Classifications

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  • 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
• • A—HUMAN NECESSITIES
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  • 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
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
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  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
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  • C07D239/72—Quinazolines; Hydrogenated quinazolines
  • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
  • C07D239/94—Nitrogen atoms
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  • 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
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  • 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
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  • 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
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  • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
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  • 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
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  • 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
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  • 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
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  • 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
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  • 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
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  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/04—Ortho-condensed systems
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  • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/08—Bridged systems
• • C—CHEMISTRY; METALLURGY
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  • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
  • C07D487/10—Spiro-condensed systems
• • C—CHEMISTRY; METALLURGY
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  • 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
  • C07D491/08—Bridged systems
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  • 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
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  • C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
  • C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
  • C07D493/08—Bridged systems

Definitions

• the present invention relates to the field of medical technology, and in particular to an aniline substituted quinazoline derivative, a pharmaceutically acceptable salt thereof, and a stereoisomer thereof, and a process for the preparation thereof, a pharmaceutical composition and a pharmaceutical preparation containing the same, and
• Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate that plays a role in normal cell growth.
• Many growth factor receptor proteins act through tyrosine kinases and through this process affect the signaling pathways that regulate cell growth. However, under certain conditions, these receptors or mutations or overexpression, become abnormal, cause uncontrolled cell reproduction, lead to tumor growth, and ultimately lead to a well-known disease, cancer.
• Growth factor receptor protein tyrosine kinase inhibitors act to treat cancer and other diseases characterized by uncontrolled or abnormal cell growth by inhibiting the above-described phosphorylation process.
• Epidermal growth factor receptor is a multifunctional glycoprotein widely distributed on the cell membrane of human tissues. It is carcinogenic to avian erythroblastic leukemia virus (v-erb-b). Gene homolog. Human EGFR/HER1/ErbB-1 and HER2 (human epidermal growth factor receptor-2)/ErbB-2/Teu/pl 85 , HER3/ErbB-3 , HER4/ErbB-4, etc. are classified into the HER/ErbB family, Belongs to protein tyrosine kinases (PTKs).
• PTKs protein tyrosine kinases
• Pan-HER tyrosine kinase inhibitors block the intracellular tyrosine autophosphorylation by blocking the intracellular kinase catalyzed site with ATP, blocking tyrosine kinase activation and inhibiting HER family activation, Thereby inhibiting cell cycle progression and accelerating apoptosis play a therapeutic role.
• EGFR Upon binding to the ligand, EGFR forms a dimer with the HER family subtype and then binds to ATP to activate EGFR's own tyrosine kinase activity, allowing autophosphorylation of several tyrosine sites in the intracellular kinase domain.
• Pan-HER tyrosine kinase inhibitors inhibit the growth of the HER family by simultaneously acting on EGFR and HER2/4, and thus play a good role in inhibiting tumor growth.
• Pan-HER tyrosine kinase irreversible inhibitors have an inhibitory effect on HER2/4 in addition to potent inhibition of EGFR, and this drug, which has irreversible inhibitory effects on the HER/ErbB family, increases the drug activity. It also reduced the development of drug resistance and significantly inhibited the erlotinib-resistant H1975 cell line.
• drugs include the selective EGFR tyrosine kinase inhibitors gefitinib (geressinb, Iressa, ZD1839), erlotinib (erceinib, Tarceva, OSI-774) and the EGFR/HER2 dual inhibitor lapatinib (Lapatinib, Tykerb, GW572016), the structure is as follows. All three drugs are reversible EGF receptor tyrosine phosphorylation kinase inhibitors. Studies have found that some tumors initially produce a good therapeutic response, but after a few months of treatment, disease progression occurs, producing natural or secondary resistance.
• Gefitinb erlotinib Lapatinib According to the literature (Bioorganic & Medicinal Chemistry (2008) 16 page 3482-3488 ), listed drugs such as gefitinib and erlotinib have been widely used in the clinic, and advanced NSCLC (non-small cell lung cancer, non- Small cell lung cancer) After long-term treatment, acquired drug resistance can occur, which affects the therapeutic effect.
• Reversible EFG receptor tyrosine kinase inhibitors and ATP compete for binding to EFG receptor tyrosine kinases, which show high activity in vitro due to the high concentration of intracellular ATP (mM).
• Reversible EGF receptor tyrosine kinase inhibitors are difficult to be effective in animal pathology models. Irreversible EGF receptor tyrosine kinase inhibitor does not interact with ATP It is expected that irreversible EGF receptor tyrosine kinase inhibitors may have better in vivo activity.
• W097/38983 discloses a class of irreversible EGF receptor tyrosine kinase inhibitors that introduce a Michael receptor at the 6-position of quinazoline to the EGF receptor tyrosine kinase active center pocket A Michael addition reaction occurs in -SH on the cysteine (Cys773) on the wall. Moreover, the activity of such inhibitors is positively related to the ease of their Michael addition reaction to -SH on cysteine.
• DE 10042061 A1 discloses a class of 4-aniline quinazoline derivatives having a lactone structure at the -7 position of the quinazoline, which is believed to have an inhibitory activity against tyrosine kinase-mediated signal transduction.
• Canertinib (CI-1033) is in the clinical phase II study, is active against some tumor types, and is not toxic in experimental models.
• the structure of C nertinib (CI-1033) is as follows:
• the present inventors have found a class of P-quinones having an irreversible inhibitory effect on Pan-HER when developing a drug having excellent antitumor effects, reducing drug resistance, and at the same time being well tolerated. Sitting porphyra (juice creature).
• the present invention provides a compound represented by the following formula (I), a pharmaceutically acceptable salt thereof, and stereoisomers thereof: among them,
• R 1 is selected from the group consisting of unsubstituted or substituted by 1 to 2 substituents: 6- 10 membered and cyclic Co. 6 alkyl, 7-10 membered spiro C G . 6 alkyl or 7-10 member a bridged ring Co.6 alkyl group, wherein 1 to 3 carbon atoms in the cyclo, spiro or bridged ring may be 1 to 3 identical or different selected from 0, S(0) m , N(H m , NCH 3 and C(O) are replaced by a hetero atom and/or a group, but O and C(O) are not adjacent to each other in the substituted ring.
• Q selected from the group consisting of: aryl, hydroxy, amino, carboxy, cyano, d- 6 alkyl, alkoxy, d. 6 alkylamino, bis(C ⁇ alkyl)amine, Ci- 6 alkylcarbonyloxy, d. 6 alkylamido, ( ⁇ 6 alkylsulfonyl, d. 6 alkylsulfinyl, d. 6 alkylsulfonylamino and C 3 -8 cycloalkyl;
• R 2 is selected from hydrogen, d. 6 alkyl or Ci -6 alkoxy which is unsubstituted or substituted with 1 to 2 substituents Q 2 , a decanoyl group substituted by a substituent Q 2 or N(H) m ,
• Q 2 is selected from the group consisting of halogen, hydroxy, amino, carboxy, cyano, C,. 6 alkyl, CL 6 alkoxy, d. 6 alkylamino, di(d. 6 alkyl) group, D_ 6 alkylcarbonyloxy, C 6 alkylamido, 6 alkylsulfonyl, d. 6 alkylsulfinyl group, d. 6 alkylsulfonylamino group, C 3. 8 cycloalkyl, .
• Q 3 is selected from the group consisting of halogen, hydroxy, amino, carboxy, cyano, d. 6 alkyl, d- 6 alkoxy, d. 6 alkylamino, bis(C ⁇ 6 alkyl) Amine, C 6 alkylcarbonyloxy,
• R 3 is selected from the group consisting of hydrogen, 13 ⁇ 4 , hydroxy, cyano, nitro, Ci. 6 alkyl, d. 6 alkoxy, halogen Substituted d. 6 alkyl or d. 6 alkoxy, d. 6 alkylcarbonyloxy, C 6 alkyl amide, C, -6 alkyl sulfonyl, d 6 alkyl sulfinyl or Alkylsulfonamide group;
• R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, halogen substituted alkyl or C 6 alkoxy, C 6 alkyl An amine group or a di(C 1 -6 alkyl)amino group; L is selected from a covalent bond, 0, S(0) m , N(H) m , NCH ⁇ C(O);
• n is selected from 1, 2 or 3;
• n is selected from 0, 1 or 2.
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
• the present invention also provides a pharmaceutical preparation comprising the compound of the above formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a pharmaceutically acceptable carrier.
• the present invention also provides the compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof
• the pharmaceutical composition is useful as a medicament for the treatment of hyperproliferative diseases and chronic obstructive pulmonary diseases.
• the present invention also provides the compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof, and a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof Use of a pharmaceutical composition for the preparation of a medicament for the treatment of hyperproliferative diseases and chronic obstructive pulmonary disease.
• the invention also provides a method of treating a hyperproliferative disorder and chronic obstructive pulmonary disease comprising administering to a subject in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt thereof, or a stereoisomer thereof or a substance thereof A step of a pharmaceutical composition of a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof.
• the present invention also provides a process for the preparation of the compound of the formula (I), which comprises the steps of:
• halogen means fluorine, chlorine, bromine or iodine.
• C ⁇ alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, and examples thereof include, but are not limited to, for example, methyl, ethyl, n-propyl, isopropyl Base, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-mercaptobutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-decylpentyl, 2-decylpentyl, 1-decylpentyl, 3,3-didecylbutyl, 2,2-didecylbutyl, 1, 1-dimercaptobutyl, 1,2-didecylbutyl, 1,3-dimercaptobutyl, 2,3-didecyl
• D_ 6 alkoxy refers to "-0- _ 6 alkyl” group, wherein alkyl CL 6 is as defined hereinbefore; examples thereof include, but are not limited to, Yue group, ethoxycarbonyl Base, C Oxyl, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy and the like.
• C 3. 8 cycloalkyl refers to a monocyclic ring containing 3 ⁇ 8 e.g. 3, 4, 5, 6, 7 or 8, more preferably 3 ⁇ 6 3 ⁇ 5 carbon atoms, e.g.
• saturated carbocyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, 1-nonylcyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
• the term ".6 alkylamino” refers to a - group, wherein the C ⁇ 6 alkyl group as hereinbefore defined “C6 alkyl NH-.”; Examples include, but are not limited to amine groups e.g. Yue, Ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino and the like.
• amine groups e.g. Yue, Ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino and the like.
• bis(d. 6 alkyl)amino refers to a "(d. 6 alkyl) 2 -N-" group, wherein two C 6 alkyl groups may be the same or different, respectively Examples are as defined above; examples thereof include, but are not limited to, diammonium, diethylamino, dipropylamine, dibutylamine, and the like.
• the term "CL 6 alkylcarbonyloxy", “d- 6 alkyl amide group”, “d_ 6 alkylsulfonyl”, “d. 6 alkylsulfonylamino group” and “C ⁇ 6 Alkylsulfinyl group means "d. 6 alkyl-C(0)0-,,,"C 1 -6 alkyl-C(0)NH-,, “C 1 -6 alkyl-S0, respectively. 2 -,, , “C, -6 alkyl-S0 2 NH-', and “d. 6 alkyl-SO-" group, wherein d. 6 alkyl is as defined above.
• the term "6-10 membered ring” means a saturated or unsaturated fused ring having 6 to 10 carbon atoms formed by joining at least two cyclic structures to each other by two adjacent atoms. a system wherein the ring carbon atom may be replaced by 1 to 3 identical or different heteroatoms and/or groups selected from the group consisting of 0, S(0) m , N(H) m , NCH 3 ⁇ C(O), However, O and C(O) in the ring after replacement are not adjacent to each other.
• Examples thereof include, but are not limited to, for example, 5,6-dihydroimidazo[1.2-a]pyrazine-7(8H)-yl, 5,6-dihydro-1,7-naphthyridin-7(8H)-yl, 5H-pyrrole [3.4-b]pyridine-6(7H)-yl, 7,8-dihydropyridine [4.3-d]pyrimidin-6(5H)-yl, 2,3,6,7-tetrahydro-1H -pyrazole [4.3-c]pyridine-5(4H)-yl, 6,7-dihydrothiazole [5.4-c]pyridine-5(4H)-yl, 3-mercapto-6,7-dihydro- 3H-pyrazole [4.5-c]pyridine-5(4H)-yl, 2-mercaptohexahydrocyclopenta[c]pyrrole-5-yl and the like.
• the term "7-10 member spiro ring” means that at least two rings share one atom.
• a saturated or unsaturated fused ring system having 7 to 10 carbon atoms, wherein the ring carbon atoms may be 1 to 3 identical or different selected from 0, S(0) m , N(H) m , The heteroatoms and/or groups of NCH 3 and C(O) are replaced, but 0 and C(O) in the substituted ring are not adjacent to each other.
• Examples thereof include, but are not limited to, for example, 6-azirospiro[2.5]octane-6-yl, 7-azirospiro[3.5]decane-7-yl, 8-azaspiro[4.5]decane-8-yl, 1 -mercapto- 1 ,7-diazaspiro[4.4]decane-7-yl, 2-methyl-2,6-diazaspiro[3.4]octane-6-yl, 6-azaspiro[3.4] Octane-6-yl, 2-oxa-7-azaspiro[4.5]decane-7-yl, 2-oxa-8-azaspiro[4.5]decane-8-yl, 2-indenyl- 2,7-diaza snail [4.5] decane, and the like.
• the term "7-10 membered bridged ring” means a saturated or unsaturated fused ring system having 7 to 10 carbon atoms formed by any two rings sharing two atoms not directly connected, wherein the ring carbon
• the atom may be replaced by 1 to 3 identical or different heteroatoms and/or groups selected from 0, S(0) m , N(H) m , NCH 3 and C(O), but in the substituted ring 0 and C(O) are not adjacent to each other.
• Examples thereof include, but are not limited to, for example, (l S,4S)-2-methyl-2-nitrobicyclo[2.2.1]hexane, 2-nitrobicyclo[2.2.1]heptane, 8-mercaptobicyclo[3.2 .1]octane, 3-oxa-8azabicyclo[3.2.1]octane, 2-azabicyclo[2.2.2]octane, 7-azabicyclo[2.2.1]heptane, 3-nitrobicyclo [3.2.1] Octane, 3-azabicyclo[3.3.2]nonane, 7-oxabicyclo[2.2.1]heptane, 8-oxabicyclo[3.2.1]octane, and the like.
• the term "unsaturated C 5-7 cycloalkyl group” means a monocyclic unsaturated carbocyclic group containing 5 to 7, for example, 5, 6 or 7 carbon atoms, and examples thereof include, but are not limited to, for example, a ring. Pentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatriene, and the like.
• 3-8 membered heterocyclic group means from 3 to 8 such as 3, 4, 5, 6,
• a cyclic system consisting of 7 or 8, preferably 5 to 8 carbon atoms and a hetero atom selected from the group consisting of nitrogen, oxygen and sulfur, examples of which include, but are not limited to, groups formed by, for example, the following rings: aziridine, 2H- Aziridine, diaziridine, 3H-diazacyclopropene, azetidine, 1,2-diazetidine, azetidin, 1,2-diaza Cyclobutene, pyrrole, dihydropyrrole, pyrrolidine, imidazole, 4,5-dihydroimidazole, imidazolidine, pyrazole, 4,5-dihydropyrazole, pyrazole, 1,2,3-triazole , 1, 2,4-triazole, tetrazole, pyrazole, 2-pyridone, 4-pyridone, piperazine, 1 set.
• the compound of the formula (I) of the present invention can be used in the form of a free form or a pharmaceutically acceptable salt thereof.
• the pharmaceutically acceptable salt of the compound of the formula (I) of the present invention includes a salt formed at a basic group site (e.g., an amino group, etc.) and a salt formed at an acidic group site (e.g., a hydroxyl group, a carboxyl group, etc.).
• Salts formed at the basic group include salts with inorganic acids such as hydrochlorides, hydrobromides, sulfates, etc.; salts with organic carboxylic acids such as tartrate, citrate, acetate , lactate, citrate, trichloroacetate, trifluoroacetate, etc.; salts with sulfonic acids, such as sulfonate, besylate, p-toluenesulfonate, naphthalene Salts and the like; salts formed at acidic sites include salts with alkali metals such as sodium, potassium, etc.; salts with alkaline earth metals such as calcium, magnesium, etc.; ammonium salts; and salts with nitrogen-containing organic bases,
• the organic base includes, but is not limited to, for example, tridecylamine, triethylamine, tributylamine, pyridine, hydrazine, hydrazine-dimercaptoaniline, hydra
• the compounds of the formula (I) according to the invention include all possible optical isomers and mixtures of diastereomers and pure or partially pure compounds.
• the present invention includes all stereoscopic differences of these compounds Form.
• the compound of the formula (I) of the present invention contains an olefinic double bond, and the present invention includes its cis isomer and trans isomer unless otherwise specified.
• the compounds of the formula (I) of the present invention may exist in tautomeric forms, and each tautomer and mixtures thereof are included in the scope of the present invention.
• each tautomer and mixtures thereof are included in the scope of the present invention.
• R 1 is selected from the group which is unsubstituted or substituted with 1 to 2 substituents: 6-10% saturated and ring C. _ 4 alkyl, 7- 10 member saturated spiro C Q . 4 alkyl or 7- 10 membered saturated bridged Q alkyl, wherein 1 to 3 carbon atoms in the cyclo, spiro or bridged ring may Replaced by 1 to 3 identical or different heteroatoms and/or groups selected from 0, S(0) M , N(H) M , NCH 3 and C(O), but O and in the substituted ring C(O) are not adjacent to each other,
• R 2 is selected from hydrogen, a CM alkyl group which is unsubstituted or substituted with 1 to 2 substituents Q 2 or a d. 4 alkoxy group, a decanoyl group substituted by a substituent Q 2 or N(H) M ,
• Q 2 is selected from the group consisting of halogen, hydroxy, amino, cyano, C M alkyl, CM alkoxy, C M alkylamino, bis(d. 4 alkyl)amine, CM alkyl Carbonyloxy, C M alkylamido, CM alkylsulfonyl, d.
• Q 3 is selected from the group consisting of halogen, hydroxy, amino, cyano, d. 4 alkyl, d. 4 alkoxy, C M alkylamino, bis(C M alkyl)amine, d 4 -alkylcarbonyloxy, C M alkylamido, C M alkylsulfonyl, C M alkylsulfinyl, C M alkylsulfonylamino and halogen substituted C M alkoxy; R 3 is selected from!
• R 4 , R 5 and R 6 are each independently selected from hydrogen, 13 ⁇ 4, C M alkyl, CM alkoxy, halogen substituted C M alkyl or CM alkoxy, C M alkylamino or di CM alkyl)amine group;
• L is selected from a covalent bond, 0, S(0) m or N(H) m ;
• n is selected from 1, 2 or 3;
• n is selected from 0, 1 or 2.
• R 1 is selected from the group consisting of the following groups which are unsubstituted or substituted by 1 to 2 substituents;
• 1 to 3 carbon atoms in the ring may be 1 to 3 identical or different heteroatoms selected from 0, S(0) m , N(H) m , NCH 3 and C(O) and/or Or a group substitution, but the O and C(O) in the ring after substitution are not adjacent to each other,
• p is selected from 0, 1 or 2
• R 2 is selected from hydrogen, C M alkyl which is unsubstituted or substituted with 1 to 2 substituents Q 2 , Substituent Q 2 substituted decanoyl or N(H) m ,
• Q 2 is selected from the group consisting of halogen, hydroxy, amino, d. 4 alkyl, C M alkoxy, C M alkylamino, bis(C M alkyl)amine, C M alkylcarbonyl An oxy group, a C M alkyl amide group, a d. 4 alkylsulfonyl group, a C M alkylsulfonylamino group, a cycloalkyl group, and a saturated or unsaturated 5-8 membered heterocyclic group, wherein the cycloalkyl group, The saturated or unsaturated 5-8 membered heterocyclic group may be further substituted with 1 to 2 substituents Q 3 ,
• Q 3 is selected from the group consisting of halogen, hydroxy, amino, d. 4 alkyl, d- 4 alkoxy, d- 4 alkylamino, bis(C M alkyl)amine, d. 4 alkane a carbonyloxy group, a d. 4 alkyl amide group, a CM alkylsulfonyl group, a CM alkylsulfonylamino group and a substituted CM alkoxy group;
• R 3 is selected from the group consisting of fluorine, chlorine, bromine, CM alkyl or d. 4 alkoxy;
• R 4 , R 5 and R 6 are each independently selected from hydrogen, fluorine or chlorine;
• L is selected from covalent bond, 0,
• n is selected from 1, 2 or 3;
• n is selected from 0, 1 or 2.
• R 1 is selected from unselected
• p is selected from 0, 1 or 2
• R 2 is selected from hydrogen, a methyl or ethyl group which is unsubstituted or substituted with 1 to 2 substituents Q 2 , a formyl group substituted by a substituent 0 2 or N(H) M ,
• Q 2 is selected from the following group of groups:
• Q 3 is selected from the group consisting of halogen, hydroxy, amino, CM alkyl, d. 4 alkoxy, d. 4 alkylamino, bis(C M alkyl)amine, ! 3 ⁇ 4 prime replacement. Alkoxy group, acetoxy group, acetamido group, mercaptosulfonyl group and mercaptosulfonylamino group;
• R 3 is selected from fluorine or chlorine; R 4 , R 5 and R 6 are hydrogen;
• L is selected from a covalent bond or 0;
• n 2;
• n is selected from 0, 1 or 2.
• R 2 is selected from hydrogen, unsubstituted or substituted with 1-2 substituents Q 2 Yue substituted ethyl group or a group Q 2 is selected from the following group:
• Q 3 is selected from the group consisting of halogen, hydroxy, amino, d. 4 alkyl, d- 4 alkoxy, d. 4 alkylamino, bis(d. 4 alkyl)amine and 13 ⁇ 4 Substituted C M alkoxy;
• R 3 is selected from fluorine or chlorine
• R 4 , R 5 and R 6 are hydrogen
• L is selected from a covalent bond or 0;
• n 2.
• R 1 is selected from the group consisting of
• R 2 is selected from the group consisting of hydrogen, fluorenyl or ethyl which is unsubstituted or substituted with 1 to 2 substituents Q 2 , and Q 2 is selected from the group consisting of decyloxy, diammonium, diethylamino , piperidinyl, piperazine. Qin and morpholinyl;
• R 3 is selected from fluorine or chlorine
• R 4 , R 5 and R 6 are hydrogen
• L is selected from a covalent bond or O; n is 2.
• the compounds of the formula (I) according to the invention can be prepared, for example, by the following specific steps:
• the reaction process is as follows:
• aprotic polar organic solvent such as THF (tetrahydrofuran), DMF (dimercaptophthalamide), acetonitrile or dioxane, etc.
• aprotic polar organic solvent such as THF (tetrahydrofuran), DMF (dimercaptophthalamide), acetonitrile or dioxane, etc.
• NaH, potassium carbonate, triethylamine or DIEA diisopropylethylamine
• a reducing agent such as iron powder, zinc powder, palladium / carbon or Raney nickel, etc.
• reaction mixture is cooled to room temperature, extracted with an organic solvent (such as dichloromethane, ethyl acetate or chloroform), and the organic layer is evaporated to dryness. Or preparative column) Intermediate 2.
• organic solvent such as dichloromethane, ethyl acetate or chloroform
• the compound of the formula (I) of the present invention and pharmaceutically acceptable salts thereof and stereoisomers thereof can be administered orally, parenterally (intravenously, intramuscularly, subcutaneously or rectally, etc.), pulmonaryly, locally, etc. Applied to mammals, such as humans.
• the daily dose of the compound of the invention may range from about 1 to about 1000 mg.
• the compound of the formula (I) of the present invention may be administered alone or in combination with other therapeutic agents, particularly selected from the group consisting of an antitumor agent and an immunosuppressive agent.
• the second therapeutic agent is selected from the group consisting of: an antimetabolite, including but not limited to, for example, capecitabine, gemcitabine, etc.; growth factor inhibitors, including but not limited to, for example, pazopanib, imatin Antibody; including, but not limited to, Herceptin, bevacizumab, etc.; mitotic inhibitors, including but not limited to, for example, paclitaxel, vinorelbine, docetaxel, doxorubicin, etc.; anti-tumor hormones , including but not limited to, for example, letrozole, tamoxifen, fulvestrant, etc.; alkylating agents, including but not limited to, for example, cyclophosphamide, carmustine, etc.; metal platinum, including but not limited to Carboplatin, cisplatin, oxaliplatin, etc.; topoisomerase inhibitors, including but not limited to, for example, Topotecan; immunosuppressive
• the compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof of the present invention can be used for the treatment of hyperproliferative diseases and chronic obstructive pulmonary diseases
• the hyperproliferative diseases include cancer and non-cancerous diseases
• the cancer being selected from the group consisting of: Brain tumor, lung cancer, non-small cell lung cancer, squamous cell, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer , kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, non-Hodgkin's lymphoma, central nervous system tumor (glioma, glioblastoma multiforme, gliosarcoma), prostate cancer Or squamous adenocarcinoma; a non-cancerous disease is
• the present invention also provides a pharmaceutical composition
• a pharmaceutical composition comprising the above formula (I) of the present invention Or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, and one or more pharmaceutically acceptable salts, or a stereoisomer thereof, and one or more conventional pharmaceutical carriers and / or diluent mixed to prepare.
• the composition may be formulated in any of a clinically or pharmaceutically acceptable dosage form for oral, parenteral, pulmonary or topical administration to a patient in need of such treatment.
• the compound of the formula (I) of the present invention can be formulated into a conventional solid preparation such as a tablet, a capsule, a pill, Granules, powders, etc.; can also be prepared as oral liquid preparations, such as oral solutions, oral suspensions, syrups and the like.
• a suitable filler, binder, disintegrant, lubricant, diluent or the like may be added.
• Commonly used fillers include starch, powdered sugar, calcium phosphate, calcium sulfate dihydrate, dextrin, microcrystalline cellulose, lactose, pregelatinized starch, mannitol, etc.; commonly used binders include sodium carboxymethyl cellulose, PVP -K30, hydroxypropyl cellulose, starch syrup, decyl cellulose, ethyl cellulose, hydroxypropyl hydrazine cellulose, gelatinized starch, etc.; commonly used disintegrating agents include dry starch, crospovidone, cross-linked carboxylate Methylcellulose sodium, sodium carboxymethyl starch, low-substituted hydroxypropylcellulose, etc.; commonly used lubricants include magnesium stearate, talc, sodium lauryl sulfate, microsilica gel, etc.; commonly used diluents include water, Ethanol, glycerol, etc.
• the compound of the formula (I) of the present invention may be formulated into an injection, including an injection, a sterile powder for injection.
• Concentrated solution with injection When it is prepared as an injection, it can be produced by a conventional method in the pharmaceutical field, and an optional aqueous solvent or a nonaqueous solvent can be used.
• aqueous solvent is water for injection, and 0.9% sodium chloride solution or other suitable aqueous solution may also be used;
• the commonly used non-aqueous solvent is vegetable oil, for example, soybean oil for injection, and others, such as ethanol, propylene glycol, polyethylene glycol, etc. Aqueous solution, etc.
• the compound of the formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, of the present invention can be formulated into a suppository by a conventional method.
• the experiment proves that the compound of the present invention has an excellent anti-tumor effect, and is expected to have an excellent therapeutic effect on hyperproliferative diseases and chronic obstructive pulmonary diseases; and the production of drug resistance is reduced; in addition, the preparation process of the compound of the present invention is simple and quality Stable and easy to carry out large-scale industrial production. detailed description
• the raw material compounds used are commercially available except for special instructions, which are obtained from Jingyan Chemical (Shanghai) Technology Co., Ltd.; Shanghai Titan Chemical Co., Ltd.; Shanghai Darui Fine Chemicals Co., Ltd.; Beijing Coupling Technology Co., Ltd.; Zhengzhou Taiji Hongnuo Pharmaceutical Technology Co., Ltd.; Sichuan Guangsheng Biotechnology Co., Ltd.; Suiyuan (Shanghai) Chemical Technology Co., Ltd.; Alfa Aesar (Tianjin) Chemical Co., Ltd.; TCI (Shanghai Huacheng Industrial Development Co., Ltd.; Beijing Bailingwei Technology Co., Ltd.; Shanghai Bi De Pharmaceutical Technology Co., Ltd. and other companies.
• THF stands for tetrahydrofuran
• DIPEA/DIEA stands for diisopropylethylamine
• ⁇ ethyl acetate
• HATU stands for 2-(7-azobenzotriazole)- ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylurea hexafluorophosphate
• DCC stands for dicyclohexylcarbodiimide
• EDC stands for 1-ethyl-3-(3-didecylaminopropyl)carbonyldiimide
• Reverse flow process 2-Amino-4-fluorobenzoic acid, acetic acid and hydrazine are heated under reflux in the presence of 2-methoxyethanol to give 7-fluoro-3-indole-quinazolin-4-one.
• the obtained product was nitrated to give 7-fluoro-6-succinyl-3-indole-quinazoline-4-S, which was treated with dichloromethane to give 4-chloro-6-nitro-7-fluoro-3? Oxazoline.
• decane-3-ol (0.4 g, 2.5 mmol) was dissolved in 60 mL DMF in an ice bath and under an atmosphere of N 2 points Add 60% sodium hydride (0.4 g, 10 mmol), stir to room temperature for 1 h, add N-(4-(3-chloro-4-fluorophenyl))-7-fluoro-6-nitroquinazole Phenyl-4-amine (1.12 g, 3.3 mmol), stirred at 50 ° C overnight. After completion of the reaction, 50 mL of water was added and extracted with EA.
• N _(4-(3-chloro-4-fluorophenyl))-7-(8-methyl-1 -oxa-8-azaspiro[4.5]decane-2- Alkyloxy)quinazoline-4,6-diamine (175 mg, 0.38 mmol) was dissolved in 30 mL of dichloromethane, 77 mg of triethylamine was added, and acryloyl chloride (31 mg was added dropwise in an ice water bath.
• N-(4-(3-Chloro-4-fluorophenyl))-7-(2-((lR,5S,6S)-3-indolyl-3-azabicyclo[3.1.0]hexane -6-Ethyloxy)quinazoline-4,6-diamine 200 mg, 0.47 mmol was dissolved in 20 mL of dichloromethane, and 200 mg of triethylamine and acryloyl chloride were added under ice bath. Mg, 0.47 mmol), stirred at room temperature for 30 min. After completion of the reaction, 50 mL of water was added, and extracted with EA. The organic layer was evaporated to dryness under reduced pressure.
• N-(4-(3-Chloro-4-fluorophenyl))-7-((5-methyl-5-azaspiro[2.4]heptanyl)methoxy)quinazoline- 4,6-Diamine 100 mg, 0.23 mmol was dissolved in 10 mL DCM, triethylamine (46 mg, 0.46 mmol) was added, and acryloyl chloride (19 mg, 0.21 mmol) was added dropwise in an ice water bath and stirred at room temperature. After 30 min, after completion of the reaction, 50 mL of water was added, extracted with EA, and evaporated to dryness under reduced pressure.
• Phenyl-4,6-diamine 200 mg, 0.45 mmol was dissolved in 10 mL of DCM, triethylamine (46 mg, 0.46 mmol) was added, and acryloyl chloride (39 mg, 0.43 mmol) was added dropwise in an ice water bath. After stirring at room temperature for 30 min, after completion of the reaction, 50 mL of water was added, and the mixture was extracted with EA.
• HATU 0.05 g, 1.32 mmol
• Trans-2-butenoic acid (98 mg, 1.1 mmol) was dissolved in 10 mL DMF then HATU (563 g, 1.32 mmol).
• DIEA (441 mg, 3.4 mmol) and N-(4-(3-chloro) 4-fluorophenyl)-7-((7-fluorenyl-7-azaspiro[3.5]decane-2-yl))nonyloxy)quinazoline-4,6-diamine (400
• the mixture was stirred at room temperature for 12 h. After the reaction was completed, 50 mL of water was added, and the mixture was extracted with methylene chloride. The organic layer was evaporated to dryness under reduced pressure.
• Trans-2-pentenoic acid (86 mg, 0.86 mmol) was dissolved in 10 mL DMF then HATU (425 g, 1.12 mmol) DIEA (333 mg, 2.6 mmol) and N-(4-(3-chloro) -4-fluorophenyl))-7-((7-fluorenyl-7-azaspiro[3.5]decane-2-yl)decyloxy)quinazoline 4,6-diamine (300 mg After stirring at room temperature for 12 h, after completion of the reaction, 50 mL of water was added, and the mixture was extracted with dichloromethane.
• N-(4-(3-Chloro-4-fluorophenyl))-7-((spiro[3.5]octane-2-yl)decyloxy)quinazoline-4,6-diamine 3 g, 6.6 mmol was dissolved in 10 mL of DCM, triethylamine (2 g, 19.8 mmol) was added, and 6-(( ⁇ )-4-didecylamino)]-crotonyl chloride (600) was added dropwise in an ice water bath. Mg, 6.6 mmol), stirred at room temperature for 30 min. After completion of the reaction, 50 mL of water was added and extracted with EA.
• Control drug Gefitinib> erlotinib hydrochloride, purchased from Anqing Ward Chemical Co., Ltd.; lapatinib di-p-benzenesulfonate, purchased from Taizhou Yuxin Pharmaceutical Chemical Co., Ltd.; CI-1033 hydrochloride, purchased from Shanghai ⁇ Fragrance & Fragrance Co., Ltd.; and the compound of the present invention: self-made, the chemical name and structural formula and preparation method are shown in the preparation examples of the respective compounds.
• HEPES hydroxyethylpiperazine ethanesulfuric acid
• DTT two stones filled with threitol
• EDTA ethylenediaminetetraacetic acid, purchased from Sigma;
• FAM-labeled peptide fluorescein-labeled peptide 22 ( GL Biochem );
• ATP adenosine triphosphate (Sigma);
• EGFR human epidermal growth factor receptor (Carna);
• HER2 human epidermal growth factor receptor 2 ( Carna ) ;
• HER4 Human epidermal growth factor receptor 4 (Carna).
• Curve fitting was performed using Xlfit software to obtain IC 50 values.
• the compound of the present invention has strong inhibitory activity against EGFR, HER2, and HER4 kinase, and is equivalent to CI-1033 hydrochloride activity; the inhibitory activity against HER2 kinase is significantly superior to that of gefitinib and erlotinib hydrochloride; The inhibitory activity of HER4 kinase was significantly better than that of erlotinib hydrochloride and lapatinib di-p-toluenesulfonate.
• Experimental Example 2 In vitro cytological inhibitory activity of the compound of the present invention
• RPMI1640 Roswell Park Memorial Institute Roswell Park Memorial Research Institute name: purchased from Hyclone;
• FBS fetal bovine serum, purchased from Hyclone
• PBS phosphate buffer, purchased from Homemade.
• test compound gradient dilution solution First, 10 mM of the test compound stock solution was diluted 4 times in DMSO with a total of 10 concentrations. Then, 2 L of DMSO-diluted compound was added to 998 ⁇ g of 10% FBS-containing medium. The maximum concentration of the compound was 20 ⁇ M, and the concentration of DMSO was 0.2%, with a total of 10 concentration gradients.
• the drug was added to the cell culture plate, and cultured at 37 ° C for 72 hours in a 5% CO 2 incubator.
• the XTT working solution was added, placed in a 5% C0 2 incubator at 37 ° C for 2 hours, and placed in a microplate reader to read 450 nm absorbance.
• % inhibition (reading (solvent) - reading (compound) / (reading (solvent) - reading (positive control) X 100%;
• the compound of the present invention is H1975 (NSCLC, non-small cell lung cancer) Cell proliferation inhibition was significantly better than erlotinib hydrochloride, lapatinib di-p-toluenesulfonate. As can be seen from Table 3, the compound of the present invention is superior to lapatinib di-p-toluenesulfonate in inhibiting cell proliferation of Calu-3 (NSCLC, non-small cell lung cancer), which is superior to erlotinib hydrochloride and CI-1033 hydrochloride. .
• the compound of the present invention is superior to CI-1033 hydrochloride in inhibiting the proliferation of A431 (Epidermoid carcinoma) cells, and is superior to erlotinib hydrochloride and lapatinib di-p-toluenesulfonate.

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