WO2023078413A1 - Inhibiteur du fgfr2, son procédé de préparation et son utilisation pharmaceutique - Google Patents

Inhibiteur du fgfr2, son procédé de préparation et son utilisation pharmaceutique 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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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

L'invention concerne un composé représenté par la formule générale (1) ou un sel pharmaceutiquement acceptable de celui-ci, une composition contenant un composé représenté par la formule générale (1), son procédé de préparation et son utilisation en tant qu'inhibiteur du récepteur 2 du facteur de croissance des fibroblastes (FGFR2) dans la préparation d'un médicament antitumoral.
PCT/CN2022/129961 2021-11-04 2022-11-04 Inhibiteur du fgfr2, son procédé de préparation et son utilisation pharmaceutique WO2023078413A1 (fr)

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CN105189504A (zh) * 2013-03-11 2015-12-23 艾伯维公司 稠合四环溴结构域抑制剂
CN105636962A (zh) * 2013-10-15 2016-06-01 靳博涵 新型化合物、用途及其制备方法
US20180008610A1 (en) * 2015-02-20 2018-01-11 Incyte Corporation Bicyclic heterocycles as fgfr4 inhibitors
CN109721600A (zh) * 2017-10-30 2019-05-07 如东凌达生物医药科技有限公司 一类含氮稠环化合物及其制备方法和用途
CN111662292A (zh) * 2019-03-08 2020-09-15 首药控股(北京)股份有限公司 Fgfr4激酶抑制剂及其制备方法和用途

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Publication number Priority date Publication date Assignee Title
CN104854107A (zh) * 2012-11-15 2015-08-19 药品循环公司 作为激酶抑制剂的吡咯并嘧啶化合物
CN105189504A (zh) * 2013-03-11 2015-12-23 艾伯维公司 稠合四环溴结构域抑制剂
CN105636962A (zh) * 2013-10-15 2016-06-01 靳博涵 新型化合物、用途及其制备方法
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