WO2018050052A1 - Composé contenant un noyau pyrimidine, inhibiteur d'egfr et son application - Google Patents

Composé contenant un noyau pyrimidine, inhibiteur d'egfr et son application Download PDF

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WO2018050052A1
WO2018050052A1 PCT/CN2017/101392 CN2017101392W WO2018050052A1 WO 2018050052 A1 WO2018050052 A1 WO 2018050052A1 CN 2017101392 W CN2017101392 W CN 2017101392W WO 2018050052 A1 WO2018050052 A1 WO 2018050052A1
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group
cycloalkyl
compound
alkyl
substituent
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吴豫生
牛成山
耿阳
梁阿朋
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郑州泰基鸿诺医药股份有限公司
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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
    • A61K31/495—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
    • 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
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the invention belongs to the technical field of medicine, in particular to a pyrimidine ring-containing compound, and also relates to an EGFR inhibitor and its preparation for regulating EGFR tyrosine kinase activity or treating EGFR related diseases, especially non-small cell lung cancer. Drug application.
  • the Epidermal Growth Factor Receptor is a transmembrane protein tyrosine kinase of the erbB receptor family.
  • a growth factor ligand eg, epidermal growth factor (EGF)
  • the receptor can homodimerize with an additional EGFR molecule, or with another family member (eg, erbB2 (HER2), erbB3 (HER3), Or erbB4 (HER4)) heterodimerization occurs.
  • HER2 erbB2
  • HER3 erbB3
  • HER4 erbB4
  • Homologous dimerization and/or heterodimerization of the erbB receptor results in phosphorylation of key tyrosine residues in the intracellular domain and results in stimulation of many intracellular signaling pathways involved in cell proliferation and survival.
  • Deregulation of erbB family signaling promotes proliferation, invasion, metastasis, angiogenesis, and tumor cell survival, and has been described in many
  • erbB family represented as legitimate targets for anticancer drug development, as many drugs targeting EGFR or erbB2 is now widely used in clinical applications, including Gefitinib (IRESSA TM), erlotinib (TARCEVA TM) and lapatinib (TYKERB TM) and the like.
  • IRESSA TM Gefitinib
  • TARCEVA TM erlotinib
  • TYKERB TM lapatinib
  • erbB receptor signaling and its involvement in tumorigenesis are provided in New England Journal of Medicine (2008, 358, 1160-1174) and Biochemical and Biophysical Research Communications (2004, 319, 1-11). Detailed discussion.
  • Lung cancer is the world's highest incidence of cancer. It ranks first among all cancers in China, and it is also the cancer with the highest morbidity and mortality in China. About 30% of lung cancer patients in China have EGFR mutations, of which L858R and exon 19 deletion mutations account for more than 90%. These patients are more sensitive to EGFR inhibitors.
  • the existing first-generation EGFR inhibitors such as erlotinib and gefitinib have good curative effect on such patients, which can reduce tumors in more than 60% of patients and significantly prolong the progression-free survival of patients. .
  • the vast majority of patients will acquire resistance within 6-12 months. This resistance pattern is a further mutation of EGFR, which reduces its sensitivity to first-generation EGFR inhibitors.
  • T790M The most common of these mutations is the so-called "gatekeeper" mutation T790M (Science, 2004, Vol. 304, 1497-1500; New England Journal of Medicine 2004, 350, 2129-2139), from the original L- at this site. Threonine (T) is replaced by L-methionine (M), and the mutated EGF tyrosine kinase R no longer binds to gefitinib or erlotinib, thus making the first generation of EGFR inhibitors No longer effective, resulting in such patients currently in a state of no drug availability. Clinically, 50% of patients who developed resistance to first-generation EGFR inhibitors had EGFR T790M mutations. The first generation of EGFR inhibitors, such as gefitinib and erlotinib, in the T790M mutant cell line H1975 were greater than 3 [mu]M and were essentially inactive.
  • the second-generation irreversible pan-EGFR inhibitor (Afatinib BIBW2992) currently on the market is significantly better than the first-generation EGFR inhibitor in patients with EGFR-mutant lung cancer.
  • the second-generation inhibitor also has a strong wild-type EGFR inhibitory activity, and the inhibitory activity against wild-type EGFR is significantly higher than that of the drug-resistant T790M mutation.
  • the toxic side effects such as rash of the patient are severe and the drug-resistant patients have poor efficacy, only small Some first-generation EGFR inhibitor-resistant patients respond to these drugs.
  • a second object of the present invention is to provide an EGFR inhibitor comprising the above pyrimidine ring-containing compound.
  • a third object of the present invention is to provide a use of the above EGFR inhibitor for the preparation of a medicament for modulating EGFR tyrosine kinase activity or treating an EGFR-related disease.
  • a pyrimidine ring-containing compound comprising a compound of formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C 1-12 alkyl, C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 3-12 cycloalkoxy, C 3-12 halocycloalkoxy a C 1-12 alkylthio group, a C 1-6 acyl group, a C 1-12 alkylamino group or a C 3-12 cycloalkylamino group, or a C 1-12 alkyl group having a substituent R 10 , C 1-12 haloalkyl group, a C 3-12 cycloalkyl group, C 3-12 halogenated cycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy group, a C 3-12 a cycloalkoxy group, a C 3-12 a
  • R 3 is selected from any one of the following structures:
  • R 4 is selected from any one of the following structures:
  • R 5 is selected from C 1-12 alkyl group, with the substituent R 10 is C 1-12 alkyl, C 3-12 cycloalkyl, and substituted with C 3-12 cycloalkyl group R 10 group, a C 6-14 aryl group, having a substituent group R C 10 6-14 aryl, C 5-12 heteroaryl, R C 5-12 substituent having 10 heteroaryl, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;
  • X 1 , X 2 , X 3 and X 5 are each independently selected from C, N, O or S;
  • X 4 is selected from C or N;
  • X 2 and X 3 are each present or absent, and are bonded by X 1 , X 4 is connected to each other;
  • the dotted line represents a single bond, and the single bond exists or does not exist, but the two single bonds do not exist at the same time;
  • R 6 , R 7 , R 8 and R 9 are each independently selected from the group consisting of H, O, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C 1-12 alkyl, C 1- 12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 3-12 naphthenic Oxyl, C 3-12 halocycloalkoxy, C 1-12 alkylthio, C 1-6 acyl, C 1-12 alkylamino, C 3-12 cycloalkylamino, C 6- 14 aryl, C 5-12 heteroaryl, or C 1-12 alkyl with substituent R 10 , C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3 12 halocycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 3-12 cycloal
  • Y 1, Y 2, Y 3 , Y 4, Y 5 are each independently selected from hydrogen, halogen, C 1-12 alkyl, C 1-12 with 10 alkyl substituent R, C 3-12 cycloalkyl, substituted with a cycloalkyl group of R 10 is C 3-12, C 1-12 alkylamino group or with a substituent R C 10 alkylamino of 1 to 12;
  • R Y is selected from an alkyl group, an alkyl group having a substituent R 10 , a cycloalkyl group, a cycloalkyl group having a substituent R 10 , or one or more of the above groups C is N, O, S Substituting one or more heteroatoms to form a group;
  • the substituent R 10 is selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, alkyl of C 1-12 , cycloalkyl of C 3-12 , alkyl of C 1-12 Oxyl, C 3-12 cycloalkoxy, C 1-12 haloalkyl, C 3-12 halocycloalkyl, C 1-6 acyl, C 2-6 halo acyl, C 1 -12 alkylamino group, a halogenated C 1-12 alkylamino, C 3-12 cycloalkylamino group, the cycloalkyl C 3-12 haloalkyl amino, C 1-12 alkylthio or C 1-12 halogenated alkylthio base;
  • the substituted phenyl group is a halogenated phenyl group or a halogenated phenyl group having R 11 ;
  • the substituted cycloalkyl group is a halogenated cycloalkyl group or has R halocycloalkyl 11; and a substituent for the alkoxy group or a haloalkoxy group with R 11 haloalkoxy;
  • cycloalkoxy group is substituted with alkoxy or haloalkoxy ring with R a halocycloalkoxy group of 11 ;
  • the alkylamino group having a substituent is a haloalkylamino group or a haloalkylamino group having R 11 ;
  • the substituted cycloalkylamino group is a halocycloalkylamino group or a halogenated group having R 11 a cycloalkylamino group;
  • R 11 is selected from the group consisting of H, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C 1-12 alkyl, C 3-12 cycloalkyl, C 1-12 alkoxy , C 3-12 cycloalkoxy, C 1-12 haloalkyl, C 3-12 halocycloalkyl, C 1-6 acyl, C 2-6 halo acyl, C 1-12 An alkylamino group, a C 1-12 haloalkylamino group, a C 3-12 cycloalkylamino group, a C 3-12 halocycloalkylamino group, a C 1-12 alkylthio group or a C 1-12 haloalkylthio group.
  • a pyrimidine ring-containing compound of the present invention which comprises a compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof; the compound inhibits one or more EGFR Activation or resistance mutations, such as L858R activating mutants, Exon19 deletion EGFR activating mutants, T790M resistant mutants.
  • the pyrimidine ring-containing compound comprises a compound represented by formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C 1-12 alkyl, C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 3-12 cycloalkoxy, C 3-12 halocycloalkoxy a C 1-12 alkylthio group, a C 1-6 acyl group, a C 1-12 alkylamino group or a C 3-12 cycloalkylamino group, or a C 1-12 alkyl group having a substituent R 10 , C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 3-12 a cycloalkoxy group, a C 3-12 halocycloalkoxy group,
  • R 3 is selected from any one of the following structures:
  • R 4 is selected from any one of the following structures:
  • R 5 is selected from C 1-12 alkyl group, with the substituent R 10 is C 1-12 alkyl, C 3-12 cycloalkyl, and substituted with C 3-12 cycloalkyl group R 10 group, a C 6-14 aryl group, having a substituent group R C 10 6-14 aryl, C 5-12 heteroaryl, R C 5-12 substituent having 10 heteroaryl, Or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;
  • R 7 and R 8 are each independently selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C 1-12 alkyl, C 3-12 cycloalkyl, C 1 Alkoxy group of -12 , cycloalkyloxy group of C 3-12 , alkylthio group of C 1-12 , acyl group of C 1-6 , alkylamino group of C 1-12 , cycloalkylamino group of C 3-12 , An aryl group of C 6-14 , a heteroaryl group of C 5-12 , or a C 1-12 alkyl group having a substituent R 10 , a C 3-12 cycloalkyl group, a C 1-12 alkoxy group.
  • Y 1, Y 2, Y 3 , Y 4, Y 5 are each independently selected from hydrogen, halogen, C 1-12 alkyl, C 1-12 with 10 alkyl substituent R, C 3-12 cycloalkyl, substituted with a cycloalkyl group of R 10 is C 3-12, C 1-12 alkylamino group or with a substituent R C 10 alkylamino of 1 to 12;
  • the Y R is selected from C 1-12 alkyl group, an alkyl substituent group R 10 is C 1-12, C 3-12 cycloalkyl, and substituted with C 3-12 cycloalkyl group R 10 a group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S;
  • the substituent R 10 is selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, alkyl of C 1-12 , cycloalkyl of C 3-12 , alkyl of C 1-12 Oxyl, C 3-12 cycloalkoxy, C 1-12 haloalkyl, C 3-12 halocycloalkyl, C 1-6 acyl, C 2-6 halo acyl, C 1 -12 alkylamino group, a halogenated C 1-12 alkylamino, C 3-12 cycloalkylamino group, the cycloalkyl C 3-12 haloalkyl amino, C 1-12 alkylthio or C 1-12 halogenated alkylthio base;
  • R 1 is preferably selected from hydrogen, halogen, trifluoromethyl or cyano.
  • R 2 is preferably selected from the group consisting of methoxy, monofluoromethoxy, difluoromethoxy, deuterated monofluoromethoxy, deuterated difluoromethoxy, trifluoromethoxy, C 2-6 alkoxy. a halogenated alkoxy group of C 2-6, a cycloalkoxy group of C 3-6 or a halogenated cycloalkoxy group of C 3-6 .
  • R 4 is selected from any one of the following structures:
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3 a halogenated cycloalkyl group of -6 or an alkylamino group of 1-6 .
  • R 5 is preferably selected from phenyl or substituted phenyl, heteroaryl or substituted heteroaryl, and the substituent may be optionally selected from halogen, cyano, nitro, ester, C 1-4 alkyl or ring.
  • the compounds of the present invention can be prepared by a variety of techniques, some of which are set forth below, and those skilled in the art will understand that these methods are representative and not limiting.
  • the compound SM 1 and the compound SM 2 can be reacted by a method such as nucleophilic substitution or coupling to obtain a final product P (that is, a compound represented by the formula (II)).
  • the synthesis method of the compound SM 1 is as follows:
  • the starting compound a-1 is first subjected to nucleophilic substitution reaction with R 5 -NH 2 to form compound a-2, and then compound a-2 is further reacted to form compound a-3 by Heck coupling reaction, and finally, ring closure is carried out to obtain compound SM 1 .
  • the starting compound 1 is firstly made into a phenol sodium salt, and then reacted with methyl iodide or ethyl difluorobromoacetate to prepare a compound 3, and the compound 3 is reduced to obtain a compound 4, which is then nitrated, and the amino group is protected with di-tert-butyl dicarbonate.
  • Compound 6 is further substituted with a precursor of the substituent R 3 to obtain a compound 7, and the compound 7 is reduced to obtain a compound 8, which is then reacted with a precursor of the substituent R 4 to obtain a compound SM 2 .
  • a still further preferred pyrimidine ring-containing compound, the compound of formula (II) is selected from the group consisting of:
  • the pharmaceutically acceptable salt is a mineral acid salt or an organic acid salt selected from the group consisting of a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a sulfate salt, a hydrogen sulfate salt, a nitrate salt, and a phosphate salt.
  • An acid phosphate is selected from the group consisting of formate, acetate, trifluoroacetate, propionate, pyruvate, glycolate, oxalate, malonate, Fumarate, maleate, lactate, malate, citrate, tartrate, methanesulfonate, ethanesulfonate, besylate, salicylate, picrate, valley Alkaloids, salicylates, ascorbates, camphorates, camphorsulfonates.
  • An EGFR inhibitor comprising the above pyrimidine ring-containing compound.
  • the EGFR inhibitor further comprises a pharmaceutically acceptable carrier.
  • the EGFR inhibitor of the present invention including the composition of any one or more of the above pyrimidine ring-containing compounds, further comprises a pharmaceutically acceptable carrier.
  • the above pyrimidine ring-containing compounds can be administered in a suitable dosage form with one or more pharmaceutically acceptable carriers.
  • These dosage forms are suitable for oral, rectal, topical, intraoral, and other parenteral administration (eg, For example, subcutaneous, muscle, vein, etc.).
  • compositions of this invention are formulated, quantified, and administered in a manner consistent with medical practice.
  • the "effective amount" of a compound administered is determined by the particular condition being treated, the individual being treated, the cause of the condition, the target of the drug, and the mode of administration.
  • the regulation of EGFR tyrosine kinase activity or treatment of EGFR-related diseases refers to cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases.
  • the EGFR inhibitor is suitable for the preparation of a medicament for regulating EGFR tyrosine kinase activity or treating EGFR-related diseases, and is particularly suitable for preparing a medicament for cancer treatment, such as non-small cell lung cancer.
  • the pyrimidine ring-containing compound of the present invention that is, the compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, can be used for the preparation of a EGFR tyrosine kinase activity or Drugs for the treatment of EGFR-related diseases, such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases, are especially suitable for the preparation of mutations by EGFR, including sensitive mutations (such as L858R mutation or deletion of exon 19) and Drug-resistant mutations (such as the EGFR T790M mutation), a therapeutic drug for non-small cell lung cancer.
  • EGFR-related diseases such as cancer, diabetes, immune system diseases, neurodegenerative diseases or cardiovascular diseases
  • sensitive mutations such as L858R mutation or deletion of exon 19
  • Drug-resistant mutations such as the EGFR T790M mutation
  • the pyrimidine ring-containing compound of the present invention that is, the compound of the formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof, can be used as a single therapeutic treatment in anticancer therapy.
  • it may be combined with conventional surgery or radiation therapy or chemotherapy or immunotherapy.
  • These therapies can be administered in parallel, simultaneously, sequentially, or separately with the compounds of the invention, and can comprise one or more of the following: such as gefitinib, erlotinib, ect.
  • Nipa lapatinib, XL647, NVP-AEE-788, ARRY-334543, vandetanib, PF00299804, cetuximab, panituzumab, pertuzumab, zarumumab, Nimotuzumab, MDX-214, CDX-110, IMC-11F8, CNF2024, tandorimycin, aspironmycin, IPI-504, NVP-AUY922, and the like.
  • the pyrimidine ring-containing compound of the present invention is a selective inhibitor of EGFR mutations discovered by the inventors after long-term and intensive research, and in vitro experiments show that it can inhibit the proliferation of EGFRT790M/L858R double mutant enzyme at nanomolar concentration.
  • the inhibition of wild-type EGFR enzyme is relatively weak. Therefore, these compounds can be used not only for the treatment of EGFR-sensitive mutant cancers, but also for the cases of secondary resistance in the current EGFR-TKI treatment; and their mutation selectivity greatly reduces the inhibition of wild-type EGFR. Toxic side effects are an ideal substitute for the first and second generation EGFR-TKI.
  • Alkyl refers to a monovalent straight or branched chain saturated hydrocarbon group containing from 1 to 12 carbon atoms consisting solely of carbon and hydrogen atoms.
  • the "alkyl group” is preferably an alkyl group of 1 to 6 carbon atoms, that is, a C 1 -C 6 alkyl group, more preferably a C 1 -C 4 alkyl group.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, and the like.
  • Alkoxy refers to a radical of the formula -OR wherein R is alkyl as defined herein. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, isopropoxy, t-butoxy, and the like.
  • Halogen (halo) means a fluorine, chlorine, bromine or iodine substituent.
  • Haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogens are replaced by the same or different halogens.
  • Examples of the haloalkyl group include -CH 2 Cl, -CH 2 CF 3 , -CH 2 CCl 3 , a perfluoroalkyl group (for example, -CF 3 ), and the like.
  • Haloalkoxy refers to a radical of the formula -OR wherein R is haloalkyl as defined herein.
  • haloalkoxy groups include, but are not limited to, trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, and the like.
  • Cycloalkyl refers to a monovalent saturated carbocyclic group consisting of a mono- or bicyclic ring having from 3 to 12, preferably from 3 to 10, more preferably from 3 to 6 ring atoms.
  • the cycloalkyl group can be optionally substituted by one or more substituents, wherein each substituent is independently hydroxy, alkyl, alkoxy, halo, haloalkyl, amino, monoalkylamino or dialkylamino.
  • substituents include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • Cycloalkoxy refers to a radical of the formula -OR wherein R is cycloalkyl as defined herein.
  • exemplary cycloalkyloxy groups include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and the like.
  • acyl refers to a radical of the formula -C(O)R wherein R is alkyl as defined herein.
  • exemplary acyl groups include acetyl, n-propionyl, isopropionyl, n-butyryl, isobutyryl, t-butyryl and the like.
  • Ester group refers to a radical of the formula -C(O)OR wherein R is alkyl as defined herein.
  • exemplary ester groups include -C(O)OMe, -C(O)OEt, and the like.
  • Alkylthio refers to a radical of the formula -SR a where R a is H or alkyl as defined herein.
  • Alkylamino refers to a radical of the formula -NR a R b wherein R a is H or alkyl as defined herein and R b is alkyl as defined herein.
  • Cycloalkylamino refers to a radical of the formula -NR a R b wherein R a is H, alkyl as defined herein or cycloalkyl as defined herein, and R b is cycloalkane as defined herein base.
  • Heteroaryl refers to a monocyclic, bicyclic or tricyclic radical of 5 to 12 ring atoms containing at least one ring heteroatom containing one, two or three selected from N, O or S, remaining
  • the ring atom is an aromatic ring of C, and it should be clear that the point of attachment of the heteroaryl group should be on the aromatic ring.
  • the heteroaryl group is preferably 5-8 ring atoms, more preferably 5-6 ring atoms.
  • heteroaryl groups include, but are not limited to, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyrazinyl, thienyl, furanyl , pyranyl, pyridyl, pyrrolyl, pyrazolyl, pyrimidinyl, quinolyl, isoquinolinyl, benzofuranyl, benzofuranyl, benzothienyl, benzothiopyranyl, benzo Imidazolyl, benzoxazolyl, benzooxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzopyranyl, fluorenyl, isodecyl, triazolyl, triazinyl , quinoxalinyl, fluorenyl, quinazolinyl, quinazinyl, naphthyridin
  • the pyrimidine ring-containing compound comprises a compound of formula (II), or a pharmaceutically acceptable salt, stereoisomer, solvate or prodrug thereof:
  • R 1 and R 2 are each independently selected from the group consisting of hydrogen, halogen, cyano, nitro, ester, C 1-12 alkyl, C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 3-12 cycloalkoxy, C 3-12 halocycloalkoxy a C 1-12 alkylthio group, a C 1-6 acyl group, a C 1-12 alkylamino group, a C 3-12 cycloalkylamino group, or one or more of the above groups C is N, O, S a group formed by replacing one or more heteroatoms in the group, or a group formed by substituting one or more of the above groups H by R 11 ;
  • R 3 is selected from any one of the following structures:
  • R 4 is selected from any one of the following structures:
  • R 5 is selected from C 1-12 alkyl, C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, aryl, haloaryl, heteroaryl Or a halogenated heteroaryl group, or a group formed by replacing one or more C of the above groups with one or more heteroatoms of N, O, S, or one or more of the above groups H a group formed by substitution of R 11 ;
  • R 7 and R 8 are each independently selected from the group consisting of H, halogen, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C 1-12 alkyl, C 1-12 haloalkyl, C 3 - 12 cycloalkyl, C 3-12 halocycloalkyl, C 1-12 alkoxy, C 1-12 haloalkoxy, C 3-12 cycloalkoxy, C 3-12 a halogenated cycloalkoxy group, a C 1-12 alkylthio group, a C 1-6 acyl group, a C 1-12 alkylamino group, a C 3-12 cycloalkylamino group or an aryl group, or one of the above groups or a group formed by replacing a plurality of C with one or more hetero atoms of N, O, S, or a group formed by substituting one or more of the above groups H by R 11 ;
  • Y 1 , Y 2 , Y 3 , Y 4 , Y 5 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl, C 3 a halogenated cycloalkyl group of -6 or an alkylamino group of C 1-6 ;
  • R Y is selected from C 1-12 alkyl, C 1-12 haloalkyl, C 3-12 cycloalkyl, C 3-12 halocycloalkyl, or one or more of the above groups a group formed by replacing one or more hetero atoms in N, O, S, or a group formed by substituting one or more of the above groups H by R 11 ;
  • R 11 is selected from the group consisting of H, hydroxy, amino, carboxy, decyl, cyano, nitro, ester, C 1-6 alkyl, C 3-6 cycloalkyl, C 1-6 alkoxy, C 3-6 cycloalkoxy, C 1-6 haloalkyl, C 3-6 halocycloalkyl, C 1-6 acyl, C 1-6 halo acyl, C 1-6 alkane
  • the compound SM 1 and the compound SM 2 can be reacted by a method such as nucleophilic substitution or coupling to obtain a final product P (that is, a compound represented by the formula (II)).
  • the synthesis method of the compound SM 1 is as follows:
  • the starting compound a-1 is first subjected to nucleophilic substitution reaction with R 5 -NH 2 to form compound a-2, and then compound a-2 is further reacted to form compound a-3 by Heck coupling reaction, and finally, ring closure is carried out to obtain compound SM 1 .
  • the starting compound 1 is firstly made into a phenol sodium salt, and then reacted with methyl iodide or ethyl difluorobromoacetate to prepare a compound 3, and the compound 3 is reduced to obtain a compound 4, which is then nitrated, and the amino group is protected with di-tert-butyl dicarbonate.
  • Compound 6 is further substituted with a precursor of the substituent R 3 to obtain a compound 7, and the compound 7 is reduced to obtain a compound 8, which is then reacted with a precursor of the substituent R 4 to obtain a compound SM 2 .
  • the synthesis of the compound A1-2 taking a 250 ml single-mouth bottle, adding 11.4 g (0.05 mol) of 2,4-dichloro-5-bromopyrimidine (compound A1-1), 6.05 g (0.06 mol) of triethyl
  • the amine, 6.66 g (0.06 mol) of 4-fluoroaniline and 150 ml of n-butanol were heated at 75 ° C overnight with stirring and protected with argon. The next day, n-butanol was distilled off, and 100 ml of ethyl acetate and 100 ml of water were added, and the mixture was stirred for 10 minutes and then layered.
  • the synthesis of the compound B1-2 50 g of the compound B1-1 was dissolved in 250 ml of tetrahydrofuran, 12.6 g of sodium hydroxide was dissolved in 250 ml of water, and then the two were mixed and stirred overnight, the tetrahydrofuran was spun off, and the aqueous layer was It was washed twice with dichloromethane, most of the water was spun off, the remaining portion was naturally evaporated, and dried in a vacuum oven to give 55 g of an orange solid.
  • the synthesis of the compound B2-2 50 g of the starting compound B2-1 was dissolved in 500 ml of methanol, and 10 g of Pd/C was added thereto, and hydrogenation was carried out at 35 ° C for two days. Point board monitoring, raw material reaction is completed, and processed. The Pd/C was directly filtered off, and the methanol phase was spun to obtain a crude product (yield: 39 g).
  • the synthesis of the compound B3-2 50 g of the starting compound B3-1 was added to 500 ml of DMF (dimethylformamide), and 1.5 eq of ethyl difluoroacetate and 2 eq of potassium carbonate were further added.
  • DMF dimethylformamide
  • 1.5 eq of ethyl difluoroacetate and 2 eq of potassium carbonate were further added.
  • the extract was dried, concentrated, and passed through a column to afford product 77 g.
  • a series of desired compounds SM 1 and SM 2 are synthesized, and then a mixture of the compound SM 1 and the compound SM 2 is used to obtain a series of final products P, and the structural formula and characterization information are as follows.
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-1).
  • the compound was synthesized by taking a 100 ml single-mouth bottle, adding 60 mg of the starting amine (compound SM 2 -1), adding 1.2 eq of p-toluenesulfonic acid monohydrate crystals, and adding 1.2 eq of the raw pyrimidine compound (SM 1-1 ). And 15 ml of 2-pentanol, and the temperature was raised to 110 ° C overnight with stirring; the next day, 2-pentanol was distilled off, 50 ml of a saturated aqueous solution of sodium carbonate and 50 ml of dichloromethane were added, and the mixture was extracted twice with dichloromethane. The organic phases were combined, dried, concentrated and purified to afford 15 mg of product.
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-2').
  • the synthesis method of the compound (P-2) is the same as in the first embodiment.
  • Compound P-2' of this example salt The acid salt is prepared by adding 200 mg of the compound P-2 to a 50 ml single-mouth bottle, adding 10 ml of acetone and 1 ml of water, and slowly adding 140 mg of a 10% by mass hydrochloric acid after the addition is completed. After the reaction was carried out for 3 h at room temperature, the reaction mixture was evaporated to dryness, and then evaporated to dryness. It is the hydrochloride salt of the compound P-2.
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-3).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-4).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-5).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-6).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-7).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-8).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-9).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-10).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-11).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-12).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-13).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-14).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-15).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-16).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-17).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-18).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-19).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-20).
  • the pyrimidine ring-containing compound of the present embodiment has a structural formula represented by the formula (P-21).
  • the method was used to determine the inhibitory effect of the test substance on the activity of double mutant EGFR kinase (EGFR T790M/L858R kinase) and wild type EGFR kinase (EGFR WT).
  • test compound was formulated into a 10 mM DMSO solution, and the control compound AZD9291 was formulated into a 1 mM DMSO solution.
  • test compound solution Serially dilute the test compound solution to 12 concentrations (or other desired test concentration) on a 384-well plate of TECAN EVO200 by 3-fold dilution.
  • test data is shown in Table 3 below.
  • control compound AZD9291 (trade name: meridinib) is as follows:

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Abstract

La présente invention concerne le domaine technique des compositions pharmaceutiques et concerne un composé contenant un anneau pyrimidine, un inhibiteur du récepteur du facteur de croissance épidermique (EGFR) et son application. Le composé contenant l'anneau pyrimidine comprend un composé représenté par la formule (I) ou un sel pharmaceutiquement acceptable, un stéréoisomère, un solvate ou un promédicament de celui-ci. L'inhibiteur d'EGFR comprend le composé contenant l'anneau pyrimidine. Le composé peut inhiber une ou plusieurs mutations d'activation ou de résistance dans EGFR et peut être utilisé pour préparer des médicaments pour réguler l'activité de la tyrosine kinase EGFR ou traiter des maladies associées à l'EGFR, tels que les cancers, le diabète, les maladies du système immunitaire, les maladies neurodégénératives ou les maladies cardiovasculaires, et est particulièrement approprié pour la préparation de médicaments pour le traitement du cancer du poumon non à petites cellules provoqué par des mutations d'EGFR comprenant des mutations sensibles (telles qu'une mutation L858R ou une mutation de délétion d'exon 19) et des mutations de résistance aux médicaments (telles qu'une mutation T790M d'EGFR).
PCT/CN2017/101392 2016-09-19 2017-09-12 Composé contenant un noyau pyrimidine, inhibiteur d'egfr et son application WO2018050052A1 (fr)

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WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11697648B2 (en) 2019-11-26 2023-07-11 Theravance Biopharma R&D Ip, Llc Fused pyrimidine pyridinone compounds as JAK inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
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WO2022188755A1 (fr) * 2021-03-08 2022-09-15 暨南大学 Composé à base de pyridopyrimidine et son utilisation

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US10882845B2 (en) 2017-05-24 2021-01-05 TYK Medicines Inc. Crystal form of deuterated AZD9291, preparation method therefor, and use thereof
WO2018214886A1 (fr) 2017-05-24 2018-11-29 浙江同源康医药股份有限公司 Forme cristalline d'azd9291 deutéré, procédé de préparation associé et utilisation correspondante
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
WO2020188015A1 (fr) 2019-03-21 2020-09-24 Onxeo Molécule dbait associée à un inhibiteur de kinase pour le traitement du cancer
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
WO2020245208A1 (fr) 2019-06-04 2020-12-10 INSERM (Institut National de la Santé et de la Recherche Médicale) Utilisation de cd9 en tant que biomarqueur et en tant que biocible dans la glomérulonéphrite ou la glomérulosclérose
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
WO2021089791A1 (fr) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Méthodes pour le traitement de cancers qui ont acquis une résistance aux inhibiteurs de kinase
US11697648B2 (en) 2019-11-26 2023-07-11 Theravance Biopharma R&D Ip, Llc Fused pyrimidine pyridinone compounds as JAK inhibitors
WO2021148581A1 (fr) 2020-01-22 2021-07-29 Onxeo Nouvelle molécule dbait et son utilisation
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US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors

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