WO2022228365A1 - Derivative of six-membered heteroaromatic urea ring and application thereof - Google Patents

Derivative of six-membered heteroaromatic urea ring and application thereof Download PDF

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Publication number
WO2022228365A1
WO2022228365A1 PCT/CN2022/088918 CN2022088918W WO2022228365A1 WO 2022228365 A1 WO2022228365 A1 WO 2022228365A1 CN 2022088918 W CN2022088918 W CN 2022088918W WO 2022228365 A1 WO2022228365 A1 WO 2022228365A1
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compound
pharmaceutically acceptable
acceptable salt
added
mmol
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PCT/CN2022/088918
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French (fr)
Chinese (zh)
Inventor
颜小兵
来巍
孙翔
丁照中
胡利红
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 CN202280031344.1A priority Critical patent/CN117279923A/en
Priority to JP2023566656A priority patent/JP2024515985A/en
Publication of WO2022228365A1 publication Critical patent/WO2022228365A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the invention discloses a class of derivatives of a six-membered heteroaromatic urea ring and applications thereof, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
  • Soluble guanylate cyclase is widely present in mammalian cytosol and is a heterodimer composed of ⁇ and ⁇ subunits, and ⁇ and ⁇ subunits have two subunits respectively. ⁇ 1, ⁇ 2 and ⁇ 1, ⁇ 2.
  • ⁇ 1 ⁇ 1 dimer is mainly distributed in cardiovascular tissues, and its expression level is positively correlated with the degree of tissue vascularization, while ⁇ 2 ⁇ 1 dimer is mainly expressed in the brain and nervous system. Although the two have large differences in tissue distribution and cellular localization, they have similar roles in maintaining sGC enzyme function.
  • Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. After sGC is activated in vivo, it catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP).
  • GTP guanosine triphosphate
  • cGMP cyclic guanosine monophosphate
  • cGMP is an important secondary messenger molecule that activates its downstream effector molecules, such as phosphodiesterase (PDE), cyclic nucleotide-gated ion channel (CNG) and protein kinase G (PKG), etc.
  • a series of downstream cascade reactions are triggered, and play important physiological functions in the gastrointestinal system, blood circulation system and nervous system, such as promoting vascular and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, apoptosis and inflammation, and participating in neurotransmission, etc.
  • the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina, heart failure, myocardial infarction, thrombosis, stroke and sexual intercourse dysfunction, etc.
  • abnormal sGC-mediated signaling pathways are also closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.
  • the present invention provides a new class of compounds, which can be used as soluble guanylate cyclase stimulators, and can be used as a stimulator for bird Glycyl cyclase has good in vitro stimulating activity and excellent pharmacokinetic properties.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is H, F or Cl
  • R 2 is C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl or -CH 2 -pyrimidinyl, wherein said C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl or -CH2 -pyrimidinyl, respectively, independently optionally substituted with 1, 2, 3, 4 or 5 R a ;
  • R3 and R4 are each independently H, F, Cl, Br, I, -OH, -CN or -NH2 ;
  • R 5 is -LR b ;
  • R b is C 1-6 alkyl, wherein the C 1-6 alkyl, each independently optionally substituted with 1, 2 or 3 R R c is H, -CH 3 or -CH 2 CH 3 ;
  • Each R is independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , C 1-3 alkoxy, or optionally 1, 2 or 3 independently selected from F, Cl , Br, I, -OH, -CN, -NH 2 and -OCH 3 substituents substituted C 1-3 alkyl;
  • R3 and R5 are joined together with their attached carbon atoms, making the structural unit selected from
  • R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 or are optionally 1, 2 or 3 independently selected from F, Cl, C 1-3 alkyl substituted with substituents of Br, I, -OH, -CN, -NH 2 and -OCH 3 .
  • the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-1) to (I-4):
  • R 1 , R 2 , R 4 and R b are as defined in the present invention.
  • each of the above R is independently F, Cl , Br, I, -OH , -CN, -NH2 , -NO2 , -CH3 , -CH2CH3, -OCH3 , -OCH2CH3 , -CF3 , -CH2CF3 , -CH2CH2CF3 , -CH2OH or -CH2CH2OH , other variables are as defined in the present invention.
  • R b is C 1-4 alkyl, wherein the C 1-4 alkyl, Each independently is optionally substituted with 1, 2 or 3 R, R and other variables as defined herein.
  • R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH (CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 , R and other variables are as defined in the present invention.
  • R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH (CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 ,
  • Other variables are as defined in the present invention.
  • the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-5) to (I-13):
  • R 4 is H or -NH 2 ; R 2 and R are as defined in the present invention.
  • the above-mentioned compounds or pharmaceutically acceptable salts thereof have structures represented by formulas (I-14) to (I-15):
  • R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are as defined in the present invention.
  • the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-16) to (I-19):
  • R 2 , R 6 , R 7 and R 8 are as defined in the present invention.
  • R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -CH 3 , -CH 2 CH3 , -CF3 , -CH2CF3 or -CH2CH2OH , other variables are as defined in the present invention.
  • the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-20) to (I-25):
  • R 2 is defined in the present invention.
  • each of the above R a is independently H, F, Cl, or -NH 2 , and other variables are as defined herein.
  • R 2 is C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -pyrimidinyl or -CH 2 -pyrazinyl, wherein The C1-6 alkyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl groups are optionally substituted with 1, 2, 3, 4 or 5 R a , R a and other variables as defined herein.
  • R 2 is Ra and other variables are as defined in the present invention.
  • each of the above R3 and R4 is independently H or -NH2 , and other variables are as defined herein.
  • the above compound has the structure represented by formula (I-15-a), (I-15-b), (I-15-c) or (I-15-d):
  • R 1 , R 4 , R 7 , R 8 and Ra are as defined in the present invention.
  • the above compound or a pharmaceutically acceptable salt thereof is selected from:
  • the present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicines for treating diabetic nephropathy or hypertensive nephropathy.
  • the present invention also provides a method for treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, the method comprising providing the subject with an effective dose of the compound as defined in any of the above technical solutions or a pharmaceutically acceptable method thereof of salt.
  • the present invention relates to a new class of soluble guanylate cyclase stimulators, and the compounds involved have significant in vitro stimulatory activity to guanylate cyclase, and have excellent pharmacokinetic properties, as well as to five All CYP isozymes were weakly inhibited.
  • 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.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • 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.
  • 3-12 membered ring means cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl consisting of 3 to 12 ring atoms.
  • Said ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a paracyclic ring and a bridged ring.
  • the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N.
  • the 3-12-membered ring includes 3-10 yuan, 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 4-10 yuan, 4-9 yuan, 4- 8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6- 9 yuan, 6-8 yuan and 6-7 yuan ring, etc.
  • the term "5-7 membered heterocycloalkyl” includes piperidinyl and the like, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.
  • 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
  • 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 C1-4 alkyl groups 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) etc.
  • 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.
  • C1-3alkoxy 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.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity 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 diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • DMF stands for N,N-dimethylformamide
  • K 2 CO 3 stands for potassium carbonate
  • MeI stands for methyl iodide
  • EtOAc stands for ethyl acetate
  • EA stands for ethyl acetate
  • THF stands for tetrahydrofuran
  • NaHMDS sodium hexamethyldisilazide
  • MeOH for methanol
  • DCM dichloromethane
  • DMSO for dimethyl sulfoxide
  • PE for petroleum ether
  • EtOH for ethanol
  • ACN for acetonitrile
  • TFA for trifluoroacetic acid
  • FA for Formic acid
  • NH 3 ⁇ H 2 O stands for ammonia
  • TEA stands for triethylamine
  • DIPEA stands for N,N-diisopropylethylamine
  • Boc 2 O stands for di-tert-butyl dicarbonate
  • Boc stands for tert-butoxycarbonyl,
  • Step A To a solution of 1-1 (2g, 12.61mmol, 1eq) in toluene (20mL) was added 2-fluorobenzylamine (1.89g, 15.14mmol, 1.72mL, 1.2eq) and cesium carbonate (6.17g, 18.92mmol) , 1.5eq). The nitrogen was replaced, and the mixture was stirred at 80°C for 12 hours under nitrogen protection.
  • reduced iron powder 3.44 g, 61.56 mmol, 8 eq
  • NH 4 Cl 4.94 g, 92.35mmol,
  • Step D To a solution of 1-2 (5.0 g, 28.89 mmol, 1 eq) in phosphorus oxychloride (49.50 g, 322.83 mmol, 30.00 mL, 11.18 eq) at 30 °C was slowly added dropwise 2,6-di Methyl pyridine (13.80 g, 128.79 mmol, 15.00 mL, 4.46 eq) was added dropwise and replaced with nitrogen three times, and the reaction solution was stirred at 80° C. for 12 hours.
  • phosphorus oxychloride 49.50 g, 322.83 mmol, 30.00 mL, 11.18 eq
  • Step E At -20°C, to a solution of compound 1-f (3.3g, 14.45mmol, 1eq) in ethanol (20mL) was added NH3 ethanol solution (20mL), the reaction solution was stirred at -20°C for 50 minutes, The reaction solution was filtered, the filter cake was collected, and then washed with water (10 mL) and ethanol (10 mL) to obtain compound 1-g.
  • Step F To a solution of 1-c (200 mg, 800.87 ⁇ mol, 1 eq) in DMF (1.00 mL) was added 1-g (403.76 mg, 800.87 ⁇ mol, 1.0 eq), cesium carbonate (521.88 mg, 1.60 mmol, 2 eq), Cuprous iodide (15.25 mg, 80.09 ⁇ mol, 0.10 eq) and 1,10-phenanthroline (28.86 mg, 160.17 ⁇ mol, 0.2 eq).
  • Step H To a solution of 1-e (120 mg, 293.82 ⁇ mol, 1 eq) in pyridine (1.5 mL) at 0 °C was added methyl chloroformate (41.65 mg, 440.72 ⁇ mol, 34.14 ⁇ L, 1.5 eq) at 0 °C Stir for half an hour, add water (10 mL) to the reaction solution, extract with EtOAc (50 mL), wash the organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter and concentrate, add EtOAc (10 mL) to the residue and stir , and compound 1 was obtained after filtration and drying.
  • methyl chloroformate 41.65 mg, 440.72 ⁇ mol, 34.14 ⁇ L, 1.5 eq
  • Step A To a solution of compound 3-1 (2g, 11.33mmol, 1eq) in toluene (20.00mL) under nitrogen protection was added cesium carbonate (5.54g, 16.99mmol, 1.5eq) and 2-fluorobenzylamine (1.70 g, 13.60 mmol, 1.55 mL, 1.2 eq). The mixture was warmed to 80°C and stirred for 12 hours.
  • Step D To a solution of 3-c (113 mg, 432.57 ⁇ mol, 1 eq) in DMF (4.00 mL) was added 1-g (261.70 mg, 519.09 ⁇ mol, 1.0 eq), cesium carbonate (281.88 mg, 865.15 ⁇ mol, 2 eq), Cuprous iodide (8.24 mg, 43.26 ⁇ mol, 0.10 eq) and 1,10-phenanthroline (15.59 mg, 86.51 ⁇ mol, 0.2 eq). The nitrogen was replaced, and the mixture was stirred at 100°C for 3 hours.
  • Step F To a solution of 3-e (42 mg, 91.06 ⁇ mol, 1 eq) in pyridine (1.5 mL) at 0 °C was added methyl chloroformate (12.91 mg, 136.60 ⁇ mol, 10.58 ⁇ L, 1.5 eq) at 0 °C After stirring for 1 hour, the reaction solution was poured into ice water (20 mL), saturated brine (10 mL) was added, extracted with EtOAc (20 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 3.
  • Step A To a solution of 3-1 (2g, 11.33mmol, 1eq) in toluene (20.00mL) under nitrogen protection was added cesium carbonate (5.54g, 16.99mmol, 1.5eq) and 2-trifluoromethylbenzylamine (2.38 g, 13.60 mmol, 1.55 mL, 1.2 eq). The mixture was warmed to 80°C and stirred for 12 hours.
  • Step D To a solution of 4-c (140 mg, 449.82 ⁇ mol, 1 eq) in DMF (1.00 mL) was added 1-g (226.78 mg, 449.82 ⁇ mol, 1.0 eq), cesium carbonate (293.12 mg, 899.64 ⁇ mol, 2 eq), Cuprous iodide (8.57 mg, 44.98 ⁇ mol, 0.10 eq) and 1,10-phenanthroline (16.21 mg, 89.96 ⁇ mol, 0.2 eq). The nitrogen was replaced, and the mixture was stirred at 100 °C for 3 hours. The reaction solution was cooled and filtered. The filter cake was washed with MeOH (10 mL) and EtOAc (10 mL). The filtrate was then added with saturated brine (20 mL), and extracted with EtOAc (30 mL). The organic phase was Washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4-d.
  • Step F To a solution of 4-e (39.55 mg, 91.06 ⁇ mol, 1 eq) in pyridine (1.0 mL) at 0 °C was added methyl chloroformate (12.91 mg, 136.60 ⁇ mol, 10.58 ⁇ L, 1.5 eq), 0 °C After stirring for 1 hour, the reaction solution was poured into ice water (10 mL), saturated brine (10 mL) was added, extracted with EtOAc (5 mL ⁇ 3), the organic phase was washed with saturated brine (10 mL), and anhydrous sodium sulfate It was dried, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 4.
  • Step A To a solution of 1-f (1.3g, 5.69mmol, 1eq) in DCM (100.00mL) at -20°C was slowly added a solution of p-methoxybenzylamine (1.56g, 11.38mmol, 1.47mL, 2eq) DCM (100.00 mL) solution, the mixture was stirred at -20°C for 1 hour, water (50.00 mL) was added to wash, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was stirred with EtOAc (15 mL), and filtered to dryness The compound 5-b is then obtained.
  • Step B To a solution of CoCl 2 ⁇ 6H 2 O (1.71 g, 7.19 mmol, 0.1 eq) in THF (200.00 mL) and water (100.00 mL) was added 5-2 (10 g, 71.89 mmol, 8.00 mL, 1 eq), Then NaBH 4 (13.60 g, 359.45 mmol, 5 eq) was added in portions, the reaction solution was stirred at 30° C.
  • Step G To a solution of 5-g (900 mg, 1.34 mmol, 1 eq) in DCM (50.00 mL) and water (5.00 mL) was added DDQ (1.52 g, 6.69 mmol, 5 eq), stirred at 30 °C for 12 hours, and added to Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, extracted with DCM (50 mL ⁇ 2), the combined organic phases were washed with water (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was washed with EtOAc (10 mL ⁇ 2). ) was stirred, filtered and dried to obtain compound 5-h.
  • Step H To a mixture of 5-h (50 mg, 85.59 ⁇ mol, 1 eq) in MeOH (3 mL) and water (1 mL) was added reduced iron powder (95.59 mg, 1.71 mmol, 20 eq) and NH 4 Cl (91.56 mg, 1.71 mmol, 20eq), stirred at 70°C for 1 hour, cooled and filtered the reaction solution, added water (20mL) to the filtrate, extracted with DCM (25mL ⁇ 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated Compound 5-i is obtained.
  • Step I To a solution of 5-i (20 mg, 49.71 ⁇ mol, 1 eq) in pyridine (1.0 mL) at 0 °C was added methyl chloroformate (7.05 mg, 74.57 ⁇ mol, 5.78 ⁇ L, 1.5 eq), at 0 °C Stirred for 30 minutes, water (10 mL) was added to the reaction solution, extracted with EtOAc (10 mL ⁇ 2), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [Mobile phase: water (0.225% FA)-ACN] Compound 5 was obtained.
  • Step A To a solution of 3-1 (2g, 11.33mmol, 1eq) in toluene (20.00mL) under nitrogen protection was added DIPEA (2.20g, 16.99mmol, 2.96mL, 1.5eq) and 2-chlorobenzylamine ( 1.60 g, 11.33 mmol, 1.37 mL, 1 eq). The mixture was warmed to 80°C and stirred for 17 hours.
  • Step B To a mixture of 7-a (3.13 g, 8.01 mmol, 1 eq) in THF (45 mL) and water (15 mL) was added reduced iron powder (2.24 g, 40.03 mmol, 5 eq) and NH 4 Cl (1.71 g, 32.02 mmol, 1.12 mL, 4 eq).
  • Step D To a solution of 7-c (0.3g, 1.08mmol, 1eq) in DMF (5.00mL) was added 1-g (245.76mg, 1.30mmol, 1.2eq), cesium carbonate (704.01mg, 2.16mmol, 2.0eq) ), cuprous iodide (20.58 mg, 108.04 ⁇ mol, 0.1 eq) and 1,10-phenanthroline (38.94 mg, 216.08 ⁇ mol, 0.2 eq).
  • reduced iron powder 715.60 mg, 12.81 mmol, 20 eq
  • NH 4 Cl 685.44 mg, 12.81mmol, 448.00 ⁇ L, 20eq
  • Step F To a solution of 7-e (20 mg, 49.90 ⁇ mol, 1 eq) in pyridine (1.0 mL) at 0 °C was added methyl chloroformate (4.72 mg, 49.95 ⁇ mol, 3.87 ⁇ L, 1.00 eq) at 0 °C After stirring for 30 minutes, the reaction solution was poured into water (1 mL), extracted with EtOAc (2 mL ⁇ 3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA) )-ACN] to obtain compound 7.
  • Step A To a solution of 3-e (40 mg, 104.06 ⁇ mol, 1 eq) in DMF (1 mL) was added trifluoroethyl trifluoromethanesulfonate (48.31 mg, 208.15 ⁇ mol, 2.0 eq) followed by DIPEA (40.35 mg, 312.22 ⁇ mol, 54.38 ⁇ L, 3.0 eq). The mixture was stirred at 80°C for 12 hours.
  • Step B To a solution of 8-a (15 mg, 32.16 ⁇ mol, 1 eq) in DMF (1 mL) was added CDI (10.43 mg, 64.33 ⁇ mol, 2.0 eq) and the mixture was stirred at 90°C for 6 hours. Saturated brine (10 mL) was added to the reaction solution, extracted with EA (8 mL ⁇ 2), the organic phase was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain a residue. The residue was purified by preparative HPLC [mobile phase: water (10 mM NH4HCO3 ) -ACN] to give compound 8.
  • Step A Ammonia (3.64g, 103.86mmol, 4.00mL, 4.03eq) and diisopropylethylamine (5.00g, 38.66mmol, 6.73mL, 1.5eq) were dissolved in dichloromethane (80mL) to obtain solution 1, 9-1 (5g, 25.78mmol, 1eq) was dissolved in dichloromethane (15mL) solution to obtain solution 2, at 0°C, solution 1 was slowly added dropwise to solution 2, and stirred at 0°C for 1 hours, the reaction solution was filtered to obtain compound 9-a.
  • 1 H NMR 400 MHz, DMSO-d 6 ): ⁇ ppm 8.57 (br s, 1H) 9.01 (s, 1H) 9.19 (br s, 1H).
  • Step B 9-a (0.2g, 1.15mmol, 1.2eq), compound 3-c (249.44mg, 954.86 ⁇ mol, 1eq) and anhydrous potassium carbonate (263.94mg, 1.91mmol, 2eq) were dissolved in DMF (5mL) ), replaced with nitrogen three times, and stirred at 25°C for 2 hours. The reaction was added dropwise to 40 mL of water, stirred for 15 minutes, and then filtered to obtain compound 9-b.
  • Step C Compound 9-b (400 mg, 879.52 ⁇ mol, 1 eq) was dissolved in MeOH (9 mL) and H 2 O (3 mL), to this solution was added Fe (982.33 mg, 17.59 mmol, 20 eq) and NH 4 Cl (940.93 mg, 17.59 mmol, 614.99 ⁇ L, 20 eq), stirred at 75° C. for 1 hour.
  • Step D Compound 9-c (45 mg, 121.84 ⁇ mol, 1 eq) was dissolved in pyridine (2 mL), methyl chloroformate (17.27 mg, 182.76 ⁇ mol, 14.16 ⁇ L, 1.5 eq) was added dropwise at 0° C. Stir at this temperature for 30 minutes, drop the reaction into 2 mL of water, extract with EA (3 mL ⁇ 3), dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 9.
  • Step A To a solution of compound 3-e (203 mg, 512.33 ⁇ mol, 1 eq) in pyridine (2.0 mL) was added compound 10-1 (219.74 mg, 1.54 mmol, 158.09 ⁇ L, 3 eq) in one portion at 0°C under nitrogen protection ), the mixture was stirred and reacted at 0° C. for 1 hour, the resulting reaction solution was added dropwise to water (20 mL), and then extracted with ethyl acetate (10 mL ⁇ 3).
  • Step B To a solution of compound 10-a (65 mg, 132.42 ⁇ mol, 1 eq) in THF (4.0 mL) was added NaHMDS (1 M, 264.85 ⁇ L, 2 eq) in one portion at 0 °C under nitrogen protection, the mixture was at 0 °C React for 1 hour.
  • Step A Tribromopyridinium (12.50 g, 7.81 mmol, 4 eq) was added to a solution of compound 15-1 (1.50 g, 9.77 mmol, 1 eq) in tert-butanol (54 mL), and stirred at 25° C. for 6 hours.
  • the reaction solution was filtered, the filter cake was washed with EA (20 mL), and water (30 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL).
  • Step B Compound 15-a (1.5g, 4.58mmol, 1eq) and ammonium chloride (1.23g, 22.91mmol, 5eq) were dissolved in tetrahydrofuran (16mL) and water (8mL), and then added to the above mixture Zinc powder (1.50 g, 22.91 mmol, 5 eq), the reaction system was stirred at 25°C for 1 hour.
  • Step C Compound 15-b (150 mg, 0.885 mmol, 1 eq) was dissolved in dry DMF (15 mL), NaH (35.38 mg, 0.885 mmol, 60% purity, 1 eq) was added to the reaction at 0°C under replacement nitrogen The solution was stirred at 25°C for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (147.5 mg, 0.885 mmol, 156.6 ⁇ L, 1 eq) was then added dropwise and stirred at 25° C. for 1 hour.
  • Step D To a solution of compound 15-c (70 mg, 213.49 ⁇ mol, 1 eq) and compound 3-c (66.92 mg, 256.19 ⁇ mol, 1.2 eq) in DMF (5.0 mL) was added cesium carbonate (139.12 mg, 426.98 ⁇ mol, 2.0 eq), replacing nitrogen. Under nitrogen atmosphere, the reaction system was stirred at 100°C for 15 hours. H 2 O (20 mL) was added to the reaction system, followed by extraction with ethyl acetate (20 mL ⁇ 2).
  • Step E Trifluoroacetic acid (154 mg, 1.35 mmol, 18.66 eq) was added to a solution of compound 15-d (40 mg, 72.38 ⁇ mol, 1 eq) in anhydrous dichloromethane (5.0 mL), and stirred at 25° C. for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (0.04% NH 3 ⁇ H 2 O)-ACN] to obtain compound 15.
  • Step A To a solution of 17-1 (3 g, 25.84 mmol, 1 eq) in DMF (30 mL) at 0 °C was added NaH (2.07 g, 51.67 mmol, 60% pure, 2 eq) carefully and slowly, and stirred at 0 °C After 0.5 hours, methyl iodide (4.40g, 31.00mmol, 1.93mL, 1.2eq) was added to the solution, gradually returned to room temperature and stirred for 0.5 hours, stirred at 45°C for 3 hours, cooled to room temperature and then added with saturated ammonium chloride solution (60 mL) to quench the reaction, add water (10 mL) to dilute, extract with DCM (30 mL ⁇ 3), wash the combined organic phases with water (30 mL ⁇ 3), dry over anhydrous sodium sulfate, filter and concentrate below 10°C to obtain compound 17 -a.
  • Step B To a solution of 17-a (0.56 g, 4.30 mmol, 1 eq) in MeOH (5 mL) was slowly added a solution of KOH (483.19 mg, 8.61 mmol, 2 eq) in water (2.5 mL). After the addition was complete the mixture was stirred at 20°C for 15 hours.
  • reaction solution was concentrated below 40°C, the concentrated solution was washed with petroleum ether (15 mL), then the aqueous phase was poured into ice water (15 mL), the pH of the solution was adjusted to 5-6 with 3M aqueous hydrochloric acid, and DCM (12 mL) was used After extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 17-b.
  • Step C To a solution of 17-b (350 mg, 3.01 mmol, 1 eq) in DCM (2.00 mL) and DMF (22.03 mg, 301.43 ⁇ mol, 23.19 ⁇ L, 0.1 eq) at 0 °C was added oxalyl chloride (344.33 mg, 2.71 mmol, 237.47 ⁇ L, 0.9 eq), replaced with nitrogen, stirred at 0 °C for 0.5 h, 9-c (261.94 mg, 602.85 ⁇ mol, 0.2 eq) in DCM (3 mL) was added dropwise to the solution, and then added Pyridine (476.85 mg, 6.03 mmol, 486.59 ⁇ L, 2 eq) was added, the mixture was stirred at 20°C for 5 hours, the reaction solution was quenched with water (20 mL), extracted with EtOAc (15 mL ⁇ 3), and the organic phase was washed with saturated brine (15 mL).
  • 21-1 (203 mg, 2.03 mmol, 1 eq) was dissolved in DCM (1 mL), oxalyl chloride (231.63 mg, 1.82 mmol, 159.74 ⁇ L, 0.9 eq) and DMF (14.82 mg, 202.77 ⁇ mol, 15.60 were added) ⁇ L, 0.1 eq), stirred until no gas evolved, and the reaction was added dropwise to a solution of compound 9-c (176.20 mg, 405.53 ⁇ mol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL) over 25 Stir at °C for 2 hours.
  • Step A Malononitrile (14.93g, 225.98mmol, 14.22mL, 1eq) was dissolved in THF (100mL), then potassium tert-butoxide (27.89g, 248.58mmol, 1.1eq) was added, and the reaction solution was heated at 50°C After stirring for 0.5 hours, compound 26-1 (45 g, 248.58 mmol, 32.14 mL, 1.1 eq) was added. The reaction solution was stirred at 50 °C for 11.5 hours.
  • DMF 60 mL
  • Step C Compound 26-b (3.8 g, 16.94 mmol, 1 eq) was dissolved in DCM (50 mL), then m-chloroperoxybenzoic acid (6.88 g, 33.89 mmol, 85% purity, 2 eq) was added. The reaction solution was stirred at 20°C for 12 hours. After the reaction was completed, the filter cake was collected by filtration, stirred with dichloromethane (100 mL), filtered and dried to obtain compound 26-c. LCMS (ESI) m/z: 257.2 [M+1] + .
  • Step D To a solution of 3-c (5.74 g, 21.98 mmol, 1.1 eq) in DMF (30 mL) at 20 °C was added potassium carbonate (8.28 g, 59.93 mmol, 3 eq) and 26-c (5.12 g, 19.98 mmol, 1.0 eq), the reaction solution was heated to 120° C. and kept for 2 hours.
  • reaction solution was cooled to room temperature, filtered, and the filter cake was washed with methanol (20 mL) and DMF (20 mL), the filtrates were combined and concentrated under reduced pressure to remove methanol, and the residue was purified by preparative HPLC [mobile phase: water (0.1% FA) -ACN] to give compound 26.
  • Step B Add wet Pd/C (1.0 g, 10% purity) to a solution of 28-a (3.0 g, 22.20 mmol, 1 eq) in methanol (10 mL) under nitrogen protection, and replace the reaction solution with hydrogen 3 times Then, the mixture was stirred at 20° C. for 2 hours under a pressure of 15 psi. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain compound 28-b.
  • Step D To 28-c (2.4 g, 9.63 mmol, 1 eq) in methanol (10 mL) was added Pd/C (1.0 g, 9.63 mmol, 10% purity) under nitrogen. After the reaction solution was replaced with hydrogen three times, the mixture was stirred at 30° C. for 2 hours under a pressure of 15 psi. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain compound 28-d.
  • Pd/C 1.0 g, 9.63 mmol, 10% purity
  • Step F To a solution of 28-e (200 mg, 815.62 ⁇ mol, 1 eq) in DMF (3 mL) was added 26-c (519 mg, 1.63 mmol, 2 eq) and potassium carbonate (338 mg, 2.45 mmol, 3 eq). The nitrogen was replaced, and the mixture was stirred at 120°C for 12 hours. The reaction solution was filtered, the filter cake was washed with 2 mL of DMF, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 28.
  • Step A Under nitrogen protection, to a solution of 3-1 (720 mg, 4.08 mmol, 1 eq) in toluene (20.00 mL) was added diisopropylethylamine (2.11 g, 16.31 mmol, 2.84 mL, 4 eq) and 3- Fluoro-2-pyridylmethanamine hydrochloride (893 mg, 4.49 mmol, 1.1 eq). The mixture was warmed to 70°C and stirred for 12 hours.
  • Step B To 29-a (650mg, 2.44mmol, 1eq) in tetrahydrofuran (15mL) and water (5mL) were added reduced zinc powder (638mg, 9.77mmol, 4eq) and ammonium chloride (653mg, 12.21mmol, 5eq) .
  • reduced zinc powder (638mg, 9.77mmol, 4eq)
  • ammonium chloride (653mg, 12.21mmol, 5eq) .
  • Step D To a solution of 29-c (200 mg, 762.73 ⁇ mol, 1 eq) in DMF (3 mL) was added potassium carbonate (316 mg, 2.29 mmol, 3 eq) and 26-c (485 mg, 1.53 mmol, 2 eq), then heated at 120°C The reaction was continued for 12 hours. The reaction solution was filtered, the filter cake was washed with DMF (2 mL), and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to give compound 29.
  • Step B Combine 30-a (200 mg, 461.67 ⁇ mol, 1 eq), cyclopropylboronic acid (118.97 mg, 1.39 mmol, 3 eq), potassium carbonate (191.42 mg, 1.39 mmol, 3 eq) and bis(triphenylphosphine)bis Palladium chloride (162.02 mg, 230.84 ⁇ mol, 0.5 eq) was dissolved in 1,4-dioxane (5 mL), replaced with nitrogen three times, and stirred at 100° C. for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 mL ⁇ 2).
  • Step B Under the protection of nitrogen, wet palladium carbon (300 mg) was added to a solution of 31-a (1.62 g, 6.52 mmol, 1 eq) in methanol (30 mL), and after the addition was completed, the hydrogen was replaced by vacuum three times, and the reaction solution was heated in hydrogen. (15 psi) at 45°C for 12 hours. The reaction solution was filtered through celite, the filter cake was washed with methanol (10 mL ⁇ 3), and the filtrate was concentrated to obtain compound 31-b.
  • Step F To a solution of 31-c (260 mg, 995.30 ⁇ mol, 1 eq) in DMF (3 mL) under nitrogen protection was added 26-c (510 mg, 1.99 mmol, 2 eq) and potassium carbonate (413 mg, 2.99 mmol, 3 eq) . The reaction solution was stirred at 120°C for 12 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to give compound 31.
  • Step A To a solution of 3-1 (1.4g, 7.93mmol, 1eq) in toluene (40mL) was added 2,4-dimethoxybenzylamine (1.33g, 7.93mmol, 1.19mL, 1eq) under nitrogen protection and triethylamine (1.60 g, 15.86 mmol, 2.21 mL, 2 eq), and the reaction solution was stirred at 100° C. for 4 hours. The reaction solution was cooled, washed with water (40 mL), separated, the organic phase was concentrated under reduced pressure, methanol was added and stirred for 1 hour, filtered, and the filter cake was vacuum-dried to obtain compound 32-a.
  • Step C To a solution of 32-b (1.6 g, 5.77 mmol, 1 eq) in tetrahydrofuran (30 mL) was added CDI (1.87 g, 11.54 mmol, 2 eq) under nitrogen. The reaction solution was stirred at 60° C. for 16 hours and then quenched by adding water (2 mL). The reaction solution was concentrated under reduced pressure. The residue was added with methanol (20 mL), stirred for 2 hours, filtered, and the filter cake was vacuum-dried to obtain compound 32-c.
  • Step D To a solution of 32-c (1.1 g, 3.63 mmol, 1 eq) in DMF (10 mL) was added 26-c (1.73 g, 5.44 mmol, 1.5 eq) and potassium carbonate (1.50 g, 10.88 mmol) under nitrogen protection , 3eq), the reaction solution was stirred at 120° C. for 4 hours, water (40 mL) was added to the reaction solution to dilute, filtered, and the filter cake was dried under vacuum to obtain compound 32-d.
  • Step E To a solution of 32-d (1.6 g, 3.34 mmol, 1 eq) in DMF (4 mL) was added potassium carbonate (922.41 mg, 6.67 mmol, 2 eq) and p-methoxybenzyl chloride (731.66 mg, 4.67 mmol, 636.23 ⁇ L, 1.4eq), stirred at 50°C for 2 hours under nitrogen protection, the reaction solution was diluted with water (25 mL), filtered, and the filter cake was vacuum-dried to obtain compound 32-e.
  • Step G To a solution of 32-f (0.6g, 1.34mmol, 1eq) in DMF (5mL) was added 1,1,1,2,2-pentafluoro-4-iodobutane (1.46g, 5.34mmol, 4eq) ) and potassium carbonate (922.55 mg, 6.68 mmol, 5 eq). The reaction solution was reacted at 50°C for 1 hour under nitrogen protection.
  • Step H To a solution of 32-g (0.2 g, 335.85 ⁇ mol, 1 eq) in TFA (2 mL) was added trifluoromethanesulfonic acid (3.40 g, 22.66 mmol, 2 mL, 67.45 eq) under nitrogen. The reaction solution was stirred at 50°C for 16 hours. The reaction solution was poured into an aqueous solution of sodium hydroxide (80 mL, 1 mol/L) for neutralization, extracted with ethyl acetate (60 mL), the organic phase was concentrated under reduced pressure and purified by preparative HPLC [water (0.075% TFA)-acetonitrile] ] to give compound 32.
  • TFA trifluoromethanesulfonic acid
  • cGMP-D2 D2-labeled cyclic guanosine monophosphate
  • LNCap medium RPMI1640+10% fetal bovine serum+1% double antibody
  • cGMP standard curve According to the ratio of cGMP concentration to 665/615, use Graphpad prism to make the standard curve.
  • Drug preparation Weigh an appropriate amount of drug and dissolve it in a mixed solvent of 10% DMSO+50% PEG400+40% H 2 O to make 0.2 mg/mL; weigh an appropriate amount of drug and dissolve it in 10% EtOH+40% In the mixed solvent of PEG400+50% H 2 O, it was prepared at 0.3 mg/mL;
  • mice in Group 1 were given a single dose of drug at 1.0 mg/kg at a concentration of 0.2 mg/mL via tail vein, and animals in Group 2 were given compound at a dose of 3 mg/kg at a concentration of 0.3 mg/mL by gavage.
  • Plasma samples were collected from animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 8 and 24 hours post-dose.
  • the drug concentration in the plasma samples was determined by LC-MS/MS method, and the kinetic parameters of the tested drugs are shown in Table 2.
  • the compounds of the present invention have good pharmacokinetic properties in rats.
  • the purpose of the research project is to use a 5-in-1 probe substrate of CYP isoenzymes to evaluate the inhibition of test articles on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4).
  • HLM human liver microsomes
  • test substance working solution of a series of diluted concentrations was added to the incubation system containing human liver microsomes, probe substrates and cofactors of the circulating system, and the control containing no test substance and solvent was used as the enzyme activity control ( 100%).
  • concentrations of metabolites generated from the probe substrates in the samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS).
  • Use SigmaPlot (V.11) to perform non-linear regression analysis on the average percent activity of the test article versus concentration.
  • IC50 values were calculated by three-parameter or four-parameter inverse logarithmic equations. The test results are shown in Table 3:
  • the compounds of the present invention have weak inhibition on the five CYP isozymes.

Abstract

A derivative of a six-membered heteroaromatic urea ring represented by formula (I) and an application thereof in the preparation of a drug for treating diabetic nephropathy or hypertensive nephropathy.

Description

六元杂芳并脲环的衍生物及其应用Derivatives of six-membered heteroaromatic urea rings and their applications
本申请主张如下优先权：This application claims the following priority:
CN202110462009.4，2021年04月27日；CN202110462009.4, April 27, 2021;
CN202210307799.3，2022年03月25日。CN202210307799.3, March 25, 2022.
技术领域technical field
本发明公开了一类六元杂芳并脲环的衍生物及其应用，具体公开了式(I)所示化合物及其药学上可接受的盐。The invention discloses a class of derivatives of a six-membered heteroaromatic urea ring and applications thereof, and specifically discloses a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.
背景技术Background technique
可溶性鸟苷酸环化酶(sGC)广泛存在于哺乳动物的细胞溶质内，是由α和β两种亚基组成的异源二聚体，α和β亚基又分别有两种亚构体α1、α2和β1、β2。α1β1二聚体主要分布于心血管组织中，表达水平与组织血管化的程度呈正相关，而α2β1二聚体主要表达在大脑和神经系统中。虽然两者在组织分布和细胞定位上有较大的差异，但它们在维持sGC酶功能方面有着相似作用。Soluble guanylate cyclase (sGC) is widely present in mammalian cytosol and is a heterodimer composed of α and β subunits, and α and β subunits have two subunits respectively. α1, α2 and β1, β2. α1β1 dimer is mainly distributed in cardiovascular tissues, and its expression level is positively correlated with the degree of tissue vascularization, while α2β1 dimer is mainly expressed in the brain and nervous system. Although the two have large differences in tissue distribution and cellular localization, they have similar roles in maintaining sGC enzyme function.
可溶性鸟苷酸环化酶是NO-sGC-cGMP信号通路中关键的信号转导酶，sGC在体内被激活后会催化三磷酸鸟苷(GTP)转化为环磷酸鸟苷(cGMP)。cGMP是一种重要的二级信使分子，通过激活其下游的多种效应分子，如磷酸二酯酶(PDE)、环核苷酸门控离子通道(CNG)和蛋白激酶G(PKG)等，进而引发下游一系列级联反应，在胃肠系统、血液循环系统和神经系统中发挥重要的生理功能，如促进血管和平滑肌舒张，抑制血小板凝聚、血管重塑、细胞凋亡和炎症发生以及参与神经传递等。在病理生理学条件下，NO/cGMP系统可被抑制，这可导致例如高血压、血小板激活、增加的细胞增生、内皮机能障碍、动脉硬化、心绞痛、心力衰竭、心肌梗死、血栓形成、中风和性功能障碍等。近两年又有研究显示，sGC介导的信号通路异常还与慢性肾脏疾病、系统性硬化病等纤维化疾病的发生有着密切的关系。Soluble guanylate cyclase is a key signal transduction enzyme in the NO-sGC-cGMP signaling pathway. After sGC is activated in vivo, it catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). cGMP is an important secondary messenger molecule that activates its downstream effector molecules, such as phosphodiesterase (PDE), cyclic nucleotide-gated ion channel (CNG) and protein kinase G (PKG), etc. In turn, a series of downstream cascade reactions are triggered, and play important physiological functions in the gastrointestinal system, blood circulation system and nervous system, such as promoting vascular and smooth muscle relaxation, inhibiting platelet aggregation, vascular remodeling, apoptosis and inflammation, and participating in neurotransmission, etc. Under pathophysiological conditions, the NO/cGMP system can be inhibited, which can lead to, for example, hypertension, platelet activation, increased cell proliferation, endothelial dysfunction, arteriosclerosis, angina, heart failure, myocardial infarction, thrombosis, stroke and sexual intercourse dysfunction, etc. In the past two years, other studies have shown that abnormal sGC-mediated signaling pathways are also closely related to the occurrence of fibrotic diseases such as chronic kidney disease and systemic sclerosis.
传统的对于可溶性鸟苷酸环化酶进行刺激性治疗，仅使用其效果以NO为基础的化合物如有机硝酸盐类。这是通过生物转化形成的并且通过进攻血红素的中心铁原子激活可溶性鸟苷酸环化酶。除了副作用，耐受性的发展也是此类治疗方法决定性的缺点之一。Traditional stimulatory treatments for soluble guanylate cyclase use only compounds whose effects are based on NO, such as organic nitrates. This is formed by biotransformation and activates soluble guanylate cyclase by attacking the central iron atom of heme. In addition to side effects, the development of tolerance is one of the decisive drawbacks of this type of treatment.
2013年10月FDA批准了一种新的鸟苷酸环化酶刺激剂，名叫利奥西呱(Riociguat)(WO2003095451A1)，是一种吡唑并吡啶类化合物，用于治疗肺动脉高血压，但其在人体内半衰期较短，清除率较高，一天需要服用3次。In October 2013, the FDA approved a new guanylate cyclase stimulator, named Riociguat (WO2003095451A1), which is a pyrazolopyridine compound for the treatment of pulmonary arterial hypertension. It has a short half-life in the human body and a high clearance rate, and needs to be taken 3 times a day.
Figure PCTCN2022088918-appb-000001
Figure PCTCN2022088918-appb-000001
针对目前市场和临床未满足的对此类可溶性鸟苷酸环化酶刺激剂的需求，本发明提供了一类新化合物，此类化合物可作为可溶性鸟苷酸环化酶的刺激剂，对鸟苷酸环化酶具有很好的体外刺激活性，并具有优良的药代动力学性质。In view of the current unmet market and clinical needs for such soluble guanylate cyclase stimulators, the present invention provides a new class of compounds, which can be used as soluble guanylate cyclase stimulators, and can be used as a stimulator for bird Glycyl cyclase has good in vitro stimulating activity and excellent pharmacokinetic properties.
发明内容SUMMARY OF THE INVENTION
一方面，本发明提供了式(I)所示化合物或其药学上可接受的盐，On the one hand, the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022088918-appb-000002
Figure PCTCN2022088918-appb-000002
其中，R 1为H、F或Cl； Wherein, R 1 is H, F or Cl;
R 2为C 1-6烷基、-CH 2-苯基、-CH 2-吡啶基或-CH 2-嘧啶基，其中所述C 1-6烷基、-CH 2-苯基、-CH 2-吡啶基或-CH 2-嘧啶基分别独立地任选被1、2、3、4或5个R a所取代； R 2 is C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl or -CH 2 -pyrimidinyl, wherein said C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl or -CH2 -pyrimidinyl, respectively, independently optionally substituted with 1, 2, 3, 4 or 5 R a ;
各R a独立地为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-C(＝O)OH、C 1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-3烷基； Each Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C(=O)OH, C1-3alkoxy or optionally , 2 or 3 C 1-3 alkyl substituted with substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 ;
R 3和R 4各自独立地为H、F、Cl、Br、I、-OH、-CN或-NH 2； R3 and R4 are each independently H, F, Cl, Br, I, -OH, -CN or -NH2 ;
R 5为-L-R b； R 5 is -LR b ;
L为单键、-NR cC(＝O)O-或-NR cC(＝O)-； L is a single bond, -NR c C(=O)O- or -NR c C(=O)-;
R b为C 1-6烷基、
Figure PCTCN2022088918-appb-000003
其中所述C 1-6烷基、
Figure PCTCN2022088918-appb-000004
Figure PCTCN2022088918-appb-000005
分别独立地任选被1、2或3个R所取代R c为H、-CH 3或-CH 2CH 3； R b is C 1-6 alkyl,
Figure PCTCN2022088918-appb-000003
wherein the C 1-6 alkyl,
Figure PCTCN2022088918-appb-000004
Figure PCTCN2022088918-appb-000005
each independently optionally substituted with 1, 2 or 3 R R c is H, -CH 3 or -CH 2 CH 3 ;
各R独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、C 1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-3烷基； Each R is independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , C 1-3 alkoxy, or optionally 1, 2 or 3 independently selected from F, Cl , Br, I, -OH, -CN, -NH 2 and -OCH 3 substituents substituted C 1-3 alkyl;
或R 3和R 5与它们相连碳原子连接在一起，使结构单元
Figure PCTCN2022088918-appb-000006
选自
Figure PCTCN2022088918-appb-000007
or R3 and R5 are joined together with their attached carbon atoms, making the structural unit
Figure PCTCN2022088918-appb-000006
selected from
Figure PCTCN2022088918-appb-000007
R 6、R 7和R 8各自独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-3烷基。 R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 or are optionally 1, 2 or 3 independently selected from F, Cl, C 1-3 alkyl substituted with substituents of Br, I, -OH, -CN, -NH 2 and -OCH 3 .
在本发明的一些方案中，上述L为单键、-NH-C(＝O)O-、-NH-C(＝O)-、-N(CH 3)-C(＝O)O-或-N(CH 3)-C(＝O)-，其他变量如本发明所定义。 In some aspects of the present invention, the above L is a single bond, -NH-C(=O)O-, -NH-C(=O)-, -N(CH 3 )-C(=O)O- or -N( CH3 )-C(=O)-, other variables are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物具有式(I-1)～(I-4)所示结构：In some embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-1) to (I-4):
Figure PCTCN2022088918-appb-000008
Figure PCTCN2022088918-appb-000008
其中，R 1、R 2、R 4和R b如本发明所定义。 wherein R 1 , R 2 , R 4 and R b are as defined in the present invention.
在本发明的一些方案中，上述各R独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-CH 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-CF 3、-CH 2CF 3、-CH 2CH 2CF 3、-CH 2OH或-CH 2CH 2OH，其他变量如本发明所定义。 In some aspects of the present invention, each of the above R is independently F, Cl , Br, I, -OH , -CN, -NH2 , -NO2 , -CH3 , -CH2CH3, -OCH3 , -OCH2CH3 , -CF3 , -CH2CF3 , -CH2CH2CF3 , -CH2OH or -CH2CH2OH , other variables are as defined in the present invention.
在本发明的一些方案中，上述R b为C 1-4烷基、
Figure PCTCN2022088918-appb-000009
其中所述C 1-4烷基、
Figure PCTCN2022088918-appb-000010
分别独立地任选被1、2或3个R所取代，R及其他变量如本发明所定义。 In some aspects of the present invention, above-mentioned R b is C 1-4 alkyl,
Figure PCTCN2022088918-appb-000009
wherein the C 1-4 alkyl,
Figure PCTCN2022088918-appb-000010
Each independently is optionally substituted with 1, 2 or 3 R, R and other variables as defined herein.
在本发明的一些方案中，上述R b为-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH 2CH 2CH 3、-CH(CH 3)CH 2CH 3、-CH 2CH(CH 3) 2、-C(CH 3) 3、
Figure PCTCN2022088918-appb-000011
Figure PCTCN2022088918-appb-000012
Figure PCTCN2022088918-appb-000013
R及其他变量如本发明所定义。 In some aspects of the present invention, the above R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH (CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 ,
Figure PCTCN2022088918-appb-000011
Figure PCTCN2022088918-appb-000012
Figure PCTCN2022088918-appb-000013
R and other variables are as defined in the present invention.
在本发明的一些方案中，上述R b为-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH 2CH 2CH 3、-CH(CH 3)CH 2CH 3、-CH 2CH(CH 3) 2、-C(CH 3) 3、
Figure PCTCN2022088918-appb-000014
Figure PCTCN2022088918-appb-000015
Figure PCTCN2022088918-appb-000016
其他变量如本发明所定义。 In some aspects of the present invention, the above R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH (CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 ,
Figure PCTCN2022088918-appb-000014
Figure PCTCN2022088918-appb-000015
Figure PCTCN2022088918-appb-000016
Other variables are as defined in the present invention.
在本发明的一些方案中，上述R 5为-NH-C(＝O)O-C 1-4烷基、-NHC(＝O)-C 1-4烷基、-N(CH 3)-C(＝O)O-C 1- 4烷基、-NH-C(＝O)-(C 3-6环烷基)、-N(CH 3)C(＝O)-(C 3-6环烷基)、-NH-C(＝O)-苯基、-N(CH 3)-C(＝O)-苯基或5-6元杂环烷基，其中所述NH-C(＝O)O-C 1-4烷基、-NHC(＝O)-C 1-4烷基、-N(CH 3)-C(＝O)O-C 1-4烷基、-NH-C(＝O)-(C 3-6环烷基)、-N(CH 3)C(＝O)-(C 3-6环烷基)、-NH-C(＝O)-苯基、-N(CH 3)-C(＝O)-苯基和5-6元杂环烷基分别独立地任选被1、2或3个R所取代，R及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 5 is -NH-C(=O)OC 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, -N(CH 3 )-C( =O) OC 1-4 alkyl, -NH-C(=O)-(C 3-6 cycloalkyl), -N(CH 3 )C(=O)-(C 3-6 cycloalkyl) , -NH-C(=O)-phenyl, -N(CH 3 )-C(=O)-phenyl or 5-6 membered heterocycloalkyl, wherein the NH-C(=O)OC 1 -4 alkyl, -NHC(=O)-C 1-4 alkyl, -N(CH 3 )-C(=O)OC 1-4 alkyl, -NH-C(=O)-(C 3 -6cycloalkyl ), -N( CH3 )C(=O)-( C3-6cycloalkyl ), -NH-C(=O)-phenyl, -N( CH3 )-C( =O)-phenyl and 5-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2 or 3 R, R and other variables as defined herein.
在本发明的一些方案中，上述R 5为-NH-C(＝O)O-CH 3、-NH-C(＝O)O-CH 2CH 3、-NH-C(＝O)O-CH 2CH 2CH 3、-NH-C(＝O)O-CH(CH 3) 2、-NH-C(＝O)-CH 3、-NH-C(＝O)-CH 2CH 3、-NH-C(＝O)-CH 2CH 2CH 3、-NH-C(＝O)-CH(CH 3) 2、-N(CH 3)-C(＝O)O-CH 3、-N(CH 3)-C(＝O)O-CH 2CH 3、-N(CH 3)-C(＝O)O-CH 2CH 2CH 3、-N(CH 3)-C(＝O)O-CH(CH 3) 2、
Figure PCTCN2022088918-appb-000017
Figure PCTCN2022088918-appb-000018
Figure PCTCN2022088918-appb-000019
R及其他变量如本发明所定义。 In some aspects of the present invention, the above R 5 is -NH-C(=O)O-CH 3 , -NH-C(=O)O-CH 2 CH 3 , -NH-C(=O)O- CH 2 CH 2 CH 3 , -NH-C(=O)O-CH(CH 3 ) 2 , -NH-C(=O)-CH 3 , -NH-C(=O)-CH 2 CH 3 , -NH-C(=O)-CH 2 CH 2 CH 3 , -NH-C(=O)-CH(CH 3 ) 2 , -N(CH 3 )-C(=O)O-CH 3 , - N(CH 3 )-C(=O)O-CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 2 CH 3 , -N(CH 3 )-C(=O )O-CH(CH 3 ) 2 ,
Figure PCTCN2022088918-appb-000017
Figure PCTCN2022088918-appb-000018
Figure PCTCN2022088918-appb-000019
R and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 5-NH-C(＝O)O-CH 3、-NH-C(＝O)O-CH 2CH 3、-NH-C(＝O)O-CH 2CH 2CH 3、-NH-C(＝O)O-CH(CH 3) 2、-NH-C(＝O)-CH 3、-NH-C(＝O)-CH 2CH 3、-NH-C(＝O)-CH 2CH 2CH 3、-NH-C(＝O)- CH(CH 3) 2、-N(CH 3)-C(＝O)O-CH 3、-N(CH 3)-C(＝O)O-CH 2CH 3、-N(CH 3)-C(＝O)O-CH 2CH 2CH 3、-N(CH 3)-C(＝O)O-CH(CH 3) 2、
Figure PCTCN2022088918-appb-000020
Figure PCTCN2022088918-appb-000021
Figure PCTCN2022088918-appb-000022
其他变量如本发明所定义。 In some aspects of the invention, the above R 5 -NH-C(=O)O-CH 3 , -NH-C(=O)O-CH 2 CH 3 , -NH-C(=O)O-CH 2 CH 2 CH 3 , -NH-C(=O)O-CH(CH 3 ) 2 , -NH-C(=O)-CH 3 , -NH-C(=O)-CH 2 CH 3 , - NH-C(=O)-CH 2 CH 2 CH 3 , -NH-C(=O)-CH(CH 3 ) 2 , -N(CH 3 )-C(=O)O-CH 3 , -N (CH 3 )-C(=O)O-CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 2 CH 3 , -N(CH 3 )-C(=O) O-CH(CH 3 ) 2 ,
Figure PCTCN2022088918-appb-000020
Figure PCTCN2022088918-appb-000021
Figure PCTCN2022088918-appb-000022
Other variables are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物具有式(I-5)～(I-13)所示结构：In some embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-5) to (I-13):
Figure PCTCN2022088918-appb-000023
Figure PCTCN2022088918-appb-000023
Figure PCTCN2022088918-appb-000024
Figure PCTCN2022088918-appb-000024
其中，p为0、1或2；R 4为H或-NH 2；R 2和R如本发明所定义。 wherein, p is 0, 1 or 2; R 4 is H or -NH 2 ; R 2 and R are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其合物具有式(I-14)～(I-15)所示结构：In some embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof have structures represented by formulas (I-14) to (I-15):
Figure PCTCN2022088918-appb-000025
Figure PCTCN2022088918-appb-000025
其中，R 1、R 2、R 4、R 6、R 7和R 8如本发明所定义。 Wherein, R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物具有式(I-16)～(I-19)所示结构：In some embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-16) to (I-19):
Figure PCTCN2022088918-appb-000026
Figure PCTCN2022088918-appb-000026
其中，R 2、R 6、R 7和R 8如本发明所定义。 Wherein, R 2 , R 6 , R 7 and R 8 are as defined in the present invention.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022088918-appb-000027
为
Figure PCTCN2022088918-appb-000028
Figure PCTCN2022088918-appb-000029
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural units
Figure PCTCN2022088918-appb-000027
for
Figure PCTCN2022088918-appb-000028
Figure PCTCN2022088918-appb-000029
Other variables are as defined in the present invention.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022088918-appb-000030
为
Figure PCTCN2022088918-appb-000031
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned structural units
Figure PCTCN2022088918-appb-000030
for
Figure PCTCN2022088918-appb-000031
Other variables are as defined in the present invention.
在本发明的一些方案中，上述R 6、R 7和R 8各自独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-CH 3、-CH 2CH 3、-CF 3、-CH 2CF 3或-CH 2CH 2OH，其他变量如本发明所定义。 In some aspects of the present invention, the above R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , -CH 3 , -CH 2 CH3 , -CF3 , -CH2CF3 or -CH2CH2OH , other variables are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其化合物具有式(I-20)～(I-25)所示结构：In some embodiments of the present invention, the above-mentioned compounds or pharmaceutically acceptable salts thereof have the structures represented by formulae (I-20) to (I-25):
Figure PCTCN2022088918-appb-000032
Figure PCTCN2022088918-appb-000032
其中，R 2本发明所定义。 Wherein, R 2 is defined in the present invention.
在本发明的一些方案中，上述各R a独立地为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-C(＝O)OH、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-CF 3、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3、 -CH 2OH或-CH 2CH 2OH，其他变量如本发明所定义。 In some aspects of the present invention, each of the above Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C(=O)OH, -CH3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 3 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , - CH2CH2CF3 , -CH2OH or -CH2CH2OH , other variables are as defined herein .
在本发明的一些方案中，上述各R a独立地为H、F、Cl、或-NH 2，其他变量如本发明所定义。 In some aspects of the present invention, each of the above R a is independently H, F, Cl, or -NH 2 , and other variables are as defined herein.
在本发明的一些方案中，上述R 2为C 1-6烷基、-CH 2-苯基、-CH 2-吡啶基、-CH 2-嘧啶基或-CH 2-吡嗪基，其中所述C 1-6烷基、苯基、吡啶基、嘧啶基和吡嗪基任选被1、2、3、4或5个R a所取代，R a及其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl, -CH 2 -pyrimidinyl or -CH 2 -pyrazinyl, wherein The C1-6 alkyl, phenyl, pyridyl, pyrimidinyl and pyrazinyl groups are optionally substituted with 1, 2, 3, 4 or 5 R a , R a and other variables as defined herein.
在本发明的一些方案中，上述R 2为
Figure PCTCN2022088918-appb-000033
Figure PCTCN2022088918-appb-000034
Figure PCTCN2022088918-appb-000035
R a及其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is
Figure PCTCN2022088918-appb-000033
Figure PCTCN2022088918-appb-000034
Figure PCTCN2022088918-appb-000035
Ra and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2为
Figure PCTCN2022088918-appb-000036
Figure PCTCN2022088918-appb-000037
Figure PCTCN2022088918-appb-000038
其他变量如本发明所定义。 In some aspects of the present invention, the above R 2 is
Figure PCTCN2022088918-appb-000036
Figure PCTCN2022088918-appb-000037
Figure PCTCN2022088918-appb-000038
Other variables are as defined in the present invention.
在本发明的一些方案中，上述R 3和R 4各自独立地为H或-NH 2，其他变量如本发明所定义。 In some aspects of the present invention, each of the above R3 and R4 is independently H or -NH2 , and other variables are as defined herein.
在本发明的一些方案中，上述化合物具有式(I-15-a)、(I-15-b)、(I-15-c)或(I-15-d)所示结构：In some embodiments of the present invention, the above compound has the structure represented by formula (I-15-a), (I-15-b), (I-15-c) or (I-15-d):
Figure PCTCN2022088918-appb-000039
Figure PCTCN2022088918-appb-000039
其中，R 1、R 4、R 7、R 8和R a如本发明所定义。 wherein R 1 , R 4 , R 7 , R 8 and Ra are as defined in the present invention.
本发明还有一些方案是由上述变量任意组合而来。There are also some solutions of the present invention that are formed by any combination of the above variables.
在本发明的一些方案中，上述化合物或其药学上可接受的盐选自：In some aspects of the invention, the above compound or a pharmaceutically acceptable salt thereof is selected from:
Figure PCTCN2022088918-appb-000040
Figure PCTCN2022088918-appb-000040
Figure PCTCN2022088918-appb-000041
Figure PCTCN2022088918-appb-000041
Figure PCTCN2022088918-appb-000042
Figure PCTCN2022088918-appb-000042
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糖尿病肾病或高血压肾病药物中的应用。The present invention also provides the use of the above-mentioned compounds or their pharmaceutically acceptable salts in the preparation of medicines for treating diabetic nephropathy or hypertensive nephropathy.
本发明还提供了一种在需要的受试者中治疗糖尿病肾病或高血压肾病的方法，所述方法包括向受试者提供有效剂量的上述任意技术方案所限定的化合物或其药学上可接受的盐。The present invention also provides a method for treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, the method comprising providing the subject with an effective dose of the compound as defined in any of the above technical solutions or a pharmaceutically acceptable method thereof of salt.
技术效果technical effect
本发明涉及的一类新的可溶性鸟苷酸环化酶刺激剂，所涉及的化合物对鸟苷酸环化酶具有显著的体外刺激活性，且其具有优良的药代动力学性质，以及对五个CYP同工酶抑制程度均较弱。The present invention relates to a new class of soluble guanylate cyclase stimulators, and the compounds involved have significant in vitro stimulatory activity to guanylate cyclase, and have excellent pharmacokinetic properties, as well as to five All CYP isozymes were weakly inhibited.
定义和说明Definition and Explanation
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2022088918-appb-000043
和楔形虚线键
Figure PCTCN2022088918-appb-000044
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022088918-appb-000045
和直形虚线键
Figure PCTCN2022088918-appb-000046
表示立体中心的相对构型，用波浪线
Figure PCTCN2022088918-appb-000047
表示楔形实线键
Figure PCTCN2022088918-appb-000048
或楔形虚线键
Figure PCTCN2022088918-appb-000049
或用波浪线
Figure PCTCN2022088918-appb-000050
表示直形实线键
Figure PCTCN2022088918-appb-000051
和直形虚线键
Figure PCTCN2022088918-appb-000052
Use solid wedge keys unless otherwise specified
Figure PCTCN2022088918-appb-000043
and wedge-dotted keys
Figure PCTCN2022088918-appb-000044
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2022088918-appb-000045
and straight dashed keys
Figure PCTCN2022088918-appb-000046
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022088918-appb-000047
Represents a solid wedge key
Figure PCTCN2022088918-appb-000048
or wedge-dotted key
Figure PCTCN2022088918-appb-000049
or with wavy lines
Figure PCTCN2022088918-appb-000050
Represents a straight solid key
Figure PCTCN2022088918-appb-000051
and straight dashed keys
Figure PCTCN2022088918-appb-000052
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例 是戊烷-2，4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the present invention may exist in particular. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound. For example, compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。When one of the variables is selected from a single bond, it means that the two groups connected to it are directly connected, for example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。 当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022088918-appb-000053
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 PCTCN2022088918-appb-000054
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 PCTCN2022088918-appb-000055
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When the listed linking group does not indicate its direction of attachment, the direction of attachment is arbitrary, for example,
Figure PCTCN2022088918-appb-000053
The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right.
Figure PCTCN2022088918-appb-000054
It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
Figure PCTCN2022088918-appb-000055
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022088918-appb-000056
直形虚线键
Figure PCTCN2022088918-appb-000057
或波浪线
Figure PCTCN2022088918-appb-000058
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 PCTCN2022088918-appb-000059
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 PCTCN2022088918-appb-000060
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 PCTCN2022088918-appb-000061
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 PCTCN2022088918-appb-000062
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022088918-appb-000063
仍包括
Figure PCTCN2022088918-appb-000064
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。 Unless otherwise specified, when a group has one or more attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. When the connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group. The chemical bond connecting the site to other groups can be represented by straight solid line bonds
Figure PCTCN2022088918-appb-000056
straight dotted key
Figure PCTCN2022088918-appb-000057
or wavy lines
Figure PCTCN2022088918-appb-000058
express. For example, a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
Figure PCTCN2022088918-appb-000059
The straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
Figure PCTCN2022088918-appb-000060
The wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
Figure PCTCN2022088918-appb-000061
Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2022088918-appb-000062
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2022088918-appb-000063
still includes
Figure PCTCN2022088918-appb-000064
The group in this connection method is only that when one chemical bond is connected, the H at the site will be correspondingly reduced by one to become the corresponding monovalent piperidinyl group.
除非另有规定，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”。Unless otherwise specified, 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.
除非另有规定，“3-12元环”表示由3至12个环原子组成的环烷基、杂环烷基、环烯基或杂环烯基。所述的环包括单环，也包括螺环、并环和桥环等双环或多环体系。除非另有规定，该环任选地包含1、2或3个独立选自O、S和N的杂原子。所述3-12元环包括3-10元、3-9元、3-8元、3-7元、3-6元、3-5元、4-10元、4-9元、4-8元、4-7元、4-6元、4-5元、5-10元、5-9元、5-8元、5-7元、5-6元、6-10元、6-9元、6-8元和6-7元环等。术语“5-7元杂环烷基”包括哌啶基等，但不包括苯基。术语“环”还包括含有至少一个环的环系，其中的每一个“环”均独立地符合上述定义。Unless otherwise specified, "3-12 membered ring" means cycloalkyl, heterocycloalkyl, cycloalkenyl or heterocycloalkenyl consisting of 3 to 12 ring atoms. Said ring includes a single ring, and also includes a bicyclic or polycyclic ring system such as a spiro ring, a paracyclic ring and a bridged ring. Unless otherwise specified, the ring optionally contains 1, 2 or 3 heteroatoms independently selected from O, S and N. The 3-12-membered ring includes 3-10 yuan, 3-9 yuan, 3-8 yuan, 3-7 yuan, 3-6 yuan, 3-5 yuan, 4-10 yuan, 4-9 yuan, 4- 8 yuan, 4-7 yuan, 4-6 yuan, 4-5 yuan, 5-10 yuan, 5-9 yuan, 5-8 yuan, 5-7 yuan, 5-6 yuan, 6-10 yuan, 6- 9 yuan, 6-8 yuan and 6-7 yuan ring, etc. The term "5-7 membered heterocycloalkyl" includes piperidinyl and the like, but does not include phenyl. The term "ring" also includes ring systems containing at least one ring, wherein each "ring" independently meets the above definition.
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
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。 Unless otherwise specified, the term "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). Examples of C 1-6 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), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl, etc.
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)。C1 -4烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)等。 Unless otherwise specified, the term "C 1-4 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 4 carbon atoms. The C 1-4 alkyl includes C 1-2 , C 1-3 and C 2-3 alkyl, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or polyvalent ( such as methine). Examples of C1-4 alkyl groups 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) etc.
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。 Unless otherwise specified, the term "C 1-3 alkyl" is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。 Unless otherwise specified, the term " C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
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(例如亲和取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, affinity substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1，1-二-(4′-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022088918-appb-000065
扫描，收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。 The structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuKα radiation, and the scanning mode is:
Figure PCTCN2022088918-appb-000065
After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
本发明所使用的溶剂可经市售获得。The solvent used in the present invention is commercially available.
本发明采用下述缩略词：DMF代表N，N-二甲基甲酰胺；K 2CO 3代表碳酸钾；MeI代表碘甲烷；EtOAc代表乙酸乙酯；EA代表乙酸乙酯；THF代表四氢呋喃；NaHMDS代表六甲基二硅基氨基钠；MeOH代表甲醇；DCM代表二氯甲烷；DMSO代表二甲基亚砜；PE代表石油醚；EtOH代表乙醇；ACN代表乙腈；TFA代表三氟乙酸；FA代表甲酸；NH 3·H 2O代表氨水；TEA代表三乙胺；DIPEA代表N，N-二异丙基乙胺；Boc 2O代表二碳酸二叔丁酯；Boc代表叔丁氧羰基，是氨基的一种保护基；EDCI代表1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐；CDI代表N，N′-羰基二咪唑；DDQ代表2，3-二氯-5，6-二氰对苯醌；LCMS代表液质联用色谱；HPLC代表液相色谱；TLC代表薄层层析；MEC代表最小有效浓度；LnCap代表前列腺癌细胞；sGC代表可溶性鸟苷酸环化酶；cGMP代表环磷酸鸟苷。 The present invention adopts the following abbreviations: DMF stands for N,N-dimethylformamide; K 2 CO 3 stands for potassium carbonate; MeI stands for methyl iodide; EtOAc stands for ethyl acetate; EA stands for ethyl acetate; THF stands for tetrahydrofuran; NaHMDS stands for sodium hexamethyldisilazide; MeOH for methanol; DCM for dichloromethane; DMSO for dimethyl sulfoxide; PE for petroleum ether; EtOH for ethanol; ACN for acetonitrile; TFA for trifluoroacetic acid; FA for Formic acid; NH 3 ·H 2 O stands for ammonia; TEA stands for triethylamine; DIPEA stands for N,N-diisopropylethylamine; Boc 2 O stands for di-tert-butyl dicarbonate; Boc stands for tert-butoxycarbonyl, which is an amino group A protecting group of ; EDCI stands for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; CDI stands for N,N'-carbonyldiimidazole; DDQ stands for 2,3-diimidazole Chloro-5,6-dicyano-p-benzoquinone; LCMS for liquid chromatography mass spectrometry; HPLC for liquid chromatography; TLC for thin layer chromatography; MEC for minimum effective concentration; LnCap for prostate cancer cells; sGC for soluble guanosine Acid cyclase; cGMP stands for cyclic guanosine monophosphate.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022088918-appb-000066
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to conventional nomenclature in the art or are used
Figure PCTCN2022088918-appb-000066
Software naming, commercially available compounds use supplier catalog names.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The present invention has been described in detail herein, and specific embodiments thereof have also been disclosed. For those skilled in the art, 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. will be obvious.
实施例1Example 1
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000067
Figure PCTCN2022088918-appb-000067
步骤A：向1-1(2g，12.61mmol，1eq)的甲苯(20mL)溶液中加入2-氟苄胺(1.89g，15.14mmol，1.72 mL，1.2eq)和碳酸铯(6.17g，18.92mmol，1.5eq)。置换氮气，在氮气保护下于80℃下搅拌12小时。向反应液中加入水(20mL)，用EtOAc(30mL)萃取，有机相用无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝50∶1-20∶1)纯化，得到的粗产物用石油醚(10mL)搅拌，过滤干燥后得化合物1-a。Step A: To a solution of 1-1 (2g, 12.61mmol, 1eq) in toluene (20mL) was added 2-fluorobenzylamine (1.89g, 15.14mmol, 1.72mL, 1.2eq) and cesium carbonate (6.17g, 18.92mmol) , 1.5eq). The nitrogen was replaced, and the mixture was stirred at 80°C for 12 hours under nitrogen protection. Water (20 mL) was added to the reaction solution, extracted with EtOAc (30 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=50:1-20:1) , the obtained crude product was stirred with petroleum ether (10 mL), filtered and dried to obtain compound 1-a.
步骤B：在1-a(2.5g，7.70mmol，1eq)的EtOH(20mL)和水(5mL)的混合物中加入还原铁粉(3.44g，61.56mmol，8eq)和NH 4Cl(4.94g，92.35mmol，3.23mL，12eq)。置换氮气，在70℃下搅拌3小时，向反应液中加入水(20mL)和EtOAc(50mL)，过滤后分液，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过硅胶柱层析(PE∶EtOAc＝10∶1-5∶1)纯化得到化合物1-b。 Step B: To a mixture of 1-a (2.5 g, 7.70 mmol, 1 eq) in EtOH (20 mL) and water (5 mL) was added reduced iron powder (3.44 g, 61.56 mmol, 8 eq) and NH 4 Cl (4.94 g, 92.35mmol, 3.23mL, 12eq). The nitrogen was replaced, and the mixture was stirred at 70° C. for 3 hours. Water (20 mL) and EtOAc (50 mL) were added to the reaction solution. After filtration, the layers were separated. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was purified by silica gel column chromatography (PE:EtOAc=10:1-5:1) to obtain compound 1-b.
步骤C：在1-b(1.1g，3.93mmol，1eq)的THF(50.00mL)溶液中缓慢加入CDI(955.69mg，5.89mmol，1.5eq)。加完后将混合物在70℃下搅拌12小时。将反应液浓缩，残留物通过硅胶柱层析(PE∶EtOAc＝4∶1-2∶1)纯化得到化合物1-c。Step C: To a solution of 1-b (1.1 g, 3.93 mmol, 1 eq) in THF (50.00 mL) was slowly added CDI (955.69 mg, 5.89 mmol, 1.5 eq). After the addition was complete the mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (PE:EtOAc=4:1-2:1) to obtain compound 1-c.
步骤D：在30℃下，向1-2(5.0g，28.89mmol，1eq)的三氯氧磷(49.50g，322.83mmol，30.00mL，11.18eq)溶液中慢慢滴加2，6-二甲基吡啶(13.80g，128.79mmol，15.00mL，4.46eq)，滴加完毕后，氮气置换3次，反应液在80℃下搅拌12小时。将反应液冷却到30℃，然后减压浓缩除掉多余溶剂，最后在0-5℃下将反应液慢慢加入到冰水(100mL)中，然后用PE/EA(100mL，1/1)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过硅胶柱层析(PE/EA＝1/0到20/1)纯化得到化合物1-f。Step D: To a solution of 1-2 (5.0 g, 28.89 mmol, 1 eq) in phosphorus oxychloride (49.50 g, 322.83 mmol, 30.00 mL, 11.18 eq) at 30 °C was slowly added dropwise 2,6-di Methyl pyridine (13.80 g, 128.79 mmol, 15.00 mL, 4.46 eq) was added dropwise and replaced with nitrogen three times, and the reaction solution was stirred at 80° C. for 12 hours. The reaction solution was cooled to 30 °C, then concentrated under reduced pressure to remove excess solvent, and finally the reaction solution was slowly added to ice water (100 mL) at 0-5 °C, and then PE/EA (100 mL, 1/1) was added. After extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by silica gel column chromatography (PE/EA=1/0 to 20/1) to obtain compound 1-f.
步骤E：在-20℃下，向化合物1-f(3.3g，14.45mmol，1eq)的乙醇(20mL)溶液中加入NH3的乙醇溶液(20mL)，反应液在-20℃下搅拌50分钟，将反应液过滤，收集滤饼，然后用水(10mL)和乙醇(10mL)洗涤，得到化合物1-g。Step E: At -20°C, to a solution of compound 1-f (3.3g, 14.45mmol, 1eq) in ethanol (20mL) was added NH3 ethanol solution (20mL), the reaction solution was stirred at -20°C for 50 minutes, The reaction solution was filtered, the filter cake was collected, and then washed with water (10 mL) and ethanol (10 mL) to obtain compound 1-g.
步骤F：向1-c(200mg，800.87μmol，1eq)的DMF(1.00mL)溶液中加入1-g(403.76mg，800.87μmol，1.0eq)，碳酸铯(521.88mg，1.60mmol，2eq)，碘化亚铜(15.25mg，80.09μmol，0.10eq)和1，10-菲啰啉(28.86mg，160.17μmol，0.2eq)。置换氮气，在90℃下搅拌3小时，向反应液中加入水(20mL)，用EtOAc(50mL×2)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩得化合物1-d。Step F: To a solution of 1-c (200 mg, 800.87 μmol, 1 eq) in DMF (1.00 mL) was added 1-g (403.76 mg, 800.87 μmol, 1.0 eq), cesium carbonate (521.88 mg, 1.60 mmol, 2 eq), Cuprous iodide (15.25 mg, 80.09 μmol, 0.10 eq) and 1,10-phenanthroline (28.86 mg, 160.17 μmol, 0.2 eq). The nitrogen was replaced, stirred at 90°C for 3 hours, water (20 mL) was added to the reaction solution, extracted with EtOAc (50 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 1-d.
步骤G：在1-d(300mg，756.94μmol，1eq)的MeOH(9mL)和水(3mL)的混合物中加入还原铁粉(845.42mg，15.14mmol，20eq)和NH 4Cl(809.79mg，15.14mmol，20eq)。置换氮气，在70℃下搅拌2小时，向反应液中加入水(10mL)，用EtOAc(25mL×2)萃取，合并的有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过薄层色谱法(DCM∶MeOH＝10∶1)纯化得到化合物1-e。 Step G: To a mixture of 1-d (300 mg, 756.94 μmol, 1 eq) in MeOH (9 mL) and water (3 mL) was added reduced iron powder (845.42 mg, 15.14 mmol, 20 eq) and NH 4 Cl (809.79 mg, 15.14 mmol, 20eq). Nitrogen was replaced, stirred at 70°C for 2 hours, water (10 mL) was added to the reaction solution, extracted with EtOAc (25 mL×2), the combined organic phases were washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was purified by thin layer chromatography (DCM:MeOH=10:1) to give compound 1-e.
步骤H：在0℃下，向1-e(120mg，293.82μmol，1eq)的吡啶(1.5mL)溶液中加入氯甲酸甲酯(41.65mg，440.72μmol，34.14μL，1.5eq)，0℃下搅拌半小时，向反应液中加入水(10mL)，用EtOAc(50mL)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物加入EtOAc(10mL)搅拌，过滤干燥后得化合物1。 1H NMR(400MHz，DMSO-d 6)：δppm 8.08-8.01(m，2H)，7.95(br s，1H)，7.35(m，1H)，7.28-7.19(m，2H)，7.18-7.08(m，2H)，6.33(br s，4H)，5.15(s，2H)，3.62(s，3H)；LCMS(ESI)m/z：425.3[M+1] +。 Step H: To a solution of 1-e (120 mg, 293.82 μmol, 1 eq) in pyridine (1.5 mL) at 0 °C was added methyl chloroformate (41.65 mg, 440.72 μmol, 34.14 μL, 1.5 eq) at 0 °C Stir for half an hour, add water (10 mL) to the reaction solution, extract with EtOAc (50 mL), wash the organic phase with saturated brine (10 mL), dry over anhydrous sodium sulfate, filter and concentrate, add EtOAc (10 mL) to the residue and stir , and compound 1 was obtained after filtration and drying. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.08-8.01 (m, 2H), 7.95 (br s, 1H), 7.35 (m, 1H), 7.28-7.19 (m, 2H), 7.18-7.08 ( m, 2H), 6.33 (br s, 4H), 5.15 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m/z: 425.3 [M+1] + .
实施例2Example 2
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000068
Figure PCTCN2022088918-appb-000068
在0℃下，向化合物1(50mg，115.04μmol，1eq)的DMF(1mL)溶液中加入NaH(6.90mg，172.55μmol，60％纯度，1.5eq)，0℃下搅拌10分钟，然后加入碘甲烷(24.49mg，172.55μmol，10.74μL，1.5eq)，所得混合物在0℃下搅拌半小时，向反应液中加入水(5mL)，用EtOAc(10mL×2)萃取，合并的有机相用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物用薄层色谱法(EtOAc)纯化得到化合物2。 1H NMR(400MHz，DMSO-d 6)：δppm 8.09-8.02(m，2H)，7.39-7.30(m，1H)，7.27-7.19(m，2H)，7.18-7.08(m，2H)，6.55(br s，4H)，5.15(s，2H)，3.66(s，1H)，3.55(s，2H)，3.00(s，3H)；LCMS(ESI)m/z：439.3[M+1] +。 To a solution of compound 1 (50 mg, 115.04 μmol, 1 eq) in DMF (1 mL) at 0 °C was added NaH (6.90 mg, 172.55 μmol, 60% pure, 1.5 eq), stirred at 0 °C for 10 min, and then iodine was added Methane (24.49 mg, 172.55 μmol, 10.74 μL, 1.5 eq), the resulting mixture was stirred at 0 °C for half an hour, water (5 mL) was added to the reaction solution, extracted with EtOAc (10 mL×2), and the combined organic phases were saturated with Washed with brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by thin layer chromatography (EtOAc) to obtain compound 2. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.09-8.02 (m, 2H), 7.39-7.30 (m, 1H), 7.27-7.19 (m, 2H), 7.18-7.08 (m, 2H), 6.55 (br s, 4H), 5.15(s, 2H), 3.66(s, 1H), 3.55(s, 2H), 3.00(s, 3H); LCMS(ESI) m/z: 439.3[M+1] + .
实施例3Example 3
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000069
Figure PCTCN2022088918-appb-000069
步骤A：在氮气保护下，向化合物3-1(2g，11.33mmol，1eq)的甲苯(20.00mL)溶液中加入碳酸铯(5.54g，16.99mmol，1.5eq)和2-氟苄胺(1.70g，13.60mmol，1.55mL，1.2eq)。将混合物升温至80℃下搅拌12小时。冷却后，加入水(40mL)，用EtOAc(40mL)萃取，有机相用盐水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE∶EtOAc＝50∶1-5∶1)得到化合物3-a。Step A: To a solution of compound 3-1 (2g, 11.33mmol, 1eq) in toluene (20.00mL) under nitrogen protection was added cesium carbonate (5.54g, 16.99mmol, 1.5eq) and 2-fluorobenzylamine (1.70 g, 13.60 mmol, 1.55 mL, 1.2 eq). The mixture was warmed to 80°C and stirred for 12 hours. After cooling, water (40 mL) was added, extracted with EtOAc (40 mL), the organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=50:1 -5:1) to give compound 3-a.
步骤B：在3-a(1.50g，5.66mmol，1eq)的THF(20mL)和水(10mL)的混合物中加入还原铁粉(1.26g，22.62mmol，4eq)和NH 4Cl(1.51g，53.49mmol，5eq)。置换氮气，在60℃下搅拌6小时，将反应液过滤，滤饼用EtOAc(40mL)洗涤，滤液再加入饱和食盐水(50mL)，用EtOAc(40mL)萃取，有机相用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝10∶1-4∶1)纯化得到化合物3-b。 Step B: To a mixture of 3-a (1.50 g, 5.66 mmol, 1 eq) in THF (20 mL) and water (10 mL) was added reduced iron powder (1.26 g, 22.62 mmol, 4 eq) and NH 4 Cl (1.51 g, 53.49mmol, 5eq). The nitrogen was replaced, stirred at 60°C for 6 hours, the reaction solution was filtered, the filter cake was washed with EtOAc (40 mL), saturated brine (50 mL) was added to the filtrate, extracted with EtOAc (40 mL), and the organic phase was washed with saturated brine (50 mL). ), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=10:1-4:1) to obtain compound 3-b.
步骤C：在3-b(1.00g，4.25mmol，1eq)的THF(20.00mL)溶液中缓慢加入CDI(1.03g，6.38mmol，1.5eq)。加完后将混合物在70℃下搅拌12小时。将反应液浓缩，残留物通过柱层析(PE∶EtOAc＝5∶1-2∶1) 纯化得到化合物3-c。 1H NMR(400MHz，CDCl 3)：δppm 9.99(br s，1H)，7.96(t，J＝2.1Hz，1H)，7.33-7.29(m，1H)，7.28-7.24(m，1H)，7.16(dd，J＝2.5，8.0Hz，1H)，7.12-7.05(m，2H)，5.27(s，2H)。 Step C: To a solution of 3-b (1.00 g, 4.25 mmol, 1 eq) in THF (20.00 mL) was slowly added CDI (1.03 g, 6.38 mmol, 1.5 eq). After the addition was complete the mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=5:1-2:1) to obtain compound 3-c. 1 H NMR (400 MHz, CDCl 3 ): δppm 9.99 (br s, 1H), 7.96 (t, J=2.1 Hz, 1H), 7.33-7.29 (m, 1H), 7.28-7.24 (m, 1H), 7.16 (dd, J=2.5, 8.0 Hz, 1H), 7.12-7.05 (m, 2H), 5.27 (s, 2H).
步骤D：在3-c(113mg，432.57μmol，1eq)的DMF(4.00mL)溶液中加入1-g(261.70mg，519.09μmol，1.0eq)，碳酸铯(281.88mg，865.15μmol，2eq)，碘化亚铜(8.24mg，43.26μmol，0.10eq)和1，10-菲啰啉(15.59mg，86.51μmol，0.2eq)。置换氮气，在100℃下搅拌3小时，反应液冷却后向反应液中加入饱和食盐水(20mL)，用EtOAc(20mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝5∶1-2∶1)得化合物3-d。Step D: To a solution of 3-c (113 mg, 432.57 μmol, 1 eq) in DMF (4.00 mL) was added 1-g (261.70 mg, 519.09 μmol, 1.0 eq), cesium carbonate (281.88 mg, 865.15 μmol, 2 eq), Cuprous iodide (8.24 mg, 43.26 μmol, 0.10 eq) and 1,10-phenanthroline (15.59 mg, 86.51 μmol, 0.2 eq). The nitrogen was replaced, and the mixture was stirred at 100°C for 3 hours. After cooling the reaction solution, saturated brine (20 mL) was added to the reaction solution, extracted with EtOAc (20 mL), the organic phase was washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. , filtered and concentrated, and the residue was subjected to column chromatography (PE:EtOAc=5:1-2:1) to obtain compound 3-d.
步骤E：在3-d(120mg，289.63μmol，1eq)的MeOH(6mL)和水(2mL)的混合物中加入还原铁粉(64.70mg，1.16mmol，4eq)和NH 4Cl(77.46mg，1.45mmol，5eq)。置换氮气，在70℃下搅拌3小时，将反应液过滤，滤饼用甲醇(10mL)和二氯甲烷(10mL)洗涤，向滤液中加入饱和食盐水(10mL)，用DCM(10mL)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过薄层色谱法(DCM∶MeOH＝10∶1)纯化得到化合物3-e。 Step E: To a mixture of 3-d (120 mg, 289.63 μmol, 1 eq) in MeOH (6 mL) and water (2 mL) was added reduced iron powder (64.70 mg, 1.16 mmol, 4 eq) and NH 4 Cl (77.46 mg, 1.45 mmol, 5eq). Nitrogen was replaced, stirred at 70°C for 3 hours, the reaction solution was filtered, the filter cake was washed with methanol (10 mL) and dichloromethane (10 mL), saturated brine (10 mL) was added to the filtrate, extracted with DCM (10 mL), The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 3-e.
步骤F：在0℃下，向3-e(42mg，91.06μmol，1eq)的吡啶(1.5mL)溶液中加入氯甲酸甲酯(12.91mg，136.60μmol，10.58μL，1.5eq)，0℃下搅拌1小时，将反应液倒入到冰水(20mL)中，加入饱和食盐水(10mL)，用EtOAc(20mL)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物3。 1H NMR(400MHz，DMSO-d 6)：δppm 8.18(dd，J＝2.5，9.4Hz，1H)，8.07(s，1H)，7.96(br s，1H)，7.41-7.31(m，1H)，7.30-7.11(m，3H)，6.37(br s，4H)，5.14(s，2H)，3.62(s，3H)；LCMS(ESI)m/z：443.1[M+1] +。 Step F: To a solution of 3-e (42 mg, 91.06 μmol, 1 eq) in pyridine (1.5 mL) at 0 °C was added methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq) at 0 °C After stirring for 1 hour, the reaction solution was poured into ice water (20 mL), saturated brine (10 mL) was added, extracted with EtOAc (20 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, and filtered. After concentration, the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 3. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.18 (dd, J=2.5, 9.4 Hz, 1H), 8.07 (s, 1H), 7.96 (br s, 1H), 7.41-7.31 (m, 1H) , 7.30-7.11 (m, 3H), 6.37 (br s, 4H), 5.14 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m/z: 443.1 [M+1] + .
实施例4Example 4
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000070
Figure PCTCN2022088918-appb-000070
步骤A：在氮气保护下，向3-1(2g，11.33mmol，1eq)的甲苯(20.00mL)溶液中加入碳酸铯(5.54g，16.99mmol，1.5eq)和2-三氟甲基苄胺(2.38g，13.60mmol，1.55mL，1.2eq)。将混合物升温至80℃下搅拌12小时。冷却后，加入水(40mL)，用EtOAc(40mL)萃取，有机相用盐水(40mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE∶EtOAc＝50∶1-5∶1)得到化合物4-a。Step A: To a solution of 3-1 (2g, 11.33mmol, 1eq) in toluene (20.00mL) under nitrogen protection was added cesium carbonate (5.54g, 16.99mmol, 1.5eq) and 2-trifluoromethylbenzylamine (2.38 g, 13.60 mmol, 1.55 mL, 1.2 eq). The mixture was warmed to 80°C and stirred for 12 hours. After cooling, water (40 mL) was added, extracted with EtOAc (40 mL), the organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=50:1 -5:1) to give compound 4-a.
步骤B：在4-a(1.70g，5.39mmol，1eq)的THF(20mL)和水(10mL)的混合物中加入还原铁粉(1.20 g，21.57mmol，4eq)和NH 4Cl(1.44g，26.97mmol，5eq)。置换氮气，在60℃下搅拌3小时，将反应液过滤，滤饼用EtOAc(40mL)洗涤，滤液再加入饱和食盐水(60mL)，用EtOAc(50mL)萃取，有机相用饱和食盐水(60mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝10∶1-4∶1)纯化得到化合物4-b。 Step B: To a mixture of 4-a (1.70 g, 5.39 mmol, 1 eq) in THF (20 mL) and water (10 mL) was added reduced iron powder (1.20 g, 21.57 mmol, 4 eq) and NH 4 Cl (1.44 g, 26.97mmol, 5eq). Nitrogen was replaced, stirred at 60°C for 3 hours, the reaction solution was filtered, the filter cake was washed with EtOAc (40 mL), saturated brine (60 mL) was added to the filtrate, extracted with EtOAc (50 mL), and the organic phase was washed with saturated brine (60 mL). ), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=10:1-4:1) to obtain compound 4-b.
步骤C：在4-b(1.21g，4.25mmol，1eq)的THF(20.00mL)溶液中缓慢加入CDI(1.03g，6.38mmol，1.5eq)。加完后将混合物在70℃下搅拌12小时。将反应液浓缩，残留物通过柱层析(PE∶EtOAc＝4∶1-2∶1)纯化得到化合物4-c。 1H NMR(400MHz，DMSO-d 6)：δppm 11.60(br s，1H)，7.91(t，J＝2.0Hz，1H)，7.80(d，J＝7.7Hz，1H)，7.63-7.53(m，1H)，7.53-7.40(m，2H)，7.02(d，J＝7.7Hz，1H)，5.19(s，2H)。 Step C: To a solution of 4-b (1.21 g, 4.25 mmol, 1 eq) in THF (20.00 mL) was slowly added CDI (1.03 g, 6.38 mmol, 1.5 eq). After the addition was complete the mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=4:1-2:1) to obtain compound 4-c. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.60 (br s, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.80 (d, J=7.7 Hz, 1H), 7.63-7.53 (m , 1H), 7.53-7.40 (m, 2H), 7.02 (d, J=7.7Hz, 1H), 5.19 (s, 2H).
步骤D：在4-c(140mg，449.82μmol，1eq)的DMF(1.00mL)溶液中加入1-g(226.78mg，449.82μmol，1.0eq)，碳酸铯(293.12mg，899.64μmol，2eq)，碘化亚铜(8.57mg，44.98μmol，0.10eq)和1，10-菲啰啉(16.21mg，89.96μmol，0.2eq)。置换氮气，在100℃下搅拌3小时，反应液冷却后过滤，滤饼用MeOH(10mL)和EtOAc(10mL)洗涤，滤液再加入饱和食盐水(20mL)，用EtOAc(30mL)萃取，有机相用饱和食盐水(20mL)洗涤，无水硫酸钠干燥，过滤后浓缩得化合物4-d。Step D: To a solution of 4-c (140 mg, 449.82 μmol, 1 eq) in DMF (1.00 mL) was added 1-g (226.78 mg, 449.82 μmol, 1.0 eq), cesium carbonate (293.12 mg, 899.64 μmol, 2 eq), Cuprous iodide (8.57 mg, 44.98 μmol, 0.10 eq) and 1,10-phenanthroline (16.21 mg, 89.96 μmol, 0.2 eq). The nitrogen was replaced, and the mixture was stirred at 100 °C for 3 hours. The reaction solution was cooled and filtered. The filter cake was washed with MeOH (10 mL) and EtOAc (10 mL). The filtrate was then added with saturated brine (20 mL), and extracted with EtOAc (30 mL). The organic phase was Washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 4-d.
步骤E：在4-d(150mg，323.04μmol，1eq)的MeOH(9mL)和水(3mL)的混合物中加入还原铁粉(360.84mg，6.46mmol，20eq)和NH 4Cl(345.59mg，6.46mmol，20eq)。置换氮气，在70℃下搅拌3小时，将反应液过滤，滤饼用甲醇(10mL)和EtOAc(10mL)洗涤，滤液浓缩后通过薄层色谱法(DCM∶MeOH＝10∶1)纯化得到化合物4-e。 Step E: To a mixture of 4-d (150 mg, 323.04 μmol, 1 eq) in MeOH (9 mL) and water (3 mL) was added reduced iron powder (360.84 mg, 6.46 mmol, 20 eq) and NH 4 Cl (345.59 mg, 6.46 mg) mmol, 20eq). The nitrogen was replaced and stirred at 70°C for 3 hours, the reaction solution was filtered, the filter cake was washed with methanol (10 mL) and EtOAc (10 mL), the filtrate was concentrated and purified by thin layer chromatography (DCM:MeOH=10:1) to obtain the compound 4-e.
步骤F：在0℃下，向4-e(39.55mg，91.06μmol，1eq)的吡啶(1.0mL)溶液中加入氯甲酸甲酯(12.91mg，136.60μmol，10.58μL，1.5eq)，0℃下搅拌1小时，将反应液倒入到冰水(10mL)中，加入饱和食盐水(10mL)，用EtOAc(5mL×3)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物4。 1H NMR(400MHz，DMSO-d 6)：δppm 8.18(dd，J＝2.5，9.4Hz，1H)，8.07(s，1H)，7.96(br s，1H)，7.41-7.31(m，1H)，7.30-7.11(m，3H)，6.37(br s，4H)，5.14(s，2H)，3.62(br s，3H)；LCMS(ESI)m/z：493.1[M+1] +。 Step F: To a solution of 4-e (39.55 mg, 91.06 μmol, 1 eq) in pyridine (1.0 mL) at 0 °C was added methyl chloroformate (12.91 mg, 136.60 μmol, 10.58 μL, 1.5 eq), 0 °C After stirring for 1 hour, the reaction solution was poured into ice water (10 mL), saturated brine (10 mL) was added, extracted with EtOAc (5 mL×3), the organic phase was washed with saturated brine (10 mL), and anhydrous sodium sulfate It was dried, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 4. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.18 (dd, J=2.5, 9.4 Hz, 1H), 8.07 (s, 1H), 7.96 (br s, 1H), 7.41-7.31 (m, 1H) , 7.30-7.11 (m, 3H), 6.37 (br s, 4H), 5.14 (s, 2H), 3.62 (br s, 3H); LCMS (ESI) m/z: 493.1[M+1] + .
实施例5Example 5
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000071
Figure PCTCN2022088918-appb-000071
Figure PCTCN2022088918-appb-000072
Figure PCTCN2022088918-appb-000072
步骤A：-20℃下，向1-f(1.3g，5.69mmol，1eq)的DCM(100.00mL)溶液中缓慢加入对甲氧基苄胺(1.56g，11.38mmol，1.47mL，2eq)的DCM(100.00mL)溶液，将混合物在-20℃下搅拌1小时，加入水(50.00mL)洗涤，有机相用无水硫酸钠干燥，过滤后浓缩，残留物用EtOAc(15mL)搅拌，过滤干燥后得到化合物5-b。Step A: To a solution of 1-f (1.3g, 5.69mmol, 1eq) in DCM (100.00mL) at -20°C was slowly added a solution of p-methoxybenzylamine (1.56g, 11.38mmol, 1.47mL, 2eq) DCM (100.00 mL) solution, the mixture was stirred at -20°C for 1 hour, water (50.00 mL) was added to wash, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, the residue was stirred with EtOAc (15 mL), and filtered to dryness The compound 5-b is then obtained.
步骤B：在CoCl 2·6H 2O(1.71g，7.19mmol，0.1eq)的THF(200.00mL)和水(100.00mL)溶液中加入5-2(10g，71.89mmol，8.00mL，1eq)，然后分批加入NaBH 4(13.60g，359.45mmol，5eq)，反应液在30℃下搅拌12小时，向反应液中缓慢加入NH 3·H 2O(25％，20mL)，再加入水(100mL)，用EtOAc(100mL×2)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE∶EtOAc＝10∶1-3∶1)得到化合物5-c。 Step B: To a solution of CoCl 2 ·6H 2 O (1.71 g, 7.19 mmol, 0.1 eq) in THF (200.00 mL) and water (100.00 mL) was added 5-2 (10 g, 71.89 mmol, 8.00 mL, 1 eq), Then NaBH 4 (13.60 g, 359.45 mmol, 5 eq) was added in portions, the reaction solution was stirred at 30° C. for 12 hours, NH 3 ·H 2 O (25%, 20 mL) was slowly added to the reaction solution, followed by water (100 mL) ), extracted with EtOAc (100 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=10:1-3:1) to obtain compound 5- c.
步骤C：向5-c(3.65g，25.49mmol，2.99mL，1.5eq)的甲苯(30.00mL)溶液中加入碳酸铯(8.31g，25.49mmol，1.5eq)和3-1(3.0g，16.99mmol，1eq)。将混合物升温至80℃下搅拌12小时，过滤后浓缩，残留物通过柱层析分离(PE∶EtOAc＝100∶1-10∶1)得到化合物5-d。Step C: To a solution of 5-c (3.65 g, 25.49 mmol, 2.99 mL, 1.5 eq) in toluene (30.00 mL) was added cesium carbonate (8.31 g, 25.49 mmol, 1.5 eq) and 3-1 (3.0 g, 16.99 mmol, 1eq). The mixture was warmed to 80°C and stirred for 12 hours, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=100:1-10:1) to give compound 5-d.
步骤D：在5-d(2.0g，7.06mmol，1eq)的EtOH(100mL)和水(50mL)的混合物中加入还原铁粉(1.97g，35.30mmol，5eq)和NH 4Cl(1.89g，35.30mmol，1.23mL，5eq)，在70℃下搅拌1小时，用EtOAc(100mL×3)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝10∶1-3∶1)纯化得到化合物5-e。 Step D: To a mixture of 5-d (2.0 g, 7.06 mmol, 1 eq) in EtOH (100 mL) and water (50 mL) was added reduced iron powder (1.97 g, 35.30 mmol, 5 eq) and NH 4 Cl (1.89 g, 35.30mmol, 1.23mL, 5eq), stirred at 70°C for 1 hour, extracted with EtOAc (100mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (PE: EtOAc=10:1-3:1) was purified to give compound 5-e.
步骤E：向5-e(1.0g，3.95mmol，1eq)的THF(100.00mL)溶液中缓慢加入CDI(960.51mg，5.92mmol，1.5eq)。加完后将混合物在70℃下搅拌2小时。将反应液浓缩，残留物通过柱层析(PE∶EtOAc＝20∶1-3∶1)纯化得到化合物5-f。Step E: To a solution of 5-e (1.0 g, 3.95 mmol, 1 eq) in THF (100.00 mL) was slowly added CDI (960.51 mg, 5.92 mmol, 1.5 eq). After the addition was complete the mixture was stirred at 70°C for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=20:1-3:1) to obtain compound 5-f.
步骤F：在5-f(450mg，1.61mmol，1eq)的DMF(10.00mL)溶液中加入5-b(1.04g，2.42mmol，1.5eq)，碳酸铯(630.13mg，1.93mmol，1.2eq)，碘化亚铜(30.69mg，161.16μmol，0.1eq)和8-羟基喹啉(23.39mg，161.16μmol，27.85μL，0.1eq)，置换氮气，在100℃下搅拌3小时，向反应液中加入水(50mL)，用EtOAc(50mL×2)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝10∶1-3∶1)纯化得化合物5-g。Step F: To a solution of 5-f (450 mg, 1.61 mmol, 1 eq) in DMF (10.00 mL) was added 5-b (1.04 g, 2.42 mmol, 1.5 eq), cesium carbonate (630.13 mg, 1.93 mmol, 1.2 eq) , cuprous iodide (30.69mg, 161.16μmol, 0.1eq) and 8-hydroxyquinoline (23.39mg, 161.16μmol, 27.85μL, 0.1eq), replaced with nitrogen, stirred at 100 ° C for 3 hours, added to the reaction solution Water (50 mL) was added, extracted with EtOAc (50 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=10:1-3:1) Compound 5-g was obtained.
步骤G：在5-g(900mg，1.34mmol，1eq)的DCM(50.00mL)和水(5.00mL)溶液中加入DDQ(1.52g，6.69mmol，5eq)，在30℃下搅拌12小时，向反应液中加入饱和碳酸氢钠水溶液(20mL)，用DCM(50mL×2)萃取，合并的有机相用水(50mL×2)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物用EtOAc(10mL)搅拌，过滤干燥后得化合物5-h。Step G: To a solution of 5-g (900 mg, 1.34 mmol, 1 eq) in DCM (50.00 mL) and water (5.00 mL) was added DDQ (1.52 g, 6.69 mmol, 5 eq), stirred at 30 °C for 12 hours, and added to Saturated aqueous sodium bicarbonate solution (20 mL) was added to the reaction solution, extracted with DCM (50 mL×2), the combined organic phases were washed with water (50 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was washed with EtOAc (10 mL×2). ) was stirred, filtered and dried to obtain compound 5-h.
步骤H：在5-h(50mg，85.59μmol，1eq)的MeOH(3mL)和水(1mL)的混合物中加入还原铁粉(95.59mg，1.71mmol，20eq)和NH 4Cl(91.56mg，1.71mmol，20eq)，在70℃下搅拌1小时，冷却后将反应液过滤，滤液加入水(20mL)，用DCM(25mL×2)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩得到化合物5-i。 Step H: To a mixture of 5-h (50 mg, 85.59 μmol, 1 eq) in MeOH (3 mL) and water (1 mL) was added reduced iron powder (95.59 mg, 1.71 mmol, 20 eq) and NH 4 Cl (91.56 mg, 1.71 mmol, 20eq), stirred at 70°C for 1 hour, cooled and filtered the reaction solution, added water (20mL) to the filtrate, extracted with DCM (25mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated Compound 5-i is obtained.
步骤I：在0℃下，向5-i(20mg，49.71μmol，1eq)的吡啶(1.0mL)溶液中加入氯甲酸甲酯(7.05mg，74.57μmol，5.78μL，1.5eq)，0℃下搅拌30分钟，向反应液中加入水(10mL)，用EtOAc(10mL×2)萃取，有机相用饱和食盐水(10mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物5。 1H NMR(400MHz，DMSO-d 6)：δppm 8.20(dd，J＝2.6，9.4Hz，1H)，8.07(t，J＝2.1Hz，1H)，7.98(br s，1H)，7.44-7.30(m，1H)，7.22-7.08(m，2H)，6.37(br s，4H)，5.17(s，2H)，3.62(s，3H)；LCMS(ESI)m/z：461.1[M+1] +。 Step I: To a solution of 5-i (20 mg, 49.71 μmol, 1 eq) in pyridine (1.0 mL) at 0 °C was added methyl chloroformate (7.05 mg, 74.57 μmol, 5.78 μL, 1.5 eq), at 0 °C Stirred for 30 minutes, water (10 mL) was added to the reaction solution, extracted with EtOAc (10 mL×2), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [Mobile phase: water (0.225% FA)-ACN] Compound 5 was obtained. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.20 (dd, J=2.6, 9.4 Hz, 1H), 8.07 (t, J=2.1 Hz, 1H), 7.98 (br s, 1H), 7.44-7.30 (m, 1H), 7.22-7.08 (m, 2H), 6.37 (br s, 4H), 5.17 (s, 2H), 3.62 (s, 3H); LCMS (ESI) m/z: 461.1 [M+1 ] + .
实施例6Example 6
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000073
Figure PCTCN2022088918-appb-000073
在0℃下，向化合物5(15mg，32.58μmol，1eq)的DMF(1.00mL)溶液中加入NaH(1.95mg，48.87μmol，60％纯度，1.5eq)，0℃下搅拌30分钟后加入碘甲烷(6.94mg，48.87μmol，3.04μL，1.5eq)，继续在0℃下搅拌30分钟，将反应液缓慢倒入水(30mL)中，然后用EtOAc(30mL×2)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物6。 1H NMR(400MHz，DMSO-d 6)：δppm 8.47(br s，1H)，8.22(br dd，J＝2.6，9.4Hz，1H)，7.45-7.30(m，1H)，7.22-7.06(m，2H)，6.64-6.49(m，4H)，5.17(s，2H)，3.66-3.55(s，3H)，3.00(s，3H)。LCMS(ESI)m/z：475.1[M+1] +。 To a solution of compound 5 (15 mg, 32.58 μmol, 1 eq) in DMF (1.00 mL) at 0°C, NaH (1.95 mg, 48.87 μmol, 60% purity, 1.5 eq) was added, and iodine was added after stirring at 0°C for 30 minutes. Methane (6.94 mg, 48.87 μmol, 3.04 μL, 1.5 eq), continued to stir at 0 °C for 30 minutes, the reaction solution was slowly poured into water (30 mL), then extracted with EtOAc (30 mL×2), the combined organic phases It was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 6. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.47 (br s, 1H), 8.22 (br dd, J=2.6, 9.4 Hz, 1H), 7.45-7.30 (m, 1H), 7.22-7.06 (m , 2H), 6.64-6.49 (m, 4H), 5.17 (s, 2H), 3.66-3.55 (s, 3H), 3.00 (s, 3H). LCMS (ESI) m/z: 475.1 [M+1] + .
实施例7Example 7
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000074
Figure PCTCN2022088918-appb-000074
步骤A：在氮气保护下，向3-1(2g，11.33mmol，1eq)的甲苯(20.00mL)溶液中加入DIPEA(2.20g，16.99mmol，2.96mL，1.5eq)和2-氯苄胺(1.60g，11.33mmol，1.37mL，1eq)。将混合物升温至80℃下搅拌17小时。冷却后，加入水(20mL)，用EtOAc(20mL×3)萃取，合并的有机相用无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析分离(PE∶EtOAc＝100∶1-50∶1)得到化合物7-a， 1H NMR(400MHz，CDCl 3)δppm 4.94(d，J＝6.02Hz，2H)7.17-7.34(m，2H)7.37-7.47(m，2H)8.22(dd，J＝7.91，2.89Hz，1H)8.40(d，J＝2.89Hz，1H)8.47-8.67(m，1H)。 Step A: To a solution of 3-1 (2g, 11.33mmol, 1eq) in toluene (20.00mL) under nitrogen protection was added DIPEA (2.20g, 16.99mmol, 2.96mL, 1.5eq) and 2-chlorobenzylamine ( 1.60 g, 11.33 mmol, 1.37 mL, 1 eq). The mixture was warmed to 80°C and stirred for 17 hours. After cooling, water (20 mL) was added, extracted with EtOAc (20 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EtOAc=100:1-50 : 1) to obtain compound 7-a, 1 H NMR (400 MHz, CDCl 3 ) δppm 4.94 (d, J=6.02 Hz, 2H) 7.17-7.34 (m, 2H) 7.37-7.47 (m, 2H) 8.22 (dd, J=7.91, 2.89Hz, 1H) 8.40 (d, J=2.89Hz, 1H) 8.47-8.67 (m, 1H).
步骤B：在7-a(3.13g，8.01mmol，1eq)的THF(45mL)和水(15mL)的混合物中加入还原铁粉(2.24g，40.03mmol，5eq)和NH 4Cl(1.71g，32.02mmol，1.12mL，4eq)。置换氮气，在80℃下搅拌17小时，将反应液过滤，滤液再加入水(80mL)，用EtOAc(80mL×3)萃取，合并的有机相用饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝100∶1-5∶1)纯化得到化合物7-b， 1H NMR(400MHz，DMSO-d 6)：δppm 7.44-7.38(m，1H)，7.35-7.30(m，1H)，7.28-7.24(m，2H)，7.22(d，J＝2.6Hz，1H)，6.64(dd，J＝2.8，10.4Hz，1H)，6.09(t，J＝5.6Hz，1H)，5.22(s，2H)，4.58(d，J＝5.6Hz，2H)。 Step B: To a mixture of 7-a (3.13 g, 8.01 mmol, 1 eq) in THF (45 mL) and water (15 mL) was added reduced iron powder (2.24 g, 40.03 mmol, 5 eq) and NH 4 Cl (1.71 g, 32.02 mmol, 1.12 mL, 4 eq). Nitrogen was replaced, stirred at 80 °C for 17 hours, the reaction solution was filtered, water (80 mL) was added to the filtrate, extracted with EtOAc (80 mL×3), the combined organic phases were washed with saturated brine (100 mL), and anhydrous sodium sulfate It was dried, filtered and concentrated, and the residue was purified by column chromatography (PE:EtOAc=100:1-5:1) to give compound 7-b, 1 H NMR (400 MHz, DMSO-d 6 ): δppm 7.44-7.38 (m , 1H), 7.35-7.30(m, 1H), 7.28-7.24(m, 2H), 7.22(d, J=2.6Hz, 1H), 6.64(dd, J=2.8, 10.4Hz, 1H), 6.09( t, J=5.6 Hz, 1H), 5.22 (s, 2H), 4.58 (d, J=5.6 Hz, 2H).
步骤C：在7-b(1.16g，3.75mmol，1eq)的THF(30.00mL)溶液中缓慢加入CDI(911.37mg，5.62mmol，1.5eq)。加完后将混合物在75℃下搅拌4小时。将反应液浓缩，残留物通过柱层析(PE∶EtOAc＝20∶1-4∶1)纯化得到化合物7-c。Step C: To a solution of 7-b (1.16 g, 3.75 mmol, 1 eq) in THF (30.00 mL) was slowly added CDI (911.37 mg, 5.62 mmol, 1.5 eq). After the addition was complete the mixture was stirred at 75°C for 4 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=20:1-4:1) to obtain compound 7-c.
步骤D：在7-c(0.3g，1.08mmol，1eq)的DMF(5.00mL)溶液中加入1-g(245.76mg，1.30mmol，1.2eq)，碳酸铯(704.01mg，2.16mmol，2.0eq)，碘化亚铜(20.58mg，108.04μmol，0.1eq)和1，10-菲啰啉(38.94mg，216.08μmol，0.2eq)。置换氮气，在90℃下搅拌3小时，反应液冷却后过滤，向滤液中加入水(10mL)，用DCM∶MeOH＝5∶1(10mL×4)萃取，合并的有机相用饱和食盐水(10mL×3)洗涤，无水硫酸钠干燥，过滤后浓缩得化合物7-d。Step D: To a solution of 7-c (0.3g, 1.08mmol, 1eq) in DMF (5.00mL) was added 1-g (245.76mg, 1.30mmol, 1.2eq), cesium carbonate (704.01mg, 2.16mmol, 2.0eq) ), cuprous iodide (20.58 mg, 108.04 μmol, 0.1 eq) and 1,10-phenanthroline (38.94 mg, 216.08 μmol, 0.2 eq). The nitrogen was replaced, stirred at 90 °C for 3 hours, the reaction solution was cooled and filtered, water (10 mL) was added to the filtrate, extracted with DCM:MeOH=5:1 (10 mL×4), and the combined organic phase was washed with saturated brine ( 10 mL × 3) was washed, dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 7-d.
步骤E：在7-d(276.00mg，640.70μmol，1eq)的MeOH(8mL)和水(2mL)的混合物中加入还原铁粉(715.60mg，12.81mmol，20eq)和NH 4Cl(685.44mg，12.81mmol，448.00μL，20eq)，在75℃下搅拌1.5小时，冷却后将反应液过滤，滤液浓缩后加入水(10mL)，用DCM∶MeOH＝10∶1(10ml×3)萃取，合并的有机相用饱和食盐水(10mL×2)洗涤，无水硫酸钠干燥，过滤，浓缩后的残留物经薄层色谱法(DCM∶MeOH＝10∶1)纯化得到化合物7-e。 Step E: To a mixture of 7-d (276.00 mg, 640.70 μmol, 1 eq) in MeOH (8 mL) and water (2 mL) was added reduced iron powder (715.60 mg, 12.81 mmol, 20 eq) and NH 4 Cl (685.44 mg, 12.81mmol, 448.00μL, 20eq), stirred at 75°C for 1.5 hours, cooled and filtered the reaction solution, concentrated the filtrate, added water (10mL), extracted with DCM:MeOH=10:1 (10ml×3), the combined The organic phase was washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the concentrated residue was purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 7-e.
步骤F：在0℃下，向7-e(20mg，49.90μmol，1eq)的吡啶(1.0mL)溶液中加入氯甲酸甲酯(4.72mg，49.95μmol，3.87μL，1.00eq)，0℃下搅拌30分钟，将反应液倒入到水(1mL)中，用EtOAc(2mL×3)萃取，无水硫酸钠干燥，过滤后浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得化合物7。 1H NMR(400MHz，DMSO-d 6)δppm 8.23(dd，J＝9.47，2.57Hz，1H)，7.98-8.14(m，1H)，7.96(br s，1H)，7.51(dd，J＝7.84，1.32Hz，1H)，7.19-7.43(m，2H)，7.08(d，J＝6.40Hz，1H)，6.37(br s，4H)，5.15(s，2H)，3.62(br s，3H)；LCMS(ESI)m/z：459.0[M+1] +。 Step F: To a solution of 7-e (20 mg, 49.90 μmol, 1 eq) in pyridine (1.0 mL) at 0 °C was added methyl chloroformate (4.72 mg, 49.95 μmol, 3.87 μL, 1.00 eq) at 0 °C After stirring for 30 minutes, the reaction solution was poured into water (1 mL), extracted with EtOAc (2 mL×3), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was purified by preparative HPLC [mobile phase: water (0.225% FA) )-ACN] to obtain compound 7. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 8.23 (dd, J=9.47, 2.57 Hz, 1H), 7.98-8.14 (m, 1H), 7.96 (br s, 1H), 7.51 (dd, J=7.84 , 1.32Hz, 1H), 7.19-7.43(m, 2H), 7.08(d, J=6.40Hz, 1H), 6.37(br s, 4H), 5.15(s, 2H), 3.62(br s, 3H) ; LCMS (ESI) m/z: 459.0 [M+1] + .
实施例8Example 8
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000075
Figure PCTCN2022088918-appb-000075
步骤A：向3-e(40mg，104.06μmol，1eq)的DMF(1mL)溶液中依次加入三氟甲磺酸三氟乙酯(48.31mg，208.15μmol，2.0eq)和DIPEA(40.35mg，312.22μmol，54.38μL，3.0eq)。将混合物在80℃下搅拌12小时。冷却后加入水(20mL)，用EA(10mL×2)萃取，合并的有机相用饱和食盐水(10mL)洗涤，有机相用无水硫酸钠干燥，过滤并浓缩，残余物通过柱层析(二氯甲烷∶甲醇＝15∶1)纯化得到化合物8-a。Step A: To a solution of 3-e (40 mg, 104.06 μmol, 1 eq) in DMF (1 mL) was added trifluoroethyl trifluoromethanesulfonate (48.31 mg, 208.15 μmol, 2.0 eq) followed by DIPEA (40.35 mg, 312.22 μmol, 54.38 μL, 3.0 eq). The mixture was stirred at 80°C for 12 hours. After cooling, water (20 mL) was added, extracted with EA (10 mL×2), the combined organic phase was washed with saturated brine (10 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography ( Dichloromethane: methanol = 15: 1) was purified to obtain compound 8-a.
步骤B：向8-a(15mg，32.16μmol，1eq)的DMF(1mL)溶液中加入CDI(10.43mg，64.33μmol，2.0eq)，将混合物在90℃下搅拌6小时。反应液中加入饱和食盐水(10mL)，用EA(8mL×2)萃取，用盐水(10mL)洗涤有机相，无水Na 2SO 4干燥，过滤并浓缩，得到残余物。残余物用制备HPLC纯化[流动相：水(10mM NH 4HCO 3)-ACN]得化合物8。 1H NMR(400MHz，DMSO-d 6)：δppm 8.19(dd，J＝2.4，9.3Hz，1H)，8.10(d，J＝1.9Hz，1H)，7.40-7.26(m，1H)，7.26-7.19(m，1H)，7.26-7.19(m，1H)，7.18-7.12(m，1H)，7.43-7.12(m，1H)，7.12-7.04(m，1H)，7.09(br s，1H)，5.16(s，2H)，4.91(q，J＝9.0Hz，2H)；LCMS(ESI)m/z：493.1[M+1] +。 Step B: To a solution of 8-a (15 mg, 32.16 μmol, 1 eq) in DMF (1 mL) was added CDI (10.43 mg, 64.33 μmol, 2.0 eq) and the mixture was stirred at 90°C for 6 hours. Saturated brine (10 mL) was added to the reaction solution, extracted with EA (8 mL×2), the organic phase was washed with brine (10 mL), dried over anhydrous Na 2 SO 4 , filtered and concentrated to obtain a residue. The residue was purified by preparative HPLC [mobile phase: water (10 mM NH4HCO3 ) -ACN] to give compound 8. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.19 (dd, J=2.4, 9.3 Hz, 1H), 8.10 (d, J=1.9 Hz, 1H), 7.40-7.26 (m, 1H), 7.26- 7.19(m, 1H), 7.26-7.19(m, 1H), 7.18-7.12(m, 1H), 7.43-7.12(m, 1H), 7.12-7.04(m, 1H), 7.09(br s, 1H) , 5.16 (s, 2H), 4.91 (q, J=9.0 Hz, 2H); LCMS (ESI) m/z: 493.1 [M+1] + .
实施例9Example 9
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000076
Figure PCTCN2022088918-appb-000076
步骤A：将氨水(3.64g，103.86mmol，4.00mL，4.03eq)和二异丙基乙胺(5.00g，38.66mmol，6.73mL，1.5eq)溶解在二氯甲烷(80mL)得到溶液1，将9-1(5g，25.78mmol，1eq)溶于二氯甲烷(15mL)溶液中得到溶液2，在0℃条件下，将溶液1缓慢滴加到溶液2中，并在0℃下搅拌1小时，将反应液过滤得到化合物9-a。 1H NMR(400MHz，DMSO-d 6)：δppm 8.57(br s，1H)9.01(s，1H)9.19(br s，1H)。 Step A: Ammonia (3.64g, 103.86mmol, 4.00mL, 4.03eq) and diisopropylethylamine (5.00g, 38.66mmol, 6.73mL, 1.5eq) were dissolved in dichloromethane (80mL) to obtain solution 1, 9-1 (5g, 25.78mmol, 1eq) was dissolved in dichloromethane (15mL) solution to obtain solution 2, at 0°C, solution 1 was slowly added dropwise to solution 2, and stirred at 0°C for 1 hours, the reaction solution was filtered to obtain compound 9-a. 1 H NMR (400 MHz, DMSO-d 6 ): δ ppm 8.57 (br s, 1H) 9.01 (s, 1H) 9.19 (br s, 1H).
步骤B：将9-a(0.2g，1.15mmol，1.2eq)、化合物3-c(249.44mg，954.86μmol，1eq)和无水碳酸钾(263.94mg，1.91mmol，2eq)溶于DMF(5mL)中，并用氮气置换3次，在25℃下搅拌2小时。将反应液滴加到40mL水中，并搅拌15分钟，然后过滤得到化合物9-b。Step B: 9-a (0.2g, 1.15mmol, 1.2eq), compound 3-c (249.44mg, 954.86μmol, 1eq) and anhydrous potassium carbonate (263.94mg, 1.91mmol, 2eq) were dissolved in DMF (5mL) ), replaced with nitrogen three times, and stirred at 25°C for 2 hours. The reaction was added dropwise to 40 mL of water, stirred for 15 minutes, and then filtered to obtain compound 9-b.
步骤C：将化合物9-b(400mg，879.52μmol，1eq)溶于MeOH(9mL)和H 2O(3mL)中，向该溶液中加入Fe(982.33mg，17.59mmol，20eq)和NH 4Cl(940.93mg，17.59mmol，614.99μL，20eq)，在75℃下搅拌1小时。将反应液冷却至25℃，用硅藻土过滤，将滤液浓缩后，用薄层色谱法(DCM∶MeOH＝10∶1)纯化得到化合物9-c。 Step C: Compound 9-b (400 mg, 879.52 μmol, 1 eq) was dissolved in MeOH (9 mL) and H 2 O (3 mL), to this solution was added Fe (982.33 mg, 17.59 mmol, 20 eq) and NH 4 Cl (940.93 mg, 17.59 mmol, 614.99 μL, 20 eq), stirred at 75° C. for 1 hour. The reaction solution was cooled to 25°C, filtered through celite, and the filtrate was concentrated and purified by thin layer chromatography (DCM:MeOH=10:1) to obtain compound 9-c.
步骤D：将化合物9-c(45mg，121.84μmol，1eq)溶于吡啶(2mL)中，在0℃下滴加氯甲酸甲酯(17.27mg，182.76μmol，14.16μL，1.5eq)，并在该温度下搅拌30分钟，将反应液滴入2mL的水中，用EA(3mL×3)萃取，合并的有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物9。 1H NMR(400MHz，DMSO-d 6)δppm 3.68(s，3H)5.15(s，2H)7.09-7.43(m，6H)8.09(d，J＝1.88Hz，1H)8.16(dd，J＝9.35，2.45Hz，1H)8.28(br s，1H)8.85(br s，1H)；LCMS(ESI)m/z：428.0[M+1] +。 Step D: Compound 9-c (45 mg, 121.84 μmol, 1 eq) was dissolved in pyridine (2 mL), methyl chloroformate (17.27 mg, 182.76 μmol, 14.16 μL, 1.5 eq) was added dropwise at 0° C. Stir at this temperature for 30 minutes, drop the reaction into 2 mL of water, extract with EA (3 mL×3), dry the combined organic phases with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 9. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 3.68 (s, 3H) 5.15 (s, 2H) 7.09-7.43 (m, 6H) 8.09 (d, J=1.88 Hz, 1H) 8.16 (dd, J=9.35 , 2.45 Hz, 1H) 8.28 (br s, 1H) 8.85 (br s, 1H); LCMS (ESI) m/z: 428.0 [M+1] + .
实施例10Example 10
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000077
Figure PCTCN2022088918-appb-000077
步骤A：在0℃和氮气保护下，向化合物3-e(203mg，512.33μmol，1eq)的吡啶(2.0mL)溶液中一次性加入化合物10-1(219.74mg，1.54mmol，158.09μL，3eq)，混合物在0℃搅拌反应1小时，所得反应液逐滴加入到水(20mL)中，然后用乙酸乙酯(10mL×3)萃取。合并的有机层用饱和食盐水(20mL)洗涤，用无水Na 2SO 4干燥，过滤，滤液减压浓缩后的残留物经薄层色谱法(SiO 2，DCM/MeOH＝15/1)纯化得到化合物10-a的粗产品，该粗产品未经进一步纯化直接用于下步反应。LCMS(ESI)m/z：491.0[M+1] +。 Step A: To a solution of compound 3-e (203 mg, 512.33 μmol, 1 eq) in pyridine (2.0 mL) was added compound 10-1 (219.74 mg, 1.54 mmol, 158.09 μL, 3 eq) in one portion at 0°C under nitrogen protection ), the mixture was stirred and reacted at 0° C. for 1 hour, the resulting reaction solution was added dropwise to water (20 mL), and then extracted with ethyl acetate (10 mL×3). The combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography (SiO 2 , DCM/MeOH=15/1). The crude product of compound 10-a was obtained, which was used in the next reaction without further purification. LCMS (ESI) m/z: 491.0 [M+1] + .
步骤B：在0℃和氮气保护下，向化合物10-a(65mg，132.42μmol，1eq)的THF(4.0mL)溶液中一次性加入NaHMDS(1M，264.85μL，2eq)，混合物在0℃下反应1小时。然后逐滴加入到冰浴(10mL)中，然后用乙酸乙酯(10mL×3)萃取，合并的有机层用饱和食盐水(20mL)洗涤，用无水Na 2SO 4干燥，抽滤，滤液减压浓缩后的残留物经制备型HPLC[流动相：水(0.04％NH 3·H 2O+10mM NH 4HCO 3)-ACN]纯化得到化合 物10。 1H NMR(400MHz，DMSO-d 6)：δppm 11.77(br s，1H)，8.17-8.05(m，2H)，7.40-7.26(m，2H)，7.26-7.12(m，2H)，6.95(br s，2H)，5.35(t，J＝4.9Hz，1H)，5.15(s，2H)，3.97(t，J＝4.8Hz，2H)，3.68-3.56(m，2H)； Step B: To a solution of compound 10-a (65 mg, 132.42 μmol, 1 eq) in THF (4.0 mL) was added NaHMDS (1 M, 264.85 μL, 2 eq) in one portion at 0 °C under nitrogen protection, the mixture was at 0 °C React for 1 hour. It was then added dropwise to an ice bath (10 mL), then extracted with ethyl acetate (10 mL×3), the combined organic layers were washed with saturated brine (20 mL), dried over anhydrous Na 2 SO 4 , filtered with suction, and the filtrate was The residue after concentration under reduced pressure was purified by preparative HPLC [mobile phase: water (0.04% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 )-ACN] to give compound 10 . 1 H NMR (400 MHz, DMSO-d 6 ): δppm 11.77 (br s, 1H), 8.17-8.05 (m, 2H), 7.40-7.26 (m, 2H), 7.26-7.12 (m, 2H), 6.95 ( br s, 2H), 5.35(t, J=4.9Hz, 1H), 5.15(s, 2H), 3.97(t, J=4.8Hz, 2H), 3.68-3.56(m, 2H);
LCMS(ESI)m/z：455.2[M+1] +。 LCMS (ESI) m/z: 455.2 [M+1] + .
实施例11Example 11
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000078
Figure PCTCN2022088918-appb-000078
将化合物9-c(200mg，349.28μmol，1eq)溶于吡啶(2mL)中，在0℃下滴加11-1(55.82mg，523.92μmol，1.5eq)，并在该温度下搅拌30分钟。反应结束后，将反应液滴入2mL的水中，用EA(4mL×3)萃取，将有机相减压浓缩。残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物11。 1H NMR(400MHz，DMSO-d 6)δppm 1.13(d，J＝6.78Hz，6H)2.67(quin，J＝6.78Hz，1H)5.15(s，2H)7.10-7.18(m，1H)7.17-7.39(m，5H)8.09(s，1H)8.16(dd，J＝9.29，2.38Hz，1H)8.37(s，1H)9.33(s，1H)。LCMS(ESI)m/z：440.1[M+1] +。 Compound 9-c (200 mg, 349.28 μmol, 1 eq) was dissolved in pyridine (2 mL), 11-1 (55.82 mg, 523.92 μmol, 1.5 eq) was added dropwise at 0° C., and stirred at this temperature for 30 minutes. After the reaction was completed, the reaction was dropped into 2 mL of water, extracted with EA (4 mL×3), and the organic phase was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 11. 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.13(d, J=6.78Hz, 6H) 2.67(quin, J=6.78Hz, 1H) 5.15(s, 2H) 7.10-7.18(m, 1H) 7.17- 7.39 (m, 5H) 8.09 (s, 1H) 8.16 (dd, J=9.29, 2.38 Hz, 1H) 8.37 (s, 1H) 9.33 (s, 1H). LCMS (ESI) m/z: 440.1 [M+1] + .
实施例12Example 12
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000079
Figure PCTCN2022088918-appb-000079
将化合物9-c(200mg，349.28μmol，1eq)溶于吡啶(2mL)中，在0℃下滴加12-1(76.81mg，523.92μmol，69.83μL，1.5eq)，并在该温度下搅拌30分钟。将反应液滴入2mL的水中，用EA(4mL×3)萃取，将有机相用无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用制备HPLC纯化[流动相：水(10mMNH 4HCO 3)-ACN]得到化合物12。 1H NMR(400MHz，DMSO-d 6)：δppm 1.15-1.56(m，3H)1.40(q，J＝12.05Hz，2H)1.66(br d，J＝11.67Hz，1H)1.76(br d，J＝12.67Hz，2H)1.88(br d，J＝11.17Hz，2H)2.31-2.43(m，1H)5.14(s，2H)7.06-7.43(m，6H)8.09(t，J＝2.07Hz，1H)8.15(dd，J＝9.22，2.45Hz，1H)8.36(s，1H)9.15(br s，1H)。LCMS(ESI)m/z：480.0[M+1] +。 Compound 9-c (200 mg, 349.28 μmol, 1 eq) was dissolved in pyridine (2 mL), 12-1 (76.81 mg, 523.92 μmol, 69.83 μL, 1.5 eq) was added dropwise at 0°C, and stirred at this temperature 30 minutes. The reaction was dropped into 2 mL of water, extracted with EA (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (10 mM NH 4 HCO) 3 )-ACN] to give compound 12. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 1.15-1.56 (m, 3H) 1.40 (q, J=12.05 Hz, 2H) 1.66 (br d, J=11.67 Hz, 1H) 1.76 (br d, J = 12.67Hz, 2H) 1.88(br d, J=11.17Hz, 2H) 2.31-2.43(m, 1H) 5.14(s, 2H) 7.06-7.43(m, 6H) 8.09(t, J=2.07Hz, 1H) ) 8.15 (dd, J=9.22, 2.45 Hz, 1H) 8.36 (s, 1H) 9.15 (br s, 1H). LCMS (ESI) m/z: 480.0 [M+1] + .
实施例13Example 13
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000080
Figure PCTCN2022088918-appb-000080
将化合物9-c(0.036g，94.06μmol，1eq)溶于DMF(1mL)中，加入DIEA(48.63mg，376.25μmol，65.54μL，4eq)和13-1(24.00mg，103.47μmol，12.97μL，1.1eq)，所得混合物在130℃下搅拌2小时。反应液用制备HPLC纯化[流动相：水(0.05％氨水)-ACN]得到化合物13。 1H NMR(400MHz，DMSO-d 6)：δppm 8.19-8.06(m，2H)，7.99(s，1H)，7.39-7.32(m，1H)，7.31-7.19(m，2H)，7.18-7.12(m，1H)，5.15(s，2H)，3.83-3.71(m，4H)，2.95-2.80(m，4H)；LCMS(ESI)m/z：440.2[M+1] +。 Compound 9-c (0.036g, 94.06μmol, 1eq) was dissolved in DMF (1mL), DIEA (48.63mg, 376.25μmol, 65.54μL, 4eq) and 13-1 (24.00mg, 103.47μmol, 12.97μL) were added, 1.1 eq) and the resulting mixture was stirred at 130°C for 2 hours. The reaction solution was purified by preparative HPLC [mobile phase: water (0.05% ammonia water)-ACN] to obtain compound 13. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.19-8.06 (m, 2H), 7.99 (s, 1H), 7.39-7.32 (m, 1H), 7.31-7.19 (m, 2H), 7.18-7.12 (m, 1H), 5.15 (s, 2H), 3.83-3.71 (m, 4H), 2.95-2.80 (m, 4H); LCMS (ESI) m/z: 440.2 [M+1] + .
实施例14Example 14
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000081
Figure PCTCN2022088918-appb-000081
在25℃下，将14-1(0.159g，1.03mmol，1eq)溶于DCM(1mL)，加入草酰氯(117.88mg，928.70μmol，81.29μL，0.9eq)和DMF(7.54mg，103.19μmol，7.94μL，0.1eq)，搅拌至无气体放出，并将该反应液滴加至化合物9-c(119.09mg，206.38μmol，0.2eq)的DCM(1mL)和吡啶(1mL)的溶液中，在25℃下搅拌2小时。向反应液中加入2mL的水，并用DCM萃取(4mL×3)，将有机相用无水硫酸钠干燥，过滤，滤液浓缩。残留物用制备HPLC纯化[流动相：水(0.04％NH 3H 2O)-ACN]得到化合物14。 1H NMR(400MHz，DMSO-d 6)δppm 1.31-1.38(m，2H)1.68(br s，2H)5.15(s，2H)7.11-7.18(m，2H)7.17-7.40(m，4H)8.05-8.12(m，2H)8.22(dd，J＝9.35，2.57Hz，1H)9.10(br s，1H)；LCMS(ESI)m/z：506.0[M+1] +。 At 25°C, 14-1 (0.159 g, 1.03 mmol, 1 eq) was dissolved in DCM (1 mL), oxalyl chloride (117.88 mg, 928.70 μmol, 81.29 μL, 0.9 eq) and DMF (7.54 mg, 103.19 μmol, oxalyl chloride) were added. 7.94 μL, 0.1 eq), stirred until no gas evolved, and the reaction was added dropwise to a solution of compound 9-c (119.09 mg, 206.38 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL), in Stir at 25°C for 2 hours. 2 mL of water was added to the reaction solution, extracted with DCM (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.04% NH3H2O ) -ACN ] to give compound 14. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 1.31-1.38 (m, 2H) 1.68 (br s, 2H) 5.15 (s, 2H) 7.11-7.18 (m, 2H) 7.17-7.40 (m, 4H) 8.05 -8.12 (m, 2H) 8.22 (dd, J=9.35, 2.57 Hz, 1H) 9.10 (br s, 1H); LCMS (ESI) m/z: 506.0 [M+1] + .
实施例15Example 15
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000082
Figure PCTCN2022088918-appb-000082
步骤A：将三溴吡啶嗡(12.50g，7.81mmol，4eq)加入到化合物15-1(1.50g，9.77mmol，1eq)的叔丁醇(54mL)溶液中，25℃搅拌6小时。将反应液过滤，EA(20mL)清洗滤饼，向滤液中加入水(30mL)，乙酸乙酯(50mL)萃取。收集有机相，用饱和食盐水(50mL×2)洗，无水硫酸钠干燥，过滤，浓缩，残留物经过柱层析纯化(SiO 2，PE∶EA＝5∶1-3∶1)分离得到化合物15-a。 Step A: Tribromopyridinium (12.50 g, 7.81 mmol, 4 eq) was added to a solution of compound 15-1 (1.50 g, 9.77 mmol, 1 eq) in tert-butanol (54 mL), and stirred at 25° C. for 6 hours. The reaction solution was filtered, the filter cake was washed with EA (20 mL), and water (30 mL) was added to the filtrate, followed by extraction with ethyl acetate (50 mL). The organic phase was collected, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was purified by column chromatography (SiO 2 , PE:EA=5:1-3:1) to obtain Compound 15-a.
步骤B：将化合物15-a(1.5g，4.58mmol，1eq)和氯化铵(1.23g，22.91mmol，5eq)溶于四氢呋喃(16mL)和水(8mL)中，然后向上述混合液中加入锌粉(1.50g，22.91mmol，5eq)，该反应体系在25℃搅拌1小时。反应液过滤，滤液用乙酸乙酯萃取(20mL×2)，收集有机相，用饱和食盐水洗(20mL×2)，无水硫酸钠干燥，过滤浓缩，残留物经柱层析分离纯化(SiO 2，PE∶EA＝5∶1-1∶1)得到化合物15-b。 Step B: Compound 15-a (1.5g, 4.58mmol, 1eq) and ammonium chloride (1.23g, 22.91mmol, 5eq) were dissolved in tetrahydrofuran (16mL) and water (8mL), and then added to the above mixture Zinc powder (1.50 g, 22.91 mmol, 5 eq), the reaction system was stirred at 25°C for 1 hour. The reaction solution was filtered, the filtrate was extracted with ethyl acetate (20 mL×2), the organic phase was collected, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated and purified by column chromatography (SiO 2 ) . , PE:EA=5:1-1:1) to obtain compound 15-b.
步骤C：将化合物15-b(150mg，0.885mmol，1eq)溶于无水DMF(15mL)中，置换氮气0℃下将NaH(35.38mg，0.885mmol，60％纯度，1eq)加入到该反应液中，25℃搅拌30分钟。随后将2-(三甲基硅基)乙氧甲基氯(147.5mg，0.885mmol，156.6μL，1eq)逐滴加入，25℃搅拌1小时。冷却到0℃，氮气保护下将NaH(70.76mg，1.77mmol，60％纯度，2eq)加入上述反应体系中，搅拌30分钟后，将碘甲烷(263.67mg，1.86mmol，115.65μL，2.1eq)逐滴加入，反应体系在25℃搅拌1小时。将反应液倒入H 2O(45mL)中，乙酸乙酯萃取(40mL×2)。合并的有机相用饱和食盐水洗(40mL×2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物经柱层析分离纯化(PE∶EA＝5∶1)得到化合物15-c。 Step C: Compound 15-b (150 mg, 0.885 mmol, 1 eq) was dissolved in dry DMF (15 mL), NaH (35.38 mg, 0.885 mmol, 60% purity, 1 eq) was added to the reaction at 0°C under replacement nitrogen The solution was stirred at 25°C for 30 minutes. 2-(Trimethylsilyl)ethoxymethyl chloride (147.5 mg, 0.885 mmol, 156.6 μL, 1 eq) was then added dropwise and stirred at 25° C. for 1 hour. Cooled to 0°C, NaH (70.76mg, 1.77mmol, 60% purity, 2eq) was added to the above reaction system under nitrogen protection, after stirring for 30 minutes, iodomethane (263.67mg, 1.86mmol, 115.65μL, 2.1eq) was added. It was added dropwise and the reaction was stirred at 25°C for 1 hour. The reaction solution was poured into H 2 O (45 mL) and extracted with ethyl acetate (40 mL×2). The combined organic phases were washed with saturated brine (40 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-c .
步骤D：向化合物15-c(70mg，213.49μmol，1eq)和化合物3-c(66.92mg，256.19μmol，1.2eq)的DMF(5.0mL)溶液中加入碳酸铯(139.12mg，426.98μmol，2.0eq)，置换氮气。氮气氛围下，该反应体系在100℃搅拌15小时。向反应体系中加入H 2O(20mL)，乙酸乙酯萃取(20mL×2)。合并的有机相用饱和食盐水洗(20mL×2)，无水硫酸钠干燥，过滤减压浓缩，残留物经柱层析分离纯化(PE∶EA＝5∶1)得到化合物15-d； 1H NMR(400MHz，CDCl 3)：δppm 8.43(s，1H)，8.15(dd，J＝8.85，2.57Hz，1H)，8.04(dd，J＝2.45，1.57Hz，1H)，7.38-7.42(m，1H)，7.23-7.25(m，1H)，7.04-7.09(m，2H)，5.31(s，2H)，5.28(s，2H)，3.70(t，J＝8.4Hz，2H)，1.52(s，6H)，0.99(t，J＝8.0Hz，2H)，0.02(s，9H)。 Step D: To a solution of compound 15-c (70 mg, 213.49 μmol, 1 eq) and compound 3-c (66.92 mg, 256.19 μmol, 1.2 eq) in DMF (5.0 mL) was added cesium carbonate (139.12 mg, 426.98 μmol, 2.0 eq), replacing nitrogen. Under nitrogen atmosphere, the reaction system was stirred at 100°C for 15 hours. H 2 O (20 mL) was added to the reaction system, followed by extraction with ethyl acetate (20 mL×2). The combined organic phases were washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure, and the residue was separated and purified by column chromatography (PE:EA=5:1) to obtain compound 15-d; 1 H NMR (400MHz, CDCl3 ): δppm 8.43 (s, 1H), 8.15 (dd, J=8.85, 2.57Hz, 1H), 8.04 (dd, J=2.45, 1.57Hz, 1H), 7.38-7.42 (m, 1H), 7.23-7.25(m, 1H), 7.04-7.09(m, 2H), 5.31(s, 2H), 5.28(s, 2H), 3.70(t, J=8.4Hz, 2H), 1.52(s) , 6H), 0.99 (t, J=8.0 Hz, 2H), 0.02 (s, 9H).
步骤E：将三氟乙酸(154mg，1.35mmol，18.66eq)加入到化合物15-d(40mg，72.38μmol，1eq)的无水二氯甲烷(5.0mL)溶液中，25℃搅拌48小时。反应液减压浓缩，残留物经制备HPLC纯化[流动相：水(0.04％ NH 3·H 2O)-ACN]得到化合物15。 1H NMR(400MHz，CDCl 3)：δppm 8.35(s，1H)，8.17(d，J＝2.8Hz，1H)，8.15(d，J＝2.8Hz，1H)，8.05-8.04(m，1H)，7.27-7.24(m，1H)，7.07-7.03(m，2H)，5.29(s，2H)，1.51(s，6H)；LCMS(ESI)m/z：423.2[M+1] +。 Step E: Trifluoroacetic acid (154 mg, 1.35 mmol, 18.66 eq) was added to a solution of compound 15-d (40 mg, 72.38 μmol, 1 eq) in anhydrous dichloromethane (5.0 mL), and stirred at 25° C. for 48 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by preparative HPLC [mobile phase: water (0.04% NH 3 ·H 2 O)-ACN] to obtain compound 15. 1 H NMR (400 MHz, CDCl 3 ): δppm 8.35 (s, 1H), 8.17 (d, J=2.8Hz, 1H), 8.15 (d, J=2.8Hz, 1H), 8.05-8.04 (m, 1H) , 7.27-7.24 (m, 1H), 7.07-7.03 (m, 2H), 5.29 (s, 2H), 1.51 (s, 6H); LCMS (ESI) m/z: 423.2[M+1] + .
实施例16Example 16
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000083
Figure PCTCN2022088918-appb-000083
在25℃下，将对氟苯甲酸(245.45mg，1.75mmol，1eq)溶于DCM(1mL)中，加入DMF(7.54mg，103.19μmol，7.94μL，0.1eq)和草酰氯(200.12mg，1.58mmol，138.01μL，0.9eq)，搅拌至无气体放出，并将该反应液滴加至化合物9-c(0.2g，350.37μmol，0.2eq)的DCM(1mL)和吡啶(1mL)的溶液中，在25℃下搅拌2小时。向反应液中加入2mL的水，并用DCM萃取(4mL×3)，将有机相用无水硫酸钠干燥，过滤，滤液浓缩。残留物用制备HPLC纯化[流动相：水(0.04％NH 3.H 2O)-ACN]得到化合物16。 1H NMR(400MHz，DMSO-d 6)δppm 5.16(s，2H)7.12-7.18(m，1H)7.19-7.26(m，1H)7.27-7.43(m，6H)8.04-8.18(m，3H)8.18-8.34(m，2H)9.82(s，1H)。LCMS(ESI)m/z：492.2[M+1] +。 At 25°C, p-fluorobenzoic acid (245.45 mg, 1.75 mmol, 1 eq) was dissolved in DCM (1 mL), DMF (7.54 mg, 103.19 μmol, 7.94 μL, 0.1 eq) and oxalyl chloride (200.12 mg, 1.58 were added) mmol, 138.01 μL, 0.9 eq), stirred until no gas evolved, and the reaction was added dropwise to a solution of compound 9-c (0.2 g, 350.37 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL) , and stirred at 25°C for 2 hours. 2 mL of water was added to the reaction solution, extracted with DCM (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC [mobile phase: water (0.04% NH3.H2O) -ACN ] to give compound 16. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 5.16 (s, 2H) 7.12-7.18 (m, 1H) 7.19-7.26 (m, 1H) 7.27-7.43 (m, 6H) 8.04-8.18 (m, 3H) 8.18-8.34 (m, 2H) 9.82 (s, 1H). LCMS (ESI) m/z: 492.2 [M+1] + .
实施例17Example 17
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000084
Figure PCTCN2022088918-appb-000084
步骤A：在0℃下，向17-1(3g，25.84mmol，1eq)的DMF(30mL)溶液中小心缓慢加入NaH(2.07g，51.67mmol，60％纯度，2eq)，在0℃下搅拌0.5小时，再向溶液中加入碘甲烷(4.40g，31.00mmol，1.93mL，1.2eq)，逐渐恢复室温并搅拌0.5小时，在45℃下搅拌3小时，冷却至室温后加入饱和氯化铵溶液(60mL)淬灭反应，加水(10mL)稀释，用DCM(30mL×3)萃取，合并的有机相用水(30ml×3)洗涤，无水硫酸钠 干燥，过滤后在10℃以下浓缩得到化合物17-a。 1HNMR(400MHz，DMSO-d 6)：δ3.65(s，3H)，3.30(s，3H)，1.31-1.27(dd，J＝4.8Hz，8.4Hz，2H)，1.17-1.14(dd，J＝4Hz，7.2Hz，2H)。 Step A: To a solution of 17-1 (3 g, 25.84 mmol, 1 eq) in DMF (30 mL) at 0 °C was added NaH (2.07 g, 51.67 mmol, 60% pure, 2 eq) carefully and slowly, and stirred at 0 °C After 0.5 hours, methyl iodide (4.40g, 31.00mmol, 1.93mL, 1.2eq) was added to the solution, gradually returned to room temperature and stirred for 0.5 hours, stirred at 45°C for 3 hours, cooled to room temperature and then added with saturated ammonium chloride solution (60 mL) to quench the reaction, add water (10 mL) to dilute, extract with DCM (30 mL×3), wash the combined organic phases with water (30 mL×3), dry over anhydrous sodium sulfate, filter and concentrate below 10°C to obtain compound 17 -a. 1 H NMR (400 MHz, DMSO-d 6 ): δ 3.65 (s, 3H), 3.30 (s, 3H), 1.31-1.27 (dd, J=4.8 Hz, 8.4 Hz, 2H), 1.17-1.14 (dd, J=4Hz, 7.2Hz, 2H).
步骤B：在17-a(0.56g，4.30mmol，1eq)的MeOH(5mL)溶液中缓慢加入KOH(483.19mg，8.61mmol，2eq)的水(2.5mL)溶液。加完后将混合物在20℃下搅拌15小时。将反应液在低于40℃浓缩，浓缩液用石油醚(15mL)洗涤，然后水相倒入冰水(15mL)中，溶液用3M的盐酸水溶液调节pH至5-6，用DCM(12mL)萃取，有机相用无水硫酸钠干燥过滤，浓缩得到化合物17-b。 1H NMR(400MHz，DMSO-d 6)：δ12.55(s，1H)，3.29(s，3H)，1.14-1.12(dd，J＝6Hz，8.8Hz，2H)，1.07-1.04(dd，J＝3.2Hz，6.4Hz，2H)。 Step B: To a solution of 17-a (0.56 g, 4.30 mmol, 1 eq) in MeOH (5 mL) was slowly added a solution of KOH (483.19 mg, 8.61 mmol, 2 eq) in water (2.5 mL). After the addition was complete the mixture was stirred at 20°C for 15 hours. The reaction solution was concentrated below 40°C, the concentrated solution was washed with petroleum ether (15 mL), then the aqueous phase was poured into ice water (15 mL), the pH of the solution was adjusted to 5-6 with 3M aqueous hydrochloric acid, and DCM (12 mL) was used After extraction, the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 17-b. 1 H NMR (400 MHz, DMSO-d 6 ): δ 12.55 (s, 1H), 3.29 (s, 3H), 1.14-1.12 (dd, J=6Hz, 8.8Hz, 2H), 1.07-1.04 (dd, J=3.2Hz, 6.4Hz, 2H).
步骤C：在0℃下，向17-b(350mg，3.01mmol，1eq)的DCM(2.00mL)和DMF(22.03mg，301.43μmol，23.19μL，0.1eq)溶液中加入草酰氯(344.33mg，2.71mmol，237.47μL，0.9eq)，置换氮气，在0℃下搅拌0.5小时，向溶液中逐滴加入9-c(261.94mg，602.85μmol，0.2eq)的DCM(3mL)溶液，再向其中加入吡啶(476.85mg，6.03mmol，486.59μL，2eq)，混合液在20℃搅拌5小时，反应液用水(20mL)淬灭，用EtOAc(15mL×3)萃取，有机相用饱和食盐水(15mL×3)洗涤，合并的有机相用无水硫酸钠干燥，过滤后浓缩，残留物通过柱层析(PE∶EtOAc＝10∶1-0.1∶1)纯化所得粗品进一步经制备HPLC[流动相：水(0.05％氨水)-ACN]纯化得化合物17。 1H NMR(400MHz，CD 3OD)：δppm 1.23-1.25(dd，J＝2.8Hz，7.2Hz，2H)，1.32-1.35(dd，J＝4Hz，6.8Hz，2H)，2.03(s，1H)，3.50(s，3H)，5.28(s，2H)，7.09-7.14(t，J＝6Hz，2H)，7.29-7.36(dd，J＝7.2Hz，14.8Hz，2H)，8.01(s，1H)，8.19(s，1H)，8.35-8.37(d，J＝2.4Hz，1H)；LCMS(ESI)m/z：468.0[M+1] +。 Step C: To a solution of 17-b (350 mg, 3.01 mmol, 1 eq) in DCM (2.00 mL) and DMF (22.03 mg, 301.43 μmol, 23.19 μL, 0.1 eq) at 0 °C was added oxalyl chloride (344.33 mg, 2.71 mmol, 237.47 μL, 0.9 eq), replaced with nitrogen, stirred at 0 °C for 0.5 h, 9-c (261.94 mg, 602.85 μmol, 0.2 eq) in DCM (3 mL) was added dropwise to the solution, and then added Pyridine (476.85 mg, 6.03 mmol, 486.59 μL, 2 eq) was added, the mixture was stirred at 20°C for 5 hours, the reaction solution was quenched with water (20 mL), extracted with EtOAc (15 mL×3), and the organic phase was washed with saturated brine (15 mL). ×3) washing, the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, the residue was purified by column chromatography (PE:EtOAc=10:1-0.1:1) and the obtained crude product was further subjected to preparative HPLC [mobile phase: Compound 17 was obtained by purification with water (0.05% ammonia)-ACN]. 1 H NMR (400MHz, CD3OD ): δppm 1.23-1.25 (dd, J=2.8Hz, 7.2Hz, 2H), 1.32-1.35 (dd, J=4Hz, 6.8Hz, 2H), 2.03 (s, 1H) ), 3.50(s, 3H), 5.28(s, 2H), 7.09-7.14(t, J=6Hz, 2H), 7.29-7.36(dd, J=7.2Hz, 14.8Hz, 2H), 8.01(s, 1H), 8.19 (s, 1H), 8.35-8.37 (d, J=2.4 Hz, 1H); LCMS (ESI) m/z: 468.0 [M+1] + .
实施例18Example 18
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000085
Figure PCTCN2022088918-appb-000085
向溶有3-e(100mg，260.18μmol，1eq)的吡啶(4mL)溶液中加入EDCI(399.02mg，2.08mmol，8eq)和14-1(80.18mg，520.37μmol，2eq)，反应混合物在30℃下搅拌2小时。将反应液用水(50mL)稀释后，用乙酸乙酯(50mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]]得化合物18。 1H NMR(400MHz，DMSO-d 6)：δppm 8.60(br s，1H)，8.22(dd，J＝2.3，9.4Hz，1H)，8.08(s，1H)，7.39-7.31(m，1H)，7.31-7.19(m，2H)，7.18-7.12(m，1H)，6.26(br s，4H)，5.14(s，2H)，1.74(br s，2H)，1.32-1.15(m，2H)；LCMS(ESI)m/z：521.2[M+1] +。 To a solution of 3-e (100 mg, 260.18 μmol, 1 eq) in pyridine (4 mL) was added EDCI (399.02 mg, 2.08 mmol, 8 eq) and 14-1 (80.18 mg, 520.37 μmol, 2 eq), and the reaction mixture was heated at 30 Stir at °C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)] -ACN]] to give compound 18. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.60 (br s, 1H), 8.22 (dd, J=2.3, 9.4 Hz, 1H), 8.08 (s, 1H), 7.39-7.31 (m, 1H) , 7.31-7.19(m, 2H), 7.18-7.12(m, 1H), 6.26(br s, 4H), 5.14(s, 2H), 1.74(br s, 2H), 1.32-1.15(m, 2H) ; LCMS (ESI) m/z: 521.2 [M+1] + .
实施例19Example 19
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000086
Figure PCTCN2022088918-appb-000086
向溶有1-e(100mg，272.96μmol，1eq)的吡啶(3mL)溶液中加入EDCI(418.62mg，2.18mmol，8eq)和14-1(84.12mg，545.92μmol，2eq)，反应混合物在30℃下搅拌2小时。将反应液用水(50mL)稀释后，用乙酸乙酯(50mL×3)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得化合物19。 1H NMR(400MHz，DMSO-d 6)：δppm 8.58(br s，1H)，8.14-8.01(m，2H)，7.38-7.32(m，1H)，7.29-7.20(m，2H)，7.18-7.11(m，2H)，6.22(br s，4H)，5.16(s，2H)，1.77-1.69(m，2H)，1.31-1.20(m，2H)；LCMS(ESI)m/z：503.2[M+1] +。 To a solution of 1-e (100 mg, 272.96 μmol, 1 eq) in pyridine (3 mL) was added EDCI (418.62 mg, 2.18 mmol, 8 eq) and 14-1 (84.12 mg, 545.92 μmol, 2 eq), and the reaction mixture was heated at 30 Stir at °C for 2 hours. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×3). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)] -ACN] to obtain compound 19. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 8.58 (br s, 1H), 8.14-8.01 (m, 2H), 7.38-7.32 (m, 1H), 7.29-7.20 (m, 2H), 7.18- 7.11 (m, 2H), 6.22 (br s, 4H), 5.16 (s, 2H), 1.77-1.69 (m, 2H), 1.31-1.20 (m, 2H); LCMS (ESI) m/z: 503.2 [ M+1] + .
实施例20Example 20
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000087
Figure PCTCN2022088918-appb-000087
在0℃下，将化合物9(169mg，395.45μmol，1eq)溶于THF(2mL)，然后向所得溶液中加入NaH(20.56mg，514.08μmol，60％纯度，1.3eq)，搅拌90min，然后加入2，2，2-三氟乙基三氟甲磺酸酯(110.14mg，474.54μmol，1.2eq)，升温至20℃，搅拌36小时。向反应液中加入2mL水，并用1M的盐酸水溶液将其pH调节至6-7，然后用EA(4mL×3)萃取，有机相用饱和食盐水洗涤，无水硫酸钠干燥、过滤、浓缩，残留物用制备HPLC纯化[流动相：水(0.04％NH 3H 2O+10mM NH 4HCO 3)-ACN]得到化合物20。 1H NMR(400MHz，DMSO-d 6)：δppm 4.85(q，J＝9.03Hz，2H)5.18(s，2H)7.14-7.19(m，1H)7.21-7.27(m，1H)7.30-7.40(m，2H)7.99(dd，J＝9.10，2.45Hz，1H)8.12(t，J＝2.13Hz，1H)8.52(s，1H)；LCMS(ESI)m/z：478.2[M+1] +。 Compound 9 (169 mg, 395.45 μmol, 1 eq) was dissolved in THF (2 mL) at 0°C, then NaH (20.56 mg, 514.08 μmol, 60% purity, 1.3 eq) was added to the resulting solution, stirred for 90 min, and then added 2,2,2-Trifluoroethyl trifluoromethanesulfonate (110.14 mg, 474.54 μmol, 1.2 eq) was heated to 20° C. and stirred for 36 hours. 2mL of water was added to the reaction solution, and the pH was adjusted to 6-7 with 1M aqueous hydrochloric acid solution, then extracted with EA (4mL×3), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, The residue was purified by preparative HPLC [mobile phase: water (0.04% NH3H2O + 10 mM NH4HCO3 ) -ACN] to give compound 20. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 4.85 (q, J=9.03 Hz, 2H) 5.18 (s, 2H) 7.14-7.19 (m, 1H) 7.21-7.27 (m, 1H) 7.30-7.40 ( m, 2H) 7.99 (dd, J=9.10, 2.45Hz, 1H) 8.12 (t, J=2.13Hz, 1H) 8.52 (s, 1H); LCMS (ESI) m/z: 478.2[M+1] + .
实施例21Example 21
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000088
Figure PCTCN2022088918-appb-000088
在25℃下，将21-1(203mg，2.03mmol，1eq)溶于DCM(1mL)，加入草酰氯(231.63mg，1.82mmol，159.74μL，0.9eq)和DMF(14.82mg，202.77μmol，15.60μL，0.1eq)，搅拌至无气体放出，并将该反应液滴加至化合物9-c(176.20mg，405.53μmol，0.2eq)的DCM(1mL)和吡啶(1mL)的溶液中，在25℃下搅拌2小时。向反应液中加入2mL的水，并用DCM萃取(4mL×3)，将有机相用无水硫酸钠干燥，过滤，滤液浓缩。残留物用制备HPLC(水(0.04％NH 3·H 2O+10mM NH 4HCO 3)-ACN]；乙腈：35％-62％，10min)纯化得到化合物21。 1H NMR(400MHz，DMSO-d 6)：δppm 0.53-0.75(m，2H)1.14(br d，J＝2.38Hz，2H)1.44(s，3H)5.16(s，2H)7.12-7.28(m，4H)7.27-7.40(m，2H)8.07(s，1H)8.11(s，1H)8.21(dd，J＝9.29，2.38Hz，1H)8.85(br s，1H)；LCMS(ESI)m/z：452.2[M+1] +。 At 25°C, 21-1 (203 mg, 2.03 mmol, 1 eq) was dissolved in DCM (1 mL), oxalyl chloride (231.63 mg, 1.82 mmol, 159.74 μL, 0.9 eq) and DMF (14.82 mg, 202.77 μmol, 15.60 were added) μL, 0.1 eq), stirred until no gas evolved, and the reaction was added dropwise to a solution of compound 9-c (176.20 mg, 405.53 μmol, 0.2 eq) in DCM (1 mL) and pyridine (1 mL) over 25 Stir at °C for 2 hours. 2 mL of water was added to the reaction solution, extracted with DCM (4 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative HPLC (water (0.04% NH 3 ·H 2 O + 10 mM NH 4 HCO 3 )-ACN]; acetonitrile: 35%-62%, 10 min) to give compound 21. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 0.53-0.75 (m, 2H) 1.14 (br d, J=2.38 Hz, 2H) 1.44 (s, 3H) 5.16 (s, 2H) 7.12-7.28 (m , 4H) 7.27-7.40(m, 2H) 8.07(s, 1H) 8.11(s, 1H) 8.21(dd, J=9.29, 2.38Hz, 1H) 8.85(br s, 1H); LCMS(ESI) m/ z: 452.2[M+1] + .
实施例22Example 22
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000089
Figure PCTCN2022088918-appb-000089
将化合物3-e(0.1g，260.18μmol，1eq)溶于吡啶(2mL)中，在0℃下滴加氯甲酸乙酯(42.35mg，390.28μmol，37.15μL，1.5eq)，并在该温度下搅拌30分钟。反应结束后，将反应液滴入4mL的水中，用乙酸乙酯(5mL×3)萃取，将有机相用饱和食盐水洗(5mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩，残留物用制备HPLC纯化[[流动相：水(0.225％FA)-ACN]得到化合物22。 1H NMR(400MHz，DMSO-d 6)：δppm 1.02-1.33(m，3H)4.06(br d，J＝6.78Hz，2H)5.13(s，2H)6.33(br s，4H)7.10-7.17(m，1H)7.18-7.29(m，2H)7.30-7.39(m，1H)7.92(br s，1H)8.06(s，1H)8.18(br d，J＝9.03Hz，1H)；LCMS(ESI)m/z：457.0[M+1] +。 Compound 3-e (0.1 g, 260.18 μmol, 1 eq) was dissolved in pyridine (2 mL), ethyl chloroformate (42.35 mg, 390.28 μmol, 37.15 μL, 1.5 eq) was added dropwise at 0 °C, and at this temperature under stirring for 30 minutes. After the reaction, the reaction was dropped into 4 mL of water, extracted with ethyl acetate (5 mL×3), the organic phase was washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The residue was purified by preparative HPLC [[mobile phase: water (0.225% FA)-ACN] to give compound 22. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 1.02-1.33 (m, 3H) 4.06 (br d, J=6.78 Hz, 2H) 5.13 (s, 2H) 6.33 (br s, 4H) 7.10-7.17 ( m, 1H) 7.18-7.29 (m, 2H) 7.30-7.39 (m, 1H) 7.92 (br s, 1H) 8.06 (s, 1H) 8.18 (br d, J=9.03Hz, 1H); LCMS (ESI) m/z: 457.0[M+1] + .
实施例23Example 23
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000090
Figure PCTCN2022088918-appb-000090
将化合物3-e(100mg，260.18μmol，1eq)和23-1(57.81mg，520.37μmol，2eq)溶于吡啶(4mL)，向其中加入EDCI(399.02mg，2.08mmol，8eq)，该反应液在30℃下反应2小时。将反应液滴入到H 2O(4mL)中，然后用EA(5mL×3)萃取，有机相用饱和食盐水洗(5mL×2)，无水硫酸钠干燥，过滤，滤液减压浓缩。残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物23。 1H NMR(400MHz，DMSO-d 6)：δppm 1.50-1.64(m，2H)1.64-1.87(m，2H)5.14(s，2H)6.47(br s，4H)7.10-7.19(m，1H)7.18-7.30(m，2H)7.35(q，J＝6.48Hz，1H)8.07(s，1H)8.22(dd，J＝9.35，2.20Hz，1H)8.60(br s，1H)；LCMS(ESI)m/z：478.0[M+1] +。 Compound 3-e (100 mg, 260.18 μmol, 1 eq) and 23-1 (57.81 mg, 520.37 μmol, 2 eq) were dissolved in pyridine (4 mL), and EDCI (399.02 mg, 2.08 mmol, 8 eq) was added to the reaction solution. The reaction was carried out at 30°C for 2 hours. The reaction was dropped into H 2 O (4 mL), then extracted with EA (5 mL×3), the organic phase was washed with saturated brine (5 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to give compound 23. 1 H NMR (400 MHz, DMSO-d 6 ): δppm 1.50-1.64 (m, 2H) 1.64-1.87 (m, 2H) 5.14 (s, 2H) 6.47 (br s, 4H) 7.10-7.19 (m, 1H) 7.18-7.30 (m, 2H) 7.35 (q, J=6.48Hz, 1H) 8.07 (s, 1H) 8.22 (dd, J=9.35, 2.20Hz, 1H) 8.60 (br s, 1H); LCMS (ESI) m/z: 478.0[M+1] + .
实施例24Example 24
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000091
Figure PCTCN2022088918-appb-000091
向溶有3-e(100mg，260.18μmol，1eq)的吡啶(5mL)溶液中加入EDCI(399.02mg，2.08mmol，8eq)和17-b(90.63mg，780.55μmol，3eq)。反应液于20℃下搅拌1小时。将反应液用水(50mL)稀释，并用EtOAc(50mL×2)萃取。有机相通过无水Na 2SO 4干燥，过滤浓缩得粗品化合物，通过制备HPLC[流动相：水(10mM碳酸氢铵)-乙腈]分离后，再通过薄层色谱法(SiO 2，DCM∶MeOH＝10∶1)纯化得到化合物24。 1H NMR(400MHz，MeOH-d 4)δ＝8.28-8.22(m，1H)，7.98-7.93(m，1H)，7.30(t，J＝7.5Hz，1H)，7.27-7.20(m，1H)，7.07-7.00(m，2H)，5.24(s，2H)，3.46(s，3H)，1.41-1.31(m，2H)，1.26-1.16(m，2H)。LCMS(ESI)m/z：483.4[M+1] +。 To a solution of 3-e (100 mg, 260.18 μmol, 1 eq) in pyridine (5 mL) was added EDCI (399.02 mg, 2.08 mmol, 8 eq) and 17-b (90.63 mg, 780.55 μmol, 3 eq). The reaction solution was stirred at 20°C for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2). The organic phase was dried over anhydrous Na2SO4 , filtered and concentrated to give the crude compound, which was separated by preparative HPLC [mobile phase: water (10 mM ammonium bicarbonate)-acetonitrile], and then by thin layer chromatography ( SiO2 , DCM:MeOH) = 10:1) purification to give compound 24. 1 H NMR (400 MHz, MeOH-d 4 ) δ=8.28-8.22 (m, 1H), 7.98-7.93 (m, 1H), 7.30 (t, J=7.5Hz, 1H), 7.27-7.20 (m, 1H) ), 7.07-7.00 (m, 2H), 5.24 (s, 2H), 3.46 (s, 3H), 1.41-1.31 (m, 2H), 1.26-1.16 (m, 2H). LCMS (ESI) m/z: 483.4 [M+1] + .
实施例25Example 25
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000092
Figure PCTCN2022088918-appb-000092
向溶有3-e(150mg，390.28μmol，1eq)的吡啶(5mL)溶液中加入EDCI(598.53mg，3.12mmol，8eq)和1-甲基环丙基-1-羧酸(117.22mg，1.17mmol，3eq)，反应混合物在20℃下搅拌1小时。将反应液用水(50mL)稀释后，用乙酸乙酯(50mL×2)萃取，有机相经过无水硫酸钠干燥后减压浓缩，残留物用制备HPLC纯化[流动相：水(0.225％FA)-ACN]得化合物25。 1H NMR(400MHz，DMSO-d 6)δ＝8.29(s，1H)，8.20(dd，J＝2.4，9.3Hz，1H)，8.08(d，J＝1.7Hz，1H)，7.35(q，J＝7.3Hz，1H)，7.31-7.19(m，2H)，7.18-7.12(m，1H)，6.21(br s，4H)，5.14(s，2H)，1.43(s，3H)，1.11(br d，J＝2.4Hz，2H)，0.63-0.46(m，2H)。LCMS(ESI)m/z：467.4[M+1] +。 To a solution of 3-e (150 mg, 390.28 μmol, 1 eq) in pyridine (5 mL) was added EDCI (598.53 mg, 3.12 mmol, 8 eq) and 1-methylcyclopropyl-1-carboxylic acid (117.22 mg, 1.17 mmol, 3 eq), the reaction mixture was stirred at 20°C for 1 hour. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.225% FA)] -ACN] to give compound 25. 1 H NMR (400 MHz, DMSO-d 6 ) δ=8.29 (s, 1H), 8.20 (dd, J=2.4, 9.3 Hz, 1H), 8.08 (d, J=1.7 Hz, 1H), 7.35 (q, J=7.3Hz, 1H), 7.31-7.19(m, 2H), 7.18-7.12(m, 1H), 6.21(br s, 4H), 5.14(s, 2H), 1.43(s, 3H), 1.11( br d, J=2.4Hz, 2H), 0.63-0.46 (m, 2H). LCMS (ESI) m/z: 467.4 [M+1] + .
实施例26Example 26
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000093
Figure PCTCN2022088918-appb-000093
步骤A：将丙二腈(14.93g，225.98mmol，14.22mL，1eq)溶于THF(100mL)中，然后加入叔丁醇钾(27.89g，248.58mmol，1.1eq)，反应液在50℃下搅拌0.5小时，然后加入化合物26-1(45g，248.58mmol，32.14mL，1.1eq)，反应液在50℃下继续搅拌11.5小时，反应完成后加入100mL水淬灭，然后用EtOAc(100mL×2)萃取，有机相通过无水硫酸钠干燥，过滤后浓缩滤液，残留物通过柱层析(PE/EtOAc＝10/1-5/1)纯化得到化合物26-a。Step A: Malononitrile (14.93g, 225.98mmol, 14.22mL, 1eq) was dissolved in THF (100mL), then potassium tert-butoxide (27.89g, 248.58mmol, 1.1eq) was added, and the reaction solution was heated at 50°C After stirring for 0.5 hours, compound 26-1 (45 g, 248.58 mmol, 32.14 mL, 1.1 eq) was added. The reaction solution was stirred at 50 °C for 11.5 hours. After the reaction was completed, 100 mL of water was added to quench, and then EtOAc (100 mL×2 ) extraction, the organic phase was dried over anhydrous sodium sulfate, the filtrate was concentrated after filtration, and the residue was purified by column chromatography (PE/EtOAc=10/1-5/1) to obtain compound 26-a.
步骤B：将化合物26-a(20g，120.35mmol，1eq)、S-甲基硫脲(27.04g，144.42mmol，1.2eq，HSO 4)和三乙胺(24.36g，240.71mmol，33.50mL，2eq)溶于DMF(60mL)中，氮气置换3次后，在100℃下搅拌12小时，反应完成后，将反应液过滤，浓缩滤液，残留物通过柱层析(PE/EtOAc＝10/1-1/1)纯化得到化合物26- b。 Step B: Compound 26-a (20 g, 120.35 mmol, 1 eq), S-methylthiourea (27.04 g, 144.42 mmol, 1.2 eq, HSO 4 ) and triethylamine (24.36 g, 240.71 mmol, 33.50 mL, 2eq) was dissolved in DMF (60 mL), after nitrogen replacement 3 times, stirred at 100 °C for 12 hours, after the reaction was completed, the reaction solution was filtered, the filtrate was concentrated, and the residue was passed through column chromatography (PE/EtOAc=10/1 -1/1) Purification to obtain compound 26-b.
步骤C：将化合物26-b(3.8g，16.94mmol，1eq)溶于DCM(50mL)中，然后加入间氯过氧苯甲酸(6.88g，33.89mmol，85％纯度，2eq)。反应液在20℃下搅拌12小时。反应完成后，过滤，收集滤饼，并用二氯甲烷(100mL)搅拌，过滤干燥得到化合物26-c。LCMS(ESI)m/z：257.2[M+1] +。 Step C: Compound 26-b (3.8 g, 16.94 mmol, 1 eq) was dissolved in DCM (50 mL), then m-chloroperoxybenzoic acid (6.88 g, 33.89 mmol, 85% purity, 2 eq) was added. The reaction solution was stirred at 20°C for 12 hours. After the reaction was completed, the filter cake was collected by filtration, stirred with dichloromethane (100 mL), filtered and dried to obtain compound 26-c. LCMS (ESI) m/z: 257.2 [M+1] + .
步骤D：在20℃下，向3-c(5.74g，21.98mmol，1.1eq)的DMF(30mL)溶液中加入碳酸钾(8.28g，59.93mmol，3eq)和26-c(5.12g，19.98mmol，1.0eq)，反应液升温至120℃并保温反应2小时。反应完毕，反应液降至室温，过滤，用甲醇(20mL)和DMF(20mL)洗涤滤饼，合并滤液并减压浓缩除甲醇，残留液用制备HPLC纯化[流动相：水(0.1％FA)-ACN]得化合物26。 1H NMR(400MHz，DMSO-d 6)δ＝11.15(s，1H)，8.27(dd，J＝2.5，9.4Hz，1H)，8.10(t，J＝2.0Hz，1H)，7.39-7.32(m，1H)，7.29(t，J＝7.6Hz，1H)，7.25-7.20(m，1H)，7.18-7.12(m，1H)，7.03(br s，2H)，5.15(s，2H)，1.35(s，6H)。LCMS(ESI)m/z：428.4[M+1] +。 Step D: To a solution of 3-c (5.74 g, 21.98 mmol, 1.1 eq) in DMF (30 mL) at 20 °C was added potassium carbonate (8.28 g, 59.93 mmol, 3 eq) and 26-c (5.12 g, 19.98 mmol, 1.0 eq), the reaction solution was heated to 120° C. and kept for 2 hours. After the reaction was completed, the reaction solution was cooled to room temperature, filtered, and the filter cake was washed with methanol (20 mL) and DMF (20 mL), the filtrates were combined and concentrated under reduced pressure to remove methanol, and the residue was purified by preparative HPLC [mobile phase: water (0.1% FA) -ACN] to give compound 26. 1 H NMR (400 MHz, DMSO-d 6 ) δ=11.15 (s, 1H), 8.27 (dd, J=2.5, 9.4 Hz, 1H), 8.10 (t, J=2.0 Hz, 1H), 7.39-7.32 ( m, 1H), 7.29(t, J=7.6Hz, 1H), 7.25-7.20(m, 1H), 7.18-7.12(m, 1H), 7.03(br s, 2H), 5.15(s, 2H), 1.35 (s, 6H). LCMS (ESI) m/z: 428.4 [M+1] + .
实施例27Example 27
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000094
Figure PCTCN2022088918-appb-000094
在5-f(200mg，670.45μmol，1eq)的DMF(2mL)溶液中加入26-c(273mg，858.58μmol，1.28eq)和碳酸钾(200mg，1.45mmol，2.16eq)。置换氮气，在120℃下搅拌12小时。将反应液过滤，滤饼用2mL的DMF洗涤，滤液经制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物27。 1H NMR(400MHz，DMSO-d 6)δppm 1.34(s，6H)5.18(s，2H)6.94-7.22(m，4H)7.37(q，J＝8.23Hz，1H)8.10(t，J＝2.14Hz，1H)8.27(dd，J＝9.48，2.63Hz，1H)；LCMS(ESI)m/z：456.1[M+1] +。 To a solution of 5-f (200 mg, 670.45 μmol, 1 eq) in DMF (2 mL) was added 26-c (273 mg, 858.58 μmol, 1.28 eq) and potassium carbonate (200 mg, 1.45 mmol, 2.16 eq). The nitrogen was replaced, and the mixture was stirred at 120°C for 12 hours. The reaction solution was filtered, the filter cake was washed with 2 mL of DMF, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 27. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 1.34 (s, 6H) 5.18 (s, 2H) 6.94-7.22 (m, 4H) 7.37 (q, J=8.23 Hz, 1H) 8.10 (t, J=2.14 Hz, 1H) 8.27 (dd, J=9.48, 2.63 Hz, 1H); LCMS (ESI) m/z: 456.1 [M+1] + .
实施例28Example 28
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000095
Figure PCTCN2022088918-appb-000095
步骤A：向28-1(3.5g，31.79mmol，1eq)的二氯甲烷(100.00mL)和甲苯(10mL)的混合物中加入叠氮磷酸二苯酯(17.49g，63.57mmol，13.78mL，2eq)和1.8-二氮杂二环[5.4.0]十一烷-7-烯(9.68g，63.57mmol，9.58mL，2eq)。反应液在20℃下搅拌2小时。反应完成后，将反应液减压浓缩，残留物通过柱层析(PE∶EtOAc＝5∶1-1∶1)纯化得到化合物28-a。Step A: To a mixture of 28-1 (3.5 g, 31.79 mmol, 1 eq) in dichloromethane (100.00 mL) and toluene (10 mL) was added diphenylphosphoryl azide (17.49 g, 63.57 mmol, 13.78 mL, 2 eq) ) and 1.8-diazabicyclo[5.4.0]undec-7-ene (9.68 g, 63.57 mmol, 9.58 mL, 2 eq). The reaction solution was stirred at 20°C for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EtOAc=5:1-1:1) to obtain compound 28-a.
步骤B：在氮气保护下，向28-a(3.0g，22.20mmol，1eq)的甲醇(10mL)溶液中加入湿Pd/C(1.0g，10％纯度)，将反应液用氢气置换3次后，在15psi压力下，于20℃下搅拌2小时，反应完成后，将反应液过滤后，浓缩滤液得到化合物28-b。Step B: Add wet Pd/C (1.0 g, 10% purity) to a solution of 28-a (3.0 g, 22.20 mmol, 1 eq) in methanol (10 mL) under nitrogen protection, and replace the reaction solution with hydrogen 3 times Then, the mixture was stirred at 20° C. for 2 hours under a pressure of 15 psi. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain compound 28-b.
步骤C：将3-1(2.5g，14.16mmol，1eq)和28-b(1.85g，16.99mmol，1.2eq)溶于甲苯(100mL)中，将混合物升温至80℃下搅拌12小时。冷却后，将反应液减压浓缩，残留物通过柱层析(PE∶EtOAc＝1∶1)纯化得到化合物28-c。Step C: 3-1 (2.5 g, 14.16 mmol, 1 eq) and 28-b (1.85 g, 16.99 mmol, 1.2 eq) were dissolved in toluene (100 mL), and the mixture was warmed to 80°C and stirred for 12 hours. After cooling, the reaction solution was concentrated under reduced pressure, and the residue was purified by column chromatography (PE:EtOAc=1:1) to obtain compound 28-c.
步骤D：在氮气保护下，向28-c(2.4g，9.63mmol，1eq)的甲醇(10mL)中加入Pd/C(1.0g，9.63mmol，10％纯度)。将反应液用氢气置换3次后，在15psi压力下，于30℃下搅拌2小时，反应完成后，将反应液过滤，浓缩滤液得到化合物28-d。Step D: To 28-c (2.4 g, 9.63 mmol, 1 eq) in methanol (10 mL) was added Pd/C (1.0 g, 9.63 mmol, 10% purity) under nitrogen. After the reaction solution was replaced with hydrogen three times, the mixture was stirred at 30° C. for 2 hours under a pressure of 15 psi. After the reaction was completed, the reaction solution was filtered, and the filtrate was concentrated to obtain compound 28-d.
步骤E：在28-d(2.1g，9.58mmol，1eq)的THF(100mL)溶液中加入CDI(3.11g，19.16mmol，2eq)。将混合物在70℃下搅拌12小时。将反应液浓缩，残留物通过柱层析(PE∶EtOAc＝1∶1-0∶1)得化合物28-e。Step E: To a solution of 28-d (2.1 g, 9.58 mmol, 1 eq) in THF (100 mL) was added CDI (3.11 g, 19.16 mmol, 2 eq). The mixture was stirred at 70°C for 12 hours. The reaction solution was concentrated, and the residue was subjected to column chromatography (PE:EtOAc=1:1-0:1) to obtain compound 28-e.
步骤F：向28-e(200mg，815.62μmol，1eq)的DMF(3mL)溶液中加入26-c(519mg，1.63mmol，2eq)和碳酸钾(338mg，2.45mmol，3eq)。置换氮气，在120℃下搅拌12小时。将反应液过滤，滤饼用2mLDMF洗涤，滤液经制备HPLC纯化[流动相：水(0.225％FA)-ACN]得到化合物28。 1H NMR(400MHz，DMSO-d 6)δppm 1.34(s，6H)5.16(s，2H)7.01(br s，2H)8.06-8.17(m，1H)8.29(dd，J＝9.48，2.63Hz，1H)8.84(s，2H)9.12(s，1H)；LCMS(ESI)m/z：422.1[M+1] +。 Step F: To a solution of 28-e (200 mg, 815.62 μmol, 1 eq) in DMF (3 mL) was added 26-c (519 mg, 1.63 mmol, 2 eq) and potassium carbonate (338 mg, 2.45 mmol, 3 eq). The nitrogen was replaced, and the mixture was stirred at 120°C for 12 hours. The reaction solution was filtered, the filter cake was washed with 2 mL of DMF, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-ACN] to obtain compound 28. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 1.34 (s, 6H) 5.16 (s, 2H) 7.01 (br s, 2H) 8.06-8.17 (m, 1H) 8.29 (dd, J=9.48, 2.63 Hz, 1H) 8.84 (s, 2H) 9.12 (s, 1H); LCMS (ESI) m/z: 422.1 [M+1] + .
实施例29Example 29
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000096
Figure PCTCN2022088918-appb-000096
步骤A：在氮气保护下，向3-1(720mg，4.08mmol，1eq)的甲苯(20.00mL)溶液中加入二异丙基乙胺(2.11g，16.31mmol，2.84mL，4eq)和3-氟-2-吡啶基甲胺盐酸盐(893mg，4.49mmol，1.1eq)。将混合物升温至70℃下搅拌12小时。冷却后，加入水(100mL)，用EtOAc(200mL)萃取，有机相用无水硫酸钠 干燥，过滤后浓缩，残留物通过柱层析(石油醚∶乙酸乙酯＝20∶1-5∶1)分离纯化得到化合物29-a。Step A: Under nitrogen protection, to a solution of 3-1 (720 mg, 4.08 mmol, 1 eq) in toluene (20.00 mL) was added diisopropylethylamine (2.11 g, 16.31 mmol, 2.84 mL, 4 eq) and 3- Fluoro-2-pyridylmethanamine hydrochloride (893 mg, 4.49 mmol, 1.1 eq). The mixture was warmed to 70°C and stirred for 12 hours. After cooling, water (100 mL) was added, extracted with EtOAc (200 mL), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to column chromatography (petroleum ether:ethyl acetate=20:1-5:1 ) was isolated and purified to obtain compound 29-a.
步骤B：在29-a(650mg，2.44mmol，1eq)的四氢呋喃(15mL)和水(5mL)中加入还原锌粉(638mg，9.77mmol，4eq)和氯化铵(653mg，12.21mmol，5eq)。反应液在70℃下搅拌12小时，将反应液过滤后浓缩，残留物通过柱层析(石油醚∶乙酸乙酯＝4∶1-2∶1)分离纯化得到化合物29-b。Step B: To 29-a (650mg, 2.44mmol, 1eq) in tetrahydrofuran (15mL) and water (5mL) were added reduced zinc powder (638mg, 9.77mmol, 4eq) and ammonium chloride (653mg, 12.21mmol, 5eq) . The reaction solution was stirred at 70°C for 12 hours, the reaction solution was filtered and concentrated, and the residue was separated and purified by column chromatography (petroleum ether:ethyl acetate=4:1-2:1) to obtain compound 29-b.
步骤C：在29-b(430mg，1.82mmol，1eq)的THF(20.00mL)溶液中加入CDI(442mg，2.73mmol，1.5eq)。氮气置换3次，将混合物在70℃下搅拌12.5小时。将反应液浓缩，残留物直接通过柱层析(石油醚∶乙酸乙酯＝4∶1-1∶1)得化合物29-c。Step C: To a solution of 29-b (430 mg, 1.82 mmol, 1 eq) in THF (20.00 mL) was added CDI (442 mg, 2.73 mmol, 1.5 eq). The nitrogen was replaced 3 times and the mixture was stirred at 70°C for 12.5 hours. The reaction solution was concentrated, and the residue was directly subjected to column chromatography (petroleum ether:ethyl acetate=4:1-1:1) to obtain compound 29-c.
步骤D：在29-c(200mg，762.73μmol，1eq)的DMF(3mL)溶液中加入碳酸钾(316mg，2.29mmol，3eq)和26-c(485mg，1.53mmol，2eq)，然后在120℃下反应12小时。将反应液过滤，滤饼用DMF(2mL)洗涤，滤液经制备HPLC纯化[流动相：水(0.225％FA)-乙腈]得到化合物29。 1H NMR(400MHz，DMSO-d 6)δppm 1.22-1.48(m，6H)5.30(s，2H)7.02(br s，2H)7.26-7.52(m，1H)7.76(ddd，J＝10.06，8.53，1.10Hz，1H)7.94-8.13(m，1H)8.15-8.36(m，2H)11.12(br s，1H)。LCMS(ESI)m/z：439.1[M+1] +。 Step D: To a solution of 29-c (200 mg, 762.73 μmol, 1 eq) in DMF (3 mL) was added potassium carbonate (316 mg, 2.29 mmol, 3 eq) and 26-c (485 mg, 1.53 mmol, 2 eq), then heated at 120°C The reaction was continued for 12 hours. The reaction solution was filtered, the filter cake was washed with DMF (2 mL), and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to give compound 29. 1 H NMR (400 MHz, DMSO-d 6 ) δppm 1.22-1.48 (m, 6H) 5.30 (s, 2H) 7.02 (br s, 2H) 7.26-7.52 (m, 1H) 7.76 (ddd, J=10.06, 8.53 , 1.10Hz, 1H) 7.94-8.13 (m, 1H) 8.15-8.36 (m, 2H) 11.12 (br s, 1H). LCMS (ESI) m/z: 439.1 [M+1] + .
实施例30Example 30
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000097
Figure PCTCN2022088918-appb-000097
步骤A：向溶有3-c(250mg，957.02μmol，1eq)的DMF(2.00mL)溶液中加入2-氯-4-氨基-5-溴嘧啶(199.49mg，957.02μmol，1eq)和碳酸钾(264.53mg，1.91mmol，2eq)。反应在120℃下搅拌12小时，反应液冷却后，用水(50mL)稀释，并用乙酸乙酯(50mL×2)萃取，合并的有机相经过无水硫酸钠干燥后减压浓缩，残留物通过薄层色谱法(SiO 2，PE∶EtOAc＝2∶1)纯化得到化合物30-a。 Step A: To a solution of 3-c (250 mg, 957.02 μmol, 1 eq) in DMF (2.00 mL) was added 2-chloro-4-amino-5-bromopyrimidine (199.49 mg, 957.02 μmol, 1 eq) and potassium carbonate (264.53 mg, 1.91 mmol, 2 eq). The reaction was stirred at 120° C. for 12 hours. After cooling, the reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Layer chromatography ( SiO2 , PE:EtOAc = 2:1 ) gave compound 30-a.
步骤B：将30-a(200mg，461.67μmol，1eq)、环丙基硼酸(118.97mg，1.39mmol，3eq)、碳酸钾(191.42mg，1.39mmol，3eq)和二(三苯基膦)二氯化钯(162.02mg，230.84μmol，0.5eq)溶于1，4-二氧六环(5mL)中，氮气置换3次后，在100℃下搅拌2小时。将反应液用水(20mL)稀释，并用乙酸乙酯(50mL×2)萃取，合并的有机相经过无水硫酸钠干燥后减压浓缩，残留物用制备HPLC纯化[流动相：水(0.1％TFA)-ACN]]得化合物30。 1H NMR(400MHz，DMSO-d 6)δ＝8.55(br d，J＝9.3Hz，1H)，8.22(d，J＝1.7Hz，1H)，7.85(s，1H)，7.41-7.33(m，2H)，7.24(m，1H)，7.20-7.11(m，1H)，5.19(s，2H)，1.67(m，1H)，0.96(dd，J＝1.9，8.3Hz，2H)，0.63(dd，J＝1.7，5.3Hz，2H)。LCMS(ESI)m/z：395.3[M+1] +。 Step B: Combine 30-a (200 mg, 461.67 μmol, 1 eq), cyclopropylboronic acid (118.97 mg, 1.39 mmol, 3 eq), potassium carbonate (191.42 mg, 1.39 mmol, 3 eq) and bis(triphenylphosphine)bis Palladium chloride (162.02 mg, 230.84 μmol, 0.5 eq) was dissolved in 1,4-dioxane (5 mL), replaced with nitrogen three times, and stirred at 100° C. for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (50 mL×2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC [mobile phase: water (0.1% TFA) )-ACN]] to give compound 30. 1 H NMR (400MHz, DMSO-d 6 )δ=8.55(br d, J=9.3Hz, 1H), 8.22(d, J=1.7Hz, 1H), 7.85(s, 1H), 7.41-7.33(m , 2H), 7.24(m, 1H), 7.20-7.11(m, 1H), 5.19(s, 2H), 1.67(m, 1H), 0.96(dd, J=1.9, 8.3Hz, 2H), 0.63( dd, J=1.7, 5.3 Hz, 2H). LCMS (ESI) m/z: 395.3 [M+1] + .
实施例31Example 31
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000098
Figure PCTCN2022088918-appb-000098
步骤A：在3-1(2g，11.33mmol，1eq)的甲苯(20mL)溶液中加入间氟苄胺(1.56g，12.46mmol，1.42mL，1.1eq)和N，N-二异丙基乙胺(4.39g，33.99mmol，5.92mL，3eq)。加完后将混合物在100℃下搅拌2小时。将反应液浓缩，残留物通过柱层析(PE∶EtOAc＝100∶1-30∶1)纯化得到化合物31-a。Step A: To a solution of 3-1 (2g, 11.33mmol, 1eq) in toluene (20mL) was added m-fluorobenzylamine (1.56g, 12.46mmol, 1.42mL, 1.1eq) and N,N-diisopropylethyl acetate Amine (4.39 g, 33.99 mmol, 5.92 mL, 3 eq). After the addition was complete the mixture was stirred at 100°C for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (PE:EtOAc=100:1-30:1) to obtain compound 31-a.
步骤B：在氮气保护下，向31-a(1.62g，6.52mmol，1eq)的甲醇(30mL)溶液中加入湿钯碳(300mg)，加料完毕后，抽真空置换氢气三次，反应液在氢气(15psi)氛围下于45℃下搅拌12小时。将反应液经硅藻土过滤，滤饼用甲醇(10mL×3)洗涤，滤液经浓缩得到化合物31-b。Step B: Under the protection of nitrogen, wet palladium carbon (300 mg) was added to a solution of 31-a (1.62 g, 6.52 mmol, 1 eq) in methanol (30 mL), and after the addition was completed, the hydrogen was replaced by vacuum three times, and the reaction solution was heated in hydrogen. (15 psi) at 45°C for 12 hours. The reaction solution was filtered through celite, the filter cake was washed with methanol (10 mL×3), and the filtrate was concentrated to obtain compound 31-b.
步骤C：向化合物31-b(2g，8.50mmol，1eq)的四氢呋喃(20mL)溶液中加入CDI(2.76g，17.00mmol，2eq)，将反应液升温至70℃并搅拌2小时。将反应液浓缩得到残留物，残留物通过柱层析(PE/EA＝5/1-1/1)纯化得到化合物31-c。LCMS(ESI)m/z：262.5[M+1] +。 Step C: To a solution of compound 31-b (2g, 8.50mmol, 1eq) in tetrahydrofuran (20mL) was added CDI (2.76g, 17.00mmol, 2eq), the reaction solution was warmed to 70°C and stirred for 2 hours. The reaction solution was concentrated to obtain a residue, and the residue was purified by column chromatography (PE/EA=5/1-1/1) to obtain compound 31-c. LCMS (ESI) m/z: 262.5 [M+1] + .
步骤F：在氮气保护下，向31-c(260mg，995.30μmol，1eq)的DMF(3mL)溶液中加入26-c(510mg，1.99mmol，2eq)和碳酸钾(413mg，2.99mmol，3eq)。反应液在120℃下搅拌12小时。将反应液过滤，滤液经制备HPLC纯化[流动相：水(0.225％FA)-乙腈]得到化合物31。 1H NMR(400MHz，DMSO-d 6)δppm 1.35(s，6H)5.10(s，2H)7.00(br s，2H)7.07-7.14(m，1H)7.15-7.23(m，2H)7.38(td，J＝8.01，6.24Hz，1H)8.10(t，J＝2.08Hz，1H)8.26(dd，J＝9.35，2.51Hz，1H)11.12(br s，1H)；LCMS(ESI)m/z：438.1[M+1] +。 Step F: To a solution of 31-c (260 mg, 995.30 μmol, 1 eq) in DMF (3 mL) under nitrogen protection was added 26-c (510 mg, 1.99 mmol, 2 eq) and potassium carbonate (413 mg, 2.99 mmol, 3 eq) . The reaction solution was stirred at 120°C for 12 hours. The reaction solution was filtered, and the filtrate was purified by preparative HPLC [mobile phase: water (0.225% FA)-acetonitrile] to give compound 31. 1 H NMR (400MHz, DMSO-d 6 ) δppm 1.35(s, 6H) 5.10(s, 2H) 7.00(br s, 2H) 7.07-7.14(m, 1H) 7.15-7.23(m, 2H) 7.38(td , J=8.01, 6.24Hz, 1H) 8.10 (t, J=2.08Hz, 1H) 8.26 (dd, J=9.35, 2.51Hz, 1H) 11.12 (br s, 1H); LCMS (ESI) m/z: 438.1[M+1] + .
实施例32Example 32
合成路线：synthetic route:
Figure PCTCN2022088918-appb-000099
Figure PCTCN2022088918-appb-000099
步骤A：氮气保护下，向3-1(1.4g，7.93mmol，1eq)的甲苯(40mL)溶液中加入2，4-二甲氧基苄胺(1.33g，7.93mmol，1.19mL，1eq)和三乙胺(1.60g，15.86mmol，2.21mL，2eq)，反应液在100℃下搅拌4小时。反应液冷却后用水(40mL)洗涤，分液，有机相减压浓缩后加入甲醇搅拌1小时，过滤，滤饼真空干燥得到化合物32-a。Step A: To a solution of 3-1 (1.4g, 7.93mmol, 1eq) in toluene (40mL) was added 2,4-dimethoxybenzylamine (1.33g, 7.93mmol, 1.19mL, 1eq) under nitrogen protection and triethylamine (1.60 g, 15.86 mmol, 2.21 mL, 2 eq), and the reaction solution was stirred at 100° C. for 4 hours. The reaction solution was cooled, washed with water (40 mL), separated, the organic phase was concentrated under reduced pressure, methanol was added and stirred for 1 hour, filtered, and the filter cake was vacuum-dried to obtain compound 32-a.
步骤B：向32-a(2g，6.51mmol，1eq)的四氢呋喃(60mL)和水(20mL)的溶液中加入锌粉(2.13g，32.54mmol，5eq)和氯化铵(1.74g，32.54mmol，5eq)，反应液在60℃下搅拌1小时。反应液用水(50mL)稀释，乙酸乙酯(50mL)萃取，有机相减压浓缩后通过柱层析分离(石油醚∶乙酸乙酯＝3∶1到1∶1)得到化合物32-b。Step B: To a solution of 32-a (2g, 6.51mmol, 1eq) in tetrahydrofuran (60mL) and water (20mL) was added zinc powder (2.13g, 32.54mmol, 5eq) and ammonium chloride (1.74g, 32.54mmol) , 5eq), the reaction solution was stirred at 60 ° C for 1 hour. The reaction solution was diluted with water (50 mL), extracted with ethyl acetate (50 mL), the organic phase was concentrated under reduced pressure and separated by column chromatography (petroleum ether:ethyl acetate=3:1 to 1:1) to obtain compound 32-b.
步骤C：氮气保护下，向32-b(1.6g，5.77mmol，1eq)的四氢呋喃(30mL)溶液中加入CDI(1.87g，11.54mmol，2eq)。反应液在60℃下搅拌16小时后加入水(2mL)淬灭，反应液减压浓缩，残留物加入甲醇(20mL)搅拌2小时，过滤，滤饼真空干燥得到化合物32-c。Step C: To a solution of 32-b (1.6 g, 5.77 mmol, 1 eq) in tetrahydrofuran (30 mL) was added CDI (1.87 g, 11.54 mmol, 2 eq) under nitrogen. The reaction solution was stirred at 60° C. for 16 hours and then quenched by adding water (2 mL). The reaction solution was concentrated under reduced pressure. The residue was added with methanol (20 mL), stirred for 2 hours, filtered, and the filter cake was vacuum-dried to obtain compound 32-c.
步骤D：氮气保护下，向32-c(1.1g，3.63mmol，1eq)的DMF(10mL)溶液中加入26-c(1.73g，5.44mmol，1.5eq)和碳酸钾(1.50g，10.88mmol，3eq)，反应液在120℃下搅拌4小时，向反应液中加入水(40mL)稀释，过滤，滤饼用真空干燥得到化合物32-d。Step D: To a solution of 32-c (1.1 g, 3.63 mmol, 1 eq) in DMF (10 mL) was added 26-c (1.73 g, 5.44 mmol, 1.5 eq) and potassium carbonate (1.50 g, 10.88 mmol) under nitrogen protection , 3eq), the reaction solution was stirred at 120° C. for 4 hours, water (40 mL) was added to the reaction solution to dilute, filtered, and the filter cake was dried under vacuum to obtain compound 32-d.
步骤E：向32-d(1.6g，3.34mmol，1eq)的DMF(4mL)溶液中加入碳酸钾(922.41mg，6.67mmol，2eq)和对甲氧基苄氯(731.66mg，4.67mmol，636.23μL，1.4eq)，氮气保护下于50℃搅拌2小时，反应液加 入水(25mL)稀释，过滤，滤饼真空干燥后得到化合物32-e。Step E: To a solution of 32-d (1.6 g, 3.34 mmol, 1 eq) in DMF (4 mL) was added potassium carbonate (922.41 mg, 6.67 mmol, 2 eq) and p-methoxybenzyl chloride (731.66 mg, 4.67 mmol, 636.23 μL, 1.4eq), stirred at 50°C for 2 hours under nitrogen protection, the reaction solution was diluted with water (25 mL), filtered, and the filter cake was vacuum-dried to obtain compound 32-e.
步骤F：将32-e(1.8g，3.00mmol，1eq)的TFA(27.72g，243.11mmol，18.00mL，80.98eq)溶液在30℃下搅拌3小时，将反应液浓缩，残留物通过柱层析分离(石油醚/乙酸乙酯＝1/1到0/1)得到化合物32-f。Step F: A solution of 32-e (1.8 g, 3.00 mmol, 1 eq) in TFA (27.72 g, 243.11 mmol, 18.00 mL, 80.98 eq) was stirred at 30 °C for 3 hours, the reaction solution was concentrated, and the residue was passed through a column layer Separation (petroleum ether/ethyl acetate=1/1 to 0/1) gave compound 32-f.
步骤G：向32-f(0.6g，1.34mmol，1eq)的DMF(5mL)溶液中加入1，1，1，2，2-五氟-4-碘丁烷(1.46g，5.34mmol，4eq)和碳酸钾(922.55mg，6.68mmol，5eq)。反应液在氮气保护下于50℃反应1小时。反应液加入稀盐酸(30mL，1mol/L)中和，然后用乙酸乙酯萃取，硫酸钠干燥后浓缩，残留物通过柱层析分离(石油醚/乙酸乙酯＝1/1到0/1)得到化合物32-g。Step G: To a solution of 32-f (0.6g, 1.34mmol, 1eq) in DMF (5mL) was added 1,1,1,2,2-pentafluoro-4-iodobutane (1.46g, 5.34mmol, 4eq) ) and potassium carbonate (922.55 mg, 6.68 mmol, 5 eq). The reaction solution was reacted at 50°C for 1 hour under nitrogen protection. The reaction solution was neutralized by adding dilute hydrochloric acid (30 mL, 1 mol/L), then extracted with ethyl acetate, dried over sodium sulfate and concentrated, and the residue was separated by column chromatography (petroleum ether/ethyl acetate=1/1 to 0/1 ) to give compound 32-g.
步骤H：氮气保护下，向32-g(0.2g，335.85μmol，1eq)的TFA(2mL)溶液中加入三氟甲烷磺酸(3.40g，22.66mmol，2mL，67.45eq)。反应液在50℃下搅拌16小时。将反应液倒入到氢氧化钠(80mL，1mol/L)的水溶液中中和，用乙酸乙酯(60mL)萃取，有机相减压浓缩后通过制备HPLC纯化[水(0.075％TFA)-乙腈]得到化合物32。 1H NMR(400MHz，DMSO-d 6)δ＝11.14(s，1H)，8.26(dd，J＝2.6，9.4Hz，1H)，8.15(t，J＝2.1Hz，1H)，7.01(br s，2H)，4.22(t，J＝6.9Hz，2H)，2.90-2.72(m，2H)，1.35(s，6H).LCMS(ESI)m/z：476.2[M+1] +。 Step H: To a solution of 32-g (0.2 g, 335.85 μmol, 1 eq) in TFA (2 mL) was added trifluoromethanesulfonic acid (3.40 g, 22.66 mmol, 2 mL, 67.45 eq) under nitrogen. The reaction solution was stirred at 50°C for 16 hours. The reaction solution was poured into an aqueous solution of sodium hydroxide (80 mL, 1 mol/L) for neutralization, extracted with ethyl acetate (60 mL), the organic phase was concentrated under reduced pressure and purified by preparative HPLC [water (0.075% TFA)-acetonitrile] ] to give compound 32. 1 H NMR (400 MHz, DMSO-d 6 ) δ=11.14 (s, 1H), 8.26 (dd, J=2.6, 9.4 Hz, 1H), 8.15 (t, J=2.1 Hz, 1H), 7.01 (br s) , 2H), 4.22 (t, J=6.9 Hz, 2H), 2.90-2.72 (m, 2H), 1.35 (s, 6H). LCMS (ESI) m/z: 476.2 [M+1] + .
生物测试biological test
实验例1：体外活性测试Experimental Example 1: In Vitro Activity Test
基于lnCap细胞的cGMP表达测试lnCap cell-based cGMP expression assay
1.实验步骤1. Experimental procedure
1)溶液配制1) Solution preparation
● 10％BSA(牛血清蛋白) ● 10% BSA (bovine serum albumin)
将10g BSA溶解于100mL双蒸水(ddH 2O)得到10％BSA。 10 g of BSA was dissolved in 100 mL of double distilled water (ddH2O) to give 10% BSA.
● 5mM DETA(二乙烯三胺)-NO ● 5mM DETA (diethylenetriamine)-NO
称取10mg DETA-NO溶解于12.2mL双蒸水(ddH 2O)得到5mM DETA-NO，分装并冻存于-20℃冰箱。 10 mg of DETA-NO was weighed and dissolved in 12.2 mL of double-distilled water (ddH 2 O) to obtain 5 mM DETA-NO, which was aliquoted and stored in a -20°C refrigerator.
● 洗涤缓冲液(Washing Buffer，50mL) ● Washing Buffer (Washing Buffer, 50mL)
Figure PCTCN2022088918-appb-000100
Figure PCTCN2022088918-appb-000100
● 分析缓冲液(Assay Buffer，50mL) ● Assay Buffer (Assay Buffer, 50mL)
Figure PCTCN2022088918-appb-000101
Figure PCTCN2022088918-appb-000101
● 检测缓冲液(Detection Buffer) ● Detection Buffer
a)将50μL cGMP-D2(D2标记的环单磷鸟苷)加入到1mL裂解液(lysis buffer)混合均匀。a) Add 50 μL of cGMP-D2 (D2-labeled cyclic guanosine monophosphate) to 1 mL of lysis buffer and mix well.
b)将50μL anti-cGMP cryptate(Eu 3+穴状化合物标记的抗环单磷鸟苷抗体)加入到1mL裂解液(lysis buffer)混合均匀。 b) 50 μL of anti-cGMP cryptate (Eu 3+ cryptate-labeled anti-cyclic monophosphate antibody) was added to 1 mL of lysis buffer and mixed well.
2)化合物稀释2) Compound dilution
(1)用DMSO将化合物稀释至5mM。转移10μL化合物到Echo用浅孔板中。(1) Compounds were diluted to 5 mM with DMSO. Transfer 10 μL of compound to a shallow-well plate for Echo.
(2)用Echo对化合物进行梯度稀释，将每个化合物稀释10个浓度梯度并分别加50nL到384微孔板中。(2) The compound was serially diluted with Echo, 10 concentration gradients of each compound were diluted and 50nL were added to a 384 microwell plate respectively.
3)准备LNCap细胞3) Prepare LNCap cells
(1)LNCap培养基：RPMI1640+10％胎牛血清+1％双抗(1) LNCap medium: RPMI1640+10% fetal bovine serum+1% double antibody
(2)将细胞传代过程中用到的磷酸盐缓冲液、胰酶、培养基放到37℃水浴锅中预热。(2) The phosphate buffer, trypsin, and medium used in the cell passaging process were placed in a 37° C. water bath to preheat.
(3)从37℃5％CO 2培养箱中取出细胞(第14代)，用移液器吸去培养瓶中的旧培养液。 (3) Remove the cells (passage 14) from the 37°C 5% CO 2 incubator, and remove the old culture medium in the culture flask with a pipette.
(4)吸取5mL磷酸盐缓冲液加入到培养瓶中漂洗细胞，然后弃去液体。(4) Pipet 5 mL of phosphate buffer into the culture flask to rinse the cells, and then discard the liquid.
(5)吸取3mL胰酶加入培养瓶，摇晃后弃去液体，将培养瓶放入培养箱中。(5) Pipet 3 mL of trypsin into the culture flask, shake and discard the liquid, and put the culture flask into the incubator.
(6)约2分钟后取出培养瓶，观察细胞都已分离后，吸取9mL培养基加入培养瓶并反复吹打几次，将细胞悬液转移至50mL离心管中。(6) After about 2 minutes, take out the culture flask and observe that the cells have been separated. Add 9 mL of medium to the culture flask and pipet repeatedly for several times, and transfer the cell suspension to a 50 mL centrifuge tube.
(7)吸取0.7mL细胞悬液加入计数杯，在ViCell XR上计数。剩余细胞，1000rpm离心5min，并去上清。(7) Pipette 0.7 mL of cell suspension into the counting cup and count on ViCell XR. The remaining cells were centrifuged at 1000 rpm for 5 min, and the supernatant was removed.
(8)加入10mL洗涤缓冲液(washing buffer)清洗细胞，1000rpm离心5min，并去上清。(8) Add 10 mL of washing buffer to wash the cells, centrifuge at 1000 rpm for 5 min, and remove the supernatant.
(9)加入分析缓冲液(assay buffer)并调整细胞浓度至1.25×10 6/mL。8μL/孔加入微孔板中。 (9) Add assay buffer and adjust the cell concentration to 1.25×10 6 /mL. 8 μL/well was added to the microplate.
4)DETA-NO配制和添加4) DETA-NO preparation and addition
(1)取10μL 5mM的DETA-NO分别加入到1240μL和1657μL分析缓冲液(assay buffer)中，得40μM和30μM的DETA-NO。(1) Add 10 μL of 5mM DETA-NO to 1240 μL and 1657 μL of assay buffer, respectively, to obtain 40 μM and 30 μM of DETA-NO.
(2)用Bravo转移2μL/孔的DETA-NO到384微孔板中。(2) Use Bravo to transfer 2 μL/well of DETA-NO into a 384 microwell plate.
(3)1500rpm离心5min。将微孔板于37℃孵育30min。(3) Centrifuge at 1500 rpm for 5 min. The microplate was incubated at 37°C for 30 min.
5)准备cGMP标准曲线5) Prepare the cGMP standard curve
(1)将1mM的cGMP存储液用试验缓冲液(assay buffer)稀释至10μM。然后4倍梯度稀释11个浓度梯度。(1) Dilute 1 mM cGMP stock solution to 10 μM with assay buffer. Eleven concentration gradients were then diluted 4-fold.
(2)将稀释好的cGMP加10μL/孔至微孔板中。(2) Add 10 μL/well of diluted cGMP to the microplate.
6)加检测试剂并读板6) Add detection reagent and read plate
(1)用Bravo转移5μL/孔的cGMP-D2到384微孔板中。1500rpm离心1min。(1) Transfer 5 μL/well of cGMP-D2 to a 384 microwell plate with Bravo. Centrifuge at 1500 rpm for 1 min.
(2)用Bravo转移5μL/孔的anti-cGMP cryptate到384微孔板中。1500rpm离心1min。(2) Transfer 5 μL/well of anti-cGMP cryptate to a 384 microwell plate with Bravo. Centrifuge at 1500 rpm for 1 min.
(3)常温孵育1h。(3) Incubate at room temperature for 1 h.
(4)用envision读取665/615。(4) Read 665/615 with envision.
7)数据分析7) Data analysis
(1)cGMP标准曲线：根据cGMP的浓度与665/615的比值用Graphpad prism做标准曲线。(1) cGMP standard curve: According to the ratio of cGMP concentration to 665/615, use Graphpad prism to make the standard curve.
(2)HTRF(均相时间分辨荧光技术)比值(665/615)转换成cGMP浓度：在Graphpad prism中，将HTRF比值(665/615)复制到cGMP标准曲线的比值列中，运行分析“Log inhibitor vs response-variable slope”，选择“interpolate”，将HTRF比值(665/615)转换成cGMP浓度。(2) Convert the HTRF (Homogeneous Time-Resolved Fluorescence) ratio (665/615) to cGMP concentration: In Graphpad prism, copy the HTRF ratio (665/615) to the ratio column of the cGMP standard curve, run the analysis "Log inhibitor vs response-variable slope", select "interpolate" to convert the HTRF ratio (665/615) to cGMP concentration.
(3)化合物激活曲线：根据转换的cGMP浓度与化合物的浓度用Graphpad prism中“Log agonist vs response-variable slope”分析方法做曲线。(3) Compound activation curve: According to the converted cGMP concentration and the compound concentration, use the "Log agonist vs response-variable slope" analysis method in Graphpad prism to make a curve.
表1本发明化合物对sGC刺激活性的MEC值Table 1 MEC value of the compounds of the present invention on sGC stimulating activity
化合物编号Compound number MEC(nM)MEC(nM)
化合物2Compound 2 320.6320.6
化合物8Compound 8 1212
化合物9Compound 9 6666
化合物10Compound 10 293293
化合物11Compound 11 234234
化合物12Compound 12 9494
化合物14Compound 14 3939
化合物15Compound 15 6161
化合物16Compound 16 150150
化合物17Compound 17 9595
化合物18Compound 18 4848
化合物19Compound 19 101101
化合物21Compound 21 151151
化合物22Compound 22 346346
化合物23Compound 23 299299
化合物26Compound 26 55
化合物27Compound 27 3.83.8
化合物28Compound 28 3737
化合物29Compound 29 7373
化合物31Compound 31 27.627.6
化合物32Compound 32 12.912.9
从实验结果可以看出，本发明化合物对sGC具有很好的刺激活性。It can be seen from the experimental results that the compounds of the present invention have good stimulating activity on sGC.
实验例2：大鼠体内药代动力学评价Experimental Example 2: Pharmacokinetic Evaluation in Rats
实验目的：Purpose:
检测本发明化合物在大鼠体内的药代动力学参数Detection of pharmacokinetic parameters of the compounds of the present invention in rats
实验方案：Experimental program:
1)实验动物：6只7-9周龄的雄性SD大鼠，随机分为2组，每组3只；1) Experimental animals: 6 male SD rats aged 7-9 weeks were randomly divided into 2 groups with 3 rats in each group;
2)药物配制：称取适量药物，溶于10％DMSO+50％PEG400+40％H 2O的混合溶剂中，配置成0.2mg/mL；称取适量药物，溶于10％EtOH+40％PEG400+50％H 2O的混合溶剂中，配置成0.3mg/mL； 2) Drug preparation: Weigh an appropriate amount of drug and dissolve it in a mixed solvent of 10% DMSO+50% PEG400+40% H 2 O to make 0.2 mg/mL; weigh an appropriate amount of drug and dissolve it in 10% EtOH+40% In the mixed solvent of PEG400+50% H 2 O, it was prepared at 0.3 mg/mL;
实验操作：Experimental operation:
第1组动物通过尾静脉单次注射给予剂量为1.0mg/kg、浓度为0.2mg/mL的药物，第2组动物通过灌胃给予剂量为3mg/kg、浓度为0.3mg/mL的化合物。动物于给药后0.0833(仅尾静脉注射组)、0.25、0.5、1、2、4、8和24小时采集血浆样品。Animals in Group 1 were given a single dose of drug at 1.0 mg/kg at a concentration of 0.2 mg/mL via tail vein, and animals in Group 2 were given compound at a dose of 3 mg/kg at a concentration of 0.3 mg/mL by gavage. Plasma samples were collected from animals at 0.0833 (tail vein injection group only), 0.25, 0.5, 1, 2, 4, 8 and 24 hours post-dose.
数据分析：data analysis:
使用LC-MS/MS方法测定血浆样品中的药物浓度，得出测试药物的动力学参数见表2。The drug concentration in the plasma samples was determined by LC-MS/MS method, and the kinetic parameters of the tested drugs are shown in Table 2.
表2本发明化合物的药代动力学测试结果Table 2 Pharmacokinetic test results of the compounds of the present invention
Figure PCTCN2022088918-appb-000102
Figure PCTCN2022088918-appb-000102
--表示不存在-- means does not exist
结论：本发明化合物具有良好的大鼠体内药代动力学性质。Conclusion: The compounds of the present invention have good pharmacokinetic properties in rats.
实验例3：人肝微粒体CYP抑制实验Experimental Example 3: Human Liver Microsome CYP Inhibition Experiment
研究项目的目的是采用CYP同工酶的5合1探针底物来评价供试品对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6、CYP3A4)的抑制性。The purpose of the research project is to use a 5-in-1 probe substrate of CYP isoenzymes to evaluate the inhibition of test articles on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6, CYP3A4).
混合人肝微粒体(HLM)购自Corning Inc.(Steuben，New York，USA)或者其他的供应商，使用前都储存在低于-70℃条件下。Mixed human liver microsomes (HLM) were purchased from Corning Inc. (Steuben, New York, USA) or other suppliers and were stored below -70°C until use.
将稀释好的系列浓度的供试品工作液加入到含有人肝微粒体、探针底物和循环体系的辅助因子的孵育体系中，不含供试品而含有溶剂的对照作为酶活性对照(100％)。探针底物生成的代谢产物在样品中的浓度采用液相色谱-串联质谱(LC-MS/MS)方法进行测定。使用SigmaPlot(V.11)对供试品平均百分比活性对浓度作非线性回归分析。通过三参数或四参数反曲对数方程来计算IC 50值。测试结果见表3： The test substance working solution of a series of diluted concentrations was added to the incubation system containing human liver microsomes, probe substrates and cofactors of the circulating system, and the control containing no test substance and solvent was used as the enzyme activity control ( 100%). The concentrations of metabolites generated from the probe substrates in the samples were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Use SigmaPlot (V.11) to perform non-linear regression analysis on the average percent activity of the test article versus concentration. IC50 values were calculated by three-parameter or four-parameter inverse logarithmic equations. The test results are shown in Table 3:
表3本发明化合物体外检测对CYP同工酶的抑制Table 3 Inhibition of CYP isozymes detected by the compounds of the present invention in vitro
Figure PCTCN2022088918-appb-000103
Figure PCTCN2022088918-appb-000103
结论：本发明化合物对五个CYP同工酶抑制程度均较弱。CONCLUSION: The compounds of the present invention have weak inhibition on the five CYP isozymes.

Claims (24)

  1. 式(I)所示化合物或其药学上可接受的盐，A compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022088918-appb-100001
    Figure PCTCN2022088918-appb-100001
    其中，R 1为H、F或Cl； Wherein, R 1 is H, F or Cl;
    R 2为C 1-6烷基、-CH 2-苯基、-CH 2-吡啶基或-CH 2-嘧啶基，其中所述C 1-6烷基、-CH 2-苯基、-CH 2-吡啶基或-CH 2-嘧啶基分别独立地任选被1、2、3、4或5个R a所取代； R 2 is C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl or -CH 2 -pyrimidinyl, wherein said C 1-6 alkyl, -CH 2 -phenyl, -CH 2 -pyridyl or -CH2 -pyrimidinyl, respectively, independently optionally substituted with 1, 2, 3, 4 or 5 R a ;
    各R a独立地为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-C(＝O)OH、C 1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-3烷基； Each Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C(=O)OH, C1-3alkoxy or optionally , 2 or 3 C 1-3 alkyl substituted with substituents independently selected from F, Cl, Br, I, -OH, -CN, -NH 2 and -OCH 3 ;
    R 3和R 4各自独立地为H、F、Cl、Br、I、-OH、-CN或-NH 2； R3 and R4 are each independently H, F, Cl, Br, I, -OH, -CN or -NH2 ;
    R 5为-L-R b； R 5 is -LR b ;
    L为单键、-NR cC(＝O)O-或-NR cC(＝O)-； L is a single bond, -NR c C(=O)O- or -NR c C(=O)-;
    R b为C 1-6烷基、
    Figure PCTCN2022088918-appb-100002
    其中所述C 1-6烷基、
    Figure PCTCN2022088918-appb-100003
    Figure PCTCN2022088918-appb-100004
    分别独立地任选被1、2或3个R所取代；     R b is C 1-6 alkyl,
    Figure PCTCN2022088918-appb-100002
    wherein the C 1-6 alkyl,
    Figure PCTCN2022088918-appb-100003
    Figure PCTCN2022088918-appb-100004
    each independently optionally substituted with 1, 2 or 3 R;
    R c为H、-CH 3或-CH 2CH 3； R c is H, -CH 3 or -CH 2 CH 3 ;
    各R独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、C 1-3烷氧基或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-3烷基； Each R is independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 , C 1-3 alkoxy, or optionally 1, 2 or 3 independently selected from F, Cl , Br, I, -OH, -CN, -NH 2 and -OCH 3 substituents substituted C 1-3 alkyl;
    或R 3和R 5与它们相连碳原子连接在一起，使结构单元
    Figure PCTCN2022088918-appb-100005
    选自
    Figure PCTCN2022088918-appb-100006
    R 6、R 7和R 8各自独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2或任选被1、2或3个独立选自F、Cl、Br、I、-OH、-CN、-NH 2和-OCH 3的取代基所取代的C 1-3烷基。     or R3 and R5 are joined together with their attached carbon atoms, making the structural unit
    Figure PCTCN2022088918-appb-100005
    selected from
    Figure PCTCN2022088918-appb-100006
    R 6 , R 7 and R 8 are each independently F, Cl, Br, I, -OH, -CN, -NH 2 , -NO 2 or are optionally 1, 2 or 3 independently selected from F, Cl, C 1-3 alkyl substituted with substituents of Br, I, -OH, -CN, -NH 2 and -OCH 3 .
  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L为单键、-NH-C(＝O)O-、-NH-C(＝O)-、-N(CH 3)-C(＝O)O-或-N(CH 3)-C(＝O)-。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein the L is a single bond, -NH-C(=O)O-, -NH-C(=O)-, -N(CH 3 )-C(=O)O- or -N(CH 3 )-C(=O)-.
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(I-1)～(I-4)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structures represented by the formulae (I-1) to (I-4):
    Figure PCTCN2022088918-appb-100007
    Figure PCTCN2022088918-appb-100007
    其中，R 1、R 2、R 4和R b如权利要求1所定义。 wherein R 1 , R 2 , R 4 and R b are as defined in claim 1 .
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述各R独立地为F、Cl、Br、-OH、-CN、-NH 2、-NO 2、-CH 3、-CH 2CH 3、-OCH 3、-OCH 2CH 3、-CF 3、-CH 2CF 3、-CH 2CH 2CF 3、-CH 2OH或-CH 2CH 2OH。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R is independently F, Cl, Br, -OH, -CN, -NH2 , -NO2 , -CH3 , - CH2CH3 , -OCH3 , -OCH2CH3 , -CF3 , -CH2CF3 , -CH2CH2CF3 , -CH2OH or -CH2CH2OH .
  5. 根据权利要求1～4任一项所述的化合物或其药学上可接受的盐，其中所述R b为C 1-4烷基、
    Figure PCTCN2022088918-appb-100008
    Figure PCTCN2022088918-appb-100009
    其中所述C 1-4烷基、
    Figure PCTCN2022088918-appb-100010
    分别独立地任选被1、2或3个R所取代。     The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein the R b is C 1-4 alkyl,
    Figure PCTCN2022088918-appb-100008
    Figure PCTCN2022088918-appb-100009
    wherein the C 1-4 alkyl,
    Figure PCTCN2022088918-appb-100010
    are each independently optionally substituted with 1, 2 or 3 Rs.
  6. 根据权利要求5所述的化合物或其药学上可接受的盐，其中所述R b为-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-CH 2CH 2CH 2CH 3、-CH(CH 3)CH 2CH 3、-CH 2CH(CH 3) 2、-C(CH 3) 3、
    Figure PCTCN2022088918-appb-100011
    Figure PCTCN2022088918-appb-100012
    The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein the R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , - CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 ,
    Figure PCTCN2022088918-appb-100011
    Figure PCTCN2022088918-appb-100012
  7. 根据权利要求4或6所述的化合物或其药学上可接受的盐，其中所述R b为-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、 -CH(CH 3) 2、-CH 2CH 2CH 2CH 3、-CH(CH 3)CH 2CH 3、-CH 2CH(CH 3) 2、-C(CH 3) 3、
    Figure PCTCN2022088918-appb-100013
    Figure PCTCN2022088918-appb-100014
    The compound of claim 4 or 6 or a pharmaceutically acceptable salt thereof, wherein the R b is -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH(CH 3 ) 2 , -CH 2 CH 2 CH 2 CH 3 , -CH(CH 3 )CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -C(CH 3 ) 3 ,
    Figure PCTCN2022088918-appb-100013
    Figure PCTCN2022088918-appb-100014
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述R 5为-NH-C(＝O)O-C 1-4烷基、-NHC(＝O)-C 1-4烷基、-N(CH 3)-C(＝O)O-C 1-4烷基、-NH-C(＝O)-(C 3-6环烷基)、-N(CH 3)C(＝O)-(C 3-6环烷基)、-NH-C(＝O)-苯基、-N(CH 3)-C(＝O)-苯基或5-6元杂环烷基，其中所述NH-C(＝O)O-C 1-4烷基、-NHC(＝O)-C 1-4烷基、-N(CH 3)-C(＝O)O-C 1-4烷基、-NH-C(＝O)-(C 3-6环烷基)、-N(CH 3)C(＝O)-(C 3-6环烷基)、-NH-C(＝O)-苯基、-N(CH 3)-C(＝O)-苯基和5-6元杂环烷基分别独立地任选被1、2或3个R所取代。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein said R 5 is -NH-C(=O)OC 1-4 alkyl, -NHC(=O)-C 1-4 alkane base, -N(CH 3 )-C(=O)OC 1-4 alkyl, -NH-C(=O)-(C 3-6 cycloalkyl), -N(CH 3 )C(=O )-(C 3-6 cycloalkyl), -NH-C(=O)-phenyl, -N(CH 3 )-C(=O)-phenyl or 5-6 membered heterocycloalkyl, wherein The NH-C(=O)OC 1-4 alkyl, -NHC(=O)-C 1-4 alkyl, -N(CH 3 )-C(=O)OC 1-4 alkyl, - NH-C(=O)-(C 3-6 cycloalkyl), -N(CH 3 )C(=O)-(C 3-6 cycloalkyl), -NH-C(=O)-benzene group, -N( CH3 )-C(=O)-phenyl, and 5-6 membered heterocycloalkyl, each independently optionally substituted with 1, 2, or 3 Rs.
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其中所述R 5为-NH-C(＝O)O-CH 3、-NH-C(＝O)O-CH 2CH 3、-NH-C(＝O)O-CH 2CH 2CH 3、-NH-C(＝O)O-CH(CH 3) 2、-NH-C(＝O)-CH 3、-NH-C(＝O)-CH 2CH 3、-NH-C(＝O)-CH 2CH 2CH 3、-NH-C(＝O)-CH(CH 3) 2、-N(CH 3)-C(＝O)O-CH 3、-N(CH 3)-C(＝O)O-CH 2CH 3、-N(CH 3)-C(＝O)O-CH 2CH 2CH 3、-N(CH 3)-C(＝O)O-CH(CH 3) 2、
    Figure PCTCN2022088918-appb-100015
    Figure PCTCN2022088918-appb-100016
    The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein said R 5 is -NH-C(=O)O-CH 3 , -NH-C(=O)O-CH 2 CH 3 , -NH-C(=O)O-CH 2 CH 2 CH 3 , -NH-C(=O)O-CH(CH 3 ) 2 , -NH-C(=O)-CH 3 , -NH- C(=O)-CH 2 CH 3 , -NH-C(=O)-CH 2 CH 2 CH 3 , -NH-C(=O)-CH(CH 3 ) 2 , -N(CH 3 )- C(=O)O-CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH(CH 3 ) 2 ,
    Figure PCTCN2022088918-appb-100015
    Figure PCTCN2022088918-appb-100016
  10. 根据权利要求9所述的化合物或其药学上可接受的盐，其中所述R 5为-NH-C(＝O)O-CH 3、-NH-C(＝O)O-CH 2CH 3、-NH-C(＝O)O-CH 2CH 2CH 3、-NH-C(＝O)O-CH(CH 3) 2、-NH-C(＝O)-CH 3、-NH-C(＝O)-CH 2CH 3、-NH-C(＝O)-CH 2CH 2CH 3、-NH-C(＝O)-CH(CH 3) 2、-N(CH 3)-C(＝O)O-CH 3、-N(CH 3)-C(＝O)O-CH 2CH 3、-N(CH 3)- C(＝O)O-CH 2CH 2CH 3、-N(CH 3)-C(＝O)O-CH(CH 3) 2、
    Figure PCTCN2022088918-appb-100017
    Figure PCTCN2022088918-appb-100018
    The compound of claim 9, or a pharmaceutically acceptable salt thereof, wherein said R 5 is -NH-C(=O)O-CH 3 , -NH-C(=O)O-CH 2 CH 3 , -NH-C(=O)O-CH 2 CH 2 CH 3 , -NH-C(=O)O-CH(CH 3 ) 2 , -NH-C(=O)-CH 3 , -NH- C(=O)-CH 2 CH 3 , -NH-C(=O)-CH 2 CH 2 CH 3 , -NH-C(=O)-CH(CH 3 ) 2 , -N(CH 3 )- C(=O)O-CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH 2 CH 2 CH 3 , -N(CH 3 )-C(=O)O-CH(CH 3 ) 2 ,
    Figure PCTCN2022088918-appb-100017
    Figure PCTCN2022088918-appb-100018
  11. 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(I-5)～(I-13)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structures represented by the formulae (I-5) to (I-13):
    Figure PCTCN2022088918-appb-100019
    Figure PCTCN2022088918-appb-100019
    Figure PCTCN2022088918-appb-100020
    Figure PCTCN2022088918-appb-100020
    其中，p为0、1或2；R 4为H或-NH 2；R 2如权利要求1所定义；R如权利要求1或4所定义。 wherein p is 0, 1 or 2 ; R4 is H or -NH2 ; R2 is as defined in claim 1 ; R is as defined in claim 1 or 4.
  12. 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物具有式(I-14)～(I-15)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has the structures represented by the formulae (I-14) to (I-15):
    Figure PCTCN2022088918-appb-100021
    Figure PCTCN2022088918-appb-100021
    其中，R 1、R 2、R 4、R 6、R 7和R 8如权利要求1所定义。 wherein R 1 , R 2 , R 4 , R 6 , R 7 and R 8 are as defined in claim 1 .
  13. 根据权利要求12所述的化合物或其药学上可接受的盐，其化合物具有式(I-16)～(I-19)所示结构：The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein the compound has the structures represented by formulae (I-16) to (I-19):
    Figure PCTCN2022088918-appb-100022
    Figure PCTCN2022088918-appb-100022
    其中，R 2、R 6、R 7和R 8如权利要求12所定义。 wherein R 2 , R 6 , R 7 and R 8 are as defined in claim 12 .
  14. 根据权利要求1或12所述的化合物或其药学上可接受的盐，其中所述结构单元
    Figure PCTCN2022088918-appb-100023
    为
    Figure PCTCN2022088918-appb-100024
    The compound of claim 1 or 12, or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022088918-appb-100023
    for
    Figure PCTCN2022088918-appb-100024
  15. 根据权利要求1或12所述的化合物或其药学上可接受的盐，其中所述结构单元
    Figure PCTCN2022088918-appb-100025
    为
    Figure PCTCN2022088918-appb-100026
    The compound of claim 1 or 12, or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022088918-appb-100025
    for
    Figure PCTCN2022088918-appb-100026
  16. 根据权利要求1、12或13任一项所述的化合物或其药学上可接受的盐，其中所述R 6、R 7和R 8各自独立地为F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-CH 3、-CH 2CH 3、-CF 3、-CH 2CF 3或-CH 2CH 2OH。 The compound of any one of claims 1, 12 or 13, or a pharmaceutically acceptable salt thereof, wherein each of said R 6 , R 7 and R 8 is independently F, Cl, Br, I, -OH, -CN , -NH2 , -NO2 , -CH3 , -CH2CH3 , -CF3 , -CH2CF3 or -CH2CH2OH .
  17. 根据权利要求13所述的化合物或其药学上可接受的盐，其化合物具有式(I-20)～(I-25)所示结构：The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the compound has the structures represented by the formulae (I-20) to (I-25):
    Figure PCTCN2022088918-appb-100027
    Figure PCTCN2022088918-appb-100027
    其中，R 2如权利要求13所定义。 wherein R 2 is as defined in claim 13 .
  18. 根据权利要求1所述的化合物或其药学上可接受的盐，其中所述各R a独立地为H、F、Cl、Br、I、-OH、-CN、-NH 2、-NO 2、-C(＝O)OH、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、-CH(CH 3) 2、-OCH 3、-OCH 2CH 3、-CF 3、-CH 2CF 3、-CF 2CF 3、-CH 2CH 2CF 3、-CH 2OH或-CH 2CH 2OH。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each Ra is independently H, F, Cl, Br, I, -OH, -CN, -NH2 , -NO2 , -C ( = O)OH, -CH3 , -CH2CH3 , -CH2CH2CH3 , -CH ( CH3 )2 , -OCH3 , -OCH2CH3 , -CF3 , -CH 2CF3 , -CF2CF3 , -CH2CH2CF3 , -CH2OH or -CH2CH2OH .
  19. 根据权利要求18所述的化合物或其药学上可接受的盐，其中各R a独立地为H、F、Cl或-CF 3。 The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein each Ra is independently H, F, Cl, or -CF3 .
  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R 2为
    Figure PCTCN2022088918-appb-100028
    Figure PCTCN2022088918-appb-100029
    The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein said R is
    Figure PCTCN2022088918-appb-100028
    Figure PCTCN2022088918-appb-100029
  21. 根据权利要求18或20所述的化合物或其药学上可接受的盐，其中所述R 2为
    Figure PCTCN2022088918-appb-100030
    Figure PCTCN2022088918-appb-100031
    The compound of claim 18 or 20 , or a pharmaceutically acceptable salt thereof, wherein said R is
    Figure PCTCN2022088918-appb-100030
    Figure PCTCN2022088918-appb-100031
    Figure PCTCN2022088918-appb-100032
    Figure PCTCN2022088918-appb-100032
  22. 下式化合物或其药学上可接受的盐：A compound of the following formula or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2022088918-appb-100033
    Figure PCTCN2022088918-appb-100033
    Figure PCTCN2022088918-appb-100034
    Figure PCTCN2022088918-appb-100034
    Figure PCTCN2022088918-appb-100035
    Figure PCTCN2022088918-appb-100035
  23. 根据权利要求1～22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糖尿病肾病或高血压肾病药物中的应用。Use of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating diabetic nephropathy or hypertensive nephropathy.
  24. 一种在需要的受试者中治疗糖尿病肾病或高血压肾病的方法，所述方法包括向受试者提供有效剂量的根据权利要求1～22中任意一项所述化合物或其药学上可接受的盐。A method of treating diabetic nephropathy or hypertensive nephropathy in a subject in need thereof, the method comprising providing the subject with an effective dose of the compound according to any one of claims 1 to 22 or a pharmaceutically acceptable of salt.
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US6903089B1 (en) * 2000-11-22 2005-06-07 Bayer Aktiengesellschaft Lactam-substituted pyrazolopyridine derivatives
CN1665811A (en) * 2002-05-08 2005-09-07 拜耳医药保健股份公司 Carbamate-substituted pyrazolopyridines
CN101076334A (en) * 2004-05-28 2007-11-21 默克公司 Benzoureas having anti-diabetic activity
CN111868037A (en) * 2018-04-09 2020-10-30 拉夸里亚创药株式会社 Fused cyclic urea derivatives as CRHR2 antagonists
WO2022057836A1 (en) * 2020-09-16 2022-03-24 南京明德新药研发有限公司 Benzourea ring derivative, and preparation method therefor and use thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6903089B1 (en) * 2000-11-22 2005-06-07 Bayer Aktiengesellschaft Lactam-substituted pyrazolopyridine derivatives
CN1665811A (en) * 2002-05-08 2005-09-07 拜耳医药保健股份公司 Carbamate-substituted pyrazolopyridines
CN101076334A (en) * 2004-05-28 2007-11-21 默克公司 Benzoureas having anti-diabetic activity
CN111868037A (en) * 2018-04-09 2020-10-30 拉夸里亚创药株式会社 Fused cyclic urea derivatives as CRHR2 antagonists
WO2022057836A1 (en) * 2020-09-16 2022-03-24 南京明德新药研发有限公司 Benzourea ring derivative, and preparation method therefor and use thereof

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