WO2023078413A1 - Fgfr2 inhibitor, preparation method therefor, and pharmaceutical use thereof - Google Patents

Fgfr2 inhibitor, preparation method therefor, and pharmaceutical use thereof Download PDF

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WO2023078413A1
WO2023078413A1 PCT/CN2022/129961 CN2022129961W WO2023078413A1 WO 2023078413 A1 WO2023078413 A1 WO 2023078413A1 CN 2022129961 W CN2022129961 W CN 2022129961W WO 2023078413 A1 WO2023078413 A1 WO 2023078413A1
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reaction solution
compound int
compound
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French (fr)
Chinese (zh)
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谢雨礼
吕永聪
钱立晖
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微境生物医药科技(上海)有限公司
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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D471/22—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 systems contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry, and more specifically relates to a novel compound with fibroblast growth factor receptor 2 (FGFR2) inhibitory effect, a preparation method thereof, and an application of the compound in the preparation of antitumor drugs.
  • FGFR2 fibroblast growth factor receptor 2
  • Fibroblast growth factor receptor is a member of the receptor tyrosine kinase (RTK) family, mainly including FGFR1, FGFR2, FGFR3 and FGFR4. Endokinase domain.
  • the signaling pathway of FGFR is that the binding of ligands to receptors induces FGFR dimerization, thereby causing the cascade activation of downstream signaling pathways (such as Ras-MAPK, PI3K-Akt, STAT and PLC ⁇ ), and affecting cell proliferation and apoptosis. , migration, and angiogenesis.
  • FGFR mutation activation or high expression is closely related to the occurrence and development of human tumors.
  • FGFR Activating mutations or overexpression of FGFR in cells can lead to the persistence and overactivation of FGFR signaling pathways, enabling cells to acquire oncogenic functions such as excessive proliferation and apoptosis evasion.
  • abnormal expression of FGFR occurs in a variety of human cancer cells, such as breast cancer, lung cancer, ovarian cancer, gastric cancer, uterine tumor, malignant glioma, bladder cancer, liver cancer, solid tumors, etc.
  • Cancer Discovery.2013; 3( 3): 264-279; Annals of Oncology. 2014; 25: 552-563 Therefore, FGFR is recognized as an important target for anti-tumor drug development, and is one of the most popular targets for drug development.
  • FGFR2 plays an important role in embryonic development and tissue repair, and it plays a more significant role in bone and angiogenesis. It is also found to be closely related to the formation of tumor blood vessels, tumor staging, metastasis, prognosis and chemotherapy efficacy. Malignant tumors all have high expression, gene amplification or missense mutations, such as gastric cancer, lung cancer, breast cancer, ovarian cancer and endometrial cancer, which are common in malignant tumors.
  • FGFR inhibitors have been approved for the treatment of hepatocholangiocarcinoma (erdafitinib, pemigatinib, infigratinib), and several FGFR inhibitors have entered the clinical trial stage.
  • most of these compounds are pan-FGFR inhibitors, lack of selectivity to FGFR1, FGFR2, FGFR3 and FGFR4, so there will be some toxic side effects, such as hyperphosphatemia (inhibition of FGFR1) and diarrhea (inhibition of FGFR4). Therefore, the development of specific and highly active FGFR2 inhibitors has important clinical value.
  • the present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
  • Cy 1 is a substituted or unsubstituted 6-membered and 5-membered heteroaromatic ring or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, S and O;
  • Cy 2 is a substituted or unsubstituted benzene ring, a 5-6 membered heteroaromatic ring, a 9-membered bis-heteroaromatic ring or a 9-12-membered partially unsaturated bis-heterocyclic ring;
  • Cy 2 is directly connected to the 5-membered ring of Cy 1 , and the divalent group -NH-(CH 2 )n- is connected to the 6-membered ring of Cy 1 and Cy 2 to form another ring, where n is 1 or 2;
  • R 1 is H, (C1-C3) alkyl or -L 1 -R 1A ;
  • L 1 is a chemical bond, -O-, -C(O)-, -NH-, -N(R L )-, -NH(CO)-, -N(R L )C(O)-, -C( O)NH-, -C(O)N(R L )-, -NHS(O) 2 -, -N(R L )S(O) 2 -, -S(O) 2 NH-, -S( O) 2 N(R L )-, -S-, -S(O)- or -S(O) 2 -;
  • R L is a (C1-C3) alkyl group, wherein the (C1-C3) alkyl group can be optionally substituted by one or more halogens;
  • R 1A is -(CH 2 ) w R, -(CH 2 ) w OR, -(CH 2 ) w NR 2 , substituted or unsubstituted (C1-C6) alkyl, (C3-C6) cycloalkyl, Phenyl, 3-9 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, or 1-4 heteroatoms independently selected from N, S and O Atomic 5-6 membered heteroaryl;
  • Cy 3 is a substituted or unsubstituted benzene ring, a 5-6 membered monoheteroaromatic ring containing 1 to 4 heteroatoms independently selected from N, S and O, and a single heteroaromatic ring containing 1 to 4 heteroatoms independently selected from N, S and O 8-10 membered diheteroaromatic rings with heteroatoms, 3-7-membered saturated or partially unsaturated carbocycles, 3-7-membered saturated or partially unsaturated heteroatoms containing 1-2 heteroatoms independently selected from N, S and O Heterocycle, 7-12 membered saturated or partially unsaturated biheterocyclic ring or bridged ring containing 1-4 heteroatoms independently selected from N, S and O, 5-6 membered aromatic ring with 4-7 membered saturated or partially Unsaturated heterocyclic rings, or 5-6 membered aromatic rings linked with 5-6 membered heteroaromatic rings;
  • R 2 is -NHCN, -CN,
  • R 2A is H, substituted or unsubstituted (C1-C6) alkyl, or substituted or unsubstituted (C3-C6) cycloalkyl;
  • R 2B , R 2C and R 2D are each independently H, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R) OR, -(CH 2 ) w R, -(CH 2 ) w OR, -(CH 2 ) w NR 2 , substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from N, S and O, substituted or unsubstituted A 5-6 membered heteroaromatic ring containing 1-4 heteroatoms independently selected from N, S and O;
  • R 2A and R 2B , R 2B and R 2C , R 2C and R 2D , R 2A and R 2D can form a substituted or unsubstituted 4 ⁇ 2 heteroatoms independently selected from N, S and O 7-membered saturated or partially unsaturated ring; or two hydrogens on the same carbon of the 4-7 membered saturated or partially unsaturated ring can be replaced by oxygen to -C(O)-;
  • Each R is independently H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted containing 1
  • w 0, 1 or 2.
  • Cy 1 is:
  • R 3 is H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted saturated or partially unsaturated (C3-C7) cycloalkyl, substituted or unsubstituted containing 1 to 2 independently selected A 3-7 membered saturated or partially unsaturated monoheterocycloalkyl group consisting of heteroatoms from N, S and O, or a substituted or unsubstituted 7- to 7-membered heteroatoms independently selected from N, S and O 12-membered saturated or partially unsaturated bicyclic heterocycloalkyl;
  • R 4 is H, -N(R) 2 , halogen, (C1-C6) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl or (C3-C6) cycloalkane The group can be substituted by 1 to 3 halogens;
  • R 5 is H, (C1-C6) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl or (C3-C6) cycloalkyl can be substituted by 1 to 3 halogens .
  • R 3 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CH 2 OH, R 3 is preferably -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH, R 3 is more preferably -CH 3 .
  • R 4 is H, F, Cl, Br, I, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ;
  • R 4 is preferably H, F, Cl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 or -CF 3 ;
  • R 4 is more preferably H, F, Cl, -N(CH 3 ) 2 or -CH 3 .
  • R 5 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ;
  • R 5 is preferably H, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , CH 2 CH 2 F or -CH 2 CF 3 ;
  • R 5 is more preferably H, -CH 3 or -CH 2 CF 3 .
  • R 6 is a substituent on Cy 2 , which is H, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , - S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -C( O)N(R)(CH 2 ) w R, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)C(O)NR 2 , -N(R)
  • n 1 or 2.
  • R 6 is H, F, Cl, Br, I, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH, R 6 is preferably H, F, Cl, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 CH 3 , -CHCH 2
  • R 7 is a substituent on Cy 3 , which is H, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC (O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N( R)C(O)NR 2 , -N( R)C(NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, substituted or unsubstituted (C1-C6) alkyl, substituted or
  • p 1 or 2.
  • R 7 is H, F, Cl, Br, I, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH, R 7 is preferably H, F, Cl, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 CH 3 , -CHCH 2
  • R 1 is H, -CH 3 or -L 1 -R 1A ;
  • L 1 is a chemical bond, -O-, -C(O)-, -NH-, -NH(CO)-, -C(O)NH-, -C(O)N(CH 3 )- or -S( O) 2 -;
  • L 1 is preferably a chemical bond, -O-, -C(O)-, -NH- or -S(O) 2 -;
  • L 1 is more preferably a chemical bond;
  • L 1 is more preferably -O-;
  • L 1 is more preferably -C(O)-;
  • R 1A is -CH 3 , R 1A is preferably -CH 3 , R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is more preferably R 1A is
  • R 2 is -NHCN, -CN, R2 is preferably -NHCN, -CN, R 2 is more preferably R 2 is more preferably R 2 is more preferably R 2 is more preferably R 2 is more preferably
  • the present invention provides compounds of the general formula (2) and (3) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvents compound:
  • R 1 , R 2 , R 3 , R 6 , R 7 , m and p are as described above, and are illustrated in specific examples.
  • the present invention provides compounds of general formula (2a) and general formula (3a) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thing:
  • R 1A , L 1 , R 2 , R 3 , R 6 , R 7 , m and p are as described above and illustrated in specific examples.
  • the compound of general formula (1) has one of the following structures:
  • Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
  • Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Use for preparing medicines for treating, regulating or preventing diseases related to FGFR2.
  • said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
  • Another object of the present invention is to provide a method for treating, regulating or preventing related diseases mediated by FGFR2, comprising administering to the subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of them Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.
  • Figure 1 is the result of tumor volume change in Example 40 of the present invention.
  • Fig. 2 is the mouse body weight change result of embodiment 40 of the present invention.
  • Figure 3 is the result of tumor volume change in Example 41 of the present invention.
  • Fig. 4 is the results of body weight changes of mice in Example 41 of the present invention.
  • the compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
  • the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below.
  • the compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs.
  • the present invention also provides a method for preparing the compound represented by the general formula, wherein the compound of the general formula can be prepared by using the following general reaction scheme 1 and general reaction scheme 2:
  • compound 2-1 undergoes a coupling reaction with compound 2-2 to generate compound 2-3
  • compound 2-3 undergoes a coupling reaction with 2-4 to generate compound 2-7.
  • compound 2-3 and compound 2-5 undergo a coupling reaction to generate compound 2-6, and compound 2-6 is deprotected with hydrochloric acid to obtain compound 2-7.
  • Compound 2-7 undergoes intramolecular reductive amination to generate compound 2-8, compound 2-8 reacts with Boc anhydride to generate compound 2-9, compound 2-9 undergoes a reduction reaction to generate compound 2-10, and compound 2-10 reacts with the corresponding The acid or acid chloride reacts to generate compound 2-11, and the compound 2-11 deprotects under acidic conditions to generate the target compound (1a).
  • “Pharmaceutically acceptable” here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
  • the term "pharmaceutically acceptable salt” refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound.
  • the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
  • an acid such as hydrochloric acid, hydrobromic acid, hydro
  • references to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs.
  • Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol.
  • Solvates of compounds of general formula are conveniently prepared or formed according to the methods described herein.
  • the hydrate of the compound of the general formula is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol.
  • the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
  • compounds of the general formula are prepared in various forms including, but not limited to, amorphous, pulverized and nano-particle sized forms.
  • the compounds of the general formula include crystalline forms and may also be polymorphic.
  • Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
  • the compounds of the general formula may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers form, and the form of cis-trans isomers.
  • Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
  • alkyl means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, “alkyl” includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens.
  • Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 )CH, iPr , nPr , iBu , nBu or tBu .
  • cycloalkyl means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl”. Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic.
  • cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups.
  • cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
  • aryl refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups.
  • aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
  • heteroaryl refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic.
  • a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups.
  • heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrole[2,3-c]pyridinyl, 1H-pyrrole[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
  • heterocycloalkyl means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members.
  • a partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl” if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl".
  • Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems.
  • heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen.
  • the ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized.
  • a heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom.
  • heterocycloalkyl groups contain 0 to 3 double bonds.
  • heterocycloalkyl groups contain 0 to 2 double bonds.
  • moieties also known as partially unsaturated heterocycles
  • having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring such as piperidine, Benzo derivatives of morpholine, azepine or thienyl, etc.
  • a heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring.
  • heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl,
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • halo or halogen substitution
  • appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
  • the substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
  • linking group When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
  • membered ring includes any ring structure.
  • member is meant to indicate the number of skeletal atoms that make up the ring.
  • cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings
  • cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
  • fragment refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to 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 or straight dotted key
  • acceptable means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
  • treatment includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom.
  • a certain compound or pharmaceutical composition after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
  • Active ingredient refers to the compound represented by the general formula, as well as the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula.
  • the compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers.
  • the asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention.
  • the present invention is meant to include all such isomeric forms of these compounds.
  • composition a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
  • administering means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
  • the present invention provides methods of treating diseases including, but not limited to, conditions involving FGFR2 (eg, cancer) using compounds of the general formula or pharmaceutical compositions of the present invention.
  • a method for treating cancer comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of the general formula to an individual in need.
  • the cancer is mediated by FGFR2.
  • the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, bile duct cancer , ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.
  • the compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts .
  • safe and effective amount means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects.
  • the safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
  • “Pharmaceutically acceptable excipient or carrier” means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity .
  • “Compatibility” herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound.
  • Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
  • cellulose and derivatives thereof such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.
  • gelatin such as stearic acid, magnesium stearate
  • calcium sulfate such as soybean oil, sesame oil,
  • the compounds of the present invention When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostea, or
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • coatings and shell materials such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner.
  • Examples of usable embedding components are polymeric substances and waxy substances.
  • the active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.
  • liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
  • inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and
  • compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • suspending agents for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
  • compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions.
  • Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants.
  • the active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
  • the compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily
  • the dosage is usually 1-2000 mg, preferably 50-1000 mg.
  • factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
  • 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in ⁇ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
  • the intermediate int_1-2 (1.0g, 3.42mmol) and bisanalyl borate (2.61g, 10.20mmol) were dissolved in dioxane (25mL), and potassium acetate (1.0g , 10.21mmol), added 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (279.55mg, 342.3 ⁇ mol) under the protection of nitrogen, and the reaction solution was stirred and reacted at 100°C under the protection of nitrogen 3 hours.
  • the intermediate int_1-5 (2.16g, 9.51mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (5.42g, 47.56mmol, 3.52mL) was added, and the reaction solution was cooled to 0°C.
  • N-iodosuccinimide (2.14 g, 9.51 mmol) was added to the reaction solution at 0°C, and the reaction solution was heated to 20°C and stirred for 2 hours.
  • intermediate int_1-7 (290mg, 832.96 ⁇ mol) and intermediate int_1-3 (423.80mg, 1.25mmol) were dissolved in dioxane (5mL), and then aqueous sodium carbonate (2M, 6mL) added to the reaction solution. Tetrakis(triphenylphosphine)palladium (96.25 mg, 83.30 ⁇ mol) was added under nitrogen protection. The reaction solution was stirred and reacted at 80° C. for 3 hours under the protection of nitrogen.
  • reaction solution was cooled to room temperature, it was diluted with water (5 mL), extracted with ethyl acetate (5 mL ⁇ 3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude intermediate int_1-8.
  • the intermediate int_1-10 (70 mg) was dissolved in anhydrous dichloromethane (5 mL), and acryloyl chloride (96.66 ⁇ mol, 8.0 ⁇ L) was added to the reaction solution under cooling in an ice-water bath, and then triethyl Amine (29.34mg, 289.99 ⁇ mol), the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and purified by C18 reverse phase chromatography to obtain compound 1 as a white solid.
  • reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (1L) was added to the reaction solution, then extracted with ethyl acetate (1L ⁇ 3), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a brown Solid intermediate int_2-1.
  • the intermediate int_2-1 (300g, 1.22mol) and 2-fluoro-6-picoline (680g, 6.12mol) were dissolved in N,N-dimethylformamide (1.5L), cesium carbonate (638g , 1.96mol).
  • the reaction solution was stirred at 120°C (external temperature) for 16 hours.
  • the reaction solution was cooled to room temperature, and the reaction solution and solid residue were poured into water (4.5L), extracted with ethyl acetate (2L ⁇ 3), the organic phase was dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to dry, separated and purified by silica gel chromatography to obtain the intermediate int_2-2.
  • the intermediate int_2-2 (110.00 g, 327.21 mmol) was dissolved in tetrahydrofuran (400 mL), and hydrochloric acid (3M, 328 mL) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (1 L) was added to the reaction solution at 0° C., then extracted with ethyl acetate (1 L ⁇ 3), the organic phase was dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was reduced to Concentrate to dryness under reduced pressure to obtain crude white solid intermediate int_2-3.
  • the intermediate int_2-3 (92.00g, 314.93mmol) was dissolved in dichloromethane (1.8L), and methoxymethyl triphenylphosphine chloride (161.94g, 472.40mmol) and tert-butyl Sodium alkoxide (45.40 g, 472.40 mmol).
  • the reaction solution was stirred at 0°C for 5 hours.
  • the intermediate int_2-5 (30.00 g, 97.99 mmol) and ethylene glycol (30.41 g, 489.95 mmol) were dissolved in toluene (500 mL), and p-toluenesulfonic acid (1.69 g, 9.80 mmol) was added. The reaction solution was stirred and reacted at 110° C. for 16 hours.
  • reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and saturated sodium carbonate (500 mL) was added to the residue, then extracted with ethyl acetate (500 mL ⁇ 3), dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure To dryness, the crude yellow oily intermediate int_2-6 was obtained.
  • reaction solution was cooled to room temperature, water (1500mL) was added, extracted with ethyl acetate (1.5L ⁇ 3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by beating to obtain the intermediate int_2 -8.
  • the intermediate int_2-8 (11.00 g, 20.43 mmol) was dissolved in tetrahydrofuran (150 mL), hydrochloric acid (3M, 34.04 mL) was added, and the reaction solution was stirred at 60° C. for 1 hour.
  • the reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (500 mL) was added to the reaction solution at 0°C, filtered, the filter cake was washed with water (200 mL) and ethyl acetate (200 mL), and the filter cake was dried under reduced pressure to obtain the crude intermediate int_2-9.
  • the intermediate int_2-9 (10.00g, 20.22mmol) was dissolved in methanol (85mL) and acetic acid (17mL), and 2-picoline borane complex (4.33g, 40.44mmol) was added, and the reaction solution was heated at 40°C The reaction was stirred for 0.5 hours.
  • the reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (200 mL) was added to the reaction solution at 0°C, filtered, the filter cake was rinsed with water (100 mL) and ethyl acetate (100 mL), and the filter cake was collected and dried under reduced pressure to obtain the crude product Intermediate int_2-10.
  • the intermediate int_2-11 (7.00 g, 12.10 mmol) was dissolved in methanol (120 mL) and water (24 mL), and iron powder (13.51 g, 241.96 mmol) and ammonium chloride (12.94 g, 241.96 mmol) were added.
  • the reaction solution was stirred and reacted at 65° C. for 3 hours.
  • the reaction solution was cooled to room temperature, filtered with suction, washed with methanol (100 mL) and dichloromethane (200 mL), and concentrated under reduced pressure.
  • the intermediate int_2-12 (2.00g, 3.65mmol) was dissolved in dichloromethane (20mL), and triethylamine (1.11g, 10.94mmol) and acryloyl chloride (494.91mg, 5.47mmol) were added at 0°C.
  • the reaction solution was stirred and reacted at 25° C. for 1 hour.
  • the intermediate int_2-13 (1.50 g, 2.49 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (17.03 g, 149.33 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate solution (50mL), extract with dichloromethane (50mL ⁇ 3), combine the organic phases to dry with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure , Compound 2 was obtained by separation and purification by silica gel chromatography.
  • the intermediate int_10-2 (4.20 g, 18.18 mmol) and ethylene glycol (4.95 mL, 88.53 mmol) were dissolved in toluene (580 mL), and p-toluenesulfonic acid (704.35 mg, 4.09 mmol) was added.
  • the reaction solution was stirred and reacted at 110° C. for 16 hours.
  • Water (500mL) was added to the reaction solution, the mixed solution was extracted with ethyl acetate (500mL ⁇ 3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product intermediate int_10 -3.
  • the intermediate int_10-6 (940 mg, 1.70 mmol) was dissolved in tetrahydrofuran (3 mL), and aqueous hydrochloric acid (3M, 1.29 mL, 3.88 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution of the intermediate int_10-7 was obtained, which was directly used in the next step without any treatment.
  • the intermediate int_10-8 (570 mg, 1.15 mmol) was dissolved in N, N-dimethylformamide (3.5 mL), and Boc anhydride (2.65 mL, 11.53 mmol), triethylamine (609.66 ⁇ L, 4.38 mmol) were added and 4-dimethylaminopyridine (70.41 mg, 576.34 ⁇ mol). The reaction solution was stirred and reacted at 50° C. for 2 hours.
  • the intermediate int_10-9 (420 mg, 706.34 ⁇ mol) was dissolved in methanol (12 mL) and water (2.4 mL), and reduced iron powder (394.4 mg, 7.06 mmol) and ammonium chloride (377.83 mg, 7.06 mmol) were added. The reaction solution was stirred and reacted at 65°C for 0.5 hours.
  • the intermediate int_10-10 (400 mg, 708.42 ⁇ mol) was dissolved in dichloromethane (8 mL), and triethylamine (302 ⁇ L, 2.17 mmol) and acryloyl chloride (118 ⁇ L, 1.45 mmol) were added. The reaction solution was stirred and reacted at 20° C. for 1 hour. Add saturated sodium carbonate solution (10mL) to the reaction solution, extract the mixture with dichloromethane (10mL ⁇ 3), combine the organic phases, dry with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the intermediate int_10-11.
  • the intermediate int_10-11 (260 mg, 420.25 ⁇ mol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (2 mL, 25.21 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Add saturated aqueous sodium carbonate solution (30mL) to the reaction solution, extract the mixture with dichloromethane (30mL ⁇ 3), combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and then use Tetrahydrofuran (15 mL) was slurried to obtain compound 10.
  • N, N-diisopropylamide lithium (2M tetrahydrofuran solution, 156mL) was dissolved in tetrahydrofuran (1L), and compound 2-fluoro-4-bromoanisole (50.0g, 244mmol) was added dropwise at -78°C Tetrahydrofuran (500 mL) solution, the reaction solution was stirred and reacted at -78°C for 0.5 hours, then N,N-dimethylformamide (26.7 g, 366 mmol) was added dropwise, and the reaction solution was stirred and reacted at 10°C for 3 hours.
  • the intermediate int_11-2 (100 g, 429 mmol) was dissolved in dichloromethane (500 mL), and boron tribromide (376 g, 1.50 mol) was added in portions at -30°C.
  • the reaction solution was stirred and reacted at 25° C. for 12 hours.
  • the reaction solution was slowly poured into ice water (2L), extracted with ethyl acetate (2L ⁇ 3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography to obtain Intermediate int_11-3.
  • the intermediate int_11-3 (410g, 1.87mol) was dissolved in toluene (2L), and then ethylene glycol (581g, 9.36mol) and p-toluenesulfonic acid (64.5g, 374mol) were added. The reaction solution was stirred and reacted at 110° C. for 16 hours. After the reaction solution was cooled, it was added to saturated sodium carbonate solution (1L), extracted with ethyl acetate (2L ⁇ 3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and subjected to silica gel chromatography. The intermediate int_11-4 was obtained by separation and purification by method.
  • the intermediate int_11-4 (150g, 570mmol) was dissolved in N,N-dimethylformamide (2L), cesium carbonate (557.36g, 1.71mol), 2-fluoro-6-methylpyridine (633.60g , 5.70mol). The reaction solution was stirred and reacted at 120° C. for 12 hours. After the reaction solution was cooled, water (5L) was added, followed by ethyl acetate (2L ⁇ 3) for extraction, the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain intermediate Body int_11-5.
  • the intermediate int_11-5 (120g, 339mmol) was dissolved in dioxane (1L), and double pinacol borate (258g, 1.02mol) was added, added under nitrogen protection, [1,1-bis (Diphenylphosphine)ferrocene]palladium dichloride dichloromethane (27.7g, 33.9mmol), potassium acetate (99.8g, 1.02mol), and the reaction solution was stirred at 100°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain the intermediate int_11-6.
  • the intermediate int_11-7 (28 g, 51.61 mmol) was dissolved in tetrahydrofuran (100 mL), and aqueous hydrochloric acid (40 mL, 3M) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution was concentrated to obtain the intermediate int_11-8, and the crude product was directly used in the next reaction.
  • the intermediate int_11-9 (12g, 24.87mmol) was dissolved in N,N-dimethylformamide (250mL), and Boc anhydride (57mL, 248.72mmol), triethylamine (13mL, 94.51mmol) and 4- Dimethylaminopyridine (1.52 mg, 12.44 mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours.
  • the intermediate int_11-10 (13g, 22.31mmol) was dissolved in methanol (300mL) and water (60mL), and reduced iron powder (12.46g, 223.15mmol) and ammonium chloride (11.94g, 223.15mmol) were added.
  • the reaction solution was stirred and reacted at 65° C. for 1 hour.
  • water (1.0L) was added, the mixture was extracted with ethyl acetate (1.0L ⁇ 3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. , and then stirred with ethyl acetate (50 mL) at 20 ° C for 0.5 hours to obtain the intermediate int_11-11.
  • the intermediate int_11-11 (2 g, 3.62 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (1.5 mL, 10.86 mmol) and acryloyl chloride (443 ⁇ L, 5.43 ⁇ mol) were added at 0°C.
  • the reaction solution was stirred and reacted at 20° C. for 1 hour.
  • the intermediate int_11-12 was obtained by separation and purification by silica gel chromatography.
  • the intermediate int_11-12 (1.88 g, 3.10 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (11.5 mL, 155 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. After the reaction solution was spin-dried, saturated aqueous sodium carbonate solution (150 mL) was added, the mixture was extracted with dichloromethane (150 mL ⁇ 3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Compound 11 was then separated and purified by silica gel chromatography.
  • reaction solution was concentrated to dryness under reduced pressure, the reaction solution was poured into water (30mL), extracted with dichloromethane (30mL ⁇ 3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, the crude product Compound int_12-6 was obtained by separation and purification by silica gel chromatography.
  • reaction solution was cooled to room temperature, water (4.5 L) was added, suction filtered, washed with ethyl acetate (500 mL), and the filter cake was purified by slurrying with ethyl acetate (500 mL) to obtain compound int_34-3.
  • reaction solution was cooled to room temperature, water (500mL) was added, extracted with ethyl acetate (500mL ⁇ 3), dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain the compound int_34- 7.
  • Step 9 Compound int_34-9 synthesis:
  • Step 7 Compound int_39-7 synthesis:
  • reaction solution was cooled to room temperature, added saturated ammonium chloride aqueous solution (500mL), stirred at room temperature for 30 minutes, extracted with ethyl acetate (500mL ⁇ 3), combined organic phases were dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was decompressed Concentrate to dryness, separate and purify by silica gel chromatography to obtain compound int_42-3.
  • Step 9 Compound int_42-10 synthesis:
  • Step 3 Compound int_88-4 synthesis:
  • Step 4 Compound int_88-5 synthesis:
  • reaction solution was stirred and reacted at 100°C for 0.5 hours. After cooling, water (20mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (20mL ⁇ 3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_88-5 was obtained by separation and purification by chromatography.
  • reaction solution was cooled to room temperature, and the reaction solution was slowly poured into water (2L), a large amount of solids precipitated, extracted with ethyl acetate (500mL ⁇ 3), and the organic phase was directly beaten and purified to obtain a yellow solid compound int_139-3.
  • reaction solution of compound int_139-4 in the previous step was diluted with tetrahydrofuran (500mL), the reaction solution was cooled to -10°C, and sodium cyanoborohydride (21.58g, 343.41mmol) was slowly added in batches, and the reaction solution was heated at 25°C (external temperature) and stirred for 1 hour.
  • Step 1 Synthesis of compound int_141-1:
  • reaction solution was concentrated to dryness under reduced pressure, the reaction solution was poured into water (30mL), extracted with dichloromethane (30mL ⁇ 3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, the crude product Compound int_141-4 was obtained by separation and purification by silica gel chromatography.
  • Step 1 Synthesis of compound int_175-1:
  • reaction solution was filtered, concentrated under reduced pressure and spin off 400mL of solvent, and then water (500mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (500mL ⁇ 3), the organic phases were combined, dried with anhydrous magnesium sulfate, and extracted The filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_175-2.
  • reaction solution was filtered, and the filtrate was concentrated under reduced pressure to spin off 900 mL of solvent, and then slurried with ethyl acetate (500 mL) to obtain a yellow solid compound int_175-3.
  • reaction solution was filtered, concentrated to dryness under reduced pressure, water (300 mL) was added, the mixture was extracted with ethyl acetate (300 mL ⁇ 3), the organic phases were combined, dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to dry, and then separated and purified by silica gel chromatography to obtain compound int_181-5.
  • reaction solution was cooled to room temperature, water (1 L) was added, suction filtered, washed with ethyl acetate (500 mL), and the filter cake was purified by slurrying with ethyl acetate (500 mL) to obtain compound int_177-3 as a yellow solid.
  • reaction solution was cooled to room temperature, water (200mL) was added, extracted with ethyl acetate (200mL ⁇ 3), dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain the compound int_177- 6.
  • Step 3 Compound int_188-4 synthesis:
  • reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure.
  • reaction solution was stirred and reacted at 100°C for 0.5 hours. After cooling, water (10mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (10mL ⁇ 3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_191-1 was obtained by separation and purification by chromatography.
  • Step 6 Compound int_193-7 synthesis:
  • Step 7 Compound int_193-8 synthesis:

Abstract

A compound represented by general formula (1) or a pharmaceutically acceptable salt thereof, a composition containing a compound represented by general formula (1), a preparation method therefor, and a use of same as a fibroblast growth factor receptor 2 (FGFR2) inhibitor in the preparation of an anti-tumor drug.

Description

FGFR2抑制剂、及其制备方法和医药用途FGFR2 inhibitor, its preparation method and medical application
本申请要求申请日为2021年11月4日的中国专利申请202111301787.1、申请日为2022年3月1日的中国专利申请202210195072.0和申请日为2022年9月8日的中国专利申请202211097520.X的优先权。本申请引用上述中国专利申请的全文。This application requires Chinese patent application 202111301787.1 with a filing date of November 4, 2021, Chinese patent application 202210195072.0 with a filing date of March 1, 2022, and Chinese patent application 202211097520.X with a filing date of September 8, 2022 priority. This application cites the full text of the above-mentioned Chinese patent application.
技术领域technical field
本发明属于药物化学领域，更具体而言，涉及一类具有成纤维细胞生长因子受体2(FGFR2)抑制作用的新化合物及其制备方法和该类化合物在抗肿瘤药物制备中的用途。The invention belongs to the field of medicinal chemistry, and more specifically relates to a novel compound with fibroblast growth factor receptor 2 (FGFR2) inhibitory effect, a preparation method thereof, and an application of the compound in the preparation of antitumor drugs.
背景技术Background technique
成纤维细胞生长因子受体(FGFR)是受体酪氨酸激酶(RTK)家族成员，主要包括FGFR1、FGFR2、FGFR3和FGFR4，其结构包括胞外结合特殊配体的区域、跨膜区域和胞内激酶区域。FGFR的信号传导途径为配体与受体的结合诱导FGFR二聚化，从而引起下游信号通路(如Ras-MAPK，PI3K-Akt，STAT和PLCγ)的级联激活，对细胞的增殖、凋亡、迁移、新生血管生成等进行调控。FGFR突变激活或高表达与人类肿瘤的发生发展密切相关。细胞中的FGFR激活突变或过表达可导致FGFR信号通路的持续性和过度激活，使细胞获得过度增殖、凋亡逃避等致癌性的功能。同时，研究发现在人体多种癌细胞中出现FGFR异常表达，如乳腺癌、肺癌、卵巢癌、胃癌、子宫瘤、恶性胶质瘤、膀胱癌、肝癌，实体瘤等(CancerDiscovery.2013；3(3)：264-279；Annals of Oncology.2014；25：552-563)。因此FGFR被公认为是抗肿瘤药物研发的重要靶点，是目前药物研发最热门靶点之一。Fibroblast growth factor receptor (FGFR) is a member of the receptor tyrosine kinase (RTK) family, mainly including FGFR1, FGFR2, FGFR3 and FGFR4. Endokinase domain. The signaling pathway of FGFR is that the binding of ligands to receptors induces FGFR dimerization, thereby causing the cascade activation of downstream signaling pathways (such as Ras-MAPK, PI3K-Akt, STAT and PLCγ), and affecting cell proliferation and apoptosis. , migration, and angiogenesis. FGFR mutation activation or high expression is closely related to the occurrence and development of human tumors. Activating mutations or overexpression of FGFR in cells can lead to the persistence and overactivation of FGFR signaling pathways, enabling cells to acquire oncogenic functions such as excessive proliferation and apoptosis evasion. At the same time, studies have found that abnormal expression of FGFR occurs in a variety of human cancer cells, such as breast cancer, lung cancer, ovarian cancer, gastric cancer, uterine tumor, malignant glioma, bladder cancer, liver cancer, solid tumors, etc. (Cancer Discovery.2013; 3( 3): 264-279; Annals of Oncology. 2014; 25: 552-563). Therefore, FGFR is recognized as an important target for anti-tumor drug development, and is one of the most popular targets for drug development.
FGFR2在胚胎发育和组织修复中发挥着重要作用，在骨骼和血管生成中的作用更为显著，也发现与肿瘤血管的形成、肿瘤的分期、转移、预后及化疗疗效密切相关，在多种人类恶性肿瘤都出现高表达、基因扩增或错义突变，如在胃癌、肺癌、乳腺癌、卵巢癌和子宫内膜癌等恶性肿瘤中普遍存在。FGFR2 plays an important role in embryonic development and tissue repair, and it plays a more significant role in bone and angiogenesis. It is also found to be closely related to the formation of tumor blood vessels, tumor staging, metastasis, prognosis and chemotherapy efficacy. Malignant tumors all have high expression, gene amplification or missense mutations, such as gastric cancer, lung cancer, breast cancer, ovarian cancer and endometrial cancer, which are common in malignant tumors.
目前已有三个FGFR抑制剂获批用于治疗肝胆管癌(erdafitinib，pemigatinib，infigratinib)，此外还有多款FGFR抑制剂已经进入临床实验阶段。但是这些化合物大都是泛FGFR抑制剂，对FGFR1、FGFR2、FGFR3和FGFR4缺乏选择性，因而会有一些毒副作用，如高磷血症(抑制FGFR1)和腹泻(抑制FGFR4)。因此，开发特异性的高活性FGFR2抑制剂具有重要的临床价值。At present, three FGFR inhibitors have been approved for the treatment of hepatocholangiocarcinoma (erdafitinib, pemigatinib, infigratinib), and several FGFR inhibitors have entered the clinical trial stage. However, most of these compounds are pan-FGFR inhibitors, lack of selectivity to FGFR1, FGFR2, FGFR3 and FGFR4, so there will be some toxic side effects, such as hyperphosphatemia (inhibition of FGFR1) and diarrhea (inhibition of FGFR4). Therefore, the development of specific and highly active FGFR2 inhibitors has important clinical value.
发明内容Contents of the invention
本发明提供了一种通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：The present invention provides a compound represented by general formula (1) or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
Figure PCTCN2022129961-appb-000001
Figure PCTCN2022129961-appb-000001
通式(1)中：In general formula (1):
Cy 1为取代或未取代的含1～4个独立选自N、S和O的杂原子的6元并5元杂芳环或部分不饱和杂环； Cy 1 is a substituted or unsubstituted 6-membered and 5-membered heteroaromatic ring or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, S and O;
Cy 2为取代或未取代的苯环、5～6元杂芳环、9元双并杂芳环或9～12元部分不饱和双并杂环； Cy 2 is a substituted or unsubstituted benzene ring, a 5-6 membered heteroaromatic ring, a 9-membered bis-heteroaromatic ring or a 9-12-membered partially unsaturated bis-heterocyclic ring;
Cy 2与Cy 1的5元环直接相连，同时二价基团-NH-(CH 2)n-连接Cy 1的6元环和Cy 2，并再形成一个环，其中n为1或2； Cy 2 is directly connected to the 5-membered ring of Cy 1 , and the divalent group -NH-(CH 2 )n- is connected to the 6-membered ring of Cy 1 and Cy 2 to form another ring, where n is 1 or 2;
R 1为H、(C1-C3)烷基或-L 1-R 1A； R 1 is H, (C1-C3) alkyl or -L 1 -R 1A ;
L 1为化学键、-O-、-C(O)-、-NH-、-N(R L)-、-NH(CO)-、-N(R L)C(O)-、-C(O)NH-、-C(O)N(R L)-、-NHS(O) 2-、-N(R L)S(O) 2-、-S(O) 2NH-、-S(O) 2N(R L)-、-S-、-S(O)-或-S(O) 2-； L 1 is a chemical bond, -O-, -C(O)-, -NH-, -N(R L )-, -NH(CO)-, -N(R L )C(O)-, -C( O)NH-, -C(O)N(R L )-, -NHS(O) 2 -, -N(R L )S(O) 2 -, -S(O) 2 NH-, -S( O) 2 N(R L )-, -S-, -S(O)- or -S(O) 2 -;
R L为(C1-C3)烷基，其中所述(C1-C3)烷基可任选被1个或多个卤素取代； R L is a (C1-C3) alkyl group, wherein the (C1-C3) alkyl group can be optionally substituted by one or more halogens;
R 1A为-(CH 2) wR、-(CH 2) wOR、-(CH 2) wNR 2、取代或未取代的(C1-C6)烷基、(C3-C6)环烷基、苯基、含1～2个独立选自N、S和O的杂原子的3～9元饱和或部分不饱和杂环烷基、或含1～4个独立选自N、S和O的杂原子的5～6元杂芳基； R 1A is -(CH 2 ) w R, -(CH 2 ) w OR, -(CH 2 ) w NR 2 , substituted or unsubstituted (C1-C6) alkyl, (C3-C6) cycloalkyl, Phenyl, 3-9 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, or 1-4 heteroatoms independently selected from N, S and O Atomic 5-6 membered heteroaryl;
Cy 3为取代或未取代的苯环、含1～4个独立选自N、S和O杂原子的5～6元单杂芳环、含1～4个独立选自N、S和O的杂原子的8～10元双杂芳环、3～7元饱和或部分不饱和碳环、含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环、含1～4个独立选自N、S和O的杂原子的7～12元饱和或部分不饱和双杂环或桥环、5～6元芳香环联4～7元饱和或部分不饱和杂环、或5～6元芳香环联5～6元杂芳环； Cy 3 is a substituted or unsubstituted benzene ring, a 5-6 membered monoheteroaromatic ring containing 1 to 4 heteroatoms independently selected from N, S and O, and a single heteroaromatic ring containing 1 to 4 heteroatoms independently selected from N, S and O 8-10 membered diheteroaromatic rings with heteroatoms, 3-7-membered saturated or partially unsaturated carbocycles, 3-7-membered saturated or partially unsaturated heteroatoms containing 1-2 heteroatoms independently selected from N, S and O Heterocycle, 7-12 membered saturated or partially unsaturated biheterocyclic ring or bridged ring containing 1-4 heteroatoms independently selected from N, S and O, 5-6 membered aromatic ring with 4-7 membered saturated or partially Unsaturated heterocyclic rings, or 5-6 membered aromatic rings linked with 5-6 membered heteroaromatic rings;
R 2为-NHCN、-CN、
Figure PCTCN2022129961-appb-000002
Figure PCTCN2022129961-appb-000003
R 2 is -NHCN, -CN,
Figure PCTCN2022129961-appb-000002
Figure PCTCN2022129961-appb-000003
R 2A为H、取代或未取代的(C1-C6)烷基、或取代或未取代的(C3-C6)环烷基； R 2A is H, substituted or unsubstituted (C1-C6) alkyl, or substituted or unsubstituted (C3-C6) cycloalkyl;
R 2B、R 2C和R 2D各自独立地为H、卤素、-CN、-C(O)R、-C(O)OR、-C(O)NR 2、-C(O)N(R)OR、-(CH 2) wR、-(CH 2) wOR、-(CH 2) wNR 2、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、取代或未取代的苯基、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环、取代或未取代的含1～4个独立选自N、S和O的杂原子的5～6元杂芳环； R 2B , R 2C and R 2D are each independently H, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R) OR, -(CH 2 ) w R, -(CH 2 ) w OR, -(CH 2 ) w NR 2 , substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from N, S and O, substituted or unsubstituted A 5-6 membered heteroaromatic ring containing 1-4 heteroatoms independently selected from N, S and O;
或者R 2A和R 2B、R 2B和R 2C、R 2C和R 2D、R 2A和R 2D可形成取代或未取代的含0～2个独立选自N、S和O的杂原子的4～7元饱和或部分不饱和环；或者所述的4～7元饱和或部分不饱和环的同一碳上的两个氢可被氧取代成-C(O)-； Or R 2A and R 2B , R 2B and R 2C , R 2C and R 2D , R 2A and R 2D can form a substituted or unsubstituted 4～2 heteroatoms independently selected from N, S and O 7-membered saturated or partially unsaturated ring; or two hydrogens on the same carbon of the 4-7 membered saturated or partially unsaturated ring can be replaced by oxygen to -C(O)-;
每个R独立地为H、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、取代或未取代的苯基、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环、或取代或未取代的含1～4个独立选自N、S和O的杂原子的5～6元杂芳环；Each R is independently H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted containing 1 A 3-7 membered saturated or partially unsaturated heterocyclic ring with ~2 heteroatoms independently selected from N, S and O, or a substituted or unsubstituted heteroatom containing 1 to 4 heteroatoms independently selected from N, S and O 5-6 membered heteroaromatic rings;
w为0，1或2。w is 0, 1 or 2.
在另一优选例中，其中所述通式(1)中，Cy 1为： In another preference, wherein in the general formula (1), Cy 1 is:
Figure PCTCN2022129961-appb-000004
Figure PCTCN2022129961-appb-000004
其中，
Figure PCTCN2022129961-appb-000005
与-NH-(CH 2)n-结构的氨基端相连，
Figure PCTCN2022129961-appb-000006
直接与Cy 2相连，
Figure PCTCN2022129961-appb-000007
与Cy 3相连； in,
Figure PCTCN2022129961-appb-000005
Connected to the amino terminal of the -NH-(CH 2 )n- structure,
Figure PCTCN2022129961-appb-000006
connected directly to Cy 2 ,
Figure PCTCN2022129961-appb-000007
Connected to Cy 3 ;
R 3为H、取代或未取代的(C1-C6)烷基、取代或未取代的饱和或部分不饱和的(C3-C7)环烷基、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和单杂环烷基、或取代或未取代的含1～4个独立选自N、S和O的杂原子的7～12元饱和或部分不饱和双环杂环烷基； R 3 is H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted saturated or partially unsaturated (C3-C7) cycloalkyl, substituted or unsubstituted containing 1 to 2 independently selected A 3-7 membered saturated or partially unsaturated monoheterocycloalkyl group consisting of heteroatoms from N, S and O, or a substituted or unsubstituted 7- to 7-membered heteroatoms independently selected from N, S and O 12-membered saturated or partially unsaturated bicyclic heterocycloalkyl;
R 4为H、-N(R) 2、卤素、(C1-C6)烷基或(C3-C6)环烷基，其中所述的(C1-C6)烷基或(C3-C6)环烷基可被1～3个卤素取代； R 4 is H, -N(R) 2 , halogen, (C1-C6) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl or (C3-C6) cycloalkane The group can be substituted by 1 to 3 halogens;
R 5为H、(C1-C6)烷基或(C3-C6)环烷基，其中所述的(C1-C6)烷基或(C3-C6)环烷基可被1～3个卤素取代。 R 5 is H, (C1-C6) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl or (C3-C6) cycloalkyl can be substituted by 1 to 3 halogens .
在另一优选例中，其中所述通式(1)中，R 3为H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
Figure PCTCN2022129961-appb-000008
Figure PCTCN2022129961-appb-000009
-CH 2F、-CHF 2、-CF 3、-CH 2OH、-CH 2CH 2F、-CH 2CH 2OH、
Figure PCTCN2022129961-appb-000010
Figure PCTCN2022129961-appb-000011
Figure PCTCN2022129961-appb-000012
R 3优选为-CH 3、-CH 2CH 3、-CH 2CH 2OH、
Figure PCTCN2022129961-appb-000013
Figure PCTCN2022129961-appb-000014
R 3更优选为-CH 3。 In another preferred example, in the general formula (1), R 3 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
Figure PCTCN2022129961-appb-000008
Figure PCTCN2022129961-appb-000009
-CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CH 2 OH,
Figure PCTCN2022129961-appb-000010
Figure PCTCN2022129961-appb-000011
Figure PCTCN2022129961-appb-000012
R 3 is preferably -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH,
Figure PCTCN2022129961-appb-000013
Figure PCTCN2022129961-appb-000014
R 3 is more preferably -CH 3 .
在另一优选例中，其中所述通式(1)中，R 4为H、F、Cl、Br、I、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3、 -CH 2CH 3、-CH 2CH 2CH 3、
Figure PCTCN2022129961-appb-000015
Figure PCTCN2022129961-appb-000016
-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F或-CH 2CF 3；R 4优选为H、F、Cl、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3或-CF 3；R 4更优选为H、F、Cl、-N(CH 3) 2或-CH 3。 In another preferred example, in the general formula (1), R 4 is H, F, Cl, Br, I, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
Figure PCTCN2022129961-appb-000015
Figure PCTCN2022129961-appb-000016
-CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ; R 4 is preferably H, F, Cl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 or -CF 3 ; R 4 is more preferably H, F, Cl, -N(CH 3 ) 2 or -CH 3 .
在另一优选例中，其中所述通式(1)中，R 5为H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
Figure PCTCN2022129961-appb-000017
Figure PCTCN2022129961-appb-000018
-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F或-CH 2CF 3；R 5优选为H、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、CH 2CH 2F或-CH 2CF 3；R 5更优选为H、-CH 3或-CH 2CF 3。 In another preferred example, in the general formula (1), R 5 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
Figure PCTCN2022129961-appb-000017
Figure PCTCN2022129961-appb-000018
-CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ; R 5 is preferably H, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , CH 2 CH 2 F or -CH 2 CF 3 ; R 5 is more preferably H, -CH 3 or -CH 2 CF 3 .
在另一优选例中，其中所述通式(1)中，Cy 2为：
Figure PCTCN2022129961-appb-000019
Figure PCTCN2022129961-appb-000020
In another preference, wherein in the general formula (1), Cy 2 is:
Figure PCTCN2022129961-appb-000019
Figure PCTCN2022129961-appb-000020
其中，
Figure PCTCN2022129961-appb-000021
与-NH-(CH 2)n-结构的烷基端相连，
Figure PCTCN2022129961-appb-000022
与Cy 1相连； in,
Figure PCTCN2022129961-appb-000021
Connected to the alkyl end of the -NH-(CH 2 )n- structure,
Figure PCTCN2022129961-appb-000022
Linked to Cy 1 ;
R 6为Cy 2上的取代基，为H、卤素、-CN、-NO 2、-OR、-SR，-NR 2、-S(O) 2R、-S(O) 2NR 2、-S(O)R、-S(O)NR 2、-C(O)R、-C(O)OR、-C(O)NR 2、-C(O)N(R)OR、-C(O)N(R)(CH 2) wR、-OC(O)R、-OC(O)NR 2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR 2、-N(R)C(NR)NR 2、-N(R)S(O) 2NR 2、-N(R)S(O) 2R、-(CH 2) wOR、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、取代或未取代的苯基、取代或未取代的含1～4个独立选自N、S和O的杂原子的5～6元单杂芳环、取代或未取代的3～7元饱和或部分不饱 和碳环、或取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环； R 6 is a substituent on Cy 2 , which is H, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , - S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -C( O)N(R)(CH 2 ) w R, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, - (CH 2 ) w OR, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 1～ 5-6 membered monoheteroaromatic rings with 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3-7 membered saturated or partially unsaturated carbocycles, or substituted or unsubstituted 1-2 A 3-7 membered saturated or partially unsaturated heterocyclic ring independently selected from N, S and O heteroatoms;
m为1或2。m is 1 or 2.
在另一优选例中，其中所述通式(1)中，R 6为H、F、Cl、Br、I、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
Figure PCTCN2022129961-appb-000023
Figure PCTCN2022129961-appb-000024
-CH 2F、-CHF 2、-CF 3、-CH 2OH、-CH 2CH 2F、-CH 2CF 3、-CH 2CH 2OH、
Figure PCTCN2022129961-appb-000025
Figure PCTCN2022129961-appb-000026
Figure PCTCN2022129961-appb-000027
R 6优选为H、F、Cl、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F或-CH 2CF 3；R 6更优选为H、F、-CN、-CH 3、-CH 2CH 3、-CHF 2、-CF 3、-CH 2CF 3、-N(CH 3) 2、-OCF 3或-OCH 2CH 3；R 6更优选为H或F；R 6更优选为H；R 6更优选为F。 In another preferred example, in the general formula (1), R 6 is H, F, Cl, Br, I, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
Figure PCTCN2022129961-appb-000023
Figure PCTCN2022129961-appb-000024
-CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH,
Figure PCTCN2022129961-appb-000025
Figure PCTCN2022129961-appb-000026
Figure PCTCN2022129961-appb-000027
R 6 is preferably H, F, Cl, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ; R 6 is more preferably H, F, -CN, -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -CH 2 CF 3 , -N(CH 3 ) 2 , -OCF 3 or -OCH 2 CH 3 ; R 6 is more preferably H or F; R 6 More preferably H; R 6 is more preferably F.
在另一优选例中，其中所述通式(1)中，
Figure PCTCN2022129961-appb-000028
为： In another preferred example, wherein in the general formula (1),
Figure PCTCN2022129961-appb-000028
for:
Figure PCTCN2022129961-appb-000029
Figure PCTCN2022129961-appb-000029
Figure PCTCN2022129961-appb-000030
Figure PCTCN2022129961-appb-000030
其中R 7为Cy 3上的取代基，为H、卤素、-CN、-NO 2、-OR、-SR，-NR 2、-S(O) 2R、-S(O) 2NR 2、-S(O)R、-S(O)NR 2、-C(O)R、-C(O)OR、-C(O)NR 2、-C(O)N(R)OR、-OC(O)R、-OC(O)NR 2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR 2、-N(R)C(NR)NR 2、-N(R)S(O) 2NR 2、-N(R)S(O) 2R、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、取代或未取代的3～7元饱和或部分不饱和碳环、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环； Wherein R 7 is a substituent on Cy 3 , which is H, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC (O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N( R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted Substituted (C3-C6) cycloalkyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated carbocycle, substituted or unsubstituted containing 1-2 heteroatoms independently selected from N, S and O 3-7 membered saturated or partially unsaturated heterocycle;
p为1或2。p is 1 or 2.
在另一优选例中，其中所述通式(1)中，R 7为H、F、Cl、Br、I、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
Figure PCTCN2022129961-appb-000031
Figure PCTCN2022129961-appb-000032
-CH 2F、-CHF 2、-CF 3、-CH 2OH、-CH 2CH 2F、-CH 2CF 3、-CH 2CH 2OH、
Figure PCTCN2022129961-appb-000033
Figure PCTCN2022129961-appb-000034
Figure PCTCN2022129961-appb-000035
R 7优选为H、F、Cl、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CF 3、-CH 2CH 2OH、
Figure PCTCN2022129961-appb-000036
R 7更优选为H、F、-CH 3、-N(CH 3) 2、-OCH 3、-OCH 2CH 2OH、
Figure PCTCN2022129961-appb-000037
R 7更优选为H或F；R 7更优选为H；R 7更优选为F。 In another preferred example, in the general formula (1), R 7 is H, F, Cl, Br, I, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
Figure PCTCN2022129961-appb-000031
Figure PCTCN2022129961-appb-000032
-CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH,
Figure PCTCN2022129961-appb-000033
Figure PCTCN2022129961-appb-000034
Figure PCTCN2022129961-appb-000035
R 7 is preferably H, F, Cl, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH,
Figure PCTCN2022129961-appb-000036
R 7 is more preferably H, F, -CH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 2 OH,
Figure PCTCN2022129961-appb-000037
R 7 is more preferably H or F; R 7 is more preferably H; R 7 is more preferably F.
在另一优选例中，其中所述通式(1)中，R 1为H、-CH 3或-L 1-R 1A； In another preferred example, in the general formula (1), R 1 is H, -CH 3 or -L 1 -R 1A ;
L 1为化学键、-O-、-C(O)-、-NH-、-NH(CO)-、-C(O)NH-、-C(O)N(CH 3)-或-S(O) 2-；L 1优选为化学键、-O-、-C(O)-、-NH-或-S(O) 2-；L 1更优选为化学键；L 1更优选为-O-；L 1更优选为-C(O)-；R 1A为-CH 3、
Figure PCTCN2022129961-appb-000038
Figure PCTCN2022129961-appb-000039
Figure PCTCN2022129961-appb-000040
R 1A优选为-CH 3、
Figure PCTCN2022129961-appb-000041
Figure PCTCN2022129961-appb-000042
Figure PCTCN2022129961-appb-000043
Figure PCTCN2022129961-appb-000044
R 1A更优选为
Figure PCTCN2022129961-appb-000045
Figure PCTCN2022129961-appb-000046
R 1A更优选为
Figure PCTCN2022129961-appb-000047
R 1A更优选为
Figure PCTCN2022129961-appb-000048
R 1A更优选为
Figure PCTCN2022129961-appb-000049
R 1A更优选为
Figure PCTCN2022129961-appb-000050
L 1 is a chemical bond, -O-, -C(O)-, -NH-, -NH(CO)-, -C(O)NH-, -C(O)N(CH 3 )- or -S( O) 2 -; L 1 is preferably a chemical bond, -O-, -C(O)-, -NH- or -S(O) 2 -; L 1 is more preferably a chemical bond; L 1 is more preferably -O-; L 1 is more preferably -C(O)-; R 1A is -CH 3 ,
Figure PCTCN2022129961-appb-000038
Figure PCTCN2022129961-appb-000039
Figure PCTCN2022129961-appb-000040
R 1A is preferably -CH 3 ,
Figure PCTCN2022129961-appb-000041
Figure PCTCN2022129961-appb-000042
Figure PCTCN2022129961-appb-000043
Figure PCTCN2022129961-appb-000044
R 1A is more preferably
Figure PCTCN2022129961-appb-000045
Figure PCTCN2022129961-appb-000046
R 1A is more preferably
Figure PCTCN2022129961-appb-000047
R 1A is more preferably
Figure PCTCN2022129961-appb-000048
R 1A is more preferably
Figure PCTCN2022129961-appb-000049
R 1A is more preferably
Figure PCTCN2022129961-appb-000050
在另一优选例中，其中所述通式(1)中，R 2为-NHCN、-CN、
Figure PCTCN2022129961-appb-000051
Figure PCTCN2022129961-appb-000052
Figure PCTCN2022129961-appb-000053
R 2优选为-NHCN、-CN、
Figure PCTCN2022129961-appb-000054
Figure PCTCN2022129961-appb-000055
R 2更优选为
Figure PCTCN2022129961-appb-000056
Figure PCTCN2022129961-appb-000057
R 2更优选为
Figure PCTCN2022129961-appb-000058
R 2更优选为
Figure PCTCN2022129961-appb-000059
R 2更优选为
Figure PCTCN2022129961-appb-000060
In another preferred example, in the general formula (1), R 2 is -NHCN, -CN,
Figure PCTCN2022129961-appb-000051
Figure PCTCN2022129961-appb-000052
Figure PCTCN2022129961-appb-000053
R2 is preferably -NHCN, -CN,
Figure PCTCN2022129961-appb-000054
Figure PCTCN2022129961-appb-000055
R 2 is more preferably
Figure PCTCN2022129961-appb-000056
Figure PCTCN2022129961-appb-000057
R 2 is more preferably
Figure PCTCN2022129961-appb-000058
R 2 is more preferably
Figure PCTCN2022129961-appb-000059
R 2 is more preferably
Figure PCTCN2022129961-appb-000060
在本发明的一些实施例中，本发明提供了如通式(2)和通式(3)所述化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：In some embodiments of the present invention, the present invention provides compounds of the general formula (2) and (3) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvents compound:
Figure PCTCN2022129961-appb-000061
Figure PCTCN2022129961-appb-000061
其中R 1、R 2、R 3、R 6、R 7、m和p的定义如前所述，并在具体实施例中举例说明。 Wherein, the definitions of R 1 , R 2 , R 3 , R 6 , R 7 , m and p are as described above, and are illustrated in specific examples.
本发明的一些实施例中，本发明提供了如通式(2a)和通式(3a)所述化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：In some embodiments of the present invention, the present invention provides compounds of general formula (2a) and general formula (3a) or their isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates thing:
Figure PCTCN2022129961-appb-000062
Figure PCTCN2022129961-appb-000062
其中R 1A、L 1、R 2、R 3、R 6、R 7、m和p的定义如前所述，并在具体实施例中举例说明。 The definitions of R 1A , L 1 , R 2 , R 3 , R 6 , R 7 , m and p are as described above and illustrated in specific examples.
在本发明的另一具体实施例中，通式(1)化合物具有以下结构之一：In another specific embodiment of the present invention, the compound of general formula (1) has one of the following structures:
Figure PCTCN2022129961-appb-000063
Figure PCTCN2022129961-appb-000063
Figure PCTCN2022129961-appb-000064
Figure PCTCN2022129961-appb-000064
Figure PCTCN2022129961-appb-000065
Figure PCTCN2022129961-appb-000065
Figure PCTCN2022129961-appb-000066
Figure PCTCN2022129961-appb-000066
Figure PCTCN2022129961-appb-000067
Figure PCTCN2022129961-appb-000067
Figure PCTCN2022129961-appb-000068
Figure PCTCN2022129961-appb-000068
Figure PCTCN2022129961-appb-000069
Figure PCTCN2022129961-appb-000069
Figure PCTCN2022129961-appb-000070
Figure PCTCN2022129961-appb-000070
本发明的另一个目的是提供了一种药物组合物，其含有药学上可接受的载体、稀释剂和/或赋形剂，以及本发明通式(1)化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。Another object of the present invention is to provide a pharmaceutical composition, which contains a pharmaceutically acceptable carrier, diluent and/or excipient, and the compound of general formula (1) of the present invention, or its various isomers, Various crystal forms, pharmaceutically acceptable salts, hydrates or solvates are used as active ingredients.
本发明的再一个目的提供了本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物用于制备治疗、调节或预防与FGFR2相关疾病的药物中的用途。其中，所述的疾病优选癌症，所述癌症为血液癌和实体瘤。Another object of the present invention provides the compound represented by the general formula (1) of the present invention, or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical composition Use for preparing medicines for treating, regulating or preventing diseases related to FGFR2. Wherein, said disease is preferably cancer, and said cancer is hematological cancer and solid tumor.
本发明的再一个目的还提供治疗、调节或预防与FGFR2介导的相关疾病的方法，包括对受试者给与治疗有效量的本发明的通式(1)所示的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或上述药物组合物。Another object of the present invention is to provide a method for treating, regulating or preventing related diseases mediated by FGFR2, comprising administering to the subject a therapeutically effective amount of the compound represented by the general formula (1) of the present invention, or each of them Isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the above-mentioned pharmaceutical compositions.
应理解，本发明的前述一般性描述和以下详细描述都是示例性和说明性的，旨在提供对所要求保护的本发明的进一步说明。It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
附图说明Description of drawings
图1是本发明实施例40的肿瘤体积变化结果；Figure 1 is the result of tumor volume change in Example 40 of the present invention;
图2是本发明实施例40的小鼠体重变化结果；Fig. 2 is the mouse body weight change result of embodiment 40 of the present invention;
图3是本发明实施例41的肿瘤体积变化结果；Figure 3 is the result of tumor volume change in Example 41 of the present invention;
图4是本发明实施例41的小鼠体重变化结果。Fig. 4 is the results of body weight changes of mice in Example 41 of the present invention.
化合物的合成compound synthesis
下面具体地描述本发明通式(1)化合物的制备方法，但这些具体方法不对本发明构成任何限制。The preparation method of the compound of general formula (1) of the present invention is specifically described below, but these specific methods do not constitute any limitation to the present invention.
以上说明的通式(1)化合物可使用标准的合成技术或公知的技术与文中结合的方法来合成。此外，在此提到的溶剂，温度和其他反应条件可以改变。用于化合物的合成的起始物料可以由合成或从商业来源上获得。本文所述的化合物和其他具有不同取代基的有关化合物可使用公知的技术和原料来合成，包括发现于March，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，(Wiley 1992)；Carey和Sundberg，ADVANCED ORGANIC CHEMISTRY 4 th Ed.，Vols.A和B(Plenum 2000，2001)，Green和Wuts，PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3 rdEd.，(Wiley 1999)中的方法。化合物制备的一般方法可通过使用适当的试剂和在此提供的分子式中引入不同基团的条件来改变。 The compounds of general formula (1) described above can be synthesized using standard synthetic techniques or known techniques combined with methods herein. In addition, solvents, temperatures and other reaction conditions mentioned herein may vary. Starting materials for the synthesis of compounds can be obtained synthetically or from commercial sources. The compounds described herein and other related compounds having various substituents can be synthesized using well known techniques and starting materials, including those found in March, ADVANCED ORGANIC CHEMISTRY 4 th Ed., (Wiley 1992); Carey and Sundberg, ADVANCED ORGANIC CHEMISTRY 4 th Ed., Vols. A and B (Plenum 2000, 2001), methods in Green and Wuts, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS 3rd Ed., (Wiley 1999). The general methods of compound preparation can be varied by using appropriate reagents and conditions to introduce different groups into the formulas provided herein.
一方面，本文所述的化合物根据工艺中公知的方法。然而方法的条件，例如反应物、溶剂、碱、所用化合物的量、反应温度、反应所需时间等不限于下面的解释。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便的制得，这样的组合可由本发明所属领域的技术人员容易的进行。一方面，本发明还提供了一种所述的通式所示化合物的制备方法，其中通式化合物可采用下列一般反应流程1和一般反应流程2制备：In one aspect, the compounds described herein are according to methods well known in the art. However, the conditions of the method, such as reactants, solvent, base, amount of the compound used, reaction temperature, time required for the reaction, etc., are not limited to those explained below. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in the specification or known in the art. Such a combination can be easily performed by those skilled in the art to which the present invention belongs. In one aspect, the present invention also provides a method for preparing the compound represented by the general formula, wherein the compound of the general formula can be prepared by using the following general reaction scheme 1 and general reaction scheme 2:
一般反应流程1General reaction scheme 1
Figure PCTCN2022129961-appb-000071
Figure PCTCN2022129961-appb-000071
Figure PCTCN2022129961-appb-000072
Figure PCTCN2022129961-appb-000072
通式(1)化合物可根据一般反应流程1制备，其中q＝0，n＝1或q＝1，n＝2；Cy 1、Cy 2、R 1、Cy 3和R 2如上文中所定义。如一般反应流程1所示，化合物1-1与化合物1-2发生偶联反应生成化合物1-3，化合物1-3再与1-4发生偶联反应生成化合物1-5，化合物1-5发生分子内的还原胺化生成目标通式化合物(1)。 Compounds of general formula (1) can be prepared according to general reaction scheme 1, wherein q=0, n=1 or q=1, n=2; Cy 1 , Cy 2 , R 1 , Cy 3 and R 2 are as defined above. As shown in general reaction scheme 1, compound 1-1 undergoes a coupling reaction with compound 1-2 to generate compound 1-3, and compound 1-3 undergoes a coupling reaction with 1-4 to generate compound 1-5, compound 1-5 Intramolecular reductive amination occurs to generate the target compound (1).
一般反应流程2 General reaction scheme 2
Figure PCTCN2022129961-appb-000073
Figure PCTCN2022129961-appb-000073
通式(1a)化合物可根据一般反应流程2制备，其中q＝0，n＝1或q＝1，n＝2；Cy 1、Cy 2、R 1、Cy 3、R 2B、R 2C和R 2D如上文中所定义。如一般反应流程2所示，化合物2-1与化合物2-2发生偶联反应生成化合物2-3，化合物2-3再与2-4发生偶联反应生成化合物2-7。或者化合物2-3与化合物2-5发生偶联反应生成化合物2-6，化合物2-6用盐酸脱保护基得到化合物2-7。化合物2-7发生分子内的还原胺化生成化合物2-8，化合物2-8和Boc酸酐反应生成化合物2-9，化合物2-9发生还原反应生成化合 物2-10，化合物2-10与相应的酸或酰氯反应生成化合物2-11，化合物2-11在酸性条件脱保护基生成目标通式化合物(1a)。 Compounds of general formula (1a) can be prepared according to general reaction scheme 2, wherein q=0, n=1 or q=1, n=2; Cy 1 , Cy 2 , R 1 , Cy 3 , R 2B , R 2C and R 2D is as defined above. As shown in general reaction scheme 2, compound 2-1 undergoes a coupling reaction with compound 2-2 to generate compound 2-3, and compound 2-3 undergoes a coupling reaction with 2-4 to generate compound 2-7. Or compound 2-3 and compound 2-5 undergo a coupling reaction to generate compound 2-6, and compound 2-6 is deprotected with hydrochloric acid to obtain compound 2-7. Compound 2-7 undergoes intramolecular reductive amination to generate compound 2-8, compound 2-8 reacts with Boc anhydride to generate compound 2-9, compound 2-9 undergoes a reduction reaction to generate compound 2-10, and compound 2-10 reacts with the corresponding The acid or acid chloride reacts to generate compound 2-11, and the compound 2-11 deprotects under acidic conditions to generate the target compound (1a).
化合物的进一步形式Further forms of compounds
“药学上可接受”这里指一种物质，如载体或稀释液，不会使化合物的生物活性或性质消失，且相对无毒，如，给予个体某物质，不会引起不想要的生物影响或以有害的方式与任何其含有的组分相互作用。"Pharmaceutically acceptable" here refers to a substance, such as a carrier or diluent, that does not abolish the biological activity or properties of the compound, and that is relatively nontoxic, e.g., does not cause unwanted biological effects or Interact in a harmful manner with any of its components.
术语“药学上可接受的盐”指一种化合物的存在形式，该形式不会引起对给药有机体的重要的刺激，且不会使化合物的生物活性和性质消失。在某些具体方面，药学上可接受的盐是通过通式(1)化合物与酸反应获得，如盐酸、氢溴酸、氢氟酸、硫酸、磷酸、硝酸、碳酸等无机酸，甲酸、乙酸、丙酸、草酸、三氟乙酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、甲磺酸、苯磺酸、对甲苯磺酸等有机酸以及天冬氨酸、谷氨酸等酸性氨基酸。The term "pharmaceutically acceptable salt" refers to a form of a compound which does not cause significant irritation to the organism to which it is administered and which does not abolish the biological activity and properties of the compound. In some specific aspects, the pharmaceutically acceptable salt is obtained by reacting the compound of general formula (1) with an acid, such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, phosphoric acid, nitric acid, carbonic acid and other inorganic acids, formic acid, acetic acid , propionic acid, oxalic acid, trifluoroacetic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and other organic acids and acidic amino acids such as aspartic acid and glutamic acid.
应理解药学上可接受的盐的参考包括溶剂添加形式或结晶形式，尤其是溶剂化物或多晶型。溶剂化物含有化学计量或非化学计量的溶剂，且是在与药学上可接受溶剂如水，乙醇等，结晶化过程中选择性形成的。当溶剂是水时形成水合物，或当溶剂是乙醇时形成醇化物。通式化合物的溶剂化物按照本文所述的方法，很方便的制得或形成。举例说明，通式化合物的水合物从水/有机溶剂的混合溶剂中重结晶而方便的制得，使用的有机溶剂包括但不限于，四氢呋喃、丙酮、乙醇或甲醇。此外，在此提到的化合物能够以非溶剂化和溶剂化形式存在。总之，对于在此提供的化合物和方法为目的，溶剂化形式被认为相当于非溶剂化形式。References to pharmaceutically acceptable salts are understood to include solvent added forms or crystalline forms, especially solvates or polymorphs. Solvates contain stoichiometric or non-stoichiometric solvents and are selectively formed during crystallization with pharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is ethanol. Solvates of compounds of general formula are conveniently prepared or formed according to the methods described herein. For example, the hydrate of the compound of the general formula is conveniently prepared by recrystallization from a mixed solvent of water/organic solvent, and the organic solvent used includes but not limited to tetrahydrofuran, acetone, ethanol or methanol. Furthermore, the compounds mentioned herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for purposes of the compounds and methods provided herein.
在其他具体实施例中，通式化合物被制备成不同的形式，包括但不限于，无定形，粉碎形和毫微-粒度形式。此外，通式化合物包括结晶型，也可以作为多晶型。多晶型包括化合物的相同元素组成的不同晶格排列。多晶型通常有不同的X-射线衍射光谱、红外光谱、熔点、密度、硬度、晶型、光和电的性质、稳定性和溶解性。不同的因素如重结晶溶剂，结晶速率和贮存温度可能引起单一晶型为主导。In other embodiments, compounds of the general formula are prepared in various forms including, but not limited to, amorphous, pulverized and nano-particle sized forms. In addition, the compounds of the general formula include crystalline forms and may also be polymorphic. Polymorphs include different lattice arrangements of the same elemental composition of a compound. Polymorphs usually have different X-ray diffraction spectra, infrared spectra, melting points, densities, hardness, crystal forms, optical and electrical properties, stability and solubility. Different factors such as recrystallization solvent, crystallization rate and storage temperature may cause a single crystal form to predominate.
在另一个方面，通式化合物可能存在手性中心和/或轴手性，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式、和顺反异构体的形式出现。每个手性中心或轴手性将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。In another aspect, the compounds of the general formula may have chiral centers and/or axial chirality and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single diastereomers form, and the form of cis-trans isomers. Each chiral center or axial chirality will independently give rise to two optical isomers, and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)、碘-125( 125I)和C-14( 14C)。又例如，可用重氢取代氢原子形成氘代化合物，氘与碳构成的键比普通氢和碳构成的键更坚固，相比于未氘代药物，通常氘代药物具有降低毒副作用、增加药物稳定性、增强疗效、延长药物体内半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包含在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds. For example, compounds can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), and C-14 ( 14 C). For another example, heavy hydrogen can be used to replace hydrogen atoms to form deuterated compounds. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Stability, enhanced curative effect, extended drug half-life in vivo and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are encompassed within the scope of the invention.
术语the term
如果无另外说明，用于本发明申请，包括说明书和权利要求书中的术语，定义如下。必须注意，在说明书和所附的权利要求书中，如果文中无另外清楚指示，单数形式“一个”包括复数意义。如果无另外说明，使用质谱、核磁、HPLC、蛋白化学、生物化学、重组DNA技术和药理的常规方法。在本 申请中，如果无另外说明，使用“或”或“和”指“和/或”。Unless otherwise stated, the terms used in the present application, including the specification and claims, are defined as follows. It must be noted that in the specification and appended claims, the singular form "a" and "an" includes plural references unless the context clearly dictates otherwise. If not stated otherwise, conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, recombinant DNA techniques and pharmacology are used. In this application, the use of "or" or "and" means "and/or" unless stated otherwise.
除非另有规定，“烷基”指饱和的脂肪烃基团，包括1至6个碳原子的直链和支链基团。优选含有1至4个碳原子的低级烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基。如本文所用，“烷基”包括未取代和取代的烷基，尤其是被一个或多个卤素所取代的烷基。优选的烷基选自CH 3、CH 3CH 2、CF 3、CHF 2、CF 3CH 2、CF 3(CH 3)CH、 iPr、 nPr、 iBu、 nBu或 tBu。 Unless otherwise specified, "alkyl" means a saturated aliphatic hydrocarbon group, including straight and branched chain groups of 1 to 6 carbon atoms. Lower alkyl groups having 1 to 4 carbon atoms are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl. As used herein, "alkyl" includes unsubstituted and substituted alkyl groups, especially alkyl groups substituted with one or more halogens. Preferred alkyl groups are selected from CH3 , CH3CH2 , CF3 , CHF2 , CF3CH2 , CF3 ( CH3 )CH, iPr , nPr , iBu , nBu or tBu .
除非另有规定，“环烷基”是指非芳香族烃环***(单环、双环或多环)，如果碳环含有至少一个双键，那么部分不饱和环烷基可被称为“环烯基”，或如果碳环含有至少一个三键，那么部分不饱和环烷基可被称为“环炔基”。环烷基可以包括单环或多环(例如具有2、3或4个稠合环)基团和螺环。在一些实施方案中，环烷基为单环的。在一些实施方案中，环烷基为单环的或双环的。环烷基的成环碳原子可以任选地被氧化以形成氧代或硫离子基。环烷基还包括亚环烷基。在一些实施方案中，环烷基含有0、1或2个双键。在一些实施方案中，环烷基含有1或2个双键(部分不饱和环烷基)。在一些实施方案中，环烷基可以与芳基、杂芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基、环烷基和杂环烷基稠合。在一些实施方案中，环烷基可以与芳基和杂环烷基稠合。一些实施方案中，环烷基可以与芳基和环烷基稠合。环烷基的实例包括环丙基、环丁基、环戊基、环己基、环庚基、环戊烯基、环己烯基、环己二烯基、环庚三烯基、降莰基、降蒎基、降蒈基、双环[1.1.1]戊烷基、双环[2.1.1]己烷基等等。Unless otherwise specified, "cycloalkyl" means a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), and if the carbocyclic ring contains at least one double bond, then a partially unsaturated cycloalkyl group may be referred to as "cycloalkyl". alkenyl", or if the carbocyclic ring contains at least one triple bond, a partially unsaturated cycloalkyl group may be referred to as a "cycloalkynyl". Cycloalkyl groups can include monocyclic or polycyclic (eg, having 2, 3 or 4 fused rings) groups and spirocycles. In some embodiments, cycloalkyl groups are monocyclic. In some embodiments, cycloalkyls are monocyclic or bicyclic. Ring-forming carbon atoms of cycloalkyl groups can be optionally oxidized to form oxo or sulfide groups. Cycloalkyl also includes cycloalkylene. In some embodiments, cycloalkyl groups contain 0, 1, or 2 double bonds. In some embodiments, the cycloalkyl contains 1 or 2 double bonds (partially unsaturated cycloalkyl). In some embodiments, cycloalkyl groups can be fused with aryl, heteroaryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl, cycloalkyl, and heterocycloalkyl groups. In some embodiments, cycloalkyl groups can be fused with aryl and heterocycloalkyl groups. In some embodiments, a cycloalkyl group can be fused with an aryl group and a cycloalkyl group. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbornyl , norpinenyl, norcarpanyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexyl, etc.
除非另有规定，“芳基”指碳氢芳香基团，芳基是单环或多环的，例如单环芳基环与一个或多个碳环芳香基团稠和。芳基的例子包括但不限于，苯基、萘基和菲基。Unless otherwise specified, "aryl" refers to a hydrocarbon aromatic group, aryl is monocyclic or polycyclic, eg a monocyclic aryl ring fused with one or more carbocyclic aromatic groups. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, and phenanthrenyl.
除非另有规定，“杂芳基”指含有一个或多个杂原子(O、S或N)的芳香基团，杂芳基是单环或多环的。例如单环杂芳基环与一个或多个碳环芳香基团或其它单环杂环烷基基团稠和。杂芳基的例子包括但不限于，吡啶基、哒嗪基、咪唑基、嘧啶基、吡唑基、***基、吡嗪基、喹啉基、异喹啉基、呋喃基、噻吩基、异噁唑基、噻唑基、噁唑基、异噻唑基、吡咯基、吲哚基、苯并咪唑基、苯并呋喃基、苯并噻唑基、苯并噻吩基、苯并噁唑基、苯并吡啶基、吡咯并嘧啶基、1H-吡咯[3，2-b]吡啶基、1H-吡咯[2，3-c]吡啶基、1H-吡咯[3，2-c]吡啶基、1H-吡咯[2，3-b]吡啶基、
Figure PCTCN2022129961-appb-000074
Figure PCTCN2022129961-appb-000075
Unless otherwise specified, "heteroaryl" refers to an aromatic group containing one or more heteroatoms (O, S or N), and the heteroaryl is monocyclic or polycyclic. For example a monocyclic heteroaryl ring is fused with one or more carbocyclic aromatic groups or other monocyclic heterocycloalkyl groups. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, quinolinyl, isoquinolyl, furyl, thienyl, Isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, indolyl, benzimidazolyl, benzofuryl, benzothiazolyl, benzothienyl, benzoxazolyl, benzene Pyridyl, pyrrolopyrimidinyl, 1H-pyrrolo[3,2-b]pyridinyl, 1H-pyrrole[2,3-c]pyridinyl, 1H-pyrrole[3,2-c]pyridinyl, 1H- Pyrrolo[2,3-b]pyridyl,
Figure PCTCN2022129961-appb-000074
Figure PCTCN2022129961-appb-000075
除非另有规定，“杂环烷基”指非芳香族环或环***，其可以任选地含有一个或多个亚烯基作为环结构的一部分，其具有至少一个独立地选自硼、磷、氮、硫、氧和磷的杂原子环成员。如果杂环烷基含有至少一个双键，那么部分不饱和杂环烷基可被称为“杂环烯基”，或如果杂环烷基含有至少一个三键，那么部分不饱和杂环烷基可被称为“杂环炔基”。杂环烷基可以包括单环、双环、螺环或多环(例如具有两个稠合或桥接环)环***。在一些实施例中，杂环烷基为具有1、2或3个独立地选自氮、硫和氧的杂原子的单环基团。杂环烷基的成环碳原子和杂原子可以任选地氧化以形成氧代或硫离子基或其他氧化键(例如C(O)、S(O)、C(S)或S(O)2、N-氧化物等)，或氮原子可以季铵化。杂环烷基可以经由成环碳原子或成环杂原子而连接。在一些实施例中，杂环烷基含有0至3个双键。在一些实施例中， 杂环烷基含有0至2个双键。杂环烷基的定义中还包括具有一个或多个与杂环烷基环稠合(即，与其共用键)的芳香族环的部分(也称为部分不饱和杂环)，例如哌啶、吗啉、氮杂环庚三烯或噻吩基等的苯并衍生物。含有稠合芳香族环的杂环烷基可以经由任何成环原子，包括稠合芳香族环的成环原子而连接。杂环烷基的实例包括但不限于氮杂环丁基、氮杂环庚基、二氢苯并呋喃基、二氢呋喃基、二氢吡喃基、N-吗啉基、3-氧杂-9-氮杂螺[5.5]十一烷基、1-氧杂-8-氮杂螺[4.5]癸烷基、哌啶基、哌嗪基、氧代哌嗪基、吡喃基、吡咯烷基、奎宁基、四氢呋喃基、四氢吡喃基、1，2，3，4-四氢喹啉基、莨菪烷基、4，5，6，7-四氢噻唑并[5，4-c]吡啶基、4，5，6，7-四氢-1H-咪唑并[4，5-c]吡啶、N-甲基哌啶基、四氢咪唑基、吡唑烷基、丁内酰胺基、戊内酰胺基、咪唑啉酮基、乙内酰脲基、二氧戊环基、邻苯二甲酰亚胺基、嘧啶-2，4(1H，3H)-二酮基、1，4-二氧六环基、吗啉基、硫代吗啉基、硫代吗啉-S-氧化物基、硫代吗啉-S，S-氧化物基、哌嗪基、吡喃基、吡啶酮基、3-吡咯啉基、噻喃基、吡喃酮基、四氢噻吩基、2-氮杂螺[3.3]庚烷基、吲哚啉基、
Figure PCTCN2022129961-appb-000076
Unless otherwise specified, "heterocycloalkyl" means a non-aromatic ring or ring system which may optionally contain as part of the ring structure one or more alkenylene groups having at least one group independently selected from boron, phosphorus, , nitrogen, sulfur, oxygen, and phosphorus heteroatom ring members. A partially unsaturated heterocycloalkyl group may be referred to as a "heterocycloalkenyl" if the heterocycloalkyl group contains at least one double bond, or a partially unsaturated heterocycloalkyl group if the heterocycloalkyl group contains at least one triple bond. may be referred to as a "heterocycloalkynyl". Heterocycloalkyl groups can include monocyclic, bicyclic, spiro, or polycyclic (eg, having two fused or bridged rings) ring systems. In some embodiments, heterocycloalkyl is a monocyclic group having 1, 2, or 3 heteroatoms independently selected from nitrogen, sulfur, and oxygen. The ring-forming carbon atoms and heteroatoms of the heterocycloalkyl group can be optionally oxidized to form oxo or sulfide groups or other oxidized linkages (e.g., C(O), S(O), C(S), or S(O) 2, N-oxide, etc.), or the nitrogen atom can be quaternized. A heterocycloalkyl group can be attached via a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, heterocycloalkyl groups contain 0 to 3 double bonds. In some embodiments, heterocycloalkyl groups contain 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties (also known as partially unsaturated heterocycles) having one or more aromatic rings fused to (i.e., sharing a bond with) the heterocycloalkyl ring, such as piperidine, Benzo derivatives of morpholine, azepine or thienyl, etc. A heterocycloalkyl group containing a fused aromatic ring may be attached via any ring-forming atom, including ring-forming atoms of a fused aromatic ring. Examples of heterocycloalkyl include, but are not limited to, azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, N-morpholinyl, 3-oxa -9-Azaspiro[5.5]undecyl, 1-oxa-8-azaspiro[4.5]decyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrole Alkyl, quinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolyl, tropane, 4,5,6,7-tetrahydrothiazolo[5,4 -c]pyridyl, 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridine, N-methylpiperidinyl, tetrahydroimidazolyl, pyrazolidinyl, butyrol Amide group, valerolactam group, imidazolinone group, hydantoin group, dioxolanyl group, phthalimide group, pyrimidine-2,4(1H,3H)-dione group, 1 , 4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazinyl, pyranyl , pyridonyl, 3-pyrrolinyl, thiopyranyl, pyroneyl, tetrahydrothiophenyl, 2-azaspiro[3.3]heptanyl, indolinyl,
Figure PCTCN2022129961-appb-000076
除非另有规定，“卤素”(或卤代基)是指氟、氯、溴或碘。在基团名前面出现的术语“卤代”(或“卤素取代”)表示该基团是部分或全部卤代，也就是说，以任意组合的方式被F，Cl，Br或I取代，优选被F或Cl取代。Unless otherwise specified, "halogen" (or halo) refers to fluorine, chlorine, bromine or iodine. The term "halo" (or "halogen substitution") appearing before the group name means that the group is partially or fully halogenated, that is, substituted by F, Cl, Br or I in any combination, preferably Substituted by F or Cl.
“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，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。"Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
取代基“-O-CH 2-O-”指该取代基中二个氧原子和杂环烷基、芳基或杂芳基二个相邻的碳原子连接，比如：
Figure PCTCN2022129961-appb-000077
The substituent "-O-CH 2 -O-" means that two oxygen atoms in the substituent are connected to two adjacent carbon atoms of heterocycloalkyl, aryl or heteroaryl, such as:
Figure PCTCN2022129961-appb-000077
当一个连接基团的数量为0时，比如-(CH 2) 0-，表示该连接基团为单键。 When the number of a linking group is 0, such as -(CH 2 ) 0 -, it means that the linking group is a single bond.
当其中一个变量选自化学键时，表示其连接的两个基团直接相连，比如X-L-Y中L代表化学键时表示该结构实际上是X-Y。When one of the variables is selected from a chemical bond, it means that the two groups connected are directly connected. For example, when L in X-L-Y represents a chemical bond, it means that the structure is actually X-Y.
术语“元环”包括任何环状结构。术语“元”意为表示构成环的骨架原子的数量。例如，环己基、吡啶基、吡喃基、噻喃基是六元环，环戊基、吡咯基、呋喃基和噻吩基是五元环。The term "membered ring" includes any ring structure. The term "member" is meant to indicate the number of skeletal atoms that make up the ring. For example, cyclohexyl, pyridyl, pyranyl, and thienyl are six-membered rings, and cyclopentyl, pyrrolyl, furyl, and thienyl are five-membered rings.
术语“片断”指分子的具体部分或官能团。化学片断通常被认为是包含在或附在分子中的化学实体。The term "fragment" refers to a specific portion or functional group of a molecule. Chemical fragments are generally considered to be chemical entities contained in or attached to molecules.
除非另有说明，用楔形实线键
Figure PCTCN2022129961-appb-000078
和楔形虚线键
Figure PCTCN2022129961-appb-000079
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022129961-appb-000080
和直形虚线键
Figure PCTCN2022129961-appb-000081
表示立体中心的相对构型，用波浪线
Figure PCTCN2022129961-appb-000082
表示楔形实线键
Figure PCTCN2022129961-appb-000083
或楔形虚线键
Figure PCTCN2022129961-appb-000084
或用波浪线
Figure PCTCN2022129961-appb-000085
表示直形实线键
Figure PCTCN2022129961-appb-000086
或直形虚线键
Figure PCTCN2022129961-appb-000087
Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022129961-appb-000078
and dotted wedge keys
Figure PCTCN2022129961-appb-000079
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2022129961-appb-000080
and straight dashed keys
Figure PCTCN2022129961-appb-000081
Indicates the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022129961-appb-000082
Indicates wedge-shaped solid-line bond
Figure PCTCN2022129961-appb-000083
or dotted wedge key
Figure PCTCN2022129961-appb-000084
or with tilde
Figure PCTCN2022129961-appb-000085
Indicates a straight solid line key
Figure PCTCN2022129961-appb-000086
or straight dotted key
Figure PCTCN2022129961-appb-000087
除非另有说明，用
Figure PCTCN2022129961-appb-000088
表示单键或双键。 Unless otherwise specified, use
Figure PCTCN2022129961-appb-000088
Indicates a single or double bond.
特定药学及医学术语Certain pharmaceutical and medical terms
术语“可接受的”，如本文所用，指一个处方组分或活性成分对一般治疗目标的健康没有过分的有害影响。The term "acceptable", as used herein, means that a formulation ingredient or active ingredient does not have an undue adverse effect on health for the general purpose of treatment.
术语“治疗”、“治疗过程”或“疗法”如本文所用，包括缓和、抑制或改善疾病的症状或状况；抑制 并发症的产生；改善或预防潜在代谢综合症；抑制疾病或症状的产生，如控制疾病或情况的发展；减轻疾病或症状；使疾病或症状减退；减轻由疾病或症状引起的并发症，或预防或治疗由疾病或症状引起的征兆。如本文所用，某一化合物或药物组合物，给药后，可以使某一疾病、症状或情况得到改善，尤指其严重度得到改善，延迟发病，减缓病情进展，或减少病情持续时间。无论固定给药或临时给药、持续给药或间歇给药，可以归因于或与给药有关的情况。The term "treatment", "course of treatment" or "therapy" as used herein includes alleviating, suppressing or improving the symptoms or conditions of a disease; inhibiting the development of complications; improving or preventing the underlying metabolic syndrome; inhibiting the development of diseases or symptoms, Such as controlling the development of a disease or condition; alleviating a disease or a symptom; causing a disease or a symptom to regress; alleviating a complication caused by a disease or a symptom, or preventing or treating a symptom caused by a disease or a symptom. As used herein, a certain compound or pharmaceutical composition, after administration, can improve a certain disease, symptom or situation, especially improve its severity, delay the onset, slow down the progression of the disease, or reduce the duration of the disease. Circumstances that may be attributable to or related to the administration, whether fixed or episodic, continuous or intermittent.
“活性成分”指通式所示化合物，以及通式化合物的药学上可接受的无机或有机盐。本发明的化合物可以含有一个或多个不对称中心(手性中心或轴手性)，并因此以消旋体、外消旋混合物、单一对映体、非对映异构体化合物和单一非对映体的形式出现。可以存在的不对称中心，取决于分子上各种取代基的性质。每个这种不对称中心将独立地产生两个旋光异构体，并且所有可能的旋光异构体和非对映体混合物以及纯或部分纯的化合物包括在本发明的范围之内。本发明意味着包括这些化合物的所有这种异构形式。"Active ingredient" refers to the compound represented by the general formula, as well as the pharmaceutically acceptable inorganic or organic salts of the compound of the general formula. The compounds of the present invention may contain one or more asymmetric centers (chiral centers or axial chirality) and thus exist as racemates, racemic mixtures, single enantiomers, diastereomeric compounds and single non- Enantiomers occur in the form of enantiomers. The asymmetric centers that can exist depend on the nature of the various substituents on the molecule. Each such asymmetric center will independently give rise to two optical isomers and all possible optical isomers and diastereomeric mixtures as well as pure or partially pure compounds are included within the scope of the invention. The present invention is meant to include all such isomeric forms of these compounds.
“化合物(compound)”、“组合物(composition)”、“药剂(agent)”或“医药品(medicine or medicament)”等词在此可交替使用，且都是指当施用于个体(人类或动物)时，能够透过局部和/或全身性作用而诱发所亟求的药学和/或生理反应的一种化合物或组合物。The terms "compound", "composition", "agent" or "medicine or medicament" are used interchangeably herein and refer to In animals), a compound or composition capable of inducing a desired pharmaceutical and/or physiological response through local and/or systemic action.
“施用(administered、administering或、administration)”一词在此是指直接施用所述的化合物或组合物，或施用活性化合物的前驱药(prodrug)、衍生物(derivative)、或类似物(analog)等。The term "administered, administering, or administration" as used herein means direct administration of the compound or composition, or administration of a prodrug, derivative, or analog of the active compound wait.
虽然用以界定本发明较广范围的数值范围与参数皆是约略的数值，此处已尽可能精确地呈现具体实施例中的相关数值。然而，任何数值本质上不可避免地含有因个别测试方法所致的标准偏差。在此处，“约”通常是指实际数值在一特定数值或范围的正负10％、5％、1％或0.5％之内。或者是，“约”一词代表实际数值落在平均值的可接受标准误差之内，视本领域技术人员的考虑而定。除了实验例之外，或除非另有明确的说明，当可理解此处所用的所有范围、数量、数值与百分比(例如用以描述材料用量、时间长短、温度、操作条件、数量比例及其它相似者)均经过“约”的修饰。因此，除非另有相反的说明，本说明书与附随权利要求书所揭示的数值参数皆为约略的数值，且可视需求而更动。至少应将这些数值参数理解为所指出的有效位数与采用一般进位法所得到的数值。Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the relative numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently inherently contain standard deviations resulting from their individual testing methodology. As used herein, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a particular value or range. Alternatively, the term "about" means that the actual value falls within an acceptable standard error of the mean, as considered by those skilled in the art. Except for the experimental examples, or unless otherwise expressly stated, all ranges, quantities, numerical values and percentages used herein should be understood (for example, to describe the amount of material used, the length of time, temperature, operating conditions, quantitative ratios and other similar Those) are modified by "about". Therefore, unless otherwise stated to the contrary, the numerical parameters disclosed in the specification and the appended claims are approximate values and may be changed as required. At a minimum, these numerical parameters should be understood as the number of significant digits indicated plus the usual rounding method.
除非本说明书另有定义，此处所用的科学与技术词汇的含义与本领域技术人员所理解的惯用的意义相同。此外，在不和上下文冲突的情形下，本说明书所用的单数名词涵盖该名词的复数型；而所用的复数名词时亦涵盖该名词的单数型。Unless otherwise defined in this specification, the meanings of scientific and technical terms used herein are the same as the usual meanings understood by those skilled in the art. In addition, the singular nouns used in this specification include the plural forms of the nouns, and the plural nouns used also include the singular forms of the nouns, unless the context conflicts with the context.
治疗用途therapeutic use
本发明提供了使用本发明通式化合物或药物组合物治疗疾病的方法，包括但不限于涉及FGFR2的病况(例如癌症)。The present invention provides methods of treating diseases including, but not limited to, conditions involving FGFR2 (eg, cancer) using compounds of the general formula or pharmaceutical compositions of the present invention.
在一些实施例中，提供了用于癌症治疗的方法，该方法包括给予有需要的个体有效量的任何前述的包括结构通式化合物的药物组合物。在一些实施例中，癌症由FGFR2介导。在其它实施例中，该癌症是血液癌和实体瘤，包括但不限于白血病、乳腺癌、肺癌、胰腺癌、结肠癌、膀胱癌、脑癌、尿路上皮癌、***癌、肝癌、胆管癌、卵巢癌、头颈癌、胃癌、间皮瘤或所有癌症转移。In some embodiments, a method for treating cancer is provided, the method comprising administering an effective amount of any of the aforementioned pharmaceutical compositions comprising the compound of the general formula to an individual in need. In some embodiments, the cancer is mediated by FGFR2. In other embodiments, the cancer is blood cancer and solid tumors, including but not limited to leukemia, breast cancer, lung cancer, pancreatic cancer, colon cancer, bladder cancer, brain cancer, urothelial cancer, prostate cancer, liver cancer, bile duct cancer , ovarian cancer, head and neck cancer, gastric cancer, mesothelioma, or all cancer metastases.
给药途径Route of administration
本发明的化合物及其药学上可接受的盐可制成各种制剂，其中包含安全、有效量范围内的本发明化合物或其药学上可接受的盐及药理上可以接受的赋形剂或载体。其中“安全、有效量”指的是：化合物的量足以明显改善病情，而不至于产生严重的副作用。化合物的安全、有效量根据治疗对象的年龄、病情、疗程等具体情况来确定。The compounds of the present invention and their pharmaceutically acceptable salts can be made into various preparations, which contain the compounds of the present invention or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients or carriers within the range of safe and effective amounts . Wherein, "safe and effective amount" means: the amount of the compound is sufficient to obviously improve the condition without causing severe side effects. The safe and effective dose of the compound is determined according to the specific conditions such as the age, condition, and course of treatment of the subject to be treated.
“药学上可以接受的赋形剂或载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能与本发明的化合物以及它们之间相互掺和，而不明显降低化合物的药效。药理上可以接受的赋形剂或载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂(如
Figure PCTCN2022129961-appb-000089
)、润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。 "Pharmaceutically acceptable excipient or carrier" means: one or more compatible solid or liquid filler or gel substances, which are suitable for human use and must be of sufficient purity and low enough toxicity . "Compatibility" herein means that the components of the composition can be blended with the compound of the present invention and with each other without significantly reducing the efficacy of the compound. Examples of pharmaceutically acceptable excipients or carrier parts include cellulose and derivatives thereof (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants ( Such as stearic acid, magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (such as
Figure PCTCN2022129961-appb-000089
), wetting agent (such as sodium lauryl sulfate), coloring agent, flavoring agent, stabilizer, antioxidant, preservative, pyrogen-free water, etc.
施用本发明化合物时，可以口服、直肠、肠胃外(静脉内、肌肉内或皮下)、局部给药。When the compounds of the present invention are administered, they can be administered orally, rectally, parenterally (intravenously, intramuscularly or subcutaneously), topically.
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compound is admixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with (a) fillers or extenders, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; (c) humectants, For example, glycerol; (d) disintegrants, such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) slow agents, such as paraffin; (f) Absorption accelerators such as quaternary ammonium compounds; (g) wetting agents such as cetyl alcohol and glyceryl monostearate; (h) adsorbents such as kaolin; and (i) lubricants such as talc, hard Calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. In capsules, tablets and pills, the dosage form may also contain buffering agents.
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shell materials, such as enteric coatings and others well known in the art. They may contain opacifying agents and, in such compositions, the release of the active compound or compounds may be in a certain part of the alimentary canal in a delayed manner. Examples of usable embedding components are polymeric substances and waxy substances. The active compounds can also be in microencapsulated form, if desired, with one or more of the above-mentioned excipients.
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, liquid dosage forms may contain inert diluents conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances, etc.
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。Besides such inert diluents, the compositions can also contain adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。Suspensions, in addition to the active compounds, may contain suspending agents, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances, and the like.
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Dosage forms for topical administration of a compound of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants which may be required, if necessary.
本发明化合物可以单独给药，或者与其他药学上可接受的化合物联合给药。使用药物组合物时，是将安全有效量的本发明化合物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选50～1000mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds. When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage when administered, for a person with a body weight of 60kg, the daily The dosage is usually 1-2000 mg, preferably 50-1000 mg. Of course, factors such as the route of administration and the health status of the patient should also be considered for the specific dosage, which are within the skill of skilled physicians.
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。The above-mentioned features mentioned in the present invention, or the features mentioned in the embodiments can be combined arbitrarily. All the features disclosed in the specification of this case can be used in combination with any combination, and each feature disclosed in the specification can be replaced by any alternative feature that can provide the same, equivalent or similar purpose. Therefore, unless otherwise specified, the disclosed features are only general examples of equivalent or similar features.
具体实施方式Detailed ways
在下面的说明中将会详细阐述上述化合物、方法、药物组合物的各个具体方面、特性和优势，使本发明的内容变得十分明了。在此应理解，下述的详细说明及实例描述了具体的实施例，仅用于参考。在阅读了本发明的说明内容后，本领域的技术人员可对本发明作各种改动或修改，这些等价形势同样落于本申请所限定的范围。In the following description, various specific aspects, characteristics and advantages of the above-mentioned compounds, methods, and pharmaceutical compositions will be described in detail, so that the content of the present invention will become very clear. It is to be understood that the following detailed description and examples describe specific embodiments and are given by reference only. After reading the description of the present invention, those skilled in the art may make various changes or modifications to the present invention, and these equivalent situations also fall within the scope defined in the present application.
所有实施例中， 1H-NMR用Varian Mercury 400核磁共振仪记录，化学位移以δ(ppm)表示；分离用硅胶未说明均为200-300目，洗脱液的配比均为体积比。 In all the examples, 1 H-NMR was recorded by a Varian Mercury 400 nuclear magnetic resonance apparatus, and the chemical shifts were expressed in δ (ppm); the silica gel used for separation was 200-300 mesh, and the ratio of the eluent was volume ratio.
实施例1化合物1的合成The synthesis of embodiment 1 compound 1
Figure PCTCN2022129961-appb-000090
Figure PCTCN2022129961-appb-000090
步骤1：化合物int_1-2的合成：Step 1: Synthesis of compound int_1-2:
Figure PCTCN2022129961-appb-000091
Figure PCTCN2022129961-appb-000091
在室温下，将2-溴-5-羟基苯甲醛(10.0g，99.5mmol)和2-氟-6-甲基吡啶(11.15g，99.50mmol) 溶于N，N-二甲基甲酰胺(50mL)中，加入碳酸钾(20.65g，149.25mmol)。反应液加热至100℃搅拌24小时。冷却后，往反应液中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，残余物经硅胶色谱法分离纯化得中间体int_1-2。At room temperature, 2-bromo-5-hydroxybenzaldehyde (10.0 g, 99.5 mmol) and 2-fluoro-6-picoline (11.15 g, 99.50 mmol) were dissolved in N, N-dimethylformamide ( 50 mL), potassium carbonate (20.65 g, 149.25 mmol) was added. The reaction solution was heated to 100°C and stirred for 24 hours. After cooling, water (500 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and the residue The intermediate int_1-2 was obtained by separation and purification by silica gel chromatography.
LC-MS(ESI)：292.1[M+H] +。 LC-MS (ESI): 292.1 [M+H] + .
步骤2：化合物int_1-3的合成：Step 2: Synthesis of compound int_1-3:
Figure PCTCN2022129961-appb-000092
Figure PCTCN2022129961-appb-000092
在室温下，将中间体int_1-2(1.0g，3.42mmol)和双联嚬哪醇硼酸酯(2.61g，10.20mmol)溶于二氧六环(25mL)中，加入乙酸钾(1.0g，10.21mmol)，在氮气保护下加入1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(279.55mg，342.3μmol)，反应液在氮气保护下于100℃搅拌反应3小时。冷却后往反应液中加入水(50mL)，然后用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，残余物经硅胶色谱法分离纯化得中间体int_1-3。At room temperature, the intermediate int_1-2 (1.0g, 3.42mmol) and bisanalyl borate (2.61g, 10.20mmol) were dissolved in dioxane (25mL), and potassium acetate (1.0g , 10.21mmol), added 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (279.55mg, 342.3μmol) under the protection of nitrogen, and the reaction solution was stirred and reacted at 100°C under the protection of nitrogen 3 hours. After cooling, water (50 mL) was added to the reaction liquid, and then extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and the residue was washed with silica gel. The intermediate int_1-3 was obtained by separation and purification by chromatography.
LC-MS(ESI)：340.1[M+H] +。 LC-MS (ESI): 340.1 [M+H] + .
步骤3：化合物int_1-5的合成：Step 3: Synthesis of compound int_1-5:
Figure PCTCN2022129961-appb-000093
Figure PCTCN2022129961-appb-000093
在室温下，将化合物5-溴-4-氯-7-甲基-7H-吡咯并[2，3-d]嘧啶(4.80g，19.52mmol)和氯化铵(5.21g，97.44mmol)溶于无水二甲基亚砜(32mL)中，加入氟化铯(5.91g，38.88mmol)和N，N-二异丙基乙胺(4.75g，36.80mmol)。反应液于120℃搅拌反应16小时。冷却后将反应液倒入水(100mL)中，有黄色固体析出。将混合液过滤，滤饼用水(5mL×3)洗涤，滤饼收集，用油泵真空干燥，得到中间体int_1-5。Compound 5-bromo-4-chloro-7-methyl-7H-pyrrolo[2,3-d]pyrimidine (4.80 g, 19.52 mmol) and ammonium chloride (5.21 g, 97.44 mmol) were dissolved at room temperature To anhydrous dimethylsulfoxide (32 mL), cesium fluoride (5.91 g, 38.88 mmol) and N,N-diisopropylethylamine (4.75 g, 36.80 mmol) were added. The reaction solution was stirred and reacted at 120° C. for 16 hours. After cooling, the reaction solution was poured into water (100 mL), and a yellow solid precipitated out. The mixture was filtered, the filter cake was washed with water (5mL×3), the filter cake was collected, and vacuum-dried with an oil pump to obtain intermediate int_1-5.
LC-MS(ESI)：227.1[M+H] +。 LC-MS (ESI): 227.1 [M+H] + .
步骤4：化合物int_1-6的合成：Step 4: Synthesis of compound int_1-6:
Figure PCTCN2022129961-appb-000094
Figure PCTCN2022129961-appb-000094
将中间体int_1-5(2.16g，9.51mmol)溶于二氯甲烷(30mL)中，加入三氟醋酸(5.42g，47.56mmol，3.52mL)，反应液冷却至0℃。在0℃下将N-碘代琥珀酰亚胺(2.14g，9.51mmol)加入到反 应液中，再将反应液升温至20℃搅拌2小时。将饱和亚硫酸钠水溶液(200mL)加入到反应液中淬灭反应，至反应液颜色由紫黑色变为黄色，再加入饱和碳酸氢钠水溶液(300mL)至反应液不再冒泡，有黄色固体析出。将混合液过滤，滤饼用水(5mL×3)洗涤，滤饼收集，用油泵真空干燥，得到中间体int_1-6。The intermediate int_1-5 (2.16g, 9.51mmol) was dissolved in dichloromethane (30mL), trifluoroacetic acid (5.42g, 47.56mmol, 3.52mL) was added, and the reaction solution was cooled to 0°C. N-iodosuccinimide (2.14 g, 9.51 mmol) was added to the reaction solution at 0°C, and the reaction solution was heated to 20°C and stirred for 2 hours. Saturated aqueous sodium sulfite (200 mL) was added to the reaction liquid to quench the reaction until the color of the reaction liquid changed from purple-black to yellow, then saturated aqueous sodium bicarbonate (300 mL) was added until the reaction liquid stopped bubbling and a yellow solid precipitated out. The mixture was filtered, the filter cake was washed with water (5mL×3), the filter cake was collected, and vacuum-dried with an oil pump to obtain intermediate int_1-6.
LC-MS(ESI)：352.9[M+H] +。 LC-MS (ESI): 352.9 [M+H] + .
步骤5：化合物int_1-7的合成：Step 5: Synthesis of compound int_1-7:
Figure PCTCN2022129961-appb-000095
Figure PCTCN2022129961-appb-000095
在室温下，将中间体int_1-6(1.8g，5.10mmol)和4-硝基苯基硼酸(851.3mg，5.10mmol)溶于二氧六环(40mL)中，将碳酸钠水溶液(2M，9mL)加入到反应液中。在氮气保护下加入1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(208.3mg，254.97μmol)。反应液在氮气保护下于80℃搅拌反应1.5小时。将反应液冷却至室温，加入水(100mL)稀释，有黄色固体析出。将混合液过滤，滤饼用水(5mL×3)洗涤，滤饼收集，用油泵真空干燥，得到中间体int_1-7。Intermediate int_1-6 (1.8g, 5.10mmol) and 4-nitrophenylboronic acid (851.3mg, 5.10mmol) were dissolved in dioxane (40mL) at room temperature, aqueous sodium carbonate (2M, 9 mL) was added to the reaction solution. 1,1-Bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (208.3 mg, 254.97 μmol) was added under nitrogen protection. The reaction solution was stirred and reacted at 80° C. for 1.5 hours under the protection of nitrogen. The reaction solution was cooled to room temperature, diluted with water (100 mL), and a yellow solid precipitated out. The mixture was filtered, the filter cake was washed with water (5mL×3), the filter cake was collected, and vacuum-dried with an oil pump to obtain intermediate int_1-7.
LC-MS(ESI)：348.1[M+H] +。 LC-MS (ESI): 348.1 [M+H] + .
步骤6：化合物int_1-8的合成：Step 6: Synthesis of compound int_1-8:
Figure PCTCN2022129961-appb-000096
Figure PCTCN2022129961-appb-000096
在室温下，将中间体int_1-7(290mg，832.96μmol)和中间体int_1-3(423.80mg，1.25mmol)溶于二氧六环(5mL)中，再将碳酸钠水溶液(2M，6mL)加入到反应液中。在氮气保护下加入四(三苯基膦)钯(96.25mg，83.30μmol)。反应液在氮气保护下于80℃搅拌反应3小时。反应液冷却至室温后，加入水(5mL)稀释，用乙酸乙酯(5mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到粗品中间体int_1-8。At room temperature, intermediate int_1-7 (290mg, 832.96μmol) and intermediate int_1-3 (423.80mg, 1.25mmol) were dissolved in dioxane (5mL), and then aqueous sodium carbonate (2M, 6mL) added to the reaction solution. Tetrakis(triphenylphosphine)palladium (96.25 mg, 83.30 μmol) was added under nitrogen protection. The reaction solution was stirred and reacted at 80° C. for 3 hours under the protection of nitrogen. After the reaction solution was cooled to room temperature, it was diluted with water (5 mL), extracted with ethyl acetate (5 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude intermediate int_1-8.
LC-MS(ESI)：481.1[M+H] +。 LC-MS (ESI): 481.1 [M+H] + .
步骤7：化合物int_1-9的合成：Step 7: Synthesis of compound int_1-9:
Figure PCTCN2022129961-appb-000097
Figure PCTCN2022129961-appb-000097
在室温下，将中间体int_1-8(400mg)溶于乙腈(5mL)中，加入冰醋酸(14.0μL，249.75μmol)和氰基硼氢化钠(62.78mg，999.01μmol)。反应液于25℃搅拌反应16小时。将反应液减压浓缩至干，加入饱和碳酸钠溶液(10mL)淬灭残留的醋酸，用乙酸乙酯(10mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，粗品经硅胶色谱法分离纯化得中间体int_1-9。Intermediate int_1-8 (400 mg) was dissolved in acetonitrile (5 mL) at room temperature, and glacial acetic acid (14.0 μL, 249.75 μmol) and sodium cyanoborohydride (62.78 mg, 999.01 μmol) were added. The reaction solution was stirred and reacted at 25°C for 16 hours. Concentrate the reaction solution to dryness under reduced pressure, add saturated sodium carbonate solution (10mL) to quench the residual acetic acid, extract with ethyl acetate (10mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and depressurize the filtrate Concentrate to dryness, and the crude product is separated and purified by silica gel chromatography to obtain intermediate int_1-9.
LC-MS(ESI)：465.0[M+H] +。 LC-MS (ESI): 465.0 [M+H] + .
步骤8：化合物int_1-10的合成：Step 8: Synthesis of compound int_1-10:
Figure PCTCN2022129961-appb-000098
Figure PCTCN2022129961-appb-000098
在室温下，将中间体int_1-9(150mg，322.95μmol)溶于乙醇(4mL)和水(2mL)中，加入氯化铵(172.75mg，3.23mmol)和还原铁粉(180.35mg，3.23mmol)，反应液于80℃搅拌反应2小时。将反应液冷却至室温，过滤，滤液减压浓缩，加入水(5mL)稀释，用乙酸乙酯(5mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到中间体int_1-10。Intermediate int_1-9 (150 mg, 322.95 μmol) was dissolved in ethanol (4 mL) and water (2 mL) at room temperature, ammonium chloride (172.75 mg, 3.23 mmol) and reduced iron powder (180.35 mg, 3.23 mmol) were added ), the reaction solution was stirred and reacted at 80° C. for 2 hours. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, diluted with water (5 mL), extracted with ethyl acetate (5 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was decompressed Concentration to dryness affords intermediate int_1-10.
LC-MS(ESI)：435.1[M+H] +。 LC-MS (ESI): 435.1 [M+H] + .
步骤9：化合物1的合成：Step 9: Synthesis of compound 1:
Figure PCTCN2022129961-appb-000099
Figure PCTCN2022129961-appb-000099
在室温下，将中间体int_1-10(70mg)溶于无水二氯甲烷(5mL)中，在冰水浴冷却下将丙烯酰氯(96.66μmol，8.0μL)加入到反应液中，再加入三乙胺(29.34mg，289.99μmol)，反应液于25℃搅拌1小时。将反应液减压浓缩至干，经C18反相色谱纯化得到白色固体化合物1。At room temperature, the intermediate int_1-10 (70 mg) was dissolved in anhydrous dichloromethane (5 mL), and acryloyl chloride (96.66 μmol, 8.0 μL) was added to the reaction solution under cooling in an ice-water bath, and then triethyl Amine (29.34mg, 289.99μmol), the reaction solution was stirred at 25°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and purified by C18 reverse phase chromatography to obtain compound 1 as a white solid.
LC-MS(ESI)：489.0[M+H] +。 LC-MS (ESI): 489.0 [M+H] + .
1H NMR(400MHz，CDCl 3)δ8.29(s，1H)，7.79(br d，J＝8.4Hz，2H)，7.62-7.41(m，4H)，7.03(d，J＝ 2.6Hz，1H)，6.89(t，J＝6.9Hz，2H)，6.75(dd，J＝2.4，8.7Hz，1H)，6.60(d，J＝8.2Hz，1H)，6.55-6.46(m，1H)，6.38(br s，1H)，6.35-6.26(m，1H)，5.85(d，J＝10.3Hz，1H)，4.49(d，J＝3.4Hz，2H)，3.69(s，3H)，2.46(s，3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.29(s, 1H), 7.79(br d, J=8.4Hz, 2H), 7.62-7.41(m, 4H), 7.03(d, J=2.6Hz, 1H ), 6.89(t, J=6.9Hz, 2H), 6.75(dd, J=2.4, 8.7Hz, 1H), 6.60(d, J=8.2Hz, 1H), 6.55-6.46(m, 1H), 6.38 (br s, 1H), 6.35-6.26(m, 1H), 5.85(d, J=10.3Hz, 1H), 4.49(d, J=3.4Hz, 2H), 3.69(s, 3H), 2.46(s , 3H).
实施例2化合物2的合成The synthesis of embodiment 2 compound 2
Figure PCTCN2022129961-appb-000100
Figure PCTCN2022129961-appb-000100
步骤1：化合物int_2-1的合成：Step 1: Synthesis of compound int_2-1:
Figure PCTCN2022129961-appb-000101
Figure PCTCN2022129961-appb-000101
将2-溴-5-羟基苯甲醛(250g，1.24mol)和乙二醇(259g，4.17mol)溶于甲苯(2.0L)中，加入无水对甲苯磺酸(4.71g，27.36mmol)。反应液于130℃(外温)，110℃(内温)回流搅拌反应16小时，用分水器除去反应产生的水。反应液冷却至室温，向反应液中加入饱和碳酸钠水溶液(1L)，然后用乙酸乙酯(1L×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到棕色固体中间 体int_2-1。2-Bromo-5-hydroxybenzaldehyde (250 g, 1.24 mol) and ethylene glycol (259 g, 4.17 mol) were dissolved in toluene (2.0 L), and anhydrous p-toluenesulfonic acid (4.71 g, 27.36 mmol) was added. The reaction solution was refluxed and stirred at 130° C. (external temperature) and 110° C. (internal temperature) for 16 hours, and the water produced by the reaction was removed with a water separator. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (1L) was added to the reaction solution, then extracted with ethyl acetate (1L×3), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a brown Solid intermediate int_2-1.
1H NMR(400MHz，DMSO-d 6)δ9.77(br s，1H)，7.37(d，J＝8.7Hz，1H)，6.99(d，J＝3.1Hz，1H)，6.79-6.71(m，1H)，5.83(s，1H)，4.08-4.02(m，2H)，3.99-3.92(m，2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.77(br s, 1H), 7.37(d, J=8.7Hz, 1H), 6.99(d, J=3.1Hz, 1H), 6.79-6.71(m , 1H), 5.83 (s, 1H), 4.08-4.02 (m, 2H), 3.99-3.92 (m, 2H).
步骤2：化合物int_2-2的合成：Step 2: Synthesis of compound int_2-2:
Figure PCTCN2022129961-appb-000102
Figure PCTCN2022129961-appb-000102
将中间体int_2-1(300g，1.22mol)和2-氟-6-甲基吡啶(680g，6.12mol)溶于N，N-二甲基甲酰胺(1.5L)中，加入碳酸铯(638g，1.96mol)。反应液于120℃(外温)搅拌16小时。反应液冷却至室温，将反应液连同固体残渣倒入水(4.5L)中，用乙酸乙酯(2L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得中间体int_2-2。The intermediate int_2-1 (300g, 1.22mol) and 2-fluoro-6-picoline (680g, 6.12mol) were dissolved in N,N-dimethylformamide (1.5L), cesium carbonate (638g , 1.96mol). The reaction solution was stirred at 120°C (external temperature) for 16 hours. The reaction solution was cooled to room temperature, and the reaction solution and solid residue were poured into water (4.5L), extracted with ethyl acetate (2L×3), the organic phase was dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to dry, separated and purified by silica gel chromatography to obtain the intermediate int_2-2.
LC-MS(ESI)：335.9[M+H] +。 LC-MS (ESI): 335.9 [M+H] + .
步骤3：化合物int_2-3的合成：Step 3: Synthesis of compound int_2-3:
Figure PCTCN2022129961-appb-000103
Figure PCTCN2022129961-appb-000103
将中间体int_2-2(110.00g，327.21mmol)溶于四氢呋喃(400mL)中，加入盐酸(3M，328mL)。反应液于60℃搅拌反应2小时。反应液冷却至室温，在0℃下向反应液中加入饱和碳酸钠水溶液(1L)，然后用乙酸乙酯萃取(1L×3)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到粗品白色固体中间体int_2-3。The intermediate int_2-2 (110.00 g, 327.21 mmol) was dissolved in tetrahydrofuran (400 mL), and hydrochloric acid (3M, 328 mL) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (1 L) was added to the reaction solution at 0° C., then extracted with ethyl acetate (1 L × 3), the organic phase was dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was reduced to Concentrate to dryness under reduced pressure to obtain crude white solid intermediate int_2-3.
LC-MS(ESI)：291.9[M+H] +。 LC-MS (ESI): 291.9 [M+H] + .
步骤4：化合物int_2-4的合成：Step 4: Synthesis of compound int_2-4:
Figure PCTCN2022129961-appb-000104
Figure PCTCN2022129961-appb-000104
将中间体int_2-3(92.00g，314.93mmol)溶于二氯甲烷(1.8L)中，在氮气氛围下加入甲氧基甲基三苯基氯化膦(161.94g，472.40mmol)和叔丁醇钠(45.40g，472.40mmol)。反应液于0℃搅拌5小时。向反应液中加入水(1L)，用乙酸乙酯萃取(1L×2)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得中间体int_2-4。The intermediate int_2-3 (92.00g, 314.93mmol) was dissolved in dichloromethane (1.8L), and methoxymethyl triphenylphosphine chloride (161.94g, 472.40mmol) and tert-butyl Sodium alkoxide (45.40 g, 472.40 mmol). The reaction solution was stirred at 0°C for 5 hours. Add water (1L) to the reaction solution, extract with ethyl acetate (1L×2), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify the intermediate by silica gel chromatography int_2-4.
LC-MS(ESI)：319.9[M+H] +。 LC-MS (ESI): 319.9 [M+H] + .
步骤5：化合物int_2-5的合成：Step 5: Synthesis of compound int_2-5:
Figure PCTCN2022129961-appb-000105
Figure PCTCN2022129961-appb-000105
将中间体int_2-4(65.00g，203.01mmol)溶于二氯甲烷(1L)中，加入三氟乙酸(578.70g，5.08mol)和水(91.43g，5.08mol)，反应液于50℃搅拌2小时。将反应液减压浓缩除去溶剂，向剩余物中加入饱和碳酸钠(1L)，用乙酸乙酯萃取(1L×2)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得中间体int_2-5。Dissolve the intermediate int_2-4 (65.00g, 203.01mmol) in dichloromethane (1L), add trifluoroacetic acid (578.70g, 5.08mol) and water (91.43g, 5.08mol), and stir the reaction solution at 50°C 2 hours. Concentrate the reaction solution under reduced pressure to remove the solvent, add saturated sodium carbonate (1L) to the residue, extract with ethyl acetate (1L×2), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to dry, separated and purified by silica gel chromatography to obtain the intermediate int_2-5.
LC-MS(ESI)：305.9[M+H] +。 LC-MS (ESI): 305.9 [M+H] + .
步骤6：化合物int_2-6的合成：Step 6: Synthesis of compound int_2-6:
Figure PCTCN2022129961-appb-000106
Figure PCTCN2022129961-appb-000106
将中间体int_2-5(30.00g，97.99mmol)和乙二醇(30.41g，489.95mmol)溶于甲苯(500mL)中，加入对甲苯磺酸(1.69g，9.80mmol)。反应液于110℃搅拌反应16小时。反应液冷却至室温，减压浓缩除去溶剂，向剩余物中加入饱和碳酸钠(500mL)，然后用乙酸乙酯萃取(500mL×3)，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到粗品黄色油状中间体int_2-6。The intermediate int_2-5 (30.00 g, 97.99 mmol) and ethylene glycol (30.41 g, 489.95 mmol) were dissolved in toluene (500 mL), and p-toluenesulfonic acid (1.69 g, 9.80 mmol) was added. The reaction solution was stirred and reacted at 110° C. for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and saturated sodium carbonate (500 mL) was added to the residue, then extracted with ethyl acetate (500 mL×3), dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure To dryness, the crude yellow oily intermediate int_2-6 was obtained.
LC-MS(ESI)：349.9[M+H] +。 LC-MS (ESI): 349.9 [M+H] + .
步骤7：化合物int_2-7的合成：Step 7: Synthesis of compound int_2-7:
Figure PCTCN2022129961-appb-000107
Figure PCTCN2022129961-appb-000107
将中间体int_2-6(32.00g，91.37mmol)和双联嚬哪醇硼酸酯(46.41g，182.75mmol)溶于二氧六环(600mL)中，在氮气保护下加入醋酸钾(26.90g，274.12mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(7.46g，9.14mmol)，反应液于100℃搅拌3小时。反应液冷却至室温，过滤，滤液减压浓缩。向剩余物中加入水(1000mL)，用乙酸乙酯萃取(1L×3)，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得中间体int_2-7。The intermediate int_2-6 (32.00g, 91.37mmol) and bisanalyl borate (46.41g, 182.75mmol) were dissolved in dioxane (600mL), and potassium acetate (26.90g , 274.12mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (7.46g, 9.14mmol), and the reaction solution was stirred at 100°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Add water (1000mL) to the residue, extract with ethyl acetate (1L×3), dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, separate and purify by silica gel chromatography to obtain intermediate int_2-7 .
LC-MS(ESI)：398.0[M+H] +。 LC-MS (ESI): 398.0 [M+H] + .
步骤8：化合物int_2-8的合成：Step 8: Synthesis of compound int_2-8:
Figure PCTCN2022129961-appb-000108
Figure PCTCN2022129961-appb-000108
将中间体int_1-7(26.29g，75.52mmol)和中间体int_2-7(30.00g，75.52mmol)溶于四氢呋喃(950mL)中，在氮气保护下加入磷酸钾水溶液(2M，188.79mL)和双(三环己基膦基)二氯化钯(II)(5.57g，7.55mmol)，反应液于100℃搅拌2小时。反应液冷却至室温，加入水(1500mL)，用乙酸乙酯萃取(1.5L×3)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，打浆纯化得到中间体int_2-8。Intermediate int_1-7 (26.29g, 75.52mmol) and intermediate int_2-7 (30.00g, 75.52mmol) were dissolved in tetrahydrofuran (950mL), and potassium phosphate aqueous solution (2M, 188.79mL) and bis (Tricyclohexylphosphino)palladium(II) dichloride (5.57g, 7.55mmol), and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, water (1500mL) was added, extracted with ethyl acetate (1.5L×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by beating to obtain the intermediate int_2 -8.
LC-MS(ESI)：539.2[M+H] +。 LC-MS (ESI): 539.2 [M+H] + .
步骤9：化合物int_2-9的合成：Step 9: Synthesis of compound int_2-9:
Figure PCTCN2022129961-appb-000109
Figure PCTCN2022129961-appb-000109
将中间体int_2-8(11.00g，20.43mmol)溶于四氢呋喃(150mL)中，加入盐酸(3M，34.04mL)，反应液于60℃搅拌1小时。反应液冷却至室温，在0℃下向反应液中加入饱和碳酸钠水溶液(500mL)，过滤，滤饼用水(200mL)和乙酸乙酯(200mL)洗涤，滤饼减压干燥，得到粗品中间体int_2-9。The intermediate int_2-8 (11.00 g, 20.43 mmol) was dissolved in tetrahydrofuran (150 mL), hydrochloric acid (3M, 34.04 mL) was added, and the reaction solution was stirred at 60° C. for 1 hour. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (500 mL) was added to the reaction solution at 0°C, filtered, the filter cake was washed with water (200 mL) and ethyl acetate (200 mL), and the filter cake was dried under reduced pressure to obtain the crude intermediate int_2-9.
LC-MS(ESI)：495.1[M+H] +。 LC-MS (ESI): 495.1 [M+H] + .
步骤10：化合物int_2-10的合成：Step 10: Synthesis of compound int_2-10:
Figure PCTCN2022129961-appb-000110
Figure PCTCN2022129961-appb-000110
将中间体int_2-9(10.00g，20.22mmol)溶于甲醇(85mL)和乙酸(17mL)中，加入2-甲基吡啶硼烷络合物(4.33g，40.44mmol)，反应液于40℃搅拌反应0.5小时。反应液冷却至室温，在0℃下向反应液中加入饱和碳酸钠水溶液(200mL)，过滤，滤饼用水(100mL)和乙酸乙酯(100mL)润洗，滤饼收集减压干燥，得到粗品中间体int_2-10。The intermediate int_2-9 (10.00g, 20.22mmol) was dissolved in methanol (85mL) and acetic acid (17mL), and 2-picoline borane complex (4.33g, 40.44mmol) was added, and the reaction solution was heated at 40°C The reaction was stirred for 0.5 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (200 mL) was added to the reaction solution at 0°C, filtered, the filter cake was rinsed with water (100 mL) and ethyl acetate (100 mL), and the filter cake was collected and dried under reduced pressure to obtain the crude product Intermediate int_2-10.
LC-MS(ESI)：479.1[M+H] +。 LC-MS (ESI): 479.1 [M+H] + .
步骤11：化合物int_2-11的合成：Step 11: Synthesis of compound int_2-11:
Figure PCTCN2022129961-appb-000111
Figure PCTCN2022129961-appb-000111
将中间体int_2-10(7.00g，14.63mmol)和溶于N，N-二甲基甲酰胺(70mL)中，加入BOC酸酐(31.93g，146.29mmol)，4-二甲氨基吡啶(893.60mg，7.31mmol)和三乙胺(4.44g，43.89mmol)。反应液于50℃搅拌反应1小时。反应液冷却至室温，加入水(300mL)，搅拌20分钟。抽滤，滤饼用乙酸乙酯(100mL)洗涤，滤饼减压干燥，得到粗品中间体int_2-11。Dissolve intermediate int_2-10 (7.00g, 14.63mmol) and N, N-dimethylformamide (70mL), add BOC anhydride (31.93g, 146.29mmol), 4-dimethylaminopyridine (893.60mg , 7.31 mmol) and triethylamine (4.44 g, 43.89 mmol). The reaction solution was stirred and reacted at 50° C. for 1 hour. The reaction solution was cooled to room temperature, water (300 mL) was added, and stirred for 20 minutes. Suction filtration, the filter cake was washed with ethyl acetate (100 mL), and the filter cake was dried under reduced pressure to obtain the crude intermediate int_2-11.
LC-MS(ESI)：579.1[M+H] +。 LC-MS (ESI): 579.1 [M+H] + .
步骤12：化合物int_2-12的合成：Step 12: Synthesis of compound int_2-12:
Figure PCTCN2022129961-appb-000112
Figure PCTCN2022129961-appb-000112
将中间体int_2-11(7.00g，12.10mmol)溶于甲醇(120mL)和水(24mL)中，加入铁粉(13.51g，241.96mmol)和氯化铵(12.94g，241.96mmol)。反应液于65℃搅拌反应3小时。反应液冷却至室温，抽滤，用甲醇(100mL)和二氯甲烷(200mL)洗涤，减压浓缩。向剩余物中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到粗品中间体int_2-12。The intermediate int_2-11 (7.00 g, 12.10 mmol) was dissolved in methanol (120 mL) and water (24 mL), and iron powder (13.51 g, 241.96 mmol) and ammonium chloride (12.94 g, 241.96 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 3 hours. The reaction solution was cooled to room temperature, filtered with suction, washed with methanol (100 mL) and dichloromethane (200 mL), and concentrated under reduced pressure. Water (200 mL) was added to the residue, extracted with ethyl acetate (200 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude intermediate int_2-12.
LC-MS(ESI)：549.2[M+H] +。 LC-MS (ESI): 549.2 [M+H] + .
步骤13：化合物int_2-13的合成：Step 13: Synthesis of compound int_2-13:
Figure PCTCN2022129961-appb-000113
Figure PCTCN2022129961-appb-000113
将中间体int_2-12(2.00g，3.65mmol)溶于二氯甲烷(20mL)中，在0℃下加入三乙胺(1.11g，10.94mmol)和丙烯酰氯(494.91mg，5.47mmol)。反应液于25℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(30mL)，用二氯甲烷(30mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤， 滤液减压浓缩至干，打浆纯化得到中间体int_2-13。The intermediate int_2-12 (2.00g, 3.65mmol) was dissolved in dichloromethane (20mL), and triethylamine (1.11g, 10.94mmol) and acryloyl chloride (494.91mg, 5.47mmol) were added at 0°C. The reaction solution was stirred and reacted at 25° C. for 1 hour. Add saturated aqueous sodium carbonate solution (30mL) to the reaction solution, extract with dichloromethane (30mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, beat and purify to obtain the intermediate int_2 -13.
LC-MS(ESI)：603.2[M+H] +。 LC-MS (ESI): 603.2 [M+H] + .
步骤14：化合物2的合成：Step 14: Synthesis of Compound 2:
Figure PCTCN2022129961-appb-000114
Figure PCTCN2022129961-appb-000114
将中间体int_2-13(1.50g，2.49mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(17.03g，149.33mmol)。反应液于30℃搅拌反应1小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得化合物2。The intermediate int_2-13 (1.50 g, 2.49 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (17.03 g, 149.33 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate solution (50mL), extract with dichloromethane (50mL×3), combine the organic phases to dry with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure , Compound 2 was obtained by separation and purification by silica gel chromatography.
LC-MS(ESI)：503.2[M+H] +。 LC-MS (ESI): 503.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.29(s，1H)8.26(s，1H)7.65-7.80(m，3H)7.36(d，J＝8.56Hz，2H)7.12(d，J＝2.32Hz，1H)6.98(d，J＝7.34Hz，1H)6.62-6.77(m，3H)6.39-6.52(m，1H)6.23-6.34(m，1H)6.15(s，1H)5.73-5.85(m，1H)3.65(s，3H)3.38-3.55(m，2H)3.07(br s，2H)2.33(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.29(s, 1H) 8.26(s, 1H) 7.65-7.80(m, 3H) 7.36(d, J=8.56Hz, 2H) 7.12(d, J= ( m, 1H) 3.65 (s, 3H) 3.38-3.55 (m, 2H) 3.07 (br s, 2H) 2.33 (s, 3H).
实施例3化合物10的合成The synthesis of embodiment 3 compound 10
Figure PCTCN2022129961-appb-000115
Figure PCTCN2022129961-appb-000115
Figure PCTCN2022129961-appb-000116
Figure PCTCN2022129961-appb-000116
步骤1：化合物int_10-2的合成：Step 1: Synthesis of compound int_10-2:
Figure PCTCN2022129961-appb-000117
Figure PCTCN2022129961-appb-000117
将3-羟基-2-甲氧基苯甲醛(6.69g，43.98mmol)溶于N，N-二甲基甲酰胺(219mL)中，在0℃下加入溶于N，N-二甲基甲酰胺(300mL)的N-溴代丁二酰亚胺(9.39g，52.77mmol)溶液。反应液于0℃搅拌反应2小时。往反应液中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得中间体int_10-2。Dissolve 3-hydroxy-2-methoxybenzaldehyde (6.69g, 43.98mmol) in N,N-dimethylformamide (219mL), and add dissolved N,N-dimethylformamide at 0°C A solution of the amide (300 mL) in N-bromosuccinimide (9.39 g, 52.77 mmol). The reaction solution was stirred at 0°C for 2 hours. Water (500mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (500mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel chromatography The intermediate int_10-2 was isolated and purified.
LC-MS(ESI)：230.8[M+H] +。 LC-MS (ESI): 230.8 [M+H] + .
步骤2：化合物int_10-3的合成：Step 2: Synthesis of compound int_10-3:
Figure PCTCN2022129961-appb-000118
Figure PCTCN2022129961-appb-000118
将中间体int_10-2(4.20g，18.18mmol)和乙二醇(4.95mL，88.53mmol)溶于甲苯(580mL)中，加入对甲苯磺酸(704.35mg，4.09mmol)。反应液于110℃搅拌反应16小时。往反应液中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到粗品中间体int_10-3。The intermediate int_10-2 (4.20 g, 18.18 mmol) and ethylene glycol (4.95 mL, 88.53 mmol) were dissolved in toluene (580 mL), and p-toluenesulfonic acid (704.35 mg, 4.09 mmol) was added. The reaction solution was stirred and reacted at 110° C. for 16 hours. Water (500mL) was added to the reaction solution, the mixed solution was extracted with ethyl acetate (500mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product intermediate int_10 -3.
LC-MS(ESI)：275.0[M+H] +。 LC-MS (ESI): 275.0 [M+H] + .
步骤3：化合物int_10-4的合成：Step 3: Synthesis of compound int_10-4:
Figure PCTCN2022129961-appb-000119
Figure PCTCN2022129961-appb-000119
将中间体int_10-3(8.0g，29.08mmol)和2-氟-6-甲基吡啶(32.31g，290.81mmol)溶于N，N-二甲基甲酰胺(160mL)中，加入碳酸铯(28.43g，87.24mmol)。反应液于120℃搅拌反应16小时。往反应液中加入水(300mL)，混合液用乙酸乙酯(300mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到粗品中间体int_10-4。Intermediate int_10-3 (8.0g, 29.08mmol) and 2-fluoro-6-picoline (32.31g, 290.81mmol) were dissolved in N,N-dimethylformamide (160mL), cesium carbonate ( 28.43 g, 87.24 mmol). The reaction solution was stirred and reacted at 120° C. for 16 hours. Water (300mL) was added to the reaction solution, the mixed solution was extracted with ethyl acetate (300mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product intermediate int_10 -4.
LC-MS(ESI)：366.1[M+H] +。 LC-MS (ESI): 366.1 [M+H] + .
步骤4：化合物int_10-5的合成：Step 4: Synthesis of compound int_10-5:
Figure PCTCN2022129961-appb-000120
Figure PCTCN2022129961-appb-000120
将中间体int_10-4(10.0g，27.31mmol)和双联嚬哪醇硼酸酯(20.80g，81.92mmol)溶于二氧六环(300mL)中，加入醋酸钾(8.04g，81.92mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(2.23g，2.73mmol)。反应液于100℃搅拌反应16小时。往反应液中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得中间体int_10-5。Intermediate int_10-4 (10.0g, 27.31mmol) and bis-incanthyl borate (20.80g, 81.92mmol) were dissolved in dioxane (300mL), and potassium acetate (8.04g, 81.92mmol) was added and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride in dichloromethane mixture (2.23 g, 2.73 mmol). The reaction solution was stirred and reacted at 100° C. for 16 hours. Water (500mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (500mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel chromatography The intermediate int_10-5 was isolated and purified.
LC-MS(ESI)：414.3[M+H] +。 LC-MS (ESI): 414.3 [M+H] + .
步骤5：化合物int_10-6的合成：Step 5: Synthesis of compound int_10-6:
Figure PCTCN2022129961-appb-000121
Figure PCTCN2022129961-appb-000121
将中间体int_1-7(1.68g，4.84mmol)和中间体int_10-5(3.0g，7.26mmol)溶于四氢呋喃(30mL)中，加入磷酸钾水溶液(2M，15mL，30.00mmol)和双(三环己基膦基)二氯化钯(II)(178.62mg，241.97μmol)。反应液于100℃搅拌反应0.5小时。往反应液中加入水(100mL)，混合液用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得中间体int_10-6。Intermediate int_1-7 (1.68g, 4.84mmol) and intermediate int_10-5 (3.0g, 7.26mmol) were dissolved in tetrahydrofuran (30mL), potassium phosphate aqueous solution (2M, 15mL, 30.00mmol) and bis(tri Cyclohexylphosphino)palladium(II) dichloride (178.62 mg, 241.97 μmol). The reaction solution was stirred and reacted at 100°C for 0.5 hours. Water (100mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (100mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel chromatography The intermediate int_10-6 was isolated and purified.
LC-MS(ESI)：555.2[M+H] +。 LC-MS (ESI): 555.2 [M+H] + .
步骤6：化合物int_10-7的合成：Step 6: Synthesis of compound int_10-7:
Figure PCTCN2022129961-appb-000122
Figure PCTCN2022129961-appb-000122
将中间体int_10-6(940mg，1.70mmol)溶于四氢呋喃(3mL)中，加入盐酸水溶液(3M，1.29mL，3.88mmol)。反应液于60℃搅拌反应2小时。得中间体int_10-7的反应液，不经任何处理直接用于下一步。The intermediate int_10-6 (940 mg, 1.70 mmol) was dissolved in tetrahydrofuran (3 mL), and aqueous hydrochloric acid (3M, 1.29 mL, 3.88 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution of the intermediate int_10-7 was obtained, which was directly used in the next step without any treatment.
LC-MS(ESI)：511.2[M+H] +。 LC-MS (ESI): 511.2 [M+H] + .
步骤7：化合物int_10-8的合成：Step 7: Synthesis of compound int_10-8:
Figure PCTCN2022129961-appb-000123
Figure PCTCN2022129961-appb-000123
将中间体int_10-7(上一步的反应液)(940mg，1.84mmol)用四氢呋喃(3mL)稀释，加入氰基硼氢化钠(578.57mg，9.21mmol)。反应液于25℃搅拌反应2小时。往反应液里加入饱和碳酸钠溶液调pH至中性，混合液用乙酸乙酯(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，用乙酸乙酯(5mL)打浆得到中间体int_10-8。Intermediate int_10-7 (reaction solution from previous step) (940 mg, 1.84 mmol) was diluted with tetrahydrofuran (3 mL), and sodium cyanoborohydride (578.57 mg, 9.21 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated sodium carbonate solution to the reaction solution to adjust the pH to neutral, extract the mixture with ethyl acetate (10mL×3), combine the organic phases, dry with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure. Slurry with ethyl acetate (5 mL) gave intermediate int_10-8.
LC-MS(ESI)：495.3[M+H] +。 LC-MS (ESI): 495.3 [M+H] + .
步骤8：化合物int_10-9的合成：Step 8: Synthesis of compound int_10-9:
Figure PCTCN2022129961-appb-000124
Figure PCTCN2022129961-appb-000124
将中间体int_10-8(570mg，1.15mmol)溶于N，N-二甲基甲酰胺(3.5mL)中，加入Boc酸酐 (2.65mL，11.53mmol)，三乙胺(609.66μL，4.38mmol)和4-二甲氨基吡啶(70.41mg，576.34μmol)。反应液于50℃搅拌反应2小时。将反应液旋干后加入水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，用乙酸乙酯(5mL)打浆得中间体int_10-9。The intermediate int_10-8 (570 mg, 1.15 mmol) was dissolved in N, N-dimethylformamide (3.5 mL), and Boc anhydride (2.65 mL, 11.53 mmol), triethylamine (609.66 μL, 4.38 mmol) were added and 4-dimethylaminopyridine (70.41 mg, 576.34 μmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. After the reaction solution was spin-dried, water (10 mL) was added, the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and washed with ethyl acetate Esters (5 mL) were beaten to obtain intermediate int_10-9.
LC-MS(ESI)：495.4[M-100+H] +。 LC-MS (ESI): 495.4 [M-100+H] + .
步骤9：化合物int_10-10的合成：Step 9: Synthesis of compound int_10-10:
Figure PCTCN2022129961-appb-000125
Figure PCTCN2022129961-appb-000125
将中间体int_10-9(420mg，706.34μmol)溶于甲醇(12mL)和水(2.4mL)中，加入还原铁粉(394.4mg，7.06mmol)和氯化铵(377.83mg，7.06mmol)。反应液于65℃搅拌反应0.5小时。将反应液过滤后旋干，加入水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，用乙酸乙酯(5mL)打浆得到中间体int_10-10。The intermediate int_10-9 (420 mg, 706.34 μmol) was dissolved in methanol (12 mL) and water (2.4 mL), and reduced iron powder (394.4 mg, 7.06 mmol) and ammonium chloride (377.83 mg, 7.06 mmol) were added. The reaction solution was stirred and reacted at 65°C for 0.5 hours. After the reaction solution was filtered and spin-dried, water (10 mL) was added, the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and used Ethyl acetate (5 mL) was slurried to obtain intermediate int_10-10.
LC-MS(ESI)：565.3[M+H] +。 LC-MS (ESI): 565.3 [M+H] + .
步骤10：化合物int_10-11的合成：Step 10: Synthesis of compound int_10-11:
Figure PCTCN2022129961-appb-000126
Figure PCTCN2022129961-appb-000126
将中间体int_10-10(400mg，708.42μmol)溶于二氯甲烷(8mL)中，加入三乙胺(302μL，2.17mmol)和丙烯酰氯(118μL，1.45mmol)。反应液于20℃搅拌反应1小时。往反应液中加入饱和碳酸钠溶液(10mL)，混合液用二氯甲烷(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到中间体int_10-11。The intermediate int_10-10 (400 mg, 708.42 μmol) was dissolved in dichloromethane (8 mL), and triethylamine (302 μL, 2.17 mmol) and acryloyl chloride (118 μL, 1.45 mmol) were added. The reaction solution was stirred and reacted at 20° C. for 1 hour. Add saturated sodium carbonate solution (10mL) to the reaction solution, extract the mixture with dichloromethane (10mL×3), combine the organic phases, dry with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the intermediate int_10-11.
LC-MS(ESI)：619.4[M+H] +。 LC-MS (ESI): 619.4 [M+H] + .
步骤11：化合物10的合成：Step 11: Synthesis of Compound 10:
Figure PCTCN2022129961-appb-000127
Figure PCTCN2022129961-appb-000127
将中间体int_10-11(260mg，420.25μmol)溶于二氯甲烷(15mL)中，加入三氟乙酸(2mL，25.21mmol)。反应液于30℃搅拌反应1小时。往反应液中加入饱和碳酸钠水溶液(30mL)，混合液用二氯甲烷(30mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后用四氢呋喃(15mL)打浆得到化合物10。The intermediate int_10-11 (260 mg, 420.25 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (2 mL, 25.21 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Add saturated aqueous sodium carbonate solution (30mL) to the reaction solution, extract the mixture with dichloromethane (30mL×3), combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and then use Tetrahydrofuran (15 mL) was slurried to obtain compound 10.
LC-MS(ESI)：519.2[M+H] +。 LC-MS (ESI): 519.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.38(s，1H)，8.16(s，1H)，7.87(d，J＝8.6Hz，2H)，7.71-7.61(m，2H)，7.55(d，J＝8.5Hz，2H)，6.93(d，J＝7.3Hz，1H)，6.79(d，J＝8.6Hz，1H)，6.71(d，J＝8.1Hz，1H)，6.59(d，J＝8.6Hz，1H)，6.53-6.42(m，1H)，6.34-6.26(m，1H)，5.83-5.76(m，1H)，4.48(br d，J＝3.5Hz，2H)，3.69(s，3H)，3.58(s，3H)，2.26(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.38(s, 1H), 8.16(s, 1H), 7.87(d, J=8.6Hz, 2H), 7.71-7.61(m, 2H), 7.55( d, J=8.5Hz, 2H), 6.93(d, J=7.3Hz, 1H), 6.79(d, J=8.6Hz, 1H), 6.71(d, J=8.1Hz, 1H), 6.59(d, J=8.6Hz, 1H), 6.53-6.42(m, 1H), 6.34-6.26(m, 1H), 5.83-5.76(m, 1H), 4.48(br d, J=3.5Hz, 2H), 3.69( s,3H), 3.58(s,3H), 2.26(s,3H).
实施例4化合物11的合成The synthesis of embodiment 4 compound 11
Figure PCTCN2022129961-appb-000128
Figure PCTCN2022129961-appb-000128
Figure PCTCN2022129961-appb-000129
Figure PCTCN2022129961-appb-000129
步骤1：化合物int_11-2的合成：Step 1: Synthesis of compound int_11-2:
Figure PCTCN2022129961-appb-000130
Figure PCTCN2022129961-appb-000130
将N，N-二异丙基氨基锂(2M四氢呋喃溶液，156mL)溶于四氢呋喃(1L)，在-78℃下滴入化合物2-氟-4-溴苯甲醚(50.0g，244mmol)的四氢呋喃(500mL)溶液，反应液于-78℃搅拌反应0.5小时，再滴入N，N-二甲基甲酰胺(26.7g，366mmol)，反应液于10℃搅拌反应3小时。反应液加入氯化铵饱和溶液(1L)稀释，用乙酸乙酯(1L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到黄色固体，黄色固体用乙酸乙酯∶石油醚＝1∶3打浆纯化，得到中间体int_11-2。N, N-diisopropylamide lithium (2M tetrahydrofuran solution, 156mL) was dissolved in tetrahydrofuran (1L), and compound 2-fluoro-4-bromoanisole (50.0g, 244mmol) was added dropwise at -78°C Tetrahydrofuran (500 mL) solution, the reaction solution was stirred and reacted at -78°C for 0.5 hours, then N,N-dimethylformamide (26.7 g, 366 mmol) was added dropwise, and the reaction solution was stirred and reacted at 10°C for 3 hours. The reaction solution was diluted with saturated ammonium chloride solution (1L), extracted with ethyl acetate (1L×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow solid, a yellow solid Slurry purification with ethyl acetate:petroleum ether=1:3 gave intermediate int_11-2.
1H NMR(400MHz，CDCl 3)δ10.34(d，J＝0.6Hz，1H)，7.41(dd，J＝1.9，8.9Hz，1H)，7.06(t，J＝8.6Hz，1H)，4.00-3.90(m，3H)。 1 H NMR (400MHz, CDCl 3 ) δ10.34 (d, J=0.6Hz, 1H), 7.41 (dd, J=1.9, 8.9Hz, 1H), 7.06 (t, J=8.6Hz, 1H), 4.00 -3.90 (m, 3H).
步骤2：化合物int_11-3的合成：Step 2: Synthesis of compound int_11-3:
Figure PCTCN2022129961-appb-000131
Figure PCTCN2022129961-appb-000131
将中间体int_11-2(100g，429mmol)溶于二氯甲烷(500mL)中，在-30℃下分批加入三溴化硼(376g，1.50mol)。反应液于25℃搅拌反应12小时。反应液缓慢倒入冰水(2L)中，用乙酸乙酯(2L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到中间体int_11-3。The intermediate int_11-2 (100 g, 429 mmol) was dissolved in dichloromethane (500 mL), and boron tribromide (376 g, 1.50 mol) was added in portions at -30°C. The reaction solution was stirred and reacted at 25° C. for 12 hours. The reaction solution was slowly poured into ice water (2L), extracted with ethyl acetate (2L×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography to obtain Intermediate int_11-3.
1H NMR(400MHz，DMSO-d 6)δ10.60(s，1H)，10.17(s，1H)，7.46-7.36(m，1H)，7.17-7.07(m，1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.60 (s, 1H), 10.17 (s, 1H), 7.46-7.36 (m, 1H), 7.17-7.07 (m, 1H).
步骤3：化合物int_11-4的合成：Step 3: Synthesis of compound int_11-4:
Figure PCTCN2022129961-appb-000132
Figure PCTCN2022129961-appb-000132
将中间体int_11-3(410g，1.87mol)溶于甲苯(2L)中，再加入乙二醇(581g，9.36mol)，对甲苯磺酸(64.5g，374mol)。反应液于110℃搅拌反应16小时。反应液冷却后，加入到饱和碳酸钠溶液(1L)中，用乙酸乙酯(2L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到中间体int_11-4。The intermediate int_11-3 (410g, 1.87mol) was dissolved in toluene (2L), and then ethylene glycol (581g, 9.36mol) and p-toluenesulfonic acid (64.5g, 374mol) were added. The reaction solution was stirred and reacted at 110° C. for 16 hours. After the reaction solution was cooled, it was added to saturated sodium carbonate solution (1L), extracted with ethyl acetate (2L×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and subjected to silica gel chromatography. The intermediate int_11-4 was obtained by separation and purification by method.
1H NMR(400MHz，DMSO-d 6)δ10.26(br s，1H)，7.26(dd，J＝1.7，8.8Hz，1H)，6.96(t，J＝8.9Hz，1H)，6.09(d，J＝1.0Hz，1H)，4.24-4.05(m，2H)，4.03-3.88(m，2H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.26(br s, 1H), 7.26(dd, J=1.7, 8.8Hz, 1H), 6.96(t, J=8.9Hz, 1H), 6.09(d , J=1.0Hz, 1H), 4.24-4.05(m, 2H), 4.03-3.88(m, 2H).
步骤4：化合物int_11-5的合成：Step 4: Synthesis of compound int_11-5:
Figure PCTCN2022129961-appb-000133
Figure PCTCN2022129961-appb-000133
将中间体int_11-4(150g，570mmol)溶于N，N-二甲基甲酰胺(2L)中，加入碳酸铯(557.36g，1.71mol)，2-氟-6-甲基吡啶(633.60g，5.70mol)。反应液于120℃搅拌反应12小时。反应液冷却后加入水(5L)，再加入乙酸乙酯(2L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到中间体int_11-5。The intermediate int_11-4 (150g, 570mmol) was dissolved in N,N-dimethylformamide (2L), cesium carbonate (557.36g, 1.71mol), 2-fluoro-6-methylpyridine (633.60g , 5.70mol). The reaction solution was stirred and reacted at 120° C. for 12 hours. After the reaction solution was cooled, water (5L) was added, followed by ethyl acetate (2L×3) for extraction, the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain intermediate Body int_11-5.
1H NMR(400MHz，DMSO-d 6)δ7.84-7.77(m，1H)，7.59-7.51(m，1H)，7.42-7.35(m，1H)，7.08-7.03(m，1H)，6.99-6.93(m，1H)，6.20(d，J＝0.9Hz，1H)，4.21-4.08(m，2H)，4.07-3.97(m，2H)，2.35-2.25(m，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.84-7.77(m, 1H), 7.59-7.51(m, 1H), 7.42-7.35(m, 1H), 7.08-7.03(m, 1H), 6.99 -6.93 (m, 1H), 6.20 (d, J=0.9Hz, 1H), 4.21-4.08 (m, 2H), 4.07-3.97 (m, 2H), 2.35-2.25 (m, 3H).
步骤5：化合物int_11-6的合成：Step 5: Synthesis of compound int_11-6:
Figure PCTCN2022129961-appb-000134
Figure PCTCN2022129961-appb-000134
将中间体int_11-5(120g，339mmol)溶于二氧六环(1L)中，加入双联频哪醇硼酸酯(258g，1.02mol)，在氮气保护下加入，[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(27.7g，33.9mmol)，醋酸钾(99.8g，1.02mol)，反应液于100℃搅拌反应16小时。反应液减压浓缩至干，然后经硅胶色谱法分离纯化得到中间体int_11-6。The intermediate int_11-5 (120g, 339mmol) was dissolved in dioxane (1L), and double pinacol borate (258g, 1.02mol) was added, added under nitrogen protection, [1,1-bis (Diphenylphosphine)ferrocene]palladium dichloride dichloromethane (27.7g, 33.9mmol), potassium acetate (99.8g, 1.02mol), and the reaction solution was stirred at 100°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain the intermediate int_11-6.
1H NMR(400MHz，DMSO-d 6)δ7.75(t，J＝7.8Hz，1H)，7.37-7.23(m，2H)，7.00(d，J＝7.4Hz，1H)，6.88(d，J＝8.2Hz，1H)，6.14(s，1H)，4.08-4.00(m，2H)，3.99-3.90(m，2H)，2.27(s，3H)，1.45-1.20(m，12H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.75(t, J=7.8Hz, 1H), 7.37-7.23(m, 2H), 7.00(d, J=7.4Hz, 1H), 6.88(d, J=8.2Hz, 1H), 6.14(s, 1H), 4.08-4.00(m, 2H), 3.99-3.90(m, 2H), 2.27(s, 3H), 1.45-1.20(m, 12H).
步骤6：化合物int_11-7的合成：Step 6: Synthesis of compound int_11-7:
Figure PCTCN2022129961-appb-000135
Figure PCTCN2022129961-appb-000135
将中间体int_1-7(30g，86.17mmol)和中间体int_11-6(69.15g，172.34mmol)溶于N，N-二甲基甲酰胺(300mL)中，加入磷酸钾水溶液(87mL，2M)和[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(3.93g，6.03mmol)。反应液用氮气置换3次，于100℃搅拌反应0.5小时。冷却后往反应液中加入水(2L)，混合液用乙酸乙酯(1.5L×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后用乙酸乙酯(100mL)在20℃搅拌16小时，打浆得到中间体int_11-7。Intermediate int_1-7 (30g, 86.17mmol) and intermediate int_11-6 (69.15g, 172.34mmol) were dissolved in N,N-dimethylformamide (300mL), and potassium phosphate aqueous solution (87mL, 2M) was added and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (3.93 g, 6.03 mmol). The reaction solution was replaced with nitrogen three times, and stirred and reacted at 100° C. for 0.5 hour. After cooling, water (2L) was added to the reaction solution, the mixture was extracted with ethyl acetate (1.5L×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then used Ethyl acetate (100 mL) was stirred at 20° C. for 16 hours and beaten to obtain intermediate int_11-7.
LC-MS(ESI)：543.0[M+H] +。 LC-MS (ESI): 543.0 [M+H] + .
步骤7：化合物int_11-8的合成：Step 7: Synthesis of compound int_11-8:
Figure PCTCN2022129961-appb-000136
Figure PCTCN2022129961-appb-000136
将中间体int_11-7(28g，51.61mmol)溶于四氢呋喃(100mL)中，加入盐酸水溶液(40mL，3M)。反应液于60℃搅拌反应2小时。将反应液浓缩得到中间体int_11-8，粗品直接用于下一步反应。The intermediate int_11-7 (28 g, 51.61 mmol) was dissolved in tetrahydrofuran (100 mL), and aqueous hydrochloric acid (40 mL, 3M) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution was concentrated to obtain the intermediate int_11-8, and the crude product was directly used in the next reaction.
LC-MS(ESI)：499.1[M+H] +。 LC-MS (ESI): 499.1 [M+H] + .
步骤8：化合物int_11-9的合成：Step 8: Synthesis of compound int_11-9:
Figure PCTCN2022129961-appb-000137
Figure PCTCN2022129961-appb-000137
将中间体int_11-8(28g，56.17mmol)溶于四氢呋喃(200mL)中，加入氰基硼氢化钠(17.65g，280.86mmol)。反应液于25℃搅拌反应2小时。往反应液里加入饱和碳酸钠水溶液(2L)调pH＝10，混合液用乙酸乙酯(1L×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到中间体int_11-9。The intermediate int_11-8 (28 g, 56.17 mmol) was dissolved in tetrahydrofuran (200 mL), and sodium cyanoborohydride (17.65 g, 280.86 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated aqueous sodium carbonate solution (2L) to the reaction solution to adjust the pH=10, extract the mixture with ethyl acetate (1L×3), combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to dry, and then separated and purified by silica gel chromatography to obtain the intermediate int_11-9.
LC-MS(ESI)：483.2[M+H] +。 LC-MS (ESI): 483.2 [M+H] + .
步骤9：化合物int_11-10的合成：Step 9: Synthesis of compound int_11-10:
Figure PCTCN2022129961-appb-000138
Figure PCTCN2022129961-appb-000138
将中间体int_11-9(12g，24.87mmol)溶于N，N-二甲基甲酰胺(250mL)中，加入Boc酸酐(57mL，248.72mmol)，三乙胺(13mL，94.51mmol)和4-二甲氨基吡啶(1.52mg，12.44mmol)。反应液于50℃搅拌反应2小时。将反应液旋干后加入水(1.0L)，混合液用乙酸乙酯(1.0L×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到中间体int_11-10。The intermediate int_11-9 (12g, 24.87mmol) was dissolved in N,N-dimethylformamide (250mL), and Boc anhydride (57mL, 248.72mmol), triethylamine (13mL, 94.51mmol) and 4- Dimethylaminopyridine (1.52 mg, 12.44 mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. After the reaction solution was spin-dried, water (1.0 L) was added, the mixture was extracted with ethyl acetate (1.0 L×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then The intermediate int_11-10 was obtained by separation and purification by silica gel chromatography.
LC-MS(ESI)：583.1[M+H] +。 LC-MS (ESI): 583.1 [M+H] + .
步骤10：化合物int_11-11的合成：Step 10: Synthesis of compound int_11-11:
Figure PCTCN2022129961-appb-000139
Figure PCTCN2022129961-appb-000139
将中间体int_11-10(13g，22.31mmol)溶于甲醇(300mL)和水(60mL)中，加入还原铁粉(12.46g，223.15mmol)和氯化铵(11.94g，223.15mmol)。反应液于65℃搅拌反应1小时。将反应液过滤后旋干，加入水(1.0L)，混合液用乙酸乙酯(1.0L×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后用乙酸乙酯(50mL)在20℃搅拌0.5小时打浆得到中间体int_11-11。The intermediate int_11-10 (13g, 22.31mmol) was dissolved in methanol (300mL) and water (60mL), and reduced iron powder (12.46g, 223.15mmol) and ammonium chloride (11.94g, 223.15mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. After the reaction solution was filtered and spin-dried, water (1.0L) was added, the mixture was extracted with ethyl acetate (1.0L×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. , and then stirred with ethyl acetate (50 mL) at 20 ° C for 0.5 hours to obtain the intermediate int_11-11.
LC-MS(ESI)：553.2[M+H] +。 LC-MS (ESI): 553.2 [M+H] + .
步骤11：化合物int_11-12的合成：Step 11: Synthesis of compound int_11-12:
Figure PCTCN2022129961-appb-000140
Figure PCTCN2022129961-appb-000140
将中间体int_11-11(2g，3.62mmol)溶于二氯甲烷(100mL)中，于0℃加入三乙胺(1.5mL，10.86mmol)和丙烯酰氯(443μL，5.43μmol)。反应液于20℃搅拌反应1小时。往反应液中加入饱和碳酸钠水溶液(50mL)，混合液用二氯甲烷(50mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到中间体int_11-12。The intermediate int_11-11 (2 g, 3.62 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (1.5 mL, 10.86 mmol) and acryloyl chloride (443 μL, 5.43 μmol) were added at 0°C. The reaction solution was stirred and reacted at 20° C. for 1 hour. Add saturated aqueous sodium carbonate solution (50mL) to the reaction solution, extract the mixture with dichloromethane (50mL×3), combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and then The intermediate int_11-12 was obtained by separation and purification by silica gel chromatography.
LC-MS(ESI)：607.1[M+H] +。 LC-MS (ESI): 607.1 [M+H] + .
步骤12：化合物11的合成：Step 12: Synthesis of compound 11:
Figure PCTCN2022129961-appb-000141
Figure PCTCN2022129961-appb-000141
将中间体int_11-12(1.88g，3.10mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(11.5mL，155mmol)。反应液于30℃搅拌反应1小时。将反应液旋干后加入饱和碳酸钠水溶液(150mL)，混合液用二氯甲烷(150mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物11。The intermediate int_11-12 (1.88 g, 3.10 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (11.5 mL, 155 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. After the reaction solution was spin-dried, saturated aqueous sodium carbonate solution (150 mL) was added, the mixture was extracted with dichloromethane (150 mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Compound 11 was then separated and purified by silica gel chromatography.
LC-MS(ESI)：507.2[M+H] +。 LC-MS (ESI): 507.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.41(s，1H)，8.19(s，1H)，7.88(d，J＝8.5Hz，2H)，7.71(t，J＝7.8Hz，1H)，7.66-7.53(m，3H)，7.01-6.90(m，2H)，6.82(d，J＝8.0Hz，1H)，6.64(d，J＝8.8Hz，1H)，6.53-6.42(m，1H)，6.36-6.25(m，1H)，5.81(d，J＝10.0Hz，1H)，4.47(s，2H)，3.59(s，3H)，2.26(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.41(s, 1H), 8.19(s, 1H), 7.88(d, J=8.5Hz, 2H), 7.71(t, J=7.8Hz, 1H) , 7.66-7.53(m, 3H), 7.01-6.90(m, 2H), 6.82(d, J=8.0Hz, 1H), 6.64(d, J=8.8Hz, 1H), 6.53-6.42(m, 1H ), 6.36-6.25 (m, 1H), 5.81 (d, J=10.0Hz, 1H), 4.47 (s, 2H), 3.59 (s, 3H), 2.26 (s, 3H).
实施例5化合物12的合成The synthesis of embodiment 5 compound 12
Figure PCTCN2022129961-appb-000142
Figure PCTCN2022129961-appb-000142
步骤1：化合物int_12-2的合成：Step 1: Synthesis of compound int_12-2:
Figure PCTCN2022129961-appb-000143
Figure PCTCN2022129961-appb-000143
将2-溴-5-羟基-4-甲氧基苯甲醛(30.8g，133.31mmol)和2-氟-6-甲基吡啶(29.63g，266.62mmol)溶于N，N-二甲基甲酰胺(450mL)中，加入碳酸钾(55.27g，399.93mmol)。反应液于100℃搅拌反应48小时。反应液减压浓缩至干得到粗品。向反应液中加入水(800mL)，用乙酸乙酯(800mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_12-2。2-Bromo-5-hydroxy-4-methoxybenzaldehyde (30.8g, 133.31mmol) and 2-fluoro-6-picoline (29.63g, 266.62mmol) were dissolved in N,N-dimethylformaldehyde To the amide (450 mL), potassium carbonate (55.27 g, 399.93 mmol) was added. The reaction solution was stirred and reacted at 100° C. for 48 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. Add water (800mL) to the reaction solution, extract with ethyl acetate (800mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product, which is separated and purified by silica gel chromatography Compound int_12-2 was obtained.
LC-MS m/z(ESI)：322.0[M+H] +。 LC-MS m/z (ESI): 322.0 [M+H] + .
步骤2：化合物int_12-3的合成：Step 2: Synthesis of compound int_12-3:
Figure PCTCN2022129961-appb-000144
Figure PCTCN2022129961-appb-000144
将化合物int_12-2(4.9g，15.21mmol)和双联嚬哪醇硼酸酯(15.45g，60.84mmol)溶于二氧六环(150mL)中，在氮气保护下加入[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(1.24g，1.52mmol)和乙酸钾(4.48g，45.63mmol)。反应液于100℃搅拌反应3小时。反应液减压浓缩至干得到粗品。 向反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_12-3。Compound int_12-2 (4.9g, 15.21mmol) and bis-incanthyl borate (15.45g, 60.84mmol) were dissolved in dioxane (150mL), and [1,1-bis (Diphenylphosphine)ferrocene]palladium dichloride dichloromethane (1.24 g, 1.52 mmol) and potassium acetate (4.48 g, 45.63 mmol). The reaction solution was stirred and reacted at 100° C. for 3 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. Add water (200mL) to the reaction solution, extract with ethyl acetate (200mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product, which is separated and purified by silica gel chromatography Compound int_12-3 was obtained.
LC-MS m/z(ESI)：370.1[M+H] +。 LC-MS m/z (ESI): 370.1 [M+H] + .
步骤3：化合物int_12-4的合成：Step 3: Synthesis of compound int_12-4:
Figure PCTCN2022129961-appb-000145
Figure PCTCN2022129961-appb-000145
将化合物int_1-7(1.8g，5.17mmol)和化合物int_12-3(2.86g，7.76mmol)溶于四氢呋喃(27mL)中，在氮气保护下加入双(三环己基膦基)二氯化钯(II)(190.82mg，258.51μmol)和磷酸钾(2M，5.40mL)。反应液于100℃搅拌反应15分钟。向反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取3次，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_12-4。Compound int_1-7 (1.8g, 5.17mmol) and compound int_12-3 (2.86g, 7.76mmol) were dissolved in tetrahydrofuran (27mL), and bis(tricyclohexylphosphino)palladium dichloride was added under nitrogen protection ( II) (190.82 mg, 258.51 μmol) and potassium phosphate (2M, 5.40 mL). The reaction solution was stirred and reacted at 100° C. for 15 minutes. Add water (200mL) to the reaction solution, extract 3 times with ethyl acetate (200mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product, which is subjected to silica gel chromatography Compound int_12-4 was obtained by separation and purification.
LC-MS m/z(ESI)：511.4[M+H] +。 LC-MS m/z (ESI): 511.4 [M+H] + .
步骤4：化合物int_12-5的合成：Step 4: Synthesis of compound int_12-5:
Figure PCTCN2022129961-appb-000146
Figure PCTCN2022129961-appb-000146
将化合物int_12-4(292mg，571.99μmol)溶于乙腈(5.5mL)和乙酸(164μL，2.86mmol)中，加入氰基硼氢化钠(179.72mg，2.86mmol)。反应液于25℃搅拌反应16小时。向反应液中加入饱和碳酸钠(10mL)减压浓缩至干得到粗品，向反应液中加入水(30mL)和乙酸乙酯(30mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_12-5。Compound int_12-4 (292 mg, 571.99 μmol) was dissolved in acetonitrile (5.5 mL) and acetic acid (164 μL, 2.86 mmol), and sodium cyanoborohydride (179.72 mg, 2.86 mmol) was added. The reaction solution was stirred and reacted at 25°C for 16 hours. Add saturated sodium carbonate (10mL) to the reaction solution and concentrate to dryness under reduced pressure to obtain the crude product, add water (30mL) and ethyl acetate (30mL×3) to the reaction solution for extraction, and dry the organic phase with anhydrous magnesium sulfate, extract After filtration, the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was separated and purified by silica gel chromatography to obtain compound int_12-5.
LC-MS m/z(ESI)：495.1[M+H] +。 LC-MS m/z (ESI): 495.1 [M+H] + .
步骤5：化合物int_12-6的合成：Step 5: Synthesis of compound int_12-6:
Figure PCTCN2022129961-appb-000147
Figure PCTCN2022129961-appb-000147
将化合物int_12-5(149mg，301.31μmol)溶于N，N-二甲基甲酰胺(2.5mL)中，加入三乙胺(126μL，903.94μmol)和BOC酸酐(693μL，3.01mmol)，二甲氨基吡啶(18.41mg，150.66μmol)，反应液于50℃搅拌反应16小时。反应液减压浓缩至干，将反应液倒入水(30mL)，用二氯甲烷(30mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，粗品经硅胶色谱法分离纯化得到化合物int_12-6。Compound int_12-5 (149 mg, 301.31 μmol) was dissolved in N,N-dimethylformamide (2.5 mL), triethylamine (126 μL, 903.94 μmol) and BOC anhydride (693 μL, 3.01 mmol) were added, and dimethyl Aminopyridine (18.41mg, 150.66μmol), the reaction solution was stirred at 50°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, the reaction solution was poured into water (30mL), extracted with dichloromethane (30mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, the crude product Compound int_12-6 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：595.1[M+H] +。 LC-MS m/z (ESI): 595.1 [M+H] + .
步骤6：化合物int_12-7的合成：Step 6: Synthesis of compound int_12-7:
Figure PCTCN2022129961-appb-000148
Figure PCTCN2022129961-appb-000148
将化合物int_12-6(150mg，252.26μmol)溶于甲醇(2mL)和水(400μL)中，加入铁粉(140.88mg，2.52mmol)和氯化铵(134.94mg，2.52mmol)。反应液于65℃搅拌反应1小时。反应液减压浓缩至干得到粗品。向反应液中加入水(40mL)和乙酸乙酯(40mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品化合物int_12-7。Compound int_12-6 (150 mg, 252.26 μmol) was dissolved in methanol (2 mL) and water (400 μL), and iron powder (140.88 mg, 2.52 mmol) and ammonium chloride (134.94 mg, 2.52 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. Water (40 mL) and ethyl acetate (40 mL×3) were added to the reaction solution for extraction, the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude compound int_12-7.
LC-MS m/z(ESI)：565.2[M+H] +。 LC-MS m/z (ESI): 565.2 [M+H] + .
步骤7：化合物int_12-8的合成：Step 7: Synthesis of compound int_12-8:
Figure PCTCN2022129961-appb-000149
Figure PCTCN2022129961-appb-000149
将化合物int_12-7(140mg，247.95μmol)溶于二氯甲烷(3mL)中，加入N，N-二异丙基乙胺(129.56μL，743.85μmol)。然后在0℃条件下向反应液中加入丙烯酰氯(41μL，495.90μmol)，反应液于25℃搅拌反应1小时。向反应液中加入饱和碳酸钠溶液(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到化合物int_12-8。Compound int_12-7 (140 mg, 247.95 μmol) was dissolved in dichloromethane (3 mL), and N,N-diisopropylethylamine (129.56 μL, 743.85 μmol) was added. Then, acryloyl chloride (41 μL, 495.90 μmol) was added to the reaction solution at 0° C., and the reaction solution was stirred and reacted at 25° C. for 1 hour. Saturated sodium carbonate solution (50 mL) was added to the reaction solution, extracted with dichloromethane (50 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_12-8.
LC-MS m/z(ESI)：619.2[M+H] +。 LC-MS m/z (ESI): 619.2 [M+H] + .
步骤8：化合物12的合成：Step 8: Synthesis of Compound 12:
Figure PCTCN2022129961-appb-000150
Figure PCTCN2022129961-appb-000150
将化合物int_12-8(140mg，226.29μmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(838μL，11.31mmol)。反应液于25℃搅拌反应1小时。反应液减压浓缩至干得到粗品，向反应液中加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，经制备液相色谱纯化得到白色固体化合物12。Compound int_12-8 (140 mg, 226.29 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (838 μL, 11.31 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. Add saturated aqueous sodium carbonate (50 mL) to the reaction solution, extract with dichloromethane (50 mL×3), dry the organic phase with anhydrous magnesium sulfate, suction filter, and depressurize the filtrate Concentration to dryness gave the crude product, which was purified by preparative liquid chromatography to give compound 12 as a white solid.
LC-MS m/z(ESI)：519.2[M+H] +。 LC-MS m/z (ESI): 519.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.38(s，1H)，8.29(s，0.2H)，8.17(s，1H)，7.89(d，J＝8.6Hz，2H)，7.66-7.51(m，4H)，7.08(s，1H)，6.88(d，J＝7.3Hz，1H)，6.61(d，J＝8.2Hz，1H)，6.54(s，1H)，6.51-6.41(m，1H)，6.34-6.25(m，1H)，5.83-5.76(m，1H)，4.30(d，J＝3.2Hz，2H)，3.60(s，3H)，3.07(s，3H)，2.25(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.38(s, 1H), 8.29(s, 0.2H), 8.17(s, 1H), 7.89(d, J=8.6Hz, 2H), 7.66-7.51 (m, 4H), 7.08(s, 1H), 6.88(d, J=7.3Hz, 1H), 6.61(d, J=8.2Hz, 1H), 6.54(s, 1H), 6.51-6.41(m, 1H), 6.34-6.25(m, 1H), 5.83-5.76(m, 1H), 4.30(d, J=3.2Hz, 2H), 3.60(s, 3H), 3.07(s, 3H), 2.25(s , 3H).
实施例6化合物34的合成The synthesis of embodiment 6 compound 34
Figure PCTCN2022129961-appb-000151
Figure PCTCN2022129961-appb-000151
Figure PCTCN2022129961-appb-000152
Figure PCTCN2022129961-appb-000152
步骤1：化合物int_34-1的合成：Step 1: Synthesis of compound int_34-1:
Figure PCTCN2022129961-appb-000153
Figure PCTCN2022129961-appb-000153
将化合物int_2-1(200g，816.09mmol)和2-氯-4-甲基嘧啶(157.37g，1.22mol)溶于N，N-二甲基甲酰胺(1.5L)中，加入碳酸钾(225.58g，1.63mol)。反应液于100℃搅拌2小时。反应液冷却至室温，过滤，滤液减压浓缩至干。向剩余物中加入水(1.5L)，用乙酸乙酯(1.5L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_34-1。Compound int_2-1 (200g, 816.09mmol) and 2-chloro-4-methylpyrimidine (157.37g, 1.22mol) were dissolved in N, N-dimethylformamide (1.5L), and potassium carbonate (225.58 g, 1.63mol). The reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Add water (1.5L) to the residue, extract with ethyl acetate (1.5L×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain Compound int_34-1.
LC-MS m/z(ESI)：336.9[M+H] +。 LC-MS m/z (ESI): 336.9 [M+H] + .
步骤2：化合物int_34-2的合成：Step 2: Synthesis of compound int_34-2:
Figure PCTCN2022129961-appb-000154
Figure PCTCN2022129961-appb-000154
将化合物int_34-1(120.0g，355.91mmol)和化合物双联频哪醇硼酸酯(135.57g，533.86mmol)溶于二氧六环(1.2L)中，在氮气保护下加入醋酸钾(104.79g，1.07mol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(20.35g，24.91mmol)，反应液于100℃搅拌5小时。反应液冷却至室温，过滤，滤液减压浓缩。向剩余物中加入水(1500mL)，用乙酸乙酯(1.5L×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_34-2。Compound int_34-1 (120.0g, 355.91mmol) and compound double pinacol borate (135.57g, 533.86mmol) were dissolved in dioxane (1.2L), and potassium acetate (104.79mmol) was added under nitrogen protection. g, 1.07mol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (20.35g, 24.91mmol), and the reaction solution was stirred at 100°C for 5 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Add water (1500mL) to the residue, extract with ethyl acetate (1.5L×3), dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, separate and purify by silica gel chromatography to obtain compound int_34-2 .
LC-MS m/z(ESI)：384.9[M+H] +。 LC-MS m/z (ESI): 384.9 [M+H] + .
步骤3：化合物int_34-3的合成：Step 3: Synthesis of compound int_34-3:
Figure PCTCN2022129961-appb-000155
Figure PCTCN2022129961-appb-000155
将化合物int_1-7(70.0g，201.06mmol)和化合物int_34-2(115.88g，301.59mmol)溶于N，N-二甲基甲酰胺(1.6L)中，在氮气保护下加入磷酸钾水溶液(2M，352mL)和[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(13.10g，20.11mmol)，反应液于100℃搅拌20分钟。反应液冷却至室温，加入水(4.5L)，抽滤，乙酸乙酯(500mL)洗涤，滤饼用乙酸乙酯(500mL)打浆纯化得到化合物int_34-3。Compound int_1-7 (70.0g, 201.06mmol) and compound int_34-2 (115.88g, 301.59mmol) were dissolved in N,N-dimethylformamide (1.6L), and potassium phosphate aqueous solution ( 2M, 352 mL) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (13.10 g, 20.11 mmol), and the reaction solution was stirred at 100°C for 20 minutes. The reaction solution was cooled to room temperature, water (4.5 L) was added, suction filtered, washed with ethyl acetate (500 mL), and the filter cake was purified by slurrying with ethyl acetate (500 mL) to obtain compound int_34-3.
LC-MS m/z(ESI)：526.1[M+H] +。 LC-MS m/z (ESI): 526.1 [M+H] + .
步骤4：化合物int_34-4的合成：Step 4: Synthesis of compound int_34-4:
Figure PCTCN2022129961-appb-000156
Figure PCTCN2022129961-appb-000156
将化合物int_34-3(55.0g，104.66mmol)溶于四氢呋喃(240mL)中，加入盐酸(3M，105mL)，反应液于60℃搅拌2小时。反应液冷却至室温，减压浓缩除去溶剂，得到黄色固体化合物int_34-4。Compound int_34-3 (55.0 g, 104.66 mmol) was dissolved in tetrahydrofuran (240 mL), hydrochloric acid (3M, 105 mL) was added, and the reaction solution was stirred at 60° C. for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove the solvent to obtain compound int_34-4 as a yellow solid.
LC-MS m/z(ESI)：482.1[M+H] +。 LC-MS m/z (ESI): 482.1 [M+H] + .
步骤5：化合物int_34-5的合成：Step 5: Synthesis of compound int_34-5:
Figure PCTCN2022129961-appb-000157
Figure PCTCN2022129961-appb-000157
将化合物int_34-4(50.0g，103.85mmol)溶于四氢呋喃(250mL)中，加入氰基硼氢化钠(13.05g，207.70mmol)和盐酸(3M，78mL)，反应液于25℃搅拌反应2小时。向反应液中加入饱和碳酸钠溶液(120mL)使pH＝8，再加入水(1.0L)，用乙酸乙酯(1.0L×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到黄色固体化合物int_34-5。Compound int_34-4 (50.0g, 103.85mmol) was dissolved in tetrahydrofuran (250mL), sodium cyanoborohydride (13.05g, 207.70mmol) and hydrochloric acid (3M, 78mL) were added, and the reaction solution was stirred at 25°C for 2 hours . Add saturated sodium carbonate solution (120mL) to the reaction solution to make the pH = 8, then add water (1.0L), extract with ethyl acetate (1.0L×3), combine the organic phases to dry with anhydrous magnesium sulfate, and filter with suction , the filtrate was concentrated to dryness under reduced pressure to obtain compound int_34-5 as a yellow solid.
LC-MS m/z(ESI)：468.0[M+H] +。 LC-MS m/z (ESI): 468.0 [M+H] + .
步骤6：化合物int_34-6的合成：Step 6: Synthesis of compound int_34-6:
Figure PCTCN2022129961-appb-000158
Figure PCTCN2022129961-appb-000158
将化合物int_34-5(36.0g，77.01mmol)溶于四氢呋喃(400mL)中，加入活性二氧化锰(33.47g，385.04mmol)。反应液于60℃搅拌反应2小时。反应液冷却至室温，抽滤，用四氢呋喃(300mL)和二氯甲烷(300mL)洗涤，减压浓缩。向剩余物中加入水(500mL)，用乙酸乙酯(500mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_34-6。Compound int_34-5 (36.0 g, 77.01 mmol) was dissolved in tetrahydrofuran (400 mL), and active manganese dioxide (33.47 g, 385.04 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution was cooled to room temperature, filtered with suction, washed with tetrahydrofuran (300 mL) and dichloromethane (300 mL), and concentrated under reduced pressure. Add water (500mL) to the residue, extract with ethyl acetate (500mL×3), combine the organic phases to dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain the compound int_34-6.
LC-MS m/z(ESI)：466.1[M+H] +。 LC-MS m/z (ESI): 466.1 [M+H] + .
步骤7：化合物int_34-7的合成：Step 7: Synthesis of compound int_34-7:
Figure PCTCN2022129961-appb-000159
Figure PCTCN2022129961-appb-000159
将化合物int_34-6(8.00g，17.19mmol)溶于N，N-二甲基甲酰胺(80mL)中，加入BOC酸酐(37.51g，171.87mmol)，4-二甲氨基吡啶(1.05g，8.59mmol)和三乙胺(6.66g，65.83mmol)。反应液于50℃搅拌反应2小时。反应液冷却至室温，加入水(500mL)，用乙酸乙酯(500mL×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_34-7。Compound int_34-6 (8.00g, 17.19mmol) was dissolved in N, N-dimethylformamide (80mL), BOC anhydride (37.51g, 171.87mmol), 4-dimethylaminopyridine (1.05g, 8.59 mmol) and triethylamine (6.66 g, 65.83 mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. The reaction solution was cooled to room temperature, water (500mL) was added, extracted with ethyl acetate (500mL×3), dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain the compound int_34- 7.
LC-MS m/z(ESI)：566.1[M+H] +。 LC-MS m/z (ESI): 566.1 [M+H] + .
步骤8：化合物int_34-8的合成：Step 8: Synthesis of compound int_34-8:
Figure PCTCN2022129961-appb-000160
Figure PCTCN2022129961-appb-000160
将化合物int_34-7(9.30g，16.44mmol)溶于甲醇(120mL)和水(25mL)中，加入铁粉(9.18g，164.43mmol)和氯化铵(8.80g，164.43mmol)。反应液于65℃搅拌反应1小时。反应液冷却至室温，抽滤，用甲醇(200mL)洗涤，减压浓缩。向剩余物中加入水(500mL)，用乙酸乙酯(500mL ×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_34-8Compound int_34-7 (9.30 g, 16.44 mmol) was dissolved in methanol (120 mL) and water (25 mL), and iron powder (9.18 g, 164.43 mmol) and ammonium chloride (8.80 g, 164.43 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. The reaction solution was cooled to room temperature, filtered with suction, washed with methanol (200 mL), and concentrated under reduced pressure. Add water (500mL) to the residue, extract with ethyl acetate (500mL × 3), dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, separate and purify by silica gel chromatography to obtain compound int_34-8
LC-m/z(ESI)：536.1[M+H] +。 LC-m/z (ESI): 536.1 [M+H] + .
步骤9：化合物int_34-9合成：Step 9: Compound int_34-9 synthesis:
Figure PCTCN2022129961-appb-000161
Figure PCTCN2022129961-appb-000161
将化合物int_34-8(2g，3.73mmol)溶于二氯甲烷(50mL)中，加入N，N-二异丙基乙胺(2mL，11.20mmol)。然后在0℃条件下向反应液中加入丙烯酰氯(600μL，7.47mmol)，反应液于25℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_34-9。Compound int_34-8 (2 g, 3.73 mmol) was dissolved in dichloromethane (50 mL), and N,N-diisopropylethylamine (2 mL, 11.20 mmol) was added. Then, acryloyl chloride (600 μL, 7.47 mmol) was added to the reaction solution at 0° C., and the reaction solution was stirred at 25° C. for 1 hour. Add saturated aqueous sodium carbonate solution (50mL) to the reaction solution, extract with dichloromethane (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and then separate by silica gel chromatography Purification afforded compound int_34-9.
LC-MS m/z(ESI)：590.2[M+H] +。 LC-MS m/z (ESI): 590.2 [M+H] + .
步骤10：化合物34合成：Step 10: Synthesis of Compound 34:
Figure PCTCN2022129961-appb-000162
Figure PCTCN2022129961-appb-000162
将化合物int_34-9(1.75g，2.97mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(11mL，148.4mmol)。反应液于25℃搅拌反应1小时。反应液减压浓缩至干得到粗品，再加入饱和碳酸钠水溶液(150mL)，用二氯甲烷(150mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，然后加入二氯甲烷(30mL)于20℃搅拌20分钟打浆得到白色固体化合物34。Compound int_34-9 (1.75 g, 2.97 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (11 mL, 148.4 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product, then added saturated aqueous sodium carbonate solution (150 mL), extracted with dichloromethane (150 mL×3), dried the organic phase with anhydrous magnesium sulfate, filtered with suction, and concentrated the filtrate to dryness under reduced pressure. The crude product was obtained, and dichloromethane (30 mL) was added to stir at 20° C. for 20 minutes to make a slurry to obtain compound 34 as a white solid.
LC-MS m/z(ESI)：490.0[M+H] +。 LC-MS m/z (ESI): 490.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.40(s，1H)，8.42(d，J＝5.0Hz，1H)，8.16(s，1H)，7.87(d，J＝8.6Hz，2H)，7.62-7.50(m，3H)，7.18(d，J＝1.9Hz，1H)，7.11(d，J＝5.0Hz，1H)，6.87-6.77(m，2H)，6.52-6.43(m，1H)，6.35-6.25(m，1H)，5.85-5.75(m，1H)，4.36(d，J＝3.6Hz，2H)，3.58(s，3H)，2.38(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.40(s, 1H), 8.42(d, J=5.0Hz, 1H), 8.16(s, 1H), 7.87(d, J=8.6Hz, 2H) , 7.62-7.50(m, 3H), 7.18(d, J=1.9Hz, 1H), 7.11(d, J=5.0Hz, 1H), 6.87-6.77(m, 2H), 6.52-6.43(m, 1H ), 6.35-6.25 (m, 1H), 5.85-5.75 (m, 1H), 4.36 (d, J=3.6Hz, 2H), 3.58 (s, 3H), 2.38 (s, 3H).
实施例7化合物39的合成The synthesis of embodiment 7 compound 39
Figure PCTCN2022129961-appb-000163
Figure PCTCN2022129961-appb-000163
步骤1：化合物int_39-1合成：Step 1: Synthesis of compound int_39-1:
Figure PCTCN2022129961-appb-000164
Figure PCTCN2022129961-appb-000164
将2-溴-5-羟基苯甲醛(8.00g，39.8mmol)溶于乙腈(130mL)中，加入2-氯嘧啶-4-甲腈(5.55g，39.8mmol)和碳酸钾(11.0g，79.6mmol)，反应液在60℃条件下，搅拌反应16小时。将反应液减压浓缩至干，再经硅胶色谱法分离纯化得到化合物int_39-1。2-Bromo-5-hydroxybenzaldehyde (8.00g, 39.8mmol) was dissolved in acetonitrile (130mL), and 2-chloropyrimidine-4-carbonitrile (5.55g, 39.8mmol) and potassium carbonate (11.0g, 79.6 mmol), the reaction solution was stirred and reacted for 16 hours at 60°C. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_39-1.
1H NMR(400MHz，DMSO-d 6)δ10.20(s，1H)，9.01(d，J＝4.8Hz，1H)，7.99-7.90(m，2H)，7.74(d，J＝2.9Hz，1H)，7.60(dd，J＝2.9，8.7Hz，1H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.20(s, 1H), 9.01(d, J=4.8Hz, 1H), 7.99-7.90(m, 2H), 7.74(d, J=2.9Hz, 1H), 7.60 (dd, J=2.9, 8.7 Hz, 1H).
步骤2：化合物int_39-2合成：Step 2: Synthesis of compound int_39-2:
Figure PCTCN2022129961-appb-000165
Figure PCTCN2022129961-appb-000165
将化合物int_39-1(5.20g，17.1mmol)溶于二氧六环(100mL)中，加入双联嚬哪醇硼酸酯(5.21g，20.5mmol)和醋酸钾(4.20g，42.8mmol)，并置换氮气三次，在氮气保护下加入1，1-双(二苯基磷)二茂铁氯化钯(626.0mg，855.0μmol)，反应物于100℃搅拌反应3小时。反应液过滤，并减压浓缩至干，再经硅胶色谱法分离纯化得到化合物int_39-2。Compound int_39-1 (5.20g, 17.1mmol) was dissolved in dioxane (100mL), bisanalyl borate (5.21g, 20.5mmol) and potassium acetate (4.20g, 42.8mmol) were added, The nitrogen was replaced three times, and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (626.0 mg, 855.0 μmol) was added under the protection of nitrogen, and the reactant was stirred and reacted at 100° C. for 3 hours. The reaction solution was filtered and concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_39-2.
1H NMR(400MHz，CDCl 3)δ10.69(s，1H)，8.79(d，J＝4.8Hz，1H)，8.05(d，J＝8.1Hz，1H)，7.80(d，J＝2.3Hz，1H)，7.46-7.39(m，2H)，1.41(s，12H)。 1 H NMR (400MHz, CDCl 3 ) δ10.69(s, 1H), 8.79(d, J=4.8Hz, 1H), 8.05(d, J=8.1Hz, 1H), 7.80(d, J=2.3Hz , 1H), 7.46-7.39 (m, 2H), 1.41 (s, 12H).
步骤3：化合物int_39-3合成：Step 3: Synthesis of compound int_39-3:
Figure PCTCN2022129961-appb-000166
Figure PCTCN2022129961-appb-000166
将化合物int_1-7(3.00g，8.62mmol)溶于二氧六环(10mL)中，加入化合物int_39-2(4.54g，12.9mmol)和磷酸钾水溶液(2M，8.62mL)，置换氮气三次，在氮气保护下加入[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(626.0mg，855.0μmol)，反应物于100℃搅拌反应1小时。反应液冷却后过滤，滤液减压浓缩至干，再经硅胶色谱法分离纯化得到化合物int_39-3。Compound int_1-7 (3.00g, 8.62mmol) was dissolved in dioxane (10mL), compound int_39-2 (4.54g, 12.9mmol) and potassium phosphate aqueous solution (2M, 8.62mL) were added, nitrogen was replaced three times, [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (626.0 mg, 855.0 μmol) was added under nitrogen protection, and the reactant was stirred at 100° C. for 1 hour. The reaction solution was cooled and filtered, and the filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_39-3.
1H NMR(400MHz，DMSO-d 6)δ8.98(d，J＝4.8Hz，1H)，8.43(d，J＝8.8Hz，2H)，8.25(s，1H)，7.95(d，J＝8.4Hz，2H)，7.90(d，J＝4.8Hz，1H)，7.32(d，J＝2.6Hz，1H)，6.97-6.89(m，1H)，6.79(d，J＝8.7Hz，1H)，5.72-5.66(m，1H)，3.62(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.98(d, J=4.8Hz, 1H), 8.43(d, J=8.8Hz, 2H), 8.25(s, 1H), 7.95(d, J= 8.4Hz, 2H), 7.90(d, J=4.8Hz, 1H), 7.32(d, J=2.6Hz, 1H), 6.97-6.89(m, 1H), 6.79(d, J=8.7Hz, 1H) , 5.72-5.66 (m, 1H), 3.62 (s, 3H).
步骤4：化合物int_39-4合成：Step 4: Synthesis of compound int_39-4:
Figure PCTCN2022129961-appb-000167
Figure PCTCN2022129961-appb-000167
将化合物int_39-3(650.0mg，1.32mmol)溶于四氢呋喃(5mL)中，加入醋酸(75.5μL)和氰基硼氢化钠(415.0mg，6.60mmol)，于25℃搅拌反应1小时。向反应液中加入饱和碳酸氢钠水溶液，调节pH＝7～8，用乙酸乙酯萃取(15mL×3)，有机相合并，用无水硫酸钠进行干燥，过滤，滤液减压浓缩至干，再经硅胶色谱法分离纯化得到化合物int_39-4。Compound int_39-3 (650.0mg, 1.32mmol) was dissolved in tetrahydrofuran (5mL), acetic acid (75.5μL) and sodium cyanoborohydride (415.0mg, 6.60mmol) were added, and the reaction was stirred at 25°C for 1 hour. Add saturated aqueous sodium bicarbonate solution to the reaction solution, adjust the pH=7~8, extract with ethyl acetate (15mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure. The compound int_39-4 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：477.2[M+H] +。 LC-MS m/z (ESI): 477.2 [M+H] + .
步骤5：化合物int_39-5合成：Step 5: Synthesis of compound int_39-5:
Figure PCTCN2022129961-appb-000168
Figure PCTCN2022129961-appb-000168
将化合物int_39-4(400.0mg，0.84mmol)溶于N，N-二甲基甲酰胺(6mL)中，加入Boc酸酐(916.0mg)，4-二甲氨基吡啶(51.3mg)和三乙胺(255.0mg)，反应物于25℃搅拌反应16小时。将反应液减压浓缩至干，再经硅胶色谱法分离纯化得到化合物int_39-5。Compound int_39-4 (400.0 mg, 0.84 mmol) was dissolved in N, N-dimethylformamide (6 mL), and Boc anhydride (916.0 mg), 4-dimethylaminopyridine (51.3 mg) and triethylamine were added (255.0mg), and the reactant was stirred at 25°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_39-5.
LC-MS m/z(ESI)：521.1[M-56+H] +。 LC-MS m/z (ESI): 521.1 [M-56+H] + .
步骤6：化合物int_39-6合成：Step 6: Synthesis of compound int_39-6:
Figure PCTCN2022129961-appb-000169
Figure PCTCN2022129961-appb-000169
将化合物int_39-5(300mg，0.52mmol)溶于甲醇(5mL)中，加入铁粉(290mg，5.20mmol)，氯化铵(278.0mg，5.20mmol)和水(1mL)，反应物于65℃搅拌反应2小时。冷却后过滤，滤液中加入水(10mL)，再用乙酸乙酯萃取(15mL×3)，合并有机相，然后用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干得到粗品化合物int_39-6。Compound int_39-5 (300mg, 0.52mmol) was dissolved in methanol (5mL), iron powder (290mg, 5.20mmol), ammonium chloride (278.0mg, 5.20mmol) and water (1mL) were added, and the reactant was heated at 65° C. The reaction was stirred for 2 hours. After cooling, filter, add water (10mL) to the filtrate, then extract with ethyl acetate (15mL×3), combine the organic phases, then dry with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product compound int_39 -6.
步骤7：化合物int_39-7合成：Step 7: Compound int_39-7 synthesis:
Figure PCTCN2022129961-appb-000170
Figure PCTCN2022129961-appb-000170
将化合物int_39-6(200mg，366μmol)溶于二氯甲烷(3mL)中，加入三乙胺(111mg，1.10mmol)，在0℃条件下加入丙烯酰氯(66.2mg，732.0μmol)，撤去冰浴，恢复到室温，反应物于25℃搅拌反应1小时。反应液减压浓缩至干，再经硅胶色谱法分离纯化得到化合物int_39-7。Compound int_39-6 (200mg, 366μmol) was dissolved in dichloromethane (3mL), triethylamine (111mg, 1.10mmol) was added, acryloyl chloride (66.2mg, 732.0μmol) was added at 0°C, and the ice bath was removed , returned to room temperature, and the reactants were stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_39-7.
LC-MS m/z(ESI)：600.9[M+H] +。 LC-MS m/z (ESI): 600.9 [M+H] + .
步骤8：化合物39合成：Step 8: Synthesis of Compound 39:
Figure PCTCN2022129961-appb-000171
Figure PCTCN2022129961-appb-000171
将化合物int_39-7(89.7mg，149μmol)溶于二氯甲烷中(2mL)中，加入三氟乙酸(51.1mg，448.0mmol)，反应物于25℃搅拌反应1小时。反应液减压浓缩至干，通过C18制备液相色谱纯化得到化合物39。Compound int_39-7 (89.7mg, 149μmol) was dissolved in dichloromethane (2mL), trifluoroacetic acid (51.1mg, 448.0mmol) was added, and the reactant was stirred at 25°C for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, and purified by C18 preparative liquid chromatography to obtain compound 39.
LC-MS m/z(ESI)：501.2[M+H] +。 LC-MS m/z (ESI): 501.2 [M+H] + .
1H NMR(400MHz，CDCl 3)δ8.78(d，J＝4.8Hz，1H)，8.34(s，1H)，7.82(d，J＝8.5Hz，2H)，7.59-7.48(m，3H)，7.39(d，J＝4.8Hz，1H)，7.12(d，J＝2.5Hz，1H)，7.01(d，J＝8.8Hz，1H)，6.86-6.77(m，1H)，6.57-6.48(m，1H)，6.40-6.27(m，1H)，6.20-6.05(m，1H)，5.89-5.83(m，1H)，4.54(d，J＝3.5Hz，2H)，3.72(s，3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.78(d, J=4.8Hz, 1H), 8.34(s, 1H), 7.82(d, J=8.5Hz, 2H), 7.59-7.48(m, 3H) , 7.39(d, J=4.8Hz, 1H), 7.12(d, J=2.5Hz, 1H), 7.01(d, J=8.8Hz, 1H), 6.86-6.77(m, 1H), 6.57-6.48( m, 1H), 6.40-6.27(m, 1H), 6.20-6.05(m, 1H), 5.89-5.83(m, 1H), 4.54(d, J=3.5Hz, 2H), 3.72(s, 3H) .
实施例8化合物42的合成The synthesis of embodiment 8 compound 42
Figure PCTCN2022129961-appb-000172
Figure PCTCN2022129961-appb-000172
步骤1：化合物int_42-2合成：Step 1: Synthesis of compound int_42-2:
Figure PCTCN2022129961-appb-000173
Figure PCTCN2022129961-appb-000173
将2-溴-5-碘苯甲醛(9.40g，30.23mmol)和乙二醇(5.63g，90.70mmol)溶于甲苯(100mL)中，加入对甲苯磺酸(104.1mg，604.6μmol)。反应液于115℃搅拌反应12小时。反应液冷却至室温，向反应液中加入碳酸钾(1g)和水(300mL)，然后用乙酸乙酯萃取(300mL×3)，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_42-2。2-Bromo-5-iodobenzaldehyde (9.40 g, 30.23 mmol) and ethylene glycol (5.63 g, 90.70 mmol) were dissolved in toluene (100 mL), and p-toluenesulfonic acid (104.1 mg, 604.6 μmol) was added. The reaction solution was stirred and reacted at 115° C. for 12 hours. The reaction solution was cooled to room temperature, and potassium carbonate (1g) and water (300mL) were added to the reaction solution, then extracted with ethyl acetate (300mL×3), dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. , separated and purified by silica gel chromatography to obtain compound int_42-2.
步骤2：化合物int_42-3合成：Step 2: Synthesis of compound int_42-3:
Figure PCTCN2022129961-appb-000174
Figure PCTCN2022129961-appb-000174
将化合物int_42-2(7.20g，20.28mmol)和1-甲基-1H-吡唑-3(2H)-酮(2.39g，24.34mmol)溶于二甲亚砜(70mL)中，加入碳酸钾(9.25g，66.94mmol)，1，10-菲啰啉(365.5mg，2.03mmol)和碘化亚铜(772.6mg，4.06mmol)。反应液于120℃搅拌6小时。反应液冷却至室温，加入饱和氯化铵水溶液(500mL)，室温下搅拌30分钟，用乙酸乙酯萃取(500mL×3)，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_42-3。Compound int_42-2 (7.20g, 20.28mmol) and 1-methyl-1H-pyrazol-3(2H)-one (2.39g, 24.34mmol) were dissolved in dimethylsulfoxide (70mL), potassium carbonate was added (9.25g, 66.94mmol), 1,10-phenanthroline (365.5mg, 2.03mmol) and cuprous iodide (772.6mg, 4.06mmol). The reaction solution was stirred at 120°C for 6 hours. The reaction solution was cooled to room temperature, added saturated ammonium chloride aqueous solution (500mL), stirred at room temperature for 30 minutes, extracted with ethyl acetate (500mL×3), combined organic phases were dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was decompressed Concentrate to dryness, separate and purify by silica gel chromatography to obtain compound int_42-3.
LC-MS m/z(ESI)：324.9[M+H] +。 LC-MS m/z (ESI): 324.9 [M+H] + .
步骤3：化合物int_42-4合成：Step 3: Synthesis of compound int_42-4:
Figure PCTCN2022129961-appb-000175
Figure PCTCN2022129961-appb-000175
将化合物int_42-3(1.90g，5.84mmol)和双联嚬哪醇硼酸酯(4.45g，17.53mmol)溶于二氧六环(25mL)中，在氮气保护下加入醋酸钾(1.72g，17.53mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(477.2mg，584.3μmol)，反应液于100℃搅拌反应2小时。反应液冷却至室温，过滤，滤液减压浓缩。向剩余物中加入水(200mL)，用乙酸乙酯萃取(200mL×3)，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_42-4。The compound int_42-3 (1.90g, 5.84mmol) and bisanalyl borate (4.45g, 17.53mmol) were dissolved in dioxane (25mL), and potassium acetate (1.72g, 17.53mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (477.2mg, 584.3μmol), and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Water (200 mL) was added to the residue, extracted with ethyl acetate (200 mL×3), dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by silica gel chromatography to obtain compound int_42-4.
LC-MS m/z(ESI)：373.0[M+H] +。 LC-MS m/z (ESI): 373.0 [M+H] + .
步骤4：化合物int_42-5合成：Step 4: Synthesis of compound int_42-5:
Figure PCTCN2022129961-appb-000176
Figure PCTCN2022129961-appb-000176
将化合物int_1-7(800.0mg，2.30mmol)和化合物int_42-4(1.28g，3.45mmol)溶于N，N-二甲基甲酰胺(35mL)中，在氮气保护下加入磷酸钾水溶液(2M，4.31mL)和[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(149.8mg，229.8μmol)，反应液于100℃搅拌20分钟。反应液冷却至室温，加入水(200mL)，抽滤，用乙酸乙酯(200mL)洗涤，滤饼经减压至干得到化合物int_42-5。Compound int_1-7 (800.0mg, 2.30mmol) and compound int_42-4 (1.28g, 3.45mmol) were dissolved in N,N-dimethylformamide (35mL), and potassium phosphate aqueous solution (2M , 4.31 mL) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (149.8 mg, 229.8 μmol), and the reaction solution was stirred at 100°C for 20 minutes. The reaction solution was cooled to room temperature, water (200 mL) was added, suction filtered, washed with ethyl acetate (200 mL), and the filter cake was decompressed to dryness to obtain compound int_42-5.
LC-MS m/z(ESI)：514.2[M+H] +。 LC-MS m/z (ESI): 514.2 [M+H] + .
步骤5：化合物int_42-6合成：Step 5: Synthesis of compound int_42-6:
Figure PCTCN2022129961-appb-000177
Figure PCTCN2022129961-appb-000177
将化合物int_42-5(1.00g，1.95mmol)溶于四氢呋喃(10mL)中，加入盐酸(3M，1.95mL)，反应液于60℃搅拌2小时。反应液冷却至室温，减压浓缩除去溶剂，得到黄色油状化合物int_42-6。Compound int_42-5 (1.00 g, 1.95 mmol) was dissolved in tetrahydrofuran (10 mL), hydrochloric acid (3M, 1.95 mL) was added, and the reaction solution was stirred at 60° C. for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove the solvent to obtain compound int_42-6 as a yellow oil.
LC-MS m/z(ESI)：470.1[M+H] +。 LC-MS m/z (ESI): 470.1 [M+H] + .
步骤6：化合物int_42-7合成：Step 6: Synthesis of compound int_42-7:
Figure PCTCN2022129961-appb-000178
Figure PCTCN2022129961-appb-000178
将化合物int_42-6(900.0mg，1.92mmol)溶于四氢呋喃(10mL)中，加入氰基硼氢化钠(602.4mg，9.59mmol)和盐酸(3M，1.92mL)，反应液于25℃搅拌反应2小时。向反应液中加入饱和碳酸钠溶液(20mL)使pH＝8，再加入水(10mL)，用乙酸乙酯萃取(30mL×3)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到黄色固体化合物int_42-7。Compound int_42-6 (900.0mg, 1.92mmol) was dissolved in tetrahydrofuran (10mL), sodium cyanoborohydride (602.4mg, 9.59mmol) and hydrochloric acid (3M, 1.92mL) were added, and the reaction solution was stirred at 25°C for reaction 2 Hour. Add saturated sodium carbonate solution (20mL) to the reaction solution to make the pH=8, then add water (10mL), extract with ethyl acetate (30mL×3), dry the organic phase with anhydrous magnesium sulfate, suction filter, and the filtrate Concentrate to dryness under reduced pressure to obtain compound int_42-7 as a yellow solid.
LC-MS m/z(ESI)：454.0[M+H] +。 LC-MS m/z (ESI): 454.0 [M+H] + .
步骤7：化合物int_42-8合成：Step 7: Synthesis of compound int_42-8:
Figure PCTCN2022129961-appb-000179
Figure PCTCN2022129961-appb-000179
将化合物int_42-7(800.0mg，1.76mmol)溶于N，N-二甲基甲酰胺(10mL)中，加入BOC酸酐(3.85g，17.64mmol)，4-二甲氨基吡啶(107.8mg，882.1μmol)和三乙胺(714.1mg，7.06mmol)。反应液于50℃搅拌反应2小时。反应液冷却至室温，加入水(30mL)，用乙酸乙酯萃取(30mL×3)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到化合物int_42-8。Compound int_42-7 (800.0 mg, 1.76 mmol) was dissolved in N, N-dimethylformamide (10 mL), BOC anhydride (3.85 g, 17.64 mmol), 4-dimethylaminopyridine (107.8 mg, 882.1 μmol) and triethylamine (714.1mg, 7.06mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. The reaction solution was cooled to room temperature, water (30 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_42-8.
LC-MS m/z(ESI)：554.1[M+H] +。 LC-MS m/z (ESI): 554.1 [M+H] + .
步骤8：化合物int_42-9合成：Step 8: Synthesis of compound int_42-9:
Figure PCTCN2022129961-appb-000180
Figure PCTCN2022129961-appb-000180
将化合物int_42-8(800.0mg，1.45mmol)溶于甲醇(15mL)和水(3mL)中，加入铁粉(807.1mg，14.5mmol)和氯化铵(773.1mg，14.5mmol)。反应液于50℃搅拌反应2小时。反应液冷却至室温，抽滤，滤渣用二氯甲烷(50mL)洗涤，滤液减压浓缩。向剩余物中加入水(50mL)，用乙酸乙酯萃取(50mL×3)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_42-9。Compound int_42-8 (800.0 mg, 1.45 mmol) was dissolved in methanol (15 mL) and water (3 mL), and iron powder (807.1 mg, 14.5 mmol) and ammonium chloride (773.1 mg, 14.5 mmol) were added. The reaction solution was stirred and reacted at 50° C. for 2 hours. The reaction solution was cooled to room temperature, suction filtered, the filter residue was washed with dichloromethane (50 mL), and the filtrate was concentrated under reduced pressure. Add water (50mL) to the residue, extract with ethyl acetate (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain compound int_42 -9.
LC-MS m/z(ESI)：524.1[M+H] +。 LC-MS m/z (ESI): 524.1 [M+H] + .
步骤9：化合物int_42-10合成：Step 9: Compound int_42-10 synthesis:
Figure PCTCN2022129961-appb-000181
Figure PCTCN2022129961-appb-000181
将化合物int_42-9(300.0mg，572.9μmol)溶于二氯甲烷(10mL)中，在0℃下加入三乙胺(173.9mg，1.72mmol)和丙烯酰氯(103.7mg，1.15mmol)。反应液于25℃搅拌反应1小时。反应液升至室温，加入饱和碳酸钠(15mL)使pH＝8，加入水(30mL)，用二氯甲烷萃取3次(50mL×3)，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_42-10。Compound int_42-9 (300.0 mg, 572.9 μmol) was dissolved in dichloromethane (10 mL), and triethylamine (173.9 mg, 1.72 mmol) and acryloyl chloride (103.7 mg, 1.15 mmol) were added at 0°C. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was raised to room temperature, added saturated sodium carbonate (15 mL) to make the pH = 8, added water (30 mL), extracted 3 times with dichloromethane (50 mL×3), dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was decompressed Concentrate to dryness, separate and purify by silica gel chromatography to obtain compound int_42-10.
LC-MS m/z(ESI)：578.1[M+H] +。 LC-MS m/z (ESI): 578.1 [M+H] + .
步骤10：化合物42合成：Step 10: Synthesis of Compound 42:
Figure PCTCN2022129961-appb-000182
Figure PCTCN2022129961-appb-000182
将化合物int_42-10(260.0mg，450.1μmol)溶于二氯甲烷(3.5mL)中，加入三氟乙酸(3.08g，27.01mmol)。反应液于30℃搅拌反应2小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(15mL)使pH＝8，用二氯甲烷萃取(15mL×3)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经制备液相色谱纯化得到化合物42。Compound int_42-10 (260.0 mg, 450.1 μmol) was dissolved in dichloromethane (3.5 mL), and trifluoroacetic acid (3.08 g, 27.01 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate (15mL) to make the pH=8, extract with dichloromethane (15mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and depressurize the filtrate Concentrate to dryness and purify by preparative liquid chromatography to obtain compound 42.
LC-MS m/z(ESI)：478.2[M+H] +。 LC-MS m/z (ESI): 478.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δppm 10.38(s，1H)8.15(s，1H)7.85(d，J＝8.56Hz，2H)7.59(d，J＝2.20Hz，1H)7.52(br d，J＝8.44Hz，3H)7.02(d，J＝2.57Hz，1H)6.74-6.83(m，1H)6.64-6.72(m，1H)6.41-6.55(m，1H)6.27-6.36(m，1H)5.72-5.90(m，2H)4.31(br d，J＝3.06Hz，2H)3.71(s，3H)3.57(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.38(s, 1H) 8.15(s, 1H) 7.85(d, J=8.56Hz, 2H) 7.59(d, J=2.20Hz, 1H) 7.52(br d , J=8.44Hz, 3H) 7.02(d, J=2.57Hz, 1H) 6.74-6.83(m, 1H) 6.64-6.72(m, 1H) 6.41-6.55(m, 1H) 6.27-6.36(m, 1H ) 5.72-5.90 (m, 2H) 4.31 (br d, J=3.06Hz, 2H) 3.71 (s, 3H) 3.57 (s, 3H).
实施例9化合物88的合成The synthesis of embodiment 9 compound 88
Figure PCTCN2022129961-appb-000183
Figure PCTCN2022129961-appb-000183
步骤1：化合物int_88-2合成：Step 1: Synthesis of compound int_88-2:
Figure PCTCN2022129961-appb-000184
Figure PCTCN2022129961-appb-000184
将2，5-二溴-4-甲基吡啶(5.0g，19.93mmol)和叔丁基二甲硅烷基乙炔(3.04mL，21.92mmol)溶于N，N-二甲基甲酰胺(25mL)中，加入三乙胺(8.32mL，59.79mmol)，碘化亚铜(759.01mg，3.99mmol)和二氯双(三苯基膦)钯(II)(1.40g，1.99mmol)。置换三次氮气，反应液于50℃搅拌反应2小时。冷却后往反应液中加入水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_88-2。2,5-Dibromo-4-methylpyridine (5.0 g, 19.93 mmol) and tert-butyldimethylsilylacetylene (3.04 mL, 21.92 mmol) were dissolved in N,N-dimethylformamide (25 mL) , triethylamine (8.32 mL, 59.79 mmol), cuprous iodide (759.01 mg, 3.99 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.40 g, 1.99 mmol) were added. Nitrogen was replaced three times, and the reaction solution was stirred and reacted at 50° C. for 2 hours. After cooling, water (50mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_88-2 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：312.2[M+H] +。 LC-MS m/z (ESI): 312.2 [M+H] + .
步骤2：化合物int_88-3合成：Step 2: Synthesis of compound int_88-3:
Figure PCTCN2022129961-appb-000185
Figure PCTCN2022129961-appb-000185
将化合物int_88-2(5.0g，16.11mmol)和双联嚬哪醇硼酸酯(12.28g，48.34mmol)溶于二氧六环(30mL)中，加入醋酸钾(4.74g，48.34mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(1.32g，1.16mmol)。反应液于100℃搅拌反应1小时。冷却后往反应液中加入水(50mL)，混合液用乙酸乙酯(50mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_88-3。Compound int_88-2 (5.0g, 16.11mmol) and bisanalyl borate (12.28g, 48.34mmol) were dissolved in dioxane (30mL), potassium acetate (4.74g, 48.34mmol) was added and 1,1-Bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (1.32g, 1.16mmol). The reaction solution was stirred and reacted at 100° C. for 1 hour. After cooling, water (50mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (50mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_88-3 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：276.0[M+H] +。 LC-MS m/z (ESI): 276.0 [M+H] + .
步骤3：化合物int_88-4合成：Step 3: Compound int_88-4 synthesis:
Figure PCTCN2022129961-appb-000186
Figure PCTCN2022129961-appb-000186
将化合物int_1-6(1.62g，4.60mmol)和化合物int_88-3(3.8g，6.90mmol)溶于四氢呋喃(80mL)中，加入磷酸钾水溶液(2M，40mL，80.00mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(375.84mg，460.23μmol)。反应液于70℃搅拌反应5小时。冷却后往反应液中加入水(100mL)，混合液用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_88-4。Compound int_1-6 (1.62g, 4.60mmol) and compound int_88-3 (3.8g, 6.90mmol) were dissolved in tetrahydrofuran (80mL), potassium phosphate aqueous solution (2M, 40mL, 80.00mmol) and 1,1-bis (Diphenylphosphine)ferrocenepalladium chloride dichloromethane mixture (375.84 mg, 460.23 μmol). The reaction solution was stirred and reacted at 70° C. for 5 hours. After cooling, water (100mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (100mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_88-4 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：456.0[M+H] +。 LC-MS m/z (ESI): 456.0 [M+H] + .
步骤4：化合物int_88-5合成：Step 4: Compound int_88-5 synthesis:
Figure PCTCN2022129961-appb-000187
Figure PCTCN2022129961-appb-000187
将化合物int_88-4(200mg，438.16μmol)和化合物int_1-3(222.93mg，657.24μmol)溶于四氢呋喃(3mL)中，加入磷酸钾水溶液(2M，1.1mL，2.18mmol)，2-二环己基磷-2，4，6-三异丙基联苯(20.89mg，43.82μmol)和(2-二环己基膦-2，4，6-三异丙基-1，1-联苯)[2-(2-氨基-1，1-联苯)](37.09mg，43.82μmol)。反应液于100℃搅拌反应0.5小时。冷却后往反应液中加入水(20mL)，混合液用乙酸乙酯(20mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_88-5。Compound int_88-4 (200 mg, 438.16 μmol) and compound int_1-3 (222.93 mg, 657.24 μmol) were dissolved in tetrahydrofuran (3 mL), potassium phosphate aqueous solution (2M, 1.1 mL, 2.18 mmol), 2-dicyclohexyl Phosphorus-2,4,6-triisopropylbiphenyl (20.89mg, 43.82μmol) and (2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)[2 -(2-Amino-1,1-biphenyl)] (37.09 mg, 43.82 μmol). The reaction solution was stirred and reacted at 100°C for 0.5 hours. After cooling, water (20mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (20mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_88-5 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：589.2[M+H] +。 LC-MS m/z (ESI): 589.2 [M+H] + .
步骤5：化合物int_88-6合成：Step 5: Synthesis of compound int_88-6:
Figure PCTCN2022129961-appb-000188
Figure PCTCN2022129961-appb-000188
将化合物int_88-5(120mg，203.81μmol)溶于乙腈(6mL)和四氢呋喃(2mL)中，加入醋酸(58μL，1.02mmol)和氰基硼氢化钠(64.04.mg，1.02mmol)。反应液于40℃搅拌反应12小时。冷却后往反应液中加入饱和碳酸钠水溶液(25mL)，调pH至8，减压浓缩去除乙腈，混合液中加入水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_88-6。Compound int_88-5 (120mg, 203.81μmol) was dissolved in acetonitrile (6mL) and tetrahydrofuran (2mL), and acetic acid (58μL, 1.02mmol) and sodium cyanoborohydride (64.04.mg, 1.02mmol) were added. The reaction solution was stirred and reacted at 40° C. for 12 hours. After cooling, add saturated aqueous sodium carbonate solution (25 mL) to the reaction solution, adjust the pH to 8, concentrate under reduced pressure to remove acetonitrile, add water (10 mL) to the mixture, extract with ethyl acetate (10 mL×3), combine the organic phases, After drying with anhydrous magnesium sulfate, suction filtration, the filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_88-6.
LC-MS m/z(ESI)：573.2[M+H] +。 LC-MS m/z (ESI): 573.2 [M+H] + .
步骤6：化合物88合成：Step 6: Synthesis of compound 88:
Figure PCTCN2022129961-appb-000189
Figure PCTCN2022129961-appb-000189
将化合物int_88-6(57mg，99.52μmol)溶于四氢呋喃(6mL)中，加入四丁基氟化铵(1M，199μL，199μmol)。反应液于25℃搅拌反应1小时。往反应液中加入水(30mL)，混合液用乙酸乙酯(30 mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经制备液相色谱纯化得到化合物88。Compound int_88-6 (57 mg, 99.52 μmol) was dissolved in tetrahydrofuran (6 mL), and tetrabutylammonium fluoride (1M, 199 μL, 199 μmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. Water (30 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (30 mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then prepared by Purification by phase chromatography afforded compound 88.
LC-MS m/z(ESI)：459.1[M+H] +。 LC-MS m/z (ESI): 459.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.62(s，1H)，8.21(s，1H)，7.76-7.68(m，2H)，7.65(br s，1H)，7.15(d，J＝2.3Hz，1H)，6.98(d，J＝7.3Hz，1H)，6.84-6.77(m，1H)，6.74(d，J＝8.1Hz，1H)，6.66(d，J＝8.6Hz，1H)，4.47(s，1H)，4.35(br d，J＝1.6Hz，2H)，3.48(s，3H)，2.30(s，3H)，2.15(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.62(s, 1H), 8.21(s, 1H), 7.76-7.68(m, 2H), 7.65(br s, 1H), 7.15(d, J= 2.3Hz, 1H), 6.98(d, J=7.3Hz, 1H), 6.84-6.77(m, 1H), 6.74(d, J=8.1Hz, 1H), 6.66(d, J=8.6Hz, 1H) , 4.47(s, 1H), 4.35(br d, J=1.6Hz, 2H), 3.48(s, 3H), 2.30(s, 3H), 2.15(s, 3H).
实施例10化合物139的合成The synthesis of embodiment 10 compound 139
Figure PCTCN2022129961-appb-000190
Figure PCTCN2022129961-appb-000190
步骤1：化合物int_139-1合成：Step 1: Synthesis of compound int_139-1:
Figure PCTCN2022129961-appb-000191
Figure PCTCN2022129961-appb-000191
将化合物int_2-1(300g，1.22mol)和2-氟-6-甲基吡啶(680g，6.12mol)溶于N，N-二甲基甲酰 胺(1.5L)中，加入碳酸铯(638g，1.96mol)。反应液于120℃(外温)搅拌16小时。反应液冷却至室温，将反应液连同固体残渣倒入水(4.5L)，用乙酸乙酯(2L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_139-1。Compound int_2-1 (300g, 1.22mol) and 2-fluoro-6-picoline (680g, 6.12mol) were dissolved in N,N-dimethylformamide (1.5L), cesium carbonate (638g, 1.96mol). The reaction solution was stirred at 120°C (external temperature) for 16 hours. The reaction solution was cooled to room temperature, the reaction solution and the solid residue were poured into water (4.5L), extracted with ethyl acetate (2L×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. , separated and purified by silica gel chromatography to obtain compound int_139-1.
LC-MS m/z(ESI)：335.9[M+H] +。 LC-MS m/z (ESI): 335.9 [M+H] + .
步骤2：化合物int_139-2合成：Step 2: Synthesis of compound int_139-2:
Figure PCTCN2022129961-appb-000192
Figure PCTCN2022129961-appb-000192
将化合物int_139-1(77g，229.0mmol)和化合物双联频哪醇硼酸酯(87g，343.5mmol)溶于二氧六环(700mL)中，在氮气保护下加入醋酸钾(67g，687.1mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(9.35g，11.5mmol)，反应液于110℃(外温)100℃(内温)搅拌16小时。反应液冷却至室温，过滤。向滤液中加入饱和食盐水(1L)，用乙酸乙酯(1L×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_139-2。Compound int_139-1 (77g, 229.0mmol) and compound double pinacol borate (87g, 343.5mmol) were dissolved in dioxane (700mL), and potassium acetate (67g, 687.1mmol) was added under nitrogen protection ) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (9.35g, 11.5mmol), the reaction solution was stirred at 110°C (external temperature) and 100°C (internal temperature) for 16 hours. The reaction solution was cooled to room temperature and filtered. Saturated brine (1L) was added to the filtrate, extracted with ethyl acetate (1L×3), dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain compound int_139-2 .
LC-MS m/z(ESI)：384.0[M+H] +。 LC-MS m/z (ESI): 384.0 [M+H] + .
步骤3：化合物int_139-3合成：Step 3: Synthesis of compound int_139-3:
Figure PCTCN2022129961-appb-000193
Figure PCTCN2022129961-appb-000193
将化合物int_1-7(80g，229.78mmol)和化合物int_139-2(132.09g，344.67mmol)溶于N，N-二甲基甲酰胺(800mL)中，在氮气保护下加入磷酸钾水溶液(2M，230mL)和[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(10.48g，16.08mmol)，反应液于100℃(内温)搅拌1小时。反应液冷却至室温，将反应液慢慢倒入水(2L)中，有大量固体析出，用乙酸乙酯(500mL×3)萃取，有机相直接打浆纯化得到黄色固体化合物int_139-3。Compound int_1-7 (80g, 229.78mmol) and compound int_139-2 (132.09g, 344.67mmol) were dissolved in N,N-dimethylformamide (800mL), and potassium phosphate aqueous solution (2M, 230 mL) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (10.48 g, 16.08 mmol), and the reaction solution was stirred at 100°C (internal temperature) for 1 hour. The reaction solution was cooled to room temperature, and the reaction solution was slowly poured into water (2L), a large amount of solids precipitated, extracted with ethyl acetate (500mL×3), and the organic phase was directly beaten and purified to obtain a yellow solid compound int_139-3.
LC-MS m/z(ESI)：525.4[M+H] +。 LC-MS m/z (ESI): 525.4 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.30-8.14(m，3H)，7.75(br t，J＝7.5Hz，1H)，7.64(br d，J＝8.3Hz，2H)，7.33-7.18(m，2H)，7.15-6.97(m，2H)，6.82(br d，J＝8.3Hz，1H)，5.57(s，1H)，4.01-3.66(m，7H)，2.33(br s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.30-8.14 (m, 3H), 7.75 (br t, J=7.5Hz, 1H), 7.64 (br d, J=8.3Hz, 2H), 7.33- 7.18(m, 2H), 7.15-6.97(m, 2H), 6.82(br d, J=8.3Hz, 1H), 5.57(s, 1H), 4.01-3.66(m, 7H), 2.33(br s, 3H).
步骤4：化合物int_139-4合成：Step 4: Synthesis of compound int_139-4:
Figure PCTCN2022129961-appb-000194
Figure PCTCN2022129961-appb-000194
将化合物int_139-3(60g，114.39mmol)溶于四氢呋喃(200mL)中，加入盐酸(3M，115mL)，反应液于60℃(外温)搅拌1小时。得到化合物int_139-4的反应液，不经任何处理直接用于下一步。Compound int_139-3 (60g, 114.39mmol) was dissolved in tetrahydrofuran (200mL), hydrochloric acid (3M, 115mL) was added, and the reaction solution was stirred at 60°C (external temperature) for 1 hour. The reaction solution of compound int_139-4 was obtained, which was directly used in the next step without any treatment.
LC-MS m/z(ESI)：481.2[M+H] +。 LC-MS m/z (ESI): 481.2 [M+H] + .
步骤5：化合物int_139-5合成：Step 5: Synthesis of compound int_139-5:
Figure PCTCN2022129961-appb-000195
Figure PCTCN2022129961-appb-000195
将上一步化合物int_139-4的反应液用四氢呋喃(500mL)稀释，将反应液冷却至-10℃，分批缓慢加入氰基硼氢化钠(21.58g，343.41mmol)，反应液于25℃(外温)搅拌反应1小时。向反应液中慢慢加入饱和碳酸钠溶液(2L)调至碱性，用乙酸乙酯(1L×3)萃取，有机相合并用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，滤渣用乙酸乙酯(100mL)打浆纯化得到黄色固体化合物int_139-5。The reaction solution of compound int_139-4 in the previous step was diluted with tetrahydrofuran (500mL), the reaction solution was cooled to -10°C, and sodium cyanoborohydride (21.58g, 343.41mmol) was slowly added in batches, and the reaction solution was heated at 25°C (external temperature) and stirred for 1 hour. Slowly add saturated sodium carbonate solution (2L) to the reaction solution to make it alkaline, extract with ethyl acetate (1L×3), combine the organic phases and dry them with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure , the filter residue was purified by slurrying with ethyl acetate (100 mL) to obtain compound int_139-5 as a yellow solid.
LC-MS m/z(ESI)：465.3[M+H] +。 LC-MS m/z (ESI): 465.3 [M+H] + .
步骤6：化合物int_139-6合成：Step 6: Synthesis of compound int_139-6:
Figure PCTCN2022129961-appb-000196
Figure PCTCN2022129961-appb-000196
将化合物int_139-5(32g，68.90mmol)溶于N，N-二甲基甲酰胺(300mL)中，加入BOC酸酐(150.36g，688.95mmol)，4-二甲氨基吡啶(4.21g，34.45mmol)和三乙胺(28.8mL，206.69mmol)。反应液于50℃(外温)搅拌反应1小时。反应液冷却至室温，加入水(600mL)，用乙酸乙酯(500mL×3)萃取，有机相合并用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_139-6。Compound int_139-5 (32g, 68.90mmol) was dissolved in N, N-dimethylformamide (300mL), BOC anhydride (150.36g, 688.95mmol), 4-dimethylaminopyridine (4.21g, 34.45mmol ) and triethylamine (28.8 mL, 206.69 mmol). The reaction solution was stirred and reacted at 50° C. (external temperature) for 1 hour. The reaction solution was cooled to room temperature, added water (600mL), extracted with ethyl acetate (500mL×3), the organic phases were combined and dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography Compound int_139-6 was obtained.
LC-MS m/z(ESI)：565.2[M+H] +。 LC-MS m/z (ESI): 565.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.67(s，1H)，8.43(br d，J＝8.7Hz，2H)，7.94(br d，J＝7.7Hz，2H)，7.72(t，J＝7.8Hz，1H)，7.09(d，J＝2.3Hz，1H)，7.01(d，J＝7.3Hz，1H)，6.89-6.81(m，1H)，6.77(t，J＝8.6Hz，2H)，5.16(br d，J＝12.8Hz，1H)，4.59(br d，J＝14.1Hz，1H)，3.68(s，3H)，2.30(s，3H)，1.39(s，9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.67(s, 1H), 8.43(br d, J=8.7Hz, 2H), 7.94(br d, J=7.7Hz, 2H), 7.72(t, J=7.8Hz, 1H), 7.09(d, J=2.3Hz, 1H), 7.01(d, J=7.3Hz, 1H), 6.89-6.81(m, 1H), 6.77(t, J=8.6Hz, 2H), 5.16 (br d, J=12.8Hz, 1H), 4.59 (br d, J=14.1Hz, 1H), 3.68 (s, 3H), 2.30 (s, 3H), 1.39 (s, 9H).
步骤7：化合物int_139-7合成：Step 7: Synthesis of compound int_139-7:
Figure PCTCN2022129961-appb-000197
Figure PCTCN2022129961-appb-000197
将化合物int_139-6(25g，44.28mmol)溶于甲醇(1L)和水(200mL)中，加入还原铁粉(49.46g，885.60mmol)和氯化铵(23.69g，442.80mmol)。反应液于65℃(外温)搅拌反应2小时。反应液冷却至室温，抽滤，用甲醇(500mL)洗涤，滤液减压浓缩。向剩余物中加入水(500mL)，用乙酸乙酯(500mL×3)萃取，有机相合并用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到黄色固体化合物int_139-7。Compound int_139-6 (25g, 44.28mmol) was dissolved in methanol (1L) and water (200mL), and reduced iron powder (49.46g, 885.60mmol) and ammonium chloride (23.69g, 442.80mmol) were added. The reaction solution was stirred and reacted at 65° C. (external temperature) for 2 hours. The reaction solution was cooled to room temperature, suction filtered, washed with methanol (500 mL), and the filtrate was concentrated under reduced pressure. Water (500 mL) was added to the residue, extracted with ethyl acetate (500 mL×3), the organic phases were combined and dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_139-7 as a yellow solid.
LC-MS m/z(ESI)：535.1[M+H] +。 LC-MS m/z (ESI): 535.1 [M+H] + .
步骤8：化合物int_139-8合成：Step 8: Synthesis of compound int_139-8:
Figure PCTCN2022129961-appb-000198
Figure PCTCN2022129961-appb-000198
将化合物int_139-7(870mg，1.63mmol)溶于二氧六环(18mL)中，加入三乙胺(1.5mL，9.76mmol)。然后加入三正丙基环磷酸酐50％乙酸乙酯溶液(6mL，9.76mmol)和(2E)-4-(二甲氨基)-2-油酸(870.0mg，6.74mmol)，反应液于100℃搅拌反应10分钟。冷却后向反应液中加入饱和碳酸钠溶液(20mL)，用二氯甲烷(20mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_139-8。Compound int_139-7 (870 mg, 1.63 mmol) was dissolved in dioxane (18 mL), and triethylamine (1.5 mL, 9.76 mmol) was added. Then add tri-n-propyl cyclic phosphoric anhydride 50% ethyl acetate solution (6mL, 9.76mmol) and (2E)-4-(dimethylamino)-2-oleic acid (870.0mg, 6.74mmol), the reaction solution was dissolved in 100 The reaction was stirred at °C for 10 minutes. After cooling, a saturated sodium carbonate solution (20 mL) was added to the reaction solution, extracted with dichloromethane (20 mL×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by silica gel chromatography. Compound int_139-8 was obtained by separation and purification.
LC-MS m/z(ESI)：646.2[M+H] +。 LC-MS m/z (ESI): 646.2 [M+H] + .
步骤9：化合物139合成：Step 9: Synthesis of compound 139:
Figure PCTCN2022129961-appb-000199
Figure PCTCN2022129961-appb-000199
将化合物int_139-8(400mg，619.44μmol)溶于二氯甲烷(5mL)中，加入三氟乙酸(2.5mL，30.97mmol)。反应液于25℃搅拌反应1小时。反应液减压浓缩至干得到粗品，向反应液中加入饱和碳酸钠(150mL)，用二氯甲烷(150mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，经硅胶色谱法分离纯化得到化合物139。Compound int_139-8 (400 mg, 619.44 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2.5 mL, 30.97 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product, saturated sodium carbonate (150 mL) was added to the reaction solution, extracted with dichloromethane (150 mL×3), the organic phase was dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure Dry to dryness to obtain a crude product, which is separated and purified by silica gel chromatography to obtain compound 139.
LC-MS m/z(ESI)：568.1[M+Na] +。 LC-MS m/z (ESI): 568.1 [M+Na] + .
1H NMR(400MHz，DMSO-d 6)δ10.30(s，1H)，8.16(s，1H)，7.85(d，J＝8.4Hz，2H)，7.69(t，J＝7.8Hz，1H)，7.61-7.48(m，3H)，7.09(d，J＝2.4Hz，1H)，6.97(d，J＝7.4Hz，1H)，6.87-6.69(m，4H)，6.31(d，J＝15.8Hz，1H)，4.34(s，2H)，3.58(s，3H)，3.07(d，J＝4.8Hz，2H)，2.30(s，3H)，2.19(s，6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.30(s, 1H), 8.16(s, 1H), 7.85(d, J=8.4Hz, 2H), 7.69(t, J=7.8Hz, 1H) , 7.61-7.48(m, 3H), 7.09(d, J=2.4Hz, 1H), 6.97(d, J=7.4Hz, 1H), 6.87-6.69(m, 4H), 6.31(d, J=15.8 Hz, 1H), 4.34(s, 2H), 3.58(s, 3H), 3.07(d, J=4.8Hz, 2H), 2.30(s, 3H), 2.19(s, 6H).
实施例11化合物141的合成The synthesis of embodiment 11 compound 141
Figure PCTCN2022129961-appb-000200
Figure PCTCN2022129961-appb-000200
步骤1：化合物int_141-1合成：Step 1: Synthesis of compound int_141-1:
Figure PCTCN2022129961-appb-000201
Figure PCTCN2022129961-appb-000201
将化合物int_1-6(2g，5.67mmol)和3-硝基苯硼酸嚬哪醇酯(1.41g，5.67mmol)溶于四氢呋喃(30mL)中，在氮气保护下加入[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(462.74mg，566.64μmol)和磷酸钾水溶液(2M，20mL)。反应液于60℃搅拌反应3小时。将反应液过滤，滤渣用乙醇(200mL)洗涤滤饼收集并旋干得到黄色固体化合物int_141-1。The compound int_1-6 (2g, 5.67mmol) and 3-nitrophenylboronic acid analcohol ester (1.41g, 5.67mmol) were dissolved in tetrahydrofuran (30mL), and [1,1-bis(di Phenylphosphino)ferrocene]palladium dichloride in dichloromethane (462.74 mg, 566.64 μmol) and aqueous potassium phosphate (2M, 20 mL). The reaction solution was stirred and reacted at 60° C. for 3 hours. The reaction solution was filtered, and the filter residue was washed with ethanol (200 mL) to collect the filter cake and spin-dried to obtain a yellow solid compound int_141-1.
LC-MS m/z(ESI)：347.9[M+H] +。 LC-MS m/z (ESI): 347.9 [M+H] + .
步骤2：化合物int_141-2合成：Step 2: Synthesis of compound int_141-2:
Figure PCTCN2022129961-appb-000202
Figure PCTCN2022129961-appb-000202
将化合物int_141-1(2.1g，5.13mmol)和化合物int_1-3(2.09g，6.15mmol)溶于四氢呋喃(21mL)中，在氮气保护下加入双(三环己基膦基)二氯化钯(II)(378.47mg，512.70μmol)和磷酸钾水溶液(2M，4.20mL)。反应液于100℃搅拌反应30分钟。冷却后向反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_141-2。Compound int_141-1 (2.1g, 5.13mmol) and compound int_1-3 (2.09g, 6.15mmol) were dissolved in tetrahydrofuran (21mL), and bis(tricyclohexylphosphino)palladium dichloride was added under nitrogen protection ( II) (378.47 mg, 512.70 μmol) and aqueous potassium phosphate (2M, 4.20 mL). The reaction solution was stirred and reacted at 100° C. for 30 minutes. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was subjected to silica gel chromatography Compound int_141-2 was obtained by separation and purification.
LC-MS m/z(ESI)：481.2[M+H] +。 LC-MS m/z (ESI): 481.2 [M+H] + .
步骤3：化合物int_141-3合成：Step 3: Synthesis of compound int_141-3:
Figure PCTCN2022129961-appb-000203
Figure PCTCN2022129961-appb-000203
将化合物int_141-2(917mg，1.91mmol)溶于乙腈(19mL)和乙酸(556μL，9.54mmol)中，加入氰基硼氢化钠(599.68mg，9.54mmol)。反应液于25℃搅拌反应16小时。向反应液中加入饱和碳酸钠水溶液(10mL)，再加入水(30mL)，用乙酸乙酯(30mL×3)萃取，有机相用无水硫酸镁进 行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_141-3。Compound int_141-2 (917 mg, 1.91 mmol) was dissolved in acetonitrile (19 mL) and acetic acid (556 μL, 9.54 mmol), and sodium cyanoborohydride (599.68 mg, 9.54 mmol) was added. The reaction solution was stirred and reacted at 25°C for 16 hours. Add saturated aqueous sodium carbonate solution (10mL) to the reaction solution, then add water (30mL), extract with ethyl acetate (30mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure The crude product was obtained, and the crude product was separated and purified by silica gel chromatography to obtain compound int_141-3.
LC-MS m/z(ESI)：465.1[M+H] +。 LC-MS m/z (ESI): 465.1 [M+H] + .
步骤4：化合物int_141-4合成：Step 4: Synthesis of compound int_141-4:
Figure PCTCN2022129961-appb-000204
Figure PCTCN2022129961-appb-000204
将化合物int_141-3(444mg，955.92μmol)溶于N，N-二甲基甲酰胺(8.5mL)中，加入三乙胺(399μL，2.87μmol)和BOC酸酐(2.20mL，9.56mmol)，二甲氨基吡啶(58.39mg，478μmol)，反应液于50℃搅拌反应16小时。反应液减压浓缩至干，将反应液倒入水(30mL)，用二氯甲烷(30mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，粗品经硅胶色谱法分离纯化得到化合物int_141-4。Compound int_141-3 (444 mg, 955.92 μmol) was dissolved in N,N-dimethylformamide (8.5 mL), triethylamine (399 μL, 2.87 μmol) and BOC anhydride (2.20 mL, 9.56 mmol) were added, and two Aminopyridine (58.39mg, 478μmol), the reaction solution was stirred at 50°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, the reaction solution was poured into water (30mL), extracted with dichloromethane (30mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, the crude product Compound int_141-4 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：565.2[M+H] +。 LC-MS m/z (ESI): 565.2 [M+H] + .
步骤5：化合物int_141-5合成：Step 5: Synthesis of compound int_141-5:
Figure PCTCN2022129961-appb-000205
Figure PCTCN2022129961-appb-000205
将化合物int_141-4(400mg，708.48μ，mol)溶于甲醇(6mL)和水(1.2mL)中，加入铁粉(395.65mg，7.08mmol)和氯化铵(378.97mg，7.08mmol)。反应液于65℃搅拌反应1小时。反应液冷却后过滤并减压浓缩至干得到粗品。向反应液中加入水(40mL)和乙酸乙酯(40mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品化合物int_141-5。Compound int_141-4 (400 mg, 708.48 μ, mol) was dissolved in methanol (6 mL) and water (1.2 mL), and iron powder (395.65 mg, 7.08 mmol) and ammonium chloride (378.97 mg, 7.08 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. After cooling, the reaction solution was filtered and concentrated to dryness under reduced pressure to obtain a crude product. Water (40 mL) and ethyl acetate (40 mL×3) were added to the reaction solution for extraction, the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude compound int_141-5.
LC-MS m/z(ESI)：535.2[M+H] +。 LC-MS m/z (ESI): 535.2 [M+H] + .
步骤6：化合物int_141-6合成：Step 6: Synthesis of compound int_141-6:
Figure PCTCN2022129961-appb-000206
Figure PCTCN2022129961-appb-000206
将化合物int_141-5(400mg，748.21μmol)溶于二氯甲烷(11mL)中，加入N，N-二异丙基乙胺(391μL，2.24mmol)。然后在0℃条件下向反应液中加入丙烯酰氯(122μL，1.5mmol)，反应液于25℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取3次，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到黄色固体化合物int_141-6。Compound int_141-5 (400 mg, 748.21 μmol) was dissolved in dichloromethane (11 mL), and N,N-diisopropylethylamine (391 μL, 2.24 mmol) was added. Then, acryloyl chloride (122 μL, 1.5 mmol) was added to the reaction solution at 0° C., and the reaction solution was stirred at 25° C. for 1 hour. Add saturated aqueous sodium carbonate solution (50mL) to the reaction solution, extract 3 times with dichloromethane (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain a yellow solid compound int_141 -6.
LC-MS m/z(ESI)：589.2[M+H] +。 LC-MS m/z (ESI): 589.2 [M+H] + .
步骤7：化合物141合成：Step 7: Synthesis of Compound 141:
Figure PCTCN2022129961-appb-000207
Figure PCTCN2022129961-appb-000207
将化合物int_141-6(400mg，679.52μmol)溶于二氯甲烷(6.5mL)中，加入三氟乙酸(2.52mL，33.98mmol)。反应液于25℃搅拌反应1小时。反应液减压浓缩至干得到粗品，再加入饱和碳酸钠(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，经制备液相色谱纯化得到白色固体化合物141。Compound int_141-6 (400 mg, 679.52 μmol) was dissolved in dichloromethane (6.5 mL), and trifluoroacetic acid (2.52 mL, 33.98 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product, then saturated sodium carbonate (50 mL) was added, extracted with dichloromethane (50 mL×3), the organic phase was dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain The crude product was purified by preparative liquid chromatography to obtain compound 141 as a white solid.
LC-MS m/z(ESI)：489.1[M+H] +。 LC-MS m/z (ESI): 489.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.39(s，1H)，8.19(s，0.2H)，8.13(s，1H)，7.84(d，J＝5.3Hz，2H)，7.57-7.48(m，3H)，6.90(s，1H)，6.73(d，J＝7.1Hz，1H)，6.60-6.57(m，1H)，6.54-6.42(m，1H)，6.30(d，J＝16.3Hz，1H)，5.80(d，J＝8.0Hz，1H)，4.32(s，2H)，3.69(s，3H)，3.56(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.39(s, 1H), 8.19(s, 0.2H), 8.13(s, 1H), 7.84(d, J=5.3Hz, 2H), 7.57-7.48 (m, 3H), 6.90(s, 1H), 6.73(d, J=7.1Hz, 1H), 6.60-6.57(m, 1H), 6.54-6.42(m, 1H), 6.30(d, J=16.3 Hz, 1H), 5.80 (d, J = 8.0 Hz, 1H), 4.32 (s, 2H), 3.69 (s, 3H), 3.56 (s, 3H).
实施例12化合物172的合成The synthesis of embodiment 12 compound 172
Figure PCTCN2022129961-appb-000208
Figure PCTCN2022129961-appb-000208
步骤1：化合物int_172-1合成：Step 1: Synthesis of compound int_172-1:
Figure PCTCN2022129961-appb-000209
Figure PCTCN2022129961-appb-000209
将化合物int_139-7(25g，46.76mmol)和2-氟丙烯酸(12.63g，140.29mmol)N，N-二甲基甲酰胺(250mL)中，慢慢加入O-(7-氮杂苯并三氮唑-1-基)-N，N，N，N-四甲基脲六氟膦盐(26.67g，70.14mmol)的N，N-二甲基甲酰胺(250mL)溶液，三乙胺(19.6mL，140.30mmol)。反应液于30℃(外温)搅拌反应2小时。加入饱和碳酸钠水溶液(500mL)，用乙酸乙酯(500mL×3)萃取，有机相合并用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_172-1。Compound int_139-7 (25g, 46.76mmol) and 2-fluoroacrylic acid (12.63g, 140.29mmol) N, N-dimethylformamide (250mL), slowly added O-(7-azabenzotri Azorazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (26.67g, 70.14mmol) in N,N-dimethylformamide (250mL) solution, triethylamine ( 19.6 mL, 140.30 mmol). The reaction solution was stirred and reacted at 30° C. (external temperature) for 2 hours. Add saturated aqueous sodium carbonate solution (500mL), extract with ethyl acetate (500mL×3), combine the organic phases and dry them with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain compound int_172 -1.
LC-MS m/z(ESI)：607.2[M+H] +。 LC-MS m/z (ESI): 607.2 [M+H] + .
1H NMR(500MHz，DMSO-d 6)δ10.57(s，1H)，8.70-8.57(m，1H)，8.11-7.94(m，2H)，7.71(t，J＝7.8Hz，1H)，7.59(br s，2H)，7.06(d，J＝2.4Hz，1H)，6.99(d，J＝7.3Hz，1H)，6.91-6.87(m，1H)，6.87-6.83(m，1H)，6.77(d，J＝8.1Hz，1H)，5.83-5.70(m，1H)，5.48(dd，J＝3.7，15.6Hz，1H)，5.14(br d，J＝13.4Hz，1H)，4.55(br d，J＝13.1Hz，1H)，3.65(s，3H)，2.30(s，3H)，1.39(s，9H)。 1 H NMR (500MHz, DMSO-d 6 ) δ10.57(s, 1H), 8.70-8.57(m, 1H), 8.11-7.94(m, 2H), 7.71(t, J=7.8Hz, 1H), 7.59(br s, 2H), 7.06(d, J=2.4Hz, 1H), 6.99(d, J=7.3Hz, 1H), 6.91-6.87(m, 1H), 6.87-6.83(m, 1H), 6.77(d, J=8.1Hz, 1H), 5.83-5.70(m, 1H), 5.48(dd, J=3.7, 15.6Hz, 1H), 5.14(br d, J=13.4Hz, 1H), 4.55( br d, J = 13.1 Hz, 1H), 3.65 (s, 3H), 2.30 (s, 3H), 1.39 (s, 9H).
步骤2：化合物172合成：Step 2: Synthesis of compound 172:
Figure PCTCN2022129961-appb-000210
Figure PCTCN2022129961-appb-000210
将化合物int_172-1(23g，37.91mmol)溶于二氯甲烷(800mL)中，加入三氟乙酸(168.43mL，2.27mol)。反应液于30℃(外温)搅拌反应2小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(500mL)调至碱性，用二氯甲烷(500mL×3)萃取，有机相合并用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至剩余200mL溶液，湿法上样，经硅胶色谱法分离纯化得到化合物172。Compound int_172-1 (23 g, 37.91 mmol) was dissolved in dichloromethane (800 mL), and trifluoroacetic acid (168.43 mL, 2.27 mol) was added. The reaction solution was stirred and reacted at 30° C. (external temperature) for 2 hours. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate (500mL) to adjust to alkalinity, extract with dichloromethane (500mL×3), combine the organic phases with anhydrous magnesium sulfate for drying, suction filter, and the filtrate Concentrate under reduced pressure to the remaining 200mL solution, apply wet method, and separate and purify by silica gel chromatography to obtain compound 172.
LC-MS m/z(ESI)：507.2[M+H] +。 LC-MS m/z (ESI): 507.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.55(s，1H)，8.64(br s，1H)，8.36(s，1H)，7.98(d，J＝8.6Hz，2H)，7.71(t，J＝7.8Hz，1H)，7.61(d，J＝8.6Hz，2H)，7.18(d，J＝2.3Hz，1H)，6.99(d，J＝7.4Hz，1H)，6.87-6.79(m，2H)，6.75(d，J＝8.1Hz，1H)，5.87-5.65(m，1H)，5.48(dd，J＝3.7，15.6Hz，1H)，4.53(br d，J＝2.9Hz，2H)，3.65(s，3H)，2.30(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.55(s, 1H), 8.64(br s, 1H), 8.36(s, 1H), 7.98(d, J=8.6Hz, 2H), 7.71(t , J=7.8Hz, 1H), 7.61(d, J=8.6Hz, 2H), 7.18(d, J=2.3Hz, 1H), 6.99(d, J=7.4Hz, 1H), 6.87-6.79(m , 2H), 6.75(d, J=8.1Hz, 1H), 5.87-5.65(m, 1H), 5.48(dd, J=3.7, 15.6Hz, 1H), 4.53(br d, J=2.9Hz, 2H ), 3.65(s, 3H), 2.30(s, 3H).
实施例13化合物173的合成The synthesis of embodiment 13 compound 173
Figure PCTCN2022129961-appb-000211
Figure PCTCN2022129961-appb-000211
步骤1：化合物int_173-1合成：Step 1: Synthesis of compound int_173-1:
Figure PCTCN2022129961-appb-000212
Figure PCTCN2022129961-appb-000212
将化合物int_34-8(3.00g，5.60mmol)溶于二氯甲烷(150mL)中，在-30℃下加入2-氟丙烯酰氯(911.6mg，8.40mmol)，三乙胺(1.70g，16.80mmol)。反应液于-30℃搅拌反应1小时。反应液升至室温，加入饱和碳酸钠水溶液(20mL)使pH＝8，加入水(80mL)，用二氯甲烷(100mL×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_173-1。Compound int_34-8 (3.00g, 5.60mmol) was dissolved in dichloromethane (150mL), and 2-fluoroacryloyl chloride (911.6mg, 8.40mmol), triethylamine (1.70g, 16.80mmol) were added at -30°C ). The reaction solution was stirred at -30°C for 1 hour. The reaction solution was raised to room temperature, and saturated aqueous sodium carbonate solution (20 mL) was added to make the pH=8, water (80 mL) was added, extracted with dichloromethane (100 mL×3), dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to dryness, separated and purified by silica gel chromatography to obtain compound int_173-1.
LC-MS m/z(ESI)：608.1[M+H] +。 LC-MS m/z (ESI): 608.1 [M+H] + .
步骤2：化合物173合成：Step 2: Synthesis of Compound 173:
Figure PCTCN2022129961-appb-000213
Figure PCTCN2022129961-appb-000213
将化合物int_173-1(1.35g，2.22mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(15.20g，133.30mmol)。反应液于30℃搅拌反应2小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(20mL)使pH＝8，加入水(30mL)，用二氯甲烷(50mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到粗品。粗品用乙酸乙酯(50mL)打浆纯化，得到白色固体化合物173。Compound int_173-1 (1.35 g, 2.22 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (15.20 g, 133.30 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate (20 mL) to make the pH = 8, add water (30 mL), extract with dichloromethane (50 mL×3), combine the organic phases and dry over anhydrous magnesium sulfate , suction filtration, the filtrate was concentrated to dryness under reduced pressure, and the crude product was obtained by separation and purification by silica gel chromatography. The crude product was purified by slurrying with ethyl acetate (50 mL) to obtain compound 173 as a white solid.
LC-MS m/z(ESI)：508.2[M+H] +。 LC-MS m/z (ESI): 508.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δppm 10.53(s，1H)8.42(d，J＝5.01Hz，1H)8.17(s，1H)7.95(d，J＝8.56Hz，2H)7.58(br d，J＝8.44Hz，3H)7.18(d，J＝0.98Hz，1H)7.11(d，J＝5.01Hz，1H)6.83(s，2H)5.66-5.86(m，1H)5.41-5.54(m，1H)4.36(br d，J＝2.93Hz，2H)3.58(s，3H)2.38(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 10.53(s, 1H) 8.42(d, J=5.01Hz, 1H) 8.17(s, 1H) 7.95(d, J=8.56Hz, 2H) 7.58(br d , J=8.44Hz, 3H) 7.18(d, J=0.98Hz, 1H) 7.11(d, J=5.01Hz, 1H) 6.83(s, 2H) 5.66-5.86(m, 1H) 5.41-5.54(m, 1H) 4.36 (br d, J = 2.93 Hz, 2H) 3.58 (s, 3H) 2.38 (s, 3H).
实施例14化合物174的合成The synthesis of embodiment 14 compound 174
Figure PCTCN2022129961-appb-000214
Figure PCTCN2022129961-appb-000214
步骤1：化合物int_174-1合成：Step 1: Synthesis of compound int_174-1:
Figure PCTCN2022129961-appb-000215
Figure PCTCN2022129961-appb-000215
将化合物int_11-11(2.0g，3.62mmol)溶于二氯甲烷(100mL)中，加入三乙胺(1.5mL，10.86mmol)。然后在0℃条件下向反应液中加入2-氟丙烯酰氯(589.03mg，5.43mmol)，反应液于0℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(50mL)，用乙酸乙酯(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_174-1。Compound int_11-11 (2.0 g, 3.62 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (1.5 mL, 10.86 mmol) was added. Then, 2-fluoroacryloyl chloride (589.03 mg, 5.43 mmol) was added to the reaction liquid at 0°C, and the reaction liquid was stirred and reacted at 0°C for 1 hour. Add saturated aqueous sodium carbonate solution (50mL) to the reaction solution, extract with ethyl acetate (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and then separate by silica gel chromatography Purification gave compound int_174-1.
LC-MS m/z(ESI)：625.1[M+H] +。 LC-MS m/z (ESI): 625.1 [M+H] + .
步骤2：化合物174合成：Step 2: Synthesis of compound 174:
Figure PCTCN2022129961-appb-000216
Figure PCTCN2022129961-appb-000216
将化合物int_174-1(1.15g，1.84mmol)溶于二氯甲烷(18mL)中，加入三氟乙酸(7mL，92.05mmol)。反应液于25℃搅拌反应1小时。反应液减压浓缩至干得到粗品，再加入饱和碳酸钠(150mL)，用二氯甲烷(150mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，然后经硅胶色谱法分离纯化得到化合物174。Compound int_174-1 (1.15 g, 1.84 mmol) was dissolved in dichloromethane (18 mL), and trifluoroacetic acid (7 mL, 92.05 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude product, then saturated sodium carbonate (150 mL) was added, extracted with dichloromethane (150 mL×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain The crude product was separated and purified by silica gel chromatography to obtain compound 174.
LC-MS m/z(ESI)：525.4[M+H] +。 LC-MS m/z (ESI): 525.4 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.54(s，1H)，8.19(s，1H)，7.96(d，J＝8.5Hz，2H)，7.72(t，J＝7.7Hz，1H)，7.65-7.55(m，3H)，7.00-6.91(m，2H)，6.82(d，J＝8.3Hz，1H)，6.62(d，J＝8.5Hz，1H)，5.87-5.64(m，1H)，5.48(dd，J＝3.8，15.6Hz，1H)，4.47(br s，2H)，3.59(s，3H)，2.26(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.54(s, 1H), 8.19(s, 1H), 7.96(d, J=8.5Hz, 2H), 7.72(t, J=7.7Hz, 1H) , 7.65-7.55(m, 3H), 7.00-6.91(m, 2H), 6.82(d, J=8.3Hz, 1H), 6.62(d, J=8.5Hz, 1H), 5.87-5.64(m, 1H ), 5.48 (dd, J=3.8, 15.6 Hz, 1H), 4.47 (br s, 2H), 3.59 (s, 3H), 2.26 (s, 3H).
实施例15化合物175的合成The synthesis of embodiment 15 compound 175
Figure PCTCN2022129961-appb-000217
Figure PCTCN2022129961-appb-000217
步骤1：化合物int_175-1合成：Step 1: Synthesis of compound int_175-1:
Figure PCTCN2022129961-appb-000218
Figure PCTCN2022129961-appb-000218
将化合物int_11-4(110g，418.16mmol)和2-氯-4-甲基嘧啶(80.64g，627.23mmol)溶于N，N-二甲基甲酰胺(1.1L)中，加入碳酸钾(115.58g，836.31mmol)。反应液于100℃搅拌反应1小时。将反应液过滤，减压浓缩旋掉1L溶剂，往反应液中加入水(300mL)，混合液用乙酸乙酯(300mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_175-1。Compound int_11-4 (110g, 418.16mmol) and 2-chloro-4-methylpyrimidine (80.64g, 627.23mmol) were dissolved in N, N-dimethylformamide (1.1L), and potassium carbonate (115.58 g, 836.31 mmol). The reaction solution was stirred and reacted at 100° C. for 1 hour. Filter the reaction solution, concentrate under reduced pressure and spin off 1L of solvent, add water (300mL) to the reaction solution, extract the mixture with ethyl acetate (300mL×3), combine the organic phases, dry with anhydrous magnesium sulfate, and filter with suction , the filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_175-1.
LC-MS m/z(ESI)：354.8[M+H] +。 LC-MS m/z (ESI): 354.8 [M+H] + .
步骤2：化合物int_175-2合成：Step 2: Synthesis of compound int_175-2:
Figure PCTCN2022129961-appb-000219
Figure PCTCN2022129961-appb-000219
将化合物int_175-1(110g，309.72mmol)和双联嚬哪醇硼酸酯(117.97g，464.58mmol)溶于二氧六环(500mL)中，在氮气保护下加入醋酸钾水溶液(91.19g，929.16mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(17.71g，21.68mmol)。反应液于100℃搅拌反应5小时。将反应液过滤，减压浓缩旋掉400mL溶剂，再往反应液中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_175-2。Compound int_175-1 (110g, 309.72mmol) and bis-analcohol borate (117.97g, 464.58mmol) were dissolved in dioxane (500mL), and an aqueous solution of potassium acetate (91.19g, 929.16 mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride in dichloromethane mixture (17.71 g, 21.68 mmol). The reaction solution was stirred and reacted at 100° C. for 5 hours. The reaction solution was filtered, concentrated under reduced pressure and spin off 400mL of solvent, and then water (500mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (500mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, and extracted The filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_175-2.
LC-MS m/z(ESI)：403.0[M+H] +。 LC-MS m/z (ESI): 403.0 [M+H] + .
步骤3：化合物int_175-3合成：Step 3: Synthesis of compound int_175-3:
Figure PCTCN2022129961-appb-000220
Figure PCTCN2022129961-appb-000220
将化合物int_1-7(57.70g，165.75mmol)和化合物int_175-2(100g，248.62mmol)溶于N，N-二甲基甲酰胺(1.0L)中，加入磷酸钾水溶液(2M，200mL，400mmol)和[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(10.80g，16.57mmol)。反应液于100℃搅拌反应3小时。冷却后将反应液过滤，滤液减压浓缩旋掉900mL溶剂，然后用乙酸乙酯(500mL)打浆得到黄色固体化合物int_175-3。Compound int_1-7 (57.70g, 165.75mmol) and compound int_175-2 (100g, 248.62mmol) were dissolved in N,N-dimethylformamide (1.0L), potassium phosphate aqueous solution (2M, 200mL, 400mmol ) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (10.80 g, 16.57 mmol). The reaction solution was stirred and reacted at 100° C. for 3 hours. After cooling, the reaction solution was filtered, and the filtrate was concentrated under reduced pressure to spin off 900 mL of solvent, and then slurried with ethyl acetate (500 mL) to obtain a yellow solid compound int_175-3.
LC-MS m/z(ESI)：544.2[M+H] +。 LC-MS m/z (ESI): 544.2 [M+H] + .
步骤4：化合物int_175-4合成：Step 4: Synthesis of compound int_175-4:
Figure PCTCN2022129961-appb-000221
Figure PCTCN2022129961-appb-000221
将化合物int_175-3(35.0g，64.40mmol)溶于四氢呋喃(140mL)中，加入盐酸水溶液(3M，70.0mL，210.0mmol)。反应液于60℃搅拌反应2小时。得到化合物int_175-4的反应液，此反应液可直接用于下一步反应。Compound int_175-3 (35.0 g, 64.40 mmol) was dissolved in tetrahydrofuran (140 mL), and aqueous hydrochloric acid (3M, 70.0 mL, 210.0 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. Obtain the reaction liquid of compound int_175-4, this reaction liquid can be directly used in next step reaction.
LC-MS m/z(ESI)：500.0[M+H] +。 LC-MS m/z (ESI): 500.0 [M+H] + .
步骤5：化合物int_175-5合成：Step 5: Synthesis of compound int_175-5:
Figure PCTCN2022129961-appb-000222
Figure PCTCN2022129961-appb-000222
向上一步化合物int_175-4的反应液中加入氰基硼氢化钠(22.02g，350.38mmol)。反应液于25℃搅拌反应2小时。往反应液里加入饱和碳酸钠水溶液调pH至中性，减压浓缩后加入水(200mL)，混合液用乙酸乙酯(200mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，用乙酸乙酯(100mL)打浆得到黄色固体化合物int_175-5。Sodium cyanoborohydride (22.02 g, 350.38 mmol) was added to the reaction solution of compound int_175-4 in the previous step. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated aqueous sodium carbonate solution to the reaction solution to adjust the pH to neutral, concentrate under reduced pressure, add water (200 mL), extract the mixture with ethyl acetate (200 mL×3), combine the organic phases, and dry with anhydrous magnesium sulfate. Suction filtration, the filtrate was concentrated to dryness under reduced pressure, and slurried with ethyl acetate (100 mL) to obtain compound int_175-5 as a yellow solid.
LC-MS m/z(ESI)：484.0[M+H] +。 LC-MS m/z (ESI): 484.0 [M+H] + .
步骤6：化合物int_175-6合成：Step 6: Synthesis of compound int_175-6:
Figure PCTCN2022129961-appb-000223
Figure PCTCN2022129961-appb-000223
将化合物int_175-5(10g，20.68mmol)溶于N，N-二甲基甲酰胺(100mL)中，加入Boc酸酐(47.5mL，206.85mmol)，三乙胺(10.9mL，78.60mmol)和4-二甲氨基吡啶(1.26g，10.34mmol)。反应液于50℃搅拌反应2小时。往反应液中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，用乙酸乙酯(50mL)打浆得到化合物int_175-6。Compound int_175-5 (10g, 20.68mmol) was dissolved in N,N-dimethylformamide (100mL), Boc anhydride (47.5mL, 206.85mmol), triethylamine (10.9mL, 78.60mmol) and 4 - Dimethylaminopyridine (1.26 g, 10.34 mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. Water (500 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and washed with ethyl acetate ( 50 mL) to obtain compound int_175-6.
LC-MS m/z(ESI)：584.1[M+H] +。 LC-MS m/z (ESI): 584.1 [M+H] + .
步骤7：化合物int_175-7合成：Step 7: Synthesis of compound int_175-7:
Figure PCTCN2022129961-appb-000224
Figure PCTCN2022129961-appb-000224
将化合物int_175-6(10g，17.14mmol)溶于甲醇(200mL)和水(40mL)中，加入还原铁粉(9.57g，171.36mmol)和氯化铵(9.17g，171.36mmol)。反应液于65℃搅拌反应1小时。将反应液过滤后旋干，加入水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，用乙酸乙酯(50mL)打浆得到白色固体化合物int_175-7。Compound int_175-6 (10 g, 17.14 mmol) was dissolved in methanol (200 mL) and water (40 mL), and reduced iron powder (9.57 g, 171.36 mmol) and ammonium chloride (9.17 g, 171.36 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. After the reaction solution was filtered and spin-dried, water (10 mL) was added, the mixture was extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and used Ethyl acetate (50 mL) was slurried to obtain compound int_175-7 as a white solid.
LC-MS m/z(ESI)：554.1[M+H] +。 LC-MS m/z (ESI): 554.1 [M+H] + .
步骤8：化合物int_175-8合成：Step 8: Synthesis of compound int_175-8:
Figure PCTCN2022129961-appb-000225
Figure PCTCN2022129961-appb-000225
将化合物int_175-7(4.0g，7.23mmol)溶于二氯甲烷(150mL)中，在0℃下加入2-氟丙烯酰氯(783.97mg，7.23mmol)和三乙胺(3.02mL，21.68mmol)。反应液于20℃搅拌反应1小时。往反应液中加入水(100mL)，混合液用二氯甲烷(100mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_175-8。Compound int_175-7 (4.0g, 7.23mmol) was dissolved in dichloromethane (150mL), and 2-fluoroacryloyl chloride (783.97mg, 7.23mmol) and triethylamine (3.02mL, 21.68mmol) were added at 0°C . The reaction solution was stirred and reacted at 20° C. for 1 hour. Water (100mL) was added to the reaction solution, the mixture was extracted with dichloromethane (100mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel chromatography Compound int_175-8 was obtained by separation and purification.
LC-MS m/z(ESI)：626.0[M+H] +。 LC-MS m/z (ESI): 626.0 [M+H] + .
步骤8：化合物175合成：Step 8: Synthesis of Compound 175:
Figure PCTCN2022129961-appb-000226
Figure PCTCN2022129961-appb-000226
将化合物int_175-8(1.9g，3.04mmol)溶于二氯甲烷(100mL)中，加入三氟乙酸(13.49mL，182.22mmol)。反应液于30℃搅拌反应1小时。将反应液浓缩干后加入饱和碳酸钠水溶液(30mL)，混合液用二氯甲烷(30mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物175。Compound int_175-8 (1.9 g, 3.04 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (13.49 mL, 182.22 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. After the reaction solution was concentrated to dryness, saturated aqueous sodium carbonate solution (30 mL) was added, the mixture was extracted with dichloromethane (30 mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Compound 175 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：526.4[M+H] +。 LC-MS m/z (ESI): 526.4 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.55(s，1H)，8.45(d，J＝5.0Hz，1H)，8.20(s，1H)，7.97(d，J＝8.7Hz，2H)，7.68-7.57(m，3H)，7.17(d，J＝5.1Hz，1H)，7.02(t，J＝8.5Hz，1H)，6.63(d，J＝8.7Hz，1H)，5.86-5.68(m，1H)，5.53-5.45(m，J＝3.7，15.5Hz，1H)，4.48(br d，J＝2.6Hz，2H)，3.61(s，3H)，2.42(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.55(s, 1H), 8.45(d, J=5.0Hz, 1H), 8.20(s, 1H), 7.97(d, J=8.7Hz, 2H) , 7.68-7.57(m, 3H), 7.17(d, J=5.1Hz, 1H), 7.02(t, J=8.5Hz, 1H), 6.63(d, J=8.7Hz, 1H), 5.86-5.68( m, 1H), 5.53-5.45 (m, J = 3.7, 15.5Hz, 1H), 4.48 (br d, J = 2.6Hz, 2H), 3.61 (s, 3H), 2.42 (s, 3H).
实施例16化合物181的合成The synthesis of embodiment 16 compound 181
Figure PCTCN2022129961-appb-000227
Figure PCTCN2022129961-appb-000227
步骤1：化合物int_181-2合成：Step 1: Synthesis of compound int_181-2:
Figure PCTCN2022129961-appb-000228
Figure PCTCN2022129961-appb-000228
将4-氟-3-甲氧基苯甲醛(18.0g，116.78mmol)溶于水(150mL)中，加入溴化钾(25.27mL，583.89mmol)和液溴(24.08mL，467.11mmol)。反应液于25℃搅拌反应12小时，有大量固体析出。将反应液过滤，滤渣进行干燥得到白色固体化合物int_181-2。4-Fluoro-3-methoxybenzaldehyde (18.0 g, 116.78 mmol) was dissolved in water (150 mL), and potassium bromide (25.27 mL, 583.89 mmol) and liquid bromine (24.08 mL, 467.11 mmol) were added. The reaction solution was stirred and reacted at 25° C. for 12 hours, and a large amount of solids precipitated out. The reaction solution was filtered, and the filter residue was dried to obtain a white solid compound int_181-2.
1H NMR(400MHz，DMSO-d 6)δ10.13(s，1H)，7.83(d，J＝10.8Hz，1H)，7.55(d，J＝9.2Hz，1H)，3.93(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.13(s, 1H), 7.83(d, J=10.8Hz, 1H), 7.55(d, J=9.2Hz, 1H), 3.93(s, 3H) .
步骤2：化合物int_181-3合成：Step 2: Synthesis of compound int_181-3:
Figure PCTCN2022129961-appb-000229
Figure PCTCN2022129961-appb-000229
将化合物int_181-2(10.0g，42.91mmol)溶于二氯甲烷(150mL)中，在-30℃下加入三溴化硼(18.61mL，193.10mmol)。反应液于25℃搅拌反应12小时。往反应液中加入冰水(500mL)，混合液用二氯甲烷(400mL×3)萃取，合并有机相，用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-3。Compound int_181-2 (10.0 g, 42.91 mmol) was dissolved in dichloromethane (150 mL), and boron tribromide (18.61 mL, 193.10 mmol) was added at -30°C. The reaction solution was stirred and reacted at 25° C. for 12 hours. Ice water (500mL) was added to the reaction solution, the mixture was extracted with dichloromethane (400mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel chromatography Compound int_181-3 was obtained by separation and purification by method.
1H NMR(400MHz，DMSO-d 6)δ10.78(s，1H)，10.07(s，1H)，7.74-7.70(m，1H)，7.44-7.42(m，1H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.78 (s, 1H), 10.07 (s, 1H), 7.74-7.70 (m, 1H), 7.44-7.42 (m, 1H).
步骤3：化合物int_181-4合成：Step 3: Synthesis of compound int_181-4:
Figure PCTCN2022129961-appb-000230
Figure PCTCN2022129961-appb-000230
将化合物int_181-3(20.0g，91.32mmol)和乙二醇(24.87mL，444.73mmol)溶于甲苯(1L)中，加入对甲苯磺酸(3.35g，19.48mmol)。反应液于120℃搅拌反应12小时。将反应液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-4。Compound int_181-3 (20.0 g, 91.32 mmol) and ethylene glycol (24.87 mL, 444.73 mmol) were dissolved in toluene (1 L), and p-toluenesulfonic acid (3.35 g, 19.48 mmol) was added. The reaction solution was stirred and reacted at 120° C. for 12 hours. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_181-4.
1H NMR(400MHz，DMSO-d 6)δ10.32(s，1H)，7.49(d，J＝10.4Hz，1H)，7.18(d，J＝9.2Hz，1H)，5.81(s，1H)，4.08-3.95(m，4H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.32(s, 1H), 7.49(d, J=10.4Hz, 1H), 7.18(d, J=9.2Hz, 1H), 5.81(s, 1H) , 4.08-3.95 (m, 4H).
步骤4：化合物int_181-5合成：Step 4: Synthesis of compound int_181-5:
Figure PCTCN2022129961-appb-000231
Figure PCTCN2022129961-appb-000231
将化合物int_181-4(20.0g，76.03mmol)和2-氟-6-甲基吡啶(78.22mL，760.28mmol)溶于N，N-二甲基甲酰胺(400mL)中，加入碳酸铯(74.31g，228.08mmol)。反应液于120℃搅拌反应12小时。将反应液过滤，减压浓缩至干，加入水(300mL)，混合液用乙酸乙酯(300mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-5。Compound int_181-4 (20.0g, 76.03mmol) and 2-fluoro-6-picoline (78.22mL, 760.28mmol) were dissolved in N,N-dimethylformamide (400mL), cesium carbonate (74.31 g, 228.08 mmol). The reaction solution was stirred and reacted at 120° C. for 12 hours. The reaction solution was filtered, concentrated to dryness under reduced pressure, water (300 mL) was added, the mixture was extracted with ethyl acetate (300 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure to dry, and then separated and purified by silica gel chromatography to obtain compound int_181-5.
1H NMR(400MHz，DMSO-d 6)δ7.81-7.75(m，2H)，7.46(d，J＝8.4Hz，1H)，7.02(d，J＝7.6Hz，1H)，6.93(d，J＝8.0Hz，1H)，5.93(s，1H)，4.07-3.97(m，4H)，2.27(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ7.81-7.75(m, 2H), 7.46(d, J=8.4Hz, 1H), 7.02(d, J=7.6Hz, 1H), 6.93(d, J=8.0Hz, 1H), 5.93(s, 1H), 4.07-3.97(m, 4H), 2.27(s, 3H).
步骤5：化合物int_181-6合成：Step 5: Synthesis of compound int_181-6:
Figure PCTCN2022129961-appb-000232
Figure PCTCN2022129961-appb-000232
将化合物int_181-5(21.0g，59.29mmol)和双联嚬哪醇硼酸酯(22.59g，88.94mmol)溶于二氧六环(100mL)中，加入醋酸钾(17.46g，177.88mmol)和1，1-双(二苯基磷)二茂铁氯化钯(3.39g，4.15mmol)。体系用氮气置换3次，反应液于100℃搅拌反应16小时。冷却后往反应液中加入水(200mL)，混合液用乙酸乙酯(200mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-6。Compound int_181-5 (21.0g, 59.29mmol) and bisanalyl borate (22.59g, 88.94mmol) were dissolved in dioxane (100mL), potassium acetate (17.46g, 177.88mmol) was added and 1,1-Bis(diphenylphosphino)ferrocenepalladium chloride (3.39 g, 4.15 mmol). The system was replaced with nitrogen three times, and the reaction solution was stirred and reacted at 100° C. for 16 hours. After cooling, water (200mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (200mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_181-6 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：401.9[M+H] +。 LC-MS m/z (ESI): 401.9 [M+H] + .
步骤6：化合物int_181-7合成：Step 6: Synthesis of compound int_181-7:
Figure PCTCN2022129961-appb-000233
Figure PCTCN2022129961-appb-000233
将化合物int_1-7(3.04g，8.72mmol)和化合物int_181-6(7.00g，17.45mmol)溶于N，N-二甲基甲酰胺(30mL)中，加入磷酸钾水溶液(2M，8.72mL，17.45mmol)和1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(568.52mg，872.31μmol)。体系用氮气置换3次，反应液于100℃搅拌反应1小时。冷却后往反应液中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-7。Compound int_1-7 (3.04g, 8.72mmol) and compound int_181-6 (7.00g, 17.45mmol) were dissolved in N,N-dimethylformamide (30mL), potassium phosphate aqueous solution (2M, 8.72mL, 17.45 mmol) and 1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (568.52 mg, 872.31 μmol). The system was replaced with nitrogen three times, and the reaction solution was stirred and reacted at 100° C. for 1 hour. After cooling, water (500mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (500mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_181-7 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：543.1[M+H] +。 LC-MS m/z (ESI): 543.1 [M+H] + .
步骤7：化合物int_181-8合成：Step 7: Synthesis of compound int_181-8:
Figure PCTCN2022129961-appb-000234
Figure PCTCN2022129961-appb-000234
将化合物int_181-7(4.00g，7.37mmol)溶于四氢呋喃(10mL)中，加入盐酸水溶液(3M，10.0 mL，30.0mmol)。反应液于60℃搅拌反应2小时。得到化合物int_181-8的反应液，直接用于下一步反应。Compound int_181-7 (4.00 g, 7.37 mmol) was dissolved in tetrahydrofuran (10 mL), and aqueous hydrochloric acid (3M, 10.0 mL, 30.0 mmol) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution of compound int_181-8 was obtained, which was directly used in the next step reaction.
LC-MS m/z(ESI)：499.0[M+H] +。 LC-MS m/z (ESI): 499.0 [M+H] + .
步骤8：化合物int_181-9合成：Step 8: Synthesis of compound int_181-9:
Figure PCTCN2022129961-appb-000235
Figure PCTCN2022129961-appb-000235
向上一步化合物int_181-8的反应液中加入氰基硼氢化钠(2.52g，40.12mmol)。反应液于25℃搅拌反应2小时。往反应液里加入饱和碳酸钠溶液调pH至中性，混合液用乙酸乙酯(200mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后用乙酸乙酯(50mL)打浆得到黄色固体化合物int_181-9。Sodium cyanoborohydride (2.52 g, 40.12 mmol) was added to the reaction solution of compound int_181-8 in the previous step. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated sodium carbonate solution to the reaction solution to adjust the pH to neutral, the mixed solution is extracted with ethyl acetate (200mL×3), the organic phases are combined, dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate is concentrated to dryness under reduced pressure. Then it was slurried with ethyl acetate (50 mL) to obtain compound int_181-9 as a yellow solid.
LC-MS m/z(ESI)：483.1[M+H] +。 LC-MS m/z (ESI): 483.1 [M+H] + .
步骤9：化合物int_181-10合成：Step 9: Synthesis of compound int_181-10:
Figure PCTCN2022129961-appb-000236
Figure PCTCN2022129961-appb-000236
将化合物int_181-9(2.50g，5.18mmol)溶于N，N-二甲基甲酰胺(10mL)中，加入Boc酸酐(11.90mL，51.82mmol)，三乙胺(2.74mL，19.69mmol)和4-二甲氨基吡啶(316.53mg，2.59mmol)。反应液于50℃搅拌反应2小时。冷却后往反应液中加入水(200mL)，混合液用乙酸乙酯(200mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-10。Compound int_181-9 (2.50g, 5.18mmol) was dissolved in N,N-dimethylformamide (10mL), Boc anhydride (11.90mL, 51.82mmol), triethylamine (2.74mL, 19.69mmol) and 4-Dimethylaminopyridine (316.53 mg, 2.59 mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. After cooling, water (200mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (200mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_181-10 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：583.1[M+H] +。 LC-MS m/z (ESI): 583.1 [M+H] + .
步骤10：化合物int_181-11合成：Step 10: Synthesis of compound int_181-11:
Figure PCTCN2022129961-appb-000237
Figure PCTCN2022129961-appb-000237
将化合物int_181-10(2.00g，3.43mmol)溶于甲醇(40mL)和水(10mL)中，加入还原铁粉(1.92g，34.33mmol)和氯化铵(1.84g，34.33mmol)。反应液于65℃搅拌反应1小时。将反应液过滤后旋干，加入水(100mL)，混合液用乙酸乙酯(100mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-11。Compound int_181-10 (2.00 g, 3.43 mmol) was dissolved in methanol (40 mL) and water (10 mL), and reduced iron powder (1.92 g, 34.33 mmol) and ammonium chloride (1.84 g, 34.33 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. After the reaction solution was filtered and spin-dried, water (100 mL) was added, the mixture was extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then Compound int_181-11 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：553.6[M+H] +。 LC-MS m/z (ESI): 553.6 [M+H] + .
步骤11：化合物int_181-12合成：Step 11: Synthesis of compound int_181-12:
Figure PCTCN2022129961-appb-000238
Figure PCTCN2022129961-appb-000238
将化合物int_181-11(1.36g，2.46mmol)溶于二氯甲烷(100mL)中，加入丙烯酰氯(401.35μL，4.92mmol)和三乙胺(1.03mL，7.38mmol)。反应液于20℃搅拌反应1小时。往反应液中加入水(100mL)，混合液用二氯甲烷(100mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_181-12。Compound int_181-11 (1.36 g, 2.46 mmol) was dissolved in dichloromethane (100 mL), and acryloyl chloride (401.35 μL, 4.92 mmol) and triethylamine (1.03 mL, 7.38 mmol) were added. The reaction solution was stirred and reacted at 20° C. for 1 hour. Water (100mL) was added to the reaction solution, the mixture was extracted with dichloromethane (100mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel chromatography Compound int_181-12 was obtained by separation and purification.
LC-MS m/z(ESI)：607.1[M+H] +。 LC-MS m/z (ESI): 607.1 [M+H] + .
步骤12：化合物181合成：Step 12: Synthesis of compound 181:
Figure PCTCN2022129961-appb-000239
Figure PCTCN2022129961-appb-000239
将化合物int_181-12(1.00g，576.94μmol)溶于二氯甲烷(50mL)中，加入三氟乙酸(7.32mL，98.90mmol)。反应液于30℃搅拌反应1小时。将反应液旋干后加入饱和碳酸钠(20mL)，混合液用二氯甲烷(50mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物181。Compound int_181-12 (1.00 g, 576.94 μmol) was dissolved in dichloromethane (50 mL), and trifluoroacetic acid (7.32 mL, 98.90 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. After the reaction solution was spin-dried, saturated sodium carbonate (20 mL) was added, the mixture was extracted with dichloromethane (50 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then Compound 181 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：507.4[M+H] +。 LC-MS m/z (ESI): 507.4 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.43(s，1H)，8.19(s，1H)，7.90(d，J＝8.6Hz，2H)，7.72(t，J＝7.8Hz，1H)，7.64(br t，J＝3.3Hz，1H)，7.58(d，J＝8.6Hz，2H)，7.33(d，J＝8.4Hz，1H)，6.97(d，J＝7.3Hz，1H)，6.83(d，J＝8.2Hz，1H)，6.57(d，J＝12.8Hz，1H)，6.54-6.43(m，1H)，6.36-6.27(m，1H)，5.86-5.77(m，1H)，4.36(br d，J＝3.2Hz，2H)，3.59(s，3H)，2.26(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.43(s, 1H), 8.19(s, 1H), 7.90(d, J=8.6Hz, 2H), 7.72(t, J=7.8Hz, 1H) , 7.64(br t, J=3.3Hz, 1H), 7.58(d, J=8.6Hz, 2H), 7.33(d, J=8.4Hz, 1H), 6.97(d, J=7.3Hz, 1H), 6.83(d, J=8.2Hz, 1H), 6.57(d, J=12.8Hz, 1H), 6.54-6.43(m, 1H), 6.36-6.27(m, 1H), 5.86-5.77(m, 1H) , 4.36 (br d, J=3.2Hz, 2H), 3.59 (s, 3H), 2.26 (s, 3H).
实施例17化合物182的合成The synthesis of embodiment 17 compound 182
Figure PCTCN2022129961-appb-000240
Figure PCTCN2022129961-appb-000240
步骤1：化合物int_182-1合成：Step 1: Synthesis of compound int_182-1:
Figure PCTCN2022129961-appb-000241
Figure PCTCN2022129961-appb-000241
将化合物int_11-11(2g，3.62mmol)溶于四氢呋喃(200mL)中，加入4-(二甲氨基)丁-2-烯酸盐酸盐(2.19g)和三乙胺(2.5mL，18.10mmol)。然后加入三正丙基环磷酸酐50％乙酸乙酯溶液(21.5mL，36.19mmol)，反应液于65℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(50mL)，用乙酸乙酯(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_182-1。Compound int_11-11 (2g, 3.62mmol) was dissolved in tetrahydrofuran (200mL), and 4-(dimethylamino)but-2-ene hydrochloride (2.19g) and triethylamine (2.5mL, 18.10mmol) were added ). Then tri-n-propyl cyclic phosphoric anhydride 50% ethyl acetate solution (21.5 mL, 36.19 mmol) was added, and the reaction solution was stirred at 65° C. for 1 hour. Add saturated aqueous sodium carbonate solution (50mL) to the reaction solution, extract with ethyl acetate (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography Compound int_182-1 was obtained.
LC-MS m/z(ESI)：664.2[M+H] +。 LC-MS m/z (ESI): 664.2 [M+H] + .
步骤2：化合物182合成：Step 2: Synthesis of compound 182:
Figure PCTCN2022129961-appb-000242
Figure PCTCN2022129961-appb-000242
将化合物int_182-1(1.32g，1.99mmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(7.5mL，99.44mmol)。反应液于30℃搅拌反应1小时。反应液减压浓缩至干得到粗品，向反应液中加入饱和碳酸钠(150mL)，用二氯甲烷(150mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，经硅胶色谱法分离纯化得到化合物182。Compound int_182-1 (1.32 g, 1.99 mmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (7.5 mL, 99.44 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product, saturated sodium carbonate (150 mL) was added to the reaction solution, extracted with dichloromethane (150 mL×3), the organic phase was dried with anhydrous magnesium sulfate, suction filtered, and the filtrate was concentrated under reduced pressure Dry to dryness to obtain a crude product, which is separated and purified by silica gel chromatography to obtain compound 182.
LC-MS m/z(ESI)：564.6[M+H] +。 LC-MS m/z (ESI): 564.6 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.31(s，1H)，8.18(s，1H)，7.87(d，J＝8.4Hz，2H)，7.71(t，J＝7.8Hz，1H)，7.62(s，1H)，7.55(d，J＝8.4Hz，2H)，7.01-6.89(m，2H)，6.84-6.72(m，2H)，6.64(d，J＝8.6Hz，1H)，6.31(d，J＝15.4Hz，1H)，4.47(s，2H)，3.59(s，3H)，3.07(d，J＝5.3Hz，2H)，2.29-2.23(m，3H)，2.18(s，6H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.31(s, 1H), 8.18(s, 1H), 7.87(d, J=8.4Hz, 2H), 7.71(t, J=7.8Hz, 1H) , 7.62(s, 1H), 7.55(d, J=8.4Hz, 2H), 7.01-6.89(m, 2H), 6.84-6.72(m, 2H), 6.64(d, J=8.6Hz, 1H), 6.31(d, J=15.4Hz, 1H), 4.47(s, 2H), 3.59(s, 3H), 3.07(d, J=5.3Hz, 2H), 2.29-2.23(m, 3H), 2.18(s , 6H).
实施例18化合物185的合成The synthesis of embodiment 18 compound 185
Figure PCTCN2022129961-appb-000243
Figure PCTCN2022129961-appb-000243
步骤1：化合物int_185-1合成：Step 1: Synthesis of compound int_185-1:
Figure PCTCN2022129961-appb-000244
Figure PCTCN2022129961-appb-000244
将化合物int_175-7(2.0g，3.61mmol)溶于二氯甲烷(120mL)中，加入丙烯酰氯(589μL，7.23mmol)和三乙胺(1.5mL，10.84mmol)。反应液于20℃搅拌反应1小时。往反应液中加入水(100mL)，混合液用二氯甲烷(100mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_185-1。Compound int_175-7 (2.0 g, 3.61 mmol) was dissolved in dichloromethane (120 mL), and acryloyl chloride (589 μL, 7.23 mmol) and triethylamine (1.5 mL, 10.84 mmol) were added. The reaction solution was stirred and reacted at 20° C. for 1 hour. Water (100mL) was added to the reaction solution, the mixture was extracted with dichloromethane (100mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then subjected to silica gel chromatography Compound int_185-1 was obtained by separation and purification.
LC-MS m/z(ESI)：608.1[M+H] +。 LC-MS m/z (ESI): 608.1 [M+H] + .
步骤2：化合物185合成：Step 2: Synthesis of compound 185:
Figure PCTCN2022129961-appb-000245
Figure PCTCN2022129961-appb-000245
将化合物int_185-1(2.1g，3.46mmol)溶于二氯甲烷(100mL)中，加入三氟乙酸(15.35mL，207.36mmol)。反应液于30℃搅拌反应1小时。将反应液浓缩干后加入饱和碳酸钠水溶液(20mL)，混合液用二氯甲烷(100mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物185。Compound int_185-1 (2.1 g, 3.46 mmol) was dissolved in dichloromethane (100 mL), and trifluoroacetic acid (15.35 mL, 207.36 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. After the reaction solution was concentrated to dryness, saturated aqueous sodium carbonate solution (20 mL) was added, the mixture was extracted with dichloromethane (100 mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Compound 185 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：508.0[M+H] +。 LC-MS m/z (ESI): 508.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.41(s，1H)，8.45(d，J＝5.0Hz，1H)，8.20(s，1H)，7.89(d，J＝8.7Hz，2H)，7.63(br t，J＝3.5Hz，1H)，7.58(d，J＝8.7Hz，2H)，7.17(d，J＝5.0Hz，1H)，7.02(t，J＝8.6Hz，1H)，6.65(d，J＝8.7Hz，1H)，6.55-6.43(m，1H)，6.36-6.26(m，1H)，5.85-5.77(m，1H)，4.47(br d，J＝2.1Hz，2H)，3.61(s，3H)，2.42(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.41(s, 1H), 8.45(d, J=5.0Hz, 1H), 8.20(s, 1H), 7.89(d, J=8.7Hz, 2H) , 7.63(br t, J=3.5Hz, 1H), 7.58(d, J=8.7Hz, 2H), 7.17(d, J=5.0Hz, 1H), 7.02(t, J=8.6Hz, 1H), 6.65(d, J=8.7Hz, 1H), 6.55-6.43(m, 1H), 6.36-6.26(m, 1H), 5.85-5.77(m, 1H), 4.47(br d, J=2.1Hz, 2H ), 3.61(s, 3H), 2.42(s, 3H).
实施例19化合物177的合成The synthesis of embodiment 19 compound 177
Figure PCTCN2022129961-appb-000246
Figure PCTCN2022129961-appb-000246
步骤1：化合物int_177-1合成：Step 1: Synthesis of compound int_177-1:
Figure PCTCN2022129961-appb-000247
Figure PCTCN2022129961-appb-000247
将化合物int_2-1(100g，408.05mmol)和2-氯嘧啶(70.10g，612.07mmol)溶于N，N-二甲基甲酰胺(1.0L)中，加入碳酸钾(112.79g，816.09mmol)。反应液于100℃搅拌反应2小时。反应液冷却至室温，过滤，滤液减压浓缩至干。向剩余物中加入水(1.5L)，用乙酸乙酯(1.5L×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到黄色固体化合物int_177-1。Compound int_2-1 (100g, 408.05mmol) and 2-chloropyrimidine (70.10g, 612.07mmol) were dissolved in N,N-dimethylformamide (1.0L), and potassium carbonate (112.79g, 816.09mmol) was added . The reaction solution was stirred and reacted at 100° C. for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated to dryness under reduced pressure. Add water (1.5L) to the residue, extract with ethyl acetate (1.5L×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain a yellow solid compound int_177-1 .
LC-MS m/z(ESI)：324.9[M+H] +。 LC-MS m/z (ESI): 324.9 [M+H] + .
步骤2：化合物int_177-2合成：Step 2: Synthesis of compound int_177-2:
Figure PCTCN2022129961-appb-000248
Figure PCTCN2022129961-appb-000248
将化合物int_177-1(100g，309.46mmol)和双联频哪醇硼酸酯(117.88g，464.19mmol)溶于二氧六环(1.5L)中，在氮气保护下加入醋酸钾(75.93g，773.65mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(22.64g，30.95mmol)，反应液于100℃搅拌反应5小时。反应液冷却至室温，过滤，滤液减压浓缩。向剩余物中加入水(1.5L)，用乙酸乙酯(1.5L×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_177-2。Compound int_177-1 (100g, 309.46mmol) and double pinacol borate (117.88g, 464.19mmol) were dissolved in dioxane (1.5L), and potassium acetate (75.93g, 773.65mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (22.64g, 30.95mmol), and the reaction solution was stirred at 100°C for 5 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Add water (1.5L) to the residue, extract with ethyl acetate (1.5L×3), dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain the compound int_177- 2.
LC-MS m/z(ESI)：371.1[M+H] +。 LC-MS m/z (ESI): 371.1 [M+H] + .
步骤3：化合物int_177-3合成：Step 3: Synthesis of compound int_177-3:
Figure PCTCN2022129961-appb-000249
Figure PCTCN2022129961-appb-000249
将化合物int_1-7(25.0g，71.81mmol)和化合物int_177-2(83.63g，215.42mmol)溶于N，N-二甲基甲酰胺(500mL)中，在氮气保护下加入磷酸钾水溶液(2M，71.81mL)和[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(3.28g，5.03mmol)，反应液于100℃搅拌30分钟。反应液冷却至室温，加入水(1L)，抽滤，乙酸乙酯(500mL)洗涤，滤饼用乙酸乙酯(500mL)打浆纯化得到黄色固体化合物int_177-3。Compound int_1-7 (25.0g, 71.81mmol) and compound int_177-2 (83.63g, 215.42mmol) were dissolved in N,N-dimethylformamide (500mL), and potassium phosphate aqueous solution (2M , 71.81mL) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) dichloride (3.28g, 5.03mmol), and the reaction solution was stirred at 100°C for 30 minutes. The reaction solution was cooled to room temperature, water (1 L) was added, suction filtered, washed with ethyl acetate (500 mL), and the filter cake was purified by slurrying with ethyl acetate (500 mL) to obtain compound int_177-3 as a yellow solid.
LC-MS m/z(ESI)：512.2[M+H] +。 LC-MS m/z (ESI): 512.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.68(d，J＝4.8Hz，2H)，8.26-8.19(m，3H)，7.66(d，J＝8.8Hz，2H)，7.39-7.23(m，4H)，5.59(s，1H)，3.99-3.87(m，2H)，3.81-3.72(m，2H)，3.71-3.68(m，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.68(d, J=4.8Hz, 2H), 8.26-8.19(m, 3H), 7.66(d, J=8.8Hz, 2H), 7.39-7.23( m, 4H), 5.59 (s, 1H), 3.99-3.87 (m, 2H), 3.81-3.72 (m, 2H), 3.71-3.68 (m, 3H).
步骤4：化合物int_177-4合成：Step 4: Synthesis of compound int_177-4:
Figure PCTCN2022129961-appb-000250
Figure PCTCN2022129961-appb-000250
将化合物int_177-3(13.0g，25.42mmol)溶于四氢呋喃(500mL)中，加入盐酸(3M，42.36mL)，反应液于60℃搅拌2小时。反应液冷却至室温，减压浓缩除去溶剂，得到黄色固体化合物int_177-4。Compound int_177-3 (13.0 g, 25.42 mmol) was dissolved in tetrahydrofuran (500 mL), hydrochloric acid (3M, 42.36 mL) was added, and the reaction solution was stirred at 60° C. for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove the solvent to obtain compound int_177-4 as a yellow solid.
LC-MS m/z(ESI)：468.0[M+H] +。 LC-MS m/z (ESI): 468.0 [M+H] + .
步骤5：化合物int_177-5合成：Step 5: Synthesis of compound int_177-5:
Figure PCTCN2022129961-appb-000251
Figure PCTCN2022129961-appb-000251
将化合物int_177-4(5.0g，10.70mmol)溶于四氢呋喃(100mL)中，加入氰基硼氢化钠(3.36g，53.48mmol)，反应液于25℃搅拌反应2小时。向反应液中加入饱和碳酸钠水溶液(90mL)使pH＝8，再加入水(500mL)，用乙酸乙酯(500mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到黄色固体化合物int_177-5。Compound int_177-4 (5.0g, 10.70mmol) was dissolved in tetrahydrofuran (100mL), sodium cyanoborohydride (3.36g, 53.48mmol) was added, and the reaction solution was stirred at 25°C for 2 hours. Add saturated sodium carbonate aqueous solution (90mL) to the reaction solution to make the pH=8, then add water (500mL), extract with ethyl acetate (500mL×3), dry the organic phase with anhydrous magnesium sulfate, suction filter, and the filtrate Concentrate to dryness under reduced pressure to obtain compound int_177-5 as a yellow solid.
1H NMR(400MHz，DMSO-d 6)δ8.64(d，J＝4.8Hz，2H)，8.45-8.38(m，2H)，8.21(s，1H)，7.94(d，J＝8.9Hz，2H)，7.76(s，1H)，7.30-7.24(m，2H)，6.87(dd，J＝2.5，8.5Hz，1H)，6.75(d，J＝8.6Hz，1H)，4.40(brd，J＝3.4Hz，2H)，3.64(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.64(d, J=4.8Hz, 2H), 8.45-8.38(m, 2H), 8.21(s, 1H), 7.94(d, J=8.9Hz, 2H), 7.76(s, 1H), 7.30-7.24(m, 2H), 6.87(dd, J=2.5, 8.5Hz, 1H), 6.75(d, J=8.6Hz, 1H), 4.40(brd, J =3.4Hz, 2H), 3.64(s, 3H).
步骤6：化合物int_177-6合成：Step 6: Synthesis of compound int_177-6:
Figure PCTCN2022129961-appb-000252
Figure PCTCN2022129961-appb-000252
将化合物int_177-5(2.00g，4.43mmol)溶于N，N-二甲基甲酰胺(80mL)中，加入BOC酸酐(4.83g，22.15mmol)，4-二甲氨基吡啶(108.25mg，886.06μmol)和三乙胺(1.79g，17.72mmol)。反应液于50℃搅拌反应2小时。反应液冷却至室温，加入水(200mL)，用乙酸乙酯(200mL×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_177-6。Compound int_177-5 (2.00g, 4.43mmol) was dissolved in N,N-dimethylformamide (80mL), BOC anhydride (4.83g, 22.15mmol), 4-dimethylaminopyridine (108.25mg, 886.06 μmol) and triethylamine (1.79g, 17.72mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. The reaction solution was cooled to room temperature, water (200mL) was added, extracted with ethyl acetate (200mL×3), dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain the compound int_177- 6.
1H NMR(400MHz，DMSO-d 6)δ8.69(s，1H)，8.64(d，J＝4.9Hz，2H)，8.45(br d，J＝8.8Hz，2H)，7.96 (br d，J＝7.1Hz，2H)，7.28(t，J＝4.8Hz，1H)，7.23(d，J＝2.5Hz，1H)，6.95(dd，J＝2.5，8.6Hz，1H)，6.80(d，J＝8.5Hz，1H)，5.20(br d，J＝14.1Hz，1H)，4.63(br d，J＝11.4Hz，1H)，3.70(s，3H)，1.42(s，9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.69 (s, 1H), 8.64 (d, J=4.9Hz, 2H), 8.45 (br d, J=8.8Hz, 2H), 7.96 (br d, J=7.1Hz, 2H), 7.28(t, J=4.8Hz, 1H), 7.23(d, J=2.5Hz, 1H), 6.95(dd, J=2.5, 8.6Hz, 1H), 6.80(d, J=8.5Hz, 1H), 5.20 (br d, J=14.1Hz, 1H), 4.63 (br d, J=11.4Hz, 1H), 3.70 (s, 3H), 1.42 (s, 9H).
步骤7：化合物int_177-7合成：Step 7: Synthesis of compound int_177-7:
Figure PCTCN2022129961-appb-000253
Figure PCTCN2022129961-appb-000253
将化合物int_177-6(1.8g，3.26mmol)溶于甲醇(40mL)和水(8mL)中，加入铁粉(3.65g，65.27mmol)和氯化铵(3.49g，65.27mmol)。反应液于65℃搅拌反应1小时。反应液冷却至室温，抽滤，用甲醇(200mL)洗涤，减压浓缩。向剩余物中加入水(500mL)，用乙酸乙酯(500mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物im_177-7。Compound int_177-6 (1.8g, 3.26mmol) was dissolved in methanol (40mL) and water (8mL), iron powder (3.65g, 65.27mmol) and ammonium chloride (3.49g, 65.27mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. The reaction solution was cooled to room temperature, filtered with suction, washed with methanol (200 mL), and concentrated under reduced pressure. Add water (500mL) to the residue, extract with ethyl acetate (500mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain compound im_177 -7.
LC-MS m/z(ESI)：522.1[M+H] +。 LC-MS m/z (ESI): 522.1 [M+H] + .
步骤8：化合物int_177-8合成：Step 8: Synthesis of compound int_177-8:
Figure PCTCN2022129961-appb-000254
Figure PCTCN2022129961-appb-000254
将化合物int_177-7(1.1g，2.11mmol)溶于N，N-二甲基甲酰胺(15mL)中，加入2-氟丙烯酸(569.77mg，6.33mmol)，O-(7-氮杂苯并三氮唑-1-YL)-N，N，N，N-四甲基脲六氟膦盐(1.60g，4.22mmol)和N，N-二异丙基乙胺(817.73mg，6.33mmol)。反应液于25℃搅拌反应3小时。加入水(30mL)用乙酸乙酯(30mL×3)萃取，无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_177-8。Compound int_177-7 (1.1g, 2.11mmol) was dissolved in N,N-dimethylformamide (15mL), 2-fluoroacrylic acid (569.77mg, 6.33mmol), O-(7-azabenzo Triazole-1-YL)-N,N,N,N-tetramethyluronium hexafluorophosphine salt (1.60g, 4.22mmol) and N,N-diisopropylethylamine (817.73mg, 6.33mmol) . The reaction solution was stirred and reacted at 25° C. for 3 hours. Water (30 mL) was added, extracted with ethyl acetate (30 mL×3), dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain compound int_177-8.
LC-MS m/z(ESI)：594.1[M+H] +。 LC-MS m/z (ESI): 594.1 [M+H] + .
步骤9：化合物177合成：Step 9: Synthesis of compound 177:
Figure PCTCN2022129961-appb-000255
Figure PCTCN2022129961-appb-000255
将化合物int_177-8(900mg，1.52mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(10mL)。反应液于30℃搅拌反应2小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(20mL)使pH＝8，加入水(30mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经制备液相色谱纯化得到白色固体化合物177。Compound int_177-8 (900 mg, 1.52 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (10 mL) was added. The reaction solution was stirred and reacted at 30° C. for 2 hours. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate (20 mL) to make the pH=8, add water (30 mL), extract with dichloromethane (50 mL×3), and dry the organic phase with anhydrous magnesium sulfate. After suction filtration, the filtrate was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography to obtain compound 177 as a white solid.
LC-MS m/z(ESI)：494.2[M+H] +。 LC-MS m/z (ESI): 494.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.53(s，1H)，8.62(d，J＝4.8Hz，2H)，8.19(s，1H)，7.95(d，J＝8.6Hz，2H)，7.68(br s，1H)，7.59(d，J＝8.6Hz，2H)，7.30-7.19(m，2H)，6.90-6.81(m，2H)，5.84-5.68(m，1H)，5.47(dd，J＝3.7，15.6Hz，1H)，4.38(br d，J＝3.1Hz，2H)，3.59(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.53(s, 1H), 8.62(d, J=4.8Hz, 2H), 8.19(s, 1H), 7.95(d, J=8.6Hz, 2H) , 7.68 (br s, 1H), 7.59 (d, J=8.6Hz, 2H), 7.30-7.19 (m, 2H), 6.90-6.81 (m, 2H), 5.84-5.68 (m, 1H), 5.47 ( dd, J = 3.7, 15.6 Hz, 1H), 4.38 (br d, J = 3.1 Hz, 2H), 3.59 (s, 3H).
实施例20化合物186的合成The synthesis of embodiment 20 compound 186
Figure PCTCN2022129961-appb-000256
Figure PCTCN2022129961-appb-000256
步骤1：化合物int_186-1合成：Step 1: Synthesis of compound int_186-1:
Figure PCTCN2022129961-appb-000257
Figure PCTCN2022129961-appb-000257
将化合物int_2-12(500.0mg，911.4μmol)和2-氟丙烯酸(246.21mg，2.73mmol)溶于N，N-二甲基甲酰胺(5mL)中，加入1-(3-二甲基氨基丙基)-3-乙基碳二亚胺(524.13mg，2.73mmol)和吡啶(4.90g，61.95mmol)，反应液于80℃搅拌2小时。反应液冷却至室温，加入水(10mL)，然后用乙酸乙酯萃取(10mL×3)，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_186-1。Compound int_2-12 (500.0 mg, 911.4 μmol) and 2-fluoroacrylic acid (246.21 mg, 2.73 mmol) were dissolved in N, N-dimethylformamide (5 mL), and 1-(3-dimethylamino Propyl)-3-ethylcarbodiimide (524.13mg, 2.73mmol) and pyridine (4.90g, 61.95mmol), and the reaction solution was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, water (10 mL) was added, and then extracted with ethyl acetate (10 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography Compound int_186-1 was obtained.
LC-MS m/z(ESI)：621.3[M+H] +。 LC-MS m/z (ESI): 621.3 [M+H] + .
步骤2：化合物186合成：Step 2: Synthesis of compound 186:
Figure PCTCN2022129961-appb-000258
Figure PCTCN2022129961-appb-000258
将化合物int_186-1(350.0mg，563.9μmol)溶于二氯甲烷(7mL)中，加入三氟乙酸(3.86g，33.83mmol)。反应液于30℃搅拌反应3小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(30mL)，用二氯甲烷萃取(30mL×3)，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经制备液相色谱纯化得到白色固体化合物186。Compound int_186-1 (350.0 mg, 563.9 μmol) was dissolved in dichloromethane (7 mL), and trifluoroacetic acid (3.86 g, 33.83 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 3 hours. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate (30mL), extract with dichloromethane (30mL×3), combine the organic phases to dry with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure , and purified by preparative liquid chromatography to obtain compound 186 as a white solid.
LC-MS m/z(ESI)：521.2[M+H] +。 LC-MS m/z (ESI): 521.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.44(br s，1H)8.27(s，1H)7.63-7.96(m，3H)7.39(br d，J＝7.88Hz，2H)6.88-7.20(m，2H)6.54-6.84(m，3H)6.17(br s，1H)5.63-5.88(m，1H)5.35-5.56(m，1H)3.65(s，3H)3.47(br s，2H)3.07(br s，2H)2.33(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.44 (br s, 1H) 8.27 (s, 1H) 7.63-7.96 (m, 3H) 7.39 (br d, J=7.88Hz, 2H) 6.88-7.20 ( m, 2H) 6.54-6.84 (m, 3H) 6.17 (br s, 1H) 5.63-5.88 (m, 1H) 5.35-5.56 (m, 1H) 3.65 (s, 3H) 3.47 (br s, 2H) 3.07 ( br s, 2H) 2.33 (s, 3H).
实施例21化合物188的合成Synthesis of Example 21 Compound 188
Figure PCTCN2022129961-appb-000259
Figure PCTCN2022129961-appb-000259
步骤1：化合物int_188-2合成：Step 1: Synthesis of compound int_188-2:
Figure PCTCN2022129961-appb-000260
Figure PCTCN2022129961-appb-000260
将2-溴-5-甲氧基苯甲醛(5g，23.25mmol)和双联嚬哪醇硼酸酯(23.62g，93.00mmol)溶于二 氧六环(230mL)中，在氮气保护下加入[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(1.90g，2.33mmol)和乙酸钾(6.85g，69.75mmol)。反应液于100℃搅拌反应3小时。将反应液减压浓缩至干，再加入水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_188-2。2-Bromo-5-methoxybenzaldehyde (5g, 23.25mmol) and bisanalyl borate (23.62g, 93.00mmol) were dissolved in dioxane (230mL), and added under nitrogen protection [1,1-Bis(diphenylphosphino)ferrocene]palladium dichloride dichloromethane (1.90 g, 2.33 mmol) and potassium acetate (6.85 g, 69.75 mmol). The reaction solution was stirred and reacted at 100° C. for 3 hours. Concentrate the reaction solution to dryness under reduced pressure, add water (200mL), extract with ethyl acetate (200mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product, the crude product Compound int_188-2 was obtained by separation and purification by silica gel chromatography.
1H NMR(400MHz，DMSO-d 6)δ10.23(s，1H)，7.75(d，J＝8.3Hz，1H)，7.39(d，J＝2.6Hz，1H)，7.30-7.25(m，1H)，3.85(s，3H)，1.33(s，12H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.23(s, 1H), 7.75(d, J=8.3Hz, 1H), 7.39(d, J=2.6Hz, 1H), 7.30-7.25(m, 1H), 3.85(s, 3H), 1.33(s, 12H).
步骤2：化合物int_188-3合成：Step 2: Synthesis of compound int_188-3:
Figure PCTCN2022129961-appb-000261
Figure PCTCN2022129961-appb-000261
将化合物int_1-7(2g，5.74mmol)和化合物int_188-2(3.01g，11.49mmol)溶于四氢呋喃(40mL)中，在氮气保护下加入双(三环己基膦基)二氯化钯(II)(212.03mg，287.23μmol)和磷酸钾水溶液(2M，8.0mL)。反应液于100℃搅拌反应15分钟。冷却后向反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_188-3。Compound int_1-7 (2g, 5.74mmol) and compound int_188-2 (3.01g, 11.49mmol) were dissolved in tetrahydrofuran (40mL), and two (tricyclohexylphosphino) dichloride palladium (II ) (212.03 mg, 287.23 μmol) and potassium phosphate aqueous solution (2M, 8.0 mL). The reaction solution was stirred and reacted at 100° C. for 15 minutes. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was subjected to silica gel chromatography Compound int_188-3 was obtained by separation and purification.
LC-MS m/z(ESI)：404.1[M+H] +。 LC-MS m/z (ESI): 404.1 [M+H] + .
步骤3：化合物int_188-4合成：Step 3: Compound int_188-4 synthesis:
Figure PCTCN2022129961-appb-000262
Figure PCTCN2022129961-appb-000262
将化合物int_188-3(345mg，855.25μmol)溶于乙腈(8.5mL)和乙酸(245μL，4.28mmol)中，加入氰基硼氢化钠(268.73mg，4.28mmol)。反应液于25℃搅拌反应16小时。向反应液中加入饱和碳酸钠水溶液(10mL)，减压浓缩，再加入水(30mL)，用乙酸乙酯(30mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_188-4。Compound int_188-3 (345 mg, 855.25 μmol) was dissolved in acetonitrile (8.5 mL) and acetic acid (245 μL, 4.28 mmol), and sodium cyanoborohydride (268.73 mg, 4.28 mmol) was added. The reaction solution was stirred and reacted at 25°C for 16 hours. Add saturated sodium carbonate aqueous solution (10mL) to the reaction solution, concentrate under reduced pressure, then add water (30mL), extract with ethyl acetate (30mL×3), dry the organic phase with anhydrous magnesium sulfate, suction filter, and the filtrate Concentrate under reduced pressure to dryness to obtain a crude product, which is separated and purified by silica gel chromatography to obtain compound int_188-4.
LC-MS m/z(ESI)：388.1[M+H] +。 LC-MS m/z (ESI): 388.1 [M+H] + .
步骤4：化合物int_188-5合成：Step 4: Synthesis of compound int_188-5:
Figure PCTCN2022129961-appb-000263
Figure PCTCN2022129961-appb-000263
将化合物int_188-4(130mg，335.58μmol)溶于N，N-二甲基甲酰胺(3.5mL)中，加入三乙胺(141μL，1.01mmol)和BOC酸酐(771μL，3.36mmol)，4-二甲氨基吡啶(20.50mg，167.79μmol)，反应液于50℃搅拌反应16小时。反应液减压浓缩至干，将反应液倒入水(30mL)中，用二氯甲烷(30mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，粗品经硅胶色谱法分离纯化得到化合物int_188-5。Compound int_188-4 (130mg, 335.58μmol) was dissolved in N,N-dimethylformamide (3.5mL), triethylamine (141μL, 1.01mmol) and BOC anhydride (771μL, 3.36mmol) were added, 4- Dimethylaminopyridine (20.50 mg, 167.79 μmol), and the reaction solution was stirred at 50° C. for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, the reaction solution was poured into water (30 mL), extracted with dichloromethane (30 mL×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. The crude product was separated and purified by silica gel chromatography to obtain compound int_188-5.
LC-MS m/z(ESI)：488.1[M+H] +。 LC-MS m/z (ESI): 488.1 [M+H] + .
步骤5：化合物int_188-6合成：Step 5: Synthesis of compound int_188-6:
Figure PCTCN2022129961-appb-000264
Figure PCTCN2022129961-appb-000264
将化合物int_188-5(130mg，266.66μmol)溶于甲醇(2mL)和水(400μL)中，加入铁粉(148.92mg，2.67mmol)和氯化铵(142.64mg，2.67mmol)。反应液于65℃搅拌反应1小时。反应液减压浓缩至干，再加入水(40mL)，用乙酸乙酯(40mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品化合物int_188-6。Compound int_188-5 (130 mg, 266.66 μmol) was dissolved in methanol (2 mL) and water (400 μL), and iron powder (148.92 mg, 2.67 mmol) and ammonium chloride (142.64 mg, 2.67 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, then water (40mL) was added, extracted with ethyl acetate (40mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude compound int_188- 6.
LC-MS m/z(ESI)：458.1[M+H] +。 LC-MS m/z (ESI): 458.1 [M+H] + .
步骤6：化合物int_188-7合成：Step 6: Synthesis of compound int_188-7:
Figure PCTCN2022129961-appb-000265
Figure PCTCN2022129961-appb-000265
将化合物int_188-6(120mg，262.28μmol)溶于二氯甲烷(4mL)中，加入N，N-二异丙基乙胺(138μL，786.85μmol)。然后在0℃条件下向反应液中加入丙烯酰氯(43μL，524.5μmol)，反应液于25℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到黄色固体化合物int_188-7。Compound int_188-6 (120 mg, 262.28 μmol) was dissolved in dichloromethane (4 mL), and N,N-diisopropylethylamine (138 μL, 786.85 μmol) was added. Then, acryloyl chloride (43 μL, 524.5 μmol) was added to the reaction solution at 0° C., and the reaction solution was stirred and reacted at 25° C. for 1 hour. Add saturated aqueous sodium carbonate solution (50mL) to the reaction solution, extract with dichloromethane (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain a yellow solid compound int_188-7 .
LC-MS m/z(ESI)：512.1[M+H] +。 LC-MS m/z (ESI): 512.1 [M+H] + .
步骤7：化合物int_188-8合成：Step 7: Synthesis of compound int_188-8:
Figure PCTCN2022129961-appb-000266
Figure PCTCN2022129961-appb-000266
将化合物int_188-7(120mg，234.57μmol)溶于二氯甲烷(2mL)中，加入三氟乙酸(868μL，11.73mmol)。反应液于25℃搅拌反应1小时。反应液减压浓缩至干得到粗品，向反应液中加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，经制备液相色谱纯化得到白色固体化合物188。Compound int_188-7 (120 mg, 234.57 μmol) was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (868 μL, 11.73 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product. Add saturated aqueous sodium carbonate (50 mL) to the reaction solution, extract with dichloromethane (50 mL×3), dry the organic phase with anhydrous magnesium sulfate, suction filter, and depressurize the filtrate Concentration to dryness gave the crude product, which was purified by preparative liquid chromatography to give compound 188 as a white solid.
LC-MS m/z(ESI)：412.1[M+H] +。 LC-MS m/z (ESI): 412.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.39(s，1H)，8.19(s，0.2H)，8.13(s，1H)，7.84(d，J＝5.3Hz，2H)，7.57-7.48(m，3H)，6.90(s，1H)，6.73(d，J＝7.1Hz，1H)，6.60-6.57(m，1H)，6.54-6.42(m，1H)，6.30(d，J＝16.3Hz，1H)，5.80(d，J＝8.0Hz，1H)，4.32(s，2H)，3.69(s，3H)，3.56(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.39(s, 1H), 8.19(s, 0.2H), 8.13(s, 1H), 7.84(d, J=5.3Hz, 2H), 7.57-7.48 (m, 3H), 6.90(s, 1H), 6.73(d, J=7.1Hz, 1H), 6.60-6.57(m, 1H), 6.54-6.42(m, 1H), 6.30(d, J=16.3 Hz, 1H), 5.80 (d, J = 8.0 Hz, 1H), 4.32 (s, 2H), 3.69 (s, 3H), 3.56 (s, 3H).
实施例22化合物189的合成Synthesis of Example 22 Compound 189
Figure PCTCN2022129961-appb-000267
Figure PCTCN2022129961-appb-000267
步骤1：化合物int_189-1合成：Step 1: Synthesis of compound int_189-1:
Figure PCTCN2022129961-appb-000268
Figure PCTCN2022129961-appb-000268
将2-溴-5-羟基苯甲醛(35.00g，174.11mmol)和2-氯-4-甲基嘧啶(33.58g，261.17mmol)溶于二氧六环(500mL)中，在氮气氛围下加入醋酸钾(51.26g，522.34mmol)和甲烷磺酸(2-二叔丁基膦基-2，4，6-三异丙基-1，1-联苯基)(2-氨基-1，1-联苯-2-基)钯(II)(6.92g，8.71mmol)，反应液于100℃搅拌反应16小时。反应液冷却至室温，过滤，滤液减压浓缩。加入水(1500mL)，用乙酸乙酯萃取(1500mL×3)，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_189-1。Dissolve 2-bromo-5-hydroxybenzaldehyde (35.00 g, 174.11 mmol) and 2-chloro-4-methylpyrimidine (33.58 g, 261.17 mmol) in dioxane (500 mL), and add Potassium acetate (51.26g, 522.34mmol) and methanesulfonic acid (2-di-tert-butylphosphino-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1 -Biphenyl-2-yl)palladium(II) (6.92g, 8.71mmol), the reaction solution was stirred at 100°C for 16 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Add water (1500mL), extract with ethyl acetate (1500mL×3), combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain compound int_189-1.
LC-MS m/z(ESI)：292.9[M+H] +。 LC-MS m/z (ESI): 292.9 [M+H] + .
步骤2：化合物int_189-2合成：Step 2: Synthesis of compound int_189-2:
Figure PCTCN2022129961-appb-000269
Figure PCTCN2022129961-appb-000269
将化合物int_189-1(8.00g，27.29mmol)和双联嚬哪醇硼酸酯(20.79g，81.88mmol)溶于二氧六环(80mL)中，在氮气氛围下加入醋酸钾(8.04g，81.88mmol)和[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(2.23g，2.73mmol)，反应液于100℃搅拌反应2小时。反应液冷却至室温，过滤，滤液减压浓缩。加入水(500mL)，用乙酸乙酯(500mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_189-2。Compound int_189-1 (8.00g, 27.29mmol) and bisanalyl borate (20.79g, 81.88mmol) were dissolved in dioxane (80mL), and potassium acetate (8.04g, 81.88mmol) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (2.23g, 2.73mmol), and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Water (500 mL) was added, extracted with ethyl acetate (500 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain compound int_189-2.
1H NMR(400MHz，DMSO-d 6)δ10.40(s，1H)8.45-8.51(m，1H)7.80-7.87(m，1H)7.63-7.69(m，1H)7.48-7.56(m，1H)7.16-7.23(m，1H)2.40(s，3H)1.35(s，12H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.40(s, 1H) 8.45-8.51(m, 1H) 7.80-7.87(m, 1H) 7.63-7.69(m, 1H) 7.48-7.56(m, 1H) ) 7.16-7.23 (m, 1H) 2.40 (s, 3H) 1.35 (s, 12H).
步骤3：化合物int_189-3合成：Step 3: Synthesis of compound int_189-3:
Figure PCTCN2022129961-appb-000270
Figure PCTCN2022129961-appb-000270
将化合物int_1-6(2.50g，7.08mmol)和叔-丁基4-(4，4，5，5-四甲基-1，3，2-二噁硼戊环-2-基)-5，6-二氢吡啶-1(2H)-甲酸基酯(2.63g，8.50mmol)溶于四氢呋喃(30mL)中，在氮气氛围下加入磷酸钾水溶液(2M，30mL)和[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(578.4mg，708.3μmol)，反应液于60℃搅拌反应12小时。冷却后往反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_189-3。Compound int_1-6 (2.50g, 7.08mmol) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5 , 6-dihydropyridine-1(2H)-carboxylate (2.63g, 8.50mmol) was dissolved in tetrahydrofuran (30mL), potassium phosphate aqueous solution (2M, 30mL) and [1,1-bis (Diphenylphosphine)ferrocene]palladium dichloride in dichloromethane (578.4mg, 708.3μmol), and the reaction solution was stirred at 60°C for 12 hours. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography Compound int_189-3 was obtained.
LC-MS m/z(ESI)：408.0[M+H] +。 LC-MS m/z (ESI): 408.0 [M+H] + .
步骤4：化合物int_189-4合成：Step 4: Synthesis of compound int_189-4:
Figure PCTCN2022129961-appb-000271
Figure PCTCN2022129961-appb-000271
将化合物int_189-3(1.80g，4.41mmol)和化合物int_189-2(2.25g，6.61mmol)溶于四氢呋喃(40mL)中，加入磷酸钾水溶液(2M，8.00mL)，在氮气保护下加入1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(720.1mg，881.7μmol)，反应液于100℃搅拌反应20分钟。冷却后往反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_189-4。Dissolve compound int_189-3 (1.80g, 4.41mmol) and compound int_189-2 (2.25g, 6.61mmol) in tetrahydrofuran (40mL), add potassium phosphate aqueous solution (2M, 8.00mL), add 1 under nitrogen protection, 1-Bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (720.1mg, 881.7μmol), the reaction solution was stirred at 100°C for 20 minutes. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography Compound int_189-4 was obtained.
LC-MS m/z(ESI)：542.2[M+H] +。 LC-MS m/z (ESI): 542.2 [M+H] + .
步骤5：化合物int_189-5合成：Step 5: Synthesis of compound int_189-5:
Figure PCTCN2022129961-appb-000272
Figure PCTCN2022129961-appb-000272
将化合物int_189-4(540.0mg，997.0μmol)溶于乙腈(9mL)和水(3mL)中，加入乙酸(218.5mg，3.64mmol)和氰基硼氢化钠(228.7mg，3.64mmol)，反应液于25℃搅拌反应12小时。向反应液中加入饱和碳酸钠水溶液(20mL)使pH＝8，减压浓缩除去乙腈。然后加入水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干。经硅胶色谱法分离纯化得到化合物int_189-5。Compound int_189-4 (540.0mg, 997.0μmol) was dissolved in acetonitrile (9mL) and water (3mL), added acetic acid (218.5mg, 3.64mmol) and sodium cyanoborohydride (228.7mg, 3.64mmol), the reaction solution The reaction was stirred at 25°C for 12 hours. Saturated aqueous sodium carbonate solution (20 mL) was added to the reaction solution to adjust the pH to 8, and the reaction mixture was concentrated under reduced pressure to remove acetonitrile. Then water (10 mL) was added, extracted with ethyl acetate (10 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Compound int_189-5 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：526.1[M+H] +。 LC-MS m/z (ESI): 526.1 [M+H] + .
步骤6：化合物int_189-6合成：Step 6: Synthesis of compound int_189-6:
Figure PCTCN2022129961-appb-000273
Figure PCTCN2022129961-appb-000273
将化合物int_189-5(100.0mg，190.3μmol)溶于二氯甲烷(6mL)中，三氟乙酸(1.30g，11.42 mmol)，反应液于30℃搅拌反应2小时。减压浓缩至干得到黄色油状化合物int_189-6。Compound int_189-5 (100.0 mg, 190.3 μmol) was dissolved in dichloromethane (6 mL), trifluoroacetic acid (1.30 g, 11.42 mmol), and the reaction solution was stirred at 30° C. for 2 hours. Concentrate to dryness under reduced pressure to obtain compound int_189-6 as a yellow oil.
LC-MS m/z(ESI)：426.1[M+H] +。 LC-MS m/z (ESI): 426.1 [M+H] + .
步骤7：化合物189合成：Step 7: Synthesis of compound 189:
Figure PCTCN2022129961-appb-000274
Figure PCTCN2022129961-appb-000274
将化合物int_189-6(75.0mg，176.3μmol)溶于二氯甲烷(5mL)中，加入N，N-二异丙基乙胺(22.8mg，176.3μmol)和丙烯酰氯(16.0mg，176.3μmol)，反应液于0℃搅拌反应20分钟。将反应液缓慢滴加至饱和碳酸钠溶液(10mL)中，用二氯甲烷(10mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干。经制备液相色谱纯化得到白色固体化合物189。The compound int_189-6 (75.0 mg, 176.3 μmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (22.8 mg, 176.3 μmol) and acryloyl chloride (16.0 mg, 176.3 μmol) were added , and the reaction solution was stirred at 0° C. for 20 minutes. The reaction solution was slowly added dropwise to saturated sodium carbonate solution (10 mL), extracted with dichloromethane (10 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography afforded compound 189 as a white solid.
LC-MS m/z(ESI)：480.4[M+H] +。 LC-MS m/z (ESI): 480.4 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.39-8.50(m，1H)8.17(s，0.05H)8.13(s，1H)7.52-7.59(m，2H)7.19-7.28(m，1H)7.13-7.17(m，1H)7.07-7.12(m，1H)6.78-6.97(m，1H)6.09-6.25(m，2H)5.68-5.77(m，1H)4.39(s，1H)4.27-4.32(m，3H)3.77-3.93(m，2H)3.66(s，3H)2.34-2.46(m，5H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.39-8.50 (m, 1H) 8.17 (s, 0.05H) 8.13 (s, 1H) 7.52-7.59 (m, 2H) 7.19-7.28 (m, 1H) 7.13-7.17(m, 1H)7.07-7.12(m, 1H)6.78-6.97(m,1H)6.09-6.25(m,2H)5.68-5.77(m,1H)4.39(s,1H)4.27-4.32( m, 3H) 3.77-3.93 (m, 2H) 3.66 (s, 3H) 2.34-2.46 (m, 5H).
实施例23化合物190的合成Synthesis of Example 23 Compound 190
Figure PCTCN2022129961-appb-000275
Figure PCTCN2022129961-appb-000275
步骤1：化合物int_190-2合成：Step 1: Synthesis of compound int_190-2:
Figure PCTCN2022129961-appb-000276
Figure PCTCN2022129961-appb-000276
将化合物int_1-6(3.00g，8.50mmol)和1-(1-BOC-4-哌啶)吡唑-4-硼酸嚬哪醇酯(3.85g，10.20mmol)溶于四氢呋喃(40mL)中，在氮气氛围下加入磷酸钾水溶液(2M，40mL)和[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(694.1mg，850.0μmol)，反应液于60℃搅拌反应24小时。冷却后往反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_190-2。The compound int_1-6 (3.00g, 8.50mmol) and 1-(1-BOC-4-piperidine)pyrazole-4-boronate (3.85g, 10.20mmol) were dissolved in tetrahydrofuran (40mL), Under nitrogen atmosphere, potassium phosphate aqueous solution (2M, 40mL) and [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane (694.1mg, 850.0μmol) were added, and the reaction solution was heated at 60°C The reaction was stirred for 24 hours. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography Compound int_190-2 was obtained.
LC-MS m/z(ESI)：476.1[M+H] +。 LC-MS m/z (ESI): 476.1 [M+H] + .
步骤2：化合物int_190-3合成：Step 2: Synthesis of compound int_190-3:
Figure PCTCN2022129961-appb-000277
Figure PCTCN2022129961-appb-000277
将化合物int_190-2(1.80g，3.78mmol)和化合物int_189-2(1.93g，5.67mmol)溶于四氢呋喃(40mL)中，加入磷酸钾水溶液(2M，8.0mL)，在氮气保护下加入1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(617.2mg，755.7μmol)，反应液于100℃搅拌反应20分钟。冷却后往反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_190-3。Compound int_190-2 (1.80g, 3.78mmol) and compound int_189-2 (1.93g, 5.67mmol) were dissolved in tetrahydrofuran (40mL), potassium phosphate aqueous solution (2M, 8.0mL) was added, and 1 was added under nitrogen protection, 1-Bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (617.2mg, 755.7μmol), the reaction solution was stirred at 100°C for 20 minutes. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and separated and purified by silica gel chromatography Compound int_190-3 was obtained.
LC-MS m/z(ESI)：610.2[M+H] +。 LC-MS m/z (ESI): 610.2 [M+H] + .
步骤3：化合物int_190-4合成：Step 3: Synthesis of compound int_190-4:
Figure PCTCN2022129961-appb-000278
Figure PCTCN2022129961-appb-000278
将化合物int_190-3(590.0mg，967.7μmol)溶于乙腈(15mL)和水(5mL)中，加入乙酸(290.6mg，4.84mmol)和氰基硼氢化钠(304.1mg，4.84mmol)，反应液于40℃搅拌反应12小时。向反应液中加入饱和碳酸钠水溶液(25mL)使pH＝8，减压浓缩除去乙腈。然后加入水(10mL)，用乙酸乙 酯(10mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干。经硅胶色谱法分离纯化得到化合物int_190-4。Compound int_190-3 (590.0mg, 967.7μmol) was dissolved in acetonitrile (15mL) and water (5mL), added acetic acid (290.6mg, 4.84mmol) and sodium cyanoborohydride (304.1mg, 4.84mmol), the reaction solution The reaction was stirred at 40°C for 12 hours. Saturated aqueous sodium carbonate solution (25 mL) was added to the reaction solution to adjust the pH to 8, and the reaction mixture was concentrated under reduced pressure to remove acetonitrile. Then water (10 mL) was added, extracted with ethyl acetate (10 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Compound int_190-4 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：594.2[M+H] +。 LC-MS m/z (ESI): 594.2 [M+H] + .
步骤4：化合物int_190-5合成：Step 4: Synthesis of compound int_190-5:
Figure PCTCN2022129961-appb-000279
Figure PCTCN2022129961-appb-000279
将化合物int_190-4(170.0mg，286.3μmol)溶于二氯甲烷(7mL)中，三氟乙酸(1.96g，17.18mmol)，反应液于30℃搅拌反应1小时。减压浓缩至干得到粗品黄色油状化合物int_190-5。Compound int_190-4 (170.0 mg, 286.3 μmol) was dissolved in dichloromethane (7 mL), trifluoroacetic acid (1.96 g, 17.18 mmol), and the reaction solution was stirred at 30° C. for 1 hour. Concentrate to dryness under reduced pressure to obtain the crude yellow oily compound int_190-5.
LC-MS m/z(ESI)：494.1[M+H] +。 LC-MS m/z (ESI): 494.1 [M+H] + .
步骤5：化合物190合成：Step 5: Synthesis of compound 190:
Figure PCTCN2022129961-appb-000280
Figure PCTCN2022129961-appb-000280
将化合物int_190-5(100.0mg，202.6μmol)溶于二氯甲烷(6mL)中，加入N，N-二异丙基乙胺(26.2mg，202.7μmol)和丙烯酰氯(18.34mg，202.6μmol)，反应液于0℃搅拌反应20分钟。将反应液缓慢滴加至饱和碳酸钠水溶液(10mL)中，用二氯甲烷(10mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干。经制备液相色谱纯化得到白色固体化合物190。The compound int_190-5 (100.0 mg, 202.6 μmol) was dissolved in dichloromethane (6 mL), and N,N-diisopropylethylamine (26.2 mg, 202.7 μmol) and acryloyl chloride (18.34 mg, 202.6 μmol) were added , and the reaction solution was stirred at 0° C. for 20 minutes. The reaction solution was slowly added dropwise to saturated aqueous sodium carbonate solution (10 mL), extracted with dichloromethane (10 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. Purification by preparative liquid chromatography afforded compound 190 as a white solid.
LC-MS m/z(ESI)：548.5[M+H] +。 LC-MS m/z (ESI): 548.5 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.39-8.47(m，1H)8.22(s，1H)8.17(s，0.06H)8.13(s，1H)7.72(s，1H)7.53-7.61(m，1H)7.17-7.20(m，1H)7.11-7.16(m，2H)6.80-6.92(m，2H)6.08-6.16(m，1H)5.65-5.73(m，1H)4.45-4.65(m，2H)4.29-4.36(m，2H)4.11-4.21(m，1H)3.62(s，3H)3.21-3.28(m，1H)2.81-2.93(m，1H)2.39(s，3H)2.10-2.20(m，2H)1.79-1.98(m，2H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ8.39-8.47 (m, 1H) 8.22 (s, 1H) 8.17 (s, 0.06H) 8.13 (s, 1H) 7.72 (s, 1H) 7.53-7.61 ( m, 1H) 7.17-7.20 (m, 1H) 7.11-7.16 (m, 2H) 6.80-6.92 (m, 2H) 6.08-6.16 (m, 1H) 5.65-5.73 (m, 1H) 4.45-4.65 (m, ( m, 2H) 1.79-1.98 (m, 2H).
实施例24化合物191的合成Synthesis of Example 24 Compound 191
Figure PCTCN2022129961-appb-000281
Figure PCTCN2022129961-appb-000281
步骤1：化合物int_191-1合成：Step 1: Synthesis of compound int_191-1:
Figure PCTCN2022129961-appb-000282
Figure PCTCN2022129961-appb-000282
将化合物int_88-4(150mg，328.62μmol)和化合物int_189-2(167.69mg，492.93μmol)溶于四氢呋喃(3mL)中，加入磷酸钾水溶液(2M，600μL，1.20mmol)，2-二环己基磷-2，4，6-三异丙基联苯(15.67mg，32.86μmol)和(2-二环己基膦-2，4，6-三异丙基-1，1-联苯)[2-(2-氨基-1，1-联苯)](27.82mg，32.86μmol)。反应液于100℃搅拌反应0.5小时。冷却后往反应液中加入水(10mL)，混合液用乙酸乙酯(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_191-1。Compound int_88-4 (150 mg, 328.62 μmol) and compound int_189-2 (167.69 mg, 492.93 μmol) were dissolved in tetrahydrofuran (3 mL), potassium phosphate aqueous solution (2M, 600 μL, 1.20 mmol), 2-dicyclohexylphosphine -2,4,6-triisopropylbiphenyl (15.67mg, 32.86μmol) and (2-dicyclohexylphosphine-2,4,6-triisopropyl-1,1-biphenyl)[2- (2-Amino-1,1-biphenyl)] (27.82 mg, 32.86 μmol). The reaction solution was stirred and reacted at 100°C for 0.5 hours. After cooling, water (10mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (10mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_191-1 was obtained by separation and purification by chromatography.
LC-MS m/z(ESI)：590.1[M+H] +。 LC-MS m/z (ESI): 590.1 [M+H] + .
步骤2：化合物int_191-2合成：Step 2: Synthesis of compound int_191-2:
Figure PCTCN2022129961-appb-000283
Figure PCTCN2022129961-appb-000283
将化合物int_191-1(150mg，254.34μmol)溶于乙腈(6mL)和四氢呋喃(2mL)中，加入醋酸(72.73μL，1.27mmol)和氰基硼氢化钠(79.91.mg，1.27mmol)。反应液于40℃搅拌反应12小时。冷却后往反应液中加入饱和碳酸钠水溶液(25mL)，调pH至8，减压浓缩去除乙腈，混合液中加入水(10mL)，用乙酸乙酯(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_191-2。Compound int_191-1 (150mg, 254.34μmol) was dissolved in acetonitrile (6mL) and tetrahydrofuran (2mL), and acetic acid (72.73μL, 1.27mmol) and sodium cyanoborohydride (79.91.mg, 1.27mmol) were added. The reaction solution was stirred and reacted at 40° C. for 12 hours. After cooling, add saturated aqueous sodium carbonate solution (25 mL) to the reaction solution, adjust the pH to 8, concentrate under reduced pressure to remove acetonitrile, add water (10 mL) to the mixture, extract with ethyl acetate (10 mL×3), combine the organic phases, After drying with anhydrous magnesium sulfate, suction filtration, the filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_191-2.
LC-MS m/z(ESI)：574.2[M+H] +； LC-MS m/z (ESI): 574.2 [M+H] + ;
步骤3：化合物int_191-3合成：Step 3: Synthesis of compound int_191-3:
Figure PCTCN2022129961-appb-000284
Figure PCTCN2022129961-appb-000284
将化合物int_191-2(50mg，87.14μmol)溶于四氢呋喃(2mL)中，加入四丁基氟化铵(1M，174.29μL，174.29μmol)。反应液于25℃搅拌反应1小时。往反应液中加入水(30mL)，混合液用乙酸乙酯(30mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经制备液相色谱纯化得到白色固体化合物191。Compound int_191-2 (50 mg, 87.14 μmol) was dissolved in tetrahydrofuran (2 mL), and tetrabutylammonium fluoride (1M, 174.29 μL, 174.29 μmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. Add water (30mL) to the reaction solution, extract the mixture with ethyl acetate (30mL×3), combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and then prepare the liquid phase Chromatography afforded compound 191 as a white solid.
LC-MS m/z(ESI)：460.5[M+H] +。 LC-MS m/z (ESI): 460.5 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ8.62(s，1H)，8.43(d，J＝5.0Hz，1H)，8.21(s，1H)，7.73(s，1H)，7.66(br s，1H)，7.23(d，J＝2.2Hz，1H)，7.13(d，J＝5.0Hz，1H)，6.91-6.85(m，1H)，6.68(d，J＝8.7Hz，1H)，4.47(s，1H)，4.37(br s，2H)，3.49(s，3H)，2.40(s，3H)，2.16(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.62(s, 1H), 8.43(d, J=5.0Hz, 1H), 8.21(s, 1H), 7.73(s, 1H), 7.66(br s , 1H), 7.23(d, J=2.2Hz, 1H), 7.13(d, J=5.0Hz, 1H), 6.91-6.85(m, 1H), 6.68(d, J=8.7Hz, 1H), 4.47 (s, 1H), 4.37 (br s, 2H), 3.49 (s, 3H), 2.40 (s, 3H), 2.16 (s, 3H).
实施例25化合物192的合成Synthesis of Example 25 Compound 192
Figure PCTCN2022129961-appb-000285
Figure PCTCN2022129961-appb-000285
步骤1：化合物int_192-1合成：Step 1: Synthesis of compound int_192-1:
Figure PCTCN2022129961-appb-000286
Figure PCTCN2022129961-appb-000286
将化合物int_11-11(170mg，153.82μmol)溶于二氯甲烷(10mL)中，加入甲基丙烯酰氯(30.05μL，307.64μmol)和三乙胺(64.23μL，461.46μmol)。反应液于20℃搅拌反应1小时。往反应液中加入水(10mL)，混合液用二氯甲烷(10mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品化合物int_192-1。Compound int_11-11 (170 mg, 153.82 μmol) was dissolved in dichloromethane (10 mL), and methacryloyl chloride (30.05 μL, 307.64 μmol) and triethylamine (64.23 μL, 461.46 μmol) were added. The reaction solution was stirred and reacted at 20° C. for 1 hour. Water (10mL) was added to the reaction solution, the mixture was extracted with dichloromethane (10mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude compound int_192-1 .
LC-MS m/z(ESI)：621.1[M+H] +。 LC-MS m/z (ESI): 621.1 [M+H] + .
步骤2：化合物192合成：Step 2: Synthesis of Compound 192:
Figure PCTCN2022129961-appb-000287
Figure PCTCN2022129961-appb-000287
将化合物int_192-1(400mg，644.46μmol)溶于二氯甲烷(20mL)中，加入三氟乙酸(2.86mL，38.67mmol)。反应液于30℃搅拌反应1小时。往反应液中加入水(30mL)，混合液用二氯甲烷(30mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经制备液相色谱纯化得到白色固体化合物192。Compound int_192-1 (400 mg, 644.46 μmol) was dissolved in dichloromethane (20 mL), and trifluoroacetic acid (2.86 mL, 38.67 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Add water (30mL) to the reaction solution, extract the mixture with dichloromethane (30mL×3), combine the organic phases, dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and then prepare the liquid phase Chromatography afforded compound 192 as a white solid.
LC-MS m/z(ESI)：521.1[M+H] +。 LC-MS m/z (ESI): 521.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.06(s，1H)，8.19(s，1H)，7.92(d，J＝8.6Hz，2H)，7.97-7.85(m，1H)，7.63(br s，1H)，7.56(d，J＝8.5Hz，2H)，7.01-6.93(m，2H)，6.83(d，J＝8.1Hz，1H)，6.66(d，J＝8.6Hz，1H)，5.85(s，1H)，5.57(s，1H)，4.47(br s，2H)，3.60(s，3H)，2.27(s，3H)，1.98(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.06(s, 1H), 8.19(s, 1H), 7.92(d, J=8.6Hz, 2H), 7.97-7.85(m, 1H), 7.63( br s, 1H), 7.56(d, J=8.5Hz, 2H), 7.01-6.93(m, 2H), 6.83(d, J=8.1Hz, 1H), 6.66(d, J=8.6Hz, 1H) , 5.85(s, 1H), 5.57(s, 1H), 4.47(br s, 2H), 3.60(s, 3H), 2.27(s, 3H), 1.98(s, 3H).
实施例26化合物193的合成Synthesis of Example 26 Compound 193
Figure PCTCN2022129961-appb-000288
Figure PCTCN2022129961-appb-000288
Figure PCTCN2022129961-appb-000289
Figure PCTCN2022129961-appb-000289
步骤1：化合物int_193-2合成：Step 1: Synthesis of compound int_193-2:
Figure PCTCN2022129961-appb-000290
Figure PCTCN2022129961-appb-000290
将2-氟-4-溴硝基苯(20g，90.91mmol)和双联嚬哪醇硼酸酯(92.34g，363.64mmol)溶于二氧六环(400mL)中，加入醋酸钾(26.77g，272.73mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(3.71g，4.55mmol)。反应液于100℃搅拌反应3小时。冷却后往反应液中加入水(200mL)，混合液用乙酸乙酯(200mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_193-2。Dissolve 2-fluoro-4-bromonitrobenzene (20g, 90.91mmol) and bisanalyl borate (92.34g, 363.64mmol) in dioxane (400mL), add potassium acetate (26.77g , 272.73mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (3.71g, 4.55mmol). The reaction solution was stirred and reacted at 100° C. for 3 hours. After cooling, water (200mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (200mL×3), the organic phases were combined, dried over anhydrous magnesium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and then filtered through silica gel Compound int_193-2 was obtained by separation and purification by chromatography.
1H NMR(400MHz，DMSO-d 6)δ8.16-8.05(m，1H)，7.76-7.56(m，2H)，1.42-1.28(s，12H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.16-8.05 (m, 1H), 7.76-7.56 (m, 2H), 1.42-1.28 (s, 12H).
步骤2：化合物int_193-3合成：Step 2: Synthesis of compound int_193-3:
Figure PCTCN2022129961-appb-000291
Figure PCTCN2022129961-appb-000291
将化合物int_1-6(6g，17.00mmol)和化合物int_193-2(9.08g，34.00mmol)溶于四氢呋喃(90mL)中，在氮气保护下加入1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(1.39g，1.70mmol)和磷酸钾水溶液(2M，90mL)。反应液于60℃搅拌反应1小时。冷却后向反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_193-3。Compound int_1-6 (6g, 17.00mmol) and compound int_193-2 (9.08g, 34.00mmol) were dissolved in tetrahydrofuran (90mL), and 1,1-bis(diphenylphosphino)ferrocene was added under nitrogen protection A mixture of palladium chloride in dichloromethane (1.39 g, 1.70 mmol) and aqueous potassium phosphate (2M, 90 mL). The reaction solution was stirred and reacted at 60° C. for 1 hour. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was subjected to silica gel chromatography Compound int_193-3 was obtained by separation and purification.
LC-MS m/z(ESI)：365.9[M+H] +。 LC-MS m/z (ESI): 365.9 [M+H] + .
步骤3：化合物int_193-4合成：Step 3: Synthesis of compound int_193-4:
Figure PCTCN2022129961-appb-000292
Figure PCTCN2022129961-appb-000292
将化合物int_193-3(2.6g，7.10mmol)和化合物int_1-3(3.13g，9.23mmol)溶于四氢呋喃(39mL)中，在氮气保护下加入双(三环己基膦基)二氯化钯(524.18mg，710.10μmol)和磷酸钾水溶液(2M，8mL)。反应液于100℃搅拌反应30分钟。冷却后向反应液中加入水(200mL)，用乙酸乙酯(200mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_193-4。Compound int_193-3 (2.6g, 7.10mmol) and compound int_1-3 (3.13g, 9.23mmol) were dissolved in tetrahydrofuran (39mL), and bis(tricyclohexylphosphino)palladium dichloride was added under nitrogen protection ( 524.18mg, 710.10μmol) and potassium phosphate aqueous solution (2M, 8mL). The reaction solution was stirred and reacted at 100° C. for 30 minutes. After cooling, water (200 mL) was added to the reaction solution, extracted with ethyl acetate (200 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product, which was subjected to silica gel chromatography Compound int_193-4 was obtained by separation and purification.
LC-MS m/z(ESI)：499.0[M+H] +。 LC-MS m/z (ESI): 499.0 [M+H] + .
步骤4：化合物int_193-5合成：Step 4: Synthesis of compound int_193-5:
Figure PCTCN2022129961-appb-000293
Figure PCTCN2022129961-appb-000293
将化合物int_193-4(900mg，1.81mmol)溶于乙腈(18mL)，加入乙酸(0.5mL，9.03mmol)和氰基硼氢化钠(567.32mg，9.03mmol)。反应液于25℃搅拌反应16小时。减压浓缩干，向反应液中加入饱和碳酸钠水溶液(30mL)，再用乙酸乙酯(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_193-5。Compound int_193-4 (900 mg, 1.81 mmol) was dissolved in acetonitrile (18 mL), and acetic acid (0.5 mL, 9.03 mmol) and sodium cyanoborohydride (567.32 mg, 9.03 mmol) were added. The reaction solution was stirred and reacted at 25°C for 16 hours. Concentrate to dryness under reduced pressure, add saturated aqueous sodium carbonate solution (30mL) to the reaction solution, then extract with ethyl acetate (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain Crude product, the crude product was separated and purified by silica gel chromatography to obtain compound int_193-5.
LC-MS m/z(ESI)：483.0[M+H] +。 LC-MS m/z (ESI): 483.0 [M+H] + .
步骤5：化合物int_193-6合成：Step 5: Synthesis of compound int_193-6:
Figure PCTCN2022129961-appb-000294
Figure PCTCN2022129961-appb-000294
将化合物int_193-5(163mg，337.85μmol)溶于N，N-二甲基甲酰胺(3mL)中，加入三乙胺(141μL，1.01mmol)和BOC酸酐(776μL，3.38mmol)，4-二甲氨基吡啶(20.64mg，168.92μmol)，反应 液于50℃搅拌反应16小时。反应液减压浓缩至干，将反应液倒入水(100mL)中，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，粗品经硅胶色谱法分离纯化得到化合物int_193-6。Compound int_193-5 (163 mg, 337.85 μmol) was dissolved in N,N-dimethylformamide (3 mL), triethylamine (141 μL, 1.01 mmol) and BOC anhydride (776 μL, 3.38 mmol) were added, 4-di Aminopyridine (20.64mg, 168.92μmol), the reaction solution was stirred at 50°C for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, the reaction solution was poured into water (100 mL), extracted with ethyl acetate (100 mL×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. The crude product was separated and purified by silica gel chromatography to obtain compound int_193-6.
LC-MS m/z(ESI)：583.1[M+H] +。 LC-MS m/z (ESI): 583.1 [M+H] + .
步骤6：化合物int_193-7合成：Step 6: Compound int_193-7 synthesis:
Figure PCTCN2022129961-appb-000295
Figure PCTCN2022129961-appb-000295
将化合物int_193-6(150mg，257.48μmol)溶于甲醇(2.5mL)和水(0.5mL)中，加入铁粉(143.79mg，2.57mmol)和氯化铵(137.73mg，2.57mmol)。反应液于65℃搅拌反应1小时。将反应液过滤，滤液减压浓缩至干得到粗品。再加入水(30mL)，用乙酸乙酯(30mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到化合物int_193-7。Compound int_193-6 (150 mg, 257.48 μmol) was dissolved in methanol (2.5 mL) and water (0.5 mL), and iron powder (143.79 mg, 2.57 mmol) and ammonium chloride (137.73 mg, 2.57 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. Water (30 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain compound int_193-7.
LC-MS m/z(ESI)：553.2[M+H] +。 LC-MS m/z (ESI): 553.2 [M+H] + .
步骤7：化合物int_193-8合成：Step 7: Compound int_193-8 synthesis:
Figure PCTCN2022129961-appb-000296
Figure PCTCN2022129961-appb-000296
将化合物int_193-7(136mg，246.11μmol)溶于二氯甲烷(5mL)中，加入N，N-二异丙基乙胺(128μL，738μmol)。然后在0℃下加入丙烯酰氯(40μL，492.22μmol)，反应液于25℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到黄色油状粗品化合物int_193-8。Compound int_193-7 (136 mg, 246.11 μmol) was dissolved in dichloromethane (5 mL), and N,N-diisopropylethylamine (128 μL, 738 μmol) was added. Then acryloyl chloride (40 μL, 492.22 μmol) was added at 0° C., and the reaction solution was stirred at 25° C. for 1 hour. Add saturated aqueous sodium carbonate solution (50mL) to the reaction solution, extract with dichloromethane (50mL×3), dry the organic phase with anhydrous magnesium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain a yellow oily crude compound int_193- 8.
LC-MS m/z(ESI)：607.2[M+H] +。 LC-MS m/z (ESI): 607.2 [M+H] + .
步骤8：化合物193合成：Step 8: Synthesis of Compound 193:
Figure PCTCN2022129961-appb-000297
Figure PCTCN2022129961-appb-000297
将化合物int_193-8(183mg，301.66μmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(1.1mL，15.08mmol)。反应液于25℃搅拌反应1小时。反应液减压浓缩至干，再加入饱和碳酸钠水溶液(50mL)，用二氯甲烷(50mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，经制备液相色谱纯化得到白色固体化合物193。Compound int_193-8 (183 mg, 301.66 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.1 mL, 15.08 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, then saturated aqueous sodium carbonate solution (50 mL) was added, extracted with dichloromethane (50 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product , and purified by preparative liquid chromatography to obtain compound 193 as a white solid.
LC-MS m/z(ESI)：507.2[M+H] +。 LC-MS m/z (ESI): 507.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.16(s，1H)，8.30(t，J＝8.3Hz，1H)，8.18(s，1H)，8.13(s，0.13H)，7.76-7.68(m，1H)，7.66-7.55(m，2H)，7.41(d，J＝8.3Hz，1H)，7.12(s，1H)，6.98(d，J＝7.3Hz，1H)，6.88-6.77(m，2H)，6.76-6.65(m，2H)，6.32(d，J＝16.9Hz，1H)，5.82(d，J＝10.1Hz，1H)，4.36(s，2H)，3.61(s，3H)，2.30(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.16(s, 1H), 8.30(t, J=8.3Hz, 1H), 8.18(s, 1H), 8.13(s, 0.13H), 7.76-7.68 (m, 1H), 7.66-7.55(m, 2H), 7.41(d, J=8.3Hz, 1H), 7.12(s, 1H), 6.98(d, J=7.3Hz, 1H), 6.88-6.77( m, 2H), 6.76-6.65(m, 2H), 6.32(d, J=16.9Hz, 1H), 5.82(d, J=10.1Hz, 1H), 4.36(s, 2H), 3.61(s, 3H ), 2.30(s, 3H).
实施例27化合物194的合成Synthesis of Example 27 Compound 194
Figure PCTCN2022129961-appb-000298
Figure PCTCN2022129961-appb-000298
步骤1：化合物int_194-2合成：Step 1: Synthesis of compound int_194-2:
Figure PCTCN2022129961-appb-000299
Figure PCTCN2022129961-appb-000299
将5-氯-2-硝基苯甲醚(10.00g，53.31mmol)和双联嚬哪醇硼酸酯(20.31g，79.97mmol)溶于二氧六环(100mL)中，在氮气氛围下加入三(二亚苄基丙酮)二钯(4.88g，5.33mmol)，三环己基膦(2.99g，10.66mmol)和醋酸钾(17.27g，175.92mmol)。反应液于85℃搅拌反应3小时。反应液冷却至室温，向反应液中加入水(1.0L)，然后用乙酸乙酯(1.0L×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_194-2。5-Chloro-2-nitroanisole (10.00g, 53.31mmol) and bisanalyl borate (20.31g, 79.97mmol) were dissolved in dioxane (100mL), under nitrogen atmosphere Tris(dibenzylideneacetone)dipalladium (4.88g, 5.33mmol), tricyclohexylphosphine (2.99g, 10.66mmol) and potassium acetate (17.27g, 175.92mmol) were added. The reaction solution was stirred and reacted at 85° C. for 3 hours. The reaction solution was cooled to room temperature, water (1.0L) was added to the reaction solution, and then extracted with ethyl acetate (1.0L×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. , separated and purified by silica gel chromatography to obtain compound int_194-2.
1H NMR(400MHz，DMSO-d 6)δppm 7.84(d，J＝7.88Hz，1H)7.45(s，1H)7.35-7.41(m，1H)3.94(s，3H)1.32(s，12H)。 1 H NMR (400 MHz, DMSO-d 6 ) δppm 7.84 (d, J=7.88 Hz, 1H) 7.45 (s, 1H) 7.35-7.41 (m, 1H) 3.94 (s, 3H) 1.32 (s, 12H).
步骤2：化合物int_194-3合成：Step 2: Synthesis of compound int_194-3:
Figure PCTCN2022129961-appb-000300
Figure PCTCN2022129961-appb-000300
将化合物int_1-6(5.00g，14.17mmol)和化合物int_194-2(3.95g，14.17mmol)溶于四氢呋喃(120mL)中，在氮气保护下加入磷酸钾水溶液(2M，25mL)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(1.16g，1.42mmol)，反应液于60℃搅拌2小时。反应液冷却至室温，向反应液中加入水(500mL)，此过程有白色固体析出，然后过滤，滤饼用乙酸乙酯(500mL)洗涤。滤饼收集经减压浓缩至干得到白色固体化合物int_194-3。Compound int_1-6 (5.00g, 14.17mmol) and compound int_194-2 (3.95g, 14.17mmol) were dissolved in tetrahydrofuran (120mL), and potassium phosphate aqueous solution (2M, 25mL) and 1,1- Bis(diphenylphosphino)ferrocenepalladium chloride dichloromethane mixture (1.16g, 1.42mmol), and the reaction solution was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature, and water (500 mL) was added to the reaction solution. During this process, a white solid was precipitated, then filtered, and the filter cake was washed with ethyl acetate (500 mL). The filter cake was collected and concentrated to dryness under reduced pressure to obtain compound int_194-3 as a white solid.
LC-MS m/z(ESI)：377.9[M+H] +。 LC-MS m/z (ESI): 377.9 [M+H] + .
步骤3：化合物int_194-4合成：Step 3: Synthesis of compound int_194-4:
Figure PCTCN2022129961-appb-000301
Figure PCTCN2022129961-appb-000301
将化合物int_194-3(2.00g，5.29mmol)和化合物int_1-3(2.69g，7.93mmol)溶于四氢呋喃(60mL)中，在氮气保护下加入磷酸钾水溶液(2M，12mL)和双(三环己基膦基)二氯化钯(II)(390.4mg，528.9μmol)，反应液于100℃搅拌20分钟。反应液冷却至室温，向反应液中加入水(500mL)，然后 用乙酸乙酯(500mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_194-4。Compound int_194-3 (2.00g, 5.29mmol) and compound int_1-3 (2.69g, 7.93mmol) were dissolved in tetrahydrofuran (60mL), and potassium phosphate aqueous solution (2M, 12mL) and bis(tricyclic Hexylphosphino)palladium(II) dichloride (390.4mg, 528.9μmol), and the reaction solution was stirred at 100°C for 20 minutes. The reaction solution was cooled to room temperature, water (500mL) was added to the reaction solution, and then extracted with ethyl acetate (500mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure. The compound int_194-4 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：511.1[M+H] +。 LC-MS m/z (ESI): 511.1 [M+H] + .
步骤4：化合物int_194-5合成：Step 4: Synthesis of compound int_194-5:
Figure PCTCN2022129961-appb-000302
Figure PCTCN2022129961-appb-000302
将化合物int_194-4(2.00g，3.92mmol)溶于乙腈(24mL)和四氢呋喃(8mL)中，加入氰基硼氢化钠(1.23g，19.59mmol)和乙酸(1.18g，19.59mmol)，反应液于25℃搅拌2小时。向反应液中加入饱和碳酸钠水溶液(15mL)使pH＝8，减压浓缩除去有机溶剂。向剩余物中加入水(30mL)，用二氯甲烷(30mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_194-5。Compound int_194-4 (2.00g, 3.92mmol) was dissolved in acetonitrile (24mL) and tetrahydrofuran (8mL), sodium cyanoborohydride (1.23g, 19.59mmol) and acetic acid (1.18g, 19.59mmol) were added, and the reaction solution Stir at 25°C for 2 hours. Saturated aqueous sodium carbonate solution (15 mL) was added to the reaction solution to adjust the pH to 8, and the organic solvent was removed by concentration under reduced pressure. Add water (30mL) to the residue, extract with dichloromethane (30mL×3), combine the organic phases to dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain the compound int_194-5.
LC-MS m/z(ESI)：495.1[M+H] +。 LC-MS m/z (ESI): 495.1 [M+H] + .
步骤5：化合物int_194-6合成：Step 5: Synthesis of compound int_194-6:
Figure PCTCN2022129961-appb-000303
Figure PCTCN2022129961-appb-000303
将化合物int_194-5(1.10g，2.22mmol)溶于N，N-二甲基甲酰胺(30mL)中，加入BOC酸酐(4.85g，22.24mmol)，4-二甲氨基吡啶(135.9mg，1.11mmol)和三乙胺(862.1mg，8.52mmol)，混合液于50℃搅拌2小时。反应液冷却至室温，减压浓缩除去有机溶剂。向剩余物中加入水(30mL)，用二氯甲烷(30mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_194-6。Compound int_194-5 (1.10g, 2.22mmol) was dissolved in N,N-dimethylformamide (30mL), BOC anhydride (4.85g, 22.24mmol), 4-dimethylaminopyridine (135.9mg, 1.11 mmol) and triethylamine (862.1mg, 8.52mmol), the mixture was stirred at 50°C for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove the organic solvent. Add water (30mL) to the residue, extract with dichloromethane (30mL×3), combine the organic phases to dry over anhydrous magnesium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain the compound int_194-6.
LC-MS m/z(ESI)：595.1[M+H] +。 LC-MS m/z (ESI): 595.1 [M+H] + .
步骤6：化合物int_194-7合成：Step 6: Compound int_194-7 synthesis:
Figure PCTCN2022129961-appb-000304
Figure PCTCN2022129961-appb-000304
将化合物int_194-6(860.0mg，1.45mmol)溶于乙醇(4mL)和水(0.8mL)中，加入铁粉(807.7mg，14.46mmol)和氯化铵(773.7mg，14.46mmol)，反应液于80℃搅拌反应2小时。反应液冷却至室温，过滤，用二氯甲烷(50mL)洗涤。滤液减压浓缩除去溶剂，向剩余物中加入水(50mL)，用二氯甲烷(50mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_194-7。Compound int_194-6 (860.0mg, 1.45mmol) was dissolved in ethanol (4mL) and water (0.8mL), iron powder (807.7mg, 14.46mmol) and ammonium chloride (773.7mg, 14.46mmol) were added, and the reaction solution The reaction was stirred at 80°C for 2 hours. The reaction solution was cooled to room temperature, filtered and washed with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure to remove the solvent, water (50 mL) was added to the residue, extracted with dichloromethane (50 mL×3), the combined organic phases were dried over anhydrous magnesium sulfate, suction filtered, the filtrate was concentrated to dryness under reduced pressure, and the Compound int_194-7 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：565.2[M+H] +。 LC-MS m/z (ESI): 565.2 [M+H] + .
步骤7：化合物int_194-8合成：Step 7: Synthesis of compound int_194-8:
Figure PCTCN2022129961-appb-000305
Figure PCTCN2022129961-appb-000305
将化合物int_194-7(250.0mg，442.8μmol)溶于二氯甲烷(8mL)中，在0℃下加入三乙胺(134.4mg，1.33mmol)和丙烯酰氯(80.2mg，885.5μmol)，反应液于25℃搅拌反应1小时。向反应液中加入饱和碳酸钠水溶液(10mL)使pH＝8，再加入水(20mL)，用二氯甲烷(30mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，得到黄色固体化合物int_194-8。The compound int_194-7 (250.0mg, 442.8μmol) was dissolved in dichloromethane (8mL), and triethylamine (134.4mg, 1.33mmol) and acryloyl chloride (80.2mg, 885.5μmol) were added at 0°C, and the reaction solution The reaction was stirred at 25°C for 1 hour. Add saturated sodium carbonate aqueous solution (10mL) to the reaction solution to make the pH=8, then add water (20mL), extract with dichloromethane (30mL×3), combine the organic phases to dry with anhydrous magnesium sulfate, suction filter, and the filtrate Concentrate to dryness under reduced pressure to obtain yellow solid compound int_194-8.
LC-MS m/z(ESI)：619.1[M+H] +。 LC-MS m/z (ESI): 619.1 [M+H] + .
步骤8：化合物194合成：Step 8: Synthesis of Compound 194:
Figure PCTCN2022129961-appb-000306
Figure PCTCN2022129961-appb-000306
将化合物int_194-8(240.0mg，387.9μmol)溶于二氯甲烷(8mL)中，加入三氟乙酸(2.65g，23.28mmol)，反应液于30℃搅拌反应2小时。反应液经减压浓缩除去三氟乙酸，向剩余物中加入饱 和碳酸钠水溶液(15mL)使pH＝8，再用二氯甲烷(15mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经制备液相色谱纯化得到白色固体化合物194。Compound int_194-8 (240.0 mg, 387.9 μmol) was dissolved in dichloromethane (8 mL), trifluoroacetic acid (2.65 g, 23.28 mmol) was added, and the reaction solution was stirred at 30° C. for 2 hours. The reaction solution was concentrated under reduced pressure to remove trifluoroacetic acid, and saturated aqueous sodium carbonate (15 mL) was added to the residue to make the pH = 8, then extracted with dichloromethane (15 mL×3), and the combined organic phases were dried over anhydrous magnesium sulfate , suction filtration, the filtrate was concentrated to dryness under reduced pressure, and purified by preparative liquid chromatography to obtain compound 194 as a white solid.
LC-MS m/z(ESI)：519.1[M+H] +。 LC-MS m/z (ESI): 519.1 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δppm 9.57(s，1H)8.31(d，J＝8.19Hz，1H)8.17(s，1H)7.69(t，J＝7.76Hz，1H)7.57(br s，1H)7.27(d，J＝1.59Hz，1H)7.12-7.17(m，1H)7.10(d，J＝2.45Hz，1H)6.96(d，J＝7.34Hz，1H)6.90(d，J＝8.68Hz，1H)6.69-6.83(m，3H)6.22-6.32(m，1H)5.70-5.80(m，1H)4.36(br d，J＝3.06Hz，2H)3.86(s，3H)3.62(s，3H)2.29(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δppm 9.57(s, 1H) 8.31(d, J=8.19Hz, 1H) 8.17(s, 1H) 7.69(t, J=7.76Hz, 1H) 7.57(br s , 1H) 7.27 (d, J = 1.59Hz, 1H) 7.12-7.17 (m, 1H) 7.10 (d, J = 2.45Hz, 1H) 6.96 (d, J = 7.34Hz, 1H) 6.90 (d, J = 8.68Hz, 1H) 6.69-6.83(m, 3H) 6.22-6.32(m, 1H) 5.70-5.80(m, 1H) 4.36(br d, J=3.06Hz, 2H) 3.86(s, 3H) 3.62(s , 3H) 2.29 (s, 3H).
实施例28化合物195的合成Synthesis of Example 28 Compound 195
Figure PCTCN2022129961-appb-000307
Figure PCTCN2022129961-appb-000307
步骤1：化合物int_195-1合成：Step 1: Synthesis of compound int_195-1:
Figure PCTCN2022129961-appb-000308
Figure PCTCN2022129961-appb-000308
将化合物int_38-4(800mg，1.49mmol)溶于四氢呋喃(10mL)中，加入4，4，4-三氟丁烯酸(417.38mg，2.98mmol)和三乙胺(1.3mL，8.94mmol)。然后加入三正丙基环磷酸酐50％乙酸乙酯溶液(5.5mL，8.94mmol)，反应液于65℃搅拌反应1小时。冷却后向反应液中加入饱和碳酸钠水溶液(100mL)，用乙酸乙酯(100mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到黄色固体化合物int_195-1。Compound int_38-4 (800 mg, 1.49 mmol) was dissolved in tetrahydrofuran (10 mL), and 4,4,4-trifluorobutenoic acid (417.38 mg, 2.98 mmol) and triethylamine (1.3 mL, 8.94 mmol) were added. Then tri-n-propyl cyclic phosphoric anhydride 50% ethyl acetate solution (5.5 mL, 8.94 mmol) was added, and the reaction solution was stirred at 65° C. for 1 hour. After cooling, saturated aqueous sodium carbonate solution (100 mL) was added to the reaction solution, extracted with ethyl acetate (100 mL×3), the organic phase was dried with anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow solid compound int_195 -1.
LC-MS m/z(ESI)：658.1[M+H] +。 LC-MS m/z (ESI): 658.1 [M+H] + .
步骤2：化合物195合成：Step 2: Synthesis of Compound 195:
Figure PCTCN2022129961-appb-000309
Figure PCTCN2022129961-appb-000309
将化合物int_195-1(400mg，608.24μmol)溶于二氯甲烷(15mL)中，加入三氟乙酸(2.5mL，30.41mmol)。反应液于30℃搅拌反应1小时。反应液减压浓缩至干，再加入饱和碳酸钠水溶液(150 mL)，用二氯甲烷(150mL×3)萃取，有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干得到粗品，经二甲基亚砜(5mL)在20℃搅拌20分钟打浆得到黄色固体化合物195。Compound int_195-1 (400 mg, 608.24 μmol) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (2.5 mL, 30.41 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. The reaction solution was concentrated to dryness under reduced pressure, then saturated aqueous sodium carbonate solution (150 mL) was added, extracted with dichloromethane (150 mL×3), the organic phase was dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to obtain The crude product was slurried with dimethyl sulfoxide (5 mL) and stirred at 20° C. for 20 minutes to obtain compound 195 as a yellow solid.
LC-MS m/z(ESI)：558.4[M+H] +。 LC-MS m/z (ESI): 558.4 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.81(s，1H)，8.42(d，J＝5.0Hz，1H)，8.17(s，1H)，7.86(d，J＝8.5Hz，2H)，7.60(d，J＝8.5Hz，3H)，7.19(s，1H)，7.12(d，J＝5.3Hz，1H)，7.02-6.97(m，2H)，6.83(s，2H)，4.36(d，J＝3.3Hz，2H)，3.59(s，3H)，2.38(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.81(s, 1H), 8.42(d, J=5.0Hz, 1H), 8.17(s, 1H), 7.86(d, J=8.5Hz, 2H) , 7.60(d, J=8.5Hz, 3H), 7.19(s, 1H), 7.12(d, J=5.3Hz, 1H), 7.02-6.97(m, 2H), 6.83(s, 2H), 4.36( d, J=3.3Hz, 2H), 3.59(s, 3H), 2.38(s, 3H).
实施例29化合物196的合成Synthesis of Example 29 Compound 196
Figure PCTCN2022129961-appb-000310
Figure PCTCN2022129961-appb-000310
步骤1：化合物int_196-2合成：Step 1: Synthesis of compound int_196-2:
Figure PCTCN2022129961-appb-000311
Figure PCTCN2022129961-appb-000311
将化合物int_1-6(6.00g，17.0mmol)溶于四氢呋喃(200mL)中，加入2-氟-4-硝基苯硼酸频哪醇酯(6.81g，25.5mmol)，磷酸钾水溶液(2M，48.0mL)和[1，1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(1.39g，1.70mmol)，反应液用氮气置换3次，于65℃搅拌反应2小时。冷却后往反应液中加入水(300mL)稀释，用乙酸乙酯(300mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_196-2。Compound int_1-6 (6.00g, 17.0mmol) was dissolved in tetrahydrofuran (200mL), 2-fluoro-4-nitrophenylboronic acid pinacol ester (6.81g, 25.5mmol), potassium phosphate aqueous solution (2M, 48.0 mL) and [1,1-bis(diphenylphosphino)ferrocene]palladium dichloride in dichloromethane (1.39g, 1.70mmol), the reaction solution was replaced with nitrogen three times, and stirred at 65°C for 2 hours. After cooling, water (300mL) was added to the reaction solution for dilution, extracted with ethyl acetate (300mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and then separated by silica gel chromatography Purification afforded compound int_196-2.
LC-MS m/z(ESI)：365.8[M+H] +。 LC-MS m/z (ESI): 365.8 [M+H] + .
步骤2：化合物int_196-3合成：Step 2: Synthesis of compound int_196-3:
Figure PCTCN2022129961-appb-000312
Figure PCTCN2022129961-appb-000312
将化合物int_196-2(2.00g，5.46mmol)溶于四氢呋喃(60mL)中，加入化合物int_1-3(3.71g，10.9mmol)，磷酸钾水溶液(2M，14.0mL)和双(三环己基膦基)二氯化钯(II)(403mg，546μmol)，反应液用氮气置换3次，于100℃搅拌反应0.5小时。冷却后往反应液中加入水(100mL)稀释，用乙酸乙酯(100mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_196-3。Compound int_196-2 (2.00g, 5.46mmol) was dissolved in tetrahydrofuran (60mL), compound int_1-3 (3.71g, 10.9mmol), potassium phosphate aqueous solution (2M, 14.0mL) and bis(tricyclohexylphosphino ) palladium(II) dichloride (403 mg, 546 μmol), the reaction solution was replaced with nitrogen three times, and stirred and reacted at 100° C. for 0.5 hour. After cooling, water (100 mL) was added to the reaction solution for dilution, extracted with ethyl acetate (100 mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and then separated by silica gel chromatography Purification afforded compound int_196-3.
LC-MS m/z(ESI)：499.1[M+H] +。 LC-MS m/z (ESI): 499.1 [M+H] + .
步骤3：化合物int_196-4合成：Step 3: Synthesis of compound int_196-4:
Figure PCTCN2022129961-appb-000313
Figure PCTCN2022129961-appb-000313
将化合物int_196-3(1.30g，2.61mmol)溶于四氢呋喃(3mL)中，加入盐酸(3M，3.00mL)和氰基硼氢化钠(819mg，13.0mmol)。反应液于25℃搅拌反应2小时。反应液加入碳酸钠饱和水溶液调节pH＝7，用乙酸乙酯(100mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到粗品黄色固体int_196-4。Compound int_196-3 (1.30 g, 2.61 mmol) was dissolved in tetrahydrofuran (3 mL), and hydrochloric acid (3M, 3.00 mL) and sodium cyanoborohydride (819 mg, 13.0 mmol) were added. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated sodium carbonate aqueous solution to the reaction solution to adjust pH=7, extract with ethyl acetate (100mL×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain the crude yellow solid int_196-4 .
LC-MS m/z(ESI)：483.1[M+H] +。 LC-MS m/z (ESI): 483.1 [M+H] + .
步骤4：化合物int_196-5合成：Step 4: Synthesis of compound int_196-5:
Figure PCTCN2022129961-appb-000314
Figure PCTCN2022129961-appb-000314
将化合物int_196-4(1.60g，3.32mmol)溶于N，N二甲基甲酰胺(30mL)中，加入三乙胺(1.34g，13.3mmol)，4-二甲基氨基吡啶(203mg，1.66mmol)和BOC酸酐(3.62g，16.6mmol)。反应液于25℃搅拌反应2小时。反应液加入水(30mL)稀释，用乙酸乙酯(30mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_196-5。Compound int_196-4 (1.60g, 3.32mmol) was dissolved in N, N dimethylformamide (30mL), triethylamine (1.34g, 13.3mmol), 4-dimethylaminopyridine (203mg, 1.66 mmol) and BOC anhydride (3.62g, 16.6mmol). The reaction solution was stirred and reacted at 25° C. for 2 hours. The reaction solution was diluted with water (30mL), extracted with ethyl acetate (30mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_196 -5.
LC-MS m/z(ESI)：583.1[M+H] +。 LC-MS m/z (ESI): 583.1 [M+H] + .
步骤5：化合物int_196-6合成：Step 5: Synthesis of compound int_196-6:
Figure PCTCN2022129961-appb-000315
Figure PCTCN2022129961-appb-000315
将化合物int_196-5(700mg，1.20mmol)溶于甲醇(5mL)中，加入水(1mL)，铁粉(671mg，12.0mmol)和氯化铵(643mg，12.0mmol)。反应液于65℃搅拌反应2小时。反应液垫硅藻土过滤，滤液减压浓缩至干，加入水(10mL)稀释，用乙酸乙酯(10mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到黄色固体化合物int_196-6。Compound int_196-5 (700 mg, 1.20 mmol) was dissolved in methanol (5 mL), and water (1 mL), iron powder (671 mg, 12.0 mmol) and ammonium chloride (643 mg, 12.0 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 2 hours. The reaction solution was filtered with Celite, the filtrate was concentrated to dryness under reduced pressure, diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure To dryness, a yellow solid compound int_196-6 was obtained.
LC-MS m/z(ESI)：453.2[M+H-Boc] +。 LC-MS m/z (ESI): 453.2 [M+H-Boc] + .
步骤6：化合物int_196-7合成：Step 6: Synthesis of compound int_196-7:
Figure PCTCN2022129961-appb-000316
Figure PCTCN2022129961-appb-000316
将化合物int_196-6(200mg，362μmol)溶于二氯甲烷(5mL)中，反应液降温至0℃后，加入丙烯酰氯(65.5mg，724μmol)和三乙胺(110mg，1.09mmol)。反应液于25℃搅拌反应2小时。将反应液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_196-7。Compound int_196-6 (200 mg, 362 μmol) was dissolved in dichloromethane (5 mL), and after the reaction solution was cooled to 0° C., acryloyl chloride (65.5 mg, 724 μmol) and triethylamine (110 mg, 1.09 mmol) were added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_196-7.
LC-MS m/z(ESI)：507.2[M+H-Boc] +。 LC-MS m/z (ESI): 507.2 [M+H-Boc] + .
步骤7：化合物int_196-8合成：Step 7: Synthesis of compound int_196-8:
Figure PCTCN2022129961-appb-000317
Figure PCTCN2022129961-appb-000317
将化合物int_196-7(110mg，181μmol)溶于二氯甲烷(3mL)中，加入三氟乙酸(1.24g，10.9mmol)。反应液于25℃搅拌反应2小时。反应液减压浓缩至干，加入碳酸钠饱和水溶液调节pH＝13，然后加入水(15mL)，用乙酸乙酯(5mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩至干，经制备液相色谱纯化得到黄色固体化合物196。Compound int_196-7 (110 mg, 181 μmol) was dissolved in dichloromethane (3 mL), and trifluoroacetic acid (1.24 g, 10.9 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and a saturated aqueous solution of sodium carbonate was added to adjust the pH=13, then water (15 mL) was added, extracted with ethyl acetate (5 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate to dryness under reduced pressure, and purify by preparative liquid chromatography to obtain Compound 196 as a yellow solid.
LC-MS m/z(ESI)：507.1[M+H] +。 LC-MS m/z (ESI): 507.1 [M+H] + .
1H NMR(400MHz，CDCl 3)δ8.33(s，1H)，7.95(d，J＝10.8Hz，1H)，7.73-7.68(m，1H)，7.57(t，J＝7.7Hz，1H)，7.43-7.31(m，2H)，7.02-6.93(m，1H)，7.06-6.96(m，2H)，6.81-6.79(m，1H)，6.61(d，J＝8.3Hz，1H)，6.56-6.47(m，1H)，6.37-6.26(m，1H)，6.18-6.03(m，1H)，5.88(d，J＝10.3Hz，1H)，4.58(d，J＝14.1Hz，1H)，4.46-4.35(m，1H)，3.69(s，3H)，2.47(s，3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.33(s, 1H), 7.95(d, J=10.8Hz, 1H), 7.73-7.68(m, 1H), 7.57(t, J=7.7Hz, 1H) , 7.43-7.31(m, 2H), 7.02-6.93(m, 1H), 7.06-6.96(m, 2H), 6.81-6.79(m, 1H), 6.61(d, J=8.3Hz, 1H), 6.56 -6.47(m, 1H), 6.37-6.26(m, 1H), 6.18-6.03(m, 1H), 5.88(d, J=10.3Hz, 1H), 4.58(d, J=14.1Hz, 1H), 4.46-4.35 (m, 1H), 3.69 (s, 3H), 2.47 (s, 3H).
实施例30化合物197的合成Synthesis of Example 30 Compound 197
Figure PCTCN2022129961-appb-000318
Figure PCTCN2022129961-appb-000318
Figure PCTCN2022129961-appb-000319
Figure PCTCN2022129961-appb-000319
步骤1：化合物int_197-1合成：Step 1: Synthesis of compound int_197-1:
Figure PCTCN2022129961-appb-000320
Figure PCTCN2022129961-appb-000320
将化合物int_11-4(40g，152.06mmol)和2-氯嘧啶(26.12g，228.08mmol)溶于N，N-二甲基甲酰胺(400mL)中，加入碳酸钾水溶液(42.03g，304.11mmol)。反应液于100℃搅拌反应1小时。将反应液过滤，减压浓缩旋掉1L溶剂，再往反应液中加入水(300mL)，混合液用乙酸乙酯(300mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_197-1。Compound int_11-4 (40g, 152.06mmol) and 2-chloropyrimidine (26.12g, 228.08mmol) were dissolved in N,N-dimethylformamide (400mL), and aqueous potassium carbonate solution (42.03g, 304.11mmol) was added . The reaction solution was stirred and reacted at 100° C. for 1 hour. Filter the reaction solution, concentrate under reduced pressure and spin off 1L of solvent, then add water (300mL) to the reaction solution, extract the mixture with ethyl acetate (300mL×3), combine the organic phases, dry with anhydrous magnesium sulfate, and extract The filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_197-1.
LC-MS m/z(ESI)：342.9[M+H] +。 LC-MS m/z (ESI): 342.9 [M+H] + .
步骤2：化合物int_197-2合成：Step 2: Synthesis of compound int_197-2:
Figure PCTCN2022129961-appb-000321
Figure PCTCN2022129961-appb-000321
将化合物int_197-1(50g，146.57mmol)和双联嚬哪醇硼酸酯(55.83g，219.86mmol)溶于二氧六环(500mL)中，在氮气保护下加入醋酸钾(43.15g，439.71mmol)和1，1-双(二苯基磷)二茂铁氯化钯二氯甲烷混合物(11.97g，14.66mmol)。体系用氮气置换三次，反应液于100℃搅拌反应5小时。将反应液过滤，滤液减压浓缩至干，往反剩余物中加入水(500mL)，混合液用乙酸乙酯(500mL×3)萃取，合并有机相，用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_197-2。Compound int_197-1 (50g, 146.57mmol) and bisanalyl borate (55.83g, 219.86mmol) were dissolved in dioxane (500mL), and potassium acetate (43.15g, 439.71mL) was added under nitrogen protection. mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride in dichloromethane mixture (11.97g, 14.66mmol). The system was replaced with nitrogen three times, and the reaction solution was stirred and reacted at 100° C. for 5 hours. The reaction solution was filtered, the filtrate was concentrated to dryness under reduced pressure, water (500 mL) was added to the reaction residue, the mixture was extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried with anhydrous magnesium sulfate, and suction filtered , the filtrate was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_197-2.
LC-MS m/z(ESI)：389.1[M+H] +。 LC-MS m/z (ESI): 389.1 [M+H] + .
步骤3：化合物int_197-3合成：Step 3: Synthesis of compound int_197-3:
Figure PCTCN2022129961-appb-000322
Figure PCTCN2022129961-appb-000322
将化合物int_1-7(18.0g，51.7mmol)溶于N，N二甲基甲酰胺(250mL)中，加入化合物int_197-2(40.1g，103.0mmol)，磷酸钾水溶液(2M，52.0mL)和[1，1-双(二叔丁基膦)二茂铁]二氯化钯(II)(2.36g，3.62mmol)，反应液进行氮气3次置换，于100℃搅拌反应3小时。冷却后往反应液中加入水(300mL)用乙酸乙酯(300mL×3)进行萃取，有机相用无水硫酸钠干燥，过滤，减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_197-3。Compound int_1-7 (18.0g, 51.7mmol) was dissolved in N, N dimethylformamide (250mL), compound int_197-2 (40.1g, 103.0mmol), potassium phosphate aqueous solution (2M, 52.0mL) and [1,1-bis(di-tert-butylphosphino)ferrocene]palladium(II) chloride (2.36g, 3.62mmol), the reaction solution was replaced with nitrogen three times, and stirred at 100°C for 3 hours. After cooling, water (300mL) was added to the reaction solution and extracted with ethyl acetate (300mL×3), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and then purified by silica gel chromatography to obtain compound int_197 -3.
LC-MS m/z(ESI)：529.9[M+H] +。 LC-MS m/z (ESI): 529.9 [M+H] + .
步骤4：化合物int_197-4合成：Step 4: Synthesis of compound int_197-4:
Figure PCTCN2022129961-appb-000323
Figure PCTCN2022129961-appb-000323
将化合物int_197-3(6.00g，11.3mmol)溶于四氢呋喃(24mL)中，加入盐酸水溶液(3M，12.0mL)，反应液于60℃搅拌反应2小时。反应液减压浓缩至干，得到粗品黄色固体化合物int_197-4。Compound int_197-3 (6.00g, 11.3mmol) was dissolved in tetrahydrofuran (24mL), aqueous hydrochloric acid (3M, 12.0mL) was added, and the reaction solution was stirred at 60°C for 2 hours. The reaction solution was concentrated to dryness under reduced pressure to obtain the crude yellow solid compound int_197-4.
LC-MS m/z(ESI)：485.9[M+H] +。 LC-MS m/z (ESI): 485.9 [M+H] + .
步骤5：化合物int_197-5合成：Step 5: Synthesis of compound int_197-5:
Figure PCTCN2022129961-appb-000324
Figure PCTCN2022129961-appb-000324
将化合物int_197-4(6.00g，12.4mmol)溶于四氢呋喃(60mL)中，加入氰基硼氢化钠(3.88g，61.8mmol)。反应液于25℃搅拌反应2小时。反应液加入碳酸钠饱和水溶液调节pH＝7，然后加入水(30mL)，用乙酸乙酯(30mL×3)进行萃取，有机相加入无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到黄色固体化合物int_197-5。Compound int_197-4 (6.00 g, 12.4 mmol) was dissolved in tetrahydrofuran (60 mL), and sodium cyanoborohydride (3.88 g, 61.8 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. Add saturated aqueous solution of sodium carbonate to the reaction solution to adjust pH=7, then add water (30 mL), extract with ethyl acetate (30 mL×3), add anhydrous sodium sulfate to the organic phase, dry, filter, and concentrate the filtrate to dryness under reduced pressure to obtain Yellow solid compound int_197-5.
LC-MS m/z(ESI)：470.0[M+H] +。 LC-MS m/z (ESI): 470.0 [M+H] + .
步骤6：化合物int_197-6合成：Step 6: Synthesis of compound int_197-6:
Figure PCTCN2022129961-appb-000325
Figure PCTCN2022129961-appb-000325
将化合物int_197-5(6.00g，12.4mmol)溶于N，N二甲基甲酰胺(40mL)中，加入三乙胺(5.17g，51.1mmol)，4-二甲基氨基吡啶(781.0mg，6.39mmol)和BOC酸酐(14.0g，63.9mmol)。反应液于25℃搅拌反应12小时。将反应液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_197-6。Compound int_197-5 (6.00g, 12.4mmol) was dissolved in N,N dimethylformamide (40mL), triethylamine (5.17g, 51.1mmol), 4-dimethylaminopyridine (781.0mg, 6.39 mmol) and BOC anhydride (14.0 g, 63.9 mmol). The reaction solution was stirred and reacted at 25° C. for 12 hours. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_197-6.
1H NMR(400MHz，DMSO-d 6)δ8.71-8.70(m，1H)，8.68-8.64(m，2H)，8.46(d，J＝8.6Hz，2H)，8.01-7.92(m，2H)，7.32(t，J＝4.8Hz，1H)，7.15-7.09(m，1H)，6.66-6.52(m，1H)，5.70-5.59(m，1H)，4.59-4.39(m，1H)，3.70(s，3H)，1.41(s，9H)。 1 H NMR (400MHz, DMSO-d 6 ) δ8.71-8.70(m, 1H), 8.68-8.64(m, 2H), 8.46(d, J=8.6Hz, 2H), 8.01-7.92(m, 2H) ), 7.32(t, J=4.8Hz, 1H), 7.15-7.09(m, 1H), 6.66-6.52(m, 1H), 5.70-5.59(m, 1H), 4.59-4.39(m, 1H), 3.70(s, 3H), 1.41(s, 9H).
步骤7：化合物int_197-7合成：Step 7: Synthesis of compound int_197-7:
Figure PCTCN2022129961-appb-000326
Figure PCTCN2022129961-appb-000326
将化合物int_197-6(2.7g，4.74mmol)溶于甲醇(20mL)中，加入水(5mL)，铁粉(2.65g，47.4mmol)和氯化铵(2.54g，47.4mmol)。反应液于65℃搅拌反应2小时。反应液冷却后，垫硅藻土过滤，滤液减压浓缩至干，加入水(30mL)，用乙酸乙酯(30mL×3)进行萃取，有机相加入无水硫酸钠干燥，过滤，滤液减压浓缩至干，得到黄色固体化合物int_197-7。Compound int_197-6 (2.7g, 4.74mmol) was dissolved in methanol (20mL), water (5mL), iron powder (2.65g, 47.4mmol) and ammonium chloride (2.54g, 47.4mmol) were added. The reaction solution was stirred and reacted at 65° C. for 2 hours. After cooling the reaction solution, filter it with a pad of diatomaceous earth, concentrate the filtrate to dryness under reduced pressure, add water (30mL), extract with ethyl acetate (30mL×3), add anhydrous sodium sulfate to the organic phase and dry, filter, and depressurize the filtrate Concentrate to dryness to obtain yellow solid compound int_197-7.
LCMS m/z(ESI)：540.1[M+H] +。 LCMS m/z (ESI): 540.1 [M+H] + .
步骤8：化合物int_197-8合成：Step 8: Synthesis of compound int_197-8:
Figure PCTCN2022129961-appb-000327
Figure PCTCN2022129961-appb-000327
将化合物int_197-7(2.00g，3.71mmol)溶于二氯甲烷(30mL)中，反应液降温至0℃加入丙烯酰氯(671.0mg，7.41mmol)和三乙胺(1.13g，11.1mmol)。反应液于25℃搅拌反应2小时。将反应液减压浓缩至干，然后经硅胶色谱法分离纯化得到化合物int_197-8。The compound int_197-7 (2.00g, 3.71mmol) was dissolved in dichloromethane (30mL), and the reaction solution was cooled to 0°C, and acryloyl chloride (671.0mg, 7.41mmol) and triethylamine (1.13g, 11.1mmol) were added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and then separated and purified by silica gel chromatography to obtain compound int_197-8.
LC-MS m/z(ESI)：494.1[M-Boc+H] +。 LC-MS m/z (ESI): 494.1 [M-Boc+H] + .
步骤9：化合物197合成：Step 9: Synthesis of Compound 197:
Figure PCTCN2022129961-appb-000328
Figure PCTCN2022129961-appb-000328
将化合物int_197-8(1.50g，2.53mmol)溶于二氯甲烷(30mL)中，加入三氟乙酸(17.3g，152mmol)。反应液于25℃搅拌反应2小时。将反应液减压浓缩至干，加入碳酸钠饱和水溶液调节pH＝7，然后加入水(30mL)，用乙酸乙酯(30mL×3)进行萃取，有机相加入无水硫酸钠干燥，过滤，减压浓缩至干，经制备液相色谱纯化得到黄色固体化合物197。Compound int_197-8 (1.50 g, 2.53 mmol) was dissolved in dichloromethane (30 mL), and trifluoroacetic acid (17.3 g, 152 mmol) was added. The reaction solution was stirred and reacted at 25° C. for 2 hours. The reaction solution was concentrated to dryness under reduced pressure, and a saturated aqueous solution of sodium carbonate was added to adjust the pH=7, then water (30 mL) was added, extracted with ethyl acetate (30 mL×3), the organic phase was dried by adding anhydrous sodium sulfate, filtered, and reduced Concentrate to dryness under reduced pressure, and purify by preparative liquid chromatography to obtain compound 197 as a yellow solid.
LC-MS m/z(ESI)：494.5[M+H] +。 LC-MS m/z (ESI): 494.5 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.39(s，1H)，8.64(d，J＝4.9Hz，2H)，8.21-8.15(m，1H)，7.92-7.80(m，2H)，7.66-7.51(m，3H)，7.36-7.21(m，1H)，7.09-7.01(m，1H)，6.75-6.61(m，1H)，6.52-6.39(m，1H)，6.33-6.18(m，1H)，5.84-5.71(m，1H)，4.44(s，2H)，3.58(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.39(s, 1H), 8.64(d, J=4.9Hz, 2H), 8.21-8.15(m, 1H), 7.92-7.80(m, 2H), 7.66-7.51(m, 3H), 7.36-7.21(m, 1H), 7.09-7.01(m, 1H), 6.75-6.61(m, 1H), 6.52-6.39(m, 1H), 6.33-6.18(m , 1H), 5.84-5.71 (m, 1H), 4.44 (s, 2H), 3.58 (s, 3H).
实施例31化合物198的合成Synthesis of Example 31 Compound 198
Figure PCTCN2022129961-appb-000329
Figure PCTCN2022129961-appb-000329
Figure PCTCN2022129961-appb-000330
Figure PCTCN2022129961-appb-000330
步骤1：化合物int_198-1合成：Step 1: Synthesis of compound int_198-1:
Figure PCTCN2022129961-appb-000331
Figure PCTCN2022129961-appb-000331
将化合物int_11-5(68.4g，193.12mmol)溶于四氢呋喃(700mL)中，氮气保护下，缓慢滴加盐酸水溶液(241.41mL，4M)，在氮气保护下反应液于60℃搅拌反应2小时。反应液冷至室温，用冰的饱和碳酸钠水溶液调至pH＝8～9，混合液用乙酸乙酯(1L×3)萃取，有机相合并，用无水硫酸钠干燥，抽滤，滤液减压浓缩至干，得到粗品黄色固体产物int_198-1。Compound int_11-5 (68.4g, 193.12mmol) was dissolved in tetrahydrofuran (700mL), under nitrogen protection, hydrochloric acid aqueous solution (241.41mL, 4M) was slowly added dropwise, and the reaction solution was stirred at 60°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, adjusted to pH = 8-9 with ice-saturated aqueous sodium carbonate solution, the mixture was extracted with ethyl acetate (1L×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was reduced to Concentrate to dryness under reduced pressure to obtain the crude product int_198-1 as a yellow solid.
步骤2：化合物int_198-2合成：Step 2: Synthesis of compound int_198-2:
Figure PCTCN2022129961-appb-000332
Figure PCTCN2022129961-appb-000332
将化合物int_198-1(56.4g，181.86mmol)和甲氧基甲基三苯基氯化磷(73.53g，218.24mmol)溶于无水二氯甲烷(600mL)中，在氮气保护下降温至0℃，分批加入叔丁醇钠(20.97g，218.24mmol)，加料过程中保持体系温度不超过5℃。加完后，反应液温度保持5℃左右搅拌反应3小时。将反应液慢慢倒入冰水中(1.5L)淬灭，分出水相，水相用乙酸乙酯萃取三次(1L×3)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_198-2。Compound int_198-1 (56.4g, 181.86mmol) and methoxymethyltriphenylphosphorous chloride (73.53g, 218.24mmol) were dissolved in anhydrous dichloromethane (600mL), and cooled to 0 under nitrogen protection. °C, sodium tert-butoxide (20.97 g, 218.24 mmol) was added in batches, and the temperature of the system was kept below 5 °C during the addition. After the addition, the temperature of the reaction solution was maintained at about 5°C and the reaction was stirred for 3 hours. Slowly pour the reaction solution into ice water (1.5L) to quench, separate the water phase, extract the water phase with ethyl acetate three times (1L×3), combine the organic phases, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure The crude product was obtained, and the crude product was separated and purified by silica gel chromatography to obtain compound int_198-2.
步骤3：化合物int_198-3合成：Step 3: Synthesis of compound int_198-3:
Figure PCTCN2022129961-appb-000333
Figure PCTCN2022129961-appb-000333
将化合物int_198-2(35.7g，105.57mmol)溶于二氯甲烷(400mL)中，缓慢加入三氟乙酸(102.42g，1060mmol)，和水(19.02g，1060mmol)，反应液在氮气保护下50℃搅拌2小时。反应液减压浓缩除掉二氯甲烷，剩余混合液用饱和碳酸钠水溶液调pH＝8～9，用乙酸乙酯萃取(500mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品黄色固体产物int_198-3。Compound int_198-2 (35.7g, 105.57mmol) was dissolved in dichloromethane (400mL), slowly added trifluoroacetic acid (102.42g, 1060mmol), and water (19.02g, 1060mmol), the reaction solution was 50 °C and stirred for 2 hours. The reaction solution was concentrated under reduced pressure to remove dichloromethane, and the remaining mixed solution was adjusted to pH=8-9 with saturated aqueous sodium carbonate solution, extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain the crude product int_198-3 as a yellow solid.
步骤4：化合物int_198-4合成：Step 4: Compound int_198-4 synthesis:
Figure PCTCN2022129961-appb-000334
Figure PCTCN2022129961-appb-000334
将化合物int_198-3(28.5g，87.92mmol)溶于无水甲苯(300mL)中，加入乙二醇(27.29g，439.61mmol)，和对甲苯磺酸(4.54g，26.38mmol)，反应液在氮气保护下110℃搅拌3小时。反应液冷却后倒入饱和碳酸钠水溶液(500mL)，用乙酸乙酯萃取(500mL×3)，有机相合并，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品黄色油状产物int_198-4。Compound int_198-3 (28.5g, 87.92mmol) was dissolved in anhydrous toluene (300mL), ethylene glycol (27.29g, 439.61mmol) was added, and p-toluenesulfonic acid (4.54g, 26.38mmol), and the reaction solution was Stir at 110° C. for 3 hours under nitrogen protection. After cooling, the reaction solution was poured into saturated aqueous sodium carbonate solution (500 mL), extracted with ethyl acetate (500 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude yellow oil product int_198-4.
步骤5：化合物int_198-5合成：Step 5: Synthesis of compound int_198-5:
Figure PCTCN2022129961-appb-000335
Figure PCTCN2022129961-appb-000335
将化合物int_198-4(30.2g，82.02mmol)溶于1，4-二氧六环(300mL)中，加入双联频哪醇硼酸酯(52.07g，205.05mmol)，醋酸钾(24.15g，246.06mmol)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯(6.00g，8.202mmol)，反应液在氮气保护下于100℃搅拌3小时。反应液冷至室温，倒入水(500mL)中，用乙酸乙酯(500mL×3)萃取，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_198-5。Compound int_198-4 (30.2g, 82.02mmol) was dissolved in 1,4-dioxane (300mL), bis-pinacol borate (52.07g, 205.05mmol), potassium acetate (24.15g, 246.06mmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (6.00g, 8.202mmol), and the reaction solution was stirred at 100°C for 3 hours under the protection of nitrogen. The reaction solution was cooled to room temperature, poured into water (500mL), extracted with ethyl acetate (500mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel chromatography Compound int_198-5 was obtained by separation and purification.
LC-MS m/z(ESI)：416.0[M+H] +。 LC-MS m/z (ESI): 416.0 [M+H] + .
步骤6：化合物int_198-6合成：Step 6: Synthesis of compound int_198-6:
Figure PCTCN2022129961-appb-000336
Figure PCTCN2022129961-appb-000336
将化合物int_198-5(6.0g，17.23mmol)，化合物int_1-7(14.31g，34.47mmol)溶于N，N-二甲基甲酰胺(60mL)和水(10mL)中，加入磷酸钾(18.29g，86.17mmol)和二氯[1，1′-双(二叔丁基膦)二茂铁钯(II)](1.12g，1.723mmol)，反应液在氮气保护下于100℃搅拌3小时。反应液冷至室温，倒入水(100mL)中，用乙酸乙酯萃取(80mL×3)，有机相合并，用无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_198-6。Compound int_198-5 (6.0g, 17.23mmol), compound int_1-7 (14.31g, 34.47mmol) were dissolved in N, N-dimethylformamide (60mL) and water (10mL), potassium phosphate (18.29 g, 86.17mmol) and dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene palladium (II)] (1.12g, 1.723mmol), the reaction solution was stirred at 100°C for 3 hours under nitrogen protection . The reaction solution was cooled to room temperature, poured into water (100mL), extracted with ethyl acetate (80mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was subjected to silica gel chromatography Compound int_198-6 was obtained by separation and purification.
LC-MS m/z(ESI)：557.2[M+H] +。 LC-MS m/z (ESI): 557.2 [M+H] + .
步骤7：化合物int_198-7合成：Step 7: Compound int_198-7 synthesis:
Figure PCTCN2022129961-appb-000337
Figure PCTCN2022129961-appb-000337
将化合物int_198-6(6.2g，11.14mmol)溶于四氢呋喃(70mL)中，缓慢加入盐酸水溶液(13.92mL，4M)，反应液在氮气保护下于60℃搅拌2小时。反应液冷至室温，用冰的饱和碳酸钠溶液调至pH＝8～9，混合液用乙酸乙酯(100mL×3)萃取，有机相合并，用无水硫酸钠干燥，抽滤，滤液减压浓缩至干，得到粗品黄色固体产物int_198-7。Compound int_198-6 (6.2g, 11.14mmol) was dissolved in tetrahydrofuran (70mL), aqueous hydrochloric acid (13.92mL, 4M) was added slowly, and the reaction solution was stirred at 60°C for 2 hours under nitrogen protection. The reaction solution was cooled to room temperature, adjusted to pH=8-9 with ice saturated sodium carbonate solution, the mixture was extracted with ethyl acetate (100mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was reduced to Concentrate to dryness under reduced pressure to obtain the crude product int_198-7 as a yellow solid.
LC-MS m/z(ESI)：512.9[M+H] +。 LC-MS m/z (ESI): 512.9 [M+H] + .
步骤8：化合物int_198-8合成：Step 8: Synthesis of compound int_198-8:
Figure PCTCN2022129961-appb-000338
Figure PCTCN2022129961-appb-000338
将化合物int_198-7(5.6g，11.14mmol)溶于无水甲醇(60mL)和冰醋酸(9.5mL)中，加入三乙胺-硼烷络合物(2.51g，21.85mmol)，反应液在氮气保护下于40℃搅拌0.5小时。反应液冷至室温，用冰的饱和碳酸钠溶液调至pH＝8～9，混合液用乙酸乙酯(100mL×3)萃取，有机相合并，用无水硫酸钠干燥，抽滤，滤液减压浓缩至干，得到粗品黄色固体产物int_198-8。Compound int_198-7 (5.6g, 11.14mmol) was dissolved in anhydrous methanol (60mL) and glacial acetic acid (9.5mL), triethylamine-borane complex (2.51g, 21.85mmol) was added, and the reaction solution was Stir at 40°C for 0.5 hours under nitrogen protection. The reaction solution was cooled to room temperature, adjusted to pH=8-9 with ice saturated sodium carbonate solution, the mixture was extracted with ethyl acetate (100mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was reduced to Concentrate to dryness under reduced pressure to obtain the crude product int_198-8 as a yellow solid.
LC-MS m/z(ESI)：496.9[M+H] +。 LC-MS m/z (ESI): 496.9 [M+H] + .
步骤9：化合物int_198-9合成：Step 9: Compound int_198-9 synthesis:
Figure PCTCN2022129961-appb-000339
Figure PCTCN2022129961-appb-000339
将化合物int_198-8(5.2g，10.47mmol)溶于无水N，N-二甲基甲酰胺(60mL)中，加入二碳酸二叔丁酯(22.86g，104.73mmol)，二甲氨基吡啶(639.76mg，5.24mmol)，三乙胺(3.18g，31.42mmol)，反应液在氮气保护下于50℃搅拌2小时。反应液冷至室温，倒入水(100mL)中，用乙酸乙酯(100mL×3)萃取，有机相合并，用饱和食盐水洗(200mL×3)，无水硫酸钠干燥，抽滤，滤液减压浓缩至干，得到粗品，粗品经硅胶色谱法分离纯化得到化合物int_198-9。Compound int_198-8 (5.2g, 10.47mmol) was dissolved in anhydrous N,N-dimethylformamide (60mL), di-tert-butyl dicarbonate (22.86g, 104.73mmol) was added, dimethylaminopyridine ( 639.76mg, 5.24mmol), triethylamine (3.18g, 31.42mmol), and the reaction solution was stirred at 50°C for 2 hours under the protection of nitrogen. The reaction solution was cooled to room temperature, poured into water (100mL), extracted with ethyl acetate (100mL×3), the organic phases were combined, washed with saturated brine (200mL×3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was reduced to Concentrate under reduced pressure to dryness to obtain a crude product, which is separated and purified by silica gel chromatography to obtain compound int_198-9.
LC-MS m/z(ESI)：597.0[M+H] +。 LC-MS m/z (ESI): 597.0 [M+H] + .
步骤10：化合物int_198-10合成：Step 10: Synthesis of compound int_198-10:
Figure PCTCN2022129961-appb-000340
Figure PCTCN2022129961-appb-000340
将化合物int_198-9(1.2g，2.01mmol)溶于甲醇(12mL)和水(2mL)中，加入还原铁粉(1.12g，20.11mmol)，氯化铵(1.08g，20.11mmol)，反应液在氮气保护下于65℃搅拌1小时。反应液冷至室温，抽滤，滤饼用乙酸乙酯(20mL×10)洗，合并滤液倒入水(100mL)中，用乙酸乙酯(100mL×3)萃取，有机相合并，用饱和食盐水洗一次(150mL)，无水硫酸钠干燥，抽滤，滤液减压浓缩至干，得到粗品黄色固体产物int_198-10。Compound int_198-9 (1.2g, 2.01mmol) was dissolved in methanol (12mL) and water (2mL), added reduced iron powder (1.12g, 20.11mmol), ammonium chloride (1.08g, 20.11mmol), the reaction solution Stir at 65°C for 1 hour under nitrogen protection. The reaction solution was cooled to room temperature, filtered with suction, the filter cake was washed with ethyl acetate (20mL×10), the combined filtrate was poured into water (100mL), extracted with ethyl acetate (100mL×3), the organic phases were combined, and washed with saturated salt Wash once with water (150 mL), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure to obtain the crude product int_198-10 as a yellow solid.
LC-MS m/z(ESI)：567.0[M+H] +。 LC-MS m/z (ESI): 567.0 [M+H] + .
步骤11：化合物int_198-11合成：Step 11: Synthesis of compound int_198-11:
Figure PCTCN2022129961-appb-000341
Figure PCTCN2022129961-appb-000341
将化合物int_198-10(820mg，1.45mmol)溶于无水二氯甲烷(8mL)中，加入三乙胺(439.32mg，4.34mmol)，丙烯酰氯(235.75mg，2.60mmol)，反应液在氮气保护下于20℃反应1小时。将反应液倒入水(10mL)中，用二氯甲烷(10mL×3)萃取，有机相合并，用饱和食盐水洗一次(20mL)，无水硫酸钠干燥，抽滤，滤液减压浓缩的粗品，粗品经硅胶色谱法分离纯化得到化合物int_198-11。Compound int_198-10 (820mg, 1.45mmol) was dissolved in anhydrous dichloromethane (8mL), triethylamine (439.32mg, 4.34mmol) and acryloyl chloride (235.75mg, 2.60mmol) were added, and the reaction solution was protected under nitrogen The reaction was carried out at 20°C for 1 hour. The reaction solution was poured into water (10 mL), extracted with dichloromethane (10 mL×3), the organic phases were combined, washed once with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a crude product , the crude product was separated and purified by silica gel chromatography to obtain compound int_198-11.
LC-MS m/z(ESI)：621.0[M+H] +。 LC-MS m/z (ESI): 621.0 [M+H] + .
步骤12：化合物198合成：Step 12: Synthesis of compound 198:
Figure PCTCN2022129961-appb-000342
Figure PCTCN2022129961-appb-000342
将化合物int_198-11(480mg，0.773mmol)溶于无水二氯甲烷(5mL)中，搅拌下缓慢滴加三氟乙酸(2.5mL)，反应液在氮气保护下25℃搅拌反应1小时。反应液减压浓缩，剩余物用饱和碳酸氢钠调pH＝8，再用二氯甲烷(10mL×3)萃取，合并有机相用无水硫酸钠干燥，抽滤，滤液减压浓缩 得粗品，粗品经硅胶色谱法分离纯化得到化合物198。Compound int_198-11 (480mg, 0.773mmol) was dissolved in anhydrous dichloromethane (5mL), trifluoroacetic acid (2.5mL) was slowly added dropwise under stirring, and the reaction solution was stirred and reacted at 25°C for 1 hour under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH=8 with saturated sodium bicarbonate, then extracted with dichloromethane (10 mL×3), the combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain compound 198.
LC-MS m/z(ESI)：520.9[M+H] +。 LC-MS m/z (ESI): 520.9 [M+H] + .
1H NMR(400MHz，CDCl 3)δ8.45(s，1H)，7.67(d，J＝8.2Hz，2H)，7.55(t，J＝7.8Hz，1H)，7.39(s，1H)，7.32(d，J＝8.4Hz，2H)，6.86(d，J＝7.4Hz，1H)，6.77(t，J＝8.3Hz，1H)，6.63(d，J＝8.2Hz，1H)，6.54(dd，J＝8.5，1.4Hz，1H)，6.47(dd，J＝16.8，1.2Hz，1H)，6.26(dd，J＝16.8，10.2Hz，1H)，5.82(dd，J＝10.2，1.2Hz，1H)，4.56(s，1H)，3.76(s，3H)，3.65(s，2H)，3.28(s，2H)，2.42(s，3H)。 1 H NMR (400MHz, CDCl 3 ) δ8.45(s, 1H), 7.67(d, J=8.2Hz, 2H), 7.55(t, J=7.8Hz, 1H), 7.39(s, 1H), 7.32 (d, J=8.4Hz, 2H), 6.86(d, J=7.4Hz, 1H), 6.77(t, J=8.3Hz, 1H), 6.63(d, J=8.2Hz, 1H), 6.54(dd , J=8.5, 1.4Hz, 1H), 6.47 (dd, J=16.8, 1.2Hz, 1H), 6.26 (dd, J=16.8, 10.2Hz, 1H), 5.82 (dd, J=10.2, 1.2Hz, 1H), 4.56(s, 1H), 3.76(s, 3H), 3.65(s, 2H), 3.28(s, 2H), 2.42(s, 3H).
实施例32 化合物199的合成Synthesis of Example 32 Compound 199
Figure PCTCN2022129961-appb-000343
Figure PCTCN2022129961-appb-000343
步骤1：化合物int_199-1合成：Step 1: Synthesis of compound int_199-1:
Figure PCTCN2022129961-appb-000344
Figure PCTCN2022129961-appb-000344
将化合物int 175-1(155.00g，436.42mmol)溶于四氢呋喃(1.6L)中，加入盐酸(3M，436mL)。反应液于60℃搅拌反应2小时。反应液冷却至室温，在0℃下向反应液中加入饱和碳酸钠水溶液(500mL)，然后用乙酸乙酯(500mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，得到粗品白色固体int_199-1。Compound int 175-1 (155.00 g, 436.42 mmol) was dissolved in tetrahydrofuran (1.6 L), and hydrochloric acid (3 M, 436 mL) was added. The reaction solution was stirred and reacted at 60° C. for 2 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (500mL) was added to the reaction solution at 0°C, then extracted with ethyl acetate (500mL×3), the combined organic phases were dried with anhydrous sodium sulfate, suction filtered, and the filtrate Concentrate to dryness under reduced pressure to obtain crude product int_199-1 as a white solid.
LC-MS m/z(ESI)：311.0[M+H] +。 LC-MS m/z (ESI): 311.0 [M+H] + .
步骤2：化合物int_199-2合成：Step 2: Synthesis of compound int_199-2:
Figure PCTCN2022129961-appb-000345
Figure PCTCN2022129961-appb-000345
将化合物int_199-1(120.50g，387.32mmol)溶于二氯甲烷(1.5L)中，在氮气氛围下加入甲氧基甲基三苯基氯化膦(199.17g，580.98mmol)，保持反应温度低于5℃，分批加入叔丁醇钠(55.84g，580.98mmol)。反应液于0℃搅拌5小时。向反应液中加入水(800mL)，用乙酸乙酯(1L×2)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_199-2。Compound int_199-1 (120.50g, 387.32mmol) was dissolved in dichloromethane (1.5L), and methoxymethyltriphenylphosphine chloride (199.17g, 580.98mmol) was added under a nitrogen atmosphere to keep the reaction temperature Below 5°C, sodium tert-butoxide (55.84 g, 580.98 mmol) was added portionwise. The reaction solution was stirred at 0°C for 5 hours. Add water (800mL) to the reaction solution, extract with ethyl acetate (1L×2), combine the organic phases to dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain the compound int_199-2.
步骤3：化合物int_199-3合成：Step 3: Synthesis of compound int_199-3:
Figure PCTCN2022129961-appb-000346
Figure PCTCN2022129961-appb-000346
将化合物int_199-2(76g，224.08mmol)溶于二氯甲烷(800mL)中，加入三氟乙酸(549.13g，5.60mol)和水(100.92g，5.60mol)，反应液于50℃搅拌2小时。将反应液减压浓缩除去溶剂，向剩余物中加入饱和碳酸钠水溶液(500mL)调节pH至8～9，用乙酸乙酯(600mL×2)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_199-3。Compound int_199-2 (76g, 224.08mmol) was dissolved in dichloromethane (800mL), trifluoroacetic acid (549.13g, 5.60mol) and water (100.92g, 5.60mol) were added, and the reaction solution was stirred at 50°C for 2 hours . Concentrate the reaction solution under reduced pressure to remove the solvent, add saturated aqueous sodium carbonate solution (500 mL) to the residue to adjust the pH to 8-9, extract with ethyl acetate (600 mL×2), combine the organic phases and dry them with anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain compound int_199-3.
步骤4：化合物int_199-4合成：Step 4: Synthesis of compound int_199-4:
Figure PCTCN2022129961-appb-000347
Figure PCTCN2022129961-appb-000347
将化合物int_199-3(68.50g，211.32mmol)和乙二醇(65.58g，1.06mol)溶于甲苯(700mL)中，加入对甲苯磺酸(3.64g，21.13mmol)。反应液于110℃搅拌反应3小时。反应液冷却至室温，减压浓缩除去溶剂，向剩余物中加入饱和碳酸钠水溶液(300mL)，然后用乙酸乙酯(600mL×3)萃取，无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_199-4。Compound int_199-3 (68.50 g, 211.32 mmol) and ethylene glycol (65.58 g, 1.06 mol) were dissolved in toluene (700 mL), and p-toluenesulfonic acid (3.64 g, 21.13 mmol) was added. The reaction solution was stirred and reacted at 110° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and saturated aqueous sodium carbonate solution (300 mL) was added to the residue, then extracted with ethyl acetate (600 mL×3), dried over anhydrous sodium sulfate, suction filtered, and the filtrate was decompressed Concentrate to dryness, separate and purify by silica gel chromatography to obtain compound int_199-4.
LC-MS m/z(ESI)：369.0[M+H] +。 LC-MS m/z (ESI): 369.0 [M+H] + .
步骤5：化合物int_199-5合成：Step 5: Synthesis of compound int_199-5:
Figure PCTCN2022129961-appb-000348
Figure PCTCN2022129961-appb-000348
将化合物int_199-4(66.50g，180.12mmol)和双联频哪醇硼酸酯(68.61g，270.19mmol)溶于二氧六环(600mL)中，在氮气保护下加入醋酸钾(53.03g，540.37mmol)和1，1-双(二苯基磷)二茂铁氯化钯(14.70g，18.01mmol)，反应液于100℃搅拌3小时。反应液冷却至室温，过滤，滤液减压浓缩。向剩余物中加入水(2L)，用乙酸乙酯(600mL×3)萃取，无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_199-5。Compound int_199-4 (66.50g, 180.12mmol) and double pinacol borate (68.61g, 270.19mmol) were dissolved in dioxane (600mL), and potassium acetate (53.03g, 540.37mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (14.70g, 18.01mmol), and the reaction solution was stirred at 100°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Water (2L) was added to the residue, extracted with ethyl acetate (600mL×3), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain compound int_199-5.
LC-MS m/z(ESI)：417.2[M+H] +。 LC-MS m/z (ESI): 417.2 [M+H] + .
步骤6：化合物int_199-6合成：Step 6: Synthesis of compound int_199-6:
Figure PCTCN2022129961-appb-000349
Figure PCTCN2022129961-appb-000349
将化合物int_1-7(8.00g，22.98mmol)和化合物int_199-5(23.91g，57.44mmol)溶于N，N-二甲基甲酰胺(300mL)中，在氮气保护下加入磷酸钾(2M，57.5mL)和二氯[1，1′-双(二叔丁基膦)二茂铁钯(II)](1.12g，1.723mmol)，反应液于100℃搅拌2小时。反应液冷却至室温，加入水(600mL)，用乙酸乙酯(500mL×3)萃取，无水硫酸钠进行干燥，减压浓缩至干，用乙酸乙酯(100mL)打浆，抽滤，得到黄色固体产物int_199-6。Compound int_1-7 (8.00g, 22.98mmol) and compound int_199-5 (23.91g, 57.44mmol) were dissolved in N,N-dimethylformamide (300mL), and potassium phosphate (2M, 57.5 mL) and dichloro[1,1′-bis(di-tert-butylphosphino)ferrocenepalladium(II)] (1.12g, 1.723mmol), and the reaction solution was stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature, added water (600mL), extracted with ethyl acetate (500mL×3), dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure, slurried with ethyl acetate (100mL), and suction filtered to obtain a yellow Solid product int_199-6.
LC-MS m/z(ESI)：558.2[M+H] +。 LC-MS m/z (ESI): 558.2 [M+H] + .
步骤7：化合物int_199-7合成：Step 7: Synthesis of compound int_199-7:
Figure PCTCN2022129961-appb-000350
Figure PCTCN2022129961-appb-000350
将化合物int_199-6(6.8g，12.20mmol)溶于四氢呋喃(70mL)中，加入盐酸(3M，20.4mL)，反应液于60℃搅拌2小时。反应液冷却至室温，向反应液中加入饱和碳酸钠水溶液(100mL)使pH ＝8～9，再加入水(100m L)，用乙酸乙酯(100mL×3)萃取，无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干减压浓缩除去溶剂，得到粗品黄色固体产物int_199-7。Compound int_199-6 (6.8g, 12.20mmol) was dissolved in tetrahydrofuran (70mL), hydrochloric acid (3M, 20.4mL) was added, and the reaction solution was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (100mL) was added to the reaction solution to make the pH = 8-9, then water (100mL) was added, extracted with ethyl acetate (100mL×3), and dried over anhydrous sodium sulfate , filtered with suction, and the filtrate was concentrated to dryness under reduced pressure to remove the solvent to obtain the crude product int_199-7 as a yellow solid.
LC-MS m/z(ESI)：513.9[M+H] +。 LC-MS m/z (ESI): 513.9 [M+H] + .
步骤8：化合物int_199-8合成：Step 8: Synthesis of compound int_199-8:
Figure PCTCN2022129961-appb-000351
Figure PCTCN2022129961-appb-000351
将化合物int_199-7(5.90g，11.49mmol)溶于无水甲醇(60mL)中，加入三乙胺硼烷络合物(1.50g，23.82mmol)和醋酸(18.8mL)，反应液于40℃搅拌反应2小时。向反应液中加入饱和碳酸钠水溶液(100mL)使pH＝8，再加入水(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，得到粗品黄色固体产物int_199-8。Compound int_199-7 (5.90g, 11.49mmol) was dissolved in anhydrous methanol (60mL), triethylamine borane complex (1.50g, 23.82mmol) and acetic acid (18.8mL) were added, and the reaction solution was heated at 40°C The reaction was stirred for 2 hours. Add saturated aqueous sodium carbonate solution (100mL) to the reaction solution to make the pH = 8, then add water (100mL), extract with ethyl acetate (100mL×3), combine the organic phases to dry with anhydrous sodium sulfate, suction filter, and the filtrate Concentration to dryness under reduced pressure afforded the crude product int_199-8 as a yellow solid.
LC-MS m/z(ESI)：497.9[M+H] +。 LC-MS m/z (ESI): 497.9 [M+H] + .
步骤9：化合物int_199-9合成：Step 9: Compound int_199-9 synthesis:
Figure PCTCN2022129961-appb-000352
Figure PCTCN2022129961-appb-000352
将化合物int_199-8(5.20g，10.45mmol)溶于N，N-二甲基甲酰胺(30mL)中，加入Boc酸酐(22.81g，104.52mmol)，4-二甲氨基吡啶(0.64g，5.23mmol)和三乙胺(10.58g，104.52mmol)。反应液于50℃搅拌反应2小时。反应液冷却至室温，加入水(200mL)，用乙酸乙酯(400mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_199-9。Compound int_199-8 (5.20g, 10.45mmol) was dissolved in N, N-dimethylformamide (30mL), Boc anhydride (22.81g, 104.52mmol), 4-dimethylaminopyridine (0.64g, 5.23 mmol) and triethylamine (10.58 g, 104.52 mmol). The reaction solution was stirred and reacted at 50° C. for 2 hours. The reaction solution was cooled to room temperature, added water (200mL), extracted with ethyl acetate (400mL×3), combined organic phases were dried over anhydrous sodium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography Compound int_199-9 was obtained.
步骤10：化合物int_199-10合成：Step 10: Synthesis of compound int_199-10:
Figure PCTCN2022129961-appb-000353
Figure PCTCN2022129961-appb-000353
将化合物int_199-9(2.30g，3.85mmol)溶于甲醇(50mL)和水(10mL)中，加入铁粉(5.37g，96.22mmol)和氯化铵(5.15g，96.22mmol)。反应液于65℃搅拌反应1小时。反应液冷却至室温， 抽滤，用甲醇(60mL)洗涤，减压浓缩。向剩余物中加入水(100mL)，用乙酸乙酯(100mL×3)萃取，无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_199-10。Compound int_199-9 (2.30 g, 3.85 mmol) was dissolved in methanol (50 mL) and water (10 mL), and iron powder (5.37 g, 96.22 mmol) and ammonium chloride (5.15 g, 96.22 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. The reaction solution was cooled to room temperature, filtered with suction, washed with methanol (60 mL), and concentrated under reduced pressure. Water (100 mL) was added to the residue, extracted with ethyl acetate (100 mL×3), dried over anhydrous sodium sulfate, filtered with suction, the filtrate was concentrated to dryness under reduced pressure, and purified by silica gel chromatography to obtain compound int_199-10.
步骤11：化合物int_199-11合成：Step 11: Synthesis of compound int_199-11:
Figure PCTCN2022129961-appb-000354
Figure PCTCN2022129961-appb-000354
将化合物int_199-10(800mg，1.41mmol)溶于二氯甲烷(10mL)中，室温加入三乙胺(428.03mg，4.23mmol)，再加入丙烯酰氯(191.34mg，2.11mmol)。反应液于20℃搅拌1小时。往反应液中加入饱和碳酸钠水溶液(3mL)使pH＝8，再加入水(30mL)，用二氯甲烷(40mL×3)萃取，无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_199-11。Compound int_199-10 (800 mg, 1.41 mmol) was dissolved in dichloromethane (10 mL), triethylamine (428.03 mg, 4.23 mmol) was added at room temperature, and acryloyl chloride (191.34 mg, 2.11 mmol) was added. The reaction solution was stirred at 20°C for 1 hour. Add saturated aqueous sodium carbonate solution (3mL) to the reaction solution to make the pH=8, then add water (30mL), extract with dichloromethane (40mL×3), dry over anhydrous sodium sulfate, filter with suction, and concentrate the filtrate under reduced pressure to dry, and separated and purified by silica gel chromatography to obtain compound int_199-11.
LC-MS m/z(ESI)：622.2[M+H] +。 LC-MS m/z (ESI): 622.2 [M+H] + .
步骤12：化合物199合成：Step 12: Synthesis of Compound 199:
Figure PCTCN2022129961-appb-000355
Figure PCTCN2022129961-appb-000355
将化合物int_199-11(280.00mg，0.450mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(1.10g，11.26mmol)。反应液于30℃搅拌反应1小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(5mL)使pH＝8，再加入水(20mL)，用二氯甲烷(40mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到粗品。粗品再用乙酸乙酯(10mL)打浆纯化，冻干，得到白色固体产物199。Compound int_199-11 (280.00 mg, 0.450 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.10 g, 11.26 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate (5 mL) to make the pH = 8, then add water (20 mL), extract with dichloromethane (40 mL×3), combine the organic phases with anhydrous sodium sulfate Dry, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain a crude product. The crude product was further purified by slurrying with ethyl acetate (10 mL) and lyophilized to give the product 199 as a white solid.
LC-MS m/z(ESI)：522.2[M+H] +。 LC-MS m/z (ESI): 522.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.31(s，1H)，8.46(d，J＝5.0Hz，1H)，8.31(s，1H)，7.76(d，J＝8.4Hz，2H)，7.41(d，J＝8.3Hz，2H)，7.16(d，J＝5.0Hz，1H)，6.94(t，J＝8.4Hz，1H)，6.55(d，J＝8.5Hz，1H)，6.45(dd，J＝17.0，10.1Hz，1H)，6.28(dd，J＝17.0，2.1Hz，1H)，6.13(q，J＝2.8Hz，1H)，5.80-5.75(m，1H)，3.66(s，3H)，3.47(d，J＝12.3Hz，2H)，3.17(d，J＝6.4Hz，2H)，2.42(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.31(s, 1H), 8.46(d, J=5.0Hz, 1H), 8.31(s, 1H), 7.76(d, J=8.4Hz, 2H) , 7.41(d, J=8.3Hz, 2H), 7.16(d, J=5.0Hz, 1H), 6.94(t, J=8.4Hz, 1H), 6.55(d, J=8.5Hz, 1H), 6.45 (dd, J=17.0, 10.1Hz, 1H), 6.28(dd, J=17.0, 2.1Hz, 1H), 6.13(q, J=2.8Hz, 1H), 5.80-5.75(m, 1H), 3.66( s, 3H), 3.47 (d, J = 12.3 Hz, 2H), 3.17 (d, J = 6.4 Hz, 2H), 2.42 (s, 3H).
实施例33 化合物200的合成The synthesis of embodiment 33 compound 200
Figure PCTCN2022129961-appb-000356
Figure PCTCN2022129961-appb-000356
步骤1：化合物int_200-1合成：Step 1: Synthesis of compound int_200-1:
Figure PCTCN2022129961-appb-000357
Figure PCTCN2022129961-appb-000357
氮气氛围下将化合物int_189-1(22.50g，76.76mmol)和甲氧基甲基三苯基氯化膦(39.47g，115.14mmol)溶于二氯甲烷(400mL)中。反应温度保持在5℃以下，分批加入叔丁醇钠(11.07g，115.14mmol)。加完后反应液于0℃搅拌5小时。向反应液中加入水(500mL)，用乙酸乙酯(600mL×2)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_200-1。Compound int_189-1 (22.50 g, 76.76 mmol) and methoxymethyltriphenylphosphine chloride (39.47 g, 115.14 mmol) were dissolved in dichloromethane (400 mL) under nitrogen atmosphere. Keeping the reaction temperature below 5°C, sodium tert-butoxide (11.07 g, 115.14 mmol) was added in portions. After the addition, the reaction solution was stirred at 0°C for 5 hours. Add water (500mL) to the reaction solution, extract with ethyl acetate (600mL×2), combine the organic phases to dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify the compound by silica gel chromatography int_200-1.
LC-MS m/z(ESI)：320.8[M+H] +。 LC-MS m/z (ESI): 320.8 [M+H] + .
步骤2：化合物int_200-2合成：Step 2: Synthesis of compound int_200-2:
Figure PCTCN2022129961-appb-000358
Figure PCTCN2022129961-appb-000358
将化合物int_200-1(18.5g，57.60mmol)溶于二氯甲烷(500mL)中，加入三氟乙酸(139.71g，1.44mol)和水(25.94g，1.44mol)，反应液于50℃搅拌2小时。将反应液减压浓缩除去溶剂，向剩余物中加入饱和碳酸钠(500mL)调节pH至8～9，再用乙酸乙酯(600mL×2)萃取，合并有机相 用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_200-2。Compound int_200-1 (18.5g, 57.60mmol) was dissolved in dichloromethane (500mL), trifluoroacetic acid (139.71g, 1.44mol) and water (25.94g, 1.44mol) were added, and the reaction solution was stirred at 50°C for 2 Hour. The reaction solution was concentrated under reduced pressure to remove the solvent, and saturated sodium carbonate (500 mL) was added to the residue to adjust the pH to 8-9, then extracted with ethyl acetate (600 mL×2), and the organic phases were combined and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated to dryness under reduced pressure, and the compound int_200-2 was obtained by separation and purification by silica gel chromatography.
LC-MS m/z(ESI)：306.7[M+H] +。 LC-MS m/z (ESI): 306.7 [M+H] + .
步骤3：化合物int_200-3合成：Step 3: Synthesis of compound int_200-3:
Figure PCTCN2022129961-appb-000359
Figure PCTCN2022129961-appb-000359
将化合物int_200-2(16.80g，54.87mmol)和乙二醇(17.03g，274.37mmol)溶于甲苯(300mL)中，加入对甲苯磺酸(944.91mg，5.49mmol)。反应液于110℃搅拌反应3小时。反应液冷却至室温，减压浓缩除去溶剂，向剩余物中加入饱和碳酸钠水溶液(300mL)调节pH至8～9，然后用乙酸乙酯(600mL×3)萃取，无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_200-3。Compound int_200-2 (16.80 g, 54.87 mmol) and ethylene glycol (17.03 g, 274.37 mmol) were dissolved in toluene (300 mL), and p-toluenesulfonic acid (944.91 mg, 5.49 mmol) was added. The reaction solution was stirred and reacted at 110° C. for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to remove the solvent, and saturated aqueous sodium carbonate solution (300 mL) was added to the residue to adjust the pH to 8-9, then extracted with ethyl acetate (600 mL×3), and dried over anhydrous sodium sulfate. Suction filtration, the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain compound int_200-3.
步骤4：化合物int_200-4合成：Step 4: Synthesis of compound int_200-4:
Figure PCTCN2022129961-appb-000360
Figure PCTCN2022129961-appb-000360
将化合物int_200-3(17.00g，48.41mmol)和双联频哪醇硼酸酯(18.44g，72.61mmol)溶于二氧六环(300mL)中，在氮气保护下加入醋酸钾(14.25g，145.22mmol)和1，1-双(二苯基磷)二茂铁氯化钯(3.95g，4.84mmol)，反应液于100℃搅拌3小时。反应液冷却至室温，过滤，滤液减压浓缩。向剩余物中加入水(1L)，用乙酸乙酯(600mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_200-4。Compound int_200-3 (17.00g, 48.41mmol) and double pinacol borate (18.44g, 72.61mmol) were dissolved in dioxane (300mL), and potassium acetate (14.25g, 145.22mmol) and 1,1-bis(diphenylphosphino)ferrocenepalladium chloride (3.95g, 4.84mmol), and the reaction solution was stirred at 100°C for 3 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. Add water (1L) to the residue, extract with ethyl acetate (600mL×3), combine the organic phases to dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain the compound int_200-4.
LC-MS m/z(ESI)：399.2[M+H] +。 LC-MS m/z (ESI): 399.2 [M+H] + .
步骤5：化合物int_200-5合成：Step 5: Synthesis of compound int_200-5:
Figure PCTCN2022129961-appb-000361
Figure PCTCN2022129961-appb-000361
将化合物int_1-7(6.00g，17.23mmol)和化合物int_200-4(17.18g，43.08mmol)溶于N，N-二甲基甲酰胺(200mL)中，在氮气保护下加入磷酸钾(2M，43.04mL)和二氯[1，1′-双(二叔丁基膦)二茂铁钯(II)](1.12g，1.723mmol)，反应液于100℃搅拌3小时。反应液冷却至室温，加入水(600mL)，用乙酸乙酯(400mL×3)萃取，无水硫酸钠进行干燥，过滤后减压浓缩至干得到黄色固体粗品，经硅 胶色谱法分离纯化得到化合物int_200-5。Compound int_1-7 (6.00g, 17.23mmol) and compound int_200-4 (17.18g, 43.08mmol) were dissolved in N,N-dimethylformamide (200mL), and potassium phosphate (2M, 43.04 mL) and dichloro[1,1′-bis(di-tert-butylphosphino)ferrocenepalladium(II)] (1.12g, 1.723mmol), and the reaction solution was stirred at 100°C for 3 hours. The reaction solution was cooled to room temperature, added water (600mL), extracted with ethyl acetate (400mL×3), dried over anhydrous sodium sulfate, filtered and concentrated to dryness under reduced pressure to obtain a yellow solid crude product, which was separated and purified by silica gel chromatography to obtain the compound int_200-5.
LC-MS m/z(ESI)：540.2[M+H] +。 LC-MS m/z (ESI): 540.2 [M+H] + .
步骤6：化合物int_200-6合成：Step 6: Synthesis of compound int_200-6:
Figure PCTCN2022129961-appb-000362
Figure PCTCN2022129961-appb-000362
将化合物int_200-5(3.5g，6.49mmol)溶于四氢呋喃(40mL)中，加入盐酸(3M，10.5mL)，反应液于60℃搅拌2小时。反应液冷却至室温，向反应液中加入饱和碳酸钠水溶液(120mL)使pH＝8～9，再加入水(200mL)，用乙酸乙酯(100mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，得到粗品黄色固体产物int_200-6。Compound int_200-5 (3.5g, 6.49mmol) was dissolved in tetrahydrofuran (40mL), hydrochloric acid (3M, 10.5mL) was added, and the reaction solution was stirred at 60°C for 2 hours. The reaction solution was cooled to room temperature, and saturated aqueous sodium carbonate solution (120 mL) was added to the reaction solution to make the pH = 8-9, then water (200 mL) was added, extracted with ethyl acetate (100 mL×3), and the combined organic phases were washed with anhydrous sulfuric acid Sodium was dried, suction filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product int_200-6 as a yellow solid.
LC-MS m/z(ESI)：496.2[M+H] +。 LC-MS m/z (ESI): 496.2 [M+H] + .
步骤7：化合物int_200-7合成：Step 7: Compound int_200-7 synthesis:
Figure PCTCN2022129961-appb-000363
Figure PCTCN2022129961-appb-000363
将化合物int_200-6(3.36g，6.78mmol)溶于无水甲醇(40mL)中，加入三乙胺硼烷(0.85g，13.56mmol)和醋酸(10.69mL)，反应液于40℃搅拌反应2小时。向反应液中加入饱和碳酸钠水溶液(120mL)使pH＝8～9，再加入水(200m L)，用乙酸乙酯(100mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，得到粗品黄色固体产物int_200-7。Compound int_200-6 (3.36g, 6.78mmol) was dissolved in anhydrous methanol (40mL), triethylamine borane (0.85g, 13.56mmol) and acetic acid (10.69mL) were added, and the reaction solution was stirred at 40°C for reaction 2 Hour. Add saturated aqueous sodium carbonate solution (120mL) to the reaction solution to make the pH = 8-9, then add water (200mL), extract with ethyl acetate (100mL×3), combine the organic phases and dry them with anhydrous sodium sulfate. Filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain the crude product int_200-7 as a yellow solid.
LC-MS m/z(ESI)：480.2[M+H] +。 LC-MS m/z (ESI): 480.2 [M+H] + .
步骤8：化合物int_200-8合成：Step 8: Synthesis of compound int_200-8:
Figure PCTCN2022129961-appb-000364
Figure PCTCN2022129961-appb-000364
将化合物int_200-7(2.80g，5.84mmol)溶于N，N-二甲基甲酰胺(30mL)中，加入Boc酸酐(12.74g，58.39mmol)，4-二甲氨基吡啶(0.36g，2.92mmol)和三乙胺(4.43g，43.80mmol)。反应液 于50℃搅拌反应2小时。反应液冷却至室温，加入水(500mL)，用乙酸乙酯(500mL×3)萃取，合并有机相用无水硫酸镁进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_200-8。Compound int_200-7 (2.80g, 5.84mmol) was dissolved in N, N-dimethylformamide (30mL), Boc anhydride (12.74g, 58.39mmol), 4-dimethylaminopyridine (0.36g, 2.92 mmol) and triethylamine (4.43 g, 43.80 mmol). The reaction solution was stirred and reacted at 50°C for 2 hours. The reaction solution was cooled to room temperature, added water (500mL), extracted with ethyl acetate (500mL×3), combined organic phases were dried over anhydrous magnesium sulfate, filtered with suction, and the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography Compound int_200-8 was obtained.
步骤9：化合物int_200-9合成：Step 9: Compound int_200-9 synthesis:
Figure PCTCN2022129961-appb-000365
Figure PCTCN2022129961-appb-000365
将化合物int_200-8(1.20g，2.12mmol)溶于甲醇(30mL)和水(6mL)中，加入铁粉(2.89g，51.76mmol)和氯化铵(2.77g，51.76mmol)。反应液于65℃搅拌反应1小时。反应液冷却至室温，抽滤，用甲醇(50mL)洗涤，减压浓缩。向剩余物中加入水(100mL)，用乙酸乙酯(100mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_200-9。Compound int_200-8 (1.20 g, 2.12 mmol) was dissolved in methanol (30 mL) and water (6 mL), and iron powder (2.89 g, 51.76 mmol) and ammonium chloride (2.77 g, 51.76 mmol) were added. The reaction solution was stirred and reacted at 65° C. for 1 hour. The reaction solution was cooled to room temperature, filtered with suction, washed with methanol (50 mL), and concentrated under reduced pressure. Add water (100mL) to the residue, extract with ethyl acetate (100mL×3), combine the organic phases to dry over anhydrous sodium sulfate, filter with suction, concentrate the filtrate to dryness under reduced pressure, and separate and purify by silica gel chromatography to obtain the compound int_200-9.
步骤10：化合物int_200-10合成：Step 10: Synthesis of compound int_200-10:
Figure PCTCN2022129961-appb-000366
Figure PCTCN2022129961-appb-000366
将化合物int_200-9(900mg，1.68mmol)溶于二氯甲烷(10mL)中，加入三乙胺(0.51g，5.04mmol)和丙烯酰氯(228.12mg，2.52mmol)。反应液20℃搅拌1小时。反应液加入饱和碳酸钠水溶液(2mL)使pH＝8～9，加入水(30mL)，用二氯甲烷(40mL×3)萃取，无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_200-10。Compound int_200-9 (900 mg, 1.68 mmol) was dissolved in dichloromethane (10 mL), and triethylamine (0.51 g, 5.04 mmol) and acryloyl chloride (228.12 mg, 2.52 mmol) were added. The reaction solution was stirred at 20°C for 1 hour. Add saturated sodium carbonate aqueous solution (2mL) to the reaction solution to make the pH=8~9, add water (30mL), extract with dichloromethane (40mL×3), dry with anhydrous sodium sulfate, filter with suction, and concentrate the filtrate to dryness under reduced pressure , separated and purified by silica gel chromatography to obtain compound int_200-10.
LC-MS m/z(ESI)：604.0[M+H] +。 LC-MS m/z (ESI): 604.0 [M+H] + .
步骤11：化合物200合成：Step 11: Synthesis of Compound 200:
Figure PCTCN2022129961-appb-000367
Figure PCTCN2022129961-appb-000367
将化合物int_200-10(560.00mg，0.928mmol)溶于无水二氯甲烷(10mL)中，加入三氟乙酸(2.27g，23.19mmol)。反应液于30℃搅拌反应1小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠(2mL)使pH＝8～9，加入水(20mL)，用二氯甲烷(40mL×3)萃取，无水硫酸钠进行干燥， 抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到粗品。粗品用乙酸乙酯(20mL)打浆纯化，冻干，得到白色固体产物200。Compound int_200-10 (560.00 mg, 0.928 mmol) was dissolved in anhydrous dichloromethane (10 mL), and trifluoroacetic acid (2.27 g, 23.19 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated sodium carbonate (2 mL) to make the pH = 8-9, add water (20 mL), extract with dichloromethane (40 mL×3), dry over anhydrous sodium sulfate, and filter with suction , the filtrate was concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain a crude product. The crude product was purified by slurrying with ethyl acetate (20 mL) and lyophilized to give the product 200 as a white solid.
LC-MS m/z(ESI)：504.0[M+H] +。 LC-MS m/z (ESI): 504.0 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ10.29(s，1H)，8.44(d，1H，J＝5.2Hz)，8.27(s，1H)，7.74(d，2H，J＝8.4Hz)，7.38(d，2H，J＝8.4Hz)，7.19(d，1H，J＝2.4Hz)，7.12(d，1H，J＝4.8Hz)，6.68-6.77(m，2H)，6.45(dd，1H，J＝17.2，10.0Hz)，6.28(dd，1H，J＝16.8，2.0Hz)，6.10-6.15(m，1H)，5.78(dd，1H，J＝10.0，2.0Hz)，3.65(s，3H)，3.41-3.53(m，2H)，3.00-3.15(m，2H)，2.40(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ10.29(s, 1H), 8.44(d, 1H, J=5.2Hz), 8.27(s, 1H), 7.74(d, 2H, J=8.4Hz) , 7.38(d, 2H, J=8.4Hz), 7.19(d, 1H, J=2.4Hz), 7.12(d, 1H, J=4.8Hz), 6.68-6.77(m, 2H), 6.45(dd, 1H, J=17.2, 10.0Hz), 6.28(dd, 1H, J=16.8, 2.0Hz), 6.10-6.15(m, 1H), 5.78(dd, 1H, J=10.0, 2.0Hz), 3.65(s , 3H), 3.41-3.53 (m, 2H), 3.00-3.15 (m, 2H), 2.40 (s, 3H).
实施例34 化合物228的合成Synthesis of Example 34 Compound 228
Figure PCTCN2022129961-appb-000368
Figure PCTCN2022129961-appb-000368
步骤1：化合物int_228-1合成：Step 1: Synthesis of compound int_228-1:
Figure PCTCN2022129961-appb-000369
Figure PCTCN2022129961-appb-000369
将化合物int_199-10(700mg，1.23mmol)溶于二氯甲烷(10mL)中，加入三乙胺(373.39mg，3.69mmol)，再加入甲基丙烯酰氯(193.37mg，1.85mmol)。反应液于20℃搅拌1小时。反应液加入饱和碳酸钠水溶液(3mL)使pH＝8～9，加入水(30mL)，用二氯甲烷(40mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到化合物int_228-1。Compound int_199-10 (700 mg, 1.23 mmol) was dissolved in dichloromethane (10 mL), triethylamine (373.39 mg, 3.69 mmol) was added, and methacryloyl chloride (193.37 mg, 1.85 mmol) was added. The reaction solution was stirred at 20°C for 1 hour. Add saturated sodium carbonate aqueous solution (3mL) to the reaction solution to make the pH = 8-9, add water (30mL), extract with dichloromethane (40mL×3), combine the organic phases to dry with anhydrous sodium sulfate, suction filter, and the filtrate Concentrated to dryness under reduced pressure, separated and purified by silica gel chromatography to obtain compound int_228-1.
LC-MS m/z(ESI)：636.0[M+H] +。 LC-MS m/z (ESI): 636.0 [M+H] + .
步骤2：化合物228合成：Step 2: Synthesis of compound 228:
Figure PCTCN2022129961-appb-000370
Figure PCTCN2022129961-appb-000370
将化合物int_228-1(330.00mg，0.531mmol)溶于二氯甲烷(10mL)中，加入三氟乙酸(1.30g，13.27mmol)。反应液于30℃搅拌反应1小时。减压浓缩除去大部分三氟乙酸，加入饱和碳酸钠水溶液(5mL)使pH＝8，加入水(20mL)，用二氯甲烷(40mL×3)萃取，合并有机相用无水硫酸钠进行干燥，抽滤，滤液减压浓缩至干，经硅胶色谱法分离纯化得到粗品。粗品用乙酸乙酯(10mL) 打浆纯化，冻干，得到白色固体产物228。Compound int_228-1 (330.00 mg, 0.531 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (1.30 g, 13.27 mmol) was added. The reaction solution was stirred and reacted at 30° C. for 1 hour. Concentrate under reduced pressure to remove most of the trifluoroacetic acid, add saturated aqueous sodium carbonate (5 mL) to make the pH = 8, add water (20 mL), extract with dichloromethane (40 mL×3), combine the organic phases and dry over anhydrous sodium sulfate , suction filtration, the filtrate was concentrated to dryness under reduced pressure, and the crude product was obtained by separation and purification by silica gel chromatography. The crude product was purified by slurrying with ethyl acetate (10 mL) and lyophilized to give the product 228 as a white solid.
LC-MS m/z(ESI)：536.2[M+H] +。 LC-MS m/z (ESI): 536.2 [M+H] + .
1H NMR(400MHz，DMSO-d 6)δ9.94(s，1H)，8.46(d，1H，J＝5.2Hz)，8.31(s，1H)，7.79(d，2H，J＝8.4Hz)，7.40(d，2H，J＝8.4Hz)，7.16(d，1H，J＝5.2Hz)，6.94(t，1H，J＝8.4Hz)，6.55(d，1H，J＝8.8Hz)，6.11(s，1H)，5.81(s，1H)，5.54(s，1H)，3.65(s，3H)，3.39-3.52(m，2H)，3.13-3.19(m，2H)，2.42(s，3H)，1.96(s，3H)。 1 H NMR (400MHz, DMSO-d 6 ) δ9.94(s, 1H), 8.46(d, 1H, J=5.2Hz), 8.31(s, 1H), 7.79(d, 2H, J=8.4Hz) , 7.40(d, 2H, J=8.4Hz), 7.16(d, 1H, J=5.2Hz), 6.94(t, 1H, J=8.4Hz), 6.55(d, 1H, J=8.8Hz), 6.11 (s, 1H), 5.81(s, 1H), 5.54(s, 1H), 3.65(s, 3H), 3.39-3.52(m, 2H), 3.13-3.19(m, 2H), 2.42(s, 3H) ), 1.96(s, 3H).
使用上述实施例1-34的类似合成方法，采用不同原料，可以得到表1中对应目标化合物。The corresponding target compounds in Table 1 can be obtained by using the similar synthesis methods of the above-mentioned Examples 1-34 and using different raw materials.
表1Table 1
Figure PCTCN2022129961-appb-000371
Figure PCTCN2022129961-appb-000371
Figure PCTCN2022129961-appb-000372
Figure PCTCN2022129961-appb-000372
Figure PCTCN2022129961-appb-000373
Figure PCTCN2022129961-appb-000373
Figure PCTCN2022129961-appb-000374
Figure PCTCN2022129961-appb-000374
Figure PCTCN2022129961-appb-000375
Figure PCTCN2022129961-appb-000375
Figure PCTCN2022129961-appb-000376
Figure PCTCN2022129961-appb-000376
Figure PCTCN2022129961-appb-000377
Figure PCTCN2022129961-appb-000377
Figure PCTCN2022129961-appb-000378
Figure PCTCN2022129961-appb-000378
Figure PCTCN2022129961-appb-000379
Figure PCTCN2022129961-appb-000379
Figure PCTCN2022129961-appb-000380
Figure PCTCN2022129961-appb-000380
Figure PCTCN2022129961-appb-000381
Figure PCTCN2022129961-appb-000381
Figure PCTCN2022129961-appb-000382
Figure PCTCN2022129961-appb-000382
Figure PCTCN2022129961-appb-000383
Figure PCTCN2022129961-appb-000383
Figure PCTCN2022129961-appb-000384
Figure PCTCN2022129961-appb-000384
Figure PCTCN2022129961-appb-000385
Figure PCTCN2022129961-appb-000385
Figure PCTCN2022129961-appb-000386
Figure PCTCN2022129961-appb-000386
Figure PCTCN2022129961-appb-000387
Figure PCTCN2022129961-appb-000387
Figure PCTCN2022129961-appb-000388
Figure PCTCN2022129961-appb-000388
实施例35本发明化合物体外抑制FGFR1-4激酶活性实验Example 35 In vitro inhibition of FGFR1-4 kinase activity by compounds of the present invention
用DMSO梯度稀释的化合物分别与FGFR1，2，3和4重组蛋白室温孵育10分钟后，加入ATP以及生物素标记的2XTK底物，室温反应50分钟。终止反应后加入streptavidin标记的Sa-XL665以 及TK-antibody-Cryptate，室温孵育1小时，在615nm(Cryptate)和665nm处读取荧光值，计算665和615nm荧光强度的比值，并与DMSO对照组相比，计算化合物抑制百分比和IC 50。结果见下表2。 Compounds diluted in DMSO gradients were incubated with FGFR1, 2, 3 and 4 recombinant proteins at room temperature for 10 minutes, then ATP and biotin-labeled 2XTK substrate were added and reacted at room temperature for 50 minutes. After terminating the reaction, add streptavidin-labeled Sa-XL665 and TK-antibody-Cryptate, incubate at room temperature for 1 hour, read the fluorescence values at 615nm (Cryptate) and 665nm, calculate the ratio of the fluorescence intensity at 665nm and 615nm, and compare with the DMSO control group ratio, and the percent inhibition and IC 50 of the compound were calculated. The results are shown in Table 2 below.
表2本发明化合物对FGFR1-4激酶的抑制活性(IC 50，nM) Table 2 The inhibitory activity of the compounds of the present invention on FGFR1-4 kinase (IC 50 , nM)
Figure PCTCN2022129961-appb-000389
Figure PCTCN2022129961-appb-000389
Figure PCTCN2022129961-appb-000390
Figure PCTCN2022129961-appb-000390
Figure PCTCN2022129961-appb-000391
Figure PCTCN2022129961-appb-000391
Figure PCTCN2022129961-appb-000392
Figure PCTCN2022129961-appb-000392
+++表示IC 50小于或等于10nM +++ means IC 50 less than or equal to 10nM
++表示IC 50为10nM至50nM ++ indicates an IC50 of 10nM to 50nM
+表示IC 50大于50nM + indicates IC50 greater than 50nM
实施例36本发明化合物体外抑制SNU-16细胞增殖实验Example 36 The compounds of the present invention inhibit the proliferation of SNU-16 cells in vitro
3000个每孔的SNU-16细胞种于96孔板，过夜贴壁后，加入梯度稀释的化合物，继续孵育三天后，通过CTG检测细胞的ATP水平，评价细胞生长。与DMSO组对比，计算化合物抑制生长的百分率以及IC 50。具体结果见下表3。 3000 SNU-16 cells per well were planted in a 96-well plate. After overnight attachment, the compound was added in a gradient dilution. After incubation for three days, the ATP level of the cells was detected by CTG to evaluate the cell growth. The percentage inhibition of growth and the IC50 of the compounds were calculated compared to the DMSO group. The specific results are shown in Table 3 below.
表3.本发明化合物对SNU-16细胞的抑制活性(IC 50，nM) Table 3. Inhibitory activity of compounds of the present invention on SNU-16 cells (IC 50 , nM)
Figure PCTCN2022129961-appb-000393
Figure PCTCN2022129961-appb-000393
Figure PCTCN2022129961-appb-000394
Figure PCTCN2022129961-appb-000394
Figure PCTCN2022129961-appb-000395
Figure PCTCN2022129961-appb-000395
+++表示IC 50小于或等于10nM +++ means IC 50 less than or equal to 10nM
++表示IC 50为10nM至50nM ++ indicates an IC50 of 10nM to 50nM
+表示IC 50大于50nM + means IC50 greater than 50nM
其中对照化合物2的合成参照专利WO2022109577，Compound I-1的操作。The synthesis of the reference compound 2 refers to the operation of the patent WO2022109577, Compound I-1.
Figure PCTCN2022129961-appb-000396
Figure PCTCN2022129961-appb-000396
实施例37本发明化合物体外抑制AN3CA细胞增殖实验Example 37 The compound of the present invention inhibits the proliferation of AN3CA cells in vitro
500个每孔的AN3CA细胞种于96孔板，过夜贴壁后，加入梯度稀释的化合物，继续孵育7天后，通过CTG检测细胞的ATP水平，评价细胞生长。与DMSO组对比，计算化合物抑制生长的百分率以及IC 50。具体结果见下表4。 500 AN3CA cells per well were planted in a 96-well plate, and after overnight attachment, the compound was added in a gradient dilution and incubated for 7 days, and the ATP level of the cells was detected by CTG to evaluate the cell growth. The percentage inhibition of growth and the IC50 of the compounds were calculated compared to the DMSO group. The specific results are shown in Table 4 below.
表4.本发明化合物对AN3CA细胞的抑制活性(IC 50，nM) Table 4. Inhibitory activity of compounds of the present invention on AN3CA cells (IC 50 , nM)
Figure PCTCN2022129961-appb-000397
Figure PCTCN2022129961-appb-000397
实施例38本发明化合物体外肝微粒体稳定性实验Example 38 In vitro liver microsomal stability test of compounds of the present invention
将1μM化合物在500μg/mL的肝微粒体以及NADPH溶液孵育不同时间后，LC-MS检测化合物剩余量，计算T 1/2，清除率。具体结果见下表5。 After incubating 1 μM compound in 500 μg/mL liver microsomes and NADPH solution for different times, LC-MS detected the remaining amount of the compound, and calculated T 1/2 , the clearance rate. The specific results are shown in Table 5 below.
表5.本发明化合物体外肝微粒体稳定性评价结果(T 1/2，分钟) Table 5. In vitro liver microsome stability evaluation results of compounds of the present invention (T 1/2 , minutes)
Figure PCTCN2022129961-appb-000398
Figure PCTCN2022129961-appb-000398
实施例39本发明化合物的体内药代动力学实验Embodiment 39 In vivo pharmacokinetic experiment of the compound of the present invention
选取7至10周龄的CD-1雌性小鼠，静脉和口服给药的剂量分别为1mg/kg和10mg/kg。小鼠在给药 前禁食至少12小时，给药4小时后恢复供食，整个实验期间自由饮水。CD-1 female mice aged 7 to 10 weeks were selected, and the doses of intravenous and oral administration were 1 mg/kg and 10 mg/kg, respectively. The mice were fasted for at least 12 hours before administration, fed again 4 hours after administration, and had free access to water throughout the experiment.
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2mL/kg；口服组动物通过灌胃单次注射给予相应化合物，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、0.167、0.5、1、2、4、8和24h。每个时间点通过眼眶静脉丛采集大约200μL全血以及用于制备血浆，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CO2窒息死。采用WinnolinTMversion 8.2(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计算药动学参数。具体结果见下表6。On the day of the experiment, the animals in the intravenous group were given the corresponding compound through a single injection of the tail vein, and the administration volume was 2 mL/kg; the animals in the oral group were given the corresponding compound through a single intragastric injection, 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 times were: 0.083, 0.167, 0.5, 1, 2, 4, 8 and 24h. Approximately 200 μL of whole blood was collected through the orbital venous plexus at each time point and used to prepare plasma for concentration determination by high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). All animals were killed by CO2 asphyxiation after collecting the PK samples at the last time point. The non-compartmental model of Winnolin™ version 8.2 (Pharsight, mountain View, CA) pharmacokinetic software was used to process plasma concentrations, and the linear logarithmic trapezoidal method was used to calculate pharmacokinetic parameters. The specific results are shown in Table 6 below.
表6.本发明化合物的体内药代动力学评价结果Table 6. In vivo pharmacokinetic evaluation results of the compounds of the present invention
Figure PCTCN2022129961-appb-000399
Figure PCTCN2022129961-appb-000399
实施例40本发明部分化合物在AN3CA移植瘤模型体内药效实验Example 40 In vivo drug efficacy experiment of some compounds of the present invention in AN3CA xenograft tumor model
AN3CA细胞贴壁培养，培养条件为DMEM培养基中加10％胎牛血清和1％AA，37℃，5％CO2培养。一周用胰酶消化常规传代2次。当细胞维持在指数增长期且细胞活力大于95％时，收取细胞，计数，接种。在每只6-8周龄的雌性BALB/c nude小鼠的右侧颈背部接种AN3CA细胞5×106+Matrigel，接种体积为0.2mL。待肿瘤平均体积达到113mm 3时，随机将小鼠分为四组(对照组，TAS-120，化合物1，化合物2)，每组5只小鼠，化合物均每天口服给药两次(间隔8小时)，并量取肿瘤体积和小鼠体重，给药17天后处理小鼠。具体结果见图1和图2。 AN3CA cells were cultured adherently, and the culture conditions were 10% fetal calf serum and 1% AA in DMEM medium, 37°C, 5% CO2 culture. Trypsinization was routinely passaged twice a week. When the cells are maintained in the exponential growth phase and the cell viability is greater than 95%, the cells are harvested, counted, and inoculated. Inoculate 5×106+Matrigel of AN3CA cells on the right side of the back of the neck of each 6-8 week old female BALB/c nude mouse, the inoculation volume is 0.2mL. When the average tumor volume reached 113 mm, the mice were randomly divided into four groups (control group, TAS-120, compound 1, compound 2), and 5 mice in each group were administered orally twice a day (interval 8 hour), and measure the tumor volume and the body weight of the mice, and treat the mice 17 days after administration. The specific results are shown in Figure 1 and Figure 2.
实施例41本发明部分化合物在AN3CA移植瘤模型体内药效实验Example 41 In vivo drug efficacy experiment of some compounds of the present invention in AN3CA xenograft tumor model
AN3CA细胞贴壁培养，培养条件为DMEM培养基中加10％胎牛血清和1％AA，37℃，5％CO2培养。一周用胰酶消化常规传代2次。当细胞维持在指数增长期且细胞活力大于95％时，收取细胞，计数，接种。在每只6-8周龄的雌性BALB/c nude小鼠的右侧颈背部接种AN3CA细胞5×10 6+Matrigel， 接种体积为0.2mL。待肿瘤平均体积达到116mm 3时，随机将小鼠分为八组(对照组，对照化合物2，化合物2，化合物11，化合物198，化合物199，化合物200，化合物228)，每组6只小鼠，化合物均每天口服给药两次(间隔8小时)，并量取肿瘤体积和小鼠体重，给药17天后处理小鼠。具体结果见图3和图4。 AN3CA cells were cultured adherently, and the culture conditions were 10% fetal calf serum and 1% AA in DMEM medium, 37°C, 5% CO2 culture. Trypsinization was routinely passaged twice a week. When the cells are maintained in the exponential growth phase and the cell viability is greater than 95%, the cells are harvested, counted, and inoculated. 5×10 6 +Matrigel cells of AN3CA were inoculated on the right side of the nape of each female BALB/c nude mouse aged 6-8 weeks, with an inoculation volume of 0.2 mL. When the average tumor volume reached 116 mm, the mice were randomly divided into eight groups (control group, control compound 2, compound 2, compound 11, compound 198, compound 199, compound 200, compound 228), with 6 mice in each group , the compounds were orally administered twice a day (with an interval of 8 hours), and the tumor volume and the body weight of the mice were measured, and the mice were treated 17 days after the administration. The specific results are shown in Figure 3 and Figure 4.
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。Although the specific implementations of the present invention have been described above, those skilled in the art should understand that these are only examples, and various changes or changes can be made to these implementations without departing from the principle and essence of the present invention. Revise. Accordingly, the protection scope of the present invention is defined by the appended claims.

Claims (15)

  1. 一种如通式(1)所示的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物：A compound represented by general formula (1) or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates:
    Figure PCTCN2022129961-appb-100001
    Figure PCTCN2022129961-appb-100001
    通式(1)中：In general formula (1):
    Cy 1为取代或未取代的含1～4个独立选自N、S和O的杂原子的6元并5元杂芳环或部分不饱和杂环； Cy 1 is a substituted or unsubstituted 6-membered and 5-membered heteroaromatic ring or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, S and O;
    Cy 2为取代或未取代的苯环、5～6元杂芳环、9元双并杂芳环或9～12元部分不饱和双并杂环； Cy 2 is a substituted or unsubstituted benzene ring, a 5-6 membered heteroaromatic ring, a 9-membered bis-heteroaromatic ring or a 9-12-membered partially unsaturated bis-heterocyclic ring;
    Cy 2与Cy 1的5元环直接相连，同时二价基团-NH-(CH 2) n-连接Cy 1的6元环和Cy 2，并再形成一个环，其中n为1或2； Cy 2 is directly connected to the 5-membered ring of Cy 1 , and the divalent group -NH-(CH 2 ) n - is connected to the 6-membered ring of Cy 1 and Cy 2 to form another ring, where n is 1 or 2;
    R 1为H、(C1-C3)烷基或-L 1-R 1A； R 1 is H, (C1-C3) alkyl or -L 1 -R 1A ;
    L 1为化学键、-O-、-C(O)-、-NH-、-N(R L)-、-NH(CO)-、-N(R L)C(O)-、-C(O)NH-、-C(O)N(R L)-、-NHS(O) 2-、-N(R L)S(O) 2-、-S(O) 2NH-、-S(O) 2N(R L)-、-S-、-S(O)-或-S(O) 2-； L 1 is a chemical bond, -O-, -C(O)-, -NH-, -N(R L )-, -NH(CO)-, -N(R L )C(O)-, -C( O)NH-, -C(O)N(R L )-, -NHS(O) 2 -, -N(R L )S(O) 2 -, -S(O) 2 NH-, -S( O) 2 N(R L )-, -S-, -S(O)- or -S(O) 2 -;
    R L为(C1-C3)烷基，其中所述(C1-C3)烷基可任选被1个或多个卤素取代； R L is a (C1-C3) alkyl group, wherein the (C1-C3) alkyl group can be optionally substituted by one or more halogens;
    R 1A为-(CH 2) wR、-(CH 2) wOR、-(CH 2) wNR 2、取代或未取代的(C1-C6)烷基、(C3-C6)环烷基、苯基、含1～2个独立选自N、S和O的杂原子的3～9元饱和或部分不饱和杂环烷基、或含1～4个独立选自N、S和O的杂原子的5～6元杂芳基； R 1A is -(CH 2 ) w R, -(CH 2 ) w OR, -(CH 2 ) w NR 2 , substituted or unsubstituted (C1-C6) alkyl, (C3-C6) cycloalkyl, Phenyl, 3-9 membered saturated or partially unsaturated heterocycloalkyl containing 1-2 heteroatoms independently selected from N, S and O, or 1-4 heteroatoms independently selected from N, S and O Atomic 5-6 membered heteroaryl;
    Cy 3为取代或未取代的苯环、含1～4个独立选自N、S和O杂原子的5～6元单杂芳环、含1～4个独立选自N、S和O的杂原子的8～10元双杂芳环、3～7元饱和或部分不饱和碳环、含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环、含1～4个独立选自N、S和O的杂原子的7～12元饱和或部分不饱和双杂环或桥环、5～6元芳香环联4～7元饱和或部分不饱和杂环、或5～6元芳香环联5～6元杂芳环； Cy 3 is a substituted or unsubstituted benzene ring, a 5-6 membered monoheteroaromatic ring containing 1 to 4 heteroatoms independently selected from N, S and O, and a single heteroaromatic ring containing 1 to 4 heteroatoms independently selected from N, S and O 8-10 membered diheteroaromatic rings with heteroatoms, 3-7-membered saturated or partially unsaturated carbocycles, 3-7-membered saturated or partially unsaturated heteroatoms containing 1-2 heteroatoms independently selected from N, S and O Heterocycle, 7-12 membered saturated or partially unsaturated biheterocyclic ring or bridged ring containing 1-4 heteroatoms independently selected from N, S and O, 5-6 membered aromatic ring with 4-7 membered saturated or partially Unsaturated heterocyclic rings, or 5-6 membered aromatic rings linked with 5-6 membered heteroaromatic rings;
    R 2为-NHCN、-CN、
    Figure PCTCN2022129961-appb-100002
    Figure PCTCN2022129961-appb-100003
    R 2 is -NHCN, -CN,
    Figure PCTCN2022129961-appb-100002
    Figure PCTCN2022129961-appb-100003
    R 2A为H、取代或未取代的(C1-C6)烷基、或取代或未取代的(C3-C6)环烷基； R 2A is H, substituted or unsubstituted (C1-C6) alkyl, or substituted or unsubstituted (C3-C6) cycloalkyl;
    R 2B、R 2C和R 2D各自独立地为H、卤素、-CN、-C(O)R、-C(O)OR、-C(O)NR 2、-C(O)N(R)OR、-(CH 2) wR、-(CH 2) wOR、-(CH 2) wNR 2、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、 取代或未取代的苯基、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环、取代或未取代的含1～4个独立选自N、S和O的杂原子的5～6元杂芳环； R 2B , R 2C and R 2D are each independently H, halogen, -CN, -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R) OR, -(CH 2 ) w R, -(CH 2 ) w OR, -(CH 2 ) w NR 2 , substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) Cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated heterocycle containing 1-2 heteroatoms independently selected from N, S and O, substituted or unsubstituted A 5-6 membered heteroaromatic ring containing 1-4 heteroatoms independently selected from N, S and O;
    或者R 2A和R 2B、R 2B和R 2C、R 2C和R 2D、R 2A和R 2D可形成取代或未取代的含0～2个独立选自N、S和O的杂原子的4～7元饱和或部分不饱和环；或者所述的4～7元饱和或部分不饱和环的同一碳上的两个氢可被氧取代成-C(O)-； Or R 2A and R 2B , R 2B and R 2C , R 2C and R 2D , R 2A and R 2D can form a substituted or unsubstituted 4～2 heteroatoms independently selected from N, S and O 7-membered saturated or partially unsaturated ring; or two hydrogens on the same carbon of the 4-7 membered saturated or partially unsaturated ring can be replaced by oxygen to -C(O)-;
    每个R独立地为H、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、取代或未取代的苯基、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环、或取代或未取代的含1～4个独立选自N、S和O的杂原子的5～6元杂芳环；Each R is independently H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted containing 1 A 3-7 membered saturated or partially unsaturated heterocyclic ring with ~2 heteroatoms independently selected from N, S and O, or a substituted or unsubstituted heteroatom containing 1 to 4 heteroatoms independently selected from N, S and O 5-6 membered heteroaromatic rings;
    w为0，1或2。w is 0, 1 or 2.
  2. 如权利要求1所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Cy 1为： The compound as claimed in claim 1 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Cy 1 is:
    Figure PCTCN2022129961-appb-100004
    Figure PCTCN2022129961-appb-100005
    Cy 1优选为
    Figure PCTCN2022129961-appb-100006
    Figure PCTCN2022129961-appb-100004
    Figure PCTCN2022129961-appb-100005
    Cy 1 is preferably
    Figure PCTCN2022129961-appb-100006
    其中，
    Figure PCTCN2022129961-appb-100007
    与-NH-(CH 2)n-结构的氨基端相连，
    Figure PCTCN2022129961-appb-100008
    直接与Cy 2相连，
    Figure PCTCN2022129961-appb-100009
    与Cy 3相连；     in,
    Figure PCTCN2022129961-appb-100007
    Connected to the amino terminal of the -NH-(CH 2 )n- structure,
    Figure PCTCN2022129961-appb-100008
    connected directly to Cy 2 ,
    Figure PCTCN2022129961-appb-100009
    Connected to Cy 3 ;
    R 3为H、取代或未取代的(C1-C6)烷基、取代或未取代的饱和或部分不饱和的(C3-C7)环烷基、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和单杂环烷基、或取代或未取代的含1～4个独立选自N、S和O的杂原子的7～12元饱和或部分不饱和双环杂环烷基； R 3 is H, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted saturated or partially unsaturated (C3-C7) cycloalkyl, substituted or unsubstituted containing 1 to 2 independently selected A 3-7 membered saturated or partially unsaturated monoheterocycloalkyl group consisting of heteroatoms from N, S and O, or a substituted or unsubstituted 7- to 7-membered heteroatoms independently selected from N, S and O 12-membered saturated or partially unsaturated bicyclic heterocycloalkyl;
    R 4为H、-N(R) 2、卤素、(C1-C6)烷基或(C3-C6)环烷基，其中所述的(C1-C6)烷基或(C3-C6)环烷基可被1～3个卤素取代； R 4 is H, -N(R) 2 , halogen, (C1-C6) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl or (C3-C6) cycloalkane The group can be substituted by 1 to 3 halogens;
    R 5为H、(C1-C6)烷基或(C3-C6)环烷基，其中所述的(C1-C6)烷基或(C3-C6)环烷基可被1～3个卤素取代。 R 5 is H, (C1-C6) alkyl or (C3-C6) cycloalkyl, wherein said (C1-C6) alkyl or (C3-C6) cycloalkyl can be substituted by 1 to 3 halogens .
  3. 如权利要求2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 3为H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
    Figure PCTCN2022129961-appb-100010
    Figure PCTCN2022129961-appb-100011
    -CH 2F、-CHF 2、-CF 3、-CH 2OH、-CH 2CH 2F、-CH 2CH 2OH、
    Figure PCTCN2022129961-appb-100012
    Figure PCTCN2022129961-appb-100013
    R 3优选为-CH 3、-CH 2CH 3、-CH 2CH 2OH、
    Figure PCTCN2022129961-appb-100014
    Figure PCTCN2022129961-appb-100015
    R 3更优选为-CH 3。     The compound as claimed in claim 2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 3 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
    Figure PCTCN2022129961-appb-100010
    Figure PCTCN2022129961-appb-100011
    -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CH 2 OH,
    Figure PCTCN2022129961-appb-100012
    Figure PCTCN2022129961-appb-100013
    R 3 is preferably -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 OH,
    Figure PCTCN2022129961-appb-100014
    Figure PCTCN2022129961-appb-100015
    R 3 is more preferably -CH 3 .
  4. 如权利要求2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 4为H、F、Cl、Br、I、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
    Figure PCTCN2022129961-appb-100016
    -CH 2F、-CHF 2、-CF 3、-CH 2CH 2F或-CH 2CF 3；R4优选为H、F、Cl、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3或-CF 3；R 4更优选为H、F、Cl、-N(CH 3) 2或-CH 3。     The compound as claimed in claim 2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 4 is H, F, Cl, Br, I, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
    Figure PCTCN2022129961-appb-100016
    -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ; R4 is preferably H, F, Cl, -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , -CH 3 or -CF 3 ; R 4 is more preferably H, F, Cl, -N(CH 3 ) 2 or -CH 3 .
  5. 如权利要求2所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 5为H、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
    Figure PCTCN2022129961-appb-100017
    Figure PCTCN2022129961-appb-100018
    -CH 2F、-CHF 2、-CF 3、-CH 2CH 2F或-CH 2CF 3；R 5优选为H、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、CH 2CH 2F或-CH 2CF 3；R 5更优选为H、-CH 3或-CH 2CF 3。     The compound as claimed in claim 2 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 5 is H, -CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
    Figure PCTCN2022129961-appb-100017
    Figure PCTCN2022129961-appb-100018
    -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ; R 5 is preferably H, -CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , CH 2 CH 2 F or -CH 2 CF 3 ; R 5 is more preferably H, -CH 3 or -CH 2 CF 3 .
  6. 如权利要求1-5中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，Cy 2为： The compound according to any one of claims 1-5 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), Cy 2 for:
    Figure PCTCN2022129961-appb-100019
    Figure PCTCN2022129961-appb-100019
    Figure PCTCN2022129961-appb-100020
    Figure PCTCN2022129961-appb-100020
    Cy 2优选为
    Figure PCTCN2022129961-appb-100021
    Cy 2 is preferably
    Figure PCTCN2022129961-appb-100021
    其中，
    Figure PCTCN2022129961-appb-100022
    与-NH-(CH 2)n-结构的烷基端相连，
    Figure PCTCN2022129961-appb-100023
    与Cy 1相连；     in,
    Figure PCTCN2022129961-appb-100022
    Connected to the alkyl end of the -NH-(CH 2 )n- structure,
    Figure PCTCN2022129961-appb-100023
    Linked to Cy 1 ;
    R 6为Cy 2上的取代基，为H、卤素、-CN、-NO 2、-OR、-SR，-NR 2、-S(O) 2R、-S(O) 2NR 2、-S(O)R、-S(O)NR 2、-C(O)R、-C(O)OR、-C(O)NR 2、-C(O)N(R)OR、-C(O)N(R)(CH 2) wR、-OC(O)R、-OC(O)NR 2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR 2、-N(R)C(NR)NR 2、-N(R)S(O) 2NR 2、-N(R)S(O) 2R、-(CH 2) wOR、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、取代或未取代的苯基、取代或未取代的含1～4个独立选自N、S和O的杂原子的5～6元单杂芳环、取代或未取代的3～7元饱和或部分不饱和碳环、或取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环； R 6 is a substituent on Cy 2 , which is H, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , - S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -C( O)N(R)(CH 2 ) w R, -OC(O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N(R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, - (CH 2 ) w OR, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted (C3-C6) cycloalkyl, substituted or unsubstituted phenyl, substituted or unsubstituted 1～ 5-6 membered monoheteroaromatic rings with 4 heteroatoms independently selected from N, S and O, substituted or unsubstituted 3-7 membered saturated or partially unsaturated carbocycles, or substituted or unsubstituted 1-2 A 3-7 membered saturated or partially unsaturated heterocyclic ring independently selected from N, S and O heteroatoms;
    m为1或2。m is 1 or 2.
  7. 如权利要求6所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 6为H、F、Cl、Br、I、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
    Figure PCTCN2022129961-appb-100024
    Figure PCTCN2022129961-appb-100025
    -CH 2F、-CHF 2、-CF 3、-CH 2OH、-CH 2CH 2F、-CH 2CF 3、-CH 2CH 2OH、
    Figure PCTCN2022129961-appb-100026
    Figure PCTCN2022129961-appb-100027
    R 6优选为H、F、Cl、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F或-CH 2CF 3；R 6更优选为H、F、-CN、-CH 3、-CH 2CH 3、-CHF 2、-CF 3、-CH 2CF 3、-N(CH 3) 2、-OCF 3或-OCH 2CH 3。     The compound as claimed in claim 6 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R is H, F, Cl, Br, I, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
    Figure PCTCN2022129961-appb-100024
    Figure PCTCN2022129961-appb-100025
    -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH,
    Figure PCTCN2022129961-appb-100026
    Figure PCTCN2022129961-appb-100027
    R 6 is preferably H, F, Cl, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F or -CH 2 CF 3 ; R 6 is more preferably H, F, -CN, -CH 3 , -CH 2 CH 3 , -CHF 2 , -CF 3 , -CH 2 CF 3 , -N(CH 3 ) 2 , -OCF 3 , or -OCH 2 CH 3 .
  8. 如权利要求1-7中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，
    Figure PCTCN2022129961-appb-100028
    为：     The compound according to any one of claims 1-7 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1),
    Figure PCTCN2022129961-appb-100028
    for:
    Figure PCTCN2022129961-appb-100029
    Figure PCTCN2022129961-appb-100030
    优选为
    Figure PCTCN2022129961-appb-100031
    Figure PCTCN2022129961-appb-100029
    Figure PCTCN2022129961-appb-100030
    preferably
    Figure PCTCN2022129961-appb-100031
    其中R 7为Cy 3上的取代基，为H、卤素、-CN、-NO 2、-OR、-SR，-NR 2、-S(O) 2R、-S(O) 2NR 2、-S(O)R、-S(O)NR 2、-C(O)R、-C(O)OR、-C(O)NR 2、-C(O)N(R)OR、-OC(O)R、-OC(O)NR 2、-N(R)C(O)OR、-N(R)C(O)R、-N(R)C(O)NR 2、-N(R)C(NR)NR 2、-N(R)S(O) 2NR 2、-N(R)S(O) 2R、取代或未取代的(C1-C6)烷基、取代或未取代的(C3-C6)环烷基、取代或未取代的3～7元饱和或部分不饱和碳环、取代或未取代的含1～2个独立选自N、S和O的杂原子的3～7元饱和或部分不饱和杂环； Wherein R 7 is a substituent on Cy 3 , which is H, halogen, -CN, -NO 2 , -OR, -SR, -NR 2 , -S(O) 2 R, -S(O) 2 NR 2 , -S(O)R, -S(O)NR 2 , -C(O)R, -C(O)OR, -C(O)NR 2 , -C(O)N(R)OR, -OC (O)R, -OC(O)NR 2 , -N(R)C(O)OR, -N(R)C(O)R, -N(R)C(O)NR 2 , -N( R)C(NR)NR 2 , -N(R)S(O) 2 NR 2 , -N(R)S(O) 2 R, substituted or unsubstituted (C1-C6) alkyl, substituted or unsubstituted Substituted (C3-C6) cycloalkyl, substituted or unsubstituted 3-7 membered saturated or partially unsaturated carbocycle, substituted or unsubstituted containing 1-2 heteroatoms independently selected from N, S and O 3-7 membered saturated or partially unsaturated heterocycle;
    p为1或2。p is 1 or 2.
  9. 如权利要求8所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 7为H、F、Cl、Br、I、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-NHCH 3、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2CH 2CH 3、
    Figure PCTCN2022129961-appb-100032
    Figure PCTCN2022129961-appb-100033
    -CH 2F、-CHF 2、-CF 3、-CH 2OH、-CH 2CH 2F、-CH 2CF 3、-CH 2CH 2OH、
    Figure PCTCN2022129961-appb-100034
    Figure PCTCN2022129961-appb-100035
    R 7优选为H、F、Cl、-CN、-NO 2、-OCH 3、-OCF 3、-OCH 2CH 3、-OCH 2CF 3、-NH 2、-N(CH 3) 2、-CH 3、-CH 2CH 3、-CH 2F、-CHF 2、-CF 3、-CH 2CH 2F、-CH 2CF 3、-CH 2CH 2OH、
    Figure PCTCN2022129961-appb-100036
    R 7更优选为H、F、-CH 3、-N(CH 3) 2、-OCH 3、-OCH 2CH 2OH、
    Figure PCTCN2022129961-appb-100037
    The compound as claimed in claim 8 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R is H, F, Cl, Br, I, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -NHCH 3 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 CH 2 CH 3 ,
    Figure PCTCN2022129961-appb-100032
    Figure PCTCN2022129961-appb-100033
    -CH 2 F, -CHF 2 , -CF 3 , -CH 2 OH, -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH,
    Figure PCTCN2022129961-appb-100034
    Figure PCTCN2022129961-appb-100035
    R 7 is preferably H, F, Cl, -CN, -NO 2 , -OCH 3 , -OCF 3 , -OCH 2 CH 3 , -OCH 2 CF 3 , -NH 2 , -N(CH 3 ) 2 , - CH 3 , -CH 2 CH 3 , -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CH 2 F, -CH 2 CF 3 , -CH 2 CH 2 OH,
    Figure PCTCN2022129961-appb-100036
    R 7 is more preferably H, F, -CH 3 , -N(CH 3 ) 2 , -OCH 3 , -OCH 2 CH 2 OH,
    Figure PCTCN2022129961-appb-100037
  10. 如权利要求1-9中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 1为H、-CH 3或-L 1-R 1A； The compound according to any one of claims 1-9 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 1 is H, -CH 3 or -L 1 -R 1A ;
    L 1为化学键、-O-、-C(O)-、-NH-、-NH(CO)-、-C(O)NH-、-C(O)N(CH 3)-或-S(O) 2-； L 1 is a chemical bond, -O-, -C(O)-, -NH-, -NH(CO)-, -C(O)NH-, -C(O)N(CH 3 )- or -S( O) 2 -;
    R 1A为-CH 3、
    Figure PCTCN2022129961-appb-100038
    Figure PCTCN2022129961-appb-100039
    Figure PCTCN2022129961-appb-100040
    Figure PCTCN2022129961-appb-100041
    R 1A优选为-CH 3、
    Figure PCTCN2022129961-appb-100042
    Figure PCTCN2022129961-appb-100043
    R 1A更优选为
    Figure PCTCN2022129961-appb-100044
    Figure PCTCN2022129961-appb-100045
    R 1A is -CH 3 ,
    Figure PCTCN2022129961-appb-100038
    Figure PCTCN2022129961-appb-100039
    Figure PCTCN2022129961-appb-100040
    Figure PCTCN2022129961-appb-100041
    R 1A is preferably -CH 3 ,
    Figure PCTCN2022129961-appb-100042
    Figure PCTCN2022129961-appb-100043
    R 1A is more preferably
    Figure PCTCN2022129961-appb-100044
    Figure PCTCN2022129961-appb-100045
  11. 如权利要求1-10中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述通式(1)中，R 2为-NHCN、-CN、
    Figure PCTCN2022129961-appb-100046
    Figure PCTCN2022129961-appb-100047
    Figure PCTCN2022129961-appb-100048
    R 2优选为-NHCN、-CN、
    Figure PCTCN2022129961-appb-100049
    Figure PCTCN2022129961-appb-100050
    R 2更优选为
    Figure PCTCN2022129961-appb-100051
    Figure PCTCN2022129961-appb-100052
    The compound according to any one of claims 1-10 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein in the general formula (1), R 2 is -NHCN, -CN,
    Figure PCTCN2022129961-appb-100046
    Figure PCTCN2022129961-appb-100047
    Figure PCTCN2022129961-appb-100048
    R2 is preferably -NHCN, -CN,
    Figure PCTCN2022129961-appb-100049
    Figure PCTCN2022129961-appb-100050
    R 2 is more preferably
    Figure PCTCN2022129961-appb-100051
    Figure PCTCN2022129961-appb-100052
  12. 如权利要求1-11中任一项所述的化合物或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物，其中所述化合物具有以下结构之一：The compound according to any one of claims 1-11 or its various isomers, various crystal forms, pharmaceutically acceptable salts, hydrates or solvates, wherein the compound has one of the following structures:
    Figure PCTCN2022129961-appb-100053
    Figure PCTCN2022129961-appb-100053
    Figure PCTCN2022129961-appb-100054
    Figure PCTCN2022129961-appb-100054
    Figure PCTCN2022129961-appb-100055
    Figure PCTCN2022129961-appb-100055
    Figure PCTCN2022129961-appb-100056
    Figure PCTCN2022129961-appb-100056
    Figure PCTCN2022129961-appb-100057
    Figure PCTCN2022129961-appb-100057
    Figure PCTCN2022129961-appb-100058
    Figure PCTCN2022129961-appb-100058
    Figure PCTCN2022129961-appb-100059
    Figure PCTCN2022129961-appb-100059
    Figure PCTCN2022129961-appb-100060
    Figure PCTCN2022129961-appb-100060
  13. 一种药物组合物，其特征在于，其含有药学上可接受的赋形剂或载体，以及如权利要求1-12中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物作为活性成分。A pharmaceutical composition, characterized in that it contains a pharmaceutically acceptable excipient or carrier, and the compound according to any one of claims 1-12, or its isomers, crystal forms, A pharmaceutically acceptable salt, hydrate or solvate is used as the active ingredient.
  14. 一种如权利要求1-12中任一项所述的化合物、或其各异构体、各晶型、药学上可接受的盐、水合物或溶剂合物或如权利要求13所述的药物组合物在制备治疗、调节和/或预防与成纤维细胞生长因子受体2(FGFR2)相关的疾病药物中的用途。A compound as described in any one of claims 1-12, or its isomers, crystal forms, pharmaceutically acceptable salts, hydrates or solvates, or the drug as claimed in claim 13 Use of the composition in preparing medicines for treating, regulating and/or preventing diseases related to fibroblast growth factor receptor 2 (FGFR2).
  15. 如权利要求14所述的用途，其中所述的疾病是癌症，所述癌症是血液癌和实体瘤。The use according to claim 14, wherein said disease is cancer, and said cancer is hematological cancer and solid tumor.
PCT/CN2022/129961 2021-11-04 2022-11-04 Fgfr2 inhibitor, preparation method therefor, and pharmaceutical use thereof WO2023078413A1 (en)

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CN105189504A (en) * 2013-03-11 2015-12-23 艾伯维公司 Fused tetracyclic bromodomain inhibitors
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US20180008610A1 (en) * 2015-02-20 2018-01-11 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors
CN109721600A (en) * 2017-10-30 2019-05-07 如东凌达生物医药科技有限公司 A kind of nitrogenous fused ring compound and its preparation method and application
CN111662292A (en) * 2019-03-08 2020-09-15 首药控股(北京)股份有限公司 FGFR4 kinase inhibitor and preparation method and application thereof

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Publication number Priority date Publication date Assignee Title
CN104854107A (en) * 2012-11-15 2015-08-19 药品循环公司 Pyrrolopyrimidine compounds as kinase inhibitors
CN105189504A (en) * 2013-03-11 2015-12-23 艾伯维公司 Fused tetracyclic bromodomain inhibitors
CN105636962A (en) * 2013-10-15 2016-06-01 靳博涵 Novel compositions, uses and methods for their preparation
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