WO2023072191A1 - 吡咯并吡唑螺环化合物 - Google Patents

吡咯并吡唑螺环化合物 Download PDF

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Publication number
WO2023072191A1
WO2023072191A1 PCT/CN2022/127937 CN2022127937W WO2023072191A1 WO 2023072191 A1 WO2023072191 A1 WO 2023072191A1 CN 2022127937 W CN2022127937 W CN 2022127937W WO 2023072191 A1 WO2023072191 A1 WO 2023072191A1
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alkyl
compound
deuterium
alternatively
independently
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PCT/CN2022/127937
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English (en)
French (fr)
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付翔宇
丁照中
胡利红
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正大天晴药业集团股份有限公司
南京明德新药研发有限公司
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Publication of WO2023072191A1 publication Critical patent/WO2023072191A1/zh

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/438—The ring being spiro-condensed with carbocyclic or 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems

Definitions

  • the application relates to a class of pyrrolopyrazole spiro compounds and their application in the preparation of medicines for treating related diseases, in particular to compounds of formula (I), their stereoisomers and pharmaceutically acceptable salts thereof.
  • SHP2 is a member of the protein tyrosine phosphatase (protein tyrosine phosphatase, PTP) family and is a non-receptor phosphatase that catalyzes the dephosphorylation of protein tyrosine.
  • SHP2 is encoded by PTP nonreceptor 11 (PTPN11), widely expressed in human body, and plays an important role in the downstream signaling pathway of growth factor receptors.
  • PTPN11 PTP nonreceptor 11
  • SHP2 plays a variety of physiological functions such as regulating cell proliferation, differentiation, migration, and apoptosis.
  • SHP2 was also found to be in the PD-1/PD-L1 pathway, playing an immune regulatory role.
  • SHP2 is indispensable for RAS-driven tumors.
  • SHP2 is upstream of RAS and mediates the activation of the RAS-ERK pathway, which is mainly achieved by dephosphorylating RAS-GAP.
  • SHP2 dephosphorylates the tyrosine phosphorylation site of RTKs, and prevents p120RasGAP from inhibiting Ras activation by dephosphorylating the site where p120RasGAP binds to RTKs, thereby activating the RAS pathway .
  • the SHP2 protein contains two Src homology domains, N-SH2 and C-SH2, followed by a catalytically active PTP domain.
  • Normal SHP2 is in a state of self-inhibition, and the active catalytic microdots are blocked by N-SH2.
  • Tyr542 and Tyr580 are phosphorylated, a conformational change occurs and SHP2 is activated.
  • SHP2 is mutated (such as: E76K, etc.), the conformation of N-SH2 undergoes a huge change, which cannot cover the active catalytic site, and SHP2 is activated without phosphorylation.
  • SHP2 mutations are found in a variety of tumors.
  • Allosteric inhibitors are another idea for inhibiting SHP2. Allosteric inhibitors of SHP2 act as "glue" to keep SHP2 in a state of autoinhibition. At present, several allosteric inhibitors of SHP2 have entered the clinical research stage, and have shown excellent efficacy in diseases such as NSCLC.
  • Ring A is selected from aryl and heteroaryl
  • R 1 is selected from H, deuterium, NH 2 , C 1-6 alkyl optionally substituted by one or more halogens, CN or OH;
  • R 3 is selected from H, halogen, OH, NO 2 , CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, the C 1-6 alkyl, C 1-6 Alkoxy and C 1-6 alkylamino are independently optionally substituted by 1, 2 or 3 R b ;
  • R 4 , R 5 and R 6 are independently selected from H, deuterium, halogen, NH 2 , NO 2 , CN, OH, C 1-6 alkyl, C 1-6 alkoxy and -NH-OC 1- 6 alkyl, said NH 2 , C 1-6 alkyl, C 1-6 alkoxy and -NH-OC 1-6 alkyl are independently optionally substituted by 1, 2 or 3 R c ;
  • R a , R b , and R c are each independently selected from deuterium, halogen, OH, NH 2 , CN, and C 1-3 alkyl.
  • Ring A is selected from aryl and heteroaryl
  • R 1 is selected from H, deuterium, NH 2 , C 1-6 alkyl optionally substituted by one or more halogens, CN or OH;
  • R 3 is selected from H, halogen, OH, NO 2 , CN, C 1-6 alkyl, C 1-6 alkoxy and C 1-6 alkylamino, the C 1-6 alkyl, C 1-6 Alkoxy and C 1-6 alkylamino are independently optionally substituted by 1, 2 or 3 R b ;
  • R 4 , R 5 and R 6 are independently selected from H, deuterium, halogen, NH 2 , NO 2 , CN, OH, C 1-6 alkyl, C 1-6 alkoxy and -NH-OC 1- 6 alkyl, said NH 2 , C 1-6 alkyl, C 1-6 alkoxy and -NH-OC 1-6 alkyl are independently optionally substituted by 1, 2 or 3 R c ;
  • R a , R b , and R c are each independently selected from deuterium, halogen, OH, NH 2 , CN, and C 1-3 alkyl.
  • the ring A is selected from aryl and 5-6 membered heteroaryl, and the 5-6 membered heteroaryl contains 1, 2 or 3 independently selected from N, O, S and A heteroatom or heteroatom group of NH.
  • the R 1 is selected from H, deuterium, NH 2 , C 1-3 alkyl optionally substituted with one or more halogen, CN or OH. In some embodiments, the R 1 is selected from H, deuterium, NH 2 , C 1-3 alkyl optionally substituted with one or more halogen. In some embodiments, the R 1 is selected from H, deuterium, NH 2 , C 1-3 alkyl optionally substituted with one or more fluorines. In some embodiments, the R 1 is selected from H, deuterium, NH 2 , CH 3 , CHF 2 , CH 2 F and CF 3 .
  • R 3 is selected from H, F, Cl, Br, I, NO 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are each independently optionally substituted by 1, 2 or 3 R b .
  • R 4 , R 5 and R 6 are each independently selected from H, deuterium, F, Cl, Br, I, NH 2 , NO 2 , CN, OH, C 1-3 alkyl, C 1 -3 alkoxy and -NH-OC 1-3 alkyl, said NH 2 , C 1-3 alkyl, C 1-3 alkoxy and -NH-OC 1-3 alkyl are independently optional Substituted by 1, 2 or 3 R c .
  • Ring A is selected from aryl and 5-6 membered heteroaryl, and said 5-6 membered heteroaryl contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from N, O, S and NH;
  • R 1 is selected from H, deuterium, NH 2 , CH 3 , CHF 2 , CH 2 F and CF 3 ;
  • R 3 is selected from H, F, Cl, Br, I, NO 2 , CN, C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino, the C 1-3 alkyl, C 1-3 alkoxy and C 1-3 alkylamino are independently optionally substituted by 1, 2 or 3 R b ;
  • R 4 , R 5 and R 6 are independently selected from H, deuterium, F, Cl, Br, I, NH 2 , NO 2 , CN, OH, C 1-3 alkyl, C 1-3 alkoxy and -NH-OC 1-3 alkyl, said NH 2 , C 1-3 alkyl, C 1-3 alkoxy and -NH-OC 1-3 alkyl are independently optionally replaced by 1, 2 or 3 R c replacement;
  • R a is independently selected from deuterium, F, Cl, Br, I, OH and NH 2 ;
  • R b are independently selected from deuterium, F, Cl, Br, I and OH;
  • R c are each independently selected from deuterium, F, Cl, Br, I, NH 2 and C 1-3 alkyl.
  • R a , R b , and R c are each independently selected from halogen, OH, NH 2 and C 1-3 alkyl. In some embodiments, R a , R b , and R c are each independently selected from halogen, OH, and C 1-3 alkyl. In some embodiments, R a , R b , and R c are each independently selected from fluorine, OH, and C 1-3 alkyl. In some embodiments, R a , R b , and R c are each independently selected from fluorine, OH, and CH 3 .
  • said Ra are each independently selected from deuterium, F, Cl, Br, I, OH and NH 2 ;
  • the R b are independently selected from deuterium, F, Cl, Br, I and OH;
  • the R c are independently selected from deuterium, F, Cl, Br, I, NH 2 and C 1-3 alkyl.
  • the R a are each independently selected from F, Cl, OH and NH 2 . In some aspects, the R a are each independently selected from OH.
  • the R b are each independently selected from F, Cl and OH.
  • the R c are each independently selected from F, Cl, Br, I and C 1-3 alkyl. In some embodiments, the R c are each independently selected from F, Cl, Br, I, NH 2 and CH 3 . In some embodiments, the R c are each independently selected from F, Cl, NH 2 and CH 3 .
  • the R c are independently selected from F and C 1-3 alkyl.
  • R c are independently selected from F and CH 3 , and other variables are as defined in the present application.
  • R 1 is selected from H, CH 3 and CHF 2 , and other variables are as defined in the present application.
  • R 1 is selected from CH 3 and CHF 2 , and other variables are as defined in the present application.
  • R 3 is selected from H, F, Cl and CH 3 , and other variables are as defined in the present application.
  • R 3 is selected from H, and other variables are as defined in the present application.
  • R 4 , R 5 and R 6 are independently selected from F, Cl, NH 2 , -NH-O-CH 3 , -NH-CH 3 , CH 3 , CF 3 and CHF 2 , other variables are as defined in this application.
  • the above-mentioned ring A is selected from C 6-10 aryl and 5-10 membered heteroaryl. In some schemes of the present application, the above-mentioned ring A is selected from C 6-10 aryl and 5-6 membered heteroaryl. In some aspects of the present application, the above ring A is selected from phenyl and 5-6 membered heteroaryl.
  • the above-mentioned ring A is selected from phenyl, pyrazolyl and pyridyl, and other variables are as defined in the present application.
  • the above ring A is selected from phenyl, pyrazolyl and pyridyl; or the above ring A is selected from pyridyl;
  • R 3 is selected from H, F, Cl and CH 3 ; or the above R 3 is selected from H;
  • R 4 , R 5 and R 6 are independently selected from F, Cl, NH 2 , -NH-O-CH 3 , -NH-CH 3 , CH 3 , CF 3 and CHF 2 ,
  • the application provides a compound of formula (I), its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is selected from the compound of formula (I)-A or formula (I)-B
  • R 1 , R 4 and R 5 are as defined in this application.
  • R 1 , R 4 and R 5 are as defined in this application.
  • the present application also provides a compound, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from
  • the present application relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present application, its stereoisomer or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present application further includes pharmaceutically acceptable excipients.
  • the present application relates to a method for preventing or treating a mammal related to SHP2 protein, comprising administering a therapeutically effective amount of the compound of the present application, its stereoisomer or its pharmaceutical preparation to a mammal in need of the treatment, preferably a human. acceptable salts, or pharmaceutical compositions thereof.
  • the present application relates to the use of the compound of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the preparation of drugs for preventing or treating diseases related to SHP2 protein.
  • the present application relates to the use of the compound of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition in the prevention or treatment of diseases related to SHP2 protein.
  • the present application relates to the compound of the present application, its stereoisomer or pharmaceutically acceptable salt thereof, or its pharmaceutical composition for preventing or treating diseases related to SHP2 protein.
  • the disease associated with SHP2 protein is selected from cancer; or, the disease associated with SHP2 protein is selected from lung cancer or pancreatic cancer.
  • the present application provides a novel allosteric inhibitor of SHP2, which has high inhibitory activity on SHP2 in vivo and in vitro, and can be used as a new and more effective cancer treatment scheme. Specifically, it can inhibit the activity of kinases or tumor cells (MIAPACA2_PANCREAS, NCIH358_LUNG) in vitro; it has excellent pharmacokinetic and pharmacodynamic properties in vivo.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to the salts of the compounds of the present application, which are prepared from the compounds with specific substituents found in the present application 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 the acid, either neat solution or in a suitable inert solvent.
  • Certain specific compounds of the present application contain basic and acidic functional groups and thus can be converted into either base or acid addition salts.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods. In general, 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 both.
  • the compounds of the present application may exist in particular geometric or stereoisomeric forms.
  • This application contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are subject to the present within the scope of the application.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of this application.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer 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%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present application is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present application may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • 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 changes in isotopic composition of the compounds of the present application, whether radioactive or not, are included within the scope of the present application.
  • 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 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 realizable basis.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations 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.
  • substituent 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 enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting 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 to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • the number of atoms in a ring is generally defined as the number of ring members, eg, "5-7 membered ring” means a “ring” with 5-7 atoms arranged around it.
  • alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of carbon atoms.
  • C 1-6 alkyl is used to indicate a straight-chain or branched saturated hydrocarbon group consisting of 1 to 6 carbon atoms
  • C 1-3 alkyl is used to indicate A straight or branched 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 (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • alkoxy means -O-alkyl.
  • C 1-6 alkoxy means those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an oxygen atom;
  • C 1-3 alkoxy means those alkyl groups containing 1 to 3 carbon atoms attached to the rest 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 groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-6 alkylamino means -NH-alkyl. Unless otherwise specified, the term “C 1-6 alkylamino” means those alkyl groups containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group; the term “C 1-3 alkylamino” means Those attached to the rest of the molecule contain alkyl groups of 1 to 3 carbon atoms.
  • the C 1-3 alkylamino group includes C 1-2 , C 3 and C 2 alkylamino groups and the like.
  • C 1-3 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 etc.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system.
  • an aryl group can have 6-20 carbon atoms, 6-14 carbon atoms, or 6-12 carbon atoms.
  • Non-limiting examples of aryl include, but are not limited to, phenyl, naphthyl, anthracenyl, tetralin, and the like.
  • heteroaryl refers to a monocyclic or fused polycyclic ring system containing at least one ring atom selected from N, O, S, for example 1, 2, 3 or 4 ring atoms selected from N, O, ring atoms of S, the remaining ring atoms are C, and have at least one aromatic ring.
  • Preferred heteroaryl groups have a single 5 to 8 membered ring or 5 to 6 membered ring, or multiple fused rings containing 6 to 14, especially 6 to 10 ring atoms.
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” can be used interchangeably in the present application, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 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 , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl 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.
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , 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, for example, 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.; similarly, n to n +m means that the number of atoms on the ring is n to n+m, for example, a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membere
  • treating means administering a compound or formulation described herein to improve or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with the disease, and includes: preventing a disease or disease state from occurring in a mammal, especially when Such mammals are susceptible to the disease state, but have not been diagnosed as having the disease state.
  • terapéuticaally effective amount means (i) treating or preventing a particular disease, condition or disorder, (ii) alleviating, ameliorating or eliminating one or more symptoms of a particular disease, condition or disorder, or (iii) preventing or delaying The amount of a compound of the application for the onset of one or more symptoms of a particular disease, condition or disorder described herein.
  • the amount of a compound of the present application that constitutes a “therapeutically effective amount” will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by a person skilled in the art according to its own knowledge and this disclosure.
  • composition refers to a mixture of one or more compounds of the present application or their salts and pharmaceutically acceptable auxiliary materials.
  • the purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.
  • pharmaceutically acceptable excipients refers to those excipients that have no obvious stimulating effect on the organism and will not impair the biological activity and performance of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
  • Therapeutic dosages of the compounds of the present application may depend, for example, on the particular use for the treatment, the mode of administration of the compound, the health and state of the patient, and the judgment of the prescribing physician.
  • the ratio or concentration of the compounds of the present application in the pharmaceutical composition may vary, depending on various factors, including dosage, chemical properties (eg, hydrophobicity) and route of administration.
  • a compound of the present application may be provided for parenteral administration as an aqueous physiologically buffered solution containing about 0.1-10% w/v of the compound.
  • Some typical dosages range from about 1 ⁇ g/kg to about 1 g/kg body weight per day. In certain embodiments, the dosage range is from about 0.01 mg/kg to about 100 mg/kg body weight/day.
  • the dosage will likely depend on such variables as the type and extent of the disease or condition, the general health of the particular patient, the relative biological potency of the compound selected, the formulation of the excipient and its route of administration. Effective doses may be obtained by extrapolation from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art In an equivalent alternative, preferred implementations include but are not limited to the examples of the present application.
  • the compounds of the present application can be prepared by those skilled in the art by the following general routes and using methods known in the art:
  • the structure of the compounds of the present application can be confirmed by conventional methods known to those skilled in the art. If the application involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • aq stands for water
  • HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate
  • EDC represents N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
  • m-CPBA 3-chloroperoxybenzoic acid
  • eq represents equivalent, equivalent
  • CDI represents Carbonyldiimidazole
  • DCM stands for dichloromethane
  • PE stands for petroleum ether
  • DIAD stands for diisopropyl azodicarboxylate
  • DMF stands for N,N-dimethylformamide
  • DMSO stands for dimethylsulfoxide
  • EtOAc stands for ethyl acetate EtOH stands for ethanol
  • MeOH stands for methanol
  • CBz stands for benzyloxycarbonyl, an amine protecting group
  • BOC stands for
  • Step A Under nitrogen protection, a solution of compound 1-1 (8.9 g, 34.59 mmol, 1 eq) in tetrahydrofuran (100 ml) was cooled to -70°C, and then lithium diisopropylamide (2 moles per liter, 20.75 milliliters, 1.2 equiv), added compound 1-2 (3.66 g, 38.05 mmol, 1.1 equiv) after stirring for 1 hour at -70 degrees Celsius, added ethyl acetate (200 milliliters) after stirring at 25 degrees Celsius for 12 hours, and then Wash with brine (300 ml ⁇ 3), dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain the crude product through preparative high-performance liquid chromatography (column: Phenomenex luna C18 (250 ⁇ 70 mm, 10 microns); flow Phase: [water (0.225% formic acid)-acetonitrile]; acetonitrile %
  • Step B To compound 1-3 (2.7 g, 7.64 mmol, 1 eq) in THF (30 mL) was added lithium aluminum hydride (376.95 mg, 9.93 mmol, 1.3 eq) at 0°C, After stirring for 12 hours at 25°C, add saturated sodium sulfate solution to quench the reaction until no bubbles are generated, add ethyl acetate (100 ml), filter, wash the filtrate with brine (100 ml ⁇ 2), and dry over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to obtain compound 1-4. MS (ESI) m/z: 256.1 [M+H + -56].
  • Step C Add imidazole (491.93 mg, 7.23 mmol, 1.5 eq) and t Butyldimethylsilyl chloride (871.29 mg, 5.78 mmol, 708.36 microliters, 1.2 equivalents), stirred at 25 degrees Celsius for 1 hour, added ethyl acetate (80 ml), washed with brine (80 ml ⁇ 5) , dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-5.
  • MS (ESI) m/z: 426.3 [M+H + ].
  • Step E To a solution of compound 1-6 (750 mg, 1.77 mmol, 1 eq) in THF (20 mL) was added tetrabutylammonium fluoride (1 mole per liter, 2.66 mL, 1.5 eq), at 25°C The mixture was stirred for 12 hours. After the reaction, ethyl acetate (50 ml) was added, washed with brine (50 ml ⁇ 5), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-7. MS (ESI) m/z: 210.0 [M+H + -100].
  • Step G Add tetraethoxytitanium (156.59 mg, 686.47 micromoles, 142.35 microliters, 2 equivalents), stirred under nitrogen protection and 110 degrees Celsius for 12 hours, after the reaction, compounds 1-10 were directly used in the next step in solution.
  • Step H Add sodium borohydride (130 mg, 3.44 mmol, 10.01 eq. ), stirred at -70 degrees Celsius for 1 hour, added methanol (5 milliliters) to quench the reaction, then added 20 milliliters of ethyl acetate, filtered, and the filtrate was washed with brine (20 milliliters ⁇ 3), dried over anhydrous sodium sulfate, filtered,
  • the crude product obtained by concentrating under reduced pressure was subjected to a preparative high-performance liquid chromatography column (column model: Phenomenex luna C18 (150 mm ⁇ 25 mm ⁇ 10 microns); mobile phase: [0.225% aqueous formic acid-acetonitrile]; gradient: 30%-60 %) was purified to obtain compound 1-11.
  • Compound 1-11A is detected by SFC (column model: Chiralpak IG-3 (50 millimeters * 4.6 millimeters * 3 microns); Mobile phase: A phase is supercritical carbon dioxide, and B phase is methanol (0.05% diethylamine); Gradient ( B%): 5%-40%) obtained: the retention time of compound 1-11A was 1.294 minutes, and the ee value was 100.00%.
  • Step I Add ethyl acetate hydrochloride (4 moles per liter, 1 ml, 9.33 equiv) to a solution of compound 1-11A (170 mg, 428.70 micromole, 1 equiv) in ethyl acetate (1 ml), at 20° C. Stir at low temperature for 30 minutes. After the reaction, add ethyl acetate (5 ml), filter, and dry the filter cake under reduced pressure to obtain compound 1-12A.
  • Step J Dissolve compound 1-13 (10 g, 39.30 mmol, 1 eq) and compound 1-14 (10.30 g, 47.16 mmol, 1.2 eq) in dioxane (100 mL) and add N, N - Diisopropylethylamine (10.16g, 78.60mmol, 13.69ml, 2eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (2.27g, 3.93mM mol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium (1.80 g, 1.96 mmol, 0.05 equiv).
  • reaction mixture was replaced with gas three times under the protection of nitrogen, and then the reaction system was heated to 105° C. and stirred for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction solution was cooled to 25 degrees Celsius, filtered, and the filtrate was concentrated to obtain the crude product. Add n-heptane (50 ml) and ethyl acetate (5 ml), stir at 25 degrees Celsius for 1 hour, filter, and dry the filter cake in vacuum to obtain Compounds 1-15. MS (ESI) m/z: 345.2 [M+H + ].
  • Step K Compound 1-15 (13.2 g, 38.27 mmol, 1 eq) was dissolved in tetrahydrofuran (130 ml), and sodium methoxide methanol solution (5.4 moles per liter, 9.21 ml, 1.3 eq) was added, and the reaction mixture was heated at 25 Stir for 1 hour at °C. After the reaction was complete, the reaction solution was directly concentrated to obtain a crude product which was dissolved in water (50 mL) and washed with ethyl acetate (50 mL ⁇ 2). The aqueous phase was adjusted to pH 6 with aqueous hydrochloric acid (1 mol per liter), filtered, and the filter cake was vacuum-dried to obtain compound 1-16. MS (ESI) m/z: 161.1 [M+H + ].
  • Step M Compound 1-19 (51.46 g, 282.47 mmol, 1 eq) was dissolved in N,N-dimethylformamide (500 mL), and N-bromosuccinyl was added at 0 °C Amine (52.79 g, 296.60 mmol, 1.05 equiv). The reaction mixture was stirred at 25 °C for 1 hour. After the reaction was complete, water (500 ml) and ethyl acetate (700 ml) were added to the reaction solution, and the reaction mixture was stirred for 2 minutes. After the reaction system was separated into layers, the aqueous phase was extracted with ethyl acetate (700 ml).
  • Step N Dissolve triphenylphosphine (18.08 g, 68.95 mmol, 3 equiv) in dioxane (200 mL), add N-chlorosuccinimide (9.36 g, 70.10 mmol, 3.05 eq), the reaction mixture was stirred at 25°C for 0.5 h, and compound 1-20 (6 g, 22.98 mmol, 1 eq) was added. The reaction solution was heated to 100°C and stirred for 1 hour. After the reaction was complete, the reaction mixture was cooled to 25° C., the reaction solution was poured into water (600 ml), and extracted with methyl tert-butyl ether (400 ml ⁇ 2).
  • Step O Compound 1-21 (5.6 g, 20.03 mmol, 1 eq) and compound 1-16 (3.22 g, 20.03 mmol, 1 eq) were dissolved in dioxane (80 mL), N was added, N-Diisopropylethylamine (7.7 g, 60.10 mmol, 10.47 mL, 3 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.16 g, 2.00 mmol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium (917.30 mg, 1.00 mmol, 0.05 equiv).
  • reaction mixture was replaced with gas three times under the protection of nitrogen, and then the reaction system was heated to 100° C. and stirred for 5 hours under the protection of nitrogen. After the reaction was complete, the reaction solution was cooled to 25 degrees Celsius, filtered, and the filtrate was concentrated to obtain the crude product. Ethyl acetate (50 ml) was added, stirred at 25 degrees Celsius for 1 hour, filtered, and the filter cake was dried under reduced pressure to obtain compound 1-22.
  • Step P Compound 1-22 (1.90 g, 5.29 mmol, 1 eq) and compound 1-12A (1.82 g, 6.88 mmol, 1.3 eq, 2 molecular hydrochloride) were dissolved in N-methylpyrrolidone (20 mL), potassium carbonate (3.65 g, 26.45 mmol, 5 eq) was added. The reaction mixture was heated to 80°C and stirred for 1 hour. After the reaction was complete, the reaction liquid was cooled to 25°C, water (100 ml) was added, filtered, and the filter cake was dried under reduced pressure to obtain compound 1-23.
  • Step E Compound 1-23 (1.1 g, 2.14 mmol, 1 eq) was dissolved in tetrahydrofuran (15 ml), and diisobutylaluminum hydride (1 mole per liter, 8.54 ml , 4 equivalents). The reaction mixture was stirred at 25 degrees Celsius for 1 hour, quenched with saturated sodium sulfate solution until no bubbles emerged, stirred at 25 degrees Celsius for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure.
  • Step A Under nitrogen protection, add 2-2 tetrahydrofuran solution (2 moles per liter, 10 mL, 5.15 equivalents), the reaction was stopped after stirring at 70°C for 0.5 hours, water (100 mL) was added, and compound 2-3 was obtained by filtration. MS (ESI) m/z: 268.9 [M+H + ].
  • Step B Compound 2-3 (0.89 g, 3.31 mmol, 1 eq) and compound 1-14 (868.60 mg, 3.98 mmol, 1.2 eq) were dissolved in dioxane (10 mL) and N, N - Diisopropylethylamine (856.86 mg, 6.63 mmol, 1.15 mL, 2 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (95.90 mg, 165.5 ⁇ g mol, 0.05 equiv) and palladium acetate (37.21 mg, 165.75 micromole, 0.05 equiv).
  • reaction mixture was replaced with gas three times under the protection of nitrogen, and then the reaction system was heated to 100° C. and stirred for 1 hour under the protection of nitrogen.
  • Step C Compound 2-4 (1.19 g, 3.30 mmol, 1 eq) was dissolved in tetrahydrofuran (10 ml), and sodium methoxide methanol solution (5.4 moles per liter, 1.22 ml, 2 eq) was added, and the reaction mixture was heated at 15 Stir at 0.5°C for 0.5 hours. After the reaction was complete, the reaction solution was directly concentrated to obtain the crude product, which was dissolved in water (20 ml), and the solution was adjusted to pH 6 with 1 mole per liter of hydrochloric acid, and then washed with ethyl acetate (20 ml ⁇ 2). After the aqueous phase was concentrated, ethanol (20 ml) was added to dissolve, filter and concentrate under reduced pressure to obtain compound 2-5. MS (ESI) m/z: 175.1 [M+H + ].
  • Step D Compound 2-5 (0.386 g, 2.21 mmol, 1.1 eq) and compound 1-21 (561.61 mg, 2.01 mmol, 1 eq) were dissolved in dioxane (5 mL), N was added, N-Diisopropylethylamine (779.03 mg, 6.03 mmol, 1.05 mL, 3 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (116.26 mg, 200.92 mol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (91.99 mg, 100.46 mol, 0.05 eq).
  • reaction mixture was replaced with gas three times under the protection of nitrogen, and then the reaction system was heated to 100° C. and stirred for 12 hours under the protection of nitrogen. After the reaction was complete, the reaction solution was cooled to 15 degrees Celsius, added dioxane (5 ml) and filtered, and the filtrate was concentrated to obtain the crude product. Add ethyl acetate (5 ml) and n-heptane (5 ml), filter, and concentrate under reduced pressure to obtain the compound 2-6. MS (ESI) m/z: 373.1 [M+H + ].
  • Step E Compound 2-6 (0.436 g, 1.17 mmol, 1 eq) and compound 1-12A (0.602 g, 2.27 mmol, 1.94 eq, 2 molecules of hydrochloride) were dissolved in N-methylpyrrolidone (7 mL), potassium carbonate (1.2 g, 8.68 mmol, 7.43 eq) was added. The reaction mixture was heated to 80°C and stirred for 2 hours. After the reaction was complete, the reaction solution was cooled to 15°C, water (20 ml) was added, and the organic phase was extracted with ethyl acetate (20 ml*2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain compound 2-7. MS (ESI) m/z: 529.3 [M+H + ].
  • Step F Compound 2-7 (0.46 g, 869.47 micromole, 1 equivalent) was dissolved in tetrahydrofuran (5 ml), and diisobutylaluminum hydride (1 mole per liter, 3.48 ml , 4 equivalents).
  • Step A Compound 3-1 (500 mg, 2.79 mmol, 1.1 eq) and compound 1-21 (709.53 mg, 2.54 mmol, 1 eq) were dissolved in dioxane (10 mL), N was added, N-Diisopropylethylamine (984.22 mg, 7.62 mmol, 1.33 mL, 3 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (146.88 mg, 253.84 ⁇ mol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (116.22 mg, 126.92 ⁇ mol, 0.05 eq).
  • Step B Compound 3-2 (460 mg, 1.22 mmol, 1 eq) and compound 1-12A (419.88 mg, 1.58 mmol, 1.3 eq, 2 molecular hydrochloride) were dissolved in N-methylpyrrolidone (6 mL), potassium carbonate (841.69 mg, 6.09 mmol, 5 eq) was added. The reaction mixture was heated to 80°C and stirred for 12 hours.
  • Step C Compound 3-3 (572 mg, 1.07 mmol, 1 equivalent) was dissolved in tetrahydrofuran (5 ml), and diisobutylaluminum hydride (1 mole per liter, 4.29 ml , 4 equivalents). The reaction mixture was stirred at 25 degrees Celsius for 0.5 hours, quenched with saturated sodium sulfate solution (10 ml) until no bubbles emerged, then stirred at 25 degrees Celsius for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step A To a solution of compound 4-1 (2 g, 8.85 mmol, 1 eq) and 1-14 (2.32 g, 10.62 mmol, 1.2 eq) in 1,4-dioxane (20 mL) was added N,N-Diisopropylethylamine (3.43 g, 26.55 mmol, 4.62 mL, 3 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (512.07 mg , 884.98 micromoles, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium (405.20 mg, 442.49 micromoles, 0.05 equiv).
  • N,N-Diisopropylethylamine 3.43 g, 26.55 mmol, 4.62 mL, 3 equiv
  • Step B To a solution of compound 4-2 (700 mg, 1.93 mmol, 1 eq) in THF (5 mL) was added a methanolic solution of sodium methoxide (5.4 moles per liter, 713.35 ⁇ l, 30% purity, 2 eq) . After stirring at 25°C for 30 minutes, the pH was adjusted to 7-8 with ethyl acetate hydrochloride (4 moles per liter), and concentrated to obtain compound 4-3, which was directly used in the next step.
  • Step C Add compound 4-3 (345.08 mg, 1.93 mmol, 1 eq) and compound 1-21 (538.37 mg, 1.93 mmol, 1 eq) in 1,4-dioxane (7 ml) solution
  • 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene 111.45 mg, 192.61 ⁇ mol, 0.1 equiv
  • tris(dibenzylideneacetone)dipalladium 88.19 mg, 96.30 ⁇ mol, 0.05 equiv).
  • Step D To compound 4-4 (210 mg, 555.90 micromole, 1 equiv) and compound 1-12A (191.64 milligram, 722.66 micromole, 1.3 equiv, 2 molecular hydrochloride) N, N-dimethyl formaldehyde Potassium carbonate (384.14 mg, 2.78 mmol, 5 eq) was added to the solution of the amide (5 mL). The mixture was stirred at 80°C for 12 hours, cooled to 25°C after the reaction, filtered, and the filtrate was concentrated to obtain the crude compound 4-5. MS (ESI) m/z: 534.2 [M+H + ].
  • Step E Add diisobutylaluminum hydride (1 mole per liter, 2.81 ml, 5 equivalents). After the dropwise addition, stir at 25°C for 1 hour, quench with saturated sodium sulfate solution until no bubbles emerge from the reaction solution, stir at 25°C for 30 minutes, filter, and concentrate the filtrate to obtain the crude product through preparation and high performance liquid chromatography (Column model: Waters Xbridge 150 ⁇ 25 mm ⁇ 5 ⁇ m; Mobile phase: [Aqueous solution of ammonia (0.05%)-acetonitrile]; Gradient: 25%-55%) Separation and purification yielded compound 4. MS (ESI) m/z: 492.1 [M+H + ].
  • Embodiment 5 Compound 5
  • Step A 1,4-dioxane (2 mL) solution was heated to 80°C in a stuffy jar and stirred at 80°C for 12 hours. Cool to 25 °C after reaction, the crude product obtained by concentrating under reduced pressure is subjected to preparative high-performance liquid chromatography (column model: Waters Xbridge 150 * 25 millimeters * 5 microns; Mobile phase: [ammonia aqueous solution (0.05%)-acetonitrile] ; Gradient: 15%-45%) separation and purification to obtain compound 5.
  • Embodiment 6 Compound 6
  • Step A Compound 6-1 (3 g, 12.45 mmol, 1 eq) was dissolved in dioxane (15 mL) and ammonia (13.65 g, 7.37 mmol, 15 mL, purity 25%, 7.92 eq) was added , the reaction solution was heated to 80 degrees centigrade in a 100 ml tetrafluoro tank and stirred for 12 hours. After the reaction was complete, the reaction liquid was cooled to 25 degrees Celsius, water (60 ml) was added to the reaction liquid, stirred at 25 degrees Celsius for 0.5 hours, filtered, and the filter cake was vacuum-dried to obtain compound 6-2. MS (ESI) m/z: 239.0 [M+H + ].
  • Step B Compound 6-2 (2.3 g, 9.66 mmol, 1 eq) and compound 1-14 (2.53 g, 11.60 mmol, 1.2 eq) were dissolved in dioxane (25 mL) and N, N - Diisopropylethylamine (3.75g, 28.99mmol, 5.05ml, 3eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (1.12g, 1.93mM mol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (884.94 mg, 966.38 micromole, 0.1 equiv).
  • Step C Compound 6-3 (500 mg, 1.52 mmol, 1 equivalent) was dissolved in tetrahydrofuran (5 ml), and sodium methoxide methanol solution (5 moles per liter, 395.81 microliters, 1.3 equivalents) was added, and the reaction mixture was Stir for 0.5 h at 25°C. After the reaction was complete, the pH value of the reaction solution was adjusted to 7 with ethyl acetate hydrochloride (4 moles per liter), and the reaction solution was directly concentrated to obtain compound 6-4. MS (ESI) m/z: 145.1 [M+H + ].
  • Step D Compound 1-21 (386.83 mg, 1.38 mmol, 1 eq) and compound 6-4 (219.47 mg, 1.52 mmol, 1.1 eq) were dissolved in dioxane (5 mL), N was added, N-diisopropylethylamine (536.57 mg, 4.15 mmol, 723.14 microliters, 3 equivalents), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (160.15 mg, 276.78 micromoles, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (126.73 mg, 138.39 micromoles, 0.1 equiv).
  • Step E Compound 6-5 (269 mg, 784.77 micromole, 1 eq) and compound 1-12A (270.54 mg, 1.02 mmol, 1.3 eq, 2 molecular hydrochloride) were dissolved in N-methylpyrrolidone (5 mL), potassium carbonate (542.31 mg, 3.92 mmol, 5 eq) was added. The reaction mixture was heated to 80°C and stirred for 12 hours.
  • Step F Compound 6-6 (215 mg, 431.23 micromole, 1 equivalent) was dissolved in tetrahydrofuran (5 ml), and diisobutylaluminum hydride (1 mole per liter, 1.72 ml , 4 equivalents). The reaction mixture was stirred at 25 degrees Celsius for 12 hours, quenched with saturated sodium sulfate solution (10 ml) until no bubbles emerged, then stirred at 25 degrees Celsius for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step A Compound 7-1 (3 g, 18.63 mmol, 1 eq) and compound 1-14 (4.88 g, 22.36 mmol, 1.2 eq) were dissolved in dioxane (30 mL) and N, N - Diisopropylethylamine (4.82 g, 37.27 mmol, 6.49 mL, 2 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (539.09 mg, 931.68 micro mol, 0.05 equiv) and palladium acetate (209.17 mg, 931.68 micromole, 0.05 equiv).
  • reaction mixture was replaced with gas three times under the protection of nitrogen, and then the reaction system was heated to 100° C. and stirred for 12 hours under the protection of nitrogen, and stirred at 120° C. for another 12 hours.
  • Step B Compound 7-2 (0.6 g, 2.01 mmol, 1 eq) was dissolved in tetrahydrofuran (6 ml), and sodium methoxide methanol solution (5.4 moles per liter, 744.60 microliters, 2 eq) was added, and the reaction mixture was Stir at 15 °C for 0.5 h. After the reaction was complete, the pH of the reaction solution was adjusted to 7 using 4 moles per liter of hydrogen chloride ethyl acetate solution, and then concentrated under reduced pressure to obtain the crude compound 7-3, which was directly injected into the next step. MS (ESI) m/z: 115.2 [M+H + ].
  • Step C Compound 7-3 (229.53 mg, 2.01 mmol, 1.1 eq) and compound 1-21 (510.87 mg, 1.83 mmol, 1 eq) were dissolved in dioxane (5 mL), N was added, N-Diisopropylethylamine (708.63 mg, 5.48 mmol, 955.02 mL, 3 equivalents), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (105.75 mg, 182.77 ⁇ mol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (83.68 mg, 91.38 ⁇ mol, 0.05 eq).
  • Step D Compound 7-4 (233 mg, 744.95 micromoles, 1 equiv) and compound 1-12A (256.81 mg, 968.43 micromoles, 1.3 equivs, 2 molecules of hydrochloride) were dissolved in N,N-dimethyl To formamide (5 mL), potassium carbonate (514.79 mg, 3.72 mmol, 5 eq) was added. The reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, the reaction liquid was cooled to 15 degrees Celsius, and the reaction liquid was filtered and concentrated under reduced pressure to obtain compound 7-5. MS (ESI) m/z: 469.3 [M+H + ].
  • Step E Compound 7-5 (307 mg, 655.18 micromole, 1 equivalent) was dissolved in tetrahydrofuran (3 ml), and diisobutylaluminum hydride (1 mole per liter, 3.28 ml , 5 equivalents).
  • Step A Compound 2-1 (1 g, 3.88 mmol, 1 eq), methoxyamine (1.62 g, 19.42 mmol, 5 eq, hydrochloride) and N, N-diisopropylethylamine (3.01 g, 23.31 mmol, 4.06 mL, 6 equiv) was dissolved in dimethyl sulfoxide (15 mL) and subjected to microwave reaction at 100 °C for 12 hours. Add water (100 milliliters) and ethyl acetate (100 milliliters) after completion of the reaction, separate the organic phase, and then use ethyl acetate (100 milliliters) to extract the aqueous phase to obtain the combined organic phase. mL ⁇ 5), washed with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 8-1. MS (ESI) m/z: 285.0 [M+H + ].
  • Step B Under nitrogen protection, compound 8-1 (2 g, 7.03 mmol, 1 eq), compound 1-14 (1.84 g, 8.44 mmol, 1.2 eq), N, N-diisopropylethyl Amine (1.82 g, 14.06 mmol, 2.45 mL, 2 equiv), palladium acetate (78.92 mg, 351.52 micromol, 0.05 equiv) and 4,5-bis(diphenylphosphine)-9,9-dimethyloxy Xanthene (203.39 mg, 351.52 micromole, 0.05 eq) was dissolved in dioxane (20 mL) and reacted at 100°C for 3 hours under nitrogen protection.
  • Step C Under nitrogen protection, compound 8-2 (0.61 g, 1.63 mmol, 1 eq) was dissolved in THF (6 mL), and potassium tert-butoxide THF solution (1 mol per liter, 3.25 mL, 2 Equivalent), stirred at 15 degrees Celsius for 0.5 hour. The pH of the reaction solution was adjusted to 7 with 1 mole per liter of hydrogen chloride ethyl acetate solution, and then concentrated under reduced pressure to obtain compound 8-3. MS (ESI) m/z: 191.1 [M+H + ].
  • Step D Under nitrogen protection, compound 8-3 (310.19 mg, 1.63 mmol, 1 equivalent), compound 1-21 (454.78 mg, 1.63 mmol, 1 equivalent), tris(dibenzylideneacetone) di Palladium (74.49 mg, 81.35 micromoles, 0.05 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (94.14 mg, 162.70 micromoles, 0.1 equiv) and N,N - Diisopropylethylamine (630.84 mg, 4.88 mmol, 850.19 microliters, 3 equivalents) was dissolved in 1,4-dioxane (3 milliliters) and reacted at 100 degrees Celsius under nitrogen protection for 12 hours.
  • 1,4-dioxane 3 milliliters
  • Step F Under the protection of nitrogen, compound 8-5 (27 mg, 49.54 micromole, 1 eq) was dissolved in tetrahydrofuran (1 mL), cooled to 0 degrees Celsius, and diisobutylaluminum hydride (1 mole per liter, 247.68 microliters, 5 equivalents), keep the temperature not exceeding 3°C, and stir at 15°C for 1 hour after the dropwise addition.
  • Step A Compound 9-1 (10 g, 68.04 mmol, 1 eq) was dissolved in acetonitrile (100 mL) and anhydrous potassium fluoride (7.91 g, 136.08 mmol, 3.19 mL, 2 eq) and bromofluoro Diethyl methylphosphonate (18.17 g, 68.04 mmol, 1 equiv), and the reaction solution was stirred at 25°C for 12 hours. After the reaction was complete, acetonitrile (20 ml) was added to the reaction liquid, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-2. MS (ESI) m/z: 197.0, 199.0 [M+H + ].
  • Step B Dissolve compound 9-2 (13.30 g, 60.92 mmol, 1.2 eq) and compound 1-14 (10 g, 50.77 mmol, 1 eq) in dioxane (100 ml) and add N, N - Diisopropylethylamine (19.68g, 152.30mmol, 26.53ml, 3eq), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (2.94g, 5.08mM mol, 0.1 equiv) and tris(dibenzylideneacetone)dipalladium (2.32 g, 2.54 mmol, 0.05 equiv).
  • Step C Compound 9-3 (1 g, 2.99 mmol, 1 eq) was dissolved in tetrahydrofuran (10 ml), and sodium methoxide methanol solution (5 moles per liter, 777.46 microliters, 1.3 eq) was added, and the reaction mixture was Stir for 0.5 h at 25°C. After the reaction was complete, the pH value of the reaction solution was adjusted to 7 with hydrochloric acid/ethyl acetate (4 moles per liter), and the reaction solution was directly concentrated to obtain compound 9-4. MS (ESI) m/z: 151.1 [M+H + ].
  • Step D Compound 1-21 (759.84 mg, 2.72 mmol, 1 eq) and compound 9-4 (448.98 mg, 2.99 mmol, 1.1 eq) were dissolved in dioxane (10 mL), N was added, N-Diisopropylethylamine (1.05 g, 8.16 mmol, 1.42 mL, 3 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (157.29 mg, 271.84 ⁇ mol, 0.1 eq) and tris(dibenzylideneacetone)dipalladium (124.46 mg, 135.92 ⁇ mol, 0.05 eq).
  • Step E Compound 9-5 (400 mg, 1.15 mmol, 1 eq) and compound 1-12A (395.39 mg, 1.49 mmol, 1.3 eq, 2 molecules of hydrochloride) were dissolved in NN dimethylformamide ( 5 ml), potassium carbonate (792.57 mg, 5.73 mmol, 5 equivalents) was added. The reaction mixture was heated to 80°C and stirred for 12 hours. After the reaction was complete, it was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 9-6. MS (ESI) m/z: 505.2 [M+H + ].
  • Step F Compound 9-6 (0.7 g, 1.39 mmol, 1 eq) was dissolved in tetrahydrofuran (7 ml), and diisobutylaluminum hydride (1 mole per liter, 6.94 ml , 5 equivalents). The reaction mixture was stirred at 25 degrees Celsius for 0.5 hours, quenched with saturated sodium sulfate solution (10 ml) until no bubbles emerged, then stirred at 25 degrees Celsius for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product.
  • Step A To a solution of compound 10-1 (1 g, 5.29 mmol, 1 eq) in 1,4-dioxane (15 mL) was added phosphorus oxychloride (4.06 g, 26.45 mmol, 2.46 mL, 5 equivalents). After stirring for 12 hours under nitrogen protection and 90°C, cool to 25°C, add water (50 ml) dropwise to quench the reaction, extract with ethyl acetate (50 ml ⁇ 2), and combine the organic phases with brine (50 ml ⁇ 2 ), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product of compound 10-2, which was directly used in the next step.
  • phosphorus oxychloride 4.06 g, 26.45 mmol, 2.46 mL, 5 equivalents.
  • Step B To compound 10-2 (800 mg, 3.86 mmol, 1 eq) and compound 1-16 (619.41 mg, 3.86 mmol, 1 eq) in 1,4-dioxane (10 mL) was added N,N-Diisopropylethylamine (1.50 g, 11.57 mmol, 2.02 mL, 3 equiv), 4,5-bis(diphenylphosphine)-9,9-dimethylxanthene (446.26 mg , 771.25 micromoles, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium (353.12 mg, 385.62 micromoles, 0.1 equiv).
  • Step C To compound 10-3 (10 mg, 34.82 micromoles, 1 equiv) and compound 1-12A (9.23 mg, 34.82 micromoles, 1 equiv, 2 molecules of hydrochloride) was N,N-dimethylformazan Potassium carbonate (24.06 mg, 174.11 micromol, 5 eq) was added to the solution of the amide (1 mL). After stirring at 100° C.
  • the compound to be tested was diluted to 100 ⁇ M with 100% DMSO as the first concentration, and then diluted 4 times to the eighth concentration with a row gun, that is, diluted from 100 ⁇ M to 6.1 nM.
  • the compound to be tested was diluted with 1-fold buffer solution into a 10% DMSO working solution, 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 value detection Take 5 ⁇ L of each gradient of the compound to be tested diluted in 100% DMSO into a new compound plate, add 45 ⁇ L of 1-fold buffer solution for 10-fold dilution, and make a 10% DMSO working solution, and then take the Put 5 ⁇ L/well of compound working solution into the detection plate, then add 45 ⁇ L 1-fold buffer solution for 10-fold dilution.
  • the final concentration of DMSO is 1%, 1000 rpm/min, and after centrifugation for 1 minute, use a multi-label analyzer to read the fluorescence value. Excitation wavelength: 360nm, test wavelength: 460nm.
  • Table 1 provides the effect of compounds of the present application on SHP2 enzyme activity.
  • the compound of the present application has excellent in vitro inhibitory activity on SHP2.
  • Cell culture medium penicillin/streptomycin antibiotics were purchased from Vicente, and fetal calf serum was purchased from Biosera.
  • Cell lines were purchased from Nanjing Kebai Biotechnology Co., Ltd. and Wuhan Punosai Life Technology Co., Ltd. Envision Multilabel Analyzer (PerkinElmer).
  • Different tumor cells were planted in an ultra-low adsorption 96-well U-shaped plate, 80 ⁇ L of cell suspension per well, and the cell density conditions were as shown in the table below. Cell plates were cultured overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 5 times to the ninth concentration, that is, diluted from 2mM to 5.12nM or 200 ⁇ M to 0.512nM, to set up a double-well experiment.
  • the concentration range of the compound transferred to the cell plate is 10 ⁇ M to 0.0256 nM, or 1 ⁇ M to 0.00256 nM.
  • the cell plate is placed in a carbon dioxide incubator and cultured for 3-6 days. Please refer to Table 1 for specific time.
  • IC 50 Convert the raw data into inhibition rate, and the value of IC 50 can be obtained by curve fitting with four parameters (obtained by "log(inhibitor) vs. response--Variable slope" mode in GraphPad Prism).
  • Table 2 provides the inhibitory activity of the compounds of the present application on the proliferation of different tumor cells.
  • the compounds of the present application of table 3 are to the inhibitory activity of MiaPaCa-2 cell proliferation
  • the compound of the present application has good anti-proliferation and inhibitory effects on KRAS mutated cancer cells H358 and MiaPaCa-2.
  • H358 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.; 1640 medium was purchased from Biological industries; fetal bovine serum was purchased from Biosera; Advanced Phospho-ERK1/2 (THR202/TYR204) KIT was purchased from Cisbio Advanced Phospho-ERK1/2 (THR202 /TYR204) KIT ingredient list
  • Blocking solution 100X stock solution storage
  • Blocking reagent stock solution 100X
  • ⁇ -16°C Lysis buffer #1 (4X stock solution storage)
  • Lysis buffer #1 (stock solution 4X)
  • Detection buffer ready-to-use
  • H358 cells are planted in a transparent 96-well cell culture plate, 80 ⁇ L of cell suspension per well, each well contains 10,000 H358 cells, the cell plate is placed in a carbon dioxide incubator, and incubated overnight at 37;
  • the compound of the present application has a strong inhibitory effect on ERK phosphorylation of KRAS mutated cancer cell H358.
  • the purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
  • the animals in the intravenous group were given the corresponding compound through a single injection of the tail vein, and the administration volume was 5 ml/kg; the animals in the oral group were given the corresponding compound through a single gavage, and the administration volume was 10 ml/kg.
  • the animals were weighed before administration, and the administration volume was calculated according to the body weight.
  • Sample collection time 0.083 hours, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 24 hours for the injection group, 0.25 hours, 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 24 hours.
  • the compound of the present application has excellent pharmacokinetic properties.
  • the compound of the present application has excellent AUC and bioavailability after oral administration in mice, and has good pharmacokinetic properties.
  • the purpose of this experiment is to evaluate the pharmacokinetic behavior of the compound after a single intravenous injection and intragastric administration, and to investigate the bioavailability after intragastric administration.
  • the compound of the present application has excellent AUC and bioavailability after oral administration in rats, and has good pharmacokinetic properties.
  • MIA PaCa-2 cell line subcutaneously xenografted female BALB/c nude mouse animal model.
  • MIA PaCa-2 cells were cultured in DMEM medium containing 2.5% HS and 10% fetal calf serum. MIA PaCa-2 cells in the exponential growth phase were collected and resuspended in PBS to a suitable concentration for subcutaneous tumor inoculation in nude mice.
  • mice were subcutaneously inoculated with 5 ⁇ 10 6 MIA PaCa-2 cells on the right back, and the cells were resuspended in 1:1 PBS and Matrigel (0.1ml/mouse). The tumor growth was observed regularly until the tumor grew to the average volume. When ⁇ 125 (100-150) mm 3 , the mice were randomly divided into groups according to tumor size and body weight.
  • tumor volume (mm 3 ) 1/2 ⁇ (a ⁇ b 2 ) (where a represents the long diameter and b represents the short diameter).
  • Table 7 shows the tumor inhibitory effects of the compounds.
  • the compound of the present application has significant inhibitory effect on MiaPaCa-2 subcutaneous xenograft tumor growth.

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Abstract

公开了一类吡咯并吡唑螺环化合物，及其在制备治疗相关疾病的药物中的应用，具体涉及式(I')化合物、其立体异构体及其药学上可接受的盐。

Description

吡咯并吡唑螺环化合物
本申请主张如下优先权：
本申请要求1)于2021年10月27日向中国国家知识产权局提交的第202111257617.8号中国专利申请的优先权和权益，2)于2021年11月19日向中国国家知识产权局提交的第202111402382.7号中国专利申请的优先权和权益，3)于2022年01月14日向中国国家知识产权局提交的第202210045128.4号中国专利申请的优先权和权益，和4)于2022年10月18日向中国国家知识产权局提交的第202211275680.9号中国专利申请的优先权和权益，所述申请公开的内容通过引用整体并入本文中。
技术领域
本申请涉及一类吡咯并吡唑螺环化合物，及其在制备治疗相关疾病的药物中的应用，具体涉及式(I)化合物、其立体异构体及其药学上可接受的盐。
背景技术
SHP2属于蛋白酪氨酸磷酸酶(protein tyrosine phosphatase，PTP)家族成员，是一种非受体型磷酸酶，催化蛋白质酪氨酸去磷酸化反应。SHP2由PTP非受体型11(PTP nonreceptor 11，PTPN11)编码，在人体中广泛表达，在生长因子受体下游信号通路中扮演重要角色。作为包括RAS-ERK、PI3K-AKT、JAK-STAT等在内的多种重要通路的上游蛋白，SHP2起到调节细胞增殖、分化、迁移、凋亡等多种生理学功能。同时，SHP2也被发现处于PD-1/PD-L1通路中，起到免疫调节的作用。
有研究证明，SHP2对RAS驱动的肿瘤是不可或缺的。SHP2处于RAS上游，介导激活RAS-ERK通路，这一功能主要通过去磷酸化RAS-GAP实现。当受到各种生长因子的刺激时，SHP2去磷酸化RTKs的酪氨酸磷酸化位点，并通过去磷酸化p120RasGAP与RTKs结合的位点，防止p120RasGAP抑制Ras活化，起到激活RAS通路的目的。
从N端开始，SHP2蛋白包含两个Src同源结构域N-SH2和C-SH2，之后是具有催化活性的PTP区域。正常的SHP2处在自抑制状态，活性催化微点被N-SH2遮挡。当Tyr542和Tyr580被磷酸化后，构象发生变化，SHP2被激活。当SHP2发生突变(如：E76K等)时，N-SH2构象发生巨大的变化，无法遮挡活性催化位点，SHP2无需磷酸化便被激活。在多种肿瘤中均发现SHP2突变。
由于PTP区域起催化磷酸酯的作用，其催化位点极性非常高，这使得直接作用于催化位点的小分子药物开发难度大。别构抑制剂是另一个抑制SHP2的思路。SHP2别构抑制剂起到“胶水”的作用，使得SHP2保持在自抑制的状态。目前已有多个SHP2别构抑制剂进入临床研究阶段，在NSCLC等疾病中展现出了优异的药效。
综上，靶向SHP2的别构抑制剂能够成为一种进步的癌症治疗方案。
发明内容
本申请提供式(I’)化合物、其立体异构体或其药学上可接受的盐
Figure PCTCN2022127937-appb-000001
其中，
环A选自芳基和杂芳基；
R 1选自H、氘、NH 2、任选地被一个或多个卤素、CN或OH取代的C 1-6烷基；
R 2选自氘、H、卤素、OH、CN、COOH、-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；
R 3选自H、卤素、OH、NO 2、CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2或3个R b取代；
R 4、R 5和R 6分别独立地选自H、氘、卤素、NH 2、NO 2、CN、OH、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1- 6烷基，所述NH 2、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1-6烷基分别独立地任选被1、2或3个R c取代；
R a、R b、R c分别独立地选自氘、卤素、OH、NH 2、CN和C 1-3烷基。
本申请提供式(I)化合物、其立体异构体或其药学上可接受的盐
Figure PCTCN2022127937-appb-000002
其中，
环A选自芳基和杂芳基；
R 1选自H、氘、NH 2、任选地被一个或多个卤素、CN或OH取代的C 1-6烷基；
R 2选自氘、H、卤素、OH、CN、COOH、-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；
R 3选自H、卤素、OH、NO 2、CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2或3个R b取代；
R 4、R 5和R 6分别独立地选自H、氘、卤素、NH 2、NO 2、CN、OH、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1- 6烷基，所述NH 2、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1-6烷基分别独立地任选被1、2或3个R c取代；
R a、R b、R c分别独立地选自氘、卤素、OH、NH 2、CN和C 1-3烷基。
在一些实施方案中，所述环A选自芳基和5-6元杂芳基，所述5-6元杂芳基包含1、2或3个分别独立地选自N、O、S和NH的杂原子或杂原子团。
在一些实施方案中，所述R 1选自H、氘、NH 2、任选地被一个或多个卤素、CN或OH取代的C 1-3烷基。在一些实施方案中，所述R 1选自H、氘、NH 2、任选地被一个或多个卤素取代的C 1-3烷基。在一些实施方案中，所述R 1选自H、氘、NH 2、任选地被一个或多个氟取代的C 1-3烷基。在一些实施方案中，所述R 1选自H、氘、NH 2、CH 3、CHF 2、CH 2F和CF 3。
在一些实施方案中，R 2选自氘、F、Cl、Br、I、CN、COOH、-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代。
在一些实施方案中，R 3选自H、F、Cl、Br、I、NO 2、CN、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代。
在一些实施方案中，R 4、R 5和R 6分别独立地选自H、氘、F、Cl、Br、I、NH 2、NO 2、CN、OH、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基，所述NH 2、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基分别独立地任选被1、2或3个R c取代。
本申请提供式(I)化合物、其立体异构体或其药学上可接受的盐
Figure PCTCN2022127937-appb-000003
其中，
环A选自芳基和5-6元杂芳基，所述5-6元杂芳基包含1、2或3个分别独立地选自N、O、S和NH的杂原子或杂原子团；
R 1选自H、氘、NH 2、CH 3、CHF 2、CH 2F和CF 3；
R 2选自氘、F、Cl、Br、I、CN、COOH、-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；
R 3选自H、F、Cl、Br、I、NO 2、CN、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代；
R 4、R 5和R 6分别独立地选自H、氘、F、Cl、Br、I、NH 2、NO 2、CN、OH、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基，所述NH 2、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基分别独立地任选被1、2或3个R c取代；
R a分别独立地选自氘、F、Cl、Br、I、OH和NH 2；
R b分别独立地选自氘、F、Cl、Br、I和OH；
R c分别独立地选自氘、F、Cl、Br、I、NH 2和C 1-3烷基。
在一些方案中，R a、R b、R c分别独立地选自卤素、OH、NH 2和C 1-3烷基。在一些方案中，R a、R b、R c分别独立地选自卤素、OH和C 1-3烷基。在一些方案中，R a、R b、R c分别独立地选自氟、OH和C 1-3烷基。在一些方案中，R a、R b、R c分别独立地选自氟、OH和CH 3。
在一些方案中，所述R a分别独立地选自氘、F、Cl、Br、I、OH和NH 2；
所述R b分别独立地选自氘、F、Cl、Br、I和OH；
所述R c分别独立地选自氘、F、Cl、Br、I、NH 2和C 1-3烷基。
在一些方案中，所述R a分别独立地选自F、Cl、OH和NH 2。在一些方案中，所述R a分别独立地选自OH。
在一些方案中，所述R b分别独立地选自F、Cl和OH。
在一些方案中，所述R c分别独立地选自F、Cl、Br、I和C 1-3烷基。在一些方案中，所述R c分别独立地选自F、Cl、Br、I、NH 2和CH 3。在一些方案中，所述R c分别独立地选自F、Cl、NH 2和CH 3。
在一些方案中，所述R c分别独立地选自F和C 1-3烷基。
在本申请的一些方案中，上述R c分别独立地选自F和CH 3，其他变量如本申请所定义。
在本申请的一些方案中，上述R 1选自H、CH 3和CHF 2，其他变量如本申请所定义。
在本申请的一些方案中，上述R 1选自CH 3和CHF 2，其他变量如本申请所定义。
在本申请的一些方案中，上述R 2选自氘、F、Cl、Br、I、CH 3和-C(＝O)NH 2，所述CH 3和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代，其他变量如本申请所定义。
在本申请的一些方案中，上述R 2选自Cl、-CH 2OH、-CH 3和-C(＝O)NH 2，其他变量如本申请所定义。
在本申请的一些方案中，上述R 2选自Cl、-CH 2OH和-C(＝O)NH 2，其他变量如本申请所定义。
在本申请的一些方案中，上述R 3选自H、F、Cl和CH 3，其他变量如本申请所定义。
在本申请的一些方案中，上述R 3选自H，其他变量如本申请所定义。
在本申请的一些方案中，上述R 4、R 5和R 6分别独立地选自H、氘、F、Cl、Br、I、NH 2、NO 2、CN、OH、＝O、CH 3、-OCH 3和-NH-O-CH 3，所述NH 2、CH 3、-OCH 3和-NH-O-CH 3分别独立地任选被1、2或3 个R c取代，其他变量如本申请所定义。
在本申请的一些方案中，上述R 4、R 5和R 6分别独立地选自F、Cl、NH 2、-NH-O-CH 3、-NH-CH 3、CH 3、CF 3和CHF 2，其他变量如本申请所定义。
在本申请的一些方案中，上述结构单元
Figure PCTCN2022127937-appb-000004
选自
Figure PCTCN2022127937-appb-000005
Figure PCTCN2022127937-appb-000006
其他变量如本申请所定义。
在本申请的一些方案中，上述结构单元
Figure PCTCN2022127937-appb-000007
选自
Figure PCTCN2022127937-appb-000008
Figure PCTCN2022127937-appb-000009
其他变量如本申请所定义。
在本申请的一些方案中，上述结构单元
Figure PCTCN2022127937-appb-000010
选自
Figure PCTCN2022127937-appb-000011
Figure PCTCN2022127937-appb-000012
其他变量如本申请所定义。
在本申请的一些方案中，上述环A选自C 6-10芳基和5-10元杂芳基。在本申请的一些方案中，上述环A选自C 6-10芳基和5-6元杂芳基。在本申请的一些方案中，上述环A选自苯基和5-6元杂芳基。
在本申请的一些方案中，上述环A选自苯基、吡唑基和吡啶基，其他变量如本申请所定义。
在本申请的一些方案中：
上述环A选自苯基、吡唑基和吡啶基；或者上述环A选自吡啶基；
上述R 2选自氘、F、Cl、Br、I、CH 3和-C(＝O)NH 2，所述CH 3和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；或者上述R 2选自Cl、-CH 2OH、CH 3和-C(＝O)NH 2；或者上述R 2选自Cl、-CH 2OH和-C(＝O)NH 2；或者上述R 2选自-CH 2OH；
上述R 3选自H、F、Cl和CH 3；或者上述R 3选自H；
上述R 4、R 5和R 6分别独立地选自F、Cl、NH 2、-NH-O-CH 3、-NH-CH 3、CH 3、CF 3和CHF 2，
其他变量如本申请所定义。
本申请还有一些技术方案是由上述各变量任意组合而来。
本申请提供式(I)化合物、其立体异构体或其药学上可接受的盐，其中式(I)化合物选自式(I)-A或式(I)-B化合物
Figure PCTCN2022127937-appb-000013
在本申请的一些方案中，上述化合物选自
Figure PCTCN2022127937-appb-000014
其中，R 1、R 4和R 5如本申请所定义。
在本申请的一些方案中，上述化合物选自
Figure PCTCN2022127937-appb-000015
Figure PCTCN2022127937-appb-000016
其中，R 1、R 4和R 5如本申请所定义。
本申请还提供化合物、其立体异构体或其药学上可接受的盐，其中，化合物选自
Figure PCTCN2022127937-appb-000017
在本申请的一些方案中，上述化合物选自
Figure PCTCN2022127937-appb-000018
Figure PCTCN2022127937-appb-000019
另一方面，本申请涉及一种药物组合物，其包含本申请的化合物、其立体异构体或其药学上可接受的盐。在一些实施方案中，本申请的药物组合物还包括药学上可接受的辅料。
另一方面，本申请涉及预防或者治疗哺乳动物与SHP2蛋白相关疾病的方法，包括对需要该治疗的哺乳动物，优选人类，给予治疗有效量的本申请的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
另一方面，本申请涉及本申请的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在制备预防或者治疗与SHP2蛋白相关疾病的药物中的用途。
另一方面，本申请涉及本申请的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物在预防或者治疗与SHP2蛋白相关疾病的用途。
另一方面，本申请涉及预防或者治疗与SHP2蛋白相关疾病的本申请的化合物、其立体异构体或其药学上可接受的盐、或其药物组合物。
在一些方案中，所述与SHP2蛋白相关疾病选自癌症；或者，所述与SHP2蛋白相关疾病选自肺癌或胰腺癌。
技术效果
本申请提供了一种新型的SHP2别构抑制剂，对SHP2具有较高体内外抑制活性，可以作为一种新的、更有效的治疗癌症的方案。具体的体外可以抑制激酶或肿瘤细胞(MIAPACA2_PANCREAS、NCIH358_LUNG)活性；体内药代动力学性质及药效学性质优异。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本申请化合物的盐，由本申请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。当本申请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。当本申请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。本申请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。
本申请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。
本申请的化合物可以存在特定的几何或立体异构体形式。本申请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申请的范围之内。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，均包括在本申请的范围之内。
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 PCTCN2022127937-appb-000020
和楔形虚线键
Figure PCTCN2022127937-appb-000021
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022127937-appb-000022
和直形虚线键
Figure PCTCN2022127937-appb-000023
表示立体中心的相对构型，用波浪线
Figure PCTCN2022127937-appb-000024
表示楔形实线键
Figure PCTCN2022127937-appb-000025
或楔形虚线键
Figure PCTCN2022127937-appb-000026
或用波浪线
Figure PCTCN2022127937-appb-000027
表示直形实线键
Figure PCTCN2022127937-appb-000028
和直形虚线键
Figure PCTCN2022127937-appb-000029
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。如果想得到本申请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)。
本申请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。本申请的化合物的所有同位素组成的变换，无论放射性与否，都包括在本申请的范围之内。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
术语“被取代的”是指特定原子上的任意一个或多个氢原子被取代基取代，取代基可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
当其中一个变量选自单键时，表示其连接的两个基团直接相连，比如A-L-Z中L代表单键时表示该结构实际上是A-Z。
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2022127937-appb-000030
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 PCTCN2022127937-appb-000031
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 PCTCN2022127937-appb-000032
所述连接基团、取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2022127937-appb-000033
直形虚线键
Figure PCTCN2022127937-appb-000034
或波浪线
Figure PCTCN2022127937-appb-000035
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 PCTCN2022127937-appb-000036
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 PCTCN2022127937-appb-000037
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 PCTCN2022127937-appb-000038
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 PCTCN2022127937-appb-000039
Figure PCTCN2022127937-appb-000040
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022127937-appb-000041
仍包括
Figure PCTCN2022127937-appb-000042
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。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
术语“烷基”用于表示直链或支链的由碳原子组成的饱和碳氢基团。除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团；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。
术语“烷氧基”表示-O-烷基。除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团；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。
术语“C 1-6烷氨基”表示-NH-烷基。除非另有规定，术语“C 1-6烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至6个碳原子的烷基基团；术语“C 1-3烷氨基”表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氨基包括C 1-2、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。
除非另有规定，术语“卤代素”或“卤素”本身或作为另一取代基的一部分表示氟、氯、溴或碘原子。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团。例如，芳基可以具有6-20个碳原子，6-14个碳原子或6-12个碳原子。芳基的非限制性实例包括但不限于苯基、萘基、蒽基和1,2,3,4-四氢化萘等。
术语“杂芳基”是指单环或稠合多环体系，其中含有至少一个选自N、O、S的环原子，例如1个、2个、3个或4个选自N、O、S的环原子，其余环原子为C，并且具有至少一个芳香环。优选的杂芳基具有单个5至8元环或5至6元环，或包含6至14个，尤其是6至10个环原子的多个稠合环。
除非另有规定，本申请术语“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)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。
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“治疗”意为将本申请所述化合物或制剂进行给药以改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)抑制疾病或疾病状态，即遏制其发展；
(ii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“预防”意为将本申请所述化合物或制剂进行给药以预防疾病或与所述疾病相关的一个或多个症状，且包括：预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时。
术语“治疗有效量”意指(i)治疗或预防特定疾病、病况或障碍，(ii)减轻、改善或消除特定疾病、病况或障碍的一种或多种症状，或(iii)预防或延迟本文中所述的特定疾病、病况或障碍的一种或多种症状发作的本申请化合物的用量。构成“治疗有效量”的本申请化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“药物组合物”是指一种或多种本申请的化合物或其盐与药学上可接受的辅料组成的混合物。药物组合物的目的是有利于对有机体给予本申请的化合物。
术语“药学上可接受的辅料”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些辅料。合适的辅料是本领域技术人员熟知的，例如碳水化合物、蜡、水溶性和/或水可膨胀的聚合物、亲水性或疏水性材料、明胶、油、溶剂、水等。
词语“包括(comprise)”或“包含(comprise)”及其英文变体例如comprises或comprising应理解为开放的、非排他性的意义，即“包括但不限于”。
本申请化合物的治疗剂量可根据例如以下而定：治疗的具体用途、给予化合物的方式、患者的健康和状态，以及签处方医师的判断。本申请化合物在药用组合物中的比例或浓度可不固定，取决于多种因素，它们包括剂量、化学特性(例如疏水性)和给药途径。例如可通过含约0.1～10％w/v该化合物的生理缓冲水溶液提供本申请化合物，用于肠胃外给药。某些典型剂量范围为约1μg/kg～约1g/kg体重/日。在某些实施方案中，剂量范围为约0.01mg/kg～约100mg/kg体重/日。剂量很可能取决于此类变量，如疾病或病症的种类和发展程度、具体患者的一般健康状态、所选择的化合物的相对生物学效力、赋形剂制剂及其给药途径。可通过由体外或动物模型试验系统导出的剂量-反应曲线外推，得到有效剂量。
本申请具体实施方式的化学反应是在合适的溶剂中完成的，所述的溶剂须适合于本申请的化学变化及其所需的试剂和物料。为了获得本申请的化合物，有时需要本领域技术人员在已有实施方式的基础上对合成步骤或者反应流程进行修改或选择。
本申请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申请的实施例。
在一些方案中，本申请的化合物可以由本领域技术人员通过以下通用路线并采用本领域已知的方法来制备：
Figure PCTCN2022127937-appb-000043
LG1和LG2为离去基团，如：卤素、-O-O 2SR(R＝任选被取代的C 1-6烷基)。
本申请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，如果本申请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 PCTCN2022127937-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。
本申请所使用的溶剂可经市售获得。
本申请采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N，N，N'，N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N，N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；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；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺；NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着对本申请任何不利限制。本申请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申请的实施例。对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请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：化合物1
Figure PCTCN2022127937-appb-000045
步骤A：在氮气保护下，将化合物1-1(8.9克，34.59毫摩尔，1当量)的四氢呋喃(100毫升)溶液冷却到-70，然后加入二异丙基氨基锂(2摩尔每升，20.75毫升，1.2当量)，在-70摄氏度搅拌1小时后加入化合物1-2(3.66克，38.05毫摩尔，1.1当量)，在25摄氏度下搅拌12小时后加入乙酸乙酯(200毫升)，然后用食盐水洗(300毫升×3)，无水硫酸钠干燥，过滤，减压浓缩得到的粗产品经制备级高效液相色谱法(柱子：Phenomenex luna C18(250×70毫米,10微米)；流动相：[水(0.225％甲酸)-乙腈]；乙腈％：25％-55％，22分钟)纯化得到化合物1-3。MS(ESI)m/z：254.2,298.2[M+H +-100,M+H +-56]。
步骤B：在0摄氏度下，向化合物1-3(2.7克，7.64毫摩尔，1当量)的四氢呋喃(30毫升)溶液中加入四氢铝锂(376.95毫克，9.93毫摩尔，1.3当量)，在25摄氏度搅拌12小时后，加入饱和的硫酸钠溶液淬灭反应，直至无气泡产生，加入乙酸乙酯(100毫升)，过滤，滤液用食盐水洗(100毫升×2)，无水硫酸钠干燥，过滤，减压浓缩得到化合物1-4。MS(ESI)m/z：256.1[M+H +-56]。
步骤C：向化合物1-4(1.5克，4.82毫摩尔，1当量)的N,N-二甲基甲酰胺(20毫升)溶液中加入咪唑(491.93毫克，7.23毫摩尔，1.5当量)和叔丁基二甲基氯硅烷(871.29毫克，5.78毫摩尔，708.36微升，1.2当量)，在25摄氏度下搅拌1小时后，加入乙酸乙酯(80毫升)，用食盐水洗(80毫升×5)，无水硫酸钠干燥，过滤，减压浓缩得到化合物1-5。MS(ESI)m/z：426.3[M+H +]。
步骤D：向化合物1-5(2.2克，5.17毫摩尔，1当量)的二氯甲烷(20毫升)溶液中加入戴斯-马丁试剂(2.63克，6.20毫摩尔，1.2当量)，在25摄氏度下搅拌12小时，反应完后加入亚硫酸钠溶液(40毫升)和饱和的碳酸氢钠溶液(40毫升)，在25摄氏度下搅拌30分钟，二氯甲烷萃取(50毫升×2)，合并的有机相用食盐水洗，无水硫酸钠干燥，过滤，减压浓缩得到的粗产品经硅胶柱层析法(洗脱液：乙酸乙酯在石油醚中百分比＝0％-50％)纯化得到化合物1-6。MS(ESI)m/z：324.5[M+H +-100]。
步骤E：向化合物1-6(750毫克，1.77毫摩尔，1当量)的四氢呋喃(20毫升)溶液中加入四丁基氟化铵(1摩尔每升，2.66毫升，1.5当量)，在25摄氏度下搅拌12小时，反应完后加入乙酸乙酯(50毫升)，食盐水洗(50毫升×5)，无水硫酸钠干燥，过滤，减压浓缩得到化合物1-7。MS(ESI)m/z：210.0[M+H +-100]。
步骤F：向化合物1-7(620毫克，2.00毫摩尔，1当量)的四氢呋喃(10毫升)溶液中加入三苯基磷(578.22毫克，2.20毫摩尔，1.1当量)和偶氮二甲酸二异丙酯(445.78毫克，2.20毫摩尔，428.63微升，1.1当量)，在25摄氏度下搅拌12小时，减压浓缩得到的粗产品经硅胶柱层析法(洗脱液：乙酸乙酯在石油醚中百分比＝0％-20％)纯化得到化合物1-8。MS(ESI)m/z：236.2[M+H +-56]。
步骤G：向化合物1-8(100毫克，343.24微摩尔，1当量)和1-9(124.80毫克，1.03毫摩尔，3当量)的甲苯(5毫升)溶液中加入四乙氧基钛(156.59毫克，686.47微摩尔，142.35微升，2当量)，在氮气保护和110摄氏度下搅拌12小时，反应完后化合物1-10直接在溶液中在下一步中使用。MS(ESI)m/z：395.5[M+H +]。
步骤H：在氮气保护和-70摄氏度下，向化合物1-10(135.42毫克，343.24微摩尔，1当量)的甲苯(3毫升)溶液中加入硼氢化钠(130毫克，3.44毫摩尔，10.01当量)，在-70摄氏度下搅拌1小时，加入甲醇(5毫升)淬灭反应，再加入20毫升乙酸乙酯，过滤，滤液用食盐水洗(20毫升×3)，无水硫酸钠干燥，过滤，减压浓缩得到的粗品经制备型高效液相色谱柱(柱型号：Phenomenex luna C18(150毫米×25毫米×10微米)；流动相：[0.225％甲酸水溶液-乙腈]；梯度：30％-60％)纯化得到化合物1-11。MS(ESI)m/z：397.5[M+H +]。将化合物1-11用制备SFC(柱型号：DAICEL CHIRALPAK IC(250毫米×30毫米×10微米)；流动相：A相为超临界二氧化碳，B相为甲醇(0.1％氨水)；梯度(B％)：35％-35％)分离得到化合物1-11A。MS(ESI)m/z：397.5[M+H +]。化合物1-11A经SFC检测(柱型号：Chiralpak IG-3(50毫米×4.6毫米×3微米)；流动相：A相为超临界二氧化碳，B相为甲醇(0.05％二乙胺)；梯度(B％)：5％-40％)得到：化合物1-11A的保留时间为1.294分钟，e.e.值为100.00％。
步骤I：向化合物1-11A(170毫克，428.70微摩尔，1当量)的乙酸乙酯(1毫升)溶液中加入盐酸乙酸乙酯(4摩尔每升，1毫升，9.33当量)，在20摄氏度下搅拌30分钟，反应完后加入乙酸乙酯(5毫升)，过滤，滤饼减压干燥得到化合物1-12A。
步骤J：将化合物1-13(10克，39.30毫摩尔，1当量)和化合物1-14(10.30克，47.16毫摩尔，1.2当量)溶解在二氧六环(100毫升)中加入N，N-二异丙基乙胺(10.16克，78.60毫摩尔，13.69毫升，2当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(2.27克，3.93毫摩尔，0.1当量)和三(二亚苄基丙酮)二钯(1.80克，1.96毫摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到105摄氏度搅拌12小时。反应完全后，将反应液冷却至25摄氏度，过滤，滤液浓缩得到粗品加入正庚烷(50毫升)和乙酸乙酯(5毫升)，在25摄氏度下搅拌1小时，过滤，滤饼真空干燥得到化合物1-15。MS(ESI)m/z：345.2[M+H +]。
步骤K：将化合物1-15(13.2克，38.27毫摩尔，1当量)溶解在四氢呋喃(130毫升)中，加入甲醇钠甲醇溶液(5.4摩尔每升，9.21毫升，1.3当量)，反应混合物在25摄氏度下搅拌1小时。反应完全后，将反应液直接浓缩得到粗品溶解在水(50毫升)中，用乙酸乙酯(50毫升×2)洗涤。水相用盐酸水溶液(1摩尔每升)调节pH到6，过滤，滤饼真空干燥得到化合物1-16。MS(ESI)m/z：161.1[M+H +]。
步骤L：将化合物1-18(29.79克，401.95毫摩尔，34.33毫升，1当量)溶解在乙醇(350毫升)中，在0摄氏度下，加入1-17(70克，401.95毫摩尔，61.95毫升，1当量)，反应混合物在25摄氏度下搅拌2小时。将反应液加热到80摄氏度搅拌20小时。反应完全后，反应液直接浓缩得到粗品经过柱层析(硅胶，乙酸乙酯：甲醇＝1：0到1：1)得到化合物1-19.MS(ESI)m/z：183.1[M+H +]。
步骤M：将化合物1-19(51.46克，282.47毫摩尔，1当量)溶解在N，N-二甲基甲酰胺(500毫升)中，在0摄氏度下，加入N-溴代丁二酰亚胺(52.79克，296.60毫摩尔，1.05当量)。反应混合物在25摄氏度下搅拌1小时。反应完全后，反应液加入水(500毫升)和乙酸乙酯(700毫升)，反应混合物搅拌2分钟，反应体系分层后水相用乙酸乙酯(700毫升)萃取。合并后的有机相用10％食盐水(500毫升×5)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品经过柱层析(硅胶，石油醚：乙酸乙酯＝1：0到7：1)得到化合物1-20。MS(ESI)m/z：261.0,263.0[M+H +]。
步骤N：将三苯基膦(18.08克，68.95毫摩尔，3当量)溶解在二氧六环(200毫升)中，加入N-氯代丁二酰亚胺(9.36克，70.10毫摩尔，3.05当量)，反应混合物在25摄氏度下搅拌0.5小时，加入化合物1-20(6克，22.98毫摩尔，1当量)。反应液加热到100摄氏度下搅拌1小时。反应完全后，反应混合物冷却至25摄氏度，反应液倒入水(600毫升)中，甲基叔丁基醚(400毫升×2)萃取。合并后的有机相用饱和食盐水(400毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到粗品经柱层析(硅胶，石油醚：乙酸乙酯＝10：1到5：1)得到化合物1-21。MS(ESI)m/z：279.0[M+H +]。
步骤O：将化合物1-21(5.6克，20.03毫摩尔，1当量)和化合物1-16(3.22克，20.03毫摩尔，1当量)溶解在二氧六环(80毫升)中，加入N，N-二异丙基乙胺(7.7克，60.10毫摩尔，10.47毫升，3当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(1.16克，2.00毫摩尔，0.1当量)和三(二亚苄基丙酮)二钯(917.30毫克，1.00毫摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌5小时。反应完全后，将反应液冷却至25摄氏度，过滤，滤液浓缩得到粗品加入乙酸乙酯(50毫升)，在25摄氏度下搅拌1小时，过滤，滤饼减压干燥得到化合物1-22。MS(ESI)m/z：359.1[M+H +]。
步骤P：将化合物1-22(1.90克，5.29毫摩尔，1当量)和化合物1-12A(1.82克，6.88毫摩尔，1.3当量，2分子盐酸盐)溶解在N-甲基吡咯烷酮(20毫升)中，加入碳酸钾(3.65克，26.45毫摩尔，5当量)。反应混合物加热到80摄氏度搅拌1小时。反应完全后，反应液冷却至25摄氏度，加入水(100毫升)，过滤，滤饼减压干燥得到化合物1-23。MS(ESI)m/z：515.3[M+H +]。
步骤E：将化合物1-23(1.1克，2.14毫摩尔，1当量)溶解在四氢呋喃(15毫升)中，在0摄氏度和氮气保护下加入二异丁基氢化铝(1摩尔每升，8.54毫升，4当量)。反应混合物在25摄氏度下搅拌1小时，用饱和硫酸钠溶液淬灭直至无气泡冒出后在25摄氏度下搅拌30分钟，过滤，滤液减压浓缩得到的粗品经制备级高效液相色谱(柱型号：Waters Xbridge BEH C18(250×50毫米×10微米)；流动相：[0.05％氨水-乙腈]；梯度：15％-45％)分离纯化得到化合物1。MS(ESI)m/z：473.3[M+H +]。 1H NMR(400MHz,DMSO-d6)δ＝7.65(d,J＝5.6Hz,1H),7.40(d,J＝1.2Hz,1H),6.34(s,2H),6.05(d,J＝1.6Hz,1H),5.75(d,J＝5.2Hz, 1H),5.45(t,J＝5.6Hz,1H),4.49(d,J＝5.6Hz,2H),4.15(d,J＝10.8Hz,1H),4.00-3.80(m,4H),3.25-3.19(m,2H),2.41(s,3H),1.97-1.92(m,3H),1.80-1.74(m,1H),1.68-1.64(m,1H),1.54-1.51(m,1H)。
实施例2：化合物2
Figure PCTCN2022127937-appb-000046
步骤A：在氮气保护下，往化合物2-1(1克，3.88毫摩尔，1当量)的二甲基亚砜(10毫升)溶液中加入2-2的四氢呋喃溶液(2摩尔每升，10毫升，5.15当量)，在70摄氏度搅拌0.5小时后停止反应加入水(100毫升)，过滤得到化合物2-3。MS(ESI)m/z：268.9[M+H +]。
步骤B：将化合物2-3(0.89克，3.31毫摩尔，1当量)和化合物1-14(868.60毫克，3.98毫摩尔，1.2当量)溶解在二氧六环(10毫升)中加入N，N-二异丙基乙胺(856.86毫克，6.63毫摩尔，1.15毫升，2当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(95.90毫克，165.5微摩尔，0.05当量)和醋酸钯(37.21毫克，165.75微摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌1小时。反应完全后，将反应液冷却至15摄氏度，加入乙酸乙酯(30毫升)过滤，滤液浓缩得到粗品加入石油醚(20毫升)，过滤，滤液浓缩经过柱层析(硅胶，石油醚：乙酸乙酯＝1：0到20：1)得到化合物2-4。MS(ESI)m/z：359.1[M+H +]。
步骤C：将化合物2-4(1.19克，3.30毫摩尔，1当量)溶解在四氢呋喃(10毫升)中，加入甲醇钠甲醇溶液(5.4摩尔每升，1.22毫升，2当量)，反应混合物在15摄氏度下搅拌0.5小时。反应完全后，将反应液直接浓缩得到粗品溶解在水(20毫升)中，使用1摩尔每升的盐酸调溶液至pH值为6，然后用乙酸乙酯(20毫升×2)洗涤。水相浓缩后加入乙醇(20毫升)溶解过滤减压浓缩得到化合物2-5。MS(ESI)m/z：175.1[M+H +]。
步骤D：将化合物2-5(0.386克，2.21毫摩尔，1.1当量)和化合物1-21(561.61毫克，2.01毫摩尔，1当量)溶解在二氧六环(5毫升)中，加入N，N-二异丙基乙胺(779.03毫克，6.03毫摩尔，1.05毫升，3当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(116.26毫克，200.92微摩尔，0.1当量)和三(二亚苄基丙酮) 二钯(91.99毫克，100.46微摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌12小时。反应完全后，将反应液冷却至15摄氏度，加入二氧六环(5毫升)过滤，滤液浓缩得到粗品加入乙酸乙酯(5毫升)和正庚烷(5毫升)，过滤，减压浓缩得到化合物2-6。MS(ESI)m/z：373.1[M+H +]。
步骤E：将化合物2-6(0.436克，1.17毫摩尔，1当量)和化合物1-12A(0.602克，2.27毫摩尔，1.94当量，2分子盐酸盐)溶解在N-甲基吡咯烷酮(7毫升)中，加入碳酸钾(1.2克，8.68毫摩尔，7.43当量)。反应混合物加热到80摄氏度搅拌2小时。反应完全后，反应液冷却至15摄氏度，加入水(20毫升)，用乙酸乙酯(20毫升*2)萃取得到有机相，无水硫酸钠干燥后过滤减压浓缩得到化合物2-7。MS(ESI)m/z：529.3[M+H +]。
步骤F：将化合物2-7(0.46克，869.47微摩尔，1当量)溶解在四氢呋喃(5毫升)中，在0摄氏度和氮气保护下加入二异丁基氢化铝(1摩尔每升，3.48毫升，4当量)。反应混合物在15摄氏度下搅拌1小时，用饱和硫酸钠溶液(10毫升)淬灭后加入四氢呋喃(30毫升)，过滤，滤液减压浓缩得到的粗品经制备级高效液相色谱(柱型号：Waters Xbridge BEH C18(150×50毫米×10微米)；流动相：[碳酸氢铵水溶液(10毫摩尔每升)-乙腈]；梯度：22％-52％)分离纯化得到化合物2。MS(ESI)m/z：487.2[M+H +]。 1H NMR(400MHz,DMSO-d6)δ＝7.74(d,J＝5.2Hz,1H),7.40(s,1H),6.59(d,J＝4.4Hz,1H),6.05(s,1H),5.74(d,J＝5.6Hz,1H),5.45(br s,1H),4.49(s,2H),4.15(d,J＝10.8Hz,1H),3.99-3.82(m,4H),3.25-3.19(m,2H),2.84(d,J＝4.0Hz,3H),2.40(s,3H),1.98-1.92(m,1H),1.80-1.75(m,1H),1.68-1.65(m,1H),1.55-1.52(m,1H)。
实施例3：化合物3
Figure PCTCN2022127937-appb-000047
步骤A：将化合物3-1(500毫克，2.79毫摩尔，1.1当量)和化合物1-21(709.53毫克，2.54毫摩尔，1当量)溶解在二氧六环(10毫升)中，加入N，N-二异丙基乙胺(984.22毫克，7.62毫摩尔，1.33毫升，3当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(146.88毫克，253.84微摩尔，0.1当量)和三(二亚苄基丙酮)二钯(116.22毫克，126.92微摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌12小时。反应完全后，向反应液中加入乙酸乙酯(10毫升)，过滤，滤液浓缩得到粗品，粗产品经硅胶薄层色谱法(石油醚/乙酸乙酯＝10:1)纯化得到化合物3-2。MS(ESI)m/z：379.0[M+H +]。
步骤B：将化合物3-2(460毫克，1.22毫摩尔，1当量)和化合物1-12A(419.88毫克，1.58毫摩尔，1.3当量，2分子盐酸盐)溶解在N-甲基吡咯烷酮(6毫升)中，加入碳酸钾(841.69毫克，6.09毫摩尔，5当量)。反应混合物加热到80摄氏度搅拌12小时。反应完全后，加入水(10毫升)用乙酸乙酯(10毫 升*3)萃取合并有机相用饱和食盐水洗(10毫升*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品化合物3-3。MS(ESI)m/z：533.3[M+H +]。
步骤C：将化合物3-3(572毫克，1.07毫摩尔，1当量)溶解在四氢呋喃(5毫升)中，在0摄氏度和氮气保护下加入二异丁基氢化铝(1摩尔每升，4.29毫升，4当量)。反应混合物在25摄氏度下搅拌0.5小时，用饱和硫酸钠溶液(10毫升)淬灭直至无气泡冒出后在25摄氏度下搅拌30分钟，过滤，滤液减压浓缩得到的粗品经制备级高效液相色谱(柱型号：Waters Xbridge C18(150×50毫米×10微米)；流动相：[碳酸氢铵水溶液(10毫摩尔每升)-乙腈]；梯度：36％-66％)分离纯化得到化合物3。MS(ESI)m/z：491.1[M+H+]。 1H NMR(400MHz,DMSO-d6)δ＝7.49(dd,J＝1.2,8.0Hz,1H),7.40(d,J＝1.6Hz,1H),7.26(t,J＝8.0Hz,1H),6.80(dd,J＝1.6,8.4Hz,1H),6.05(d,J＝1.6Hz,1H),5.36(t,J＝5.6Hz,1H),4.47(d,J＝5.6Hz,2H),4.15(d,J＝11.2Hz,1H),4.02-3.92(m,2H),3.90-3.77(m,2H),3.25-3.16(m,2H),2.43(s,3H),2.02-1.86(m,3H),1.82-1.72(m,1H),1.71-1.63(m,1H),1.53(br d,J＝13.6Hz,1H)。
实施例4：化合物4
Figure PCTCN2022127937-appb-000048
步骤A：向化合物4-1(2克，8.85毫摩尔，1当量)和1-14(2.32克，10.62毫摩尔，1.2当量)的1，4-二氧六环(20毫升)溶液中加入N，N-二异丙基乙胺(3.43克，26.55毫摩尔，4.62毫升，3当量)，4，5-双(二苯基磷)-9,9-二甲基氧杂蒽(512.07毫克，884.98微摩尔，0.1当量)和三(二亚苄基丙酮)二钯(405.20毫克，442.49微摩尔，0.05当量)。氮气置换3次后在100℃下搅拌12小时。反应完后冷却到室温，过滤，滤液浓缩得到的粗品经硅胶柱层层析法(洗脱液:石油醚/乙酸乙酯＝1：0-5：1)分离纯化得到化合物4-2。MS(ESI)m/z：364.2[M+H +]。
步骤B：向化合物4-2(700毫克，1.93毫摩尔，1当量)的四氢呋喃(5毫升)溶液中加入甲醇钠的甲醇溶液(5.4摩尔每升，713.35微升，30％纯度，2当量)。在25℃下搅拌30分钟后，用盐酸乙酸乙酯(4摩尔每升)调节pH到7-8，浓缩得到化合物4-3直接用于下一步。
步骤C：向化合物4-3(345.08毫克，1.93毫摩尔，1当量)和化合物1-21(538.37毫克，1.93毫摩尔，1当量)的1，4-二氧六环(7毫升)溶液中加入N，N-二异丙基乙胺(746.79毫克，5.78毫摩尔，1.01毫升，3当量)，4，5-双(二苯基磷)-9,9-二甲基氧杂蒽(111.45毫克，192.61微摩尔，0.1当量)和三(二亚苄基丙酮)二钯(88.19毫克，96.30微摩尔，0.05当量)。氮气置换3次后在100℃下搅拌12小时。反应完 后冷却到室温，过滤，滤液浓缩得到的粗品经硅胶柱层层析法(洗脱液:石油醚/乙酸乙酯＝1：0-5：1)分离纯化得到化合物4-4。MS(ESI)m/z：378.1[M+H +]。
步骤D：向化合物4-4(210毫克，555.90微摩尔，1当量)和化合物1-12A(191.64毫克，722.66微摩尔，1.3当量，2分子盐酸盐)的N，N-二甲基甲酰胺(5毫升)溶液中加入碳酸钾(384.14毫克，2.78毫摩尔，5当量)。混合物在80℃下搅拌12小时，反应完后冷却到25℃，过滤，滤液浓缩得到化合物4-5的粗品。MS(ESI)m/z：534.2[M+H +]。
步骤E：在0℃和氮气保护下，向化合物4-5(300毫克，562.25微摩尔，1当量)的四氢呋喃(3毫升)溶液中滴加二异丁基氢化铝(1摩尔每升，2.81毫升，5当量)。滴加完后，在25℃下搅拌1小时，用饱和硫酸钠溶液淬灭到反应液无气泡冒出，在25℃下搅拌30分钟，过滤，滤液浓缩得到的粗品经制备及高效液相色谱(柱型号：Waters Xbridge 150×25毫米×5微米；流动相：[氨的水溶液(0.05％)-乙腈]；梯度：25％-55％)分离纯化得到化合物4。MS(ESI)m/z：492.1[M+H +]。 1H NMR(400MHz,DMSO-d6)δ＝8.56(dd,J＝1.6,4.4Hz,1H),7.63-7.57(m,2H),7.40(d,J＝2.0Hz,1H),6.05(d,J＝1.6Hz,1H),5.34(t,J＝5.6Hz,1H),4.44(d,J＝5.6Hz,2H),4.14(d,J＝10.8Hz,1H),3.98-3.94(m,2H),3.85-3.76(m,2H),3.22-3.15(m,2H),2.42(s,3H),2.03(br s,2H),1.97-1.90(m,1H),1.79-1.73(m,1H),1.67-1.64(m,1H),1.53-1.50(m,1H)。
实施例5：化合物5
Figure PCTCN2022127937-appb-000049
步骤A：将化合物1-23(100毫克，194.16微摩尔，1当量)和氨水(1.13克，9.71毫摩，1.25毫升，30％纯度，50当量)的1，4-二氧六环(2毫升)溶液在闷罐中加热到80℃并在80℃下搅拌12小时。反应完后冷却到25℃，减压浓缩得到的粗品经制备级高效液相色谱法(柱型号:Waters Xbridge 150×25毫米×5微米；流动相：[氨的水溶液(0.05％)-乙腈]；梯度：15％-45％)分离纯化得到化合物5。MS(ESI)m/z：486.1[M+H +]。 1H NMR(400MHz,DMSO-d6)δ＝7.94(s,1H),7.67(d,J＝5.6Hz,1H),7.60(s,1H),7.41(d,J＝2.0Hz,1H),6.36(s,2H),6.06(d,J＝1.6Hz,1H),5.77(d,J＝5.2Hz,1H),4.16(d,J＝11.2Hz,1H),4.05-3.87(m,4H),3.30-3.27(m,2H),2.41(s,3H),1.92-1.86(m,1H),1.73-1.61(m,2H),1.54-1.50(m,1H)。
实施例6：化合物6
Figure PCTCN2022127937-appb-000050
步骤A：将化合物6-1(3克，12.45毫摩尔，1当量)溶解在二氧六环(15毫升)中加入氨水(13.65克，7.37毫摩尔，15毫升，纯度25％，7.92当量)，反应液在100毫升的四氟闷罐中加热到80摄氏度搅拌12小时。反应完全后，将反应液冷却至25摄氏度，向反应液中加入水(60毫升)，在25摄氏度下搅拌0.5小时，过滤，滤饼真空干燥得到化合物6-2。MS(ESI)m/z：239.0[M+H +]。
步骤B：将化合物6-2(2.3克，9.66毫摩尔，1当量)和化合物1-14(2.53克，11.60毫摩尔，1.2当量)溶解在二氧六环(25毫升)中加入N，N-二异丙基乙胺(3.75克，28.99毫摩尔，5.05毫升，3当量)，4，5-双(二苯基磷)-9,9-二甲基氧杂蒽(1.12克，1.93毫摩尔，0.2当量)和三(二亚苄基丙酮)二钯(884.94毫克，966.38微摩尔，0.1当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌12小时。反应完全后，向反应液中加入乙酸乙酯(10毫升)，过滤，滤液浓缩得到粗品加入正庚烷(40毫升)和乙酸乙酯(2毫升)，在25摄氏度下搅拌0.5小时，过滤，滤饼真空干燥得到化合物6-3。MS(ESI)m/z：329.3[M+H +]。
步骤C：将化合物6-3(500毫克，1.52毫摩尔，1当量)溶解在四氢呋喃(5毫升)中，加入甲醇钠甲醇溶液(5摩尔每升，395.81微升，1.3当量)，反应混合物在25摄氏度下搅拌0.5小时。反应完全后，用盐酸乙酸乙酯(4摩尔每升)将反应液pH值调到7，直接浓缩反应液得到得到化合物6-4。MS(ESI)m/z：145.1[M+H +]。
步骤D：将化合物1-21(386.83毫克，1.38毫摩尔，1当量)和化合物6-4(219.47毫克，1.52毫摩尔，1.1当量)溶解在二氧六环(5毫升)中，加入N，N-二异丙基乙胺(536.57毫克，4.15毫摩尔，723.14微升，3当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(160.15毫克，276.78微摩尔，0.2当量)和三(二亚苄基丙酮)二钯(126.73毫克，138.39微摩尔，0.1当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌12小时。反应完全后，向反应液中加入乙酸乙酯(10毫升)，过滤，滤液浓缩得到粗品，粗产品经硅胶薄层色谱法(石油醚/乙酸乙酯＝2:1)纯化得到化合物6-5。MS(ESI)m/z：343.1[M+H +]。
步骤E：将化合物6-5(269毫克，784.77微摩尔，1当量)和化合物1-12A(270.54毫克，1.02毫摩尔，1.3当量，2分子盐酸盐)溶解在N-甲基吡咯烷酮(5毫升)中，加入碳酸钾(542.31毫克，3.92毫摩尔，5当量)。反应混合物加热到80摄氏度搅拌12小时。反应完全后，加入水(10毫升)用乙酸乙酯(10毫升*3)萃取合并有机相用饱和食盐水洗(10毫升*2)，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品经 制备级高效液相色谱(柱型号：Waters Xbridge C18 150×50毫米×10微米；流动相：[碳酸氢铵水溶液(10毫摩尔每升)-乙腈]；梯度B％：22％-52％)分离纯化得到化合物6-6。MS(ESI)m/z：499.1[M+H +]。
步骤F：将化合物6-6(215毫克，431.23微摩尔，1当量)溶解在四氢呋喃(5毫升)中，在0摄氏度和氮气保护下加入二异丁基氢化铝(1摩尔每升，1.72毫升，4当量)。反应混合物在25摄氏度下搅拌12小时，用饱和硫酸钠溶液(10毫升)淬灭直至无气泡冒出后在25摄氏度下搅拌30分钟，过滤，滤液减压浓缩得到的粗品经制备级高效液相色谱(柱型号：Waters Xbridge C18 150×50毫米×10微米；流动相：[碳酸氢铵水溶液(10毫摩尔每升)-乙腈]；梯度：15％-45％)分离纯化得到化合物6。MS(ESI)m/z：457.1[M+H+]。 1H NMR(400MHz,DMSO-d6)δ＝7.56(d,J＝5.6Hz,1H),7.40(d,J＝1.6Hz,1H),6.28(s,2H),6.05(d,J＝1.6Hz,1H),5.93(t,J＝5.2Hz,1H),5.43(t,J＝5.6Hz,1H),4.47(d,J＝5.6Hz,2H),4.15(d,J＝11.2Hz,1H),4.02-3.91(m,2H),3.89-3.76(m,2H),3.25-3.14(m,2H),2.47-2.39(m,3H),2.01-1.87(m,1H),1.82-1.71(m,1H),1.71-1.62(m,1H),1.52(br d,J＝13.6Hz,1H)。
实施例7：化合物7
Figure PCTCN2022127937-appb-000051
步骤A：将化合物7-1(3克，18.63毫摩尔，1当量)和化合物1-14(4.88克，22.36毫摩尔，1.2当量)溶解在二氧六环(30毫升)中加入N，N-二异丙基乙胺(4.82克，37.27毫摩尔，6.49毫升，2当量)，4，5-双(二苯基磷)-9,9-二甲基氧杂蒽(539.09毫克，931.68微摩尔，0.05当量)和醋酸钯(209.17毫克，931.68微摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌12小时，在120摄氏度再继续搅拌12小时。反应完后，将反应液冷却至15摄氏度，加入甲醇(30毫升)，过滤，滤液浓缩得到粗品，经过柱层析(硅胶，石油醚：乙酸乙酯＝1：0到30：1)得到化合物7-2。MS(ESI)m/z：299.3[M+H +]。
步骤B：将化合物7-2(0.6克，2.01毫摩尔，1当量)溶解在四氢呋喃(6毫升)中，加入甲醇钠甲醇溶液(5.4摩尔每升，744.60微升，2当量)，反应混合物在15摄氏度下搅拌0.5小时。反应完全后，使用4摩尔每升的氯化氢乙酸乙酯溶液将反应液的pH调至7，然后减压浓缩得到粗品化合物7-3，直接投下一步。MS(ESI)m/z：115.2[M+H +]。
步骤C：将化合物7-3(229.53毫克，2.01毫摩尔，1.1当量)和化合物1-21(510.87毫克，1.83毫摩尔，1当量)溶解在二氧六环(5毫升)中，加入N，N-二异丙基乙胺(708.63毫克，5.48毫摩尔，955.02毫升，3当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(105.75毫克，182.77微摩尔，0.1当量)和三(二亚苄基丙酮)二钯(83.68毫克，91.38微摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后 反应体系在氮气保护下加热到100摄氏度搅拌12小时。反应完全后，将反应液冷却至15摄氏度，加入二氧六环(5毫升)过滤，滤液浓缩得到粗品，经过柱层析(硅胶，石油醚：乙酸乙酯＝1：0到10：1)得到化合物7-4。MS(ESI)m/z：313.1[M+H +]。
步骤D：将化合物7-4(233毫克，744.95微摩尔，1当量)和化合物1-12A(256.81毫克，968.43微摩尔，1.3当量，2分子盐酸盐)溶解在N,N-二甲基甲酰胺(5毫升)中，加入碳酸钾(514.79毫克，3.72毫摩尔，5当量)。反应混合物加热到80摄氏度搅拌12小时。反应完全后，反应液冷却至15摄氏度，将反应液过滤减压浓缩得到化合物7-5。MS(ESI)m/z：469.3[M+H +]。
步骤E：将化合物7-5(307毫克，655.18微摩尔，1当量)溶解在四氢呋喃(3毫升)中，在0摄氏度和氮气保护下加入二异丁基氢化铝(1摩尔每升，3.28毫升，5当量)。反应混合物在15摄氏度下搅拌1小时，用饱和硫酸钠溶液(10毫升)淬灭后加入四氢呋喃(20毫升)，过滤，滤液减压浓缩得到的粗品经制备级高效液相色谱(柱型号：Waters Xbridge BEH C18 150×25毫米×5微米；流动相：[氨的水溶液(0.05％)-乙腈]；梯度：20％-50％)分离纯化得到化合物7。MS(ESI)m/z：427.3[M+H +]。 1H NMR(400MHz,CDCl 3)δ＝7.60(d,J＝2Hz,1H),7.52(d,J＝1.6Hz,1H),6.52(d,J＝2Hz,1H),6.12(d,J＝1.6Hz,1H),4.53(s,2H),4.19(d,J＝11.2Hz,1H),4.08(s,1H),4.01(d,J＝10.8Hz,1H),3.89(s,3H),3.41-3.33(m,2H),3.06–2.982(m,2H),2.55(s,3H),2.04–1.97(m,1H),1.92–1.85(m,1H),1.76–1.60(m,2H)。
实施例8：化合物8
Figure PCTCN2022127937-appb-000052
步骤A：将化合物2-1(1克，3.88毫摩尔，1当量)，甲氧基胺(1.62克，19.42毫摩尔，5当量，盐酸 盐)和N，N-二异丙基乙胺(3.01克，23.31毫摩尔，4.06毫升，6当量)溶于二甲基亚砜(15毫升)中，在100摄氏度进行微波反应12小时。反应完后加入水(100毫升)和乙酸乙酯(100毫升)，分离出有机相，然后再用乙酸乙酯(100毫升)对水相进行萃取，得到联合的有机相用饱和食盐水(100毫升×5)洗，无水硫酸钠进行干燥，过滤，减压浓缩得到化合物8-1。MS(ESI)m/z：285.0[M+H +]。
步骤B：在氮气保护下，将化合物8-1(2克，7.03毫摩尔，1当量)、化合物1-14(1.84克，8.44毫摩尔，1.2当量)、N，N-二异丙基乙胺(1.82克，14.06毫摩尔，2.45毫升，2当量)、醋酸钯(78.92毫克，351.52微摩尔，0.05当量)和4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(203.39毫克，351.52微摩尔，0.05当量)溶于二氧六环(20毫升)中，在100摄氏度和氮气保护下反应3小时。反应完成后，往反应液中加入乙酸乙酯(30毫升)，过滤，滤液减压浓缩得到的粗品经硅胶柱层层析法(石油醚：乙酸乙酯＝1：0到30：1)分离纯化得到化合物8-2。MS(ESI)m/z：375.2[M+H +]。
步骤C：在氮气保护下，将化合物8-2(0.61克，1.63毫摩尔，1当量)溶于四氢呋喃(6毫升)中，加入叔丁醇钾四氢呋喃溶液(1摩尔每升，3.25毫升，2当量)，在15摄氏度下搅拌0.5小时。用1摩尔每升的氯化氢乙酸乙酯溶液调节反应液的pH至7，然后减压浓缩得到化合物8-3。MS(ESI)m/z：191.1[M+H +]。
步骤D：在氮气保护下，将化合物8-3(310.19毫克，1.63毫摩尔，1当量)、化合物1-21(454.78毫克，1.63毫摩尔，1当量)、三(二亚苄基丙酮)二钯(74.49毫克，81.35微摩尔，0.05当量)、4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(94.14毫克，162.70微摩尔，0.1当量)和N，N-二异丙基乙胺(630.84毫克，4.88毫摩尔，850.19微升，3当量)溶于1，4-二氧六环(3毫升)中，在100摄氏度和氮气保护下反应12小时。反应完后，减压浓缩得到的粗品经硅胶柱层层析法(石油醚：乙酸乙酯＝1：0到10：1)分离纯化得到化合物8-4。MS(ESI)m/z：389.0[M+H +]。
步骤E：将化合物8-4(80毫克，205.52微摩尔，1当量)，化合物1-12A(70.85毫克，267.18微摩尔，1.3当量，2分子盐酸盐)和N，N-二异丙基乙胺(159.37毫克，1.23毫摩尔，214.79微升，6当量)溶于N，N-二甲基甲酰胺(1毫升)中，在80摄氏度下反应1.5小时。冷却至室温，过滤，滤液减压浓缩得到的粗品经薄层层析色谱法(二氯甲烷：乙醇＝8:1)分离纯化得到化合物8-5。MS(ESI)m/z：545.3[M+H +]。
步骤F：在氮气保护下，将化合物8-5(27毫克，49.54微摩尔，1当量)溶于四氢呋喃(1毫升)中，冷却至0摄氏度，滴加二异丁基氢化铝(1摩尔每升，247.68微升，5当量)，保持温度不超过3℃，滴加完后在15摄氏度下搅拌1小时。反应完后，滴加饱和的硫酸钠溶液至反应液中无气泡产生，然后加入四氢呋喃(10毫升)，减压抽滤，滤液减压浓缩得到的粗品经制备级高效液相色谱法(柱型号：Phenomenex Synergi Polar-RP100×25毫米×4微米；流动相：[三氟乙酸的水溶液(0.1％)-乙腈]；梯度：14％-34％)分离纯化得到化合物8的三氟乙酸盐。MS(ESI)m/z：503.3[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ＝8.53(brs,3H),7.65(brs,1H),7.58(s,1H),6.31(s,1H),5.84(brs,1H),4.49(brs,3H),4.36(d,J＝11.2Hz,1H),4.22(d,J＝11.2Hz,1H),4.04(d,J＝13.6Hz,1H),3.94(d,J＝13.6Hz,1H),3.71(s,3H),3.31-3.25(m,1H),3.16-3.11(m,1H),2.43(s,3H),2.07-1.97(m,1H),1.91–1.84(m,2H),1.69(d,J＝12.4Hz,1H)。
实施例9：化合物9
Figure PCTCN2022127937-appb-000053
步骤A：将化合物9-1(10克，68.04毫摩尔，1当量)溶解在乙腈(100毫升)中加入无水氟化钾(7.91克，136.08毫摩尔，3.19毫升，2当量)和溴氟甲基膦酸二乙酯(18.17克，68.04毫摩尔，1当量)，反应液在25摄氏度搅拌12小时。反应完全后，乙腈(20毫升)加入到反应液中，过滤，滤液减压浓缩得到化合物9-2。MS(ESI)m/z：197.0,199.0[M+H +]。
步骤B：将化合物9-2(13.30克，60.92毫摩尔，1.2当量)和化合物1-14(10克，50.77毫摩尔，1当量)溶解在二氧六环(100毫升)中加入N，N-二异丙基乙胺(19.68克，152.30毫摩尔，26.53毫升，3当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(2.94克，5.08毫摩尔，0.1当量)和三(二亚苄基丙酮)二钯(2.32克，2.54毫摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌12小时。反应完全后，向反应液中加入乙酸乙酯(10毫升)，过滤，滤液浓缩得到粗品，粗产品经硅胶薄层色谱法(石油醚/乙酸乙酯＝5:1)纯化得到化合物9-3。MS(ESI)m/z：335.2[M+H+]。
步骤C：将化合物9-3(1克，2.99毫摩尔，1当量)溶解在四氢呋喃(10毫升)中，加入甲醇钠甲醇溶液(5摩尔每升，777.46微升，1.3当量)，反应混合物在25摄氏度下搅拌0.5小时。反应完全后，用盐酸/乙酸乙酯(4摩尔每升)将反应液pH值调到7，直接浓缩反应液得到得到化合物9-4。MS(ESI)m/z：151.1[M+H +]。
步骤D：将化合物1-21(759.84毫克，2.72毫摩尔，1当量)和化合物9-4(448.98毫克，2.99毫摩尔，1.1当量)溶解在二氧六环(10毫升)中，加入N，N-二异丙基乙胺(1.05克，8.16毫摩尔，1.42毫升，3当量)，4,5-双(二苯基磷)-9,9-二甲基氧杂蒽(157.29毫克，271.84微摩尔，0.1当量)和三(二亚苄基丙酮)二钯(124.46毫克，135.92微摩尔，0.05当量)。反应混合物在氮气保护下置换气体三次，然后反应体系在氮气保护下加热到100摄氏度搅拌12小时。反应完全后，向反应液中加入乙酸乙酯(10毫升)，过滤，滤液浓缩得到粗品，粗产品经硅胶薄层色谱法(石油醚/乙酸乙酯＝3:1)纯化得到化合物9-5。MS(ESI)m/z：349.0[M+H +]。
步骤E：将化合物9-5(400毫克，1.15毫摩尔，1当量)和化合物1-12A(395.39毫克，1.49毫摩尔，1.3当量，2分子盐酸盐)溶解在N-N二甲基甲酰胺(5毫升)中，加入碳酸钾(792.57毫克，5.73毫摩尔，5当量)。反应混合物加热到80摄氏度搅拌12小时。反应完全后，过滤，滤液减压浓缩得到化合物9-6。MS(ESI)m/z：505.2[M+H +]。
步骤F：将化合物9-6(0.7克，1.39毫摩尔，1当量)溶解在四氢呋喃(7毫升)中，在0摄氏度和氮气保护下加入二异丁基氢化铝(1摩尔每升，6.94毫升，5当量)。反应混合物在25摄氏度下搅拌0.5小 时，用饱和硫酸钠溶液(10毫升)淬灭直至无气泡冒出后在25摄氏度下搅拌30分钟，过滤，滤液减压浓缩得到的粗品经制备级高效液相色谱(柱子：Waters Xbridge C18 150×50毫米×10微米；流动相：[碳酸氢铵的水溶液(10毫摩尔每升)-乙腈]；B％：22％-52％，10分钟)分离纯化得到化合物9。MS(ESI)m/z：463.1[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ＝8.17-7.74(m,2H),7.38(s,1H),6.73(s,1H),6.03(d,J＝1.2Hz,1H),5.08(t,J＝5.6Hz,1H),4.40(d,J＝5.6Hz,2H),4.11(d,J＝11.2Hz,1H),3.98-3.87(m,2H),3.78-3.59(m,2H),3.16-3.02(m,2H),2.48(br s,3H),2.03-1.83(m,3H),1.78-1.68(m,1H),1.66-1.58(m,1H),1.48(br d,J＝13.2Hz,1H)。
实施例10：化合物10
Figure PCTCN2022127937-appb-000054
步骤A：向化合物10-1(1克，5.29毫摩尔，1当量)的1,4-二氧六环(15毫升)溶液中加入三氯氧磷(4.06克，26.45毫摩尔，2.46毫升，5当量)。在氮气保护和90℃下搅拌12小时后，冷却到25℃，滴加水(50毫升)淬灭反应，乙酸乙酯(50毫升×2)萃取，联合的有机相用食盐水(50毫升×2)洗，无水硫酸钠干燥，减压浓缩后得到化合物10-2的粗品，直接用于下一步。
步骤B：向化合物10-2(800毫克，3.86毫摩尔，1当量)和化合物1-16(619.41毫克，3.86毫摩尔，1当量)的1，4-二氧六环(10毫升)中加入N，N-二异丙基乙胺(1.50克，11.57毫摩尔，2.02毫升，3当量)，4，5-双(二苯基磷)-9,9-二甲基氧杂蒽(446.26毫克，771.25微摩尔，0.2当量)和三(二亚苄基丙酮)二钯(353.12毫克，385.62微摩尔，0.1当量)。氮气置换3次后在90℃下搅拌12小时。反应完后冷却到室温，过滤，滤液浓缩得到的粗品经制备级高效液相色谱(柱型号：Phenomenex luna C18 250×50毫米×10微米；流动相：[盐酸水溶液(0.05％)-乙腈]；梯度：30％-60％)分离纯化得到化合物10-3。MS(ESI)m/z：287.0[M+H +]
步骤C：向化合物10-3(10毫克，34.82微摩尔，1当量)和化合物1-12A(9.23毫克，34.82微摩尔，1当量，2分子盐酸盐)是N,N-二甲基甲酰胺(1毫升)溶液中加入碳酸钾(24.06毫克，174.11微摩尔，5当量)。在100℃下搅拌12小时后，冷却到室温，过滤，滤液减压浓缩得到的粗品制备级高效液相色谱(柱型号：Waters Xbridge 150×25毫米×5微米；流动相：[氨水(0.05％)-乙腈]；梯度：19％-49％)分离纯化得到化合物10。MS(ESI)m/z：443.3[M+H +]。 1H NMR(400MHz,DMSO-d 6)δ＝8.30(s,1H),7.67(d,J＝5.6Hz,1H),7.44(s,1H),6.37(s,2H),6.10(s,1H),5.89(d,J＝5.2Hz,1H),4.18-4.01(m,3H),3.67-3.59(m,2H),3.19-3.07(m,2H),2.50(s,3H),2.01-1.93(m,1H),1.84-1.75(m,1H),1.71-1.57(m,2H)。
实验例1：SHP2体外酶学实验
实验材料：Homogeneous Full Length SHP-2 Assay Kit购自BPS Bioscience，多标记分析仪NIVO。
实验方法：
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。
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。
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(250mM)。1000转每分钟，离心1分钟。
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。
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-2Substrate(DiFMUP)(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。
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45μL 1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。
数据分析：
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。表1提供了本申请的化合物对SHP2酶活性的影响。
实验结果：见表1。
表1
样品 SHP2 IC 50(纳摩尔每升)
化合物1 1.73
化合物2 2.87
化合物3 2.28
化合物4 2.14
化合物5 3.24
化合物6 3.15
化合物8 3.99
化合物10 1.09
结论：本申请化合物对SHP2具有优异的体外抑制活性。
实验例2：KRAS突变肿瘤细胞抗增殖实验研究
实验材料：
细胞培养基，盘尼西林/链霉素抗生素购自维森特，胎牛血清购自Biosera。3D CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。细胞系购自南京科佰生物科技有限公司和武汉普诺赛生命科技有限公司。Envision多标记分析仪(PerkinElmer)。
实验方法：
将不同肿瘤细胞种于超低吸附96孔U型板中，80μL细胞悬液每孔，细胞密度条件如下表。细胞板置于二氧化碳培养箱中过夜培养。
细胞名称 铺板密度 化合物给药天数
MIAPACA2_PANCREAS 1000 3
NCIH358_LUNG 2000 5
将待测化合物用排枪进5倍稀释至第9个浓度，即从2mM稀释至5.12nM或200μM至0.512nM，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0.0256nM，或1μM 至0.00256nM细胞板置于二氧化碳培养箱中培养3-6天。具体时间见表1.
向细胞板中加入每100μL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。
数据分析：
将原始数据换算成抑制率，IC 50的值即可通过四参数进行曲线拟合得出(GraphPad Prism中"log(inhibitor)vs.response--Variable slope"模式得出)。表2提供了本申请的化合物对不同肿瘤细胞增殖的抑制活性。
实验结果：见表2、表3。
表2本申请的化合物对H358细胞增殖的抑制活性
样品 H358抗增殖IC 50(纳摩尔每升)
化合物1 22.10
化合物2 61.43
化合物3 62.09
化合物4 144.80
化合物5 43.10
化合物6 120.20
化合物10 38.86
表3本申请的化合物对MiaPaCa-2细胞增殖的抑制活性
样品 MiaPaCa-2抗增殖IC 50(纳摩尔每升)
化合物1 22.56
化合物2 24.40
化合物3 35.00
化合物4 56.90
化合物5 48.47
化合物6 62.15
化合物10 19.31
实验结论：
本申请化合物对KRAS突变的癌细胞H358和MiaPaCa-2均有很好的抗增殖抑制效果。
实验例3：对H358细胞ERK磷酸化的抑制活性研究
实验材料：
H358细胞购自南京科佰生物科技有限公司；1640培养基购自Biological industries；胎牛血清购自Biosera；Advanced Phospho-ERK1/2(THR202/TYR204)KIT购自Cisbio Advanced Phospho-ERK1/2(THR202/TYR204)KIT成分表
成分名称 储存温度
定制磷酸化ERK1/2 Eu Cryptate抗体(Advanced PhosphoERK1/2 Eu Cryptate antibody) ≤-16℃
定制磷酸化ERK1/2 d2抗体(Advanced PhosphoERK1/2 d2 antibody) ≤-16℃
封闭液(100X母液储存)(Blocking reagent(stock solution 100X)) ≤-16℃
裂解液1号(4X母液储存)(Lysis buffer#1(stock solution 4X)) ≤-16℃
检测液(现配现用)(Detection buffer(ready-to-use)) ≤-16℃
实验方法：
1.H358细胞种于透明96孔细胞培养板中，80μL细胞悬液每孔，每孔包含10000个H358细胞，细胞板放入二氧化碳培养箱，37度过夜孵育；
2.弃掉细胞上清，加入80μL每孔饥饿培养基(1640+0.02％胎牛血清+1％双抗)，细胞板放入二氧化碳培养箱，细胞饥饿处理过夜；
3.将待测化合物用100％DMSO稀释到4mM作为第一个浓度，然后再用移液器进行5倍稀释至第8个浓度，即从4mM稀释至10.24μM。取1μL化合物加入79μL细胞饥饿培养基，混匀后，取20μL化合物溶液加入到对应细胞板孔中，细胞板放回二氧化碳培养箱继续孵育1小时，此时化合物浓度为10μM至0.0256nM，DMSO浓度为0.25％；
4.结束孵育后，弃掉细胞上清加入50μL细胞裂解液每孔，室温摇晃孵育30分钟；
5.使用Detection buffer将Phospho-ERK1/2 Eu Cryptate antibody和Phospho-ERK1/2 d2 antibody稀释20倍；
6.取16μL细胞裂解物上清每孔到新的384白色微孔板中，再加入2μL Phospho-ERK1/2 Eu Cryptate antibody稀释液和2μL Phospho-ERK1/2 d2 antibody稀释液，常温孵育4小时；
7.孵育结束后使用多标记分析仪读取HTRF excitation:320nm,emission:615nm，665nm。
数据分析：
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。
实验结果：见表4。
表4本申请的化合物对H358细胞ERK磷酸化的抑制活性
样品 H358细胞ERK磷酸化IC 50(纳摩尔每升)
化合物1 21.24
化合物2 84.14
化合物3 55.62
化合物4 75.78
化合物5 45.26
化合物6 57.11
实验结论：
本申请化合物对KRAS突变的癌细胞H358的ERK磷酸化有很强的抑制效果。
实验例4：小鼠体内药代动力学研究
实验目的：
本实验目的是评价化合物单次静脉注射和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度。
实验操作：
选取7至10周龄的CD-1雄性小鼠。小鼠在给药前禁食至少12小时，给药4小时后恢复供食，整个试验期间自由饮水。
实验当天静脉组动物通过尾静脉单次注射给予相应化合物，给药体积为5毫升每公斤；口服组动物通过单次灌胃给予相应化合物，给药体积为10毫升每公斤。在给药前称量动物体重，根据体重计算给药体 积。样品采集时间：注射组为0.083小时、0.25小时、0.5小时、1小时、2小时、4小时、8小时、24小时，灌胃组为0.25小时、0.5小时、1小时、2小时、4小时、6小时、8小时、24小时。每个时间点通过隐静脉采集大约30μL全血用于制备血浆供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定。所有动物在采集完最后一个时间点的PK样品后进行CO 2麻醉安乐死。采用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。实验结果：PK性质评价结果见表5。
实验结论：
本申请化合物具有优异的药代动力学性质。
表5 小鼠体内PK性质评价结果
Figure PCTCN2022127937-appb-000055
实验结论：
本申请化合物在小鼠体内口服AUC、生物利用度优异，具有良好的药代动力学性质。
实验例5：大鼠体内药代动力学研究
实验目的：
本实验目的是评价化合物单次静脉注射和灌胃给药后的药代动力学行为，考察灌胃给药后的生物利用度。
实验操作：
选取7至10周龄的SD雄性大鼠。大鼠在给药前禁食至少12小时，给药4小时后恢复供食，整个试验期间自由饮水。
实验当天静脉组动物通过尾静脉单次注射给予相应化合物，给药体积为5mL/kg；口服组和通过单次灌胃给予相应化合物，给药体积为10mL/kg。在给药前称量动物体重，根据体重计算给药体积。样品采集时间为：0.083(注射组)，0.25,0.5,1,2,4,6,8,24h。每个时间点通过颈静脉采集大约200μL全血用于制备血浆供高效液相色谱-串联质谱(LC-MS/MS)进行浓度测定。所有动物在采集完最后一个时间点的PK样品后进行CO 2麻醉安乐死。采用WinNonlin TM Version 6.3(Pharsight,Mountain View,CA)药动学软件的非房室模型处理血浆浓度，使用线性对数梯形法方法计算药动学参数。
实验结果：大鼠体内PK性质评价结果见表6。
表6 大鼠体内PK性质评价结果
Figure PCTCN2022127937-appb-000056
实验结论：
本申请化合物在大鼠体内口服AUC、生物利用度优异，具有良好的药代动力学性质。
实验例6：MiaPaCa-2皮下异种移植肿瘤抑制体内实验
实验目的：
评价测试药物在人源胰腺癌MIA PaCa-2细胞株皮下异种移植雌性BALB/c裸小鼠动物模型中的抗肿瘤作用。
实验操作：
MIA PaCa-2细胞培养在含2.5％HS和10％胎牛血清的DMEM培养液中。收集指数生长期的MIA PaCa-2细胞，PBS重悬至适合浓度用于裸鼠皮下肿瘤接种。
实验小鼠于右侧背部皮下接种5×10 6MIA PaCa-2细胞，细胞重悬在1：1的PBS与基质胶中(0.1ml/只)定期观察肿瘤生长情况，待肿瘤生长至平均体积～125(100-150)mm 3时根据肿瘤大小和小鼠体重随机分组给药。
开始给药后，每周测量两次小鼠的体重和肿瘤的大小。肿瘤体积计算公式：肿瘤体积(mm 3)＝1/2×(a×b 2)(其中a表示长径，b表示短径)。
实验结果：化合物肿瘤抑制效果见表7。
表7 MiaPaCa-2异种异位移植实验结果
Figure PCTCN2022127937-appb-000057
实验结论：
本申请化合物对MiaPaCa-2皮下异种移植肿瘤生长有显著抑制作用。

Claims (15)

  1. 式(I’)化合物、其立体异构体或其药学上可接受的盐
    Figure PCTCN2022127937-appb-100001
    其中，
    环A选自芳基和杂芳基；
    R 1选自H、氘、NH 2、任选地被一个或多个卤素、CN或OH取代的C 1-6烷基；
    R 2选自氘、H、卤素、OH、CN、COOH、-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；
    R 3选自H、卤素、OH、NO 2、CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2或3个R b取代；
    R 4、R 5和R 6分别独立地选自H、氘、卤素、NH 2、NO 2、CN、OH、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1- 6烷基，所述NH 2、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1-6烷基分别独立地任选被1、2或3个R c取代；
    R a、R b、R c分别独立地选自氘、卤素、OH、NH 2和C 1-3烷基。
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其选自式(I)化合物或其药学上可接受的盐
    Figure PCTCN2022127937-appb-100002
    其中，
    环A选自芳基和杂芳基；
    R 1选自H、氘、NH 2、任选地被一个或多个卤素、CN或OH取代的C 1-6烷基；
    R 2选自氘、H、卤素、OH、CN、COOH、-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-6烷基、-COO-C 1-6烷基、C 1-6烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；
    R 3选自H、卤素、OH、NO 2、CN、C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基，所述C 1-6烷基、C 1-6烷氧基和C 1-6烷氨基分别独立地任选被1、2或3个R b取代；
    R 4、R 5和R 6分别独立地选自H、氘、卤素、NH 2、NO 2、CN、OH、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1- 6烷基，所述NH 2、C 1-6烷基、C 1-6烷氧基和-NH-O-C 1-6烷基分别独立地任选被1、2或3个R c取代；
    R a、R b、R c分别独立地选自氘、卤素、OH、NH 2和C 1-3烷基。
  3. 根据权利要求1或2所述的化合物、其立体异构体或其药学上可接受的盐，其中
    环A选自芳基和5-6元杂芳基，所述5-6元杂芳基包含1、2或3个分别独立地选自N、O、S和NH的杂原子或杂原子团；
    R 1选自H、氘、NH 2、CH 3、CHF 2、CH 2F和CF 3；
    R 2选自氘、F、Cl、Br、I、CN、COOH、-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；
    R 3选自H、F、Cl、Br、I、NO 2、CN、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代；
    R 4、R 5和R 6分别独立地选自H、氘、F、Cl、Br、I、NH 2、NO 2、CN、OH、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基，所述NH 2、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基分别独立地任选被1、2或3个R c取代；
    R a分别独立地选自氘、F、Cl、Br、I、OH和NH 2；
    R b分别独立地选自氘、F、Cl、Br、I和OH；
    Rc分别独立地选自氘、F、Cl、Br、I、NH 2和C 1-3烷基。
  4. 根据权利要求1-3任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，环A选自C 6-10芳基和5-10元杂芳基；
    或者，环A选自C 6-10芳基和5-6元杂芳；
    或者，环A选自苯基和5-6元杂芳基；
    或者，环A选自芳基和5-6元杂芳基，所述5-6元杂芳基包含1、2或3个分别独立地选自N、O、S和NH的杂原子或杂原子团；
    或者，环A选自苯基、吡唑基和吡啶基；
    或者，环A选自吡啶基。
  5. 据权利要求1-4任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，R a、R b、R c分别独立地选自卤素、OH、NH 2和C 1-3烷基；
    或者，R a、R b、R c分别独立地选自卤素、OH和C 1-3烷基；
    或者，R a、R b、R c分别独立地选自氟、OH和C 1-3烷基；
    或者，R a分别独立地选自OH；
    或者，R c分别独立地选自F和CH 3。
  6. 根据权利要求1-5任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，所述R 1选自H、氘、NH 2、任选地被一个或多个卤素、CN或OH取代的C 1-3烷基；
    或者，R 1选自H、氘、NH 2、任选地被一个或多个卤素取代的C 1-3烷基；
    或者，R 1选自H、氘、NH 2、任选地被一个或多个氟取代的C 1-3烷基；
    或者，R 1选自H、氘、NH 2、CH 3、CHF 2、CH 2F和CF 3；
    或者，R 1选自H、CH 3和CHF 2；或者，R 1选自CH 3和CHF 2。
  7. 根据权利要求1-6任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，R 2选自氘、F、Cl、Br、I、CN、COOH、-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2，所述-C(＝O)-C 1-3烷基、-COO-C 1-3烷基、C 1-3烷基和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；
    或者，R 2选自氘、F、Cl、Br、I、CH 3和-C(＝O)NH 2，所述CH 3和-C(＝O)NH 2分别独立地任选被1、2或3个R a取代；或者，R 2选自Cl、-CH 2OH、-CH 3和-C(＝O)NH 2；
    或者，其中，R 2选自Cl、-CH 2OH和-C(＝O)NH 2。
  8. 根据权利要求1-7任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，R 3选自H、F、Cl、Br、I、NO 2、CN、C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基，所述C 1-3烷基、C 1-3烷氧基和C 1-3烷氨基分别独立地任选被1、2或3个R b取代；
    或者，R 3选自H、F、Cl和CH 3；或者，R 3选自H。
  9. 根据权利要求1-8任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，R 4、R 5和R 6分别独立地选自H、氘、F、Cl、Br、I、NH 2、NO 2、CN、OH、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基，所述NH 2、C 1-3烷基、C 1-3烷氧基和-NH-O-C 1-3烷基分别独立地任选被1、2或3个R c取代；
    或者，R 4、R 5和R 6分别独立地选自H、氘、F、Cl、Br、I、NH2、NO2、CN、OH、＝O、CH 3、-OCH 3和-NH-O-CH 3，所述NH2、CH 3、-OCH 3和-NH-O-CH 3分别独立地任选被1、2或3个Rc取代；
    或者，R 4、R 5和R 6分别独立地选自F、Cl、NH 2、-NH-O-CH 3、-NH-CH 3、CH 3、CF 3和CHF 2。
  10. 根据权利要求1-9任一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022127937-appb-100003
    选自
    Figure PCTCN2022127937-appb-100004
    和/或，结构单元
    Figure PCTCN2022127937-appb-100005
    选自
    Figure PCTCN2022127937-appb-100006
    Figure PCTCN2022127937-appb-100007
  11. 根据权利要求1-10任意一项所述的化合物、其立体异构体或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2022127937-appb-100008
    Figure PCTCN2022127937-appb-100009
  12. 化合物、其立体异构体或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2022127937-appb-100010
    Figure PCTCN2022127937-appb-100011
  13. 化合物、其立体异构体或其药学上可接受的盐，其中，化合物选自
    Figure PCTCN2022127937-appb-100012
    Figure PCTCN2022127937-appb-100013
    Figure PCTCN2022127937-appb-100014
  14. 一种药物组合物，其包含权利要求1-13任一项所述的化合物、其立体异构体或其药学上可接受的盐。
  15. 权利要求1-13任一项所述的化合物、其立体异构体或其药学上可接受的盐、或权利要求14所述的药物组合物在制备预防或者治疗与SHP2蛋白相关疾病的药物中的用途；任选地，所述与SHP2蛋白相关疾病选自癌症；任选地，所述与SHP2蛋白相关疾病选自肺癌或胰腺癌。
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CN110143949A (zh) * 2018-05-09 2019-08-20 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
WO2020073949A1 (zh) * 2018-10-10 2020-04-16 江苏豪森药业集团有限公司 含氮杂芳类衍生物调节剂、其制备方法和应用
WO2022207924A1 (en) * 2021-04-02 2022-10-06 C.N.C.C.S. S.C.A.R.L. Collezione Nazionale Dei Composti Chimici E Centro Screening (s)-1-(5-((pyridin-3-yl)thio)pyrazin-2-yl)-4'h,6'h-spiro[piperidine-4,5'-pyrrolo [1,2-b]pyrazol]-4'-amine derivatives and similar compounds as shp2 inhibitors for the treatment of e.g. cancer

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CN110143949A (zh) * 2018-05-09 2019-08-20 北京加科思新药研发有限公司 可用作shp2抑制剂的新型杂环衍生物
WO2020073949A1 (zh) * 2018-10-10 2020-04-16 江苏豪森药业集团有限公司 含氮杂芳类衍生物调节剂、其制备方法和应用
WO2022207924A1 (en) * 2021-04-02 2022-10-06 C.N.C.C.S. S.C.A.R.L. Collezione Nazionale Dei Composti Chimici E Centro Screening (s)-1-(5-((pyridin-3-yl)thio)pyrazin-2-yl)-4'h,6'h-spiro[piperidine-4,5'-pyrrolo [1,2-b]pyrazol]-4'-amine derivatives and similar compounds as shp2 inhibitors for the treatment of e.g. cancer

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