WO2022206684A1 - Series of se-containing pyrazine compounds and application thereof - Google Patents

Series of se-containing pyrazine compounds and application thereof Download PDF

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Publication number
WO2022206684A1
WO2022206684A1 PCT/CN2022/083413 CN2022083413W WO2022206684A1 WO 2022206684 A1 WO2022206684 A1 WO 2022206684A1 CN 2022083413 W CN2022083413 W CN 2022083413W WO 2022206684 A1 WO2022206684 A1 WO 2022206684A1
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compound
pharmaceutically acceptable
acceptable salt
independently selected
optionally substituted
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PCT/CN2022/083413
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French (fr)
Chinese (zh)
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陈新海
姜奋
胡国平
张丽
陈兆国
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to CN202280025158.7A priority Critical patent/CN117083285A/en
Publication of WO2022206684A1 publication Critical patent/WO2022206684A1/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
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System

Definitions

  • the present invention relates to a series of Se-containing pyrazine compounds and their applications, in particular to the compounds represented by formula (I) and their pharmaceutically acceptable salts.
  • Src homeodomain-2 phosphatase is a subtype of the SH2 domain-containing phosphatase family, encoded by the protein tyrosine phosphatase non-receptor 11 (PTPN11) gene.
  • SHP2 is a non-receptor tyrosine phosphatase that can catalyze the dephosphorylation of phosphorylated substrates (such as receptors, kinases, and phospholipids), thereby regulating downstream signaling. Excessive activation of SHP2 is closely related to the occurrence and development of various diseases.
  • activating mutations of SHP2 exist in about 50% of patients with Noonan syndrome (a type of autosomal-related genetic disease) and about 35% of patients with juvenile myelomonocytic leukemia (a type of rare leukemia).
  • SHP2 mutations are rarely found in solid tumors, but can activate SHP2 signaling through other pathways.
  • SHP2 is a common node of multiple activated RAS signaling pathways. Activation of RAS is very important for the growth and survival of cancer cells. Almost all receptor tyrosine kinases (RTKs) activate RAS signaling pathways by activating SHP2, and then mediate Oncogenic signaling pathways, such as PI3K/AKT, RAS/Raf/MAPK, etc.
  • RTKs receptor tyrosine kinases
  • SHP2 inhibitors can "catch all" tumors mediated by different RTKs, and have the potential to become broad-spectrum anticancer drugs.
  • SHP2 can also promote the formation of natural or acquired drug resistance in tumors, so SHP2 inhibitors can be combined with kinase inhibitors to dually inhibit related signaling pathways. This combination therapy is more effective than monotherapy, is less prone to resistance and reverses acquired resistance to RTK inhibitors.
  • PD-1 relies on the participation of SHP2 protein when it works, so SHP2 inhibitor can play a synergistic effect with PD-1 monoclonal antibody in vivo, thereby enhancing the anti-tumor effect of PD-1 monoclonal antibody. Therefore, SHP2 has become a popular target for the treatment of tumors and other related diseases.
  • SHP2 adopts an autoinhibited conformation in which the N-SH2 domain binds to the PTP domain, preventing substrate access to the active site.
  • the conformation of SHP2 changes, exposing the catalytically active site of the PTP domain, which initiates downstream signaling cascades. Based on this mechanism, inhibitors targeting the allosteric site of SHP2 were developed to inhibit its activity by locking the SHP2 protein in an inactive conformation.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from phenyl and 5-6 membered heteroaryl
  • R 1 and R 2 are each independently selected from H, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy being any is optionally substituted with 1, 2 or 3 Ra ;
  • R 3 is each independently selected from H, F, Cl, Br, I, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1- 3 alkoxy is optionally substituted with 1, 2 or 3 R b ;
  • R 4 and R 5 are each independently selected from OH, NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R c ;
  • X 1 and X 2 are each independently selected from CH 2 and O;
  • X 3 is selected from CH and N;
  • R 6 and R 7 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R d ;
  • R 8 and R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally replaced by 1 , 2 or 3 R e substitutions;
  • n, m and p are each independently selected from 0, 1, 2 and 3;
  • R a is each independently selected from H, OH, F, Cl, Br and I;
  • Rb , Rc , Rd and Re are each independently selected from H, F, Cl, Br and I.
  • the above-mentioned Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl and thienyl, and other variables are as defined herein .
  • the above-mentioned Ring A is selected from pyridyl, and other variables are as defined herein.
  • the above R 1 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH2OH and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , -CH2 OH and -OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
  • the above R 1 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 , the -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 are optionally replaced by 1, 2 or 3 R a substitutions, other variables are as defined in the present invention.
  • R 1 is selected from H, NH 2 and CH 3 , and other variables are as defined herein.
  • the above R 2 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH2OH and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , -CH2 OH and -OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
  • the above R 2 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 , the -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 are optionally replaced by 1, 2 or 3 R a substitutions, other variables are as defined in the present invention.
  • R 2 is selected from H and -CH 2 OH, and other variables are as defined herein.
  • the above R3 is selected from H, F, Cl , Br, I, NH2 , -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2 CH3 , CH( CH3 ) 2 and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 and -OCH 3 is optionally substituted with 1, 2 or 3 R b , other variables are as defined in the present invention.
  • R3 is selected from H, Cl and NH2 , and other variables are as defined herein.
  • R 4 is selected from NH 2 and CH 3 , and other variables are as defined herein.
  • R 5 is selected from NH 2 and CH 3 , and other variables are as defined herein.
  • each of the above R 6 and R 7 is independently selected from H, and other variables are as defined herein.
  • each of the above R 8 is independently selected from H, NH 2 and CH 3 , and other variables are as defined herein.
  • each of the above R 9s is independently selected from H and F, and other variables are as defined herein.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , R 2 , R 3 and R 8 are as defined in the present invention.
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • R 8 is selected from F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F; R 1 , R 2 and R3 are as defined in the present invention.
  • the present invention also provides the following compounds or their pharmaceutically acceptable salts,
  • the above-mentioned compound, or a pharmaceutically acceptable salt thereof is selected from,
  • the compounds of the present invention can significantly inhibit the SHP2 enzyme activity, and can also significantly inhibit the proliferation of NCI-H358 cells; meanwhile, the compounds of the present invention have good in vivo pharmacokinetic properties and exhibit excellent tumor-inhibiting effects.
  • 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.
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2)
  • the following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or exists in two forms of formula (B-1) and formula (B-2) exists as a mixture of isomers.
  • the following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) exists in the form of a mixture.
  • 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
  • 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% .
  • 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.
  • variable e.g. R
  • the variable e.g. R
  • 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.
  • 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 line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • 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.
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • 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
  • 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.
  • Compounds are named according to conventional nomenclature in the art or are used Software naming, commercially available compounds use supplier catalog names.
  • Raw material 1-3 (5g, 18.26mmol, 1eq) was dissolved in dimethyl sulfoxide (50mL), selenium powder (5.91g, 73.02mmol, 4eq), potassium hydroxide (2.05g, 36.51mmol, 2eq) and selenium powder were added. Copper oxide (145.22 mg, 1.83 mmol, 0.1 eq) was stirred under nitrogen protection at 90°C for 2 hours. The reaction solution was cooled to room temperature.
  • reaction solution was cooled to room temperature, and the crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (0.225% formic acid)-acetonitrile]; B (acetonitrile)% : 15%-38%, 5 min) to obtain compound 1.
  • the raw material 2-1 (2g, 7.77mmol, 1eq) was dissolved in N-methylpyrrolidone (20mL), ammonia water (18.20g, 145.39mmol, 20mL, 28% purity, 18.71eq) was added, and stirred at 100°C 16 hours.
  • the reaction solution was cooled to room temperature.
  • Methyl tert-butyl ether 50 mL*3 was added to the reaction solution for extraction, the organic phases were combined, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • the reaction solution was cooled to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to dilute the reaction solution, filtered, the filter cake was washed with ethyl acetate (10 mL*3), the filtrate was collected, separated, the organic phase was collected and saturated with Washed with brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • Compound 2-2 (10g, 39.30mmol, 1.20mL, 1eq) was dissolved in dimethyl sulfoxide (100mL), selenium powder (12.73g, 157.20mmol, 12.48mL, 4eq), potassium hydroxide (6.62g, 117.90 mmol, 3 eq) and copper oxide (1.56 g, 19.65 mmol, 247.33 ⁇ L, 0.5 eq), replaced with nitrogen three times, and stirred at 90° C. for 12 hours.
  • reaction solution was cooled to room temperature, quenched by adding water (10 mL), extracted with dichloromethane (10 mL ⁇ 3), the organic phases were combined, washed with saturated aqueous sodium sulfite solution (10 mL ⁇ 2), saturated brine ( 10 mL ⁇ 2) washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product.
  • reaction solution was heated to 0°C, quenched by adding saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL ⁇ 3), and the organic phases were combined and washed with saturated brine (10 mL ⁇ 2). , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product.
  • reaction solution was cooled to room temperature, filtered, ethyl acetate (10 mL) and water (10 mL) were added to the filtrate, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL ⁇ 2), and the organic phases were combined, Washed with saturated brine (10 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product.
  • Compound 5 was separated by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B%: 60%-60%) to obtain compound 5a and compound 5b.
  • SFC separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B%: 60%-60%) to obtain compound 5a and compound 5b.
  • reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (5 mL ⁇ 2), the organic phases were combined, washed with water (5 mL ⁇ 2), saturated brine (5 mL), and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product.
  • Compound 7 was resolved by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B %: 60%-60%) to obtain compound 7a (impure) and compound 7b.
  • Compound 7a (impure, SFC analysis conditions: Column: Cellulose 2 100 x 4.6 mm ID, 3 ⁇ m, Mobile phase: Phase A: CO 2 , Phase B: Ethanol (0.05% diethylamine); Gradient: B%: 60 %; flow rate: 2.8mL/min, retention time is 2.540min) and then prepared, separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile]; Acetonitrile %: 27%-57%) to give compound 7a.
  • chromatographic column: Phenomenex C18 80*40mm*3 ⁇ m; mobile phase: [water (0.05% ammonia water)-acetonitrile]; Acetonitrile %: 27%-57%) to give compound 7a.
  • 1-fold buffer preparation (for current use): Dilute 5-fold buffer with deionized water to 1-fold buffer, and place on ice for later use.
  • the compounds to be tested were diluted with 100% DMSO to 100 ⁇ M as the first concentration, and then 4-fold diluted to the eighth concentration with a drain gun, ie, from 100 ⁇ M to 6.1 nM.
  • Each compound to be tested was diluted with 1-fold buffer into a working solution with 10% DMSO, and 5 ⁇ L/well was added to the corresponding well to set up a double-well experiment. Centrifuge at 1000 rpm for 1 minute.
  • Compound background reading detection Take 5 ⁇ L of each compound to be tested diluted in 100% DMSO into a new compound plate, add 45 ⁇ L of 1-fold buffer for 10-fold dilution, prepare a working solution of 10% DMSO, and then take the compound 5 ⁇ L/well of working solution was added to the detection plate, and then 45 ⁇ L of 1-fold buffer was added for 10-fold dilution. At this time, the final concentration of DMSO was 1%, 1000 rpm/min. Wavelength: 360nm, test wavelength: 460nm.
  • Table 1 shows the inhibitory results of the compounds of the present invention on SHP2 enzymatic activity.
  • NCI-H358 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 4000 NCI-H358 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the ninth concentration, that is, from 2000 ⁇ M to 5.12 nM, and a double-well experiment was set up. Add 78 ⁇ L of medium to the middle plate, and then transfer 2 ⁇ L of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 ⁇ L of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.026 nM. The cell plates were placed in a carbon dioxide incubator for 5 days.
  • Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • Table 2 shows the results of the inhibitory activity of the compounds of the present invention on the proliferation of NCI-H358 cells.
  • test compound was dissolved in 5% DMSO+95% (10% hydroxypropyl- ⁇ -cyclodextrin aqueous solution), vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Balb/c male mice of 17 to 20 grams were selected, and the candidate compound solution was administered intravenously or orally at a dose of 1 or 2 mg/kg, respectively.
  • Whole blood was collected at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and plasma was prepared.
  • the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3.
  • Table 3 The test results are shown in Table 3:
  • C max maximum drug concentration
  • T 1/2 half-life
  • V dss apparent volume of distribution
  • Cl drug clearance rate
  • AUC 0-last plasma concentration-time curve from 0 to the last time point Area under
  • AUCo -inf area under the plasma concentration-time curve from 0 to infinity
  • F bioavailability
  • "--" means not tested or data not obtained.
  • the compound of the present invention has good pharmacokinetic properties in mice.
  • mice To study the in vivo efficacy of the compounds of the present invention in the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358 cells BALB/c nude mice
  • mice Female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams, supplier: Laboratory Animal Management Department, Shanghai Institute of Family Planning Science
  • NCI-H358 cells Human non-small cell lung cancer NCI-H358 cells were cultured in monolayer in vitro, and the culture conditions were Gibco RMPI1640 medium plus 10% fetal bovine serum, 37°C, 5% CO 2 incubator. Conventional digestion with trypsin-EDTA was performed twice a week for passage. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded.
  • 0.2mL (1 ⁇ 10 7 cells) of NCI-H358 cells were subcutaneously inoculated into the right back of each mouse, and the group administration started when the average tumor volume reached about 138 mm 3 (Vehicle control group and compound group).
  • the vehicle was 5% DMSO + 95% (10% hydroxypropyl-beta-cyclodextrin in water).
  • Tumor diameters were measured twice a week with a caliper, and tumor volume (V) and tumor growth inhibition (TGI) were calculated.
  • V tumor volume
  • TGI tumor growth inhibition
  • Table 4 Tumor inhibition results of compounds of the present invention on NCI-H358 cell BALB/c nude mice subcutaneous xenograft tumor model
  • the compounds of the present invention exhibit excellent tumor-inhibiting effect in the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358 cells BALB/c nude mice.

Abstract

Provided are a series of Se-containing pyrazine compounds and an application thereof. Specifically disclosed are a compound represented by formula (I) and a pharmaceutically acceptable salt thereof.

Description

一系列含Se的吡嗪类化合物及其应用A series of Se-containing pyrazine compounds and their applications
本发明主张如下优先权：The present invention claims the following priority:
CN202110349881.8，申请日：2021年03月31日；CN202110349881.8, application date: March 31, 2021;
CN202111291249.9，申请日：2021年10月28日。CN202111291249.9, application date: October 28, 2021.
技术领域technical field
本发明涉及一系列含Se的吡嗪类化合物及其应用，具体涉及式(I)所示化合物及其药学上可接受的盐。The present invention relates to a series of Se-containing pyrazine compounds and their applications, in particular to the compounds represented by formula (I) and their pharmaceutically acceptable salts.
背景技术Background technique
Src同源域-2磷酸酶(SHP2)是含有SH2结构域的磷酸酶家族中的一个亚型，由蛋白酪氨酸磷酸酶非受体11(PTPN11)基因编码。SHP2是非受体型酪氨酸磷酸酶，可以催化磷酸化的底物(如受体、激酶和磷脂等)去磷酸化，从而调控下游信号。SHP2的过度活化与多种疾病的发生发展密切相关。如在约50％的努南综合征(一类常染色体相关的遗传病)患者和约35％的幼年型粒单核细胞白血病(一类罕见性白血病)患者中都存在SHP2的活化突变。在实体瘤中很少发现SHP2突变，但可以通过其他的途径来激活SHP2信号。SHP2是多条激活RAS信号通路的共同节点，激活RAS对癌细胞的生长和存活都非常重要，几乎所有的受体酪氨酸激酶(RTK)都通过激活SHP2来启动RAS信号通路，进而介导致癌信号传导通路，如PI3K/AKT，RAS/Raf/MAPK等。因此SHP2抑制剂可以对不同RTK介导的肿瘤“一网打尽”，有潜力成为广谱抗癌药物。SHP2还可以促进肿瘤形成天然性或获得性耐药，因此SHP2抑制剂可以与激酶抑制剂联用对相关信号通路进行双重抑制。这种组合疗法比单一疗法更有效，既不易产生耐药，又能逆转RTK抑制剂的获得性耐药。此外，PD-1发挥作用时需要依赖SHP2蛋白的参与，因此SHP2抑制剂在体内可以和PD-1单抗发挥协同作用，从而增强PD-1单抗的抗肿瘤效果。因此，SHP2已经成为肿瘤等相关疾病治疗的热门靶点。Src homeodomain-2 phosphatase (SHP2) is a subtype of the SH2 domain-containing phosphatase family, encoded by the protein tyrosine phosphatase non-receptor 11 (PTPN11) gene. SHP2 is a non-receptor tyrosine phosphatase that can catalyze the dephosphorylation of phosphorylated substrates (such as receptors, kinases, and phospholipids), thereby regulating downstream signaling. Excessive activation of SHP2 is closely related to the occurrence and development of various diseases. For example, activating mutations of SHP2 exist in about 50% of patients with Noonan syndrome (a type of autosomal-related genetic disease) and about 35% of patients with juvenile myelomonocytic leukemia (a type of rare leukemia). SHP2 mutations are rarely found in solid tumors, but can activate SHP2 signaling through other pathways. SHP2 is a common node of multiple activated RAS signaling pathways. Activation of RAS is very important for the growth and survival of cancer cells. Almost all receptor tyrosine kinases (RTKs) activate RAS signaling pathways by activating SHP2, and then mediate Oncogenic signaling pathways, such as PI3K/AKT, RAS/Raf/MAPK, etc. Therefore, SHP2 inhibitors can "catch all" tumors mediated by different RTKs, and have the potential to become broad-spectrum anticancer drugs. SHP2 can also promote the formation of natural or acquired drug resistance in tumors, so SHP2 inhibitors can be combined with kinase inhibitors to dually inhibit related signaling pathways. This combination therapy is more effective than monotherapy, is less prone to resistance and reverses acquired resistance to RTK inhibitors. In addition, PD-1 relies on the participation of SHP2 protein when it works, so SHP2 inhibitor can play a synergistic effect with PD-1 monoclonal antibody in vivo, thereby enhancing the anti-tumor effect of PD-1 monoclonal antibody. Therefore, SHP2 has become a popular target for the treatment of tumors and other related diseases.
在基础状态下，SHP2采用一种自抑制的构象，其结构中的N-SH2结构域与PTP结构域结合，阻止底物接触到活性位点。当含有磷酸化酪氨酸残基的配体与N-SH2结构域结合后，SHP2的构象发生改变，暴露出PTP结构域的催化活性位点，从而引发下游信号传导级联反应。基于该机制，开发了靶向SHP2变构位点的抑制剂，通过将SHP2蛋白锁定在非活化构象从而抑制它的活性。In the basal state, SHP2 adopts an autoinhibited conformation in which the N-SH2 domain binds to the PTP domain, preventing substrate access to the active site. When ligands containing phosphorylated tyrosine residues bind to the N-SH2 domain, the conformation of SHP2 changes, exposing the catalytically active site of the PTP domain, which initiates downstream signaling cascades. Based on this mechanism, inhibitors targeting the allosteric site of SHP2 were developed to inhibit its activity by locking the SHP2 protein in an inactive conformation.
发明内容SUMMARY OF THE INVENTION
本发明提供了式(I)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022083413-appb-000001
Figure PCTCN2022083413-appb-000001
其中，in,
环A选自苯基和5-6元杂芳基；Ring A is selected from phenyl and 5-6 membered heteroaryl;
R 1和R 2各自独立地选自H、-NR 6R 7、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 and R 2 are each independently selected from H, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy being any is optionally substituted with 1, 2 or 3 Ra ;
R 3各自独立地选自H、F、Cl、Br、I、-NR 6R 7、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代； R 3 is each independently selected from H, F, Cl, Br, I, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1- 3 alkoxy is optionally substituted with 1, 2 or 3 R b ;
R 4和R 5各自独立地选自OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代； R 4 and R 5 are each independently selected from OH, NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R c ;
或者R 4和R 5与它们共同连接的原子一起使结构单元
Figure PCTCN2022083413-appb-000002
选自
Figure PCTCN2022083413-appb-000003
Figure PCTCN2022083413-appb-000004
or R4 and R5 together with the atoms to which they are attached together make building blocks
Figure PCTCN2022083413-appb-000002
selected from
Figure PCTCN2022083413-appb-000003
Figure PCTCN2022083413-appb-000004
X 1和X 2各自独立地选自CH 2和O； X 1 and X 2 are each independently selected from CH 2 and O;
X 3选自CH和N； X 3 is selected from CH and N;
R 6和R 7各自独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代； R 6 and R 7 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R d ;
R 8和R 9各自独立地选自H、F、Cl、Br、I、-OH、-NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R e取代； R 8 and R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally replaced by 1 , 2 or 3 R e substitutions;
n、m和p各自独立地选自0、1、2和3；n, m and p are each independently selected from 0, 1, 2 and 3;
R a各自独立地选自H、OH、F、Cl、Br和I； R a is each independently selected from H, OH, F, Cl, Br and I;
R b、R c、R d和R e各自独立地选自H、F、Cl、Br和I。 Rb , Rc , Rd and Re are each independently selected from H, F, Cl, Br and I.
在本发明的一些方案中，上述环A选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、咪唑基、吡唑基和噻吩基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned Ring A is selected from phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl and thienyl, and other variables are as defined herein .
在本发明的一些方案中，上述环A选自吡啶基，其他变量如本发明所定义。In some embodiments of the present invention, the above-mentioned Ring A is selected from pyridyl, and other variables are as defined herein.
在本发明的一些方案中，上述R 1选自H、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、-CH 2OH和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、-CH 2OH和-OCH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the present invention, the above R 1 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH2OH and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , -CH2 OH and -OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
在本发明的一些方案中，上述R 1选自H、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the present invention, the above R 1 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 , the -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 are optionally replaced by 1, 2 or 3 R a substitutions, other variables are as defined in the present invention.
在本发明的一些方案中，上述R 1选自H、NH 2和CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 1 is selected from H, NH 2 and CH 3 , and other variables are as defined herein.
在本发明的一些方案中，上述R 2选自H、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、-CH 2OH和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、-CH 2OH和-OCH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the invention, the above R 2 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , -CH2OH and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 , -CH2 OH and -OCH3 are optionally substituted with 1, 2 or 3 R a , other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2选自H、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3任选被1、2或3个R a取代，其他变量如本发明所定义。 In some aspects of the invention, the above R 2 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 , the -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 and -OCH 3 are optionally replaced by 1, 2 or 3 R a substitutions, other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2选自H和-CH 2OH，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is selected from H and -CH 2 OH, and other variables are as defined herein.
在本发明的一些方案中，上述R 3选自H、F、Cl、Br、I、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3任选被1、2或3个R b取代，其他变量如本发明所定义。 In some aspects of the invention, the above R3 is selected from H, F, Cl , Br, I, NH2 , -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2 CH3 , CH( CH3 ) 2 and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 and -OCH 3 is optionally substituted with 1, 2 or 3 R b , other variables are as defined in the present invention.
在本发明的一些方案中，上述R 3选自H、Cl和NH 2，其他变量如本发明所定义。 In some embodiments of the present invention, the above R3 is selected from H, Cl and NH2 , and other variables are as defined herein.
在本发明的一些方案中，上述R 4选自NH 2和CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 4 is selected from NH 2 and CH 3 , and other variables are as defined herein.
在本发明的一些方案中，上述R 5选自NH 2和CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 5 is selected from NH 2 and CH 3 , and other variables are as defined herein.
在本发明的一些方案中，上述R 4和R 5与它们共同连接的原子一起使结构单元
Figure PCTCN2022083413-appb-000005
选自
Figure PCTCN2022083413-appb-000006
其他变量如本发明所定义。 In some aspects of the invention, the above R4 and R5 together with the atoms to which they are commonly attached make a structural unit
Figure PCTCN2022083413-appb-000005
selected from
Figure PCTCN2022083413-appb-000006
Other variables are as defined in the present invention.
在本发明的一些方案中，上述R 4和R 5与它们共同连接的原子一起使结构单元
Figure PCTCN2022083413-appb-000007
选自
Figure PCTCN2022083413-appb-000008
其他变量如本发明所定义。 In some aspects of the invention, the above R4 and R5 together with the atoms to which they are commonly attached make a structural unit
Figure PCTCN2022083413-appb-000007
selected from
Figure PCTCN2022083413-appb-000008
Other variables are as defined in the present invention.
在本发明的一些方案中，上述R 4和R 5与它们共同连接的原子一起使结构单元
Figure PCTCN2022083413-appb-000009
选自
Figure PCTCN2022083413-appb-000010
Figure PCTCN2022083413-appb-000011
其他变量如本发明所定义。 In some aspects of the invention, the above R4 and R5 together with the atoms to which they are commonly attached make a structural unit
Figure PCTCN2022083413-appb-000009
selected from
Figure PCTCN2022083413-appb-000010
Figure PCTCN2022083413-appb-000011
Other variables are as defined in the present invention.
在本发明的一些方案中，上述R 6和R 7各自独立地选自H，其他变量如本发明所定义。 In some aspects of the present invention, each of the above R 6 and R 7 is independently selected from H, and other variables are as defined herein.
在本发明的一些方案中，上述R 8各自独立地选自H、NH 2和CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, each of the above R 8 is independently selected from H, NH 2 and CH 3 , and other variables are as defined herein.
在本发明的一些方案中，上述R 9各自独立地选自H和F，其他变量如本发明所定义。 In some aspects of the present invention, each of the above R 9s is independently selected from H and F, and other variables are as defined herein.
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，其选自，In some aspects of the invention, the above-mentioned compound, or a pharmaceutically acceptable salt thereof, is selected from,
Figure PCTCN2022083413-appb-000012
Figure PCTCN2022083413-appb-000012
其中，X 1、X 2、X 3、n、m、p、环A、R 1、R 2、R 3、R 8和R 9如本发明所定义。 wherein X 1 , X 2 , X 3 , n, m, p, ring A, R 1 , R 2 , R 3 , R 8 and R 9 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，其选自，In some aspects of the invention, the above-mentioned compound, or a pharmaceutically acceptable salt thereof, is selected from,
Figure PCTCN2022083413-appb-000013
Figure PCTCN2022083413-appb-000013
其中，R 1、R 2、R 3和R 8如本发明所定义。 Wherein, R 1 , R 2 , R 3 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，其选自，In some aspects of the invention, the above-mentioned compound, or a pharmaceutically acceptable salt thereof, is selected from,
Figure PCTCN2022083413-appb-000014
Figure PCTCN2022083413-appb-000014
其中，in,
R 8选自F、Cl、Br、I、-OH、-NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个F取代；R 1、R 2和R 3如本发明所定义。 R 8 is selected from F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F; R 1 , R 2 and R3 are as defined in the present invention.
本发明还有一些方案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.
本发明还提供了下列所示化合物或其药学上可接受的盐，The present invention also provides the following compounds or their pharmaceutically acceptable salts,
Figure PCTCN2022083413-appb-000015
Figure PCTCN2022083413-appb-000015
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，其选自，In some aspects of the invention, the above-mentioned compound, or a pharmaceutically acceptable salt thereof, is selected from,
Figure PCTCN2022083413-appb-000016
Figure PCTCN2022083413-appb-000016
技术效果technical effect
本发明化合物可以显著抑制SHP2酶活性，还可以显著抑制NCI-H358细胞的增殖；同时，本发明化合物具有良好的体内药代动力学性质，展现出优异的抑瘤效果。The compounds of the present invention can significantly inhibit the SHP2 enzyme activity, and can also significantly inhibit the proliferation of NCI-H358 cells; meanwhile, the compounds of the present invention have good in vivo pharmacokinetic properties and exhibit excellent tumor-inhibiting effects.
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 PCTCN2022083413-appb-000017
和楔形虚线键
Figure PCTCN2022083413-appb-000018
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022083413-appb-000019
和直形虚线键
Figure PCTCN2022083413-appb-000020
表示立体中心的相对构型，用波浪线
Figure PCTCN2022083413-appb-000021
表示楔形实线键
Figure PCTCN2022083413-appb-000022
或楔形虚线键
Figure PCTCN2022083413-appb-000023
或用波浪线
Figure PCTCN2022083413-appb-000024
表示直形实线键
Figure PCTCN2022083413-appb-000025
和直形虚线键
Figure PCTCN2022083413-appb-000026
Use solid wedge keys unless otherwise specified
Figure PCTCN2022083413-appb-000017
and wedge-dotted keys
Figure PCTCN2022083413-appb-000018
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2022083413-appb-000019
and straight dashed keys
Figure PCTCN2022083413-appb-000020
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022083413-appb-000021
Represents a solid wedge key
Figure PCTCN2022083413-appb-000022
or wedge-dotted key
Figure PCTCN2022083413-appb-000023
or with wavy lines
Figure PCTCN2022083413-appb-000024
Represents a straight solid key
Figure PCTCN2022083413-appb-000025
and straight dashed keys
Figure PCTCN2022083413-appb-000026
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)， 如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2022083413-appb-000027
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形式存在。 Unless otherwise specified, when there is a double bond structure in the compound, such as carbon-carbon double bond, carbon-nitrogen double bond and nitrogen-nitrogen double bond, and each atom on the double bond has two different substituents attached (including nitrogen atom) In the double bond, a lone pair of electrons on the nitrogen atom is regarded as a substituent for its connection), if a wavy line is used between the atom on the double bond and its substituent in the compound
Figure PCTCN2022083413-appb-000027
If connected, it means the (Z) isomer, (E) isomer or a mixture of both isomers of the compound. For example, the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) The following formula (B) indicates that the compound exists in the form of a single isomer of formula (B-1) or formula (B-2) or exists in two forms of formula (B-1) and formula (B-2) exists as a mixture of isomers. The following formula (C) represents that the compound exists in the form of a single isomer of formula (C-1) or formula (C-2) or in the form of two isomers of formula (C-1) and formula (C-2) exists in the form of a mixture.
Figure PCTCN2022083413-appb-000028
Figure PCTCN2022083413-appb-000028
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。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% .
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.
当变量(例如R)取代在多环体系的其中一个环上时，除非另有规定，所述变量(例如R)指定为在该环上取代，而不能取代在多环体系的其它环上，例如
Figure PCTCN2022083413-appb-000029
表示环A与环B并环且取代基R 1为环A的取代基、取代基R 2为环B的取代基，
Figure PCTCN2022083413-appb-000030
表示螺环体系中的五元环被n个R所取代。 When a variable (e.g. R) is substituted on one of the rings of a polycyclic ring system, unless otherwise specified, the variable (e.g. R) is designated to be substituted on that ring and not on the other ring of the polycyclic ring system, E.g
Figure PCTCN2022083413-appb-000029
Represents ring A and ring B together, and substituent R 1 is a substituent of ring A, and substituent R 2 is a substituent of ring B,
Figure PCTCN2022083413-appb-000030
Indicates that the five-membered ring in the spiro ring system is substituted with n Rs.
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 PCTCN2022083413-appb-000031
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 PCTCN2022083413-appb-000032
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 PCTCN2022083413-appb-000033
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 PCTCN2022083413-appb-000031
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 PCTCN2022083413-appb-000032
It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
Figure PCTCN2022083413-appb-000033
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 PCTCN2022083413-appb-000034
直形虚线键
Figure PCTCN2022083413-appb-000035
或波浪线
Figure PCTCN2022083413-appb-000036
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 PCTCN2022083413-appb-000037
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 PCTCN2022083413-appb-000038
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 PCTCN2022083413-appb-000039
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 PCTCN2022083413-appb-000040
Figure PCTCN2022083413-appb-000041
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022083413-appb-000042
仍包括
Figure PCTCN2022083413-appb-000043
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 PCTCN2022083413-appb-000034
straight dotted key
Figure PCTCN2022083413-appb-000035
or wavy lines
Figure PCTCN2022083413-appb-000036
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 PCTCN2022083413-appb-000037
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 PCTCN2022083413-appb-000038
The wavy line in the phenyl group indicates that it is connected to other groups through the 1 and 2 carbon atoms in the phenyl group;
Figure PCTCN2022083413-appb-000039
Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2022083413-appb-000040
Figure PCTCN2022083413-appb-000041
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2022083413-appb-000042
still includes
Figure PCTCN2022083413-appb-000043
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，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.
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基 等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、哒嗪基、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2- -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyridazinyl, pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。 Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one range from n to n+m, for example, 3-12-membered ring includes 3-6 membered ring, 3-9 membered ring, 5-6 membered ring ring, 5-7 membered ring, 6-7 membered ring, 6-8 membered ring, and 6-10 membered ring, etc.
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 PCTCN2022083413-appb-000044
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 PCTCN2022083413-appb-000044
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。化合物依据本领域常规命名原则或者使用
Figure PCTCN2022083413-appb-000045
软件命名，市售化合物采用供应商目录名称。 The solvent used in the present invention is commercially available. Compounds are named according to conventional nomenclature in the art or are used
Figure PCTCN2022083413-appb-000045
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
Figure PCTCN2022083413-appb-000046
Figure PCTCN2022083413-appb-000046
第一步first step
将原料1-1(3g,14.39mmol,1eq)和二碳酸二叔丁酯(7.85g,35.98mmol,8.27mL,2.5eq)用二氯甲烷 (30mL)溶解，加入4-二甲氨基吡啶(879.14mg,7.20mmol,0.5eq)，在20℃条件下，搅拌16小时。向反应液中加入水(30mL)将其淬灭，加入二氯甲烷(20mL*3)进行萃取，合并有机相，用饱和食盐水洗涤(20mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-10:1)，得到化合物1-2。 1H NMR(400MHz,CDCl 3)δppm 8.35(s,1H),1.44(s,18H)。 Raw material 1-1 (3g, 14.39mmol, 1eq) and di-tert-butyl dicarbonate (7.85g, 35.98mmol, 8.27mL, 2.5eq) were dissolved in dichloromethane (30mL), 4-dimethylaminopyridine ( 879.14 mg, 7.20 mmol, 0.5 eq), and stirred for 16 hours at 20°C. Water (30 mL) was added to the reaction solution to quench it, dichloromethane (20 mL*3) was added for extraction, the organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrate under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-10:1) to obtain compound 1-2. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.35 (s, 1H), 1.44 (s, 18H).
第二步second step
将原料1-3(5g,18.26mmol,1eq)用二甲基亚砜(50mL)溶解，加入硒粉(5.91g,73.02mmol,4eq)、氢氧化钾(2.05g,36.51mmol,2eq)和氧化铜(145.22mg,1.83mmol,0.1eq)，在氮气保护、90℃条件下，搅拌2小时。将反应液冷却至室温。将乙酸乙酯(100mL)加入反应液中，过滤，滤饼用乙酸乙酯(50mL*2)荡洗，收集滤液，滤液用饱和食盐水(50mL*2)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-10:1)，得到化合物1-4。MS:m/z 452.4[M+H] +。 1H NMR(400MHz,CDCl 3)δppm 8.14(d,J＝5.02Hz,2H),7.39(d,J＝5.27Hz,2H)。 Raw material 1-3 (5g, 18.26mmol, 1eq) was dissolved in dimethyl sulfoxide (50mL), selenium powder (5.91g, 73.02mmol, 4eq), potassium hydroxide (2.05g, 36.51mmol, 2eq) and selenium powder were added. Copper oxide (145.22 mg, 1.83 mmol, 0.1 eq) was stirred under nitrogen protection at 90°C for 2 hours. The reaction solution was cooled to room temperature. Ethyl acetate (100mL) was added to the reaction solution, filtered, the filter cake was washed with ethyl acetate (50mL*2), the filtrate was collected, the filtrate was washed with saturated brine (50mL*2), dried over anhydrous sodium sulfate, filtered , the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-10:1) to obtain compound 1-4. MS: m/z 452.4 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.14 (d, J=5.02 Hz, 2H), 7.39 (d, J=5.27 Hz, 2H).
第三步third step
将化合物1-4(753.65mg,1.84mmol,1eq)和化合物1-2(500mg,1.11mmol,0.6eq)用水(10mL)和二甲基亚砜(10mL)混合溶剂溶解，加入锌粉(180.88mg,2.77mmol,1.5eq)和铜粉(117.19mg,1.84mmol,1eq)，在100℃条件下，搅拌12小时。将反应液冷却至室温，加入乙酸乙酯(20mL*3)进行萃取，合并有机相，饱和食盐水洗(20mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(二氯甲烷：乙酸乙酯＝1:0-10:1)，得到化合物1-5。MS:m/z 356.7[M+H] +。 Compound 1-4 (753.65mg, 1.84mmol, 1eq) and compound 1-2 (500mg, 1.11mmol, 0.6eq) were dissolved in a mixed solvent of water (10mL) and dimethyl sulfoxide (10mL), and zinc powder (180.88 g) was added. mg, 2.77mmol, 1.5eq) and copper powder (117.19mg, 1.84mmol, 1eq), were stirred at 100° C. for 12 hours. The reaction solution was cooled to room temperature, ethyl acetate (20 mL*3) was added for extraction, the organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:ethyl acetate=1:0-10:1) to obtain compound 1-5. MS: m/z 356.7 [M+H] + .
第四步the fourth step
将化合物1-6(41.16mg,169.26μmol,2eq)和化合物1-5(30mg,84.63μmol,1eq)用二甲基亚砜(0.5mL)溶解，加入N,N-二异丙基乙胺(109.38mg,846.31μmol,147.41uL,10eq)，在100℃条件下，搅拌12小时。将反应液冷却至室温，粗品经高效液相色谱制备分离纯化(色谱柱:Phenomenex Gemini-NX C18 75*30mm*3μm；流动相:[水(0.225％甲酸)-乙腈]；B(乙腈)％:15％-38％,5min)得到化合物1。MS:m/z 489.0[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 7.96(d,J＝5.27Hz,1H),7.60(s,1H),6.75(d,J＝5.27Hz,1H),4.33-4.29(m,2H),4.24(br d,J＝14.05Hz,1H),4.01-3.86(m,2H),3.41(br d,J＝4.02Hz,1H),3.11-3.25(m,2H),1.79-1.91(m,3H),1.71(br d,J＝13.05Hz,1H),1.33(d,J＝6.27Hz,3H)。 Compound 1-6 (41.16mg, 169.26μmol, 2eq) and compound 1-5 (30mg, 84.63μmol, 1eq) were dissolved in dimethyl sulfoxide (0.5mL), and N,N-diisopropylethylamine was added (109.38 mg, 846.31 μmol, 147.41 uL, 10 eq), stirred at 100° C. for 12 hours. The reaction solution was cooled to room temperature, and the crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; B (acetonitrile)% : 15%-38%, 5 min) to obtain compound 1. MS: m/z 489.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 7.96 (d, J=5.27 Hz, 1H), 7.60 (s, 1H), 6.75 (d, J=5.27 Hz, 1H), 4.33-4.29 (m, 2H) ,4.24(br d,J=14.05Hz,1H),4.01-3.86(m,2H),3.41(br d,J=4.02Hz,1H),3.11-3.25(m,2H),1.79-1.91(m , 3H), 1.71 (br d, J=13.05Hz, 1H), 1.33 (d, J=6.27Hz, 3H).
实施例2Example 2
Figure PCTCN2022083413-appb-000047
Figure PCTCN2022083413-appb-000047
第一步first step
将原料2-1(2g,7.77mmol,1eq)用N-甲基吡咯烷酮(20mL)溶解，加入氨水(18.20g,145.39mmol,20mL,28％纯度,18.71eq)，在100℃条件下，搅拌16小时。将反应液冷却至室温。向反应液中加入甲基叔丁基醚(50mL*3)进行萃取，合并有机相，饱和食盐水洗(30mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(二氯甲烷：乙酸乙酯＝1:0-10:1)，得到化合物2-2。MS:m/z 254.8[M+H] +。 1H NMR(400MHz,CDCl 3)δppm 7.53(d,J＝5.27Hz,1H),7.05(d,J＝5.27Hz,1H),6.51(br s,2H)。 The raw material 2-1 (2g, 7.77mmol, 1eq) was dissolved in N-methylpyrrolidone (20mL), ammonia water (18.20g, 145.39mmol, 20mL, 28% purity, 18.71eq) was added, and stirred at 100°C 16 hours. The reaction solution was cooled to room temperature. Methyl tert-butyl ether (50 mL*3) was added to the reaction solution for extraction, the organic phases were combined, washed with saturated brine (30 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane:ethyl acetate=1:0-10:1) to obtain compound 2-2. MS: m/z 254.8 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.53 (d, J=5.27 Hz, 1H), 7.05 (d, J=5.27 Hz, 1H), 6.51 (br s, 2H).
第二步second step
将化合物2-2(1g,3.93mmol,1eq)和二碳酸二叔丁酯(3.43g,15.72mmol,3.61mL,4eq)用二氯甲烷(10mL)溶解，加入4-二甲氨基吡啶(240.06mg,1.96mmol,0.5eq)，在20℃条件下，搅拌16小时。向反应液中加入水(10mL)将其淬灭，加入二氯甲烷(10mL*3)进行萃取，合并有机相，饱和食盐水洗(10mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(二氯甲烷：乙酸乙酯＝1:0-100:5)，得到化合物2-3。 1H NMR(400MHz,CDCl 3)δppm 8.05(d,J＝5.02Hz,1H),7.78(d,J＝5.02Hz,1H),1.44(s,18H)。 Compound 2-2 (1 g, 3.93 mmol, 1 eq) and di-tert-butyl dicarbonate (3.43 g, 15.72 mmol, 3.61 mL, 4 eq) were dissolved in dichloromethane (10 mL), and 4-dimethylaminopyridine (240.06 g) was added. mg, 1.96 mmol, 0.5 eq), and stirred for 16 hours at 20°C. Water (10 mL) was added to the reaction solution to quench it, dichloromethane (10 mL*3) was added for extraction, the organic phases were combined, washed with saturated brine (10 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was decompressed. concentrate. The crude product was purified by column chromatography (dichloromethane:ethyl acetate=1:0-100:5) to obtain compound 2-3. 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.05 (d, J=5.02 Hz, 1H), 7.78 (d, J=5.02 Hz, 1H), 1.44 (s, 18H).
第三步third step
将硒粉(1.85g,22.87mmol,4eq)、氢氧化钾(641.65mg,11.44mmol,2eq)和氧化铜(45.49mg,571.82μmol,0.1eq)用二甲基亚砜(20mL)溶解，加入化合物2-3(2.6g,5.72mmol,1eq)，在90℃条件下，搅拌2小时。将反应液冷却至室温。将乙酸乙酯(20mL)加入反应液中，过滤，滤饼用乙酸乙酯(20mL*2)荡洗，收集滤液，滤液用饱和食盐水(20mL*2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-2:1)，得到化合物2-4。MS:m/z 814.9[M+H] +。 1H NMR(400MHz,CDCl 3)δppm 8.22(d,J＝5.27Hz,2H),7.43(d,J＝5.27Hz,2H),1.45(s,36H)。 Dissolve selenium powder (1.85g, 22.87mmol, 4eq), potassium hydroxide (641.65mg, 11.44mmol, 2eq) and copper oxide (45.49mg, 571.82μmol, 0.1eq) with dimethyl sulfoxide (20mL), add Compound 2-3 (2.6 g, 5.72 mmol, 1 eq) was stirred at 90°C for 2 hours. The reaction solution was cooled to room temperature. Ethyl acetate (20mL) was added to the reaction solution, filtered, the filter cake was washed with ethyl acetate (20mL*2), the filtrate was collected, the filtrate was washed with saturated brine (20mL*2), dried over anhydrous sodium sulfate, filtered , the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-2:1) to obtain compound 2-4. MS: m/z 814.9 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.22 (d, J=5.27 Hz, 2H), 7.43 (d, J=5.27 Hz, 2H), 1.45 (s, 36H).
第四步the fourth step
将化合物1-2(321.52mg,786.74μmol,1eq)和化合物2-4(640mg,786.74μmol,1eq)用水(6mL)和二甲基亚砜(6mL)混合溶剂溶解，加入锌粉(77.17mg,1.18mmol,1.5eq)和铜粉(50.00mg,786.74μmol,1eq)，在100℃条件下，搅拌12小时。将反应液冷却至室温，加入乙酸乙酯(10mL)和水(10mL)稀释反应液，过滤，滤饼用乙酸乙酯(10mL*3)荡洗，收集滤液，分液，收集有机相并用饱和食盐水洗(10mL*2)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-1:1)，得到化合物2-5。MS:m/z 335.8[M+H] +。 Compound 1-2 (321.52 mg, 786.74 μmol, 1 eq) and compound 2-4 (640 mg, 786.74 μmol, 1 eq) were dissolved in a mixed solvent of water (6 mL) and dimethyl sulfoxide (6 mL), and zinc powder (77.17 mg) was added. , 1.18mmol, 1.5eq) and copper powder (50.00mg, 786.74μmol, 1eq) were stirred at 100°C for 12 hours. The reaction solution was cooled to room temperature, ethyl acetate (10 mL) and water (10 mL) were added to dilute the reaction solution, filtered, the filter cake was washed with ethyl acetate (10 mL*3), the filtrate was collected, separated, the organic phase was collected and saturated with Washed with brine (10 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-1:1) to obtain compound 2-5. MS: m/z 335.8 [M+H] + .
第五步the fifth step
将化合物1-6(24.68mg,101.48μmol,2eq)和化合物2-5(17mg,50.74μmol,1eq)用N,N-二甲基乙酰胺(0.5mL)溶解，加入碳酸钾(97.40mg,253.69μmol,5eq)的水溶液，在100℃条件下，搅拌12小时。原料反应完全，将反应液冷却至室温，粗品经高效液相色谱制备分离纯化(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm；流动相:[水(0.05％氨水)-乙腈]；B％(乙腈):14％-44％,8min)得到化合物2。MS:m/z 470.0[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 7.54(d,J＝5.52Hz,1H),7.53(s,1H),6.03(d,J＝5.52Hz,1H),4.27-4.20(m,1H),4.07-3.99(m,2H),3.87(d,J＝8.78Hz,1H),3.72(d,J＝8.78Hz,1H),3.39-3.35(m,1H),3.28-3.24(m,1H),3.02(d,J＝5.02Hz,1H),1.85-1.73(m,2H),1.69-1.63(m,2H),1.22(d,J＝6.53Hz,3H)。 Compound 1-6 (24.68mg, 101.48μmol, 2eq) and compound 2-5 (17mg, 50.74μmol, 1eq) were dissolved in N,N-dimethylacetamide (0.5mL), potassium carbonate (97.40mg, 253.69 μmol, 5eq) aqueous solution, stirred at 100°C for 12 hours. The reaction of the raw materials was completed, the reaction solution was cooled to room temperature, and the crude product was prepared, separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3 μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; B% (acetonitrile): 14%-44%, 8 min) to give compound 2. MS: m/z 470.0 [M+H] + . 1 H NMR (400 MHz, CD 3 OD) δppm 7.54 (d, J=5.52 Hz, 1H), 7.53 (s, 1H), 6.03 (d, J=5.52 Hz, 1H), 4.27-4.20 (m, 1H) ,4.07-3.99(m,2H),3.87(d,J=8.78Hz,1H),3.72(d,J=8.78Hz,1H),3.39-3.35(m,1H),3.28-3.24(m,1H ), 3.02 (d, J=5.02Hz, 1H), 1.85-1.73 (m, 2H), 1.69-1.63 (m, 2H), 1.22 (d, J=6.53Hz, 3H).
实施例3Example 3
Figure PCTCN2022083413-appb-000048
Figure PCTCN2022083413-appb-000048
第一步first step
将化合物2-2(10g,39.30mmol,1.20mL,1eq)用二甲基亚砜(100mL)溶解，加入硒粉(12.73g,157.20mmol,12.48mL,4eq)、氢氧化钾(6.62g,117.90mmol,3eq)和氧化铜(1.56g,19.65mmol,247.33μL,0.5eq)，氮气置换三次，在90℃条件下，搅拌12小时。原料反应完全，将反应液冷却至室温，加入乙酸乙酯(200mL)稀释，过滤，滤饼用乙酸乙酯(200mL*2)荡洗，合并滤液，加入水(500mL)分液，合并有机相并用饱和食盐水洗(300mL*2)，无水硫酸钠干燥。过滤，滤液减压浓缩。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-1:2)，得到化合物3-1。MS:m/z 414.9[M+H] +。 Compound 2-2 (10g, 39.30mmol, 1.20mL, 1eq) was dissolved in dimethyl sulfoxide (100mL), selenium powder (12.73g, 157.20mmol, 12.48mL, 4eq), potassium hydroxide (6.62g, 117.90 mmol, 3 eq) and copper oxide (1.56 g, 19.65 mmol, 247.33 μL, 0.5 eq), replaced with nitrogen three times, and stirred at 90° C. for 12 hours. The reaction of the raw materials was completed, the reaction solution was cooled to room temperature, diluted with ethyl acetate (200 mL), filtered, the filter cake was washed with ethyl acetate (200 mL*2), the filtrates were combined, water (500 mL) was added to separate the layers, and the organic phases were combined. and washed with saturated brine (300 mL*2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-1:2) to obtain compound 3-1. MS: m/z 414.9 [M+H] + .
第二步second step
将化合物3-1(1g,2.42mmol,1eq)和化合物1-1(1.16g,5.57mmol,2.3eq)用二甲基亚砜(15mL)溶解，加入碳酸钾(669.24mg,4.84mmol,2eq)、硫化铜(462.98mg,4.84mmol,2eq)和铁粉(540.84mg,9.68mmol,4eq)，氮气置换三次。在110℃条件下，搅拌12小时。将反应液冷却至室温，过滤，滤饼用乙酸乙酯(20 mL*3)荡洗，合并有机相，饱和食盐水洗(20mL*3)，无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-1:1)得到化合物2-5。MS:m/z 335.7[M+H] +。 Compound 3-1 (1g, 2.42mmol, 1eq) and compound 1-1 (1.16g, 5.57mmol, 2.3eq) were dissolved in dimethyl sulfoxide (15mL), potassium carbonate (669.24mg, 4.84mmol, 2eq) was added ), copper sulfide (462.98mg, 4.84mmol, 2eq) and iron powder (540.84mg, 9.68mmol, 4eq), nitrogen was replaced three times. Stir at 110°C for 12 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (20 mL*3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-1:1) to obtain compound 2-5. MS: m/z 335.7 [M+H] + .
第三步third step
将化合物2-5(200mg,596.92μmol,1eq)和化合物3-2(197.14mg,716.31μmol,1.2eq)用乙腈(5mL)溶解，加入碳酸钾(825.01mg,5.97mmol,10eq)，氮气保护，在100℃条件下，搅拌10小时。原料反应完全，粗品经高效液相色谱制备分离纯化(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm；流动相:[水(0.05％氨水)-乙腈]；B％(乙腈):33％-63％,8min)得到化合物3。MS:m/z 502.1[M+H] +。 1H NMR(400MHz,CD 3OD)δ7.51-7.57(m,2H),7.32-7.40(m,1H),7.17-7.24(m,3H),6.05(d,J＝5.52Hz,1H),4.25(br d,J＝10.54Hz,2H),3.94(s,1H),3.19-3.29(m,2H),3.15(d,J＝15.56Hz,1H),2.79(d,J＝15.81Hz,1H),1.73-1.86(m,2H),1.57(br d,J＝13.55Hz,1H),1.41(br d,J＝13.80Hz,1H)。 Compound 2-5 (200mg, 596.92μmol, 1eq) and compound 3-2 (197.14mg, 716.31μmol, 1.2eq) were dissolved in acetonitrile (5mL), potassium carbonate (825.01mg, 5.97mmol, 10eq) was added, under nitrogen protection , and stirred at 100 °C for 10 hours. The reaction of the raw materials was completed, and the crude product was prepared, separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; B% (acetonitrile): 33%- 63%, 8 min) to obtain compound 3. MS: m/z 502.1 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ 7.51-7.57 (m, 2H), 7.32-7.40 (m, 1H), 7.17-7.24 (m, 3H), 6.05 (d, J=5.52Hz, 1H) ,4.25(br d,J＝10.54Hz,2H),3.94(s,1H),3.19-3.29(m,2H),3.15(d,J＝15.56Hz,1H),2.79(d,J＝15.81Hz , 1H), 1.73-1.86 (m, 2H), 1.57 (br d, J=13.55Hz, 1H), 1.41 (br d, J=13.80Hz, 1H).
实施例4Example 4
Figure PCTCN2022083413-appb-000049
Figure PCTCN2022083413-appb-000049
将化合物2-5(39.55mg,118.03μmol,1.3eq)和化合物4-1(20mg,90.79μmol,1eq)用乙腈(1mL)溶解，加入碳酸钾(125.48mg,907.91μmol,10eq)，氮气保护，在100℃条件下，搅拌5小时。原料反应完全，粗品经高效液相色谱制备分离纯化(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm；流动相:[水(0.05％氨水)-乙腈]；B(乙腈)％:33％-63％,8min)得到化合物4。MS:m/z 520.1[M+H] +。 1H NMR(400MHz,CD 3OD)δ7.53-7.58(m,2H),7.20(dd,J＝5.13,8.00Hz,1H),7.10(br d,J＝7.00Hz,1H),6.88-6.94(m,1H),6.05(d,J＝5.38Hz,1H),4.27(br d,J＝5.50Hz,2H),3.93(s,1H),3.17-3.24(m,2H),3.13(br d,J＝15.63Hz,1H),2.74(br d,J＝15.63Hz,1H),1.87(dt,J＝4.25,12.57Hz,1H),1.74(dt,J＝3.81,12.48Hz,1H),1.60(br d,J＝11.76Hz,1H),1.38(br d,J＝12.51Hz,1H)。 Compound 2-5 (39.55mg, 118.03μmol, 1.3eq) and compound 4-1 (20mg, 90.79μmol, 1eq) were dissolved in acetonitrile (1mL), potassium carbonate (125.48mg, 907.91μmol, 10eq) was added, under nitrogen protection , and stirred for 5 hours at 100 °C. The reaction of the raw materials was completed, and the crude product was prepared, separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; B (acetonitrile)%: 33%- 63%, 8 min) to obtain compound 4. MS: m/z 520.1 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ 7.53-7.58 (m, 2H), 7.20 (dd, J=5.13, 8.00Hz, 1H), 7.10 (br d, J=7.00Hz, 1H), 6.88- 6.94(m, 1H), 6.05(d, J=5.38Hz, 1H), 4.27(br d, J=5.50Hz, 2H), 3.93(s, 1H), 3.17-3.24(m, 2H), 3.13( br d, J＝15.63Hz, 1H), 2.74 (br d, J＝15.63Hz, 1H), 1.87 (dt, J＝4.25, 12.57Hz, 1H), 1.74 (dt, J＝3.81, 12.48Hz, 1H) ), 1.60 (br d, J=11.76Hz, 1H), 1.38 (br d, J=12.51Hz, 1H).
实施例5Example 5
Figure PCTCN2022083413-appb-000050
Figure PCTCN2022083413-appb-000050
Figure PCTCN2022083413-appb-000051
Figure PCTCN2022083413-appb-000051
第一步first step
将化合物5-1(1g,5.81mmol,1eq)溶于四氯化碳(10mL)中，加入N-溴代丁二酰亚胺(1.14g,6.39mmol,1.1eq)和偶氮二异丁腈(95.46mg,581.32μmol,0.1eq)，反应液在氮气保护下在75℃下搅拌12小时。原料反应完全后，将反应液冷却至室温，加入水(10mL)淬灭，用二氯甲烷(10mL×3)萃取，合并有机相，用饱和亚硫酸钠水溶液(10mL×2)洗，饱和食盐水(10mL×2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-9:1)得到化合物5-2。MS:m/z 251.8[M+H] +。 Compound 5-1 (1 g, 5.81 mmol, 1 eq) was dissolved in carbon tetrachloride (10 mL), N-bromosuccinimide (1.14 g, 6.39 mmol, 1.1 eq) and azobisisobutylene were added Nitrile (95.46 mg, 581.32 μmol, 0.1 eq), the reaction solution was stirred at 75° C. for 12 hours under nitrogen protection. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, quenched by adding water (10 mL), extracted with dichloromethane (10 mL×3), the organic phases were combined, washed with saturated aqueous sodium sulfite solution (10 mL×2), saturated brine ( 10 mL×2) washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-9:1) to obtain compound 5-2. MS: m/z 251.8 [M+H] + .
第二步second step
将化合物5-3(0.8g,3.80mmol,1eq)溶于四氢呋喃(14mL)中，冷却至-78℃下，缓慢滴加二异丙基氨基锂(2M,2.47mL,1.3eq)，反应液在氮气保护下在-78℃下搅拌1小时，缓慢滴加化合物5-2(1.05g,4.19mmol,1.1eq)的四氢呋喃(2mL)溶液，反应液在氮气保护下在-78℃下搅拌2小时。原料反应完全后，将反应液升温至0℃，加入饱和氯化铵水溶液(10mL)淬灭，用乙酸乙酯(10mL×3)萃取，合并有机相，用饱和食盐水(10mL×2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝1:0-7:3)得到化合物5-4。 1H NMR(400MHz,CDCl 3)δ8.56(dd,J＝1.38,4.64Hz,1H),7.89(dd,J＝1.38,8.16Hz,1H),7.11(dd,J＝4.52,8.03Hz,1H),4.13(q,J＝7.03Hz,2H),3.30(s,2H),3.09(br s,2H),2.12(br d,J＝12.55Hz,2H),1.67(dt,J＝4.52,13.18Hz,2H),1.47(s,9H)。 Compound 5-3 (0.8g, 3.80mmol, 1eq) was dissolved in tetrahydrofuran (14mL), cooled to -78°C, and lithium diisopropylamide (2M, 2.47mL, 1.3eq) was slowly added dropwise to the reaction solution. Stir at -78 °C for 1 hour under nitrogen protection, slowly add compound 5-2 (1.05 g, 4.19 mmol, 1.1 eq) in tetrahydrofuran (2 mL) dropwise, and stir the reaction solution at -78 °C under nitrogen protection for 2 Hour. After the reaction of the raw materials was completed, the reaction solution was heated to 0°C, quenched by adding saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL×3), and the organic phases were combined and washed with saturated brine (10 mL×2). , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-7:3) to obtain compound 5-4. 1 H NMR (400 MHz, CDCl 3 ) δ 8.56 (dd, J=1.38, 4.64 Hz, 1H), 7.89 (dd, J=1.38, 8.16 Hz, 1H), 7.11 (dd, J=4.52, 8.03 Hz, 1H), 4.13(q, J＝7.03Hz, 2H), 3.30(s, 2H), 3.09(br s, 2H), 2.12(br d, J＝12.55Hz, 2H), 1.67(dt, J＝4.52 , 13.18Hz, 2H), 1.47(s, 9H).
第三步third step
将化合物5-4(970mg,2.55mmol,1eq)溶于N,N-二甲基乙酰胺(15mL)和水(1.5mL)中，加入二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(II)(180.61mg,255.08μmol,180.61μL,0.1eq)和三乙胺(1.03g,10.20mmol,1.42mL,4eq)，反应液在氮气保护下在130℃下搅拌12小时。原料反应完全后，将反应液冷却至室温，过滤，向滤液中加入乙酸乙酯(10mL)和水(10mL)，分层，水相用乙酸乙酯(10mL×2)萃取，合并有机相，用饱和食盐水(10mL×2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品柱层析纯化(石油醚：乙酸乙酯＝1:0-3:2)得到化合物5-5。MS:m/z 303.0[M+H] +。 1H NMR(400MHz,CDCl 3)δ8.85(dd,J＝1.51, 4.77Hz,1H),8.04(dd,J＝1.51,7.78Hz,1H),7.36(dd,J＝4.89,7.65Hz,1H),4.14(br s,2H),3.20(s,2H),3.00-3.11(m,2H),1.90-2.00(m,2H),1.49(s,9H),1.42-1.47(m,2H)。 Compound 5-4 (970mg, 2.55mmol, 1eq) was dissolved in N,N-dimethylacetamide (15mL) and water (1.5mL), and dichlorobis[di-tert-butyl-(4-dimethylacetate) was added (ylaminophenyl)phosphine]palladium(II) (180.61mg, 255.08μmol, 180.61μL, 0.1eq) and triethylamine (1.03g, 10.20mmol, 1.42mL, 4eq), the reaction solution was under nitrogen protection at 130°C under stirring for 12 hours. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, filtered, ethyl acetate (10 mL) and water (10 mL) were added to the filtrate, the layers were separated, the aqueous phase was extracted with ethyl acetate (10 mL×2), and the organic phases were combined, Washed with saturated brine (10 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=1:0-3:2) to obtain compound 5-5. MS: m/z 303.0 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ 8.85 (dd, J=1.51, 4.77Hz, 1H), 8.04 (dd, J=1.51, 7.78Hz, 1H), 7.36 (dd, J=4.89, 7.65Hz, 1H), 4.14(br s, 2H), 3.20(s, 2H), 3.00-3.11(m, 2H), 1.90-2.00(m, 2H), 1.49(s, 9H), 1.42-1.47(m, 2H) ).
第四步the fourth step
将化合物5-5(5.28g,17.46mmol,1eq)溶于四乙氧基钛(27.88g,122.24mmol,25.35mL,7eq)中，加入(R)-(+)-2-甲基-2-丙亚磺酰胺(6.35g,52.39mmol,3eq)，反应液在氮气保护下在90℃下搅拌12小时。原料反应完全后，将反应液冷却至室温，加入乙酸乙酯(50mL)和饱和食盐水(30mL)，搅拌0.5小时，将反应液通过硅藻土过滤，滤液用乙酸乙酯(50mL×2)进行萃取，合并有机相，用水(30mL×2)洗，饱和食盐水(30mL×2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝9:1-1:4)得到化合物5-6。MS:m/z 406.1[M+H] +。 Compound 5-5 (5.28g, 17.46mmol, 1eq) was dissolved in tetraethoxytitanium (27.88g, 122.24mmol, 25.35mL, 7eq), and (R)-(+)-2-methyl-2 was added -Propanesulfinamide (6.35g, 52.39mmol, 3eq), the reaction solution was stirred at 90°C for 12 hours under nitrogen protection. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, ethyl acetate (50 mL) and saturated brine (30 mL) were added, and stirred for 0.5 hours. The reaction solution was filtered through celite, and the filtrate was washed with ethyl acetate (50 mL×2). Extraction was performed, the organic phases were combined, washed with water (30 mL×2), washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=9:1-1:4) to obtain compound 5-6. MS: m/z 406.1 [M+H] + .
第五步the fifth step
将化合物5-6(5.13g,12.65mmol,1eq)溶于四氢呋喃(102.6mL)中，冷却至0℃，缓慢加入硼氢化锂(413.32mg,18.97mmol,1.5eq)，反应液在0℃下搅拌1小时。原料反应完全后，向反应液中加入甲醇(15mL)，搅拌5min，加入饱和氯化铵水溶液(40mL)和乙酸乙酯(50mL)，分层，水相用乙酸乙酯(50mL×2)萃取，合并有机相，用饱和食盐水(50mL×2)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经柱层析纯化(石油醚：乙酸乙酯＝9:1-1:4)得到化合物5-7a和化合物5-7b的混合物。MS:m/z 408.1[M+H] +。 Compound 5-6 (5.13g, 12.65mmol, 1eq) was dissolved in tetrahydrofuran (102.6mL), cooled to 0°C, and lithium borohydride (413.32mg, 18.97mmol, 1.5eq) was slowly added to the reaction solution at 0°C Stir for 1 hour. After the reaction of the raw materials was completed, methanol (15 mL) was added to the reaction solution, stirred for 5 min, saturated aqueous ammonium chloride solution (40 mL) and ethyl acetate (50 mL) were added, the layers were separated, and the aqueous phase was extracted with ethyl acetate (50 mL×2). , the organic phases were combined, washed with saturated brine (50 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=9:1-1:4) to obtain a mixture of compound 5-7a and compound 5-7b. MS: m/z 408.1 [M+H] + .
第六步Step 6
将化合物5-7a和化合物5-7b的混合物(1.93g,4.74mmol,1eq)溶于二氯甲烷(4mL)和甲醇(4mL)中，加入盐酸/二氧六环(4M,10mL,8.45eq)，反应液在50℃下搅拌2小时。将反应液冷却至室温，减压浓缩干得到粗品。向粗品中加入甲基叔丁基醚(10mL)，搅拌10分钟，过滤，向滤饼中加入乙酸乙酯(10mL)，搅拌10分钟，过滤，将滤饼减压浓缩干得到粗品化合物5-8a和化合物5-8b的混合物(盐酸盐，SFC分析条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：异丙醇(0.05％二乙胺)；梯度：B％：40％；流速：4mL/min，保留时间为0.689min和1.229min的两个异构体的含量分别为37.35％和62.65％)。 1H NMR(400MHz,DMSO-d 6)δ8.74(br d,J＝5.27Hz,1H),8.58(br d,J＝7.78Hz,1H),7.71-7.80(m,1H),4.63(br s,1H),3.60(br d,J＝17.57Hz,1H),3.32(br s,1H),3.26(br d,J＝17.57Hz,1H),3.16(br s,1H),3.04(br d,J＝8.53Hz,2H),2.11-2.22(m,1H),1.96(br d,J＝12.05Hz,1H),1.75-1.87(m,1H),1.64(br d,J＝14.05Hz,1H)。 A mixture of compound 5-7a and compound 5-7b (1.93g, 4.74mmol, 1eq) was dissolved in dichloromethane (4mL) and methanol (4mL), and hydrochloric acid/dioxane (4M, 10mL, 8.45eq) was added ), the reaction solution was stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature and concentrated to dryness under reduced pressure to obtain the crude product. To the crude product was added methyl tert-butyl ether (10 mL), stirred for 10 minutes, filtered, added ethyl acetate (10 mL) to the filter cake, stirred for 10 minutes, filtered, and concentrated the filter cake to dryness under reduced pressure to obtain the crude compound 5- Mixture of 8a and compound 5-8b (hydrochloride, SFC analysis conditions: Column: Chiralpak AD-3 50 x 4.6 mm ID, 3 μm, mobile phase: A phase: CO 2 , B phase: isopropanol (0.05%) diethylamine); gradient: B%: 40%; flow rate: 4 mL/min, the contents of the two isomers with retention times of 0.689 min and 1.229 min were 37.35% and 62.65%, respectively). 1 H NMR (400MHz, DMSO-d 6 )δ8.74 (br d, J=5.27Hz, 1H), 8.58 (br d, J=7.78Hz, 1H), 7.71-7.80 (m, 1H), 4.63 ( br s,1H),3.60(br d,J=17.57Hz,1H),3.32(br s,1H),3.26(br d,J=17.57Hz,1H),3.16(br s,1H),3.04( br d, J=8.53Hz, 2H), 2.11-2.22 (m, 1H), 1.96 (br d, J=12.05Hz, 1H), 1.75-1.87 (m, 1H), 1.64 (br d, J=14.05 Hz, 1H).
第七步Step 7
将化合物2-5(30mg,89.54μmol,1eq)溶于N,N-二甲基乙酰胺(0.5mL)和水(0.5mL)中，加入化合物5-8a和化合物5-8b的混合物(33.59mg,盐酸盐粗品)和碳酸钾(123.75mg,895.39μmol,10eq)，反应液在氮气保护下在100℃下搅拌12小时。将反应液冷却至室温，过滤，收集滤液。粗品经高效液相色谱分离纯化 (色谱柱:Phenomenex Gemini-NX 80*40mm*3μm；流动相:[水(0.05％氨水)-乙腈]；B(乙腈)％:19％-49％)得到化合物5。MS:m/z 503.1[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.33(br d,J＝4.77Hz,1H),7.82(br d,J＝7.53Hz,1H),7.54-7.55(m,2H),7.27(dd,J＝5.27,7.28Hz,1H),6.05(d,J＝5.52Hz,1H),4.30(br d,J＝13.30Hz,2H),4.02(s,1H),3.18-3.28(m,3H),2.91(br d,J＝16.56Hz,1H),1.75-1.92(m,2H),1.61(br d,J＝13.05Hz,1H),1.40(br d,J＝13.30Hz,1H)。 Compound 2-5 (30 mg, 89.54 μmol, 1 eq) was dissolved in N,N-dimethylacetamide (0.5 mL) and water (0.5 mL), and a mixture of compound 5-8a and compound 5-8b (33.59 mL) was added. mg, crude hydrochloride) and potassium carbonate (123.75 mg, 895.39 μmol, 10 eq), the reaction solution was stirred at 100° C. for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; B (acetonitrile)%: 19%-49%) to obtain the compound 5. MS: m/z 503.1[M+H] + ; 1 H NMR (400MHz, CD 3 OD) δ 8.33 (br d, J=4.77Hz, 1H), 7.82 (br d, J=7.53Hz, 1H) ,7.54-7.55(m,2H),7.27(dd,J＝5.27,7.28Hz,1H),6.05(d,J＝5.52Hz,1H),4.30(br d,J＝13.30Hz,2H),4.02 (s,1H),3.18-3.28(m,3H),2.91(br d,J=16.56Hz,1H),1.75-1.92(m,2H),1.61(br d,J=13.05Hz,1H), 1.40 (br d, J=13.30 Hz, 1H).
第八步Step 8
化合物5再经SFC拆分(分离条件：色谱柱：Phenomenex-Cellulose-2(250mm*30mm,10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)乙醇]；梯度：B％:60％-60％)得到化合物5a和化合物5b。 Compound 5 was separated by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B%: 60%-60%) to obtain compound 5a and compound 5b.
化合物5a的SFC分析条件：色谱柱：Cellulose 2 100×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度：B％：60％；流速：2.8mL/min，保留时间为2.243min，ee＝100％。MS:m/z 525.1[M+Na] +； 1H NMR(400MHz,CD 3OD)δ8.34(br s,1H),7.82(br d,J＝5.8Hz,1H),7.56(br s,2H),7.27(br s,1H),6.06(br s,1H),4.29-4.32(m,2H),4.02(br s,1H),3.21-3.25(m,3H),2.90-2.94(m,1H),1.75-1.94(m,2H),1.60-1.63(m,1H),1.39-1.42(m,1H)。 SFC analysis conditions for compound 5a: Column: Cellulose 2 100×4.6 mm ID, 3 μm, Mobile phase: Phase A: CO 2 , Phase B: Ethanol (0.05% diethylamine); Gradient: B%: 60%; Flow rate : 2.8mL/min, retention time is 2.243min, ee=100%. MS: m/z 525.1 [M+Na] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.34 (br s, 1H), 7.82 (br d, J=5.8 Hz, 1H), 7.56 (br s ,2H),7.27(br s,1H),6.06(br s,1H),4.29-4.32(m,2H),4.02(br s,1H),3.21-3.25(m,3H),2.90-2.94( m, 1H), 1.75-1.94 (m, 2H), 1.60-1.63 (m, 1H), 1.39-1.42 (m, 1H).
化合物5b的SFC分析条件：色谱柱：Cellulose 2 100×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度：B％：60％；流速：2.8mL/min，保留时间为3.974min，ee＝100％。MS:m/z 503.0[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.34(d,J＝5.02Hz,1H),7.82(d,J＝7.53Hz,1H),7.53-7.58(m,2H),7.27(dd,J＝5.27,7.28Hz,1H),6.05(d,J＝5.52Hz,1H),4.30(br d,J＝13.30Hz,2H),4.02(s,1H),3.18-3.28(m,3H),2.91(br d,J＝16.56Hz,1H),1.75-1.93(m,2H),1.62(br d,J＝12.05Hz,1H),1.40(br d,J＝12.80Hz,1H)。 SFC analysis conditions for compound 5b: Column: Cellulose 2 100×4.6 mm ID, 3 μm, mobile phase: A phase: CO 2 , B phase: ethanol (0.05% diethylamine); gradient: B%: 60%; flow rate : 2.8mL/min, retention time is 3.974min, ee=100%. MS: m/z 503.0 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.34 (d, J=5.02 Hz, 1 H), 7.82 (d, J=7.53 Hz, 1 H), 7.53 -7.58(m,2H),7.27(dd,J＝5.27,7.28Hz,1H),6.05(d,J＝5.52Hz,1H),4.30(br d,J＝13.30Hz,2H),4.02(s ,1H),3.18-3.28(m,3H),2.91(br d,J＝16.56Hz,1H),1.75-1.93(m,2H),1.62(br d,J＝12.05Hz,1H),1.40( br d, J=12.80Hz, 1H).
实施例6Example 6
Figure PCTCN2022083413-appb-000052
Figure PCTCN2022083413-appb-000052
第一步first step
将化合物3-1(50mg,121.06μmol,1eq)和化合物6-1(58.54mg,302.65μmol,2.5eq)溶于二甲基亚砜(0.5mL)和水(0.5mL)中，加入锌粉(15.83mg,242.12μmol,2eq)和铜粉(11.54mg,181.59μmol,1.29μL,1.5eq)，反应液在氮气保护下在100℃下搅拌12小时。原料反应完全后，将反应液冷却至室温，过滤，滤饼用乙酸乙酯(5mL×2)荡洗，合并有机相，用水(5mL×2)洗，饱和食盐水(5mL)洗，无水硫酸钠干燥，过滤，滤液减压浓缩干得到粗品。粗品经硅胶薄层板(石油醚:乙酸乙酯＝1:1)纯化得到化合物6-2。MS:m/z 320.8[M+H] +。 Compound 3-1 (50mg, 121.06μmol, 1eq) and compound 6-1 (58.54mg, 302.65μmol, 2.5eq) were dissolved in dimethyl sulfoxide (0.5mL) and water (0.5mL), and zinc powder was added (15.83mg, 242.12μmol, 2eq) and copper powder (11.54mg, 181.59μmol, 1.29μL, 1.5eq), the reaction solution was stirred at 100° C. for 12 hours under nitrogen protection. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, filtered, the filter cake was washed with ethyl acetate (5 mL×2), the organic phases were combined, washed with water (5 mL×2), saturated brine (5 mL), and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product. The crude product was purified by silica gel thin layer plate (petroleum ether:ethyl acetate=1:1) to obtain compound 6-2. MS: m/z 320.8 [M+H] + .
第二步second step
将化合物6-2(20mg,62.49μmol,1eq)溶于乙腈(1mL)中，加入化合物3-2(20.64mg,74.99μmol,1.2eq)和碳酸钾(86.37mg,624.93μmol,10eq)。反应液在氮气保护下在100℃下搅拌6小时。原料反应完全后，将反应液冷却至室温，过滤，收集滤液。粗品经高效液相色谱制备分离纯化(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm；流动相:[水(0.05％氨水)-乙腈]；B(乙腈)％:37％-67％,8min)得到化合物6。MS:m/z 486.8[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.32(br d,J＝10.79Hz,2H),7.55(br s,1H),7.37(br s,1H),7.21(br s,3H),6.06(br s,1H),4.32(br d,J＝11.54Hz,2H),3.95(br s,1H),3.28-3.34(m,2H),3.17(br d,J＝14.81Hz,1H),2.81(br d,J＝15.56Hz,1H),1.73-1.96(m,2H),1.63(br d,J＝12.00Hz,1H),1.45(br d,J＝10.54Hz,1H)。 Compound 6-2 (20 mg, 62.49 μmol, 1 eq) was dissolved in acetonitrile (1 mL), and compound 3-2 (20.64 mg, 74.99 μmol, 1.2 eq) and potassium carbonate (86.37 mg, 624.93 μmol, 10 eq) were added. The reaction solution was stirred at 100°C for 6 hours under nitrogen protection. After the reaction of the raw materials was completed, the reaction solution was cooled to room temperature, filtered, and the filtrate was collected. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; B (acetonitrile)%: 37%-67%, 8min ) to give compound 6. MS: m/z 486.8 [M+H] + . 1 H NMR (400MHz, CD 3 OD) δ 8.32 (br d, J=10.79Hz, 2H), 7.55 (br s, 1H), 7.37 (br s, 1H), 7.21 (br s, 3H), 6.06 (br s, 1H), 4.32 (br d, J=11.54Hz, 2H), 3.95 (br s, 1H), 3.28-3.34 (m, 2H), 3.17 (br d, J=14.81Hz, 1H), 2.81 (br d, J=15.56Hz, 1H), 1.73-1.96 (m, 2H), 1.63 (br d, J=12.00Hz, 1H), 1.45 (br d, J=10.54Hz, 1H).
实施例7Example 7
Figure PCTCN2022083413-appb-000053
Figure PCTCN2022083413-appb-000053
第一步first step
将化合物6-2(95mg,296.84μmol,1eq)溶于N,N-二甲基乙酰胺(1.5mL)和水(1.5mL)中，加入化合物5-8a和化合物5-8b的混合物(98.39mg,盐酸盐粗品)和碳酸钾(307.70mg,2.23mmol,7.5eq)，反应液在氮气保护下在100℃下搅拌12小时。将反应液冷却至室温，过滤，收集滤液。粗品经高效液相色谱制备分离纯化(色谱柱:Phenomenex Gemini-NX 80*40mm*3μm；流动相:[水(0.05％氨水)-乙腈]；B(乙腈)％:28％-58％)得到化合物7。MS:m/z 488.1[M+H] +； 1H NMR(400MHz,CD 3OD)δ8.30-8.36(m,3H),7.82(br d,J＝5.88Hz,1H),7.55(br s,1H),7.27(br s,1H),6.06(br s,1H),4.35(br d,J＝12.26Hz,2H),4.03(br s,1H),3.34-3.46(m,1H),3.25(br d,J＝16.88Hz,2H),2.93(br d,J＝16.38Hz,1H),1.78-1.95(m,2H),1.65(br d,J＝12.26Hz,1H),1.43(br d,J＝11.63Hz,1H)。 Compound 6-2 (95 mg, 296.84 μmol, 1 eq) was dissolved in N,N-dimethylacetamide (1.5 mL) and water (1.5 mL), and a mixture of compound 5-8a and compound 5-8b (98.39 mL) was added. mg, crude hydrochloride) and potassium carbonate (307.70 mg, 2.23 mmol, 7.5 eq), the reaction solution was stirred at 100° C. for 12 hours under nitrogen protection. The reaction solution was cooled to room temperature, filtered, and the filtrate was collected. The crude product was separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80*40mm*3μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; B (acetonitrile)%: 28%-58%) to obtain Compound 7. MS: m/z 488.1 [M+H] + ; 1 H NMR (400 MHz, CD 3 OD) δ 8.30-8.36 (m, 3H), 7.82 (br d, J=5.88 Hz, 1H), 7.55 (br d s,1H),7.27(br s,1H),6.06(br s,1H),4.35(br d,J=12.26Hz,2H),4.03(br s,1H),3.34-3.46(m,1H) ,3.25(br d,J＝16.88Hz,2H),2.93(br d,J＝16.38Hz,1H),1.78-1.95(m,2H),1.65(br d,J＝12.26Hz,1H),1.43 (br d, J=11.63 Hz, 1H).
第二步second step
化合物7经SFC拆分(分离条件：色谱柱：Phenomenex-Cellulose-2(250mm*30mm,10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)乙醇]；梯度：B％:60％-60％)得到化合物7a(不纯)和化合物7b。化合物7a(不 纯，SFC分析条件：色谱柱：Cellulose 2 100×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度：B％：60％；流速：2.8mL/min，保留时间为2.540min)再经高效液相色谱制备分离纯化(色谱柱:Phenomenex C18 80*40mm*3μm；流动相:[水(0.05％氨水)-乙腈]；乙腈％:27％-57％)得到化合物7a。 Compound 7 was resolved by SFC (separation conditions: chromatographic column: Phenomenex-Cellulose-2 (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; gradient: B %: 60%-60%) to obtain compound 7a (impure) and compound 7b. Compound 7a (impure, SFC analysis conditions: Column: Cellulose 2 100 x 4.6 mm ID, 3 μm, Mobile phase: Phase A: CO 2 , Phase B: Ethanol (0.05% diethylamine); Gradient: B%: 60 %; flow rate: 2.8mL/min, retention time is 2.540min) and then prepared, separated and purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80*40mm*3 μm; mobile phase: [water (0.05% ammonia water)-acetonitrile]; Acetonitrile %: 27%-57%) to give compound 7a.
化合物7a：SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度：B％：40％；流速：4mL/min，保留时间为1.182min，ee＝99.64％。MS:m/z 488.1[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.33-8.35(m,3H),7.83(br d,J＝7.53Hz,1H),7.56(d,J＝5.27Hz,1H),7.26-7.29(m,1H),6.06(d,J＝5.27Hz,1H),4.37(br d,J＝13.55Hz,2H),4.05(s,1H),3.32-3.36(m,2H),3.25(br d,J＝17.07Hz,1H),2.94(br d,J＝16.81Hz,1H),1.79-1.97(m,2H),1.66(br d,J＝12.05Hz,1H),1.45(br d,J＝14.05Hz,1H)。 Compound 7a: SFC Analysis Conditions: Column: Chiralcel OD-3 50 x 4.6 mm ID, 3 μm, Mobile Phase: Phase A: CO2 , Phase B: Ethanol (0.05% Diethylamine); Gradient: B%: 40% ; Flow rate: 4mL/min, retention time is 1.182min, ee=99.64%. MS: m/z 488.1 [M+H] + . 1 H NMR(400MHz, CD 3 OD)δ8.33-8.35(m,3H),7.83(br d,J=7.53Hz,1H),7.56(d,J=5.27Hz,1H),7.26-7.29( m,1H),6.06(d,J=5.27Hz,1H),4.37(br d,J=13.55Hz,2H),4.05(s,1H),3.32-3.36(m,2H),3.25(br d , J=17.07Hz, 1H), 2.94 (br d, J=16.81Hz, 1H), 1.79-1.97 (m, 2H), 1.66 (br d, J=12.05Hz, 1H), 1.45 (br d, J =14.05Hz, 1H).
化合物7b：SFC分析条件：色谱柱：Cellulose 2 100×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度：B％：60％；流速：2.8mL/min，保留时间为3.567min，ee＝100％。MS:m/z 487.9[M+H] +。 1H NMR(400MHz,CD 3OD)δ8.31-8.35(m,3H),7.82(br d,J＝7.53Hz,1H),7.54(br d,J＝5.52Hz,1H),7.22-7.32(m,1H),6.05(d,J＝5.27Hz,1H),4.35(br d,J＝13.55Hz,2H),4.03(s,1H),3.29-3.35(m,2H),3.25(br d,J＝16.56Hz,1H),2.93(br d,J＝16.56Hz,1H),1.77-1.96(m,2H),1.65(br d,J＝13.05Hz,1H),1.43(br d,J＝13.05Hz,1H)。 Compound 7b: SFC Analysis Conditions: Column: Cellulose 2 100 x 4.6 mm ID, 3 μm, Mobile Phase: Phase A: CO 2 , Phase B: Ethanol (0.05% Diethylamine); Gradient: B%: 60%; Flow Rate : 2.8mL/min, retention time is 3.567min, ee=100%. MS: m/z 487.9 [M+H] + . 1 H NMR (400MHz, CD 3 OD)δ8.31-8.35(m,3H),7.82(br d,J=7.53Hz,1H),7.54(br d,J=5.52Hz,1H),7.22-7.32 (m,1H),6.05(d,J=5.27Hz,1H),4.35(br d,J=13.55Hz,2H),4.03(s,1H),3.29-3.35(m,2H),3.25(br d, J=16.56Hz, 1H), 2.93 (br d, J=16.56Hz, 1H), 1.77-1.96 (m, 2H), 1.65 (br d, J=13.05Hz, 1H), 1.43 (br d, J=13.05Hz, 1H).
生物检测数据Biometric data
实验例1 酶活性评价Experimental Example 1 Enzyme activity evaluation
实验材料：Homogeneous Full Length SHP-2 Assay Kit(购自BPS Bioscience)，多标记分析仪NIVO。Experimental materials: Homogeneous Full Length SHP-2 Assay Kit (purchased from BPS Bioscience), multi-label analyzer NIVO.
实验方法：experimental method:
1倍缓冲液配制(现配现用)：将5倍缓冲液用去离子水稀释成1倍缓冲液，冰上放置备用。1-fold buffer preparation (for current use): Dilute 5-fold buffer with deionized water to 1-fold buffer, and place on ice for later use.
将待测化合物用100％DMSO稀释到100μM作为第一个浓度，然后再用排枪进行4倍稀释至第8个浓度，即从100μM稀释至6.1nM。用1倍缓冲液将待测化合物各梯度稀释成DMSO为10％的工作液，5μL/孔加到对应孔中，设置双复孔实验。1000转每分钟，离心1分钟。The compounds to be tested were diluted with 100% DMSO to 100 μM as the first concentration, and then 4-fold diluted to the eighth concentration with a drain gun, ie, from 100 μM to 6.1 nM. Each compound to be tested was diluted with 1-fold buffer into a working solution with 10% DMSO, and 5 μL/well was added to the corresponding well to set up a double-well experiment. Centrifuge at 1000 rpm for 1 minute.
每孔加入18μL配制的反应混合液，其中含12.25μL去离子水；5μL 5倍缓冲液；0.25μL SHP-2底物多肽(100μM)；0.5μL DTT(二硫苏糖醇)(250mM)。1000转每分钟，离心1分钟。Add 18 μL of the prepared reaction mixture to each well, which contains 12.25 μL deionized water; 5 μL 5x buffer; 0.25 μL SHP-2 substrate polypeptide (100 μM); 0.5 μL DTT (dithiothreitol) (250 mM). Centrifuge at 1000 rpm for 1 minute.
用1倍缓冲液将SHP-2酶稀释到0.1ng/μL，取2μL/孔加入到对应孔中，阴性对照孔中加入2μL 1倍缓冲液，SHP-2(0.2ng)，该步在冰上操作，反应体系置于25度孵育60分钟做化合物预孵育。Dilute the SHP-2 enzyme to 0.1ng/μL with 1x buffer, add 2μL/well to the corresponding well, add 2μL 1x buffer, SHP-2 (0.2ng) to the negative control well, and keep this step on ice. In the above operation, the reaction system was incubated at 25 degrees for 60 minutes for compound pre-incubation.
化合物预孵育结束后每孔加入25μL底物工作液，其中含19.45μL去离子水；5μL 5倍缓冲液；0.5μL DTT(250mM)和0.05μL SHP-2底物DiFMUP(6,8-二氟-4-甲基-7-羟基香豆素磷酸酯)(10mM)，反应体系置于25度反应30分钟。此时化合物终浓度梯度为1μM至0.061nM。反应结束后采用多标记分析仪NIVO读 取荧光值，激发波长：360nm，测试波长：460nm。After compound pre-incubation, 25μL of substrate working solution was added to each well, which contained 19.45μL of deionized water; 5μL of 5x buffer; 0.5μL of DTT (250mM) and 0.05μL of SHP-2 substrate DiFMUP (6,8-difluoro -4-methyl-7-hydroxycoumarin phosphate) (10 mM), the reaction system was placed at 25 degrees for 30 minutes. The final compound concentration gradient at this point was 1 μM to 0.061 nM. After the reaction, the multi-label analyzer NIVO was used to read the fluorescence value, the excitation wavelength: 360 nm, and the test wavelength: 460 nm.
化合物本底读值检测：取100％DMSO稀释好的待测化合物各梯度5μL到新的化合物板中，加入45μL1倍缓冲液进行10倍稀释，配成10％DMSO的工作液，再取该化合物工作液5μL/孔到检测板中，然后加入45μL 1倍缓冲液进行10倍稀释，此时DMSO终浓度为1％，1000rpm/min，离心1分钟后采用多标记分析仪读取荧光值，激发波长：360nm，测试波长：460nm。Compound background reading detection: Take 5 μL of each compound to be tested diluted in 100% DMSO into a new compound plate, add 45 μL of 1-fold buffer for 10-fold dilution, prepare a working solution of 10% DMSO, and then take the compound 5 μL/well of working solution was added to the detection plate, and then 45 μL of 1-fold buffer was added for 10-fold dilution. At this time, the final concentration of DMSO was 1%, 1000 rpm/min. Wavelength: 360nm, test wavelength: 460nm.
数据分析：data analysis:
原始数据换算成抑制率，IC 50的值可通过四参数进行曲线拟合得出。本发明的化合物对SHP2酶活性的抑制结果见表1。 The raw data were converted into inhibition rates, and IC50 values were obtained by curve fitting with four parameters. Table 1 shows the inhibitory results of the compounds of the present invention on SHP2 enzymatic activity.
表1：本发明化合物对SHP2酶活性的抑制结果Table 1: Inhibition results of the compounds of the present invention on SHP2 enzymatic activity
化合物编号Compound number SHP2 IC 50(nM) SHP2 IC50 (nM) 化合物编号Compound number SHP2 IC 50(nM) SHP2 IC50 (nM)
化合物1Compound 1 1.501.50 化合物5aCompound 5a 1.451.45
化合物2Compound 2 2.072.07 化合物6Compound 6 0.930.93
化合物3Compound 3 1.041.04 化合物7Compound 7 1.591.59
化合物4Compound 4 1.041.04 化合物7aCompound 7a 0.690.69
化合物5Compound 5 2.432.43 化合物7bCompound 7b 14.114.1
结论：SHP2酶活性抑制结果显示，本发明化合物可以显著抑制SHP2酶活性。Conclusion: The results of inhibition of SHP2 enzyme activity show that the compounds of the present invention can significantly inhibit the activity of SHP2 enzyme.
实验例2：NCI-H358细胞增殖抑制活性评价Experimental Example 2: Evaluation of NCI-H358 Cell Proliferation Inhibitory Activity
实验方法：experimental method:
将NCI-H358细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含4000个NCI-H358细胞。细胞板置于二氧化碳培养箱中过夜培养。将待测化合物用排枪进5倍稀释至第9个浓度，即从2000μM稀释至5.12nM，设置双复孔实验。向中间板中加入78μL培养基，再按照对应位置，转移2μL每孔的梯度稀释化合物至中间板，混匀后转移20μL每孔到细胞板中。转移到细胞板中的化合物浓度范围是10μM至0.026nM。细胞板置于二氧化碳培养箱中培养5天。另准备一块细胞板，在加药当天读取信号值作为最大值(下面方程式中Max值)参与数据分析。向此细胞板每孔加入25μL细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。加入化合物的细胞板结束孵育后，向细胞板中加入每孔25μL的细胞活率化学发光检测试剂，室温孵育10分钟使发光信号稳定。采用多标记分析仪读数。NCI-H358 cells were seeded in a white 96-well plate, 80 μL of cell suspension per well, which contained 4000 NCI-H358 cells. Cell plates were incubated overnight in a carbon dioxide incubator. The compounds to be tested were diluted 5-fold to the ninth concentration, that is, from 2000 μM to 5.12 nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 [mu]M to 0.026 nM. The cell plates were placed in a carbon dioxide incubator for 5 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer. After the incubation of the compound-added cell plate, 25 μL of cell viability chemiluminescence detection reagent was added to the cell plate, and incubated at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.
数据分析：data analysis:
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。本发明的化合物对 NCI-H358细胞增殖抑制活性的结果见表2。 Using the equation (Sample-Min)/(Max-Min)*100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode). Table 2 shows the results of the inhibitory activity of the compounds of the present invention on the proliferation of NCI-H358 cells.
表2：本发明化合物对NCI-H358细胞增殖抑制活性的结果Table 2: Results of the compounds of the present invention on the proliferation inhibitory activity of NCI-H358 cells
化合物编号Compound number IC 50(nM) IC50 (nM) 化合物编号Compound number IC 50(nM) IC50 (nM)
化合物1Compound 1 121121 化合物5aCompound 5a 3.13.1
化合物2Compound 2 137137 化合物6Compound 6 4.24.2
化合物3Compound 3 2.52.5 化合物7Compound 7 1717
化合物4Compound 4 1212 化合物7aCompound 7a 1.11.1
化合物5Compound 5 2828 -- --
结论：NCI-H358细胞增殖抑制活性测试结果显示，本发明化合物可以显著抑制NCI-H358细胞的增殖。Conclusion: The test results of NCI-H358 cell proliferation inhibitory activity show that the compounds of the present invention can significantly inhibit the proliferation of NCI-H358 cells.
实验例3：小鼠药代动力学性质评价Experimental Example 3: Evaluation of Pharmacokinetic Properties in Mice
实验方法：experimental method:
受试化合物溶于5％DMSO+95％(10％羟丙基-β-环糊精水溶液)中，涡旋并超声，制备得到相应浓度的澄清溶液，微孔滤膜过滤后备用。选取17至20克的Balb/c雄性小鼠，静脉或口服给予候选化合物溶液，剂量分别为1或2mg/kg。收集0.083、0.25、0.5、1、2、4、8、24小时时间点的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin 6.3计算药代动力学参数。测试结果如表3所示：The test compound was dissolved in 5% DMSO+95% (10% hydroxypropyl-β-cyclodextrin aqueous solution), vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use. Balb/c male mice of 17 to 20 grams were selected, and the candidate compound solution was administered intravenously or orally at a dose of 1 or 2 mg/kg, respectively. Whole blood was collected at time points of 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours, and plasma was prepared. The drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3. The test results are shown in Table 3:
表3：本发明化合物小鼠血浆中的药物代谢动力学测试结果Table 3: Pharmacokinetic test results of the compounds of the present invention in mouse plasma
Figure PCTCN2022083413-appb-000054
Figure PCTCN2022083413-appb-000054
注：C max，最大药物浓度；T 1/2，半衰期；V dss，表观分布容积；Cl，药物清除率；AUC 0-last，从0时到最后一个时间点的血药浓度-时间曲线下面积；AUC 0-inf，从0时到无穷大时间的血药浓度-时间曲线下面积；F， 生物利用度；“--”是指未测试或未获得数据。 Note: C max , maximum drug concentration; T 1/2 , half-life; V dss , apparent volume of distribution; Cl, drug clearance rate; AUC 0-last , plasma concentration-time curve from 0 to the last time point Area under; AUCo -inf , area under the plasma concentration-time curve from 0 to infinity; F, bioavailability; "--" means not tested or data not obtained.
实验结论：本发明化合物具有良好的小鼠体内药代动力学性质。Experimental conclusion: The compound of the present invention has good pharmacokinetic properties in mice.
实验例4：体内药效学研究Experimental Example 4: In Vivo Pharmacodynamic Study
实验目的：研究本发明化合物在人非小细胞肺癌NCI-H358细胞BALB/c裸小鼠皮下异种移植瘤模型中的体内药效Experimental purpose: To study the in vivo efficacy of the compounds of the present invention in the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358 cells BALB/c nude mice
实验动物:雌性BALB/c裸小鼠，6-8周龄，体重18-22克，供应商：上海市计划生育科学研究所实验动物经营部Experimental animal: Female BALB/c nude mice, 6-8 weeks old, weighing 18-22 grams, supplier: Laboratory Animal Management Department, Shanghai Institute of Family Planning Science
实验方法与步骤：Experimental methods and steps:
(1)细胞培养(1) Cell culture
人非小细胞肺癌NCI-H358细胞体外单层培养，培养条件为Gibco RMPI1640培养基中加10％胎牛血清，37℃，5％CO 2孵箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％，数量到达要求时，收取细胞，计数，接种。 Human non-small cell lung cancer NCI-H358 cells were cultured in monolayer in vitro, and the culture conditions were Gibco RMPI1640 medium plus 10% fetal bovine serum, 37°C, 5% CO 2 incubator. Conventional digestion with trypsin-EDTA was performed twice a week for passage. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and seeded.
(2)肿瘤细胞接种及分组(2) Inoculation and grouping of tumor cells
将0.2mL(1×10 7个)NCI-H358细胞(加基质胶，体积比为1:1)皮下接种于每只小鼠的右后背，肿瘤平均体积达到约138mm 3时开始分组给药(溶媒对照组和化合物组)。溶媒为5％DMSO+95％(10％羟丙基-β-环糊精水溶液)。 0.2mL (1×10 7 cells) of NCI-H358 cells (plus Matrigel, volume ratio of 1:1) were subcutaneously inoculated into the right back of each mouse, and the group administration started when the average tumor volume reached about 138 mm 3 (Vehicle control group and compound group). The vehicle was 5% DMSO + 95% (10% hydroxypropyl-beta-cyclodextrin in water).
(3)肿瘤测量和实验指标：(3) Tumor measurement and experimental indicators:
每周两次用游标卡尺测量肿瘤直径，计算肿瘤体积(V)和肿瘤生长抑制率(TGI)。计算公式：V＝0.5a×b 2，其中a和b分别是肿瘤的长径和短径；TGI(％)＝[1–(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶媒对照组治疗结束时平均瘤体积－溶媒对照组开始治疗时平均瘤体积)]×100％。实验结果：实验结果见表4。 Tumor diameters were measured twice a week with a caliper, and tumor volume (V) and tumor growth inhibition (TGI) were calculated. Calculation formula: V=0.5a×b 2 , where a and b are the long and short diameters of the tumor, respectively; TGI(%)=[1-(average tumor volume at the end of the administration of a treatment group-the start of administration of the treatment group; Average tumor volume at the time of drug administration)/(average tumor volume of vehicle control group at the end of treatment-average tumor volume of vehicle control group at the beginning of treatment)]×100%. Experimental results: The experimental results are shown in Table 4.
表4：本发明化合物对NCI-H358细胞BALB/c裸小鼠皮下异种移植肿瘤模型的抑瘤结果Table 4: Tumor inhibition results of compounds of the present invention on NCI-H358 cell BALB/c nude mice subcutaneous xenograft tumor model
组别(剂量)Group (dose) 肿瘤体积*(mm 3)(第29天) Tumor volume* (mm 3 ) (day 29) TGI(％)TGI(%)
溶媒组vehicle group 487±39487±39 ----
化合物5a(3mg/kg)Compound 5a (3mg/kg) 196±13196±13 83.383.3
化合物5a(10mg/kg)Compound 5a (10mg/kg) 154±19154±19 95.395.3
化合物7a(1mg/kg)Compound 7a (1mg/kg) 182±10182±10 87.587.5
化合物7a(3mg/kg)Compound 7a (3mg/kg) 112±7112±7 107.6107.6
注：“--”：不需计算；*：平均值±SEM，n＝6。Note: "--": no calculation required; *: mean±SEM, n=6.
结论：本发明化合物在人非小细胞肺癌NCI-H358细胞BALB/c裸小鼠皮下异种移植肿瘤模型中展现出优异的抑瘤效果。CONCLUSION: The compounds of the present invention exhibit excellent tumor-inhibiting effect in the subcutaneous xenograft tumor model of human non-small cell lung cancer NCI-H358 cells BALB/c nude mice.

Claims (22)

  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 PCTCN2022083413-appb-100001
    Figure PCTCN2022083413-appb-100001
    其中，in,
    环A选自苯基和5-6元杂芳基；Ring A is selected from phenyl and 5-6 membered heteroaryl;
    R 1和R 2各自独立地选自H、-NR 6R 7、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R a取代； R 1 and R 2 are each independently selected from H, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy being any is optionally substituted with 1, 2 or 3 Ra ;
    R 3各自独立地选自H、F、Cl、Br、I、-NR 6R 7、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代； R 3 is each independently selected from H, F, Cl, Br, I, -NR 6 R 7 , C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1- 3 alkoxy is optionally substituted with 1, 2 or 3 R b ;
    R 4和R 5各自独立地选自OH、NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R c取代； R 4 and R 5 are each independently selected from OH, NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R c ;
    或者R 4和R 5与它们共同连接的原子一起使结构单元
    Figure PCTCN2022083413-appb-100002
    选自
    Figure PCTCN2022083413-appb-100003
    Figure PCTCN2022083413-appb-100004
    or R4 and R5 together with the atoms to which they are attached together make building blocks
    Figure PCTCN2022083413-appb-100002
    selected from
    Figure PCTCN2022083413-appb-100003
    Figure PCTCN2022083413-appb-100004
    X 1和X 2各自独立地选自CH 2和O； X 1 and X 2 are each independently selected from CH 2 and O;
    X 3选自CH和N； X 3 is selected from CH and N;
    R 6和R 7各自独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R d取代； R 6 and R 7 are each independently selected from H and C 1-3 alkyl optionally substituted with 1 , 2 or 3 R d ;
    R 8和R 9各自独立地选自H、F、Cl、Br、I、-OH、-NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R e取代； R 8 and R 9 are each independently selected from H, F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally replaced by 1 , 2 or 3 R e substitutions;
    n、m和p各自独立地选自0、1、2和3；n, m and p are each independently selected from 0, 1, 2 and 3;
    R a各自独立地选自H、OH、F、Cl、Br和I； R a is each independently selected from H, OH, F, Cl, Br and I;
    R b、R c、R d和R e各自独立地选自H、F、Cl、Br和I。 Rb , Rc , Rd and Re are each independently selected from H, F, Cl, Br and I.
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，环A选自苯基、吡啶基、嘧啶基、吡嗪基、哒嗪基、吡咯基、咪唑基、吡唑基和噻吩基。The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl and thiophene base.
  3. 根据权利要求1或2所述化合物或其药学上可接受的盐，其中，环A选自吡啶基。The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from pyridyl.
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自H、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3任选被1、2或3个R a取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2CH3 , CH ( CH3 ) 2 and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 and -OCH 3 is optionally substituted with 1, 2 or 3 R a .
  5. 根据权利要求1或4所述化合物或其药学上可接受的盐，其中，R 1选自H、NH 2和CH 3。 The compound of claim 1 or 4, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from H, NH 2 and CH 3 .
  6. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2选自H、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3任选被1、2或3个R a取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH 3 , CH 2 CH 3 , CH 2 CH 2CH3 , CH ( CH3 ) 2 and -OCH3 , the -NHCH3 , -N( CH3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 and -OCH 3 is optionally substituted with 1, 2 or 3 R a .
  7. 根据权利要求1或6所述化合物或其药学上可接受的盐，其中，R 2选自H和-CH 2OH。 The compound of claim 1 or 6, or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from H and -CH 2 OH.
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 3各自独立地选自H、F、Cl、Br、I、NH 2、-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3，所述-NHCH 3、-N(CH 3) 2、CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2和-OCH 3任选被1、2或3个R b取代。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from H, F, Cl, Br, I, NH 2 , -NHCH 3 , -N(CH 3 ) 2 , CH3 , CH2CH3 , CH2CH2CH3 , CH ( CH3 ) 2 and -OCH3 , the -NHCH3 , -N ( CH3 ) 2 , CH3 , CH2CH3 , CH2 CH2CH3 , CH( CH3 ) 2 and -OCH3 are optionally substituted with 1, 2 or 3 Rb .
  9. 根据权利要求1或8所述化合物或其药学上可接受的盐，其中，R 3各自独立地选自H、Cl和NH 2。 The compound of claim 1 or 8, or a pharmaceutically acceptable salt thereof, wherein each R 3 is independently selected from H, Cl and NH 2 .
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4选自NH 2和CH 3。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from NH 2 and CH 3 .
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 5选自NH 2和CH 3。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from NH 2 and CH 3 .
  12. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4和R 5与它们共同连接的原子一起使结构单元
    Figure PCTCN2022083413-appb-100005
    选自
    Figure PCTCN2022083413-appb-100006
    其中，m、p、R 8和R 9如权利要求1所定义。     The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the atoms to which they are commonly attached make a structural unit
    Figure PCTCN2022083413-appb-100005
    selected from
    Figure PCTCN2022083413-appb-100006
    wherein m, p, R 8 and R 9 are as defined in claim 1 .
  13. 根据权利要求1或12所述化合物或其药学上可接受的盐，其中，R 4和R 5与它们共同连接的原子一起使结构单元
    Figure PCTCN2022083413-appb-100007
    选自
    Figure PCTCN2022083413-appb-100008
    The compound of claim 1 or 12 , or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the atoms to which they are commonly attached make a structural unit
    Figure PCTCN2022083413-appb-100007
    selected from
    Figure PCTCN2022083413-appb-100008
  14. 根据权利要求13所述化合物或其药学上可接受的盐，其中，R 4和R 5与它们共同连接的原子一起使结构单元
    Figure PCTCN2022083413-appb-100009
    选自
    Figure PCTCN2022083413-appb-100010
    Figure PCTCN2022083413-appb-100011
     The compound of claim 13 , or a pharmaceutically acceptable salt thereof, wherein R4 and R5 together with the atoms to which they are commonly attached make a structural unit
    Figure PCTCN2022083413-appb-100009
    selected from
    Figure PCTCN2022083413-appb-100010
    Figure PCTCN2022083413-appb-100011
  15. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 6和R 7各自独立地选自H。 The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are each independently selected from H.
  16. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 8各自独立地选自H、NH 2和CH 3。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 8 is independently selected from H, NH 2 and CH 3 .
  17. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 9各自独立地选自H和F。 The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein each R 9 is independently selected from H and F.
  18. 根据权利要求1～17任意一项所述化合物或其药学上可接受的盐，其选自，The compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, which is selected from,
    Figure PCTCN2022083413-appb-100012
    Figure PCTCN2022083413-appb-100012
    其中，X 1、X 2、X 3、n、m、p、环A、R 1、R 2、R 3、R 8和R 9如权利要求1～17任意一项所定义。 wherein X 1 , X 2 , X 3 , n, m, p, ring A, R 1 , R 2 , R 3 , R 8 and R 9 are as defined in any one of claims 1 to 17 .
  19. 根据权利要求18所述化合物或其药学上可接受的盐，其中，式(I-3)化合物或其药学上可接受的盐选自，The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I-3) or a pharmaceutically acceptable salt thereof is selected from,
    Figure PCTCN2022083413-appb-100013
    Figure PCTCN2022083413-appb-100013
    其中，R 1、R 2、R 3和R 8如权利要求18所定义。 wherein R 1 , R 2 , R 3 and R 8 are as defined in claim 18 .
  20. 根据权利要求19所述化合物或其药学上可接受的盐，其化合物选自，The compound according to claim 19 or a pharmaceutically acceptable salt thereof, which compound is selected from,
    Figure PCTCN2022083413-appb-100014
    Figure PCTCN2022083413-appb-100014
    其中，in,
    R 8选自F、Cl、Br、I、-OH、-NH 2和C 1-3烷基，所述C 1-3烷基任选被1、2或3个F取代； R 8 is selected from F, Cl, Br, I, -OH, -NH 2 and C 1-3 alkyl optionally substituted with 1 , 2 or 3 F;
    R 1、R 2和R 3如权利要求19所定义。 R 1 , R 2 and R 3 are as defined in claim 19 .
  21. 下列所示化合物或其药学上可接受的盐，The following compounds or their pharmaceutically acceptable salts,
    Figure PCTCN2022083413-appb-100015
    Figure PCTCN2022083413-appb-100015
  22. 根据权利要求21所述化合物或其药学上可接受的盐，其选自，The compound according to claim 21, or a pharmaceutically acceptable salt thereof, selected from,
    Figure PCTCN2022083413-appb-100016
    Figure PCTCN2022083413-appb-100016
    Figure PCTCN2022083413-appb-100017
    Figure PCTCN2022083413-appb-100017
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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105916845A (en) * 2014-01-17 2016-08-31 诺华股份有限公司 N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2
CN109983001A (en) * 2016-07-12 2019-07-05 锐新医药公司 Tri- substituted type 3- methylpyrazine of the disubstituted type 3- methylpyrazine of 2,5- and 2,5,6- as allosteric SHP2 inhibitor
WO2020061101A1 (en) * 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as src homology-2 phosphatase inhibitors
WO2020063760A1 (en) * 2018-09-26 2020-04-02 Jacobio Pharmaceuticals Co., Ltd. Novel heterocyclic derivatives useful as shp2 inhibitors
WO2020073949A1 (en) * 2018-10-10 2020-04-16 江苏豪森药业集团有限公司 Regulator of nitrogen-containing heteroaromatic derivatives, preparation method therefor and use thereof
WO2020201991A1 (en) * 2019-04-02 2020-10-08 Array Biopharma Inc. Protein tyrosine phosphatase inhibitors

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105916845A (en) * 2014-01-17 2016-08-31 诺华股份有限公司 N-azaspirocycloalkane substituted n-heteroaryl compounds and compositions for inhibiting the activity of shp2
CN109983001A (en) * 2016-07-12 2019-07-05 锐新医药公司 Tri- substituted type 3- methylpyrazine of the disubstituted type 3- methylpyrazine of 2,5- and 2,5,6- as allosteric SHP2 inhibitor
WO2020061101A1 (en) * 2018-09-18 2020-03-26 Nikang Therapeutics, Inc. Tri-substituted heteroaryl derivatives as src homology-2 phosphatase inhibitors
WO2020063760A1 (en) * 2018-09-26 2020-04-02 Jacobio Pharmaceuticals Co., Ltd. Novel heterocyclic derivatives useful as shp2 inhibitors
WO2020073949A1 (en) * 2018-10-10 2020-04-16 江苏豪森药业集团有限公司 Regulator of nitrogen-containing heteroaromatic derivatives, preparation method therefor and use thereof
WO2020201991A1 (en) * 2019-04-02 2020-10-08 Array Biopharma Inc. Protein tyrosine phosphatase inhibitors

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