Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • 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
  • A61K31/47—Quinolines; Isoquinolines
• • 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
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms
• • 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
  • C07D471/08—Bridged systems
• • 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
  • C07D471/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/10—Spiro-condensed systems
  • C07D491/113—Spiro-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/04—Ortho-condensed systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
  • C07D498/10—Spiro-condensed systems

Definitions

• the present invention relates to the use of a quinazolinamine derivative and a pharmaceutical composition containing the same for the preparation of a medicament for treating cancer, wherein the cancer is a drug resistant cancer, preferably resistant to a reversible inhibitor of EGFR
• the cancer is particularly preferably cancer resistant to gefitinib, erlotinib or lapatinib, or the cancer carries an EGFR mutation.
• signal transduction transmits various extracellular signals to the interior of cells, allowing cells to respond to biological processes such as proliferation, differentiation, and apoptosis.
• Intracellular control systems are disrupted by genetic and environmental factors, causing abnormal amplification or disruption of the signaling system, resulting in the production of tumor cells.
• Protein tyrosine kinases play an important role in such cell regulation, and abnormal expression or mutation has been observed in cancer cells.
• the epidermal growth factor receptor is expressed by the protooncogene c-ErbB, a transmembrane glycoprotein receptor-type tyrosine kinase of about 170 kDa, which is a member of the ErbB protein family. Activation, affecting cell growth and differentiation.
• the ErbB family includes ErbB-1/EGFR, ErbB-2/Her2, ErbB-3/Her3, and ErbB-4/Her4.
• the receptor dimerizes to form a homologous or heterodimer. Subsequently, the tyrosine residue on the dimerization receptor is phosphorylated, triggering the downstream signaling pathway to be activated.
• Abnormal EGFR activation mechanisms include amplification of the receptor itself, overexpression of receptor ligands, activating mutations, and lack of a negative regulatory pathway, so EGFR-induced cancer can at least through three mechanisms: EGFR ligand overexpression, EGFR Amplification or mutational activation of EGFR.
• mutational activation of EGFR is the most important factor leading to abnormal biological behavior of tumor cells.
• malignant tumors such as breast cancer, prostate cancer, non-small cell lung cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, etc.
• both EGFR and HER-2 are known to significantly promote the formation of heterodimeric signaling complexes, thereby further confirming their association with tumorigenesis.
• Gefitinib or erlotinib selectively and reversibly inhibits EGFR, while lapatinib reversibly inhibits both EGFR and HER-2, thereby inhibiting tumor growth, thereby significantly prolonging patient life or Provide therapeutic benefits.
• the currently reported mutations are mainly directed to the following two types: 45% of which are exon 19 sequence deletions, mainly base deletion mutations at codons 746-752, resulting in loss of amino acid sequence in EGFR protein, altering receptor ATP binding The angle of the pocket; 40% is the missense mutation of exon 21, mainly the change of codon 851, which causes the amino acid of this site in EGFR protein to change from leucine to arginine (L858R).
• the T790M mutation is a base pair change.
• the threonine at the 790 site of the kinase domain is converted to methionine (T790M), which leads to changes in the structure of EGFR, and the steric effect of TKI binding. , producing acquired resistance to TKI.
• T790M methionine
• the EGFR T790M mutation was detected in both in non-small cell lung cancer patient tumor cells with acquired resistant EGFR mutations and in in vitro cell lines with gefitinib-resistant EGFR mutations. Mutations make the structural activation of EGFR outperform other pathways, so that the survival of tumor cells depends mainly on the EGFR signaling pathway.
• the object of the present invention is to provide a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and tautomers, mesomers, racemates, enantiomers thereof, The use of diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and metabolites and metabolic precursors or prodrugs for the preparation of a medicament for the treatment of cancer, wherein the compound of formula (I)
• the structure is as follows:
• R 1 is an alkoxy group, wherein the alkoxy group is optionally further further selected from one or more selected from halogen or alkoxy Substituted by a substituent;
• A is selected from a carbon atom or a nitrogen atom
• R 2 is a self-cyano group
• R 2 is unsubstituted
• R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group or -(CH 2 )r-Ar or -0(CH 2 )r-Ar;
• Ar is selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently, optionally, further substituted with one or more substituents of halo, alkyl or trifluoromethyl;
• R is selected from aryl, pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinyl or -NR 8 R 9 wherein said aryl, pyridyl, tetrahydropyranyl, piperidine
• the pyridyl, pyrrolidinyl, morphinolyl group is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, oxo, hydroxy or hydroxyalkyl; or pyrrolidin Is an N-oxide;
• R 8 and R 9 together with the N atom to which they are bonded form a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group, wherein the monospiroheterocyclic group, the bicyclic fused heterocyclic group or the bicyclic bridged
• the cyclo group is optionally further substituted with one or more substituents selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy or hydroxyalkyl;
• r 0, 1 or 2;
• n 0 or 1.
• the drug-resistant cancer may be a drug resistant to a plurality of drugs, preferably a cancer resistant to a reversible inhibitor of EGFR, particularly preferably resistant to gefitinib, erlotinib or lapatinib. Cancer.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein the cancer is a solid tumor, preferably a head and neck tumor, a colorectal cancer, a bladder cancer, a lung cancer, a pancreatic cancer, a breast cancer, Prostate cancer, gastric cancer, oral cancer, liver cancer, glioblastoma, ovarian cancer or non-small cell lung cancer. More preferably, it is non-small cell lung cancer.
• the cancer carries an EGFR mutation, and/or carries a HER2 mutation;
• the EGFR mutation comprises a deletion mutation EGFR del 746-750 on the ELREA sequence, a T790M point mutation in exon 20, EGFR del 746-750/ T790M double mutation or L858R/T790M double mutation.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and Use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein R is selected from the group consisting of pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, a morphinolinyl group, preferably a pyrrolidinyl group, more preferably a chiral pyrrolidinyltetrahydro group; the pyridyl group, tetrahydropyranyl group, piperidinyl group, pyrrolidinyl group, morphinolyl group optionally further one or Substituted by a plurality of alkyl or oxo groups; or the pyrrolidinyl group is an N-oxide.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, in the manufacture of a medicament for the treatment of cancer, wherein A is preferably a nitrogen atom and R 2 is unsubstituted.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein R 3 , R 6 and R 7 are preferably a hydrogen atom; R 4 and R 5 are preferably a halogen, more preferably fluorine or chlorine.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for the treatment of cancer, wherein Ar is preferably a pyridyl group.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein R 8 and R 9 together with the N atom to which they are attached form a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group Wherein the monospiroheterocyclyl, bicyclic fused heterocyclyl or bicyclic bridge heterocyclyl optionally further is taken from one or more substituents selected from alkyl, alkoxy, hydroxy or hydroxyalkyl
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein a typical compound represented by the formula (I) or a tautomer, a mesogen, a racemate, a pair thereof
• the enantiomers, diastereomers, and mixtures thereof include, but are not limited to:
• R 1 is an alkoxy group, wherein the alkoxy group is optionally further substituted with one or more substituents selected from halogen or alkoxy;
• A is selected from a carbon atom or a nitrogen atom
• R 2 is a self-cyano group
• R 2 is unsubstituted
• R 3 , R 4 , R 5 , R 6 and R 7 are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group or -(CH 2 )r-Ar or -0(CH 2 )r-Ar;
• Ar is selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently, optionally, further substituted with one or more substituents of halo, alkyl or trifluoromethyl;
• R is selected from aryl, pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinyl or -NR 8 R 9 wherein said aryl, pyridyl, tetrahydropyranyl, piperidine
• the pyridyl, pyrrolidinyl, morphinolyl group is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, oxo, hydroxy or hydroxyalkyl; or pyrrolidin Is an N-oxide;
• R 8 and R 9 together with the N atom to which they are bonded form a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group, wherein the monospiroheterocyclic group, the bicyclic fused heterocyclic group or the bicyclic bridged
• the cyclo group is optionally further substituted with one or more substituents selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy or hydroxyalkyl;
• r 0, 1 or 2;
• n 0 or 1.
• a compound of the formula (I), a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof Form, and pharmaceutically acceptable salts, of which R Is pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinolyl, preferably pyrrolidinyl, more preferably chiral pyrrolidine tetrahydro; pyridyl, tetrahydropyranyl
• the piperidinyl, pyrrolidinyl, morphinolyl group is optionally further substituted with one or more alkyl or oxo substituents; or the pyrrolidinyl group is an N-oxide.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and In the form of a mixture, and a pharmaceutically acceptable salt, wherein A is preferably a nitrogen atom and R 2 is unsubstituted.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture form, and a pharmaceutically acceptable salt, wherein
• R 3 , R 6 and R 7 are preferably a hydrogen atom; R 4 and R 5 are preferably a halogen, more preferably fluorine or chlorine.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and In the form of a mixture, and a pharmaceutically acceptable salt, wherein Ar is preferably a pyridyl group.
• a compound of the formula (I) a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof a form, and a pharmaceutically acceptable salt, wherein R 8 and R 9 together with the N atom to which they are attached form a monospiroheterocyclyl, a bicyclic fused heterocyclyl or a bicyclic heterocyclyl, said monospiroheterocyclyl,
• the bicyclic fused heterocyclic group or the bicyclic bridged heterocyclic group is optionally further substituted with one or more substituents selected from an alkyl group, an alkoxy group, a hydroxyl group or a hydroxyalkyl group.
• a preferred embodiment of the invention a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture form, and a pharmaceutically acceptable salt, selected from the group consisting of:
• the diastereomers, and mixtures thereof include, but are not limited to:
• compositions comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.
• the present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a tautomer, a racemate, an enantiomer thereof, a diastereomer thereof. And combinations thereof, and pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable carrier or diluent.
• a compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof as a medicament for treating cancer exhibits outstanding efficacy and fewer side effects in the treatment of cancer, wherein the cancer is selected from the group consisting of head and neck cancer, colon cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, ovarian cancer or Non-small cell lung cancer, preferably colon cancer, breast cancer or non-small cell lung cancer, more preferably non-small cell lung cancer.
• the cancer cells of the cancer are mutated in EGFR, and/or mutated in HER-2;
• the EGFR mutation includes a L858R point mutation and a deletion/insertion mutation in the ELREA sequence, and T790M in exon 20 Point mutation, or L858R/T790 double mutation;
• the HER-2 mutation is M774_A775insAYVM.
• EGFR mutation-activated cancer cells such as mutations occur in the EGF receptor region of tyrosine kinases, which It can be sensitive to the treatment of EGFR inhibitors.
• cancer cells activated by HER-2 mutations such as M774_A775insAYVM, may be sensitive to the treatment of HER-2 inhibitors.
• Cancer cells that are mutated by both EGFR and HER-2 mutations may be sensitive to the treatment of dual inhibitors of EGFR and HER-2.
• Non-reversible tyrosine kinase inhibitors such as HKI-272, which are capable of inhibiting the proliferation and EGF induction of EGFR receptors that express double mutations on the cell line, compared to reversible tyrosine kinase inhibitors such as gefitinib EGFR ⁇ - .V (Proceedings of the National Acadamy of Science of the United States 102 7665 (2005).
• a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. It exhibits outstanding efficacy and fewer side effects in the treatment of cancer, wherein the cancer is selected from the group consisting of head and neck cancer, colon cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, ovarian cancer or Non-small cell lung cancer, preferably colon cancer, breast cancer or non-small cell lung cancer, more preferably non-small cell lung cancer.
• the cancer cells of the cancer described therein are mutated in EGFR, and/or mutated in HER-2;
• the EGFR mutation includes a L858R point mutation and a deletion/insertion mutation in the ELREA sequence, and T790M in exon 20 Point mutation, or L858R/T790 double mutation;
• the HER-2 mutation is M774_A775insAYVM.
• the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
• Oral compositions can be prepared according to any method known in the art for preparing a pharmaceutical composition, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
• excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc.
• These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
• a water-soluble taste masking substance such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or an extended-time substance such as ethylcellulose or cellulose acetate butyrate may be used.
• hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, Soft gelatin capsules mixed with liquid paraffin or olive oil provide oral preparations.
• an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin
• a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil
• Soft gelatin capsules mixed with liquid paraffin or olive oil provide oral preparations.
• the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
• excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents can be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecyl ethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
• the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.
• preservatives such as ethylparaben or n-propylparaben
• coloring agents such as ethylparaben or n-propylparaben
• flavoring agents such as sucrose, saccharin or aspartame.
• the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
• the oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
• the above sweeteners and flavoring agents may be added to provide a palatable preparation.
• These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.
• the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
• the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
• the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
• Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate.
• the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
• Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
• sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
• Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
• the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
• the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
• the active ingredient is dissolved in a mixture of soybean oil and lecithin.
• the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
• the injection or microemulsion can be injected into the patient's bloodstream by local injection.
• the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
• a continuous intravenous delivery device can be used.
• An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.
• the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
• the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injection solution or a mixture prepared in a non-toxic parenterally acceptable diluent or solvent.
• a suspension such as a solution prepared in 1,3-butanediol.
• sterile fixed oils may be conveniently employed as a solvent or suspending medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
• fatty acids such as oleic acid can also be prepared as an injection.
• the compounds of the invention may be administered in the form of a suppository for rectal administration.
• These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
• suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
• the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt It can be verified according to traditional treatment options.
• the preferred mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt
• alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms.
• Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpent
• lower alkyl groups having 1 to 6 carbon atoms More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like.
• the alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of alkane Base, alkenyl, block, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, A cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.
• alkane Base alkenyl, block, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy
• cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms. One carbon atom.
• monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
• Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.
• spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
• it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl.
• fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring.
• fused cycloalkyl groups include:
• bridged cycloalkyl refers to 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
• Bridged cycloalkyl preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
• the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached
• the ring that is joined together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like.
• the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group.
• heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(0)
• a hetero atom of m (where m is an integer of 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are hetero atoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms.
• Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, morphinolinyl, homopiperazinyl and the like.
• the polycyclic heterocyclic group includes a spiro ring, a fused ring, and a bridged ring heterocyclic group; preferably a bicyclic heterocyclic group, and a non-limiting example includes a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a specific ring bridged heterocyclic group.
• spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (0).
• m (where m is an integer 0 to 2) of a hetero atom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspirocyclic group according to the number of the shared spiro atoms between the rings, preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6
• fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(0) m (where m is an integer from 0 to 2), and the remaining rings
• the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• the bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5- to 5- or 5-membered/6-membered bicyclic fused heterocyclic group.
• fused heterocyclic groups include fused heterocyclic groups:
• bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total ⁇ electron conjugated system in which one or more ring atoms selected from nitrogen, oxygen, or S (0) m hetero atoms (wherein m is an integer of 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
• bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
• heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterogeneous, non-limiting examples of which include:
• the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group.
• aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl.
• the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
• the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, Alkylamino, thiol, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy or carboxylate groups.
• heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
• the heteroaryl group is preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like.
• the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the parent structure is attached
• the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide a heterocyclic alkylthio group, a carboxyl group or a carboxylate group.
• decyloxy refers to -0-(fluorenyl) and -0-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
• alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
• the alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group.
• haloalkyl refers to an alkyl group substituted by one or more halogens, wherein the alkyl group is as defined above.
• hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
• the pyrrolidinyl group is an N-oxide and refers to a pyrrolidine-N-oxide.
• hydroxy refers to an -OH group.
• halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
• amino refers to -NH 2 .
• cyano refers to -CN.
• nitro refers to -N0 2 .
• carboxylate group means -c(o)o(alkyl) or -c(o)o(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.
• heterocyclic group optionally substituted by an alkyl group means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group.
• Substituted means one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.
• “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
• the purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby the biological activity.
• “Pharmaceutically acceptable salt” refers to a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity. Method for synthesizing the compound of the present invention
• Synthesis A a preparation method of the compound of the formula (I) or a salt thereof of the present invention, comprising the following steps:
• the reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and the like.
• organic bases include, but are not limited to, sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate;
• R is - NR 8 R 9 ;
• X is a halogen
• a phosphate compound of the formula (IB) is reacted with an aldehyde RCHO under lithium hexamethyldisilazide under an acetone bath to obtain a compound of the formula (I);
• R is selected from pyrrolidinyl, pyridyl, tetrahydropyranyl, piperidinyl, or morpholinyl
• A, R ⁇ R 7 as defined in formula (I) of the, n is 1.
• the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
• NMR nuclear magnetic resonance
• MS mass spectrometry
• the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide ( ) 3 ⁇ 4>- ), deuterated chloroform (CDC1 3 ) deuterated methanol (CD 3 OD), and the internal standard was tetramethyl.
• silane CTMS chemical shifts are given 10- 6 Cppm) as a unit.
• the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).
• the average inhibition rate of the kinase and the IC 5Q value were determined using a NovoStar plate reader (BMG, Germany).
• the silica gel plate used has a specification of 0.15 mm ⁇ 0.2 mm, and the thin layer chromatography separation and purification product is adopted.
• the specifications are 0.4 mm to 0.5 mm silica gel plates.
• An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
• the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
• the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
• the hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.
• the microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.
• the solution in the reaction means an aqueous solution unless otherwise specified.
• the temperature of the reaction was room temperature unless otherwise specified.
• Room temperature is the optimum reaction temperature, and the temperature range is from 20 ° C to 30 ° C.
• the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
• TLC thin layer chromatography
• the system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
• the system of the eluent for column chromatography and the system for developing the thin layer chromatography of the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone System, D: hexamethylene, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.
• reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted eluted eluted elution -6-yl)-4--3-hydroxy-8-azabicyclo[3.2.1]octane-8-yl)-2-butenamide 3 (20 mg, pale yellow solid), yield: 16.6% .
• N-Boc-3-pyrroline 4a (100 g, 0.59 mol) was dissolved in 300 mL of ethylene glycol. Add bromine in batches Desuccinimide C108.0 g, 0.61 mol), about 10.0 g per batch, added in about 2 hours, stirred for 16 hours. After adding 500 mL of water, extracting with ethyl acetate (300 mL of EtOAc), EtOAc (EtOAc) tert-Butyl 4-bromo-4-(2-hydroxyethoxy)pyrrolidine-l-carboxylate 4b (178.0 g, pale yellow oily). Yield: 97%.
• Hexahydropyrrolo[3,4-b][l,4]oxazine-6 (tert-butyl 2H carboxylic acid hexahydro-4-benzyl-B is compared to [3,4-b]-l, 4-oxazine-6 (2H carboxylic acid tert-butyl ester 4d (50 g, 157 mmol) was dissolved in 7 L of methanol, palladium/carbon (5 g, 10%) was added, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 16 hours.
• the reaction mixture was filtered, and the filtrate was evaporated toluzzojjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj
• reaction solution was cooled to 0 ° C, 10 M sodium hydroxide solution was added dropwise until the reaction liquid was 9 , and dichloromethane (100 mL X 3 ) was extracted.
• the organic phase was combined and washed with saturated sodium chloride solution (100 mL X) l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 4-methylhexahydropyrrolo[3,4-b][l,4]oxazin-6 (2H carboxylic acid tert-butyl ester) 4f (2.0 g, colorless oil), used directly in the next step.
• Ethyl 8-allyl-1,4-dioxospiro[4.5]decane-8-carboxylate Ethyl 4-oxocyclohexanecarboxylate 5b (10 g, 0.047 mol) was dissolved in 55 mL of tetrahydrofuran In the dry ice-acetone bath, the mixture was cooled to -78 ° C, and hexamethyldisilazide lithium C1 M (57 mL) was added dropwise. After the addition, the reaction was stirred for 1 hour, and 3-bromopropene (4.9 mL, 56.20 mmol), after completion, the reaction was stirred at room temperature for 16 hours. The reaction was quenched with aq.
• Ethyl 8-(2-oxoethyl)-1,4-dioxospiro[4.5]decane-8-carboxylate 8-Allyl-1,4-dioxospiro[4.5]decane-8 - Ethyl carboxylate 5c (11.5 g, 45.27 mmol) was dissolved in 300 mL of dichloromethane, cooled to -78 °C with dry ice-acetone bath, three times with ozone, stirred for 5 to 6 hours, air was exchanged three times, stirred After reacting for 1 hour, triphenylphosphine (15.4 g, 58.71 mmol) was added, and the reaction was stirred for 16 hours.
• 2,4-Dichloro-5-nitrobenzoic acid 8a (11.8 g, 0.05 mol) was dissolved in 150 mL of methanol, and sodium methoxide G3.5 g, 0.25 mol) was added in portions, and the mixture was heated to 80 °. C, The reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and 50 mL of ice water was added to the residue, and 20% hydrochloric acid was added dropwise to adjust the pH to 2 to 3, and a large amount of solid was precipitated, filtered, and the filter cake was washed with water (100 mL) and dried to give the title product. 2,4-Dimethoxy-5-nitrobenzoic acid 8b (10.4 g, white solid), Yield: 92%.
• reaction solution was cooled to room temperature, concentrated under reduced pressure, and 1 L of ice water was added to the residue, and the mixture was adjusted to pH 1 by dropwise addition of 4 M hydrochloric acid, and stirred for 15 minutes, and the pH was adjusted to 7 by dropwise addition of saturated sodium hydrogen carbonate solution. ⁇ 8, a large amount of solid precipitated. 50 mL of ethyl acetate was added, stirred for 15 minutes, filtered, and the filter cake was washed with water (50 mL) and dried to give the title product 3-(2,4-dimethoxy-5-nitrophenyl)-3-carbonylpropane Nitrile 8c (8 g, yellow solid), Yield: 70%.
• 4-methylmorpholine-3-carbaldehyde 9b (185 mg, 1.43 mmol) was dissolved in 2.5 mL of tetrahydrofuran, added dropwise to the above reaction mixture, added, stirred for 0.5 hour, the reaction solution was naturally warmed to room temperature, stirred 16 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The resulting residue was purified by EtOAc (EtOAc) elut elut Phenyl-6-yl)-3-(4-methylmorphinolin-3-yl)acrylamide 9 (100 mg, pale yellow solid), yield: 53%.
• ⁇ , ⁇ '-carbonyldiimidazole (526 mg, 3.24 mmol) was added to 5 mL of tetrahydrofuran, and diethylphosphoric acid (700 mg, 3.57 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour, and was taken.
• 4-((6-Amino-7-methoxyquinazolin-4-yl)amino)-2-chlorophenol 14a (633 mg, 2.00 mmol, prepared according to document WO2011095053) was added to 5 mL of tetrahydrofuran. The mixture was heated to 40 ° C, added dropwise to the above-mentioned alternate reaction solution, and the reaction was stirred for 16 hours.
• the hydrazine, ⁇ '-carbonyldiimidazole (486.45 mg, 3 mmol) was dissolved in 4 mL of tetrahydrofuran at 40 ° C, the oil bath was heated to 40 ° C, and 4 mL of diethyl phosphate-based acetic acid was added dropwise to the reaction solution. A solution of 588.42 mg, 3 mmol) in tetrahydrofuran was stirred for 30 minutes.
• W-[4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl-acetamide will be ⁇ , ⁇ '-
• the carbonyl diimidazole (292 mg, 1.80 mmol) was dissolved in 4 mL of tetrahydrofuran, the oil bath was heated to 50 ° C, and 3 mL of a solution of diethyl phosphate phosphate (353 mg, 1.8 mmol) in tetrahydrofuran was added dropwise to the reaction solution. The reaction was allowed to stand for 1.5 hours.
• N-[4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 19b (300 mg, 0.59 mmol) dissolved in 10 mL of tetrahydrofuran, cooled to -78 °C in a dry ice bath, and added 1 M solution of ditrimethylsilylamino lithium in toluene (1.2 mL, 1.18 mmol) under argon.
• N-[4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 19b (100 mg, 0.20 mmol) dissolved in 10 mL of tetrahydrofuran, cooled to -78 °C in a dry ice bath, and added 1 M solution of ditrimethylsilylamine lithium in toluene (400 ⁇ , 0.40 mmol), and stirred for 45 minutes.
• test examples of the present invention The experimental methods in which the specific conditions are not specified in the test examples of the present invention are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer of the product. Reagents not specified for specific sources, are routine reagents purchased by the market. Test Example 1. Determination of inhibition of activity of EGFR mutant kinase by the compound of the present invention
• kits for in vitro activity assays of VEGFR-2 inhibitors were performed using Invitrogen's U-box Z'-LYTE® Kinase Assay Kit- Tyrosine 4 Peptide (Invitrogen, PV3193). According to the kit instructions, configure the enzyme buffer (50mM HEPES PH7.5, 0.01% BRIJ-35, 10mM MgCl 2 , 4mM MnCl 2 , ImM EGTA, 2mMDTT), enzyme/substrate peptide solution, ATP solution. And completely phosphorylate the substrate peptide, mix gently; dilute water to prepare 4X concentration of the test compound solution, mix well.
• the enzyme buffer 50mM HEPES PH7.5, 0.01% BRIJ-35, 10mM MgCl 2 , 4mM MnCl 2 , ImM EGTA, 2mMDTT
• the configured enzyme/substrate peptide solution and the fully phosphorylated substrate peptide 5uL were added to a 384-well plate, then 2.5 uL ATP solution and 2.5 uL compound solution were added to the experimental group, and 2.5 uL was added to the completely inhibited control group.
• Enzyme buffer and 2.5uL of the corresponding concentration of DMSO solution, 2.5uL ATP solution and 2.5uL corresponding DMSO solution were added to the non-inhibited control group, 2.5uL enzyme buffer and 2.5uL corresponding concentration were added to the completely phosphorylated substrate control group.
• DMSO solution paste the plate and shake it on the shaker for 30 seconds to mix the solutions uniformly, and incubate for 1 hour at room temperature.
• the developing solution was prepared according to the corresponding ratio. After mixing, add 5 uL of each reaction well, and attach the sealing plate to the shaker for 30 seconds to mix the solutions uniformly, and incubate for 1 hour at room temperature. Every The wells were added with 5 uL of stop solution, and after mixing uniformly, fluorescence was read at 445 nm and 520 nm by excitation at 400 nm. Biochemical activity of the compounds of the present invention measured by the above test, measured EGFR and mutant EGFR activity inhibition value IC 5Q 1 to Table 3 in the table below.
• the compounds of the examples of the present invention have a significant inhibitory effect on the proliferation of EGFR kinase.
• Table 2 ICs for inhibition of EGFR T790M, L858R and T790M/L858R enzyme activities by the compounds of the present invention
• the compounds of the present invention have significant inhibitory effects on the proliferation of EGFR T790M, L858R and T790M/L858R kinases.
• Table 3 IC 5 o inhibition of EGFR del 746-750, EGFR del 746-750/T790M enzyme activity by the compounds of the invention
• the compounds of the present invention have significant inhibitory effects on the proliferation of EGFR del 746-750 and EGFR del 746-750/T790M kinases.
• Test Example 2 Determination of the inhibition of the activity of the compound of the present invention on EGFR mutant cells
• EGFR mutant cells (NCI-H-1975 or PC-9 GR) were cultured in IMDM medium (Hyclone, SH30228.01B) (containing 20% FBS, 100 units/ml P/S, 5 ng/ml VEGF). When cells cover 80 to 90%, they are digested with 0.25% trypsin (EDTA) and then planted in 96-well plates at 2000 cells per well ( ⁇ IMDM (2% FBS, P/S) medium), placed at 37°. C. Incubate for 24 hours in a 5% CO 2 incubator.
• IMDM medium Hyclone, SH30228.01B
• IMDM 2% FBS, 100 units/ml P/S
• ⁇ drug 2% FBS, 100 units/ml P/S
• ⁇ drug was added to each well, gently shaken and mixed, control group and blank.
• the group only contained ⁇ (IMDM, 10% FBS, P/S, 5ng/ml VEGF), and was placed in a 37°C, 5% CO 2 incubator. After 72 hours, add ⁇ CCK-8 to each well, then add 37 Incubate for 4 hours at °C, 5% CO 2 incubator, and absorb the absorbance at 450 nm.
• the biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC 5Q values are shown in Table 4 below.

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