WO2022156765A1 - 吡唑并吡嗪联三环类化合物及其应用 - Google Patents

吡唑并吡嗪联三环类化合物及其应用 Download PDF

Info

Publication number
WO2022156765A1
WO2022156765A1 PCT/CN2022/073167 CN2022073167W WO2022156765A1 WO 2022156765 A1 WO2022156765 A1 WO 2022156765A1 CN 2022073167 W CN2022073167 W CN 2022073167W WO 2022156765 A1 WO2022156765 A1 WO 2022156765A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
pharmaceutically acceptable
reaction
acceptable salt
ethyl acetate
Prior art date
Application number
PCT/CN2022/073167
Other languages
English (en)
French (fr)
Inventor
付志飞
罗妙荣
帅斌
张杨
黎健
陈曙辉
Original Assignee
南京明德新药研发有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 南京明德新药研发有限公司 filed Critical 南京明德新药研发有限公司
Priority to TW111107620A priority Critical patent/TW202246272A/zh
Publication of WO2022156765A1 publication Critical patent/WO2022156765A1/zh

Links

Classifications

    • 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
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to a class of pyrazolopyrazine tricyclic compounds and applications thereof, in particular to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • SHP2 SH2domain-containing protein-tyrosine phosphatase-2
  • PTP protein tyrosine phosphatase
  • the molecule is encoded by the PTPN11 gene, which can not only positively regulate the downstream signal transduction pathway through the catalytic activity of phosphatase, but also play a positive regulatory role as a phosphatase-independent adaptor protein, and can also play a negative role under specific conditions. Therefore, it is widely involved in the regulation of biological functions such as cell differentiation and migration and related signal transduction processes.
  • PTPN11 mutation is considered to be a high-risk factor for juvenile myelomonocytic leukemia (JMML). At the same time, it is considered to be the proto-oncogene of leukemia because of the abnormal activation and mutation of SHP2 in different types of leukemia.
  • SHP2 In cancer, pancreatic cancer, gastric cancer, and glioma, SHP2 has also been reported to be overactivated; in lung cancer, SHP2, as an oncogene, promotes the occurrence and development of tumors by regulating various mechanisms. But in the process of hepatocarcinogenesis, SHP2 plays the role of tumor suppressor gene under the influence of specific environment. In conclusion, as an important node molecule, SHP2 plays an important regulatory role in the process of tumorigenesis and development, and is a potential therapeutic target.
  • the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • T 1 is CR 4 or N
  • R 3 is H, F, Cl, Br, I or C 1-3 alkyl optionally substituted with 1 , 2 or 3 R a ;
  • R 3 is H, Cl, Br, I or C 1-3 alkyl optionally substituted with 1 , 2 or 3 R a ;
  • R 1 , R 2 and R 4 are each independently H, F, Cl, Br, I or C 1-3 alkyl optionally substituted with 1 , 2 or 3 R b ;
  • R 5 is C 1-3 alkyl substituted by OH
  • R 6 is each independently H, F, Cl, Br, I, OH, NH 2 or C 1-3 alkyl optionally substituted with 1 , 2 or 3 R c ;
  • R a , R b and R c are each independently F, Cl, Br, I, OH or NH 2 ;
  • n 1, 2, 3 or 4.
  • R 1 , R 2 and R 4 are each independently H, F, Cl, Br or I, and other variables are as defined in the present invention.
  • R 5 is -CH 2 -OH, and other variables are as defined in the present invention.
  • R 6 are each independently Cl or NH 2 , and other variables are as defined in the present invention.
  • T 1 , E 1 , R 1 , R 2 , R 3 , R 5 , R 6 and m are as defined in the present invention.
  • T 1 , E 1 , R 1 , R 2 and R are as defined in the present invention.
  • the present invention also provides the following compounds or pharmaceutically acceptable salts thereof,
  • the above compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from,
  • the second aspect of the present invention also provides a pharmaceutical composition, which comprises the compound defined in any of the above technical solutions or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also provides a method for treating a disease associated with SHP2 in a subject in need thereof, comprising providing the subject with an effective dose of a compound as defined in any of the above technical solutions or a pharmaceutically acceptable salt or pharmaceutical combination thereof thing.
  • the present invention also provides the use of the above compound or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating SHP2-related diseases; wherein the SHP2-related diseases refer to lung cancer, preferably non-small cell lung cancer.
  • the compounds of the present invention exhibit good inhibitory activity on protein tyrosine phosphatase SHP2, and will have excellent therapeutic effect in patients with abnormal SHP2 tumors.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely due to double bonds or single bonds to ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
  • C 1-3 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.
  • 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 one 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
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl (TMS),
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction method (SXRD), the cultured single crystal is collected by Bruker D8 venture diffractometer, the light source is CuK ⁇ radiation, and the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • SXRD single crystal X-ray diffraction method
  • the cultured single crystal is collected by Bruker D8 venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning mode is: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • the following abbreviations are used in the present invention: aq stands for water; DMF stands for N,N-dimethylformamide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol; group; HOAc for acetic acid; rt for room temperature; THF for tetrahydrofuran; Boc 2 O for di-tert-butyl dicarbonate; TFA for trifluoroacetic acid; DIPEA for diisopropylethylamine ; Sulfone; CS 2 for carbon disulfide; TsOH for p-toluenesulfonic acid; mp for melting point; LDA for lithium diisopropylamide; EDTA for ethylenediaminetetraacetic acid; SEM for 2-trimethylsilylethoxymethyl ; PMB stands for p-methoxybenzyl; TBDPS stands for tert-
  • Embodiment 1 is a diagrammatic representation of Embodiment 1:
  • Step 1 Synthesis of Compound 001-3:
  • compound 001-1 (5.0 g, 19.43 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (60 mL), replaced with nitrogen three times and then cooled to -78°C.
  • anhydrous tetrahydrofuran 60 mL
  • To the reaction mixture was slowly added dropwise a solution of lithium diisopropylamide (2.0 M, 10.69 mL, 1.1 eq) in tetrahydrofuran, the mixture was stirred at -78°C for 1 hour, and then the tetrahydrofuran of compound 001-2 was slowly added dropwise to the system The solution was reacted at -78°C for 30 minutes, and then the reaction system was slowly warmed to -25°C for 15 hours.
  • compound 001-3 (6.91g, 18.91mmol, 1eq) was dissolved in dioxane (80mL) and methanol (32mL), and then sodium hydroxide aqueous solution (6M, 16mL, 5.08eq) was added. Then, the temperature was raised to 100°C and the reaction was refluxed for 15 hours. After the reaction was completed, it was cooled to room temperature, the organic solvent was removed under reduced pressure, and the pH was adjusted to 3-4 with dilute hydrochloric acid (1.0M), filtered, and the filter cake was washed with water.
  • dioxane 80mL
  • methanol 32mL
  • sodium hydroxide aqueous solution 6M, 16mL, 5.08eq
  • Step 3 Synthesis of Compound 001-5:
  • compound 001-4 (6.10 g, 18.08 mmol, 1 eq) and polyphosphoric acid (40 mL, 1.0 eq) were added to a single-neck flask, and reacted at 120° C. for 1 hour. After the reaction was completed, it was cooled to room temperature, the reaction mixture was poured into ice water to quench, and the pH was adjusted to 9 with aqueous sodium hydroxide solution (6M) slowly under ice bath.
  • aqueous sodium hydroxide solution (6M) slowly under ice bath.
  • Step 5 Synthesis of Compound 001-8:
  • Step 7 Synthesis of Compound 001-11:
  • Step 8 Synthesis of Compounds 001-12:
  • reaction solution was concentrated under reduced pressure to remove ethanol, the aqueous phase was washed with dichloromethane (200 mL ⁇ 2), concentrated hydrochloric acid was added dropwise to the aqueous phase until pH ⁇ 4, diluted with ethyl acetate (200 mL), separated, and the aqueous phase was washed with ethyl acetate (200 mL). ), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 001-14.
  • Step 10 Synthesis of Compounds 001-15:
  • Step 12 Synthesis of Compounds 001-17:
  • Step 14 Synthesis of Compounds 001-19:
  • Step 15 Synthesis of Compounds 001-20:
  • Step 16 Synthesis of Compound 001-21:
  • Step 17 Synthesis of Compounds 001-22:
  • 001-21 (1.4g, 3.39mmol, 1eq) and 001-9 (1.10g, 3.39mmol, 1.0eq) were dissolved in acetonitrile (20mL), diisopropylethylamine (1.32g, 10.18mmol, 1.77mL, 3.0eq), then warmed to 75°C and stirred for 16 hours.
  • the reaction liquid was cooled to 25°C, and concentrated under reduced pressure at 43°C.
  • the concentrate was dissolved in water (30 mL) and ethyl acetate (30 mL), and the layers were extracted while the aqueous phase was extracted three times with ethyl acetate (20 mL, 20 mL, 20 mL).
  • Step 18 Synthesis of Compounds 001-24:
  • Embodiment 2 is a diagrammatic representation of Embodiment 1:
  • Step 1 Synthesis of Compound 002-2:
  • 002-2 (1.1g, 3.58mmol, 1eq) and 001-21 (1.48g, 3.58mmol, 1.0eq) were dissolved in acetonitrile (20mL), diisopropylethylamine (1.39g, 10.73mmol, 3.0eq), then warmed to 75°C and stirred for 16 hours.
  • the reaction liquid was cooled to 25°C, and concentrated under reduced pressure at 43°C.
  • the concentrate was dissolved in water (30 mL) and ethyl acetate (30 mL), and the layers were extracted while the aqueous phase was extracted three times with ethyl acetate (20 mL, 20 mL, 20 mL).
  • Embodiment 3 is a diagrammatic representation of Embodiment 3
  • Step 1 Synthesis of Compound 003-2:
  • 003-2 (520mg, 1.33mmol, 1.2eq) and 001-21 (548mg, 1.33mmol, 1.0eq) were dissolved in acetonitrile (20mL), and diisopropylethylamine (0.97g, 7.2mmol, 3.0ml) was added at one time eq), then warmed to 75°C and stirred for 16 hours.
  • the reaction liquid was cooled to 25°C, and concentrated under reduced pressure at 43°C.
  • the concentrate was dissolved in water (30 mL) and ethyl acetate (30 mL), and the layers were extracted while the aqueous phase was extracted three times with ethyl acetate (20 mL, 20 mL, 20 mL).
  • Embodiment 4 is a diagrammatic representation of Embodiment 4:
  • Step 1 Synthesis of Compound 004-3:
  • compound 004-3 (12.00 g, 30.21 mmol, 1 eq) was dissolved in a mixed solution of NN dimethylacetamide (100 mL) and water (10 mL), and dichlorobis[di-tert-butyl] was added.
  • the system was purged with nitrogen three times, The temperature was raised to 130°C for 5 hours.
  • reaction solution was cooled to room temperature, 150 ml of water was added, extracted with ethyl acetate (200 mL ⁇ 3), the organic phases were combined, concentrated under reduced pressure to a concentrated solution volume of about 150 ml, washed 4 times with water, twice with saturated brine, and anhydrous Dry over sodium sulfate and concentrate under reduced pressure to obtain crude product.
  • the crude product was isolated by column chromatography (30%-35% ethyl acetate in petroleum ether) to give 004-4, MS (ESI) m/z: 263.9 [M-56+H] + .
  • 004-4 (8.83g, 27.65mmol, 1eq) was dissolved in tetraethyl titanate (85ml), 001-6 (10.05g, 82.94mmol, 3eq) was added, the system was purged with nitrogen three times, and then heated to 130°C The reaction was carried out for 3 hours.
  • reaction solution was cooled to room temperature, the reaction solution was added to ice water, stirred for 40 minutes, the supernatant was added to a separatory funnel, and then ethyl acetate was added for extraction (200 mL ⁇ 3), and the organic phases were combined and used Washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product.
  • the crude product was isolated by column chromatography (25%-35% ethyl acetate in petroleum ether) to give compound 004-5.
  • Step 5 Synthesis of Compound 004-7:
  • 004-7 (783.67mg, 1.90mmol, 1eq) and 001-21 (740.00mg, 2.28mmol, 1.2eq) were dissolved in acetonitrile (12mL), diisopropylethylamine (736.69mg, 5.70mmol, 992.84uL, 3eq), the system was purged with nitrogen three times, then heated to 75°C and stirred for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The concentrate was dissolved in water (50 mL) and ethyl acetate (50 mL), and extracted three times with ethyl acetate (50 mL ⁇ 3).
  • Step 7 Synthesis of Compound 004-9:
  • Step 8 Synthesis of Compound 004-10:
  • Reaction buffer 60 mM hydroxyethylpiperazine ethanethiosulfonic acid (HEPES) (pH 7.4), 1 mM ethylenediaminetetraacetic acid (EDTA), 75 mM KCl, 75 mM NaCl, 0.01% Brij-35, 5 mM dithiothreitol ( DTT) and 10% DMSO (final).
  • HPES hydroxyethylpiperazine ethanethiosulfonic acid
  • EDTA ethylenediaminetetraacetic acid
  • 75 KCl 75 mM KCl
  • 75 mM NaCl 75 mM NaCl
  • Brij-35 5 mM dithiothreitol
  • DTT dithiothreitol
  • DMSO 10% DMSO
  • Enzyme PTPN11/SHP2-FL (FL denotes full-length enzyme) (produced by RBC, no CAS number);
  • the compounds of the present invention have good inhibitory activity on PTPN11/SHP2-FL.
  • the purpose of this experiment is to verify the inhibitory effect of the compounds of the present invention on the proliferation of KRAS G12C-mutated NCI-H358 human non-small cell lung cancer cells.
  • Cell line NCI-H358 (purchased from Proceedings), RPMI1640 medium, penicillin/streptomycin antibiotics were purchased from Vicente, and fetal bovine serum was purchased from Biosera.
  • CellTiter-Glo Cell Viability Chemiluminescence Detection Reagent
  • 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 cell activity screening test of the compound H358 of the present invention.
  • Trifluoroacetate salt of compound 001 46.5 Trifluoroacetate salt of compound 003 136.0 Formate salt of compound 004 16.0
  • the compounds of the present invention have good inhibitory activity on H358 cells.
  • Intravenous and oral vehicles are a certain proportion of hydroxypropyl ⁇ -cyclodextrin aqueous solution or physiological saline solution. Collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times the volume of acetonitrile solution containing the internal standard to precipitate proteins, centrifuge the supernatant, add equal volume of water, mix well, and then centrifuge to get the samples.
  • the supernatant was injected, and the plasma drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters, such as peak concentration, peak time, clearance rate, half-life, area under the drug-time curve, bioavailability, etc., were calculated.
  • the compounds of the present invention can significantly improve the pharmacokinetics single or partial indexes in mice.
  • the full-automatic patch-clamp method was used to detect the effect of Example 1 to be tested on the hERG potassium channel.
  • the cells stably expressing the hERG potassium channel used in the experiment were obtained from CHO-hERE of Aviva Biosciences, and CHO-hERG was cultured in 5% CO 2 at 37°C.
  • CHO hERG medium is shown in Table 4.
  • CHO-hERG cells ready to be used in the experiment should be cultured for at least two days, and the cell density should reach more than 75%. Before the experiment, cells were digested with TrypLE and then resuspended in extracellular fluid to collect cells.
  • Extracellular fluid needs to be prepared once a month.
  • the intracellular fluid must be aliquoted and stored at -20°C.
  • the composition of intracellular and extracellular fluids is shown in Table 5.
  • Extracellular fluid Extracellular fluid (mM) Intracellular fluid (mM) NaCl 145 - KCl 4 120 KOH - 31.25 CaCl 2 2 5.374 MgCl 2 1 1.75 Glucose 10 - Na 2 ATP - 4 HEPES 10 10 EGTA - 10 pH 7.4with NaOH 7.2with KOH Osmotic pressure 295mOsm 285mOsm
  • the compound to be tested and the positive control Amitriptyline were dissolved in DMSO into a stock solution of a certain concentration, then diluted according to different gradients, and finally added to the extracellular fluid according to a certain proportion to be diluted to the concentration to be tested. Visually inspect for the presence or absence of precipitation prior to the start of the experiment. Finally, in the test solution and the positive control Amitriptyline, the maximum concentration of DMSO should not exceed 0.3%.
  • Hold the clamping potential at -80mv first give -50mv voltage stimulation for 80ms to record the cell leakage current value, then depolarize to +20mv, maintain 4800ms, open the hERG channel, and then repolarize to -50mv for 5000ms , elicited the hERG tail current and recorded, and finally, the voltage returned to the clamping potential -80mv and maintained for 3100ms.
  • the above voltage stimulation was repeated every 15000ms.
  • hERG QPatch HTX experiments were performed at room temperature. Whole cell protocols, voltage stimulation protocols and compound detection protocols were established on the software of QPatch Assay Software 5.2 (Sophion Bioscience).
  • I (C) I b +(I fr -I b )*c n /(IC 50 n +c n )
  • C is the compound test concentration
  • n is the slope
  • Curve fitting and inhibition rate calculation are both completed by Qpatch analysis software. If the inhibition rate at the lowest concentration exceeds half inhibition or the inhibition rate at the highest concentration does not reach half inhibition, the corresponding IC 50 of the compound is lower than the lowest concentration or IC 50 value. greater than the highest concentration.
  • Table 6 shows the hERG IC 50 values of the compounds of the examples.
  • Test sample hERG IC50 (nM) Trifluoroacetate salt of compound 001 18.3 Trifluoroacetate salt of compound 003 6.4 Formate salt of compound 004 9.8
  • Human and animal microsomes were purchased from Corning or Xenotech and stored in a -80°C freezer.
  • Control compounds testosterone, diclofenac, propafenone
  • T60 incubation plate Prepare two 96-well incubation plates, named T60 incubation plate and NCF60 incubation plate respectively.
  • stop solution 200ng/mL tolbutamide and 200ng/mL labetalol in acetonitrile
  • the compounds of the present invention have better stability of liver microsomes.

Abstract

公开了式(I)所示的吡唑并吡嗪联三环类化合物或其药学上可接受的盐，所述化合物对蛋白酪氨酸磷酸酶SHP2具有抑制活性，可用于治疗与SHP2相关的疾病，例如肺癌。

Description

吡唑并吡嗪联三环类化合物及其应用
本申请主张如下优先权：
CN202110091198.9，申请日：2021年01月22日；
CN202110264689.9，申请日：2021年03月11日；
CN202110414584.7，申请日：2021年04月16日。
技术领域
本发明涉及一类吡唑并吡嗪联三环类化合物及其应用，具体涉及式(Ⅰ)所示化合物或其药学上可接受的盐。
背景技术
酪氨酸激酶的磷酸化作用与酪氨酸磷酸酶的去磷酸化作用足生物体内普遍存在的信号转导机制，它们共同调节细胞内蛋白质的酪氨酸磷酸化水平。SHP2(SH2domain-containing protein-tyrosine phosphatase-2)就是起去磷酸化作用的一种非跨膜型蛋白酪氨酸磷酸酶，是蛋白酪氨酸磷酸酶(PTP)家族的重要成员之一，其分子由PTPN11基因编码，既可以通过磷酸酶的催化活性来正向调控下游信号转导通路，也可以作为磷酸酶非依赖性的接头蛋白发挥正向调控作用，在特定的条件下亦可发挥负向调控作用，从而广泛参与细胞的分化、迁移等生物学功能的调控及相关的信号转导过程。PTPN11突变被认为是青少年粒单细胞白血病(JMML)的高危因素，同时，因其在不同类型白血病中均存在着SHP2的异常活化和突变而被认为是白血病的原癌基因；在***癌、乳腺癌、胰腺癌、胃癌和神经胶质瘤中，SHP2也被报道呈过度活化状态；在肺癌中SHP2作为癌基因通过调控多种机制促进肿瘤的发生、发展。但在肝癌发生过程中，SHP2却在特定环境的影响下发挥抑癌基因的作用。总之，作为重要的节点分子，SHP2在肿瘤发生、发展的过程中发挥着重要的调控作用，是潜在的治疗靶点。
发明内容
本发明提供了式(Ⅰ)化合物或其药学上可接受的盐，
Figure PCTCN2022073167-appb-000001
其中，
T 1为CR 4或N；
当E 1为O时，R 3为H、F、Cl、Br、I或C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
当E 1为CH 2时，R 3为H、Cl、Br、I或C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
R 1、R 2和R 4分别独立地为H、F、Cl、Br、I或C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
R 5为被OH取代的C 1-3烷基；
R 6分别独立地为H、F、Cl、Br、I、OH、NH 2或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 a、R b和R c分别独立地为F、Cl、Br、I、OH或NH 2；
m为1、2、3或4。
本发明的一些方案中，当上述E 1为O时，上述R 3为H或F，其他变量如本发明所定义。
本发明的1一些方案中，当上述E 1为CH 2时，上述R 3为H，其他变量如本发明所定义。
本发明的一些方案中，上述R 1、R 2和R 4分别独立地为H、F、Cl、Br或I，其他变量如本发明所定义。
本发明的一些方案中，上述R 5为-CH 2-OH，其他变量如本发明所定义。
本发明的一些方案中，上述R 6分别独立地为Cl或NH 2，其他变量如本发明所定义。
本发明的一些方案中，上述结构单元
Figure PCTCN2022073167-appb-000002
为
Figure PCTCN2022073167-appb-000003
Figure PCTCN2022073167-appb-000004
本发明的一些方案中，上述化合物为
Figure PCTCN2022073167-appb-000005
其中，
T 1、E 1、R 1、R 2、R 3、R 5、R 6和m如本发明所定义。
本发明的一些方案中，上述化合物为
Figure PCTCN2022073167-appb-000006
其中，
T 1、E 1、R 1、R 2和R如本发明所定义。
本发明还提供了下列化合物或其药学上可接受的盐，
Figure PCTCN2022073167-appb-000007
本发明的一些方案中，上述化合物或其药学上可接受的盐，其中化合物选自，
Figure PCTCN2022073167-appb-000008
本发明第二方面还提供一种药物组合物，其包含上述任意技术方案所限定的化合物或其药学上可 接受的盐和药学上可接受的载体。
本发明还提供一种在需要的受试者中治疗与SHP2相关的疾病的方法，包括向受试者提供有效剂量的上述任意技术方案所限定的化合物或其药学上可接受的盐或药物组合物。
本发明还提供了上述化合物或其药学上可接受的盐在制备治疗与SHP2相关疾病的药物中的应用；其中所述与SHP2相关疾病是指肺癌，优选非小细胞肺癌。
技术效果
本发明化合物对蛋白酪氨酸磷酸酶SHP2展现出较好的抑制活性，将会在SHP2异常肿瘤患者中具有优异的治疗效果。
定义与说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式 和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2022073167-appb-000009
和楔形虚线键
Figure PCTCN2022073167-appb-000010
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022073167-appb-000011
和直形虚线键
Figure PCTCN2022073167-appb-000012
表示立体中心的相对构型，用波浪线
Figure PCTCN2022073167-appb-000013
表示楔形实线键
Figure PCTCN2022073167-appb-000014
或楔形虚线键
Figure PCTCN2022073167-appb-000015
或用波浪线
Figure PCTCN2022073167-appb-000016
表示直形实线键
Figure PCTCN2022073167-appb-000017
和直形虚线键
Figure PCTCN2022073167-appb-000018
除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来 制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
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。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022073167-appb-000019
直形虚线键
Figure PCTCN2022073167-appb-000020
或波浪线
Figure PCTCN2022073167-appb-000021
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 PCTCN2022073167-appb-000022
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 PCTCN2022073167-appb-000023
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。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1-3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS),2-(三甲基硅)乙氧基甲基(SEM)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022073167-appb-000024
扫描， 收集相关数据后，进一步采用直接法(Shelxs97)解析晶体结构，便可以确证绝对构型。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；DMF代表N，N-二甲基甲酰胺；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；r.t.代表室温；THF代表四氢呋喃；Boc 2O代表二-叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；mp代表熔点；LDA代表二异丙基胺基锂；EDTA代表乙二胺四乙酸；SEM代表2-三甲基硅基乙氧基甲基；PMB代表对甲氧基苄基；TBDPS代表叔丁基二苯基硅基；TBS代表叔丁基二甲基硅基；OTf代表三氟甲磺酰基。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2022073167-appb-000025
软件命名，市售化合物采用供应商目录名称。
具体实施方式
下面经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。
实施例1:
Figure PCTCN2022073167-appb-000026
Figure PCTCN2022073167-appb-000027
Figure PCTCN2022073167-appb-000028
步骤1：化合物001-3的合成：
在氮气的保护下，将化合物001-1(5.0g,19.43mmol,1eq)溶解于无水四氢呋喃中(60mL)中，氮气置换三次后降温至-78℃。向反应混合物中缓慢滴加二异丙基氨基锂(2.0M,10.69mL,1.1eq)的四氢呋喃溶液后混合物在-78℃下搅拌1小时，之后往体系中缓慢滴加化合物001-2的四氢呋喃溶液并在-78℃下反应30分钟，然后将反应体系缓慢升温至-25℃反应15小时。反应结束后用饱和氯化铵溶液(100mL)淬灭，乙酸乙酯萃取三次(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，旋蒸除去溶剂。柱层析：粗品经柱层析(石油醚：乙酸乙酯＝0-10％)分离得到化合物001-3。MS(ESI)m/z:388.2[M+Na] +。
步骤2：化合物001-4的合成：
在氮气的保护下，将化合物001-3(6.91g,18.91mmol,1eq)溶于二氧六环(80mL)和甲醇(32mL)中，再加入氢氧化钠水溶液(6M,16mL,5.08eq)后，升温至100℃回流反应15小时。反应结束后冷却至室温，减压除去有机溶剂后用稀盐酸(1.0M)调节pH为3-4，过滤，滤饼用水洗涤，洗涤后的滤饼重新溶解于乙酸乙酯中，无水硫酸钠干燥后旋干得化合物001-4，MS(ESI)m/z:360.1[M+Na] +。
步骤3：化合物001-5的合成：
在氮气的保护下，将化合物001-4(6.10g,18.08mmol,1eq)和多聚磷酸(40mL，1.0eq)加入单口瓶中，120℃下反应1小时。反应结束后冷却至室温，将反应混合物倒入冰水中淬灭，冰浴下缓慢用氢氧化钠水溶液(6M)调节pH至9。乙酸乙酯萃取三次(50mL×3)，合并有机相，无水硫酸钠干燥， 过滤，旋蒸除去溶剂后将粗品溶于二氯甲烷(100mL)中。加入二碳酸二叔丁酯(6.12g,28.05mmol,6.44mL,3.0eq)和三乙胺(5.68g,56.10mmol,7.81mL,6.0eq)后反应混合物在25℃下反应2小时。反应结束后加水，分液，水相用乙酸乙酯萃取(50mL×3)，合并有机相，无水硫酸钠干燥，过滤，旋蒸除去溶剂得化合物001-5。MS(ESI)m/z:342.1[M+Na] +。
步骤4：化合物001-7的合成：
在氮气的保护下，将化合物001-5(2g,6.26mmol,1.0eq)和化合物001-6(2.28g,18.79mol,3.0eq)加入单口瓶中，随后加入钛酸四乙酯(5mL)，100℃回流反应18小时。反应结束后冷却至室温，将混合物倒入冰水中淬灭，加入乙酸乙酯(50mL)后搅拌1小时，分液，水相用乙酸乙酯萃取(50mL×3)。合并有机相，无水硫酸钠干燥，过滤，旋蒸除去溶剂。柱层析：粗品经柱层析(石油醚：乙酸乙酯＝0-20％)分离，得到化合物001-7。MS(ESI)m/z:445.1[M+Na] +。
步骤5：化合物001-8的合成：
在氮气的保护下，将化合物001-7(2.54g,6.01mmol,1eq)溶于四氢呋喃(25mL)中，降温至-20℃后加入硼氢化钠(455mg,12.02mmol,2.0eq)。反应体系逐渐恢复至25℃反应12小时。反应结束后，冰浴下加水淬灭反应，乙酸乙酯萃取(50mL×3)后合并有机相，无水硫酸钠干燥，过滤，旋蒸除去溶剂得到化合物001-8。MS(ESI)m/z:447.1[M+Na] +。
步骤6：化合物001-9的合成：
将化合物001-8(34mg,80μmol,1eq)溶于二氯甲烷(5mL)中，加入三氟乙酸(91.2mg,800μmol,59.23μL,10eq)。反应混合物在25℃下反应2小时后加入碳酸钾中和反应体系至中性，旋干溶剂得化合物001-9。MS(ESI)m/z:325.1[M+H] +。
步骤7：化合物001-11的合成：
化合物001-10(5g,44.22mmol,1eq)溶于N,N-二甲基甲酰胺(40mL)，加入4-甲氧基苄氯(6.93g,44.22mmol,6.02mL,1eq)和碳酸钾(6.11g,44.22mmol,1eq)，80℃反应3小时。将反应液逐滴滴入水(200mL)中，乙酸乙酯(300mL)稀释，分液，水相用乙酸乙酯洗(200mL)，合并有机相，饱和氯化钠洗(200mL×4)，有机相无水硫酸钠干燥，过滤，滤液减压浓缩得化合物001-11。 1H NMR(400MHz,CDCl 3)δppm 3.75(s,3H)5.12-5.20(m,2H)6.82-6.89(m,2H)7.16-7.19(m,2H)7.92(s,1H)7.99-8.08(m,1H)。
步骤8：化合物001-12的合成：
化合物001-11(5.2g,22.30mmol,1eq)溶于四氢呋喃(150mL)，-60℃下滴入双(三甲硅基)氨基锂(1M,26.76mL,1.2eq)，反应1小时，-60℃下滴入溶于30mL四氢呋喃的六氯乙烷(6.33g,26.76mmol,3.03mL,1.2eq)，-60℃反应1小时。加入饱和氯化铵溶液(100mL)，逐渐升至20℃，乙酸乙酯稀释(300mL)，分液，水相乙酸乙酯洗(200mL)，合并有机相，饱和氯化钠溶液洗(100mL)，无水硫酸 钠干燥，过滤，滤液减压浓缩，得到的粗品经硅胶柱层析(石油醚/乙酸乙酯＝100:1-10：1)纯化得化合物001-12。 1H NMR(400MHz,CDCl 3)δppm 8.08-8.47(m,1H)7.12-7.42(m,2H)6.77-7.01(m,2H)5.33(s,2H)3.82(s,3H).
步骤9：化合物001-14的合成：
化合物001-12(5g,18.68mmol,1eq)、化合物001-13(9.50g,56.04mmol,3eq)溶于乙醇(75mL)和水(75mL)，加入碳酸氢钠(12.55g,149.44mmol,5.81mL,8eq)，90℃反应60小时。反应液减压浓缩除去乙醇，水相二氯甲烷洗(200mL×2)，水相滴加浓盐酸至pH<4，乙酸乙酯稀释(200mL)，分液，水相乙酸乙酯洗(200mL)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩得化合物001-14。 1H NMR(400MHz,DMSO-d 6)δppm 8.07-8.20(m,1H)7.31(d,J＝9.79Hz,1H)7.11(d,J＝8.53Hz,2H)6.91-6.94(m,1H)5.22-5.36(m,2H)4.45(dt,J＝9.79,3.39Hz,1H)3.82(br dd,J＝11.04,3.51Hz,2H)3.73(s,3H)3.65(br d,J＝3.26Hz,1H)3.18(s,1H)。
步骤10：化合物001-15的合成：
化合物001-14(4g,11.89mmol,1eq)溶于甲醇(100mL)，加入Pd/C(0.4g,10％)，置换氢气(400mg,11.89mmol,10％纯度,1eq)，50Psi 30℃下反应88小时。抽滤(硅藻土助滤)，滤液减压除去溶剂，得化合物001-15，粗产物直接进行下一步反应。MS(ESI)m/z:307.1[M+H] +。
步骤11：化合物001-16的合成：
化合物001-15(3.6g,11.75mmol,1eq)溶于甲醇(100mL)，加入盐酸甲醇溶液(4M,293.81μL,0.1eq)，50℃反应16小时。减压浓缩得化合物001-16。MS(ESI)m/z:289.1[M+H] +。
步骤12：化合物001-17的合成：
化合物001-16(3g,10.41mmol,1eq)溶于DMF(10mL)，加入咪唑(2.13g,31.22mmol,3eq)，0℃下加入叔丁基二苯基氯硅烷(8.58g,31.22mmol,8.02mL,3eq)，逐渐升至20℃反应1小时。将饱和氯化钠溶液(50mL)逐滴滴入反应体系，乙酸乙酯稀释(100mL)，分液，水相乙酸乙酯洗(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩，得到的粗品经硅胶柱层析(PE/EA＝10:1-0:1)纯化得化合物001-17。MS(ESI)m/z:527.2[M+H] +。
步骤13：化合物001-18的合成：
化合物001-17(4.2g,7.97mmol,1eq)溶于二氧六环(50mL)，加入二氧化锰(3.47g,39.87mmol,5eq)，20℃反应1小时。抽滤(硅藻土助滤)，滤液减压浓缩得化合物001-18。MS(ESI)m/z:525.2[M+H] +。
步骤14：化合物001-19的合成：
化合物001-18(30mg,57.18μmol,1eq)溶于N,N-二甲基甲酰胺(1mL)，加入三乙胺(23.14mg,228.72μmol,31.83μL,4eq)，0℃下加入N-苯基双(三氟甲烷磺酰)亚胺(40.86mg,114.36μmol,2eq)，逐 渐升至20℃反应20分钟。饱和氯化钠溶液(10mL)和乙酸乙酯稀释(20mL)，分液，有机相无水硫酸钠干燥，过滤，滤液减压浓缩，粗品经薄层层析板分离(PE/EA＝10：1)，得化合物001-19。MS(ESI)m/z:657.3[M+H] +
步骤15：化合物001-20的合成：
将001-19(5g,9.39mmol,1eq)溶解到二氯乙烷(20mL)中，25℃下一次加入三氯化铝(10.0g,75.1mmol,8eq)，混合物在40℃搅拌1小时。将反应液溶解在水(10mL)和二氯甲烷(10mL)中，萃取分层，同时水相用二氯甲烷(100mL，100mL，100mL)萃取三次。合并有机相，用饱和氯化钠溶液(100mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩。柱层析：粗品经硅胶柱层析(0％-10％甲醇在二氯甲烷中)(TLC检测PE：EA＝2:1-1:1)分离，得到化合物001-20。MS(ESI)m/z:299.0[M+H] +。
步骤16：化合物001-21的合成：
将001-20(2.2g,7.38mmol,1eq)溶于DMF(10mL)，加入2,6-二甲基吡啶(3.95g,36.89mmol,5.0eq)，0℃下加入叔丁基二甲硅基三氟甲磺酸酯(4.29g,16.23mmol,3.73mL,2.2eq)，逐渐升至20℃反应1小时。将饱和氯化钠溶液(50mL)逐滴滴入反应体系，乙酸乙酯稀释(100mL)，分液，水相乙酸乙酯洗(100mL×3)，合并有机相，无水硫酸钠干燥，过滤，滤液减压旋去溶剂。粗品经硅胶柱层析(PE/EA＝5:1-2:1)，得化合物001-21。MS(ESI)m/z:413.0[M+H] +。
步骤17：化合物001-22的合成：
将001-21(1.4g,3.39mmol,1eq)和001-9(1.10g,3.39mmol,1.0eq)溶解到乙腈(20mL)中，一次加入二异丙基乙胺(1.32g,10.18mmol,1.77mL,3.0eq)，然后升温至75℃搅拌16小时。将反应液冷却到25℃，并且在43℃减压浓缩。将浓缩物溶解在水(30mL)和乙酸乙酯中(30mL)，萃取分层，同时水相用乙酸乙酯(20mL，20mL，20mL)萃取三次。合并有机相，用饱和氯化钠溶液(20mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩。柱层析：粗品经柱层析(10％-70％乙酸乙酯在石油醚中)(TLC检测石油醚：乙酸乙酯＝1:1)分离，得到化合物001-22。MS(ESI)m/z:587.2[M+H] +。
步骤18：化合物001-24的合成：
将001-22(500mg,852.0μmol,1eq)，001-23(150mg,852.0μmol,1.0eq)溶解于二甲基亚砜(5mL)，一次性加入碳酸钾(141mg,846.42μmol,1.2eq),混合物在25℃搅拌3小时。将反应液溶解在20mL水和20mL乙酸乙酯中，萃取分层，同时水相用乙酸乙酯(10mL，10mL，10mL)萃取三次。合并有机相，用饱和氯化钠溶液(15mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩。得到化合物001-24的粗品，无需进一步纯化，直接用于下一步反应。MS(ESI)m/z:743.2，744.2[M+H] +。
步骤19：化合物001-25的合成：
将001-24(240mg,381.49μμmol,1eq)溶解于乙酸乙酯(8mL)，再加入饱和氯化铵水溶液(8mL)，一次性加入铁粉(170.44mg,3.05mmol,8eq)，然后升温至50℃搅拌3小时。将反应液冷却到25℃，用硅藻土助滤，并减压浓缩滤液。将反应液直接旋干得到粗品。得到化合物001-25的粗品，无需进一步纯化，直接用于下一步反应。MS(ESI)m/z:713.2，714.2[M+H] +。
步骤20：化合物001的合成：
将001-25(200mg,280.3μmol,1.0eq)溶解到盐酸/甲醇(4M,3.13mL,25eq)，混合物在25℃搅拌1小时。将反应液直接旋干得到粗品。将得到的粗品，用水(5mL)溶解，滤出不溶物，用制备高效液相色谱(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；乙腈％:17％-47％,8min)分离纯化。得到化合物001的三氟乙酸盐。MS(ESI)m/z:495.1[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 8.41(s,1H),8.08(d,J＝6.02Hz,1H),7.48-7.36(m,2H),7.20-7.18(m,1H),7.08(m,1H),4.87(s,2H),4.55(s,1H),3.66–3.63(m,1H),3.57–3.54(m,1H),3.27-3.14(m,4H),2.10-2.08(m,1H),2.05–1.99(m,1H),1.99–1.84(m,1H),1.75–1.72(m,1H)。
实施例2:
Figure PCTCN2022073167-appb-000029
步骤1：化合物002-2的合成：
将化合物002-1(1.5g,3.68mmol,1eq)溶于二氯甲烷(10mL)中，加入三氟乙酸(5mL)。反应 混合物在25℃下反应2小时后加入碳酸钾中和反应体系至中性，旋干溶剂得化合物002-2。MS(ESI)m/z:308.1[M+H] +。
步骤2：化合物002-3的合成：
将002-2(1.1g,3.58mmol,1eq)和001-21(1.48g,3.58mmol,1.0eq)溶解到乙腈(20mL)中，一次加入二异丙基乙胺(1.39g,10.73mmol,3.0eq)，然后升温至75℃搅拌16小时。将反应液冷却到25℃，并且在43℃减压浓缩。将浓缩物溶解在水(30mL)和乙酸乙酯(30mL)中，萃取分层，同时水相用乙酸乙酯(20mL，20mL，20mL)萃取三次。合并有机相，用饱和氯化钠溶液(20mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩，得到化合物002-3。MS(ESI)m/z:570.2，571.2[M+H] +。
步骤3：化合物002-4的合成：
将002-3(700mg,1.23mmol,1eq)，001-23(217mg,1.23mmol,1.0eq)溶解于二甲基亚砜(5mL)，一次性加入碳酸钾(339mg,2.46μmol,2eq),混合物在25℃搅拌3小时。将反应液溶解在水(20mL)和乙酸乙酯(20mL)中，萃取分层，同时水相用乙酸乙酯(10mL，10mL，10mL)萃取三次。合并有机相，用饱和氯化钠溶液(15mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩。得到的粗品，无需进一步纯化，直接用于下一步反应。化合物002-4。MS(ESI)m/z:726.2，727.2[M+H] +。
步骤4：化合物002-5的合成：
将002-4(500mg,688μmol,1eq)溶解于乙酸乙酯(8mL)，再加入饱和氯化铵水溶液(8mL)，一次性加入铁粉(114.4mg,2.04mmol,3eq)，然后升温至50℃搅拌3小时。将反应液冷却到25℃，用硅藻土助滤，并减压浓缩滤液。将反应液直接旋干得到粗品。得到的粗品，无需进一步纯化，直接用于下一步反应。化合物002-5。MS(ESI)m/z:696.2，697.2[M+H] +。
步骤5：化合物002的合成：
将002-5(350mg,502.6μmol,1.0eq)溶解到盐酸/甲醇(4M,3.13mL,25eq)，混合物在25℃搅拌1小时。将反应液直接旋干得到粗品。粗产品通过制备高效液相色谱分离(色谱柱:Welch Xtimate C18 100*40mm*3μm；流动相:[水(0.075％三氟乙酸)-乙腈]；乙腈％:2％-32％,8min)分离纯化。得到化合物002的三氟乙酸盐。MS(ESI)m/z:478.2，479.0[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 8.62(d,J＝4.4Hz,1H),8.46(s,1H),8.11–8.06(m,2H),7.52-7.49(m,1H),7.28(d,J＝6.4Hz,1H),4.89–4.85(s,2H),4.65(s,1H),3.73–3.65(m,1H),3.63–3.55(m,1H),3.31-3.20(m,4H),2.20-2.00(m,2H),1.90–1.84(m,1H),1.75–1.72(m,1H)。
实施例3:
Figure PCTCN2022073167-appb-000030
步骤1：化合物003-2的合成：
将化合物003-1(1.1g,2.45mmol,1eq)溶于二氯甲烷(10mL)中，加入三氟乙酸(5mL)。反应混合物在25℃下反应2小时后加入碳酸钾中和反应体系至中性，旋干溶剂得化合物003-2。MS(ESI)m/z:327.1[M+H] +。
步骤2：化合物003-3的合成：
将003-2(520mg,1.33mmol,1.2eq)和001-21(548mg,1.33mmol,1.0eq)溶解到乙腈(20mL)中，一次加入二异丙基乙胺(0.97g,7.2mmol,3.0eq)，然后升温至75℃搅拌16小时。将反应液冷却到25℃，并且在43℃减压浓缩。将浓缩物溶解在水(30mL)和乙酸乙酯(30mL)中，萃取分层，同时水相用乙酸乙酯(20mL，20mL，20mL)萃取三次。合并有机相，用饱和氯化钠溶液(20mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩，得到化合物003-3。MS(ESI)m/z:589.2[M+H] +。
步骤3：化合物003-4的合成：
将003-3(300mg,645.3μmol,1eq)，001-23(217mg,1.23μmol,1.0eq)溶解于二甲基亚砜(5mL)，一次性加入碳酸钾(133.8mg,968.1μmol,2eq),混合物在25℃搅拌3小时。将反应液溶解在水(20mL)和乙酸乙酯(20mL)中，萃取分层，同时水相用乙酸乙酯(10mL，10mL，10mL)萃取三次。合并有机相，用饱和氯化钠溶液(15mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩，得 到的粗品，无需进一步纯化，直接用于下一步反应。化合物003-4。MS(ESI)m/z:745.2[M+H] +。
步骤4：化合物003-5的合成：
将003-4(470mg,630.6μmol,1eq)溶解于乙酸乙酯(8mL)，再加入饱和氯化铵水溶液(8mL)，一次性加入铁粉(281.7mg,5.04mmol,8eq)，然后升温至50℃搅拌3小时。将反应液冷却到25℃，用硅藻土助滤，并减压浓缩滤液。将反应液直接旋干得到粗品。得到的粗品，无需进一步纯化，直接用于下一步反应。化合物003-5。MS(ESI)m/z:715.2[M+H] +。
步骤5：化合物003的合成：
将003-5(448mg,626.26μmol,1.0eq)溶解到盐酸/甲醇(4M,1.0mL,25eq)，混合物在25℃搅拌1小时。将反应液直接旋干得到粗品。粗产品通过制备高效液相色谱分离(色谱柱:Welch Xtimate C18 100*40mm*3um；流动相:[水(0.075％三氟乙酸)-乙腈]；乙腈％:16％-46％,8min)分离纯化。得到化合物003的三氟乙酸盐。MS(ESI)m/z:497.0[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 8.43(s,1H),8.08(d,J＝6.02Hz,1H),7.56(dd,J＝8.16,5.65Hz,1H),7.12(d,J＝5.77Hz,1H),6.83(m,2H),4.87(s,2H),3.80–3.75(m,1H),3.64-3.36(m,3H),2.42-2.32(m,1H),2.18–1.97(m,4H)。
实施例4:
Figure PCTCN2022073167-appb-000031
Figure PCTCN2022073167-appb-000032
步骤1：化合物004-3的合成：
将化合物004-1(7.13g,33.93mmol,1eq)溶于四氢呋喃(160mL)中，待温度降低至-78℃下加入双异丙基氨基锂的四氢呋喃溶液(2M,22.06mL,1.3eq)，反应体系在-78℃下反应1小时，加入004-2(10g,37.32mmol,1.1eq)，体系在-78℃下再反应1小时，而后在搅拌下缓慢升温至25℃。反应结束后用饱和氯化铵溶液(25mL)淬灭，乙酸乙酯萃取三次(150mL×3)，合并有机相，无水硫酸钠干燥，过滤，旋蒸除去溶剂。柱层析：粗品经柱层析(石油醚：乙酸乙酯＝0-10％)分离得到化合物004-3。MS(ESI)m/z:296.8&298.8[M-100+H] +。
步骤2：化合物004-4的合成：
在氮气的保护下，将化合物004-3(12.00g,30.21mmol,1eq)溶于N-N二甲基乙酰铵(100mL)和水(10mL)的混合溶液中，加入二氯双[二叔丁基-(4-二甲基氨基苯基)膦]钯(2.14g,3.02mmol,2.14mL,0.1eq)和三乙胺(12.23g,120.82mmol,16.82mL,4eq)，体系抽换氮气三次，升温至130℃反应5小时。将反应液冷却至室温，加入水150ml，用乙酸乙酯萃取(200mL×3)，合并有机相，减压浓缩至浓缩液体积为150ml左右，水洗4次，饱和食盐水洗涤2次，无水硫酸钠干燥，减压浓缩得粗产物。粗品经柱层析(30％～35％乙酸乙酯在石油醚中)分离得到004-4，MS(ESI)m/z:263.9[M-56+H] +。
步骤3：化合物004-5的合成：
将004-4(8.83g,27.65mmol,1eq)溶于钛酸四乙酯(85ml)中，加入001-6(10.05g,82.94mmol,3eq)，体系抽换氮气三次，而后升温至130℃反应3小时。反应结束后，将反应液冷却至室温，将反应液 加入至冰水中，搅拌40分钟，将上清液加入分液漏斗中，再加入乙酸乙酯萃取(200mL×3)，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，减压浓缩得粗产物。粗产物经柱层析(25％～35％乙酸乙酯在石油醚中)分离得到化合物004-5。MS(ESI)m/z:322.9[M-100+H] +。
步骤4：化合物004-6的合成：
将004-5(7.34g,17.37mmol,1eq)溶于四氢呋喃中(70mL)，降温至0℃搅拌下加入硼氢化钠(1.31g,34.74mmol,2eq)，反应体系逐渐恢复至25℃下反应16小时。向反应液中加入水淬灭(150ml)未反应完的硼氢化钠，乙酸乙酯萃取(200mL×3)，合并有机相用无水硫酸钠干燥，减压浓缩的粗产物。粗产物经SFC纯化得到化合物004-6。MS(ESI)m/z:325.0[M-100+H] +
步骤5：化合物004-7的合成：
将004-6(1.10g,2.59mmol,1eq)溶于二氯甲烷(10mL)中，加入三氟乙酸(3.84g,33.68mmol,2.49mL,13eq)，混合液在25℃下反应50分钟。反应结束后，减压浓缩除掉部分三氟乙酸，再向浓缩液中加入水(30ml)，加入碳酸钾(3g)除掉多余三氟乙酸，乙酸乙酯萃取(50mL×3)，有机相合并后用无水硫酸钠干燥，过滤，旋蒸除去溶剂得到化合物004-7。MS(ESI)m/z:325.1[M+H] +。
步骤6：化合物004-8的合成：
将004-7(783.67mg,1.90mmol,1eq)和001-21(740.00mg,2.28mmol,1.2eq)溶解到乙腈(12mL)中，一次加入二异丙基乙胺(736.69mg,5.70mmol,992.84uL,3eq)，体系抽换氮气三次，然后升温至75℃搅拌16小时。将反应液冷却到室温，减压浓缩。将浓缩物溶解在水(50mL)和乙酸乙酯(50mL)中，乙酸乙酯(50mL×3)萃取三次。合并有机相，用饱和氯化钠溶液(50mL)洗涤一次，最后用无水硫酸钠干燥有机相，过滤并减压浓缩，得到化合物004-8粗品。MS(ESI)m/z:587.3[M+H] +。
步骤7：化合物004-9的合成：
将004-8(970mg,1.65mmol,1eq)和001-23(291.80mg,1.65mmol,1eq)溶于二甲亚砜(2ml)，加入碳酸钾(456.89mg,3.31mmol,2eq)，混合物在25℃下反应1.5小时。反应结束后，向反应液中加入水50ml，乙酸乙酯(50mL×3)萃取三次，合并有机相，有机相用饱和食盐水洗涤3次，无水硫酸钠干燥，减压浓缩得粗产物004-9，MS(ESI)m/z:743.2[M+H] +。
步骤8：化合物004-10的合成：
将004-9(1.20g,1.62mmol,1eq)溶解于乙酸乙酯(8mL)，再加入饱和氯化铵水溶液(8mL)，一次性加入铁粉(723.12mg,12.95mmol,8eq)，然后升温至50℃搅拌3小时。将反应液冷却到25℃，用硅藻土助滤，并减压浓缩滤液。将反应液直接旋干得到粗品。得到的粗品，无需进一步纯化，直接用于下一步反应。化合物004-10。MS(ESI)m/z:713.2[M+H] +。
步骤9：化合物004的合成：
将004-10(1.06g,1.48mmol,1eq)溶解到盐酸/甲醇(4M,1.0mL,25eq)，混合物在25℃搅拌1小时。将反应液直接旋干得到粗品。
粗产品通过制备高效液相色谱分离(色谱柱:Phenomenex Genimi NX C18 150*40mm*5μm；流动相:[水(0.225％三氟乙酸)-乙腈]；乙腈％:1％-30％,10min)分离纯化。得到化合物004的三氟乙酸盐。MS(ESI)m/z:495.1[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 8.41(s,1H),8.08(d,J＝6.02Hz,1H),7.48-7.36(m,2H),7.20-7.18(m,1H),7.08(m,1H),4.87(s,2H),4.55(s,1H),3.66–3.63(m,1H),3.57–3.54(m,1H),3.27-3.14(m,4H),2.10-2.08(m,1H),2.05–1.99(m,1H),1.99–1.84(m,1H),1.75–1.72(m,1H)。
粗产品通过制备高效液相色谱分离(色谱柱:Welch Xtimate C18 150*25mm*5μm；流动相:[水(0.225％甲酸)-乙腈]；乙腈％:1％-30％,10min)分离纯化。得到化合物004的甲酸盐。MS(ESI)m/z:495.1[M+H] +。 1H NMR(400MHz,CD 3OD)δppm 8.41(s,1H),8.08(d,J＝6.02Hz,1H),7.40-7.30(m,1H),7.27-7.18(m,1H),7.08(m,1H),6.94(d,J＝6.02Hz,1H),4.87(s,2H),4.31(s,1H),3.62-3.45(m,2H),3.27-3.14(m,3H),3.05-2.92(m,1H),2.15-1.99(m,2H),1.81-1.65(m,2H)。
生物测试
实验例1：体外评价
反应缓冲液：60mM羟乙基哌嗪乙硫磺酸(HEPES)(pH 7.4)，1mM乙二胺四乙酸(EDTA)，75mM KCl，75mM NaCl，0.01％Brij-35,5mM二硫苏糖醇(DTT)和10％DMSO(最终)。
酶：PTPN11/SHP2-FL(FL表示全长的酶)(RBC生产，没有CAS号)；
重组人PTPN11全长(Genbank登录号#NM_002834；aa 2-597)；
同种型1(规范))在大肠杆菌中表达，具有N-端StrepII-TEV，C-端组氨酸的标签。Mw＝71.93kDa。
活化肽：H 2N-LN(pY)IDLDLV(dPEG8)LST(pY)ASINFQK-amide(基于出版物)
底物：DiFMUP[6,8-二氟-7-羟基-4-甲基香豆素]
测定中的最终浓度：0.35μM活化肽；100μM DiFMUP
步骤：
1.在新制备的反应缓冲液中制备指定的酶/肽和底物
2.将酶/肽溶液加入到反应孔中
3.通过声学技术将化合物在100％DMSO中提供到酶溶液中(Echo550；纳升范围)，在室温下孵育30分钟
4.将底物溶液加入到反应孔中以引发反应
5.监测酶活性(Ex/Em 355/460)，作为室温下荧光底物荧光信号增加60分钟的时程测量。
数据分析：取时间过程测量的线性部分的斜率×(信号/分钟)，并计算相对于DMSO对照的％酶活性。减去酶基础活性(无肽)的背景斜率。本发明化合物体外筛选试验结果如表1：
表1.本发明化合物体外筛选试验结果
化合物 PTPN11/SHP2-FL(IC 50nM)
化合物001的三氟乙酸盐 1.61
化合物002的三氟乙酸盐 23.4
化合物003的三氟乙酸盐 4.22
化合物004的三氟乙酸盐 2.60
结论：本发明化合物对PTPN11/SHP2-FL的抑制活性良好。
实验例2：化合物H358细胞活性评价
实验目的：
本实验旨在验证本发明化合物对KRAS G12C突变的NCI-H358人非小细胞肺癌细胞增殖抑制效果。
实验材料：
细胞株NCI-H358(购自普诺赛)、RPMI1640培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。
实验方法：
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与数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。
数据分析：
利用方程式(Sample-Min)/(Max-Min)*100％将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。
本发明化合物H358细胞活性筛选试验结果如表2所示。
表2.本发明化合物体外筛选试验结果
化合物编号 H358(IC 50nM)
化合物001的三氟乙酸盐 46.5
化合物003的三氟乙酸盐 136.0
化合物004的甲酸盐 16.0
结论：本发明化合物对H358细胞的抑制活性良好。
实验例3：化合物药代动力学评价
实验目的：测试化合物在CD-1小鼠体内药代动力学
实验材料：CD-1小鼠(雄性,32-33g)
实验操作：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液，单次静脉注射及口服给予小鼠。静注及口服溶媒为一定比例的羟丙基β环糊***溶液或生理盐水溶液。收集24小时内的全血样品，3000g离心15分钟，分离上清得血浆样品，加入4倍体积含内标的乙腈溶液沉淀蛋白，离心取上清液加入等倍体积的水混匀后再离心取上清进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如达峰浓度，达峰时间，清除率，半衰期，药时曲线下面积，生物利用度等。
本发明化合物药代动力学测试结果如表3所示。
表3.化合物药代动力学测试结果
Figure PCTCN2022073167-appb-000033
结论：本发明化合物可以显著提高小鼠药代动力学单项或部分指标。
实验例4：hERG钾离子通道的抑制试验
1.实验目的：
用全自动膜片钳的方法检测待测实施例1对hERG钾离子通道的影响。
2.实验方法
2.1.细胞培养
实验所用的稳定表达hERG钾离子通道的细胞来自于Aviva Biosciences的CHO-hERE，CHO-hERG培养于5％CO 2，37℃的环境下。CHO hERG培养液见表4。
表4.CHO hERG培养液
Reagent Supplier Catalog Number Volume(mL)
F12Hams Invitrogen 31765-092 500
FBS Invitrogen 10099-141 50
G418/Geneticin Invitrogen 10131-027 1
Hygromycin B Invitrogen 10687-010 1
2.2.细胞的前期准备
准备用于实验的CHO-hERG细胞至少培养两天以上，且细胞密度达到75％以上。实验开始之前，用TrypLE消化细胞，然后用细胞外液重悬收集细胞。
2.3.细胞内外液的配制
细胞外液需每个月配制一次。细胞内液须分装冻存在-20℃。细胞内外液成分见表5。
表5.细胞内外液成分
组成成分 细胞外液(mM) 细胞内液(mM)
NaCl 145 -
KCl 4 120
KOH - 31.25
CaCl 2 2 5.374
MgCl 2 1 1.75
Glucose 10 -
Na 2ATP - 4
HEPES 10 10
EGTA - 10
pH 7.4with NaOH 7.2with KOH
渗透压 295mOsm 285mOsm
2.4.化合物的配制
将待测化合物和阳性对照Amitriptyline用DMSO溶解成一定浓度的储备液，然后按照不同的梯度稀释，最后按一定的比例加入细胞外液中，稀释成待测浓度。在实验开始前用肉眼检查看有无沉淀。最后，待测溶液和阳性对照Amitriptyline中，DMSO的浓度最高不能超过0.3％。
2.5.电压刺激方案
保持钳制电位在-80mv，首先是给予-50mv的电压刺激，持续80ms以记录细胞漏电流值，随后去极化至+20mv，维持4800ms，打开hERG的通道，然后复极化至-50mv维持5000ms，引出hERG尾电流并记录，最后，电压恢复至钳制电位-80mv，维持3100ms。以上电压刺激，每15000ms重复一次。
2.6.QPatch HTX全细胞膜片钳记录
hERG QPatch HTX实验是在室温下进行的。在QPatch Assay Software 5.2(Sophion Bioscience)的软件上建立全细胞方案，电压刺激方案和化合物检测方案。
首先进行30次重复设定电压刺激，该区段为后续分析的基线区域，随后加入5μL细胞外液，重复三次。依次加入各个化合物的作用浓度，仍旧以5μL加入体积重复三次。每一测试浓度孵育细胞至少不低于5mins。整个记录过程中，各项指标需达到数据分析接收标准，若未达到该标准，则该细胞不计入分析范围，化合物将重新进行测试，以上记录过程由均由Qpatch分析软件自动化操作。每一化合物测试浓度依次为0.24μM、1.20μM、6.00μM、30.00μM，每一浓度至少重复两个细胞。
2.7.数据分析
在每一个完整电流记录中，基于峰值电流在阴性对照中所占的百分比，可以计算出每一化合物作用浓度的抑制百分比。利用标准希式方程拟合得到量效关系曲线，具体方程如下：
I (C)＝I b+(I fr-I b)*c n/(IC 50 n+c n)
C为化合物测试浓度，n为斜率
曲线拟合和抑制率计算均由Qpatch分析软件分析完成，若最低浓度下抑制率超过半数抑制或最高浓度下抑制率未达到半数抑制，则该化合物相应的IC 50低于最低浓度或IC 50值大于最高浓度。
2.8.测试结果
实施例化合物hERG IC 50值结果见表6。
表6.实施例化合物hERG IC 50值结果
供试样品 hERG IC 50(nM)
化合物001的三氟乙酸盐 18.3
化合物003的三氟乙酸盐 6.4
化合物004的甲酸盐 9.8
结论：本发明化合物对hERG抑制不明显。
实验例5：体外微粒体稳定性实验
1.实验材料
人和动物微粒体购买于Corning或Xenotech，储存于-80℃冰箱。
还原型烟酰胺腺嘌呤二核苷酸磷酸(NADPH)，供应商：Chem-impex international，货号：00616
对照化合物：睾酮，双氯芬酸，普罗帕酮
2.实验步骤
2.1工作液的配制
储备液：10mM的DMSO溶液
工作浓度配制：100％乙腈稀释到100μM(有机相含量：99％ACN，1％DMSO)
2.2实验步骤
准备2块96孔孵育板，分别命名为T60孵育板和NCF60孵育板。
在T60孵育板和NCF60孵育板上分别加入445μL微粒体工作液(肝微粒体蛋白浓度为0.56mg/mL)，然后将上述孵育板放置于37℃水浴锅中预孵育大约10分钟。
预孵育结束后，在T60孵育板和NCF60孵育板上分别加入5μL供试品或对照化合物工作液，混匀。在NCF60孵育板上每孔添加50μL磷酸钾盐缓冲液启动反应；在T0终止板中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)和6μL的NADPH再生体系工作液，从T60孵育板中取出54μL样品至T0终止板(T0样品产生)。在T60孵育板上每孔添加44μL NADPH再生体系工作液启动反应。在Blank板中只添加54μL微粒体工作液、6μL的NADPH再生体系工作液和180μL的终止液。因此，在供试品或对照化合物的样品中，化合物、睾酮、双氯芬酸和普罗帕酮的反应终浓度为1μM，肝微粒体的终浓度为0.5mg/mL，DMSO和乙腈在反应体系中的终浓度分别为0.01％(v/v)和0.99％(v/v)。
孵育适当时间(如5、15、30、45和60分钟)后，分别在每个终止板的样品孔中加入180μL的终止液(含200ng/mL tolbutamide和200ng/mL labetalol的乙腈溶液)，之后从T60孵育板中取出60μL样品以终止反应。
所有样品板摇匀并在3220×g离心20分钟，然后每孔取80μL上清液稀释到240μL纯水中用于液相色谱串联质谱分析。
本发明化合物MMS结果结果如表7所示。
表7.本发明化合物MMS结果
供试样品 MMS(mL/min/kg),H(人),M(小鼠)
化合物001的三氟乙酸盐 11.9,57.5
化合物004的甲酸盐 11.9,64.1
结论：本发明化合物具有较好的肝微粒体稳定性。

Claims (13)

  1. 式(Ⅰ)化合物或其药学上可接受的盐，
    Figure PCTCN2022073167-appb-100001
    其中，
    T 1为CR 4或N；
    当E 1为O时，R 3为H、F、Cl、Br、I或C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
    当E 1为CH 2时，R 3为H、Cl、Br、I或C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代；
    R 1、R 2和R 4分别独立地为H、F、Cl、Br、I或C 1-3烷基，所述C 1-3烷基任选被1、2或3个R b取代；
    R 5为被OH取代的C 1-3烷基；
    R 6分别独立地为H、F、Cl、Br、I、OH、NH 2或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 a、R b和R c分别独立地为F、Cl、Br、I、OH或NH 2；
    m为1、2、3或4。
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，当E 1为O时，R 3为H或F。
  3. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，当E 1为CH 2时，R 3为H。
  4. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 1、R 2和R 4分别独立地为H、F、Cl、Br或I。
  5. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 5为-CH 2-OH。
  6. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，R 6分别独立地为Cl或NH 2。
  7. 根据权利要求1所述的化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022073167-appb-100002
    为
    Figure PCTCN2022073167-appb-100003
  8. 根据权利要求1所述的化合物或其药学上可接受的盐，其化合物为
    Figure PCTCN2022073167-appb-100004
    其中，
    T 1、E 1、R 1、R 2、R 3、R 5、R 6和m如权利要求1-7所定义。
  9. 根据权利要求8所述的化合物或其药学上可接受的盐，其化合物为
    Figure PCTCN2022073167-appb-100005
    其中，
    T 1、E 1、R 1、R 2和R如权利要求8所定义。
  10. 下列化合物或其药学上可接受的盐，
    Figure PCTCN2022073167-appb-100006
  11. 根据权利要求10所述的化合物或其药学上可接受的盐，化合物选自：
    Figure PCTCN2022073167-appb-100007
  12. 一种药物组合物，其包含权利要求1-11任意一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  13. 根据权利要求1～11任意一项所述化合物或其药学上可接受的盐或根据权利要求12所述的药物组合物在制备治疗与SHP2相关疾病的药物中的应用，其中所述与SHP2相关疾病是指肺癌，优选非小细胞肺癌。
PCT/CN2022/073167 2021-01-22 2022-01-21 吡唑并吡嗪联三环类化合物及其应用 WO2022156765A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
TW111107620A TW202246272A (zh) 2021-03-11 2022-03-02 吡唑並吡嗪三環類化合物及其應用

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
CN202110091198.9 2021-01-22
CN202110091198 2021-01-22
CN202110264689.9 2021-03-11
CN202110264689 2021-03-11
CN202110414584.7 2021-04-16
CN202110414584 2021-04-16

Publications (1)

Publication Number Publication Date
WO2022156765A1 true WO2022156765A1 (zh) 2022-07-28

Family

ID=82548522

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/073167 WO2022156765A1 (zh) 2021-01-22 2022-01-21 吡唑并吡嗪联三环类化合物及其应用

Country Status (1)

Country Link
WO (1) WO2022156765A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2018172984A1 (en) * 2017-03-23 2018-09-27 Jacobio Pharmaceuticals Co., Ltd. Novel heterocyclic derivatives useful as shp2 inhibitors
WO2019183367A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
CN111138412A (zh) * 2018-11-06 2020-05-12 上海奕拓医药科技有限责任公司 一种螺芳环化合物及其应用
CN111704611A (zh) * 2019-07-25 2020-09-25 上海凌达生物医药有限公司 一类芳基螺环类shp2抑制剂化合物、制备方法和用途
WO2021148010A1 (zh) * 2020-01-22 2021-07-29 南京明德新药研发有限公司 吡唑并杂芳环类化合物及其应用

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016203404A1 (en) * 2015-06-19 2016-12-22 Novartis Ag Compounds and compositions for inhibiting the activity of shp2
WO2018172984A1 (en) * 2017-03-23 2018-09-27 Jacobio Pharmaceuticals Co., Ltd. Novel heterocyclic derivatives useful as shp2 inhibitors
WO2019183367A1 (en) * 2018-03-21 2019-09-26 Relay Therapeutics, Inc. Shp2 phosphatase inhibitors and methods of use thereof
CN111138412A (zh) * 2018-11-06 2020-05-12 上海奕拓医药科技有限责任公司 一种螺芳环化合物及其应用
CN111704611A (zh) * 2019-07-25 2020-09-25 上海凌达生物医药有限公司 一类芳基螺环类shp2抑制剂化合物、制备方法和用途
WO2021148010A1 (zh) * 2020-01-22 2021-07-29 南京明德新药研发有限公司 吡唑并杂芳环类化合物及其应用

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023172940A1 (en) 2022-03-08 2023-09-14 Revolution Medicines, Inc. Methods for treating immune refractory lung cancer

Similar Documents

Publication Publication Date Title
WO2021148010A1 (zh) 吡唑并杂芳环类化合物及其应用
WO2022063190A1 (zh) 吡嗪硫联苯基类化合物及其应用
JP7323748B2 (ja) ピラゾロピリミジン誘導体及びその使用
EP3428161A1 (en) 2,3-dihydro-isoindole-1-on derivative as btk kinase suppressant, and pharmaceutical composition including same
WO2018137644A1 (zh) Lsd1抑制剂及其制备方法和应用
TWI810550B (zh) 3-氮雜二環烷基衍生物及包含其之醫藥組成物
TWI826509B (zh) 作為vanin抑制劑之雜芳族化合物
TW202128715A (zh) 作為erk抑制劑的螺環類化合物及其應用
TW202220995A (zh) 一種作為ｂｔｋ抑制劑的化合物及其製備方法與用途
TW202317097A (zh) 戊二醯亞胺類化合物與其應用
WO2022156765A1 (zh) 吡唑并吡嗪联三环类化合物及其应用
JP7374532B2 (ja) 選択性の高いｒｏｓ１阻害剤としての化合物、及びその使用
WO2021129817A1 (zh) 具有果糖激酶(khk)抑制作用的嘧啶类化合物
KR20220024199A (ko) Ccr2/ccr5 길항제로서의 헤테로시클로알킬류 화합물
WO2020063965A1 (zh) 作为选择性Trk抑制剂的吡唑并嘧啶衍生物
WO2020011227A1 (zh) 吡咯烷基脲衍生物及其在TrkA相关疾病的应用
JP7296017B2 (ja) ベンゾスルタムを含む化合物
WO2022237797A1 (zh) 烷基羧酸化合物及其应用
WO2023001069A1 (zh) 大环酰胺类化合物及其应用
WO2021004533A1 (zh) 作为irak4和btk多靶点抑制剂的噁唑类化合物
WO2022179578A1 (zh) 含有亚磺酰基吡啶结构的化合物以及应用
WO2020156564A1 (zh) 作为pd-l1免疫调节剂的乙烯基吡啶甲酰胺基化合物
TW202246272A (zh) 吡唑並吡嗪三環類化合物及其應用
KR20210124328A (ko) Pd-l1 면역조절제인 플루오로 비닐 벤즈아미드 화합물
CN114945576B (zh) 氘代噻吩并吡啶类化合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22742244

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22742244

Country of ref document: EP

Kind code of ref document: A1