这类疾病的药物具有重大的意义。Obesity, non-alcoholic steatohepatitis, diabetes and other metabolic diseases are intractable diseases that have been plaguing people for a long time, and there is no clinically effective therapeutic drug so far. With the improvement of people's living standards, people eat a variety of high-fat foods, leading to increasingly serious obesity, and obesity brings a series of metabolic syndromes, such as non-alcoholic steatohepatitis, diabetes, hyperuricemia, hypertension, stroke and atherosclerosis, so the development of drugs to treat these diseases is of great significance.
发明详述Detailed description of the invention
本申请涉及式I化合物或其药学上可接受的盐，The present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000001
Figure PCTCN2022074327-appb-000001
其中，in,
R 1和R 2独立地选自氢或C 1-6烷基，可任选被选自羟基、-O-C 1-6烷基、氨基、卤素、氰基和硝基的基团取代； R 1 and R 2 are independently selected from hydrogen or C 1-6 alkyl, which may be optionally substituted with a group selected from hydroxy, -OC 1-6 alkyl, amino, halogen, cyano and nitro;
R 4选自氢、-R’、-O-R’；R’独立地选自任选被R取代的以下各项的基团：C 1-6烷基，3-8元环烷基，3-8元环烯基，6-10元芳基、3-10元杂环基、5-10元杂芳基； R 4 is selected from hydrogen, -R', -O-R';R' is independently selected from the following groups optionally substituted by R: C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8-membered cycloalkenyl, 6-10-membered aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl;
A选自任选被R取代的-O-C 1-6亚烷基，或化学键； A is selected from -OC 1-6 alkylene optionally substituted by R, or a chemical bond;
L选自化学键，或者任选被R取代的选自3-10元环烷基、6-10元芳基、3-10元杂环基、 5-10元杂芳基的二价基团；L is selected from a chemical bond, or a divalent group optionally substituted by R selected from a 3-10-membered cycloalkyl group, a 6-10-membered aryl group, a 3-10-membered heterocyclic group, and a 5-10-membered heteroaryl group;
Z选自-COOR 3； Z is selected from -COOR 3 ;
R 3选自氢，或者任选被R取代的C 1-6烷基、苯基C 1-6烷基、硅烷基； R 3 is selected from hydrogen, or optionally R-substituted C 1-6 alkyl, phenyl C 1-6 alkyl, silyl;
其中A和L之一为化学键；One of A and L is a chemical bond;
R独立地为氢、氟、氯、溴、碘、羟基、氨基、硝基、氰基、硅烷基、C 1-6烷基、C 1-6烷氧基、C 2-5烯基、C 2-5炔基、卤代C 1-6烷基、卤代C 1-6烷氧基、氰基C 1-6烷基、羟基C 1-6烷基、苯基C 1-6烷基、3-8元环烷基、苯基、苯基C 1-6烷基、卤代苯基、氰基苯基、具有1、2或3个独立地选自氮、氧和硫的杂原子的3-8元杂环基，具有1、2、3或4个独立地选自氮、氧和硫的杂原子的5-6元杂芳基。 R is independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, silyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-5 alkenyl, C 2-5 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano C 1-6 alkyl, hydroxy C 1-6 alkyl, phenyl C 1-6 alkyl , 3-8 membered cycloalkyl, phenyl, phenyl C 1-6 alkyl, halophenyl, cyanophenyl, with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-8 membered heterocyclyl, 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
在一些实施方案中，当A为化学键时，A和Z与L的连接位点不同。In some embodiments, when A is a chemical bond, the sites of attachment of A and Z to L are different.
在一些实施方案中，R 1和R 2独立地选自甲基、乙基。 In some embodiments, R 1 and R 2 are independently selected from methyl, ethyl.
在一些实施方案中，R 4选自氢、-O-R’，其中R’独立地选自任选被R取代的以下各项的基团：C 1-6烷基，3-8元环烷基，5-8元环烯基，6-10元芳基，具有1、2或3个独立选自氮、氧和硫的杂原子的4-10元杂环基，具有1、2、3或4个独立选自氮、氧和硫的杂原子的5-8元杂芳基。 In some embodiments, R is selected from hydrogen, -O-R', wherein R' is independently selected from a group optionally substituted by R: C 1-6 alkyl, 3-8 membered ring Alkyl, 5-8 membered cycloalkenyl, 6-10 membered aryl, 4-10 membered heterocyclyl with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1, 2, 5-8 membered heteroaryl with 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
在一些实施方案中，R 4选自氢、-O-R’，其中R’选自任选被R取代的以下各项的基团：-C 1-4烷基，5、6、7或8元环烷基，具有1、2或3个独立选自氮、氧和硫的杂原子的5、6、7、8、9或10元杂环基，具有1或2个独立选自氮、氧和硫的杂原子的5-6元杂芳基。 In some embodiments, R is selected from hydrogen, -O-R', wherein R' is selected from a group optionally substituted with R: -C 1-4 alkyl, 5, 6, 7 or 8 membered cycloalkyl, 5, 6, 7, 8, 9 or 10 membered heterocyclyl with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, with 1 or 2 independently selected from nitrogen 5-6 membered heteroaryl with heteroatoms of , oxygen and sulfur.
在一些实施方案中，R 4选自氢、-O-R’，其中R’选自任选被R取代的具有1或2个独立地选自氮、氧和硫的杂原子的饱和5-8元杂环基。 In some embodiments, R is selected from hydrogen, -O-R', wherein R' is selected from a saturated 5- optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur 8-membered heterocyclyl.
在一些实施方案中，R 4选自氢、-O-R’，其中R’选自任选被R取代的具有1或2个独立地选自氮、氧和硫的杂原子的不饱和5-8元杂环基。 In some embodiments, R4 is selected from hydrogen, -O-R', wherein R' is selected from unsaturated 5 optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur -8-membered heterocyclyl.
在一些实施方案中，R 4选自氢、-O-R’，其中R’选自任选被R取代的具有1个氮原子的饱和5-8元杂环基，具有1个氮原子的不饱和5-8元杂环基，具有1个氧原子的饱和5-8元杂环基、具有1个氧原子的不饱和5-8元杂环基、具有1个硫原子的饱和5-8元杂环基、具有1个硫原子的不饱和5-8元杂环基、具有2个氮原子的5-6元饱和杂环基、具有2个氮原子的5-6元不饱和杂环基、具有1个氮原子和1个氧原子的5-6元饱和杂环基、具有1个氮原子和1个氧原子的5-6元不饱和杂环基、具有2个氧原子的5-6元饱和杂环基、具有2个氧原子的5-6元不饱和杂环基、具有1个氮原子和1个硫原子的5-6元饱和杂环基、具有1个氮原子和1个硫原子的5-6元不饱和杂环基、具有1个氧原子和1个硫原子的饱和5-6元杂环基。 In some embodiments, R is selected from hydrogen, -O-R', wherein R' is selected from saturated 5-8 membered heterocyclyl with 1 nitrogen atom optionally substituted with R, Unsaturated 5-8 membered heterocyclic group, saturated 5-8 membered heterocyclic group with 1 oxygen atom, unsaturated 5-8 membered heterocyclic group with 1 oxygen atom, saturated 5-membered heterocyclic group with 1 sulfur atom 8-membered heterocyclic group, unsaturated 5-8-membered heterocyclic group with 1 sulfur atom, 5-6-membered saturated heterocyclic group with 2 nitrogen atoms, 5-6-membered unsaturated heterocyclic group with 2 nitrogen atoms Ring group, 5-6 membered saturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 5-6 membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 2 oxygen atoms 5-6 membered saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group with 2 oxygen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 nitrogen atom 5-6 membered unsaturated heterocyclic group with 1 sulfur atom, saturated 5-6 membered heterocyclic group with 1 oxygen atom and 1 sulfur atom.
在一些实施方案中，R 4选自氢、-O-R’，其中R’选自任选被R取代的具有1个氮原子的 5-6元饱和杂环基，具有1个氧原子的5-6元饱和杂环基、具有1个硫原子的5-6元饱和杂环基。 In some embodiments, R4 is selected from hydrogen, -O-R', wherein R' is selected from 5-6 membered saturated heterocyclyl optionally substituted by R with 1 nitrogen atom, with 1 oxygen atom 5-6 membered saturated heterocyclic group, 5-6 membered saturated heterocyclic group having 1 sulfur atom.
在一些实施方案中，R 4选自氢、或任选被R取代的以下各项的基团：甲氧基、乙氧基、
Figure PCTCN2022074327-appb-000002
 In some embodiments, R is selected from hydrogen, or a group optionally substituted with R: methoxy, ethoxy,
Figure PCTCN2022074327-appb-000002
在一些实施方案中，R 4为
Figure PCTCN2022074327-appb-000003
In some embodiments, R 4 is
Figure PCTCN2022074327-appb-000003
在一些实施方案中，R 3选自氢，或者任选被R取代的C 1-4烷基、苯基C 1-4烷基、C 1-6硅烷基； In some embodiments, R 3 is selected from hydrogen, or optionally R-substituted C 1-4 alkyl, phenyl C 1-4 alkyl, C 1-6 silyl;
在一些实施方案中，R 3选自氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基、甲基苯基、乙基苯基、三甲基硅烷基、三乙基硅烷基、三异丙基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基。 In some embodiments, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, methylphenyl, ethylphenyl, trimethyl Silyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
在一些实施方案中，R 3选自氢、甲基、乙基、叔丁基、苄基、叔丁基二苯基硅烷基。 In some embodiments, R3 is selected from hydrogen, methyl, ethyl, tert-butyl, benzyl, tert-butyldiphenylsilyl.
在一些实施方案中，A选自任选被R取代的-O-C 1-6亚烷基。 In some embodiments, A is selected from -OC 1-6 alkylene optionally substituted with R.
在一些实施方案中，A选自以下基团：-O-CH 2-、-O-CH(CH 3)-、-O-CH 2CH 2-、-O-CH(CH 2CH 3)-、-O-CH(CH 3)CH 2-、-O-CH 2CH(CH 3)-、-O-C(CH 3) 2-、-O-CH 2CH 2CH 2-、-O-CH 2CH 2CH 2CH 2-、-O-CH 2CH(CH 3)CH 2-、-O-CH(CH 3)CH 2CH 2-、-O-CH 2CH 2CH(CH 3)-、-O-CH 2C(CH 3) 2-、-O-C(CH 3) 2CH 2-、-O-CH 2CH(CH 2CH 3)-、-O-CH(CH 2CH 3)CH 2-、-O-CH(CH 2CH 2CH 3)-、-O-C(CH 2CH 3)(CH 3)-。 In some embodiments, A is selected from the following groups: -O-CH2-, -O- CH ( CH3 )-, -O-CH2CH2-, -O - CH ( CH2CH3 ) - , -O-CH(CH 3 )CH 2 -, -O-CH 2 CH(CH 3 )-, -OC(CH 3 ) 2 -, -O-CH 2 CH 2 CH 2 -, -O-CH 2 CH2CH2CH2- , -O-CH2CH( CH3 )CH2-, -O - CH ( CH3 ) CH2CH2-, -O - CH2CH2CH ( CH3 ) -, -O-CH 2 C(CH 3 ) 2 -, -OC(CH 3 ) 2 CH 2 -, -O-CH 2 CH(CH 2 CH 3 )-, -O-CH(CH 2 CH 3 )CH 2 -, -O- CH ( CH2CH2CH3 )-, -OC( CH2CH3 ) ( CH3 ) -.
在一些实施方案中，A选自以下基团：-O-CH 2-、-O-CH(CH 3)-、-O-CH 2CH 2-、-O-CH(CH 2CH 3)-、-O-CH(CH 3)CH 2-、-O-CH 2CH(CH 3)-、-O-C(CH 3) 2-、-O-CH 2CH 2CH 2-。 In some embodiments, A is selected from the following groups: -O-CH2-, -O- CH ( CH3 )-, -O-CH2CH2-, -O - CH ( CH2CH3 ) - , -O- CH ( CH3 )CH2-, -O-CH2CH( CH3 )-, -OC( CH3 ) 2- , -O - CH2CH2CH2- .
在一些实施方案中，A为-O-C(CH 3) 2-。 In some embodiments, A is -OC( CH3 ) 2- .
在一些实施方案中，L选自任选被R取代的选自3-10元环烷基、苯基、具有1、2或3 个独立地选自氮、氧和硫的杂原子的3-8元杂环基，具有1、2、3或4个独立地选自氮、氧和硫的杂原子的5-6元杂芳基的二价基团。In some embodiments, L is selected from 3-10 membered cycloalkyl, phenyl, 3- with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur optionally substituted with R 8-membered heterocyclyl, divalent group of 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
在一些实施方案中，L选自任选被R取代的3-8元环烷基的二价基团。In some embodiments, L is selected from a divalent group of 3-8 membered cycloalkyl optionally substituted with R.
在一些实施方案中，L选自任选被R取代的具有1或2个独立地选自氮、氧和硫的杂原子的饱和3-8元杂环基的二价基团。In some embodiments, L is selected from a saturated 3-8 membered heterocyclyl divalent group optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
在一些实施方案中，L选自任选被R取代的具有1或2个独立地选自氮、氧和硫的杂原子的不饱和3-8元杂环基的二价基团。In some embodiments, L is selected from an unsaturated 3-8 membered heterocyclyl divalent group optionally substituted with R having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
在一些实施方案中，L选自任选被R取代的选自具有1个氮原子的饱和3-8元杂环基、具有1个氮原子的不饱和3-8元杂环基、具有1个氧原子的饱和3-8元杂环基、具有1个氧原子的不饱和3-8元杂环基、具有1个硫原子的饱和3-8元杂环基、具有1个硫原子的不饱和3-8元杂环基、具有2个氮原子的5-6元饱和杂环基、具有2个氮原子的5-6元不饱和杂环基、具有1个氮原子和1个氧原子的5-6元饱和杂环基、具有1个氮原子和1个氧原子的5-6元不饱和杂环基、具有2个氧原子的5-6元饱和杂环基、具有2个氧原子的5-6元不饱和杂环基、具有1个氮原子和1个硫原子的5-6元饱和杂环基、具有1个氮原子和1个硫原子的5-6元不饱和杂环基、具有1个氧原子和1个硫原子的饱和5-6元杂环基的二价基团。In some embodiments, L is selected from saturated 3-8 membered heterocyclyl with 1 nitrogen atom, unsaturated 3-8 membered heterocyclyl with 1 nitrogen atom, optionally substituted with R, with 1 A saturated 3-8-membered heterocyclic group with 1 oxygen atom, an unsaturated 3-8-membered heterocyclic group with 1 oxygen atom, a saturated 3-8-membered heterocyclic group with 1 sulfur atom, a saturated 3-8-membered heterocyclic group with 1 sulfur atom Unsaturated 3-8 membered heterocyclic group, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 1 nitrogen atom and 1 oxygen 5-6 membered saturated heterocyclic group of atoms, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered saturated heterocyclic group with 2 oxygen atoms, 2 5-6 membered unsaturated heterocyclic group with oxygen atom, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated group with 1 nitrogen atom and 1 sulfur atom Heterocyclic group, divalent group of saturated 5-6 membered heterocyclic group having 1 oxygen atom and 1 sulfur atom.
在一些实施方案中，L选自任选被R取代的具有1、2或3个独立地选自氮、氧和硫的杂原子的5-6元杂芳基的二价基团。In some embodiments, L is selected from a divalent group of 5-6 membered heteroaryl optionally substituted with R having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
在一些实施方案中，L选自任选被R取代的选自具有1个氮原子的4-6元杂芳基，具有1个氧原子的5-6元杂芳基、具有1个硫原子的5-6元杂芳基、具有2个氮原子的5-6元杂芳基、具有3个氮原子的5-6元杂芳基的二价基团。In some embodiments, L is selected from 4-6 membered heteroaryl with 1 nitrogen atom, 5-6 membered heteroaryl with 1 oxygen atom, optionally substituted with R, with 1 sulfur atom 5-6-membered heteroaryl group, 5-6-membered heteroaryl group with 2 nitrogen atoms, divalent group of 5-6-membered heteroaryl group with 3 nitrogen atoms.
在一些实施方案中，L选自任选被R取代的选自环丙基、环丁基、环戊基、环己基、环庚基、环辛基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.1.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.1]壬烷基、双环[4.2.2]癸烷基、双环[3.3.2]癸烷基、苯基、环氧基、四氢呋喃基、2,3-二氢呋喃基、2,5-二氢呋喃基、呋喃基、四氢吡喃基、吡咯基、2,3-二氢吡咯基、2,5-二氢吡咯基、吡咯烷基、咪唑烷基、四氢吡唑基、噁唑烷基、异噁唑烷基、吗啉基、硫代吗啉基、吡啶基、哌啶基、哌嗪基、嘧啶基、哒嗪基、噻吩基、噻吩烷基、噻唑烷基的二价基团。In some embodiments, L is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[1.1.1]pentyl, optionally substituted with R, Bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[3.2.1]octyl, Bicyclo[3.3.1]nonyl, bicyclo[4.2.2]decyl, bicyclo[3.3.2]decyl, phenyl, epoxy, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2 ,5-dihydrofuranyl, furanyl, tetrahydropyranyl, pyrrolyl, 2,3-dihydropyrrolyl, 2,5-dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, tetrahydropyrazole base, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, pyridyl, piperidinyl, piperazinyl, pyrimidinyl, pyridazinyl, thienyl, thienyl, thiazolidine base divalent group.
在一些实施方案中，L选自任选被R取代的以下各项的基团：In some embodiments, L is selected from a group optionally substituted with R:
Figure PCTCN2022074327-appb-000004
Figure PCTCN2022074327-appb-000005
Figure PCTCN2022074327-appb-000006
等。
Figure PCTCN2022074327-appb-000004
Figure PCTCN2022074327-appb-000005
Figure PCTCN2022074327-appb-000006
Wait.
在一些实施方案中，L选自任选被R取代的选自环丁基、双环[1.1.1]戊烷基、苯基、吡啶基的二价基团。In some embodiments, L is selected from a divalent group optionally substituted with R selected from cyclobutyl, bicyclo[1.1.1]pentyl, phenyl, pyridyl.
在一些实施方案中，L选自任选被R取代的以下各项的基团
Figure PCTCN2022074327-appb-000007
Figure PCTCN2022074327-appb-000008
In some embodiments, L is selected from groups optionally substituted with R
Figure PCTCN2022074327-appb-000007
Figure PCTCN2022074327-appb-000008
在一些实施方案中，R选自C 1-4烷基、C 1-4烷氧基、C 2-4烯基、C 2-4炔基、卤代C 1-4烷基、卤代C 1-4烷氧基、氰基C 1-4烷基、羟基C 1-4烷基、苯基C 1-3烷基、3-6元环烷基、苯基、苯基C 1-3烷基、卤代苯基、氰基苯基。 In some embodiments, R is selected from C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, halo C 1-4 alkyl, halo C 1-4 alkoxy, cyano C 1-4 alkyl, hydroxy C 1-4 alkyl, phenyl C 1-3 alkyl, 3-6 membered cycloalkyl, phenyl, phenyl C 1-3 Alkyl, halophenyl, cyanophenyl.
在一些实施方案中，R选自具有1、2或3个独立地选自氮、氧和硫的杂原子的饱和3-8元杂环基。In some embodiments, R is selected from saturated 3-8 membered heterocyclyl having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
在一些实施方案中，R选自具有1、2或3个独立地选自氮、氧和硫的杂原子的不饱和3-8元杂环基。In some embodiments, R is selected from unsaturated 3-8 membered heterocyclyl groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
在一些实施方案中，R选自具有1个氮原子的饱和3-8元杂环基、具有1个氮原子的不 饱和3-8元杂环基，具有1个氧原子的饱和3-8元杂环基、具有1个氧原子的不饱和3-8元杂环基、具有1个硫原子的饱和3-8元杂环基、具有1个硫原子的不饱和3-8元杂环基、具有2个氮原子的4-8元饱和杂环基、具有2个氮原子的4-8元不饱和杂环基、具有1个氮原子和1个氧原子的4-8元饱和杂环基、具有1个氮原子和1个氧原子的4-8元不饱和杂环基、具有2个氧原子的4-8元饱和杂环基、具有2个氧原子的4-8元不饱和杂环基、具有1个氮原子和1个硫原子的4-8元饱和杂环基、具有1个氮原子和1个硫原子的4-8元不饱和杂环基、具有1个氧原子和1个硫原子的饱和4-8元杂环基。In some embodiments, R is selected from saturated 3-8 membered heterocyclyl having 1 nitrogen atom, unsaturated 3-8 membered heterocyclyl having 1 nitrogen atom, saturated 3-8 membered heterocyclyl having 1 oxygen atom Member heterocyclic group, unsaturated 3-8 membered heterocyclic group with 1 oxygen atom, saturated 3-8 membered heterocyclic group with 1 sulfur atom, unsaturated 3-8 membered heterocyclic group with 1 sulfur atom base, 4-8 membered saturated heterocyclic group with 2 nitrogen atoms, 4-8 membered unsaturated heterocyclic group with 2 nitrogen atoms, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom Ring group, 4-8-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 4-8-membered saturated heterocyclic group having 2 oxygen atoms, 4-8-membered non-saturated heterocyclic group having 2 oxygen atoms Saturated heterocyclic group, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 4-8 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen A saturated 4-8 membered heterocyclic group with 1 sulfur atom.
在一些实施方案中，R选自具有1个氮原子的4-6元饱和杂环基、具有1个氮原子的4-6元不饱和杂环基、具有1个氧原子的4-6元饱和杂环基、具有1个氧原子的4-6元不饱和杂环基、具有1个硫原子的4-6元饱和杂环基、具有1个硫原子的4-6元不饱和杂环基、具有2个氮原子的5-6元饱和杂环基、具有2个氮原子的5-6元不饱和杂环基、具有1个氮原子和1个氧原子的5-6元饱和杂环基、具有1个氮原子和1个氧原子的5-6元不饱和杂环基、具有2个氧原子的5-6元饱和杂环基、具有2个氧原子的5-6元不饱和杂环基、具有1个氮原子和1个硫原子的5-6元饱和杂环基、具有1个氮原子和1个硫原子的5-6元不饱和杂环基、具有1个氧原子和1个硫原子的饱和5-6元杂环基。In some embodiments, R is selected from 4-6 membered saturated heterocyclyl having 1 nitrogen atom, 4-6 membered unsaturated heterocyclyl having 1 nitrogen atom, 4-6 membered having 1 oxygen atom Saturated heterocyclic group, 4-6 membered unsaturated heterocyclic group with 1 oxygen atom, 4-6 membered saturated heterocyclic group with 1 sulfur atom, 4-6 membered unsaturated heterocyclic group with 1 sulfur atom base, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom Ring group, 5-6-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 5-6-membered saturated heterocyclic group having 2 oxygen atoms, 5-6-membered non-saturated heterocyclic group having 2 oxygen atoms Saturated heterocyclic group, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen A saturated 5-6 membered heterocyclic group with 1 sulfur atom.
在一些实施方案中，R选自具有1、2或3个独立地选自氮、氧和硫的杂原子的5-6元杂芳基。In some embodiments, R is selected from 5-6 membered heteroaryl groups having 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, and sulfur.
在一些实施方案中，R选自具有1个氮原子的4-6元杂芳基，具有1个氧原子的5-6元杂芳基、具有1个硫原子的5-6元杂芳基、具有2个氮原子的5-6元杂芳基、具有3个氮原子的5-6元杂芳基。In some embodiments, R is selected from 4-6 membered heteroaryl with 1 nitrogen atom, 5-6 membered heteroaryl with 1 oxygen atom, 5-6 membered heteroaryl with 1 sulfur atom , 5-6-membered heteroaryl with 2 nitrogen atoms, 5-6-membered heteroaryl with 3 nitrogen atoms.
在一些实施方案中，R选自氢、氟、氯、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、苯基、苄基、甲基苯基、乙基苯基、呋喃基、吡喃基、吡咯烷基、吡啶基、哌啶基、哌嗪基、嘧啶基、噻吩基、三甲基硅烷基、三乙基硅烷基、三异丙基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基。In some embodiments, R is selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, methoxy, ethoxy, phenyl, benzyl , methylphenyl, ethylphenyl, furanyl, pyranyl, pyrrolidinyl, pyridyl, piperidinyl, piperazinyl, pyrimidinyl, thienyl, trimethylsilyl, triethylsilyl , Triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
在一些实施方案中，R选自氢、甲基、乙基、叔丁基、甲氧基、乙氧基、苯基、苄基、三甲基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基。In some embodiments, R is selected from hydrogen, methyl, ethyl, tert-butyl, methoxy, ethoxy, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-Butyldiphenylsilyl.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式II化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula II, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000009
Figure PCTCN2022074327-appb-000009
其中A、L、Z、R 3、R 4、R’和R和如上定义。 wherein A , L, Z, R3 , R4, R' and R are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式III化合物或其药学上可接受的盐，In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula III, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000010
Figure PCTCN2022074327-appb-000010
其中A、L、R 1、R 4、R’和R和如上定义。 wherein A , L, R1, R4 , R' and R are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式II-A化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula II-A or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000011
Figure PCTCN2022074327-appb-000011
其中A、L、Z、R 3、R’和R如上定义。 wherein A, L, Z, R3 , R' and R are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式II-B化合物或其药学上可接受的盐，In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula II-B, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000012
Figure PCTCN2022074327-appb-000012
其中A、L、R’和R如上定义。wherein A, L, R' and R are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式III-A化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula III-A, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000013
Figure PCTCN2022074327-appb-000013
其中L、R 1、R’和R如上定义。 wherein L, R1, R ' and R are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式III-A-1～III-A-6化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula III-A-1 to III-A-6 or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000014
Figure PCTCN2022074327-appb-000014
其中R 1、R’和R如上定义。 wherein R 1 , R' and R are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式III-B化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula III-B or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000015
Figure PCTCN2022074327-appb-000015
其中A、R 1、R’和R如上定义。 wherein A , R1, R' and R are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式IV化合物或其药学上可接受的盐，In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IV, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000016
Figure PCTCN2022074327-appb-000016
其中A、L和R 1如上定义。 wherein A, L and R 1 are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式IV-A化合物或其药学上可接受的盐，In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula IV-A, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000017
Figure PCTCN2022074327-appb-000017
其中L和R 1如上定义。 wherein L and R1 are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式IV-A-1～IV-A-6化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula IV-A-1 to IV-A-6 or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000018
Figure PCTCN2022074327-appb-000018
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式IV-B化合物或其 药学上可接受的盐，In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from a compound of formula IV-B or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000019
Figure PCTCN2022074327-appb-000019
其中A和R 1如上定义。 wherein A and R 1 are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式V化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula V, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000020
Figure PCTCN2022074327-appb-000020
其中A和L如上定义。wherein A and L are as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式V-A化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from compounds of formula V-A, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000021
Figure PCTCN2022074327-appb-000021
其中L如上定义。wherein L is as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式V-A-1～V-A-6化合物或其药学上可接受的盐，In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from compounds of formula V-A-1 to V-A-6 or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000022
Figure PCTCN2022074327-appb-000022
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自式V-B化合物或其药学上可接受的盐，In some embodiments, a compound of formula I of the present application, or a pharmaceutically acceptable salt thereof, is selected from a compound of formula V-B, or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022074327-appb-000023
Figure PCTCN2022074327-appb-000023
其中A如上定义。wherein A is as defined above.
在一些实施方案中，本申请的式I化合物或其药学上可接受的盐选自以下化合物或其药学上可接受的盐：In some embodiments, the compound of formula I of the present application or a pharmaceutically acceptable salt thereof is selected from the following compounds or a pharmaceutically acceptable salt thereof:
Figure PCTCN2022074327-appb-000024
Figure PCTCN2022074327-appb-000024
Figure PCTCN2022074327-appb-000025
Figure PCTCN2022074327-appb-000025
另一方面，本申请涉及药物组合物，其包含本申请的式I化合物或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。In another aspect, the present application relates to pharmaceutical compositions comprising a compound of formula I of the present application or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical compositions of the present application further include pharmaceutically acceptable excipients.
另一方面，本申请涉及治疗哺乳动物由乙酰辅酶A羧化酶(ACC)介导的疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的式I化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present application relates to a method of treating a disease mediated by acetyl-CoA carboxylase (ACC) in a mammal, comprising administering to a mammal, preferably a human, in need of such treatment, a therapeutically effective amount of a compound of formula I or a pharmacy an acceptable salt thereof, or a pharmaceutical composition thereof.
另一方面，本申请涉及式I化合物或其药学上可接受的盐、或其药物组合物在制备预防或者治疗乙酰辅酶A羧化酶(ACC)介导的疾病的药物中的用途。In another aspect, the present application relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.
另一方面，本申请涉及式I化合物或其药学上可接受的盐、或其药物组合物在预防或者治疗乙酰辅酶A羧化酶(ACC)介导的疾病中的用途。In another aspect, the present application relates to the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.
另一方面，本申请涉及预防或者治疗乙酰辅酶A羧化酶(ACC)介导的疾病的式I化合物或其药学上可接受的盐、或其药物组合物。In another aspect, the present application relates to a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the prevention or treatment of acetyl-CoA carboxylase (ACC) mediated diseases.
在一些实施方案中，乙酰辅酶A羧化酶(ACC)介导的疾病包括但不限于胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、肺癌、胰腺癌。In some embodiments, diseases mediated by acetyl-CoA carboxylase (ACC) include, but are not limited to, insulin resistance, obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic fatty liver disease Steatohepatitis, lung cancer, pancreatic cancer.
本发明的化合物能够高活性的抑制ACC1酶、ACC2酶，对ACC介导的疾病例如肺癌、胰腺癌具有良好的抑制作用，体内代谢稳定性好，药代吸收良好。The compound of the present invention can inhibit ACC1 enzyme and ACC2 enzyme with high activity, has good inhibitory effect on ACC-mediated diseases such as lung cancer and pancreatic cancer, has good metabolic stability in vivo and good pharmacokinetic absorption.
定义definition
除非另有说明，本申请中所用的下列术语具有下列含义。一个特定的术语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照本领域普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered indeterminate or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
术语“被取代”是指特定原子上的任意一个或多个氢原子被取代基取代，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧代(即＝O)时，意味着两个氢原子被取代，氧代不会发生在芳香基上。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are substituted and oxo does not occur on an aromatic group.
术语“任选”或“任选地”是指随后描述的事件或情况可以发生或不发生，该描述包括发生所述事件或情况和不发生所述事件或情况。例如，乙基“任选”被卤素取代，指乙基可以是未被取代的(CH 2CH 3)、单取代的(如CH 2CH 2F)、多取代的(如CHFCH 2F、CH 2CHF 2等)或完全被取代的(CF 2CF 3)。本领域技术人员可理解，对于包含一个或多个取代基的任何基团，不会引入任何在空间上不可能存在和/或不能合成的取代或取代模式。 The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the non-occurrence of said event or circumstance. For example, an ethyl group "optionally" substituted with halogen means that the ethyl group can be unsubstituted ( CH2CH3 ) , monosubstituted (eg CH2CH2F ) , polysubstituted (eg CHFCH2F , CH 2 CHF 2 etc.) or fully substituted (CF 2 CF 3 ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.
本文中的C m-n，是该部分具有给定范围中的整数个碳原子。例如“C 1-6”是指该基团可具有1个碳原子、2个碳原子、3个碳原子、4个碳原子、5个碳原子或6个碳原子。 Cmn in this context, is that the moiety has an integer number of carbon atoms in the given range. For example " C1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被2个R所取代，则每个R都有独立的选项。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为化学键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a chemical bond.
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表化学键时表示该结构实际上是A-Z。When one of the variables is selected from a chemical bond, it means that the two groups connected to it are directly connected. For example, when L in A-L-Z represents a chemical bond, it means that the structure is actually A-Z.
当一个取代基的键交叉连接到一个环上的两个原子时，这种取代基可以与这个环上的任意原子相键合。例如，结构单元
Figure PCTCN2022074327-appb-000026
表示其可在环己基或者环己二烯上的任意一个位置发生取代。 When a substituent's bond is cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring. For example, structural unit
Figure PCTCN2022074327-appb-000026
Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.
术语“卤”或“卤素”是指氟、氯、溴和碘。The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.
术语“羟基”指-OH基团。The term "hydroxyl" refers to the -OH group.
术语“氰基”指-CN基团。The term "cyano" refers to the -CN group.
术语“氨基”指-NH 2基团。 The term "amino" refers to the -NH2 group.
术语“硝基”指-NO 2基团。 The term "nitro" refers to the -NO 2 group.
术语“烷基”是指通式为C nH 2n+1的烃基。该烷基可以是直链或支链的。例如，术语“C 1- 6烷基”指含有1至6个碳原子的烷基(例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、1-甲基丁基、2-甲基丁基、3-甲基丁基、新戊基、己基、2-甲基戊 基等)。类似地，烷氧基、烷基氨基、二烷基氨基、烷基磺酰基和烷硫基的烷基部分(即烷基)具有上述相同定义。 The term "alkyl" refers to a hydrocarbon group of the general formula CnH2n+1 . The alkyl group can be straight or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio (ie, alkyl) have the same definitions above.
术语“硅烷基”是指烷基取代的硅基，烷基可以是直链或支链。例如，三甲基硅烷基、三乙基硅烷基、三异丙基硅烷基、叔丁基二甲基硅烷基，硅烷基也可以进一步被苯基取代，例如叔丁基二苯基硅烷基。The term "silyl" refers to a silyl group substituted with an alkyl group, which may be straight or branched chain. For example, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, silyl groups can also be further substituted with phenyl groups, such as tert-butyldiphenylsilyl.
术语“亚烷基”是指由碳原子和氢原子组成的直链或者直链的饱和的脂肪烃基，其通过两个连接点与其余部分连接。该术语的非限制性实例包括-CH 2-、-CH(CH 3)-、-CH 2CH 2-、-CH(CH 2CH 3)-、-CH 2CH(CH 3)-、-CH 2CH 2CH 2-、-C(CH 3) 2-、-CH 2CH 2CH 2CH 2-、-CH 2CH(CH 3)CH 2-、-CH(CH 3)CH 2CH 2-、-CH 2C(CH 3) 2-。 The term "alkylene" refers to a straight-chain or straight-chain saturated aliphatic hydrocarbon group consisting of carbon and hydrogen atoms, which is attached to the remainder through two points of attachment. Non-limiting examples of this term include -CH2- , -CH( CH3 )-, -CH2CH2- , -CH( CH2CH3 ) - , -CH2CH( CH3 ) -, -CH 2 CH 2 CH 2 -, -C(CH 3 ) 2 -, -CH 2 CH 2 CH 2 CH 2 -, -CH 2 CH(CH 3 )CH 2 -, -CH(CH 3 )CH 2 CH 2 - , -CH 2 C(CH 3 ) 2 -.
术语“烷氧基”指-O-烷基。The term "alkoxy" refers to -O-alkyl.
术语“烷基氨基”指-NH-烷基。The term "alkylamino" refers to -NH-alkyl.
术语“二烷基氨基”指-N(烷基) 2。 The term "dialkylamino" refers to -N(alkyl) 2 .
术语“烷基磺酰基”指-SO 2-烷基。 The term "alkylsulfonyl" refers to -SO2 -alkyl.
术语“烷硫基”指-S-烷基。The term "alkylthio" refers to -S-alkyl.
术语“烯基”是指由碳原子和氢原子组成的直链或支链的具有至少一个双键的不饱和脂肪族烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基、1,3-丁二烯基等。The term "alkenyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group composed of carbon atoms and hydrogen atoms having at least one double bond. Non-limiting examples of alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, 1,3-butadienyl, and the like.
术语“炔基”是指由碳原子和氢原子组成的直链或支链的具有至少一个三键的不饱和脂肪族烃基。炔基的非限制性实例包括但不限于乙炔基(-C≡CH)、1-丙炔基(-C≡C-CH 3)、2-丙炔基(-CH 2-C≡CH)、1,3-丁二炔基(-C≡C-C≡CH)等。 The term "alkynyl" refers to a straight or branched chain unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms having at least one triple bond. Non-limiting examples of alkynyl groups include, but are not limited to, ethynyl (-C≡CH), 1-propynyl (-C≡C- CH3 ), 2-propynyl ( -CH2 -C≡CH), 1,3-Butadiynyl (-C≡CC≡CH) and the like.
术语“环烷基”指完全饱和的并且可以以呈单环、桥环或螺环存在的碳环。除非另有指示，该碳环通常为3至10元环。环烷基非限制性实例包括但不限于
Figure PCTCN2022074327-appb-000027
Figure PCTCN2022074327-appb-000028
金刚烷基等。 The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 3- to 10-membered ring. Non-limiting examples of cycloalkyl groups include, but are not limited to
Figure PCTCN2022074327-appb-000027
Figure PCTCN2022074327-appb-000028
Adamantyl etc.
术语“环烯基”是指不完全饱和的并且可以以呈单环、桥环或螺环存在的非芳族碳环。除非另有指示，该碳环通常为5至8元环。环烯基的非限制性实例包括但不限于环戊烯基、环戊二烯基、环己烯基、环己二烯基、环庚烯基、环庚二烯基等。The term "cycloalkenyl" refers to a non-aromatic carbocyclic ring that is not fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 5- to 8-membered ring. Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, and the like.
术语“杂环基”是指完全饱和的或部分不饱和的(但不是完全不饱和的杂芳族，例如具有1 或2个双键)，并且可以以单环、桥环或螺环存在的非芳族环。除非另有指示，该杂环通常为含有1、2、3或4个独立地选自硫S(O) n(其中，n为0、1或2)、氧和/或氮的杂原子(优选1或2个杂原子)的3、4、5、6、7、8、9、10元环。 The term "heterocyclyl" refers to fully saturated or partially unsaturated (but not fully unsaturated heteroaromatic, eg, having 1 or 2 double bonds), and may exist as a monocyclic, bridged or spirocyclic ring non-aromatic ring. Unless otherwise indicated, the heterocycle is typically one containing 1, 2, 3 or 4 heteroatoms independently selected from sulfur S(O) n (wherein n is 0, 1 or 2), oxygen and/or nitrogen ( 3, 4, 5, 6, 7, 8, 9, 10 membered rings with 1 or 2 heteroatoms) are preferred.
饱和的3元杂环基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，饱和的4元杂环基的非限制性实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，饱和的5元杂环基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基，饱和的6元杂环基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,3-二噻烷基、1,4-二噻烷基，饱和的7元杂环基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。Examples of saturated 3-membered heterocyclyl groups include, but are not limited to, oxiranyl, oxiranyl, azithryl, and non-limiting examples of saturated 4-membered heterocyclyl groups include, but are not limited to, azetidinyl, Examples of oxetanyl, thibutanyl, saturated 5-membered heterocyclyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl , thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, examples of saturated 6-membered heterocyclic groups include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazine base, 1,4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, saturated 7-membered heterocycle Examples of cyclic groups include, but are not limited to, azepanyl, oxepanyl, thiepanyl.
部分不饱和的杂环基的非限制性实例包括但不限于
Figure PCTCN2022074327-appb-000029
Figure PCTCN2022074327-appb-000030
Figure PCTCN2022074327-appb-000031
等。 Non-limiting examples of partially unsaturated heterocyclyl groups include, but are not limited to
Figure PCTCN2022074327-appb-000029
Figure PCTCN2022074327-appb-000030
Figure PCTCN2022074327-appb-000031
Wait.
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。The term "aryl" refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated pi electron system. For example, an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms. Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracenyl, and 1,2,3,4-tetralin, and the like.
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个4至8元环，尤其是5至8元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。杂芳基的非限制性实例包括但不限于
Figure PCTCN2022074327-appb-000032
Figure PCTCN2022074327-appb-000033
等。 The term "heteroaryl" refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, the remaining ring atoms being C, and having at least one aromatic ring. Preferred heteroaryl groups have a single 4 to 8 membered ring, especially 5 to 8 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms. Non-limiting examples of heteroaryl groups include, but are not limited to
Figure PCTCN2022074327-appb-000032
Figure PCTCN2022074327-appb-000033
Wait.
术语“治疗”意为将本申请所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：The term "treating" means administering a compound or formulation described herein to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；(i) preventing the emergence of a disease or disease state in mammals, particularly when such mammals are susceptible to, but have not been diagnosed with, the disease state;
(ii)抑制疾病或疾病状态，即遏制其发展；(ii) inhibiting the disease or disease state, i.e. arresting its development;
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。(iii) Alleviation of the disease or disease state, even if the disease or disease state resolves.
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。The term "therapeutically effective amount" means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the present application for the onset of one or more symptoms of a particular disease, condition or disorder described herein. The amount of a compound of the present application that constitutes a "therapeutically effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to its own knowledge and the present disclosure.
术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
作为药学上可接受的盐，例如，可以提及金属盐、铵盐、与有机碱形成的盐、与无机酸形成的盐、与有机酸形成的盐、与碱性或者酸性氨基酸形成的盐等。As the pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned .
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。The term "pharmaceutically acceptable excipients" refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, ie, "including but not limited to".
本申请的化合物和中间体还可以以不同的互变异构体形式存在，并且所有这样的形式包含于本申请的范围内。术语“互变异构体”或“互变异构体形式”是指可经由低能垒互变的不同能量的结构异构体。例如，质子互变异构体(也称为质子转移互变异构体)包括经由质子迁移的互变，如酮-烯醇及亚胺-烯胺异构化。质子互变异构体的具体实例是咪唑部分，其中质子可在两个环氮间迁移。价互变异构体包括通过一些成键电子的重组的互变。The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogens. Valence tautomers include interconversions through recombination of some of the bonding electrons.
本申请还包括与本文中记载的那些相同的，但一个或多个原子被原子量或质量数不同于自然中通常发现的原子量或质量数的原子置换的同位素标记的本申请化合物。可结合到本申请化合物的同位素的实例包括氢、碳、氮、氧、磷、硫、氟、碘和氯的同位素，诸如分别为 2H、 3H、 11C、 13C、 14C、 13N、 15N、 15O、 17O、 18O、 31P、 32P、 35S、 18F、 123I、 125I和 36Cl等。某些同位素标记的本申请化合物(例如用 3H及 14C标记的那些)可用于化合物和/或底物组织分布分析中。氚化(即 3H)和碳-14(即 14C)同位素对于由于它们易于制备和可检测性是尤其优选的。正电子发射同位素，诸如 15O、 13N、 11C和 18F可用于正电子发射断层扫描(PET)研究以测定底物占有率。通常可以通过与公开于下文的方案和/或实施例中的那些类似的下列程序， 通过同位素标记试剂取代未经同位素标记的试剂来制备同位素标记的本申请化合物。 The present application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, 3H , 11C , 13C , 14C , 13 , respectively N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 123 I, 125 I and 36 Cl and the like. Certain isotopically-labeled compounds of the present application (eg, those labeled with3H and14C ) are useful in compound and/or substrate tissue distribution assays. Tritiated (ie 3 H) and carbon-14 (ie 14 C) isotopes are especially preferred for their ease of preparation and detectability. Positron emitting isotopes such as15O , 13N , 11C and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
此外，用较重同位素(诸如氘(即 2H))取代可以提供某些由更高的代谢稳定性产生的治疗优点(例如增加的体内半衰期或降低的剂量需求)，并且因此在某些情形下可能是优选的，其中氘取代可以是部分或完全的，部分氘取代是指至少一个氢被至少一个氘取代。 In addition, substitution with heavier isotopes such as deuterium (ie 2H ) may provide certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, where the deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.
本申请化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本申请的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。例示性的立体异构体化合物如下所示，但不限于此。The compounds of the present application may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents. Exemplary stereoisomeric compounds are shown below, but are not limited thereto.
本申请的药物组合物可通过将本申请的化合物与适宜的药学上可接受的辅料组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.
给予本申请化合物或其药学上可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、局部、吸入、肠胃外、舌下、***内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.
本申请的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等。The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.
在一些实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的辅料混合，来配制该药物组合物。这些辅料能使本申请的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体辅料混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅料，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally grinding the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to give tablets or icing core. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.
本申请的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本申请的实施例。The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application.
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在 已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。The chemical reactions of the specific embodiments of the present application are carried out in suitable solvents suitable for the chemical changes of the present application and the required reagents and materials. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.
在一些实施方案中，本申请通式IV的化合物可以由以下路线来制备，包括以下步骤：In some embodiments, the compounds of general formula IV of the present application can be prepared by the following routes, including the following steps:
Figure PCTCN2022074327-appb-000034
Figure PCTCN2022074327-appb-000034
1)式A化合物、式B化合物与缩合剂反应，得到式C化合物；1) the compound of formula A, the compound of formula B react with a condensing agent to obtain the compound of formula C;
Figure PCTCN2022074327-appb-000035
Figure PCTCN2022074327-appb-000035
2)式C化合物发生环合反应，得到式D化合物；2) the compound of formula C undergoes cyclization reaction to obtain the compound of formula D;
Figure PCTCN2022074327-appb-000036
Figure PCTCN2022074327-appb-000036
3)在溶剂的存在下，式D化合物与卤代物反应，得到式E化合物；3) in the presence of a solvent, the compound of formula D is reacted with a halide to obtain a compound of formula E;
Figure PCTCN2022074327-appb-000037
Figure PCTCN2022074327-appb-000037
4)式E化合物与R 1C≡CH反应，得到式F化合物； 4) The compound of formula E is reacted with R 1 C≡CH to obtain the compound of formula F;
Figure PCTCN2022074327-appb-000038
Figure PCTCN2022074327-appb-000038
5)式F化合物与2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙烷-1-醇反应，得到式G化合物；5) The compound of formula F is reacted with 2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethane-1-ol to obtain the compound of formula G;
Figure PCTCN2022074327-appb-000039
Figure PCTCN2022074327-appb-000039
6)式G化合物可按照本领域的常规方法，脱去R 3基团，制备得到式IV化合物。 6) The compound of formula G can be prepared by removing the R 3 group according to conventional methods in the art to obtain the compound of formula IV.
其中，A、L、R 1、R 3和R如上定义，X为F、Cl、Br、I；C*为R构型、S构型或外消旋体。 Wherein, A, L, R 1 , R 3 and R are as defined above, X is F, Cl, Br, I; C* is R configuration, S configuration or racemate.
在一些实施方案中，X为Br。In some embodiments, X is Br.
在一些实施方案中，步骤5)中式F化合物与(R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙烷-1-醇反应。In some embodiments, the compound of formula F in step 5) is combined with (R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethane -1-ol reaction.
在一些实施方案中，本申请通式IV的化合物还可以由以下路线来制备，包括以下步骤：In some embodiments, the compound of general formula IV of the present application can also be prepared by the following route, including the following steps:
Figure PCTCN2022074327-appb-000040
Figure PCTCN2022074327-appb-000040
1)式A化合物、式B化合物与缩合剂反应，得到式C化合物；1) the compound of formula A, the compound of formula B react with a condensing agent to obtain the compound of formula C;
Figure PCTCN2022074327-appb-000041
Figure PCTCN2022074327-appb-000041
2)式C化合物发生环合反应，得到式D化合物；2) the compound of formula C undergoes cyclization reaction to obtain the compound of formula D;
Figure PCTCN2022074327-appb-000042
Figure PCTCN2022074327-appb-000042
3)式D化合物与式H化合物反应，在溶剂的存在下反应，得到式J化合物；3) the compound of formula D reacts with the compound of formula H, and reacts in the presence of a solvent to obtain the compound of formula J;
Figure PCTCN2022074327-appb-000043
Figure PCTCN2022074327-appb-000043
4)式J化合物与卤化物反应，得到式K化合物；4) the compound of formula J is reacted with a halide to obtain the compound of formula K;
Figure PCTCN2022074327-appb-000044
Figure PCTCN2022074327-appb-000044
5)式K化合物与R 1C≡CH反应，得到式G化合物； 5) The compound of formula K is reacted with R 1 C≡CH to obtain the compound of formula G;
Figure PCTCN2022074327-appb-000045
Figure PCTCN2022074327-appb-000045
6)式G化合物可按照本领域的常规方法，脱去R 3基团，制备得到式IV化合物。 6) The compound of formula G can be prepared by removing the R 3 group according to conventional methods in the art to obtain the compound of formula IV.
其中，A、L、R 1、R 3和R如上定义，X为F、Cl、Br、I；C*为R构型、S构型或外消旋体。 Wherein, A, L, R 1 , R 3 and R are as defined above, X is F, Cl, Br, I; C* is R configuration, S configuration or racemate.
在一些实施方案中，X为Br。In some embodiments, X is Br.
在一些实施方案中，式H化合物为(R)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃。本申请采用下述缩略词：In some embodiments, the compound of formula H is (R)-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran. This application uses the following acronyms:
Cbz代表苄氧基羰基；TMS代表三甲基硅烷基；TES代表三乙基硅烷基；TIPS代表三异丙基硅烷基；TBS代表叔丁基二甲基硅烷基；TBDPS代表叔丁基二苯基硅烷基；MS代表甲磺酰基；DCM代表二氯甲烷；PE代表石油醚；DMF代表N,N-二甲基甲酰胺；EtOAc代表乙酸乙酯；i-PrOH代表异丙醇；EtOH代表乙醇；MeOH是甲醇；THF代表四氢呋喃。Cbz stands for benzyloxycarbonyl; TMS stands for trimethylsilyl; TES stands for triethylsilyl; TIPS stands for triisopropylsilyl; TBS stands for tert-butyldimethylsilyl; TBDPS stands for tert-butyldiphenyl silyl; MS for methanesulfonyl; DCM for dichloromethane; PE for petroleum ether; DMF for N,N-dimethylformamide; EtOAc for ethyl acetate; i-PrOH for isopropanol; EtOH for ethanol ; MeOH is methanol; THF is tetrahydrofuran.
具体实施例specific embodiment
为清楚起见，进一步用实施例来阐述本发明，但是实施例并非限制本申请的范围。本申请所使用的所有试剂是市售的，无需进一步纯化即可使用。For the sake of clarity, the present invention is further illustrated by examples, which do not limit the scope of the application. All reagents used in this application were commercially available and used without further purification.
实施例1：(R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸(式I-1化合物)Example 1: (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Bicyclo[1.1.1]pentane-1-carboxylic acid (compound of formula I-1)
Figure PCTCN2022074327-appb-000046
Figure PCTCN2022074327-appb-000046
步骤一：3-(((苄氧基)羰基)氨基)双环[1.1.1]戊烷-1-羧酸甲酯的合成Step 1: Synthesis of methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate
将3-(甲氧基羰基)双环[1.1.1]戊烷-1-羧酸(22g，129mmol)，甲苯(660mL)和三乙胺(54.1mL，388mmol)，二苯基磷酰肼(57.4mL，259mmol)混合，加热回流反应3小时后加入苄醇(41.9g,388mmol)，继续回流反应4小时。反应液降至室温，浓缩，所得粗品用乙酸乙酯溶解(200mL)，分别用水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，所得粗品用柱层析分离纯化(石油醚:乙酸乙酯＝5:1)，得到标题化合物24.5g。Combine 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (22 g, 129 mmol), toluene (660 mL) and triethylamine (54.1 mL, 388 mmol), diphenylphosphoric hydrazide ( 57.4 mL, 259 mmol) were mixed, heated and refluxed for 3 hours, then benzyl alcohol (41.9 g, 388 mmol) was added, and the reflux reaction was continued for 4 hours. The reaction solution was cooled to room temperature and concentrated. The obtained crude product was dissolved in ethyl acetate (200 mL), washed with water and saturated brine, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=5:1) to obtain 24.5 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ8.10(s,1H),7.50-7.27(m,5H),5.01(s,2H),3.61(s,3H),2.19(s,6H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ8.10(s, 1H), 7.50-7.27(m, 5H), 5.01(s, 2H), 3.61(s, 3H), 2.19(s, 6H) ).
13C-NMR(125MHz,DMSO-d 6):δ169.87,155.51,137.37,128.84,128.31,65.66,54.05,51.97,45.86,35.43。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 169.87, 155.51, 137.37, 128.84, 128.31, 65.66, 54.05, 51.97, 45.86, 35.43.
MS(ESI)m/z:276.4[M+H] +。 MS (ESI) m/z: 276.4 [M+H] + .
步骤二：3-氨基双环[1.1.1]戊烷-1-羧酸甲酯盐酸盐的合成Step 2: Synthesis of 3-aminobicyclo[1.1.1]pentane-1-carboxylate methyl ester hydrochloride
将3-(((苄氧基)羰基)氨基)双环[1.1.1]戊烷-1-羧酸甲酯(24.5g，89mmol)、甲醇(800mL)和钯碳(2.45g,23.02mmol)混合，氢气氛围下室温反应7小时，硅藻土过滤，浓缩，残余物以乙酸乙酯(200mL)溶解，向其中加入4M的盐酸二氧六环溶液(22.25mL,89mmol)，抽滤，得到标题化合物14.3g。Combine methyl 3-(((benzyloxy)carbonyl)amino)bicyclo[1.1.1]pentane-1-carboxylate (24.5 g, 89 mmol), methanol (800 mL) and palladium on carbon (2.45 g, 23.02 mmol) The mixture was mixed, reacted at room temperature for 7 hours under a hydrogen atmosphere, filtered through celite, concentrated, the residue was dissolved in ethyl acetate (200 mL), 4M hydrochloric acid dioxane solution (22.25 mL, 89 mmol) was added thereto, and suction filtered to obtain The title compound 14.3 g.
1H-NMR(500MHz,DMSO-d 6):δ9.21(s,3H),3.62(s,3H),2.24(s,6H)。 1 H-NMR (500 MHz, DMSO-d 6 ): δ 9.21 (s, 3H), 3.62 (s, 3H), 2.24 (s, 6H).
13C-NMR(125MHz,DMSO-d 6):δ168.48,53.18,52.31,43.68,35.31。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 168.48, 53.18, 52.31, 43.68, 35.31.
步骤三：2-(3-(3-(甲氧基羰基)双环[1.1.1]戊-1-基)脲基)-4-甲基噻吩-3-羧酸乙酯的合成Step 3: Synthesis of ethyl 2-(3-(3-(methoxycarbonyl)bicyclo[1.1.1]pent-1-yl)ureido)-4-methylthiophene-3-carboxylate
将2-氨基-4-甲基噻吩-3-羧酸乙酯(12g，64.8mmol)溶于二氯甲烷(120mL)，0℃下向其中分批加入N,N-羰基二咪唑(11.55g，71.3mmol)，室温反应12小时，依次加入三乙胺(9.93mL，71.3mmol)和3-氨基双环[1.1.1]戊烷-1-羧酸甲酯盐酸盐(12.66g，71.3mmol)，室温反应2小时。向反应液中加入水(200mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，残余物以石油醚(800mL)打浆，抽滤，得到标题化合物21.5g。Ethyl 2-amino-4-methylthiophene-3-carboxylate (12 g, 64.8 mmol) was dissolved in dichloromethane (120 mL), to which was added N,N-carbonyldiimidazole (11.55 g in portions at 0°C) , 71.3 mmol), reacted at room temperature for 12 hours, followed by adding triethylamine (9.93 mL, 71.3 mmol) and 3-aminobicyclo[1.1.1]pentane-1-carboxylate methyl ester hydrochloride (12.66 g, 71.3 mmol) ) for 2 hours at room temperature. Water (200 mL) was added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration, concentrated, the residue was slurried with petroleum ether (800 mL), and suction filtered to obtain 21.5 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ10.29(s,1H),8.64(s,1H),6.46(s,1H),4.30(q,J＝7.0Hz,2H),3.63(s,3H),2.27(s,3H),2.26(s,6H),1.31(t,J＝7.0Hz,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 10.29(s, 1H), 8.64(s, 1H), 6.46(s, 1H), 4.30(q, J=7.0Hz, 2H), 3.63( s, 3H), 2.27 (s, 3H), 2.26 (s, 6H), 1.31 (t, J=7.0 Hz, 3H).
13C-NMR(125MHz,DMSO-d 6):δ169.81,165.76,153.29,152.83,133.93,112.03,109.57,60.48,54.22,52.02,45.79,35.73,18.22,14.58。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 169.81, 165.76, 153.29, 152.83, 133.93, 112.03, 109.57, 60.48, 54.22, 52.02, 45.79, 35.73, 18.22, 14.58.
MS(ESI)m/z:351.1[M-H] -。 MS(ESI) m/z: 351.1 [MH] − .
步骤四：3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸甲酯的合成Step 4: 3-(5-Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)bicyclo[1.1.1]pentane Synthesis of Alkane-1-Carboxylic Acid Methyl Esters
将2-(3-(3-(甲氧基羰基)双环[1.1.1]戊-1-基)脲基)-4-甲基噻吩-3-羧酸乙酯(21.5g，61.0mmol)，碳酸铯(39.8g，122mmol)和N,N-二甲基甲酰胺(300mL)混合，80℃反应1小时。反应液降至室温，加入饱和氯化铵溶液(500mL)和乙酸乙酯(500mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，残余物以石油醚和乙酸乙酯的混合溶剂(100mL，石油醚：乙酸乙酯＝10:1)打浆，抽滤，得到标题化合物16g。Ethyl 2-(3-(3-(methoxycarbonyl)bicyclo[1.1.1]pent-1-yl)ureido)-4-methylthiophene-3-carboxylate (21.5 g, 61.0 mmol) , cesium carbonate (39.8 g, 122 mmol) and N,N-dimethylformamide (300 mL) were mixed and reacted at 80° C. for 1 hour. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (500 mL) and ethyl acetate (500 mL) were added, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After suction filtration, concentration, the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (100 mL, petroleum ether:ethyl acetate=10:1), and suction filtered to obtain 16 g of the title compound.
MS(ESI)m/z:305.2[M-H] -。 MS(ESI) m/z: 305.2 [MH] - .
步骤五：3-(6-溴-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸甲酯的合成Step 5: 3-(6-Bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)bicyclo[1.1 .1]Synthesis of methyl pentane-1-carboxylate
0℃下，将N-溴代丁二酰亚胺(9.47g，53.2mmol)分三批加入3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3]-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸甲酯(16.3g，53.2mmol)的二氯甲烷(380mL)溶液中，0℃反应30分钟，反应液用二氯甲烷(200mL)稀释，有机相分别以水和饱 和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩，残余物以石油醚和乙酸乙酯的混合溶剂(360mL，石油醚：乙酸乙酯＝5:1)打浆，抽滤，得到标题化合物20.67g。At 0 °C, N-bromosuccinimide (9.47 g, 53.2 mmol) was added in three portions to 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[ 2,3]-d]pyrimidin-3(2H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid methyl ester (16.3 g, 53.2 mmol) in dichloromethane (380 mL), 0 °C The reaction was carried out for 30 minutes, the reaction solution was diluted with dichloromethane (200 mL), the organic phase was washed with water and saturated brine respectively, dried over anhydrous sodium sulfate, filtered with suction, concentrated, and the residue was mixed with petroleum ether and ethyl acetate in a mixed solvent ( 360 mL, petroleum ether: ethyl acetate = 5: 1), slurried, and suction filtered to obtain 20.67 g of the title compound.
MS(ESI)m/z:383.2[M-H] -。 MS(ESI) m/z: 383.2 [MH] - .
步骤六：3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸甲酯的合成Step Six: 3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine- Synthesis of 3(2H)-yl)bicyclo[1.1.1]pentane-1-carboxylate methyl ester
将3-(6-溴-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸甲酯(0.5g，1.298mmol)，三乙胺(5.23mL，37.5mmol)，N,N-二甲基甲酰胺(5mL)，二(三苯基膦)二氯化钯(0.046g，0.065mmol)，碘化亚铜(0.025g，0.130mmol)，丙炔(1M四氢呋喃溶液)(5.19mL，5.19mmol)加入耐压管中，混合物80℃封管反应4小时。反应液降至室温，加入水(20mL)和乙酸乙酯(20mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，所得粗品用柱层析分离纯化(二氯甲烷:甲醇＝20:1)，得到标题化合物0.147g。3-(6-Bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)bicyclo[1.1.1 ]pentane-1-carboxylate methyl ester (0.5 g, 1.298 mmol), triethylamine (5.23 mL, 37.5 mmol), N,N-dimethylformamide (5 mL), bis(triphenylphosphine)bis Palladium chloride (0.046g, 0.065mmol), cuprous iodide (0.025g, 0.130mmol), propyne (1M tetrahydrofuran solution) (5.19mL, 5.19mmol) were added to a pressure-resistant tube, and the mixture was sealed at 80°C for reaction 4 Hour. The reaction solution was cooled to room temperature, water (20 mL) and ethyl acetate (20 mL) were added, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 0.147 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.05(s,1H),3.64(s,3H),2.62(s,6H),2.36(s,3H),2.11(s,3H)。 1 H-NMR (500 MHz, DMSO-d 6 ): δ 12.05 (s, 1H), 3.64 (s, 3H), 2.62 (s, 6H), 2.36 (s, 3H), 2.11 (s, 3H).
13C-NMR(125MHz,DMSO-d 6):δ169.25,159.73,150.48,138.67,112.70,108.88,94.56,71.51,56.01,52.09,48.04,37.12,15.15,4.75。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 169.25, 159.73, 150.48, 138.67, 112.70, 108.88, 94.56, 71.51, 56.01, 52.09, 48.04, 37.12, 15.15, 4.75.
MS(ESI)m/z:343.2[M-H] -。 MS(ESI) m/z: 343.2 [MH] − .
步骤七：3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸的合成Step Seven: 3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine- Synthesis of 3(2H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid
将3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸甲酯(3.1g，9.00mmol)，甲醇(30mL)，水(6mL)混合，冰浴下加入氢氧化锂(1.889g，45.0mmol)，室温反应1小时。反应液以1N盐酸溶液调pH至酸性，加入乙酸乙酯(100mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩得标题化合物2.652g。3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine-3( 2H)-yl)bicyclo[1.1.1]pentane-1-carboxylate methyl ester (3.1 g, 9.00 mmol), methanol (30 mL) and water (6 mL) were mixed, and lithium hydroxide (1.889 g, 45.0 mmol), react at room temperature for 1 hour. The pH of the reaction solution was adjusted to acidity with 1N hydrochloric acid solution, ethyl acetate (100 mL) was added, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration and concentration to obtain 2.652 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.40(brs,2H),2.57(s,6H),2.35(s,3H),2.10(s,3H)。 1 H-NMR (500 MHz, DMSO-d 6 ): δ 12.40 (brs, 2H), 2.57 (s, 6H), 2.35 (s, 3H), 2.10 (s, 3H).
13C-NMR(125MHz,DMSO-d 6):δ170.58,159.75,150.40,138.54,112.68,108.99,94.46,71.56,55.80,47.94,37.43,15.13,4.76。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 170.58, 159.75, 150.40, 138.54, 112.68, 108.99, 94.46, 71.56, 55.80, 47.94, 37.43, 15.13, 4.76.
MS(ESI)m/z:329.2[M-H] -。 MS(ESI) m/z: 329.2 [MH] - .
步骤八：3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸叔丁基二苯基硅烷基酯的合成Step Eight: 3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine- Synthesis of 3(2H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid tert-butyldiphenylsilyl ester
将3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸(1g，3.03mmol)，1H-咪唑(0.495g，7.26mmol)，N,N-二甲基甲酰胺(30mL)，N,N-二甲基吡啶-4-胺(0.037g，0.303mmol)和叔丁基氯二苯基硅烷(0.998g，3.63mmol)混合，室 温反应4小时。向反应液加入水(100mL)和乙酸乙酯(100mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，所得粗品用柱层析分离纯化(二氯甲烷:甲醇＝20:1)，得到标题化合物1.19g。3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine-3( 2H)-yl)bicyclo[1.1.1]pentane-1-carboxylic acid (1 g, 3.03 mmol), 1H-imidazole (0.495 g, 7.26 mmol), N,N-dimethylformamide (30 mL), N , N-lutidine-4-amine (0.037 g, 0.303 mmol) and tert-butylchlorodiphenylsilane (0.998 g, 3.63 mmol) were mixed and reacted at room temperature for 4 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (dichloromethane:methanol=20:1) to obtain 1.19 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.12(s,1H),7.66-7.64(m,2H),7.63-7.62(m,2H),7.52-7.48(m,2H),7.47-7.44(m,4H),2.73(s,6H),2.37(s,3H),2.11(s,3H),1.04(s,9H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 12.12 (s, 1H), 7.66-7.64 (m, 2H), 7.63-7.62 (m, 2H), 7.52-7.48 (m, 2H), 7.47 -7.44(m, 4H), 2.73(s, 6H), 2.37(s, 3H), 2.11(s, 3H), 1.04(s, 9H).
13C-NMR(125MHz,DMSO-d 6):δ168.07,159.74,150.50,150.35,138.66,135.11,131.57,130.76,128.43,112.75,108.98,94.55,71.50,56.12,48.06,38.53,26.84,19.13,15.13,4.76。 13 C-NMR (125MHz, DMSO-d 6 ): δ168.07,159.74,150.50,150.35,138.66,135.11,131.57,130.76,128.43,112.75,108.98,94.55,71.50,56.12,48.016,19.38. , 4.76.
MS(ESI)m/z:567.4[M-H] -。 MS (ESI) m/z: 567.4 [MH] - .
步骤九：(R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸叔丁基二苯基硅烷基酯(式I-9化合物)的合成Step 9: (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)bicyclo [1.1.1] Synthesis of pentane-1-carboxylic acid tert-butyldiphenylsilyl ester (compound of formula I-9)
将3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)双环[1.1.1]戊烷-1-羧酸叔丁基二苯基硅烷基酯(0.6g，1.055mmol)，(R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙烷-1-醇(0.399g，1.582mmol)，四氢呋喃(6mL)、三苯基膦(0.830g，3.16mmol)和偶氮二甲酸二异丙酯(0.615mL，3.16mmol)混合，室温反应12小时。向反应液加入水(50mL)和乙酸乙酯(50mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，所得粗品用C18柱分离纯化(水：乙腈＝1:20)，得到式I-9化合物0.1g。3-(5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine-3( 2H)-yl)bicyclo[1.1.1]pentane-1-carboxylate tert-butyldiphenylsilyl ester (0.6 g, 1.055 mmol), (R)-2-(2-methoxyphenyl) -2-((tetrahydro-2H-pyran-4-yl)oxy)ethane-1-ol (0.399 g, 1.582 mmol), tetrahydrofuran (6 mL), triphenylphosphine (0.830 g, 3.16 mmol) It was mixed with diisopropyl azodicarboxylate (0.615 mL, 3.16 mmol) and reacted at room temperature for 12 hours. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration, and the obtained crude product is separated and purified by a C18 column (water:acetonitrile=1:20) to obtain 0.1 g of the compound of formula I-9.
MS(ESI)m/z:803.7[M+H] +。 MS (ESI) m/z: 803.7 [M+H] + .
步骤十：式I-1化合物的合成Step 10: Synthesis of the compound of formula I-1
将式I-9化合物(0.1g，0.097mmol)，四丁基氟化铵(1mL，1mmol)和四氢呋喃(0.5mL)混合，室温反应1小时。向反应液加入水(50mL)和乙酸乙酯(50mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，所得粗品用柱层析分离纯化(二氯甲烷：甲醇＝40:1)，得到式I-1化合物0.025g。The compound of formula I-9 (0.1 g, 0.097 mmol), tetrabutylammonium fluoride (1 mL, 1 mmol) and tetrahydrofuran (0.5 mL) were mixed and reacted at room temperature for 1 hour. Water (50 mL) and ethyl acetate (50 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration, and the obtained crude product was separated and purified by column chromatography (dichloromethane:methanol=40:1) to obtain 0.025 g of the compound of formula I-1.
1H-NMR(500MHz,DMSO-d 6):δ12.53(s,1H),7.47-7.43(m,1H),7.32-7.27(m,1H),7.04-6.99(m,1H),6.97(d,J＝8.0Hz,1H),5.25-5.23(m,1H),4.01-3.83(m,2H),3.74(s,3H),3.62-3.56(m,1H),3.54-3.49(m,1H),3.40-3.35(m,1H),3.30-3.27(m,1H),3.26-3.23(m,1H),2.59(s,6H),2.38(s,3H),2.12(s,3H),1.68-1.61(m,2H),1.37-1.31(m,1H),1.23-1.16(m,1H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 12.53 (s, 1H), 7.47-7.43 (m, 1H), 7.32-7.27 (m, 1H), 7.04-6.99 (m, 1H), 6.97 (d, J＝8.0Hz, 1H), 5.25-5.23(m, 1H), 4.01-3.83(m, 2H), 3.74(s, 3H), 3.62-3.56(m, 1H), 3.54-3.49(m ,1H),3.40-3.35(m,1H),3.30-3.27(m,1H),3.26-3.23(m,1H),2.59(s,6H),2.38(s,3H),2.12(s,3H ), 1.68-1.61 (m, 2H), 1.37-1.31 (m, 1H), 1.23-1.16 (m, 1H).
MS(ESI)m/z:563.6[M-H] -。 MS(ESI) m/z: 563.6 [MH] - .
实施例2：(1R，3R)-3-(1-((R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)环丁烷-1-羧酸(式I-2化合物)Example 2: (1R,3R)-3-(1-((R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy )ethyl)-5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine-3 (2H)-yl)cyclobutane-1-carboxylic acid (compound of formula I-2)
Figure PCTCN2022074327-appb-000047
Figure PCTCN2022074327-appb-000047
步骤一：(1S，3S)-3-羟基环丁烷-1-羧酸叔丁酯的合成Step 1: Synthesis of (1S,3S)-3-hydroxycyclobutane-1-carboxylic acid tert-butyl ester
将3-氧代环丁烷-1-羧酸叔丁酯(45g，264mmol)，四氢呋喃(432mL)及甲醇(54mL)混合，0℃下向其中分批加入硼氢化钠(5.00g，132mmol)，保持0℃反应1小时。反应液中加入20％碳酸钾溶液(500mL)和乙酸乙酯(500mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩得到标题化合物44.96g。tert-butyl 3-oxocyclobutane-1-carboxylate (45 g, 264 mmol), tetrahydrofuran (432 mL) and methanol (54 mL) were mixed, and sodium borohydride (5.00 g, 132 mmol) was added in portions at 0°C. , kept at 0 °C for 1 hour. 20% potassium carbonate solution (500 mL) and ethyl acetate (500 mL) were added to the reaction solution, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. Suction filtration and concentration to obtain 44.96 g of the title compound.
1H-NMR(500MHz,CDCl 3):δ4.16-4.08(m,1H),2.83(s,1H),2.57-2.43(m,3H),2.13-2.02(m,2H),1.41(s,9H)。 1 H-NMR (500MHz, CDCl 3 ): δ 4.16-4.08(m, 1H), 2.83(s, 1H), 2.57-2.43(m, 3H), 2.13-2.02(m, 2H), 1.41(s) , 9H).
13C-NMR(125MHz,CDCl 3):δ174.42,80.42,63.16,36.86,30.04,28.02。 13 C-NMR (125 MHz, CDCl 3 ): δ 174.42, 80.42, 63.16, 36.86, 30.04, 28.02.
MS(EI)m/z:172[M] +。 MS (EI) m/z: 172 [M] + .
步骤二：((1R，3R)-3-(1,3-二氧代异吲哚啉-2-基)环丁烷-1-羧酸叔丁酯的合成Step 2: Synthesis of ((1R,3R)-3-(1,3-dioxoisoindolin-2-yl)cyclobutane-1-carboxylic acid tert-butyl ester
将(1S，3S)-3-羟基环丁烷-1-羧酸叔丁酯(25g，145mmol)，异吲哚啉-1,3-二酮(25.6g，174mmol)，三苯基膦(57.1g，218mmol)和四氢呋喃(600mL)混合，0℃下向其中滴加偶氮二甲酸二异丙酯(45.4g，218mmol)，室温反应18小时。反应液中加入水(300mL)和乙酸乙酯(300mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，所得粗品用柱层析分离纯化(石油醚：乙酸乙酯＝20:1)，得到标题化合物29.2g。Combine (1S,3S)-3-hydroxycyclobutane-1-carboxylate tert-butyl ester (25 g, 145 mmol), isoindoline-1,3-dione (25.6 g, 174 mmol), triphenylphosphine ( 57.1 g, 218 mmol) and tetrahydrofuran (600 mL) were mixed, and diisopropyl azodicarboxylate (45.4 g, 218 mmol) was added dropwise thereto at 0°C, and the mixture was reacted at room temperature for 18 hours. Water (300 mL) and ethyl acetate (300 mL) were added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. Suction filtration and concentration, the obtained crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate=20:1) to obtain 29.2 g of the title compound.
1H-NMR(500MHz,CDCl 3):δ7.85-7.80(m,2H),7.74-7.69(m,2H),5.06-4.98(m,1H),3.22-3.16(m,1H),3.14-3.06(m,2H),2.61-2.54(m,2H),1.50(s,9H)。 1 H-NMR (500MHz, CDCl 3 ): δ 7.85-7.80 (m, 2H), 7.74-7.69 (m, 2H), 5.06-4.98 (m, 1H), 3.22-3.16 (m, 1H), 3.14 -3.06(m, 2H), 2.61-2.54(m, 2H), 1.50(s, 9H).
13C-NMR(125MHz,CDCl 3):δ174.86,168.25,133.97,131.89,123.15,80.44,42.62,33.75,30.31,28.08。 13 C-NMR (125 MHz, CDCl 3 ): δ 174.86, 168.25, 133.97, 131.89, 123.15, 80.44, 42.62, 33.75, 30.31, 28.08.
MS(ESI)m/z:302.3[M+H] +。 MS (ESI) m/z: 302.3 [M+H] + .
步骤三：(1R，3R)-3-氨基环丁烷-1-羧酸叔丁酯盐酸盐的合成Step 3: Synthesis of (1R,3R)-3-aminocyclobutane-1-carboxylic acid tert-butyl ester hydrochloride
将((1R，3R)-3-(1,3-二氧代异吲哚啉-2-基)环丁烷-1-羧酸叔丁酯(30g，100mmol)，乙醇(400mL)和水合肼(17.59g，299mmol)混合，室温反应12小时。过滤，浓缩，残余物以乙酸乙酯(500mL)溶解，向其中加入4M的盐酸二氧六环溶液(25.00mL,100mmol)，抽滤，得到标题化合物17.69g。Combine ((1R,3R)-3-(1,3-dioxoisoindolin-2-yl)cyclobutane-1-carboxylate tert-butyl ester (30 g, 100 mmol), ethanol (400 mL) and hydrate Hydrazine (17.59 g, 299 mmol) was mixed and reacted at room temperature for 12 hours. Filtration, concentration, the residue was dissolved in ethyl acetate (500 mL), 4M hydrochloric acid dioxane solution (25.00 mL, 100 mmol) was added thereto, suction filtered, 17.69 g of the title compound was obtained.
1H-NMR(500MHz,DMSO-d 6):δ8.53(s,3H),3.75-3.64(m,1H),3.19-3.12(m,1H),2.40-2.35(m,4H),1.41(s,9H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ8.53(s, 3H), 3.75-3.64(m, 1H), 3.19-3.12(m, 1H), 2.40-2.35(m, 4H), 1.41 (s, 9H).
13C-NMR(125MHz,DMSO-d 6):δ174.02,80.52,43.54,34.05,29.87,28.12。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 174.02, 80.52, 43.54, 34.05, 29.87, 28.12.
步骤四：2-(3-((1R，3R)-3-(叔丁氧基羰基)环丁基)脲基)-4-甲基噻吩-3-羧酸乙酯的合成Step 4: Synthesis of 2-(3-((1R,3R)-3-(tert-butoxycarbonyl)cyclobutyl)ureido)-4-methylthiophene-3-carboxylic acid ethyl ester
将2-氨基-4-甲基噻吩-3-羧酸乙酯(14g,76mmol)溶于二氯甲烷(140mL)，0℃向其中分批加入N,N-羰基二咪唑(13.76g,83mmol)，室温反应12小时，依次向其中加入三乙胺(1.59mL,83mmol)和(1R，3R)-3-氨基环丁烷-1-羧酸叔丁酯盐酸盐(17.27g,83mmol)，室温反应2小时。向反应液加入水(200mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，残余物以石油醚(800mL)打浆，抽滤，得到标题化合物27.85g。Ethyl 2-amino-4-methylthiophene-3-carboxylate (14 g, 76 mmol) was dissolved in dichloromethane (140 mL), and N,N-carbonyldiimidazole (13.76 g, 83 mmol) was added in portions at 0°C. ), reacted at room temperature for 12 hours, and added triethylamine (1.59 mL, 83 mmol) and (1R, 3R)-3-aminocyclobutane-1-carboxylate tert-butyl ester hydrochloride (17.27 g, 83 mmol) successively to it , and react at room temperature for 2 hours. Water (200 mL) was added to the reaction solution, and the organic phase was washed with water and saturated brine, respectively, and dried over anhydrous sodium sulfate. After suction filtration, concentrated, the residue was slurried with petroleum ether (800 mL), and suction filtered to obtain 27.85 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ10.31(s,1H),8.23(s,1H),6.43(s,1H),4.34-4.19(m,3H),2.94-2.85(m,1H),2.44-2.37(m,2H),2.27(s,3H),2.19-2.10(m,2H),1.43(s,9H),1.32(t,J＝7.0Hz,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 10.31(s, 1H), 8.23(s, 1H), 6.43(s, 1H), 4.34-4.19(m, 3H), 2.94-2.85(m , 1H), 2.44-2.37(m, 2H), 2.27(s, 3H), 2.19-2.10(m, 2H), 1.43(s, 9H), 1.32(t, J=7.0Hz, 3H).
13C-NMR(125MHz,DMSO-d 6):δ174.77,165.91,153.47,152.99,133.83,111.81,109.18,80.18,60.44,43.57,33.58,33.41,28.15,18.26,14.58。 13 C-NMR (125MHz, DMSO-d 6 ): δ 174.77, 165.91, 153.47, 152.99, 133.83, 111.81, 109.18, 80.18, 60.44, 43.57, 33.58, 33.41, 28.15, 18.26, 14.58.
MS(ESI)m/z:383.4[M+H] +。 MS (ESI) m/z: 383.4 [M+H] + .
步骤五：(1R，3R)-3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)环丁烷-1-羧酸叔丁酯的合成Step five: (1R,3R)-3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) ring Synthesis of tert-butyl butane-1-carboxylate
将2-(3-((1R，3R)-3-(叔丁氧基羰基)环丁基)脲基)-4-甲基噻吩-3-羧酸乙酯(19.85g,51.9mmol)、碳酸铯(33.8g,104mmol)和N,N-二甲基甲酰胺(240mL)混合，混合物在100℃反应1小时。反应液降至室温，加入饱和氯化铵溶液(500mL)和乙酸乙酯(500mL)，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥。抽滤，浓缩，残余物以石油醚和乙酸乙酯的混合溶剂(100mL，石油醚：乙酸乙酯＝10:1)打浆，抽滤，得到标题化合物16.21g。Ethyl 2-(3-((1R,3R)-3-(tert-butoxycarbonyl)cyclobutyl)ureido)-4-methylthiophene-3-carboxylate (19.85 g, 51.9 mmol), Cesium carbonate (33.8 g, 104 mmol) and N,N-dimethylformamide (240 mL) were mixed, and the mixture was reacted at 100° C. for 1 hour. The reaction solution was cooled to room temperature, saturated ammonium chloride solution (500 mL) and ethyl acetate (500 mL) were added, the organic phase was washed with water and saturated brine, and dried over anhydrous sodium sulfate. After suction filtration, concentrated, the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (100 mL, petroleum ether:ethyl acetate=10:1), and suction filtered to obtain 16.21 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.06(s,1H),6.65(s,1H),5.50-5.41(m,1H),3.32-3.00(m,3H),2.51-2.29(m,5H),1.44(s,9H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ12.06(s, 1H), 6.65(s, 1H), 5.50-5.41(m, 1H), 3.32-3.00(m, 3H), 2.51-2.29 (m, 5H), 1.44 (s, 9H).
13C-NMR(125MHz,DMSO-d 6):δ175.12,159.93,151.91,150.87,134.66,113.34,111.89,80.15,44.30,33.39,29.92,28.18,16.27。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 175.12, 159.93, 151.91, 150.87, 134.66, 113.34, 111.89, 80.15, 44.30, 33.39, 29.92, 28.18, 16.27.
步骤六：(1R，3R)-3-(6-溴-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)环丁烷-1-羧酸叔丁酯的合成Step six: (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine-3(2H) -Synthesis of tert-butyl)cyclobutane-1-carboxylate
0℃下，将N-溴代丁二酰亚胺(8.58g,48.2mmol)分三批加入到(1R，3R)-3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)环丁烷-1-羧酸叔丁酯(16.21g,48.2mmol)的二氯甲烷(350mL)溶液中，0℃反应30分钟，反应液用二氯甲烷(200mL)稀释，有机相分别以水和饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩，残余物以石油醚和乙酸乙酯的混合溶剂(150mL，石油醚：乙酸乙酯＝5:1)打浆，抽滤，得到标题化合物21g。At 0°C, N-bromosuccinimide (8.58 g, 48.2 mmol) was added to (1R,3R)-3-(5-methyl-2,4-dioxo-1 in three batches, A solution of tert-butyl 4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)cyclobutane-1-carboxylate (16.21 g, 48.2 mmol) in dichloromethane (350 mL), The reaction was carried out at 0°C for 30 minutes, the reaction solution was diluted with dichloromethane (200 mL), the organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated, and the residue was mixed with petroleum ether and ethyl acetate The solvent (150 mL, petroleum ether:ethyl acetate=5:1) was slurried, and suction filtered to obtain 21 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.06(s,1H),5.47-5.38(m,1H),3.12-3.00(m,3H),2.38-2.27(m,5H),1.44(s,9H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 12.06(s, 1H), 5.47-5.38(m, 1H), 3.12-3.00(m, 3H), 2.38-2.27(m, 5H), 1.44 (s, 9H).
13C-NMR(125MHz,DMSO-d 6):δ179.82,159.05,151.19,150.32,134.23,112.84,99.95,80.20,44.56,33.42,29.99,28.18,14.92。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 179.82, 159.05, 151.19, 150.32, 134.23, 112.84, 99.95, 80.20, 44.56, 33.42, 29.99, 28.18, 14.92.
步骤七：(1R，3R)-3-(6-溴-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)环丁烷-1-羧酸的合成Step 7: (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine-3(2H) -Synthesis of cyclobutane-1-carboxylic acid
0℃下，将三氟醋酸(45ml,584mmol)缓慢加入到(1R，3R)-3-(6-溴-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)环丁烷-1-羧酸叔丁酯(18g,43.3mmol)的二氯甲烷(225mL)溶液中，混合物室温反应12小时。将反应液倒入冰水(1500mL)中，抽滤，得到标题化合物13.5g。Trifluoroacetic acid (45 ml, 584 mmol) was slowly added to (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno at 0°C In a solution of [2,3-d]pyrimidin-3(2H)-yl)cyclobutane-1-carboxylate tert-butyl ester (18 g, 43.3 mmol) in dichloromethane (225 mL), the mixture was reacted at room temperature for 12 hours. The reaction solution was poured into ice water (1500 mL) and filtered with suction to obtain 13.5 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.06(s,1H),5.49-5.39(m,1H),3.12-3.02(m,3H),2.41-2.33(m,2H),2.28(s,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ12.06(s, 1H), 5.49-5.39(m, 1H), 3.12-3.02(m, 3H), 2.41-2.33(m, 2H), 2.28 (s, 3H).
13C-NMR(125MHz,DMSO-d 6):δ177.28,159.01,151.14,150.31,134.19,112.78,99.93,44.58,32.39,29.96,14.89。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 177.28, 159.01, 151.14, 150.31, 134.19, 112.78, 99.93, 44.58, 32.39, 29.96, 14.89.
MS(ESI)m/z:357.1[M-H] -。 MS (ESI) m/z: 357.1 [MH] - .
步骤八：(1R,3R)-3-(6-溴-5-甲基-2,4-二氧-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-甲酸甲酯的合成Step 8: (1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine-3-(2H) -Synthesis of methyl)cyclobutane-1-carboxylate
将(1R,3R)-3-(6-溴-5-甲基-2,4-二氧-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-甲酸(5.0g,13.92mmol)和二氯甲烷(50mL)混合，0℃下向其中分批加入N,N-羰基二咪唑(2.7g,16.70 mmol)，加毕室温反应3小时。反应液减压浓缩至干，残余物中加入乙酸乙酯(50mL)和水(50mL)搅拌30分钟，抽滤，滤饼以水洗涤，干燥后得到标题化合物4.1g。(1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3-(2H)-yl ) cyclobutane-1-carboxylic acid (5.0 g, 13.92 mmol) and dichloromethane (50 mL) were mixed, N,N-carbonyldiimidazole (2.7 g, 16.70 mmol) was added to it in portions at 0°C, and the addition was completed at room temperature. The reaction was carried out for 3 hours. The reaction solution was concentrated to dryness under reduced pressure, ethyl acetate (50 mL) and water (50 mL) were added to the residue, stirred for 30 minutes, suction filtered, the filter cake was washed with water, and dried to obtain 4.1 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.18(s,1H),5.45(m,1H),3.66(s,3H),3.18(m,1H),3.11(m,2H),2.40(m,2H),2.30(s,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ12.18(s, 1H), 5.45(m, 1H), 3.66(s, 3H), 3.18(m, 1H), 3.11(m, 2H), 2.40(m, 2H), 2.30(s, 3H).
MS(ESI)m/z:373.1[M+H] +。 MS (ESI) m/z: 373.1 [M+H] + .
步骤九：(1R,3R)-3-(5-甲基-2,4-二氧-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-甲酸甲酯的合成Step 9: (1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3 Synthesis of -d]pyrimidin-3-(2H)-yl)cyclobutane-1-carboxylic acid methyl ester
将(1R,3R)-3-(6-溴-5-甲基-2,4-二氧-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-甲酸甲酯(4.0g,10.72mmol)、三乙胺(43.2ml,310mmol)、N,N-二甲基甲酰胺(50mL)、二(三苯基膦)二氯化钯(0.38g,0.536mmol)、碘化亚铜(0.21g,1.072mmol)，丙炔(1M四氢呋喃溶液)(21.84mL,21.84mmol)加入耐压管中，混合物80℃封管反应6小时。反应液冷却至室温，将反应液倒入水(300mL)中，以乙酸乙酯(3×100mL)萃取，合并有机相，以饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩所得粗品以硅胶柱层析纯化(二氯甲烷：甲醇＝50:1)得到标题化合物870mg。(1R,3R)-3-(6-bromo-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3-(2H)-yl ) methyl cyclobutane-1-carboxylate (4.0 g, 10.72 mmol), triethylamine (43.2 ml, 310 mmol), N,N-dimethylformamide (50 mL), bis(triphenylphosphine)dichloride Palladium (0.38g, 0.536mmol), cuprous iodide (0.21g, 1.072mmol), propyne (1M tetrahydrofuran solution) (21.84mL, 21.84mmol) were added to a pressure-resistant tube, and the mixture was sealed at 80°C for 6 hours . The reaction solution was cooled to room temperature, poured into water (300 mL), extracted with ethyl acetate (3×100 mL), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and concentrated to the crude product obtained It was purified by silica gel column chromatography (dichloromethane:methanol=50:1) to obtain 870 mg of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.13(s,1H),5.44(m,1H),3.66(s,3H),3.18(m,1H),3.10(m,2H),2.40(m,2H),2.37(s,3H),2.11(s,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ12.13(s, 1H), 5.44(m, 1H), 3.66(s, 3H), 3.18(m, 1H), 3.10(m, 2H), 2.40(m, 2H), 2.37(s, 3H), 2.11(s, 3H).
MS(ESI)m/z:331.3[M-H] -。 MS(ESI) m/z: 331.3 [MH] - .
步骤十：(1R,3R)-3-(5-甲基-2,4-二氧-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-甲酸的合成Step ten: (1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3 Synthesis of -d]pyrimidin-3-(2H)-yl)cyclobutane-1-carboxylic acid
将(1R,3R)-3-(5-甲基-2,4-二氧-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-甲酸甲酯(0.80g,2.407mmol)、四氢呋喃(10mL)、水(10mL)和一水合氢氧化锂(0.12g,4.81mmol)混合，室温反应10分钟。以1N盐酸溶液将反应液pH值调至5-6，向反应液中加入乙酸乙酯(40mL)萃取，分取有机相，以饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，残余物以石油醚和乙酸乙酯的混合溶剂(15mL，石油醚：乙酸乙酯＝1:1)打浆，得到标题化合物0.73g。(1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d ]pyrimidin-3-(2H)-yl)cyclobutane-1-carboxylic acid methyl ester (0.80 g, 2.407 mmol), tetrahydrofuran (10 mL), water (10 mL) and lithium hydroxide monohydrate (0.12 g, 4.81 mmol) Mix and react at room temperature for 10 minutes. The pH of the reaction solution was adjusted to 5-6 with 1N hydrochloric acid solution, ethyl acetate (40 mL) was added to the reaction solution for extraction, the organic phase was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated , the residue was slurried with a mixed solvent of petroleum ether and ethyl acetate (15 mL, petroleum ether:ethyl acetate=1:1) to obtain 0.73 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.18(br,2H),5.62-5.18(m,1H),3.19-2.92(m,3H),2.44-2.25(m,5H),2.11(s,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ12.18(br,2H), 5.62-5.18(m,1H), 3.19-2.92(m,3H), 2.44-2.25(m,5H), 2.11 (s, 3H).
MS(ESI)m/z:317.3[M-H] -。 MS (ESI) m/z: 317.3 [MH] - .
步骤十一：(1R,3R)-3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-羧酸叔丁基二苯基硅烷基酯的合成Step eleven: (1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2 Synthesis of ,3-d]pyrimidin-3-(2H)-yl)cyclobutane-1-carboxylic acid tert-butyldiphenylsilyl ester
将(1R,3R)-3-(5-甲基-2,4-二氧-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-甲酸(0.68g,2.136mmol)、咪唑(0.18g,2.56mmol)、四氢呋喃(10mL)、叔丁基二苯基 氯硅烷(0.71g,0.658ml,2.56mmol)混合，室温反应4小时。将反应液抽滤，滤液浓缩，残余物以硅胶柱层析纯化(石油醚:乙酸乙酯＝8:1)，得到标题化合物0.9g。(1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d ]pyrimidin-3-(2H)-yl)cyclobutane-1-carboxylic acid (0.68 g, 2.136 mmol), imidazole (0.18 g, 2.56 mmol), tetrahydrofuran (10 mL), tert-butyldiphenylchlorosilane (0.71 g, 0.658 ml, 2.56 mmol) were mixed and reacted at room temperature for 4 hours. The reaction solution was suction filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=8:1) to obtain 0.9 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.16(s,1H),7.84-7.60(m,4H),7.57-7.41(m,6H),5.55(m,1H),3.45-3.35(m,1H),3.20(m,2H),2.56-2.51(m,2H),2.39(s,3H),2.11(s,3H),1.06(s,9H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ12.16(s, 1H), 7.84-7.60(m, 4H), 7.57-7.41(m, 6H), 5.55(m, 1H), 3.45-3.35 (m, 1H), 3.20 (m, 2H), 2.56-2.51 (m, 2H), 2.39 (s, 3H), 2.11 (s, 3H), 1.06 (s, 9H).
步骤十二：式I-2化合物的合成Step 12: Synthesis of the compound of formula I-2
将(1R,3R)-3-(5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3-(2H)-基)环丁烷-1-羧酸叔丁基二苯基硅烷基酯(0.83g,1.491mmol)、(R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙烷-1-醇(0.38g,1.491mmol)、四氢呋喃(2.5mL)及三苯基膦(1.17g,4.47mmol)混合，氮气置换三次，冰盐浴降温至0℃以下，向反应液滴加偶氮二甲酸二异丙酯(0.91g,4.47mmol)，加毕室温反应5小时。将反应液倒入水(30mL)中，乙酸乙酯(30mL)萃取，有机相以饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，残余物用Biotage C18 120g反相色谱柱进行分离纯化(水:乙腈＝1:1)，得到标题化合物70mg。(1R,3R)-3-(5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3- d] Pyrimidine-3-(2H)-yl)cyclobutane-1-carboxylate tert-butyldiphenylsilyl ester (0.83g, 1.491mmol), (R)-2-(2-methoxybenzene yl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethane-1-ol (0.38 g, 1.491 mmol), tetrahydrofuran (2.5 mL) and triphenylphosphine (1.17 g, 4.47 mmol) were mixed, nitrogen was replaced three times, the ice-salt bath was cooled to below 0 °C, diisopropyl azodicarboxylate (0.91 g, 4.47 mmol) was added dropwise to the reaction, and the reaction was completed at room temperature for 5 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (30 mL), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the residue was subjected to Biotage C18 120 g reverse phase chromatography column Separation and purification (water:acetonitrile=1:1) gave 70 mg of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ12.27(s,1H),7.46(dd,J＝7.5,1.4Hz,1H),7.34-7.25(m,1H),7.03(t,J＝7.3Hz,1H),6.97-6.96(m,1H),5.59-5.44(m,1H),5.30-5.25(m,1H),4.05-3.96(m,2H),3.73(s,3H),3.63-3.55(m,1H),3.54-3.48(m,1H),3.38(m,2H),3.30-3.15(m,3H),3.14-2.98(m,3H),2.45-2.33(m,5H),2.12(s,3H),1.64(m,2H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 12.27 (s, 1H), 7.46 (dd, J=7.5, 1.4 Hz, 1H), 7.34-7.25 (m, 1H), 7.03 (t, J ＝7.3Hz,1H),6.97-6.96(m,1H),5.59-5.44(m,1H),5.30-5.25(m,1H),4.05-3.96(m,2H),3.73(s,3H), 3.63-3.55(m, 1H), 3.54-3.48(m, 1H), 3.38(m, 2H), 3.30-3.15(m, 3H), 3.14-2.98(m, 3H), 2.45-2.33(m, 5H ), 2.12(s, 3H), 1.64(m, 2H).
MS(ESI)m/z:551.5[M-H] -。 MS(ESI) m/z: 551.5 [MH] - .
实施例3：(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸(式I-3化合物)Example 3: (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Benzoic acid (compound of formula I-3)
Figure PCTCN2022074327-appb-000048
Figure PCTCN2022074327-appb-000048
步骤一：2-(3-(4-(乙氧基羰基)苯基)脲基)-4-甲基噻吩-3-羧酸乙酯的合成Step 1: Synthesis of 2-(3-(4-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylic acid ethyl ester
将2-氨基-4-甲基噻吩-3-羧酸乙酯(10g,54mmol)溶于二氯甲烷(70mL)，冰水浴降温，缓慢分批加入N,N-羰基二咪唑(9.63g,59.4mmol)，加毕移去冰浴，室温反应过夜。依次向反应液加入三乙胺(8.25ml,59.4mmol)和4-氨基苯甲酸乙酯(9.81g,59.4mmol)，室温反应过夜。向反应液中加入水(100mL)，有固体析出，抽滤，滤饼干燥后得到标题化合物5.7g。所得滤液分取有机相，以无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝4:1)，得到标题化合物3.8g。Ethyl 2-amino-4-methylthiophene-3-carboxylate (10 g, 54 mmol) was dissolved in dichloromethane (70 mL), cooled in an ice-water bath, and N,N-carbonyldiimidazole (9.63 g, 59.4 mmol), remove the ice bath after the addition, and react at room temperature overnight. Triethylamine (8.25 ml, 59.4 mmol) and 4-aminobenzoic acid ethyl ester (9.81 g, 59.4 mmol) were sequentially added to the reaction solution, and the reaction was carried out at room temperature overnight. Water (100 mL) was added to the reaction solution, and a solid was precipitated, which was filtered off with suction, and the filter cake was dried to obtain 5.7 g of the title compound. The organic phase of the obtained filtrate was separated, dried over anhydrous sodium sulfate, suction filtered, concentrated, and purified by silica gel column chromatography (petroleum ether:ethyl acetate=4:1) to obtain 3.8 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ10.77(s,1H),10.63(s,1H),7.92(d,J＝8.5Hz,2H),7.64(d,J＝8.5Hz,2H),6.58(s,1H),4.35-4.27(m,4H),2.31(s,3H),1.36-1.30(m,6H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ10.77(s, 1H), 10.63(s, 1H), 7.92(d, J=8.5Hz, 2H), 7.64(d, J=8.5Hz, 2H), 6.58 (s, 1H), 4.35-4.27 (m, 4H), 2.31 (s, 3H), 1.36-1.30 (m, 6H).
13C-NMR(125MHz,DMSO-d 6):δ165.92,165.83,152.08,151.37,144.12,134.16,130.87,123.93,118.05,112.82,110.60,60.83,60.70,18.24,14.70,14.56。 13 C-NMR (125MHz, DMSO-d 6 ): δ 165.92, 165.83, 152.08, 151.37, 144.12, 134.16, 130.87, 123.93, 118.05, 112.82, 110.60, 60.83, 60.70, 18.24, 14.70, 14.56.
MS(ESI)m/z:377.3[M+H] +。 MS (ESI) m/z: 377.3 [M+H] + .
步骤二：4-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成Step 2: Synthesis of ethyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
将2-(3-(4-(乙氧基羰基)苯基)脲基)-4-甲基噻吩-3-羧酸乙酯(7.5g,19.92mmol)与N,N-二甲基甲酰胺(75mL)混合，氮气保护下，分三批加入氢化钠(1.20g,29.9mmol)，将混合物加热至100℃反应2小时。冷却至室温后加入饱和氯化铵水溶液(225mL)，有固体析出。抽滤，滤饼干燥后得到标题化合物3.6g。Combine 2-(3-(4-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylate ethyl ester (7.5 g, 19.92 mmol) with N,N-dimethylmethane The amides (75 mL) were mixed, and sodium hydride (1.20 g, 29.9 mmol) was added in three batches under nitrogen protection, and the mixture was heated to 100° C. to react for 2 hours. After cooling to room temperature, saturated aqueous ammonium chloride solution (225 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 3.6 g of the title compound.
MS(ESI)m/z:329.2[M-H] -。 MS(ESI) m/z: 329.2 [MH] - .
步骤三：(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成Step 3: (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Synthesis of ethyl methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
将4-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(3.0g,9.08mmol)，碳酸铯(4.14g,12.71mmol)，(R)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃(4.01g,12.71mmol)及N-甲基吡咯烷酮(30mL)混合，加热至100℃反应20小时。向反应液加入水(100mL)和乙酸乙酯(100mL)，水相以乙酸乙酯萃取(100mL×2)，合并有机相，依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝1:1)，得到标题化合物2.1g。Ethyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (3.0 g, 9.08 g mmol), cesium carbonate (4.14g, 12.71mmol), (R)-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran (4.01g, 12.71 mmol) and N-methylpyrrolidone (30 mL) were mixed, heated to 100° C. and reacted for 20 hours. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, the aqueous phase was extracted with ethyl acetate (100 mL×2), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, and filtered with suction , concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 2.1 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ8.09(d,J＝8.5Hz,2H),7.47(d,J＝7.0Hz,1H),7.40(d,J＝8.0Hz,2H),7.32(t,J＝7.5Hz,1H),7.05-7.00(m,2H),6.89(s,1H),5.33(s,1H),4.37(q,J＝7.0Hz,2H),4.09-4.01(m,2H),3.78(s,3H),3.58-3.56(m,2H),3.39(s,1H),3.30-3.28(m,2H),2.37(s,3H),1.65(s,2H),1.38-1.35(m,4H),1.25(s,1H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ8.09 (d, J=8.5Hz, 2H), 7.47 (d, J=7.0Hz, 1H), 7.40 (d, J=8.0Hz, 2H) ,7.32(t,J＝7.5Hz,1H),7.05-7.00(m,2H),6.89(s,1H),5.33(s,1H),4.37(q,J＝7.0Hz,2H),4.09- 4.01(m, 2H), 3.78(s, 3H), 3.58-3.56(m, 2H), 3.39(s, 1H), 3.30-3.28(m, 2H), 2.37(s, 3H), 1.65(s, 2H), 1.38-1.35 (m, 4H), 1.25 (s, 1H).
13C-NMR(125MHz,DMSO-d 6):δ165.71,158.66,157.08,156.11,150.29,140.80,135.28,130.32,130.26,130.03,129.73,127.69,127.05,121.28,113.66,113.20,111.45,71.91,69.61,64.59,64.29,61.45,55.98,53.45,33.31,31.41,16.45,14.64。 13 C-NMR(125MHz,DMSO-d 6 ):δ165.71,158.66,157.08,156.11,150.29,140.80,135.28,130.32,130.26,130.03,129.73,127.69,127.05,121.28,113.66,113.20,111.45,71.91,69.61 , 64.59, 64.29, 61.45, 55.98, 53.45, 33.31, 31.41, 16.45, 14.64.
MS(ESI)m/z:565.4[M+H] +。 MS (ESI) m/z: 565.4 [M+H] + .
步骤四：(R)-4-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成Step 4: (R)-4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid ethyl ester
将(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(1.5g,2.66mmol)与二氯甲烷(15mL)混合，冰水浴降温，加入溴代丁二酰亚胺(0.52g,2.92mmol)，0℃反应1小时。反应液依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝9:1)，得到标题化合物1.45g。(R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -2,4-Dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid ethyl ester (1.5 g, 2.66 mmol) and dichloromethane (15 mL) ) mixed, cooled in an ice-water bath, added bromosuccinimide (0.52 g, 2.92 mmol), and reacted at 0° C. for 1 hour. The reaction solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, suction filtered, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=9:1) to obtain 1.45 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ8.10(d,J＝8.0Hz,2H),7.48(d,J＝7.0Hz,1H),7.41(d,J＝8.0Hz,2H),7.33(t,J＝7.0Hz,1H),7.06-7.00(m,2H),5.27(s,1H),4.37(q,J＝7.0Hz,2H),4.10-4.07(m,1H),3.92(s,1H),3.77(s,3H),3.61-3.60(m,2H),3.41(s,1H),3.29-3.27(m,2H),2.34(s,3H),1.68(t,J＝14.5Hz,2H),1.36(t,J＝7.0Hz,3H),1.35-1.25(m,2H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 8.10 (d, J=8.0 Hz, 2H), 7.48 (d, J=7.0 Hz, 1H), 7.41 (d, J=8.0 Hz, 2H) ,7.33(t,J＝7.0Hz,1H),7.06-7.00(m,2H),5.27(s,1H),4.37(q,J＝7.0Hz,2H),4.10-4.07(m,1H), 3.92(s, 1H), 3.77(s, 3H), 3.61-3.60(m, 2H), 3.41(s, 1H), 3.29-3.27(m, 2H), 2.34(s, 3H), 1.68(t, J=14.5Hz, 2H), 1.36 (t, J=7.0Hz, 3H), 1.35-1.25 (m, 2H).
MS(ESI)m/z:643.5[M+H] +。 MS (ESI) m/z: 643.5 [M+H] + .
步骤五：(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(式I-10化合物)的合成Step 5: (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzene Synthesis of ethyl formate (compound of formula I-10)
将(R)-4-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(750mg,1.165mmol)，双三苯基膦二氯化钯(82mg,0.117mmol)，碘化亚铜(44.4mg,0.233mmol)与N,N-二甲基甲酰胺(7.5mL)混合。氮气吹扫后，加入三乙胺(0.487mL,3.50mmol)及丙炔(1M四氢呋喃溶液)(2.91mL,2.91mmol)，80℃封管反应10小时。向反应液中加入水(20mL)，水相以乙酸乙酯萃取(20mL×3)，合并有机相，依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝10:1)，得到标题化合物456mg。(R)-4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- Ethyl 5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (750 mg, 1.165 mmol), bistris Phenylphosphine palladium dichloride (82 mg, 0.117 mmol), cuprous iodide (44.4 mg, 0.233 mmol) were mixed with N,N-dimethylformamide (7.5 mL). After nitrogen purging, triethylamine (0.487 mL, 3.50 mmol) and propyne (1M tetrahydrofuran solution) (2.91 mL, 2.91 mmol) were added, and the reaction was carried out at 80° C. for 10 hours. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and filtered through a silica gel column. Purification by chromatography (petroleum ether:ethyl acetate=10:1) gave 456 mg of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ8.10(d,J＝8.0Hz,2H),7.48-7.40(m,3H),7.32(t,J＝7.0Hz,1H),7.06-7.00(m,2H),5.29(s,1H),4.37(q,J＝7.0Hz,2H),4.10-4.07(m,1H),3.95-3.91(m,1H),3.76(s,3H),3.60(s,2H),3.41(s,1H),3.30-3.27(m,2H),2.40(s,3H),2.15(s,3H),1.69-1.65(m,2H),1.36(t,J＝7.0Hz,3H),1.35-1.25(m,2H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ8.10 (d, J=8.0Hz, 2H), 7.48-7.40 (m, 3H), 7.32 (t, J=7.0Hz, 1H), 7.06- 7.00(m, 2H), 5.29(s, 1H), 4.37(q, J=7.0Hz, 2H), 4.10-4.07(m, 1H), 3.95-3.91(m, 1H), 3.76(s, 3H) ,3.60(s,2H),3.41(s,1H),3.30-3.27(m,2H),2.40(s,3H),2.15(s,3H),1.69-1.65(m,2H),1.36(t , J=7.0Hz, 3H), 1.35-1.25 (m, 2H).
MS(ESI)m/z:603.5[M+H] +。 MS (ESI) m/z: 603.5 [M+H] + .
步骤六：I-3化合物的合成Step 6: Synthesis of Compound I-3
将(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸甲酯(400mg,0.664mmol)与甲醇(1.5mL)，四氢呋喃(1mL)，氢氧化锂水合物(278mg,6.64mmol)的水溶液(0.5mL)混合，室温反应5小时。冰浴下加入2N稀盐酸调pH至5-6，加入水(10mL)和乙酸乙酯(10mL)，分取水相，以乙酸乙酯萃取(10mL×4)。合并有机相，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(二氯甲烷:甲醇＝10:1)，得到I-3化合物75mg。(R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl Methyl 2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate The ester (400 mg, 0.664 mmol) was mixed with methanol (1.5 mL), tetrahydrofuran (1 mL), and an aqueous solution (0.5 mL) of lithium hydroxide hydrate (278 mg, 6.64 mmol) and reacted at room temperature for 5 hours. 2N dilute hydrochloric acid was added under ice bath to adjust pH to 5-6, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was separated and extracted with ethyl acetate (10 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (dichloromethane:methanol=10:1) to obtain 75 mg of compound I-3.
1H-NMR(500MHz,CDCl 3):δ8.25(d,J＝8.0Hz,2H),7.57(d,J＝7.0Hz,1H),7.36-7.32(m,3H),7.06(t,J＝7.5Hz,1H),6.89(d,J＝8.5Hz,1H),5.46(dd,J 1＝8.5Hz,J 2＝4.5Hz,1H),4.25-4.23(m,1H),4.05-4.02(m,1H),3.85(s,3H),3.81-3.77(m,2H),3.51-3.47(m,1H),3.43-3.39(m,2H),2.54(s,3H),2.17(s,3H),1.83-1.77(m,2H),1.63-1.57(m,1H),1.51-1.45(m,1H)。 1 H-NMR (500MHz, CDCl 3 ): δ8.25 (d, J=8.0Hz, 2H), 7.57 (d, J=7.0Hz, 1H), 7.36-7.32 (m, 3H), 7.06 (t, J=7.5Hz,1H),6.89(d,J=8.5Hz,1H),5.46(dd,J1 = 8.5Hz,J2=4.5Hz,1H),4.25-4.23(m,1H), 4.05- 4.02(m, 1H), 3.85(s, 3H), 3.81-3.77(m, 2H), 3.51-3.47(m, 1H), 3.43-3.39(m, 2H), 2.54(s, 3H), 2.17( s, 3H), 1.83-1.77 (m, 2H), 1.63-1.57 (m, 1H), 1.51-1.45 (m, 1H).
13C-NMR(125MHz,CDCl 3):δ169.82,158.38,156.95,154.21,150.29,140.17,140.00,131.38,129.70,129.37,129.00,127.29,127.07,120.99,113.46,110.96,110.35,94.03,72.12,70.87,69.70,65.34,65.02,55.45,53.85,33.19,31.38,15.06,4.84。 13 C-NMR(125MHz,CDCl 3 ):δ169.82,158.38,156.95,154.21,150.29,140.17,140.00,131.38,129.70,129.37,129.00,127.29,127.07,120.99,113.46,110.96,110.35,94.03,72.12,70.87 , 69.70, 65.34, 65.02, 55.45, 53.85, 33.19, 31.38, 15.06, 4.84.
MS(ESI)m/z:575.3[M+H] +。 MS (ESI) m/z: 575.3 [M+H] + .
实施例4：(R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸(式I-4化合物)Example 4: (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Benzoic acid (compound of formula I-4)
Figure PCTCN2022074327-appb-000049
Figure PCTCN2022074327-appb-000049
步骤一：2-(3-(3-(乙氧基羰基)苯基)脲基)-4-甲基噻吩-3-羧酸乙酯的合成Step 1: Synthesis of 2-(3-(3-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylic acid ethyl ester
将2-氨基-4-甲基噻吩-3-羧酸乙酯(15g,81mmol)与二氯甲烷(140mL)混合，冰水浴降温，分批加入羰基二咪唑(14.44g,89mmol)，加毕移去冰浴，室温反应过夜。向反应液依次加入三乙胺(12.42mL,89mmol)和3-氨基苯甲酸乙酯(14.71g,89mmol)，室温反应过夜。向反应液中加入水(100mL)，以二氯甲烷(100mL×3)萃取，合并有机相，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(二氯甲烷)，得到标题化合物4.3g。Ethyl 2-amino-4-methylthiophene-3-carboxylate (15 g, 81 mmol) was mixed with dichloromethane (140 mL), cooled in an ice-water bath, carbonyldiimidazole (14.44 g, 89 mmol) was added in batches, and the addition was completed. The ice bath was removed and the reaction was carried out at room temperature overnight. Triethylamine (12.42 mL, 89 mmol) and 3-aminobenzoic acid ethyl ester (14.71 g, 89 mmol) were sequentially added to the reaction solution, and the reaction was carried out at room temperature overnight. Water (100 mL) was added to the reaction solution, extracted with dichloromethane (100 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (dichloromethane) to obtain the title Compound 4.3g.
1H-NMR(500MHz,DMSO-d 6):δ10.72(s,1H),10.50(s,1H),8.16(d,J＝2.5Hz,1H),7.76(d,J＝8.2Hz,1H),7.61(d,J＝7.8Hz,1H),7.46(t,J＝8.0Hz,1H),6.55(s,1H),4.33(q,J＝7.2Hz,4H),2.30(s,3H),1.34(td,J＝7.2,3.5Hz,6H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ10.72(s, 1H), 10.50(s, 1H), 8.16(d, J=2.5Hz, 1H), 7.76(d, J=8.2Hz, 1H), 7.61(d, J=7.8Hz, 1H), 7.46(t, J=8.0Hz, 1H), 6.55(s, 1H), 4.33(q, J=7.2Hz, 4H), 2.30(s, 3H), 1.34 (td, J=7.2, 3.5Hz, 6H).
13C-NMR(125MHz,DMSO-d 6):δ166.04,165.94,152.32,151.53,140.01,134.10,130.99,129.78,123.55,123.11,119.08,112.61,110.33,61.27,60.65,18.24,14.65,14.56。 13 C-NMR (125MHz, DMSO-d 6 ): δ166.04, 165.94, 152.32, 151.53, 140.01, 134.10, 130.99, 129.78, 123.55, 123.11, 119.08, 112.61, 110.33, 61.27, 60.65, 18.27, 60.65, 18.
MS(ESI)m/z:377.4[M+H] +。 MS (ESI) m/z: 377.4 [M+H] + .
步骤二：3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成Step 2: Synthesis of ethyl 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
将2-(3-(3-(乙氧基羰基)苯基)脲基)-4-甲基噻吩-3-羧酸乙酯(4g,10.63mmol)与N,N-二甲基甲酰胺(40mL)混合，冰水浴降温，氮气吹扫下，分三批加入氢化钠(0.638g,15.94mmol)， 将混合物加热至100℃反应1h。冷却至室温后加入饱和氯化铵水溶液(100mL)，有固体析出。抽滤，滤饼干燥后得到标题化合物2.3g。Combine 2-(3-(3-(ethoxycarbonyl)phenyl)ureido)-4-methylthiophene-3-carboxylate ethyl ester (4 g, 10.63 mmol) with N,N-dimethylformamide (40 mL) were mixed, cooled in an ice-water bath, and under nitrogen purging, sodium hydride (0.638 g, 15.94 mmol) was added in three batches, and the mixture was heated to 100° C. to react for 1 h. After cooling to room temperature, saturated aqueous ammonium chloride solution (100 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 2.3 g of the title compound.
MS(ESI)m/z:329.2[M-H] -。 MS(ESI) m/z: 329.2 [MH] - .
步骤三：(R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成Step 3: (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Synthesis of ethyl methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
将3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(2.3g,3.48mmol)，碳酸铯(1.361g,4.18mmol)，(R)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃(1.207g,3.83mmol)与N-甲基吡咯烷酮(20mL)混合，氮气保护下，加热至100℃反应过夜。向反应液加入水(100mL)和乙酸乙酯(100mL)，分取水相，水相以乙酸乙酯(100mL×2)萃取。合并有机相，依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚：乙酸乙酯＝1：1)，得到标题化合物550mg。Ethyl 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (2.3 g, 3.48 g mmol), cesium carbonate (1.361g, 4.18mmol), (R)-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran (1.207g, 3.83 mmol) was mixed with N-methylpyrrolidone (20 mL), heated to 100°C under nitrogen protection, and reacted overnight. Water (100 mL) and ethyl acetate (100 mL) were added to the reaction solution, the aqueous phase was separated, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 550 mg of the title compound.
1H NMR(500MHz,DMSO-d 6):δ8.04(d,J＝7.9Hz,1H),7.81(s,1H),7.68(t,J＝7.9Hz,1H),7.54(d,J＝8.0Hz,1H),7.47(d,J＝7.6Hz,1H),7.32(t,J＝8.0Hz,1H),7.08-6.98(m,2H),6.89(s,1H),5.34(t,J＝6.7Hz,1H),4.36(q,J＝7.4Hz,2H),4.12-3.93(m,2H),3.83(s,1H),3.79(s,3H),3.66-3.53(m,2H),3.44-3.35(m,2H),3.30(d,J＝8.8Hz,2H),2.37(s,3H),1.75-1.61(m,2H),1.36-1.32(m,3H)。 1 H NMR (500MHz, DMSO-d 6 ): δ 8.04 (d, J=7.9 Hz, 1H), 7.81 (s, 1H), 7.68 (t, J=7.9 Hz, 1H), 7.54 (d, J =8.0Hz,1H),7.47(d,J=7.6Hz,1H),7.32(t,J=8.0Hz,1H),7.08-6.98(m,2H),6.89(s,1H),5.34(t , J=6.7Hz, 1H), 4.36(q, J=7.4Hz, 2H), 4.12-3.93(m, 2H), 3.83(s, 1H), 3.79(s, 3H), 3.66-3.53(m, 2H), 3.44-3.35(m, 2H), 3.30(d, J=8.8Hz, 2H), 2.37(s, 3H), 1.75-1.61(m, 2H), 1.36-1.32(m, 3H).
MS(ESI)m/z:565.3[M+H] +。 MS (ESI) m/z: 565.3 [M+H] + .
步骤四：(R)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成Step 4: (R)-3-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid ethyl ester
将(R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(0.53g,0.939mmol)与二氯甲烷(5mL)混合，冰水浴降温，加入溴代丁二酰亚胺(0.184g,1.032mmol)，0℃下反应3小时。反应液依次以水、饱和食盐水洗涤，合并有机相，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚：乙酸乙酯＝1：1)，得标题化合物475mg。(R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -2,4-Dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoic acid ethyl ester (0.53 g, 0.939 mmol) and dichloromethane (5 mL) ) mixed, cooled in an ice-water bath, added bromosuccinimide (0.184 g, 1.032 mmol), and reacted at 0° C. for 3 hours. The reaction solution was washed successively with water and saturated brine, and the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:1) to obtain 475 mg of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ8.05(d,J＝7.9Hz,1H),7.82(s,1H),7.68(t,J＝7.9Hz,1H),7.54(d,J＝7.9Hz,1H),7.51-7.45(m,1H),7.32(t,J＝7.7Hz,1H),7.08-6.97(m,2H),5.29(dd,J＝8.5,4.6Hz,1H),4.35(q,J＝7.2Hz,2H),4.08(d,J＝13.3Hz,1H),3.93(s,1H),3.83(s,1H),3.78(s,3H),3.62(dd,J＝11.9,5.8Hz,2H),3.52-3.38(m,2H),3.32-3.24(m,2H),2.34(s,3H),1.76-1.60(m,2H),1.34(t,J＝7.0Hz,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ8.05 (d, J=7.9Hz, 1H), 7.82 (s, 1H), 7.68 (t, J=7.9Hz, 1H), 7.54 (d, J=7.9Hz, 1H), 7.51-7.45(m, 1H), 7.32(t, J=7.7Hz, 1H), 7.08-6.97(m, 2H), 5.29(dd, J=8.5, 4.6Hz, 1H) ), 4.35(q, J=7.2Hz, 2H), 4.08(d, J=13.3Hz, 1H), 3.93(s, 1H), 3.83(s, 1H), 3.78(s, 3H), 3.62(dd , J=11.9, 5.8Hz, 2H), 3.52-3.38(m, 2H), 3.32-3.24(m, 2H), 2.34(s, 3H), 1.76-1.60(m, 2H), 1.34(t, J =7.0Hz, 3H).
MS(ESI)m/z:643.4[M+H] +。 MS(ESI) m/z: 643.4 [M+H] + .
步骤五：(R)-3-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(式I-11化合物)的合成Step 5: (R)-3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzene Synthesis of ethyl formate (compound of formula I-11)
将(R)-3-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯(213mg,0.331mmol)，双三苯基膦二氯化钯(23.23mg,0.033mmol)，碘化亚铜(12.61mg,0.066mmol)与N,N-二甲基甲酰胺(3mL)混合。氮气吹扫后，加入三乙胺(0.138ml,0.993mmol)，丙炔(1M四氢呋喃溶液)(0.824mL,0.824mmol)，80℃封管反应过夜。向反应液中加入水(20mL)，水相以乙酸乙酯萃取(20mL×3)，合并有机相，依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝5:1)，得到式I-11化合物77mg。(R)-3-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- Ethyl 5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (213 mg, 0.331 mmol), bistris Phenylphosphine palladium dichloride (23.23 mg, 0.033 mmol), cuprous iodide (12.61 mg, 0.066 mmol) were mixed with N,N-dimethylformamide (3 mL). After purging with nitrogen, triethylamine (0.138 ml, 0.993 mmol), propyne (1M tetrahydrofuran solution) (0.824 mL, 0.824 mmol) were added, and the tube was sealed at 80° C. to react overnight. Water (20 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and filtered through a silica gel column. Purified by chromatography (petroleum ether:ethyl acetate=5:1) to obtain 77 mg of the compound of formula I-11.
MS(ESI)m/z:603.4[M+H] +。 MS (ESI) m/z: 603.4 [M+H] + .
步骤六：式I-4化合物的合成Step 6: Synthesis of the compound of formula I-4
将式I-11化合物(77mg,0.128mmol)，甲醇(6mL)，四氢呋喃(2mL)与氢氧化锂水合物(107mg,2.56mmol)的水溶液(2mL)混合，室温反应1小时。冰浴下加入2N盐酸溶液调pH至5-6，加入水(10mL)和乙酸乙酯(10mL)，水相以乙酸乙酯(10mL×2)萃取。合并有机相，依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝3:2)，得到式I-4化合物44mg。The compound of formula I-11 (77 mg, 0.128 mmol), methanol (6 mL), tetrahydrofuran (2 mL) and an aqueous solution (2 mL) of lithium hydroxide hydrate (107 mg, 2.56 mmol) were mixed and reacted at room temperature for 1 hour. 2N hydrochloric acid solution was added under ice bath to adjust pH to 5-6, water (10 mL) and ethyl acetate (10 mL) were added, and the aqueous phase was extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:2) to obtain 44 mg of the compound of formula I-4 .
1H NMR(500MHz,DMSO-d 6):13.22(br,1H),8.02(d,J＝7.8Hz,1H),7.79(s,1H),7.65(t,J＝7.8Hz,1H),7.49(t,J＝7.9Hz,2H),7.32(t,J＝7.8Hz,1H),7.10–6.94(m,2H),5.30(dd,J＝8.5,4.9Hz,1H),4.08(s,1H),3.93(s,1H),3.77(s,3H),3.60(dt,J＝10.8,5.7Hz,2H),3.47–3.39(m,3H),2.40(s,3H),2.15(s,3H),1.68(t,J＝15.8Hz,2H),1.41–1.32(m,1H),1.28(s,1H)。 1 H NMR (500MHz, DMSO-d 6 ): 13.22 (br, 1H), 8.02 (d, J=7.8Hz, 1H), 7.79 (s, 1H), 7.65 (t, J=7.8Hz, 1H), 7.49(t,J＝7.9Hz,2H),7.32(t,J＝7.8Hz,1H),7.10-6.94(m,2H),5.30(dd,J＝8.5,4.9Hz,1H),4.08(s ,1H),3.93(s,1H),3.77(s,3H),3.60(dt,J=10.8,5.7Hz,2H),3.47–3.39(m,3H),2.40(s,3H),2.15( s, 3H), 1.68 (t, J=15.8 Hz, 2H), 1.41–1.32 (m, 1H), 1.28 (s, 1H).
MS(ESI)m/z:573.4[M-H] -。 MS(ESI) m/z: 573.4 [MH] - .
实施例5：(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸(式I-5化合物)Example 5: (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Pyridine-2-carboxylic acid (compound of formula I-5)
Figure PCTCN2022074327-appb-000050
Figure PCTCN2022074327-appb-000050
步骤一：4-甲基-2-((苯氧基羰基)氨基)噻吩-3-羧酸乙酯的合成Step 1: Synthesis of ethyl 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate
将2-氨基-4-甲基噻吩-3-羧酸乙酯(60.2g,325mmol)与乙酸乙酯(500mL)，饱和碳酸氢钠水溶液(500mL)混合，向其中加入氯甲酸苯酯(61.1g,390mmol)，室温反应17h。向反应液加入乙酸乙酯(1L)至固体全溶，分取水相，水相以乙酸乙酯(200mL×2)萃取。合并有机相，以饱和食盐水洗涤，无水硫酸钠干燥，浓缩，所得粗品以石油醚打浆，抽滤，滤饼干燥后得到标题化合物88.3g。Ethyl 2-amino-4-methylthiophene-3-carboxylate (60.2 g, 325 mmol) was mixed with ethyl acetate (500 mL) and saturated aqueous sodium bicarbonate solution (500 mL), to which was added phenyl chloroformate (61.1 g, 390 mmol), and reacted at room temperature for 17 h. Ethyl acetate (1 L) was added to the reaction solution until the solid was completely dissolved, the aqueous phase was separated, and the aqueous phase was extracted with ethyl acetate (200 mL×2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The obtained crude product was slurried with petroleum ether, filtered with suction, and the filter cake was dried to obtain 88.3 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ10.74(s,1H),7.45-7.48(m,2H),7.29-7.33(m,3H),6.74(s,1H),4.33(q,J＝7.0Hz,2H),2.32(s,3H),1.34(t,J＝7.0Hz,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ10.74(s, 1H), 7.45-7.48(m, 2H), 7.29-7.33(m, 3H), 6.74(s, 1H), 4.33(q , J=7.0Hz, 2H), 2.32 (s, 3H), 1.34 (t, J=7.0Hz, 3H).
13C-NMR(125MHz,DMSO-d 6):δ165.6,151.3,150.6,150.2,135.1,130.1,126.6,122.1,113.7,61.2,17.9,14.5。 13 C-NMR (125 MHz, DMSO-d 6 ): δ 165.6, 151.3, 150.6, 150.2, 135.1, 130.1, 126.6, 122.1, 113.7, 61.2, 17.9, 14.5.
MS(ESI)m/z:327.9[M+Na] +。 MS (ESI) m/z: 327.9 [M+Na] + .
步骤二：4-(3-(3-(乙氧基羰基)-4-甲基噻吩-2-基)脲基)吡啶-2-甲酸甲酯的合成Step 2: Synthesis of methyl 4-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate
将4-氨基吡啶-2-甲酸甲酯(10g,65.7mmol)，4-甲基-2-((苯氧基羰基)氨基)噻吩-3-羧酸乙酯(24.08g,79mmol)，三乙胺(12.83ml,92mmol)与甲苯(100mL)混合，将混合物加热至110℃反应5小时。反应液冷却至室温，抽滤，滤饼以石油醚和乙酸乙酯打浆，抽滤，滤饼干燥后得到标题化合物17.6g。Methyl 4-aminopyridine-2-carboxylate (10 g, 65.7 mmol), ethyl 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (24.08 g, 79 mmol), triplicate Ethylamine (12.83 ml, 92 mmol) was mixed with toluene (100 mL), and the mixture was heated to 110° C. for 5 hours. The reaction solution was cooled to room temperature, filtered with suction, the filter cake was slurried with petroleum ether and ethyl acetate, filtered with suction, and the filter cake was dried to obtain 17.6 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ10.93(s,1H),10.85(s,1H),8.52(d,J＝5.5Hz,1H),8.23(s,1H),7.63(d,J＝5.0Hz,1H),6.62(s,1H),4.33(q,J＝7.0Hz,2H),3.89(s,3H),2.31(s,3H),1.35(t,J＝7.0Hz,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 10.93(s, 1H), 10.85(s, 1H), 8.52(d, J=5.5Hz, 1H), 8.23(s, 1H), 7.63( d, J=5.0Hz, 1H), 6.62(s, 1H), 4.33(q, J=7.0Hz, 2H), 3.89(s, 3H), 2.31(s, 3H), 1.35(t, J=7.0 Hz, 3H).
13C-NMR(125MHz,DMSO-d 6):δ165.94,165.74,151.53,151.27,150.97,148.80,147.56,134.27,115.55,113.96,113.09,111.07,60.81,52.88,18.18,14.54。 13 C-NMR (125MHz, DMSO-d 6 ): δ165.94, 165.74, 151.53, 151.27, 150.97, 148.80, 147.56, 134.27, 115.55, 113.96, 113.09, 111.07, 60.81, 52.88, 18.18, 14.
MS(ESI)m/z:364.4[M+H] +。 MS (ESI) m/z: 364.4 [M+H] + .
步骤三：4-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯/4-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的合成Step 3: Methyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate / Synthesis of ethyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
将4-(3-(3-(乙氧基羰基)-4-甲基噻吩-2-基)脲基)吡啶-2-甲酸甲酯(9g,24.77mmol)与N,N-二甲基甲酰胺(140mL)混合，氮气保护下，分三批加入氢化钠(1.19g,29.7mmol)，将混合物加热至60℃反应1小时。将反应液冷却至室温，加入饱和氯化铵水溶液(420mL)，有固体析出。抽滤，滤饼干燥后得到标题化合物4.1g(甲酯与乙酯的混合物，两者比例为3：2)。Combine methyl 4-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate (9 g, 24.77 mmol) with N,N-dimethyl Formamide (140 mL) was mixed, and sodium hydride (1.19 g, 29.7 mmol) was added in three batches under nitrogen protection, and the mixture was heated to 60° C. to react for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (420 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 4.1 g of the title compound (a mixture of methyl ester and ethyl ester, the ratio of the two being 3:2).
MS(ESI)m/z:316.1[M-H] -(甲酯)，330.2[M-H] -(乙酯)。 MS (ESI) m/z: 316.1 [MH] - (methyl ester), 330.2 [MH] - (ethyl ester).
步骤四：(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯/(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的合成Step 4: (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate/(R)-4-( 1-(2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo - Synthesis of ethyl 1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
将4-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯与4-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯混合物(3g)，(R)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃(4.17g,13.24mmol)，碳酸铯(4.31g,13.24mmol)与N-甲基吡咯烷酮(30ml)混合，将混合物加热至100℃反应7小时。抽滤，滤饼以乙酸乙酯洗涤，向滤液中加入水(100mL)，分取水相，以乙酸乙酯萃取(100ml×3)，合并有机相，依次以水、饱和食盐水洗涤。有机相以无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(乙酸乙酯:石油醚＝1:1)，得到标题化合物2.7g(甲酯与乙酯比例为1：1)。Combine methyl 4-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate with 4 -(5-Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester mixture (3g) , (R)-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran (4.17g, 13.24mmol), cesium carbonate (4.31g, 13.24mmol) ) was mixed with N-methylpyrrolidone (30 ml), and the mixture was heated to 100° C. to react for 7 hours. Suction filtration, the filter cake was washed with ethyl acetate, water (100 mL) was added to the filtrate, the aqueous phase was separated, extracted with ethyl acetate (100 ml×3), the organic phases were combined and washed with water and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 2.7g of the title compound (the ratio of methyl ester to ethyl ester was 1:1) .
MS(ESI)m/z:552.4[M+H] +(甲酯),566.4[M+H] +(乙酯)。 MS (ESI) m/z: 552.4 [M+H] + (methyl ester), 566.4 [M+H] + (ethyl ester).
步骤五：(R)-4-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯/(R)-4-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯的合成Step 5: (R)-4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester/(R) -4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl - Synthesis of methyl 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
将(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯与(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H- 吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯混合物(2.7g)与二氯甲烷(30mL)混合，冰水浴降温，加入溴代丁二酰亚胺(0.871g,4.89mmol)，0℃反应1小时。反应液依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以乙腈溶解，用Biotage C18 120g反相色谱柱纯化(水:乙腈＝2:3)，得到标题化合物0.89g(甲酯与乙酯比例为1：1)。(R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -2,4-Dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester with (R)-4-(1- (2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1 ,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester mixture (2.7g) was mixed with dichloromethane (30mL), cooled in an ice-water bath, and bromine was added. Succinimide (0.871 g, 4.89 mmol) was reacted at 0°C for 1 hour. The reaction solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, dissolved in acetonitrile after concentration, and purified with a Biotage C18 120g reverse phase chromatography column (water:acetonitrile=2:3) to obtain the title compound 0.89g (1:1 ratio of methyl ester to ethyl ester).
MS(ESI)m/z:630.3[M+H] +(甲酯)，644.4[M+H] +(乙酯)。 MS (ESI) m/z: 630.3 [M+H] + (methyl ester), 644.4 [M+H] + (ethyl ester).
步骤六：(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯(式I-12化合物)/(R)-4-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯(式I-13化合物)的合成Step 6: (R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine -Methyl 2-carboxylate (compound of formula I-12)/(R)-4-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d ] Synthesis of pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester (compound of formula I-13)
将(R)-4-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯与(R)-4-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯混合物(700mg)，二(三苯基膦)二氯化钯(78mg,0.111mmol)，碘化亚铜(42.3mg,0.222mmol)与N,N-二甲基甲酰胺(10mL)混合。氮气吹扫后，加入三乙胺(0.464mL,3.33mmol)及丙炔(1M四氢呋喃溶液)(2.78mL,2.78mmol)，80℃封管反应2小时。向反应液中加入水(30mL)，水相以乙酸乙酯萃取(30mL×3)，合并有机相，依次以水、饱和食盐水洗涤。有机相以无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝3:2)，得到式I-12化合物、式I-13化合物混合物456mg(甲酯与乙酯比例为1：1)。(R)-4-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- 5-Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester with (R)-4 -(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2 ,4-Dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester mixture (700mg), bis(triphenylphosphine) Palladium dichloride (78 mg, 0.111 mmol), cuprous iodide (42.3 mg, 0.222 mmol) were mixed with N,N-dimethylformamide (10 mL). After purging with nitrogen, triethylamine (0.464 mL, 3.33 mmol) and propyne (1M tetrahydrofuran solution) (2.78 mL, 2.78 mmol) were added, and the reaction was sealed at 80° C. for 2 hours. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed with water and saturated brine in this order. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:2) to obtain 456 mg of a mixture of compounds of formula I-12 and compound of formula I-13 (methyl ester) The ratio to ethyl ester is 1:1).
式I-12化合物：MS(ESI)m/z:590.5[M+H] +；式I-13化合物：MS(ESI)m/z:604.5[M+H] +。 Compound of formula 1-12: MS (ESI) m/z: 590.5 [M+H] + ; compound of formula 1-13: MS (ESI) m/z: 604.5 [M+H] + .
步骤七：式I-5化合物的合成Step 7: Synthesis of the compound of formula I-5
将式I-12化合物、式I-13化合物混合物(250mg)，甲醇(1.5mL)，氢氧化锂水合物(49.7mg,1.185mmol)的水溶液(0.5mL)混合，室温反应2小时。向反应液加入水(10mL)和乙酸乙酯(10mL)，冰浴下加入2N盐酸溶液调pH至5-6。分取水相，水相以乙酸乙酯(10mL×4)萃取，合并有机相，无水硫酸钠干燥，抽滤，浓缩后以四氢呋喃溶解，用Biotage C18 120g反相色谱柱纯化(水:乙腈＝2:3)，得到式I-5化合物87mg。The compound of formula I-12, a mixture of compounds of formula I-13 (250 mg), methanol (1.5 mL), and an aqueous solution (0.5 mL) of lithium hydroxide hydrate (49.7 mg, 1.185 mmol) were mixed and reacted at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6. Separate the aqueous phase, extract the aqueous phase with ethyl acetate (10 mL×4), combine the organic phases, dry over anhydrous sodium sulfate, filter with suction, dissolve in tetrahydrofuran after concentration, and purify with a Biotage C18 120 g reverse-phase chromatographic column (water:acetonitrile= 2:3) to obtain 87 mg of the compound of formula I-5.
1H-NMR(500MHz,CDCl 3):δ8.77(s,1H),8.13(s,1H),7.54(d,J＝7.0Hz,1H),7.45(s,1H),7.34(t,J＝7.8Hz,1H),7.05(t,J＝7.5Hz,1H),6.88(d,J＝8.5Hz,1H),5.43(dd,J1＝8.3Hz,J2＝4.8Hz,1H),4.22-4.19(m,1H),4.05-4.02(m,1H),3.83(s,3H),3.81-3.79(m,2H),3.51-3.46(m,1H),3.41-3.37(m,2H),2.50(s,3H),2.16(s,3H),1.84-1.75(m,2H),1.62-1.55(m,1H),1.50-1.44(m,1H)。 1 H-NMR (500MHz, CDCl 3 ): δ8.77(s, 1H), 8.13(s, 1H), 7.54(d, J=7.0Hz, 1H), 7.45(s, 1H), 7.34(t, J=7.8Hz, 1H), 7.05 (t, J=7.5Hz, 1H), 6.88 (d, J=8.5Hz, 1H), 5.43 (dd, J1=8.3Hz, J2=4.8Hz, 1H), 4.22 -4.19(m,1H),4.05-4.02(m,1H),3.83(s,3H),3.81-3.79(m,2H),3.51-3.46(m,1H),3.41-3.37(m,2H) , 2.50(s, 3H), 2.16(s, 3H), 1.84-1.75(m, 2H), 1.62-1.55(m, 1H), 1.50-1.44(m, 1H).
13C-NMR(125MHz,CDCl 3):δ157.40,156.95,154.35,149.53,139.77,129.51,127.12,127.04,121.00,113.20,110.43,94.26,72.04,70.70,69.69,65.40,65.10,55.50,53.90,33.23,31.52,14.99,4.81。 13 C-NMR(125MHz,CDCl 3 ):δ157.40,156.95,154.35,149.53,139.77,129.51,127.12,127.04,121.00,113.20,110.43,94.26,72.04,70.70,69.69,65.40,65.10,55.50,53.90,33.23 , 31.52, 14.99, 4.81.
HRMS(ESI)m/z:576.1832[M+H] +。 HRMS (ESI) m/z: 576.1832 [M+H] + .
实施例6：(R)-6-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸(式I-6化合物)Example 6: (R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Pyridine-2-carboxylic acid (compound of formula I-6)
Figure PCTCN2022074327-appb-000051
Figure PCTCN2022074327-appb-000051
步骤一：6-(3-(3-(乙氧基羰基)-4-甲基噻吩-2-基)脲基)吡啶-2-甲酸甲酯的合成Step 1: Synthesis of methyl 6-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate
将6-氨基吡啶-2-甲酸甲酯(10g,65.7mmol)，4-甲基-2-((苯氧基羰基)氨基)噻吩-3-羧酸乙酯(24.08g,79mmol)，三乙胺(12.83mL,92mmol)与甲苯(100mL)混合，将混合物加热至110℃反应12小时。反应液冷却至室温，抽滤，滤饼以石油醚和乙酸乙酯打浆，抽滤，滤饼干燥后得到标题化合物16.6g。6-Aminopyridine-2-carboxylic acid methyl ester (10 g, 65.7 mmol), 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (24.08 g, 79 mmol), trimethylate Ethylamine (12.83 mL, 92 mmol) was mixed with toluene (100 mL), and the mixture was heated to 110°C for 12 hours. The reaction solution was cooled to room temperature, filtered with suction, the filter cake was slurried with petroleum ether and ethyl acetate, filtered with suction, and the filter cake was dried to obtain 16.6 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ11.23(s,1H),11.01(s,1H),8.08(d,J＝7.5Hz,1H),7.96(t,J＝8.0Hz,1H),7.71(d,J＝7.5Hz,1H),6.60(s,1H),4.32(q,J＝7.3Hz,2H),3.88(s,3H),2.31(s,3H),1.32(t,J＝7.0Hz,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ 11.23 (s, 1H), 11.01 (s, 1H), 8.08 (d, J=7.5Hz, 1H), 7.96 (t, J=8.0Hz, 1H), 7.71(d, J=7.5Hz, 1H), 6.60(s, 1H), 4.32(q, J=7.3Hz, 2H), 3.88(s, 3H), 2.31(s, 3H), 1.32( t, J=7.0 Hz, 3H).
13C-NMR(125MHz,DMSO-d 6):δ165.34,164.82,152.83,151.69,150.80,146.19,140.08,134.49,119.79,116.60,113.16,111.58,60.49,52.80,18.18,14.66。 13 C-NMR (125MHz, DMSO-d 6 ): δ165.34, 164.82, 152.83, 151.69, 150.80, 146.19, 140.08, 134.49, 119.79, 116.60, 113.16, 111.58, 60.49, 52.66.80, 18.18, 14
MS(ESI)m/z:364.4[M+H] +. MS(ESI) m/z: 364.4[M+H] + .
步骤二：6-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯/6-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的合成Step 2: Methyl 6-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate /Synthesis of ethyl 6-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
将6-(3-(3-(乙氧基羰基)-4-甲基噻吩-2-基)脲基)吡啶-2-甲酸甲酯(8g,22.02mmol)与N,N-二甲基甲酰胺(50mL)混合，氮气保护下，分三批加入氢化钠(1.23g,30.8mmol)，将混合物加热至60℃反应1小时。将反应液冷却至室温，加入饱和氯化铵水溶液(250mL)，有固体析出。抽滤，滤饼干燥后得到标题化合物3.5g(甲酯与乙酯的混合物，两者比例为3：2)。Combine methyl 6-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)pyridine-2-carboxylate (8 g, 22.02 mmol) with N,N-dimethyl Formamide (50 mL) was mixed, and under nitrogen protection, sodium hydride (1.23 g, 30.8 mmol) was added in three batches, and the mixture was heated to 60° C. to react for 1 hour. The reaction solution was cooled to room temperature, a saturated aqueous ammonium chloride solution (250 mL) was added, and a solid was precipitated. After suction filtration, the filter cake was dried to obtain 3.5 g of the title compound (a mixture of methyl ester and ethyl ester, the ratio of the two being 3:2).
MS(ESI)m/z:316.1[M-H] -(甲酯)，330.2[M-H] -(乙酯)。 MS (ESI) m/z: 316.1 [MH] - (methyl ester), 330.2 [MH] - (ethyl ester).
步骤三：(R)-6-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯/(R)-6-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的合成Step 3: (R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester/(R)-6-( 1-(2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo - Synthesis of ethyl 1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
将6-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯与6-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的混合物(3g)，(R)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃(4.17g,13.24mmol)，碳酸铯(4.31g,13.24mmol)与N-甲基吡咯烷酮(30mL)混合，将混合物加热至100℃反应7小时。抽滤，滤饼以乙酸乙酯洗涤，向滤液中加入水(100mL)，分取水相，以乙酸乙酯萃取(100mL×3)，合并有机相，依次以水、饱和食盐水洗涤。有机相以无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(乙酸乙酯:石油醚＝1:1)，得到标题化合物1.5g(甲酯与乙酯比例为1：1)。Combine methyl 6-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate with 6 -(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester mixture (3 g ), (R)-4-(2-bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran (4.17g, 13.24mmol), cesium carbonate (4.31g, 13.24g) mmol) was mixed with N-methylpyrrolidone (30 mL), and the mixture was heated to 100° C. to react for 7 hours. Suction filtration, the filter cake was washed with ethyl acetate, water (100 mL) was added to the filtrate, the aqueous phase was separated, extracted with ethyl acetate (100 mL×3), the organic phases were combined and washed with water and saturated brine successively. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=1:1) to obtain 1.5 g of the title compound (the ratio of methyl ester to ethyl ester was 1:1) .
MS(ESI)m/z:552.4[M+H] +(甲酯)，566.4[M+H] +(乙酯)。 MS (ESI) m/z: 552.4 [M+H] + (methyl ester), 566.4 [M+H] + (ethyl ester).
步骤四：(R)-6-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯/(R)-6-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的合成Step 4: (R)-6-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester/(R) -6-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl - Synthesis of ethyl 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate
将(R)-6-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯与(R)-6-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的混合物(1.1g)与二氯甲烷(30mL)混合，冰水浴降温，加入溴代丁二酰亚胺(0.355g,1.994mmol)，0℃反应1小时。反应液依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以乙腈溶解，用Biotage C18 120g反相色谱柱纯化(水:乙腈＝2:3)，得到标题化合物0.43g(甲酯与乙酯比例为1：1)。(R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl -2,4-Dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester with (R)-6-(1- (2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1 , A mixture of ethyl 4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylate (1.1 g) was mixed with dichloromethane (30 mL), cooled in an ice-water bath, and added Bromosuccinimide (0.355 g, 1.994 mmol) was reacted at 0°C for 1 hour. The reaction solution was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered with suction, dissolved in acetonitrile after concentration, and purified with a Biotage C18 120g reverse phase chromatography column (water:acetonitrile=2:3) to obtain the title compound 0.43g (1:1 ratio of methyl ester to ethyl ester).
MS(ESI)m/z:630.4[M+H] +(甲酯)，644.4[M+H] +(乙酯)。 MS (ESI) m/z: 630.4 [M+H] + (methyl ester), 644.4 [M+H] + (ethyl ester).
步骤五：(R)-6-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯(式I-14化合物)/(R)-6-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯(式I-15化合物)的合成Step 5: (R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine -Methyl 2-carboxylate (compound of formula I-14)/(R)-6-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- yl)oxy)ethyl)-5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d ] Synthesis of pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl ester (compound of formula I-15)
将(R)-6-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸甲酯与(R)-6-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)吡啶-2-甲酸乙酯的混合物(400mg)，二(三苯基膦)二氯化钯(44.5mg,0.063mmol)，碘化亚铜(24.16mg,0.127mmol)与N,N-二甲基甲酰胺(10mL)混合。氮气吹扫后，加入三乙胺(0.265mL,1.903mmol)及丙炔(1M四氢呋喃溶液)(1.586mL,1.586mmol)，80℃封管反应2小时。向反应液中加入水(30mL)，水相以乙酸乙酯萃取(30mL×3)，合并有机相，依次以水、饱和食盐水洗涤。有机相以无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(石油醚:乙酸乙酯＝3:2)，得到式I-14化合物、式I-15化合物混合物326mg(式I-14化合物与式I-15化合物比例为1：1)。(R)-6-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- 5-Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid methyl ester with (R)-6 -(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2 A mixture of ,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)pyridine-2-carboxylic acid ethyl esters (400mg), bis(triphenylphosphine) ) palladium dichloride (44.5 mg, 0.063 mmol), cuprous iodide (24.16 mg, 0.127 mmol) was mixed with N,N-dimethylformamide (10 mL). After purging with nitrogen, triethylamine (0.265 mL, 1.903 mmol) and propyne (1M tetrahydrofuran solution) (1.586 mL, 1.586 mmol) were added, and the reaction was carried out at 80° C. for 2 hours. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed with water and saturated brine in this order. The organic phase was dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (petroleum ether:ethyl acetate=3:2) to obtain 326 mg of a mixture of compounds of formula I-14 and compound of formula I-15 (formula I The ratio of the -14 compound to the formula I-15 compound is 1:1).
式I-14化合物：MS(ESI)m/z:590.4[M+H] +；式I-15化合物：MS(ESI)m/z:604.4[M+H] +。步骤六：式I-6化合物的合成 Compound of formula 1-14: MS (ESI) m/z: 590.4 [M+H] + ; compound of formula 1-15: MS (ESI) m/z: 604.4 [M+H] + . Step 6: Synthesis of the compound of formula I-6
将式I-14化合物、式I-15化合物混合物(300mg)，甲醇(5mL)，氢氧化锂水合物(64mg,1.526mmol)的水溶液(1.5mL)混合，室温反应2小时。向反应液加入水(10mL)和乙酸乙酯(10mL)，冰浴下加入2N盐酸溶液调pH至5-6。分取水相，水相以乙酸乙酯(10mL×3)萃取，合并有机相，无水硫酸钠干燥，抽滤，浓缩后以四氢呋喃溶解，用Biotage C18 120g反相色谱柱纯化(水:乙腈＝1:1)，得到式I-6化合物76mg。The compound of formula I-14, a mixture of compounds of formula I-15 (300 mg), methanol (5 mL), and an aqueous solution (1.5 mL) of lithium hydroxide hydrate (64 mg, 1.526 mmol) were mixed and reacted at room temperature for 2 hours. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, and 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6. The aqueous phase was separated, the aqueous phase was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, dissolved in tetrahydrofuran after concentration, and purified with a Biotage C18 120 g reverse-phase chromatographic column (water:acetonitrile= 1:1) to obtain 76 mg of the compound of formula I-6.
1H-NMR(500MHz,CDCl 3):δ8.34(s,1H),8.12(s,1H),7.54(d,J＝7.5Hz,2H),7.33(t,J＝7.8Hz,1H),7.04(t,J＝7.3Hz,1H),6.90(d,J＝8.0Hz,1H),5.42(dd,J 1＝8.5Hz,J 2＝4.0Hz,1H),4.26-4.20(m,1H),4.08-4.05(m,1H),3.88(s,3H),3.85-3.81(m,2H),3.52-3.47(m,3H),2.51(s,3H),2.17(s,3H),1.82-1.75(m,2H),1.63-1.60(m,1H),1.50-1.46(m,1H)。 1 H-NMR (500MHz, CDCl 3 ): δ 8.34 (s, 1H), 8.12 (s, 1H), 7.54 (d, J=7.5Hz, 2H), 7.33 (t, J=7.8Hz, 1H) ,7.04(t,J=7.3Hz,1H),6.90(d,J=8.0Hz,1H),5.42(dd,J1 = 8.5Hz,J2=4.0Hz,1H ) ,4.26-4.20(m, 1H), 4.08-4.05(m, 1H), 3.88(s, 3H), 3.85-3.81(m, 2H), 3.52-3.47(m, 3H), 2.51(s, 3H), 2.17(s, 3H) , 1.82-1.75 (m, 2H), 1.63-1.60 (m, 1H), 1.50-1.46 (m, 1H).
HRMS(ESI)m/z:576.1783[M+H] +。 HRMS (ESI) m/z: 576.1783 [M+H] + .
实施例7：(R)-5-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸(式I-7化合物)Example 7: (R)-5-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Niacin (compound of formula I-7)
Figure PCTCN2022074327-appb-000052
Figure PCTCN2022074327-appb-000052
步骤一：5-(3-(3-(乙氧基羰基)-4-甲基噻吩-2-基)脲基)烟酸甲酯的合成Step 1: Synthesis of methyl 5-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)nicotinate
将4-甲基-2-((苯氧基羰基)氨基)噻吩-3-羧酸乙酯(10g,32.7mmol)，5-氨基烟酸甲酯(5.98g,39.3mmol)，三乙胺(6.85mL,49.1mmol)和甲苯(200mL)混合，将混合物加热至110℃反应10小时。反应液冷却至室温，抽滤，滤饼以水洗涤，干燥。所得粗品以二氯甲烷打浆纯化，抽滤，滤饼干燥后得到标题化合物9.9g。Ethyl 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (10 g, 32.7 mmol), methyl 5-aminonicotinate (5.98 g, 39.3 mmol), triethylamine (6.85 mL, 49.1 mmol) and toluene (200 mL) were mixed, and the mixture was heated to 110° C. to react for 10 hours. The reaction solution was cooled to room temperature, filtered with suction, and the filter cake was washed with water and dried. The obtained crude product was purified by beating with dichloromethane, suction filtered, and the filter cake was dried to obtain 9.9 g of the title compound.
1H-NMR(500MHz,DMSO-d 6):δ10.80(s,1H),10.70(s,1H),8.75(d,J＝2.6Hz,1H),8.72(d,J＝2.4Hz,1H),8.56(d,J＝2.4Hz,1H),6.57(s,1H),4.32(q,J＝7.1Hz,2H),3.90(s,3H),2.29(s,3H),1.34(t,J＝7.1Hz,3H)。 1 H-NMR (500MHz, DMSO-d 6 ): δ10.80(s, 1H), 10.70(s, 1H), 8.75(d, J=2.6Hz, 1H), 8.72(d, J=2.4Hz, 1H), 8.56(d, J=2.4Hz, 1H), 6.57(s, 1H), 4.32(q, J=7.1Hz, 2H), 3.90(s, 3H), 2.29(s, 3H), 1.34( t, J=7.1 Hz, 3H).
13C-NMR(125MHz,DMSO-d 6):δ165.94,165.60,151.94,151.57,143.95,143.94,136.54,134.15,125.93,125.31,112.80,110.64,60.72,52.94,18.19,14.53。 13 C-NMR (125MHz, DMSO-d 6 ): δ 165.94, 165.60, 151.94, 151.57, 143.95, 143.94, 136.54, 134.15, 125.93, 125.31, 112.80, 110.64, 60.72, 52.94, 18.19, 14.
MS(ESI)m/z:364.4[M+H] +. MS(ESI) m/z: 364.4[M+H] + .
步骤二：3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸甲酯/3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的合成Step 2: Methyl 3-(5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate/3- Synthesis of ethyl (5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate
将5-(3-(3-(乙氧基羰基)-4-甲基噻吩-2-基)脲基)烟酸甲酯(5g,13.76mmol)与N,N-二甲基甲酰胺(50mL)混合，冰水浴降温，氮气吹扫下，分批加入氢化钠(0.660g,16.51mmol)，将 混合物加热至100℃反应1小时。反应液冷却至室温，加入饱和氯化铵水溶液，抽滤，滤饼以水洗涤，干燥。所得粗品以二氯甲烷和甲醇打浆纯化，抽滤，滤饼干燥后得到标题化合物3.1g(甲酯与乙酯的混合物，两者比例为3：2)。Combine methyl 5-(3-(3-(ethoxycarbonyl)-4-methylthiophen-2-yl)ureido)nicotinate (5 g, 13.76 mmol) with N,N-dimethylformamide ( 50 mL) and mixed, cooled in an ice-water bath, and under nitrogen purge, sodium hydride (0.660 g, 16.51 mmol) was added in batches, and the mixture was heated to 100° C. to react for 1 hour. The reaction solution was cooled to room temperature, saturated aqueous ammonium chloride solution was added, suction filtered, and the filter cake was washed with water and dried. The obtained crude product was purified by slurrying with dichloromethane and methanol, suction filtered, and the filter cake was dried to obtain 3.1 g of the title compound (a mixture of methyl ester and ethyl ester, the ratio of the two being 3:2).
MS(ESI)m/z:318.4[M+H] +(甲酯)。 MS (ESI) m/z: 318.4 [M+H] + (methyl ester).
步骤三：(R)-5-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸甲酯/(R)-5-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸乙酯的合成Step 3: (R)-5-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid methyl ester/(R)-5-(1-( 2-(2-Methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1, Synthesis of 4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid ethyl ester
将(R)-4-(2-溴-1-(2-甲氧基苯基)乙氧基)四氢-2H-吡喃(1.093g,3.47mmol)，3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸甲酯/3-(5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)苯甲酸乙酯的混合物(1g)，碳酸铯(1.540g,4.73mmol)与N-甲基吡咯烷酮(30mL)混合，将混合物加热至100℃反应5小时。反应液加入水(100mL)，水相以乙酸乙酯(100mL×2)萃取。合并有机相，依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(乙酸乙酯:石油醚＝3:2)，得到标题化合物740mg(甲酯与乙酯比例为1.2：1)。(R)-4-(2-Bromo-1-(2-methoxyphenyl)ethoxy)tetrahydro-2H-pyran (1.093 g, 3.47 mmol), 3-(5-methyl- Methyl 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate/3-(5-methyl-2,4-di A mixture of ethyl oxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)benzoate (1 g), cesium carbonate (1.540 g, 4.73 mmol) and N-methyl pyrrolidone (30 mL), and the mixture was heated to 100°C for 5 hours. Water (100 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (100 mL×2). The organic phases were combined, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, filtered with suction, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=3:2) to obtain 740 mg of the title compound (methyl ester) The ratio to ethyl ester is 1.2:1).
MS(ESI)m/z:552.4[M+H] +(甲酯)。 MS (ESI) m/z: 552.4 [M+H] + (methyl ester).
步骤四：(R)-5-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸甲酯/(R)-5-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸乙酯的合成Step 4: (R)-5-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl )-5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid methyl ester/(R)-5- (6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2, Synthesis of 4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid ethyl ester
将(R)-5-(1-(2-(2-甲氧基苯基)-2((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸甲酯与(R)-5-(1-(2-(2-甲氧基苯基)-2((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸乙酯的化合物(0.31g)与二氯甲烷(5mL)混合，冰水浴降温，加入溴代丁二酰亚胺(0.091g,0.513mmol)，0℃反应1小时。加入二氯甲烷(50mL)稀释，依次以水、饱和食盐水洗涤，无水硫酸钠干燥，抽滤，浓缩后以硅胶柱层析纯化(乙酸乙酯:石油醚＝4:1)，得到标题化合物280mg(甲酯与乙酯比例为1.1：1)。(R)-5-(1-(2-(2-methoxyphenyl)-2((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl- Methyl 2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinate and (R)-5-(1-(2-( 2-Methoxyphenyl)-2((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4-dioxo-1,4-dihydro Thieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid ethyl ester compound (0.31 g) was mixed with dichloromethane (5 mL), cooled in an ice-water bath, and bromosuccinimide ( 0.091 g, 0.513 mmol), react at 0 °C for 1 hour. Dichloromethane (50 mL) was added to dilute, washed with water and saturated brine successively, dried over anhydrous sodium sulfate, suction filtered, concentrated and purified by silica gel column chromatography (ethyl acetate:petroleum ether=4:1) to obtain the title Compound 280 mg (1.1:1 ratio of methyl ester to ethyl ester).
MS(ESI)m/z:630.4[M+H] +(甲酯)。 MS (ESI) m/z: 630.4 [M+H] + (methyl ester).
步骤五：(R)-5-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸甲酯(式I-16化合物)/(R)-5-(1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸乙酯(式I-17化合物)的合成Step 5: (R)-5-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5- Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotine Methyl acid (compound of formula I-16)/(R)-5-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy yl)ethyl)-5-methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidine- Synthesis of 3(2H)-yl)nicotinic acid ethyl ester (compound of formula I-17)
将(R)-5-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸甲酯与(R)-5-(6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)烟酸乙酯的混合物(200mg)，二(三苯基膦)二氯化钯(22.26mg,0.032mmol)，碘化亚铜(12.08mg,0.063mmol)与N,N-二甲基甲酰胺(3mL)混合。氮气吹扫后，加入三乙胺(0.133mL,0.952mmol)，丙炔(1M四氢呋喃溶液)(0.824mL,0.824mmol)，80℃封管反应24小时。向反应液中加入水(30mL)，水相以乙酸乙酯萃取(30mL×3)，合并有机相，依次以水、饱和食盐水洗涤。有机相以无水硫酸钠干燥，抽滤，浓缩后以Biotage C18 120g反相色谱柱纯化(水:乙腈＝1:2)，得到式I-16化合物、式I-17化合物混合物100mg(式I-16化合物与式I-17化合物比例为1：1)。(R)-5-(6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- Methyl 5-methyl-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinate and (R)-5-(6 -Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl-2,4- A mixture of dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)nicotinic acid ethyl esters (200mg), bis(triphenylphosphine)palladium dichloride ( 22.26 mg, 0.032 mmol), cuprous iodide (12.08 mg, 0.063 mmol) was mixed with N,N-dimethylformamide (3 mL). After purging with nitrogen, triethylamine (0.133 mL, 0.952 mmol), propyne (1M tetrahydrofuran solution) (0.824 mL, 0.824 mmol) were added, and the reaction was carried out at 80° C. for 24 hours. Water (30 mL) was added to the reaction solution, the aqueous phase was extracted with ethyl acetate (30 mL×3), and the organic phases were combined and washed with water and saturated brine in this order. The organic phase was dried with anhydrous sodium sulfate, filtered with suction, concentrated and purified with a Biotage C18 120g reverse-phase chromatographic column (water:acetonitrile=1:2) to obtain 100mg of a compound of formula I-16 and a mixture of compounds of formula I-17 (formula I The ratio of the compound of -16 to the compound of formula I-17 is 1:1).
式I-16化合物：MS(ESI)m/z:590.4[M+H] +。 Compound of formula 1-16: MS (ESI) m/z: 590.4 [M+H] + .
步骤六：式I-7化合物的合成Step 6: Synthesis of the compound of formula I-7
将式I-16化合物、式I-17化合物混合物(100mg)，甲醇(6mL)，氢氧化锂水合物(142mg,3.39mmol)的水溶液(2mL)混合，室温反应1小时。冰浴下加入2N盐酸溶液调pH至5-6，有固体析出。抽滤，所得粗品以Biotage C18 120g反相色谱柱纯化(水:乙腈＝1:1)，得到式I-7化合物6mg。The compound of formula I-16, a mixture of compounds of formula I-17 (100 mg), methanol (6 mL), and an aqueous solution (2 mL) of lithium hydroxide hydrate (142 mg, 3.39 mmol) were mixed and reacted at room temperature for 1 hour. 2N hydrochloric acid solution was added under ice bath to adjust the pH to 5-6, and a solid was precipitated. After suction filtration, the obtained crude product was purified by Biotage C18 120g reverse-phase chromatography column (water:acetonitrile=1:1) to obtain 6mg of the compound of formula I-7.
1H NMR(500MHz,DMSO-d 6):δ13.56(br,1H),9.12(s,1H),8.66(s,1H),8.21(s,1H),7.48(d,J＝7.5Hz,1H),7.32(t,J＝7.8Hz,1H),7.12–6.87(m,2H),5.30(d,J＝6.2Hz,1H),4.11(s,1H),3.95(s,1H),3.77(s,3H),3.61(s,2H),3.41(s,3H),2.41(s,3H),2.15(s,3H),1.78–1.57(m,2H),1.32(d,J＝21.1Hz,2H)。 1 H NMR (500MHz, DMSO-d 6 ): δ13.56(br,1H), 9.12(s,1H), 8.66(s,1H), 8.21(s,1H), 7.48(d,J=7.5Hz ,1H),7.32(t,J＝7.8Hz,1H),7.12–6.87(m,2H),5.30(d,J＝6.2Hz,1H),4.11(s,1H),3.95(s,1H) , 3.77(s, 3H), 3.61(s, 2H), 3.41(s, 3H), 2.41(s, 3H), 2.15(s, 3H), 1.78–1.57(m, 2H), 1.32(d, J = 21.1 Hz, 2H).
HRMS(ESI)m/z:576.1832[M+H] +。 HRMS (ESI) m/z: 576.1832 [M+H] + .
实施例8：(R)-2-((1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸(式I-8化合物)Example 8: (R)-2-((1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)- 5-Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl ) oxy)-2-methylpropionic acid (compound of formula I-8)
Figure PCTCN2022074327-appb-000053
Figure PCTCN2022074327-appb-000053
步骤一：2-((1,3-二氧异吲哚-2-基)氧基)-2-甲基丙酸叔丁酯的合成Step 1: Synthesis of tert-butyl 2-((1,3-dioxoisoindol-2-yl)oxy)-2-methylpropanoate
将2-溴-2-甲基丙酸叔丁酯(5g，22.41mmol)，N-羟基邻苯二甲酰亚胺(3.66g，22.41mmol)，碳酸钾(3.72g，26.9mmol)，DMF(60ml)混合，90℃反应20小时。反应液抽滤，滤液加入水和乙酸乙酯，分液，水相用乙酸乙酯萃取(200mL*3)，合并有机相，分别用水洗(200mL*3)，饱和食盐水洗(100mL)，无水硫酸钠干燥。抽滤，滤液浓缩后得到黄色油状物，柱层析纯化(乙酸乙酯：石油醚＝2：3)，得到标题化合物720mg。2-Bromo-2-methylpropionic acid tert-butyl ester (5 g, 22.41 mmol), N-hydroxyphthalimide (3.66 g, 22.41 mmol), potassium carbonate (3.72 g, 26.9 mmol), DMF (60ml) mixed and reacted at 90°C for 20 hours. The reaction solution was suction filtered, water and ethyl acetate were added to the filtrate, and the layers were separated. The aqueous phase was extracted with ethyl acetate (200 mL*3), and the organic phases were combined, washed with water (200 mL*3) and saturated brine (100 mL), respectively. Dry over sodium sulfate. After suction filtration, the filtrate was concentrated to obtain a yellow oil, which was purified by column chromatography (ethyl acetate:petroleum ether=2:3) to obtain 720 mg of the title compound.
1H NMR(500MHz,CDCl 3):δ7.86-7.84(m,2H),7.78-7.76(m,2H),1.60(s,6H),1.53(s,9H)。 1 H NMR (500 MHz, CDCl 3 ): δ 7.86-7.84 (m, 2H), 7.78-7.76 (m, 2H), 1.60 (s, 6H), 1.53 (s, 9H).
MS(ESI)m/z:328.3[M+Na] +。 MS (ESI) m/z: 328.3 [M+Na] + .
步骤二：2-(氨基氧基)-2-甲基丙酸叔丁酯的合成Step 2: Synthesis of 2-(aminooxy)-2-methylpropionic acid tert-butyl ester
将2-((1,3-二氧异吲哚-2-基)氧基)-2-甲基丙酸叔丁酯(7g,22.93mmol)，溶于二氯甲烷(33ml)和甲醇(6mL)的混合溶液中，室温搅拌下向其中滴加水合肼(4.59g,92mmol)，滴加完毕搅拌反应1.5小时。抽滤，滤饼用二氯甲烷(30ml)洗涤，滤液浓缩，残留物用乙酸乙酯(50ml)稀释后，依次用水(50mL)，饱和食盐水(50ml)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩后得到标题化合物3.4g。Dissolve tert-butyl 2-((1,3-dioxoisoindol-2-yl)oxy)-2-methylpropanoate (7 g, 22.93 mmol) in dichloromethane (33 ml) and methanol ( 6 mL) of the mixed solution, hydrazine hydrate (4.59 g, 92 mmol) was added dropwise thereto under stirring at room temperature, and the dropwise addition was completed and the reaction was stirred for 1.5 hours. Suction filtration, the filter cake was washed with dichloromethane (30ml), the filtrate was concentrated, the residue was diluted with ethyl acetate (50ml), washed with water (50ml) and saturated brine (50ml) successively, dried over anhydrous sodium sulfate, suction After filtration, the filtrate was concentrated to obtain 3.4 g of the title compound.
1H NMR(500MHz,CDCl 3):δ5.313(s,2H),1.489(s,9H),1.378(s,6H)。 1 H NMR (500 MHz, CDCl 3 ): δ 5.313 (s, 2H), 1.489 (s, 9H), 1.378 (s, 6H).
GCMS m/z:119[M-C 4H 8] + GCMS m/z: 119[MC 4 H 8 ] +
步骤三：4-甲基-2-((苯氧基羰基)氨基)噻吩-3-羧酸乙酯的合成Step 3: Synthesis of ethyl 4-methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate
将2-氨基-4-甲基噻吩-3-羧酸乙酯(1g,5.40mmol)，乙酸乙酯(15mL)和饱和碳酸氢钠水溶液(15mL)混合后室温搅拌，向其中加入氯甲酸苯酯(0.845g,5.40mmol)，加完后继续室温搅拌反应2小时。反应液分液，水相用乙酸乙酯(20mL)洗涤，合并有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，残留固体用石油醚(10mL)打浆得到标题化合物1.25g。Ethyl 2-amino-4-methylthiophene-3-carboxylate (1 g, 5.40 mmol), ethyl acetate (15 mL) and saturated aqueous sodium bicarbonate solution (15 mL) were mixed and stirred at room temperature, to which was added benzene chloroformate Ester (0.845 g, 5.40 mmol) was added and the reaction was continued to stir at room temperature for 2 hours. The reaction liquid was separated, the aqueous phase was washed with ethyl acetate (20 mL), the combined organic phases were washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, suction filtered, the filtrate was concentrated, and the residual solid was slurried with petroleum ether (10 mL) to obtain The title compound 1.25 g.
步骤四：2-(3-((1-(叔丁氧基)-2-甲基-1-氧代丙烷-2-基)氧基)脲基)-4-甲基噻吩-3-羧酸乙酯的合成Step 4: 2-(3-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)ureido)-4-methylthiophene-3-carboxyl Synthesis of Ethyl Acetate
将4-甲基-2-((苯氧基羰基)氨基)噻吩-3-羧酸乙酯(0.5g,1.637mmol)，甲苯(5ml)，2-(氨基氧基)-2-甲基丙酸叔丁酯(0.344g,1.965mmol)和三乙胺(0.199g,1.965mmol)混合，90℃搅拌反应7小时。停止反应，反应液冷却至室温后减压除去甲苯，残留黄色油状物用石油醚：甲基叔丁基醚＝3:1混合溶剂(10mL)打浆得到标题化合物0.376g。4-Methyl-2-((phenoxycarbonyl)amino)thiophene-3-carboxylate (0.5g, 1.637mmol), toluene (5ml), 2-(aminooxy)-2-methyl Tert-butyl propionate (0.344 g, 1.965 mmol) and triethylamine (0.199 g, 1.965 mmol) were mixed, and the reaction was stirred at 90° C. for 7 hours. The reaction was stopped, the reaction solution was cooled to room temperature, toluene was removed under reduced pressure, and the remaining yellow oil was slurried with petroleum ether:methyl tert-butyl ether=3:1 mixed solvent (10 mL) to obtain 0.376 g of the title compound.
1H NMR(500MHz,DMSO-d 6):δ11.29(s,1H),10.10(s,1H),6.59(s,1H),4.31(q,J＝7.0Hz,2H),2.31(s,3H),1.44(s,6H),1.30-1.33(m,12H)。 1 H NMR (500MHz, DMSO-d 6 ): δ 11.29(s, 1H), 10.10(s, 1H), 6.59(s, 1H), 4.31(q, J=7.0Hz, 2H), 2.31(s , 3H), 1.44 (s, 6H), 1.30-1.33 (m, 12H).
MS(ESI)m/z:409.02[M+Na] +。 MS (ESI) m/z: 409.02 [M+Na] + .
步骤五：5-溴-2-(3-((1-(叔丁氧基)-2-甲基-1-氧代丙烷-2-基)氧基)脲基)-4-甲基噻吩-3-羧酸乙酯的合成Step 5: 5-Bromo-2-(3-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)ureido)-4-methylthiophene Synthesis of -3-Carboxylic Acid Ethyl Ester
将2-(3-((1-(叔丁氧基)-2-甲基-1-氧代丙烷-2-基)氧基)脲基)-4-甲基噻吩-3-羧酸乙酯(0.35g,0.906mmol)和DMF(5ml)混合，混合物搅拌降温至0℃，向其中加入N-溴代丁二酰亚胺(0.161g,0.906mmol)，加完后升至室温搅拌反应1.5小时。反应液用水(20mL)稀释，乙酸乙酯(20mL)萃取，有机相依次用水(10mL)，饱和食盐水洗涤(10mL)，无水硫酸钠干燥，抽滤，滤液浓缩，残留物用石油醚：甲基叔丁基醚＝3:1混合溶剂(10mL)打浆，得到标题化合物0.408g。Ethyl 2-(3-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)ureido)-4-methylthiophene-3-carboxylate Ester (0.35g, 0.906mmol) was mixed with DMF (5ml), the mixture was stirred and cooled to 0°C, N-bromosuccinimide (0.161g, 0.906mmol) was added to it, and the reaction was stirred at room temperature after the addition 1.5 hours. The reaction solution was diluted with water (20 mL), extracted with ethyl acetate (20 mL), the organic phase was washed successively with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the residue was washed with petroleum ether: Methyl tert-butyl ether=3:1 mixed solvent (10 mL) was slurried to obtain 0.408 g of the title compound.
1H NMR(500MHz,DMSO-d 6):δ11.34(s,1H),10.34(s,1H),4.32(q,J＝7.0Hz,2H),2.29(s,3H),1.44(s,6H),1.31-1.33(m,12H)。 1 H NMR (500MHz, DMSO-d 6 ): δ 11.34(s, 1H), 10.34(s, 1H), 4.32(q, J=7.0Hz, 2H), 2.29(s, 3H), 1.44(s) , 6H), 1.31-1.33 (m, 12H).
MS(ESI)m/z:486.87[M+Na] +. MS(ESI) m/z: 486.87[M+Na] + .
步骤六：2-((6-溴-5-甲基-2,4-二氧基-1,4-二氢噻吩[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸的合成Step Six: 2-((6-Bromo-5-methyl-2,4-dioxy-1,4-dihydrothiophen[2,3-d]pyrimidin-3(2H)-yl)oxy) Synthesis of -2-methylpropionic acid
将5-溴-2-(3-((1-(叔丁氧基)-2-甲基-1-氧代丙烷-2-基)氧基)脲基)-4-甲基噻吩-3-羧酸乙酯(10g,21.49mmol)分散于无水乙醇(120mL)中，混合物在氮气氛围中，室温下搅拌，向其中滴加甲醇钠25％m/v甲醇溶液(16.24ml,75mmol)，滴加完毕室温搅拌反应20小时。将反应液加入水(600mL)中，用2M盐酸调pH至酸性，用乙酸乙酯(200mL*2)萃取，合并有机相用饱和食盐水(200mL)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩残留物用硅胶柱柱分离纯化(石油醚：乙酸乙酯＝2:1)，得到标题化合物1.3g。5-Bromo-2-(3-((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)ureido)-4-methylthiophene-3 - Ethyl carboxylate (10 g, 21.49 mmol) was dispersed in absolute ethanol (120 mL), the mixture was stirred at room temperature under nitrogen atmosphere, and sodium methoxide 25% m/v methanol solution (16.24 ml, 75 mmol) was added dropwise thereto. , the dropwise addition was completed and the reaction was stirred at room temperature for 20 hours. The reaction solution was added to water (600 mL), the pH was adjusted to acidity with 2M hydrochloric acid, extracted with ethyl acetate (200 mL*2), the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered with suction, The filtrate was concentrated and the residue was separated and purified with a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain 1.3 g of the title compound.
1H NMR(500MHz,DMSO-d 6):δ12.85(br,1H),12.50(br,1H),2.31(s,3H),1.44(s,6H)。 1 H NMR (500 MHz, DMSO-d 6 ): δ 12.85 (br, 1H), 12.50 (br, 1H), 2.31 (s, 3H), 1.44 (s, 6H).
MS(ESI)m/z:364.8[M+H] +。 MS(ESI) m/z: 364.8 [M+H] + .
步骤七：2-((6-溴-5-甲基-2,4-二氧基-1,4-二氢噻吩[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸苄酯的合成Step 7: 2-((6-Bromo-5-methyl-2,4-dioxy-1,4-dihydrothiophen[2,3-d]pyrimidin-3(2H)-yl)oxy) Synthesis of -2-methylpropionic acid benzyl ester
将2-((6-溴-5-甲基-2,4-二氧基-1,4-二氢噻吩[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸(7g,19.3mmol)，苄醇(14g,129.5mmol)，对甲苯磺酸(6.65g,38.6mmol)和甲苯(50mL)混合，混合物用微波加热至120℃反应1小时。反应液用乙酸乙酯(150mL)稀释，依次用饱和碳酸氢钠水溶液(100mL)和饱和食盐水(100mL)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩得到标题化合物6.25g直接用于下一步反应。2-((6-Bromo-5-methyl-2,4-dioxy-1,4-dihydrothiophen[2,3-d]pyrimidin-3(2H)-yl)oxy)-2 -Methylpropionic acid (7 g, 19.3 mmol), benzyl alcohol (14 g, 129.5 mmol), p-toluenesulfonic acid (6.65 g, 38.6 mmol) and toluene (50 mL) were mixed, and the mixture was heated to 120 °C by microwave for 1 hour. The reaction solution was diluted with ethyl acetate (150 mL), washed with saturated aqueous sodium bicarbonate solution (100 mL) and saturated brine (100 mL) successively, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to obtain 6.25 g of the title compound, which was used directly in the next step. one-step reaction.
步骤八：(R)-2-((6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧基-1,4-二氢噻吩[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸苄酯的合成Step 8: (R)-2-((6-Bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl yl)-5-methyl-2,4-dioxy-1,4-dihydrothiophene[2,3-d]pyrimidin-3(2H)-yl)oxy)-2-methylpropionic acid benzyl Synthesis of Esters
将(R)-2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙烷-1-醇(6.01g,23.82mmol)、2-((6-溴-5-甲基-2,4-二氧基-1,4-二氢噻吩[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸苄酯(9g,19.85mmol)、三苯基膦(8.18g,31.2mmol)和四氢呋喃(120.000mL)混合，氮气保护下，0℃搅拌，向其中滴加偶氮二甲酸二叔丁酯(7.18g,31.2mmol)的四氢呋喃(5mL)溶液，混合物升至室温搅拌反应17小时。浓缩反应液，残留物用C18柱分离纯化(乙腈：水＝60:40-90:10),得到标题化合物4.86g。(R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethane-1-ol (6.01 g, 23.82 mmol), 2-((6-Bromo-5-methyl-2,4-dioxy-1,4-dihydrothiophen[2,3-d]pyrimidin-3(2H)-yl)oxy)-2- Benzyl methylpropionate (9 g, 19.85 mmol), triphenylphosphine (8.18 g, 31.2 mmol) and tetrahydrofuran (120.000 mL) were mixed, stirred at 0°C under nitrogen protection, and added dropwise di-tertiary azodicarboxylate. A solution of butyl ester (7.18 g, 31.2 mmol) in tetrahydrofuran (5 mL), the mixture was warmed to room temperature and stirred for 17 hours. The reaction solution was concentrated, and the residue was separated and purified by a C18 column (acetonitrile:water=60:40-90:10) to obtain 4.86 g of the title compound.
1H NMR(500MHz,DMSO-d 6):δ7.31-7.47(m,7H),7.00-7.05(m,2H),5.16-5.25(m,3H),4.03-4.06(m,1H),3.83-3.85(m,1H),3.77(s,3H),3.59-3.61(m,1H),3.47-3.50(m,1H),3.34-3.36(m,1H),3.16-3.25(m,2H),2.30(m,3H),1.49-1.63(m,8H),1.32-1.34(m,1H),1.17-1.89(m,1H)。 1 H NMR (500MHz, DMSO-d 6 ): δ 7.31-7.47 (m, 7H), 7.00-7.05 (m, 2H), 5.16-5.25 (m, 3H), 4.03-4.06 (m, 1H), 3.83-3.85(m, 1H), 3.77(s, 3H), 3.59-3.61(m, 1H), 3.47-3.50(m, 1H), 3.34-3.36(m, 1H), 3.16-3.25(m, 2H ), 2.30(m, 3H), 1.49-1.63(m, 8H), 1.32-1.34(m, 1H), 1.17-1.89(m, 1H).
MS(ESI)m/z:709.3[M+Na] + MS(ESI) m/z: 709.3[M+Na] +
步骤九：(R)-2-((1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧代-6-(丙-1-炔-1-基)-1,4-二氢噻吩并[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸苄酯(式I-18化合物)的合成Step 9: (R)-2-((1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5 -Methyl-2,4-dioxo-6-(prop-1-yn-1-yl)-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl) Synthesis of benzyl oxy)-2-methylpropanoate (compound of formula I-18)
48mL耐压瓶中依次加入苄基(R)-2-((6-溴-1-(2-(2-甲氧基苯基)-2-((四氢-2H-吡喃-4-基)氧基)乙基)-5-甲基-2,4-二氧基-1,4-二氢噻吩[2,3-d]嘧啶-3(2H)-基)氧基)-2-甲基丙酸酯(0.5g,0.727mmol)、丙炔(0.146g,3.64mmol)、双三苯基膦二氯化钯(0.051g,0.073mmol)及碘化亚铜(0.014g,0.073mmol)，三乙胺(10mL)氮气保护，将混合物加热至80℃反应过夜。反应液冷却至室温，硅藻土抽滤，滤液加入水(100mL)中，乙酸乙酯(50mL*2)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，残留物硅胶柱分离纯化(石油醚：乙酸乙酯＝4:1)，得到式I-18化合物0.412g。Benzyl (R)-2-((6-bromo-1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4- (yl)oxy)ethyl)-5-methyl-2,4-dioxy-1,4-dihydrothiophen[2,3-d]pyrimidin-3(2H)-yl)oxy)-2 - methyl propionate (0.5g, 0.727mmol), propyne (0.146g, 3.64mmol), bistriphenylphosphine palladium dichloride (0.051g, 0.073mmol) and cuprous iodide (0.014g, 0.073g) mmol), triethylamine (10 mL) under nitrogen, and the mixture was heated to 80 °C for overnight reaction. The reaction solution was cooled to room temperature, filtered through celite with suction, the filtrate was added to water (100 mL), extracted with ethyl acetate (50 mL*2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered with suction. The filtrate was concentrated, and the residue was separated and purified by silica gel column (petroleum ether:ethyl acetate=4:1) to obtain 0.412 g of the compound of formula I-18.
1H NMR(500MHz,DMSO-d 6):δ7.45-7.47(m,1H),7.40-7.41(m,2H),7.31-7.37(m,4H),7.00-7.05(m,2H),5.24-5.27(m,1H),5.13-5.18(m,2H),4.03-4.06(m,1H),3.82-3.86(m,1H),3.76(s,3H),3.58-3.60(m,1H),3.46-3.48(m,1H),3.15-3.24(m,2H),2.37(s,3H),2.14(s,3H),1.61-1.64(m,2H),1.52(s,3H),1.49(s,3H),1.24-1.34(m,2H),1.14-1.16(m,1H)。 1 H NMR (500 MHz, DMSO-d 6 ): δ 7.45-7.47 (m, 1H), 7.40-7.41 (m, 2H), 7.31-7.37 (m, 4H), 7.00-7.05 (m, 2H), 5.24-5.27(m, 1H), 5.13-5.18(m, 2H), 4.03-4.06(m, 1H), 3.82-3.86(m, 1H), 3.76(s, 3H), 3.58-3.60(m, 1H) ),3.46-3.48(m,1H),3.15-3.24(m,2H),2.37(s,3H),2.14(s,3H),1.61-1.64(m,2H),1.52(s,3H), 1.49(s, 3H), 1.24-1.34(m, 2H), 1.14-1.16(m, 1H).
MS(ESI)m/z:669.5[M+Na] +。 MS (ESI) m/z: 669.5 [M+Na] + .
步骤十：式I-8化合物的合成Step 10: Synthesis of the compound of formula I-8
将式I-18化合物(0.3g,0.464mmol)与氢氧化锂(0.012g,0.510mmol)、四氢呋喃(6mL)及水(3mL)混合，混合物室温下反应过夜。用1M稀盐酸将反应液pH调至中性，用乙酸乙酯(50mL*2)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，抽滤，滤液浓缩，残留物硅胶柱分离纯化(石油醚：乙酸乙酯＝1:1)，得到式I-8化合物38mg。The compound of formula I-18 (0.3 g, 0.464 mmol) was mixed with lithium hydroxide (0.012 g, 0.510 mmol), tetrahydrofuran (6 mL) and water (3 mL), and the mixture was reacted at room temperature overnight. The pH of the reaction solution was adjusted to neutral with 1M dilute hydrochloric acid, extracted with ethyl acetate (50 mL*2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated, and the residue was silica gel Column separation and purification (petroleum ether:ethyl acetate=1:1) to obtain 38 mg of the compound of formula I-8.
1H NMR(500MHz,CDCl 3)δ13.13(s,1H),7.52(d,J＝7.6Hz,1H),7.33(t,J＝7.9Hz,1H),7.03(t,J＝7.5Hz,1H),6.89(d,J＝8.3Hz,1H),5.41(t,J＝6.5Hz,1H),4.24–4.01(m,2H),3.87(s,3H),3.80(d,J＝11.9Hz,1H),3.76–3.66(m,1H),3.44(s,1H),3.38–3.26(m,2H),2.55(s,3H),2.16(s,3H),1.82–1.51(m,10H)。 1 H NMR (500 MHz, CDCl 3 ) δ 13.13 (s, 1H), 7.52 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.9 Hz, 1H), 7.03 (t, J=7.5 Hz) ,1H),6.89(d,J=8.3Hz,1H),5.41(t,J=6.5Hz,1H),4.24–4.01(m,2H),3.87(s,3H),3.80(d,J= 11.9Hz, 1H), 3.76–3.66 (m, 1H), 3.44 (s, 1H), 3.38–3.26 (m, 2H), 2.55 (s, 3H), 2.16 (s, 3H), 1.82–1.51 (m , 10H).
MS(ESI)m/z:579.5[M+Na] +。 MS (ESI) m/z: 579.5 [M+Na] + .
实施例9Example 9
1.体外酶抑制活性1. In vitro enzyme inhibitory activity
1.1 ACC1抑制活性筛选1.1 Screening of ACC1 inhibitory activity
制备底物混合物0.84μl 5倍浓度的酶缓冲液(150mM HEPES、10mM MgCl 2、5mM DTT、10mM柠檬酸钠)+1.2μl ATP(100μM)+0.06μl Acetyl-CoA(2mM)+0.18μl NaHCO 3(1M)+ 1.92μl水，4.2μL/孔加入96半孔板中，用纳升加样仪将DMSO溶解的待测化合物加入到孔中，离心，使化合物终浓度经过4倍稀释，7个浓度梯度，最高浓度为500nM，最低浓度为0.12nM，每一浓度设置2个复孔。同时设空白对照孔(不含酶)与阴性对照孔(含酶)，设5个复孔。用1倍浓度的酶缓冲液(30mM HEPES、2mM MgCl 2、1mM DTT、2mM柠檬酸钠)将ACC1酶稀释至8.25ng/μL，每孔加入1.8μL，空白对照孔加入1.8μL 1倍浓度的酶缓冲液，离心，室温反应60分钟。每孔加入5μL的ADP-Glo试剂，离心，室温反应40分钟；每孔加入10μL激酶检测试剂，离心，室温避光孵育30分钟；PE Envision多功能酶标仪读取化学发光数据，采用四参数拟合，计算IC 50。 Prepare substrate mixture 0.84 μl 5x concentration of enzyme buffer (150 mM HEPES, 10 mM MgCl 2 , 5 mM DTT, 10 mM sodium citrate) + 1.2 μl ATP (100 μM) + 0.06 μl Acetyl-CoA (2 mM) + 0.18 μl NaHCO 3 (1M) + 1.92μl water, 4.2μL/well was added to the 96 half-well plate, the compound to be tested dissolved in DMSO was added to the well with a nanoliter sampler, and centrifuged to make the final concentration of the compound diluted 4 times, 7 Concentration gradient, the highest concentration is 500nM, the lowest concentration is 0.12nM, and 2 duplicate wells are set for each concentration. At the same time, a blank control well (without enzyme) and a negative control well (with enzyme) were set, and 5 duplicate wells were set. ACC1 enzyme was diluted to 8.25ng/μL with 1x concentration of enzyme buffer (30mM HEPES, 2mM MgCl 2 , 1mM DTT, 2mM sodium citrate), 1.8μL was added to each well, and 1.8μL of 1x concentration was added to blank control wells. Enzyme buffer, centrifuge, and react at room temperature for 60 minutes. Add 5 μL of ADP-Glo reagent to each well, centrifuge, and react at room temperature for 40 minutes; add 10 μL of kinase detection reagent to each well, centrifuge, and incubate in the dark at room temperature for 30 minutes; PE Envision multi-function microplate reader reads chemiluminescence data using four parameters Fitted and IC50 calculated.
1.2 ACC2抑制活性筛选1.2 Screening of ACC2 inhibitory activity
制备底物混合物0.84μl 5倍浓度的酶缓冲液(150mM HEPES、10mM MgCl 2、5mM DTT、10mM柠檬酸钠)+1.2μl ATP(100μM)+0.06μl Acetyl-CoA(2mM)+0.18μl NaHCO 3(400mM)+1.92μl水，4.2μL/孔加入96半孔板中，用纳升加样仪将DMSO溶解的待测化合物加入到孔中，离心，使化合物终浓度经过4倍稀释，8个浓度梯度，最高浓度为5000nM，最低浓度为0.31nM，每一浓度设置2个复孔。同时设空白对照孔(不含酶)与阴性对照孔(含酶)，设5个复孔。用1倍浓度的酶缓冲液(30mM HEPES、2mM MgCl 2、1mM DTT、2mM柠檬酸钠)将ACC2酶稀释至5.4ng/μL，每孔加入1.8μL，空白对照孔加入1.8μL 1倍浓度的酶缓冲液，离心，室温反应60分钟。每孔加入5μL的ADP-Glo试剂，离心，室温反应40分钟；每孔加入10μL激酶检测试剂，离心，室温避光孵育30分钟；PE Envision多功能酶标仪读取化学发光数据，采用四参数拟合，计算IC 50。 Prepare substrate mixture 0.84 μl 5x concentration of enzyme buffer (150 mM HEPES, 10 mM MgCl 2 , 5 mM DTT, 10 mM sodium citrate) + 1.2 μl ATP (100 μM) + 0.06 μl Acetyl-CoA (2 mM) + 0.18 μl NaHCO 3 (400mM)+1.92μl water, 4.2μL/well was added to the 96 half-well plate, the compound to be tested dissolved in DMSO was added to the well with a nanoliter sampler, and centrifuged to make the final compound concentration 4-fold diluted, 8 Concentration gradient, the highest concentration is 5000nM, the lowest concentration is 0.31nM, and 2 duplicate wells are set for each concentration. At the same time, a blank control well (without enzyme) and a negative control well (with enzyme) were set, and 5 duplicate wells were set. ACC2 enzyme was diluted to 5.4ng/μL with 1x concentration of enzyme buffer (30mM HEPES, 2mM MgCl 2 , 1mM DTT, 2mM sodium citrate), 1.8μL was added to each well, and 1.8μL of 1x concentration was added to blank control wells. Enzyme buffer, centrifuge, and react at room temperature for 60 minutes. Add 5 μL of ADP-Glo reagent to each well, centrifuge, and react at room temperature for 40 minutes; add 10 μL of kinase detection reagent to each well, centrifuge, and incubate in the dark at room temperature for 30 minutes; PE Envision multi-function microplate reader reads chemiluminescence data using four parameters Fitted and IC50 calculated.
2.体外细胞水平抗肿瘤活性筛选2. Screening of antitumor activity at the cellular level in vitro
2.1化合物对A549、NCI-H460的增殖抑制作用2.1 Inhibitory effect of compounds on the proliferation of A549 and NCI-H460
取对数生长期的A549(腺癌人类肺泡基底上皮细胞系)、NCI-H460(大细胞肺癌细胞系)细胞消化收集，使用含5％FBS的完全培养基制成单细胞悬液，按1×10 4个/mL的密度接种于96孔板中，每孔100μL，置于37℃、含5％CO 2饱和湿度的细胞培养箱中培养过夜，纳升加样仪进行化合物加样，测试化合物的终浓度分别为10000.0、3333.3、1111.1、370.4、123.5、41.2、13.7、4.6nM，每一浓度设置2个复孔。同时设置加棕榈酸和不加棕榈酸处理组。以不加化合物的细胞作为阴性对照，以不含细胞空白组作为空白对照。细胞置于37℃、含5％CO 2饱和湿度的细胞培养箱中继续培养6天，培养6天后每孔加入10μL CCK-8，继续培养2～4h。在酶标仪450nm处测定各孔的吸光度值A，并按以下公式计算抑制率：抑制率(％)＝(阴性对照组平均A值-实验组平均A值)/(阴性对照组平均A值-空白对照组平均A值)×100％，所得数据计算得到IC 50。 Digest and collect A549 (adenocarcinoma human alveolar basal epithelial cell line) and NCI-H460 (large cell lung cancer cell line) cells in logarithmic growth phase, use complete medium containing 5% FBS to make single cell suspension, press 1 The density of ×10 4 cells/mL was inoculated into a 96-well plate, 100 μL per well, and placed in a cell incubator at 37°C with a saturated humidity of 5% CO 2 for overnight incubation. The nanoliter dispenser was used for compound addition and testing. The final concentrations of the compounds were 10000.0, 3333.3, 1111.1, 370.4, 123.5, 41.2, 13.7, and 4.6 nM, respectively, and two replicate wells were set for each concentration. At the same time, the groups with and without palmitic acid were set. The cells without compound were used as negative control, and the blank group without cells was used as blank control. The cells were placed in a cell culture incubator containing 5% CO 2 saturated humidity at 37° C. for 6 days, and after 6 days of culture, 10 μL of CCK-8 was added to each well, and the culture was continued for 2-4 h. Measure the absorbance value A of each well at 450nm of the microplate reader, and calculate the inhibition rate according to the following formula: inhibition rate (%) = (average A value of negative control group - average A value of experimental group)/(average A value of negative control group) -The average A value of the blank control group)×100%, and the IC 50 was calculated from the obtained data.
所测得体外ACC酶抑制活性以及细胞水平的增殖抑制活性结果如表1所示。The measured in vitro ACC enzyme inhibitory activity and the cell-level proliferation inhibitory activity results are shown in Table 1.
表1Table 1
Figure PCTCN2022074327-appb-000054
Figure PCTCN2022074327-appb-000054
注：“/”表示未测量。Note: "/" means not measured.
实施例10体外药代动力学Example 10 In vitro pharmacokinetics
体外肝微粒体稳定性：In vitro liver microsome stability:
肝微粒体温孵样本制备：混合PBS缓冲液(pH 7.4)，肝微粒体溶液(0.5mg/mL)，待测化合物及NADPH+MgCl 2溶液，于37℃及300rpm下孵育60min。 Preparation of liver microsome body temperature incubation sample: mix PBS buffer (pH 7.4), liver microsome solution (0.5mg/mL), test compound and NADPH+MgCl 2 solution, incubate at 37°C and 300rpm for 60min.
0小时样本制备：混合PBS缓冲液(pH 7.4)，肝微粒体溶液(0.5mg/mL)，待测化合物。样本加入含内标的乙腈溶液经蛋白沉淀制备上清液，稀释后用于LC/MS/MS测定。试验结果见表2。0-hour sample preparation: mix PBS buffer (pH 7.4), liver microsome solution (0.5 mg/mL), and test compound. The samples were added to the acetonitrile solution containing the internal standard, and the supernatant was prepared by protein precipitation. After dilution, it was used for LC/MS/MS determination. The test results are shown in Table 2.
表2Table 2
Figure PCTCN2022074327-appb-000055
Figure PCTCN2022074327-appb-000055
Figure PCTCN2022074327-appb-000056
Figure PCTCN2022074327-appb-000056
注：“/”表示未测量。Note: "/" means not measured.

Claims (14)

  1. 式I化合物或其药学上可接受的盐，A compound of formula I or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022074327-appb-100001
    Figure PCTCN2022074327-appb-100001
    其中，in,
    R 1和R 2独立地选自氢或C 1-6烷基，可任选被选自羟基、-O-C 1-6烷基、氨基、卤素、氰基和硝基的基团取代； R 1 and R 2 are independently selected from hydrogen or C 1-6 alkyl, which may be optionally substituted with a group selected from hydroxy, -OC 1-6 alkyl, amino, halogen, cyano and nitro;
    R 4选自氢、-R’、-O-R’；R’独立地选自任选被R取代的以下各项的基团：C 1-6烷基，3-8元环烷基，3-8元环烯基，6-10元芳基、3-10元杂环基、5-10元杂芳基； R 4 is selected from hydrogen, -R', -O-R';R' is independently selected from the following groups optionally substituted by R: C 1-6 alkyl, 3-8 membered cycloalkyl, 3-8-membered cycloalkenyl, 6-10-membered aryl, 3-10-membered heterocyclyl, 5-10-membered heteroaryl;
    A选自任选被R取代的-O-C 1-6亚烷基，或化学键； A is selected from -OC 1-6 alkylene optionally substituted by R, or a chemical bond;
    L选自化学键，或者任选被R取代的选自3-10元环烷基、6-10元芳基、3-10元杂环基、5-10元杂芳基的二价基团；L is selected from a chemical bond, or a divalent group optionally substituted by R selected from a 3-10-membered cycloalkyl group, a 6-10-membered aryl group, a 3-10-membered heterocyclic group, and a 5-10-membered heteroaryl group;
    Z选自-COOR 3； Z is selected from -COOR 3 ;
    R 3选自氢，或者任选被R取代的C 1-6烷基、苯基C 1-6烷基、硅烷基； R 3 is selected from hydrogen, or optionally R-substituted C 1-6 alkyl, phenyl C 1-6 alkyl, silyl;
    其中A和L之一为化学键；One of A and L is a chemical bond;
    R独立地为氢、氟、氯、溴、碘、羟基、氨基、硝基、氰基、硅烷基、C 1-6烷基、C 1-6烷氧基、C 2-5烯基、C 2-5炔基、卤代C 1-6烷基、卤代C 1-6烷氧基、氰基C 1-6烷基、羟基C 1-6烷基、苯基C 1-6烷基、3-8元环烷基、苯基、苯基C 1-6烷基、卤代苯基、氰基苯基、具有1、2或3个独立地选自氮、氧和硫的杂原子的3-8元杂环基，具有1、2、3或4个独立地选自氮、氧和硫的杂原子的5-6元杂芳基。 R is independently hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, amino, nitro, cyano, silyl, C 1-6 alkyl, C 1-6 alkoxy, C 2-5 alkenyl, C 2-5 alkynyl, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, cyano C 1-6 alkyl, hydroxy C 1-6 alkyl, phenyl C 1-6 alkyl , 3-8 membered cycloalkyl, phenyl, phenyl C 1-6 alkyl, halophenyl, cyanophenyl, with 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur 3-8 membered heterocyclyl, 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中当A为化学键时，A和Z与L的连接位点不同。The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein when A is a chemical bond, the sites of attachment of A and Z to L are different.
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中L选自任选被R取代的选自3-10元环烷基、苯基、具有1、2或3个独立地选自氮、氧和硫的杂原子的3-8元杂环基，具有1、2、3或4个独立地选自氮、氧和硫的杂原子的5-6元杂芳基的二价基团；The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of 3-10 membered cycloalkyl, phenyl, optionally substituted by R, having 1, 2 or 3 independent 3-8 membered heterocyclyl with heteroatoms independently selected from nitrogen, oxygen and sulfur, 5-6 membered heteroaryl with 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur divalent group;
    优选地，L选自任选被R取代的选自3-8元环烷基、苯基、具有1或2个独立地选自氮、氧和硫的杂原子的饱和3-8元杂环基或具有1或2个独立地选自氮、氧和硫的杂原子的不饱和3-8元杂环基、具有1、2或3个独立地选自氮、氧和硫的杂原子的5-6元杂芳基的二价基 团；Preferably, L is selected from 3-8 membered cycloalkyl optionally substituted by R, phenyl, saturated 3-8 membered heterocycle with 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur radicals or unsaturated 3-8 membered heterocyclic groups having 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur, unsaturated 3-8 membered heterocyclic groups having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur Divalent group of 5-6 membered heteroaryl;
    进一步优选地，L选自任选被R取代的选自3-8元环烷基、苯基、具有1个氮原子的饱和3-8元杂环基，具有1个氮原子的不饱和3-8元杂环基、具有1个氧原子的饱和3-8元杂环基、具有1个氧原子的不饱和3-8元杂环基、具有1个硫原子的饱和3-8元杂环基、具有1个硫原子的不饱和3-8元杂环基、具有2个氮原子的5-6元饱和杂环基、具有2个氮原子的5-6元不饱和杂环基、具有1个氮原子和1个氧原子的5-6元饱和杂环基、具有1个氮原子和1个氧原子的5-6元不饱和杂环基、具有2个氧原子的5-6元饱和杂环基、具有2个氧原子的5-6元不饱和杂环基、具有1个氮原子和1个硫原子的5-6元饱和杂环基、具有1个氮原子和1个硫原子的5-6元不饱和杂环基、具有1个氧原子和1个硫原子的饱和5-6元杂环基、具有1个氮原子的4-6元杂芳基，具有1个氧原子的5-6元杂芳基、具有1个硫原子的5-6元杂芳基、具有2个氮原子的5-6元杂芳基、具有3个氮原子的5-6元杂芳基的二价基团。Further preferably, L is selected from the group consisting of 3-8 membered cycloalkyl, phenyl, saturated 3-8 membered heterocyclic group with 1 nitrogen atom, unsaturated 3 with 1 nitrogen atom optionally substituted by R. -8-membered heterocyclic group, saturated 3-8-membered heterocyclic group with 1 oxygen atom, unsaturated 3-8-membered heterocyclic group with 1 oxygen atom, saturated 3-8-membered heterocyclic group with 1 sulfur atom Ring group, unsaturated 3-8 membered heterocyclic group with 1 sulfur atom, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered with 2 oxygen atoms Member saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group with 2 oxygen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 nitrogen atom and 1 5-6 membered unsaturated heterocyclic group with sulfur atom, saturated 5-6 membered heterocyclic group with 1 oxygen atom and 1 sulfur atom, 4-6 membered heteroaryl group with 1 nitrogen atom, with 1 5-6-membered heteroaryl with oxygen atom, 5-6-membered heteroaryl with 1 sulfur atom, 5-6-membered heteroaryl with 2 nitrogen atoms, 5-6-membered heteroaryl with 3 nitrogen atoms The divalent group of an aryl group.
  4. 根据权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中L选自任选被R取代的选自环丙基、环丁基、环戊基、环己基、环庚基、环辛基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基、双环[2.2.1]庚烷基、双环[3.1.1]庚烷基、双环[2.2.2]辛烷基、双环[3.2.1]辛烷基、双环[3.3.1]壬烷基、双环[4.2.2]癸烷基、双环[3.3.2]癸烷基、苯基、环氧基、四氢呋喃基、2,3-二氢呋喃基、2,5-二氢呋喃基、呋喃基、四氢吡喃基、吡咯基、2,3-二氢吡咯基、2,5-二氢吡咯基、吡咯烷基、咪唑烷基、四氢吡唑基、噁唑烷基、异噁唑烷基、吗啉基、硫代吗啉基、吡啶基、哌啶基、哌嗪基、嘧啶基、哒嗪基、噻吩基、噻吩烷基、噻唑烷基的二价基团；The compound according to any one of claims 1-3, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropyl, optionally substituted by R, or a pharmaceutically acceptable salt thereof. Heptyl, cyclooctyl, bicyclo[1.1.1]pentyl, bicyclo[2.1.1]hexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.1]heptyl, bicyclo[2.2 .2]octyl, bicyclo[3.2.1]octyl, bicyclo[3.3.1]nonyl, bicyclo[4.2.2]decyl, bicyclo[3.3.2]decyl, phenyl, Epoxy, tetrahydrofuranyl, 2,3-dihydrofuranyl, 2,5-dihydrofuranyl, furanyl, tetrahydropyranyl, pyrrolyl, 2,3-dihydropyrrolyl, 2,5- Dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, tetrahydropyrazolyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, pyridyl, piperidinyl, piperazinyl , pyrimidinyl, pyridazinyl, thienyl, thienyl, thiazolyl divalent groups;
    优选地，L选自任选被R取代的以下各项的基团：
    Figure PCTCN2022074327-appb-100002
    Figure PCTCN2022074327-appb-100003
    Preferably, L is selected from groups optionally substituted by R:
    Figure PCTCN2022074327-appb-100002
    Figure PCTCN2022074327-appb-100003
    Figure PCTCN2022074327-appb-100004
    Figure PCTCN2022074327-appb-100004
  5. 根据权利要求1-4任一项所述的化合物或其药学上可接受的盐，其中L选自任选被R取代的选自环丁基、双环[1.1.1]戊烷基、苯基、吡啶基的二价基团；优选地，L选自任选被R取代的以下各项的基团
    Figure PCTCN2022074327-appb-100005
    Figure PCTCN2022074327-appb-100006
    The compound according to any one of claims 1-4, or a pharmaceutically acceptable salt thereof, wherein L is selected from the group consisting of cyclobutyl, bicyclo[1.1.1]pentyl, phenyl optionally substituted by R , a divalent group of pyridyl; preferably, L is selected from the following groups optionally substituted by R
    Figure PCTCN2022074327-appb-100005
    Figure PCTCN2022074327-appb-100006
  6. 根据权利要求1所述的化合物或其药学上可接受的盐，其中A选自任选被R取代的-O-C 1-6亚烷基，优选为-O-CH 2-、-O-CH(CH 3)-、-O-CH 2CH 2-、-O-CH(CH 2CH 3)-、-O-CH(CH 3)CH 2-、-O-CH 2CH(CH 3)-、-O-C(CH 3) 2-、-O-CH 2CH 2CH 2-、-O-CH 2CH 2CH 2CH 2-、-O-CH 2CH(CH 3)CH 2-、-O-CH(CH 3)CH 2CH 2-、-O-CH 2CH 2CH(CH 3)-、-O-CH 2C(CH 3) 2-、-O-C(CH 3) 2CH 2-、-O-CH 2CH(CH 2CH 3)-、-O-CH(CH 2CH 3)CH 2-、-O-CH(CH 2CH 2CH 3)-、-O-C(CH 2CH 3)(CH 3)-，进一步优选为-O-CH 2-、-O-CH(CH 3)-、-O-CH 2CH 2-、-O-CH(CH 2CH 3)-、-O-CH(CH 3)CH 2-、-O-CH 2CH(CH 3)-、-O-C(CH 3) 2-、-O-CH 2CH 2CH 2-，更进一步优选为-O-C(CH 3) 2-。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein A is selected from -OC 1-6 alkylene optionally substituted by R, preferably -O-CH 2 -, -O-CH( CH 3 )-, -O-CH 2 CH 2 -, -O-CH(CH 2 CH 3 )-, -O-CH(CH 3 )CH 2 -, -O-CH 2 CH(CH 3 )-, -OC( CH3 ) 2- , -O - CH2CH2CH2- , -O - CH2CH2CH2CH2- , -O - CH2CH ( CH3 ) CH2-, -O- CH(CH 3 )CH 2 CH 2 -, -O-CH 2 CH 2 CH(CH 3 )-, -O-CH 2 C(CH 3 ) 2 -, -OC(CH 3 ) 2 CH 2 -, - O-CH 2 CH(CH 2 CH 3 )-, -O-CH(CH 2 CH 3 )CH 2 -, -O-CH(CH 2 CH 2 CH 3 )-, -OC(CH 2 CH 3 )( CH 3 )-, more preferably -O-CH 2 -, -O-CH(CH 3 )-, -O-CH 2 CH 2 -, -O-CH(CH 2 CH 3 )-, -O-CH (CH 3 )CH 2 -, -O-CH 2 CH(CH 3 )-, -OC(CH 3 ) 2 -, -O-CH 2 CH 2 CH 2 -, more preferably -OC(CH 3 ) 2- .
  7. 根据权利要求1-6任一项所述的化合物或其药学上可接受的盐，其中R 1和R 2独立地选自甲基、乙基。 The compound of any one of claims 1-6, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are independently selected from methyl, ethyl.
  8. 根据权利要求1-7任一项所述的化合物或其药学上可接受的盐，其中R 3选自氢，或者任选被R取代的C 1-4烷基、苯基C 1-4烷基、C 1-6硅烷基；优选地，R 3选自氢、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、苄基、甲基苯基、乙基苯基、三甲基硅烷基、三乙基硅烷基、三异丙基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基；进一步优选地，R 3选自氢、甲基、乙基、叔丁基、苄基、叔丁基二苯基硅烷基。 The compound according to any one of claims 1-7, or a pharmaceutically acceptable salt thereof, wherein R is selected from hydrogen, or optionally R-substituted C 1-4 alkyl, phenyl C 1-4 alkane base, C 1-6 silyl; preferably, R is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, benzyl, methylphenyl, ethyl phenyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl; further preferably, R is selected from hydrogen, Methyl, ethyl, tert-butyl, benzyl, tert-butyldiphenylsilyl.
  9. 根据权利要求1-8任一项所述的化合物或其药学上可接受的盐，其中R 4选自氢、-O-R’，其中R’独立地选自任选被R取代的以下各项的基团：C 1-6烷基，3-8元环烷基，5-8元环烯基，6-10元芳基，具有1、2或3个独立选自氮、氧和硫的杂原子的4-10元杂环基，具有1、2、3或4个独立选自氮、氧和硫的杂原子的5-8元杂芳基； The compound of any one of claims 1-8, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, -O - R', wherein R' is independently selected from each of the following optionally substituted by R Item groups: C 1-6 alkyl, 3-8 membered cycloalkyl, 5-8 membered cycloalkenyl, 6-10 membered aryl, with 1, 2 or 3 independently selected from nitrogen, oxygen and sulfur 4-10-membered heterocyclic group of heteroatoms, 5-8-membered heteroaryl group with 1, 2, 3 or 4 heteroatoms independently selected from nitrogen, oxygen and sulfur;
    优选地，R’选自任选被R取代的以下各项的基团：-C 1-4烷基，5、6、7或8元环烷基，具有1、2或3个独立选自氮、氧和硫的杂原子的5、6、7、8、9或10元杂环基，具有1或2个独立选自氮、氧和硫的杂原子的5-6元杂芳基； Preferably, R' is selected from groups optionally substituted by R: -C 1-4 alkyl, 5, 6, 7 or 8 membered cycloalkyl, with 1, 2 or 3 independently selected from 5, 6, 7, 8, 9 or 10 membered heterocyclyl with heteroatoms of nitrogen, oxygen and sulfur, 5-6 membered heteroaryl with 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur;
    进一步优选地，R’选自任选被R取代的具有1或2个独立地选自氮、氧和硫的杂原子的饱和5-8元杂环基或具有1或2个独立地选自氮、氧和硫的杂原子的不饱和5-8元杂环基；Further preferably, R' is selected from a saturated 5-8 membered heterocyclyl optionally substituted by R with 1 or 2 heteroatoms independently selected from nitrogen, oxygen and sulfur or with 1 or 2 independently selected from Unsaturated 5- to 8-membered heterocyclic groups of heteroatoms of nitrogen, oxygen and sulfur;
    更进一步优选地，R’选自任选被R取代的具有1个氮原子的饱和5-8元杂环基，具有1个氮原子的不饱和5-8元杂环基，具有1个氧原子的饱和5-8元杂环基、具有1个氧原子的不饱和5-8元杂环基、具有1个硫原子的饱和5-8元杂环基、具有1个硫原子的不饱和5-8元杂环基、具有2个氮原子的5-6元饱和杂环基、具有2个氮原子的5-6元不饱和杂环基、具有1个氮原子和1个氧原子的5-6元饱和杂环基、具有1个氮原子和1个氧原子的5-6元不饱和杂环基、具有2个氧原子的5-6元饱和杂环基、具有2个氧原子的5-6元不饱和杂环基、具有1个氮原子和1个硫原子的5-6元饱和杂环基、具有1个氮原子和1个硫原子的5-6元不饱和杂环基、具有1个氧原子和1个硫原子的饱和5-6元杂环基。More preferably, R' is selected from the saturated 5-8 membered heterocyclic group with 1 nitrogen atom optionally substituted by R, the unsaturated 5-8 membered heterocyclic group with 1 nitrogen atom, with 1 oxygen Atomic saturated 5-8 membered heterocyclic group, unsaturated 5-8 membered heterocyclic group with 1 oxygen atom, saturated 5-8 membered heterocyclic group with 1 sulfur atom, unsaturated with 1 sulfur atom 5-8 membered heterocyclic group, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 1 nitrogen atom and 1 oxygen atom 5-6 membered saturated heterocyclic group, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered saturated heterocyclic group with 2 oxygen atoms, with 2 oxygen atoms 5-6 membered unsaturated heterocyclic group, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom group, a saturated 5-6 membered heterocyclic group with 1 oxygen atom and 1 sulfur atom.
  10. 根据权利要求1-9任一项所述的化合物或其药学上可接受的盐，其中R 4选自氢、或任选被R取代的以下各项的基团：甲氧基、乙氧基、
    Figure PCTCN2022074327-appb-100007
    Figure PCTCN2022074327-appb-100008
    Figure PCTCN2022074327-appb-100009
    优选为
    Figure PCTCN2022074327-appb-100010
     The compound of any one of claims 1-9, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from hydrogen, or a group optionally substituted by R: methoxy, ethoxy ,
    Figure PCTCN2022074327-appb-100007
    Figure PCTCN2022074327-appb-100008
    Figure PCTCN2022074327-appb-100009
    preferably
    Figure PCTCN2022074327-appb-100010
  11. 根据权利要求1-10任一项所述的化合物或其药学上可接受的盐，R选自具有1、2或3个独立地选自氮、氧和硫的杂原子的饱和3-8元杂环基，或具有1、2或3个独立地选自氮、氧和硫的杂原子的不饱和3-8元杂环基，或具有1、2或3个独立地选自氮、氧和硫的杂原子的5-6元杂芳基；The compound of any one of claims 1-10, or a pharmaceutically acceptable salt thereof, wherein R is selected from saturated 3-8 membered having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur Heterocyclyl, or unsaturated 3-8 membered heterocyclyl having 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen and sulfur, or 1, 2 or 3 heteroatoms independently selected from nitrogen, oxygen 5-6 membered heteroaryl with heteroatom of sulfur;
    优选地，R选自具有1个氮原子的饱和3-8元杂环基、具有1个氮原子的不饱和3-8元杂 环基，具有1个氧原子的饱和3-8元杂环基、具有1个氧原子的不饱和3-8元杂环基、具有1个硫原子的饱和3-8元杂环基、具有1个硫原子的不饱和3-8元杂环基、具有2个氮原子的4-8元饱和杂环基、具有2个氮原子的4-8元不饱和杂环基、具有1个氮原子和1个氧原子的4-8元饱和杂环基、具有1个氮原子和1个氧原子的4-8元不饱和杂环基、具有2个氧原子的4-8元饱和杂环基、具有2个氧原子的4-8元不饱和杂环基、具有1个氮原子和1个硫原子的4-8元饱和杂环基、具有1个氮原子和1个硫原子的4-8元不饱和杂环基、具有1个氧原子和1个硫原子的饱和4-8元杂环基，或具有1个氮原子的4-6元杂芳基，具有1个氧原子的5-6元杂芳基、具有1个硫原子的5-6元杂芳基、具有2个氮原子的5-6元杂芳基、具有3个氮原子的5-6元杂芳基；Preferably, R is selected from saturated 3-8 membered heterocyclic groups having 1 nitrogen atom, unsaturated 3-8 membered heterocyclic groups having 1 nitrogen atom, saturated 3-8 membered heterocyclic groups having 1 oxygen atom base, unsaturated 3-8 membered heterocyclic group with 1 oxygen atom, saturated 3-8 membered heterocyclic group with 1 sulfur atom, unsaturated 3-8 membered heterocyclic group with 1 sulfur atom, with 4-8 membered saturated heterocyclic group with 2 nitrogen atoms, 4-8 membered unsaturated heterocyclic group with 2 nitrogen atoms, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 4-8-membered unsaturated heterocyclic group having 1 nitrogen atom and 1 oxygen atom, 4-8-membered saturated heterocyclic group having 2 oxygen atoms, 4-8-membered unsaturated heterocyclic group having 2 oxygen atoms base, 4-8 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 4-8 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen atom and 1 Saturated 4-8-membered heterocyclic group with 1 sulfur atom, or 4-6-membered heteroaryl with 1 nitrogen atom, 5-6-membered heteroaryl with 1 oxygen atom, 5-membered heteroaryl with 1 sulfur atom 6-membered heteroaryl, 5-6 membered heteroaryl with 2 nitrogen atoms, 5-6 membered heteroaryl with 3 nitrogen atoms;
    进一步优选地，R选自具有1个氮原子的4-6元饱和杂环基、具有1个氮原子的4-6元不饱和杂环基、具有1个氧原子的4-6元饱和杂环基、具有1个氧原子的4-6元不饱和杂环基、具有1个硫原子的4-6元饱和杂环基、具有1个硫原子的4-6元不饱和杂环基、具有2个氮原子的5-6元饱和杂环基、具有2个氮原子的5-6元不饱和杂环基、具有1个氮原子和1个氧原子的5-6元饱和杂环基、具有1个氮原子和1个氧原子的5-6元不饱和杂环基、具有2个氧原子的5-6元饱和杂环基、具有2个氧原子的5-6元不饱和杂环基、具有1个氮原子和1个硫原子的5-6元饱和杂环基、具有1个氮原子和1个硫原子的5-6元不饱和杂环基、具有1个氧原子和1个硫原子的饱和5-6元杂环基。Further preferably, R is selected from a 4-6 membered saturated heterocyclic group with 1 nitrogen atom, a 4-6 membered unsaturated heterocyclic group with 1 nitrogen atom, and a 4-6 membered saturated heterocyclic group with 1 oxygen atom. Ring group, 4-6 membered unsaturated heterocyclic group with 1 oxygen atom, 4-6 membered saturated heterocyclic group with 1 sulfur atom, 4-6 membered unsaturated heterocyclic group with 1 sulfur atom, 5-6 membered saturated heterocyclic group with 2 nitrogen atoms, 5-6 membered unsaturated heterocyclic group with 2 nitrogen atoms, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom , 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 oxygen atom, 5-6 membered saturated heterocyclic group with 2 oxygen atoms, 5-6 membered unsaturated heterocyclic group with 2 oxygen atoms Ring group, 5-6 membered saturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, 5-6 membered unsaturated heterocyclic group with 1 nitrogen atom and 1 sulfur atom, with 1 oxygen atom and A saturated 5-6 membered heterocyclic group with 1 sulfur atom.
  12. 根据权利要求1-10任一项所述的化合物或其药学上可接受的盐，R选自氢、氟、氯、甲基、乙基、正丙基、异丙基、正丁基、叔丁基、甲氧基、乙氧基、苯基、苄基、甲基苯基、乙基苯基、呋喃基、吡喃基、吡咯烷基、吡啶基、哌啶基、哌嗪基、嘧啶基、噻吩基、三甲基硅烷基、三乙基硅烷基、三异丙基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基，优选为氢、甲基、乙基、叔丁基、甲氧基、乙氧基、苯基、苄基、三甲基硅烷基、叔丁基二甲基硅烷基、叔丁基二苯基硅烷基。The compound according to any one of claims 1-10 or a pharmaceutically acceptable salt thereof, R is selected from hydrogen, fluorine, chlorine, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert- Butyl, methoxy, ethoxy, phenyl, benzyl, methylphenyl, ethylphenyl, furyl, pyranyl, pyrrolidinyl, pyridyl, piperidinyl, piperazinyl, pyrimidine group, thienyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, preferably hydrogen, methyl, ethyl group, tert-butyl, methoxy, ethoxy, phenyl, benzyl, trimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl.
  13. 根据权利要求1-12任一项所述的化合物或其药学上可接受的盐，所述的化合物具有如下之一的结构：The compound according to any one of claims 1-12 or a pharmaceutically acceptable salt thereof, wherein the compound has one of the following structures:
    Figure PCTCN2022074327-appb-100011
    Figure PCTCN2022074327-appb-100011
    Figure PCTCN2022074327-appb-100012
    Figure PCTCN2022074327-appb-100012
  14. 根据权利要求1-13任一项所述的化合物或其药学上可接受的盐在制备用于预防或者治疗乙酰辅酶A羧化酶介导的疾病的药物中的用途，包括但不限于胰岛素抵抗、肥胖症、血脂异常、代谢综合征、II型糖尿病、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、肺癌、胰腺癌。Use of the compound according to any one of claims 1-13 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of acetyl-CoA carboxylase-mediated diseases, including but not limited to insulin resistance , obesity, dyslipidemia, metabolic syndrome, type II diabetes, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, lung cancer, pancreatic cancer.
PCT/CN2022/074327 2021-02-07 2022-01-27 Thienopyrimidine derivative WO2022166761A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280012196.9A CN116745299A (en) 2021-02-07 2022-01-27 Thienopyrimidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110177167.5 2021-02-07
CN202110177167 2021-02-07

Publications (1)

Publication Number Publication Date
WO2022166761A1 true WO2022166761A1 (en) 2022-08-11

Family

ID=82741962

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/074327 WO2022166761A1 (en) 2021-02-07 2022-01-27 Thienopyrimidine derivative

Country Status (3)

Country Link
CN (1) CN116745299A (en)
TW (1) TW202233632A (en)
WO (1) WO2022166761A1 (en)

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (en) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
CN108341830A (en) * 2017-01-22 2018-07-31 广东东阳光药业有限公司 Thienopyrimidine derivative and its application in drug
WO2018228369A1 (en) * 2017-06-15 2018-12-20 浙江海正药业股份有限公司 Heteroarylpyrimidinone derivative, method for preparation thereof, and medicinal use thereof
CN109305976A (en) * 2017-07-26 2019-02-05 南京圣和药业股份有限公司 Compound and its application as ACC inhibitor
CN110950884A (en) * 2018-09-27 2020-04-03 上海翰森生物医药科技有限公司 Bicyclic derivative-containing inhibitor, preparation method and application thereof
CN111201234A (en) * 2017-07-17 2020-05-26 南京瑞捷医药科技有限公司 Novel compounds and their use as ACC inhibitors
CN111484504A (en) * 2019-01-25 2020-08-04 南京圣和药业股份有限公司 Optical isomer of ACC inhibitor and application thereof
CN111848678A (en) * 2019-04-30 2020-10-30 正大天晴药业集团股份有限公司 Phosphorus-containing thienopyrimidine derivatives

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104105485A (en) * 2011-11-11 2014-10-15 尼普斯阿波罗有限公司 Acc inhibitors and uses thereof
CN108341830A (en) * 2017-01-22 2018-07-31 广东东阳光药业有限公司 Thienopyrimidine derivative and its application in drug
WO2018228369A1 (en) * 2017-06-15 2018-12-20 浙江海正药业股份有限公司 Heteroarylpyrimidinone derivative, method for preparation thereof, and medicinal use thereof
CN111201234A (en) * 2017-07-17 2020-05-26 南京瑞捷医药科技有限公司 Novel compounds and their use as ACC inhibitors
CN109305976A (en) * 2017-07-26 2019-02-05 南京圣和药业股份有限公司 Compound and its application as ACC inhibitor
CN110950884A (en) * 2018-09-27 2020-04-03 上海翰森生物医药科技有限公司 Bicyclic derivative-containing inhibitor, preparation method and application thereof
CN111484504A (en) * 2019-01-25 2020-08-04 南京圣和药业股份有限公司 Optical isomer of ACC inhibitor and application thereof
CN111848678A (en) * 2019-04-30 2020-10-30 正大天晴药业集团股份有限公司 Phosphorus-containing thienopyrimidine derivatives

Also Published As

Publication number Publication date
TW202233632A (en) 2022-09-01
CN116745299A (en) 2023-09-12

Similar Documents

Publication Publication Date Title
WO2019020070A1 (en) Piperazine heteroaryl derivative, preparation method therefor and use of same in medicine
TWI672304B (en) Substituted ethynyl heterobicyclic compounds as tyrosine kinase inhibitors
WO2022100623A1 (en) Nitrogen-substituted heterocyclic thiophene compounds and use thereof
TW201602109A (en) Imidazopyridazines useful as inhibitors of the PAR-2 signaling pathway
CN107735401B (en) Substituted dihydropyrrolopyrazole derivatives
CN111918868A (en) Diaryl macrocycles as protein kinase modulators
WO2022100624A1 (en) Oxy-substituted aminocarbonate thiophene-based compound and use thereof
WO2020007322A1 (en) Compound targeted to degrade bet protein and application thereof
WO2019206069A1 (en) Diaryl macrocyclic compound and pharmaceutical composition, and use thereof
EP3187492A1 (en) Pyrimidinone derivative having autotaxin-inhibitory activity
WO2022100625A1 (en) Nitrogen-substituted aminocarbonate thiophene compound and use thereof
WO2022033544A1 (en) Substituted heteroaryl compound, and composition and application thereof
TW202110848A (en) A substituted fused bicyclic derivative, a preparation method thereof, and medical applications thereof
TW202206434A (en) JAK inhibitor compound for treating severe pneumonia capable of preventing cytokine storm or acute lung injury
CN115768769A (en) Tetrahydroisoquinoline compound and application thereof
WO2021078227A1 (en) Fused heteroaryl derivative, preparation method therefor, and application thereof in medicine
WO2023125708A1 (en) P38 mapk/mk2 pathway modulator, composition thereof, preparation method therefor, and use thereof
WO2022166761A1 (en) Thienopyrimidine derivative
WO2019085996A1 (en) Pyridopyrimidine compounds acting as mtorc 1/2 double-kinase inhibitors
JP2021526545A (en) Indene derivatives useful for treating pain and inflammation
WO2022222911A1 (en) Pyrimidone compound and use thereof
CN111718351B (en) Oxygen-containing substituted pyrazolopyrimidine compound, pharmaceutical composition and application thereof
TWI836822B (en) P38 mapk/mk2 pathway regulator, and composition, preparation method, and use thereof
WO2023109883A1 (en) Aromatic heterocycle-substituted compounds, and preparation method therefor and use thereof
WO2024046471A9 (en) Usp1 inhibitor

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: 22749040

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280012196.9

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22749040

Country of ref document: EP

Kind code of ref document: A1