CN111777620A - Novel use of tyrosine kinase inhibitor - Google Patents

Novel use of tyrosine kinase inhibitor Download PDF

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CN111777620A
CN111777620A CN201910272840.6A CN201910272840A CN111777620A CN 111777620 A CN111777620 A CN 111777620A CN 201910272840 A CN201910272840 A CN 201910272840A CN 111777620 A CN111777620 A CN 111777620A
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radical
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史澂空
欧娜
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Shandong Xuanzhu Pharma Co Ltd
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Shandong Xuanzhu Pharma Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • 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
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    • 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
    • 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
    • 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
    • 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

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a Chinese medicinal compositionAnd a compound shown as a formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof and new application of a crystal form thereof, R1、R2、R3、R4、R5、R6L, n are as defined in the specification; the invention particularly relates to application of the compounds, pharmaceutical preparations containing the compounds and pharmaceutical compositions in preparing medicines for treating tumor patients carrying EGFR20 exon insertion mutation.

Description

Novel use of tyrosine kinase inhibitor
1. Field of the invention
The invention belongs to the field of medicines, and particularly relates to a quinazoline derivative tyrosine kinase inhibitor, a stereoisomer thereof, a pharmaceutically acceptable salt thereof and a new application of a crystal form thereof.
2. Background of the invention
Epidermal Growth Factor Receptor (EGFR) is a multifunctional glycoprotein widely distributed on cell membranes of various tissues of human bodies, and is an avian erythroblastic leukemia virus (v-erb-b) oncogene homolog. Research has shown that the high expression of EGFR exists in glioma, head and neck cancer, non-small cell lung cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer and other solid tumors, and the inhibition of the activity of EGFR tyrosine kinase can effectively inhibit the growth of tumors. At present, small molecule EGFR inhibitors can be divided into a first generation reversible EGFR tyrosine kinase inhibitor, representing drugs of gefitinib, erlotinib and erlotinib, a second generation irreversible EGFR tyrosine kinase inhibitor, representing drug of afatinib, a third generation irreversible EGFR tyrosine kinase inhibitor, representing drug of oxitinib (AZD9291), which is approved to be marketed in the United states in 2015, AZD9291 is a third generation targeting EGFR-TKI of Aslicon, and has excellent response rate for drug resistance caused by T790M mutation. EGFR20 exon insertion mutation is the third largest type of mutation, in addition to EGFR 19 exon deletion mutation and 21 exon L858R mutation, which is often associated with targeted drug resistance, a very tricky type of genetic mutation.
WO2012027960A1 discloses a series of quinazoline derivatives tyrosine kinase inhibitors irreversibly inhibited by Pan-HER, and researches show that the irreversible inhibitors for Pan-HER tyrosine kinase can inhibit HER2/4 besides EGFR effectively, the drugs with irreversible inhibition on HER/ErbB families can improve drug activity and reduce drug resistance, and have significant inhibition effect on Erlotinib-resistant H1975 cell lines and good antitumor activity.
In the process of researching the patent compounds, the inventor unexpectedly finds that part of the compounds have good inhibition effect on insertion mutation of exon at position 20 of EGFR besides the inhibition effect on HER 2/4.
3. Summary of the invention
The invention relates to a compound shown in a formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a new application of a crystal form thereof.
The technical scheme of the invention is as follows:
scheme 1: use of a compound of formula (I), its stereoisomers, and its pharmaceutically acceptable salt forms in the preparation of a medicament for treating a patient having a tumor that carries an EGFR exon insertion mutation at position 20,
Figure BDA0002018970070000021
wherein the content of the first and second substances,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted of the following groups: 6-to 10-membered fused ring C0-6Alkyl, 7-10 membered spirocyclic C0-6Alkyl or 7-to 10-membered bridged ring C0-6Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be the same or different by 1 to 3 atoms selected from O, S (O)m、N(H)m、NCH3And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,
Q1selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonamide group and C3-8A cycloalkyl group;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted C1-6Alkyl or C1-6Alkoxy radicals, substituted radicals Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonamido radical, C3-8Cycloalkyl, unsaturated C5-7Cycloalkyl and a saturated or unsaturated 3-to 8-membered heterocyclic group, wherein said C3-8Cycloalkyl, unsaturated C5-7The cycloalkyl group and the saturated or unsaturated 3-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonamido and halogen substituted C1-6An alkoxy group;
R3selected from hydrogen, halogen, hydroxy, cyano, nitro, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl or C1-6Alkoxy radical, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl or C1-6An alkylsulfonamide group;
R4、R5and R6Each independently selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl or C1-6Alkoxy radical, C1-6Alkylamino or di (C)1-6Alkyl) amino;
l is selected from the group consisting of a covalent bond, O, S (O)m，N(H)m，NCH3Or C (O);
n is selected from 1,2 or 3; and
m is independently selected from 0, 1 or 2.
Scheme 2, the use according to scheme 1, wherein,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted of the following groups: 6-10 membered saturated fused ring C0-4Alkyl, 7-10 membered saturated spirocyclic ring C0-4Alkyl or 7-10 membered saturated bridged ring C0-4Alkyl, wherein 1 to 3 carbon atoms in the bicyclic, spiro or bridged ring may be substituted by 1 to 3The same or different is selected from O, S (O)m、N(H)m、NCH3And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,
Q1selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonamide group and C3-6A cycloalkyl group;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted C1-4Alkyl or C1-4Alkoxy radicals, substituted radicals Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of: halogen, hydroxy, amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonamido radical, C3-6Cycloalkyl, unsaturated C5-7Cycloalkyl and a saturated or unsaturated 5-to 8-membered heterocyclic group, wherein said C3-6Cycloalkyl, unsaturated C5-7The cycloalkyl group and the saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonamido and halogen substituted C1-4An alkoxy group;
R3selected from halogen, cyano, nitro, C1-4Alkyl radical, C1-4Alkoxy, halogen substituted C1-4Alkyl or C1-4Alkoxy radical, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl or C1-4An alkylsulfonamide group;
R4、R5and R6Each independently selected from hydrogen, halogen, C1-4Alkyl radical, C1-4Alkoxy, halogen substituted C1-4Alkyl or C1-4Alkoxy radical, C1-4Alkylamino or di (C)1-4Alkyl) amino;
l is selected from the group consisting of a covalent bond, O, S (O)mOr N (H)m；
n is selected from 1,2 or 3; and
m is independently selected from 0, 1 or 2.
The use according to scheme 3, scheme 1 or 2, wherein,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted of the following groups:
Figure BDA0002018970070000031
Figure BDA0002018970070000041
Figure BDA0002018970070000042
wherein 1 to 3 carbon atoms in the ring may be the same or different by 1 to 3 atoms selected from O, S (O)m、N(H)m、NCH3And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement, p is selected from 0, 1 or 2,
Q1selected from the group consisting of: halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino and C3-6A cycloalkyl group;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted C1-4Alkyl radicals, substituted radicals Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfonamido radical, C3-5Cycloalkyl and saturated or unsaturated 5-8 membered heterocyclyl, wherein said C3-5The cycloalkyl group, saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfonamido and halogen substituted C1-4An alkoxy group;
R3selected from fluorine, chlorine, bromine, C1-4Alkyl or C1-4An alkoxy group;
R4、R5and R6Each independently selected from hydrogen, fluorine or chlorine;
l is selected from the group consisting of a covalent bond, O, S (O)mOr N (H)m；
n is selected from 1,2 or 3; and
m is selected from 0, 1 or 2.
The use according to scheme 4, according to any one of schemes 1 to 3, wherein,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted of the following groups:
Figure BDA0002018970070000051
Figure BDA0002018970070000052
p is selected from the group consisting of 0, 1 or 2,
Q1selected from the group consisting of: halogen, amino, C1-4Alkyl radical, C1-4Alkylamino and di (C)1-4Alkyl) amino;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted methyl or ethyl radicals, by substituents Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of:
(1) halogen, hydroxy, amino, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, acetoxy, acetamido, methylsulfonyl and methylsulfonylamino,
(2) cyclopropyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyrazinyl and pyrimidinyl, said Q2The radicals may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, halogen-substituted C1-4Alkoxy, acetoxy, acetamido, methylsulfonyl, and methylsulfonylamino;
R3selected from fluorine or chlorine;
R4、R5and R6Is hydrogen;
l is selected from a covalent bond or O;
n is 2; and
m is independently selected from 0, 1 or 2.
The use according to scheme 5, according to any one of schemes 1 to 4, wherein,
R1selected from:
Figure BDA0002018970070000061
Figure BDA0002018970070000062
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2A substituted methyl group or an ethyl group,
Q2selected from the group consisting of:
(1) methoxy and di (C)1-4Alkyl) amino groups, in the presence of a nitrogen atom,
(2) piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, cyclopropylalkyl, cyclopentylalkyl, pyrrolyl, pyridinyl, pyrimidinyl and thiazolyl, said Q2The radicals may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino and halogen substituted C1-4An alkoxy group;
R3selected from fluorine or chlorine;
R4、R5and R6Is hydrogen;
l is selected from a covalent bond or O; and
n is 2.
The use according to scheme 6, according to any one of schemes 1 to 5, wherein,
R1selected from:
Figure BDA0002018970070000071
Figure BDA0002018970070000072
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2A substituted methyl group or an ethyl group,
Q2selected from the group consisting of: methoxy, dimethylamino, diethylamino, piperidinyl, piperazinyl and morpholinyl;
R3selected from fluorine or chlorine;
R4、R5and R6Is hydrogen;
l is selected from a covalent bond or O; and
n is 2.
Scheme 7: the use according to any one of schemes 1 to 6, wherein,
R1selected from:
Figure BDA0002018970070000081
preferably R1Selected from:
Figure BDA0002018970070000082
scheme 8: the use according to any one of schemes 1 to 7, wherein,
R2selected from hydrogen;
R3independently selected from fluorine or chlorine;
l is selected from O; and
n is selected from 2.
Scheme 9: the use according to scheme 1 wherein the compound of formula (I) is selected from:
Figure BDA0002018970070000083
Figure BDA0002018970070000091
Figure BDA0002018970070000101
Figure BDA0002018970070000111
scheme 10: the use according to any of schemes 1 to 9, wherein the EGFR20 exon insertion mutation is selected from the group consisting of a763_ Y764insFQEA, a763_ Y764insFHEA, a767_ V769dupASV, D770_ N771insNPG, D770_ N771insSVD, D770_ N771insSVQ, H773_ V774insNPH, Y764_ V765insHH, M766_ a767insAI, H773_ V774insH, D770_ N771insGL, D770_ N771insGT, P772_ H773insYNP, delD770 insGY.
Scheme 11: the use according to any of schemes 1 to 10, wherein the exon 20 insertion mutation of EGFR is selected from the group consisting of A763_ Y764insFQEA, A763_ Y764 insFHAA, A767_ V769dupASV, D770_ N771insNPG, D770_ N771insSVD, D770_ N771insSVQ, H773_ V774 insNPH. Preferably, the EGFR20 exon insertion mutation is selected from the group consisting of A763_ Y764insFQEA, A763_ Y764 insFHAA, D770_ N771insNPG, D770_ N771insSVD, H773_ V774 insNPH.
Scheme 12: the use according to any of schemes 1-11, wherein the crystalline form is selected from an isolated crystalline form of the compound of formula (I), a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), a solvate crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), or a co-crystal of the compound of formula (I).
Scheme 13: the use according to scheme 12, wherein,
the crystal form of the pharmaceutically acceptable salt of the compound of formula (I) is selected from a hydrochloride crystal form, a phosphate crystal form, a mesylate crystal form, a triflate crystal form, a malate crystal form, a fumarate crystal form, a succinate crystal form, a tartrate crystal form, a benzoate crystal form or a maleate crystal form of the compound of formula (I), preferably a hydrochloride crystal form, a maleate crystal form, a succinate crystal form or a benzoate crystal form;
the solvate crystal form of the compound of formula (I) is selected from a hydrate crystal form, a methoxide crystal form, an ethoxide crystal form, an etherate crystal form and an acetonide crystal form, preferably a hydrate crystal form;
the solvate of a pharmaceutically acceptable salt of the compound of formula (I) is selected from the group consisting of a hydrochloride hydrate crystal form, a hydrochloride methoxide crystal form, a hydrochloride etherate crystal form, a benzoate hydrate crystal form, a benzoate methoxide crystal form, a benzoate etherate crystal form, a maleate hydrate crystal form, a maleate methoxide crystal form, or a maleate etherate crystal form, preferably a hydrochloride hydrate crystal form, more preferably a dihydrochloride monohydrate crystal form;
the co-crystal of the compound of formula (I) is selected from co-crystal of the compound of formula (I) and one or more of proline, gallic acid, oxalic acid, maleic acid, tartaric acid and saccharin, preferably co-crystal of proline, tartaric acid or saccharin.
Scheme 14: the use according to any one of claims 1 to 13, wherein the tumor is selected from one or more of brain cancer, head and neck cancer, thyroid cancer, oral cancer, esophageal adenocarcinoma, lung cancer, stomach cancer, liver cancer, bile duct cancer, kidney cancer, pancreatic cancer, peritoneal cancer, colorectal cancer, gallbladder cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, epidermal carcinoma, non-hodgkin lymphoma, glioma, glioblastoma.
Scheme 15: the use according to any of claims 1 to 13, wherein the tumor is selected from non-small cell lung cancer.
Scheme 16: use of a pharmaceutical preparation of a compound shown as a formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystal form thereof in preparing a medicament for treating a tumor patient carrying EGFR20 exon insertion mutation,
Figure BDA0002018970070000131
wherein R is1、R2、R3、R4、R5、R6L and n are as defined in scheme 1.
Scheme 17: the use according to scheme 16 wherein the EGFR20 exon insertion mutation is selected from the group consisting of a763_ Y764insFQEA, a763_ Y764insFHEA, a767_ V769dupASV, D770_ N771insNPG, D770_ N771insSVD, D770_ N771insSVQ, H773_ V774insNPH, Y764_ V765insHH, M766_ a767insAI, H773_ V774insH, D770_ N771insGL, D770_ N771insGT, P772_ H773insYNP, delD770 insGY.
Scheme 18: the use according to any of schemes 16 or 17, wherein the exon 20 insertion mutation of EGFR is selected from A763_ Y764insFQEA, A763_ Y764 insFHAA, A767_ V769dupASV, D770_ N771insNPG, D770_ N771insSVD, D770_ N771insSVQ or H773_ V774 insNPH. Preferably, the EGFR20 exon insertion mutation is selected from A763_ Y764insFQEA, A763_ Y764 insFHAA, D770_ N771insNPG, D770_ N771insSVD or H773_ V774 insNPH.
Scheme 19: the use according to any of claims 16-18, wherein the tumor is selected from one or more of brain cancer, head and neck cancer, thyroid cancer, oral cancer, esophageal adenocarcinoma, lung cancer, stomach cancer, liver cancer, bile duct cancer, kidney cancer, pancreatic cancer, peritoneal cancer, colorectal cancer, gallbladder cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, epidermal carcinoma, non-hodgkin lymphoma, glioma, and glioblastoma.
Scheme 20: the use according to any of claims 16-18, wherein the tumor is selected from the group consisting of non-small cell lung cancer.
Scheme 21: the use according to any of claims 16 to 20, wherein the crystalline form is selected from:
1) a compound of formula (I) in a crystalline form of hydrochloride, mesylate, triflate, malate, fumarate, succinate, tartrate, benzoate or maleate;
2) hydrate crystal form, methoxide crystal form, ethoxide crystal form, ether crystal form, and acetonide crystal form of the compound of formula (I);
3) a crystalline form of hydrochloride hydrate, a crystalline form of hydrochloride methoxide, a crystalline form of hydrochloride etherate, a crystalline form of benzoate hydrate, a crystalline form of benzoate methoxide, a crystalline form of benzoate etherate, a crystalline form of maleate hydrate, a crystalline form of maleate methoxide or a crystalline form of maleate etherate of the compound of formula (I), preferably a crystalline form of dihydrochloride monohydrate of the compound of formula (I);
4) co-crystals of the compound of formula (I) with one or more of proline, gallic acid, oxalic acid, maleic acid, tartaric acid, and saccharin.
Scheme 22: the application of the composition of the compound shown in the formula (I), the stereoisomer, the pharmaceutically acceptable salt or the crystal form thereof and one or more other anti-tumor drugs in the preparation of drugs for treating tumor patients carrying EGFR20 exon insertion mutation,
Figure BDA0002018970070000141
wherein R is1、R2、R3、R4、R5、R6L and n are as defined in scheme 1.
Scheme 23: the use according to scheme 22 wherein the EGFR20 exon insertion mutation is selected from the group consisting of a763_ Y764insFQEA, a763_ Y764insFHEA, a767_ V769dupASV, D770_ N771insNPG, D770_ N771insSVD, D770_ N771insSVQ, H773_ V774insNPH, Y764_ V765insHH, M766_ a767insAI, H773_ V774insH, D770_ N771insGL, D770_ N771insGT, P772_ H773insYNP, delD770 insGY.
Scheme 24: the use according to either of schemes 22 or 23, wherein the EGFR20 exon insertion mutation is selected from a763_ Y764insFQEA, a763_ Y764insFHEA, a767_ V769dupASV, D770_ N771insNPG, D770_ N771insSVD, D770_ N771insSVQ or H773_ V774 insNPH. Preferably, the EGFR20 exon insertion mutation is selected from A763_ Y764insFQEA, A763_ Y764 insFHAA, D770_ N771insNPG, D770_ N771insSVD or H773_ V774 insNPH.
Scheme 25: the use according to any of the regimens 22-24, wherein the tumor is selected from one or more of brain cancer, head and neck cancer, thyroid cancer, oral cancer, esophageal adenocarcinoma, lung cancer, stomach cancer, liver cancer, bile duct cancer, kidney cancer, pancreatic cancer, peritoneal cancer, colorectal cancer, gallbladder cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, epidermal carcinoma, non-hodgkin lymphoma, glioma, glioblastoma.
Scheme 26: the use according to any one of claims 22-25, wherein the composition further comprises any pharmaceutically acceptable carrier.
Scheme 27: the use according to any of claims 22-26, wherein the crystalline form is selected from the group consisting of:
1) a compound of formula (I) in a crystalline form of hydrochloride, mesylate, triflate, malate, fumarate, succinate, tartrate, benzoate or maleate;
2) hydrate crystal form, methoxide crystal form, ethoxide crystal form, ether crystal form, and acetonide crystal form of the compound of formula (I);
3) a crystalline form of hydrochloride hydrate, a crystalline form of hydrochloride methoxide, a crystalline form of hydrochloride etherate, a crystalline form of benzoate hydrate, a crystalline form of benzoate methoxide, a crystalline form of benzoate etherate, a crystalline form of maleate hydrate, a crystalline form of maleate methoxide or a crystalline form of maleate etherate of the compound of formula (I), preferably a crystalline form of dihydrochloride monohydrate of the compound of formula (I);
4) co-crystals of the compound of formula (I) with one or more of proline, gallic acid, oxalic acid, maleic acid, tartaric acid, and saccharin.
In the specification and claims of this application, compounds are named according to chemical structural formula, and if the name of a compound does not match the chemical structural formula when the same compound is represented, the chemical structural formula or chemical reaction formula is the standard.
Detailed Description
The EGFR20 exon of the present invention refers to the coding amino acid position from 762 to 823 on the EGFR gene, and the EGFR20 exon insertion mutation of the present invention refers to the insertion of at least 1 (e.g., 5, 4, 3, 2 or 1) amino acid coding position between any two adjacent or non-adjacent coding amino acid positions of the EGFR20 exon.
The term "D770-N771 insNPG mutation" of the present invention refers to the insertion of 3 amino acid coding sites between 770 and 771 coding amino acid sites on the EGFR gene, i.e., three amino acid coding sites of N, P, G, wherein the letter D, N, P, G is an amino acid abbreviation representing aspartic acid, asparagine, proline and glycine, respectively, and the numbers 770 and 771 represent amino acid coding sites on the EGFR gene.
The term "A767 _ V769 dupASV" of the present invention refers to the site of EGFR gene where the amino acid ASV is inserted between 767 and 769 of repetitive coding, and is equivalent to the site of EGFR gene where three coded amino acids A, S, V are inserted between 769 and 770 of coded amino acids, wherein the amino acid abbreviations A, S and V represent alanine, serine and valine, respectively. That is, the term "A767 _ V769 dupASV" is equivalent to V769_ D770 insASV. Similarly, the term "D770 _ N771 insSVD" is equivalent to "S768 _ D770 dupSVD"; the term "H773 _ V774 insH" is equivalent to "P772 _ H773 insH".
In the present invention, "halo" means substituted by "halogen" and the term "halogen" means fluorine, chlorine, bromine or iodine.
In the present invention, the term "C1-6Alkyl "refers to a straight or branched alkyl group having 1 to 6 carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1-methyl-2-methylpropyl, and the like. "C" according to the invention1-4Alkyl "means C1-6Specific examples of the alkyl group having 1 to 4 carbon atoms.
In the present invention, the term "C1-6Alkoxy "means" C1-6alkyl-O- "group, wherein C1-6Alkyl is as previously defined; examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, neopentyloxy, hexyloxy, and the like. "C" according to the invention1-4Alkoxy "means C1-6Specific examples of the alkoxy group having 1 to 4 carbon atoms.
In the present invention, the term "C3-8Cycloalkyl "refers to a monocyclic saturated carbocyclic group containing 3 to 8, e.g. 3,4, 5,6, 7 or 8 carbon atoms, preferably 3 to 6 or 3 to 5 carbon atoms, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, 1-methylcyclobutyl, cyclopentyl, cyclohexylCycloheptyl, cyclooctyl, and the like.
In the present invention, the term "C1-6Alkylamino "refers to" C1-6alkyl-NH- "group, wherein C1-6Alkyl is as previously defined; examples include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino, tert-butylamino, sec-butylamino, pentylamino, neopentylamino, hexylamino and the like.
In the present invention, the term "di (C)1-6Alkyl) amino "refers to" (C)1-6Alkyl radical)2-N- "group, two of which are C1-6The alkyl groups may be the same or different and are each as defined above; examples include, but are not limited to, dimethylamino, diethylamino, dipropylamino, dibutylamino and the like.
In the present invention, the term "C1-6Alkylcarbonyloxy group and C1-6Alkylamide group "," C1-6Alkylsulfonyl group "," C1-6Alkylsulfonamido "and" C1-6Alkylsulfinyl "means respectively" C1-6alkyl-C (O) O- "," C1-6alkyl-C (O) NH-, "C1-6alkyl-SO2-”、“C1-6alkyl-SO2NH- "and" C1-6alkyl-SO- "group, wherein C1-6Alkyl is as defined above.
In the present invention, the term "6-to 10-membered fused ring" means a saturated or unsaturated fused ring system containing 6 to 10 carbon atoms, wherein the ring carbon atoms may be substituted by 1 to 3 same or different atoms selected from O, S (O), which is formed by connecting at least two cyclic structures sharing two adjacent atomsm、N(H)m、NCH3And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement. Examples include, but are not limited to, 5, 6-dihydroimidazole [1.2-a ]]Pyrazin-7 (8H) -yl, 5, 6-dihydro-1, 7-naphthyridin-7 (8H) -yl, 5H-pyrrolo [3.4-b ]]Pyridin-6 (7H) -yl, 7, 8-dihydropyridine [4.3-d ]]Pyrimidin-6 (5H) -yl, 2,3,6, 7-tetrahydro-1H-pyrazolo [4.3-c]Pyridin-5 (4H) -yl, 6, 7-dihydrothiazole [5.4-c]Pyridin-5 (4H) -yl, 3-methyl-6, 7-dihydro-3H-pyrazolo [4.5-c]Pyridin-5 (4H) -yl, 2-methylhexahydropenta [ c ]]Pyrrol-5-ylAnd the like.
In the present invention, the term "7-to 10-membered spirocyclic ring" refers to a saturated or unsaturated fused ring system containing 7 to 10 carbon atoms, wherein the ring carbon atoms may be substituted by 1 to 3 identical or different atoms selected from O, S (O)m、N(H)m、NCH3And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement. Examples include, but are not limited to, 6-azaspiro [2.5]]Octane-6-yl, 7-azaspiro [3.5]]Nonan-7-yl, 8-azaspiro [4.5]]Decan-8-yl, 1-methyl-1, 7-diazaspiro [4.4 ]]Nonan-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]]Decan-7-yl, 2-oxa-8-azaspiro [4.5]]Decan-8-yl, 2-methyl-2, 7-diazaspiro [4.5]]Decane, etc.
In the present invention, the term "7-to 10-membered bridged ring" means a saturated or unsaturated fused ring system containing 7 to 10 carbon atoms, wherein any two rings share two atoms which are not directly bonded, and wherein the ring carbon atoms may be substituted by 1 to 3 same or different atoms selected from the group consisting of O, S (O)m、N(H)m、NCH3And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement. Examples include, but are not limited to, (1S,4S) -2-methyl-2-azabicyclo [2.2.1]Hexane, 2-azabicyclo [2.2.1]]Heptane, 8-methylbicyclo [3.2.1]]Octane, 3-oxa-8-azabicyclo [3.2.1]Octane, 2-azabicyclo [2.2.2]Octane, 7-azabicyclo [2.2.1]Heptane, 3-azabicyclo [3.2.1]Octane, 3-azabicyclo [3.3.2 ]]Decane, 7-oxabicyclo [2.2.1]Heptane, 8-oxabicyclo [3.2.1]]Octane, and the like.
In the present invention, the term "unsaturated C5-7Cycloalkyl "refers to a monocyclic unsaturated carbocyclic group containing 5 to 7, e.g., 5,6, or 7, carbon atoms, examples of which include, but are not limited to, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, and the like.
In the present invention, the term "3-8 membered heterocyclic group" means a cyclic system composed of 3 to 8, for example, 3,4, 5,6, 7 or 8, preferably 5 to 8 carbon atoms and 1 to 4 (preferably 1 to 3, more preferably 1 to 2) heteroatoms selected from nitrogen, oxygen and sulfur, examples of which include, but are not limited to, the following ring-forming groups: aziridine, 2H-aziridine, diazirine, 3H-diazirine, azetidine, 1, 2-diazetidine, azetidine, 1, 2-diazacyclobutene, pyrrole, dihydropyrrole, pyrrolidine, imidazole, 4, 5-dihydroimidazole, imidazolidine, pyrazole, 4, 5-dihydropyrazole, pyrazolidine, 1,2, 3-triazole, 1,2, 4-triazole, tetrazole, pyridine, 2-pyridone, 4-pyridone, piperidine, pyridazine, pyrimidine, pyrazine, piperazine, 1,2, 3-triazine, 1,2, 4-triazine, 1,3, 5-triazine, 1,2,4, 5-tetrazine, azepane, 1, 2-diazepatriene, 1, 3-diazepatriene, 1, 4-diazacyclotriene, azacyclooctatetraene, 1, 4-dihydro-1, 4-diazacyclooctatriene, ethylene oxide, dioxirane, thietane, oxetane, 1, 2-dioxetane, thietane, 1, 2-dithiocyclobutene, furan, tetrahydrofuran, thiophene, 2, 5-dihydrothiophene, tetrahydrothiophene, 1, 3-dioxolane, 1, 3-dioxol-2-one, 1, 2-dithiole, 1, 3-dithiolane, 2H-pyran-2-one, 3, 4-dihydro-2H-pyran, 4H-pyran, tetrahydropyran, 4H-pyran-4-one, 1, 4-dihydro-1, 4-dithiacyclooctatriene, thiolane, 2H-pyran-2-one, 3, 4-dihydro-, 1, 4-dioxane, 1, 4-dithiine, 1, 4-oxathiadiene, 1, 4-dioxanone, 1, 3-dioxane, 1, 3-oxathiahexane, oxepitriene, thiepin, 1, 4-dioxacyclooctatriene, oxaziridine, oxazole, 4, 5-dihydrooxazole, isoxazole, 4, 5-dihydroisoxazole, 2, 3-dihydroisoxazole, 1,2, 3-oxadiazole, 1,2, 5-oxadiazole, thiazole, 4, 5-dihydrothiazole, isothiazole, 1,2, 3-thiadiazole, 1,2, 4-thiadiazole, 1,3, 4-thiadiazole, 2H-1, 2-oxazine, 4H-1, 2-oxazine, 6H-1, 2-oxazine, 2H-1, 3-oxazine, 4H-1, 3-oxazine, 5, 6-dihydro-4H-1, 3-oxazine, 6H-1, 3-oxazine, 2H-1, 4-oxazine, 4H-1, 4-oxazine, 2H-1, 3-thiazine, 4H-1, 3-thiazine, 5, 6-dihydro-4H-1, 3-thiazine, 6H-1, 3-thiazine, 2H-1, 4-thiazine, 4H-1, 4-thiazine, morpholine and the like.
"C" according to the invention0-6Alkyl "refers to a straight or branched chain alkyl group containing 0 to 6 carbon atoms, when the alkyl group contains 0 carbon atoms it means that the alkyl group is absent, when the alkyl group contains 1 to 6When carbon atom, it is as defined above for "C1-6Alkyl groups "as described.
The "halo C" of the present invention1-6Alkyl "means one or more halogen atoms substituted for C1-6Radicals derived from one or more hydrogen atoms of the alkyl radical, the said "halogens" and "C1-6Alkyl "is as defined above.
The "halo C" of the present invention1-6Alkoxy "means one or more halogen atoms substituted for C1-6Radicals derived from one or more hydrogen atoms of alkoxy radicals, said "halogen" and "C1-6Alkoxy "is as defined above.
The stereoisomers of the compounds of formula (I) according to the invention include all possible optical isomers and diastereoisomeric mixtures and pure or partially pure compounds. Optical isomers are meant when the compounds of the present invention contain one or more asymmetric centers and thus may exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
The compounds of formula (I) according to the invention contain olefinic double bonds, and unless otherwise specified, the stereoisomers according to the invention include cis-and trans-isomers thereof.
The compounds of formula (I) according to the invention may exist in tautomeric forms, the individual tautomers as well as mixtures thereof being included within the scope of the invention.
The crystal form of the compound shown in the formula (I) comprises free crystal form of the compound shown in the formula (I), pharmaceutically acceptable salt crystal form of the compound shown in the formula (I), solvate crystal form of the compound shown in the formula (I), pharmaceutically acceptable salt solvate crystal form of the compound shown in the formula (I), co-crystal of the compound shown in the formula (I) and the like. The "solvent" in the "solvate" includes one or more of water, methanol, ethanol, isopropanol, diethyl ether, acetone, ethyl acetate, tetrahydrofuran, dichloromethane, N' -dimethylformamide, dimethyl sulfoxide, and the like.
The "solvate crystal form of the compound of formula (I)" and "solvate crystal form of a pharmaceutically acceptable salt of the compound of formula (I)" described in the present invention have any molecular ratio of the compound of formula (I) to the solvent, preferably 10:1 to 1:10, more preferably 3:1 to 1:3, and examples thereof include, but are not limited to, 10:1, 8:1, 7:1, 5:1, 3:1, 2:1, 1.5:1, 1:2, 1:3, 1:5, and the like.
The 'co-crystal of the compound of the formula (I)' described in the invention includes a co-crystal system formed by combining the compound of the formula (I) and one or more of amino acid, carboxylic acid compound, saccharide, mineral, vitamin, pharmaceutical excipient and the like through non-covalent bonds.
The pharmaceutically acceptable salts of the compounds of formula (I) described in the present invention include alkali metal salts, such as sodium salt, potassium salt, lithium salt, etc.; alkaline earth metal salts such as calcium salts, magnesium salts, and the like; other metal salts such as aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts, etc.; inorganic base salts such as ammonium salts; organic base salts such as t-octylamine salt, dibenzylamine salt, morpholine salt, glucosamine salt, phenylglycine alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N' -dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, piperazine salt, tetramethylamine salt, tris (hydroxymethyl) aminomethane salt, and the like; inorganic acid salts such as hydrohalic acid salts, e.g., hydrofluoride salts, hydrochloride salts, dihydrochloride salts, hydrobromide salts, hydroiodide salts, etc., nitrate salts, perchlorate salts, sulfate salts, phosphate salts, etc.; organic acid salts, for example, lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate and the like, arylsulfonate such as benzenesulfonate, p-toluenesulfonate and the like, carboxylates such as acetate, malate, fumarate, succinate, citrate, tartrate, oxalate, maleate, benzoate and the like, amino acid salts such as glycinate, trimethylglycinate, arginate, ornithine, glutamate, aspartate and the like.
In the "pharmaceutically acceptable salt of the compound of formula (I)" and "solvate crystal form of the pharmaceutically acceptable salt of the compound of formula (I)" of the present invention, the molecular ratio of the compound of formula (I) to the corresponding alkali metal, other metal, organic base, inorganic acid, organic acid may be any value, preferably 10:1 to 1:10, more preferably 3:1 to 1:3, and examples thereof include, but are not limited to, 10:1, 8:1, 7:1, 5:1, 3:1, 2:1, 1.5:1, 1:2, 1:3, 1:5, and the like.
The "pharmaceutical preparation" of the present invention is any pharmaceutically acceptable dosage form, and is administered to a patient in need thereof by oral, parenteral, rectal or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.
The present invention also provides a method of treating a patient having a tumor bearing an exon 20 insertion mutation of EGFR comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I), which may be administered by any conventional and acceptable means known in the art, the therapeutically effective amount being adjusted according to the race, sex, age, body weight, medical condition, type of disease, severity of disease, route of administration and associated health condition of the patient and other factors known to those skilled in the art.
The invention also provides a combination of a compound of formula (I) and one or more other anti-neoplastic agents which may be administered simultaneously or sequentially with the compound of formula (I) for the treatment of patients having tumours which carry an exon 20 insertion mutation in EGFR.
The composition may further comprise any pharmaceutically acceptable carrier, wherein the carrier includes but is not limited to: fillers, diluents, binders, wetting agents, disintegrants, lubricants, surfactants, preservatives, colorants, flavors, fragrances, effervescent agents, emulsifiers, flocculants, deflocculants, bacteriostats, and solubilizers.
The "other antitumor drug" according to the present invention is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, metal platins, topoisomerase inhibitors, and immunosuppressive drugs.
The tumor, cancer or carcinoma of the present invention also includes metastases in the primary organ, tissue and/or any other location, regardless of the location of the tumor metastasis.
4. Detailed description of the preferred embodiments
The above-mentioned contents of the present invention will be described in further detail with reference to experimental examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following experimental examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
The following abbreviations represent the following definitions:
DMSO, DMSO: dimethyl sulfoxide
1000 × wherein "x": multiple times
Experimental example 1in vitro enzymatic Activity experiment
And (3) testing the sample: form I of compound 18-2, self-made, the chemical name, XRPD pattern and method of preparation refer to the preparation examples of international patent application WO2017107985a 1.
The experimental method comprises the following steps:
compounds were screened on the kinases EGFR D770_ N771insNPG, EGFR a763_ Y764insFHEA using the method of Mobility Shift Assay with Km ATP.
Test concentrations of compounds: the highest concentration is 1Um, the gradient is 3 times diluted, and the total concentration is 10.
The experimental results are as follows:
TABLE 1 IC of the Compounds of the invention on selected enzymes50(nM) value
Figure BDA0002018970070000201
And (4) experimental conclusion:
the results show that the compound 18 has good inhibitory effect on EGFR D770_ N771insNPG and EGFR A763_ Y764 insFHAA, and has potential research value for treating 20-bit insertion mutation on EGFR gene.
Experimental example 2 in vitro cytological inhibitory Activity experiment
Materials and methods
And (3) testing the sample: form I of compound 18-2, self-made, the chemical name, XRPD pattern and method of preparation refer to the preparation examples of international patent application WO2017107985a 1.
Control drug: AZD9291, purchased or prepared according to prior art methods, has the structural formula shown below.
Figure BDA0002018970070000202
Fetal calf serum purchased from GBICO, cat # 10099-141;
Figure BDA0002018970070000203
luminescent Cell Viability Assay (CTG kit) was purchased from Promega under cat number G7572.
Method of producing a composite material
The CTG kit is used for detecting the influence of the compound 18-2 crystal form I on cell proliferation of Ba/F3EGFR-D770-N771insSVD and Ba/F3EGFR-H773-V774insNPH cells.
Compound preparation
339. mu.l DMSO was added to an EP tube containing 2.11mg of Compound 18-2 form I, and mixed well (10mM) with shaking;
1000 × compound stock solution preparation:
compounds were diluted three-fold from 10mM down to 1000. mu.M, 333.33. mu.M, 111.11. mu.M, 37.04. mu.M, 12.35. mu.M, 4.12. mu.M, 1.37. mu.M, 0.46. mu.M, 0.15. mu.M with DMSO.
10 XCompound 2. mu.l of 1000 Xtest compound were added to 198. mu.l of medium, and mixed by shaking.
Addition of the Compounds
The prepared 10X compound was added to the cells (10. mu.l) according to the compound profile using a lining gun to a final concentration of 1000nM,333.33nM,111.11nM,37.04nM,12.35nM,4.12nM,1.37nM,0.46nM,0.15 nM.
Cell culture method
Figure BDA0002018970070000211
Cell plating
1) Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was checked by trypan blue exclusion to ensure cell viability above 90%.
2) Adjusting the cell concentration; each 90 μ L of cell suspension was added to a 96-well plate and the culture medium control wells were supplemented with 90 μ L of medium.
3) Cells in 96-well plates were incubated at 37 ℃ with 5% CO2And cultured overnight under 95% humidity conditions.
Drug treatment
1) In 96-well plates seeded with cells, 10. mu.L of 10 Xcompound solution was added per well, 10. mu.L of medium was added to each of the media control and cell control wells, three replicates per drug concentration were set, and the final DMSO concentration was 0.1%.
2) The cells in the dosed 96-well plate were placed at 37 ℃ in 5% CO2And further cultured under 95% humidity conditions for 72 hours, after which CTG analysis was performed.
Data processing
Data were analyzed using GraphPad Prism 5.0 software, fitted to the data using non-linear sigmoidal regression to derive a dose-effect curve, and IC was calculated therefrom50The value is obtained.
The cell survival rate (%) × (Lum test drug-Lum culture solution control)/(Lum cell control-Lum culture solution control) × 100%.
Results of the experiment
TABLE 2 inhibitory Effect of the Compounds of the present invention on cells
Figure BDA0002018970070000212
Figure BDA0002018970070000221
Conclusion of the experiment
The compound KBP-5209 has good inhibitory effect on cells containing EGFR20 insertion mutation.

Claims (16)

1. Use of a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystal form thereof in the preparation of a medicament for treating a patient with a tumor carrying an EGFR exon 20 insertion mutation,
Figure FDA0002018970060000011
wherein the content of the first and second substances,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted of the following groups: 6-to 10-membered fused ring C0-6Alkyl, 7-10 membered spirocyclic C0-6Alkyl or 7-to 10-membered bridged ring C0-6Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be the same or different by 1 to 3 atoms selected from O, S (O)m、N(H)m、NCH3And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,
Q1selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonamide group and C3-8A cycloalkyl group;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted C1-6Alkyl or C1-6Alkoxy radicals, substituted radicals Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonamido radical, C3-8Cycloalkyl, unsaturated C5-7Cycloalkyl and a saturated or unsaturated 3-to 8-membered heterocyclic group, wherein said C3-8Cycloalkyl, unsaturated C5-7The cycloalkyl group and the saturated or unsaturated 3-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-6Alkyl radical, C1-6Alkoxy radical, C1-6Alkylamino radical, di (C)1-6Alkyl) amino, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl radical, C1-6Alkylsulfonamido and halogen substituted C1-6An alkoxy group;
R3selected from hydrogen, halogen, hydroxy, cyano, nitro, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl or C1-6Alkoxy radical, C1-6Alkyl carbonyloxy, C1-6Alkylamido radical, C1-6Alkylsulfonyl radical, C1-6Alkylsulfinyl or C1-6An alkylsulfonamide group;
R4、R5and R6Each independently selected from hydrogen, halogen, C1-6Alkyl radical, C1-6Alkoxy, halogen substituted C1-6Alkyl or C1-6Alkoxy radical, C1-6Alkylamino or di (C)1-6Alkyl) amino;
l is selected from the group consisting of a covalent bond, O, S (O)m，N(H)m，NCH3Or C (O);
n is selected from 1,2 or 3; and
m is independently selected from 0, 1 or 2.
2. The use according to claim 1, wherein,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted of the following groups: 6-10 membered saturated fused ring C0-4Alkyl, 7-10 membered saturated spirocyclic ring C0-4Alkyl or 7-10 membered saturated bridged ring C0-4Alkyl, wherein 1 to 3 carbon atoms in the fused, spiro or bridged ring may be the same or different by 1 to 3 atoms selected from O, S (O)m、N(H)m、NCH3And C (O) but wherein O and C (O) are not adjacent to each other in the ring after the substitution,
Q1selected from the group consisting of: halogen, hydroxy, amino, carboxy, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonamide group and C3-6A cycloalkyl group;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted C1-4Alkyl or C1-4Alkoxy radicals, substituted radicals Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of: halogen, hydroxy, amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonamido radical, C3-6Cycloalkyl, unsaturated C5-7Cycloalkyl and a saturated or unsaturated 5-to 8-membered heterocyclic group, wherein said C3-6Cycloalkyl, unsaturated C5-7The cycloalkyl group and the saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, cyano, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4An alkyl-carbonyloxy group, or a salt thereof,C1-4alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl radical, C1-4Alkylsulfonamido and halogen substituted C1-4An alkoxy group;
R3selected from halogen, cyano, nitro, C1-4Alkyl radical, C1-4Alkoxy, halogen substituted C1-4Alkyl or C1-4Alkoxy radical, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfinyl or C1-4An alkylsulfonamide group;
R4、R5and R6Each independently selected from hydrogen, halogen, C1-4Alkyl radical, C1-4Alkoxy, halogen substituted C1-4Alkyl or C1-4Alkoxy radical, C1-4Alkylamino or di (C)1-4Alkyl) amino;
l is selected from the group consisting of a covalent bond, O, S (O)mOr N (H)m；
n is selected from 1,2 or 3; and
m is independently selected from 0, 1 or 2.
3. The use according to any one of claims 1 to 2, wherein,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted of the following groups:
Figure FDA0002018970060000021
Figure FDA0002018970060000031
Figure FDA0002018970060000032
wherein 1 to 3 carbon atoms in the ring may be the same or different by 1 to 3 atoms selected from O, S (O)m、N(H)m、NCH3And C (O), but O and C (O) are not adjacent to each other in the ring after the replacement, p is selected from 0, 1 or 2,
Q1is selected from the following oneGroup (b): halogen, hydroxy, amino, carboxyl, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino and C3-6A cycloalkyl group;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted C1-4Alkyl radicals, substituted radicals Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfonamido radical, C3-5Cycloalkyl and saturated or unsaturated 5-8 membered heterocyclyl, wherein said C3-5The cycloalkyl group, saturated or unsaturated 5-8 membered heterocyclic group may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, C1-4Alkyl carbonyloxy, C1-4Alkylamido radical, C1-4Alkylsulfonyl radical, C1-4Alkylsulfonamido and halogen substituted C1-4An alkoxy group;
R3selected from fluorine, chlorine, bromine, C1-4Alkyl or C1-4An alkoxy group;
R4、R5and R6Each independently selected from hydrogen, fluorine or chlorine;
l is selected from the group consisting of a covalent bond, O, S (O)mOr N (H)m；
n is selected from 1,2 or 3; and
m is selected from 0, 1 or 2.
4. The use according to any one of claims 1 to 3, wherein,
R1selected from unsubstituted or substituted by 1 to 2 substituents Q1Substituted the following groupsAnd (3) clustering:
Figure FDA0002018970060000041
Figure FDA0002018970060000042
p is selected from the group consisting of 0, 1 or 2,
Q1selected from the group consisting of: halogen, amino, C1-4Alkyl radical, C1-4Alkylamino and di (C)1-4Alkyl) amino;
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2Substituted methyl or ethyl radicals, by substituents Q2Substituted formyl or N (H)m，
Q2Selected from the group consisting of:
(1) halogen, hydroxy, amino, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, acetoxy, acetamido, methylsulfonyl and methylsulfonylamino,
(2) cyclopropyl, cyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, thienyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, pyridinyl, pyrazinyl and pyrimidinyl, said Q2The radicals may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino, halogen-substituted C1-4Alkoxy, acetoxy, acetamido, methylsulfonyl, and methylsulfonylamino;
R3selected from fluorine or chlorine;
R4、R5and R6Is hydrogen;
l is selected from a covalent bond or O;
n is 2; and
m is independently selected from 0, 1 or 2.
5. The use according to any one of claims 1 to 4,
R1selected from:
Figure FDA0002018970060000051
Figure FDA0002018970060000052
R2selected from hydrogen, unsubstituted or substituted by 1 to 2 substituents Q2A substituted methyl group or an ethyl group,
Q2selected from the group consisting of:
(1) methoxy and di (C)1-4Alkyl) amino groups, in the presence of a nitrogen atom,
(2) piperidinyl, piperazinyl, morpholinyl, pyrrolidinyl, furanyl, cyclopropylalkyl, cyclopentylalkyl, pyrrolyl, pyridinyl, pyrimidinyl and thiazolyl, said Q2The radicals may be further substituted by 1 to 2 substituents Q3The substitution is carried out by the following steps,
Q3selected from the group consisting of: halogen, hydroxy, amino, C1-4Alkyl radical, C1-4Alkoxy radical, C1-4Alkylamino radical, di (C)1-4Alkyl) amino and halogen substituted C1-4An alkoxy group;
R3selected from fluorine or chlorine;
R4、R5and R6Is hydrogen;
l is selected from a covalent bond or O; and
n is 2.
6. The use according to any one of claims 1 to 5, wherein,
R1selected from:
Figure FDA0002018970060000061
Figure FDA0002018970060000062
R2selected from hydrogenUnsubstituted or substituted by 1 to 2 substituents Q2A substituted methyl group or an ethyl group,
Q2selected from the group consisting of: methoxy, dimethylamino, diethylamino, piperidinyl, piperazinyl and morpholinyl;
R3selected from fluorine or chlorine;
R4、R5and R6Is hydrogen;
l is selected from a covalent bond or O; and
n is 2.
7. The use according to claim 1, wherein the compound of formula (I) is selected from:
(E) -N- [7- (8-oxabicyclo [3.2.1] octan-3-yloxy) -4- (3-chloro-4-fluoroanilino) quinazolin-6-yl ] -4- (piperidin-1-yl) -2-butenamide,
(E) -N- [7- (7-oxabicyclo [2.2.1] heptan-2-yloxy) -4- (3-chloro-4-fluoroanilino) quinazolin-6-yl ] -4- (piperidin-1-yl) -2-butenamide,
(E) -N- [4- (3-chloro-4-fluoroanilino) -7- (2-methyl-2, 7-diazaspiro [4.5] decan-7-yl) quinazolin-6-yl ] -4- (piperidin-1-yl) -2-butenamide,
n- [4- (3-chloro-4-fluoroanilino) -7- (8-methyl-8-azabicyclo [3.2.1] octan-3-yloxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- (8-methyl-1-oxa-8-azaspiro [4.5] decan-3-yloxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- ((8-methyl-1-oxa-8-azaspiro [4,5] decan-3-yl) methoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- (8-methyl-1-oxa-8-azaspiro [4,5] decan-2-ylmethoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- (2- ((1R,5S,6S) -3-methyl-3-azabicyclo [3.1.0] hex-6-ylethoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- ((2-methyloctahydrocyclopenta [ c ] pyrrol-4-yl) methoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azabicyclo [2.2.1] heptan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- (2- (3-methyl-3-azabicyclo [3.2.1] octan-8-yl) ethoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- ((5-methyl-5-azaspiro [2.4] heptan-1-yl) methoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- ((6-methyl-6-azaspiro [2.5] octan-1-yl) methoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- (2- (6-methyl-6-azaspiro [2.5] octan-1-yl) ethoxy) quinazolin-6-yl ] -acrylamide,
(E) -N- [4- (3-chloro-4-fluoroanilino) -7- (2- ((1R,5S,6S) -3-methyl-3-azabicyclo [3.1.0] hex-6-yl) ethoxy) quinazolin-6-yl ] -2-butenamide,
(E) -N- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -2-butenamide,
(E) -N- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -2-pentenamide,
n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide,
n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide dihydrochloride,
n- [4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl ] -acrylamide dihydrochloride monohydrate,
n- [4- (3-chloro-4-fluoroanilino) -7- (2- (7-methyl-7-azaspiro [3.5] nonan-2-yl) ethoxy) quinazolin-6-yl ] -acrylamide,
(E) -N- (4- (3-chloro-4-fluoroanilino) -7- ((7-methyl-7-azaspiro [3.5] nonan-2-yl) methoxy) quinazolin-6-yl) -4-dimethylamino-2-butenamide,
(E) -N- [4- (3-chloro-4-fluoroanilino) -7- ((2- (3-methyl-3-aza-bicyclo [3.1.0] -6-hexyl) -ethoxy) quinazolin-6-yl) -4-dimethylamino ] -crotonamide,
(E) -N- [4- (3-chloro-4-fluoroanilino) -7- (((spiro [3.5] octan-2-yl) methoxy) quinazolin-6-yl) -4-dimethylamino ] -crotonamide, and
(E) -N- (7- (bicyclo [3.1.0] hex-6-ylmethoxy) -4- (3-chloro-4-fluoroanilino) quinazolin-6-yl) -4- (dimethylamino) butyl-2-enamide.
8. The use of any one of claims 1-7, wherein the exon 20 insertion mutation of EGFR is selected from the group consisting of A763_ Y764insFQEA, A763_ Y764 insFHAA, A767_ V769dupASV, D770_ N771insNPG, D770_ N771insSVD, D770_ N771insSVQ, H773_ V774insNPH, Y764_ V765insHH, M766_ A767insAI, H773_ V774insH, D770_ N771insGL, D770_ N771insGT, P772_ H773insYNP, and delD770 insGY.
9. The use of any one of claims 1-7, wherein the crystalline form is selected from an isolated crystalline form of the compound of formula (I), a crystalline form of a pharmaceutically acceptable salt of the compound of formula (I), a crystalline form of a solvate of a pharmaceutically acceptable salt of the compound of formula (I), or a co-crystal of the compound of formula (I) with other compound molecules.
10. The use according to claim 9, wherein,
the crystal form of the pharmaceutically acceptable salt of the compound of formula (I) is selected from a hydrochloride crystal form, a phosphate crystal form, a mesylate crystal form, a triflate crystal form, a malate crystal form, a fumarate crystal form, a succinate crystal form, a tartrate crystal form, a benzoate crystal form or a maleate crystal form of the compound of formula (I);
the solvate crystal form of the compound shown in the formula (I) is selected from a hydrate crystal form, a methoxide crystal form, an ethoxide crystal form, an ether crystal form and an acetonide crystal form of the compound shown in the formula (I);
the solvate crystalline form of the pharmaceutically acceptable salt of the compound of formula (I) is selected from the hydrochloride hydrate crystalline form, the hydrochloride methoxide crystalline form, the hydrochloride etherate crystalline form, the benzoate hydrate crystalline form, the benzoate methoxide crystalline form, the benzoate etherate crystalline form, the maleate hydrate crystalline form, the maleate methoxide crystalline form, or the maleate etherate crystalline form of the compound of formula (I);
the co-crystal of the compound of the formula (I) is selected from co-crystals formed by the compound of the formula (I) and one or more of proline, gallic acid, oxalic acid, maleic acid, tartaric acid and saccharin.
11. Use of a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystalline form thereof, optionally together with one or more other anti-tumor drugs, in the manufacture of a medicament for treating a patient with a tumor that carries an exon insertion mutation at EGFR 20.
12. Use according to claim 11, wherein the further antineoplastic agent is selected from the group consisting of antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antineoplastic hormones, alkylating agents, metalloplatins, topoisomerase inhibitors, immunosuppressions.
13. The use according to any one of claims 1 to 12, wherein the tumour is selected from one or more of brain cancer, head and neck cancer, thyroid cancer, oral cancer, oesophageal adenocarcinoma, lung cancer, stomach cancer, liver cancer, bile duct cancer, kidney cancer, pancreatic cancer, peritoneal cancer, colorectal cancer, gallbladder cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, epidermal carcinoma, non-hodgkin lymphoma, glioma, glioblastoma.
14. The use according to claim 13, wherein the tumor is selected from non-small cell lung cancer.
15. Use of a pharmaceutical preparation of a compound shown in formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystal form thereof in preparing a medicament for treating a patient with tumor carrying EGFR20 exon insertion mutation,
Figure FDA0002018970060000091
wherein R is1、R2、R3、R4、R5、R6L and n are as defined in claim 1.
16. Use of a composition of a compound shown as a formula (1), a stereoisomer thereof, a pharmaceutically acceptable salt thereof or a crystal form thereof and one or more other anti-tumor drugs in the preparation of drugs for treating tumor patients carrying EGFR20 exon insertion mutation,
Figure FDA0002018970060000092
wherein R is1、R2、R3、R4、R5、R6L and n are as defined in claim 1.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023185468A1 (en) * 2022-04-01 2023-10-05 浙江同源康医药股份有限公司 Compound used as kinase inhibitor and use thereof

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005075439A1 (en) * 2004-02-03 2005-08-18 Astrazeneca Ab Quinazoline derivatives
CN101304978A (en) * 2005-11-08 2008-11-12 韩美药品株式会社 Quinazoline derivatives as a multiplex inhibitor and method for the preparation thereof
WO2012027960A1 (en) * 2010-08-30 2012-03-08 山东轩竹医药科技有限公司 Quinazoline derivatives substituted by aniline, preparation method and use thereof
CN103987700A (en) * 2012-03-09 2014-08-13 江苏豪森药业股份有限公司 4-quinazoline amine derivative and application thereof
US20160039838A1 (en) * 2013-04-28 2016-02-11 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use thereof
CN106559991A (en) * 2014-06-19 2017-04-05 阿里亚德医药股份有限公司 For the heteroaryl compound of kinase inhibition
WO2017107985A1 (en) * 2015-12-25 2017-06-29 山东轩竹医药科技有限公司 Crystals of quinazoline derivative and preparation method therefor
CN108148071A (en) * 2016-11-25 2018-06-12 广东东阳光药业有限公司 Salt of amido quinazoline derivatives and application thereof

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005075439A1 (en) * 2004-02-03 2005-08-18 Astrazeneca Ab Quinazoline derivatives
CN101304978A (en) * 2005-11-08 2008-11-12 韩美药品株式会社 Quinazoline derivatives as a multiplex inhibitor and method for the preparation thereof
WO2012027960A1 (en) * 2010-08-30 2012-03-08 山东轩竹医药科技有限公司 Quinazoline derivatives substituted by aniline, preparation method and use thereof
CN102382106A (en) * 2010-08-30 2012-03-21 黄振华 Aniline substituted quinazoline derivative
CN103987700A (en) * 2012-03-09 2014-08-13 江苏豪森药业股份有限公司 4-quinazoline amine derivative and application thereof
US20160039838A1 (en) * 2013-04-28 2016-02-11 Sunshine Lake Pharma Co., Ltd. Aminoquinazoline derivatives and their salts and methods of use thereof
CN106559991A (en) * 2014-06-19 2017-04-05 阿里亚德医药股份有限公司 For the heteroaryl compound of kinase inhibition
WO2017107985A1 (en) * 2015-12-25 2017-06-29 山东轩竹医药科技有限公司 Crystals of quinazoline derivative and preparation method therefor
CN108148071A (en) * 2016-11-25 2018-06-12 广东东阳光药业有限公司 Salt of amido quinazoline derivatives and application thereof

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
JAEBONG JANG ET AL.: "Discovery of a Highly Potent and Broadly Effective Epidermal Growth Factor Receptor and HER2 Exon 20 Insertion Mutant Inhibitor", 《ANGEW. CHEM. INT. ED.》 *
吕扬等: "《晶型药物》", 31 October 2009, 人民卫生出版社 *
王天宝等: "《实用胃肠恶性肿瘤诊疗学》", 31 July 2018, 广东科技出版社 *
黄卫: "EGFR酪氨酸激酶抑制剂的设计、合成和生物活性筛选以及多取代吡唑的合成方法研究", 《中国博士学位论文全文数据库医药卫生科技辑》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023185468A1 (en) * 2022-04-01 2023-10-05 浙江同源康医药股份有限公司 Compound used as kinase inhibitor and use thereof

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