WO2022228365A1 - Dérivé d'un cycle d'urée hétéroaromatique à six chaînons et son application - Google Patents

Dérivé d'un cycle d'urée hétéroaromatique à six chaînons et son application 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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English (en)
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/zh
Priority to JP2023566656A priority patent/JP2024515985A/ja
Publication of WO2022228365A1 publication Critical patent/WO2022228365A1/fr

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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.

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Abstract

L'invention concerne un dérivé d'un cycle d'urée hétéroaromatique à six chaînons représenté par la formule (I) et une application de celui-ci dans la préparation d'un médicament pour le traitement d'une néphropathie diabétique ou d'une néphropathie hypertensive.
PCT/CN2022/088918 2021-04-27 2022-04-25 Dérivé d'un cycle d'urée hétéroaromatique à six chaînons et son application WO2022228365A1 (fr)

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CN202280031344.1A CN117279923A (zh) 2021-04-27 2022-04-25 六元杂芳并脲环的衍生物及其应用
JP2023566656A JP2024515985A (ja) 2021-04-27 2022-04-25 ６員芳香族ヘテロ尿素環の誘導体及びその使用

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Citations (5)

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Publication number Priority date Publication date Assignee Title
US6903089B1 (en) * 2000-11-22 2005-06-07 Bayer Aktiengesellschaft Lactam-substituted pyrazolopyridine derivatives
CN1665811A (zh) * 2002-05-08 2005-09-07 拜耳医药保健股份公司 氨基甲酸酯－取代的吡唑并吡啶类化合物
CN101076334A (zh) * 2004-05-28 2007-11-21 默克公司 具有抗糖尿病活性的苯并脲类化合物
CN111868037A (zh) * 2018-04-09 2020-10-30 拉夸里亚创药株式会社 作为crhr2拮抗剂的稠合环状脲衍生物
WO2022057836A1 (fr) * 2020-09-16 2022-03-24 南京明德新药研发有限公司 Dérivé cyclique de benzourée, son procédé de préparation et son utilisation

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 (zh) * 2002-05-08 2005-09-07 拜耳医药保健股份公司 氨基甲酸酯－取代的吡唑并吡啶类化合物
CN101076334A (zh) * 2004-05-28 2007-11-21 默克公司 具有抗糖尿病活性的苯并脲类化合物
CN111868037A (zh) * 2018-04-09 2020-10-30 拉夸里亚创药株式会社 作为crhr2拮抗剂的稠合环状脲衍生物
WO2022057836A1 (fr) * 2020-09-16 2022-03-24 南京明德新药研发有限公司 Dérivé cyclique de benzourée, son procédé de préparation et son utilisation

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