WO2022199635A1 - Benzylaminoquinazoline derivatives - Google Patents

Benzylaminoquinazoline derivatives Download PDF

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Publication number
WO2022199635A1
WO2022199635A1 PCT/CN2022/082591 CN2022082591W WO2022199635A1 WO 2022199635 A1 WO2022199635 A1 WO 2022199635A1 CN 2022082591 W CN2022082591 W CN 2022082591W WO 2022199635 A1 WO2022199635 A1 WO 2022199635A1
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compound
mmol
added
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/082591
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French (fr)
Chinese (zh)
Inventor
吴凌云
展震
赵乐乐
代天资
孙建军
周建光
李不鱼
葛广存
李秋
胡国平
黎健
陈曙辉
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南京明德新药研发有限公司
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Publication of WO2022199635A1 publication Critical patent/WO2022199635A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings

Definitions

  • the present invention relates to a class of benzylaminoquinazoline derivatives and a preparation method thereof, in particular to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.
  • RAS protein is a 21kDa guanosine-binding protein located on the cell membrane with guanosine triphosphate hydrolase (GTPase) activity.
  • the RAS family includes KRAS, NRAS and HRAS, and the mutation rate in human cancers is as high as 20% to 30%.
  • the RAS pathway has a binary molecular switch controlled by GDP/GTP cycling: cycling between an active GTP-bound state (GTP-RAS) and an inactive GDP-bound state (GDP-RAS). In the absence of a stimulus signal, this switch state transitions very slowly (Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-1335).
  • RAS-GDP When RAS-GDP binds to guanosine exchange factors (GEFs) such as SOS1, it will rapidly release GDP and combine with a high concentration of intracellular GTP into the "on" state, activating a series of downstream signaling pathways, including: MEK/ ERK, PI3K/AKT/mTOR, RalGDS, etc.
  • GAPs GTPase activating proteins
  • the GTPase activity of RAS increases thousands of times, the GTP bound to it is hydrolyzed into GDP, and RAS re-enters the “off” state of GDP binding, thus completing a complete cycle (Simanshu DK et al., Cell, 2017, 170:17–33). This cycle has important regulatory functions in cells and is closely related to cell proliferation, survival, metabolism, migration, immunity and growth.
  • Oncogenic RAS mutations inhibit both intrinsic GTPase activity and GAP-activated GTPase activity, keeping the RAS cycle in the "on" state of RAS-GTP, leading to continuous activation of downstream signaling pathways that lead to cancer.
  • KRAS mutations account for about 19% of lung cancers, about 71% of pancreatic cancers, and about 35% of colorectal cancers (Andrew et al., Cancer Cell, 2014, 25:272-281). Therefore, inhibition of KRAS mutants and abnormal activation of downstream pathways has become one of the hot targets for the treatment of cancer.
  • SOS1 (Son of Sevenless 1) is a GEF that regulates the GDP/GTP cycle of the RAS protein.
  • Small molecule SOS1 inhibitors that bind to the catalytic site can block the binding of SOS1 to RAS proteins and reduce RAS-GTP levels. Such inhibitors can effectively reduce the abnormal activation of RAS downstream signaling pathways (such as ERK phosphorylation) in cancer cells, thus playing a therapeutic role in cancer.
  • RAS downstream signaling pathways such as ERK phosphorylation
  • AMG-510 is a potent, orally bioavailable, selective KRAS G12C covalent inhibitor developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring a KRAS G12C mutation. Its structure is as follows:
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • E is selected from -(CH 2 CH 2 O) m -;
  • E 1 is selected from -(CR 7 R 8 ) v -;
  • E 2 is selected from -(CH 2 CH 2 O) w -;
  • the heterocycloalkenyl groups are each independently optionally substituted with 1, 2, 3 or 4 R e ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
  • R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
  • R 6 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 2 , R 6 and the carbon atoms to which they are attached together form
  • R 7 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy, wherein said C 1-4 alkyl and C 1-4 alkoxy are each independently optionally substituted with 1, 2, or 3 R f ;
  • R 8 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • two R7 on adjacent carbon atoms and the carbon atom to which they are attached together form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 R g substitutions;
  • R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R 10 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkylamino;
  • the two R 9 and the carbon atoms to which they are attached are taken together to form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl, wherein The C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;
  • R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R e is each independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and -N( CH3 ) 2 ;
  • R f is independently selected from D, F, Cl, Br, I, -OH , -NH and -CN;
  • R is independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and
  • n is selected from 0 or 1;
  • v is selected from 2, 3 or 4;
  • w is selected from 0 or 1;
  • hetero means 1, 2, 3 or 4, respectively A heteroatom or heteroatom group independently selected from -O-, -NH-, -S- and -N-.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • n 0 or 1
  • the heterocycloalkenyl groups are each independently optionally substituted with 1, 2, 3 or 4 R e ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
  • R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl, wherein The C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;
  • R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • Re is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • Hetero in the 3-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl means 1, 2, 3 or 4 are independently selected from -O-, -NH-, -S- and -N- heteroatoms or heteroatomic groups.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • n 0 or 1
  • R 1 is selected from H, F, Cl, Br and -NH 2 ;
  • R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
  • R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
  • R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
  • R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl is selected from 1, 2 , 3 or 4 R substitutions;
  • R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
  • R is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
  • Hetero in the 3-6 membered heterocycloalkyl represents 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S- and -N-.
  • the above compound has the structure represented by formula (II-1) or (II-2):
  • E, E 1 , E 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • n, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • the above R a are independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -C 1-3 alkoxy and 5-membered heterocycloalkyl, wherein The -C 1-3 alkoxy and 5-membered heterocycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R, and other variables are as defined in the present invention.
  • the above R a are independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -C 1-3 alkoxy, tetrahydrofuranyl and pyrrolidinyl, wherein the -C 1-3 alkoxy, tetrahydrofuranyl and pyrrolidinyl are each independently optionally substituted with 1, 2, 3 or 4 R, other variables are as defined herein.
  • R a are independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -OCH 3 , wherein -OCH 3 , Each independently is optionally substituted with 1, 2, 3 or 4 R, other variables are as defined herein.
  • R a are independently selected from F, -OH, -OCH 3 ,
  • R a are independently selected from F, -OH, -OCH 3 , and Other variables are as defined in the present invention.
  • R a are independently selected from F, -OH and Other variables are as defined in the present invention.
  • R b , R c , and R d are each independently selected from F, and other variables are as defined in the present invention.
  • R e are independently selected from -OH, -NH 2 and -N(CH 3 ) 2 , and other variables are as defined in the present invention.
  • R e are independently selected from -OH, and other variables are as defined in the present invention.
  • R f are independently selected from D and F, and other variables are as defined in the present invention.
  • R f are independently selected from D, and other variables are as defined in the present invention.
  • R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , wherein -CH 3 , Each independently is optionally substituted with 1, 2, 3 or 4 R e , R e and other variables as defined herein.
  • R 1 is selected from H, -NH 2 , -CN, Re and other variables are as defined in the present invention.
  • R 1 is selected from H, -NH 2 , -CN, Other variables are as defined in the present invention.
  • R 1 is selected from H and -NH 2 , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and 5-membered heteroaryl, wherein the C 1 -4- alkyl and 5-membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R a , R a and other variables as defined herein.
  • the above R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 and imidazolyl, wherein the -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 and and imidazolyl are each independently optionally substituted with 1, 2, 3 or 4 R a , R a and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 , wherein -CH 3 , -CH 2 CH 3 and -CH2CH( CH3 ) 2 are each independently optionally substituted with 1, 2 , 3 or 4 R a , R a and other variables as defined herein.
  • R 2 is selected from H, F, -CN, -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 , wherein -CH 3 , -CH 2 CH 3 and -CH2CH( CH3 ) 2 are optionally substituted with 1, 2 or 3 R a , R a and other variables as defined herein.
  • R 2 is selected from H, F, -CN, Ra and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, Ra and other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 , Other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 , Other variables are as defined in the present invention.
  • R 2 is selected from H, F, -CN, -CF 3 , Other variables are as defined in the present invention.
  • R 3 is selected from H, F and -CH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H and F, and other variables are as defined in the present invention.
  • R 4 is selected from -CH 3 , and other variables are as defined in the present invention.
  • R 5 is selected from H, F, Cl and Br, and other variables are as defined in the present invention.
  • R 5 is selected from H, and other variables are as defined in the present invention.
  • R 6 is selected from H, and other variables are as defined in the present invention.
  • R 7 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkoxy, wherein the C 1-3 alkoxy Oxygen is optionally substituted with 1, 2, or 3 Rf , Rf and other variables as defined herein.
  • R 7 is selected from H, D, F, Cl, Br, I and -OCH 3 , wherein the -OCH 3 is optionally substituted by 1, 2, or 3 R f , R f and other variables as defined herein.
  • R 7 is selected from H, D, F, -OCH 3 and -OCD 3 , and other variables are as defined in the present invention.
  • R 8 is selected from H, D, F, Cl and Br, and other variables are as defined in the present invention.
  • R 9 is selected from H, and other variables are as defined in the present invention.
  • R 10 is selected from H and -NHCH 3 , and other variables are as defined in the present invention.
  • the two R 7 on the above adjacent carbon atoms and the carbon atoms to which they are attached together form a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is optionally composed of 1, 2, 3 or 4 Rg substitutions, Rg and other variables are as defined herein.
  • the two R 7 on the above adjacent carbon atoms form together with the carbon atom to which they are attached.
  • the Optionally substituted with 1, 2, 3 or 4 Rg , Rg and other variables are as defined herein.
  • the two R 7 on the above adjacent carbon atoms form together with the carbon atom to which they are attached.
  • Other variables are as defined in the present invention.
  • the above two R 9 and the carbon atoms to which they are attached together form a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is optionally surrounded by 1, 2, 3 or 4 R h Substitution, Rh and other variables are as defined herein.
  • the above two R 9 and the carbon atoms to which they are attached together form wherein the Optionally substituted with 1, 2, 3 or 4 R h , R h and other variables as defined herein.
  • the above-mentioned compound has the structure represented by formula (II-3), (II-4) or (II-5):
  • n is selected from 0 and 1;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the above-mentioned compound has the structure represented by formula (II-3A), (II-3B), (II-4A), (II-4B), (II-5A) or (II-5B):
  • n is selected from 0 and 1;
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the above-mentioned compound has the structure represented by formula (II-6), (II-7), (II-8) or (II-9):
  • n is selected from 0 and 1;
  • Ring A is selected from 4-6 membered heterocycloalkyl
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 and R g are as defined in the present invention.
  • the above-mentioned ring A is selected from 5-membered heterocycloalkyl, and other variables are as defined in the present invention.
  • the above-mentioned compounds have formulae (II-6A), (II-6B), (II-7A), (II-7B), (II-8A), (II-8B), (II- 9A) or the structure shown in (II-9B):
  • n is selected from 0 and 1;
  • Ring A is selected from 4-6 membered heterocycloalkyl
  • R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 and R g are as defined in the present invention.
  • n, R 1 , R 2 and R 3 are as defined in the present invention.
  • n, R 1 , R 2 and R 3 are as defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicaments for treating KRAS mutant solid tumor diseases.
  • the compound of the present invention has good KRAS(G12C)-SOS1 binding inhibitory activity, and has significant inhibitory activity on the proliferation of KRAS(G12C) mutant H358 cells and DLD-1 cells p-ERK, thereby obtaining excellent tumor growth inhibitory activity. active.
  • 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 excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
  • C 1-4 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms.
  • the C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-4alkoxy refers to those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-4 alkoxy group includes C 1-3 , C 1-2 , C 2-4 , C 4 and C 3 alkoxy and the like.
  • Examples of C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) oxy, s-butoxy and t-butoxy) and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-4 alkylamino refers to those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-4 alkylamino includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino and the like.
  • C 1-4 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH2CH3 ) , -NHCH2CH2CH3 , -NHCH2 ( CH3 ) 2 , -NHCH2CH2CH2CH3 , etc.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • C 1-4 haloalkyl refers to monohaloalkyl and polyhaloalkyl groups containing 1 to 4 carbon atoms.
  • the C 1-4 haloalkyl includes C 1-4 , C 1-3 , C 1-2 , C 3-4 , C 2-4 , C 2-3 , C 4 , C 3 , C 2 and C 1 haloalkyl, etc.
  • Examples of C 1-4 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl, 4 - Chlorobutyl etc.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxiranyl, thioethane, azetidinyl, oxetanyl, thietanyl, Pyrrolidine, pyrazolidine, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), Linyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithi
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 5-6 membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl.
  • 5-6 membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl or hex
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • 5-membered heterocycloalkyl examples include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuran base (including tetrahydrofuran-2-yl, etc.) and the like.
  • bicyclic ring systems include spiro, paracyclic and bridged rings, any ring of this system is non-aromatic.
  • a heteroatom may occupy the position of attachment of the heterocycloalkenyl to the rest of the molecule.
  • the 5-6 membered heterocyclenyl includes 5-membered and 6-membered heterocyclenyl and the like. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
  • bicyclic ring systems include spiro, paracyclic and bridged rings, any ring of this system is non-aromatic.
  • a heteroatom may occupy the position at which the heterocycloalkenyl is attached to the rest of the molecule. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • the terms “5-membered heteroaryl ring” and “5-membered heteroaryl” can be used interchangeably in the present invention, and the term “5-membered heteroaryl” refers to a 5-membered ring atom having a conjugated ⁇ -electron system The monocyclic group of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole) base, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl,
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl (TMS),
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in 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 embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the volumes used in the present invention are commercially available.
  • Alloc stands for allyloxycarbonyl
  • SEM stands for trimethylsilylethoxymethyl
  • OTs stands for 4-toluenesulfonyl
  • Boc stands for tert-butoxycarbonyl
  • DCM stands for dichloromethane
  • DIEA represents N,N-diisopropylethylamine
  • MeI represents methyl iodide
  • PE represents petroleum ether
  • EA represents ethyl acetate
  • THF represents tetrahydrofuran
  • EtOH represents ethanol
  • MeOH represents methanol
  • Boc 2 O represents di-tert-butyl dicarbonate ;
  • NH 4 Cl for ammonium chloride
  • T 3 P for 1-propylphosphoric acid tricyclic anhydride
  • Pd/C for palladium/carbon catalyst
  • TMSN 3 for azidotrimethylsilane
  • NCS for N-chlorobutanedi Imide
  • HBr hydrobromic acid
  • the present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in 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 embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
  • compound A-3 (15.2 g, 89.5 mmol) was dissolved in acetonitrile (100 mL), triethylamine (14.6 g, 144 mmol) and magnesium chloride (9.33 g, 98.0 mmol) were added successively at 0 °C, and at 15 °C The reaction was stirred for 2 hours. After cooling to 0 °C, a solution of compound A-2 (10.8 g, 42.6 mmol) in acetonitrile (50 mL) was added dropwise, and the reaction was stirred at 15 °C for 12 hours.
  • compound 3-1 (1.00 g, 5.00 mmol) was dissolved in toluene (2 mL), and then compound 3-2 (3.61 g, 10.0 mmol) and bistriphenylphosphine palladium dichloride (351 mg, 0.50 mmol) were added. mmol), and the reaction was stirred at 120 °C for 12 h. Saturated potassium fluoride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL ⁇ 2), filtered, and concentrated under reduced pressure to obtain compound 3-3.
  • the concentrated residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm ⁇ 40mm ⁇ 4 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 28%-58%, 9min) to obtain The hydrochloride salt of compound 4.
  • compound 5-5 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), and compound 3-2 (1.87 g, 5.19 mmol) and bistriphenylphosphonium palladium dichloride (109 mg, 0.16 mmol) were added. , the reaction solution was stirred at 120 ° C for 12 hours. Saturated potassium fluoride solution (20 mL) was added to quench, and extracted with ethyl acetate (15 mL ⁇ 2). Filter and concentrate under reduced pressure to obtain compound 5-6.
  • Compound 5 was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm ⁇ 40mm ⁇ 4 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 28%-58%, 9min) to obtain the salt of compound 5 acid salt.
  • Compound 5 was subjected to SFC (chromatographic column: Chiralcel AD-3 150mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%), measure ee value.
  • compound 6-5 (1.35 g, 4.87 mmol) was dissolved in toluene (10 mL), 3-2 (586 g, 16.2 mmol) and bistriphenylphosphonium palladium dichloride (342 mg, 0.49 mmol) were added, The reaction solution was stirred and reacted at 120°C for 12 hours. Saturated potassium fluoride solution (20 mL) was added to quench the reaction and extracted with ethyl acetate (15 mL ⁇ 2). Filter and concentrate under reduced pressure to obtain compound 6-6.
  • reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 17%-41%, 10min) to obtain the salt of compound 8 acid salt.
  • compound 1-8 (784 mg, 1.37 mmol) was dissolved in dimethyl sulfoxide (5 mL), 9-4 (500 mg, 1.64 mmol) and N,N-diisopropylethylamine (1.77 g g, 13.7 mmol), the reaction solution was stirred at 90 °C for 12 hours.
  • compound 9-5 (60.0 mg, 108 ⁇ mol) was dissolved in dimethyl sulfoxide (1 mL), compound 9-6 (93.9 mg, 1.08 mmol), cuprous iodide (10.3 mg, 53.9 ⁇ mol) were added. , potassium carbonate (29.8mg, 216 ⁇ mol) and L-proline (12.4mg, 108 ⁇ mol), the reaction solution was stirred at 120 ° C for 12 hours.
  • reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm ⁇ 30mm ⁇ 4 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile: 26%-56%, 9min) to obtain compound 9. Hydrochloride.
  • compound 11-1 (344 mg, 970 ⁇ mol) was dissolved in toluene (5 mL), 3-2 (701 mg, 1.94 mmol) and bistriphenylphosphonium palladium dichloride (68.1 mg, 97.0 ⁇ mol) were added, The reaction solution was stirred and reacted at 120°C for 7 hours. Saturated potassium fluoride solution (5 mL) was added to quench, and it was extracted with ethyl acetate (5 mL ⁇ 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11-2.
  • compound 9-5 120 mg, 216 ⁇ mol was dissolved in N,N-dimethylformamide (5 mL), zinc cyanide (50.1 mg, 431 ⁇ mol), 2-dicyclohexylphosphorus-2,4 were added. , 6-triisopropylbiphenyl (20.6 mg, 43.1 ⁇ mol), tris(dibenzylideneacetone)dipalladium (19.7 mg, 21.6 ⁇ mol), and the reaction was stirred at 90° C. for 6 hours.
  • reaction solution was filtered, ethyl acetate (20 mL) was added to the filtrate, the organic phase was washed with saturated brine (50 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Genimi NX C18 150 ⁇ 40 mm ⁇ 5 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile 15%-45%, 10 min) to obtain the hydrochloride salt of compound 13.
  • SFC chromatographic column: Chiralcel IC-3 100mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%
  • compound 14-1 (3.00 g, 14.8 mmol) was dissolved in anhydrous dichloromethane (30 mL), and diethylaminosulfur trifluoride (3.57 g, 22.2 mmol) was added dropwise at 0 °C, and the reaction solution was Stir at 25°C for 12 hours, add ice water (20 mL) to the reaction solution, extract with dichloromethane (20 mL ⁇ 1), wash the organic phase with saturated brine (20 mL ⁇ 1), dry over anhydrous sodium sulfate, filter , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 10/1, V/V) to obtain compound 14-2.
  • compound 14-2 (3.10 g, 13.8 mmol) was dissolved in dry toluene (50 mL), tributyl (1-ethoxyethylene) tin (9.95 g, 27.6 mmol) was added, and bistris Phenylphosphine palladium dichloride (967 mg, 1.38 mmol), the reaction solution was stirred at 110 ° C for 12 hours, a saturated aqueous potassium fluoride solution (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL ⁇ 1), the organic The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14-3.
  • compound 14-4 (1.85 g, 9.83 mmol) was dissolved in dry tetrahydrofuran (50 mL), tetraethyl titanate (8.97 g, 39.3 mmol) and compound A-6 (2.38 g, 19.7 mmol) were added , the reaction solution was stirred at 72 °C for 36 hours, cooled to 0 °C, and saturated aqueous ammonium chloride solution (20 mL) was added dropwise, then ethyl acetate (20 mL) was added, filtered, and the filter cake was washed with ethyl acetate (10 mL), and the organic phase was washed with ethyl acetate (10 mL).
  • the hydrochloride salt of compound 13 (20.0 mg, 39.8 ⁇ mol) was dissolved in anhydrous tetrahydrofuran (5 mL), a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 66.3 ⁇ L) was added dropwise to the reaction solution, and the solution was stirred for 30 minutes. After minutes, tetraisopropyl titanate (11.8 ⁇ L, 39.8 ⁇ mol) was added, and the reaction was stirred at 25° C. for 12 hours.
  • 1,2-Dibromoethane (10.9uL, 144 ⁇ mol) was dissolved in N,N-dimethylformamide (3mL), zinc powder (118mg, 1.80mmol,) was added, and the reaction was stirred at 70°C for 10 minutes . After cooling to 20°C, trimethylchlorosilane (18.3uL, 144 ⁇ mol) was added dropwise, and the reaction was stirred for 50 minutes. A solution of compound 17-1 (76.3 mg, 270 ⁇ mol, ) in N,N-dimethylformamide (3 mL) was added dropwise, and the reaction was stirred at 40° C. for 1 hour.
  • Compound 17 was obtained by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80mm ⁇ 30mm ⁇ 3 ⁇ m; mobile phase: 10mM aqueous ammonium bicarbonate solution-acetonitrile; gradient: acetonitrile 30%-90%, 9min).
  • compound 22-4 (580 mg, 904 ⁇ mol) was dissolved in dioxane/water solution (4:1, 1.25 mL), 22-5 (191 mg, 603 ⁇ mol), [1,1′-bis( Diphenylphosphino)ferrocene]palladium dichloride (44.1 mg, 60.2 ⁇ mol) and sodium carbonate (128 mg, 1.21 mmol).
  • the reaction solution was stirred and reacted at 100°C for 12 hours.
  • the reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-10/1, V/V) to obtain compound 22-6.
  • MS-ESI calculated [M+H] + 645, found 645.
  • compound 27-3 (700 mg, 1.80 mmol) was dissolved in toluene (10 mL), compound 3-2 (1.57 g, 4.35 mmol) and bistriphenylphosphonium palladium dichloride (126 mg, 180 ⁇ mol) were added ), the reaction solution was stirred at 120 °C for 12 hours. Saturated potassium fluoride solution (5 mL) was added to quench, and it was extracted with ethyl acetate (5 mL ⁇ 2). Filter and concentrate under reduced pressure to get the crude product which can be directly used in the next step.
  • the hydrochloride salt of compound 33 (50 mg, 99.3 ⁇ mol) was dissolved in dichloromethane (2 mL), acetic anhydride (20.3 mg, 199 ⁇ mol) and triethylamine (27.7 ⁇ l, 199 ⁇ mol) were added, and the reaction was stirred at 25° C. 6 Hour. Filtration, the residue after the filtrate was concentrated under reduced pressure was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm ⁇ 40mm ⁇ 5 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 15%-45%, 10 min) to obtain the hydrochloride salt of compound 34.
  • compound 35-1 (6.00 g, 23.3 mmol) was dissolved in dry toluene (100 mL), compound 3-2 (12.6 g, 34.9 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.63 g, 2.33 mmol), the reaction solution was stirred at 120 ° C for 12 hours, and after cooling to room temperature, a saturated aqueous potassium fluoride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL ⁇ 2), and the organic phase was Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 35-2, which is directly used in the next step.
  • compound 36-1 (5.00 g, 25.5 mmol) was dissolved in dry toluene (50 mL), compound 3-2 (10.2 g, 28.3 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.79 g, 2.55 mmol), the reaction solution was stirred at 120 °C for 12 hours, and after cooling to room temperature, saturated aqueous potassium fluoride solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL ⁇ 2), and the organic phase was Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 36-2, which is directly used in the next step.
  • Small molecule compounds bind to the catalytic site of SOS1 and inhibit the binding of SOS1 to KRAS(G12C).
  • SOS1 When the binding of fluorescently labeled SOS1 protein to fluorescently labeled KRAS(G12C) protein is inhibited, the emitted fluorescence changes.
  • fluorescence changes By detecting fluorescence changes, the ability of small molecules to prevent SOS1 from binding to KRAS(G12C) can be tested.
  • a homogeneous time-resolved fluorescence (HTRF) binding assay was used to examine the ability of the compounds of the present invention to inhibit the mutual binding of SOS1 and KRAS(G12C).
  • HTRF time-resolved fluorescence
  • KRAS (G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd., SOS1 exchange domin (564-1049) protein (H ⁇ man recombinant) was purchased from Cytoskeleton, Mab Anti 6HIS-XL665 and Mab Anti GST-E ⁇ cryptate were purchased from Cisbio.
  • the multi-plate reader Nivo5 was purchased from PerkinElmer.
  • 1X buffer preparation Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 005%;
  • the compounds to be tested were diluted 5-fold with DMSO to the 8th concentration, that is, from 1 mM to 0.064 ⁇ M.
  • the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
  • Table 1 shows the results of the inhibitory activity of the compounds of the present invention on the binding of KRAS(G12C) and SOS1.
  • test compound IC50 (nM) Compound 1 hydrochloride 21.45 Compound 5 hydrochloride 12.56 Compound 6 hydrochloride 52.94 Compound 11 37.63 The hydrochloride salt of compound 14 35.13 Compound 18 hydrochloride 56.85 Compound 20 9.50 Compound 25 128.30 Compound 26 21.47 Compound 29 17.10 Compound 31 28.82 Compound 34 105.7 Compound 35 60.78
  • the compound of the present invention has a significant inhibitory effect on the combination of KRAS(G12C) and SOS1.
  • KRAS(G12C) mutant H358 cells the KRAS signaling pathway is abnormally activated.
  • Small molecule SOS1 inhibitors reduce the GEF activity and the ratio of activated RAS-GTP by inhibiting the binding of SOS1 to RAS protein. Further down-regulate the phosphorylation level of MEK/ERK pathway downstream of RAS to achieve the effect of inhibiting cell proliferation. Small molecules were co-cultured with H358 cells in 3D space, and then the cell readout indirectly reflected the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.
  • RPMI1640 medium fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low melting point agarose was purchased from Sigma. Almar blue reagent was purchased from Invitrogen.
  • the NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
  • the H358 cells were seeded in a 96-well U-shaped plate, and the low-melting point agarose was first made into a 2% stock solution.
  • the agarose stock solution was first heated in a microwave oven to completely melt it, and then the agarose was placed in a 42°C water bath. Sugar remains liquid.
  • the gel was added to the serum-containing medium to prepare a gel concentration of 0.6% as the bottom gel, and 50 ⁇ L per well was spread into a 96-well U-shaped plate.
  • After the bottom gel has solidified add 2% gel to the cell-containing medium to prepare a cell-containing top gel with a gel concentration of 0.4%, and the cell density is 4 ⁇ 10 4 cells/ml.
  • 75 ⁇ l was added to the 96-well U-shaped plate with the bottom gel, and the cell density was 3000 cells per well. After the supernatant gel was solidified, the cell plate was placed in a carbon dioxide incubator for overnight incubation.
  • the compound to be tested was diluted 3-fold to the ninth concentration, that is, from 6mM to 0.9 ⁇ M, and a double-well experiment was set up. For example, add 198 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of the compound diluted in each well to the first middle plate according to the corresponding position, then add 100 ⁇ L of medium to the second middle plate, and take the first middle plate. Add 100 ⁇ L of the mixed compound, and transfer 40 ⁇ L per well to the cell plate after mixing. Compound concentrations transferred to cell plates ranged from 30 [mu]M to 4.5 nM. The cell plates were placed in a carbon dioxide incubator for an additional 7 days.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • test compound IC50 (nM) Compound 1 hydrochloride 140
  • the compounds of the present invention can inhibit the proliferation of H358 cells under 3D conditions.
  • DLD-1 cells were purchased from Nanjing Kebai; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio.
  • the composition of Advanced Phospho-ERK1/2 (THR202/TYR204) KIT is shown in Table 3.
  • DLD-1 cells were seeded in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well containing 8000 DLD-1 cells, the cell plate was placed in a carbon dioxide incubator, and incubated overnight at 37°C;
  • the compounds to be tested were diluted with 100% DMSO to 2 mM as the first concentration, and then 5-fold diluted with a pipette to the eighth concentration, ie, from 2 mM to 0.026 [mu]M.
  • Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody were diluted 20-fold with Detection buffer;
  • the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode).
  • Table 4 shows the test results of the inhibitory effect of the compounds of the present invention on p-ERK.
  • Min well negative control well reads 0.5% DMSO cell well cell lysate
  • test compound IC50 (nM) Compound 1 hydrochloride 140.5 Compound 5 hydrochloride 54.5 Compound 6 hydrochloride 112.1 The hydrochloride salt of compound 14 119.5 Compound 16 227.6
  • the compound of the present invention has inhibitory effect on the proliferation of p-ERK in DLD-1 cells.
  • CD-1 mice male, 7-9 weeks old, Beijing Weitonglihua
  • the pharmacokinetic characteristics of the compounds in rodents after intravenous bolus injection and oral administration were tested according to the standard protocol.
  • the candidate compounds were formulated into clear solutions and administered to mice by a single intravenous injection and oral administration.
  • the vehicle for intravenous injection and oral administration is a mixed solvent of 5% dimethyl sulfoxide, 5% polyethylene glycol-15 hydroxystearate and 10% water.
  • Four male CD-1 mice were used in this project, two mice were administered intravenously at a dose of 10 mg/kg, and the 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration were collected.
  • Plasma samples were given oral gavage at a dose of 50 mg/kg, and the plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. Centrifuge at x g for 10 minutes, separate the supernatant to obtain the plasma sample, add 20 times the volume of acetonitrile solution containing internal standard to precipitate the protein, stir at 12,000 x g for 15 minutes, centrifuge at 4°C to take 50 ⁇ L of the supernatant and transfer it to a 96-well plate for secondary centrifugation to take the supernatant for Quantitative analysis of blood drug concentration by LC-MS/MS analysis method, and calculation of pharmacokinetic parameters, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss) , area under the drug-time curve (AUC 0-last ), bioavailability (F) and so on.
  • C max peak concentration
  • CL clearance rate
  • T 1/2 half-life
  • Vdss tissue
  • the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • Human pancreatic cancer cells (Miapaca2) were cultured in an adherent monolayer in vitro, and the culture conditions were DMEM medium plus 10% fetal bovine serum, 37 °C, 5% CO 2 incubator. Routine digestion with trypsin-EDTA was performed two to three times a week. When the cell saturation is 80%–90% and the number reaches the requirement, the cells are harvested, counted, and seeded.
  • Balb/c nude mice female, 6-7 weeks old, were purchased from Shanghai Sipple-Bike Laboratory Animal Co., Ltd.
  • Miapaca2 cells were subcutaneously inoculated into the right back of each mouse, and the group administration started when the average tumor volume reached 118 mm 3 .
  • the tumor-inhibitory efficacy of the test compounds was evaluated by using TGI (%).
  • TGI (%) reflects the tumor growth inhibition rate.
  • TGI(%) [1-(average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group)/(average tumor volume at the end of treatment in the solvent control group-average at the beginning of treatment in the solvent control group tumor volume)] ⁇ 100%.

Abstract

Provided are benzylaminoquinazoline derivatives and a preparation method therefor, specifically relating to the compound as represented by formula (II) and a pharmaceutically acceptable salt thereof, for use in the preparation of a drug for treating KRAS mutant solid tumors.

Description

苄氨基喹唑啉类衍生物Benzylaminoquinazoline derivatives
本申请主张如下优先权：This application claims the following priority:
CN202110321143.2，2021年03月25日。CN202110321143.2, March 25, 2021.
技术领域technical field
本发明涉及一类苄氨基喹唑啉类衍生物及其制备方法，具体涉及式(Ⅱ)所示化合物及其药学上可接受的盐。The present invention relates to a class of benzylaminoquinazoline derivatives and a preparation method thereof, in particular to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.
背景技术Background technique
RAS蛋白是一种21kDa大小，位于细胞膜上的，拥有鸟苷三磷酸水解酶(GTPase)活性的鸟嘌呤核苷结合蛋白。RAS家族包含KRAS，NRAS和HRAS，在人类癌症中的突变率高达20％～30％。RAS通路存在GDP/GTP循环控制的二进制分子开关：在活性的GTP结合状态(GTP-RAS)和无活性的GDP结合状态(GDP-RAS)之间循环。没有刺激信号时，这种开关状态的转换非常缓慢(Hunter et al.,Mol.Cancer Res.,2015,13(9):1325-1335)。当RAS-GDP与鸟嘌呤核苷交换因子(GEFs)如SOS1结合时，会迅速释放GDP并与细胞内高浓度的GTP结合进入“开”的状态，激活下游一系列信号通路，包括：MEK/ERK，PI3K/AKT/mTOR，RalGDS等。而在GTPase激活蛋白(GAPs)的作用下，RAS的GTPase的活性提高上千倍，与之结合的GTP被水解成GDP，RAS重新进入GDP结合的“关”的状态，从而完成一个完整的循环(Simanshu DK et al.,Cell,2017,170:17–33)。这一循环在细胞中具有重要的调控功能，同细胞的增殖，存活，代谢，迁移，免疫和生长密切相关。RAS protein is a 21kDa guanosine-binding protein located on the cell membrane with guanosine triphosphate hydrolase (GTPase) activity. The RAS family includes KRAS, NRAS and HRAS, and the mutation rate in human cancers is as high as 20% to 30%. The RAS pathway has a binary molecular switch controlled by GDP/GTP cycling: cycling between an active GTP-bound state (GTP-RAS) and an inactive GDP-bound state (GDP-RAS). In the absence of a stimulus signal, this switch state transitions very slowly (Hunter et al., Mol. Cancer Res., 2015, 13(9):1325-1335). When RAS-GDP binds to guanosine exchange factors (GEFs) such as SOS1, it will rapidly release GDP and combine with a high concentration of intracellular GTP into the "on" state, activating a series of downstream signaling pathways, including: MEK/ ERK, PI3K/AKT/mTOR, RalGDS, etc. Under the action of GTPase activating proteins (GAPs), the GTPase activity of RAS increases thousands of times, the GTP bound to it is hydrolyzed into GDP, and RAS re-enters the “off” state of GDP binding, thus completing a complete cycle (Simanshu DK et al., Cell, 2017, 170:17–33). This cycle has important regulatory functions in cells and is closely related to cell proliferation, survival, metabolism, migration, immunity and growth.
致癌的RAS突变会同时抑制内在GTPase活性和GAP激活的GTPase活性，使RAS循环始终处于RAS-GTP的“开”状态，导致下游信号通路持续激活引发癌症。KRAS突变在肺癌中约占19％，在胰腺癌中约占71％，在结直肠癌中约占35％(Andrew et al.,Cancer Cell,2014,25:272-281)。因此，抑制KRAS的突变体及下游通路的异常激活成为治疗癌症的热门靶点之一。Oncogenic RAS mutations inhibit both intrinsic GTPase activity and GAP-activated GTPase activity, keeping the RAS cycle in the "on" state of RAS-GTP, leading to continuous activation of downstream signaling pathways that lead to cancer. KRAS mutations account for about 19% of lung cancers, about 71% of pancreatic cancers, and about 35% of colorectal cancers (Andrew et al., Cancer Cell, 2014, 25:272-281). Therefore, inhibition of KRAS mutants and abnormal activation of downstream pathways has become one of the hot targets for the treatment of cancer.
SOS1(英文全称Son of Sevenless 1)是一类调控RAS蛋白GDP/GTP循环的GEF。结合在催化位点的小分子SOS1抑制剂，可以阻断SOS1与RAS蛋白的结合，降低RAS-GTP水平。这类抑制剂可以有效降低癌细胞中RAS下游信号通路的异常激活(如ERK磷酸化)，从而对癌症起到治疗作用。目前SOS1小分子抑制剂只有勃林格殷格翰公司开发的BI-1701963(WO2018115380，WO2019122129)进入了I期临床实验。拜耳公司(WO2018172250，WO2019201848)开发的SOS1抑制剂仍处于临床前研究阶段。近年来有研究认为，RAS通路的药物在临床应用中很容易产生耐药，部分耐药产生的原因是ERK磷酸化被抑制后会负反馈激活上游RAS通路。而这一负反馈调节机制与SOS1密切相关。因此，开发SOS1小分子抑制剂具有广阔的应用前景。SOS1 (Son of Sevenless 1) is a GEF that regulates the GDP/GTP cycle of the RAS protein. Small molecule SOS1 inhibitors that bind to the catalytic site can block the binding of SOS1 to RAS proteins and reduce RAS-GTP levels. Such inhibitors can effectively reduce the abnormal activation of RAS downstream signaling pathways (such as ERK phosphorylation) in cancer cells, thus playing a therapeutic role in cancer. At present, only BI-1701963 (WO2018115380, WO2019122129) developed by Boehringer Ingelheim is the only SOS1 small molecule inhibitor that has entered phase I clinical trials. The SOS1 inhibitor developed by Bayer (WO2018172250, WO2019201848) is still in the preclinical research stage. In recent years, some studies have suggested that drugs in the RAS pathway are prone to drug resistance in clinical applications, and part of the reason for drug resistance is that the inhibition of ERK phosphorylation will negatively activate the upstream RAS pathway. This negative feedback regulation mechanism is closely related to SOS1. Therefore, the development of small molecule inhibitors of SOS1 has broad application prospects.
AMG-510是安进公司开发的一种有效的，口服生物可利用的，选择性的KRAS G12C共价抑制剂，用于治疗携带KRAS G12C突变的局部晚期或转移性非小细胞肺癌。其结构如下所示：AMG-510 is a potent, orally bioavailable, selective KRAS G12C covalent inhibitor developed by Amgen for the treatment of locally advanced or metastatic non-small cell lung cancer harboring a KRAS G12C mutation. Its structure is as follows:
Figure PCTCN2022082591-appb-000001
Figure PCTCN2022082591-appb-000001
发明内容SUMMARY OF THE INVENTION
本发明提供了式(Ⅱ)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022082591-appb-000002
Figure PCTCN2022082591-appb-000002
其中，in,
E选自-(CH 2CH 2O) m-； E is selected from -(CH 2 CH 2 O) m -;
E 1选自-(CR 7R 8) v-； E 1 is selected from -(CR 7 R 8 ) v -;
E 2选自-(CH 2CH 2O) w-； E 2 is selected from -(CH 2 CH 2 O) w -;
R 1选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、-NHC(＝O)-C 1-4烷基、4-6元杂环烷基和5-6元杂环烯基，其中所述C 1-4烷基、-NHC(＝O)-C 1-4烷基、4-6元杂环烷基和5-6元杂环烯基分别独立地任选被1、2、3或4个R e取代； R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, 4-6 membered hetero Cycloalkyl and 5-6 membered heterocycloalkenyl, wherein said C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, 4-6 membered heterocycloalkyl and 5-6 membered The heterocycloalkenyl groups are each independently optionally substituted with 1, 2, 3 or 4 R e ;
R 2选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3- 6环烷基、3-6元杂环烷基和5-6元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3-6环烷基、3-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2、3或4个R a取代； R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, -S(= O) 2 - C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, -S(=O) 2 -C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl each independently optionally substituted with 1, 2, 3 or 4 Ra ;
R 3选自H、F、Cl、Br、I和C 1-4烷基，其中所述C 1-4烷基任选被1、2、3或4个R b取代； R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
R 4选自C 1-4烷基和C 1-4卤代烷基，其中所述C 1-4烷基和C 1-4卤代烷基分别独立地任选被1、2、3或4个R c取代； R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
R 5选自H、F、Cl、Br、I、-NH 2、C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基，其中所述C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基分别独立地任选被1、2、3或4个R d取代； R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
R 6选自H、F、Cl、Br、I、-OH、-NH 2和-CN； R 6 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
或者，R 2、R 6和与它们相连的碳原子一起形成
Figure PCTCN2022082591-appb-000003
Alternatively, R 2 , R 6 and the carbon atoms to which they are attached together form
Figure PCTCN2022082591-appb-000003
R 7选自H、D、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2、或3个R f取代； R 7 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy, wherein said C 1-4 alkyl and C 1-4 alkoxy are each independently optionally substituted with 1, 2, or 3 R f ;
R 8选自H、D、F、Cl、Br、I、-OH、-NH 2和-CN； R 8 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 and -CN;
或者，相邻碳原子上的两个R 7和与它们相连的碳原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基任选被1、2、3或4个R g取代； Alternatively, two R7 on adjacent carbon atoms and the carbon atom to which they are attached together form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 R g substitutions;
R 9分别独立地选自H、F、Cl、Br、I、-OH、-NH 2和-CN； R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
R 10选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷氨基； R 10 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkylamino;
或者，两个R 9和与它们相连的碳原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基任选被1、2、3或4个R h取代； Alternatively, the two R 9 and the carbon atoms to which they are attached are taken together to form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R;
R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基和3-6元杂环烷基，其中所述C 1-4烷基、C 1-4烷氧基和3-6元杂环烷基分别独立地任选被1、2、3或4个R取代； R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl, wherein The C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;
R b分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
R c分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
R d分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
R e分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN和-N(CH 3) 2； R e is each independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and -N( CH3 ) 2 ;
R f分别独立地选自D、F、Cl、Br、I、-OH、-NH 2和-CN； R f is independently selected from D, F, Cl, Br, I, -OH , -NH and -CN;
R g分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基和-C(＝O)CH 3； R g is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl and -C(=O)CH 3 ;
R h分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2、-CN和C 1-3烷基； R h is independently selected from F, Cl, Br, I, =O, -OH, -NH 2 , -CN and C 1-3 alkyl;
R分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN和
Figure PCTCN2022082591-appb-000004
R is independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and
Figure PCTCN2022082591-appb-000004
m选自0或1；m is selected from 0 or 1;
v选自2、3或4；v is selected from 2, 3 or 4;
w选自0或1；w is selected from 0 or 1;
当R 4为-CH 3且R 5、R 6、R 7、R 8均为H时，条件是： When R 4 is -CH 3 and R 5 , R 6 , R 7 and R 8 are all H, the conditions are:
(1)当m为1，w为1，v为2，R 1为H，R 3为F时，R 2不为-CHF 2或
Figure PCTCN2022082591-appb-000005
(1) When m is 1, w is 1 , v is 2 , R1 is H, R3 is F, R2 is not -CHF2 or
Figure PCTCN2022082591-appb-000005
(2)当m为1，w为1，v为2，R 1为H，R 3为-CH 3时，R 2不为-CHF 2或-CF 3； (2) When m is 1, w is 1, v is 2, R 1 is H, and R 3 is -CH 3 , R 2 is not -CHF 2 or -CF 3 ;
(3)当m为1，w为1，v为4，R 1为H，R 3为F时，R 2不为-CHF 2； (3) When m is 1, w is 1, v is 4, R 1 is H, and R 3 is F, R 2 is not -CHF 2 ;
(4)当v为2，R 2为-NH 2，R 2为-CF 3，R 3为H时，m与w之和不为0、1或2； (4) When v is 2, R 2 is -NH 2 , R 2 is -CF 3 , and R 3 is H, the sum of m and w is not 0, 1 or 2;
(5)当m与w之和为1，v为2，R 1为H，R 3为F时，R 2不为-CHF 2或
Figure PCTCN2022082591-appb-000006
(5) When the sum of m and w is 1, v is 2, R 1 is H, and R 3 is F, R 2 is not -CHF 2 or
Figure PCTCN2022082591-appb-000006
所述3-6元杂环烷基、4-6元杂环烷基、5-6元杂环烯基和5-6元杂芳基中“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。In the 3-6-membered heterocycloalkyl, 4-6-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl, "hetero" means 1, 2, 3 or 4, respectively A heteroatom or heteroatom group independently selected from -O-, -NH-, -S- and -N-.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022082591-appb-000007
Figure PCTCN2022082591-appb-000007
其中，in,
n为0或1；n is 0 or 1;
R 1选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、-NHC(＝O)-C 1-4烷基、5-6元杂环烷基和5-6元杂环烯基，其中所述C 1-4烷基、-NHC(＝O)-C 1-4烷基、5-6元杂环烷基和5-6元杂环烯基分别独立地任选被1、2、3或4个R e取代； R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, 5-6 membered hetero Cycloalkyl and 5-6 membered heterocycloalkenyl, wherein said C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, 5-6 membered heterocycloalkyl and 5-6 membered The heterocycloalkenyl groups are each independently optionally substituted with 1, 2, 3 or 4 R e ;
R 2选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3- 6环烷基和3-6元杂环烷基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3-6环烷基和3-6元杂环烷基分别独立地任选被1、2、3或4个R a取代； R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, -S(= O) 2 - C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 Alkylamino, -S(=O) 2 -C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally replaced by 1, 2, 3 or 4 R a replace;
R 3选自H、F、Cl、Br、I和C 1-4烷基，其中所述C 1-4烷基任选被1、2、3或4个R b取代； R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
R 4选自C 1-4烷基和C 1-4卤代烷基，其中所述C 1-4烷基和C 1-4卤代烷基分别独立地任选被1、2、3或4个R c取代； R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
R 5选自H、F、Cl、Br、I、-NH 2、C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基，其中所述C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基分别独立地任选被1、2、3或4个R d取代； R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基和3-6元杂环烷基，其中所述C 1-4烷基、C 1-4烷氧基和3-6元杂环烷基分别独立地任选被1、2、3或4个R取代； R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl, wherein The C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;
R b分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
R c分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
R d分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
R e分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； Re is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
R分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
所述3-6元杂环烷基、5-6元杂环烷基和5-6元杂环烯基中“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。"Hetero" in the 3-6-membered heterocycloalkyl, 5-6-membered heterocycloalkyl and 5-6-membered heterocycloalkenyl means 1, 2, 3 or 4 are independently selected from -O-, -NH-, -S- and -N- heteroatoms or heteroatomic groups.
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022082591-appb-000008
Figure PCTCN2022082591-appb-000008
其中，in,
n为0或1；n is 0 or 1;
R 1选自H、F、Cl、Br和-NH 2； R 1 is selected from H, F, Cl, Br and -NH 2 ;
R 2选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3- 6环烷基和3-6元杂环烷基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3-6环烷基和3-6元杂环烷基分别独立地任选被1、2、3或4个R a取代； R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, -S(= O) 2 - C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl, wherein the C 1-4 alkyl, C 1-4 alkoxy, C 1-4 Alkylamino, -S(=O) 2 -C 1-4 alkyl, C 3-6 cycloalkyl and 3-6 membered heterocycloalkyl are each independently optionally replaced by 1, 2, 3 or 4 R a replace;
R 3选自H、F、Cl、Br、I和C 1-4烷基，其中所述C 1-4烷基任选被1、2、3或4个R b取代； R 3 is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
R 4选自C 1-4烷基和C 1-4卤代烷基，其中所述C 1-4烷基和C 1-4卤代烷基分别独立地任选被1、2、3或4个R c取代； R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
R 5选自H、F、Cl、Br、I、-NH 2、C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基，其中所述C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基分别独立地选被1、2、3或4个R d取代； R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN和3-6元杂环烷基，其中所述3-6元杂环烷基选被1、2、3或4个R取代； R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN and 3-6 membered heterocycloalkyl, wherein the 3-6 membered heterocycloalkyl is selected from 1, 2 , 3 or 4 R substitutions;
R b分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
R c分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
R d分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
R分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
所述3-6元杂环烷基中“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。"Hetero" in the 3-6 membered heterocycloalkyl represents 1, 2, 3 or 4 heteroatoms or heteroatomic groups independently selected from -O-, -NH-, -S- and -N-.
本发明的一些方案中，上述化合物具有式(Ⅱ-1)或(Ⅱ-2)所示结构：In some schemes of the present invention, the above compound has the structure represented by formula (II-1) or (II-2):
Figure PCTCN2022082591-appb-000009
Figure PCTCN2022082591-appb-000009
其中，E、E 1、E 2、R 1、R 2、R 3、R 4、R 5和R 6如本发明所定义。 Wherein, E, E 1 , E 2 , R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(I-1)和(I-2)所示结构：In some schemes of the present invention, the above-mentioned compounds have structures represented by formulas (I-1) and (I-2):
Figure PCTCN2022082591-appb-000010
Figure PCTCN2022082591-appb-000010
其中，n、R 1、R 2、R 3、R 4和R 5如本发明所定义。 wherein n, R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
本发明的一些方案中，上述R分别独立地选自
Figure PCTCN2022082591-appb-000011
其他变量如本发明所定义。 In some aspects of the present invention, the above R are independently selected from
Figure PCTCN2022082591-appb-000011
Other variables are as defined in the present invention.
本发明的一些方案中，上述R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-C 1-3烷氧基和5元杂环烷基，其中所述-C 1-3烷氧基和5元杂环烷基分别独立地任选被1、2、3或4个R取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above R a are independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, -C 1-3 alkoxy and 5-membered heterocycloalkyl, wherein The -C 1-3 alkoxy and 5-membered heterocycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R, and other variables are as defined in the present invention.
本发明的一些方案中，上述R a分别独立地选自F、Cl、Br、-OH、-NH 2、-CN、-C 1-3烷氧基、四氢呋喃基和吡咯烷基，其中所述-C 1-3烷氧基、四氢呋喃基和吡咯烷基分别独立地任选被1、2、3或4个R取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above R a are independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -C 1-3 alkoxy, tetrahydrofuranyl and pyrrolidinyl, wherein the -C 1-3 alkoxy, tetrahydrofuranyl and pyrrolidinyl are each independently optionally substituted with 1, 2, 3 or 4 R, other variables are as defined herein.
本发明的一些方案中，上述R a分别独立地选自F、Cl、Br、-OH、-NH 2、-CN、-OCH 3、
Figure PCTCN2022082591-appb-000012
Figure PCTCN2022082591-appb-000013
其中所述-OCH 3、
Figure PCTCN2022082591-appb-000014
分别独立地任选被1、2、3或4个R取代，其他变量如本发明所定义。 In some embodiments of the present invention, the above R a are independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -OCH 3 ,
Figure PCTCN2022082591-appb-000012
Figure PCTCN2022082591-appb-000013
wherein -OCH 3 ,
Figure PCTCN2022082591-appb-000014
Each independently is optionally substituted with 1, 2, 3 or 4 R, other variables are as defined herein.
本发明的一些方案中，上述R a分别独立地选自F、-OH、-OCH 3、
Figure PCTCN2022082591-appb-000015
In some aspects of the present invention, the above R a are independently selected from F, -OH, -OCH 3 ,
Figure PCTCN2022082591-appb-000015
本发明的一些方案中，上述R a分别独立地选自F、-OH、-OCH 3、和
Figure PCTCN2022082591-appb-000016
其他变量如本发明所定义。 In some aspects of the present invention, the above R a are independently selected from F, -OH, -OCH 3 , and
Figure PCTCN2022082591-appb-000016
Other variables are as defined in the present invention.
本发明的一些方案中，上述R a分别独立地选自F、-OH和
Figure PCTCN2022082591-appb-000017
其他变量如本发明所定义。 In some aspects of the present invention, the above R a are independently selected from F, -OH and
Figure PCTCN2022082591-appb-000017
Other variables are as defined in the present invention.
本发明的一些方案中，上述R b、R c、R d分别独立地选自F，其他变量如本发明所定义。 In some solutions of the present invention, the above R b , R c , and R d are each independently selected from F, and other variables are as defined in the present invention.
本发明的一些方案中，上述R e分别独立地选自-OH、-NH 2和-N(CH 3) 2，其他变量如本发明所定义。 In some embodiments of the present invention, the above R e are independently selected from -OH, -NH 2 and -N(CH 3 ) 2 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R e分别独立地选自-OH，其他变量如本发明所定义。 In some embodiments of the present invention, the above R e are independently selected from -OH, and other variables are as defined in the present invention.
本发明的一些方案中，上述R f分别独立地选自D和F，其他变量如本发明所定义。 In some aspects of the present invention, the above R f are independently selected from D and F, and other variables are as defined in the present invention.
本发明的一些方案中，上述R f分别独立地选自D，其他变量如本发明所定义。 In some embodiments of the present invention, the above R f are independently selected from D, and other variables are as defined in the present invention.
本发明的一些方案中，上述R g分别独立地选自-C(＝O)CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R g are independently selected from -C(=O)CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R h分别独立地选自＝O和-CH 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R h are independently selected from =O and -CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基、-NHC(＝O)-C 1-3烷基、4-6元杂环烷基和6元杂环烯基，其中所述C 1-3烷基、-NHC(＝O)-C 1-3烷基、4-6元杂环烷基和6元杂环烯基分别独立地任选被1、2、3或4个R e取代，R e及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl, -NHC(=O)-C 1-3 Alkyl, 4-6-membered heterocycloalkyl and 6-membered heterocycloalkenyl, wherein the C 1-3 alkyl, -NHC(=O)-C 1-3 alkyl, 4-6-membered heterocycloalkane and 6-membered heterocycloalkenyl are each independently optionally substituted with 1, 2, 3 or 4 R e , R e and other variables as defined herein.
本发明的一些方案中，上述R 1选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、
Figure PCTCN2022082591-appb-000018
Figure PCTCN2022082591-appb-000019
其中所述-CH 3、
Figure PCTCN2022082591-appb-000020
Figure PCTCN2022082591-appb-000021
分别独立地任选被1、2、3或4个R e取代，R e及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 ,
Figure PCTCN2022082591-appb-000018
Figure PCTCN2022082591-appb-000019
wherein -CH 3 ,
Figure PCTCN2022082591-appb-000020
Figure PCTCN2022082591-appb-000021
Each independently is optionally substituted with 1, 2, 3 or 4 R e , R e and other variables as defined herein.
本发明的一些方案中，上述R 1选自H、-NH 2、-CN、
Figure PCTCN2022082591-appb-000022
Figure PCTCN2022082591-appb-000023
R e及其他变量如本发明所定义。 In some schemes of the present invention, the above R 1 is selected from H, -NH 2 , -CN,
Figure PCTCN2022082591-appb-000022
Figure PCTCN2022082591-appb-000023
Re and other variables are as defined in the present invention.
本发明的一些方案中，上述R 1选自H、-NH 2、-CN、
Figure PCTCN2022082591-appb-000024
Figure PCTCN2022082591-appb-000025
其他变量如本发明所定义。 In some schemes of the present invention, the above R 1 is selected from H, -NH 2 , -CN,
Figure PCTCN2022082591-appb-000024
Figure PCTCN2022082591-appb-000025
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 1选自H和-NH 2，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 1 is selected from H and -NH 2 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和5元杂芳基，其中所述C 1-4烷基和5元杂芳基分别独立地任选被1、2、3或4个R a取代，R a及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and 5-membered heteroaryl, wherein the C 1 -4- alkyl and 5-membered heteroaryl are each independently optionally substituted with 1, 2, 3 or 4 R a , R a and other variables as defined herein.
本发明的一些方案中，上述R 2选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-CH 2CH 3、-CH 2CH(CH 3) 2和咪唑基，其中所述-CH 3、-CH 2CH 3、-CH 2CH(CH 3) 2和和咪唑基分别独立地任选被1、2、3或4个R a取代，R a及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 and imidazolyl, wherein the -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 and and imidazolyl are each independently optionally substituted with 1, 2, 3 or 4 R a , R a and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、-CN、-CH 3、-CH 2CH 3和-CH 2CH(CH 3) 2，其中所述-CH 3、-CH 2CH 3和-CH 2CH(CH 3) 2分别独立地任选被1、2、3或4个R a取代，R a及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is selected from H, F, -CN, -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 , wherein -CH 3 , -CH 2 CH 3 and -CH2CH( CH3 ) 2 are each independently optionally substituted with 1, 2 , 3 or 4 R a , R a and other variables as defined herein.
本发明的一些方案中，上述R 2选自H、F、-CN、-CH 3、-CH 2CH 3和-CH 2CH(CH 3) 2，其中所述-CH 3、-CH 2CH 3和-CH 2CH(CH 3) 2任选被1、2或3个R a取代，R a及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is selected from H, F, -CN, -CH 3 , -CH 2 CH 3 and -CH 2 CH(CH 3 ) 2 , wherein -CH 3 , -CH 2 CH 3 and -CH2CH( CH3 ) 2 are optionally substituted with 1, 2 or 3 R a , R a and other variables as defined herein.
本发明的一些方案中，上述R 2选自H、F、-CN、
Figure PCTCN2022082591-appb-000026
Figure PCTCN2022082591-appb-000027
R a及其他变量如本发明所定义。 In some schemes of the present invention, above-mentioned R 2 is selected from H, F, -CN,
Figure PCTCN2022082591-appb-000026
Figure PCTCN2022082591-appb-000027
Ra and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、-CN、
Figure PCTCN2022082591-appb-000028
R a及其他变量如本发明所定义。 In some schemes of the present invention, above-mentioned R 2 is selected from H, F, -CN,
Figure PCTCN2022082591-appb-000028
Ra and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、-CN、-CHF 2、-CF 3、
Figure PCTCN2022082591-appb-000029
Figure PCTCN2022082591-appb-000030
其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 ,
Figure PCTCN2022082591-appb-000029
Figure PCTCN2022082591-appb-000030
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、-CN、-CHF 2、-CF 3、
Figure PCTCN2022082591-appb-000031
Figure PCTCN2022082591-appb-000032
其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 ,
Figure PCTCN2022082591-appb-000031
Figure PCTCN2022082591-appb-000032
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 2选自H、F、-CN、-CF 3、
Figure PCTCN2022082591-appb-000033
其他变量如本发明所定义。 In some schemes of the present invention, the above R 2 is selected from H, F, -CN, -CF 3 ,
Figure PCTCN2022082591-appb-000033
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 3选自H、F和-CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 3 is selected from H, F and -CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 3选自H和F，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 3 is selected from H and F, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 4选自-CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 4 is selected from -CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 5选自H、F、Cl和Br，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 5 is selected from H, F, Cl and Br, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 5选自H，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 5 is selected from H, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 6选自H，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 6 is selected from H, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 7选自H、D、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷氧基，其中所述C 1-3烷氧基任选被1、2、或3个R f取代，R f及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkoxy, wherein the C 1-3 alkoxy Oxygen is optionally substituted with 1, 2, or 3 Rf , Rf and other variables as defined herein.
本发明的一些方案中，上述R 7选自H、D、F、Cl、Br、I和-OCH 3，其中所述-OCH 3任选被1、2、或3个R f取代，R f及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 is selected from H, D, F, Cl, Br, I and -OCH 3 , wherein the -OCH 3 is optionally substituted by 1, 2, or 3 R f , R f and other variables as defined herein.
本发明的一些方案中，上述R 7选自H、D、F、-OCH 3和-OCD 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 7 is selected from H, D, F, -OCH 3 and -OCD 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 8选自H、D、F、Cl和Br，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 8 is selected from H, D, F, Cl and Br, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 9选自H，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 9 is selected from H, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 10选自H和-NHCH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 10 is selected from H and -NHCH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述相邻碳原子上的两个R 7和与它们相连的碳原子一起形成5元杂环烷基，其中所述5元杂环烷基任选被1、2、3或4个R g取代，R g及其他变量如本发明所定义。 In some embodiments of the present invention, the two R 7 on the above adjacent carbon atoms and the carbon atoms to which they are attached together form a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is optionally composed of 1, 2, 3 or 4 Rg substitutions, Rg and other variables are as defined herein.
本发明的一些方案中，上述相邻碳原子上的两个R 7和与它们相连的碳原子一起形成
Figure PCTCN2022082591-appb-000034
其中所述
Figure PCTCN2022082591-appb-000035
任选被1、2、3或4个R g取代，R g及其他变量如本发明所定义。 In some embodiments of the present invention, the two R 7 on the above adjacent carbon atoms form together with the carbon atom to which they are attached.
Figure PCTCN2022082591-appb-000034
wherein the
Figure PCTCN2022082591-appb-000035
Optionally substituted with 1, 2, 3 or 4 Rg , Rg and other variables are as defined herein.
本发明的一些方案中，上述相邻碳原子上的两个R 7和与它们相连的碳原子一起形成
Figure PCTCN2022082591-appb-000036
Figure PCTCN2022082591-appb-000037
其他变量如本发明所定义。 In some embodiments of the present invention, the two R 7 on the above adjacent carbon atoms form together with the carbon atom to which they are attached.
Figure PCTCN2022082591-appb-000036
Figure PCTCN2022082591-appb-000037
Other variables are as defined in the present invention.
本发明的一些方案中，上述两个R 9和与它们相连的碳原子一起形成5元杂环烷基，其中所述5元杂环烷基任选被1、2、3或4个R h取代，R h及其他变量如本发明所定义。 In some embodiments of the present invention, the above two R 9 and the carbon atoms to which they are attached together form a 5-membered heterocycloalkyl, wherein the 5-membered heterocycloalkyl is optionally surrounded by 1, 2, 3 or 4 R h Substitution, Rh and other variables are as defined herein.
本发明的一些方案中，上述两个R 9和与它们相连的碳原子一起形成
Figure PCTCN2022082591-appb-000038
其中所述
Figure PCTCN2022082591-appb-000039
任选被1、2、3或4个R h取代，R h及其他变量如本发明所定义。 In some embodiments of the present invention, the above two R 9 and the carbon atoms to which they are attached together form
Figure PCTCN2022082591-appb-000038
wherein the
Figure PCTCN2022082591-appb-000039
Optionally substituted with 1, 2, 3 or 4 R h , R h and other variables as defined herein.
本发明的一些方案中，上述两个R 9和与它们相连的碳原子一起形成
Figure PCTCN2022082591-appb-000040
其他变量如本发明所定义。 In some embodiments of the present invention, the above two R 9 and the carbon atoms to which they are attached together form
Figure PCTCN2022082591-appb-000040
Other variables are as defined in the present invention.
本发明的一些方案中，上述结构单元
Figure PCTCN2022082591-appb-000041
选自
Figure PCTCN2022082591-appb-000042
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural units
Figure PCTCN2022082591-appb-000041
selected from
Figure PCTCN2022082591-appb-000042
Other variables are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(Ⅱ-3)、(Ⅱ-4)或(Ⅱ-5)所示结构：In some embodiments of the present invention, the above-mentioned compound has the structure represented by formula (II-3), (II-4) or (II-5):
Figure PCTCN2022082591-appb-000043
Figure PCTCN2022082591-appb-000043
其中，in,
n选自0和1；n is selected from 0 and 1;
R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8如本发明所定义。 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(Ⅱ-3A)、(Ⅱ-3B)、(Ⅱ-4A)、(Ⅱ-4B)、(Ⅱ-5A)或(Ⅱ-5B)所示结构：In some embodiments of the present invention, the above-mentioned compound has the structure represented by formula (II-3A), (II-3B), (II-4A), (II-4B), (II-5A) or (II-5B):
Figure PCTCN2022082591-appb-000044
Figure PCTCN2022082591-appb-000044
其中，in,
n选自0和1；n is selected from 0 and 1;
R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8如本发明所定义。 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(Ⅱ-6)、(Ⅱ-7)、(Ⅱ-8)或(Ⅱ-9)所示结构：In some embodiments of the present invention, the above-mentioned compound has the structure represented by formula (II-6), (II-7), (II-8) or (II-9):
Figure PCTCN2022082591-appb-000045
Figure PCTCN2022082591-appb-000045
其中，in,
n选自0和1；n is selected from 0 and 1;
环A选自4-6元杂环烷基；Ring A is selected from 4-6 membered heterocycloalkyl;
R 1、R 2、R 3、R 7、R 8、R 9、R 10和R g如本发明所定义。 R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 and R g are as defined in the present invention.
本发明的一些方案中，上述环A选自5元杂环烷基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned ring A is selected from 5-membered heterocycloalkyl, and other variables are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(Ⅱ-6A)、(Ⅱ-6B)、(Ⅱ-7A)、(Ⅱ-7B)、(Ⅱ-8A)、(Ⅱ-8B)、(Ⅱ-9A)或(Ⅱ-9B)所示结构：In some embodiments of the present invention, the above-mentioned compounds have formulae (II-6A), (II-6B), (II-7A), (II-7B), (II-8A), (II-8B), (II- 9A) or the structure shown in (Ⅱ-9B):
Figure PCTCN2022082591-appb-000046
Figure PCTCN2022082591-appb-000046
Figure PCTCN2022082591-appb-000047
Figure PCTCN2022082591-appb-000047
其中，in,
n选自0和1；n is selected from 0 and 1;
环A选自4-6元杂环烷基；Ring A is selected from 4-6 membered heterocycloalkyl;
R 1、R 2、R 3、R 7、R 8、R 9、R 10和R g如本发明所定义。 R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 and R g are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(I-3)所示结构：In some schemes of the present invention, the above-mentioned compound has the structure represented by formula (I-3):
Figure PCTCN2022082591-appb-000048
Figure PCTCN2022082591-appb-000048
其中，n、R 1、R 2和R 3如本发明所定义。 wherein n, R 1 , R 2 and R 3 are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(I-4)和(I-5)所示结构：In some schemes of the present invention, the above-mentioned compounds have structures represented by formulas (I-4) and (I-5):
Figure PCTCN2022082591-appb-000049
Figure PCTCN2022082591-appb-000049
其中，n、R 1、R 2和R 3如本发明所定义。 wherein n, R 1 , R 2 and R 3 are as defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are still some solutions of the present invention which are obtained by any combination of the above variables.
本发明还提供了下式化合物或其药学上可接受的盐，The present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022082591-appb-000050
Figure PCTCN2022082591-appb-000050
Figure PCTCN2022082591-appb-000051
Figure PCTCN2022082591-appb-000051
Figure PCTCN2022082591-appb-000052
Figure PCTCN2022082591-appb-000052
本发明还提供了下式化合物或其药学上可接受的盐，The present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022082591-appb-000053
Figure PCTCN2022082591-appb-000053
Figure PCTCN2022082591-appb-000054
Figure PCTCN2022082591-appb-000054
Figure PCTCN2022082591-appb-000055
Figure PCTCN2022082591-appb-000055
Figure PCTCN2022082591-appb-000056
Figure PCTCN2022082591-appb-000056
Figure PCTCN2022082591-appb-000057
Figure PCTCN2022082591-appb-000057
Figure PCTCN2022082591-appb-000058
Figure PCTCN2022082591-appb-000058
Figure PCTCN2022082591-appb-000059
Figure PCTCN2022082591-appb-000059
Figure PCTCN2022082591-appb-000060
Figure PCTCN2022082591-appb-000060
Figure PCTCN2022082591-appb-000061
Figure PCTCN2022082591-appb-000061
Figure PCTCN2022082591-appb-000062
Figure PCTCN2022082591-appb-000062
Figure PCTCN2022082591-appb-000063
Figure PCTCN2022082591-appb-000063
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗KRAS突变实体瘤疾病的药物中的应用。The present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicaments for treating KRAS mutant solid tumor diseases.
技术效果technical effect
本发明化合物具有良好的KRAS(G12C)-SOS1结合抑制活性，以及对KRAS(G12C)突变的H358细胞和DLD-1细胞p-ERK增殖具有显著的抑制活性，进而获得了优良的抑制肿瘤生长的活性。The compound of the present invention has good KRAS(G12C)-SOS1 binding inhibitory activity, and has significant inhibitory activity on the proliferation of KRAS(G12C) mutant H358 cells and DLD-1 cells p-ERK, thereby obtaining excellent tumor growth inhibitory activity. active.
定义和说明Definition and Explanation
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短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 and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
这里所采用的术语“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。As used herein, 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 excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2022082591-appb-000064
和楔形虚线键
Figure PCTCN2022082591-appb-000065
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022082591-appb-000066
和直形虚线键
Figure PCTCN2022082591-appb-000067
表示立体中心的相对构型，用波浪线
Figure PCTCN2022082591-appb-000068
表示楔形实线键
Figure PCTCN2022082591-appb-000069
或楔形虚线键
Figure PCTCN2022082591-appb-000070
或用波浪线
Figure PCTCN2022082591-appb-000071
表示直形实线键
Figure PCTCN2022082591-appb-000072
和直形虚线键
Figure PCTCN2022082591-appb-000073
Use solid wedge keys unless otherwise specified
Figure PCTCN2022082591-appb-000064
and wedge-dotted keys
Figure PCTCN2022082591-appb-000065
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2022082591-appb-000066
and straight dashed keys
Figure PCTCN2022082591-appb-000067
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022082591-appb-000068
Represents a solid wedge key
Figure PCTCN2022082591-appb-000069
or wedge-dotted key
Figure PCTCN2022082591-appb-000070
or with wavy lines
Figure PCTCN2022082591-appb-000071
Represents a straight solid key
Figure PCTCN2022082591-appb-000072
and straight dashed keys
Figure PCTCN2022082591-appb-000073
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the present invention may exist in particular. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％， 或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，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(即＝O)时，意味着两个氢原子被取代。氧取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, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
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0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022082591-appb-000074
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2022082591-appb-000075
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2022082591-appb-000076
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example,
Figure PCTCN2022082591-appb-000074
The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right.
Figure PCTCN2022082591-appb-000075
It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
Figure PCTCN2022082591-appb-000076
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022082591-appb-000077
直形虚线键
Figure PCTCN2022082591-appb-000078
或波浪线
Figure PCTCN2022082591-appb-000079
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2022082591-appb-000080
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2022082591-appb-000081
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连。
Figure PCTCN2022082591-appb-000082
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2022082591-appb-000083
Figure PCTCN2022082591-appb-000084
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022082591-appb-000085
仍包括
Figure PCTCN2022082591-appb-000086
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。 Unless otherwise specified, when a group has one or more attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. When the connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group. The chemical bond connecting the site to other groups can be represented by straight solid line bonds
Figure PCTCN2022082591-appb-000077
straight dotted key
Figure PCTCN2022082591-appb-000078
or wavy lines
Figure PCTCN2022082591-appb-000079
express. For example, a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
Figure PCTCN2022082591-appb-000080
The straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
Figure PCTCN2022082591-appb-000081
The wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
Figure PCTCN2022082591-appb-000082
Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2022082591-appb-000083
Figure PCTCN2022082591-appb-000084
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2022082591-appb-000085
still includes
Figure PCTCN2022082591-appb-000086
For the group in this connection mode, when one chemical bond is connected, the H at the site will be correspondingly reduced by one to become the corresponding monovalent piperidinyl group.
除非另有规定，术语“C 1-4烷基”用于表示直链或支链的由1至4个碳原子组成的饱和碳氢基团。所述C 1-4烷基包括C 1-2、C 1-3和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。 Unless otherwise specified, the term "C 1-4 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent ( such as methine). Examples of C 1-4 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl) and so on.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C 1-4烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C 1-4烷氧基包括C 1-3、C 1-2、C 2-4、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和 t-丁氧基)等。 Unless otherwise specified, the term " C1-4alkoxy " refers to those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-4 alkoxy group includes C 1-3 , C 1-2 , C 2-4 , C 4 and C 3 alkoxy and the like. Examples of C 1-6 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy) oxy, s-butoxy and t-butoxy) and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term " C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“C 1-4烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至4个碳原子的烷基基团。所述C 1-4烷氨基包括C 1-3、C 1-2、C 2-4、C 4、C 3和C 2烷氨基等。C 1-4烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-N(CH 2CH 3)(CH 2CH 3)、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2、-NHCH 2CH 2CH 2CH 3等。 Unless otherwise specified, the term "C 1-4 alkylamino" refers to those alkyl groups containing 1 to 4 carbon atoms attached to the remainder of the molecule through an amino group. The C 1-4 alkylamino includes C 1-3 , C 1-2 , C 2-4 , C 4 , C 3 and C 2 alkylamino and the like. Examples of C 1-4 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )( CH2CH3 ) , -NHCH2CH2CH3 , -NHCH2 ( CH3 ) 2 , -NHCH2CH2CH2CH3 , etc.
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。Unless otherwise specified, the term "halogen" or "halogen" by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
除非另有规定，术语“C 1-4卤代烷基”表示包含1至4个碳原子的单卤代烷基和多卤代烷基。所述C 1-4卤代烷基包括C 1-4、C 1-3、C 1-2、C 3-4、C 2-4、C 2-3、、C 4、C 3、C 2和C 1卤代烷基等。C 1-4卤代烷基的实例包括但不限于三氟甲基、三氯甲基、2,2,2-三氟乙基、五氟乙基、五氯乙基、3-溴丙基、4-氯丁基等。 Unless otherwise specified, the term "C 1-4 haloalkyl" refers to monohaloalkyl and polyhaloalkyl groups containing 1 to 4 carbon atoms. The C 1-4 haloalkyl includes C 1-4 , C 1-3 , C 1-2 , C 3-4 , C 2-4 , C 2-3 , C 4 , C 3 , C 2 and C 1 haloalkyl, etc. Examples of C 1-4 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl, 4 - Chlorobutyl etc.
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, "C 3-6 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which are monocyclic and bicyclic ring systems, said C 3-6 cycloalkyl including C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent. Examples of C3-6 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
除非另有规定，术语“3-6元杂环烷基”本身或者与其他术语联合分别表示由3至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-6元杂环烷基包括4-6元、5-6元、4元、5元和6元杂环烷基等。3-6元杂环烷基的实例包括但不限于环氮乙烷基、环氧乙烷基、环硫乙烷基、氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "3-6 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 3 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO and S(O) p , where p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings. Furthermore, with respect to the "3-6 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. The 3-6 membered heterocycloalkyl includes 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like. Examples of 3-6 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxiranyl, thioethane, azetidinyl, oxetanyl, thietanyl, Pyrrolidine, pyrazolidine, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydrofuranyl Hydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), Linyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2 -thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperidinyl, etc.
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基或六氢哒嗪基等。 Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO and S(O) p , where p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings. Furthermore, with respect to the "4-6 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl and the like.
除非另有规定，术语“5-6元杂环烷基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(＝O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-6元杂环烷基包括5元和6元杂环烷基。5-6元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基或六氢哒嗪基等。 Unless otherwise specified, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (i.e., C(=O), NO and S(=O) p , where p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings. Furthermore, with respect to the "5-6 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. The 5-6 membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl or hexahydropyridazinyl, etc.
除非另有规定，术语“5元杂环烷基”本身或者与其他术语联合分别表示由5个环原子组成的饱和单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(O) p，p是1或2)。此外，就该“5元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。5元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)或四氢呋喃基(包括四氢呋喃-2-基等)等。 Unless otherwise specified, the term "5-membered heterocycloalkyl" by itself or in combination with other terms respectively denotes a saturated monocyclic group consisting of 5 ring atoms, wherein 1, 2, 3 or 4 ring atoms are independently selected from O, S, and N heteroatoms, the remainder being carbon atoms, where the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms are optionally oxidized (ie, C(=O), NO, and S(O) ) p , where p is 1 or 2). Furthermore, with respect to the "5-membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. Examples of 5-membered heterocycloalkyl include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuran base (including tetrahydrofuran-2-yl, etc.) and the like.
除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(＝O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“5-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于
Figure PCTCN2022082591-appb-000087
Figure PCTCN2022082591-appb-000088
Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms respectively denotes a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond , whose 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen and sulfur heteroatoms can be optionally The choice is oxidized (ie C(=O), NO and S(=O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings, any ring of this system is non-aromatic. Furthermore, in the case of the "5-6 membered heterocycloalkenyl", a heteroatom may occupy the position of attachment of the heterocycloalkenyl to the rest of the molecule. The 5-6 membered heterocyclenyl includes 5-membered and 6-membered heterocyclenyl and the like. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
Figure PCTCN2022082591-appb-000087
Figure PCTCN2022082591-appb-000088
除非另有规定，术语“6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由6个环原子组成的部分不饱和的环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，碳、氮和硫杂原子可任选被氧化(即C(＝O)、NO和S(＝O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。5-6元杂环烯基的实例包括但不限于
Figure PCTCN2022082591-appb-000089
Unless otherwise specified, the term "6-membered heterocycloalkenyl" by itself or in combination with other terms respectively denotes a partially unsaturated cyclic group consisting of 6 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized and the carbon, nitrogen and sulfur heteroatoms are optionally oxidized ( Namely C(=O), NO and S(=O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings, any ring of this system is non-aromatic. Furthermore, in the case of the "6-membered heterocycloalkenyl", a heteroatom may occupy the position at which the heterocycloalkenyl is attached to the rest of the molecule. Examples of 5-6 membered heterocycloalkenyl include but are not limited to
Figure PCTCN2022082591-appb-000089
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示 由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2- -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，本发明术语“5元杂芳环”和“5元杂芳基”可以互换使用，术语“5元杂芳基”表示由5个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、***基(1H-1,2,3-***基、2H-1,2,3-***基、1H-1,2,4-***基和4H-1,2,4-***基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)。 Unless otherwise specified, the terms "5-membered heteroaryl ring" and "5-membered heteroaryl" can be used interchangeably in the present invention, and the term "5-membered heteroaryl" refers to a 5-membered ring atom having a conjugated π-electron system The monocyclic group of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. Examples of the 5-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.) etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5-oxazole) base, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1,2, 4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-isoxazolyl, etc.) -thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.).
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)，2-(三甲基硅)乙氧基甲基(SEM)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基 甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert-butyldiphenyl Methylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
本发明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发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in 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 embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022082591-appb-000090
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is:
Figure PCTCN2022082591-appb-000090
After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
本发明所使用的容积可经市售获得。The volumes used in the present invention are commercially available.
本发明采用下述缩略词：Alloc代表烯丙氧羰基；SEM代表三甲基硅烷基乙氧甲基；OTs代表4-甲苯磺酰基；Boc代表叔丁氧羰基；DCM代表二氯甲烷；DIEA代表N,N-二异丙基乙胺；MeI代表碘甲烷；PE代表石油醚；EA代表乙酸乙酯；THF代表四氢呋喃；EtOH代表乙醇；MeOH代表甲醇；Boc 2O代表二碳酸二叔丁酯；NH 4Cl代表氯化铵；T 3P代表1-丙基磷酸三环酸酐；Pd/C代表钯/碳催化剂；TMSN 3代表叠氮基三甲基硅烷；NCS代表N-氯代丁二酰亚胺；HBr代表氢溴酸；AcOH代表醋酸；HATU代表O-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；DBU代表1,8-二氮杂二环十一碳-7-烯；FA代表甲酸；ACN代表乙腈；TLC代表薄层色谱；HPLC代表高压液相色谱；LCMS代表液质联用色谱；SFC代表超临界流体色谱法；RT代表保留时间；DMSO代表二甲亚砜；DMSO-d 6代表氘代二甲亚砜；CD 3OD代表氘代甲醇；CDCl 3代表氘代氯仿；D 2O代表氘水。 The following abbreviations are used in the present invention: Alloc stands for allyloxycarbonyl; SEM stands for trimethylsilylethoxymethyl; OTs stands for 4-toluenesulfonyl; Boc stands for tert-butoxycarbonyl; DCM stands for dichloromethane; DIEA Represents N,N-diisopropylethylamine; MeI represents methyl iodide; PE represents petroleum ether; EA represents ethyl acetate; THF represents tetrahydrofuran; EtOH represents ethanol; MeOH represents methanol; Boc 2 O represents di-tert-butyl dicarbonate ; NH 4 Cl for ammonium chloride; T 3 P for 1-propylphosphoric acid tricyclic anhydride; Pd/C for palladium/carbon catalyst; TMSN 3 for azidotrimethylsilane; NCS for N-chlorobutanedi Imide; HBr for hydrobromic acid; AcOH for acetic acid; HATU for O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DBU stands for 1,8-diazabicycloundec-7-ene; FA stands for formic acid; ACN stands for acetonitrile; TLC stands for thin layer chromatography; HPLC stands for high pressure liquid chromatography; Critical fluid chromatography; RT stands for retention time; DMSO stands for dimethyl sulfoxide; DMSO-d 6 stands for deuterated dimethyl sulfoxide; CD 3 OD stands for deuterated methanol; CDCl 3 stands for deuterated chloroform; D 2 O stands for deuterated water .
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022082591-appb-000091
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to conventional nomenclature in the art or are used
Figure PCTCN2022082591-appb-000091
Software naming, commercially available compounds use supplier catalog names.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本发明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发明的实施例。对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in 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 embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
中间体AIntermediate A
Figure PCTCN2022082591-appb-000092
Figure PCTCN2022082591-appb-000092
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000093
Figure PCTCN2022082591-appb-000093
第一步first step
将化合物A-1(10.0g,42.5mmol)溶于二氯亚砜(30mL)中,加入N,N-二甲基甲酰胺(164μL,2.13mmol)。反应液在80℃搅拌反应3小时。向反应液中加入无水甲苯(100mL×2),减压浓缩后得到化合物A-2。Compound A-1 (10.0 g, 42.5 mmol) was dissolved in thionyl chloride (30 mL), and N,N-dimethylformamide (164 μL, 2.13 mmol) was added. The reaction solution was stirred and reacted at 80°C for 3 hours. Anhydrous toluene (100 mL×2) was added to the reaction solution, and compound A-2 was obtained after concentration under reduced pressure.
第二步second step
氮气保护下,将化合物A-3(15.2g,89.5mmol)溶于乙腈(100mL)中,0℃下依次加入三乙胺(14.6g,144mmol)和氯化镁(9.33g,98.0mmol),15℃下搅拌反应2小时。冷却至0℃,逐滴加入化合物A-2(10.8g,42.6mmol)的乙腈(50mL)溶液,15℃下搅拌反应12小时。在0℃下向反应液中加入稀盐酸(4M,100mL),分液后浓缩除去乙腈,水相用乙酸乙酯(150mL×2)萃取,有机相用饱和碳酸氢钠水溶液(200mL)及饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物A-4。MS-ESI计算值为[M-H] -304,实测值304。 Under nitrogen protection, compound A-3 (15.2 g, 89.5 mmol) was dissolved in acetonitrile (100 mL), triethylamine (14.6 g, 144 mmol) and magnesium chloride (9.33 g, 98.0 mmol) were added successively at 0 °C, and at 15 °C The reaction was stirred for 2 hours. After cooling to 0 °C, a solution of compound A-2 (10.8 g, 42.6 mmol) in acetonitrile (50 mL) was added dropwise, and the reaction was stirred at 15 °C for 12 hours. Dilute hydrochloric acid (4M, 100 mL) was added to the reaction solution at 0°C, the layers were separated and concentrated to remove acetonitrile, the aqueous phase was extracted with ethyl acetate (150 mL×2), and the organic phase was washed with saturated aqueous sodium bicarbonate (200 mL) and saturated Washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound A-4. The MS - ESI calculated value was [MH]-304, and the observed value was 304.
第三步third step
将化合物A-4(12.8g,41.9mmol)溶于乙酸(40mL)中,加入水(20mL)和浓硫酸(5mL),100℃下反应3小时。反应液浓缩除去乙酸,加入冰水(300mL),用乙酸乙酯(100mL×3)萃取,用饱和碳酸氢钠水溶液(100mL×2),氢氧化钠水溶液(2mol/L,100mL×2)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗产物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物A-5。MS-ESI计算值为[M-H] -232,实测值232。 Compound A-4 (12.8 g, 41.9 mmol) was dissolved in acetic acid (40 mL), water (20 mL) and concentrated sulfuric acid (5 mL) were added, and the reaction was carried out at 100° C. for 3 hours. The reaction solution was concentrated to remove acetic acid, ice water (300 mL) was added, extracted with ethyl acetate (100 mL×3), washed with saturated aqueous sodium bicarbonate solution (100 mL×2), aqueous sodium hydroxide solution (2mol/L, 100 mL×2) , dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound A-5. The MS-ESI calculated value was [MH] - 232, and the observed value was 232.
第四步the fourth step
将化合物A-5(8.00g,34.3mmol)溶于四氢呋喃(80mL)中,加入A-6(6.24g,51.5mmol)和钛酸四异丙酯(30.5g,85.8mmol,80％纯度),80℃下反应16小时。向反应液中加入水(300mL),过滤,滤液经无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～3/1,V/V)得到化合物A-7。MS-ESI计算值为[M+H] +337,实测值337。 Compound A-5 (8.00 g, 34.3 mmol) was dissolved in tetrahydrofuran (80 mL), A-6 (6.24 g, 51.5 mmol) and tetraisopropyl titanate (30.5 g, 85.8 mmol, 80% purity) were added, The reaction was carried out at 80°C for 16 hours. Water (300 mL) was added to the reaction solution, filtered, the filtrate was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1 , V/V) to obtain compound A-7. MS-ESI calculated [M+H] + 337, found 337.
第五步the fifth step
于-78℃下,将化合物A-7(8.00g,23.8mmol)溶于四氢呋喃(100mL)和水(2mL)中,加入硼氢化钠(1.80g,47.5mmol),20℃下反应1小时。向反应液中加入水(300mL),用乙酸乙酯(100mL×3)萃取,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,5/1～2/1,V/V)得到化合 物A-8。MS-ESI计算值为[M-H] -337,实测值337。 Compound A-7 (8.00 g, 23.8 mmol) was dissolved in tetrahydrofuran (100 mL) and water (2 mL) at -78 °C, sodium borohydride (1.80 g, 47.5 mmol) was added, and the reaction was carried out at 20 °C for 1 hour. Water (300 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) to obtain compound A-8. The MS-ESI calculated value was [MH] - 337, the observed value was 337.
第六步Step 6
将化合物A-8(5.50g,16.3mmol)溶于乙酸乙酯(10mL),加入氯化氢乙酸乙酯溶液(4M,50.0mL)。15℃反应1小时。减压浓缩后,加入二氯甲烷(50mL)搅拌,过滤,真空干燥得到化合物A-9。MS-ESI计算值为[M+H] +235,实测值235。 Compound A-8 (5.50 g, 16.3 mmol) was dissolved in ethyl acetate (10 mL), and a solution of hydrogen chloride in ethyl acetate (4 M, 50.0 mL) was added. The reaction was carried out at 15°C for 1 hour. After concentration under reduced pressure, dichloromethane (50 mL) was added, stirred, filtered, and dried in vacuo to obtain compound A-9. MS-ESI calculated [M+H] + 235, found 235.
第七步Step 7
将化合物A-9(3.50g,12.9mmol)溶于乙酸乙酯(70mL),加入钯碳(0.70g,10％纯度),15℃氢气(15Psi)气氛下反应2小时。过滤滤除钯碳,减压浓缩得到中间体A的盐酸盐。MS-ESI计算值为[M+H] +205,实测值205。 Compound A-9 (3.50 g, 12.9 mmol) was dissolved in ethyl acetate (70 mL), palladium carbon (0.70 g, 10% purity) was added, and the reaction was carried out at 15° C. under a hydrogen (15 Psi) atmosphere for 2 hours. The palladium carbon was filtered off and concentrated under reduced pressure to obtain the hydrochloride of intermediate A. MS-ESI calculated value was [M+H] + 205, found 205.
实施例1Example 1
Figure PCTCN2022082591-appb-000094
Figure PCTCN2022082591-appb-000094
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000095
Figure PCTCN2022082591-appb-000095
第一步first step
将化合物1-1(99.0g,469mmol)溶于乙腈(1500mL)中,向反应液中通入干燥的HCl气体,1小时后将反应液减压浓缩,剩余物溶于水(1500mL)中,用10％的碳酸氢钠溶液调pH值到8,过滤,滤饼干燥,得到化合物1-2。MS-ESI计算值[M+H] +221,实测值221。 Compound 1-1 (99.0 g, 469 mmol) was dissolved in acetonitrile (1500 mL), dry HCl gas was passed into the reaction solution, after 1 hour, the reaction solution was concentrated under reduced pressure, and the residue was dissolved in water (1500 mL), The pH value was adjusted to 8 with 10% sodium bicarbonate solution, filtered, and the filter cake was dried to obtain compound 1-2. MS-ESI calculated [M+H] + 221, found 221.
第二步second step
将化合物1-2(20.0g,90.8mmol)溶于甲基磺酸(150mL)中,加入L-蛋氨酸(20.3g,136mmol),在80℃下搅拌反应48小时。将反应液倒入冰水中,用4M的氢氧化钠溶液碱化pH至3,抽滤,将滤饼溶解在少量2M的氢氧化钠溶液中,用1M稀盐酸酸化pH至6,过滤,滤饼干燥,得到化合物1-3。 1H NMR(400MHz,DMSO-d 6)δ7.33(s,1H),7.01(s,1H),3.87(s,3H),2.28(s,3H)。MS-ESI计算值[M+H] +207,实测值207。 Compound 1-2 (20.0 g, 90.8 mmol) was dissolved in methanesulfonic acid (150 mL), L-methionine (20.3 g, 136 mmol) was added, and the reaction was stirred at 80° C. for 48 hours. Pour the reaction solution into ice water, basify pH to 3 with 4M sodium hydroxide solution, filter with suction, dissolve the filter cake in a small amount of 2M sodium hydroxide solution, acidify pH to 6 with 1M dilute hydrochloric acid, filter, filter The cake was dried to obtain compound 1-3. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.33 (s, 1H), 7.01 (s, 1H), 3.87 (s, 3H), 2.28 (s, 3H). MS-ESI calculated [M+H] + 207, found 207.
第三步third step
氮气保护下将化合物1-3(10.0g,48.5mmol)溶于二氯甲烷(150mL)中,然后在0℃下缓慢加入三溴化硼(28mL,388mmol),在25℃下搅拌反应48小时。反应液用饱和氯化铵溶液淬灭,过滤,剩余物经制备高效液相色谱法分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:1％-15％,10min)得到化合物1-4的盐酸盐。MS-ESI计算值[M+H] +193,实测值193。 Compound 1-3 (10.0 g, 48.5 mmol) was dissolved in dichloromethane (150 mL) under nitrogen protection, then boron tribromide (28 mL, 388 mmol) was slowly added at 0 °C, and the reaction was stirred at 25 °C for 48 hours . The reaction solution was quenched with saturated ammonium chloride solution, filtered, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile : 1%-15%, 10 min) to obtain the hydrochloride of compound 1-4. MS-ESI calculated [M+H] + 193, found 193.
第四步the fourth step
将化合物1-4的盐酸盐(0.80g,4.16mmol)和碳酸钾(2.30g,16.7mmol)溶于N,N-二甲基甲酰胺(15mL)中,再缓慢加入化合物1-5(1.91g,4.16mmol),在80℃下搅拌反应12小时。将反应液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Genimi NX C18 150mm×40mm×5μm；流动相:(0.04％氨水溶液和10mM碳酸氢铵水溶液)-乙腈；梯度:乙腈:1％-30％,10min)得到化合物1-6。 1H NMR(400MHz,CD 3OD)δ8.59(s,1H),8.01(s,1H),5.17-5.12(m,4H),4.81-4.77(m,2H),4.72-4.68(m,2H),4.19(s,7H)。MS-ESI计算值[M+H] +307,实测值307。 The hydrochloride salt of compound 1-4 (0.80 g, 4.16 mmol) and potassium carbonate (2.30 g, 16.7 mmol) were dissolved in N,N-dimethylformamide (15 mL), and then compound 1-5 ( 1.91 g, 4.16 mmol), and the reaction was stirred at 80 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Genimi NX C18 150mm×40mm×5μm; mobile phase: (0.04% aqueous ammonia solution and 10mM aqueous ammonium bicarbonate solution)-acetonitrile; gradient : acetonitrile: 1%-30%, 10 min) to obtain compound 1-6. 1 H NMR (400MHz, CD 3 OD) δ 8.59(s, 1H), 8.01(s, 1H), 5.17-5.12(m, 4H), 4.81-4.77(m, 2H), 4.72-4.68(m, 2H), 4.19(s, 7H). MS-ESI calculated [M+H] + 307, found 307.
第五步the fifth step
氮气保护下将化合物1-6(30.0mg,97.9μmol)和化合物1-7(44.5mg,147μmol)溶于二氯甲烷(5mL)中,加入4-二甲氨基吡啶(1.20mg,9.79μmol)和三乙胺(40.9μL,294μmol),在25℃下搅拌反应12小时。将反应液浓缩,剩余物经过薄层色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V)得到化合物1-8。 1H NMR(400MHz,CD 3Cl)δ7.57(s,1H),7.25(s,1H),7.18(s,2H),4.35-4.26(m,6H),3.96-3.92(m,2H),3.88-3.84(m,2H),3.79(s,4H),2.96-2.87(m,1H),2.50(s,3H),1.24(d,J＝4.0Hz,18H)。 Compound 1-6 (30.0 mg, 97.9 μmol) and compound 1-7 (44.5 mg, 147 μmol) were dissolved in dichloromethane (5 mL) under nitrogen protection, and 4-dimethylaminopyridine (1.20 mg, 9.79 μmol) was added. and triethylamine (40.9 μL, 294 μmol), and the reaction was stirred at 25 °C for 12 hours. The reaction solution was concentrated, and the residue was separated and purified by thin layer chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 1-8. 1 H NMR (400MHz, CD 3 Cl) δ 7.57(s, 1H), 7.25(s, 1H), 7.18(s, 2H), 4.35-4.26(m, 6H), 3.96-3.92(m, 2H) , 3.88-3.84(m, 2H), 3.79(s, 4H), 2.96-2.87(m, 1H), 2.50(s, 3H), 1.24(d, J=4.0Hz, 18H).
第六步Step 6
氮气保护下将化合物1-8(20.0mg,34.8μmol)和中间体A的盐酸盐(8.53mg,41.8μmol)溶于二甲基亚砜(2mL)中,滴加三乙胺(14.5μL,104μmol),在90℃下搅拌反应12小时。向反应液中加入水(5mL),用二氯甲烷/甲醇萃取(10/1,10mL×3),有机相用饱和食盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:24％-54％,9min)得到化合物1的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.22(s,1H),7.71(s,1H),7.65(s,1H),7.43(s,1H),7.14(s,1H),5.89-5.82(m,1H),4.36-4.32(m,4H),3.95-3.91(m,2H),3.88-3.84(m,2H),3.76(s,4H),2.63(s,3H),1.78(d,J＝8.0Hz,3H)。MS-ESI计算值[M+H] +439,实测值439。 Compound 1-8 (20.0 mg, 34.8 μmol) and intermediate A hydrochloride (8.53 mg, 41.8 μmol) were dissolved in dimethyl sulfoxide (2 mL) under nitrogen protection, and triethylamine (14.5 μL) was added dropwise. , 104 μmol), and the reaction was stirred at 90 °C for 12 h. Water (5 mL) was added to the reaction solution, extracted with dichloromethane/methanol (10/1, 10 mL×3), the organic phase was washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. Concentrated, the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×30mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 24%-54%, 9min) to obtain the compound 1 of the hydrochloride. 1 H NMR (400MHz, CD 3 OD) δ 8.22(s, 1H), 7.71(s, 1H), 7.65(s, 1H), 7.43(s, 1H), 7.14(s, 1H), 5.89-5.82 (m,1H),4.36-4.32(m,4H),3.95-3.91(m,2H),3.88-3.84(m,2H),3.76(s,4H),2.63(s,3H),1.78(d , J=8.0Hz, 3H). MS-ESI calculated [M+H] + 439, found 439.
实施例2Example 2
Figure PCTCN2022082591-appb-000096
Figure PCTCN2022082591-appb-000096
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000097
Figure PCTCN2022082591-appb-000097
第一步first step
氮气保护下将化合物1-2(1.00g,4.54mmol)和化合物1-7(2.06g,6.81mmol)溶于二氯甲烷(10mL)中,加入4-二甲氨基吡啶(55.5mg,454μmol)和三乙胺(2mL,13.6mmol),在25℃下搅拌反应12小时。将反应液浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,100/1～2/1,V/V)得到化合物2-1。 1H NMR(400MHz,DMSO-d 6)δ7.46(s,1H),7.08(s,1H),6.95(s,2H),4.61-4.54(m,2H),3.93(s,3H),3.90(s,3H),2.84-2.76(m,1H),2.49(s,3H),1.16-1.08(m,18H)。MS-ESI计算值[M+H] +487,实测值487。 Compound 1-2 (1.00 g, 4.54 mmol) and compound 1-7 (2.06 g, 6.81 mmol) were dissolved in dichloromethane (10 mL) under nitrogen protection, and 4-dimethylaminopyridine (55.5 mg, 454 μmol) was added. and triethylamine (2 mL, 13.6 mmol), and the reaction was stirred at 25 °C for 12 hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～2/1, V/V) to obtain compound 2-1. 1 H NMR (400MHz, DMSO-d 6 )δ7.46(s,1H), 7.08(s,1H), 6.95(s,2H), 4.61-4.54(m,2H), 3.93(s,3H), 3.90(s, 3H), 2.84-2.76(m, 1H), 2.49(s, 3H), 1.16-1.08(m, 18H). MS-ESI calculated [M+H] + 487, found 487.
第二步second step
氮气保护下将化合物2-1(1.30g,2.67mmol)和中间体A(771mg,3.78mmol)溶于二甲基亚砜(10mL)中,滴加三乙胺(1mL,8.01mmol),在90℃下搅拌反应12小时。向反应液中加入水(100mL),用二氯甲烷/甲醇(V/V,8:1,150mL×3)萃取,有机相用饱和食盐水(100mL×4)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～12/1,V/V)得到化合物2-2。1H NMR(400MHz,CD3OD)δ7.62(s,1H),7.02-6.97(m,3H),6.79(s,1H),5.61(q,J＝6.8Hz,1H),3.96(s,3H),3.93(s,3H),2.44(s,3H),1.63(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] +407,实测值407。 Compound 2-1 (1.30 g, 2.67 mmol) and Intermediate A (771 mg, 3.78 mmol) were dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, triethylamine (1 mL, 8.01 mmol) was added dropwise, and The reaction was stirred at 90°C for 12 hours. Water (100 mL) was added to the reaction solution, extracted with dichloromethane/methanol (V/V, 8:1, 150 mL×3), the organic phase was washed with saturated brine (100 mL×4), dried over anhydrous sodium sulfate, and filtered. , concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～12/1, V/V) to obtain compound 2-2. 1H NMR (400MHz, CD3OD)δ7.62( s, 1H), 7.02-6.97(m, 3H), 6.79(s, 1H), 5.61(q, J=6.8Hz, 1H), 3.96(s, 3H), 3.93(s, 3H), 2.44(s , 3H), 1.63 (d, J=7.2Hz, 3H). MS-ESI calculated [M+H] + 407, found 407.
第三步third step
氮气保护下将化合物2-2(1.00g,2.46mmol)溶于二氯甲烷(10mL)中,然后在0℃下缓慢加入三溴化硼(2mL,24.6mmol),在25℃下搅拌36小时。反应液用饱和氯化铵溶液淬灭,过滤,剩余物经过制备高效液相色谱法分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯 度:乙腈:6％-36％,10min)得到化合物2-3的盐酸盐。MS-ESI计算值[M+H] +379,实测值379。 Compound 2-2 (1.00 g, 2.46 mmol) was dissolved in dichloromethane (10 mL) under nitrogen protection, then boron tribromide (2 mL, 24.6 mmol) was slowly added at 0 °C, and the mixture was stirred at 25 °C for 36 hours . The reaction solution was quenched with saturated ammonium chloride solution, filtered, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile : 6%-36%, 10 min) to obtain the hydrochloride of compound 2-3. MS-ESI calculated [M+H] + 379, found 379.
第四步the fourth step
将化合物2-3的盐酸盐(200mg,443μmol)和碳酸钾(245mg,1.77mmol)溶于N,N-二甲基甲酰胺(15mL)中,再缓慢加入化合物2-4(183mg,443μmol),在80℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯萃取(30mL×4),有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:10％-40％,10min)得到化合物2的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.27(s,1H),7.77-7.62(m,2H),7.44(d,J＝12.0Hz,1H),7.13(s,1H),5.85(s,1H),4.43(s,2H),3.93(s,4H),2.60(s,3H),1.78(d,J＝8.0Hz,3H)。MS-ESI计算值[M+H] +449,实测值449。 The hydrochloride of compound 2-3 (200 mg, 443 μmol) and potassium carbonate (245 mg, 1.77 mmol) were dissolved in N,N-dimethylformamide (15 mL), and then compound 2-4 (183 mg, 443 μmol) was slowly added ), and the reaction was stirred at 80 °C for 12 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×4), the organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was prepared by High performance liquid chromatography separation and purification (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% hydrochloric acid aqueous solution-acetonitrile; gradient: acetonitrile: 10%-40%, 10min) to obtain the hydrochloride of compound 2. 1 H NMR (400MHz, CD 3 OD) δ 8.27(s, 1H), 7.77-7.62(m, 2H), 7.44(d, J=12.0Hz, 1H), 7.13(s, 1H), 5.85(s , 1H), 4.43(s, 2H), 3.93(s, 4H), 2.60(s, 3H), 1.78(d, J=8.0Hz, 3H). MS-ESI calculated [M+H] + 449, found 449.
实施例3Example 3
Figure PCTCN2022082591-appb-000098
Figure PCTCN2022082591-appb-000098
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000099
Figure PCTCN2022082591-appb-000099
第一步first step
氮气保护下将化合物3-1(1.00g,5.00mmol)溶于甲苯(2mL)中,再加入化合物3-2(3.61g,10.0mmol)和双三苯基膦二氯化钯(351mg,0.50mmol),在120℃下搅拌反应12小时。向反应液中加入饱和氟化钾溶液(10mL),用乙酸乙酯(5mL×2)萃取,过滤,减压浓缩,得到化合物3-3。Under nitrogen protection, compound 3-1 (1.00 g, 5.00 mmol) was dissolved in toluene (2 mL), and then compound 3-2 (3.61 g, 10.0 mmol) and bistriphenylphosphine palladium dichloride (351 mg, 0.50 mmol) were added. mmol), and the reaction was stirred at 120 °C for 12 h. Saturated potassium fluoride solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL×2), filtered, and concentrated under reduced pressure to obtain compound 3-3.
第二步second step
氮气保护下将化合物3-3(950mg,4.97mmol)溶于丙酮(30mL)中,然后在0℃下逐滴加入盐酸溶液(12M,3.31mL),在25℃下搅拌反应1小时。用饱和碳酸氢钠溶液碱化pH至8,用乙酸乙酯萃取(30mL×2), 有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离纯化得到化合物3-4。Compound 3-3 (950 mg, 4.97 mmol) was dissolved in acetone (30 mL) under nitrogen protection, then hydrochloric acid solution (12 M, 3.31 mL) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 1 hour. The pH was adjusted to 8 with saturated sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), the organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel Column chromatography (petroleum ether/ethyl acetate, 100/1～10/1, V/V) was used for separation and purification to obtain compound 3-4.
第三步third step
将化合物3-4(736mg,4.51mmol)溶于四氢呋喃(15mL)中,加入A-6(820mg,6.77mmol)和钛酸乙酯(3.09g,13.5mmol),在80℃下搅拌反应14小时。在-5℃下向反应液中加入硼氢化钠(171mg,4.51mmol),然后在25℃下搅拌反应1小时。将反应液倒入冰水中,过滤,用乙酸乙酯萃取(10mL×2),有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离纯化得到化合物3-5。MS-ESI计算值[M+H] +269,实测值269。 Compound 3-4 (736 mg, 4.51 mmol) was dissolved in tetrahydrofuran (15 mL), A-6 (820 mg, 6.77 mmol) and ethyl titanate (3.09 g, 13.5 mmol) were added, and the reaction was stirred at 80 °C for 14 hours . Sodium borohydride (171 mg, 4.51 mmol) was added to the reaction solution at -5°C, and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into ice water, filtered, extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography Method (petroleum ether/ethyl acetate, 100/1～1/1, V/V) separation and purification to obtain compound 3-5. MS-ESI calculated [M+H] + 269, found 269.
第四步the fourth step
将化合物3-5(910mg,3.39mmol)溶于二氧六环(8mL)中,加入氯化氢二氧六环溶液(4mol/L,3.73mL),在25℃下搅拌反应6小时。反应液减压浓缩,剩余物用乙酸乙酯(2mL)洗涤,得到化合物3-6的盐酸盐。MS-ESI计算值[M+H] +165,实测值165。 Compound 3-5 (910 mg, 3.39 mmol) was dissolved in dioxane (8 mL), hydrogen chloride dioxane solution (4 mol/L, 3.73 mL) was added, and the reaction was stirred at 25° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate (2 mL) to obtain the hydrochloride salt of compound 3-6. MS-ESI calculated [M+H] + 165, found 165.
第五步the fifth step
氮气保护下将化合物1-8(200mg,348μmol)和化合物3-6的盐酸盐(83.8mg,418μmol)溶于二甲基亚砜(20mL)中,滴加三乙胺(145μL,1.04mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷/甲醇萃取(V/V,10/1,30mL×3),有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:16％-46％,9min)得到化合物3的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.93(s,1H),7.75(dt,J＝4.0,8.0Hz,1H),7.64-7.58(m,1H),7.27(t,J＝8.0Hz,1H),7.10(s,1H),5.77(q,J＝8.0Hz,1H),4.32-4.24(m,4H),3.93-3.89(m,2H),3.87-3.83(m,2H),3.80-3.75(m,4H),2.39(s,3H),1.67(d,J＝4.0Hz,3H)。MS-ESI计算值[M+H] +453,实测值453。 Compound 1-8 (200 mg, 348 μmol) and compound 3-6 hydrochloride (83.8 mg, 418 μmol) were dissolved in dimethyl sulfoxide (20 mL) under nitrogen protection, and triethylamine (145 μL, 1.04 mmol) was added dropwise. ), and the reaction was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution, extracted with dichloromethane/methanol (V/V, 10/1, 30 mL×3), the organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, Filtered, concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×30mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 16%-46%, 9 min) to obtain the hydrochloride salt of compound 3. 1 H NMR (400MHz, CD 3 OD) δ 7.93 (s, 1H), 7.75 (dt, J=4.0, 8.0Hz, 1H), 7.64-7.58 (m, 1H), 7.27 (t, J=8.0Hz) ,1H),7.10(s,1H),5.77(q,J＝8.0Hz,1H),4.32-4.24(m,4H),3.93-3.89(m,2H),3.87-3.83(m,2H), 3.80-3.75(m, 4H), 2.39(s, 3H), 1.67(d, J=4.0Hz, 3H). MS-ESI calculated [M+H] + 453, found 453.
实施例4Example 4
Figure PCTCN2022082591-appb-000100
Figure PCTCN2022082591-appb-000100
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000101
Figure PCTCN2022082591-appb-000101
第一步first step
将化合物4-1(600mg,4.13mmol)溶于四氢呋喃(10mL)中,加入A-6(751mg,6.20mmol)和钛酸乙酯(2.83g,12.4mmol),在80℃下搅拌反应16小时。在-5℃下向反应液中加入硼氢化钠(156mg,4.13mmol),然后在25℃下搅拌反应1小时。将反应液倒入冰水中,过滤,滤液用乙酸乙酯(5mL×2)萃取,有机相用饱和食盐水(5mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离纯化得到化合物4-2。MS-ESI计算值[M+H] +251,实测值251。 Compound 4-1 (600 mg, 4.13 mmol) was dissolved in tetrahydrofuran (10 mL), A-6 (751 mg, 6.20 mmol) and ethyl titanate (2.83 g, 12.4 mmol) were added, and the reaction was stirred at 80 °C for 16 hours . Sodium borohydride (156 mg, 4.13 mmol) was added to the reaction solution at -5°C, and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into ice water, filtered, the filtrate was extracted with ethyl acetate (5 mL×2), the organic phase was washed with saturated brine (5 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) was used for separation and purification to obtain compound 4-2. MS-ESI calculated [M+H] + 251, found 251.
第二步second step
将化合物4-2(500mg,2.00mmol)溶于二氧六环(8mL)中,加入氯化氢二氧六环溶液(4mol/L,2mL),在25℃搅拌反应6小时。反应液减压浓缩,剩余物用乙酸乙酯(2mL)洗涤，得到化合物4-3的盐酸盐。MS-ESI计算值[M+H] +147,实测值147。 Compound 4-2 (500 mg, 2.00 mmol) was dissolved in dioxane (8 mL), hydrogen chloride dioxane solution (4 mol/L, 2 mL) was added, and the reaction was stirred at 25° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethyl acetate (2 mL) to obtain the hydrochloride salt of compound 4-3. MS-ESI calculated [M+H] + 147, found 147.
第三步third step
氮气保护下将化合物1-8(200mg,348μmol)和化合物4-3的盐酸盐(83.8mg,418μmol)溶于二甲基亚砜(10mL)中,滴加三乙胺(145μL,1.04mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷/甲醇(10:1,30mL×3)萃取,有机相用饱和食盐水(100mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×40mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:28％-58％,9min)得到化合物4的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.16(s,1H),7.85(s,1H),7.81(d,J＝8.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.58-7.53(m,1H),7.14(s,1H),5.87-5.79(m,1H),4.35-4.31(m,4H),3.95-3.90(m,2H),3.88-3.83(m,2H),3.76(s,4H),2.62(s,3H),1.75(d,J＝7.0Hz,3H)。MS-ESI计算值[M+H] +435实测值435。 Compound 1-8 (200 mg, 348 μmol) and compound 4-3 hydrochloride (83.8 mg, 418 μmol) were dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and triethylamine (145 μL, 1.04 mmol) was added dropwise. ), and the reaction was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution, extracted with dichloromethane/methanol (10:1, 30 mL×3), the organic phase was washed with saturated brine (100 mL×2), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. The concentrated residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×40mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 28%-58%, 9min) to obtain The hydrochloride salt of compound 4. 1 H NMR (400MHz, CD 3 OD) δ 8.16(s, 1H), 7.85(s, 1H), 7.81(d, J=8.0Hz, 1H), 7.65(d, J=8.0Hz, 1H), 7.58-7.53(m, 1H), 7.14(s, 1H), 5.87-5.79(m, 1H), 4.35-4.31(m, 4H), 3.95-3.90(m, 2H), 3.88-3.83(m, 2H ), 3.76(s, 4H), 2.62(s, 3H), 1.75(d, J=7.0Hz, 3H). MS-ESI calculated [M+H] + 435 found 435.
实施例5Example 5
Figure PCTCN2022082591-appb-000102
Figure PCTCN2022082591-appb-000102
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000103
Figure PCTCN2022082591-appb-000103
Figure PCTCN2022082591-appb-000104
Figure PCTCN2022082591-appb-000104
第一步first step
将化合物5-2(3.37g,16.6mmol)溶于二甲亚砜(20mL)中,加入铜粉(1.06g,16.6mmol),在25℃下搅拌反应1小时,向反应液中加入化合物5-1(2.00g,6.65mmol),70℃下搅拌反应12小时。将反应液倒入20mL冰水中,加入乙酸乙酯(20mL),过滤,滤液用乙酸乙酯(20mL×3)萃取。有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,1/0～20/1,V/V)分离纯化得到化合物5-3。 1H NMR(400MHz,CD 3Cl)δ7.75-7.68(m,1H),7.64-7.57(m,1H),7.16(t,J＝8.0Hz,1H),4.38(q,J＝8.0Hz,2H),1.34(t,J＝8.0Hz,3H)。 Compound 5-2 (3.37 g, 16.6 mmol) was dissolved in dimethyl sulfoxide (20 mL), copper powder (1.06 g, 16.6 mmol) was added, and the reaction was stirred at 25 ° C for 1 hour, and compound 5 was added to the reaction solution. -1 (2.00 g, 6.65 mmol), the reaction was stirred at 70°C for 12 hours. The reaction solution was poured into 20 mL of ice water, ethyl acetate (20 mL) was added, filtered, and the filtrate was extracted with ethyl acetate (20 mL×3). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 1/0～20/1, V/ V) separation and purification to obtain compound 5-3. 1 H NMR (400MHz, CD 3 Cl) δ 7.75-7.68 (m, 1H), 7.64-7.57 (m, 1H), 7.16 (t, J=8.0Hz, 1H), 4.38 (q, J=8.0Hz , 2H), 1.34 (t, J=8.0Hz, 3H).
第二步second step
氮气保护下将化合物5-3(677mg,1.82mmol)溶于甲苯(10mL)中,0℃下加入化合物5-4(2.43mL,3mol/L的四氢呋喃溶液),反应液在25℃下搅拌反应2小时。加入饱和氯化铵溶液(10mL)淬灭，用乙酸乙酯(10mL×2)萃取,有机相用饱和食盐水(10mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,1/0～10/1,V/V)分离纯化得到化合物5-5。 1H NMR(400MHz,CD 3Cl)δ7.66(t,J＝6.4Hz,1H),7.51-7.34(m,1H),7.16-6.93(m,1H),2.01(s,1H),1.35(s,6H)。 Compound 5-3 (677 mg, 1.82 mmol) was dissolved in toluene (10 mL) under nitrogen protection, compound 5-4 (2.43 mL, 3 mol/L tetrahydrofuran solution) was added at 0 °C, and the reaction solution was stirred at 25 °C. 2 hours. Saturated ammonium chloride solution (10 mL) was added to quench, extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue Compound 5-5 was obtained by separation and purification by silica gel column chromatography (petroleum ether/ethyl acetate, 1/0～10/1, V/V). 1 H NMR (400 MHz, CD 3 Cl) δ 7.66 (t, J=6.4 Hz, 1H), 7.51-7.34 (m, 1H), 7.16-6.93 (m, 1H), 2.01 (s, 1H), 1.35 (s, 6H).
第三步third step
氮气保护下将化合物5-5(441mg,1.56mmol)溶于甲苯(5mL)中,加入化合物3-2(1.87g,5.19mmol)和双三苯基磷二氯化钯(109mg,0.16mmol),反应液在120℃下搅拌反应12小时。加入饱和氟化钾溶液(20mL)淬灭,用乙酸乙酯(15mL×2)萃取。过滤,减压浓缩得化合物5-6。Under nitrogen protection, compound 5-5 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), and compound 3-2 (1.87 g, 5.19 mmol) and bistriphenylphosphonium palladium dichloride (109 mg, 0.16 mmol) were added. , the reaction solution was stirred at 120 ° C for 12 hours. Saturated potassium fluoride solution (20 mL) was added to quench, and extracted with ethyl acetate (15 mL×2). Filter and concentrate under reduced pressure to obtain compound 5-6.
第四步the fourth step
氮气保护下将化合物5-6(425mg,1.55mmol)溶于丙酮(10mL)中,0℃下逐滴加入盐酸溶液(12M,1.03mL),在25℃下搅拌反应1小时。加入饱和碳酸氢钠溶液碱化至pH＝8,用乙酸乙酯(10mL)萃取。有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～4/1,V/V)分离纯化得到化合物5-7。MS-ESI计算值[M+H] +247,实测值247。 Compound 5-6 (425 mg, 1.55 mmol) was dissolved in acetone (10 mL) under nitrogen protection, hydrochloric acid solution (12 M, 1.03 mL) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 1 hour. Saturated sodium bicarbonate solution was added to basify to pH=8, and extracted with ethyl acetate (10 mL). The organic phase was washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～4/1, V/ V) separation and purification to obtain compound 5-7. MS-ESI calculated [M+H] + 247, found 247.
第五步the fifth step
在25℃下将化合物5-7(346mg,1.41mmol)溶于四氢呋喃(5mL)中,加入A-6(511mg,4.22mmol)和 四乙氧基钛(2.00g,7.03mmol)。反应液在80℃搅拌反应36小时。然后在-5℃下向反应液降中加入硼氢化钠(64.0mg,1.69mmol),在25℃下搅拌反应1小时。将反应液倒入冰水中,过滤,滤液用乙酸乙酯(5mL×2)萃取。有机相用饱和食盐水(5mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,2/1～0/1,V/V)分离纯化得到化合物5-8。MS-ESI计算值[M+H] +352,实测值352。 Compound 5-7 (346 mg, 1.41 mmol) was dissolved in tetrahydrofuran (5 mL) at 25°C, A-6 (511 mg, 4.22 mmol) and tetraethoxytitanium (2.00 g, 7.03 mmol) were added. The reaction solution was stirred at 80°C for 36 hours. Then, sodium borohydride (64.0 mg, 1.69 mmol) was added to the reaction drop at -5°C, and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into ice water, filtered, and the filtrate was extracted with ethyl acetate (5 mL×2). The organic phase was washed with saturated brine (5 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 2/1～0/1, V /V) separation and purification to obtain compound 5-8. MS-ESI calculated [M+H] + 352, found 352.
第六步Step 6
将化合物5-8(366mg,1.04mmol)溶于二氧六环(3mL)中,加入氯化氢二氧六环溶液(4mol/L,1.15mL),反应液在25℃搅拌反应6小时。反应液减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,1/0～8/1,V/V)分离纯化得到化合物5-9的盐酸盐。MS-ESI计算值[M+H] +248,实测值248。 Compound 5-8 (366 mg, 1.04 mmol) was dissolved in dioxane (3 mL), hydrogen chloride dioxane solution (4 mol/L, 1.15 mL) was added, and the reaction solution was stirred at 25° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-8/1, V/V) to obtain the hydrochloride of compound 5-9. MS-ESI calculated [M+H] + 248, found 248.
第七步Step 7
氮气保护下将化合物1-8(67.5mg,117μmol)和化合物5-9的盐酸盐(50.0mg,176μmol)溶于二甲基亚砜(10mL)中,滴加N,N-二异丙基乙胺(61.4μL,352μmol),在90℃下搅拌反应12小时。向反应液中加入水(50mL),用二氯甲烷/甲醇(V/V,10/1,50mL×3)萃取,有机相用饱和食盐水(200mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经SFC(色谱柱:DAICEL CHIRALPAK IC 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液:30％-30％)分离得到化合物5。化合物5经高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×40mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:28％-58％,9min)得到化合物5的盐酸盐。化合物5经SFC(色谱柱:Chiralcel AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％),测e.e.值。e.e.％＝99.88％,RT＝4.832min, 1H NMR(400MHz,CD 3OD)δ8.16(s,1H),7.63-7.57(m,1H),7.46-7.39(m,1H),7.27-7.20(m,1H),7.11(s,1H),5.04-5.96(m,1H),4.37-4.30(m,4H),3.96-3.90(m,2H),3.88-3.83(m,2H),3.79-3.73(m,4H),2.59(s,3H),1.75(d,J＝7.2Hz,3H),1.29(s,6H)。MS-ESI计算值[M+H] +536,实测值536。 Compound 1-8 (67.5 mg, 117 μmol) and compound 5-9 hydrochloride (50.0 mg, 176 μmol) were dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and N,N-diisopropyl was added dropwise. Ethylamine (61.4 μL, 352 μmol), and the reaction was stirred at 90 °C for 12 hours. Water (50 mL) was added to the reaction solution, extracted with dichloromethane/methanol (V/V, 10/1, 50 mL×3), the organic phase was washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate, The residue after filtration and concentration under reduced pressure was filtered through SFC (chromatographic column: DAICEL CHIRALPAK IC 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of ammonia water: 30% -30%) was isolated to give compound 5. Compound 5 was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×40mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 28%-58%, 9min) to obtain the salt of compound 5 acid salt. Compound 5 was subjected to SFC (chromatographic column: Chiralcel AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%), measure ee value. ee%=99.88%, RT=4.832min, 1 H NMR (400MHz, CD 3 OD) δ 8.16(s, 1H), 7.63-7.57(m, 1H), 7.46-7.39(m, 1H), 7.27- 7.20(m, 1H), 7.11(s, 1H), 5.04-5.96(m, 1H), 4.37-4.30(m, 4H), 3.96-3.90(m, 2H), 3.88-3.83(m, 2H), 3.79-3.73(m, 4H), 2.59(s, 3H), 1.75(d, J=7.2Hz, 3H), 1.29(s, 6H). MS-ESI calculated [M+H] + 536, found 536.
实施例6Example 6
Figure PCTCN2022082591-appb-000105
Figure PCTCN2022082591-appb-000105
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000106
Figure PCTCN2022082591-appb-000106
Figure PCTCN2022082591-appb-000107
Figure PCTCN2022082591-appb-000107
第一步first step
将化合物6-1(5.00g,43.1mmol)溶于二氯甲烷(50mL)中,0℃下加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(12.4g,64.6mmol),三乙胺(6.54g,64.6mmol),4-二甲氨基吡啶(52.6mg,0.43mmol)和二甲羟胺盐酸盐(6.30g,64.6mmol),反应液在25℃搅拌反应16小时。加入1M盐酸溶液(20mL),用二氯甲烷(50mL×2)萃取。有机相用饱和碳酸氢钠溶液(50mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,4/1～0/1,V/V)分离纯化得到化合物6-2。MS-ESI计算值[M+H] +160,实测值160。 Compound 6-1 (5.00 g, 43.1 mmol) was dissolved in dichloromethane (50 mL), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride ( 12.4g, 64.6mmol), triethylamine (6.54g, 64.6mmol), 4-dimethylaminopyridine (52.6mg, 0.43mmol) and dimethylhydroxylamine hydrochloride (6.30g, 64.6mmol), the reaction solution was at 25 The reaction was stirred for 16 hours. 1M hydrochloric acid solution (20 mL) was added and extracted with dichloromethane (50 mL×2). The organic phase was washed with saturated sodium bicarbonate solution (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 4/1～0/1, V/V) separation and purification to obtain compound 6-2. MS-ESI calculated [M+H] + 160, found 160.
第二步second step
将化合物6-3(2.33g,9.86mmol)溶于四氢呋喃(20.0mL)中,-78℃下加入正丁基锂的四氢呋喃溶液(2.5mol/L,4.74mL),反应液在-78℃下搅拌反应30分钟。加入化合物6-2(1.76g,9.86mmol)的四氢呋喃(20mL)溶液,反应液在25℃搅拌反应3小时。加入饱和氯化铵溶液(20mL)淬灭，用乙酸乙酯(30mL×2)萃取。有机相用饱和食盐水(30mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,1/0～10/1,V/V)分离纯化得到化合物6-4。MS-ESI计算值[M+H] +255,实测值255。 Compound 6-3 (2.33 g, 9.86 mmol) was dissolved in tetrahydrofuran (20.0 mL), a solution of n-butyllithium in tetrahydrofuran (2.5 mol/L, 4.74 mL) was added at -78 °C, and the reaction solution was heated at -78 °C The reaction was stirred for 30 minutes. A solution of compound 6-2 (1.76 g, 9.86 mmol) in tetrahydrofuran (20 mL) was added, and the reaction solution was stirred at 25° C. for 3 hours. It was quenched by adding saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL×2). The organic phase was washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 1/0～10/1, V/ V) separation and purification to obtain compound 6-4. MS-ESI calculated [M+H] + 255, found 255.
第三步third step
将化合物6-4(1.6g,6.27mmol)溶于二氯甲烷(20mL)中,0℃下加入二乙胺基三氟化硫(3.03g,18.8mmol),反应液在25℃搅拌反应48小时。将反应液倒入20mL冰水中,用乙酸乙酯(20mL×2)萃取。有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离纯化得到化合物6-5。 1H NMR(400MHz,CD 3Cl)δ7.69(s,1H),7.58(d,J＝8.0Hz,1H),7.47(d,J＝8.0Hz,1H),7.34-7.28(m,1H),4.31(m,1H),3.84(t,J＝6.8Hz,2H),2.09-1.995(m,2H),1.90-1.81(m,2H)。 Compound 6-4 (1.6 g, 6.27 mmol) was dissolved in dichloromethane (20 mL), diethylaminosulfur trifluoride (3.03 g, 18.8 mmol) was added at 0 °C, and the reaction solution was stirred at 25 °C for reaction 48 Hour. The reaction solution was poured into 20 mL of ice water, and extracted with ethyl acetate (20 mL×2). The organic phase was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～10/1, V/ V) separation and purification to obtain compound 6-5. 1 H NMR (400MHz, CD 3 Cl) δ 7.69 (s, 1H), 7.58 (d, J=8.0 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.34-7.28 (m, 1H) ), 4.31(m, 1H), 3.84(t, J=6.8Hz, 2H), 2.09-1.995(m, 2H), 1.90-1.81(m, 2H).
第四步the fourth step
氮气保护下将化合物6-5(1.35g,4.87mmol)溶于甲苯(10mL)中,加入3-2(586g,16.2mmol)和双三苯基磷二氯化钯(342mg,0.49mmol),反应液在120℃下搅拌反应12小时。加入饱和氟化钾溶液(20mL)淬灭反应,用乙酸乙酯(15mL×2)萃取。过滤,减压浓缩得化合物6-6。Under nitrogen protection, compound 6-5 (1.35 g, 4.87 mmol) was dissolved in toluene (10 mL), 3-2 (586 g, 16.2 mmol) and bistriphenylphosphonium palladium dichloride (342 mg, 0.49 mmol) were added, The reaction solution was stirred and reacted at 120°C for 12 hours. Saturated potassium fluoride solution (20 mL) was added to quench the reaction and extracted with ethyl acetate (15 mL×2). Filter and concentrate under reduced pressure to obtain compound 6-6.
第五步the fifth step
在氮气保护下，将化合物6-6(1.3g,4.85mmol)溶于丙酮(30mL)中,0℃下逐滴加入盐酸溶液(12M,3.23mL),在25℃搅拌反应1小时,用饱和碳酸氢钠溶液碱化pH至8,用乙酸乙酯(30mL)萃取。有机相用饱和食盐水(30mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离纯化得到化合物6-7。MS-ESI计算值[M+H] +241,实测值241。 Under nitrogen protection, compound 6-6 (1.3 g, 4.85 mmol) was dissolved in acetone (30 mL), hydrochloric acid solution (12 M, 3.23 mL) was added dropwise at 0 °C, the reaction was stirred at 25 °C for 1 hour, and saturated The sodium bicarbonate solution was basified to pH 8 and extracted with ethyl acetate (30 mL). The organic phase was washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～10/1, V/ V) separation and purification to obtain compound 6-7. MS-ESI calculated [M+H] + 241, found 241.
第六步Step 6
在25℃下将化合物6-7(828mg,3.45mmol)溶于四氢呋喃(10mL)中,加入A-6(627mg,5.17mmol)和四乙基氧钛(2.94g,10.4mmol)。反应液在80℃搅拌反应32小时,然后在-5℃下向反应液中加入硼氢化钠(156mg,4.14mmol),在25℃下搅拌反应1小时。将反应液倒入冰水中,过滤,滤液用乙酸乙酯(10mL×2)萃取。有机相用饱和食盐水(10mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,2/1～1/2,V/V)分离纯化得到化合物6-8。MS-ESI计算值[M+H] +346,实测值346。 Compound 6-7 (828 mg, 3.45 mmol) was dissolved in tetrahydrofuran (10 mL) at 25°C, A-6 (627 mg, 5.17 mmol) and tetraethoxytitanium (2.94 g, 10.4 mmol) were added. The reaction solution was stirred at 80°C for 32 hours, then sodium borohydride (156 mg, 4.14 mmol) was added to the reaction solution at -5°C, and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into ice water, filtered, and the filtrate was extracted with ethyl acetate (10 mL×2). The organic phase was washed with saturated brine (10 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 2/1～1/2, V/ V) separation and purification to obtain compound 6-8. MS-ESI calculated [M+H] + 346, found 346.
第七步Step 7
将化合物6-8(988mg,2.86mmol)溶于二氧六环(7mL)中,加入氯化氢二氧六环溶液(4mol/L,3.15mL),反应液在25℃下搅拌反应6小时。反应液减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,1/0～10/1,V/V)分离纯化得到化合物6-9的盐酸盐。MS-ESI计算值[M+H] +242,实测值242。 Compound 6-8 (988 mg, 2.86 mmol) was dissolved in dioxane (7 mL), hydrogen chloride dioxane solution (4 mol/L, 3.15 mL) was added, and the reaction solution was stirred at 25 °C for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-10/1, V/V) to obtain the hydrochloride of compound 6-9. MS-ESI calculated [M+H] + 242, found 242.
第七步Step 7
氮气保护下将化合物1-8(64.8mg,113μmol)和化合物6-9的盐酸盐(40.8mg,169μmol)溶于二甲基亚砜(10mL)中,滴加N,N-二异丙基乙胺(58.9μL,338μmol),在90℃下搅拌反应12小时。向反应液中加入水(50mL),用二氯甲烷/甲醇(V/V,10/1,50mL×3)萃取,有机相用饱和食盐水(200mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Gemini-NX80mm×30mm×3μm；流动相:10mM碳酸氢铵水溶液-乙腈；梯度:乙腈:37％-67％,9min)得到粗产品，粗产品再经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:31％-61％,9min)得到化合物6的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.14(d,J＝4.0Hz,1H),7.68-7.57(m,2H),7.46-7.41(m,2H),7.12(s,1H),5.88-5.81(m,1H),4.41-4.27(m,5H),3.97-3.90(m,2H),3.89-3.82(m,2H),3.80-3.60(m,6H),2.62(s,3H),2.07-1.92(m,2H),1.86-1.64(m,5H)。MS-ESI计算值[M+H] +530实测值530。 Compound 1-8 (64.8 mg, 113 μmol) and compound 6-9 hydrochloride (40.8 mg, 169 μmol) were dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and N,N-diisopropyl was added dropwise. Ethylethylamine (58.9 μL, 338 μmol), and the reaction was stirred at 90 °C for 12 hours. Water (50 mL) was added to the reaction solution, extracted with dichloromethane/methanol (V/V, 10/1, 50 mL×3), the organic phase was washed with saturated brine (200 mL×2), dried over anhydrous sodium sulfate, The residue after filtration and concentration under reduced pressure was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80mm×30mm×3μm; mobile phase: 10mM aqueous ammonium bicarbonate solution-acetonitrile; gradient: acetonitrile: 37%-67% , 9min) to obtain the crude product, and the crude product was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×30mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 31%-61 %, 9 min) to obtain the hydrochloride of compound 6. 1 H NMR (400 MHz, CD 3 OD) δ 8.14 (d, J=4.0 Hz, 1H), 7.68-7.57 (m, 2H), 7.46-7.41 (m, 2H), 7.12 (s, 1H), 5.88 -5.81(m,1H),4.41-4.27(m,5H),3.97-3.90(m,2H),3.89-3.82(m,2H),3.80-3.60(m,6H),2.62(s,3H) , 2.07-1.92 (m, 2H), 1.86-1.64 (m, 5H). MS-ESI calculated [M+H] + 530 found 530.
实施例7Example 7
Figure PCTCN2022082591-appb-000108
Figure PCTCN2022082591-appb-000108
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000109
Figure PCTCN2022082591-appb-000109
将化合物1(70.0mg,142μmol)溶于二氯甲烷(1mL)中,加入7-1(14.5mg,142μmol)和三乙胺(15.8mg,156μmol),在25℃下搅拌反应12小时。将反应液减压浓缩,经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈26％-56％,9min)得到化合物7的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.16(s,1H),8.03(s,1H),7.79(s,1H),7.50(s,1H),7.13(s,1H),5.82(q,J＝6.8Hz,1H),4.38-4.27(m,4H),3.96-3.89(m,2H),3.87-3.80(m,2H),3.77-3.69(m,4H),2.63(s,3H),2.13(s,3H),1.75(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +535,实测值535。 Compound 1 (70.0 mg, 142 μmol) was dissolved in dichloromethane (1 mL), 7-1 (14.5 mg, 142 μmol) and triethylamine (15.8 mg, 156 μmol) were added, and the reaction was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure, separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×30mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile 26%-56%, 9min) The hydrochloride salt of compound 7 was obtained. 1 H NMR (400MHz, CD 3 OD) δ 8.16(s, 1H), 8.03(s, 1H), 7.79(s, 1H), 7.50(s, 1H), 7.13(s, 1H), 5.82(q , J=6.8Hz, 1H), 4.38-4.27(m, 4H), 3.96-3.89(m, 2H), 3.87-3.80(m, 2H), 3.77-3.69(m, 4H), 2.63(s, 3H ), 2.13(s, 3H), 1.75(d, J=6.8Hz, 3H). MS-ESI calculated [M+H] + 535, found 535.
实施例8Example 8
Figure PCTCN2022082591-appb-000110
Figure PCTCN2022082591-appb-000110
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000111
Figure PCTCN2022082591-appb-000111
将化合物1(100mg,203μmol)溶于N,N-二甲基甲酰胺(2mL)中,加入8-1(63.4mg,609μmol),N,N,N′,N′-四甲基-O-(7-氮杂苯并***-1-基)六氟磷酸脲(232mg,609μmol)和三乙胺(61.6mg,609μmol)。反应液在31℃下搅拌反应12小时。反应液经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:17％-41％,10min)得到化合物8的盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ14.46(s,1H),9.99(s,1H),8.39(s,1H),8.29-8.08(m,2H),7.55(s,1H),7.25(s,1H),5.82-5.70(m,1H),4.49-4.23(m,4H),3.80-3.62(m,8H),2.58(s,3H),1.79-1.56(m,3H),1.34(s,6H)。MS-ESI计算值[M+H] +579,实测值579。 Compound 1 (100 mg, 203 μmol) was dissolved in N,N-dimethylformamide (2 mL), and 8-1 (63.4 mg, 609 μmol), N,N,N′,N′-tetramethyl-O was added. -(7-Azabenzotriazol-1-yl)urea hexafluorophosphate (232 mg, 609 μmol) and triethylamine (61.6 mg, 609 μmol). The reaction solution was stirred at 31°C for 12 hours. The reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 17%-41%, 10min) to obtain the salt of compound 8 acid salt. 1 H NMR (400MHz, DMSO-d 6 )δ14.46(s,1H), 9.99(s,1H), 8.39(s,1H), 8.29-8.08(m,2H), 7.55(s,1H), 7.25(s, 1H), 5.82-5.70(m, 1H), 4.49-4.23(m, 4H), 3.80-3.62(m, 8H), 2.58(s, 3H), 1.79-1.56(m, 3H), 1.34(s, 6H). MS-ESI calculated [M+H] + 579, found 579.
实施例9Example 9
Figure PCTCN2022082591-appb-000112
Figure PCTCN2022082591-appb-000112
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000113
Figure PCTCN2022082591-appb-000113
第一步first step
将化合物9-1(2.14g,8.01mmol)溶于四氢呋喃(25mL)中,加入A-6(2.91g,24.0mmol)和四乙氧基钛(9.14g,40.1mmol),反应在80℃下搅拌反应12小时,过滤,减压浓缩得粗产品化合物9-2,直接用于下一步反应。MS-ESI计算值[M+H] +370,实测值370。 Compound 9-1 (2.14 g, 8.01 mmol) was dissolved in tetrahydrofuran (25 mL), A-6 (2.91 g, 24.0 mmol) and tetraethoxytitanium (9.14 g, 40.1 mmol) were added, and the reaction was carried out at 80 °C The reaction was stirred for 12 hours, filtered, and concentrated under reduced pressure to obtain the crude product compound 9-2, which was directly used in the next reaction. MS-ESI calculated [M+H] + 370, found 370.
第二步second step
将化合物9-2(2.97g,8.02mmol)溶于四氢呋喃(30mL)中,在-5℃下向反应液中加入硼氢化钠(364mg,9.63mmol),然后在25℃下搅拌反应1小时。将反应液倒入冰水中,过滤,滤液用乙酸乙酯萃取(30mL×2),有机相用饱和食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,30/1～5/1,V/V)分离纯化得到化合物9-3。MS-ESI计算值[M+H] +372,实测值372。 Compound 9-2 (2.97 g, 8.02 mmol) was dissolved in tetrahydrofuran (30 mL), sodium borohydride (364 mg, 9.63 mmol) was added to the reaction solution at -5°C, and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into ice water, filtered, the filtrate was extracted with ethyl acetate (30 mL×2), the organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was passed through a silica gel column Chromatography (petroleum ether/ethyl acetate, 30/1～5/1, V/V) was used for separation and purification to obtain compound 9-3. MS-ESI calculated [M+H] + 372, found 372.
第三步third step
将化合物9-3(2.48g,6.66mmol)溶于二氧六环(14mL)中,加入氯化氢二氧六环溶液(4mol/L,7.33mL),在25℃下搅反应6小时。反应液减压浓缩,剩余物用二氯甲烷(10mL)洗涤,得到化合物9-4的盐酸盐。化合物9-4经SFC(色谱柱:ChiralPak AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的甲醇溶液；梯度:甲醇:5％-40％)测e.e.值。e.e.％＝100.00％,RT＝1.500min。MS-ESI计算值[M+H] +268,实测值268。 Compound 9-3 (2.48 g, 6.66 mmol) was dissolved in dioxane (14 mL), hydrogen chloride dioxane solution (4 mol/L, 7.33 mL) was added, and the reaction was stirred at 25° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and the residue was washed with dichloromethane (10 mL) to obtain the hydrochloride salt of compound 9-4. Compound 9-4 was determined by SFC (chromatographic column: ChiralPak AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in methanol; gradient: methanol: 5%-40%) value. ee%=100.00%, RT=1.500min. MS-ESI calculated [M+H] + 268, found 268.
第四步the fourth step
在氮气保护下，将化合物1-8(784mg,1.37mmol)溶于二甲亚砜(5mL)中,加入9-4(500mg,1.64mmol)和N,N-二异丙基乙胺(1.77g,13.7mmol),反应液在90℃下搅拌反应12小时。向反应液中加入水(5mL),用乙酸乙酯(5mL×3)萃取,有机相用饱和食盐水(5mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Welch Xtimate C18 150mm×25mm×5μm；流动相:10mM的碳酸氢铵水溶液-乙腈；梯度:乙腈:50％-80％,9min)得到化合物9-5的盐酸盐。MS-ESI计算值[M+H] +556,实测值556。 Under nitrogen protection, compound 1-8 (784 mg, 1.37 mmol) was dissolved in dimethyl sulfoxide (5 mL), 9-4 (500 mg, 1.64 mmol) and N,N-diisopropylethylamine (1.77 g g, 13.7 mmol), the reaction solution was stirred at 90 °C for 12 hours. Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL×3), the organic phase was washed with saturated brine (5 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was prepared by High performance liquid chromatography separation and purification (chromatographic column: Welch Xtimate C18 150mm×25mm×5μm; mobile phase: 10mM aqueous ammonium bicarbonate solution-acetonitrile; gradient: acetonitrile: 50%-80%, 9min) to obtain the salt of compound 9-5 acid salt. MS-ESI calculated [M+H] + 556, found 556.
第五步the fifth step
氮气保护下，将化合物9-5(60.0mg,108μmol)溶于二甲亚砜(1mL)中,加入化合物9-6(93.9mg,1.08mmol),碘化亚铜(10.3mg,53.9μmol),碳酸钾(29.8mg,216μmol)和L-脯氨酸(12.4mg,108μmol),反应液在120℃下搅拌反应12小时。反应液经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:26％-56％,9min)得到化合物9的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.17(s,1H),7.14(s,1H),7.02(s,1H),6.94(s,1H),6.70(s,1H),5.79(q,J＝6.8Hz,1H),4.58-4.53(m,1H),4.36-4.30(m,4H),3.93-3.88(m,2H),3.87-3.82(s,2H),3.77-3.72(m,4H),3.56-3.38(m,3H),3.27-3.21(m,1H),2.64(s,3H),2.23-2.03(m,2H),1.74(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +563,实测值563。 Under nitrogen protection, compound 9-5 (60.0 mg, 108 μmol) was dissolved in dimethyl sulfoxide (1 mL), compound 9-6 (93.9 mg, 1.08 mmol), cuprous iodide (10.3 mg, 53.9 μmol) were added. , potassium carbonate (29.8mg, 216μmol) and L-proline (12.4mg, 108μmol), the reaction solution was stirred at 120 ° C for 12 hours. The reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×30mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile: 26%-56%, 9min) to obtain compound 9. Hydrochloride. 1 H NMR (400MHz, CD 3 OD) δ 8.17(s, 1H), 7.14(s, 1H), 7.02(s, 1H), 6.94(s, 1H), 6.70(s, 1H), 5.79(q , J=6.8Hz, 1H), 4.58-4.53(m, 1H), 4.36-4.30(m, 4H), 3.93-3.88(m, 2H), 3.87-3.82(s, 2H), 3.77-3.72(m , 4H), 3.56-3.38(m, 3H), 3.27-3.21(m, 1H), 2.64(s, 3H), 2.23-2.03(m, 2H), 1.74(d, J=6.8Hz, 3H). MS-ESI calculated [M+H] + 563, found 563.
实施例10Example 10
Figure PCTCN2022082591-appb-000114
Figure PCTCN2022082591-appb-000114
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000115
Figure PCTCN2022082591-appb-000115
第一步first step
将化合物9-5(180mg,324μmol)溶于二氯甲烷(9mL),N,N-二甲基甲酰胺(3mL)和三乙胺(3mL)中,加入1,1-双(二苯基磷)二茂铁氯化钯(23.7mg,32.4μmol),反应液在一氧化碳气体氛围(45psi)下,80℃搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×5)萃取,有机相用饱和食盐水(50mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～5/1,V/V)分离纯化得到化合物10-1。MS-ESI计算值[M+H] +535,实测值536。 Compound 9-5 (180 mg, 324 μmol) was dissolved in dichloromethane (9 mL), N,N-dimethylformamide (3 mL) and triethylamine (3 mL), and 1,1-bis(diphenyl) was added. Phosphorus) ferrocene palladium chloride (23.7 mg, 32.4 μmol), the reaction solution was stirred at 80° C. for 12 hours under a carbon monoxide gas atmosphere (45 psi). Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×5), the organic phase was washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel Column chromatography (dichloromethane/methanol, 100/1～5/1, V/V) was used for separation and purification to obtain compound 10-1. MS-ESI calculated [M+H] + 535, found 536.
第二步second step
氮气保护下将化合物10-1(160mg,299μmol)溶于无水甲苯(10mL)中,0℃下滴加甲基溴化镁的四氢呋喃溶液(3M,399μL),在25℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经高效液相色谱分离纯化(色谱柱:Welch Xtimate C18 150×25mm×5μm；流动相:10mM的碳酸氢铵；梯度:乙腈47％-77％,9min)得到化合物10。化合物10经SFC(色谱柱:Chiralcel AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。e.e.％＝100％,RT＝3.300min。 1H NMR(400MHz,CD 3OD)δ7.87(s,1H),7.85(s,1H),7.65(s,1H),7.63(s,1H),7.09(s,1H),5.67(q,J＝7.2Hz,1H),4.31-4.23(m,4H),3.93-3.88(m,2H),3.86-3.82(m,2H),3.80-3.75(m,4H),2.43(s,3H),1.68(d,J＝7.2Hz,3H),1.54(s,3H),1.52(s,3H)。MS-ESI计算值[M+H] +535,实测值536。 Compound 10-1 (160 mg, 299 μmol) was dissolved in anhydrous toluene (10 mL) under nitrogen protection, a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 399 μL) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 12 hours . Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Chromatographic separation and purification (chromatographic column: Welch Xtimate C18 150×25 mm×5 μm; mobile phase: 10 mM ammonium bicarbonate; gradient: acetonitrile 47%-77%, 9 min) to obtain compound 10. Compound 10 was subjected to SFC (chromatographic column: Chiralcel AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. ee%=100%, RT=3.300min. 1 H NMR (400MHz, CD 3 OD) δ 7.87(s, 1H), 7.85(s, 1H), 7.65(s, 1H), 7.63(s, 1H), 7.09(s, 1H), 5.67(q , J=7.2Hz, 1H), 4.31-4.23(m, 4H), 3.93-3.88(m, 2H), 3.86-3.82(m, 2H), 3.80-3.75(m, 4H), 2.43(s, 3H) ), 1.68(d, J=7.2Hz, 3H), 1.54(s, 3H), 1.52(s, 3H). MS-ESI calculated [M+H] + 535, found 536.
实施例11Example 11
Figure PCTCN2022082591-appb-000116
Figure PCTCN2022082591-appb-000116
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000117
Figure PCTCN2022082591-appb-000117
第一步first step
将化合物5-5(50.0mg,177μmol)溶于四氢呋喃(1mL)中,0℃下加入氢化钠(14.1mg,353μmol,60％纯度),随后加入碘甲烷(50.1mg,353μmol),反应液在25℃搅拌反应12小时。将反应液倒入冰水(2mL)中,用乙酸乙酯(2mL×2)萃取。有机相用饱和食盐水(1mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～10/1,V/V)分离纯化得到化合物11-1。 1H NMR(400MHz,CD 3Cl)δ7.64(t,J＝6.8Hz,1H),7.40(t,J＝6.8Hz,1H),7.07(t,J＝7.8Hz,1H),3.32(s,3H),1.32(s,6H)。 Compound 5-5 (50.0 mg, 177 μmol) was dissolved in tetrahydrofuran (1 mL), sodium hydride (14.1 mg, 353 μmol, 60% purity) was added at 0° C., followed by methyl iodide (50.1 mg, 353 μmol), and the reaction solution was The reaction was stirred at 25°C for 12 hours. The reaction solution was poured into ice water (2 mL) and extracted with ethyl acetate (2 mL×2). The organic phase was washed with saturated brine (1 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 1/0～10/1, V /V) separation and purification to obtain compound 11-1. 1 H NMR (400 MHz, CD 3 Cl) δ 7.64 (t, J=6.8 Hz, 1H), 7.40 (t, J=6.8 Hz, 1H), 7.07 (t, J=7.8 Hz, 1H), 3.32 ( s, 3H), 1.32 (s, 6H).
第二步second step
氮气保护下，将化合物11-1(344mg,970μmol)溶于甲苯(5mL)中,加入3-2(701mg,1.94mmol)和双三苯基磷二氯化钯(68.1mg,97.0μmol),反应液在120℃搅拌反应7小时。加入饱和氟化钾溶液(5mL)淬灭,用乙酸乙酯(5mL×2)萃取。有机相用无水硫酸钠干燥,过滤,减压浓缩得化合物11-2。Under nitrogen protection, compound 11-1 (344 mg, 970 μmol) was dissolved in toluene (5 mL), 3-2 (701 mg, 1.94 mmol) and bistriphenylphosphonium palladium dichloride (68.1 mg, 97.0 μmol) were added, The reaction solution was stirred and reacted at 120°C for 7 hours. Saturated potassium fluoride solution (5 mL) was added to quench, and it was extracted with ethyl acetate (5 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 11-2.
第三步third step
氮气保护下，将化合物11-2(270mg,937μmol)溶于丙酮(6mL)中,0℃下逐滴加入盐酸溶液(12M,624μL),在25℃搅拌反应1小时,用饱和碳酸氢钠溶液碱化pH至8,用乙酸乙酯(6mL×3)萃取。有机相用饱和食盐水(6mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,20/1～4/1,V/V)分离纯化得到化合物11-3。 1H NMR(400MHz,CD 3Cl)δ7.99-7.89(m,1H),7.70-7.58(m,1H),7.24(s,1H),3.32(s,3H),2.67(d,J＝5.2Hz,3H),1.34(s,6H)。 Under nitrogen protection, compound 11-2 (270 mg, 937 μmol) was dissolved in acetone (6 mL), hydrochloric acid solution (12 M, 624 μL) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 1 hour. The pH was basified to 8 and extracted with ethyl acetate (6 mL×3). The organic phase was washed with saturated brine (6 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～4/1, V /V) separation and purification to obtain compound 11-3. 1 H NMR (400MHz, CD 3 Cl) δ 7.99-7.89(m, 1H), 7.70-7.58(m, 1H), 7.24(s, 1H), 3.32(s, 3H), 2.67(d, J= 5.2Hz, 3H), 1.34 (s, 6H).
第四步the fourth step
将化合物11-3(240mg,922μmol)溶于四氢呋喃(5mL)中,加入化合物A-6(335mg,2.77mmol)和钛酸四乙酯(1.05g,4.61mmol),在80℃下搅拌反应12小时后。过滤,减压浓缩得粗产品化合物11-4,直接用于下一步反应。MS-ESI计算值[M+H] +364,实测值364。 Compound 11-3 (240 mg, 922 μmol) was dissolved in tetrahydrofuran (5 mL), compound A-6 (335 mg, 2.77 mmol) and tetraethyl titanate (1.05 g, 4.61 mmol) were added, and the reaction was stirred at 80 °C for 12 hours later. Filtration and concentration under reduced pressure gave the crude product compound 11-4, which was directly used in the next reaction. MS-ESI calculated [M+H] + 364, found 364.
第五步the fifth step
将化合物11-4(335mg,922μmol)溶于四氢呋喃(1mL)中,在-5℃下加入硼氢化钠(41.8mg,1.11mmol),在25℃下搅拌反应1小时。向反应液中加入水(1mL),用乙酸乙酯(1mL×2)萃取,有机相用饱和食盐水(1mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,5/1～2/1,V/V)分离纯化得到化合物11-5。MS-ESI计算值[M+H] +366,实测值366。 Compound 11-4 (335 mg, 922 μmol) was dissolved in tetrahydrofuran (1 mL), sodium borohydride (41.8 mg, 1.11 mmol) was added at -5°C, and the reaction was stirred at 25°C for 1 hour. Water (1 mL) was added to the reaction solution, extracted with ethyl acetate (1 mL×2), the organic phase was washed with saturated brine (1 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel Column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) was used for separation and purification to obtain compound 11-5. MS-ESI calculated [M+H] + 366, found 366.
第六步Step 6
将化合物11-5(315mg,862μmol)溶于二氧六环(4mL)中,加入氯化氢二氧六环溶液(4mol/L,948μL)。反应液在25℃下搅拌反应8小时。反应液减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到化合物11-6的盐酸盐。MS-ESI计算值[M+H] +262,实测值262。 Compound 11-5 (315 mg, 862 μmol) was dissolved in dioxane (4 mL), and a solution of hydrogen chloride in dioxane (4 mol/L, 948 μL) was added. The reaction solution was stirred and reacted at 25°C for 8 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain the hydrochloride of compound 11-6. MS-ESI calculated [M+H] + 262, found 262.
第七步Step 7
氮气保护下，将化合物11-6的盐酸盐(263mg,459μmol)溶于二甲亚砜(1mL)中,加入1-8(144mg,551μmol)和N,N-二异丙基乙胺(890mg,6.89mmol)。反应液在90℃搅拌反应12小时,过滤,用甲醇(1mL)洗涤得到化合物11。化合物11经SFC(色谱柱:Chiralcel OD-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。e.e.％＝100％,RT＝2.984min。 1H NMR(400MHz,CD 3OD)δ8.22(s,1H),7.63(s,1H),7.35-7.01(m,3H),6.15-5.87(m,1H), 4.50-4.25(m,4H),4.01-3.67(m,8H),3.30(s,3H),2.61(s,3H),1.77(s,3H),1.31(s,6H)。MS-ESI计算值[M+H] +550,实测值550。 Under nitrogen protection, the hydrochloride salt of compound 11-6 (263 mg, 459 μmol) was dissolved in dimethyl sulfoxide (1 mL), 1-8 (144 mg, 551 μmol) and N,N-diisopropylethylamine ( 890 mg, 6.89 mmol). The reaction solution was stirred at 90 °C for 12 hours, filtered, and washed with methanol (1 mL) to obtain compound 11. Compound 11 was subjected to SFC (chromatographic column: Chiralcel OD-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. ee%=100%, RT=2.984min. 1 H NMR (400MHz, CD 3 OD) δ 8.22(s, 1H), 7.63(s, 1H), 7.35-7.01(m, 3H), 6.15-5.87(m, 1H), 4.50-4.25(m, 4H), 4.01-3.67(m, 8H), 3.30(s, 3H), 2.61(s, 3H), 1.77(s, 3H), 1.31(s, 6H). MS-ESI calculated [M+H] + 550, found 550.
实施例12Example 12
Figure PCTCN2022082591-appb-000118
Figure PCTCN2022082591-appb-000118
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000119
Figure PCTCN2022082591-appb-000119
第一步first step
氮气保护下,将9-5(200mg,359μmol)溶于二氧六环/水溶液(V/V,4/1,1.25mL)中,加入12-1(167mg,539μmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(26.3mg,35.9μmol)和磷酸钾(153mg,719μmol)。反应液在80℃搅拌反应12小时。将反应液倒入2mL水中,用乙酸乙酯(2mL×3)萃取。有机相用饱和食盐水(2mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,40/1～10/1,V/V)分离纯化得到化合物12-2。MS-ESI计算值[M+H] +659,实测值659。 Under nitrogen protection, 9-5 (200mg, 359μmol) was dissolved in dioxane/water solution (V/V, 4/1, 1.25mL), 12-1 (167mg, 539μmol), [1,1' - bis(diphenylphosphino)ferrocene]palladium dichloride (26.3 mg, 35.9 μmol) and potassium phosphate (153 mg, 719 μmol). The reaction solution was stirred and reacted at 80°C for 12 hours. The reaction solution was poured into 2 mL of water, and extracted with ethyl acetate (2 mL×3). The organic phase was washed with saturated brine (2 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (dichloromethane/methanol, 40/1～10/1, V/ V) separation and purification to obtain compound 12-2. MS-ESI calculated [M+H] + 659, found 659.
第二步second step
将化合物12-2(60.0mg,91.1μmol)溶于乙酸乙酯(1mL)中,加入氯化氢乙酸乙酯溶液(4mol/L,2mL),在25℃搅拌反应2小时。反应液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈14％-44％,9min)得到化合物12的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.21(s,1H),7.92(s,1H),7.76(s,1H),7.67(s,1H),7.14(s,1H),6.29(s,1H),5.93-5.82(m,1H),4.40-4.25(m,4H),3.98-3.81(m,6H),3.80-3.70(m,4H),3.49(t,J＝5.6Hz,2H),2.90-2.75(m,2H),2.62(s,3H),1.78(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] +559,实测值559。 Compound 12-2 (60.0 mg, 91.1 μmol) was dissolved in ethyl acetate (1 mL), hydrogen chloride ethyl acetate solution (4 mol/L, 2 mL) was added, and the reaction was stirred at 25° C. for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150 × 30 mm × 4 μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile 14%-44%, 9min ) to give compound 12 as the hydrochloride salt. 1 H NMR (400MHz, CD 3 OD) δ 8.21(s, 1H), 7.92(s, 1H), 7.76(s, 1H), 7.67(s, 1H), 7.14(s, 1H), 6.29(s ,1H),5.93-5.82(m,1H),4.40-4.25(m,4H),3.98-3.81(m,6H),3.80-3.70(m,4H),3.49(t,J=5.6Hz,2H ), 2.90-2.75(m, 2H), 2.62(s, 3H), 1.78(d, J=7.2Hz, 3H). MS-ESI calculated [M+H] + 559, found 559.
实施例13Example 13
Figure PCTCN2022082591-appb-000120
Figure PCTCN2022082591-appb-000120
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000121
Figure PCTCN2022082591-appb-000121
氮气保护下将化合物9-5(120mg,216μmol)溶于N,N-二甲基甲酰胺(5mL)中,加入氰化锌(50.1mg,431μmol),2-二环己基磷-2,4,6-三异丙基联苯(20.6mg,43.1μmol),三(二亚苄基丙酮)二钯(19.7mg,21.6μmol),在90℃下搅拌反应6小时。将反应液过滤,滤液中加入乙酸乙酯(20mL),有机相用饱和食盐水(50mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex Genimi NX C18 150×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈15％-45％,10min)得到化合物13的盐酸盐。化合物13经SFC(色谱柱:Chiralcel IC-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值,e.e.％＝100％,RT＝3.346min。 1H NMR(400MHz,CD 3OD)δ8.18-8.09(m,3H),8.04(s,1H),7.13(s,1H),5.84(q,J＝7.2Hz,1H),4.37-4.30(s,4H),3.97-3.91(m,2H),3.88-3.84(m,2H),3.78-3.74(m,4H),2.61(s,3H),1.78(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] +503,实测值503。 Under nitrogen protection, compound 9-5 (120 mg, 216 μmol) was dissolved in N,N-dimethylformamide (5 mL), zinc cyanide (50.1 mg, 431 μmol), 2-dicyclohexylphosphorus-2,4 were added. , 6-triisopropylbiphenyl (20.6 mg, 43.1 μmol), tris(dibenzylideneacetone)dipalladium (19.7 mg, 21.6 μmol), and the reaction was stirred at 90° C. for 6 hours. The reaction solution was filtered, ethyl acetate (20 mL) was added to the filtrate, the organic phase was washed with saturated brine (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Genimi NX C18 150×40 mm×5 μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile 15%-45%, 10 min) to obtain the hydrochloride salt of compound 13. Compound 13 was subjected to SFC (chromatographic column: Chiralcel IC-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value, ee%=100%, RT=3.346min. 1 H NMR (400MHz, CD 3 OD) δ 8.18-8.09 (m, 3H), 8.04 (s, 1H), 7.13 (s, 1H), 5.84 (q, J=7.2Hz, 1H), 4.37-4.30 (s,4H),3.97-3.91(m,2H),3.88-3.84(m,2H),3.78-3.74(m,4H),2.61(s,3H),1.78(d,J=7.2Hz,3H ). MS-ESI calculated [M+H] + 503, found 503.
实施例14Example 14
Figure PCTCN2022082591-appb-000122
Figure PCTCN2022082591-appb-000122
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000123
Figure PCTCN2022082591-appb-000123
第一步first step
氮气保护下,将化合物14-1(3.00g,14.8mmol)溶于无水二氯甲烷(30mL)中,0℃下滴加二乙氨基三氟化硫(3.57g,22.2mmol),反应液在25℃下搅拌12小时,向反应液中加入冰水(20mL),用二氯甲烷(20mL×1)萃取,有机相用饱和食盐水洗涤(20mL×1),无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离得到化合物14-2。 1H NMR(400MHz,CD 3Cl)δ7.72-7.67(m,1H),7.52-7.59(m,1H),7.16(t,J＝7.6Hz,1H),7.05-6.75(m,1H)。 Under nitrogen protection, compound 14-1 (3.00 g, 14.8 mmol) was dissolved in anhydrous dichloromethane (30 mL), and diethylaminosulfur trifluoride (3.57 g, 22.2 mmol) was added dropwise at 0 °C, and the reaction solution was Stir at 25°C for 12 hours, add ice water (20 mL) to the reaction solution, extract with dichloromethane (20 mL×1), wash the organic phase with saturated brine (20 mL×1), dry over anhydrous sodium sulfate, filter , concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～10/1, V/V) to obtain compound 14-2. 1 H NMR (400MHz, CD 3 Cl) δ 7.72-7.67 (m, 1H), 7.52-7.59 (m, 1H), 7.16 (t, J=7.6Hz, 1H), 7.05-6.75 (m, 1H) .
第二步second step
氮气保护下,将化合物14-2(3.10g,13.8mmol)溶于干燥甲苯(50mL)中,加入三丁基(1-乙氧基乙烯)锡(9.95g,27.6mmol),再加入双三苯基膦二氯化钯(967mg,1.38mmol),反应液在110℃下搅拌12小时,向反应液中加入饱和氟化钾水溶液(200mL),用乙酸乙酯(200mL×1)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到化合物14-3。Under nitrogen protection, compound 14-2 (3.10 g, 13.8 mmol) was dissolved in dry toluene (50 mL), tributyl (1-ethoxyethylene) tin (9.95 g, 27.6 mmol) was added, and bistris Phenylphosphine palladium dichloride (967 mg, 1.38 mmol), the reaction solution was stirred at 110 ° C for 12 hours, a saturated aqueous potassium fluoride solution (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×1), the organic The phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14-3.
第三步third step
氮气保护下,将化合物14-3(2.98g,13.8mmol)溶于丙酮(90mL)中,0℃下滴加浓盐酸(12mol/L,9.19mL),反应液在25℃下搅拌1小时,反应液用饱和碳酸氢钠水溶液碱化PH至8,用乙酸乙酯(200mL×2)萃取,饱和食盐水(200mL×1)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离得到化合物14-4。 1H NMR(400MHz,CD 3Cl)δ8.06-7.97(m,1H),7.84-7.76(m,1H),7.38-7.32(m,1H),7.10-6.80(m,1H),2.68(d,J＝4.8Hz,3H)。 Under nitrogen protection, compound 14-3 (2.98 g, 13.8 mmol) was dissolved in acetone (90 mL), concentrated hydrochloric acid (12 mol/L, 9.19 mL) was added dropwise at 0 °C, and the reaction solution was stirred at 25 °C for 1 hour, The reaction solution was alkalized to pH 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (200 mL×2), the organic phase was washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～10/1, V/V) to obtain compound 14-4. 1 H NMR (400MHz, CD 3 Cl) δ 8.06-7.97 (m, 1H), 7.84-7.76 (m, 1H), 7.38-7.32 (m, 1H), 7.10-6.80 (m, 1H), 2.68 ( d, J=4.8 Hz, 3H).
第四步the fourth step
氮气保护下,将化合物14-4(1.85g,9.83mmol)溶于干燥四氢呋喃(50mL)中,加入钛酸四乙酯(8.97g,39.3mmol)和化合物A-6(2.38g,19.7mmol),反应液在72℃下搅拌36小时,降温至0℃滴加饱和氯化铵水溶液(20mL),再加入乙酸乙酯(20mL),过滤,滤饼用乙酸乙酯(10mL)洗涤,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～4/1, V/V)分离得到化合物14-5。MS-ESI计算值[M+H] +292,实测值292。 Under nitrogen protection, compound 14-4 (1.85 g, 9.83 mmol) was dissolved in dry tetrahydrofuran (50 mL), tetraethyl titanate (8.97 g, 39.3 mmol) and compound A-6 (2.38 g, 19.7 mmol) were added , the reaction solution was stirred at 72 °C for 36 hours, cooled to 0 °C, and saturated aqueous ammonium chloride solution (20 mL) was added dropwise, then ethyl acetate (20 mL) was added, filtered, and the filter cake was washed with ethyl acetate (10 mL), and the organic phase was washed with ethyl acetate (10 mL). Washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～4/1, V/V ) was isolated to give compound 14-5. MS-ESI calculated [M+H] + 292, found 292.
第五步the fifth step
将化合物14-5(2.33g,8.00mmol)溶于无水四氢呋喃(20mL),加入硼氢化钠(303mg,8.00mmol),反应液在25℃下搅拌1小时,降温至0℃滴加饱和氯化铵水溶液(50mL),再加入乙酸乙酯(50mL),有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得到化合物14-6。MS-ESI计算值[M+H] +294,实测值294。 Compound 14-5 (2.33 g, 8.00 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL), sodium borohydride (303 mg, 8.00 mmol) was added, the reaction solution was stirred at 25 ° C for 1 hour, cooled to 0 ° C, and saturated chlorine was added dropwise Aqueous ammonium chloride solution (50 mL) was added, ethyl acetate (50 mL) was added, the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 14-6. MS-ESI calculated [M+H] + 294, found 294.
第六步Step 6
将化合物14-6(200mg,0.682mmol)溶于乙酸乙酯(5mL)中,25℃下滴加氯化氢乙酸乙酯溶液(4mol/L,5mL),反应液于25℃搅拌2小时,将反应液减压浓缩得到粗品化合物14-7的盐酸盐,直接用于下一步反应。Compound 14-6 (200 mg, 0.682 mmol) was dissolved in ethyl acetate (5 mL), ethyl acetate solution of hydrogen chloride (4 mol/L, 5 mL) was added dropwise at 25 °C, the reaction solution was stirred at 25 °C for 2 hours, and the reaction was The liquid was concentrated under reduced pressure to obtain the hydrochloride salt of the crude compound 14-7, which was directly used in the next reaction.
第七步Step 7
将化合物14-7的盐酸盐(70.0mg,310μmol)溶于二甲基亚砜(5mL)中,加入1-8(178mg,310μmol),滴加N,N-二异丙基乙胺(120mg,931μmol),在90℃下搅拌反应12小时。过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:10％-50％,10min),得到化合物14的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.19(s,1H),7.74-7.46(m,2H),7.38-7.24(m,1H),7.13(s,1H),7.07-6.81(m,1H),6.07-5.89(m,1H),4.43-4.25(m,4H),3.97-3.89(m,2H),3.89-3.82(m,2H),3.80-3.70(m,4H),2.60(s,3H),1.83-1.70(m,3H)。MS-ESI计算值[M+H] +478,实测值478。 The hydrochloride of compound 14-7 (70.0 mg, 310 μmol) was dissolved in dimethyl sulfoxide (5 mL), 1-8 (178 mg, 310 μmol) was added, and N,N-diisopropylethylamine ( 120 mg, 931 μmol), and the reaction was stirred at 90 °C for 12 hours. Filter and concentrate under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 10%-50%, 10min) to obtain compound 14. Hydrochloride. 1 H NMR (400MHz, CD 3 OD) δ8.19(s, 1H), 7.74-7.46(m, 2H), 7.38-7.24(m, 1H), 7.13(s, 1H), 7.07-6.81(m, 1H), 6.07-5.89(m, 1H), 4.43-4.25(m, 4H), 3.97-3.89(m, 2H), 3.89-3.82(m, 2H), 3.80-3.70(m, 4H), 2.60( s, 3H), 1.83-1.70 (m, 3H). MS-ESI calculated [M+H] + 478, found 478.
实施例15Example 15
Figure PCTCN2022082591-appb-000124
Figure PCTCN2022082591-appb-000124
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000125
Figure PCTCN2022082591-appb-000125
第一步first step
氮气保护下,将化合物12-2(112mg,170μmol)溶于乙醇(5mL)中,加入氢氧化钯(12mg,10％纯度)。反应液在80℃氢气氛围(45psi)下搅拌反应12小时。将反应液过滤,减压浓缩得到化合物15-1。MS-ESI计算值[M+H] +661,实测值661。 Under nitrogen protection, compound 12-2 (112 mg, 170 μmol) was dissolved in ethanol (5 mL), and palladium hydroxide (12 mg, 10% purity) was added. The reaction solution was stirred under a hydrogen atmosphere (45 psi) at 80°C for 12 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 15-1. MS-ESI calculated [M+H] + 661, found 661.
第二步second step
将化合物15-1(120mg,182μmol)溶于乙酸乙酯(2mL)中,加入氯化氢乙酸乙酯溶液(4mol/L,3.99mL),在25℃下搅拌反应12小时。反应液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:6％-36％,10min)得到化合物15的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.28(s,1H),7.81(s,1H),7.69(s,1H),7.50(s,1H),7.16(s,1H),5.86(q,J＝6.8Hz,1H),4.46-4.43(m,4H),3.97-3.88(m,2H),3.87-3.81(m,2H),3.79-3.64(m,4H),3.58-3.44(m,2H),3.25-3.03(m,3H),2.64(s,3H),2.13-1.93(m,4H),1.78(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +561,实测值561。 Compound 15-1 (120 mg, 182 μmol) was dissolved in ethyl acetate (2 mL), hydrogen chloride ethyl acetate solution (4 mol/L, 3.99 mL) was added, and the reaction was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 6%-36%, 10min ) to give compound 15 as the hydrochloride salt. 1 H NMR (400MHz, CD 3 OD) δ 8.28(s, 1H), 7.81(s, 1H), 7.69(s, 1H), 7.50(s, 1H), 7.16(s, 1H), 5.86(q , J=6.8Hz, 1H), 4.46-4.43(m, 4H), 3.97-3.88(m, 2H), 3.87-3.81(m, 2H), 3.79-3.64(m, 4H), 3.58-3.44(m , 2H), 3.25-3.03 (m, 3H), 2.64 (s, 3H), 2.13-1.93 (m, 4H), 1.78 (d, J=6.8Hz, 3H). MS-ESI calculated [M+H] + 561, found 561.
实施例16Example 16
Figure PCTCN2022082591-appb-000126
Figure PCTCN2022082591-appb-000126
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000127
Figure PCTCN2022082591-appb-000127
氮气保护下将化合物13的盐酸盐(20.0mg,39.8μmol)溶于无水四氢呋喃(5mL)中,向反应液中滴加甲基溴化镁的四氢呋喃溶液(3M,66.3μL),搅拌30分钟后加入钛酸四异丙酯(11.8μL,39.8μmol),在25℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷/甲醇(10/1,30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 150mm×30mm×4μm；流动相:0.05％盐酸-乙腈；梯度:乙腈:22％-52％,9min)得到化合物16的盐酸盐。化合物16的盐酸盐经SFC(色谱柱:Chiralcel OD-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝92.80％,RT＝2.611min。 1H NMR(400MHz,CD 3OD)δ8.27(s,1H),8.06(s,1H),7.88(s,1H),7.78(s,1H),7.16(s,1H),5.95-5.87(m,1H),4.44-4.32(m,4H),3.99-3.92(m,2H),3.91-3.84(m,2H),3.82-3.73(m,4H),2.65(s,3H),1.88-1.77(m,9H)。MS-ESI计算值[M+H] +535,实测值535。 Under nitrogen protection, the hydrochloride salt of compound 13 (20.0 mg, 39.8 μmol) was dissolved in anhydrous tetrahydrofuran (5 mL), a solution of methylmagnesium bromide in tetrahydrofuran (3 M, 66.3 μL) was added dropwise to the reaction solution, and the solution was stirred for 30 minutes. After minutes, tetraisopropyl titanate (11.8 μL, 39.8 μmol) was added, and the reaction was stirred at 25° C. for 12 hours. Water (20 mL) was added to the reaction solution, extracted with dichloromethane/methanol (10/1, 30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×30mm×4μm; mobile phase: 0.05% hydrochloric acid-acetonitrile; gradient: acetonitrile: 22%-52%, 9min) to obtain the hydrochloric acid of compound 16 Salt. The hydrochloride of compound 16 was purified by SFC (chromatographic column: Chiralcel OD-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol :5%-40%). Measured ee value, ee%=92.80%, RT=2.611min. 1 H NMR (400MHz, CD 3 OD) δ 8.27(s, 1H), 8.06(s, 1H), 7.88(s, 1H), 7.78(s, 1H), 7.16(s, 1H), 5.95-5.87 (m,1H),4.44-4.32(m,4H),3.99-3.92(m,2H),3.91-3.84(m,2H),3.82-3.73(m,4H),2.65(s,3H),1.88 -1.77(m, 9H). MS-ESI calculated [M+H] + 535, found 535.
实施例17Example 17
Figure PCTCN2022082591-appb-000128
Figure PCTCN2022082591-appb-000128
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000129
Figure PCTCN2022082591-appb-000129
第一步first step
将1,2-二溴乙烷(10.9uL,144μmol)溶于N,N-二甲基甲酰胺(3mL)中,加入锌粉(118mg,1.80mmol,),在70℃下搅拌反应10分钟。冷却至20℃,滴加三甲基氯硅烷(18.3uL,144μmol),搅拌反应50分钟。滴加化合物17-1(76.3mg,270μmol,)的N,N-二甲基甲酰胺(3mL)溶液,在40℃搅拌反应1小时。加入化合物9-5(100mg,180μmol),三(二亚苄基丙酮)二钯(3.29mg,3.59μmol)和3-(2-呋喃基)-膦(1.67mg,7.19μmol)的N,N-二甲基甲酰胺(3mL)溶液,在100℃搅拌12小时。过滤,将滤液倒入水(50mL)中,用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(200mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经制备高效液相色谱(色谱柱:Phenomenex Genimi NX C18 150mm×40mm×5μm；流动相:(0.04％氨水+10mM碳酸氢铵水溶液)-乙腈；梯度:乙腈:55％-65％,10min)分离纯化得到化合物17-2。 1H NMR(400MHz,CDCl 3)δ7.65-7.57(m,2H),7.45(s,1H),7.34(s,1H),7.19(s,1H),5.98-5.70(m,1H),5.70-5.55(m,1H),4.41-4.30(m,2H),4.30-4.18(m,4H),4.01-3.89(m,4H),3.87-3.81(m,2H),3.79(s,5H),2.55(s,3H),1.76-1.62(m,3H),1.47(s,9H)。MS-ESI计算值[M+H] +633，实测值633。 1,2-Dibromoethane (10.9uL, 144μmol) was dissolved in N,N-dimethylformamide (3mL), zinc powder (118mg, 1.80mmol,) was added, and the reaction was stirred at 70°C for 10 minutes . After cooling to 20°C, trimethylchlorosilane (18.3uL, 144μmol) was added dropwise, and the reaction was stirred for 50 minutes. A solution of compound 17-1 (76.3 mg, 270 μmol, ) in N,N-dimethylformamide (3 mL) was added dropwise, and the reaction was stirred at 40° C. for 1 hour. Compound 9-5 (100 mg, 180 μmol), tris(dibenzylideneacetone)dipalladium (3.29 mg, 3.59 μmol) and 3-(2-furyl)-phosphine (1.67 mg, 7.19 μmol) were added in N,N - A solution of dimethylformamide (3 mL) was stirred at 100°C for 12 hours. Filter, pour the filtrate into water (50 mL), extract with ethyl acetate (50 mL×3), wash the organic phase with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, and concentrate the residue under reduced pressure. Preparative high performance liquid chromatography (chromatographic column: Phenomenex Genimi NX C18 150mm×40mm×5μm; mobile phase: (0.04% ammonia water+10mM ammonium bicarbonate aqueous solution)-acetonitrile; gradient: acetonitrile: 55%-65%, 10min) separation and purification Compound 17-2 was obtained. 1 H NMR (400MHz, CDCl 3 ) δ 7.65-7.57(m, 2H), 7.45(s, 1H), 7.34(s, 1H), 7.19(s, 1H), 5.98-5.70(m, 1H), 5.70-5.55(m, 1H), 4.41-4.30(m, 2H), 4.30-4.18(m, 4H), 4.01-3.89(m, 4H), 3.87-3.81(m, 2H), 3.79(s, 5H) ), 2.55(s, 3H), 1.76-1.62(m, 3H), 1.47(s, 9H). MS-ESI calculated [M+H] + 633, found 633.
第二步second step
将化合物17-2(24.0mg,37.9μmol)溶于二氯甲烷(5mL)溶液中，在0℃下滴加三氟甲磺酸三甲基硅酯(16.9mg,75.9μmol)，在0℃搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液(10mL)，用乙酸乙酯(10mL×3)萃取,有机相用饱和食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的经制备高效液相色谱(色谱柱:Phenomenex Gemini-NX 80mm×30mm×3μm；流动相:10mM碳酸氢铵水溶液-乙腈；梯度:乙腈30％-90％,9min)分离得到化合物17。 1H NMR(400MHz,CD 3OD)δ7.87(s,1H),7.71-7.64(m,2H),7.55-7.42(m,1H),7.10(s,1H),5.70-5.63(m,1H),4.33-4.23(m,4H),4.17-4.10(m,1H),4.05-3.96(m,2H),3.94-3.82(m,6H),3.81-3.68(m,5H),2.50-2.38(m,3H), 1.68(d,J＝8.0Hz,3H)。MS-ESI计算值[M+H] +533，实测值533。 Compound 17-2 (24.0 mg, 37.9 μmol) was dissolved in dichloromethane (5 mL) solution, trimethylsilyl trifluoromethanesulfonate (16.9 mg, 75.9 μmol) was added dropwise at 0 °C, and at 0 °C The reaction was stirred for 1 hour. Saturated aqueous sodium bicarbonate solution (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×3), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Compound 17 was obtained by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80mm×30mm×3μm; mobile phase: 10mM aqueous ammonium bicarbonate solution-acetonitrile; gradient: acetonitrile 30%-90%, 9min). 1 H NMR (400MHz, CD 3 OD) δ 7.87(s, 1H), 7.71-7.64(m, 2H), 7.55-7.42(m, 1H), 7.10(s, 1H), 5.70-5.63(m, 1H), 4.33-4.23(m, 4H), 4.17-4.10(m, 1H), 4.05-3.96(m, 2H), 3.94-3.82(m, 6H), 3.81-3.68(m, 5H), 2.50- 2.38(m, 3H), 1.68(d, J=8.0Hz, 3H). MS-ESI calculated [M+H] + 533, found 533.
实施例18Example 18
Figure PCTCN2022082591-appb-000130
Figure PCTCN2022082591-appb-000130
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000131
Figure PCTCN2022082591-appb-000131
第一步first step
将化合物18-1(1.10g,4.69mmol)溶于四氢呋喃(10mL)中,加入A-6(853mg,7.04mmol)和钛酸四乙酯(2.14g,9.38mmol),在80℃下搅拌反应1小时后,向反应液中加入水(50mL),用乙酸乙酯(50mL×1)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～5/1,V/V)分离纯化得到化合物18-2。MS-ESI计算值[M+H] +310,实测值310。 Compound 18-1 (1.10 g, 4.69 mmol) was dissolved in tetrahydrofuran (10 mL), A-6 (853 mg, 7.04 mmol) and tetraethyl titanate (2.14 g, 9.38 mmol) were added, and the reaction was stirred at 80 °C After 1 hour, water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×1), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～5/1, V/V) to obtain compound 18-2. MS-ESI calculated [M+H] + 310, found 310.
第二步second step
将化合物18-2(1.44g,4.66mmol)溶于四氢呋喃(10mL)中,在0℃下加入硼氢化钠(211mg,5.59mmol),在20℃下搅拌反应1小时。向反应液中加入水(20mL),用乙酸乙酯(20mL×1)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,1/1～1/2,V/V)分离纯化得到化合物18-3。MS-ESI计算值[M+H] +312,实测值312。 Compound 18-2 (1.44 g, 4.66 mmol) was dissolved in tetrahydrofuran (10 mL), sodium borohydride (211 mg, 5.59 mmol) was added at 0°C, and the reaction was stirred at 20°C for 1 hour. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×1), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel Column chromatography (petroleum ether/ethyl acetate, 1/1-1/2, V/V) was used for separation and purification to obtain compound 18-3. MS-ESI calculated [M+H] + 312, found 312.
第三步third step
将化合物18-3(721mg,2.32mmol)溶于二氧六环(10mL)中,加入氯化氢二氧六环溶液(4mol/L,5.00mL),在20℃下搅拌反应0.5小时。反应液减压浓缩,得到化合物18-4的盐酸盐。 1H NMR(400MHz,CD 3OD)δ7.86(t,J＝7.2Hz,1H),7.80(t,J＝7.6Hz,1H),7.50(t,J＝8Hz,1H),3.86-3.79(m,1H),1.69(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] +208,实测值208。 Compound 18-3 (721 mg, 2.32 mmol) was dissolved in dioxane (10 mL), hydrogen chloride dioxane solution (4 mol/L, 5.00 mL) was added, and the reaction was stirred at 20° C. for 0.5 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of compound 18-4. 1 H NMR (400MHz, CD 3 OD) δ 7.86 (t, J=7.2Hz, 1H), 7.80 (t, J=7.6Hz, 1H), 7.50 (t, J=8Hz, 1H), 3.86-3.79 (m, 1H), 1.69 (d, J=7.2Hz, 3H). MS-ESI calculated [M+H] + 208, found 208.
第四步the fourth step
将化合物18-4的盐酸盐(80.0mg,328μmol)溶于二甲基亚砜(5mL)中,加入1-8(188mg,328μmol),滴加N,N-二异丙基乙胺(127mg,985μmol),在90℃下搅拌反应12小时。过滤,将滤液减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:30％-60％,10min),得到化合物18的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.17(s,1H),7.84-7.73(m,1H),7.69-7.58(m,1H),7.69-7.58(m,1H),7.12(s,1H),6.03-5.93(m,1H),4.39-4.31(m,4H),3.97-3.90(m,2H),3.89-3.82(m,2H),3.80-3.73(m,4H),2.58(s,3H),1.77(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +496,实测值496。 The hydrochloride of compound 18-4 (80.0 mg, 328 μmol) was dissolved in dimethyl sulfoxide (5 mL), 1-8 (188 mg, 328 μmol) was added, and N,N-diisopropylethylamine ( 127 mg, 985 μmol), and the reaction was stirred at 90 °C for 12 hours. After filtration, the filtrate was concentrated under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 30%-60%, 10min) to obtain compound 18. Hydrochloride. 1 H NMR (400MHz, CD 3 OD) δ8.17(s, 1H), 7.84-7.73(m, 1H), 7.69-7.58(m, 1H), 7.69-7.58(m, 1H), 7.12(s, 1H), 6.03-5.93(m, 1H), 4.39-4.31(m, 4H), 3.97-3.90(m, 2H), 3.89-3.82(m, 2H), 3.80-3.73(m, 4H), 2.58( s, 3H), 1.77 (d, J=6.8 Hz, 3H). MS-ESI calculated [M+H] + 496, found 496.
实施例19Example 19
Figure PCTCN2022082591-appb-000132
Figure PCTCN2022082591-appb-000132
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000133
Figure PCTCN2022082591-appb-000133
第一步first step
氮气保护下将化合物10-1(200mg,373μmol)溶于无水二氯甲烷(5mL)中,-78℃下向反应液中滴加二异丁基氢化铝的甲苯溶液(1M,747μL),在-78℃下搅拌反应2小时。25℃下向反应液中加入饱和碳酸氢钠溶液(10mL),搅拌2小时,用二氯甲烷(20mL×2)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～10/1,V/V)分离纯化得到化合物19-1。MS-ESI计算值[M+H] +508,实测值508。 Compound 10-1 (200 mg, 373 μmol) was dissolved in anhydrous dichloromethane (5 mL) under nitrogen protection, and a solution of diisobutylaluminum hydride in toluene (1 M, 747 μL) was added dropwise to the reaction solution at -78°C, The reaction was stirred at -78°C for 2 hours. Saturated sodium bicarbonate solution (10 mL) was added to the reaction solution at 25°C, stirred for 2 hours, extracted with dichloromethane (20 mL × 2), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. , the residue after concentration under reduced pressure was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 19-1. MS-ESI calculated [M+H] + 508, found 508.
第二步second step
将化合物19-1(110mg,217μmol)溶于无水二氯甲烷(10mL)中,向反应液中加入二氧化锰(188mg,2.17mmol),在25℃下搅拌反应2小时。将反应液过滤,减压浓缩后得到化合物19-2。MS-ESI计算值[M+H] +506,实测值506。 Compound 19-1 (110 mg, 217 μmol) was dissolved in anhydrous dichloromethane (10 mL), manganese dioxide (188 mg, 2.17 mmol) was added to the reaction solution, and the reaction was stirred at 25° C. for 2 hours. The reaction solution was filtered and concentrated under reduced pressure to obtain compound 19-2. MS-ESI calculated [M+H] + 506, found 506.
第三步third step
氮气保护下将化合物19-2(50.0mg,98.9μmol)溶于1,2-二氯乙烷(5mL)中,向反应液中加钛酸四乙酯(67.7mg,297μmol)和二甲胺盐酸盐(16.1mg,198μmol),在60℃搅拌反应12小时,然后加入三乙酰氧基硼氢化钠(62.9mg,297μmol),在60℃下搅拌反应2小时。向反应液中加入饱和碳酸氢钠溶液碱化至pH＝8, 减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸-乙腈；梯度:乙腈1％-30％,10min)得到化合物19的盐酸盐。化合物19的盐酸盐经SFC(色谱柱:Chiralpak AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％,RT＝1.204min。 1H NMR(400MHz,CD 3OD)δ8.25(s,1H),8.05(s,1H),7.95(s,1H),7.81(s,1H),7.14(s,1H),5.94-5.90(m,1H),4.45-4.40(m,2H),4.39-4.30(m,4H),3.94-3.90(m,2H),3.88-3.84(m,2H),3.80-3.70(m,4H),2.87(d,J＝8.0Hz,6H),3.62(s,3H),1.80(d,J＝4.0Hz,3H)。MS-ESI计算值[M+H] +536,实测值536。 Compound 19-2 (50.0 mg, 98.9 μmol) was dissolved in 1,2-dichloroethane (5 mL) under nitrogen protection, and tetraethyl titanate (67.7 mg, 297 μmol) and dimethylamine were added to the reaction solution. The hydrochloride (16.1 mg, 198 μmol) was stirred at 60° C. for 12 hours, then sodium triacetoxyborohydride (62.9 mg, 297 μmol) was added, and the reaction was stirred at 60° C. for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to basify to pH=8, and the residue after concentration under reduced pressure was separated and purified by high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% hydrochloric acid- Acetonitrile; gradient: acetonitrile 1%-30%, 10 min) to give compound 19 as the hydrochloride salt. The hydrochloride of compound 19 was analyzed by SFC (chromatographic column: Chiralpak AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol :5%-40%). Measured ee value, ee%=100.00%, RT=1.204min. 1 H NMR (400MHz, CD 3 OD) δ 8.25(s, 1H), 8.05(s, 1H), 7.95(s, 1H), 7.81(s, 1H), 7.14(s, 1H), 5.94-5.90 (m,1H),4.45-4.40(m,2H),4.39-4.30(m,4H),3.94-3.90(m,2H),3.88-3.84(m,2H),3.80-3.70(m,4H) , 2.87 (d, J=8.0 Hz, 6H), 3.62 (s, 3H), 1.80 (d, J=4.0 Hz, 3H). MS-ESI calculated [M+H] + 536, found 536.
实施例20Example 20
Figure PCTCN2022082591-appb-000134
Figure PCTCN2022082591-appb-000134
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000135
Figure PCTCN2022082591-appb-000135
第一步first step
将化合物20-1(1.00g,15.1mmol)溶于四氢呋喃(100mL)和N,N-二甲基甲酰胺(100mL)中,25℃下加入钠氢(3.03g,75.7μmol,60％纯度),反应液在25℃搅拌30分钟,并升温至65℃搅拌反应30分钟。25℃下加入20-2(6.96g,33.3mmol),反应液在45℃搅拌反应12小时。0℃下加入甲醇(10mL),25℃搅拌10分 钟,用乙酸乙酯(100mL×2)萃取。有机相用饱和食盐水(100mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～3/1,V/V)分离纯化得到化合物20-3。 1H NMR(400MHz,CDCl 3)δ4.64(t,J＝3.6Hz,2H),3.92-3.83(m,4H),3.72-3.66(m,4H),3.65-3.58(m,2H),3.56-3.47(m,2H),1.90-1.78(m,2H),1.77-1.68(m,2H),1.64-1.49(m,8H)。 Compound 20-1 (1.00 g, 15.1 mmol) was dissolved in tetrahydrofuran (100 mL) and N,N-dimethylformamide (100 mL), and sodium hydrogen (3.03 g, 75.7 μmol, 60% purity) was added at 25° C. , the reaction solution was stirred at 25°C for 30 minutes, and then heated to 65°C and stirred for 30 minutes. 20-2 (6.96 g, 33.3 mmol) was added at 25°C, and the reaction solution was stirred at 45°C for 12 hours. Methanol (10 mL) was added at 0°C, stirred at 25°C for 10 minutes, and extracted with ethyl acetate (100 mL×2). The organic phase was washed with saturated brine (100 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 1/0～3/1, V /V) separation and purification to obtain compound 20-3. 1 H NMR (400 MHz, CDCl 3 ) δ 4.64 (t, J=3.6 Hz, 2H), 3.92-3.83 (m, 4H), 3.72-3.66 (m, 4H), 3.65-3.58 (m, 2H), 3.56-3.47 (m, 2H), 1.90-1.78 (m, 2H), 1.77-1.68 (m, 2H), 1.64-1.49 (m, 8H).
第二步second step
将化合物20-3(1.76g,5.46mmol)溶于四氢呋喃(10mL)和甲醇(10mL)中,加入4-甲基苯磺酸吡啶(137mg,546μmol),反应液在25℃下搅拌反应30分钟,随后升温至45℃反应12小时。将反应液减压浓缩得到化合物20-4。Compound 20-3 (1.76 g, 5.46 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL), pyridine 4-methylbenzenesulfonate (137 mg, 546 μmol) was added, and the reaction solution was stirred at 25° C. for 30 minutes , and then the temperature was raised to 45 °C for 12 hours. The reaction solution was concentrated under reduced pressure to obtain compound 20-4.
第三步third step
将化合物20-4(840mg,5.45mmol)溶于二氯甲烷(5mL)中,然后在0℃下缓慢加入对甲苯磺酰氯(3.12g,16.3mmol)和三乙胺(1.65g,16.3mmol),在25℃下搅拌反应12小时。将反应液倒入冰水(5mL)中,用二氯甲烷(5mL×2)萃取。有机相用饱和食盐水(5mL×2)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离纯化得到化合物20-5。 1H NMR(400MHz,CDCl 3)δ7.80(d,J＝8.4Hz,4H),7.35(d,J＝8.4Hz,4H),4.21-4.09(m,4H),3.72-3.61(m,4H),2.45(s,6H)。 Compound 20-4 (840 mg, 5.45 mmol) was dissolved in dichloromethane (5 mL), then p-toluenesulfonyl chloride (3.12 g, 16.3 mmol) and triethylamine (1.65 g, 16.3 mmol) were slowly added at 0 °C , the reaction was stirred at 25 °C for 12 hours. The reaction solution was poured into ice water (5 mL) and extracted with dichloromethane (5 mL×2). The organic phase was washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V /V) separation and purification to obtain compound 20-5. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J=8.4 Hz, 4H), 7.35 (d, J=8.4 Hz, 4H), 4.21-4.09 (m, 4H), 3.72-3.61 (m, 4H), 2.45(s, 6H).
第四步the fourth step
将化合物20-5(1.50g,7.80mmol)溶于N,N-二甲基甲酰胺(45mL)中,加入化合物1-4(3.61g,7.80mmol)和碳酸钾(4.31g,31.2mmol),在80℃下搅拌反应12小时。将反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,1/0～5/1,V/V)分离纯化得到化合物20-6。MS-ESI计算值[M+H] +311,实测值311。 Compound 20-5 (1.50 g, 7.80 mmol) was dissolved in N,N-dimethylformamide (45 mL), compound 1-4 (3.61 g, 7.80 mmol) and potassium carbonate (4.31 g, 31.2 mmol) were added , the reaction was stirred at 80 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-5/1, V/V) to obtain compound 20-6. MS-ESI calculated [M+H] + 311, found 311.
第五步the fifth step
氮气保护下将化合物20-6(160mg,272μmol)和化合物1-7(123mg,407μmol)溶于二氯甲烷(10mL)中,加入4-二甲氨基吡啶(3.32mg,27.2μmol)和三乙胺(82.4mg,815μmol),在25℃下搅拌反应12小时。将反应液浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/0,V/V)分离纯化得到化合物20-7。MS-ESI计算值[M+H] +577,实测值577。 Compound 20-6 (160 mg, 272 μmol) and compound 1-7 (123 mg, 407 μmol) were dissolved in dichloromethane (10 mL) under nitrogen protection, and 4-dimethylaminopyridine (3.32 mg, 27.2 μmol) and triethylamine were added. amine (82.4 mg, 815 μmol), and the reaction was stirred at 25° C. for 12 hours. The reaction solution was concentrated, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/0, V/V) to obtain compound 20-7. MS-ESI calculated [M+H] + 577, found 577.
第三步third step
氮气保护下将化合物20-7(50.0mg,86.7μmol)溶于二甲亚砜(5mL)中,向反应液中化合物5-9(25.7mg,104μmol),N,N-二异丙基乙胺(45.3μL,260μmol),在90℃下搅拌反应1小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经过薄层色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V)得到化合物20。化合物20经SFC(色谱柱:Chiralpak AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝99.90％,RT＝1.605min。 1H NMR(400MHz,CD 3OD)δ＝7.92(s,1H),7.53(t,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.20-7.04(m,2H),5.89-5.80(m,1H),4.35-4.20(m,4H),3.95-3.77(m,4H),2.39(s,3H),1.65(d,J＝8.0Hz,3H),1.30(d,J＝8.0Hz,6H)。MS-ESI计算值[M+H] +540,实测值540。 Compound 20-7 (50.0 mg, 86.7 μmol) was dissolved in dimethyl sulfoxide (5 mL) under nitrogen protection, and compound 5-9 (25.7 mg, 104 μmol), N,N-diisopropylethyl acetate was added to the reaction solution. amine (45.3 μL, 260 μmol), and the reaction was stirred at 90 °C for 1 hour. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL × 3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was passed through a thin layer Chromatography separation and purification (dichloromethane/methanol, 100/1～10/1, V/V) gave compound 20. Compound 20 was subjected to SFC (chromatographic column: Chiralpak AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%). Measured ee value, ee%=99.90%, RT=1.605min. 1 H NMR (400 MHz, CD 3 OD) δ=7.92 (s, 1H), 7.53 (t, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.20-7.04 (m, 2H) ), 5.89-5.80(m, 1H), 4.35-4.20(m, 4H), 3.95-3.77(m, 4H), 2.39(s, 3H), 1.65(d, J=8.0Hz, 3H), 1.30( d, J=8.0 Hz, 6H). MS-ESI calculated [M+H] + 540, found 540.
实施例21Example 21
Figure PCTCN2022082591-appb-000136
Figure PCTCN2022082591-appb-000136
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000137
Figure PCTCN2022082591-appb-000137
第一步first step
氮气保护下将化合物21-1(430mg,1.15mmol)溶于甲苯(10mL)中,加入3-2(663mg,1.84mmol)和双(三苯基膦)二氯化钯(80.5mg,115μmol),在120℃下搅拌反应12小时。向反应液加入饱和氟化钾水溶液(20mL),用乙酸乙酯(20mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物21-2。Compound 21-1 (430 mg, 1.15 mmol) was dissolved in toluene (10 mL) under nitrogen protection, 3-2 (663 mg, 1.84 mmol) and bis(triphenylphosphine)palladium dichloride (80.5 mg, 115 μmol) were added , the reaction was stirred at 120 °C for 12 hours. Saturated potassium fluoride aqueous solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 21-2.
第二步second step
将化合物21-2(295mg,1.15mmol)溶于丙酮(15mL)中,滴加盐酸溶液(12mol/L,1.00mL),在20℃下搅拌反应0.5小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物21-3。MS-ESI计算值[M+H] +230,实测值230。 Compound 21-2 (295 mg, 1.15 mmol) was dissolved in acetone (15 mL), hydrochloric acid solution (12 mol/L, 1.00 mL) was added dropwise, and the reaction was stirred at 20° C. for 0.5 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to basify the pH to 8, extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. After concentration, the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain compound 21-3. MS-ESI calculated [M+H] + 230, found 230.
第三步third step
将化合物21-3(160mg,620μmol)溶于四氢呋喃(10mL)中,加入A-6(113mg,930μmol)和钛酸四乙酯(283mg,1.24mmol),在80℃下搅拌反应72小时后,在0℃下加入硼氢化钠(28mg,744μmol),在20℃下搅拌反应1小时。向反应液中加入水(20mL),用乙酸乙酯(20mL×1)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,1/1～0/1,V/V),得到化合物21-4。MS-ESI计算值[M+H] +335,实测值335。 Compound 21-3 (160 mg, 620 μmol) was dissolved in tetrahydrofuran (10 mL), A-6 (113 mg, 930 μmol) and tetraethyl titanate (283 mg, 1.24 mmol) were added, and the reaction was stirred at 80° C. for 72 hours. Sodium borohydride (28 mg, 744 μmol) was added at 0°C, and the reaction was stirred at 20°C for 1 hour. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×1), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was filtered through silica gel After separation and purification by column chromatography (petroleum ether/ethyl acetate, 1/1～0/1, V/V), compound 21-4 was obtained. MS-ESI calculated [M+H] + 335, found 335.
第四步the fourth step
将化合物21-4(155mg,463μmol)溶于二氧六环(5mL)中,加入氯化氢二氧六环溶液(4mol/L,1.00mL),在20℃下搅拌反应12小时。反应液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate  C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:10％-40％,10min)得到化合物21-5的盐酸盐。MS-ESI计算值[M+H] +231,实测值231。 Compound 21-4 (155 mg, 463 μmol) was dissolved in dioxane (5 mL), hydrogen chloride dioxane solution (4 mol/L, 1.00 mL) was added, and the reaction was stirred at 20° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 10%-40%, 10min ) to obtain the hydrochloride salt of compound 21-5. MS-ESI calculated [M+H] + 231, found 231.
第五步the fifth step
将化合物21-5的盐酸盐(72.0mg,270μmol)溶于二甲基亚砜(3mL)中,加入1-8(185mg,324μmol)和N,N-二异丙基乙胺(105mg,810μmol),在90℃下搅拌反应12小时。过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:1％-30％,10min)得到化合物21的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.26(s,1H),7.75-7.60(m,1H),7.43-7.31(m,1H),7.29-7.20(m,1H),7.19-7.10(m,1H),5.92-5.80(m,1H),4.40-4.28(m,4H),3.94-3.89(m,2H),3.86-3.82(m,2H),3.78-3.72(m,4H),3.69-3.36(m,1H),3.31(s,3H),3.10-2.99(m,3H),2.98-2.90(m,2H),2.65(s,3H),2.52-2.08(m,4H),1.75(d,J＝6.4Hz,3H)。MS-ESI计算值[M+H] +519,实测值519。 The hydrochloride of compound 21-5 (72.0 mg, 270 μmol) was dissolved in dimethyl sulfoxide (3 mL), 1-8 (185 mg, 324 μmol) and N,N-diisopropylethylamine (105 mg, 324 μmol) were added. 810 μmol), and the reaction was stirred at 90 °C for 12 h. Filter and concentrate under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 1%-30%, 10min) to obtain the salt of compound 21 acid salt. 1 H NMR (400MHz, CD 3 OD) δ8.26(s, 1H), 7.75-7.60(m, 1H), 7.43-7.31(m, 1H), 7.29-7.20(m, 1H), 7.19-7.10( m,1H),5.92-5.80(m,1H),4.40-4.28(m,4H),3.94-3.89(m,2H),3.86-3.82(m,2H),3.78-3.72(m,4H), 3.69-3.36(m, 1H), 3.31(s, 3H), 3.10-2.99(m, 3H), 2.98-2.90(m, 2H), 2.65(s, 3H), 2.52-2.08(m, 4H), 1.75 (d, J=6.4 Hz, 3H). MS-ESI calculated [M+H] + 519, found 519.
实施例22Example 22
Figure PCTCN2022082591-appb-000138
Figure PCTCN2022082591-appb-000138
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000139
Figure PCTCN2022082591-appb-000139
第一步first step
将化合物22-1(1.19g,2.08mmol)溶于二甲基亚砜(5mL)中,加入中间体1-8的盐酸盐(500mg,2.50 mmol)和N,N-二异丙基乙胺(4.04g,31.2mmol),在90℃下搅拌反应12小时。向反应液中加入水(10mL),用乙酸乙酯(10mL×2)萃取,有机相用饱和食盐水(10mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,1/0～10/1,V/V)分离纯化得到化合物22-2。MS-ESI计算值[M+H] +488,实测值488。 Compound 22-1 (1.19 g, 2.08 mmol) was dissolved in dimethyl sulfoxide (5 mL), and the hydrochloride of intermediate 1-8 (500 mg, 2.50 mmol) and N,N-diisopropylethyl acetate were added. Amine (4.04 g, 31.2 mmol), and the reaction was stirred at 90 °C for 12 hours. Water (10 mL) was added to the reaction solution, extracted with ethyl acetate (10 mL×2), the organic phase was washed with saturated brine (10 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was filtered through silica gel Column chromatography (dichloromethane/methanol, 1/0～10/1, V/V) was used for separation and purification to obtain compound 22-2. MS-ESI calculated [M+H] + 488, found 488.
第二步second step
氮气保护下,将化合物22-2(100mg,205μmol)溶于二氧六环溶液(2mL)中,加入22-3(62.4mg,246μmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(15.0mg,20.5mmol)和乙酸钾(50.2mg,512μmol)。反应液在100℃搅拌反应12小时。将反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,1/0～10/1,V/V)分离纯化得到化合物22-4。MS-ESI计算值[M+H] +536,实测值536。 Under nitrogen protection, compound 22-2 (100 mg, 205 μmol) was dissolved in dioxane solution (2 mL), 22-3 (62.4 mg, 246 μmol), [1,1'-bis(diphenylphosphino) was added ) ferrocene]palladium dichloride (15.0 mg, 20.5 mmol) and potassium acetate (50.2 mg, 512 μmol). The reaction solution was stirred and reacted at 100°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-10/1, V/V) to obtain compound 22-4. MS-ESI calculated [M+H] + 536, found 536.
第三步third step
氮气保护下,将化合物22-4(580mg,904μmol)溶于二氧六环/水溶液(4:1,1.25mL)中,加入22-5(191mg,603μmol),[1,1'-双(二苯基膦基)二茂铁]二氯化钯(44.1mg,60.2μmol)和碳酸钠(128mg,1.21mmol)。反应液在100℃搅拌反应12小时。将反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,1/0～10/1,V/V)分离纯化得到化合物22-6。MS-ESI计算值[M+H] +645,实测值645。 Under nitrogen protection, compound 22-4 (580 mg, 904 μmol) was dissolved in dioxane/water solution (4:1, 1.25 mL), 22-5 (191 mg, 603 μmol), [1,1′-bis( Diphenylphosphino)ferrocene]palladium dichloride (44.1 mg, 60.2 μmol) and sodium carbonate (128 mg, 1.21 mmol). The reaction solution was stirred and reacted at 100°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 1/0-10/1, V/V) to obtain compound 22-6. MS-ESI calculated [M+H] + 645, found 645.
第四步the fourth step
将化合物22-6(500mg,775μmol)溶于无水甲醇(5mL)中,向反应液中氯化氢甲醇溶液(4mol/L,10.0mL),在25℃下搅拌反应2小时。将反应液减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex Genimi NX C18 150mm×40mm×5μm；流动相:0.05％盐酸-乙腈；梯度:乙腈:1％-25％,10min)得到化合物22的盐酸盐。化合物22的盐酸盐经SFC(色谱柱:Chiralpak AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％,RT＝2.354min。 1H NMR(400MHz,CD 3OD)δ8.27-8.21(m,1H),8.09-7.92(m,2H),7.77-7.70(m,1H),7.62-7.48(m,2H),7.12(s,1H),5.95-5.87(m,1H),5.22-5.08(m,1H),4.41-4.29(m,4H),3.95-3.90(m,2H),3.88-3.82(m,2H),3.76(s,4H),3.63-3.53(m,2H),2.73-2.65(m,1H),2.63(s,3H),2.58-2.47(m,1H),2.44-2.33(m,1H),2.27-2.17(m,1H),1.79(d,J＝7.0Hz,3H)。MS-ESI计算值[M+H] +545,实测值545。 Compound 22-6 (500 mg, 775 μmol) was dissolved in anhydrous methanol (5 mL), hydrogen chloride methanol solution (4 mol/L, 10.0 mL) was added to the reaction solution, and the reaction was stirred at 25° C. for 2 hours. The residue after the reaction solution was concentrated under reduced pressure was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Genimi NX C18 150mm×40mm×5μm; mobile phase: 0.05% hydrochloric acid-acetonitrile; gradient: acetonitrile: 1%-25%, 10 min) to obtain the hydrochloride salt of compound 22. The hydrochloride of compound 22 was analyzed by SFC (column: Chiralpak AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol :5%-40%). Measured ee value, ee%=100.00%, RT=2.354min. 1 H NMR (400MHz, CD 3 OD) δ 8.27-8.21 (m, 1H), 8.09-7.92 (m, 2H), 7.77-7.70 (m, 1H), 7.62-7.48 (m, 2H), 7.12 ( s,1H),5.95-5.87(m,1H),5.22-5.08(m,1H),4.41-4.29(m,4H),3.95-3.90(m,2H),3.88-3.82(m,2H), 3.76(s, 4H), 3.63-3.53(m, 2H), 2.73-2.65(m, 1H), 2.63(s, 3H), 2.58-2.47(m, 1H), 2.44-2.33(m, 1H), 2.27-2.17 (m, 1H), 1.79 (d, J=7.0Hz, 3H). MS-ESI calculated [M+H] + 545, found 545.
实施例23Example 23
Figure PCTCN2022082591-appb-000140
Figure PCTCN2022082591-appb-000140
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000141
Figure PCTCN2022082591-appb-000141
第一步first step
氮气保护下将化合物23-1(430mg,1.62mmol)溶于甲苯(10mL)中,加入3-2(642mg,1.78mmol)和双(三苯基膦)二氯化钯(113mg,162μmol),在120℃下搅拌反应12小时。向反应液加入饱和氟化钾水溶液(20mL),用乙酸乙酯(20mL×2)萃取,无水硫酸钠干燥有机相,过滤浓缩得到化合物23-2。Compound 23-1 (430 mg, 1.62 mmol) was dissolved in toluene (10 mL) under nitrogen protection, 3-2 (642 mg, 1.78 mmol) and bis(triphenylphosphine)palladium dichloride (113 mg, 162 μmol) were added, The reaction was stirred at 120°C for 12 hours. Saturated potassium fluoride aqueous solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 23-2.
第二步second step
将化合物23-2(415mg,1.61mmol)溶于丙酮(15mL)中,滴加盐酸溶液(12mol/L,1.00mL),在20℃下搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～0/1,V/V),得到化合物23-3。MS-ESI计算值[M+H] +230,实测值230。 Compound 23-2 (415 mg, 1.61 mmol) was dissolved in acetone (15 mL), hydrochloric acid solution (12 mol/L, 1.00 mL) was added dropwise, and the reaction was stirred at 20° C. for 1 hour. Saturated aqueous sodium bicarbonate solution was added to the reaction solution to basify the pH to 8, extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. After concentration, the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V) to obtain compound 23-3. MS-ESI calculated [M+H] + 230, found 230.
第三步third step
将化合物23-3(186mg,679μmol)溶于四氢呋喃(10mL)中,加入A-6(123mg,1.02mmol)和钛酸四乙酯(310mg,1.36mmol),在80℃下搅拌反应48小时后,向反应液中加入水(50mL),用乙酸乙酯(50mL×1)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～10/1,V/V)分离纯化得到化合物23-4。MS-ESI计算值[M+H] +333,实测值333。 Compound 23-3 (186 mg, 679 μmol) was dissolved in tetrahydrofuran (10 mL), A-6 (123 mg, 1.02 mmol) and tetraethyl titanate (310 mg, 1.36 mmol) were added, and the reaction was stirred at 80 °C for 48 hours. , water (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×1), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) was used for separation and purification to obtain compound 23-4. MS-ESI calculated [M+H] + 333, found 333.
第四步the fourth step
将化合物23-4(255mg,676μmol)溶于四氢呋喃(10mL)中,在0℃下加入硼氢化钠(30.7mg,811μmol),在20℃下搅拌反应1小时。向反应液中加入水(20mL),用乙酸乙酯(20mL×1)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～10/1,V/V)分离纯化得到化合物23-5。MS-ESI计算值[M+H] +335,实测值335。 Compound 23-4 (255 mg, 676 μmol) was dissolved in tetrahydrofuran (10 mL), sodium borohydride (30.7 mg, 811 μmol) was added at 0°C, and the reaction was stirred at 20°C for 1 hour. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×1), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel Column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) was used for separation and purification to obtain compound 23-5. MS-ESI calculated [M+H] + 335, found 335.
第五步the fifth step
将化合物23-5(200mg,522μmol)溶于二氧六环(5mL)中,加入氯化氢二氧六环溶液(4mol/L,2.00mL),在20℃下搅拌反应12小时。反应液减压浓缩,得到化合物23-6的盐酸盐。MS-ESI计算值[M+H-17] +214,实测值214。 Compound 23-5 (200 mg, 522 μmol) was dissolved in dioxane (5 mL), hydrogen chloride dioxane solution (4 mol/L, 2.00 mL) was added, and the reaction was stirred at 20° C. for 12 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride of compound 23-6. MS-ESI calculated [M+H-17] + 214, found 214.
第六步Step 6
将化合物23-6的盐酸盐(80.0mg,300μmol)溶于二甲基亚砜(3mL)中,加入1-8(189mg,330μmol),滴加N,N-二异丙基乙胺(116mg,900μmol),在90℃下搅拌反应12小时。过滤,减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:10％-40％,10min),得到化合物23的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.11(s,1H),7.45-7.38(m,1H),7.36-7.30(m,1H),7.26-7.20(m,1H),7.10(s,1H),5.86-5.77(m,1H),4.37-4.27(m,4H),3.96-3.89(m,2H),3.88-3.81(m,2H),3.78-3.71(m,4H),3.55-3.43(m,2H),2.98-2.83(m,2H),2.63(s,1H),2.60-2.45(m,2H),2.30-2.13(m,2H),1.71(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +519,实测值519。 The hydrochloride of compound 23-6 (80.0 mg, 300 μmol) was dissolved in dimethyl sulfoxide (3 mL), 1-8 (189 mg, 330 μmol) was added, and N,N-diisopropylethylamine ( 116 mg, 900 μmol), and the reaction was stirred at 90 °C for 12 hours. Filter and concentrate under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 10%-40%, 10min) to obtain compound 23. Hydrochloride. 1 H NMR (400MHz, CD 3 OD) δ 8.11(s, 1H), 7.45-7.38(m, 1H), 7.36-7.30(m, 1H), 7.26-7.20(m, 1H), 7.10(s, 1H), 5.86-5.77(m, 1H), 4.37-4.27(m, 4H), 3.96-3.89(m, 2H), 3.88-3.81(m, 2H), 3.78-3.71(m, 4H), 3.55- 3.43(m, 2H), 2.98-2.83(m, 2H), 2.63(s, 1H), 2.60-2.45(m, 2H), 2.30-2.13(m, 2H), 1.71(d, J=6.8Hz, 3H). MS-ESI calculated [M+H] + 519, found 519.
实施例24Example 24
Figure PCTCN2022082591-appb-000142
Figure PCTCN2022082591-appb-000142
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000143
Figure PCTCN2022082591-appb-000143
第一步first step
将化合物22的盐酸盐(162mg,248μmol)和化合物24-1(47.7mg,272μmol)和苯并***-1-氧代-三(二甲氨基磷)六氟磷盐(110mg,248μmol)溶于无水N,N-二甲基甲酰胺(5mL)中,向反应液中加入N,N-二异丙基乙胺(86.3μL,495μmol)和苯并***-1-氧代-三(二甲氨基磷)六氟磷盐(110mg,248μmol),在25℃下搅拌反应2小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex Genimi NX C18 150mm×40mm×5μm；流动相:0.05％盐酸-乙腈；梯度:乙腈:1％-30％,10min)得到化合物24的盐酸盐。化合物24的盐酸盐经SFC(色谱柱:Chiralcel OD-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％, RT＝2.354min。 1H NMR(400MHz,CD 3OD)δ8.27(s,1H),7.94(s,1H),7.88(s,1H),7.67-7.63(m,1H),7.60-7.56(m,1H),7.55-7.48(m,1H),7.15(s,1H),5.94-5.86(m,1H),5.23(t,J＝8.0Hz,1H),4.38-4.33(m,4H),4.21(d,J＝8.0Hz,1H),4.13-4.05(m,1H),3.94-3.91(m,2H),3.87-3.93(m,2H),3.76(s,4H),3.65(s,3H),2.63(s,3H),2.60-2.54(m,1H),2.33-2.13(m,3H),2.09-2.01(m,1H),1.79(d,J＝8.0Hz,3H),0.99-0.83(m,7H)。MS-ESI计算值[M+H] +702,实测值702。 The hydrochloride salt of compound 22 (162 mg, 248 μmol) and compound 24-1 (47.7 mg, 272 μmol) and benzotriazole-1-oxo-tris(dimethylaminophosphorus) hexafluorophosphorus salt (110 mg, 248 μmol) Dissolved in anhydrous N,N-dimethylformamide (5mL), to the reaction solution were added N,N-diisopropylethylamine (86.3μL, 495μmol) and benzotriazole-1-oxo- Tris(dimethylaminophosphorus)hexafluorophosphorus salt (110 mg, 248 μmol) was stirred at 25°C for 2 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Phenomenex Genimi NX C18 150mm×40mm×5μm; mobile phase: 0.05% hydrochloric acid-acetonitrile; gradient: acetonitrile: 1%-30%, 10min) to obtain the hydrochloride salt of compound 24. The hydrochloride of compound 24 was purified by SFC (column: Chiralcel OD-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol :5%-40%). Measured ee value, ee%=100.00%, RT=2.354min. 1 H NMR (400MHz, CD 3 OD) δ 8.27(s, 1H), 7.94(s, 1H), 7.88(s, 1H), 7.67-7.63(m, 1H), 7.60-7.56(m, 1H) ,7.55-7.48(m,1H),7.15(s,1H),5.94-5.86(m,1H),5.23(t,J＝8.0Hz,1H),4.38-4.33(m,4H),4.21(d , J=8.0Hz, 1H), 4.13-4.05(m, 1H), 3.94-3.91(m, 2H), 3.87-3.93(m, 2H), 3.76(s, 4H), 3.65(s, 3H), 2.63(s, 3H), 2.60-2.54(m, 1H), 2.33-2.13(m, 3H), 2.09-2.01(m, 1H), 1.79(d, J=8.0Hz, 3H), 0.99-0.83( m, 7H). MS-ESI calculated [M+H] + 702, found 702.
实施例25Example 25
Figure PCTCN2022082591-appb-000144
Figure PCTCN2022082591-appb-000144
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000145
Figure PCTCN2022082591-appb-000145
第一步first step
将化合物25-1(30.0g,200mmol)溶于甲醇(20mL)中,加入浓硫酸(600μL,11.3mmol),在60℃下搅拌反应2小时。向反应液中加入饱和碳酸氢钠溶液(30mL),用乙酸乙酯(30mL×3)萃取,过滤,将滤液减压浓缩得化合物25-2。 1H NMR(400MHz,CDCl 3)δ4.57(d,J＝4.0Hz,2H),3.87(s,6H),3.24(s,2H)。 Compound 25-1 (30.0 g, 200 mmol) was dissolved in methanol (20 mL), concentrated sulfuric acid (600 μL, 11.3 mmol) was added, and the reaction was stirred at 60° C. for 2 hours. Saturated sodium bicarbonate solution (30 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), filtered, and the filtrate was concentrated under reduced pressure to obtain compound 25-2. 1 H NMR (400 MHz, CDCl 3 ) δ 4.57 (d, J=4.0 Hz, 2H), 3.87 (s, 6H), 3.24 (s, 2H).
第二步second step
将化合物25-2(3.00g,16.8mmol)溶于碘甲烷(10mL)中,加入氧化银(9.76g,42.1mmol),在45℃ 下搅拌反应10小时。将反应液过滤,将滤液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离纯化得得化合物25-3。 1H NMR(400MHz,CDCl 3)δ4.19(s,2H),3.77(s,6H),3.42(s,6H)。 Compound 25-2 (3.00 g, 16.8 mmol) was dissolved in iodomethane (10 mL), silver oxide (9.76 g, 42.1 mmol) was added, and the reaction was stirred at 45° C. for 10 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V) to obtain compound 25-3. 1 H NMR (400 MHz, CDCl 3 ) δ 4.19 (s, 2H), 3.77 (s, 6H), 3.42 (s, 6H).
第三步third step
将化合物25-3(1.60g,7.76mmol)溶于四氢呋喃(30mL)中,0℃下加入四氢锂铝(589mg,15.5mmol),在25℃下搅拌反应2小时。向反应液中加入水(1mL),无水硫酸镁干燥,过滤,将滤液减压浓缩得化合物25-4。 1H NMR(400MHz,CDCl 3)δ3.80(d,J＝12.0Hz,2H),3.69(d,J＝12.0Hz,2H),3.51-3.45(m,8H),2.17(s,2H)。 Compound 25-3 (1.60 g, 7.76 mmol) was dissolved in tetrahydrofuran (30 mL), lithium aluminum tetrahydride (589 mg, 15.5 mmol) was added at 0°C, and the reaction was stirred at 25°C for 2 hours. Water (1 mL) was added to the reaction solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 25-4. 1 H NMR (400 MHz, CDCl 3 ) δ 3.80 (d, J=12.0 Hz, 2H), 3.69 (d, J=12.0 Hz, 2H), 3.51-3.45 (m, 8H), 2.17 (s, 2H) .
第四步the fourth step
-78℃下将化合物25-4(1.20g,7.99mmol)溶于吡啶(25mL)中,加入对甲苯磺酰氯(4.57mg,24.0mmol),在25℃下搅拌反应12小时。0℃下向反应液中加入冰水,过滤得化合物25-5。 1H NMR(400MHz,CDCl 3)δ7.78(d,J＝8.0Hz,4H),7.36(d,J＝8.0Hz,4H),4.16-4.12(m,2H),4.07-4.02(m,2H),3.52-3.49(m,2H),3.29(m,6H),2.46(s,6H)。 Compound 25-4 (1.20 g, 7.99 mmol) was dissolved in pyridine (25 mL) at -78 °C, p-toluenesulfonyl chloride (4.57 mg, 24.0 mmol) was added, and the reaction was stirred at 25 °C for 12 hours. Ice water was added to the reaction solution at 0°C, and compound 25-5 was obtained by filtration. 1 H NMR (400 MHz, CDCl 3 ) δ 7.78 (d, J=8.0 Hz, 4H), 7.36 (d, J=8.0 Hz, 4H), 4.16-4.12 (m, 2H), 4.07-4.02 (m, 2H), 3.52-3.49(m, 2H), 3.29(m, 6H), 2.46(s, 6H).
第五步the fifth step
将化合物25-5(587mg,3.05mmol)和化合物1-4(1.40g,3.05mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入碳酸钾(1.69g,12.2mmol),在80℃下搅拌反应12小时。将反应液过滤,将滤液减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～5/1,V/V)分离纯化得得化合物25-6。Compound 25-5 (587 mg, 3.05 mmol) and compound 1-4 (1.40 g, 3.05 mmol) were dissolved in N,N-dimethylformamide (30 mL), potassium carbonate (1.69 g, 12.2 mmol) was added, The reaction was stirred at 80°C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～5/1, V/V) to obtain compound 25-6.
第六步Step 6
氮气保护下将化合物25-6(400mg,653μmol)和化合物1-7(297mg,979μmol)溶于二氯甲烷(25mL)中,加入4-二甲氨基吡啶(7.98mg,65.3μmol)和三乙胺(273μL,1.96mmol),在25℃下搅拌反应12小时。将反应液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离纯化得得化合物25-7。 1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.45(s,1H),7.21(s,2H),4.60-4.54(m,1H),4.47-4.40(m,1H),4.38-4.27(m,4H),3.58-3.53(m,8H),2.97-2.89(m,1H),2.53(s,3H),1.28-1.25(m,18H)。MS-ESI计算值[M+H] +573,实测值573。 Compound 25-6 (400 mg, 653 μmol) and compound 1-7 (297 mg, 979 μmol) were dissolved in dichloromethane (25 mL) under nitrogen protection, and 4-dimethylaminopyridine (7.98 mg, 65.3 μmol) and triethylamine were added. amine (273 μL, 1.96 mmol), and the reaction was stirred at 25° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 25-7. 1 H NMR (400MHz, CDCl 3 )δ7.72(s,1H), 7.45(s,1H), 7.21(s,2H), 4.60-4.54(m,1H), 4.47-4.40(m,1H), 4.38-4.27(m,4H), 3.58-3.53(m,8H), 2.97-2.89(m,1H), 2.53(s,3H), 1.28-1.25(m,18H). MS-ESI calculated [M+H] + 573, found 573.
第六步Step 6
氮气保护下将化合物25-7(100mg,175μmol)溶于二甲亚砜(5mL)中,向反应液中化合物5-9(56.1mg,227μmol),N,N-二异丙基乙胺(91.2μL,524μmol),在90℃下搅拌反应25小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex Genimi NX C18 80mm×30mm×3μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈:42％-72％,9min)得到化合物25。化合物25经SFC(色谱柱:Chiralpak AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％,RT＝3.662min和3.824min。 1H NMR(400MHz,CD 3OD)δ7.94(s,1H),7.55-7.49(m,1H),7.39-7.30(s,1H),7.18-7.11(m,2H),5.86-5.80(m,1H),4.59-4.54(m,1H),4.42-4.31(m,2H),4.25m 4.17(m,1H),3.59-3.48(m,8H),2.37(s,3H),1.66-1.62(m,1H),1.63(d,J＝4.0Hz,2H),1.30(d,J＝8.0Hz,6H)。MS-ESI计算值[M+H] +536,实测值536。 Compound 25-7 (100 mg, 175 μmol) was dissolved in dimethyl sulfoxide (5 mL) under nitrogen protection, and into the reaction solution compound 5-9 (56.1 mg, 227 μmol), N,N-diisopropylethylamine ( 91.2 μL, 524 μmol), and the reaction was stirred at 90 °C for 25 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Phenomenex Genimi NX C18 80mm×30mm×3μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile: 42%-72%, 9min) to obtain compound 25. Compound 25 was subjected to SFC (chromatographic column: Chiralpak AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%). Measured ee value, ee%=100.00%, RT=3.662min and 3.824min. 1 H NMR (400MHz, CD 3 OD) δ 7.94(s, 1H), 7.55-7.49(m, 1H), 7.39-7.30(s, 1H), 7.18-7.11(m, 2H), 5.86-5.80( m, 1H), 4.59-4.54(m, 1H), 4.42-4.31(m, 2H), 4.25m 4.17(m, 1H), 3.59-3.48(m, 8H), 2.37(s, 3H), 1.66- 1.62 (m, 1H), 1.63 (d, J=4.0Hz, 2H), 1.30 (d, J=8.0Hz, 6H). MS-ESI calculated [M+H] + 536, found 536.
实施例26Example 26
Figure PCTCN2022082591-appb-000146
Figure PCTCN2022082591-appb-000146
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000147
Figure PCTCN2022082591-appb-000147
第一步first step
将化合物25-2(5.00g,28.1mmol)溶于氘代碘甲烷(10mL)中,加入氧化银(16.3g,70.2mmol),在45℃下搅拌反应10小时。将反应液过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离纯化得得化合物26-1。 1H NMR(400MHz,CDCl 3)δ4.20(s,2H),3.77(s,6H)。 Compound 25-2 (5.00 g, 28.1 mmol) was dissolved in deuterated iodomethane (10 mL), silver oxide (16.3 g, 70.2 mmol) was added, and the reaction was stirred at 45° C. for 10 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V) to obtain compound 26-1. 1 H NMR (400 MHz, CDCl 3 ) δ 4.20 (s, 2H), 3.77 (s, 6H).
第二步second step
将化合物26-1(4.90g,23.1mmol)溶于四氢呋喃(50mL)中,0℃下加入四氢锂铝(1.75g,46.2mmol),在25℃下搅拌反应2小时。向反应液中加入水(2mL),无水硫酸镁干燥,过滤,将滤液减压浓缩的剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离纯化化合物26-2。 1H NMR(400MHz,CDCl 3)δ3.85-3.75(m,2H),3.70-3.62(m,2H),3.46-3.39(m,2H),2.82(s,2H)。 Compound 26-1 (4.90 g, 23.1 mmol) was dissolved in tetrahydrofuran (50 mL), lithium aluminum tetrahydride (1.75 g, 46.2 mmol) was added at 0°C, and the reaction was stirred at 25°C for 2 hours. Water (2 mL) was added to the reaction solution, dried over anhydrous magnesium sulfate, filtered, and the residue obtained by concentrating the filtrate under reduced pressure was subjected to silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V ) isolated and purified compound 26-2. 1 H NMR (400 MHz, CDCl 3 ) δ 3.85-3.75 (m, 2H), 3.70-3.62 (m, 2H), 3.46-3.39 (m, 2H), 2.82 (s, 2H).
第四步the fourth step
-78℃下将化合物26-2(1.50g,9.60mmol)溶于吡啶(15mL)中,加入化合物对甲苯磺酰氯(7.32mg,38.4mmol),在25℃下搅拌反应2小时。0℃下向反应液中加入冰水,过滤得化合物26-3。 1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.0Hz,4H),7.37(d,J＝8.0Hz,4H),4.17-4.11(m,2H),4.08-4.02(m,2H),3.53-3.48(m,2H),2.47(s,6H)。 Compound 26-2 (1.50 g, 9.60 mmol) was dissolved in pyridine (15 mL) at -78 °C, compound p-toluenesulfonyl chloride (7.32 mg, 38.4 mmol) was added, and the reaction was stirred at 25 °C for 2 hours. Ice water was added to the reaction solution at 0°C, and compound 26-3 was obtained by filtration. 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J=8.0 Hz, 4H), 7.37 (d, J=8.0 Hz, 4H), 4.17-4.11 (m, 2H), 4.08-4.02 (m, 2H), 3.53-3.48 (m, 2H), 2.47 (s, 6H).
第五步the fifth step
将化合物26-3(2.80g,6.03mmol)和化合物1-4(1.16g,6.03mmol)溶于N,N-二甲基甲酰胺(30mL)中,加入碳酸钾(3.33g,24.1mmol),在80℃下搅拌反应12小时。将反应液过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～5/1,V/V)分离纯化得得化合物26-4。Compound 26-3 (2.80 g, 6.03 mmol) and compound 1-4 (1.16 g, 6.03 mmol) were dissolved in N,N-dimethylformamide (30 mL), and potassium carbonate (3.33 g, 24.1 mmol) was added. , the reaction was stirred at 80 °C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～5/1, V/V) to obtain compound 26-4.
第六步Step 6
氮气保护下将化合物26-4(1.2mg,3.84mmol)和化合物1-8(1.75g,5.76mmol)溶于二氯甲烷(25mL)中,加入4-二甲氨基吡啶(46.9mg,384μmol)和三乙胺(1.60mL,11.5mmol),在25℃下搅拌反应12小时。将反应液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离纯化得化合物26-5。 1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.45(s,1H),7.21(s,2H),4.60-4.53(m,1H),4.47-4.40(m,1H),4.39-4.25(m,4H),3.58-3.52(m,2H),2.99-2.88(m,1H),2.53(s,3H),1.31-1.24(m,18H)。MS-ESI计算值[M+H] +579,实测值579。 Compound 26-4 (1.2 mg, 3.84 mmol) and compound 1-8 (1.75 g, 5.76 mmol) were dissolved in dichloromethane (25 mL) under nitrogen protection, and 4-dimethylaminopyridine (46.9 mg, 384 μmol) was added. and triethylamine (1.60 mL, 11.5 mmol), and the reaction was stirred at 25 °C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 26-5. 1 H NMR (400MHz, CDCl 3 ) δ 7.72(s, 1H), 7.45(s, 1H), 7.21(s, 2H), 4.60-4.53(m, 1H), 4.47-4.40(m, 1H), 4.39-4.25(m, 4H), 3.58-3.52(m, 2H), 2.99-2.88(m, 1H), 2.53(s, 3H), 1.31-1.24(m, 18H). MS-ESI calculated [M+H] + 579, found 579.
第六步Step 6
氮气保护下将化合物26-5(200mg,346μmol)溶于二甲亚砜(15mL)中,向反应液中化合物5-9(128mg,518μmol),N,N-二异丙基乙胺(181μL,1.04mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex Genimi NX C18 80mm×30mm×3μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈:36％-66％,9min)得到化合物26。化合物26经SFC(色谱柱:Chiralpak AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％,RT＝3.647min和3.802min。 1H NMR(400MHz,CD 3OD)δ7.94(s,1H),7.52(t,J＝8.0Hz,1H),7.35(t,J＝8.0Hz,1H),7.17-7.12(m,2H),5.87-5.79(m,1H),4.57(d,J＝12.0Hz,1H),4.41-4.31(m,2H),4.25-4.17(m,1H),3.59-3.51(m,2H),2.37(s,3H),1.63(d,J＝4.0Hz,3H),1.30(d,J＝8.0Hz,6H)。MS-ESI计算值[M+H] +542,实测值542。 Compound 26-5 (200 mg, 346 μmol) was dissolved in dimethyl sulfoxide (15 mL) under nitrogen protection, and compound 5-9 (128 mg, 518 μmol), N,N-diisopropylethylamine (181 μL) were added to the reaction solution. , 1.04 mmol), and the reaction was stirred at 90 °C for 12 h. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Phenomenex Genimi NX C18 80mm×30mm×3μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile: 36%-66%, 9min) to obtain compound 26. Compound 26 was subjected to SFC (chromatographic column: Chiralpak AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%). Measured ee value, ee%=100.00%, RT=3.647min and 3.802min. 1 H NMR (400 MHz, CD 3 OD) δ 7.94 (s, 1H), 7.52 (t, J=8.0 Hz, 1H), 7.35 (t, J=8.0 Hz, 1H), 7.17-7.12 (m, 2H) ), 5.87-5.79(m, 1H), 4.57(d, J=12.0Hz, 1H), 4.41-4.31(m, 2H), 4.25-4.17(m, 1H), 3.59-3.51(m, 2H), 2.37 (s, 3H), 1.63 (d, J=4.0 Hz, 3H), 1.30 (d, J=8.0 Hz, 6H). MS-ESI calculated [M+H] + 542, found 542.
实施例27Example 27
Figure PCTCN2022082591-appb-000148
Figure PCTCN2022082591-appb-000148
合成路线:synthetic route:
Figure PCTCN2022082591-appb-000149
Figure PCTCN2022082591-appb-000149
第一步first step
将化合物27-1(500mg,2.37mmol)溶于异丙醇(10mL)中,加入甲胺乙醇溶液(1.23g,11.9mmol,30％纯度)和钛酸四异丙酯(1.48g,5.21mmol),在35℃下搅拌反应16小时。0℃下加入硼氢化钠(134mg,3.55mmol),25℃搅拌反应1小时。将反应液倒入冰水(10mL)中,过滤,滤液用乙酸乙酯(10mL×2)萃取,减压浓缩得到化合物27-2。MS-ESI计算值[M+H] +226和228,实测值226和228。 Compound 27-1 (500 mg, 2.37 mmol) was dissolved in isopropanol (10 mL), methylamine ethanol solution (1.23 g, 11.9 mmol, 30% purity) and tetraisopropyl titanate (1.48 g, 5.21 mmol) were added ), and the reaction was stirred at 35°C for 16 hours. Sodium borohydride (134 mg, 3.55 mmol) was added at 0°C, and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into ice water (10 mL), filtered, the filtrate was extracted with ethyl acetate (10 mL×2), and concentrated under reduced pressure to obtain compound 27-2. MS-ESI calculated [M+H] + 226 and 228, found 226 and 228.
第二步second step
将化合物27-2(535mg,2.37mmol)溶于二氯甲烷(15mL)中,加入二碳酸二叔丁酯(1.03g,4.73mmol)和三乙胺(718mg,7.10mmol),在25℃下搅拌反应12小时。将反应液减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～10/1,V/V)分离纯化得到化合物27-3。MS-ESI计算值[M+H] +326和328,实测值326和328。 Compound 27-2 (535 mg, 2.37 mmol) was dissolved in dichloromethane (15 mL), di-tert-butyl dicarbonate (1.03 g, 4.73 mmol) and triethylamine (718 mg, 7.10 mmol) were added, and the mixture was heated at 25 °C. The reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/0-10/1, V/V) to obtain compound 27-3. MS-ESI calculated [M+H] + 326 and 328, found 326 and 328.
第三步third step
在氮气保护下，将化合物27-3(700mg,1.80mmol)溶于甲苯(10mL)中,加入化合物3-2(1.57g,4.35mmol)和双三苯基磷二氯化钯(126mg,180μmol),反应液在120℃搅拌反应12小时。加入饱和氟化钾溶液(5mL)淬灭,用乙酸乙酯(5mL×2)萃取。过滤,减压浓缩得粗产品可直接用于投入下一步。Under nitrogen protection, compound 27-3 (700 mg, 1.80 mmol) was dissolved in toluene (10 mL), compound 3-2 (1.57 g, 4.35 mmol) and bistriphenylphosphonium palladium dichloride (126 mg, 180 μmol) were added ), the reaction solution was stirred at 120 °C for 12 hours. Saturated potassium fluoride solution (5 mL) was added to quench, and it was extracted with ethyl acetate (5 mL×2). Filter and concentrate under reduced pressure to get the crude product which can be directly used in the next step.
第四步the fourth step
在氮气保护下，将化合物27-4(570mg,1.80mmol)溶于丙酮(12mL)中,0℃下逐滴加入盐酸溶液(12M,1.20mL),在25℃搅拌反应1小时。将反应液减压浓缩得到化合物27-5。MS-ESI计算值[M+H] +290,实测 值290。 Under nitrogen protection, compound 27-4 (570 mg, 1.80 mmol) was dissolved in acetone (12 mL), hydrochloric acid solution (12 M, 1.20 mL) was added dropwise at 0 °C, and the reaction was stirred at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 27-5. MS-ESI calculated [M+H] + 290, found 290.
第五步the fifth step
将化合物27-5(400mg,1.38mmol)溶于甲醇(3mL)中,加入盐酸甲醇溶液(4M,1.38mL),在25℃搅拌反应1小时。将反应液减压浓缩得到化合物27-6的盐酸盐。MS-ESI计算值[M+H] +190,实测值190。 Compound 27-5 (400 mg, 1.38 mmol) was dissolved in methanol (3 mL), methanol solution of hydrochloric acid (4 M, 1.38 mL) was added, and the reaction was stirred at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 27-6. MS-ESI calculated [M+H] + 190, found 190.
第六步Step 6
将化合物27-6的盐酸盐(300mg,1.33mmol)溶于四氢呋喃(5mL)中,加入氯甲酸烯丙酯(240mg,1.99mmol)和碳酸氢钠(1.12g,13.3mmol),在25℃下搅拌反应12小时。将反应液减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～10/1,V/V)分离纯化得到化合物27-7。MS-ESI计算值[M+H] +274,实测值274。 The hydrochloride salt of compound 27-6 (300 mg, 1.33 mmol) was dissolved in tetrahydrofuran (5 mL), allyl chloroformate (240 mg, 1.99 mmol) and sodium bicarbonate (1.12 g, 13.3 mmol) were added, and the mixture was heated at 25 °C. The reaction was stirred for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 1/0-10/1, V/V) to obtain compound 27-7. MS-ESI calculated [M+H] + 274, found 274.
第七步Step 7
将化合物27-7(304mg,1.11mmol)溶于四氢呋喃(10mL)中,加入化合物A-6(404mg,3.34mmol)和钛酸四乙酯(1.27g,5.56mmol),在80℃下搅拌反应12小时后，得到化合物27-8的四氢呋喃混合液。反应液不经处理直接用于下一步。MS-ESI计算值[M+H] +377,实测值377。 Compound 27-7 (304 mg, 1.11 mmol) was dissolved in tetrahydrofuran (10 mL), compound A-6 (404 mg, 3.34 mmol) and tetraethyl titanate (1.27 g, 5.56 mmol) were added, and the reaction was stirred at 80 °C After 12 hours, a tetrahydrofuran mixture of compound 27-8 was obtained. The reaction solution was directly used in the next step without treatment. MS-ESI calculated [M+H] + 377, found 377.
第八步Step 8
将化合物27-8的四氢呋喃混合液,在-5℃下加入硼氢化钠(50.4mg,1.33mmol),在25℃下搅拌反应1小时。向反应液中加入水(1mL),用乙酸乙酯(1mL×2)萃取,有机相用饱和食盐水(1mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,5/1～2/1,V/V)分离纯化得到化合物27-9。MS-ESI计算值[M+H] +379,实测值379。 To the tetrahydrofuran mixture of compound 27-8, sodium borohydride (50.4 mg, 1.33 mmol) was added at -5°C, and the reaction was stirred at 25°C for 1 hour. Water (1 mL) was added to the reaction solution, extracted with ethyl acetate (1 mL×2), the organic phase was washed with saturated brine (1 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was washed with silica gel Column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) was used for separation and purification to obtain compound 27-9. MS-ESI calculated [M+H] + 379, found 379.
第九步Step 9
将化合物27-9(354mg,935μmol)溶于二氧六环(4mL)中,加入氯化氢二氧六环溶液(4mol/L,1.03mL)。反应液在25℃搅拌反应8小时。将反应液减压浓缩得到化合物27-10的盐酸盐。MS-ESI计算值[M+H] +275,实测值275。 Compound 27-9 (354 mg, 935 μmol) was dissolved in dioxane (4 mL), and a solution of hydrogen chloride in dioxane (4 mol/L, 1.03 mL) was added. The reaction solution was stirred at 25°C for 8 hours. The reaction solution was concentrated under reduced pressure to obtain the hydrochloride salt of compound 27-10. MS-ESI calculated [M+H] + 275, found 275.
第十步Step 10
在氮气保护下，将化合物27-10的盐酸盐(200mg,349μmol)溶于二甲亚砜(2mL)中,加入1-8(130mg,419μmol)和N,N-二异丙基乙胺(677mg,5.24mmol)。反应液在90℃搅拌反应12小时。反应液经制备高效液相色谱分离纯化(色谱柱:Phenomenex Gemini-NX 80mm×40mm×3μm；流动相:0.05％的氨水溶液-乙腈；梯度:乙腈:37％-67％,8min)得到化合物27-11。MS-ESI计算值[M+H] +563,实测值563。 Under nitrogen protection, the hydrochloride salt of compound 27-10 (200 mg, 349 μmol) was dissolved in dimethyl sulfoxide (2 mL), 1-8 (130 mg, 419 μmol) and N,N-diisopropylethylamine were added (677 mg, 5.24 mmol). The reaction solution was stirred and reacted at 90°C for 12 hours. The reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80mm×40mm×3μm; mobile phase: 0.05% ammonia solution-acetonitrile; gradient: acetonitrile: 37%-67%, 8min) to obtain compound 27 -11. MS-ESI calculated [M+H] + 563, found 563.
第十一步Step 11
氮气保护下,将化合物27-11(40.0mg,71.1μmol)溶于四氢呋喃(5mL)中,加入乙二胺(28.6mg,476μmol)和四(三苯基膦)钯(82.1mg,71.1μmol),反应液在65℃下搅拌12小时。反应液经过制备高效液相色谱法(色谱柱:Phenomenex Synergi C18 150mm×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈:22％-52％,9min)分离得到化合物27的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.25(s,1H),7.58(d,J＝7.6Hz,1H),7.53(s,1H),7.48(d,J＝7.6Hz,1H),7.18(s,1H),5.88-5.80(m,1H),4.77-4.69(m,1H),4.38-4.29(m,4H),3.93-3.88(m,2H),3.86-3.81(m,2H),3.76-3.71(m,4H),3.25-3.14(m,1H),3.08-2.94(m,1H),2.72(s,3H),2.62(s,3H),2.59-2.50(m,1H),2.32-2.19(m,1H),1.74 (d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +479,实测值479。 Under nitrogen protection, compound 27-11 (40.0 mg, 71.1 μmol) was dissolved in tetrahydrofuran (5 mL), ethylenediamine (28.6 mg, 476 μmol) and tetrakis(triphenylphosphine)palladium (82.1 mg, 71.1 μmol) were added , the reaction solution was stirred at 65°C for 12 hours. The reaction solution was separated by preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150mm×30mm×4μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 22%-52%, 9min) to obtain compound 27. Hydrochloride. 1 H NMR (400MHz, CD 3 OD) δ8.25(s, 1H), 7.58(d, J=7.6Hz, 1H), 7.53(s, 1H), 7.48(d, J=7.6Hz, 1H), 7.18(s, 1H), 5.88-5.80(m, 1H), 4.77-4.69(m, 1H), 4.38-4.29(m, 4H), 3.93-3.88(m, 2H), 3.86-3.81(m, 2H ),3.76-3.71(m,4H),3.25-3.14(m,1H),3.08-2.94(m,1H),2.72(s,3H),2.62(s,3H),2.59-2.50(m,1H) ), 2.32-2.19 (m, 1H), 1.74 (d, J=6.8Hz, 3H). MS-ESI calculated [M+H] + 479, found 479.
实施例28Example 28
Figure PCTCN2022082591-appb-000150
Figure PCTCN2022082591-appb-000150
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000151
Figure PCTCN2022082591-appb-000151
氮气保护下将化合物26-5(250mg,432μmol)溶于二甲亚砜(10mL)中,向反应液中化合物14-7(123mg,543μmol),N,N-二异丙基乙胺(226μL,1.30mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex Gemini-NX C18 80mm×40mm×3μm；流动相:0.05％氨水-乙腈；梯度:乙腈43％-73％,8min)得到粗产品,粗产品经高效液相色谱分离纯化(色谱柱:Phenomenex Gemini-NX C18 150mm×40mm×5μm；流动相:0.05％盐酸-乙腈；梯度:乙腈:30％-60％,10min)得到化合物28的盐酸盐。化合物28的盐酸经SFC(色谱柱:ChiralCel OJ-H 150mm×4.6mm×5μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％,RT＝2.963min和3.014min。 1H NMR(400MHz,CD 3OD)δ8.22(s,1H),7.65(t,J＝8.0Hz,1H),7.53(t,J＝8.0Hz,1H),730(t,J＝8.0Hz,1H),7.17(s,1H),7.00(t,J＝16.0Hz,1H),6.03-5.94(m,1H),4.73(d,J＝12.0Hz,1H),4.57-4.47(m,1H),4.37-4.23(m,2H),3.64-3.51(m,2H),2.58(s,3H),1.74(d,J＝8.0Hz,3H)。MS-ESI计算值[M+H] +484,实测值484。 Compound 26-5 (250 mg, 432 μmol) was dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and compound 14-7 (123 mg, 543 μmol), N,N-diisopropylethylamine (226 μL) were added to the reaction solution. , 1.30 mmol), and the reaction was stirred at 90 °C for 12 h. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Phenomenex Gemini-NX C18 80mm×40mm×3μm; mobile phase: 0.05% ammonia water-acetonitrile; gradient: acetonitrile 43%-73%, 8min) to obtain the crude product, which was subjected to high performance liquid chromatography Separation and purification (chromatographic column: Phenomenex Gemini-NX C18 150mm×40mm×5μm; mobile phase: 0.05% hydrochloric acid-acetonitrile; gradient: acetonitrile: 30%-60%, 10min) to obtain the hydrochloride salt of compound 28. The hydrochloric acid of compound 28 was analyzed by SFC (chromatographic column: ChiralCel OJ-H 150mm×4.6mm×5μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5 %-40%). Measured ee value, ee%=100.00%, RT=2.963min and 3.014min. 1 H NMR (400 MHz, CD 3 OD) δ 8.22 (s, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H), 730 (t, J=8.0 Hz, 1H), 7.17(s, 1H), 7.00(t, J=16.0Hz, 1H), 6.03-5.94(m, 1H), 4.73(d, J=12.0Hz, 1H), 4.57-4.47(m , 1H), 4.37-4.23 (m, 2H), 3.64-3.51 (m, 2H), 2.58 (s, 3H), 1.74 (d, J=8.0Hz, 3H). MS-ESI calculated [M+H] + 484, found 484.
实施例29Example 29
Figure PCTCN2022082591-appb-000152
Figure PCTCN2022082591-appb-000152
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000153
Figure PCTCN2022082591-appb-000153
第一步first step
将化合物29-1(50.0g,333mmol)溶于甲醇(30mL)中,加入浓硫酸(17.7mL,333mmol),在60℃下搅拌反应10小时。向反应液中加入饱和碳酸氢钠溶液(100mL),用乙酸乙酯(30mL×3)萃取,过滤,减压浓缩得化合物29-2。 1H NMR(400MHz,CDCl 3)δ4.56(s,2H),3.85(s,6H),3.36(s,2H)。 Compound 29-1 (50.0 g, 333 mmol) was dissolved in methanol (30 mL), concentrated sulfuric acid (17.7 mL, 333 mmol) was added, and the reaction was stirred at 60° C. for 10 hours. Saturated sodium bicarbonate solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), filtered, and concentrated under reduced pressure to obtain compound 29-2. 1 H NMR (400 MHz, CDCl 3 ) δ 4.56 (s, 2H), 3.85 (s, 6H), 3.36 (s, 2H).
第二步second step
将化合物29-2(12.3g,69.0mmol)溶于氘代碘甲烷(43mL)中,加入氧化银(48.0g,207mmol),在45℃下搅拌反应10小时。将反应液过滤,将滤液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离纯化得得化合物29-3。 1H NMR(400MHz,CDCl 3)δ4.21(d,J＝12.0Hz,2H),3.83-3.74(m,6H)。 Compound 29-2 (12.3 g, 69.0 mmol) was dissolved in deuterated iodomethane (43 mL), silver oxide (48.0 g, 207 mmol) was added, and the reaction was stirred at 45° C. for 10 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V) to obtain compound 29-3. 1 H NMR (400 MHz, CDCl 3 ) δ 4.21 (d, J=12.0 Hz, 2H), 3.83-3.74 (m, 6H).
第三步third step
将化合物29-3(7.00g,33.0mmol)溶于四氢呋喃(50mL)中,0℃下加入四氢锂铝(2.50g,66.0mmol),在25℃下搅拌反应2小时。向反应液中加入水(2.5mL),然后缓慢加入15％氢氧化钠水溶液(2.5mL)，再缓慢加入水(7.5mL),室温搅拌15分钟,无水硫酸镁干燥,过滤,减压浓缩得化合物29-4。 1H NMR(400MHz,CDCl 3)δ3.82(d,J＝12.0Hz,2H),3.69(d,J＝12.0Hz,2H),3.50-3.45(m,2H),2.58(s,2H)。 Compound 29-3 (7.00 g, 33.0 mmol) was dissolved in tetrahydrofuran (50 mL), lithium aluminum tetrahydride (2.50 g, 66.0 mmol) was added at 0°C, and the reaction was stirred at 25°C for 2 hours. Water (2.5 mL) was added to the reaction solution, then 15% aqueous sodium hydroxide solution (2.5 mL) was slowly added, then water (7.5 mL) was slowly added, stirred at room temperature for 15 minutes, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure Compound 29-4 was obtained. 1 H NMR (400 MHz, CDCl 3 ) δ 3.82 (d, J=12.0 Hz, 2H), 3.69 (d, J=12.0 Hz, 2H), 3.50-3.45 (m, 2H), 2.58 (s, 2H) .
第四步the fourth step
-78℃下将化合物29-4(3.60g,23.1mmol)溶于吡啶(45mL)中,加入对甲苯磺酰氯(17.6mg,92.2mmol),在25℃下搅拌反应12小时。0℃下向反应液中加入冰水,过滤得化合物29-5。 1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.0Hz,4H),7.37(d,J＝8.0Hz,4H),4.17-4.12(m,2H),4.08-4.02(m,2H),3.53-3.46(m,1H),3.53-3.46(m,1H),2.47(s,6H)。 Compound 29-4 (3.60 g, 23.1 mmol) was dissolved in pyridine (45 mL) at -78 °C, p-toluenesulfonyl chloride (17.6 mg, 92.2 mmol) was added, and the reaction was stirred at 25 °C for 12 hours. Ice water was added to the reaction solution at 0°C, and compound 29-5 was obtained by filtration. 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J=8.0 Hz, 4H), 7.37 (d, J=8.0 Hz, 4H), 4.17-4.12 (m, 2H), 4.08-4.02 (m, 2H), 3.53-3.46 (m, 1H), 3.53-3.46 (m, 1H), 2.47 (s, 6H).
第五步the fifth step
将化合物29-5(16.7g,36.0mmol)和化合物1-4(6.91g,36.0mmol)溶于N,N-二甲基甲酰胺(200mL) 中,加入碳酸钾(19.9g,144mmol),在80℃下搅拌反应12小时。将反应液过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～5/1,V/V)分离纯化得得化合物29-6。MS-ESI计算值[M+H] +313,实测值313。 Compound 29-5 (16.7 g, 36.0 mmol) and compound 1-4 (6.91 g, 36.0 mmol) were dissolved in N,N-dimethylformamide (200 mL), potassium carbonate (19.9 g, 144 mmol) was added, The reaction was stirred at 80°C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～5/1, V/V) to obtain compound 29-6. MS-ESI calculated [M+H] + 313, found 313.
第六步Step 6
氮气保护下将化合物29-6(3.00g,9.60mmol)和化合物1-7(4.36g,14.4mmol)溶于二氯甲烷(25mL)中,加入4-二甲氨基吡啶(117mg,960μmol)和三乙胺(4.01mL,28.8mmol),在25℃下搅拌反应12小时。将反应液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离纯化得化合物29-7。 1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.47(s,1H),7.22(s,2H),4.61-4.56(m,1H),4.48-4.42(m,1H),4.40-4.30(m,4H),3.58-3.54(m,2H),2.99-2.90(m,1H),2.55(s,3H),1.32-1.28(m,18H)。 Compound 29-6 (3.00 g, 9.60 mmol) and compound 1-7 (4.36 g, 14.4 mmol) were dissolved in dichloromethane (25 mL) under nitrogen protection, 4-dimethylaminopyridine (117 mg, 960 μmol) and 4-dimethylaminopyridine (117 mg, 960 μmol) were added. Triethylamine (4.01 mL, 28.8 mmol), and the reaction was stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 29-7. 1 H NMR (400MHz, CDCl 3 ) δ 7.74(s, 1H), 7.47(s, 1H), 7.22(s, 2H), 4.61-4.56(m, 1H), 4.48-4.42(m, 1H), 4.40-4.30(m, 4H), 3.58-3.54(m, 2H), 2.99-2.90(m, 1H), 2.55(s, 3H), 1.32-1.28(m, 18H).
第七步Step 7
氮气保护下将化合物29-7(200mg,346μmol)溶于二甲亚砜(10mL)中,向反应液中化合物5-9(128mg,518μmol),N,N-二异丙基乙胺(181μL,1.04mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Welch Xtimate C18 150mm×25mm×5μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈:37％-57％,10min)得到化合物29。化合物29经SFC(色谱柱:Chiralcel OJ-3100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝96.14％,RT＝2.311min。 1H NMR(400MHz,CD 3OD)δ7.93(s,1H),7.99-7.88(m,1H),7.41-7.29(m,1H),7.20-7.09(m,2H),5.89-5.77(m,1H),4.56(d,J＝12.0Hz,1H),4.41-4.28(m,2H),4.26-4.16(m,1H),3.54(s,2H),2.37(s,3H),1.69-1.53(m,3H),1.30(d,J＝8.0Hz,6H)。MS-ESI计算值[M+H] +542,实测值542。 Compound 29-7 (200 mg, 346 μmol) was dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and compound 5-9 (128 mg, 518 μmol), N,N-diisopropylethylamine (181 μL) were added to the reaction solution. , 1.04 mmol), and the reaction was stirred at 90 °C for 12 h. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Welch Xtimate C18 150mm×25mm×5μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile: 37%-57%, 10min) to obtain compound 29. Compound 29 was purified by SFC (chromatographic column: Chiralcel OJ-3100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%-40 %). Measured ee value, ee%=96.14%, RT=2.311min. 1 H NMR (400MHz, CD 3 OD) δ 7.93(s, 1H), 7.99-7.88(m, 1H), 7.41-7.29(m, 1H), 7.20-7.09(m, 2H), 5.89-5.77( m,1H),4.56(d,J＝12.0Hz,1H),4.41-4.28(m,2H),4.26-4.16(m,1H),3.54(s,2H),2.37(s,3H),1.69 -1.53(m, 3H), 1.30(d, J=8.0Hz, 6H). MS-ESI calculated [M+H] + 542, found 542.
实施例30Example 30
Figure PCTCN2022082591-appb-000154
Figure PCTCN2022082591-appb-000154
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000155
Figure PCTCN2022082591-appb-000155
氮气保护下将化合物29-7(200mg,346μmol)溶于二甲亚砜(10mL)中,向反应液中化合物14-7(98.1 mg,518μmol),N,N-二异丙基乙胺(181μL,1.04mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Welch Xtimate C18 150mm×25mm×5μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈37％-57％,10min)得到化合物30。化合物30经SFC(色谱柱:Chiralcel OJ-3100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％,RT＝2.204min。 1H NMR(400MHz,CD 3OD)δ7.93(s,1H),7.57(t,J＝8.0Hz,1H),7.46(t,J＝8.0Hz,1H),7.21(t,J＝8.0Hz,1H),7.15(s,1H),7.00(t,J＝12.0Hz,1H),5.85-5.75(m,1H),4.61-4.55(m,1H),4.42-4.30(m,2H),4.26-4.18(m,1H),3.60-3.50(m,2H),2.37(s,3H),1.65(d,J＝8.0Hz,3H)。MS-ESI计算值[M+H] +484,实测值484。 Compound 29-7 (200 mg, 346 μmol) was dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and compound 14-7 (98.1 mg, 518 μmol), N,N-diisopropylethylamine ( 181 μL, 1.04 mmol), and the reaction was stirred at 90 °C for 12 h. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Welch Xtimate C18 150mm×25mm×5μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile 37%-57%, 10min) to obtain compound 30. Compound 30 was subjected to SFC (chromatographic column: Chiralcel OJ-3100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%-40 %). Measured ee value, ee%=100.00%, RT=2.204min. 1 H NMR (400 MHz, CD 3 OD) δ 7.93 (s, 1H), 7.57 (t, J=8.0 Hz, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.21 (t, J=8.0 Hz, 1H), 7.15(s, 1H), 7.00(t, J＝12.0Hz, 1H), 5.85-5.75(m, 1H), 4.61-4.55(m, 1H), 4.42-4.30(m, 2H) , 4.26-4.18 (m, 1H), 3.60-3.50 (m, 2H), 2.37 (s, 3H), 1.65 (d, J=8.0Hz, 3H). MS-ESI calculated [M+H] + 484, found 484.
实施例31Example 31
Figure PCTCN2022082591-appb-000156
Figure PCTCN2022082591-appb-000156
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000157
Figure PCTCN2022082591-appb-000157
第一步first step
将化合物31-1(30.0g,333mmol)溶于甲醇(30mL)中,加入浓硫酸(500μL,9.38mmol),在60℃下搅拌反应2小时。向反应液中加入饱和碳酸氢钠溶液(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩得化合物31-2。 1H NMR(400MHz,CDCl 3)δ4.55(s,2H),3.83(s,6H),3.44(s,2H)。 Compound 31-1 (30.0 g, 333 mmol) was dissolved in methanol (30 mL), concentrated sulfuric acid (500 μL, 9.38 mmol) was added, and the reaction was stirred at 60° C. for 2 hours. Saturated sodium bicarbonate solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain Compound 31-2. 1 H NMR (400 MHz, CDCl 3 ) δ 4.55 (s, 2H), 3.83 (s, 6H), 3.44 (s, 2H).
第二步second step
将化合物31-2(12.3g,69.0mmol)溶于氘代碘甲烷(100mL)中,加入氧化银(48.0g,207mmol),在45℃下搅拌反应12小时。将反应液过滤,将滤液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到化合物31-3。 1H NMR(400MHz,CDCl 3)δ4.24(s,2H),3.81(s,6H)。 Compound 31-2 (12.3 g, 69.0 mmol) was dissolved in deuterated iodomethane (100 mL), silver oxide (48.0 g, 207 mmol) was added, and the reaction was stirred at 45° C. for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1-1/1, V/V) to obtain compound 31-3. 1 H NMR (400 MHz, CDCl 3 ) δ 4.24 (s, 2H), 3.81 (s, 6H).
第三步third step
将化合物31-3(7.00g,33.0mmol)溶于四氢呋喃(200mL)中,0℃下加入四氢锂铝(2.50g,66.0mmol),在25℃下搅拌反应2小时。向反应液中缓慢加入水(200mL),用乙酸乙酯(200mL×1)萃取,有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到化合物31-4。 1H NMR(400MHz,CDCl 3)δ3.82(d,J＝9.2Hz,2H),3.69(d,J＝10.8Hz,2H),3.55-3.42(m,2H),2.43(s,2H)。 Compound 31-3 (7.00 g, 33.0 mmol) was dissolved in tetrahydrofuran (200 mL), lithium aluminum tetrahydride (2.50 g, 66.0 mmol) was added at 0°C, and the reaction was stirred at 25°C for 2 hours. Water (200 mL) was slowly added to the reaction solution, extracted with ethyl acetate (200 mL×1), the organic phase was washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) was used for separation and purification to obtain compound 31-4. 1 H NMR (400 MHz, CDCl 3 ) δ 3.82 (d, J=9.2 Hz, 2H), 3.69 (d, J=10.8 Hz, 2H), 3.55-3.42 (m, 2H), 2.43 (s, 2H) .
第四步the fourth step
-78℃下将化合物31-4(7.20g,46.1mmol)溶于吡啶(100mL)中,加入对甲苯磺酰氯(35.2mg,184mmol),在25℃下搅拌反应12小时。向反应液中缓慢加入水(200mL),用乙酸乙酯(200mL×1)萃取,有机相用饱和食盐水(200mL×10)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离纯化得到化合物31-5。 1H NMR(400MHz,CDCl 3)δ7.79(d,J＝8.4Hz,4H),7.37(d,J＝8.4Hz,4H),4.17-4.12(m,2H),4.08-4.00(m,2H),3.55-3.45(m,2H),2.46(s,6H)。 Compound 31-4 (7.20 g, 46.1 mmol) was dissolved in pyridine (100 mL) at -78 °C, p-toluenesulfonyl chloride (35.2 mg, 184 mmol) was added, and the reaction was stirred at 25 °C for 12 hours. Water (200 mL) was slowly added to the reaction solution, extracted with ethyl acetate (200 mL×1), the organic phase was washed with saturated brine (200 mL×10), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) was used for separation and purification to obtain compound 31-5. 1 H NMR (400 MHz, CDCl 3 ) δ 7.79 (d, J=8.4 Hz, 4H), 7.37 (d, J=8.4 Hz, 4H), 4.17-4.12 (m, 2H), 4.08-4.00 (m, 2H), 3.55-3.45 (m, 2H), 2.46 (s, 6H).
第五步the fifth step
将化合物31-5(18.0g,38.7mmol)和化合物1-4(7.45g,38.7mmol)溶于N,N-二甲基甲酰胺(200mL)中,加入碳酸钾(21.4g,155mmol),在80℃下搅拌反应12小时。将反应液过滤,滤液减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～5/1,V/V)分离纯化得化合物31-6。MS-ESI计算值[M+H] +313,实测值313。 Compound 31-5 (18.0 g, 38.7 mmol) and compound 1-4 (7.45 g, 38.7 mmol) were dissolved in N,N-dimethylformamide (200 mL), potassium carbonate (21.4 g, 155 mmol) was added, The reaction was stirred at 80°C for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (dichloromethane/methanol, 100/1～5/1, V/V) to obtain compound 31-6. MS-ESI calculated [M+H] + 313, found 313.
第六步Step 6
氮气保护下将化合物31-6(5.30g,17.0mmol)和化合物1-7(7.71g,25.5mmol)溶于二氯甲烷(25mL)中,加入4-二甲氨基吡啶(207mg,1.70mmol)和三乙胺(7.09mL,50.9mmol),在25℃下搅拌反应12小时。向反应液中加入水(50mL),用二氯甲烷(50mL×1)萃取,有机相用饱和食盐水50mL×1)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离纯化得化合物31-7。MS-ESI计算值[M+H] +580,实测值580。 Compound 31-6 (5.30 g, 17.0 mmol) and compound 1-7 (7.71 g, 25.5 mmol) were dissolved in dichloromethane (25 mL) under nitrogen protection, and 4-dimethylaminopyridine (207 mg, 1.70 mmol) was added. and triethylamine (7.09 mL, 50.9 mmol), and the reaction was stirred at 25 °C for 12 hours. Water (50 mL) was added to the reaction solution, extracted with dichloromethane (50 mL×1), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was washed with silica gel Compound 31-7 was isolated and purified by column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V). MS-ESI calculated [M+H] + 580, found 580.
第七步Step 7
氮气保护下将化合物31-7(200mg,346μmol)溶于二甲亚砜(10mL)中,向反应液中化合物5-9(128mg,518μmol),N,N-二异丙基乙胺(181μL,1.04mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(20mL×5)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,剩余物经高效液相色谱分离纯化(色谱柱:Welch Xtimate C18 150mm×25mm×5μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈:38％-68％,10min)得到化合物31。化合物31经SFC(色谱柱:Chiralcel OJ-3 100mm×4.6mm I.D.,3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值,e.e.％＝95.62％,RT＝2.290min。 1H NMR(400MHz,CD 3OD)δ7.92(s,1H),7.62-7.42(m,1H),7.42-7.24(m,1H),7.21-7.06(m,2H),5.95-5.71(m,1H),4.56(d,J＝12.0Hz,1H),4.42-4.25(m,2H),4.25-4.07(m,1H),3.53(s,2H),2.37(s,3H),1.63(d,J＝6.0Hz,3H),1.40-1.23(m,6H)。MS-ESI计算值[M+H] + 542,实测值542。 Compound 31-7 (200 mg, 346 μmol) was dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and compound 5-9 (128 mg, 518 μmol), N,N-diisopropylethylamine (181 μL) were added to the reaction solution. , 1.04 mmol), and the reaction was stirred at 90 °C for 12 h. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL × 3), the organic phase was washed with saturated brine (20 mL × 5), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified. High performance liquid chromatography separation and purification (chromatographic column: Welch Xtimate C18 150mm×25mm×5μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile: 38%-68%, 10min) to obtain compound 31. Compound 31 was purified by SFC (column: Chiralcel OJ-3 100mm×4.6mm ID, 3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5% -40%) measured ee value, ee%=95.62%, RT=2.290min. 1 H NMR (400MHz, CD 3 OD) δ 7.92 (s, 1H), 7.62-7.42 (m, 1H), 7.42-7.24 (m, 1H), 7.21-7.06 (m, 2H), 5.95-5.71 ( m,1H),4.56(d,J＝12.0Hz,1H),4.42-4.25(m,2H),4.25-4.07(m,1H),3.53(s,2H),2.37(s,3H),1.63 (d, J=6.0 Hz, 3H), 1.40-1.23 (m, 6H). MS-ESI calculated [M+H] + 542, found 542.
实施例32Example 32
Figure PCTCN2022082591-appb-000158
Figure PCTCN2022082591-appb-000158
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000159
Figure PCTCN2022082591-appb-000159
氮气保护下将化合物30-7(200mg,346μmol)溶于二甲亚砜(10mL)中,向反应液中化合物5-9(98.1mg,518μmol),N,N-二异丙基乙胺(181μL,1.04mmol),在90℃下搅拌反应12小时。降至室温,向反应液中加入水(20mL),用乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(20mL×5)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Welch Xtimate C18 150mm×25mm×5μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈:43％-73％,10min)得到化合物32。化合物32经SFC检测(色谱柱:Chiralcel OJ-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值,e.e.％＝100.00％,RT＝2.162min。 1H NMR(400MHz,CD 3OD)δ7.93(s,1H),7.60(t,J＝8.0Hz,1H),7.46(t,J＝7.6Hz,1H),7.25-7.17(m,1H),7.15(s,1H),7.15-6.84(m,1H),5.86-5.77(m,1H),4.58-4.54(m,1H),4.41-4.31(m,2H),4.26-4.16(m,1H),3.58-3.50(m,2H),2.37(s,3H),1.65(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] +484,实测值484。 Compound 30-7 (200 mg, 346 μmol) was dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and compound 5-9 (98.1 mg, 518 μmol), N,N-diisopropylethylamine ( 181 μL, 1.04 mmol), and the reaction was stirred at 90 °C for 12 h. It was cooled to room temperature, water (20 mL) was added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated and purified by high performance liquid chromatography (chromatographic column: Welch Xtimate C18 150mm×25mm×5μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile: 43%-73%, 10min) to obtain compound 32. Compound 32 was detected by SFC (chromatographic column: Chiralcel OJ-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5% -40%) measured ee value, ee%=100.00%, RT=2.162min. 1 H NMR (400 MHz, CD 3 OD) δ 7.93 (s, 1H), 7.60 (t, J=8.0 Hz, 1H), 7.46 (t, J=7.6 Hz, 1H), 7.25-7.17 (m, 1H) ),7.15(s,1H),7.15-6.84(m,1H),5.86-5.77(m,1H),4.58-4.54(m,1H),4.41-4.31(m,2H),4.26-4.16(m , 1H), 3.58-3.50 (m, 2H), 2.37 (s, 3H), 1.65 (d, J=7.2Hz, 3H). MS-ESI calculated [M+H] + 484, found 484.
实施例33Example 33
Figure PCTCN2022082591-appb-000160
Figure PCTCN2022082591-appb-000160
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000161
Figure PCTCN2022082591-appb-000161
第一步first step
将化合物33-1(5.00g,29.6mmol)溶于丙酮(60mL)和水(30mL)中,加入N-甲基吗啉-N-氧化物水合物(4.85g,41.4mmol),和二水合锇酸钾(544mg,1.48mmol),在25℃下搅拌反应12小时。向反应液中加入亚硫酸钠(54g),在25℃下搅拌反应1小时后减压浓缩,再向反应液中加入水(100mL),用乙酸乙酯(50mL×1)萃取,有机相用饱和食盐水(20mL×1)洗涤,无水硫酸钠干燥,过滤,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～0/1,V/V)分离纯化得到化合物33-2。 1H NMR(400MHz,CDCl 3)δ4.34-4.15(m,2H),3.65-3.51(m,2H),3.42-3.24(m,2H),1.46(s,9H)。 Compound 33-1 (5.00 g, 29.6 mmol) was dissolved in acetone (60 mL) and water (30 mL), N-methylmorpholine-N-oxide hydrate (4.85 g, 41.4 mmol) was added, and dihydrate Potassium osmate (544 mg, 1.48 mmol), and the reaction was stirred at 25°C for 12 hours. Sodium sulfite (54 g) was added to the reaction solution, the reaction was stirred at 25°C for 1 hour, and then concentrated under reduced pressure. Water (100 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×1), and the organic phase was saturated with common salt. Washed with water (20 mL×1), dried over anhydrous sodium sulfate, filtered, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V) to obtain compound 33-2 . 1 H NMR (400 MHz, CDCl 3 ) δ 4.34-4.15 (m, 2H), 3.65-3.51 (m, 2H), 3.42-3.24 (m, 2H), 1.46 (s, 9H).
第二步second step
将化合物33-2(2.00g,9.84mmol)溶于二氯甲烷(30mL)中,加入对甲苯磺酰氯(9.38g,49.2mmol)和三乙胺(8.22ml,59.0mmol),在25℃下搅拌反应12小时。向反应液中缓慢加入水(50mL),用二氯甲烷(50mL×3)萃取,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离纯化得到化合物33-3。 1H NMR(400MHz,CDCl 3)δ7.87-7.55(m,2H),7.76-7.66(m,2H),7.41-7.28(m,4H),4.90-4.76(m,2H),3.59-3.52(m,2H),3.52-3.39(m,2H),2.49-2.44(m,6H),1.42(s,9H)。MS-ESI计算值[M-100+H] +512,实测值512。 Compound 33-2 (2.00 g, 9.84 mmol) was dissolved in dichloromethane (30 mL), p-toluenesulfonyl chloride (9.38 g, 49.2 mmol) and triethylamine (8.22 ml, 59.0 mmol) were added, and the mixture was heated at 25°C. The reaction was stirred for 12 hours. Water (50 mL) was slowly added to the reaction solution, extracted with dichloromethane (50 mL×3), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) was used for separation and purification to obtain compound 33-3. 1 H NMR (400 MHz, CDCl 3 ) δ 7.87-7.55 (m, 2H), 7.76-7.66 (m, 2H), 7.41-7.28 (m, 4H), 4.90-4.76 (m, 2H), 3.59-3.52 (m, 2H), 3.52-3.39 (m, 2H), 2.49-2.44 (m, 6H), 1.42 (s, 9H). MS-ESI calculated [M-100+H] + 512, found 512.
第三步third step
将化合物33-3(4.45g,8.70mmol)和化合物1-4(1.67g,8.70mmol)溶于N,N-二甲基甲酰胺(35mL)中,加入碳酸钾(4.81g,34.8mmol),在80℃下搅拌反应12小时。向反应液中缓慢加入水(20mL),用乙酸乙酯(20mL×4)萃取,有机相用饱和食盐水(20mL×3)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～0/1,V/V)分离纯化得化合物33-4。MS-ESI计算值[M+H] +360,实测值360。 Compound 33-3 (4.45 g, 8.70 mmol) and compound 1-4 (1.67 g, 8.70 mmol) were dissolved in N,N-dimethylformamide (35 mL), and potassium carbonate (4.81 g, 34.8 mmol) was added. , the reaction was stirred at 80 °C for 12 hours. Water (20 mL) was slowly added to the reaction solution, extracted with ethyl acetate (20 mL×4), the organic phase was washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The compound 33-4 was isolated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V). MS-ESI calculated [M+H] + 360, found 360.
第四步the fourth step
将化合物33-4(1.51g,3.49mmol)溶于二氯甲烷(20mL)中,加入化合物1-7(1.59g,5.24mmol),4-二甲基氨基吡啶(42.7mg,349μmol)和三乙胺(1.46ml,10.5mmol),在25℃下搅拌反应12小时。反应液过滤,减压浓缩,剩余物经过硅胶柱色谱法分离纯化(石油醚/乙酸乙酯,10/1～2/1,V/V),得到化合物33-5。MS-ESI计算值[M+H] +626,实测值626。 Compound 33-4 (1.51 g, 3.49 mmol) was dissolved in dichloromethane (20 mL), compound 1-7 (1.59 g, 5.24 mmol), 4-dimethylaminopyridine (42.7 mg, 349 μmol) and trimethylamine were added. Ethylamine (1.46 ml, 10.5 mmol), and the reaction was stirred at 25°C for 12 hours. The reaction solution was filtered, concentrated under reduced pressure, and the residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 33-5. MS-ESI calculated [M+H] + 626, found 626.
第五步the fifth step
将化合物33-5(200mg,320μmol)溶于二甲基亚砜(5mL)中,加入14-7(90.7mg,479μmol)和三乙胺(223μl,1.28mmol),在90℃下搅拌反应12小时。向反应液中缓慢加入水(20mL),用乙酸乙酯(20mL×3)萃取,有机相用饱和食盐水(20mL×5)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物33-6。MS-ESI计算值[M+H]+531,实测值531。Compound 33-5 (200 mg, 320 μmol) was dissolved in dimethyl sulfoxide (5 mL), 14-7 (90.7 mg, 479 μmol) and triethylamine (223 μl, 1.28 mmol) were added, and the reaction was stirred at 90 °C for 12 Hour. Water (20 mL) was slowly added to the reaction solution, extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (20 mL×5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) gave compound 33-6. MS-ESI calculated value [M+H]+531, found 531.
第六步Step 6
将化合物33-6(140mg,264μmol)溶于乙酸乙酯(5mL)中,加入氯化氢乙酸乙酯溶液(4mol/L,1.98mL),在20℃下搅拌反应12小时。反应液减压浓缩,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈:10％-40％,10min)得到化合物33的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.25(s,1H),7.73-7.61(m,1H),7.59-7.47(m,1H),7.35-7.27(m,1H),7.26(s,1H),7.17-6.81(m,1H),6.08-5.93(m,1H),5.22-5.17(m,1H),5.14-5.10(m,1H),3.90-3.75(m,2H),3.66-3.49(m,2H),2.59(s,3H),1.75(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] +431,实测值431。 Compound 33-6 (140 mg, 264 μmol) was dissolved in ethyl acetate (5 mL), hydrogen chloride ethyl acetate solution (4 mol/L, 1.98 mL) was added, and the reaction was stirred at 20° C. for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 10%-40%, 10min) The hydrochloride salt of compound 33 was obtained. 1 H NMR (400MHz, CD 3 OD) δ8.25(s, 1H), 7.73-7.61(m, 1H), 7.59-7.47(m, 1H), 7.35-7.27(m, 1H), 7.26(s, 1H), 7.17-6.81(m, 1H), 6.08-5.93(m, 1H), 5.22-5.17(m, 1H), 5.14-5.10(m, 1H), 3.90-3.75(m, 2H), 3.66- 3.49(m, 2H), 2.59(s, 3H), 1.75(d, J=7.2Hz, 3H). MS-ESI calculated [M+H] + 431, found 431.
实施例34Example 34
Figure PCTCN2022082591-appb-000162
Figure PCTCN2022082591-appb-000162
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000163
Figure PCTCN2022082591-appb-000163
将化合物33的盐酸盐(50mg,99.3μmol)溶于二氯甲烷(2mL)中,加入乙酸酐(20.3mg,199μmol)和三乙胺(27.7μl,199μmol),在25℃下搅拌反应6小时。过滤,滤液减压浓缩后的剩余物经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈:15％-45％,10min)得到化合物34的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.14(s,1H),7.70-7.59(m,1H),7.58-7.48(m,1H),7.36-7.24(m,1H),7.18(s,1H),7.16-6.81(m,1H),6.03-5.92(m,1H),5.58-5.03(m,1H),4.77-4.17(m,1H),4.11-4.00(m,1H),3.95-3.81(m,1H),3.81-3.66(m,1H),3.66-3.54(m,1H),2.58(s,3H),2.07(s,3H),1.74(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +473,实测值473。 The hydrochloride salt of compound 33 (50 mg, 99.3 μmol) was dissolved in dichloromethane (2 mL), acetic anhydride (20.3 mg, 199 μmol) and triethylamine (27.7 μl, 199 μmol) were added, and the reaction was stirred at 25° C. 6 Hour. Filtration, the residue after the filtrate was concentrated under reduced pressure was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile: 15%-45%, 10 min) to obtain the hydrochloride salt of compound 34. 1 H NMR (400MHz, CD 3 OD) δ8.14(s, 1H), 7.70-7.59(m, 1H), 7.58-7.48(m, 1H), 7.36-7.24(m, 1H), 7.18(s, 1H), 7.16-6.81(m, 1H), 6.03-5.92(m, 1H), 5.58-5.03(m, 1H), 4.77-4.17(m, 1H), 4.11-4.00(m, 1H), 3.95- 3.81(m,1H),3.81-3.66(m,1H),3.66-3.54(m,1H),2.58(s,3H),2.07(s,3H),1.74(d,J=6.8Hz,3H) . MS-ESI calculated [M+H] + 473, found 473.
实施例35Example 35
Figure PCTCN2022082591-appb-000164
Figure PCTCN2022082591-appb-000164
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000165
Figure PCTCN2022082591-appb-000165
第一步first step
氮气保护下,将化合物35-1(6.00g,23.3mmol)溶于干燥甲苯(100mL)中,加入化合物3-2(12.6g,34.9mmol),再加入双三苯基膦二氯化钯(1.63g,2.33mmol),反应液在120℃下搅拌12小时,降至室温后,向反应液中加入饱和氟化钾水溶液(100mL),用乙酸乙酯(100mL×2)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品化合物35-2,直接用于下一步。Under nitrogen protection, compound 35-1 (6.00 g, 23.3 mmol) was dissolved in dry toluene (100 mL), compound 3-2 (12.6 g, 34.9 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.63 g, 2.33 mmol), the reaction solution was stirred at 120 ° C for 12 hours, and after cooling to room temperature, a saturated aqueous potassium fluoride solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×2), and the organic phase was Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 35-2, which is directly used in the next step.
第二步second step
将化合物35-2(5.83g,23.4mmol)溶于丙酮(80mL)中,0℃下滴加浓盐酸(12M,9.96mL),反应液在25℃下搅拌1小时,反应液用饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(50mL×3)萃取,饱和食盐水(50mL×1)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～4/1,V/V)分离得到化合物35-3。 1H NMR(400MHz,CDCl 3)δ7.30-7.26(m,1H),7.08-7.00(m,1H),2.66-2.63(m,3H)。MS-ESI计算值[M+H] +222,实测值222。 Compound 35-2 (5.83 g, 23.4 mmol) was dissolved in acetone (80 mL), concentrated hydrochloric acid (12 M, 9.96 mL) was added dropwise at 0 °C, the reaction solution was stirred at 25 °C for 1 hour, and the reaction solution was washed with saturated hydrogen carbonate The sodium aqueous solution was alkalized to pH 8, extracted with ethyl acetate (50 mL×3), the organic phase was washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was chromatographed on silica gel column method (petroleum ether/ethyl acetate, 100/1～4/1, V/V) to obtain compound 35-3. 1 H NMR (400 MHz, CDCl 3 ) δ 7.30-7.26 (m, 1H), 7.08-7.00 (m, 1H), 2.66-2.63 (m, 3H). MS-ESI calculated [M+H] + 222, found 222.
第三步third step
将化合物35-3(4.84g,16.7mmol)溶于干燥四氢呋喃(50mL)中,加入钛酸四乙酯(7.62g,33.4mmol)和化合物A-6(3.04g,25.1mmol),反应液在80℃下搅拌24小时,降温至0℃将水(50mL)倒入反应液中,再加入乙酸乙酯(50mL×1)洗涤,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～2/1,V/V)分离得到化合物35-4。MS-ESI计算值[M+H] +325,实测值325。 Compound 35-3 (4.84 g, 16.7 mmol) was dissolved in dry tetrahydrofuran (50 mL), tetraethyl titanate (7.62 g, 33.4 mmol) and compound A-6 (3.04 g, 25.1 mmol) were added, and the reaction solution was Stir at 80°C for 24 hours, cool down to 0°C, pour water (50 mL) into the reaction solution, add ethyl acetate (50 mL×1) to wash, the organic phase is washed with saturated brine (50 mL×1), anhydrous sulfuric acid Dry over sodium, filter and concentrate under reduced pressure, and the residue is separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～2/1, V/V) to obtain compound 35-4. MS-ESI calculated [M+H] + 325, found 325.
第四步the fourth step
将化合物35-4(4.68g,11.8mmol)溶于无水四氢呋喃(60mL),在0℃加入硼氢化钠(535mg,14.2mmol),反应液在25℃下搅拌1小时,降温至0℃滴加水(100mL),再加入乙酸乙酯(100mL×1),有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,1/1～1/2,V/V)分离得到化合物35-5。MS-ESI计算值[M+H] +327,实测值327。 Compound 35-4 (4.68 g, 11.8 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), sodium borohydride (535 mg, 14.2 mmol) was added at 0 °C, the reaction solution was stirred at 25 °C for 1 hour, cooled to 0 °C dropwise Water (100 mL) was added, followed by ethyl acetate (100 mL×1), the organic phase was washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate, 1/1～1/2, V/V) to obtain compound 35-5. MS-ESI calculated [M+H] + 327, found 327.
第五步the fifth step
将化合物35-5(2.16g,6.62mmol)溶于二氧六环(30mL)中,滴加氯化氢二氧六环溶液(4M,16.6mL),反应液于20℃搅拌2小时,将反应液减压浓缩后在20℃加入二氯甲烷(5ml)搅拌10分钟,过滤,收集滤饼干燥得到35-6的盐酸盐。MS-ESI计算值[M+H] +223,实测值223。 Compound 35-5 (2.16 g, 6.62 mmol) was dissolved in dioxane (30 mL), hydrogen chloride dioxane solution (4 M, 16.6 mL) was added dropwise, the reaction solution was stirred at 20 ° C for 2 hours, and the reaction solution was added dropwise. After concentration under reduced pressure, dichloromethane (5 ml) was added at 20° C. and stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain the hydrochloride of 35-6. MS-ESI calculated [M+H] + 223, found 223.
第六步Step 6
氮气保护下将化合物29-7(250mg,432μmol)溶于二甲亚砜(15mL)中,向反应液中化合物35-6的盐酸盐(144mg,648μmol),N,N-二异丙基乙胺(226μL,1.30mmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Phenomenex C18 80mm×40mm×3μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈:45％-75％,10min)得到化合物35。化合物35经SFC(色谱柱:ChiralPak AD-3 15mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝67.50％,RT＝3.330min。 1H NMR(400MHz,CD 3OD)δ7.97(s,1H),7.17(s,1H),6.95-6.91(m 1H),6.83-6.79(m,1H),5.78-5.68(m,1H),4.62-4.55(m,1H),4.42-4.33(m,2H),4.28-4.20(m,1H),3.60-3.53(m,2H),2.40(s,3H),1.63(d,J＝8.0Hz,3H)。MS-ESI计算值[M+H] +517,实测值517。 Compound 29-7 (250 mg, 432 μmol) was dissolved in dimethyl sulfoxide (15 mL) under nitrogen protection, and the hydrochloride of compound 35-6 (144 mg, 648 μmol), N,N-diisopropyl was added to the reaction solution. Ethylamine (226 μL, 1.30 mmol), and the reaction was stirred at 90° C. for 12 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Phenomenex C18 80mm×40mm×3μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile: 45%-75%, 10min) to obtain compound 35. Compound 35 was purified by SFC (column: ChiralPak AD-3 15mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%). Measured ee value, ee%=67.50%, RT=3.330min. 1 H NMR (400MHz, CD 3 OD) δ 7.97 (s, 1H), 7.17 (s, 1H), 6.95-6.91 (m 1H), 6.83-6.79 (m, 1H), 5.78-5.68 (m, 1H) ), 4.62-4.55(m, 1H), 4.42-4.33(m, 2H), 4.28-4.20(m, 1H), 3.60-3.53(m, 2H), 2.40(s, 3H), 1.63(d, J =8.0Hz, 3H). MS-ESI calculated [M+H] + 517, found 517.
实施例36Example 36
Figure PCTCN2022082591-appb-000166
Figure PCTCN2022082591-appb-000166
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000167
Figure PCTCN2022082591-appb-000167
Figure PCTCN2022082591-appb-000168
Figure PCTCN2022082591-appb-000168
第一步first step
氮气保护下,将化合物36-1(5.00g,25.5mmol)溶于干燥甲苯(50mL)中,加入化合物3-2(10.2g,28.3mmol),再加入双三苯基膦二氯化钯(1.79g,2.55mmol),反应液在120℃下搅拌12小时,降至室温后,向反应液中加入饱和氟化钾水溶液(50mL),用乙酸乙酯(50mL×2)萃取,有机相用无水硫酸钠干燥,过滤,减压浓缩得到粗品化合物36-2,直接用于下一步。Under nitrogen protection, compound 36-1 (5.00 g, 25.5 mmol) was dissolved in dry toluene (50 mL), compound 3-2 (10.2 g, 28.3 mmol) was added, and bistriphenylphosphine palladium dichloride ( 1.79 g, 2.55 mmol), the reaction solution was stirred at 120 °C for 12 hours, and after cooling to room temperature, saturated aqueous potassium fluoride solution (50 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL×2), and the organic phase was Dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain crude compound 36-2, which is directly used in the next step.
第二步second step
将化合物36-2(5.00g,26.7mmol)溶于丙酮(80mL)中,0℃下滴加浓盐酸(12M,8.00mL),反应液在20℃下搅拌1小时,反应液用饱和碳酸氢钠水溶液碱化pH至8,用乙酸乙酯(20mL×3)萃取,饱和食盐水(20mL×1)洗涤有机相,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,100/1～5/1,V/V)分离得到化合物36-3。 1H NMR(400MHz,CDCl 3)δ7.89-7.80(m,1H),7.80-7.68(m,1H),7.73(dd,J＝1.56,8.0Hz,1H),2.70(s,3H),2.63-2.58(m,3H)。MS-ESI计算值[M+H] +160,实测值160。 Compound 36-2 (5.00 g, 26.7 mmol) was dissolved in acetone (80 mL), concentrated hydrochloric acid (12 M, 8.00 mL) was added dropwise at 0 °C, the reaction solution was stirred at 20 °C for 1 hour, and the reaction solution was washed with saturated hydrogen carbonate The aqueous sodium solution was basified to pH 8, extracted with ethyl acetate (20 mL×3), the organic phase was washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography method (petroleum ether/ethyl acetate, 100/1～5/1, V/V) to obtain compound 36-3. 1 H NMR (400MHz, CDCl 3 ) δ 7.89-7.80 (m, 1H), 7.80-7.68 (m, 1H), 7.73 (dd, J=1.56, 8.0Hz, 1H), 2.70 (s, 3H), 2.63-2.58 (m, 3H). MS-ESI calculated [M+H] + 160, found 160.
第三步third step
将化合物36-3(3.53g,19.5mmol)溶于干燥四氢呋喃(40mL)中,加入钛酸四乙酯(8.89g,39.0mmol)和化合物A-6(3.54g,29.2mmol),反应液在80℃下搅拌24小时,降温至0℃将水(50mL)倒入反应液中,再加入乙酸乙酯(50mL×1)洗涤,有机相用饱和食盐水(50mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物36-4。MS-ESI计算值[M+H] +263,实测值263。 Compound 36-3 (3.53 g, 19.5 mmol) was dissolved in dry tetrahydrofuran (40 mL), tetraethyl titanate (8.89 g, 39.0 mmol) and compound A-6 (3.54 g, 29.2 mmol) were added, and the reaction solution was Stir at 80°C for 24 hours, cool down to 0°C, pour water (50 mL) into the reaction solution, add ethyl acetate (50 mL×1) to wash, the organic phase is washed with saturated brine (50 mL×1), anhydrous sulfuric acid Dry over sodium, filter and concentrate under reduced pressure, and the residue is separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 36-4. MS-ESI calculated [M+H] + 263, found 263.
第四步the fourth step
将化合物36-4(5.37g,17.7mmol)溶于无水四氢呋喃(60mL),在0℃加入硼氢化钠(804mg,21.3mmol),反应液在20℃下搅拌1小时,降温至0℃滴加水(200mL),再加入乙酸乙酯(200mL×2),有机相用饱和食盐水(200mL×1)洗涤,无水硫酸钠干燥,过滤,减压浓缩,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,1/1～1/2,V/V)分离得到化合物36-5。MS-ESI计算值[M+H] +265,实测值265。 Compound 36-4 (5.37 g, 17.7 mmol) was dissolved in anhydrous tetrahydrofuran (60 mL), sodium borohydride (804 mg, 21.3 mmol) was added at 0 °C, the reaction solution was stirred at 20 °C for 1 hour, cooled to 0 °C dropwise Water (200 mL) was added, followed by ethyl acetate (200 mL×2), the organic phase was washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography ( Petroleum ether/ethyl acetate, 1/1～1/2, V/V) to obtain compound 36-5. MS-ESI calculated [M+H] + 265, found 265.
第五步the fifth step
将化合物36-5(5.40g,20.4mmol)溶于二氧六环(30mL)中,滴加氯化氢二氧六环溶液(4M,25.5mL),反应液于20℃搅拌2小时,将反应液减压浓缩后在20℃加入二氯甲烷(5ml)搅拌10分钟,过滤,收集滤饼,干燥得到36-6的盐酸盐。MS-ESI计算值[M+H] +161,实测值161。 Compound 36-5 (5.40 g, 20.4 mmol) was dissolved in dioxane (30 mL), hydrogen chloride dioxane solution (4 M, 25.5 mL) was added dropwise, the reaction solution was stirred at 20 ° C for 2 hours, and the reaction solution was added dropwise. After concentration under reduced pressure, dichloromethane (5 ml) was added at 20° C. and stirred for 10 minutes, filtered, and the filter cake was collected and dried to obtain the hydrochloride of 36-6. MS-ESI calculated [M+H] + 161, found 161.
第六步Step 6
氮气保护下将化合物29-7(100mg,173μmol)溶于二甲亚砜(10mL)中,向反应液中化合物36-6的盐 酸盐(41.5mg,259μmol),N,N-二异丙基乙胺(90.3μL,518μmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用乙酸乙酯(30mL×3)萃取,有机相用饱和食盐水(50mL)洗涤,无水硫酸钠干燥,过滤,减压浓缩后的剩余物经高效液相色谱分离纯化(色谱柱:Welch Xtimate C18 150mm×25mm×5μm；流动相:10mM碳酸氢铵-乙腈；梯度:乙腈:37％-67％,10min)得到化合物36。化合物36经SFC(色谱柱:ChiralPak AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)。测e.e.值,e.e.％＝100.00％,RT＝1.599min。 1H NMR(400MHz,CD 3OD)δ7.95-7.84(m,1H),7.75-7.66(m,1H),7.55-7.45(m,1H),7.33-7.23(m,1H),7.16-7.07(m,1H),5.74-5.61(m,1H),4.58-4.50(m,1H),4.40-4.26(m,2H),4.24-4.15(m,1H),3.59-3.47(m,2H),2.75(s,3H),2.37(s,3H),1.64-1.52(s,3H)。MS-ESI计算值[M+H] +455,实测值455。 Compound 29-7 (100 mg, 173 μmol) was dissolved in dimethyl sulfoxide (10 mL) under nitrogen protection, and the hydrochloride of compound 36-6 (41.5 mg, 259 μmol), N,N-diisopropyl was added to the reaction solution. Ethylamine (90.3 μL, 518 μmol), and the reaction was stirred at 90 °C for 12 hours. Water (20 mL) was added to the reaction solution, extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the residue after concentration under reduced pressure was filtered by high-efficiency solution Phase chromatography separation and purification (chromatographic column: Welch Xtimate C18 150mm×25mm×5μm; mobile phase: 10mM ammonium bicarbonate-acetonitrile; gradient: acetonitrile: 37%-67%, 10min) to obtain compound 36. Compound 36 was purified by SFC (chromatographic column: ChiralPak AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%). Measure ee value, ee%=100.00%, RT=1.599min. 1 H NMR (400MHz, CD 3 OD) δ 7.95-7.84 (m, 1H), 7.75-7.66 (m, 1H), 7.55-7.45 (m, 1H), 7.33-7.23 (m, 1H), 7.16- 7.07(m, 1H), 5.74-5.61(m, 1H), 4.58-4.50(m, 1H), 4.40-4.26(m, 2H), 4.24-4.15(m, 1H), 3.59-3.47(m, 2H ), 2.75(s, 3H), 2.37(s, 3H), 1.64-1.52(s, 3H). MS-ESI calculated [M+H] + 455, found 455.
实施例37Example 37
Figure PCTCN2022082591-appb-000169
Figure PCTCN2022082591-appb-000169
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000170
Figure PCTCN2022082591-appb-000170
第一步first step
将化合物1-4(2.00g,10.4mmol)溶于N,N-二甲基甲酰胺(150mL)中,加入碳酸钾(7.19g,52.0mmol),搅拌30分钟,随后加入37-1(4.49g,20.8mmol),在25℃下搅拌反应12小时。减压浓缩。剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈10％-30％,10min),得到化合物37-2的盐酸盐。MS-ESI计算值[M+H] +247,实测247。 Compound 1-4 (2.00 g, 10.4 mmol) was dissolved in N,N-dimethylformamide (150 mL), potassium carbonate (7.19 g, 52.0 mmol) was added, stirred for 30 minutes, followed by 37-1 (4.49 g, 20.8 mmol), and the reaction was stirred at 25 °C for 12 h. Concentrate under reduced pressure. The residue was separated and purified by preparative high performance liquid chromatography (chromatographic column: Phenomenex C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile 10%-30%, 10min) to obtain compound 37-2. Hydrochloride. MS-ESI calculated [M+H] + 247, found 247.
第二步second step
将化合物37-2(110mg,447μmol)溶于二氯甲烷(5mL)中,依次加入1-7(203mg,670μmol),三乙胺(271mg,2.68mmol),4-二甲氨基吡啶(5.46mg,44.7μmol),在25℃下搅拌反应12小时。减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10/1～4/1,V/V),分离纯化得到化合物37-3。MS-ESI计算值[M+H] +513, 实测513。 Compound 37-2 (110 mg, 447 μmol) was dissolved in dichloromethane (5 mL), followed by adding 1-7 (203 mg, 670 μmol), triethylamine (271 mg, 2.68 mmol), 4-dimethylaminopyridine (5.46 mg) , 44.7 μmol), and the reaction was stirred at 25 °C for 12 h. Concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～4/1, V/V) to obtain compound 37-3. MS-ESI calculated [M+H] + 513, found 513.
第三步third step
将化合物37-3(135mg,263μmol)溶于二甲亚砜(1.5mL)中,依次加入5-9(98.0mg,395μmol),N,N-二异丙胺乙胺(340mg,2.63mmol),在80℃下搅拌反应12小时。反应液经制备高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×40mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈25％-55％,10min),得到化合物37的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.20(s,1H),7.58(t,J＝6.8Hz,1H),7.44-7.40(m,1H),7.23(t,J＝6.8Hz,1H),7.11(s,1H),5.99(q,J＝6.8Hz,1H),4.71(t,J＝5.6Hz,2H),4.36(t,J＝5.6Hz,2H),2.57(s,3H),2.12-2.01(m,2H),1.91-1.85(m,2H),1.72(d,J＝6.8Hz,3H),1.29(d,J＝4.0Hz,6H),1.25-1.21(m,1H),。MS-ESI计算值[M+H] +476,实测476。 Compound 37-3 (135 mg, 263 μmol) was dissolved in dimethyl sulfoxide (1.5 mL), followed by adding 5-9 (98.0 mg, 395 μmol), N,N-diisopropylamine ethylamine (340 mg, 2.63 mmol), The reaction was stirred at 80°C for 12 hours. The reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: Xtimate C18 150mm×40mm×5μm; mobile phase: 0.05% aqueous hydrochloric acid solution-acetonitrile; gradient: acetonitrile 25%-55%, 10min) to obtain the hydrochloric acid of compound 37 Salt. 1 H NMR (400MHz, CD 3 OD) δ 8.20 (s, 1H), 7.58 (t, J=6.8Hz, 1H), 7.44-7.40 (m, 1H), 7.23 (t, J=6.8Hz, 1H) ), 7.11(s, 1H), 5.99(q, J＝6.8Hz, 1H), 4.71(t, J＝5.6Hz, 2H), 4.36(t, J＝5.6Hz, 2H), 2.57(s, 3H ), 2.12-2.01(m, 2H), 1.91-1.85(m, 2H), 1.72(d, J=6.8Hz, 3H), 1.29(d, J=4.0Hz, 6H), 1.25-1.21(m, 1H),. MS-ESI calculated [M+H] + 476, found 476.
实施例38Example 38
Figure PCTCN2022082591-appb-000171
Figure PCTCN2022082591-appb-000171
合成路线：synthetic route:
Figure PCTCN2022082591-appb-000172
Figure PCTCN2022082591-appb-000172
第一步first step
将38-1(1.00g,6.17mmol)溶于二氯甲烷(40mL)中,向反应液中加入对甲苯磺酰氯(3.53g,18.51mmol)和三乙胺(6.24g,61.7mmol)。反应液在室温下搅拌12小时。减压浓缩除去溶剂,剩余物用硅胶柱层析法(石油醚/乙酸乙酯,10:1～2:1,V/V),分离得到化合物38-2。 1H NMR(400MHz,CDCl 3)δ7.80(d,J＝8.0Hz 4H),7.39(d,J＝8.0Hz,4H),4.38-4.35(m,4H)。MS-ESI计算值[M+H] +471,实测471。 38-1 (1.00 g, 6.17 mmol) was dissolved in dichloromethane (40 mL), and p-toluenesulfonyl chloride (3.53 g, 18.51 mmol) and triethylamine (6.24 g, 61.7 mmol) were added to the reaction solution. The reaction solution was stirred at room temperature for 12 hours. The solvent was concentrated under reduced pressure to remove the solvent, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1-2:1, V/V) to obtain compound 38-2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.80 (d, J=8.0 Hz 4H), 7.39 (d, J=8.0 Hz, 4H), 4.38-4.35 (m, 4H). MS-ESI calculated [M+H] + 471, found 471.
第二步second step
将化合物1-4(0.50g,2.60mmol)溶于N,N-二甲基甲酰胺(20mL)中,加入碳酸钾(1.80g,13.0mmol), 搅拌30min,加入38-2(1.22g,2.60mmol),在室温下搅拌反应12小时。减压浓缩。剩余物使用二氯甲烷/甲醇＝10:1(150mL)洗涤,过滤，收集滤液，滤液旋除溶剂，剩余物用硅胶柱色谱法(二氯甲烷/甲醇,100:1～20:1,V/V),分离纯化得到得到化合物38-3。MS-ESI计算值[M+H] +319,实测319。 Compound 1-4 (0.50g, 2.60mmol) was dissolved in N,N-dimethylformamide (20mL), potassium carbonate (1.80g, 13.0mmol) was added, stirred for 30min, 38-2 (1.22g, 2.60 mmol), and the reaction was stirred at room temperature for 12 hours. Concentrate under reduced pressure. The residue was washed with dichloromethane/methanol=10:1 (150 mL), filtered, the filtrate was collected, the filtrate was spun to remove the solvent, and the residue was subjected to silica gel column chromatography (dichloromethane/methanol, 100:1～20:1, V /V), isolated and purified to obtain compound 38-3. MS-ESI calculated [M+H] + 319, found 319.
第三步third step
将化合物38-3(161mg,505μmol)溶于二氯甲烷(6mL)中,依次加入1-7(229.84mg,759μmol),三乙胺(307mg,3.04mmol),4-二甲氨基吡啶(6mg,50.6μmol),在室温下搅拌反应12小时。减压浓缩。剩余物用硅胶柱色谱法(石油醚/乙酸乙酯,10:1-4:1,V/V),分离纯化得到化合物38-4。MS-ESI计算值[M+H] +585,实测585。 Compound 38-3 (161 mg, 505 μmol) was dissolved in dichloromethane (6 mL), followed by adding 1-7 (229.84 mg, 759 μmol), triethylamine (307 mg, 3.04 mmol), 4-dimethylaminopyridine (6 mg) , 50.6 μmol), and the reaction was stirred at room temperature for 12 hours. Concentrate under reduced pressure. The residue was separated and purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10:1-4:1, V/V) to obtain compound 38-4. MS-ESI calculated [M+H] + 585, found 585.
第四步the fourth step
将化合物38-4(80.0mg,137μmol)溶于二甲亚砜(1.5mL)中,依次加入5-9(58.0mg,205μmol),N,N-二异丙胺乙胺(177mg,1.37mmol),在80℃下搅拌反应12小时。反应液经制备高效液相色谱分离纯化(色谱柱:column:Xtimate C18 150*40mm*5um；流动相:盐酸水溶液-乙腈；梯度:乙腈30％-60％,10min),得到化合物38的盐酸。 1H NMR(400MHz,CD 3OD)δ8.37(s,1H),7.62(t,J＝6.8Hz,1H),7.45-7.41(m,1H),7.31(s,1H),7.24(t,J＝6.8Hz,1H),6.01(q,J＝6.8Hz,1H),4.73(t,J＝5.6Hz,2H),4.67(t,J＝5.6Hz,2H),2.60(s,3H),1.74(d,J＝6.8Hz,3H),1.28(d,J＝4.0Hz,6H)。MS-ESI计算值[M+H] +548,实测548。 Compound 38-4 (80.0 mg, 137 μmol) was dissolved in dimethyl sulfoxide (1.5 mL), followed by adding 5-9 (58.0 mg, 205 μmol), N,N-diisopropylamine ethylamine (177 mg, 1.37 mmol) , the reaction was stirred at 80 °C for 12 hours. The reaction solution was separated and purified by preparative high performance liquid chromatography (chromatographic column: column: Xtimate C18 150*40mm*5um; mobile phase: aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 30%-60%, 10min) to obtain the hydrochloric acid of compound 38. 1 H NMR (400MHz, CD 3 OD) δ 8.37(s, 1H), 7.62(t, J=6.8Hz, 1H), 7.45-7.41(m, 1H), 7.31(s, 1H), 7.24(t , J＝6.8Hz, 1H), 6.01(q, J＝6.8Hz, 1H), 4.73(t, J＝5.6Hz, 2H), 4.67(t, J＝5.6Hz, 2H), 2.60(s, 3H ), 1.74 (d, J=6.8 Hz, 3H), 1.28 (d, J=4.0 Hz, 6H). MS-ESI calculated [M+H] + 548, found 548.
活性测试：Active test:
实验例1：KRAS(G12C)和SOS1结合实验Experimental Example 1: Binding Experiment of KRAS(G12C) and SOS1
实验原理：Experimental principle:
小分子化合物结合在SOS1的催化位点而抑制SOS1与KRAS(G12C)的结合,当荧光标记的SOS1蛋白与荧光标记的KRAS(G12C)蛋白的结合被抑制时,发出的荧光发生改变。通过检测荧光改变,可以测试小分子阻止SOS1与KRAS(G12C)结合的能力。采用均相时间分辨荧光(HTRF)结合试验来检测本发明的化合物抑制SOS1与KRAS(G12C)相互结合的能力。Small molecule compounds bind to the catalytic site of SOS1 and inhibit the binding of SOS1 to KRAS(G12C). When the binding of fluorescently labeled SOS1 protein to fluorescently labeled KRAS(G12C) protein is inhibited, the emitted fluorescence changes. By detecting fluorescence changes, the ability of small molecules to prevent SOS1 from binding to KRAS(G12C) can be tested. A homogeneous time-resolved fluorescence (HTRF) binding assay was used to examine the ability of the compounds of the present invention to inhibit the mutual binding of SOS1 and KRAS(G12C).
实验材料：Experimental Materials:
KRAS(G12C)蛋白由武汉普健生物科技有限公司表达纯化,SOS1 exchange domin(564-1049)protein(Hμman recombinant)购自Cytoskeleton,Mab Anti 6HIS-XL665和Mab Anti GST-Eμcryptate购自Cisbio。多功能酶标仪Nivo5购自于PerkinElmer。KRAS (G12C) protein was expressed and purified by Wuhan Pujian Biotechnology Co., Ltd., SOS1 exchange domin (564-1049) protein (Hμman recombinant) was purchased from Cytoskeleton, Mab Anti 6HIS-XL665 and Mab Anti GST-Eμcryptate were purchased from Cisbio. The multi-plate reader Nivo5 was purchased from PerkinElmer.
实验方法：experimental method:
1X buffer配制(现配现用):Hepes:5mM；NaCl:150mM；EDTA:10mM；Igepal:0.0025％；KF:100mM；DTT:1mM；BSA:005％；1X buffer preparation (currently used): Hepes: 5mM; NaCl: 150mM; EDTA: 10mM; Igepal: 0.0025%; KF: 100mM; DTT: 1mM; BSA: 005%;
用DMSO将待测化合物用排枪进行5倍稀释至第8个浓度,即从1mM稀释至0.064μM。The compounds to be tested were diluted 5-fold with DMSO to the 8th concentration, that is, from 1 mM to 0.064 μM.
用1X buffer将待测化合物各梯度稀释成DMSO为2％的工作液,5μL/孔加到对应孔中,对应浓度梯度为20μM至0.00128nM,置双复孔实验。1000转,离心1分钟。Use 1X buffer to dilute each compound to be tested into a working solution with 2% DMSO, add 5 μL/well to the corresponding well, and the corresponding concentration gradient is 20 μM to 0.00128 nM, and set up a double-well experiment. Centrifuge at 1000 rpm for 1 minute.
用1X buffer配制KRAS(G12C)(200nM)和Mab Anti GST-Eμcryptate(1ng/μL)的混和工作液,将该混合工作液放置25℃中孵育5分钟,2.5μL/孔加入到对应孔。Prepare a mixed working solution of KRAS(G12C) (200nM) and Mab Anti GST-Eμcryptate (1ng/μL) with 1X buffer, incubate the mixed working solution at 25°C for 5 minutes, and add 2.5μL/well to the corresponding well.
用1X buffer配制SOS1(80nM)和Mab Anti 6HIS-XL665(8g/μL)的混和工作液,2.5μL/孔加入到对应孔中,Blank孔中加入2.5μL Mab Anti 6HIS-XL665(8g/μL)稀释液,此时化合物终浓度梯度为10μM稀释至0.64nM,KRAS(G12C)(500nM),MAb Anti GST-Eu cryptate(0.25ng/μL),SOS1(20nM),Mab Anti 6HIS-XL665(2g/μL),反应体系置于25℃反应60分钟。反应结束后采用多标记分析仪读取HTRF。Prepare a mixed working solution of SOS1 (80nM) and Mab Anti 6HIS-XL665 (8g/μL) with 1X buffer, add 2.5μL/well to the corresponding well, and add 2.5μL Mab Anti 6HIS-XL665 (8g/μL) to the Blank well At this time, the final concentration of the compound was diluted from 10μM to 0.64nM, KRAS(G12C) (500nM), MAb Anti GST-Eu cryptate (0.25ng/μL), SOS1 (20nM), Mab Anti 6HIS-XL665 (2g/μL) μL), the reaction system was placed at 25 °C for 60 minutes. After the reaction, the HTRF was read using a multi-label analyzer.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率,IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。本发明化合物对KRAS(G12C)和SOS1结合的抑制活性结果见表1。 Using the equation (Sample-Min)/(Max-Min)×100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode). Table 1 shows the results of the inhibitory activity of the compounds of the present invention on the binding of KRAS(G12C) and SOS1.
表1本发明化合物对KRAS(G12C)和SOS1结合的IC 50值测试结果 Table 1 Test results of IC 50 values of the compounds of the present invention for binding to KRAS (G12C) and SOS1
受试化合物test compound IC 50(nM) IC50 (nM)
化合物1的盐酸盐Compound 1 hydrochloride 21.4521.45
化合物5的盐酸盐Compound 5 hydrochloride 12.5612.56
化合物6的盐酸盐Compound 6 hydrochloride 52.9452.94
化合物11Compound 11 37.6337.63
化合物14的盐酸盐The hydrochloride salt of compound 14 35.1335.13
化合物18的盐酸盐Compound 18 hydrochloride 56.8556.85
化合物20Compound 20 9.509.50
化合物25Compound 25 128.30128.30
化合物26Compound 26 21.4721.47
化合物29Compound 29 17.1017.10
化合物31Compound 31 28.8228.82
化合物34Compound 34 105.7105.7
化合物35Compound 35 60.7860.78
实验结论：本发明化合物对KRAS(G12C)和SOS1结合有显著的抑制效果。Experimental conclusion: The compound of the present invention has a significant inhibitory effect on the combination of KRAS(G12C) and SOS1.
实验例2：H358细胞3D增殖抑制活性测试Experimental Example 2: 3D Proliferation Inhibitory Activity Test of H358 Cells
实验原理：Experimental principle:
KRAS(G12C)突变的H358细胞中,KRAS信号通路异常激活。小分子SOS1抑制剂通过抑制SOS1与RAS蛋白的结合,降低其GEF活性,减少激活状态RAS-GTP的比例。进一步下调RAS下游的MEK/ERK通路的磷酸化水平,达到抑制细胞增殖的效果。将小分子与H358细胞在3D空间内共培养,然后通过细胞读数,间接反映SOS1抑制剂对H358细胞的增殖抑制活性。In KRAS(G12C) mutant H358 cells, the KRAS signaling pathway is abnormally activated. Small molecule SOS1 inhibitors reduce the GEF activity and the ratio of activated RAS-GTP by inhibiting the binding of SOS1 to RAS protein. Further down-regulate the phosphorylation level of MEK/ERK pathway downstream of RAS to achieve the effect of inhibiting cell proliferation. Small molecules were co-cultured with H358 cells in 3D space, and then the cell readout indirectly reflected the proliferation inhibitory activity of SOS1 inhibitors on H358 cells.
实验材料：Experimental Materials:
RPMI1640培养基,胎牛血清,盘尼西林/链霉素抗生素购自维森特,低熔点琼脂糖购自Sigma。Almar  blue试剂购自Invitrogen。NCI-H358细胞系购自南京科佰生物科技有限公司。Nivo多标记分析仪(PerkinElmer)。RPMI1640 medium, fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente, and low melting point agarose was purchased from Sigma. Almar blue reagent was purchased from Invitrogen. The NCI-H358 cell line was purchased from Nanjing Kebai Biotechnology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
实验方法：experimental method:
将H358细胞种于96孔U型板中,先将低熔点琼脂糖配成2％的母液,使用时先将琼脂糖母液在微波炉中加热使其完全融化,之后至于42℃水浴锅中使琼脂糖保持液体状态。将凝胶加入含血清的培养基中配成凝胶浓度为0.6％作为底层胶,按照每孔50μL铺到96孔U型板中。待底层胶凝固后,再将2％凝胶加入到含细胞的培养基中,配成凝胶浓度为0.4％的含细胞的上层胶,细胞密度为4×10 4细胞/毫升,按照每孔75μl加到铺有底层胶的96孔U型板中,细胞密度为3000个每孔。待上层胶凝固后细胞板置于二氧化碳培养箱中过夜培养。 The H358 cells were seeded in a 96-well U-shaped plate, and the low-melting point agarose was first made into a 2% stock solution. When using, the agarose stock solution was first heated in a microwave oven to completely melt it, and then the agarose was placed in a 42°C water bath. Sugar remains liquid. The gel was added to the serum-containing medium to prepare a gel concentration of 0.6% as the bottom gel, and 50 μL per well was spread into a 96-well U-shaped plate. After the bottom gel has solidified, add 2% gel to the cell-containing medium to prepare a cell-containing top gel with a gel concentration of 0.4%, and the cell density is 4×10 4 cells/ml. 75μl was added to the 96-well U-shaped plate with the bottom gel, and the cell density was 3000 cells per well. After the supernatant gel was solidified, the cell plate was placed in a carbon dioxide incubator for overnight incubation.
加化合物当天,在铺好细胞的96孔U型板中加入85μL液体培养基。将待测化合物用排枪进行3倍稀释至第9个浓度,即从6mM稀释至0.9μM，设置双复孔实验。向中间板中加入97μL培养基,再按照对应位置,转移2.5μL每孔的梯度稀释化合物至中间板,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中培养7天,第8天,将待测化合物用排枪进行3倍稀释至第九个浓度,即从6mM稀释至0.9μM,设置双复孔实验。像中间板中加入198μL培养基,再按照对应位置,转移2μL每孔的梯度稀释化合物至第一块中间板中,再向第二块中间板中加入100μL培养基,取第一块中间板中的混匀化合物100μL加入,混匀后转移40μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是30μM至4.5nM。细胞板置于二氧化碳培养箱中再培养7天。化合物与细胞共孵育14天,向细胞板中加入每孔20μL的Almar blue检测试剂,将加染料的板子置于水平摇床上震荡15分钟,再将板子至于室温孵育至5小时使发光信号稳定。采用多标记分析仪读数。On the day of compound addition, add 85 μL of liquid medium to the 96-well U-plate plated with cells. The compound to be tested was diluted 3-fold to the ninth concentration, that is, from 6 mM to 0.9 μM, and a double-well experiment was set up. Add 97 μL of medium to the middle plate, and then transfer 2.5 μL of the compound diluted in each well to the middle plate according to the corresponding position. After mixing, transfer 40 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 30 [mu]M to 4.5 nM. The cell plate was cultured in a carbon dioxide incubator for 7 days. On the 8th day, the compound to be tested was diluted 3-fold to the ninth concentration, that is, from 6mM to 0.9μM, and a double-well experiment was set up. For example, add 198 μL of medium to the middle plate, and then transfer 2 μL of the compound diluted in each well to the first middle plate according to the corresponding position, then add 100 μL of medium to the second middle plate, and take the first middle plate. Add 100 μL of the mixed compound, and transfer 40 μL per well to the cell plate after mixing. Compound concentrations transferred to cell plates ranged from 30 [mu]M to 4.5 nM. The cell plates were placed in a carbon dioxide incubator for an additional 7 days. Compounds were incubated with cells for 14 days, 20 μL of Almar blue detection reagent per well was added to the cell plate, the dye-added plate was placed on a horizontal shaker and shaken for 15 minutes, and then the plate was incubated at room temperature for 5 hours to stabilize the luminescence signal. Read using a multi-label analyzer.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率,IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。 Using the equation (Sample-Min)/(Max-Min)×100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
实验结果：见表2。Experimental results: see Table 2.
表2 H358细胞3D增殖抑制活性测试结果Table 2 3D proliferation inhibitory activity test results of H358 cells
受试化合物test compound IC 50(nM) IC50 (nM)
化合物1的盐酸盐Compound 1 hydrochloride 140140
化合物2的盐酸盐The hydrochloride salt of compound 2 528528
化合物5的盐酸盐Compound 5 hydrochloride 3939
实验结论：本发明化合物能在3D条件下抑制H358细胞的增殖。Experimental conclusion: The compounds of the present invention can inhibit the proliferation of H358 cells under 3D conditions.
实验例3：DLD-1细胞p-ERK增殖抑制活性测试Experimental example 3: DLD-1 cell p-ERK proliferation inhibitory activity test
实验材料：Experimental Materials:
DLD-1细胞购自南京科佰；1640培养基购自Biological Industries；胎牛血清购自Biosera；Advanced Phospho-ERK1/2(THR202/TYR204)KIT购自Cisbio。Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表见表3。DLD-1 cells were purchased from Nanjing Kebai; 1640 medium was purchased from Biological Industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio. The composition of Advanced Phospho-ERK1/2 (THR202/TYR204) KIT is shown in Table 3.
表3 Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表Table 3 Advanced Phospho-ERK1/2 (THR202/TYR204) KIT ingredient list
成分名称Ingredient name 储存温度Storage temperature
Advanced PhosphoERK1/2 Eu Cryptate antibodyAdvanced PhosphoERK1/2 Eu Cryptate antibody ≤-16℃≤-16℃
Advanced PhosphoERK1/2 d2 antibodyAdvanced PhosphoERK1/2 d2 antibody ≤-16℃≤-16℃
Blocking reagent(stock solution 100X)Blocking reagent(stock solution 100X) ≤-16℃≤-16℃
Lysis buffer#1(stock solution 4X)Lysis buffer#1(stock solution 4X) ≤-16℃≤-16℃
Detection buffer(ready-to-use)Detection buffer(ready-to-use) ≤-16℃≤-16℃
实验方法：experimental method:
DLD-1细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含8000个DLD-1细胞，细胞板放入二氧化碳培养箱，37℃过夜孵育；DLD-1 cells were seeded in a transparent 96-well cell culture plate, 80 μL of cell suspension per well, each well containing 8000 DLD-1 cells, the cell plate was placed in a carbon dioxide incubator, and incubated overnight at 37°C;
将待测化合物用100％DMSO稀释到2mM作为第一个浓度，然后再用移液器进行5倍稀释至第8个浓度，即从2mM稀释至0.026μM。取2μL化合物加入78μL细胞饥饿培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时，此时化合物浓度为10μM至0.128nM，DMSO浓度为0.5％；The compounds to be tested were diluted with 100% DMSO to 2 mM as the first concentration, and then 5-fold diluted with a pipette to the eighth concentration, ie, from 2 mM to 0.026 [mu]M. Add 2 μL of compound to 78 μL of cell starvation medium. After mixing, add 20 μL of compound solution to the corresponding cell plate wells, put the cell plate back into the carbon dioxide incubator and continue to incubate for 1 hour. At this time, the compound concentration is 10 μM to 0.128nM, and the DMSO concentration is 0.5%;
结束孵育后，弃掉细胞上清加入50μL细胞裂解液每孔，室温摇晃孵育30分钟；After the incubation, discard the cell supernatant and add 50 μL of cell lysate to each well, and incubate with shaking at room temperature for 30 minutes;
使用Detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；Phospho-ERK1/2 Eu Cryptate antibody and Phospho-ERK1/2 d2 antibody were diluted 20-fold with Detection buffer;
取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育4小时；Take 16μL of cell lysate supernatant per well into a new 384 white microplate, add 2μL of Phospho-ERK1/2 Eu Cryptate antibody dilution and 2μL of Phospho-ERK1/2 d2 antibody dilution, and incubate at room temperature for 4 hours;
孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm。After the incubation, use a multi-label analyzer to read HTRF excitation: 320nm, emission: 615nm, 665nm.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)×100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中log(inhibitor)vs.response--Variable slope模式得出)。本发明化合物对p-ERK的抑制作用测试结果见表4。 Using the equation (Sample-Min)/(Max-Min)×100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism --Variable slope mode). Table 4 shows the test results of the inhibitory effect of the compounds of the present invention on p-ERK.
Max孔:阳性对照孔读值为1X裂解液Max well: positive control well reads 1X lysate
Min孔:阴性对照孔读值为0.5％DMSO细胞孔细胞裂解液Min well: negative control well reads 0.5% DMSO cell well cell lysate
表4本发明化合物对DLD-1细胞p-ERK增殖抑制活性测试结果Table 4 Test results of the compounds of the present invention on the proliferation inhibition activity of DLD-1 cells p-ERK
受试化合物test compound IC 50(nM) IC50 (nM)
化合物1的盐酸盐Compound 1 hydrochloride 140.5140.5
化合物5的盐酸盐Compound 5 hydrochloride 54.554.5
化合物6的盐酸盐Compound 6 hydrochloride 112.1112.1
化合物14的盐酸盐The hydrochloride salt of compound 14 119.5119.5
化合物16Compound 16 227.6227.6
化合物20Compound 20 89.6989.69
化合物29Compound 29 139.6139.6
化合物31Compound 31 295.4295.4
化合物34的盐酸盐The hydrochloride salt of compound 34 399.5399.5
化合物35Compound 35 307.8307.8
实验结论：本发明化合物对DLD-1细胞p-ERK增殖有抑制效果。Experimental conclusion: The compound of the present invention has inhibitory effect on the proliferation of p-ERK in DLD-1 cells.
实验例4：化合物药代动力学评价Experimental Example 4: Compound Pharmacokinetic Evaluation
实验材料：Experimental Materials:
CD-1小鼠(雄性,7～9周龄,北京维通利华)CD-1 mice (male, 7-9 weeks old, Beijing Weitonglihua)
实验操作：Experimental operation:
以标准方案测试化合物静脉推注及口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予小鼠单次静脉注射及口服给药。静注及口服溶媒为5％二甲基亚砜,5％的聚乙二醇-15羟基硬脂酸酯与10％的水配成的混合溶媒。该项目使用四只雄性CD-1小鼠,两只小鼠进行静脉注射给药,给药剂量为10mg/kg,收集给药后0.083,0.25,0.5,1,2,4,8,24h的血浆样品；另外两只小鼠口服灌胃给药,给药剂量为50mg/kg,收集给药后0.25、0.5,1,2,4,8,12,24h的血浆样品,在4℃下3,200x g离心10分钟,分离上清得血浆样品,加入20倍体积含内标的乙腈溶液沉淀蛋白,12000x g搅拌15min,4℃离心取上清液50μL转移至96-well plate二次离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如达峰浓度(C max),清除率(CL),半衰期(T 1/2),组织分布(Vdss),药时曲线下面积(AUC 0-last),生物利用度(F)等。 The pharmacokinetic characteristics of the compounds in rodents after intravenous bolus injection and oral administration were tested according to the standard protocol. In the experiment, the candidate compounds were formulated into clear solutions and administered to mice by a single intravenous injection and oral administration. The vehicle for intravenous injection and oral administration is a mixed solvent of 5% dimethyl sulfoxide, 5% polyethylene glycol-15 hydroxystearate and 10% water. Four male CD-1 mice were used in this project, two mice were administered intravenously at a dose of 10 mg/kg, and the 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after administration were collected. Plasma samples; the other two mice were given oral gavage at a dose of 50 mg/kg, and the plasma samples were collected at 0.25, 0.5, 1, 2, 4, 8, 12, and 24 hours after administration. Centrifuge at x g for 10 minutes, separate the supernatant to obtain the plasma sample, add 20 times the volume of acetonitrile solution containing internal standard to precipitate the protein, stir at 12,000 x g for 15 minutes, centrifuge at 4°C to take 50 μL of the supernatant and transfer it to a 96-well plate for secondary centrifugation to take the supernatant for Quantitative analysis of blood drug concentration by LC-MS/MS analysis method, and calculation of pharmacokinetic parameters, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), tissue distribution (Vdss) , area under the drug-time curve (AUC 0-last ), bioavailability (F) and so on.
实验结果：见表5。Experimental results: see Table 5.
表5药代动力学测试结果Table 5 Pharmacokinetic test results
Figure PCTCN2022082591-appb-000173
Figure PCTCN2022082591-appb-000173
实验结论：本发明化合物具有良好的药代动力学性质,包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。Experimental conclusion: The compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
实验例5：化合物在Miapaca2裸鼠移植瘤模型的体内药效评价Experimental Example 5: In vivo efficacy evaluation of the compound in Miapaca2 nude mouse xenograft model
细胞培养：Cell Culture:
人胰腺癌细胞(Miapaca2),体外贴壁单层培养,培养条件为DMEM培养基中加10％胎牛血清,37℃,5％CO 2孵箱培养。一周两到三次用胰酶–EDTA进行常规消化处理传代。当细胞饱和度为80％–90％,数量到达要求时,收取细胞,计数,接种。 Human pancreatic cancer cells (Miapaca2) were cultured in an adherent monolayer in vitro, and the culture conditions were DMEM medium plus 10% fetal bovine serum, 37 °C, 5% CO 2 incubator. Routine digestion with trypsin-EDTA was performed two to three times a week. When the cell saturation is 80%–90% and the number reaches the requirement, the cells are harvested, counted, and seeded.
实验动物：Experimental animals:
Balb/c裸小鼠,雌性,6-7周,购自上海西普尔-必凯实验动物有限公司。Balb/c nude mice, female, 6-7 weeks old, were purchased from Shanghai Sipple-Bike Laboratory Animal Co., Ltd.
模型制备：Model preparation:
将0.2mL(5×10 6个)Miapaca2细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背,肿瘤平均体积达到118mm 3时开始分组给药。 0.2mL (5×10 6 cells) Miapaca2 cells (plus Matrigel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each mouse, and the group administration started when the average tumor volume reached 118 mm 3 .
给药方案：见表6。Dosing regimen: see Table 6.
表6实验动物分组及给药方案Table 6 Grouping and dosing schedule of experimental animals
Figure PCTCN2022082591-appb-000174
Figure PCTCN2022082591-appb-000174
肿瘤测量和实验指标：Tumor measurements and experimental indicators:
每周两次用游标卡尺测量肿瘤直径,肿瘤体积以立方毫米计量,通过以下的公式计算:V＝0.5a×b 2,其中a和b分别是肿瘤的长径和短径。受试化合物的抑瘤疗效通过使用TGI(％)来评价。TGI(％),反映肿瘤生长抑制率。TGI(％)＝[1–(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)]×100％。 Tumor diameter was measured with vernier calipers twice a week, and tumor volume was measured in cubic millimeters and calculated by the following formula: V=0.5a×b 2 , where a and b are the long and short diameters of the tumor, respectively. The tumor-inhibitory efficacy of the test compounds was evaluated by using TGI (%). TGI (%) reflects the tumor growth inhibition rate. TGI(%)=[1-(average tumor volume at the end of administration in a certain treatment group-average tumor volume at the beginning of administration in this treatment group)/(average tumor volume at the end of treatment in the solvent control group-average at the beginning of treatment in the solvent control group tumor volume)] × 100%.
实验结果：见表7。Experimental results: see Table 7.
表7本发明化合物在Miapaca2裸鼠移植瘤模型中的抑瘤药效评价(基于给药后第19天肿瘤体积计算得出)Table 7 Evaluation of the antitumor efficacy of the compounds of the present invention in Miapaca2 nude mouse xenograft model (calculated based on the tumor volume on the 19th day after administration)
Figure PCTCN2022082591-appb-000175
Figure PCTCN2022082591-appb-000175
实验结论：本发明化合物与AMG510联用在Miapaca2裸鼠移植瘤模型中展现出优异的抑瘤效果。Experimental conclusion: The compound of the present invention combined with AMG510 showed excellent tumor inhibition effect in Miapaca2 nude mouse xenograft model.

Claims (29)

  1. 式(Ⅱ)化合物或其药学上可接受的盐，A compound of formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022082591-appb-100001
    Figure PCTCN2022082591-appb-100001
    其中，in,
    E选自-(CH 2CH 2O) m-； E is selected from -(CH 2 CH 2 O) m -;
    E 1选自-(CR 7R 8) v-； E 1 is selected from -(CR 7 R 8 ) v -;
    E 2选自-(CH 2CH 2O) w-； E 2 is selected from -(CH 2 CH 2 O) w -;
    R 1选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、-NHC(＝O)-C 1-4烷基、4-6元杂环烷基和5-6元杂环烯基，其中所述C 1-4烷基、-NHC(＝O)-C 1-4烷基、4-6元杂环烷基和5-6元杂环烯基分别独立地任选被1、2、3或4个R e取代； R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, 4-6 membered hetero Cycloalkyl and 5-6 membered heterocycloalkenyl, wherein said C 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, 4-6 membered heterocycloalkyl and 5-6 membered The heterocycloalkenyl groups are each independently optionally substituted with 1, 2, 3 or 4 R e ;
    R 2选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3- 6环烷基、3-6元杂环烷基和5-6元杂芳基，其中所述C 1-4烷基、C 1-4烷氧基、C 1-4烷氨基、-S(＝O) 2-C 1-4烷基、C 3-6环烷基、3-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2、3或4个R a取代；R 3选自H、F、Cl、Br、I和C 1-4烷基，其中所述C 1-4烷基任选被1、2、3或4个R b取代； R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, -S(= O) 2 - C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl, wherein the C 1-4 alkyl, C 1-4 Alkoxy, C 1-4 alkylamino, -S(=O) 2 -C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl and 5-6 membered heteroaryl Each independently is optionally substituted with 1, 2, 3 or 4 R a ; R is selected from H, F, Cl, Br, I and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R b ;
    R 4选自C 1-4烷基和C 1-4卤代烷基，其中所述C 1-4烷基和C 1-4卤代烷基分别独立地任选被1、2、3或4个R c取代； R 4 is selected from C 1-4 alkyl and C 1-4 haloalkyl, wherein said C 1-4 alkyl and C 1-4 haloalkyl are each independently optionally surrounded by 1, 2, 3 or 4 R c replace;
    R 5选自H、F、Cl、Br、I、-NH 2、C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基，其中所述C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基分别独立地任选被1、2、3或4个R d取代； R 5 is selected from H, F, Cl, Br, I, -NH 2 , C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino, wherein the C 1-4 alkyl, C 1-4 alkoxy and C 1-4 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R d ;
    R 6选自H、F、Cl、Br、I、-OH、-NH 2和-CN； R 6 is selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
    或者，R 2、R 6和与它们相连的碳原子一起形成
    Figure PCTCN2022082591-appb-100002
    Alternatively, R 2 , R 6 and the carbon atoms to which they are attached together form
    Figure PCTCN2022082591-appb-100002
    R 7选自H、D、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基和C 1-4烷氧基，其中所述C 1-4烷基和C 1-4烷氧基分别独立地任选被1、2、或3个R f取代； R 7 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl and C 1-4 alkoxy, wherein said C 1-4 alkyl and C 1-4 alkoxy are each independently optionally substituted with 1, 2, or 3 R f ;
    R 8选自H、D、F、Cl、Br、I、-OH、-NH 2和-CN； R 8 is selected from H, D, F, Cl, Br, I, -OH, -NH 2 and -CN;
    或者，相邻碳原子上的两个R 7和与它们相连的碳原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基任选被1、2、3或4个R g取代； Alternatively, two R7 on adjacent carbon atoms and the carbon atom to which they are attached together form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 R g substitutions;
    R 9分别独立地选自H、F、Cl、Br、I、-OH、-NH 2和-CN； R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and -CN;
    R 10选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷氨基； R 10 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkylamino;
    或者，两个R 9和与它们相连的碳原子一起形成4-6元杂环烷基，其中所述4-6元杂环烷基任选被1、2、3或4个R h取代； Alternatively, the two R 9 and the carbon atoms to which they are attached are taken together to form a 4-6 membered heterocycloalkyl, wherein the 4-6 membered heterocycloalkyl is optionally substituted with 1, 2, 3 or 4 R;
    R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-4烷基、C 1-4烷氧基和3-6元杂环烷基，其中所述C 1-4烷基、C 1-4烷氧基和3-6元杂环烷基分别独立地任选被1、2、3或4个R取代； R a is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl, wherein The C 1-4 alkyl, C 1-4 alkoxy and 3-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, 3 or 4 R;
    R b分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R b is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
    R c分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R c is independently selected from F, Cl, Br, I, -OH , -NH and -CN;
    R d分别独立地选自F、Cl、Br、I、-OH、-NH 2和-CN； R d are independently selected from F, Cl, Br, I, -OH, -NH 2 and -CN;
    R e分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN和-N(CH 3) 2； R e is each independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and -N( CH3 ) 2 ;
    R f分别独立地选自D、F、Cl、Br、I、-OH、-NH 2和-CN； R f is independently selected from D, F, Cl, Br, I, -OH , -NH and -CN;
    R g分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基和-C(＝O)CH 3； R g is independently selected from F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl and -C(=O)CH 3 ;
    R h分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2、-CN和C 1-3烷基； R h is independently selected from F, Cl, Br, I, =O, -OH, -NH 2 , -CN and C 1-3 alkyl;
    R分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN和
    Figure PCTCN2022082591-appb-100003
    R is independently selected from F, Cl, Br, I, -OH, -NH2 , -CN and
    Figure PCTCN2022082591-appb-100003
    m选自0或1；m is selected from 0 or 1;
    v选自2、3或4；v is selected from 2, 3 or 4;
    w选自0或1；w is selected from 0 or 1;
    当R 4为-CH 3且R 5、R 6、R 7、R 8均为H时，条件是： When R 4 is -CH 3 and R 5 , R 6 , R 7 and R 8 are all H, the conditions are:
    (1)当m为1，w为1，v为2，R 1为H，R 3为F时，R 2不为-CHF 2或
    Figure PCTCN2022082591-appb-100004
    (1) When m is 1, w is 1 , v is 2 , R1 is H, R3 is F, R2 is not -CHF2 or
    Figure PCTCN2022082591-appb-100004
    (2)当m为1，w为1，v为2，R 1为H，R 3为-CH 3时，R 2不为-CHF 2或-CF 3； (2) When m is 1, w is 1, v is 2, R 1 is H, and R 3 is -CH 3 , R 2 is not -CHF 2 or -CF 3 ;
    (3)当m为1，w为1，v为4，R 1为H，R 3为F时，R 2不为-CHF 2； (3) When m is 1, w is 1, v is 4, R 1 is H, and R 3 is F, R 2 is not -CHF 2 ;
    (4)当v为2，R 2为-NH 2，R 2为-CF 3，R 3为H时，m与w之和不为0、1或2； (4) When v is 2, R 2 is -NH 2 , R 2 is -CF 3 , and R 3 is H, the sum of m and w is not 0, 1 or 2;
    (5)当m与w之和为1，v为2，R 1为H，R 3为F时，R 2不为-CHF 2或
    Figure PCTCN2022082591-appb-100005
    (5) When the sum of m and w is 1, v is 2, R 1 is H, and R 3 is F, R 2 is not -CHF 2 or
    Figure PCTCN2022082591-appb-100005
    所述3-6元杂环烷基、4-6元杂环烷基、5-6元杂环烯基和5-6元杂芳基中“杂”表示1、2、3或4个分别独立地选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。In the 3-6-membered heterocycloalkyl, 4-6-membered heterocycloalkyl, 5-6-membered heterocycloalkenyl and 5-6-membered heteroaryl, "hetero" means 1, 2, 3 or 4, respectively A heteroatom or heteroatom group independently selected from -O-, -NH-, -S- and -N-.
  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，R分别独立地选自
    Figure PCTCN2022082591-appb-100006
    The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R is independently selected from
    Figure PCTCN2022082591-appb-100006
  3. 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，R a分别独立地选自F、Cl、Br、-OH、- NH 2、-CN、-OCH 3、
    Figure PCTCN2022082591-appb-100007
    其中所述-OCH 3、
    Figure PCTCN2022082591-appb-100008
    分别独立地任选被1、2、3或4个R取代。     The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R a is independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -OCH 3 ,
    Figure PCTCN2022082591-appb-100007
    wherein -OCH 3 ,
    Figure PCTCN2022082591-appb-100008
    are each independently optionally substituted with 1, 2, 3 or 4 R.
  4. 根据权利要求3所述的化合物或其药学上可接受的盐，其中，R a分别独立地选自F、-OH、-OCH 3、
    Figure PCTCN2022082591-appb-100009
    The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R a is independently selected from F, -OH, -OCH 3 ,
    Figure PCTCN2022082591-appb-100009
  5. 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，R e分别独立地选自-OH、-NH 2和-N(CH 3) 2。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R e is each independently selected from -OH, -NH 2 and -N(CH 3 ) 2 .
  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，R f分别独立地选自D。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R f is each independently selected from D.
  7. 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，R g分别独立地选自-C(＝O)CH 3。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R g is each independently selected from -C(=O)CH 3 .
  8. 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，R h分别独立地选自＝O和-CH 3。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R h is independently selected from =O and -CH 3 .
  9. 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，R 1选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、
    Figure PCTCN2022082591-appb-100010
    其中所述-CH 3、
    Figure PCTCN2022082591-appb-100011
    分别独立地任选被1、2、3或4个R e取代。     The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 ,
    Figure PCTCN2022082591-appb-100010
    wherein -CH 3 ,
    Figure PCTCN2022082591-appb-100011
    Each independently is optionally substituted with 1, 2, 3 or 4 Re .
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中，R 1选自H、-NH 2、-CN、
    Figure PCTCN2022082591-appb-100012
    Figure PCTCN2022082591-appb-100013
    The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, -NH 2 , -CN,
    Figure PCTCN2022082591-appb-100012
    Figure PCTCN2022082591-appb-100013
  11. 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，R 2选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3、-CH 2CH 3、-CH 2CH(CH 3) 2和5元杂芳基，其中所述-CH 3、-CH 2CH 3、-CH 2CH(CH 3) 2和5元杂芳基分别独立地任选被1、2、3或4个R a取代。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2- and 5-membered heteroaryl groups, wherein the -CH 3 , -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2- and 5-membered heteroaryl groups are each independently Optionally substituted with 1, 2, 3 or 4 Ra .
  12. 根据权利要求11所述的化合物或其药学上可接受的盐，其中，R 2选自H、F、-CN、-CHF 2、-CF 3、 The compound of claim 11 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, F, -CN, -CHF 2 , -CF 3 ,
    Figure PCTCN2022082591-appb-100014
    Figure PCTCN2022082591-appb-100014
  13. 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，R 3选自H和F。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R3 is selected from H and F.
  14. 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，R 4选自-CH 3。 The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R4 is selected from -CH3 .
  15. 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，R 5选自H。 The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R5 is selected from H.
  16. 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，R 6选自H。 The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R6 is selected from H.
  17. 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，R 7选自H、D、F、-OCH 3和-OCD 3。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 7 is selected from H, D, F, -OCH 3 and -OCD 3 .
  18. 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，R 8选自H、D、F、Cl和Br。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R8 is selected from the group consisting of H, D, F, Cl and Br.
  19. 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，R 9选自H。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from H.
  20. 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，R 10选自H和-NHCH 3。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 10 is selected from H and -NHCH 3 .
  21. 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，相邻碳原子上的两个R 7和与它们相连的碳原子一起形成
    Figure PCTCN2022082591-appb-100015
    The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein two R7 on adjacent carbon atoms and the carbon atom to which they are attached together form
    Figure PCTCN2022082591-appb-100015
  22. 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，两个R 9和与它们相连的碳原子一起形成
    Figure PCTCN2022082591-appb-100016
    The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the two R 9 and the carbon atom to which they are attached together form
    Figure PCTCN2022082591-appb-100016
  23. 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，结构单元
    Figure PCTCN2022082591-appb-100017
    选自
    Figure PCTCN2022082591-appb-100018
    The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022082591-appb-100017
    selected from
    Figure PCTCN2022082591-appb-100018
  24. 根据权利要求1～23任意一项所述的化合物或其药学上可接受的盐，其化合物具有式(Ⅱ-3)、(Ⅱ-4)或(Ⅱ-5)所示结构：The compound according to any one of claims 1 to 23 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure represented by formula (II-3), (II-4) or (II-5):
    Figure PCTCN2022082591-appb-100019
    Figure PCTCN2022082591-appb-100019
    其中，in,
    n选自0和1；n is selected from 0 and 1;
    R 1、R 2、R 3、R 4、R 5、R 6、R 7和R 8如权利要求1～23任意一项所定义。 R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in any one of claims 1-23.
  25. 根据权利要求24所述的化合物或其药学上可接受的盐，其化合物具有式(Ⅱ-6)、(Ⅱ-7)、(Ⅱ-8)或 (Ⅱ-9)所示结构：The compound according to claim 24 or a pharmaceutically acceptable salt thereof, wherein the compound has the structure represented by formula (II-6), (II-7), (II-8) or (II-9):
    Figure PCTCN2022082591-appb-100020
    Figure PCTCN2022082591-appb-100020
    其中，in,
    n选自0和1；n is selected from 0 and 1;
    环A选自4-6元杂环烷基；Ring A is selected from 4-6 membered heterocycloalkyl;
    R 1、R 2、R 3、R 7、R 8、R 9、R 10和R g如权利要求24所定义。 R 1 , R 2 , R 3 , R 7 , R 8 , R 9 , R 10 and R g are as defined in claim 24 .
  26. 下式化合物或其药学上可接受的盐，A compound of the formula or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022082591-appb-100021
    Figure PCTCN2022082591-appb-100021
    Figure PCTCN2022082591-appb-100022
    Figure PCTCN2022082591-appb-100022
    Figure PCTCN2022082591-appb-100023
    Figure PCTCN2022082591-appb-100023
    Figure PCTCN2022082591-appb-100024
    Figure PCTCN2022082591-appb-100024
  27. 根据权利要求26所述的化合物或其药学上可接受的盐，其化合物为，The compound of claim 26 or a pharmaceutically acceptable salt thereof, wherein the compound is,
    Figure PCTCN2022082591-appb-100025
    Figure PCTCN2022082591-appb-100025
    Figure PCTCN2022082591-appb-100026
    Figure PCTCN2022082591-appb-100026
    Figure PCTCN2022082591-appb-100027
    Figure PCTCN2022082591-appb-100027
    Figure PCTCN2022082591-appb-100028
    Figure PCTCN2022082591-appb-100028
    Figure PCTCN2022082591-appb-100029
    Figure PCTCN2022082591-appb-100029
    Figure PCTCN2022082591-appb-100030
    Figure PCTCN2022082591-appb-100030
    Figure PCTCN2022082591-appb-100031
    Figure PCTCN2022082591-appb-100031
    Figure PCTCN2022082591-appb-100032
    Figure PCTCN2022082591-appb-100032
    Figure PCTCN2022082591-appb-100033
    Figure PCTCN2022082591-appb-100033
    Figure PCTCN2022082591-appb-100034
    Figure PCTCN2022082591-appb-100034
    Figure PCTCN2022082591-appb-100035
    Figure PCTCN2022082591-appb-100035
  28. 根据权利要求1～27任意一项所述的化合物或其药学上可接受的盐，其中药学上可接受的盐为盐酸盐。The compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
  29. 根据权利要求1～28任意一项所述的化合物或其药学上可接受的盐在制备治疗KRAS突变实体瘤疾病的药物中的应用。Use of the compound according to any one of claims 1 to 28 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating KRAS mutant solid tumor diseases.
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