WO2022199670A1 - 6-氨基甲酸酯取代的杂芳环衍生物 - Google Patents

6-氨基甲酸酯取代的杂芳环衍生物 Download PDF

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WO2022199670A1
WO2022199670A1 PCT/CN2022/082862 CN2022082862W WO2022199670A1 WO 2022199670 A1 WO2022199670 A1 WO 2022199670A1 CN 2022082862 W CN2022082862 W CN 2022082862W WO 2022199670 A1 WO2022199670 A1 WO 2022199670A1
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compound
mmol
alkyl
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/082862
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English (en)
French (fr)
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吴凌云
代天资
赵乐乐
孙建军
钱薏
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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Priority to EP22774324.2A priority Critical patent/EP4317157A1/en
Priority to KR1020237035917A priority patent/KR20230159543A/ko
Priority to JP2023559125A priority patent/JP2024511507A/ja
Priority to CN202280016466.3A priority patent/CN116917286A/zh
Priority to AU2022244957A priority patent/AU2022244957A1/en
Publication of WO2022199670A1 publication Critical patent/WO2022199670A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D405/12—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 linked by a chain containing hetero atoms as chain links
    • 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
    • C07D405/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring

Definitions

  • the present invention relates to a new class of 6-carbamate-substituted heteroaromatic ring 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 guanosine nucleoside binding protein with guanosine triphosphate hydrolase (GTPase) activity, which mainly contains three isoforms, KRAS, NRAS and HRAS.
  • GTPase guanosine nucleoside binding protein with guanosine triphosphate hydrolase
  • KRAS guanosine triphosphate hydrolase
  • NRAS guanosine triphosphate hydrolase
  • HRAS guanosine triphosphate hydrolase
  • SOS1 (Son of Sevenless 1) is a GEF that regulates the GDP/GTP cycle of the RAS protein. After cell surface receptors are activated and bind to intracellular Grb2, Grb2 recruits SOS1 to the cell membrane, and then SOS1 catalyzes the exchange of RAS-GDP/GTP, thereby activating downstream signaling pathways.
  • the small molecule SOS1 inhibitor bound to the catalytic site can block the binding of SOS1 to the RAS protein, thereby effectively reducing the abnormal activation of the downstream signaling pathway of RAS in cancer cells and playing a role in the treatment of cancer.
  • 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,
  • R 1 and R 2 are each independently selected from H, C 1-6 alkyl, C 3-12 cycloalkyl, 3-12 membered heterocycloalkyl, C 6-10 aryl and 5-10 membered heteroaryl , wherein the C 1-6 alkyl group, C 3-12 cycloalkyl group, 3-12-membered heterocycloalkyl group, C 6-10 -membered aryl group and 5-10-membered heteroaryl group are independently optionally replaced by 1, 2, 3 or 4 Ra ;
  • R 1 , R 2 and the nitrogen atom to which they are attached together form a 3-12 membered heterocycloalkyl, wherein the 3-12 membered heterocycloalkyl is optionally surrounded by 1, 2, 3 or 4 R b replace;
  • R 3 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, wherein the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R c ;
  • R 5 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, wherein the C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino are each independently optionally substituted with 1, 2, 3 or 4 R c ;
  • R 4 , R 5 and the carbon atoms to which they are attached form together in optionally substituted with 1, 2, 3 or 4 R d ;
  • T 1 is selected from CR 6 and N;
  • the membered heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 R;
  • the membered heteroaryl groups are each independently optionally substituted with 1, 2, 3 or 4 R;
  • the present invention provides a compound represented by formula (I-2) or a pharmaceutically acceptable salt thereof,
  • R3 is selected from H, F, Cl, Br, I, -OH and -NH2 ;
  • R 4 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-4 alkyl, wherein said C 1-4 alkyl is optionally replaced by 1, 2, 3 or 4 R c substitutions;
  • R 5 is selected from H, F, Cl, Br, I, and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2, 3 or 4 R c ;
  • R 4 , R 5 and the carbon atoms to which they are attached form together in optionally substituted with 1, 2, 3 or 4 R d ;
  • Hetero in the 6-10-membered heterocycloalkyl and 4-5-membered heterocycloalkyl means 1, 2, 3 or 4 are independently selected from -O-, -NH-, -S- and - N- heteroatom or heteroatom group.
  • T 1 , R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • a carbon atom with "*" is a chiral carbon atom and exists in (R) or (S) single enantiomeric form or enriched in one enantiomeric form.
  • the 1-3 alkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R, and other variables are as defined herein.
  • R a are independently selected from F, Cl, Br, -OH, -NH 2 , -CN, -CH 3 and -OCH 3 , wherein -CH 3 and -OCH 3 are respectively Independently optionally substituted with 1, 2, 3 or 4 R, R and other variables are as defined herein.
  • R 1 and R 2 are independently selected from H and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally represented by 1, 2, 3 or 4 R a Substitution, Ra and other variables are as defined herein.
  • the variables are as defined in the present invention.
  • R b are independently selected from F, Cl, Br, -NH 2 , -CH 3 , -CH 2 -CH 3 , wherein -CH 3 , -CH 2 -CH 3 , Each independently is optionally substituted with 1, 2, 3 or 4 R, R and other variables as defined herein.
  • R b are independently selected from F, Cl, Br, -NH 2 , -CH 3 , -CH 2 -CH 3 , Other variables are as defined in the present invention.
  • R c are independently selected from F, Cl , Br, -OH, -OCH and Other variables are as defined in the present invention.
  • the cycloalkyl groups are each independently optionally substituted with 1, 2, 3 or 4 R, R and other variables as defined herein.
  • R c are independently selected from F, -OH and Other variables are as defined in the present invention.
  • R d are independently selected from F, Cl and Br, and other variables are as defined in the present invention.
  • R d are independently selected from F, and other variables are as defined in the present invention.
  • R3 is selected from H, F, Cl, Br and -NH2 , and other variables are as defined in the present invention.
  • R3 is selected from H and -NH2 , and other variables are as defined in the present invention.
  • R 4 is selected from H, -CN and C 1-4 alkyl, wherein the C 1-4 alkyl is optionally substituted with 1, 2, 3 or 4 R c , R c and other variables as defined herein.
  • the above R 4 is selected from H, F, Cl, Br, -CN, -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 and -CH 2 CH(CH 3 ) 2 , wherein the -CH 3 , -CH 2 CH 3 , -CH(CH 3 ) 2 and -CH 2 CH(CH 3 ) 2 are independently optionally substituted by 1, 2, 3 or 4 R c , R c and other variables are as defined in the present invention.
  • R 4 is selected from H, F, Cl, Br, -CN, R c and other variables are as defined in the present invention.
  • R 4 is selected from H, F, Cl, Br, -CN, Other variables are as defined in the present invention.
  • R 5 is selected from H, F, Cl, Br and -CH 3 , and other variables are as defined in the present invention.
  • R 5 is selected from H, F and -CH 3 , and other variables are as defined in the present invention.
  • R 6 is selected from -OCH 3 , and other variables are as defined in the present invention.
  • m is selected from 0, 1 and 2, and other variables are as defined in the present invention.
  • the above R 1 , R 2 and the nitrogen atom to which they are attached together form a 5-11 membered heterocycloalkyl, wherein the 5-11 membered heterocycloalkyl is optionally composed of 1, 2, 3 or 4 R b substitutions, R b and other variables are as defined herein.
  • the above-mentioned compound has the structure represented by formula (II-2) or (II-3):
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined in the present invention.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • R 1 , R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • a carbon atom with "*" is a chiral carbon atom and exists in (R) or (S) single enantiomeric form or enriched in one enantiomeric form.
  • the above-mentioned compound has the structure represented by formula (I-4), (I-5) or (I-6):
  • T and V are each independently selected from CH2 , NH and O;
  • n is selected from 0, 1, 2, 3 and 4;
  • n, p, q, r and s are each independently selected from 0, 1 and 2;
  • W is selected from NH, -CH2 - CH2- and -O-CH2- ;
  • Y is selected from N and CH;
  • R 3 , R 4 , R 5 and R b are as defined in the present invention.
  • T is selected from CH2 , NH and O;
  • R7 , R8 and the carbon atom to which they are attached together form a C3-4 membered cycloalkyl
  • n is selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1 and 2;
  • R, R3 , R4 and R5 are as defined in the present invention .
  • T is selected from CH2 , NH and O;
  • R7 , R8 and the carbon atom to which they are attached together form a C3-4 membered cycloalkyl
  • n is selected from 0, 1, 2, 3 and 4;
  • n is selected from 0, 1 and 2;
  • R, R3 , R4 and R5 are as defined in the present invention .
  • T, m, n, R b , R 3 , R 4 , R 5 , R 7 and R 8 are as defined in the present invention.
  • T 1 is selected from CHR b , NH, NR b and O;
  • n is selected from 1 and 2;
  • R, R3 , R4 and R5 are as defined in the present invention .
  • the above compound has the structure represented by formula (III-5) or (III-6):
  • T 1 , n, R 3 , R 4 , R 5 and R 7 are as defined in the present invention.
  • R 7 and R 8 are independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 and -CH 2 -CH 3 , Other variables are as defined in the present invention.
  • R 7 and R 8 are independently selected from H and -CH 3 respectively, and other variables are as defined in the present invention.
  • R 7 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, -CH 3 and -CH 2 -CH 3 , and other variables are as defined in the present invention .
  • R 7 is selected from H and -CH 3 , and other variables are as defined in the present invention.
  • R 8 is selected from H, and other variables are as defined in the present invention.
  • the above R7 , R8 and the carbon atom to which they are attached are taken together to form a cyclopropyl group.
  • T, V, W, Y, m, n, p, q, r, s, R 3 , R 4 , R 5 , R b , R 7 and R 8 are as defined in the present invention
  • a carbon atom with "*" is a chiral carbon atom and exists in (R) or (S) single enantiomeric form or enriched in one enantiomeric form.
  • the above-mentioned compound has the structure represented by formula (I-10), (I-11) or (I-12):
  • T, V, W, Y, m, n, p, q, r, s, R 3 , R 4 , R 5 and R b 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 above compound or a pharmaceutically acceptable salt thereof, wherein the pharmaceutically acceptable salt is a hydrochloride salt.
  • 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, as well as significant inhibitory activity on DLD-1 cells and KRAS(G12C) mutant H358 cells, and has good pharmacokinetic properties, and further obtained Excellent tumor growth inhibitory activity.
  • 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.
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” refers to a “ring” of 5-7 atoms arranged around it.
  • C 1-6 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl and the like; it can be Is monovalent (eg methyl), divalent (eg methylene) or polyvalent (eg methine).
  • C 1-6 alkyl examples 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), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
  • 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.
  • C1-6alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-6 alkoxy groups include C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy groups, etc. .
  • 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), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy 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 1-6 alkylamino refers to those alkyl groups containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-6 alkylamino includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 alkylamino Wait.
  • C 1-6 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.
  • C 1-3 alkylamino refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group.
  • the C 1-3 alkylamino groups include C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 and the like.
  • the heteroatom or heteroatom group may be located within or outside the ring system (eg, cyclopropylsulfone, cyclopropylacyl), where so-called heterocycloalkyl and heteroaryl are represented by carbon
  • the atom is attached to the rest of the molecule, i.e.
  • the heteroatom can be located anywhere in the group (except where the group is attached to the rest of the molecule); the so-called heterocycloalkyl and heteroaryl groups are attached to the molecule through the heteroatom
  • the rest of the molecule is connected, that is, the heteroatom is located at the position where the group is attached to the rest of the molecule; the so-called heterocycloalkyl heteroyl and heteroaryl heteroyl are connected to the rest of the molecule through a heteroatom, where the heteroatom can be located at Any position of the group (including where the group is attached to the rest of the molecule).
  • C 3-12 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 12 carbon atoms, including monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiro, condensed and bridged rings.
  • the C 3-12 cycloalkyl includes C 3-10 , C 3-10 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 and C 5-6 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • C 3-12 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [ 4.4.0] Dicyclodecane, etc.
  • C 3-10 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 10 carbon atoms, which includes monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include Spiro, condensed and bridged rings.
  • the C 3-10 cycloalkyl includes C 3-8 , C 3-6 , C 3-5 , C 4-10 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 etc.; it can be monovalent, bivalent or polyvalent.
  • C 3-10 cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, [2.2.2]bicyclooctane, [ 4.4.0] Dicyclodecane, etc.
  • C 3-4 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 4 carbon atoms, which is a monocyclic ring system, said C 3-5 cycloalkyl group includes C 3 and C 4 cycloalkyl, etc.; it may be monovalent, divalent or polyvalent.
  • Examples of C3-4cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, and the like.
  • the 3-12 membered heterocycloalkyl includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic rings include spiro, paracyclic and bridged rings. Furthermore, with respect to the "3-12 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the rest of the molecule.
  • the 3-12 membered heterocycloalkyl includes 3-10 membered, 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocyclic Cycloalkyl, etc.
  • 3-12 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
  • the 3-10 membered heterocycloalkyl includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, paracyclic and bridged rings. Furthermore, with respect to the "3-10 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 3-10 membered heterocycloalkyl includes 3-8 membered, 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • 3-10 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
  • the 5-11 membered heterocycloalkyl includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic rings include spiro, paracyclic and bridged rings. Furthermore, with respect to the "5-11 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 5-11 membered heterocycloalkyl includes 5-6 member, 5-7 member, 5-8 member, 5-9 member, 5-10 member, 5-11 member, 6-7 member, 6-8 member , 6-9-membered, 6-10-membered, 6-11-membered, 5-membered, 6-membered and 7-membered heterocycloalkyl, etc.
  • Examples of 5-11 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, he
  • the 6-10 membered heterocycloalkyl includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, paracyclic and bridged rings. Furthermore, with respect to the "6-10 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 6-10-membered heterocycloalkyl includes 6-membered, 6-7-membered, 6-8-membered, 6-9-membered, 5-10-membered, 7-membered, 7-8-membered, 7-9-membered, 7-10 membered membered, 8 membered, 8-9 membered, 8-10 membered, 9 membered and 10 membered heterocycloalkyl, etc.
  • 6-10 membered heterocycloalkyl examples include, but are not limited to, 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, isothiazolidinyl, 1, 2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl 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 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, hex
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 4-5 membered heterocycloalkyl includes 4 and 5 membered heterocycloalkyl.
  • Examples of 4-5 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) or tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.) and the like.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • 4-membered heterocycloalkyl groups include, but are not limited to, azetidine, oxetanyl, thietanyl, and the like.
  • C 6-10 aryl ring and “C 6-10 aryl group” can be used interchangeably in the present invention
  • C 6-10 aryl ring” or C 6-10 aryl group means by A cyclic hydrocarbon group composed of 6 to 10 carbon atoms with a conjugated ⁇ -electron system, which may be a monocyclic, fused bicyclic or fused tricyclic system, wherein each ring is aromatic. It may be monovalent, divalent or polyvalent, and C6-10 aryl groups include C6-9 , C9 , C10 and C6 aryl groups and the like. Examples of C6-10 aryl groups include, but are not limited to, phenyl, naphthyl (including 1-naphthyl and 2-naphthyl, and the like).
  • 5-10-membered heteroaryl ring and “5-10-membered heteroaryl” can be used interchangeably in the present invention, and the term “5-10-membered heteroaryl” refers to a ring consisting of 5 to 10 rings.
  • a cyclic group composed of atoms 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. It can be a monocyclic, fused bicyclic or fused tricyclic ring system, wherein each ring is aromatic.
  • the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-10 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-10-membered heteroaryl groups include 5-8-membered, 5-7-membered, 5-6-membered, 5- and 6-membered heteroaryl groups, and the like.
  • Examples of the 5-10 membered heteroaryl group 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 (
  • 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, such as 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) and tert-
  • 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 diffractometry (SXRD), using Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal, the light source is CuK ⁇ radiation, scanning mode: ⁇ / ⁇ scanning, after collecting the relevant data, further adopt the direct method (Shelxs97) analysis of the crystal structure, the absolute configuration can be confirmed.
  • SXRD single crystal X-ray diffractometry
  • Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultivated single crystal
  • the light source is CuK ⁇ radiation
  • scanning mode: ⁇ / ⁇ scanning after collecting the relevant data
  • the absolute configuration can 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 B-2 (1.3M tetrahydrofuran solution, 96.5 mL) was added dropwise to a solution of compound B-1 (20,0 g, 83.7 mmol) in tetrahydrofuran (50 mL), and the reaction solution was stirred at 70°C under nitrogen protection 3 hours.
  • a solution of acetic anhydride (12.8 g, 125 mmol) in tetrahydrofuran (50 mL) was added to the reaction system at 0°C, and the mixture was stirred at 40°C for 1 hour.
  • compound B-5 (6.50 g, 21.3 mmol) was dissolved in tetrahydrofuran (100 mL) and water (2 mL), sodium borohydride (1.45 g, 38.3 mmol) was added, and the reaction solution was stirred at 25 °C 5 hours.
  • compound C-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 C-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.
  • Ethyl bromodifluoroacetate (3.37 g, 16.6 mmol) was dissolved in dimethyl sulfoxide (20 mL), and copper powder (1.06 g, 16.6 mmol) was added. The reaction solution was stirred and reacted at 25°C for 1 hour. Then, compound 14-1 (2.00 g, 6.65 mmol) was added to the reaction solution, and 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).
  • compound 14-3 (677 mg, 1.82 mmol) was dissolved in toluene (10 mL), and methylmagnesium bromide solution (compound 14-4) (3M, 2.43 mL) was added at 0°C.
  • the reaction solution was stirred at 25°C for 2 hours. It was quenched by adding saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate (10 mL ⁇ 2). The organic phase was washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 14-5 (441 mg, 1.56 mmol) was dissolved in toluene (5 mL), compound 14-6 (1.87 g, 5.19 mmol) and bistriphenylphosphonium palladium dichloride (109 mg, 0.16 mmol) were added mmol), 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 14-7.
  • the hydrochloride salt of compound 14-10 (374 mg, 0.61 mmol) was dissolved in dimethyl sulfoxide (3 mL), and compound 4-5 (181 mg, 0.73 mmol) and triethylamine (926 mg, 9.15 mmol) were added. mmol).
  • the reaction solution was stirred and reacted at 90°C for 12 hours.
  • Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 15-7 (1.37 g, 4.64 mmol) was dissolved in toluene (10 mL), compound 14-6 (5.58 g, 15.5 mmol) and bistriphenylphosphonium palladium dichloride (326 mg, 15.5 mmol) were added. 464 ⁇ mol), 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 get the crude product which can be directly used in the next step.
  • the hydrochloride salt of compound 15-11 (778 mg, 1.27 mmol) was dissolved in dimethyl sulfoxide (5 mL), and compound 4-5 (395 mg, 1.52 mmol) and triethylamine (1.93 g, 1.52 mmol) were added. 19.0 mmol).
  • the reaction solution was stirred and reacted at 90°C for 12 hours.
  • Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 16-1 (2.00 g, 8.62 mmol) was dissolved in tetrahydrofuran (20 mL), and methylmagnesium bromide solution (compound 14-4) (3M, 4.31 mL) was added at -78°C.
  • the reaction solution was stirred at -78°C for 3 hours. It was quenched by adding saturated ammonium chloride solution (10 mL), and extracted with ethyl acetate (20 mL ⁇ 2). The organic phase was washed with saturated brine (20 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the hydrochloride salt of compound 16-7 (777 mg, 1.27 mmol) was dissolved in dimethyl sulfoxide (10 mL), and compound 4-5 (306 mg, 1.52 mmol) and triethylamine (1.93 g, 1.93 g, 1.52 mmol) were added. 19.0 mmol).
  • the reaction solution was stirred and reacted at 90°C for 12 hours.
  • Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 17-3 (1.35 g, 4.87 mmol) was dissolved in toluene (10 mL), compound 14-6 (586 g, 16.2 mmol) and bistriphenylphosphonium palladium dichloride (342 mg, 0.49 mmol) were added. mmol), 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 17-4.
  • the hydrochloride salt of compound 17-7 (798 mg, 1.30 mmol) was dissolved in dimethyl sulfoxide (5 mL), and compound 4-5 (377 mg, 1.56 mmol) and triethylamine (1.98 g, 1.56 mmol) were added. 19.5 mmol).
  • the reaction solution was stirred and reacted at 90°C for 12 hours.
  • Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 18-1 (3.86 g, 15.4 mmol) was dissolved in tetrahydrofuran (30 mL), and methylmagnesium bromide solution (3 M, 7.72 mL) was added at -78°C.
  • the reaction solution was stirred at -78°C for 3 hours. It was quenched by adding saturated ammonium chloride solution (30 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 hydrochloride salt of compound 18-6 (452 mg, 738 ⁇ mol) was dissolved in dimethyl sulfoxide (10 mL), and compound 4-5 (194 mg, 885 ⁇ mol) and triethylamine (1.12 g, 1.54 mmol) were added. ). The reaction solution was stirred and reacted at 90°C for 12 hours. Water (5 mL) was added to the reaction solution, extracted with ethyl acetate (5 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 19-1 (3.00 g, 14.8 mmol) was dissolved in dry dichloromethane (30 mL), and diethylaminosulfur trifluoride (3.57 g, 22.2 mmol) was added dropwise at 0 °C, and the reaction solution was in 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, It was 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 19-2.
  • compound 19-2 (3.10 g, 13.8 mmol) was dissolved in dry toluene (50 mL), and tributyl(1-ethoxyethylene)tin (compound 14-6) (9.95 g, 27.6 mmol) was added. ), then bistriphenylphosphine palladium dichloride (967 mg, 1.38 mmol) was added, 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, and ethyl acetate (200 mL) was added to the reaction solution. ⁇ 1) extraction, the organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude compound 19-3, which was directly used in the next step.
  • compound 19-4 (1.85 g, 9.83 mmol) was dissolved in dry tetrahydrofuran (50 mL), and tetraethyl titanate (8.97 g, 39.3 mmol) and (R)-(+)-tert-butyl were added.
  • the hydrochloride salt of compound 19-7 (200 mg, 0.326 mmol) was dissolved in dimethyl sulfoxide (10 mL), and then compound 7 (110 mg, 0.490 mmol) and triethylamine (165 mg, 1.63 mmol) were added. , the reaction solution was stirred at 100°C for 12 hours, and the reaction solution was subjected to preparative high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150 ⁇ 30 mm ⁇ 4 ⁇ m; mobile phase: 0.05% aqueous hydrochloric acid-acetonitrile; gradient: acetonitrile 25%- 55%, 9 min) to obtain the hydrochloride salt of compound 19.
  • the hydrochloride salt of compound 20-2 (177 mg, 288 ⁇ mol) was dissolved in dimethyl sulfoxide (2 mL), and compound 4-5 (62 mg, 346 ⁇ mol) and triethylamine (437 mg, 4.33 mmol) were added. .
  • the reaction solution was stirred and reacted at 90°C for 12 hours.
  • Water (3 mL) was added to the reaction solution, extracted with ethyl acetate (3 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 21-1 (1.00 g, 5.00 mmol) was dissolved in toluene (2 mL), and then compound 14-6 (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 the filtrate was concentrated under reduced pressure to obtain compound 21-2.
  • the hydrochloride salt of compound 21-5 (198 mg, 291 ⁇ mol) was dissolved in dimethyl sulfoxide (2 mL), and compound 4-5 (70 mg, 249 ⁇ mol) and triethylamine (441 mg, 4.36 mmol) were added. .
  • the reaction solution was stirred and reacted at 90°C for 12 hours.
  • Water (3 mL) was added to the reaction solution, extracted with ethyl acetate (3 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the hydrochloride salt of compound 22-3 (218 mg, 319 ⁇ mol) was dissolved in dimethyl sulfoxide (2 mL), and compound 4-5 (70 mg, 383 ⁇ mol) and triethylamine (441 mg, 4.36 mmol) were added. .
  • the reaction solution was stirred and reacted at 90°C for 12 hours.
  • Water (3 mL) was added to the reaction solution, extracted with ethyl acetate (3 mL ⁇ 3) and dichloromethane/methanol solution (8:1, 5 mL), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • compound 23-2 (606 mg, 2.60 mmol) was dissolved in toluene (10 mL), and then compound 14-6 (1.13 g, 3.12 mmol) and bistriphenylphosphine palladium dichloride (182 mg, 260 ⁇ mol) were added. , the reaction was stirred at 120 °C for 12 hours. Saturated potassium fluoride solution (20 mL) was added to the reaction solution, extracted with ethyl acetate (50 mL ⁇ 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 23-3. MS-ESI calculated [M+H] + 225, found 225.
  • compound 27-1 (6.00 g, 23.3 mmol) was dissolved in dry toluene (100 mL), compound 14-6 (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 27-2, 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 was inhibited, the emitted fluorescence changed.
  • 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 provides the inhibitory activity of compounds of the invention on KRAS(G12C) and SOS1 binding.
  • test compound IC50 (nM) Compound 2 109.8 The hydrochloride salt of compound 4 71.1 Compound 5 hydrochloride 77.3 Compound 6 hydrochloride 87.6 Compound 7 92.8 Compound 8 hydrochloride 73.7 Compound 9 83.6 Compound 11 78.6 Compound 13 70.4 The hydrochloride salt of compound 14 40.4 Compound 15 hydrochloride 149.4 The hydrochloride salt of compound 16 59.6 Compound 18 hydrochloride 23.4 The hydrochloride salt of compound 19 104.9 Compound 24 47.9 Compound 25 86.1 Compound 26 65.9 Compound 27 40.64
  • 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 agar was placed in a 42°C water bath to make the agarose solution. 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 a 96-well U-shaped plate with submerged gel at a density of 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).
  • 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.
  • 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).
  • Min well negative control well reads 0.5% DMSO cell well cell lysate
  • Table 3 provides the inhibitory activity of the compounds of the present invention on p-ERK in DLD-1 cells.
  • test compound IC50 (nM) Compound 2 121.7
  • the compound of the present invention has a significant inhibitory effect on the proliferation of p-ERK in DLD-1 cells.
  • CD-1 mice male, 7-9 weeks old, Shanghai Slack
  • Intravenous and oral vehicle is a mixed vehicle of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl beta cyclodextrin.
  • mice Four female CD-1 mice were used in this project, two mice were administered intravenously at a dose of 1 mg/kg, and after administration, 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, 12h plasma samples; the other two mice were given oral gavage at a dose of 2 mg/kg, and the plasma samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 12 h after administration, and stored at 4°C.
  • the compound of the present invention has good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • Intravenous and oral vehicles are mixed vehicles of 5% dimethyl sulfoxide, 5% solutol and 90% water.
  • This project uses four male Balb/c mice, two mice are administered intravenously, and the dose is 10mg/kg. Plasma samples; the other two mice were given oral gavage at a dose of 50 mg/kg, and plasma samples were collected at 0.25, 0.5, 1, 2, 4, 6, 8, 12, and 24 hours after administration, and blood samples were collected.
  • Plasma samples were stored in a -80°C freezer prior to analysis. Quantitative analysis of blood drug concentration by LC-MS/MS analysis method, and calculation of pharmacokinetic parameters, such as peak concentration (C max ), clearance (CL), half-life (T 1/2 ), tissue distribution (Vdss), drug Area under the curve (AUC 0-last ), bioavailability (F) and so on.
  • C max peak concentration
  • CL clearance
  • T 1/2 half-life
  • Vdss tissue distribution
  • AUC 0-last drug Area under the curve
  • bioavailability F
  • 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 dosing schedule is shown in Table 6.
  • 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

公开了一类6-氨基甲酸酯取代的杂芳环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。

Description

6-氨基甲酸酯取代的杂芳环衍生物
本申请主张如下优先权：
CN202110327907.9，2021年03月26日；
CN202210068496.0，2022年01月20日。
技术领域
本发明涉及一类新的6-氨基甲酸酯取代的杂芳环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。
背景技术
RAS蛋白是一种拥有鸟苷三磷酸水解酶(GTPase)活性的鸟嘌呤核苷结合蛋白，主要包含三种亚型，KRAS，NRAS和HRAS。作为GDP/GTP循环控制的二进制分子开关，RAS蛋白可以在活性的GTP结合状态(GTP-RAS)和无活性的GDP结合状态(GDP-RAS)之间循环。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。
研究表明，约15％的肿瘤病例中存在RAS基因突变。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。其中，约85％的RAS突变集中在KRAS(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。
SOS1(英文全称Son of Sevenless 1)是一类调控RAS蛋白GDP/GTP循环的GEF。细胞表面受体被激活并与胞内Grb2结合后，Grb2招募SOS1至细胞膜，随后SOS1催化RAS-GDP/GTP交换，进而激活下游信号通路。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，从而有效降低癌细胞中RAS下游信号通路的异常激活，起到治疗癌症的作用。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。
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：
Figure PCTCN2022082862-appb-000001
发明内容
本发明提供了式(Ⅱ)所示化合物或其药学上可接受的盐，
Figure PCTCN2022082862-appb-000002
其中，
R 1和R 2分别独立地选自H、C 1-6烷基、C 3-12环烷基、3-12元杂环烷基、C 6-10芳基和5-10元杂芳基，其中所述C 1-6烷基、C 3-12环烷基、3-12元杂环烷基、C 6-10芳基和5-10元杂芳基分别独立地任选被1、2、3或4个R a所取代；
或者，R 1、R 2和与它们相连接的氮原子一起形成3-12元杂环烷基，其中所述3-12元杂环烷基任选被1、2、3或4个R b取代；
R 3选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，其中所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2、3或4个R c取代；
R 4选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基和3-10元杂环烷基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基和3-10元杂环烷基分别独立地任选被1、2、3或4个R c取代；
R 5选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，其中所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2、3或4个R c取代；
或者，R 4、R 5和与它们相连接的碳原子一起形成
Figure PCTCN2022082862-appb-000003
其中
Figure PCTCN2022082862-appb-000004
任选被1、2、3或4个R d取代；T 1选自CR 6和N；
R 6选自-OCH 3、-CN和-S(＝O) 2-CH 3；
R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基分别独立地任选被1、2、3或4个R取代；
R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基分别独立地任选被1、2、3或4个R取代；
R c分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、＝O、-C(＝O)H、-C(＝O)-NH 2、C 1-3烷基、C 1-3烷氧基和5-6元杂环烷基，其中所述C 1-3烷基、C 1-3烷氧基和5-6元杂环烷基分别独立地任选被1、2、 3或4个R取代；
R d分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、＝O、-C(＝O)H、-C(＝O)-NH 2和C 1-3烷基；R分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、＝O、-C(＝O)H、-C(＝O)-NH 2和C 1-3烷基；所述5-6元杂环烷基、3-10元杂环烷基、3-12元杂环烷基、5-10元杂芳基和-O-5-10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。
本发明提供了式(I-2)所示化合物或其药学上可接受的盐，
Figure PCTCN2022082862-appb-000005
其中，
R 1、R 2和与他们相连接的氮原子一起形成6-10元杂环烷基，其中所述6-10元杂环烷基任选被1、2、3或4个R b取代；
R 3选自H、F、Cl、Br、I、-OH和-NH 2；
R 4选自H、F、Cl、Br、I、-OH、-NH 2、-CN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 c取代；
R 5选自H、F、Cl、Br、I、和C 1-3烷基，其中所述C 1-3烷基任选被1、2、3或4个R c取代；
或者，R 4、R 5和与它们相连接的碳原子一起形成
Figure PCTCN2022082862-appb-000006
其中
Figure PCTCN2022082862-appb-000007
任选被1、2、3或4个R d取代；R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-3烷基、C 1-3烷氨基和4-5元杂环烷基，其中所述C 1-3烷基、C 1-3烷氨基和4-5元杂环烷基分别独立地任选被1、2、3或4个R取代；
R c分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、-C(＝O)H、-C(＝O)-NH 2和
Figure PCTCN2022082862-appb-000008
R d分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、-C(＝O)H和-C(＝O)-NH 2；
所述6-10元杂环烷基和4-5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。
本发明的一些方案中，上述化合物具有式(Ⅱ-1)所示结构：
Figure PCTCN2022082862-appb-000009
其中，
T 1、R 1、R 2、R 3、R 4和R 5如本发明所定义；
带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述R分别独立地选自F、Cl、Br和＝O，其他变量如本发明所定义。
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烷基、C 1-3烷氧基、C 1-3烷氨基和-C(＝O)-O-C 1-3烷基，其中所述C 1-3烷基、C 1-3烷氧基、C 1-3烷氨基和-C(＝O)-O-C 1-3烷基分别独立地任选被1、2、3或4个R取代，R及其他变量如本发明所定义。
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、-CH 3和-OCH 3，其中所述-CH 3和-OCH 3分别独立地任选被1、2、3或4个R取代，R及其他变量如本发明所定义。
本发明的一些方案中，上述R 1和R 2分别独立地选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2、3或4个R a所取代，R a及其他变量如本发明所定义。
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-3烷基、C 1- 3烷氨基和3-6元杂环烷基，其中所述C 1-3烷基、C 1-3烷氨基和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及其他变量如本发明所定义。
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-3烷基、C 1- 3烷氨基和4元杂环烷基，其中所述C 1-3烷基、C 1-3烷氨基和4元杂环烷基分别独立地任选被1、2、3或4个R取代，R及其他变量如本发明所定义。
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、-NH 2、-CH 3、-CH 2-CH 3、
Figure PCTCN2022082862-appb-000010
其中所述-CH 3、-CH 2-CH 3、
Figure PCTCN2022082862-appb-000011
分别独立地任选被1、2、3或4个R取代，R及其他变量如本发明所定义。
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、-NH 2、-CH 3、-CH 2-CH 3、
Figure PCTCN2022082862-appb-000012
Figure PCTCN2022082862-appb-000013
其他变量如本发明所定义。
本发明的一些方案中，上述R c分别独立地选自F、Cl、Br、-OH、-OCH 3和
Figure PCTCN2022082862-appb-000014
其他变量如本发明所定义。
本发明的一些方案中，上述R c分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、＝O、-C(＝O)H、-C(＝O)-NH 2、C 1-3烷基、C 1-3烷氧基和5元杂环烷基，其中所述C 1-3烷基、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，R及其他变量如本发明所定义。
本发明的一些方案中，上述R c分别独立地选自F、-OH和
Figure PCTCN2022082862-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述R d分别独立地选自F、Cl和Br，其他变量如本发明所定义。
本发明的一些方案中，上述R d分别独立地选自F，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H、F、Cl、Br和-NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H和-NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、-CN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 c取代，R c及其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br、-CN、-CH 3、-CH 2CH 3、-CH(CH 3) 2和-CH 2CH(CH 3) 2，其中所述-CH 3、-CH 2CH 3、-CH(CH 3) 2和-CH 2CH(CH 3) 2分别独立地任选被1、2、3或4个R c取代，R c及其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br、-CN、
Figure PCTCN2022082862-appb-000016
Figure PCTCN2022082862-appb-000017
R c及其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自H、F、Cl、Br、-CN、
Figure PCTCN2022082862-appb-000018
Figure PCTCN2022082862-appb-000019
其他变量如本发明所定义。
本发明的一些方案中，上述R 5选自H、F、Cl、Br和-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 5选自H、F和-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 6选自-OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述m选自0、1和2，其他变量如本发明所定义。
本发明的一些方案中，上述R 1、R 2和与他们相连接的氮原子一起形成5-11元杂环烷基，其中所述5-11元杂环烷基任选被1、2、3或4个R b取代，R b及其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000020
选自
Figure PCTCN2022082862-appb-000021
Figure PCTCN2022082862-appb-000022
其中所述
Figure PCTCN2022082862-appb-000023
Figure PCTCN2022082862-appb-000024
分别独立地任选被1、2、3或4个R b取代，R b及其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000025
选自
Figure PCTCN2022082862-appb-000026
Figure PCTCN2022082862-appb-000027
其中所述
Figure PCTCN2022082862-appb-000028
Figure PCTCN2022082862-appb-000029
分别独立地任选被1、2、3或4个R b取代，R b及其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000030
选自
Figure PCTCN2022082862-appb-000031
Figure PCTCN2022082862-appb-000032
Figure PCTCN2022082862-appb-000033
R b及其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000034
选自
Figure PCTCN2022082862-appb-000035
Figure PCTCN2022082862-appb-000036
Figure PCTCN2022082862-appb-000037
R b及其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000038
选自
Figure PCTCN2022082862-appb-000039
Figure PCTCN2022082862-appb-000040
Figure PCTCN2022082862-appb-000041
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000042
选自
Figure PCTCN2022082862-appb-000043
Figure PCTCN2022082862-appb-000044
Figure PCTCN2022082862-appb-000045
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000046
选自
Figure PCTCN2022082862-appb-000047
其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022082862-appb-000048
选自
Figure PCTCN2022082862-appb-000049
其他变量如本发明所定义。
本发明的一些方案中，上述化合物具有式(Ⅱ-2)或(Ⅱ-3)所示结构：
Figure PCTCN2022082862-appb-000050
其中，R 1、R 2、R 3、R 4、R 5和R 6如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-2)所示结构：
Figure PCTCN2022082862-appb-000051
其中，R 1、R 2、R 3、R 4和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(I-3)所示结构：
Figure PCTCN2022082862-appb-000052
其中，R 1、R 2、R 3、R 4和R 5如本发明所定义；
带“*”的碳原子为手性碳原子，以(R))或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述化合物具有式(I-4)、(I-5)或(I-6)所示结构：
Figure PCTCN2022082862-appb-000053
其中，
T和V分别独立地选自CH 2、NH和O；
m选自0、1、2、3和4；
n、p、q、r和s分别独立地选自0、1和2；
且p+q≤3；
W选自NH、-CH 2-CH 2-和-O-CH 2-；
Y选自N和CH；
R 3、R 4、R 5和R b如本发明所定义。
本发明的一些方案中，上述化合物具有式(Ⅲ)所示结构：
Figure PCTCN2022082862-appb-000054
其中，
T选自CH 2、NH和O；
R b选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-3烷基、C 1-3烷氨基和3-6元杂环烷基，其中所述C 1-3烷基、C 1-3烷氨基和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 6选自-OCH 3、-CN和-S(＝O) 2-CH 3；
R 7和R 8分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、＝O和C 1-3烷基；
或者，R 7、R 8和与它们相连接的碳原子一起形成C 3-4元环烷基；
m选自0、1、2、3和4；
n选自0、1和2；
R、R 3、R 4和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(Ⅲ-1)所示结构：
Figure PCTCN2022082862-appb-000055
其中，
T选自CH 2、NH和O；
R b选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-3烷基、C 1-3烷氨基和3-6元杂环烷基，其中所述C 1-3烷基、C 1-3烷氨基和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 7和R 8分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、＝O和C 1-3烷基；
或者，R 7、R 8和与它们相连接的碳原子一起形成C 3-4元环烷基；
m选自0、1、2、3和4；
n选自0、1和2；
R、R 3、R 4和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(Ⅲ-2)和(Ⅲ-3)所示结构：
Figure PCTCN2022082862-appb-000056
其中，
T、m、n、R b、R 3、R 4、R 5、R 7和R 8如本发明所定义。
本发明的一些方案中，上述化合物具有式(Ⅲ-4)所示结构：
Figure PCTCN2022082862-appb-000057
其中，
T 1选自CHR b、NH、NR b和O；
R b选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-3烷基、C 1-3烷氨基和4-5元杂环烷基，其中所述C 1-3烷基、C 1-3烷氨基和4-5元杂环烷基分别独立地任选被1、2、3或4个R取代；
R 7选自H、F、Cl、Br、I、-OH、-NH 2、-CN、＝O和C 1-3烷基；
n选自1和2；
R、R 3、R 4和R 5如本发明所定义。
本发明的一些方案中，上述化合物具有式(Ⅲ-5)或(Ⅲ-6)所示结构：
Figure PCTCN2022082862-appb-000058
其中，T 1、n、R 3、R 4、R 5和R 7如本发明所定义。
本发明的一些方案中，上述R 7和R 8与分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3和-CH 2-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 7和R 8与分别独立地选自H和-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 7选自H、F、Cl、Br、I、-OH、-NH 2、-CN、-CH 3和-CH 2-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 7选自H和-CH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 8选自H，其他变量如本发明所定义。
本发明的一些方案中，上述R 7、R 8和与它们相连接的碳原子一起形成环丙基。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其中所述化合物具有式(I-7)、(I-8)、(I-9)或(Ⅲ-1A)所示结构：
Figure PCTCN2022082862-appb-000059
其中，T、V、W、Y、m、n、p、q、r、s、R 3、R 4、R 5、R b、R 7和R 8如本发明所定义；
带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
本发明的一些方案中，上述化合物具有式(I-10)、(I-11)或(I-12)所示结构：
Figure PCTCN2022082862-appb-000060
其中，T、V、W、Y、m、n、p、q、r、s、R 3、R 4、R 5和R b如本发明所定义。
本发明还有一些方案是由上述各变量任意组合而来。
本发明还提供了下式化合物或其药学上可接受的盐，
Figure PCTCN2022082862-appb-000061
Figure PCTCN2022082862-appb-000062
本发明还提供了下式化合物或其药学上可接受的盐，
Figure PCTCN2022082862-appb-000063
Figure PCTCN2022082862-appb-000064
Figure PCTCN2022082862-appb-000065
Figure PCTCN2022082862-appb-000066
本发明还提供了上述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。
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。
技术效果
本发明化合物具有良好的KRAS(G12C)-SOS1结合抑制活性，以及对DLD-1细胞和KRAS(G12C)突变的H358细胞具有显著的抑制活性，并具有良好的药代动力学性质，进而获得了优良的抑制肿瘤生长的活性。
定义和说明
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。
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。
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。
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。
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。
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。
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。
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。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022082862-appb-000067
和楔形虚线键
Figure PCTCN2022082862-appb-000068
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022082862-appb-000069
和直形虚线键
Figure PCTCN2022082862-appb-000070
表示立体中心的相对构型，用波浪线
Figure PCTCN2022082862-appb-000071
表示楔形实线键
Figure PCTCN2022082862-appb-000072
或楔形虚线键
Figure PCTCN2022082862-appb-000073
或用波浪线
Figure PCTCN2022082862-appb-000074
表示直形实线键
Figure PCTCN2022082862-appb-000075
和直形虚线键
Figure PCTCN2022082862-appb-000076
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。
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％。
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％。
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)。
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。
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。
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。
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。
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。
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。
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。
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。
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 PCTCN2022082862-appb-000077
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 PCTCN2022082862-appb-000078
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 PCTCN2022082862-appb-000079
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。
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 PCTCN2022082862-appb-000080
直形虚线键
Figure PCTCN2022082862-appb-000081
或波浪线
Figure PCTCN2022082862-appb-000082
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 PCTCN2022082862-appb-000083
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 PCTCN2022082862-appb-000084
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 PCTCN2022082862-appb-000085
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 PCTCN2022082862-appb-000086
Figure PCTCN2022082862-appb-000087
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022082862-appb-000088
仍包括
Figure PCTCN2022082862-appb-000089
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。
当某取代基的化学键与连接环上两原子的化学键相交时，说明该取代基可与环上任意原子成键。当某取代基连接的原子并没有指明的时候，该取代基可以与任意原子成键，如果取代基连接的原子在双环或者三环体系中，则说明该取代基可与该体系中任意环的任意原子成键。取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。例如，结构单元
Figure PCTCN2022082862-appb-000090
表示其可在环己基或者环戊基上的任意一个位置发生取代。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5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 1-6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)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
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。
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。
除非另有规定，术语“C 1-6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6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、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)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
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。
除非另有规定，术语“C 1-6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6个碳原子的烷基基团。所述C 1-6烷氨基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4、C 3和C 2烷氨基等。C 1-6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。
除非另有规定，术语“C 1-3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3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3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、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，所述杂环烷基和杂芳基是指特定基团上含有杂原子或杂原子团，杂原子或杂原子团包括但不限于N、O、S、NH、被取代或者被保护的-N(H)-、-S(＝O)-、-S(＝O) 2-、-C(＝O)-、-C(＝S)-、C(＝O)O-、-C(＝O)N(H)-、-C(＝NH)-、-S(＝O) 2N(H)-和-S(＝O)N(H)-，其中氮和硫原子任选地被氧化，氮杂原子任选地被季铵化。对于环系而言，杂原子或杂原子团可以位于环系之内或环系之外(比如环丙基砜基、环丙基酰基)，其中，所谓杂环烷基和杂芳基是通过碳原子与分子其余部分相连接，即杂原子可以位于该基团的任何位置(除该基团附着于分子其余部分的位置之外)；所谓杂环烷基和杂芳基是通过杂原子与分子其余部分相连接，即杂原子位于该基团附着于分子其余部分的位置上；所谓杂环烷基杂基、杂芳基杂基是通过杂原子与分子其余部分相连接，其中杂原子可以位于该基团的任何位置(包括该基团附着于分子其余部分的位置)。
除非另有规定，“C 3-12环烷基”表示由3至12个碳原子组成的饱和环状碳氢基团，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。所述C 3-12环烷基包括C 3-10、C 3-10、C 3-6、C 3-5、C 4-10、C 4-8、C 4-6、C 4-5、C 5-8和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-12环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，“C 3-10环烷基”表示由3至10个碳原子组成的饱和环状碳氢基团，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。所述C 3-10环烷基包括C 3-8、C 3-6、C 3-5、C 4-10、C 4-8、C 4-6、C 4-5、C 5-8或C 5-6等；其可以是一价、二价或者多价。C 3-10环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基、[2.2.2]二环辛烷、[4.4.0]二环癸烷等。
除非另有规定，“C 3-4环烷基”表示由3至4个碳原子组成的饱和环状碳氢基团，其为单环体系，所述C 3-5环烷基包括C 3和C 4环烷基等；其可以是一价、二价或者多价。C 3-4环烷基的实例包括，但不限于，环丙基、环丁基等。
除非另有规定，术语“3-12元杂环烷基”本身或者与其他术语联合分别表示由3至12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)。所述3-12元杂环烷基包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“3-12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3-12元杂环烷基包括3-10元、3-8元、3-6元、3-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-12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、高哌啶基或二氧杂环庚烷基等。
除非另有规定，术语“3-10元杂环烷基”本身或者与其他术语联合分别表示由3至10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)。所述3-10元杂环烷基包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“3-10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3-10元杂环烷基包括3-8元、3-6元、3-5元、4-6元、5-6元、4元、5元和6元杂环烷基等。3-10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、高哌啶基或二氧杂环庚烷基等。
除非另有规定，术语“5-11元杂环烷基”本身或者与其他术语联合分别表示由5至11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)。所述5-11元杂环烷基包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“5-11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5-11元杂环烷基包括5-6元、5-7元、5-8元、5-9元、5-10元、5-11元、6-7元、6-8元、6-9元、6-10元、6-11元、5元、6元和7元杂环烷基 等。5-11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、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。
除非另有规定，术语“6-10元杂环烷基”本身或者与其他术语联合分别表示由6至10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)。所述6-10元杂环烷基包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“6-10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6-10元杂环烷基包括6元、6-7元、6-8元、6-9元、5-10元、7元、7-8元、7-9元、7-10元、8元、8-9元、8-10元、9元和10元杂环烷基等。6-10元杂环烷基的实例包括但不限于哌啶基(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、高哌啶基或二氧杂环庚烷基等。
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。
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、六氢哒嗪基等。
除非另有规定，术语“4-5元杂环烷基”本身或者与其他术语联合分别表示由4至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“4-5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。所述4-5元杂环烷基包括4元和5元杂环烷基。4-5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)或四氢呋喃基(包括四氢呋喃-2-基等)等。
除非另有规定，术语“4元杂环烷基”本身或者与其他术语联合分别表示由4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“4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。4元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基等。
除非另有规定，本发明术语“C 6-10芳环”和“C 6-10芳基”可以互换使用，术语“C 6-10芳环”或“C 6-10芳基”表示由6至10个碳原子组成的具有共轭π电子体系的环状碳氢基团，它可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。其可以是一价、二价或者多价，C 6-10芳基包括C 6-9、C 9、C 10和C 6芳基等。C 6-10芳基的实例包括但不限于苯基、萘基(包括1-萘基和2-萘基等)。
除非另有规定，本发明术语“5-10元杂芳环”和“5-10元杂芳基”可以互换使用，术语“5-10元杂芳基”是表示由5至10个环原子组成的具有共轭π电子体系的环状基团，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。其可以是单环、稠合双环或稠合三环体系，其中各个环均为芳香性的。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)。5-10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5-10元杂芳基包括5-8元、5-7元、5-6元、5元和6元杂芳基等。所述5-10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)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、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、嘧啶基(包括2-嘧啶基和4-嘧啶基等)、苯并噻唑基(包括5-苯并噻唑基等)、嘌呤基、苯并咪唑基(包括2-苯并咪唑基等)、苯并噁唑基、吲哚基(包括5-吲哚基等)、异喹啉基(包括1-异喹啉基和5-异喹啉基等)、喹喔啉基(包括2-喹喔啉基和5-喹喔啉基等)或喹啉基(包括3-喹啉基和6-喹啉基等)。
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
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。
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)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。
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。
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：φ/ω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。
本发明所使用的容积可经市售获得。
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。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。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022082862-appb-000091
软件命名，市售化合物采用供应商目录名称。
具体实施方式
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。
中间体A
Figure PCTCN2022082862-appb-000092
合成路线：
Figure PCTCN2022082862-appb-000093
第一步
将化合物A-1(10.0g,47.3mmoL)溶解在A-2乙腈(24mL)中,在25℃下向其中通入干燥氯化氢气体0.5小时,反应液在90℃下搅拌3小时,反应液冷却至25℃,过滤,收集滤饼并溶解在水(100mL)中,溶液用10％碳酸氢钠(100mL)溶液中和,将溶液过滤,滤饼用冰水(100mL)洗涤,干燥得到化合物A-3。 1H NMR(400MHz,CD 3OD)δ7.55(s,1H),7.07(s,1H),3.98(s,3H),3.95(s,3H),2.45(s,3H)。
第二步
将化合物A-3(3.00g,13.6mmol)溶解在甲基磺酸(15mL)中,向化合物中加入DL-蛋氨酸(2.44g,16.4mmol),反应液在110℃下反应12小时,反应液用水(90mL)和氢氧化钠(2mol/L,150ml)淬灭,反应液过滤,收集滤饼并真空干燥,得到中间体A。 1H NMR(400MHz,DMSO-d 6)δ7.33(s,1H),7.02(s,1H),3.88(s,3H),2.88(s,3H)。
中间体B
Figure PCTCN2022082862-appb-000094
合成路线：
Figure PCTCN2022082862-appb-000095
第一步
氮气保护下，向化合物B-1(20,0g,83.7mmol)的四氢呋喃(50mL)溶液中滴加化合物B-2(1.3M的四氢呋喃溶液,96.5mL),反应液在氮气保护下70℃搅拌3小时。0℃下向反应体系加入乙酸酐(12.8g,125 mmol)的四氢呋喃(50mL)溶液,40℃搅拌1小时。向反应液中加入水(100mL),用乙酸乙酯(100mL×3)萃取,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分离纯化(3/1,石油醚/乙酸乙酯,Rf＝0.63)得到化合物B-3。 1H NMR(400MHz,CDCl 3)δ7.74(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.37(t,J＝8.0Hz,1H),2.60(s,3H),2.54(s,3H)。
第二步
将化合物B-3(8.00g,39.6mmol)溶于四氢呋喃(150mL)中,加入B-4(7.19g,59.4mmol)和钛酸四乙酯(22.6g,98.9mmol),反应液在70℃下搅拌4小时。向反应液中加入水(300mL),用乙酸乙酯(150mL×3)萃取,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分离纯化(2/1,石油醚/乙酸乙酯,Rf＝0.41)得到化合物B-5。MS-ESI计算值为[M+H] +306,实测值306。
第三步
于-78℃下,将化合物B-5(6.50g,21.3mmol)溶于四氢呋喃(100mL)和水(2mL)中,加入硼氢化钠(1.45g,38.3mmol),反应液在25℃下搅拌5小时。向反应液中加入水(100mL),用乙酸乙酯(100mL×3)萃取,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分离纯化(2/1,石油醚/乙酸乙酯,Rf＝0.21)得到化合物B-6。MS-ESI计算值为[M+H] +308,实测值308。
第四步
将化合物B-6(3.60g,11.7mmol)溶于乙酸乙酯(10mL),加入氯化氢乙酸乙酯溶液(4M,15.0mL)。反应液在25℃搅拌反应6小时。减压浓缩，过滤，乙酸乙酯(200mL)洗涤滤饼，真空干燥得到中间体B的盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ8.71(s,3H),7.97(d,J＝7.8Hz,1H),7.70(d,J＝7.8Hz,1H),7.52(t,J＝7.8Hz,1H),4.73-4.69(m,1H),2.45(s,3H),1.52(d,J＝6.8Hz,3H)。
中间体C
Figure PCTCN2022082862-appb-000096
合成路线：
Figure PCTCN2022082862-appb-000097
第一步
将化合物C-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C-2。
第二步
氮气保护下,将化合物C-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C-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C-4。MS-ESI计算值为[M-H] -304,实测值304。
第三步
将化合物C-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C-5。MS-ESI计算值为[M-H] -232,实测值232。
第四步
将化合物C-5(8.00g,34.3mmol)溶于四氢呋喃(80mL)中,加入B-4(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C-6。MS-ESI计算值为[M+H] +337,实测值337。
第五步
于-78℃下,将化合物C-6(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C-7。MS-ESI计算值为[M-H] -337,实测值337。
第六步
将化合物C-7(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C-8。MS-ESI计算值为[M+H] +235,实测值235。
第七步
将化合物C-8(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C的盐酸盐。MS-ESI计算值为[M+H] +205,实测值205。
实施例1
Figure PCTCN2022082862-appb-000098
合成路线：
Figure PCTCN2022082862-appb-000099
第一步
将中间体A(200mg,970μmol),4-二甲氨基吡啶(11.9mg,97.0μmol),三乙胺(393mg,3.88mmol)和化合物1-1(232mg,1.16mmol)溶于N,N-二甲基甲酰胺(3mL)中,20℃反应12小时。反应液浓缩后，粗产物经过硅胶柱层析法(10/1,二氯甲烷/甲醇,Rf＝0.2)分离得到化合物1-2。 1H NMR(400MHz,DMSO-d 6)δ12.14(s,1H),7.66(s,1H),7.17(s,1H),3.88(s,3H),3.63(s,2H),3.49-3.40(m,2H),2.48-2.40(m,4H),2.33(s,3H),2.29(s,3H)。MS-ESI计算值[M+H] +333,实测值333。
第二步
将化合物1-2(140mg,421μmol),4-二甲氨基吡啶(10.3mg,84.3μmol),三乙胺(128mg,1.26mmol)和化合物1-3(255mg,842μmol)溶于二氯甲烷(5mL)中,15℃反应56小时。反应液浓缩后，粗产物经过硅胶柱层析法(10/1,二氯甲烷/甲醇,Rf＝0.45)分离得到化合物1-4。 1H NMR(400MHz,DMSO-d 6)δ7.79(s,1H),7.47(s,1H),7.35(s,2H),4.24-4.14(m,2H),4.03(q,J＝7.2Hz,1H),3.97(s,3H),3.69-3.58(m,2H),3.47-3.41(m,1H),3.02-2.91(m,1H),2.45(s,3H),2.43-2.34(m,4H),2.25(s,3H),1.23-1.17(m,18H)。MS-ESI计算值[M+H] +599,实测值599。
第三步
将化合物1-4(55mg,91.9μmol),三乙胺(72.7mg,718μmol)和中间体B的盐酸盐(28.0mg,138μmol)溶于二甲亚砜(1mL)中,90℃反应34小时。反应液浓缩后,所得粗品经制备高效液相色谱(色谱柱:Phenomenex Lμna C18 75×30mm×3μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈19％-39％,7min)分离得到化合物1的盐酸盐。 1H NMR(400MHz,DMSO-d 6)δ14.91(br s,1H),11.56(br s,1H),10.52(br s,1H),9.04(br s,1H),8.01(br d,J＝8.0Hz,1H),7.58(br d,J＝7.2Hz,1H),7.43-7.36(m,2H),5.99-5.83(m,1H),4.40- 4.19(m,1H),4.18-4.04(m,2H),3.96(s,3H),3.71-3.44(m,1H),3.26-3.12(m,3H),2.85(br s,3H),2.60(br s,3H),2.57(br s,3H),2.55-2.53(m,1H),1.65(br d,J＝6.4Hz,3H)。MS-ESI计算值[M+H] +518,实测值518。
实施例2
Figure PCTCN2022082862-appb-000100
合成路线：
Figure PCTCN2022082862-appb-000101
第一步
将中间体A(300mg,1.45mmol),化合物2-1(348mg,1.75mmol)溶解在N,N-二甲基甲酰胺(5mL)中,向反应液中加入三乙胺(589mg,5.75mmol)和4-二甲氨基吡啶(17.8mg,0.145mmol),反应液在20℃下搅拌12小时,反应液减压浓缩,粗产物经过硅胶柱层析法(20/1,二氯甲烷/甲醇,Rf＝0.62)分离得到化合物2-2。 1H NMR(400MHz,CD 3OD)δ7.82(s,1H),7.17(s,1H),3.98(s,3H),3.83-3.80(br s,2H),3.65(br s,2H),3.37(s,3H),2.76(br s 2H),2.53(br s,2H),2.47(s,3H)。
第二步
将化合物2-2(442mg,1.33mmol),1-3(604mg,1.99mmol)溶解在二氯甲烷(10mL)中,向反应液中加入4-(二甲氨基)吡啶(32.5mg,0.266mmol)和三乙胺(404mg,3.99mmol),反应液在20℃下搅拌12小时,反应液用二氯甲烷(30mL)稀释,用饱和碳酸氢钠水溶液(20mL×2),食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(30/1,二氯甲烷/甲醇,Rf＝0.47)分离得到化合物2-3。MS-ESI计算值[M+H] +599,实测值599。
第三步
将化合物2-3(200mg,0.314mmol),中间体C的盐酸盐(77.0mg,0.320mmol)溶解在二甲基亚砜(5mL)中,向反应液中加入三乙胺(153mg,1.51mmol),反应液在100℃下搅拌12小时,反应液用水(10mL) 淬灭,用乙酸乙酯(15mL×3)萃取,有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,经过制备高效液相色谱法(色谱柱:Waters Xbridge 150×25mm×5μm；流动相:水(10mmol/L的碳酸氢铵水溶液-乙腈；梯度:乙腈28％-58％,9min)分离得到化合物2。 1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.12(s,1H),7.99-6.96(m,2H),6.81(s,1H),5.61(q,J＝7.2Hz,1H),3.97(s,3H),3.79(br s,2H),3.60(br s,2H),2.59-2.56(m,4H),2.50(s,3H),2.39(s,3H),1.63(d,J＝7.2Hz,3H)。MS-ESI计算值为[M+H] +519,实测值519。
实施例3
Figure PCTCN2022082862-appb-000102
合成路线：
Figure PCTCN2022082862-appb-000103
第一步
将中间体A(300mg,1.45mmol),3-1(260mg,1.74mmol)溶解在N,N-二甲基甲酰胺(5mL)中,向反应液中加入三乙胺(587mg,5.80mmol),4-二甲氨基吡啶(17.7mg,0.145mmol),反应液在25℃搅拌12小时,反应液减压浓缩,粗产物经过硅胶柱层析法分离(30/1,二氯甲烷/甲醇,Rf＝0.37)得到化合物3-2。 1H NMR(400MHz,CDCl 3)δ7.86(s,1H),7.06(s,1H),3.88(s,3H),3.70-3.69(br s,2H),3.66(br s,2H),3.52(br s,2H),2.46(s,3H),1.60(br s,2H)。
第二步
将化合物3-2(342mg,1.07mmol),1-3(357mg,1.18mmol)溶解在二氯甲烷(5mL)中,向反应液中加入4-(二甲氨基)吡啶(26.2mg,0.214mmol)和三乙胺(325mg,3.21mmol),反应液在20℃下搅拌12小时,反应液减压浓缩,粗产物经过薄层层析法分离(40/1,二氯甲烷/甲醇,Rf＝0.35)得到化合物3-3。MS-ESI计算值[M-tBu+H] +586,实测值586。
第三步
将化合物3-3(201mg,0.343mmol),中间体C的盐酸盐(90.8mg,0.377mmol)溶解在二甲基亚砜(3mL)中,向反应液中加入三乙胺(977mg,9.66mmol),反应液在100℃下搅拌2小时,反应液用水(10mL)淬灭,用乙酸乙酯(15mL×3)萃取,有机相用饱和食盐水(150mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,经过制备高效液相色谱法(色谱柱:3_Phenomenex Luna C18 75×30mm×3μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈23％-43％,7min)分离得到化合物3的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.28(s,1H),7.72(s,1H),7.65(s,1H),7.43-7.42(m,1H),7.10(s,1H),5.77(q,J＝7.2Hz,1H),3.95(s,3H),3.65(br s,6H),3.45(br s,2H),2.55(s,3H),1.67(d,J＝1.2Hz,3H)。MS-ESI计算值为[M+H] +506,实测值506。
实施例4
Figure PCTCN2022082862-appb-000104
合成路线：
Figure PCTCN2022082862-appb-000105
第一步
将化合物4-1(200mg,1.75mmol)溶解在二氯甲烷(3mL)中,向反应液中加入三光气(345mg,1.16mmol),将反应液冷却至-78℃,氮气氛下向反应液中加入吡啶(383mg,4.84mmol)反应液缓慢升温至0℃再至25℃,反应液在25℃下搅拌6小时,反应液减压浓缩得到化合物4-2。
第二步
将化合物4-2(201mg,1.14mmol),中间体A(258mg,1.25mmol)溶解在N,N-二甲基甲酰胺(5mL)中,向反应液中加入碳酸钾(315mg,2.28mmol)反应液在25℃下搅拌12小时,反应液减压浓缩,粗产物经过薄层层析法(20/1,二氯甲烷/甲醇,Rf＝0.63)分离得到化合物4-3。 1H NMR(CD 3OD,400MHz)δ7.80(s,1H),7.16(s,1H),4.61-4.35(m,3H),3.98(s,3H),2.90-2.87(m,1H),2.81-2.78(m,1H),2.46(s,3H),2.33(s,3H),2.31-2.27(m,1H),2.13-2.06(m,1H),1.43(d,J＝4.8Hz,3H)。
第三步
将化合物4-3(231mg,0.667mmol),1-3(242mg,0.8mmol)溶解在二氯甲烷(10mL)中,向反应液中加入4-(二甲氨基)吡啶(16.3mg,0.133mmol)和三乙胺(202mg,0.278mmol),反应液在25℃下搅拌12小时,反应液减压浓缩,粗产物经过薄层层析法(40/1,二氯甲烷/甲醇,Rf＝0.22)分离得到化合物4-4。MS-ESI计算值[M-H] +613,实测值613。
第四步
将化合物4-4(315mg,0.502mmol),中间体C的盐酸盐(123mg,0.511mmol)溶解在二甲基亚砜(3mL)中,向反应液中加入三乙胺(0.3mL),反应液在100℃下搅拌12小时,反应液用水(10mL)淬灭,用二氯甲烷/甲醇混合溶剂(10:1,20mL×3)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过制备高效液相色谱法(色谱柱:3_Phenomenex Luna C18 75×30mm×3μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈12％-32％,7min)分离得到化合物4的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.47(s,1H),7.43(s,1H),7.40(s,1H),7.43(s,2H),5.83(q,J＝7.2Hz,1H),4.71-4.24(m,1H),4.06(s,3H),3.68-3.55(m,2H),3.47-3.37(m,2H),3.27-3.14(m,2H),3.03(s,3H),2.68(s,3H),1.76(d,J＝7.2Hz,3H),1.59-1.49(m,3H)。MS-ESI计算值为[M+H] +533,实测值533。
实施例5
Figure PCTCN2022082862-appb-000106
合成路线：
Figure PCTCN2022082862-appb-000107
第一步
将化合物5-1(100mg,876μmol)溶于二氯甲烷(5mL)中,在0℃下加入化合物5-2(190mg,641μmol), 再加入吡啶(192mg,2.43mmol),反应液由0℃逐渐升温至25℃,在25℃下搅拌反应12小时。将反应液减压浓缩得到化合物5-3。
第二步
将化合物5-3(154mg,872μmol)溶于N,N-二甲基甲酰胺(5mL)中,加入碳酸钾(241mg,1.74mmol)和中间体A(198mg,959μmol),在25℃下搅拌反应5小时。反应液减压浓缩后向反应液中加入水(20mL),用二氯甲烷(20mL×1)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5-4。 1H NMR(400MHz,CD 3Cl)δ7.94(s,1H),7.12(s,1H),3.94(s,3H),3.79-3.71(m,2H),3.66-3.58(m,2H),2.55-2.52(m,4H),2.51-2.48(m,2H),1.95(s,3H),1.16-1.11(m,3H)。MS-ESI计算值[M+H] +347,实测值347。
第三步
将化合物5-4(140mg,404μmol)溶于二氯甲烷(5mL)中,加入化合物1-3(147mg,485μmol),4-二甲基氨基吡啶(9.88mg,80.8μmol)和三乙胺(123mg,1.21mmol),在25℃下搅拌反应12小时。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5-5。 1H NMR(400MHz,CD 3Cl)δ7.83(s,1H),7.29-7.27(m,1H),7.22-7.20(m,2H),4.49-4.10(m,3H),3.97(s,3H),3.81-3.75(m,2H),3.67-3.61(m,2H),2.96-2.90(m,1H),2.60-2.56(m,3H),2.54(s,3H),2.53-2.49(m,2H),1.28-1.25(m,18H),1.20-1.15(m,3H)。MS-ESI计算值[M+H] +613,实测值613。
第四步
将化合物5-5(178mg,290μmol)溶于二甲基亚砜(5mL)中,加入中间体C的盐酸盐(105mg,436μmol)和三乙胺(88.2mg,871μmol),在100℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷(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,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Synergi C18 100×21.2mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈5％-35％,9min)得到化合物5的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.55(s,1H),7.65-7.50(m,2H),7.33(s,1H),7.22(s,1H),5.89-5.78(m,1H),4.61-4.20(m,4H),4.04(s,3H),3.76-3.56(m,2H),3.31-3.02(m,4H),2.66(s,3H),1.87-1.68(m,3H),1.54-1.35(m,3H)。MS-ESI计算值[M+H] +533,实测值533。
实施例6
Figure PCTCN2022082862-appb-000108
合成路线：
Figure PCTCN2022082862-appb-000109
第一步
将中间体A(200mg,970μmol),化合物6-1(219mg,882μmol)溶解在N,N-二甲基甲酰胺(5mL)中,向反应液中加入碳酸钾(244mg,1.76mmol),反应液在20℃下搅拌12小时,反应液减压浓缩,加入水(20mL),用乙酸乙酯(20mL×2)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,经过硅胶柱层析法(10/1,二氯甲烷/甲醇,Rf＝0.74)分离得到化合物6-2。MS-ESI计算值[M+H] +419,实测值419。
第二步
将化合物6-2(280mg,522μmol),化合物1-3(190mg,626μmol)溶解在二氯甲烷(5mL)中,向反应液中加入4-(二甲氨基)吡啶(12.8mg,104μmol)和三乙胺(158mg,1.57mmol),反应液在20℃下搅拌12小时,反应液减压浓缩,粗品经过硅胶柱层析法(2/1,石油醚/乙酸乙酯,Rf＝0.35)分离得到化合物6-3。MS-ESI计算值[M+H] +685,实测值685。
第三步
将化合物6-3(220mg,321μmol),中间体C的盐酸盐(98.4mg,482μmol)溶解在二甲基亚砜(5mL)中,向反应液中加入三乙胺(97.5mg,964μmol),反应液在100℃下搅拌12小时,反应液用水(20mL)淬灭,用乙酸乙酯(20mL×2)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到化合物6-4。MS-ESI计算值为[M+H] +605,实测值605。
第四步
将化合物6-4(192mg,318μmol)溶于氯化氢乙酸乙酯溶液(4M,10mL)。反应液在25℃下搅拌12小时。反应液减压浓缩。粗品经过制备高效液相色谱法(色谱柱:Venusil ASB Phenyl 150×30mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈11％-41％,9min)分离得到化合物6的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.58(s,1H),7.83(s,1H),7.78(s,1H),7.52(s,1H),7.25(s,1H),5.90(q,J＝6.8Hz,1H),4.07(s,3H),4.01-4.06(m,2H),3.86(s,2H),3.40(s,4H),2.68(s,3H),1.81(d,J＝6.8Hz,3H)。MS-ESI计算值为[M+H] +505,实测值505。
实施例7
Figure PCTCN2022082862-appb-000110
合成路线：
Figure PCTCN2022082862-appb-000111
第一步
将中间体A(300mg,2.91mmol)溶于四氢呋喃(5mL)中,然后加入化合物7-1(674mg,3.35mmol)和N,N-二异丙基乙胺(1.13g,8.73mmol),反应液在25℃下搅拌反应1小时。将反应液倒入水(20mL)中,过滤,滤液用乙酸乙酯(20mL×3)萃取,有机相用无水硫酸钠干燥,减压浓缩得到化合物7-2。
第二步
将化合物7-2(600mg,1.62mmol)和化合物7-3(431mg,2.42mmol)溶于N,N-二甲基甲酰胺(10mL)中,加入三乙胺(654mg,6.46mmol),在25℃下6小时。将反应液减压浓缩得到粗品化合物。粗品经过硅胶柱层析法(二氯甲烷/甲醇,30/1～10/1,V/V)分离得到化合物7-4。MS-ESI计算值[M+H] +374,实测值374。
第三步
将化合物7-4(200mg,0.314mmol)溶解在二氯甲烷(2mL)中,向反应液中加入4-二甲氨基吡啶(9.82mg,80.3μmol),三乙胺(243mg,2.41mmol)和化合物1-3(487mg,1.61mmol),反应液在25℃下搅拌16小时。反应液用水(10mL)淬灭,用乙酸乙酯(10mL×3)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩,粗产物经过硅胶柱层析法分离(1/1,石油醚/乙酸乙酯,Rf＝0.3)得到化合物7-5。MS-ESI计算值[M+H] +640,实测值640。
第四步
将化合物7-5(130mg,0.203mmol)溶解在二甲基亚砜(1mL)中,向反应液中加入三乙胺(102mg,1.02mmol)和中间体C的盐酸盐(73.4mg,305μmol),反应液在90℃下搅拌2小时。反应液用水(0.5mL)淬灭,粗品经过高效液相色谱法(色谱柱:Waters Xbridge 75×30mm×3μm；流动相:10mM的碳酸氢钠水 溶液-乙腈；梯度:30％-50％,6min)分离得到化合物7。 1H NMR(400MHz,CD 3OD)δ8.13-8.08(m,2H),7.14(s,1H),6.88-6.84(m,2H),6.89(s,1H),5.54-5.49(m,3H),3.87(s,3H),3.80-3.77(m,2H),3.52(s,6H),2.38(s,3H),1.81-1.77(m,2H),1.06-1.50(m,7H)。MS-ESI计算值为[M+H] +560,实测值560。
实施例8
Figure PCTCN2022082862-appb-000112
合成路线：
Figure PCTCN2022082862-appb-000113
第一步
将化合物7-2(165mg,444μmol)溶于N,N-二甲基甲酰胺(10mL)中,滴加三乙胺(180mg,1.78mmol)和化合物8-1(57mg,444μmol),在25℃下搅拌反应1小时。将反应液过滤,减压浓缩,剩余物经薄层色谱法分离纯化(二氯甲烷/甲醇,10/1,V/V)得到化合物8-2。MS-ESI计算值[M+H]+361,实测值361。
第二步
将化合物8-2(82mg,179μmol)溶于二氯甲烷(10mL)中,加入化合物1-3(64.9mg,214μmol),4-二甲基氨基吡啶(4.36mg,35.7μmol)和三乙胺(54.2mg,536μmol),在25℃下搅拌反应12小时。反应液过滤,减压浓缩,剩余物经薄层色谱法分离纯化(二氯甲烷/甲醇,10/1,V/V)得到化合物8-3。MS-ESI计算值[M+H] +627,实测值627。
第三步
将化合物8-3(68.0mg,81.4μmol)溶于二甲基亚砜(5mL)中,加入中间体C的盐酸盐(29.4mg,122μmol)和三乙胺(34.0μL,244μmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷(20mL×1)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,剩余物经制 备高效液相色谱分离纯化(色谱柱:Venusil ASB Phenyl 150×30mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈20％-50％,9min)得到化合物8的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.50(s,1H),7.70-7.60(m,2H),7.39(s,1H),7.21(s,1H),5.90-5.81(m,1H),4.81-4.74(m,2H),4.60-4.25(m,2H),4.04(s,3H),3.66-3.42(m,1H),3.24-3.01(m,2H),3.01-2.84(m,6H),2.66(m,3H),2.33-2.13(m,2H),1.77(d,J＝6.4Hz,3H)。MS-ESI计算值[M+H] +547,实测值547。
实施例9
Figure PCTCN2022082862-appb-000114
合成路线：
Figure PCTCN2022082862-appb-000115
第一步
将化合物7-2(160mg,431μmol)和化合物9-1(61mg,431μmol)溶于N,N-二甲基甲酰胺(10mL)中,然后加入三乙胺(174mg,172mmol),反应在25℃下反应1小时。将反应液减压浓缩得到粗品化合物。粗品经过薄层层析法(10/1,V/V,二氯甲烷/甲醇,Rf＝0.08)分离得到化合物9-2。MS-ESI计算值[M+H] +375,实测值375。
第二步
将化合物9-2(60mg,160μmol)溶解在二氯甲烷(5mL)中,向反应液中加入4-二甲氨基吡啶(4mg,32μmol)和三乙胺(49mg,481μmol)和化合物1-3(58mg,192μmol),反应液减压浓缩,粗产物经过硅胶柱层析法分离(2/1,V/V,石油醚/乙酸乙酯,Rf＝0.5)得到化合物9-4。MS-ESI计算值[M+H] +641,实测值 641。
第三步
将化合物9-4(30mg,46.8μmol)溶解在二甲基亚砜(2mL)中,向反应液中加入三乙胺(14.2mg,140μmol)和中间体C的盐酸盐(16.9mg,70.2μmol),反应液在100℃下搅拌2小时,反应液用水(20mL)淬灭,用乙酸乙酯(20mL×2)萃取,有机相用饱和食盐水(20mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过制备高效液相色谱法(色谱柱：Phenomenex Gemini-NX 80×30mm×3μm；流动相:10mM碳酸氢钠水溶液-乙腈；梯度:乙腈10％-80％,9min)分离得到化合物9。 1H NMR(400MHz,DMSO-d 6)δ8.02(s,1H),7.12(s,1H),6.97(s,1H),6.81(s,1H),6.81(s,1H),5.59(q,J＝6.8Hz,1H),4.72-4.78(m,2H),4.65-4.69(m,2H),3.96(s,3H),3.81(s,2H),3.58-3.67(m,2H),2.48(s,7H),1.62(d,J＝6.8Hz,3H)。MS-ESI计算值为[M+H] +561,实测值561。
实施例10
Figure PCTCN2022082862-appb-000116
合成路线：
Figure PCTCN2022082862-appb-000117
第一步
将化合物7-2(183mg,493μmol)溶于N,N-二甲基甲酰胺(10mL)中,滴加三乙胺(199mg,1.97mmol)和化合物10-1(62.2mg,493μmol),在25℃下搅拌反应1小时。将反应液过滤,减压浓缩,剩余物经薄层层析法分离纯化(二氯甲烷/甲醇,10/1,V/V)得到化合物10-2。MS-ESI计算值[M+H]+359,实测值359。
第二步
将化合物10-2(42mg,102μmol)溶于二氯甲烷(10mL)中,加入化合物1-3(37.1mg,122μmol),4-二甲基氨基吡啶(2.49mg,20.4μmol)和三乙胺(31.0mg,306μmol),在25℃下搅拌反应12小时。反应液过 滤,减压浓缩,剩余物经薄层层析法分离纯化(二氯甲烷/甲醇,10/1,V/V),得到化合物10-3。MS-ESI计算值[M+H] +625,实测值625。
第三步
将化合物10-3(18mg,28.8μmol)溶于二甲基亚砜(3mL)中,加入中间体C的盐酸盐(10.4mg,43.2μmol)和三乙胺(8.75mg,86.4μmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷(20mL×1)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,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Gemini-NX 80×30mm×3μm；流动相:10mM的碳酸氢铵水溶液-乙腈；梯度:乙腈10％-80％,9min),得到化合物10。 1H NMR(400MHz,CD 3OD)δ8.01(s,1H),7.11(s,1H),7.00-6.93(m,2H),6.79(s,1H),5.61-5.55(m,1H),4.49-4.10(m,2H),3.94(s,3H),3.28-3.06(m,3H),2.99-2.66(m,1H),2.46(s,3H),2.37-2.21(m,2H),2.20-2.03(m,1H),2.00-1.78(m,3H),1.60(d,J＝7.2Hz,3H),1.53-1.41(m,1H)。MS-ESI计算值[M+H] +545,实测545。
实施例11
Figure PCTCN2022082862-appb-000118
合成路线：
Figure PCTCN2022082862-appb-000119
第一步
将化合物7-2(293mg,789μmol)溶于N,N-二甲基甲酰胺(5mL)中,滴加三乙胺(319mg,3.16mmol)和化合物11-1(148mg,868μmol),在25℃下搅拌反应1小时。向反应液中加入水(20mL),用二氯甲烷(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,剩余物经薄层色谱法分离纯化(二氯甲烷/甲醇,10/1,V/V),得到化合物11-2。MS-ESI计算值[M+H]+403,实测值403。
第二步
将化合物11-2(50mg,124μmol)溶于二氯甲烷(10mL)中,加入化合物1-3(45.2mg,149μmol),4-二甲基氨基吡啶(3.04mg,24.9μmol)和三乙胺(37.7mg,373μmol),在25℃下搅拌反应12小时。反应液过滤,减压浓缩,剩余物经薄层色谱法分离纯化(二氯甲烷/甲醇,10/1,V/V)得到化合物11-3。MS-ESI计算值[M+H] +669,实测值669。
第三步
将化合物11-3(20mg,29.9μmol)溶于二甲基亚砜(2mL)中,加入中间体C的盐酸盐(10.8mg,44.9μmol)和三乙胺(9.08mg,89.7μmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷(20mL×1)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,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Gemini-NX 80×30mm×3μm；流动相:10mM的碳酸氢铵水溶液-乙腈；梯度:乙腈37％-67％,9min)得到化合物11。 1H NMR(400MHz,CD 3OD)δ8.00(s,1H),7.11(s,1H),7.01-6.93(m,2H),6.80(s,1H),5.61-5.53(m,1H),4.31-4.19(m,1H),3.95(s,3H),3.89-3.85(m,1H),3.77-3.70(m,1H),3.11-3.05(m,1H),2.46(s,3H),1.86-1.77(m,1H),1.60(d,J＝6.8Hz,3H),1.36-1.31(m,2H),1.31-1.26(m,4H),1.24(d,J＝6.0Hz,3H),0.92-0.86(m,1H)。MS-ESI计算值[M+H] +589,实测值589。
实施例12
Figure PCTCN2022082862-appb-000120
合成路线：
Figure PCTCN2022082862-appb-000121
第一步
将化合物7-2(390mg,1.05mmol)溶于N,N-二甲基甲酰胺(10mL)中,滴加三乙胺(425mg,4.20mmol) 和化合物12-1(131mg,1.16mmol),在25℃下搅拌反应1小时。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12-2。MS-ESI计算值[M+H]+346,实测值346。
第二步
将化合物12-2(150mg,434μmol)溶于二氯甲烷(10mL)中,加入化合物1-3(197mg,652μmol),4-二甲基氨基吡啶(10.6mg,86.9μmol)和三乙胺(132mg,1.30mmol),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(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物12-3。MS-ESI计算值[M+H] +612,实测值612。
第三步
将化合物12-3(54.0mg,88.3μmol)溶于二甲基亚砜(3mL)中,加入中间体C的盐酸盐(31.9mg,132μmol)和三乙胺(26.8mg,265μmol),在90℃下搅拌反应12小时。向反应液中加入水(20mL),用二氯甲烷(20mL×1)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,剩余物经制备高效液相色谱分离纯化(色谱柱:Phenomenex Gemini-NX 80×30mm×3μm；流动相:10mM的碳酸氢铵水溶液-乙腈；梯度:乙腈38％-68％,9min)得到化合物12。 1H NMR(400MHz,CD 3OD)δ8.01(s,1H),7.11(s,1H),7.03-6.94(m,2H),6.80(s,1H),5.62-5.52(m,1H),4.00-3.95(m,1H),3.94(s,3H),3.91-3.82(m,1H),3.75-3.61(m,4H),3.52-3.41(m,1H),3.15-3.01(m,2H),2.46(s,3H),1.60(d,J＝7.2Hz,3H),1.36-1.15(m,1H)。MS-ESI计算值[M+H] +532,实测值532。
实施例13
Figure PCTCN2022082862-appb-000122
合成路线:
Figure PCTCN2022082862-appb-000123
第一步
将化合物7-2(700mg,1.89mmol)溶于N,N-二甲基甲酰胺(10mL)中,滴加三乙胺(763mg,7.54mmol)和化合物13-1(404mg,1.89mmol),在25℃下搅拌反应1小时。将反应液过滤,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13-2。 1H NMR(400MHz,CD 3Cl)δ7.94-7.87(m,1H),7.14-7.08(m,1H),4.73-4.45(m,1H),4.24-3.99(m,2H),3.94(s,3H),3.21-2.94(m,2H),2.89-2.75(m,2H),2.52(s,3H),2.01-1.78(m,2H),1.68(d,J＝14Hz,3H),1.55-1.46(m,9H)。MS-ESI计算值[M+H]+447,实测值447。
第二步
将化合物13-2(325mg,728μmol)溶于乙酸乙酯(10mL)中,加入氯化氢乙酸乙酯溶液(4M,3.64mL),在25℃下搅拌反应12小时。反应液减压浓缩,剩余物加入乙酸乙酯(20mL)在20℃下搅拌30分钟后过滤,将上层固体减压浓缩,得到化合物13-3的盐酸盐。MS-ESI计算值[M+H] +347,实测值347。
第三步
将化合物13-3的盐酸盐(318mg,521μmol)溶于二氯甲烷(5mL)和甲醇(5mL)中,加入37％甲醛水溶液(127mg,1.56mmol,纯度：37％),三乙酰氧基硼氢化钠(442mg,2.08mmol)和乙酸(62.6mg,1.04mmol),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(二氯甲烷/甲醇,100/1～10/1,V/V),分离得到化合物13-5。MS-ESI计算值[M+H] +361,实测值361。
第四步
将化合物13-5(160mg,444μmol),N,N-二异丙基乙胺(172mg,1.33mmol)和六氟磷酸苯并三唑-1-基-氧基三吡咯烷(347mg,666μmol)溶于N,N-二甲基甲酰胺(7mL)中,在25℃下搅拌反应1小时后加入溶于N,N-二甲基甲酰胺(3mL)的化合物C的盐酸盐(160mg,666μmol),在25℃下搅拌反应12小时。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-NX 80×30mm×3μm；流动相:10mM的碳酸氢铵水溶液-乙腈；梯度:乙腈41％-71％,9min)得到化合物13。 1H NMR(400MHz,CD 3OD)δ8.02(s,1H),7.10(s,1H),7.00-6.93(m,2H),6.79(s,1H),5.61-5.54(m,1H),4.62-4.55(m,4H),3.94(s,3H),3.04-2.87(m,2H),2.53-2.48(m,2H),2.49-2.43(m,5H),1.60(d,J＝7.2Hz,3H),1.33-1.27(m,1H),1.27-1.20(m,2H),1.15-1.06(m,2H)。MS-ESI计算值[M+H] +547,实测值547。
实施例14
Figure PCTCN2022082862-appb-000124
合成路线:
Figure PCTCN2022082862-appb-000125
第一步
将溴二氟乙酸乙酯(3.37g,16.6mmol)溶于二甲亚砜(20mL)中,加入铜粉(1.06g,16.6mmol)。反应液在25℃搅拌反应1小时。然后在向反应液中加入化合物14-1(2.00g,6.65mmol),在70℃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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～20/1,V/V)分离纯化得到化合物14-3。 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(m,2H),1.34(t,J＝8.0Hz,3H)。
第二步
在氮气保护下,将化合物14-3(677mg,1.82mmol)溶于甲苯(10mL)中,0℃下加入甲基溴化镁溶液(化合物14-4)(3M,2.43mL)。反应液在25℃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14-5。 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)。
第三步
在氮气保护下,将化合物14-5(441mg,1.56mmol)溶于甲苯(5mL)中,加入化合物14-6(1.87g,5.19mmol)和双三苯基磷二氯化钯(109mg,0.16mmol),反应液在120℃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14-7。
第四步
在氮气保护下,将化合物14-7(425mg,1.55mmol)溶于丙酮(10mL)中,0℃下逐滴加入盐酸溶液(12M,1.03mL),在25℃搅拌反应1小时。加入饱和碳酸氢钠溶液中和至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14-8。MS-ESI计算值[M+H] +247,实测值247。
第五步
在25℃下将化合物14-8(346mg,1.41mmol)溶于四氢呋喃(5mL)中,加入化合物B-4(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℃搅拌反应1小时。将反应液倒入20mL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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,2/1～0/1,V/V)分离纯化得到化合物14-9。MS-ESI计算值[M+H] +352,实测值352。
第六步
将化合物14-9(366mg,1.04mmol)溶于二氧六环(2.5mL)中,加入氯化氢二氧六环溶液(4M,1.15mL)。反应液在25℃搅拌反应6小时。反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,1/0～8/1,V/V)分离纯化得到化合物14-10的盐酸盐。MS-ESI计算值[M+H] +248,实测值248。
第七步
在氮气保护下,将化合物14-10的盐酸盐(374mg,0.61mmol)溶于二甲亚砜(3mL)中,加入化合物4-5(181mg,0.73mmol)和三乙胺(926mg,9.15mmol)。反应液在90℃搅拌反应12小时。向反应液中加入水(5mL),用乙酸乙酯(5mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 150×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈29％-59％,9min)得到化合物14的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.46(s,1H),7.63(t,J＝6.8Hz,1H),7.42(t,J＝6.8Hz,1H),7.26-7.19(m,2H),6.01(q,J＝6.8Hz,1H),4.82-4.59(m,1H),4.50-4.19(m,1H),4.04(s,3H),3.76-3.50(m,3H),3.41(s,1H),3.25(s,1H),3.00(s,3H),2.63(s,3H),1.74(d,J＝7.2Hz,3H),1.66-1.43(m,3H),1.29(s,6H)。MS-ESI计算值[M+H] +576,实测值576。
实施例15
Figure PCTCN2022082862-appb-000126
合成路线:
Figure PCTCN2022082862-appb-000127
第一步
将化合物15-1(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(化合物15-2)(12.4g,64.6mmol),三乙胺(6.54g,64.6mmol)和4-二甲氨基吡啶(52.6mg,0.43mmol),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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,4/1～0/1,V/V)分离纯化得到化合物15-3。MS-ESI计算值[M+H] +160,实测值160。
第二步
将化合物15-3(2.85g,11.2mmol)溶于四氢呋喃(10mL)中,-78℃下加入正丁基锂的四氢呋喃溶液(2.5M,5.38mL),反应液在-78℃搅拌反应30分钟。加入化合物15-4(2.00g,11.2mmol)的四氢呋喃(10mL)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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～4/1,V/V)分离纯化得到化合物15-5。MS-ESI计算值[M+H] +273,实测值273。
第三步
将化合物15-5(1.70g,5.23mmol)溶于二氯甲烷(20mL)中,0℃下加入二乙胺基三氟化硫(1.26g,7.84mmol),反应液在25℃搅拌反应16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×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,100/1～10/1,V/V)分离纯化得到化合物15-7。MS-ESI计算值[M+H] +295,实测值295。
第四步
在氮气保护下,将化合物15-7(1.37g,4.64mmol)溶于甲苯(10mL)中,加入化合物14-6(5.58g,15.5mmol)和双三苯基磷二氯化钯(326mg,464μmol),反应液在120℃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,减压浓缩得粗产品可直接用于投入下一步。
第五步
在氮气保护下,将化合物15-8(1.32g,4.61mmol)溶于丙酮(30mL)中,0℃下逐滴加入盐酸溶液(12M,3.07mL),在25℃搅拌反应1小时。加入饱和碳酸氢钠溶液中和至PH＝8,用乙酸乙酯(30mL)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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,50/1～10/1,V/V)分离纯化得到化合物15-9。MS-ESI计算值[M+H] +259,实测值259。
第六步
在25℃下将化合物15-9(936mg,3.62mmol)溶于四氢呋喃(10mL)中,加入化合物B-4(659mg,5.44mmol)和四乙氧基钛(3.09g,10.9mmol)。反应液在80℃搅拌反应23小时。然后在-5℃下向反应液降中加入硼氢化钠(165mg,4.35mmol),在25℃搅拌反应1小时。将反应液倒入20mL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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,2/1～1/2,V/V)分离纯化得到化合物15-10。MS-ESI计算值[M+H] +364,实测值364。
第七步
将化合物15-10(366mg,1.04mmol)溶于二氧六环(2.5mL)中,加入氯化氢二氧六环溶液(4M,1.15mL)。反应液在25℃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(二氯甲烷/甲醇,1/0～8/1,V/V)分离纯化得到化合物15-11的盐酸盐。MS-ESI计算值[M+H] +260,实测值260。
第八步
在氮气保护下,将化合物15-11的盐酸盐(778mg,1.27mmol)溶于二甲亚砜(5mL)中,加入化合物4-5(395mg,1.52mmol)和三乙胺(1.93g,19.0mmol)。反应液在90℃搅拌反应12小时。向反应液中加入水(5mL),用乙酸乙酯(5mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 150×40mm×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15的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.46(s,1H),7.65(t,J＝6.8Hz,1H),7.46(s,1H),7.29-7.14(m,2H),5.94-6.04(m,1H),4.70-4.12(m,3H),4.04(s,3H),3.88-3.75(m,2H),3.72-3.48(m,3H),3.45-3.35(m,1H),3.25(s,1H),3.00(s,3H),2.63(s,3H),2.18-1.99(m,2H),1.97-1.85(m,2H),1.75(d,J＝7.2Hz,3H),1.67-1.41(m,3H)。MS-ESI计算值[M+H] +588,实测值588。
实施例16
Figure PCTCN2022082862-appb-000128
合成路线:
Figure PCTCN2022082862-appb-000129
第一步
在氮气保护下,将化合物16-1(2.00g,8.62mmol)溶于四氢呋喃(20mL)中,-78℃下加入甲基溴化镁溶液(化合物14-4)(3M,4.31mL)。反应液在-78℃搅拌反应3小时。加入饱和氯化铵溶液(10mL)淬灭,用乙酸乙酯(20mL×2)萃取。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16-2。 1H NMR(400MHz,CD 3OD)δ7.73(d,J＝1.2Hz,1H),7.60(d,J＝8.0Hz,1H),7.32(d,J＝7.2Hz,1H),7.08(t,J＝8.0Hz,1H),4.86-4.76(m,1H),1.48-1.43(m,3H)。
第二步
将化合物16-2(3.01g,12.1mmol)溶于乙腈(30mL)中,25℃下加入N-甲基-N-氧化吗啉(2.13g,18.1mmol)和四丁基高钌酸铵(427mg,1.21mmol)。反应液在25℃搅拌反应4小时。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16-4。ESI计算值[M+H] +247,实测值247。
第三步
将化合物溴二氟乙酸乙酯(6.43g,31.7mmol)溶于二甲亚砜(30mL)中,加入铜粉(2.01g,31.7mmol)和化合物16-4(2.60g,10.6mmol)。反应液在90℃搅拌反应16小时。将反应液倒入20mL冰水中,加入10mL乙酸乙酯,过滤,滤液用乙酸乙酯(10mL×3)萃取。有机相用饱和食盐水(15mL×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,1/0～20/1,V/V)分离纯化得到化合物16-5。MS-ESI计算值[M+H] +243,实测值243。
第四步
在25℃下将化合物16-5(1.12g,4.62mmol)溶于四氢呋喃(10mL)中,加入化合物B-4(841mg,6.94mmol)和四乙氧基钛(3.16g,13.9mmol)。反应液在80℃搅拌反应12小时。然后在-78℃下向反应液降中加入硼氢化钠(525mg,13.9mmol)和水(200μL),在25℃搅拌反应3小时。将反应液倒入20mL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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,4/1～1/2,V/V)分离纯化得到化合物16-6。MS-ESI计算 值[M+H] +306,实测值306。
第五步
将化合物16-6(1.05mg,3.44mmol)溶于二氧六环(8mL)中,加入氯化氢二氧六环溶液(4M,3.78mL)。反应液在25℃搅拌反应6小时。反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/石油醚,0/1～10/1,V/V)分离纯化得到化合物16-7的盐酸盐。MS-ESI计算值[M+H] +202,实测值202。
第六步
在氮气保护下,将化合物16-7的盐酸盐(777mg,1.27mmol)溶于二甲亚砜(10mL)中,加入化合物4-5(306mg,1.52mmol)和三乙胺(1.93g,19.0mmol)。反应液在90℃搅拌反应12小时。向反应液中加入水(5mL),用乙酸乙酯(5mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 150×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈12％-42％,10min)得到化合物16的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.52-8.41(m,1H),7.73-7.58(m,2H),7.50-7.35(m,2H),7.27-7.17(m,1H),5.84(d,J＝5.6Hz,1H),4.71-4.16(m,2H),4.04(s,3H),3.90(t,J＝13.2Hz,2H),3.76-3.51(m,3H),3.42(s,1H),3.29-3.13(m,1H),3.00(s,3H),2.66(s,3H),1.76(d,J＝5.6Hz,3H),1.67-1.37(m,3H)。MS-ESI计算值[M+H] +530,实测值530。
实施例17
Figure PCTCN2022082862-appb-000130
合成路线:
Figure PCTCN2022082862-appb-000131
第一步
将化合物15-3(2.33g,9.86mmol)溶于四氢呋喃(20mL)中,-78℃下加入正丁基锂的四氢呋喃溶液(2.5M,4.74mL),反应液在-78℃搅拌反应30分钟。加入化合物17-1(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17-2。MS-ESI计算值[M+H] +255,实测值255。
第二步
将化合物17-2(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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～10/1,V/V)分离纯化得到化合物17-3。 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＝6.0Hz,2H),2.05(m,2H),1.90-1.81(m,2H),1.82-1.81(m,2H)。
第三步
在氮气保护下,将化合物17-3(1.35g,4.87mmol)溶于甲苯(10mL)中,加入化合物14-6(586g,16.2mmol)和双三苯基磷二氯化钯(342mg,0.49mmol),反应液在120℃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17-4。
第四步
在氮气保护下,将化合物17-4(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。加入饱和碳酸氢钠溶液中和至pH＝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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,50/1～10/1,V/V)分离纯化得到化合物17-5。MS-ESI计算值[M+H] +241,实测值241。
第五步
在25℃下将化合物17-5(828mg,3.45mmol)溶于四氢呋喃(10mL)中,加入化合物B-4(627mg,5.17mmol)和四乙氧基钛(2.94g,10.3mmol)。反应液在80℃搅拌反应32小时。然后在-5℃下向反应液降中加入硼氢化钠(156mg,4.14mmol),在25℃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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,2/1～1/2,V/V)分离纯化得到化合物17-6。MS-ESI计算值[M+H] +346,实测值346。
第六步
将化合物17-6(988mg,2.86mmol)溶于二氧六环(7mL)中,加入氯化氢二氧六环溶液(4M,3.15mL)。反应液在25℃搅拌反应6小时。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17-7的盐酸盐。MS-ESI计算值[M+H] +242,实测值242。
第七步
在氮气保护下,将化合物17-7的盐酸盐(798mg,1.30mmol)溶于二甲亚砜(5mL)中,加入化合物4-5(377mg,1.56mmol)和三乙胺(1.98g,19.5mmol)。反应液在90℃搅拌反应12小时。向反应液中加入 水(5mL),用乙酸乙酯(5mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 150×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈3％-33％,10min)得到化合物17的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.58-8.37(m,1H),7.71-7.56(m,2H),7.43(s,2H),7.30-7.15(m,1H),5.82(s,1H),4.83-4.57(m,1H),4.50-4.15(m,2H),4.04(s,3H),3.80-3.52(m,5H),3.43(s,1H),3.26(s,1H),3.00(s,3H),2.65(s,3H),1.98(d,J＝6.0Hz,2H),1.85-1.67(m,5H),1.63-1.43(m,3H)。MS-ESI计算值[M+H] +570,实测值570。
实施例18
Figure PCTCN2022082862-appb-000132
合成路线:
Figure PCTCN2022082862-appb-000133
第一步
在氮气保护下,将化合物18-1(3.86g,15.4mmol)溶于四氢呋喃(30mL)中,-78℃下加入甲基溴化镁溶液(3M,7.72mL)。反应液在-78℃搅拌反应3小时。加入饱和氯化铵溶液(30mL)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18-2。MS-ESI计算值[M+H] +267,实测值267。
第二步
将化合物18-2(2.98g,11.2mmol)溶于乙腈(25mL)中,25℃下加入N-甲基-N-氧化吗啉(1.97g,16.8mmol)和四丁基高钌酸铵(394mg,1.12mmol)。反应液在25℃搅拌反应4小时。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18-3。MS-ESI计算值[M+H] +265,实测值265。
第三步
将化合物溴二氟乙酸乙酯(4.84g,23.9mmol)溶于二甲亚砜(20mL)中,加入铜粉(1.52g,23.9mmol)和化合物18-3(2.10g,7.95mmol)。反应液在90℃搅拌反应16小时。将反应液倒入20mL冰水中,加入20mL乙酸乙酯,过滤,滤液用乙酸乙酯(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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/0～20/1,V/V)分离纯化得到化合物18-4。MS-ESI计算值[M+H] +261,实测值261。
第四步
在25℃下将化合物18-4(820mg,3.15mmol)溶于四氢呋喃(5mL)中,加入化合物B-4(573mg,4.73mmol)和四乙氧基钛(2.16g,9.45mmol)。反应液在80℃搅拌反应16小时。然后在-78℃下向反应液中加入硼氢化钠(358mg,9.45mmol)和水(100μL),升温至25℃并在25℃下搅拌反应3小时。将反应液倒入5mL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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,4/1～0/1,V/V)分离纯化得到化合物18-5。MS-ESI计算值[M+H] +324,实测值324。
第五步
将化合物18-5(295mg,912μmol)溶于二氧六环(2mL)中,加入氯化氢二氧六环溶液(4M,1.00mL)。反应液在25℃搅拌反应6小时。反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,20/1～10/1,V/V)分离纯化得到化合物18-6的盐酸盐。MS-ESI计算值[M+H] +220,实测值220。
第六步
在氮气保护下,将化合物18-6的盐酸盐(452mg,738μmol)溶于二甲亚砜(10mL)中,加入化合物4-5(194mg,885μmol)和三乙胺(1.12g,1.54mmol)。反应液在90℃搅拌反应12小时。向反应液中加入水(5mL),用乙酸乙酯(5mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 150×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈10％-80％,9min)得到化合物18的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.53-8.44(m,1H),7.67(t,J＝6.8Hz,1H),7.51(t,J＝6.8Hz,1H),7.26(t,J＝8.0Hz,1H),7.23-7.19(m,1H),6.00(d,J＝7.2Hz,1H),4.83-4.59(m,1H),4.50-4.18(m,1H),4.07-3.97(m,5H),3.77-3.50(m,3H),3.46-3.34(m,1H),3.20-15(m,1H),3.00(s,3H),2.63(s,3H),1.75(d,J＝6.8Hz,3H),1.66-1.44(m,3H)。MS-ESI计算值[M+H] +548,实测值548。
实施例19
Figure PCTCN2022082862-appb-000134
合成路线：
Figure PCTCN2022082862-appb-000135
第一步
氮气保护下,将化合物19-1(3.00g,14.8mmol)溶于干燥二氯甲烷(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19-2。 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)。
第二步
氮气保护下,将化合物19-2(3.10g,13.8mmol)溶于干燥甲苯(50mL)中,加入三丁基(1-乙氧基乙烯)锡(化合物14-6)(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,减压浓缩得到粗品化合物19-3,直接用于下一步。
第三步
氮气保护下,将化合物19-3(2.98g,13.8mmol)溶于丙酮(90mL)中,0℃下滴加浓盐酸(12M,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19-4。 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)。
第四步
氮气保护下,将化合物19-4(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(R)-(+)-叔丁基亚磺酰胺(化合物B-4)(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19-5。MS-ESI计算值[M+H] +292,实测值292。
第五步
将化合物19-5(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19-6。MS-ESI计算值[M+H] +294,实测值294。
第六步
将化合物19-6(200mg,0.682mmol)溶于乙酸乙酯(5mL)中,25℃下滴加氯化氢乙酸乙酯溶液(4M,5.00mL),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19-7的盐酸盐,直接用于下一步。
第七步
氮气保护下,将化合物19-7的盐酸盐(200mg,0.326mmol)溶于二甲亚砜(10mL)中,再加入化合物7(110mg,0.490mmol)和三乙胺(165mg,1.63mmol),反应液在100℃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 150×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈25％-55％,9min)分离得到化合物19的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.46(s,1H),7.74-7.65(m,1H),7.58-7.49(m,1H),7.30(t,J＝8.0Hz,1H),7.19(s,1H),7.15-6.85(m,1H),6.00(q,J＝7.2Hz,1H),4.84-4.58(m,1H),4.51-4.20(m,1H),4.04(s,3H),3.74-3.49(m,3H),3.48-3.35(m,1H),3.29-3.15(m,1H),3.00(s,3H),2.63(s,3H),1.76(d,J＝7.2Hz,3H),1.65-1.44(m,3H)。MS-ESI计算值[M+H] +518,实测值518。
实施例20
Figure PCTCN2022082862-appb-000136
合成路线:
Figure PCTCN2022082862-appb-000137
第一步
将化合物18-5(121mg,374μmol)溶于二氧六环(2mL)中,加入碳酸铯(366mg,1.12mmol)和18-冠醚-6(50mg,187μmol)。反应液在80℃搅拌反应36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,15/1～3/1,V/V)分离纯化得到化合物20-1的盐酸盐。MS-ESI计算值[M+H] +284,实测值284。
第二步
将化合物20-1(104mg,367μmol)溶于二氧六环(1mL)中,加入氯化氢二氧六环溶液(4M,404μL)。反应液在25℃搅拌反应6小时。反应液减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,20/1～10/1,V/V)分离纯化得到化合物20-2的盐酸盐。MS-ESI计算值[M+H] +180,实测值180。
第三步
在氮气保护下,将化合物20-2的盐酸盐(177mg,288μmol)溶于二甲亚砜(2mL)中,加入化合物4-5(62mg,346μmol)和三乙胺(437mg,4.33mmol)。反应液在90℃搅拌反应12小时。向反应液中加入水(3mL),用乙酸乙酯(3mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 150×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈20％-50％,9min)得到化合物20的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.45(s,1H),7.93-7.87(m,1H),7.54(d,J＝8.0Hz,1H),7.47(d,J＝7.2Hz,1H),7.33-7.27(m,1H),7.19(s,1H),6.23(d,J＝6.8Hz,1H),4.74-4.57(s,1H),4.46-4.22(m,1H),4.04(s,3H),3.59(t,J＝12.4Hz,3H),3.46-3.35(s,1H),3.27-3.15(s,1H),3.00(s,3H),2.59(s,3H),1.83(d,J＝7.2Hz,3H),1.62-1.45(m,3H)。MS-ESI计算值[M+H] +508,实测值508。
实施例21
Figure PCTCN2022082862-appb-000138
合成路线:
Figure PCTCN2022082862-appb-000139
第一步
氮气保护下将化合物21-1(1.00g,5.00mmol)溶于甲苯(2mL)中,再加入化合物14-6(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,滤液减压浓缩后得到化合物21-2。
第二步
氮气保护下将化合物21-2(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℃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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,50/1～10/1,V/V)分离纯化得到化合物21-3。
第三步
将化合物21-3(736mg,4.51mmol)溶于四氢呋喃(15mL)中,加入化合物B-4(820mg,6.77mmol)和四乙氧基钛(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,滤液用乙酸乙酯萃取(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,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,2/1～1/1,V/V)分离纯化得到化合物21-4。MS-ESI计算值[M+H] +269,实测值269。
第四步
将化合物21-4(910mg,3.39mmol)溶于二氧六环(8mL)中,加入氯化氢二氧六环溶液(4M,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)搅拌,过滤，收集滤饼得到化合物21-5的盐酸盐。MS-ESI计算值[M+H] +165,实测值165。
第五步
在氮气保护下,将化合物21-5的盐酸盐(198mg,291μmol)溶于二甲亚砜(2mL)中,加入化合物4-5(70mg,249μmol)和三乙胺(441mg,4.36mmol)。反应液在90℃搅拌反应12小时。向反应液中加入水(3mL),用乙酸乙酯(3mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 150×30mm×4μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈20％-50％,9min)得到化合物21的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.45(s,1H),7.93-7.83(m,1H),7.75-7.65(m,1H),7.41-7.32(m,1H),7.18(s,1H),5.96(d,J＝7.2Hz,1H),4.80-4.62(m,1H),4.58-4.15(m,1H),4.04(s,3H),3.78-3.44(m,3H),3.44-3.34(m,1H),3.25-3.10(m,1H),3.00(s,3H),2.63(s,3H),1.76(d,J＝7.2Hz,3H),1.61-1.43(m,3H)。MS-ESI计算值[M+H] +493,实测值493。
实施例22
Figure PCTCN2022082862-appb-000140
合成路线:
Figure PCTCN2022082862-appb-000141
第一步
将化合物22-1(600mg,4.13mmol)溶于四氢呋喃(10mL)中,加入化合物B-4(751mg,6.20mmol)和四乙氧基钛(2.83g,12.4mmol),在80℃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,滤液用乙酸乙酯萃取(5mL×2),有机相用饱和食盐水(5mL)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,6/1～1/1,V/V)分离纯化得到化合物22-2。MS-ESI计算值[M+H] +251,实测值251。
第二步
将化合物22-2(500mg,2.00mmol)溶于二氧六环(8mL)中,加入氯化氢二氧六环溶液(4M,2mL),在25℃搅拌反应6小时。反应液减压浓缩,剩余物经过乙酸乙酯(2mL)搅拌，过滤，收集滤饼得到化合物22-3的盐酸盐。MS-ESI计算值[M+H] +147,实测值147。
第三步
在氮气保护下,将化合物22-3的盐酸盐(218mg,319μmol)溶于二甲亚砜(2mL)中,加入化合物4-5(70mg,383μmol)和三乙胺(441mg,4.36mmol)。反应液在90℃搅拌反应12小时。向反应液中加入水(3mL),用乙酸乙酯(3mL×3)和二氯甲烷/甲醇溶液(8:1,5mL)萃取,有机相用无水硫酸钠干燥,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 Genimi NX C18 150×40mm×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22的盐酸盐。 1H NMR(400MHz,CD 3OD)δ8.47(s,1H),7.91-7.75(m,2H),7.67-7.61(s,1H),7.57-7.49(s,1H),7.22(s,1H),5.90-5.76(s,1H),4.65-4.18(m,2H),4.04(s,3H),3.77-3.51(m,2H),3.49-3.32(m,2H),3.26-3.14(m,1H),3.00(s,3H),2.65(s,3H),1.74(s,3H),1.65-1.32(m,3H)。MS-ESI计算值[M+H] +475,实测值475。
实施例23
Figure PCTCN2022082862-appb-000142
合成路线:
Figure PCTCN2022082862-appb-000143
第一步
氮气保护下将化合物23-1(1.00g,4.61mmol)溶于四氢呋喃(15mL)中,在0℃下滴加化合物14-4(3M四氢呋喃溶液,7.68mL),在25℃下搅拌反应1小时。向反应液加入饱和氯化铵溶液,用乙酸乙酯(50mL×2)萃取,有机相用饱和食盐水(50mL×2)洗涤,无水硫酸钠干燥有机相,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23-2。 1H NMR(400MHz,CD 3Cl)δ7.59-7.50(m,1H),7.50-7.37(m,1H),7.06-6.97(m,1H),1.67-1.64(m,6H)。
第二步
氮气保护下将化合物23-2(606mg,2.60mmol)溶于甲苯(10mL)中,再加入化合物14-6(1.13g,3.12mmol)和双三苯基膦二氯化钯(182mg,260μmol),在120℃下搅拌反应12小时。向反应液加入饱和氟化钾溶液(20mL),用乙酸乙酯(50mL×2)萃取,无水硫酸钠干燥有机相,过滤,减压浓缩,得到化合物23-3。MS-ESI计算值[M+H] +225,实测值225。
第三步
氮气保护下将化合物23-3(583mg,2.60mmol)溶于丙酮(6mL)中,逐滴加入盐酸溶液(12M,0.60mL),在20℃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(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,10/1～2/1,V/V)分离纯化得到化合物23-4。 1H NMR(400MHz,CD 3Cl)δ7.85-7.77(m,1H),7.78-7.67(m,1H),7.20(t,J＝7.6Hz,1H),2.68-2.63(m,3H),1.70-1.67(m,6H)。
第四步
将化合物23-4(430mg,2.19mmol)溶于四氢呋喃(10mL)中,加入化合物B-4(398mg,3.29mmol)和 钛酸四乙酯(1.00g,4.38mmol),在80℃下搅拌反应12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,10/1～1/1,V/V)分离纯化得到化合物23-5。 1H NMR(400MHz,CD 3Cl)δ7.75-7.65(m,1H),7.58-7.41(m,1H),7.16(t,J＝7.6Hz,1H),1.68-1.66(m,6H),1.32(s,9H),1.24(s,3H)。MS-ESI计算值[M+H] +300,实测值300。
第五步
将化合物23-5(650mg,1.85mmol)溶于四氢呋喃(10mL)中,在0℃下加入硼氢化钠(77.1mg,2.04mmol),在20℃下搅拌反应1小时。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,10/1～1/1,V/V)分离纯化得到化合物23-6。 1H NMR(400MHz,CD 3Cl)δ7.54-7.44(m,1H),7.34-7.25(m,1H),7.12(t,J＝7.6Hz,1H),4.99-4.69(m,1H),1.68-1.60(m,6H),1.61-1.50(m,3H),1.27-1.15(m,9H)。MS-ESI计算值[M+H] +302,实测值302。
第六步
将化合物23-6(116mg,385μmol)溶于二氧六环(5mL)中,加入氯化氢二氧六环溶液(4M,96.2μL),在25℃下搅拌反应1小时。反应液减压浓缩,剩余物用二氯甲烷(5mL)搅拌,过滤，收集滤饼得到化合物23-7的盐酸盐。MS-ESI计算值[M+H] +198,实测值198。
第七步
将化合物23-7的盐酸盐(69.0mg,295μmol)溶于二甲基亚砜(3mL)中,加入化合物4-5(199mg,325μmol),滴加三乙胺(149mg,1.48mmol),在100℃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:Phenomenex Genimi NX C18 150×40mm×5μm；流动相:(0.04％的氨水溶液+10mM的碳酸氢铵水溶液)-乙腈；梯度:乙腈30％-60％,10min),得到化合物23。 1H NMR(400MHz,CD 3OD)δ8.04(s,1H),7.53-7.42(m,1H),7.35-7.24(m,1H),7.09(s,1H),7.08-6.98(m,1H),5.91-5.77(m,1H),4.68-4.55(m,1H),4.56-4.17(m,1H),3.94(s,3H),2.96-2.74(m,2H),2.42(s,3H),2.31(s,3H),2.26-2.01(m,2H),1.80-1.49(m,9H),1.48-1.37(m,3H),1.37-1.10(m,2H)。MS-ESI计算值[M+H] +526,实测值526。
实施例24
Figure PCTCN2022082862-appb-000144
合成路线:
Figure PCTCN2022082862-appb-000145
第一步
将化合物7-2(200mg,1.62mmol)溶于N,N-二甲基甲酰胺(5mL)中,滴加三乙胺(1.12ml,8.08mmol)和24-1(686mg,3.23mmol),在25℃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×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(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物24-2。MS-ESI计算值[M+H] +445,实测值445。
第二步
将化合物24-2(425mg,839μmol)溶于二氯甲烷(10mL)中,加入化合物1-3(305mg,1.01mmol),4-二甲基氨基吡啶(10.3mg,83.9μmol)和三乙胺(350μl,2.52mmol),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(二氯甲烷/甲醇,100/1～10/1,V/V),得到化合物24-3。MS-ESI计算值[M+H] +711,实测值711。
第三步
将化合物24-3(220mg,309μmol)溶于二甲基亚砜(5mL)中,加入14-10的盐酸盐(116mg,402μmol)和三乙胺(129μl,928μmol),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24-4。MS-ESI计算值[M+H] +674,实测值674。
第四步
将化合物24-4(224mg,236μmol)溶于乙酸乙酯(5mL)中,加入氯化氢乙酸乙酯溶液(4mol/L,3.53mL),在20℃下搅拌反应12小时。反应液减压浓缩,得到化合物24-5的盐酸盐。MS-ESI计算值[M+H] + 574,实测值574。
第五步
将化合物24-5的盐酸盐(130mg,201μmol)溶于四氢呋喃(5mL)中,加入24-6(145mg,2.01mmol),在70℃下搅拌反应1小时后加入三乙酰氧基硼氢化钠(213mg,1.01mmol),在70℃下搅拌反应1小时。降至室温,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:Phenomenex C18 80mm×40mm×3μm；流动相:0.05％氨水溶液-乙腈；梯度:乙腈40％-70％,8min)得到化合物24。 1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.57-7.46(m,1H),7.40-7.31(m,1H),7.18-7.11(m,1H),7.12-7.08(m,1H),5.87-5.78(m,1H),4.75-4.67(m,2H),4.64-4.59(m,6H),3.97-3.90(m,3H),3.91-3.63(m,2H),3.64-3.52(m,1H),2.41(s,3H),1.63(d,J＝7.2Hz,3H),1.33-1.27(m,6H),1.23-0.86(m,4H)。MS-ESI计算值[M+H] +630,实测值630。
实施例25
Figure PCTCN2022082862-appb-000146
合成路线:
Figure PCTCN2022082862-appb-000147
第一步
将化合物24-3(1.01g,1.18mmol)溶于二甲基亚砜(10mL)中,加入19-7的盐酸盐(245mg,1.30mmol)和三乙胺(492μL,3.54mmol),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25-1。MS-ESI计算值[M+H]+616,实测值616。
第二步
将化合物25-1(675mg,900μmol)溶于乙酸乙酯(10mL)中,加入氯化氢乙酸乙酯溶液(4mol/L,13.5mL),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％氨水溶液-乙腈；梯度:乙腈35％-65％,10min)得到化合物25。 1H NMR(400MHz,CD 3OD)δ8.05(s,1H),7.61-7.48(m,1H),7.43(t,J＝6.4Hz,1H),7.29-7.09(m,2H),7.10-6.81(m,1H),5.87-5.73(m,1H),3.96(s,3H),3.90-3.50(m,2H),3.15-2.70(m,4H),2.40(s,3H),1.62(d,J＝6.8Hz,3H),1.40-1.05(m,2H),1.01-0.84(m,2H)。MS-ESI计算值[M+H] +516,实测值516。
实施例26
Figure PCTCN2022082862-appb-000148
合成路线:
Figure PCTCN2022082862-appb-000149
将化合物25(280mg,476μmol)溶于四氢呋喃(5mL)中,加入24-6(343mg,4.76mmol),在70℃下搅拌反应1小时后加入三乙酰氧基硼氢化钠(504mg,2.38mmol),在70℃下搅拌反应1小时。降至室温,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:Xtimate C18 150mm×40mm×5μm；流动相:氨水溶液-乙腈；梯度:乙腈40％-60％,10min)得到化合物26。 1H NMR(400MHz,CD 3OD)δ8.04(s,1H),7.57-7.47(m,1H),7.47-7.33(m,1H),7.28-7.08(m,2H),7.08-6.75(m,1H),5.86-5.70(m,1H),4.74-4.54(m,5H),3.93(s,3H),3.89-3.63(m,2H),3.62-3.46(m,1H),2.69-2.43(m,2H),2.40(s,3H),2.37-2.30(m,1H),1.62(d,J＝6.8Hz,3H),1.39-1.08(m,2H),1.04-0.86(m,2H)。MS-ESI计算值[M+H] +572,实测值572。
实施例27
Figure PCTCN2022082862-appb-000150
合成路线:
Figure PCTCN2022082862-appb-000151
第一步
氮气保护下,将化合物27-1(6.00g,23.3mmol)溶于干燥甲苯(100mL)中,加入化合物14-6(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27-2,直接用于下一步。
第二步
将化合物27-2(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27-3。 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。
第三步
将化合物27-3(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B-4(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27-4。MS-ESI计算值[M+H] +325,实测值325。
第四步
将化合物27-4(4.68g,11.8mmol)溶于无水四氢呋喃(60mL),在0℃加入硼氢化钠(535mg,14.2 mmol),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27-5。MS-ESI计算值[M+H] +327,实测值327。
第五步
将化合物27-5(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,收集滤饼干燥得到中间体27-6的盐酸盐。MS-ESI计算值[M+H] +223,实测值223。
第六步
将化合物4-5(100mg,163μmol)溶于二甲基亚砜(3mL)中,加入27-6的盐酸盐(43.5mg,196μmol)和三乙胺(68.1μL,490μmol),在90℃下搅拌反应12小时。降至室温,过滤,减压浓缩,剩余物经高效液相色谱分离纯化(色谱柱:Xtimate C18 150mm×25mm×5μm；流动相:0.05％盐酸水溶液-乙腈；梯度:乙腈5％-35％,10min),再经制备SFC(分离柱:DAICEL CHIRALCEL OD 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:35％-35％)分离得到化合物27。 1H NMR(400MHz,CD 3OD)δ8.36(s,1H),7.16(s,1H),6.96(s,1H),6.83(s,1H),5.92-5.81(m,1H),4.29-4.07(m,1H),4.03(s,3H),3.55-3.39(m,1H),3.31-3.03(m,4H),2.94-2.72(m,1H),2.67(s,3H),2.61(s,3H),1.70(d,J＝7.2Hz,3H),1.56-1.43(m,3H)。MS-ESI计算值[M+H] +551,实测值551。
实施例28
Figure PCTCN2022082862-appb-000152
合成路线:
Figure PCTCN2022082862-appb-000153
第一步
将化合物28-1(10.0g,49.9mmol)溶于甲醇(100mL)中,加入甲醛水溶液(20.3g,250mmol,纯度：37％),氰基硼氢化钠(9.41g,150mmol)和乙酸(15.0g,250mmol),在25℃下搅拌反应12小时。向反应液中加入水(200mL),用二氯甲烷(200mL×3)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,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,100/1～10/1,V/V),分离得到化合物28-2。 1H NMR(400MHz,CDCl 3)δ4.27-4.13(m,1H),3.87-3.75(m,1H),3.17-3.04(m,1H),2.77-2.69(m,1H),2.63-2.55(m,1H),2.24(s,3H),2.14-2.06(m,1H),1.95-1.86(m,1H),1.46(s,9H),1.24(d,J＝6.8Hz,3H)。MS-ESI计算值[M+H] +215,实测值215。
第二步
将化合物28-2(6.00g,28.0mmol)溶于二氧六环(50mL)中,滴加氯化氢二氧六环溶液(4M,20.0mL),反应液于25℃搅拌12小时,将反应液减压浓缩得到粗品化合物28-3的盐酸盐。 1H NMR(400MHz,CD 3OD)δ3.89-3.74(m,3H),3.74-3.66(m,1H),3.66-3.31(m,3H),2.99(s,3H),1.43(d,J＝6.4Hz,3H)。
第三步
将化合物28-3的盐酸盐(2.65g,14.1mmol)溶于N,N-二甲基甲酰胺(20mL)中,滴加三乙胺(4.77g,47.1mmol)和化合物7-2(3.5g,9.43mmol),在25℃下搅拌反应12小时。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28-4。MS-ESI计算值[M+H] +347,实测值347。
第四步
将化合物28-4(500mg,1.44mmol)溶于二氯甲烷(15mL)中,加入化合物1-3(525mg,1.73mmol),4-二甲基氨基吡啶(17.6mg,144μmol)和三乙胺(438mg,4.33mmol),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×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28-5。MS-ESI计算值[M+H] +613,实测值613。
第五步
将化合物28-5(360mg,523μmol)溶于二甲基亚砜(10mL)中,加入14-10(194mg,784μmol)和三乙胺(159mg,1.57mmol),在90℃下搅拌反应12小时。向反应液中加入水(50mL),用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×5)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 C18 150×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈5％-35％,10min)得到化合物28的盐酸盐。 1H NMR(400MHz,MeOD)δ8.41(s,1H),7.61(t,J＝7.2Hz,1H),7.42(t,J＝7.2Hz,1H),7.23(t,J＝7.2Hz,1H),7.17(s,1H),6.01-5.99(m,1H),4.73-4.58(m,1H)4.51-4.20(m,1H),4.04(s,3H),3.63-3.56(m,3H),3.43-3.37(m,1H),3.25-3.18(m,1H),3.00(s,3H),2.62(s,3H),1.74(d,J＝7.2Hz,3H),1.57-1.47(m,3H),1.29(s,6H)。MS-ESI计算值[M+H] +576,实测值576。
实施例29
Figure PCTCN2022082862-appb-000154
合成路线:
Figure PCTCN2022082862-appb-000155
第一步
将化合物29-1(10.0g,49.9mmol)溶于甲醇(100mL)中,加入甲醛水溶液(20.3g,250mmol,纯度：37％),氰基硼氢化钠(9.41g,150mmol)和乙酸(15.0g,250mmol),在25℃下搅拌反应12小时。向反应液中加入水(300mL),用乙酸乙酯(200mL×3)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,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,1/0～10/1,V/V),分离得到化合物29-2。 1H NMR(400MHz,CDCl 3)δ4.21-4.18(m,1H),3.82-3.79(m,1H),3.13-3.06(m,1H),2.74-2.70(m,1H),2.60-2.52(m,1H),2.24(s,3H),2.11-2.07(m,1H),1.93-1.86(m,1H),1.45(s,9H),1.29(d,J＝7.2Hz,3H)。MS-ESI计算值[M+H] +215,实测值215。
第二步
将化合物29-2(7.25g,33.8mmol)溶于二氧六环(50mL)中,滴加氯化氢二氧六环溶液(4M,67.6mL),反应液于25℃搅拌12小时,将反应液减压浓缩得到粗品化合物29-3的盐酸盐。 1H NMR(400MHz,CD 3OD)δ3.82-3.73(m,3H),3.74-3.66(m,1H),3.66-3.31(m,3H),3.02(s,3H),1.47(d,J＝7.2Hz,3H)。
第三步
将化合物29-3的盐酸盐(811mg,5.39mmol)溶于N,N-二甲基甲酰胺(15mL)中,滴加三乙胺(1.64g,16.2mmol)和化合物7-2(1.00g,2.69mmol),在25℃下搅拌反应12小时。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,20/1～1/1,V/V),得到化合物29-4。MS-ESI计算值[M+H] +347,实测值347。
第四步
将化合物29-4(254mg,733μmol)溶于二氯甲烷(5mL)中,加入化合物1-3(333mg,1.10mmol),4-二甲基氨基吡啶(8.96mg,73.3μmol)和N,N-二异丙基乙胺(284mg,2.20mmol),在25℃下搅拌反应12小时。向反应液中加入水(50mL),用乙酸乙酯(40mL×5)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,剩余物经过硅胶柱色谱法分离纯化(二氯甲烷/甲醇,1/0～10/1,V/V),得到化合物29-5。MS-ESI计算值[M+H] +613,实测值613。
第五步
将化合物29-5(154mg,251μmol)溶于二甲基亚砜(5mL)中,加入14-10(93.2mg,377μmol)和三乙胺(76.3mg,754μmol),在90℃下搅拌反应12小时。向反应液中加入水(50mL),用乙酸乙酯(50mL×3)萃取,有机相用饱和食盐水(50mL×5)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 150×40mm×5μm；流动相:0.05％的盐酸水溶液-乙腈；梯度:乙腈5％-30％,10min)得到化合物29的盐酸盐。 1H NMR(400MHz,MeOD)δ8.40(s,1H),7.61(t,J＝7.2Hz,1H),7.42(t,J＝6.8Hz,1H),7.23(t,J＝7.2Hz,1H),7.16(s,1H),6.01-5.99(m,1H),4.93-4.86(m,1H)4.68-4.22(m,1H),4.04(s,3H),3.62-3.55(m,4H),3.23-3.19(m,1H),2.99(s,3H),2.62(s,3H),1.74(d,J＝6.8Hz,3H),1.57-1.48(m,3H),1.29(s,6H)。MS-ESI计算值[M+H] +576,实测值576。
生物学活性：
实验例1：KRAS(G12C)和SOS1结合实验
实验原理：
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。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。
实验材料：
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。
实验方法：
1X buffer配制(现配现用):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。
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。
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。
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。
数据分析：
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)。表1提供了本发明的化合物对KRAS(G12C)和SOS1结合的抑制活性。
表1本发明化合物对KRAS(G12C)和SOS1结合的IC 50值测试结果
受试化合物 IC 50(nM)
化合物2 109.8
化合物4的盐酸盐 71.1
化合物5的盐酸盐 77.3
化合物6的盐酸盐 87.6
化合物7 92.8
化合物8的盐酸盐 73.7
化合物9 83.6
化合物11 78.6
化合物13 70.4
化合物14的盐酸盐 40.4
化合物15的盐酸盐 149.4
化合物16的盐酸盐 59.6
化合物18的盐酸盐 23.4
化合物19的盐酸盐 104.9
化合物24 47.9
化合物25 86.1
化合物26 65.9
化合物27 40.64
化合物28的盐酸盐 14.49
化合物29的盐酸盐 14.66
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。
实验例2：H358细胞3D增殖抑制活性测试
实验原理：
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。
实验材料：
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)。
实验方法：
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。
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。
数据分析：
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)。
实验结论：本发明化合物能在3D条件下抑制H358细胞的增殖。
实验例3：DLD-1细胞p-ERK增殖抑制活性测试
实验材料：
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。
表2 Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表
成分名称 储存温度
Advanced PhosphoERK1/2 Eu Cryptate antibody ≤--16℃
Advanced PhosphoERK1/2 d2 antibody ≤--16℃
Blocking reagent(stock solution 100X) ≤--16℃
Lysis buffer#1(stock solution 4X) ≤--16℃
Detection buffer(ready-to-use) ≤--16℃
实验方法：
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；
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％；
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；
使用Detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；
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；
孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm。
数据分析：
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)。
Max孔:阳性对照孔读值为1X裂解液
Min孔：阴性对照孔读值为0.5％DMSO细胞孔细胞裂解液
表3提供了本发明的化合物对DLD-1细胞p-ERK的抑制活性。
表3本发明化合物对DLD-1细胞p-ERK增殖的IC 50值测试结果
受试化合物 IC 50(nM)
化合物2 121.7
化合物4的盐酸盐 113.2
化合物5的盐酸盐 219.4
化合物10 86.2
化合物13 281.9
化合物14 78.9
化合物16的盐酸盐 222
化合物18的盐酸盐 242.9
化合物26 283.1
化合物27 111.9
化合物28的盐酸盐 91.55
化合物29的盐酸盐 135.4
实验结论：本发明化合物对DLD-1细胞p-ERK增殖有显著的抑制效果。
实验例4A：化合物药代动力学评价
实验材料：
CD-1小鼠(雄性,7～9周龄,上海斯莱克)
实验操作：
以标准方案测试化合物静脉注射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10％二甲基亚砜与90％的10％的羟丙基β环糊精配成的混合溶媒。该项目使用四只雌性CD-1小鼠,两只小鼠进行静脉注射给药,给药剂量为1mg/kg,收集给药后0.033,0.083,0.25,0.5,1,2,4,8,12h的血浆样品；另外两只小鼠口服灌胃给药,给药剂量为2mg/kg,收集给药后0.083,0.25、0.5,1,2,4,8,12h的血浆样品,在4℃下3,200x g搅拌10分钟,分离上清得血浆样品,加入20倍体积含内标的甲醇溶液沉淀蛋白,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。
实验结果如表4所示：
表4本发明化合物的药代动力学测试结果
Figure PCTCN2022082862-appb-000156
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。
实验例4B：化合物药代动力学评价
实验材料：
Balb/c小鼠(雄性,北京维通利华实验动物技术有限公司)
实验操作：
以标准方案测试化合物静脉注射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％solutol与90％水配成的混合溶媒。该项目使用四只雄性Balb/c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、0.5,1,2,4,6,8,12,24h的血浆样品,血液样本采集后置于冰上，并于1小时之内离心分离血浆(离心条件：6000g，3分钟，2-8℃)。血浆样本在分析前存放时则放于-80℃冰箱内。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。
实验结果如表5所示：
表5本发明化合物的药代动力学测试结果
Figure PCTCN2022082862-appb-000157
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。
实验例5：化合物在Miapaca2裸鼠移植瘤模型的体内药效评价
细胞培养：
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。
实验动物：
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。
模型制备：
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。
给药方案见表6。
表6实验动物分组及给药方案
Figure PCTCN2022082862-appb-000158
Figure PCTCN2022082862-appb-000159
肿瘤测量和实验指标：
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％。
实验结果见表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22天肿瘤体积计算得出)
Figure PCTCN2022082862-appb-000160
实验结论：本发明的化合物与AMG-510联用在Miapaca2裸鼠移植瘤模型中展现出优异的抑瘤效果。

Claims (31)

  1. 式(Ⅱ)化合物或其药学上可接受的盐，
    Figure PCTCN2022082862-appb-100001
    其中，
    R 1和R 2分别独立地选自H、C 1-6烷基、C 3-12环烷基、3-12元杂环烷基、C 6-10芳基和5-10元杂芳基，其中所述C 1-6烷基、C 3-12环烷基、3-12元杂环烷基、C 6-10芳基和5-10元杂芳基分别独立地任选被1、2、3或4个R a所取代；
    或者，R 1、R 2和与它们相连接的氮原子一起形成3-12元杂环烷基，其中所述3-12元杂环烷基任选被1、2、3或4个R b取代；
    R 3选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，其中所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2、3或4个R c取代；
    R 4选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基和3-10元杂环烷基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基和3-10元杂环烷基分别独立地任选被1、2、3或4个R c取代；
    R 5选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，其中所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2、3或4个R c取代；
    或者，R 4、R 5和与它们相连接的碳原子一起形成
    Figure PCTCN2022082862-appb-100002
    其中
    Figure PCTCN2022082862-appb-100003
    任选被1、2、3或4个R d取代；T 1选自CR 6和N；
    R 6选自-OCH 3、-CN和-S(＝O) 2-CH 3；
    R a分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基分别独立地任选被1、2、3或4个R取代；
    R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基，其中所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、-C(＝O)-O-C 1-6烷基、C 3-10环烷基、3-10元杂环烷基、C 6-10芳基、5-10元杂芳基、-O-C 6-10芳基和-O-5-10元杂芳基分别独立地任选被1、2、3或4个R取代；
    R c分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、＝O、-C(＝O)H、-C(＝O)-NH 2、C 1-3烷基、C 1-3烷氧基和5-6元杂环烷基，其中所述C 1-3烷基、C 1-3烷氧基和5-6元杂环烷基分别独立地任选被1、2、 3或4个R取代；
    R d分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、＝O、-C(＝O)H、-C(＝O)-NH 2和C 1-3烷基；
    R分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、-COOH、＝O、-C(＝O)H、-C(＝O)-NH 2和C 1-3烷基；
    所述5-6元杂环烷基、3-10元杂环烷基、3-12元杂环烷基、5-10元杂芳基和-O-5-10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。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅱ-1)所示结构：
    Figure PCTCN2022082862-appb-100004
    其中，T 1、R 1、R 2、R 3、R 4和R 5如权利要求1所定义；
    带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  3. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R分别独立地选自F、Cl、Br和＝O。
  4. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R b分别独立地选自F、Cl、Br、I、-OH、-NH 2、-CN、＝O、C 1-3烷基、C 1-3烷氨基和3-6元杂环烷基，其中所述C 1-3烷基、C 1-3烷氨基和3-6元杂环烷基分别独立地任选被1、2、3或4个R取代。
  5. 根据权利要求4所述的化合物或其药学上可接受的盐，其中，R b分别独立地选自F、Cl、Br、-NH 2、-CH 3、-CH 2-CH 3、
    Figure PCTCN2022082862-appb-100005
    其中所述-CH 3、-CH 2-CH 3、
    Figure PCTCN2022082862-appb-100006
    分别独立地任选被1、2、3或4个R取代。
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中，R b分别独立地选自F、Cl、Br、-NH 2、-CH 3、-CH 2-CH 3、
    Figure PCTCN2022082862-appb-100007
  7. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R c分别独立地选自F、Cl、Br、-OH、-OCH 3和
    Figure PCTCN2022082862-appb-100008
  8. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R d分别独立地选自F、Cl和Br。
  9. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 3选自H、F、Cl、Br和-NH 2。
  10. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 4选自H、F、Cl、Br、-CN、-CH 3、-CH 2CH 3、-CH(CH 3) 2和-CH 2CH(CH 3) 2，其中所述-CH 3、-CH 2CH 3、-CH(CH 3) 2和-CH 2CH(CH 3) 2分别独立地任选被1、2、3或4个R c取代。
  11. 根据权利要求10所述的化合物或其药学上可接受的盐，其中，R 4选自H、F、Cl、Br、-CN、
    Figure PCTCN2022082862-appb-100009
    Figure PCTCN2022082862-appb-100010
  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 4选自H、F、Cl、Br、-CN、
    Figure PCTCN2022082862-appb-100011
    Figure PCTCN2022082862-appb-100012
  13. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 5选自H、F、Cl、Br和-CH 3。
  14. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，R 1、R 2和与他们相连接的氮原子一起形成5-11元杂环烷基，其中所述5-11元杂环烷基任选被1、2、3或4个R b取代。
  15. 根据权利要求14所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082862-appb-100013
    选自
    Figure PCTCN2022082862-appb-100014
    Figure PCTCN2022082862-appb-100015
    其中所述
    Figure PCTCN2022082862-appb-100016
    Figure PCTCN2022082862-appb-100017
    分别独立地任选被1、2、3或4个R b取代。
  16. 根据权利要求15所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082862-appb-100018
    选自
    Figure PCTCN2022082862-appb-100019
    Figure PCTCN2022082862-appb-100020
  17. 根据权利要求6或16所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082862-appb-100021
    选自
    Figure PCTCN2022082862-appb-100022
    Figure PCTCN2022082862-appb-100023
    Figure PCTCN2022082862-appb-100024
  18. 根据权利要求1或2所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082862-appb-100025
    选自
    Figure PCTCN2022082862-appb-100026
  19. 根据权利要求18所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022082862-appb-100027
    选自
    Figure PCTCN2022082862-appb-100028
  20. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物具有式(Ⅱ-2)或(Ⅱ-3)所示结构：
    Figure PCTCN2022082862-appb-100029
    其中，R 1、R 2、R 3、R 4、R 5和R 6如权利要求1所定义。
  21. 根据权利要求20所述的化合物或其药学上可接受的盐，其中所述化合物具有式(I-2)所示结构：
    Figure PCTCN2022082862-appb-100030
    其中，R 1、R 2、R 3、R 4和R 5如权利要求20所定义。
  22. 根据权利要求21所述的化合物或其药学上可接受的盐，其中所述化合物具有式(I-3)所示结构：
    Figure PCTCN2022082862-appb-100031
    其中，R 1、R 2、R 3、R 4和R 5如权利要求21所定义；
    带“*”的碳原子为手性碳原子，以(R))或(S)单一对映体形式或富含一种对映体形式存在。
  23. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述化合物具有式(I-4)、(I-5)、(I-6)或(Ⅲ-1)所示结构：
    Figure PCTCN2022082862-appb-100032
    其中，
    T和V分别独立地选自CH 2、NH和O；
    m选自0、1、2、3和4；
    n、p、q、r和s分别独立地选自0、1和2；
    且p+q≤3；
    W选自NH、-CH 2-CH 2-和-O-CH 2-；
    Y选自N和CH；
    R 7和R 8分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、＝O和C 1-3烷基；
    或者，R 7、R 8和与它们相连接的碳原子一起形成C 3-4元环烷基；
    R 3、R 4、R 5和R b如权利要求1所定义。
  24. 根据权利要求23所述的化合物或其药学上可接受的盐，其中，R 7和R 8与分别独立地选自H和-CH 3。
  25. 根据权利要求23所述的化合物或其药学上可接受的盐，其中，R 7、R 8和与它们相连接的碳原子一起形成环丙基。
  26. 根据权利要求23所述的化合物或其药学上可接受的盐，其中所述化合物具有式(I-7)、(I-8)、(I-9)或(Ⅲ-1A)所示结构：
    Figure PCTCN2022082862-appb-100033
    其中，T、V、W、Y、m、n、p、q、r、s、R 3、R 4、R 5、R b、R 7和R 8如权利要求23所定义；
    带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。
  27. 根据权利要求26所述的化合物或其药学上可接受的盐，其中所述化合物具有式(I-10)、(I-11)、(I-12)或(Ⅲ-2)所示结构：
    Figure PCTCN2022082862-appb-100034
    其中，T、V、W、Y、m、n、p、q、r、s、R 3、R 4、R 5和R b、R 7和R 8如权利要求26所定义。
  28. 下式化合物或其药学上可接受的盐，
    Figure PCTCN2022082862-appb-100035
    Figure PCTCN2022082862-appb-100036
  29. 根据权利要求28所述的化合物或其药学上可接受的盐，其中所述化合物为：
    Figure PCTCN2022082862-appb-100037
    Figure PCTCN2022082862-appb-100038
    Figure PCTCN2022082862-appb-100039
    Figure PCTCN2022082862-appb-100040
  30. 根据权利要求1～29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。
  31. 根据权利要求1～29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。
PCT/CN2022/082862 2021-03-26 2022-03-24 6-氨基甲酸酯取代的杂芳环衍生物 WO2022199670A1 (zh)

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