CN115260194A - Novel EGFR degradation agent - Google Patents

Novel EGFR degradation agent Download PDF

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CN115260194A
CN115260194A CN202210449444.8A CN202210449444A CN115260194A CN 115260194 A CN115260194 A CN 115260194A CN 202210449444 A CN202210449444 A CN 202210449444A CN 115260194 A CN115260194 A CN 115260194A
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CN115260194B (en
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潘建峰
孙大庆
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Shanghai Qilu Pharmaceutical Research and Development Centre Ltd
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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention provides a novel class of compounds that degrade the EGFR protein, pharmaceutical compositions containing such compounds, useful intermediates for preparing such compounds and methods of treating cell proliferative disorders, such as cancer, using the compounds of the invention.

Description

Novel EGFR degradation agent
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a novel compound capable of degrading EGFR protein, a medicinal composition containing the compound, a useful intermediate for preparing the compound and a method for treating cell proliferative diseases, such as cancer, by using the compound.
Background
EGFR, i.e., epidermal growth factor receptor (epidermal growth factor receptor), is widely distributed on the cell surface of mammalian epithelial cells, fibroblasts, glial cells, and the like. The EGFR signaling pathway plays an important role in physiological processes such as growth, proliferation and differentiation of cells. EGFR mutations are also one of the most common types of mutations in NSCLC patients, and can account for 40% to 50% of the asian population, among others. EGFR has therefore been one of the hottest targets in the field of drug development.
Currently, EGFR inhibitors on the market are classified into the first, second and third generations. The first generation are reversible targeted drugs such as gefitinib, erlotinib. The second generation is irreversible targeted drugs such as afatinib and dacatinib. Although the first and second generation targeted drugs have remarkable curative effect, most patients have drug resistance after 1-2 years of drug use. Of the patients resistant to EGFR inhibitors, 50% of resistance is associated with the T790M mutation. The third generation EGFR targeting drug oxicetinib can overcome tumor drug resistance caused by T790M mutation, and brings better survival benefit to more lung cancer patients. However, the third generation of targeting drugs inevitably generates drug resistance, and the drug resistance is mainly caused by C797S mutation. The C797S mutation is embodied by mutation of a cysteine residue to serine, which disrupts the binding of the EGFR protein to third generation targeted drugs, thereby failing to prevent phosphorylation of the EGFR protein and activation of downstream signaling pathways. At present, no mature treatment means exists for the reaction of the oxitinib resistance, the clinical requirement is urgent, and the invention is based on solving the problem.
Disclosure of Invention
The invention aims to provide a novel compound capable of degrading EGFR protein, a pharmaceutical composition containing the compound, a useful intermediate for preparing the compound and application of the compound in preparing a medicament for treating cancer.
The invention provides a compound shown in a formula (I-A) or a pharmaceutically acceptable salt thereof,
Figure BDA0003618020270000021
wherein, the first and the second end of the pipe are connected with each other,
R1is selected from C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -S (O)2Ra、-C(O)RbSubstituted or unsubstituted 4-6 membered heterocycloalkyl;
Rais selected from C1-6Alkyl, halo C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRaaRab、C3-6Cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein RaaAnd RabEach independently selected from H and C1-4Alkyl, phenyl or 5-6 membered heteroaryl optionally substituted by one or more C1-4Alkyl, halo C1-4Alkyl-, C1-4Alkoxy, halogen substituted;
Rbis selected from C1-6Alkyl, halo C1-6Alkyl-, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRbaRbb、C3-6Cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein RbaAnd RbbEach independently selected from H and C1-4Alkyl, phenyl or 5-6 membered heteroaryl optionally substituted by one or more C1-4Alkyl, halo C1-4Alkyl-, C1-4Alkoxy, halogen substituted;
R2selected from optionally substituted by one or more RcSubstituted C5-10Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl, phenyl-ethynyl-, RcCan be RcaOr Rcb，RcaSelected from halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl-, halo-C1-4Alkoxy-, -C1-6alkyl-OH or C1-4Alkyl-ethynyl-, RcbSelected from optionally substituted by C1-4C substituted by alkyl3-6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R3is selected from H or C1-3Alkyl, n is selected from 0, 1, 2, 3 or 4;
a is selected from substituted or unsubstituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms, which may be O, S or N;
b is selected from optionally substituted by one or more RdSubstituted 5-10 membered heteroaryl or C5-10Aryl radical, RdIs selected from C1-4Alkyl, halogen, C2-6Alkynyl, C1-4Alkoxy, -P (O) RdaRdb、-S(O)2RdcRddPhenyl, phenoxy-, 5-6 membered heteroaryl; wherein R isdThe phenyloxy-, phenyl, 5-6 membered heteroaryl group in (a) may further optionally be substituted by one or more C1-4Alkyl, halogen or C1-4Alkoxy substituted, RdaAnd RdbIs selected from C1-4Alkyl radical, RdcAnd RddIs selected from C1-4An alkyl group;
L1is a bond or is selected from C1-4Alkylene, wherein said C1-4The carbon atoms in the alkylene group may be further optionally substituted by one or more U groups selected from O, S, NH or NRuaWherein R isuaIs selected from C1-4An alkyl group;
L2is a bond or selected from C1-4Alkylene, wherein said C1-4The carbon atoms of the alkylene group may be further optionally substituted by one or more Q groups selected from C ≡ C, O, S, NH, NRqa-NHC (O) -or-C (O) NH-, wherein RqaIs selected from C1-4An alkyl group.
The invention provides a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof,
Figure BDA0003618020270000031
wherein the content of the first and second substances,
R1is selected from C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -S (O)2Ra、-C(O)RbSubstituted or unsubstituted 4-6 membered heterocycloalkyl;
Rais selected from C1-6Alkyl, halo C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRaaRab、C3-6Cycloalkyl, wherein RaaAnd RabEach independently selected from H and C1-4An alkyl group;
Rbis selected from C1-6Alkyl, halo C1-6Alkyl-, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRbaRbb、C3-6Cycloalkyl, wherein RbaAnd RbbEach independently selected from H, C1-4An alkyl group;
R2selected from optionally substituted by one or more RcSubstituted C5-10Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl-, phenyl-ethynyl-, RcCan be RcaOr Rcb，RcaSelected from halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl-, halo-C1-4Alkoxy-, -C1-6alkyl-OH or C1-4Alkyl-ethynyl-, RcbSelected from optionally substituted C1-4C substituted by alkyl3-6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R3is selected from H or C1-3Alkyl, n is selected from0.1, 2, 3 or 4;
a is selected from substituted or unsubstituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S or N;
b is selected from optionally substituted by one or more RdSubstituted 5-10 membered heteroaryl or C5-10Aryl radical, RdIs selected from C1-4Alkyl, halogen, C2-6Alkynyl, C1-4Alkoxy, -P (O) RdaRdb、-S(O)2RdcRddPhenyl, phenyloxy-, 5-6 membered heteroaryl; wherein R isdThe phenyloxy-, phenyl, 5-6 membered heteroaryl group in (A) may further optionally be substituted by one or more C1-4Alkyl, halogen or C1-4Alkoxy substituted, RdaAnd RdbIs selected from C1-4Alkyl radical, RdcAnd RddIs selected from C1-4An alkyl group.
The invention provides a compound shown in a formula (I) or a pharmaceutically acceptable salt thereof,
R1is selected from C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -S (O)2Ra、-C(O)RbSubstituted or unsubstituted 4-6 membered heterocycloalkyl;
Rais selected from C1-6Alkyl, halo C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRaaRab、C3-6Cycloalkyl, wherein RaaAnd RabEach independently selected from H and C1-4An alkyl group;
Rbis selected from C1-6Alkyl, halo C1-6Alkyl-, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRbaRbb、C3-6Cycloalkyl, wherein RbaAnd RbbEach independently selected from H and C1-4An alkyl group;
R2selected from the group consisting of optionally substituted by one or more RcSubstituted C5-10Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl-, phenyl-ethynyl-, RcCan be RcaOr Rcb，RcaSelected from halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl-, halo-C1-4Alkoxy-, -C1-6alkyl-OH or C1-4Alkyl-ethynyl-, RcbSelected from optionally substituted by C1-4C substituted by alkyl3-6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R3is selected from H or C1-3Alkyl, n is selected from 0, 1, 2, 3 or 4;
a is selected from substituted or unsubstituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S or N;
b is selected optionally by one or more RdSubstituted 5-10 membered heteroaryl or C5-10Aryl, RdIs selected from C1-4Alkyl, halogen, C2-6Alkynyl, C1-4Alkoxy, -P (O) RdaRdb、-S(O)2RdcRddPhenyl, phenyloxy-; wherein R isdThe phenyloxy-phenyl group in (a) may further optionally be substituted by one or more C1-4Alkyl, halogen or C1-4Alkoxy substituted, RdaAnd RdbIs selected from C1-4Alkyl radical, RdcAnd RddIs selected from C1-4An alkyl group.
In some embodiments of the present invention, in the compound represented by the above formula (I-A) or a pharmaceutically acceptable salt thereof, L1Is a bond or is selected from-CH2-、-CH2CH2-、-CH2NH-。
In some embodiments of the present invention, in the compound represented by the above formula (I-A) or a pharmaceutically acceptable salt thereof, L2Is a bond or is selected from-CH2-、-CH2CH2-、-NHCH2-、-CH2NH-、-NH-、-NHC(O)-。
In some embodiments of the invention, the compounds of formulae (I-A) and (I) above or a pharmaceutically acceptable salt thereofIn the salt, RaSelected from methyl, ethyl, isopropyl, cyclopropyl, -CHF2、-CH2CH2OH、-CH2CH2OCH3、-CH2CH2N(CH3)2。
In some embodiments of the present invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, RcaSelected from F, br, cl, -CH3、-CHF2、-OCF3、-OCH3、CH3C≡C-、-C(CH3)2OH、-CN；RcbIs selected from
Figure BDA0003618020270000051
Figure BDA0003618020270000052
In some embodiments of the present invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, R1Is selected from-CH3、
Figure BDA0003618020270000053
Figure BDA0003618020270000054
In some embodiments of the invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, R1Is selected from-S (O)2Ra，RaAs defined above.
In some embodiments of the invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, R1Is selected from
Figure BDA0003618020270000055
In some embodiments of the present invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, R2Is selected from
Figure BDA0003618020270000061
Figure BDA0003618020270000062
Figure BDA0003618020270000063
RcaAnd RcbAs defined above, m is selected from 0, 1, 2, 3 or 4.
In some embodiments of the present invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, R2Is selected from
Figure BDA0003618020270000064
Figure BDA0003618020270000065
Figure BDA0003618020270000071
In some embodiments of the present invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, R2Is selected from
Figure BDA0003618020270000072
In some embodiments of the invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, R3Selected from H or methyl.
In some embodiments of the invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, A is selected from
Figure BDA0003618020270000073
Figure BDA0003618020270000074
a represents the end attached to the olefinic bond and B represents the end attached to B.
In some embodiments of the invention, the compounds of formulae (I-A) and (I) above areIn the compound or the pharmaceutically acceptable salt thereof, A is selected from
Figure BDA0003618020270000075
In some embodiments of the present invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, RdIs selected from-CH3、-CH2CH3、-F、-C≡C、-P(O)(CH3)CH3、-S(O)2CH3A phenyl group,
Figure BDA0003618020270000076
In some embodiments of the invention, in the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, B is selected from
Figure BDA0003618020270000077
Figure BDA0003618020270000078
Figure BDA0003618020270000081
RdAs defined above, p is selected from 0, 1, 2, 3 or 4.
In some embodiments of the invention, the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, are characterized in that B is selected from
Figure BDA0003618020270000082
Figure BDA0003618020270000083
In some embodiments of the invention, the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, wherein B is selected from,
Figure BDA0003618020270000084
In some embodiments of the invention, the aboveA compound represented by the formula (I-A) or (I) or a pharmaceutically acceptable salt thereof, wherein B is selected from the group consisting of
Figure BDA0003618020270000085
In some embodiments of the invention, the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, are selected from formula (II),
Figure BDA0003618020270000091
wherein R is1、R2、R3B and n are as defined above.
In some embodiments of the invention, the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, are selected from formulae (III) or (IV),
Figure BDA0003618020270000092
wherein R is1、R3、Rc、RdB, n, m, p are as defined above.
In some embodiments of the invention, the compounds of formulae (I-A) and (I) above, or a pharmaceutically acceptable salt thereof, are selected from formula (V),
Figure BDA0003618020270000093
wherein R is1、R3、Rc、m、n、RdP is as defined above.
The present invention also provides a compound selected from,
Figure BDA0003618020270000101
Figure BDA0003618020270000111
Figure BDA0003618020270000121
Figure BDA0003618020270000131
Figure BDA0003618020270000141
the invention also provides a pharmaceutical composition which contains a therapeutically effective amount of the compound or the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be formulated for specific routes of administration, such as oral, parenteral, rectal, and the like. Oral, e.g., tablets, capsules (including sustained release or timed release formulations), pills, powders, granules, elixirs, tinctures, suspensions (including nanosuspensions, microsuspensions, spray-dried dispersions), syrups, and emulsions; sublingual administration; taking orally; parenterally, e.g., by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as sterile injectable aqueous or nonaqueous solutions or suspensions); nasally, including administration to the nasal mucosa, e.g., by inhalation spray; topically, e.g., in the form of a cream or ointment; or rectally, e.g., in the form of suppositories. They may be administered alone, but will generally be administered with a pharmaceutical carrier selected according to the chosen route of administration and standard pharmaceutical practice.
The dosage regimen for the compounds of the present invention will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent and its mode and route of administration, the species, age, sex, health, medical condition and weight of the recipient, the nature and extent of the symptoms, the type of concurrent therapy, the frequency of therapy, the route of administration, the function of the patient's kidney and liver, and the desired effect. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof will depend on the species, weight, age and individual condition of the subject, the condition or disease being treated or the severity thereof. A physician, clinician or veterinarian of ordinary skill can readily determine the effective amount of each active ingredient to prevent, treat or inhibit the disease state or disease progression.
The present invention also provides a method of modulating EGFR and inducing EGFR degradation, comprising administering to a subject in need thereof an effective amount of the above-described compound or a pharmaceutically acceptable salt thereof.
The invention also provides application of the compound or the pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing a medicament for treating cancer.
The above cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumor (GIST), acute Myelogenous Leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, and melanoma.
The present invention also provides a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition described above. The above cancers include lymphoma, non-Hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumor (GIST), acute Myelogenous Leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.
In some embodiments of the invention, the cancer is lung cancer.
The invention also provides an intermediate compound shown as the formulas (Z-1), (Z-2), (Z-3) and (Z-4), and the intermediate compound or the stereoisomer and pharmaceutically acceptable salt thereof are used for preparing the compound:
Figure BDA0003618020270000161
wherein R is2、R3PG is a commonly used protecting group for an amino group, and PG may be selected from t-butoxycarbonyl, benzyloxycarbonyl and p-toluenesulfonyl.
In some embodiments of the invention, the intermediate compounds of formulae (Z-1), (Z-2), (Z-3), and (Z-4) may be selected from formulae (Z-1 a), (Z-2 a), (Z-3 a), and (Z-4 a),
Figure BDA0003618020270000162
wherein PG and Rc、R3B, m, n are as defined above.
In some embodiments of the present invention, the compound represented by formula (II) is deprotected from the compound represented by formula (Z-3) to obtain a compound represented by formula (Z-4), and R is introduced1The compound shown in the formula (II) is prepared,
Figure BDA0003618020270000171
wherein R is1、PG、R2、R3B, n are as defined above.
In some embodiments of the invention, the compound of formula (Z-3) is prepared by dehydrating a compound of formula (Z-2),
Figure BDA0003618020270000172
wherein the dehydrating agent can be a Burgis reagent, PG, R2、R3B, n are as defined above.
In some embodiments of the invention, the compound represented by formula (Z-2) is obtained by reacting a compound represented by formula (Z-1) with a Z-5 compound under the action of a condensing agent,
Figure BDA0003618020270000173
wherein the condensing agent can be DMTMM (4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride), PG, R2、R3B and n are as defined above.
The present invention also provides a process for preparing the above compound or a pharmaceutically acceptable salt thereof, wherein the representative preparation route is as shown in the following scheme:
Figure BDA0003618020270000181
wherein R is1、PG、R2、R3B, n are as defined above.
The intermediate compound Z-1 with the amino group protected by PG group reacts with the Z-5 compound under the action of a condensing agent to obtain an intermediate compound Z-2. Wherein PG is a commonly used amino protecting group, including but not limited to tert-butyloxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, fluorenyl methoxycarbonyl, p-methoxybenzyl, benzyl, trityl and the like. The condensing agent is a commonly used agent for promoting the reaction of carboxyl and amino to generate amide, and includes but is not limited to 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride (DMTMM), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), and the like.
Cyclization of the Z-2 compound to give the intermediate Z-3 compound is carried out by the action of a dehydrating agent, which is commonly used and includes but is not limited to a Burgey reagent and the like.
The Z-3 compound is generally deprotected under acidic or basic action to give Z-4. Commonly used acids include, but are not limited to, hydrochloric acid, acetic acid, trifluoroacetic acid, hydrobromic acid, and the like.
Introduction of R onto amino group of Z-4 compound1Radical, to give a compound of the formula (II), R1The groups may be introduced by nucleophilic substitution reactions, e.g. using R1X is a halogen as a reactant, including but not limited to introduction of 2-methoxyethyl by using 1-iodo-2 methoxyethane, introduction of methanesulfonyl chloride, introduction of methyl iodide to methyl, and the like. The methyl group can be introduced by using an aqueous solution of formaldehyde and then reducing the aqueous solution by sodium borohydride acetate or the like.
In some embodiments of the present invention, PG is selected from t-butoxycarbonyl; (Z-1) preparation of (Z-2) the condensing agent used is selected from 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride (DMTMM); (Z-2) preparation of (Z-3) the dehydrating agent used is selected from among Burgis' reagents.
In some embodiments of the present invention, compounds of formula (I-A), formula (I), (III), (IV), formula (V), and the like, can be prepared according to the synthetic methods described above.
The technical effects are as follows:
the compound has good inhibition effect on cell proliferation of Ba/F3 Del19/T790M/C797S EGFR triple mutation cell lines and Ba/F3L858R/T790M/C797S EGFR triple mutation cell lines.
Definitions and explanations
As used herein, the following terms and phrases are intended to have the following meanings, unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be considered as indefinite or unclear, but rather construed according to ordinary meaning.
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "pharmaceutically acceptable salts" refers to derivatives of the compounds of the present invention which are prepared with relatively nontoxic acids or bases. These salts may be prepared during synthesis, isolation, purification of the compounds, or by reacting the free form of the purified compound with a suitable acid or base. When the compound contains relatively acidic functional groups, the compound can be reacted with alkali metal, alkaline earth metal hydroxides or organic amines to obtain base addition salts, including cations based on alkali metal and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, amine cations, and the like. When the compound contains a relatively basic functional group, the compound is reacted with an organic acid or an inorganic acid to obtain an acid addition salt.
The compounds of the present invention exist as geometric isomers as well as stereoisomers, such as cis-trans isomers, enantiomers, diastereomers, and racemic and other mixtures thereof, all of which are within the scope of the present invention.
The term "enantiomer" refers to stereoisomers that are mirror images of each other.
The term "diastereomer" refers to a stereoisomer in which the molecules have two or more chiral centers and a non-mirror image relationship between the molecules.
The term "cis-trans isomer" refers to a configuration in which a double bond or a single bond of ring-forming carbon atoms in a molecule does not exist freely rotating.
Unless otherwise indicated, with solid wedge-shaped keys
Figure BDA0003618020270000201
And wedge dotted bond
Figure BDA0003618020270000202
Showing the absolute configuration of a solid centre, by means of straight solid keys
Figure BDA0003618020270000203
And straight dotted line bond
Figure BDA0003618020270000204
Showing the relative configuration of the stereocenters.
Stereoisomers of the compounds of the invention may be prepared by chiral synthesis or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the invention may be prepared by asymmetric catalysis techniques or by chiral auxiliary derivatization techniques. Or a compound with a single spatial configuration is obtained from a mixture by a chiral resolution technology. Or by using chiral starting materials. The separation of optically pure compounds in the present invention is usually accomplished using preparative chromatography, employing chiral chromatographic columns to achieve the separation of chiral compounds.
The term "pharmaceutically acceptable carrier" refers to vehicles generally accepted in the art for delivering biologically active agents to animals, particularly mammals, and includes, depending on the mode of administration and nature of the dosage form, for example, adjuvants, excipients, or vehicles such as diluents, preservatives, fillers, flow control agents, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, fragrances, antimicrobials, antifungals, lubricants, and dispersants. Pharmaceutically acceptable carriers are formulated by one of ordinary skill in the art based on a number of factors within the purview of one skilled in the art. Which include but are not limited to: the type and nature of the active agent formulated, the subject to which the composition containing the agent is to be administered, the intended route of administration of the composition, and the targeted therapeutic indication. Pharmaceutically acceptable carriers include both aqueous and non-aqueous media as well as a variety of solid and semi-solid dosage forms. Such carriers include many different ingredients and additives in addition to the active agent, and such additional ingredients as may be included in the formulation for a variety of reasons (e.g., to stabilize the active agent, binder, etc.) are well known to those of ordinary skill in the art.
The term "excipient" generally refers to a carrier, diluent, and/or vehicle necessary to formulate an effective pharmaceutical composition.
The term "effective prophylactic or therapeutic amount" refers to a sufficient amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, to treat a disorder at a reasonable benefit/risk ratio applicable to any medical treatment and/or prevention. It will be appreciated, however, that the total daily amount of a compound of formula I or a pharmaceutically acceptable salt thereof and a composition of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dose level will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the particular compound employed; the specific composition employed; the age, weight, general health, sex, and diet of the patient; the time of administration, route of administration, and rate of excretion of the particular compound employed; the duration of the treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is known in the art to start doses of the compound at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. In general, the dosage of a compound of formula I or a pharmaceutically acceptable salt thereof of the present invention for use in a mammal, particularly a human, can be from about 0.001 to about 1000mg/kg body weight/day, such as from about 0.01 to about 100mg/kg body weight/day, such as from about 0.01 to about 10mg/kg body weight/day.
The term "optionally substituted" or "optionally" means that it may or may not be substituted, and unless otherwise specified, the nature and number of substituents may be arbitrary on a chemically realizable basis, e.g., the term "optionally substituted with one or more R2Substituted means that they may be substituted by one or more R2Substituted or not substituted by R2And (4) substitution.
When any variable (e.g. R)2) When a compound occurs more than one time in its composition or structure, its definition in each case is independent. For example, if a group is substituted by 0-2R2Substituted, said group may optionally be substituted with up to two R2Substituted, and R in each case2There are separate options.
When the number of one linking group is 0, for example, -O (CH)2)nCH3N =0 denotes that the linking group is a single bond, i.e. -OCH3。
When L in the structural unit A-L-B is defined as a "bond", it means that L is absent and the A group and the B group are directly connected to form the structure of A-B.
When a substituent bond can be cross-linked to two atoms on a ring, such substituent may be attached to the ringAre bonded to each other. For example, a structural unit
Figure BDA0003618020270000211
Represents a substituent R1The substitution may occur at any position on the phenyl ring.
Unless otherwise specified, structural elements appearing herein
Figure BDA0003618020270000212
Represents a substituent RdThe substitution may be performed not only at any position on the pyrazine ring on the right side but also at any position on the benzene ring on the left side.
When the substituents listed are not indicated by which atom they are attached to the compounds included in the general chemical structure formula but not specifically mentioned, such substituents may be bonded through any atom thereof. For example, pyrazole as a substituent means that any one of carbon atoms on the pyrazole ring is bonded to a substituted group; when present in the structure
Figure BDA0003618020270000221
Or
Figure BDA0003618020270000224
When it is indicated that the atom is a bonding atom, e.g.
Figure BDA0003618020270000222
And
Figure BDA0003618020270000223
all represent the N atom on the morpholine ring as the bonding atom.
Unless otherwise specified, "ring" refers to saturated, partially saturated or unsaturated monocyclic and polycyclic rings, and "polycyclic" includes spiro, fused or bridged rings. Representative "rings" include substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl, or heteroaryl. The term "hetero" denotes a substituted or unsubstituted heteroatom as well as oxidized forms of a heteroatomThe hetero atoms are typically selected from N, O, S, and the oxidized forms typically include NO, SO, S (O)2The nitrogen atom may be substituted, i.e. NR (R is H or other substituent as defined herein); the number of atoms in a ring is generally defined as the number of ring members, e.g., "3-6 membered heterocycloalkyl" refers to a ring of 3-6 atoms arranged around, each ring optionally containing 1-3 heteroatoms, i.e., N, O, S, NO, SO, S (O)2Or NR, each ring optionally substituted with an R group, R being a group as defined herein.
Unless otherwise specified, the term "aryl" refers to an unsaturated hydrocarbon group having aromatic character, which may be a single ring or multiple rings fused together. Preferably C5-10Aryl, more preferably C5-8Aryl, most preferably monocyclic C5-6An aryl group; examples of aryl groups include, but are not limited to, phenyl, naphthyl.
Unless otherwise specified, the term "heteroaryl" means a stable monocyclic or polycyclic aromatic hydrocarbon containing at least one heteroatom (N, O, S, NO, SO, S (O)2Or NR). Preferably 5-or 6-membered monocyclic heteroaryl. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl.
Unless otherwise specified, the term "alkyl" is used to denote a straight or branched chain saturated hydrocarbon group. Preferably C1-6More preferably C1-3Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, neopentyl, n-hexyl, and the like.
Unless otherwise specified, the term "heteroalkyl" refers to an alkyl group in which one or more carbon atoms are replaced with a heteroatom selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, the nitrogen heteroatom is optionally quaternized, including but not limited to "alkoxy", "alkylamino", and "alkylthio", and the like; examples of "heteroalkyl" include, but are not limited to, -OCH3、-OCH2CH3、-OCH2CH2CH3、-OCH(CH3)2、-N(CH3)2、-CH2-CH2-O-CH3、-CH2-CH2-NH-CH3、-CH2-CH2-N(CH3)-CH3、-CH2-S-CH2-CH3、-CH2-CH2、-S(O)-CH3、-S(O)2-CH3、-CH2-CH2-S(O)2-CH3And the like.
Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Preferably C2-8Examples of alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.
Unless otherwise specified, "alkynyl" refers to an alkyl group having one or more carbon-carbon triple bonds. Preferably C2-8Alkynyl, examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
Unless otherwise specified, the term "halogen" denotes a fluorine, chlorine, bromine or iodine atom.
Unless otherwise specified, the term "haloalkyl" refers to an alkyl group having one or more hydrogen atoms replaced with a halogen atom. Preferably halogenated C1-6Alkyl, more preferably halogenated C1-3Examples of alkyl, haloalkyl include, but are not limited to, monofluoromethyl, difluoromethyl, trifluoromethyl, trichloromethyl, tribromomethyl, 2-trifluoroethyl, 2-trichloroethyl, and the like.
Unless otherwise specified, the term "alkoxy" refers to an alkyl group attached through an oxygen bridge, i.e., a group resulting from substitution of a hydrogen atom in a hydroxyl group by an alkyl group. Preferably C1-6Alkoxy, more preferably C1-3An alkoxy group. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexoxy.
Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group. The cycloalkyl group is preferably a 3-to 8-membered monocyclic alkyl group, more preferably a 3-to 6-membered monocyclic alkyl group, and examples of these monocyclic alkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
Unless otherwise specified, "heterocycloalkyl" refers to mono-and poly-heterocycloalkyl rings containing a number of heteroatoms in the ring, typically selected from N, O, S, NO, SO, S (O)2And NR. The heterocycloalkyl group is preferably a 3-to 8-membered monocyclic heterocycloalkyl group, more preferably a 3-to 6-membered monocyclic heterocycloalkyl group, and examples of these monocyclic heterocycloalkyl groups include, but are not limited to, oxirane groups, tetrahydropyrrolyl groups, piperidyl groups, piperazinyl groups, morpholinyl groups, tetrahydrofuryl groups, tetrahydrothienyl groups, tetrahydropyranyl groups, 1, 3-dioxolane groups, 1, 4-dioxane groups, and the like.
Unless otherwise specified, "heterocycloalkenyl" refers to cyclic mono-olefins containing heteroatoms, including 3-10 membered heterocycloalkenyl, preferably 3-6 membered heterocycloalkenyl, and most preferably 5-6 membered heterocycloalkenyl, examples of heterocycloalkenyl include, but are not limited to
Figure BDA0003618020270000231
And the like.
It is specifically stated that all combinations of substituents and/or variants thereof herein are permissible only if such combinations result in stable compounds.
Unless otherwise specified, the concentration unit M in this context represents mol/L, for example, a 1M NaOH solution is a 1mol/L NaOH solution.
In the examples of the invention, the title compound was named after the structural transformation of the compound by means of Chemdraw. If the name of the compound is inconsistent with the structure of the compound, the name of the compound can be determined by integrating related information and assisting a reaction route; otherwise, the given structural formula of the compound is subject to no confirmation.
The preparation methods of some compounds in the invention refer to the preparation methods of the similar compounds. It will be understood by those skilled in the art that the ratio of the reactants, the reaction solvent, the reaction temperature, etc. may be appropriately adjusted depending on the reactants when the preparation method cited herein is used or referred to.
The compounds of the present invention may be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combinations thereof with other chemical synthetic methods, and equivalents thereof known to those skilled in the art, with preferred embodiments including, but not limited to, examples of the present invention.
Abbreviations and their corresponding chemical names used in the examples of the present invention are as follows:
abbreviations Description of the preferred embodiment
DMTMM 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride
Bergis reagent N- (Triethylammonium sulfonyl) carbamic acid methyl ester
Detailed Description
The structure of the compounds of the invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid mass chromatography (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR was measured using a Bruker Neo 400M or Bruker Ascend 400 NMR instrument using deuterated dimethyl sulfoxide (DMSO-d 6), deuterated methanol (CD)3OD) and/or deuterated chloroform (CDCl 3) with internal standard Tetramethylsilane (TMS).
LC-MS measurement was performed by Agilent 1260-6125B single square spectrometer or Waters H-Class SQD2 spectrometer (electrospray ionization as ion source). HPLC measurements were performed using Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
Preparative high performance liquid chromatography was performed using Waters 2555-2489 (10 μm, ODS 250 cm. Times.5 cm) or GILSON Trilution LC, a Welch XB-C18 column (5 um, 21.2X 150mm).
The thin-layer chromatography silica gel plate is a GF254 silica gel plate of Yangtze friend silica gel development company Limited or a GF254 silica gel plate of New Material company Limited on the city of the breast mountain, the specification adopted by TLC is 0.15-0.20 mm, the preparation type is 20x20cm, and column chromatography is generally used for forming 200-300 mesh silica gel in chemical engineering as a carrier.
The starting materials in the examples of the present invention are known and commercially available, or can be synthesized according to methods known in the art with reference to the prior art.
All reactions of the present invention are carried out under continuous magnetic stirring in a dry nitrogen or argon atmosphere without specific indication, the solvent is a dry solvent, and the reaction temperature is given in degrees centigrade.
Example 1:
(E) -2- (2- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (Compound 1)
Figure BDA0003618020270000251
The reaction process comprises the following steps:
Figure BDA0003618020270000252
the reaction steps are as follows:
step 1: the compound (E) -3- (3- (4-bromophenyl) -8- (tert-butoxycarbonyl) -1,4, 8-triazaspiro-cyclo [4.5] decan-1, 3-dien-2-yl) acrylic acid (800mg, 1.7 mmol) and quinoline-3-carboxylic acid hydrazide (390mg, 2.1 mmol) were dissolved in tetrahydrofuran (30 mL) and methanol (10 mL), DMTMM (577 mg,2.1 mmol) was added, and stirring was carried out at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (40 mL) was added and extracted with ethyl acetate (30 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/2) to give 320mg of (E) -2- (4-bromophenyl) -3- (3-oxo-3- (2- (quinoline-3-carbonyl) hydrazino) propyl-1-en-1-yl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylic acid tert-butyl ester.
MS(ESI)M/Z:631.1[M+H]+.
And 2, step: to the microwave tube was added (E) -tert-butyl 2- (4-bromophenyl) -3- (3-oxo-3- (2- (quinoline-3-carbonyl) hydrazino) propyl-1-en-1-yl) -1,4, 8-triazaspiro [4.5] dec-1, 3-diene-8-carboxylate (25mg, 0.04mmol) and tetrahydrofuran (3 mL), followed by Burgis' reagent (30mg, 0.12mmol). The microwave tube is sealed and heated to 100 ℃ for reaction for 5 hours. 8 reactions were run in parallel. Cool to room temperature and combine 8 reactions and concentrate under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 1/1) to give 100mg of (E) -tert-butyl 2- (4-bromophenyl) -3- (2- (5- (quinolin-3-yl) -1,3, 4-oxadiazol-2-yl) vinyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate.
MS(ESI)M/Z:613.2[M+H]+.
1H NMR(400MHz,CDCl3):δ9.60(s,1H),8.97(s,1H),8.33(d,J＝8.4Hz,1H),8.04(d,J＝8.4Hz,1H),7.93(t,J＝7.6Hz,1H),7.79-7.66(m,4H),7.64-7.57(m,3H),3.90-3.80(m,4H),1.91-1.76(m,4H),1.53(s,9H).
And step 3: to a solution of (E) -tert-butyl 2- (4-bromophenyl) -3- (2- (5- (quinolin-3-yl) -1,3, 4-oxadiazol-2-yl) vinyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (100mg, 0.16mmol) in dichloromethane (5 mL) was added trifluoroacetic acid (1 mL) and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate (20 mL) was added and the mixture was extracted with dichloromethane (20 mL. Times.3). The organic phases were combined, washed with saturated brine (30 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give 100mg of crude (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole.
MS(ESI)M/Z:513.2[M+H]+.
And 4, step 4: (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (100 mg, crude), 36% aqueous formaldehyde (41mg, 0.49mmol) and acetic acid (20mg, 0.33mmol) were dissolved in tetrahydrofuran (5 mL), and sodium borohydride acetate (104mg, 0.49mmol) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (20 mL) was added and extracted with ethyl acetate (20 mL. Times.3). The combined organic phases were dried over anhydrous sodium sulfate, filtered and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to give 37.7mg of the final product (E) -2- (2- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole.
MS(ESI)M/Z:526.6[M+H]+.
1H NMR(400MHz,DMSO-d6):δ9.55(d,J＝2.2Hz,1H),9.18(d,J＝2.2Hz,1H),8.25(d,J＝8.4Hz,1H),8.19-8.12(m,1H),7.97-7.93(m,1H),7.83-7.73(m,6H),7.45(d,J＝16.0Hz,1H),3.02(br s,4H),2.62(s,3H),1.83(br s,4H).
Example 2:
(E) -2- (2- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) ethenyl) -5- (5-ethynylpyridin-3-yl) -1,3, 4-oxadiazole (Compound 2)
Figure BDA0003618020270000271
The reaction process comprises the following steps:
Figure BDA0003618020270000281
the reaction steps are as follows:
step 1: methyl 5-bromonicotinate (1.5g, 7.0 mmol), trimethylsilylacetylene (2.0 g,20.4 mmol), cuprous iodide (66mg, 0.35mmol), and bis (triphenylphosphine) palladium dichloride (243mg, 0.35mmol) were added to triethylamine (20 mL), replaced with nitrogen 3 times, and the temperature was raised to 80 ℃ for 1 hour. The reaction mixture was cooled to room temperature, and poured into water (100 mL). The mixture was extracted with ethyl acetate (50 mL × 3 times), and the organic phases were combined, washed with saturated brine (50 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was used directly in the next step.
MS(ESI)M/Z:234.7[M+H]+.
Step 2: the crude product from the previous step was dissolved in methanol (20 mL), potassium carbonate (2.4g, 17.4mmol) was added, and the mixture was stirred at room temperature for 1 hour. TLC detection raw materials are mostly reacted completely, and reaction liquid is concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether/ethyl acetate = 5/1) to give 620mg of 5-ethynyl nicotinic acid methyl ester.
MS(ESI)M/Z:162.1[M+H]+.
1H NMR(400MHz,CDCl3):δ9.17(s,1H),8.87(s,1H),8.38(t,J＝2.0Hz,1H),3.97(s,3H),3.29(s,1H).
And 3, step 3: methyl 5-ethynylnicotinate (620mg, 3.9mmol) was dissolved in methanol (15 mL), and hydrazine hydrate (962mg, 19.2mmol) was added thereto, followed by heating and refluxing overnight. TLC detection starting material reaction was complete, and the reaction mixture was concentrated to dryness under reduced pressure to give 5-ethynylnicotinic acid hydrazide (600 mg, yield 97%).
MS(ESI)M/Z:162.0[M+H]+.
Starting from 5-ethynylnicotinic acid hydrazide, 3.7 mg of the final product (E) -2- (2- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) ethenyl) -5- (5-ethynylpyridin-3-yl) -1,3, 4-oxadiazole were prepared according to the synthetic procedure of example 1.
MS(ESI)M/Z:501.1[M+H]+.
1H NMR(400MHz,CDCl3):δ9.25(s,1H),8.88(s,1H),8.45(d,J＝2.0Hz,1H),7.70-7.58(m,6H),3.36(d,J＝1.2Hz,1H),2.96(br s,4H),2.55(s,3H),2.20-1.83(m,4H).
Example 3:
(E) -2- (2- (3- (4-bromophenyl) -8- (2-methoxyethyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (Compound 3)
Figure BDA0003618020270000291
The reaction process comprises the following steps:
Figure BDA0003618020270000292
the reaction steps are as follows:
step 1: (E) -tert-butyl 2- (4-bromophenyl) -3- (2- (5- (quinolin-3-yl) -1,3, 4-oxadiazol-2-yl) vinyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (90mg, 0.15mmol) was dissolved in ethyl acetate (5 mL), and a 6M hydrochloric acid gas/ethyl acetate solution (0.15mL, 0.90mmol) was added and stirred at room temperature for 1 hour. TLC detection showed disappearance of the starting material and concentration of the reaction solution under reduced pressure gave 87.2mg of (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole dihydrochloride.
MS(ESI)M/Z:513.2[M+H]+.
Step 2: (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole dihydrochloride (87.2 mg, crude) was dissolved in N, N-dimethylformamide (5 mL), and 1-iodo-2-methoxyethane (27.3mg, 0.15mmol) and potassium carbonate (82.8mg, 0.60mmol) were added in that order. Stir at room temperature overnight. TLC showed disappearance of starting material and quenched by addition of water (20 mL). The mixture was extracted with ethyl acetate (30 mL. Times.2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by HPLC to give 17.2mg of (E) -2- (2- (3- (4-bromophenyl) -8- (2-methoxyethyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole.
MS(ESI)M/Z:570.9[M+H]+.
1H NMR(400MHz,CDCl3):δ9.57(s,1H),8.87(s,1H),8.21(d,J＝8.4Hz,1H),7.99(d,J＝8.0Hz,1H),7.90-7.56(m,8H),3.66(br s,2H),3.41(s,3H),3.02-2.78(m,6H),2.16-1.67(m,4H).
Example 4:
(E) -2- (2- (3- (4-bromophenyl) -8- (methylsulfonyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (Compound 4)
Figure BDA0003618020270000301
The reaction process comprises the following steps:
Figure BDA0003618020270000311
the reaction steps are as follows:
(E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole dihydrochloride (76mg, 0.13 mmol) was dissolved in dichloromethane (5 mL), followed by the addition of methanesulfonyl chloride (15.8mg, 0.14 mmol) and triethylamine (42mg, 0.42mmol). Stir at room temperature overnight. TLC showed disappearance of starting material and quenched by addition of water (20 mL). The mixture was extracted with dichloromethane (20 mL × 2 times), the organic phases were combined, washed with saturated brine (30 mL), then dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by HPLC to give 13.9mg of (E) -2- (2- (3- (4-bromophenyl) -8- (methylsulfonyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole.
MS(ESI)M/Z:590.9[M+H]+.
1H NMR(400MHz,CDCl3):δ9.58(s,1H),8.90(s,1H),8.22(d,J＝8.4Hz,1H),7.99(d,J＝8.4Hz,1H),7.71(t,J＝8.0Hz,1H),7.73-7.26(m,7H),3.73-3.69(m,4H),2.94(s,3H),2.06-2.00(m,4H).
The following target product was prepared according to the synthesis method of example 4:
Figure BDA0003618020270000312
Figure BDA0003618020270000321
Figure BDA0003618020270000331
example 15:
(E) -2- (2- (3- (4-bromophenyl) -8- (methylsulfonyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1,3, 4-oxadiazole (Compound 15)
Figure BDA0003618020270000341
The reaction process comprises the following steps:
Figure BDA0003618020270000342
the reaction steps are as follows:
step 1: to a mixed solution of methyl 5-bromonicotinate (5.0g, 23.1mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (5.3g, 27.7mmol) and potassium carbonate (7.99g, 57.9mmol) in 1, 4-dioxane/water (50 mL/10 mL) was added bis- (triphenylphosphine) -palladium dichloride (800mg, 1.14mmol), the mixture was replaced with nitrogen 3 times, and the mixture was stirred at 100 ℃ for 12 hours. TLC monitored most of the starting material as reacted, the reaction was cooled to room temperature and quenched by addition of water (50 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3 times), and the organic phases were combined. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (eluent: petroleum ether-ethyl acetate) to give methyl 5- (1-methyl-1H-pyrazol-4-yl) nicotinate (4.5 g).
1H NMR(400MHz,CDCl3)δ9.05(d,J＝2.3Hz,1H),8.90(d,J＝2.3Hz,1H),8.36-8.34(m,1H),7.85(s,1H),7.74(s,1H),3.99-3.97(m,6H).
And 2, step: to a solution of methyl 5- (1-methyl-1H-pyrazol-4-yl) nicotinate (3.0 g,13.8 mmol) in ethanol (40 mL) was added hydrazine (3.6 mL, 98%), and the mixture was refluxed at 90 ℃ for 2 days. TLC was used to monitor most of the starting material for completion of the reaction, the reaction was allowed to cool to room temperature and a solid precipitated, which was filtered and the filter cake was dried to give 5- (1-methyl-1H-pyrazol-4-yl) nicotinic hydrazide (2.5 g).
1H NMR(400MHz,DMSO-d6)δ9.95(s,1H),8.91(d,J＝2.0Hz,1H),8.78(d,J＝2.0Hz,1H),8.35-8.30(m,1H),8.26(s,1H),7.96(s,1H),4.58(s,2H),3.91(s,3H).
And 3, step 3: (E) -3- (3- (4-bromophenyl) -8- (tert-butoxycarbonyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) acrylic acid (200mg, 0.43mmol), 5- (1-methyl-1H-pyrazol-4-yl) nicotinohydrazide (100mg, 0.46mmol), triethylamine (130mg, 1.29mmol) and 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium hexafluorophosphate (250mg, 0.65mg) were dissolved in dichloromethane (5 mL) and stirred at room temperature for 12 hours. TLC monitored most of the starting material for completion of the reaction and quenched by addition of saturated sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: dichloromethane to dichloromethane/methanol = 10) to give tert-butyl (E) -2- (4-bromophenyl) -3- (3- (2- (5- (1-methyl-1H-pyrazolyl-4-yl) nicotinoyl) hydrazino) -3-oxoprop-1-en-1-yl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (230 mg).
MS(ESI)M/Z:661.1[M+H+].
And 4, step 4: to a solution of (E) -2- (4-bromophenyl) -3- (3- (2- (5- (1-methyl-1H-pyrazolyl-4-yl) nicotinoyl) hydrazino) -3-oxoprop-1-en-1-yl) -1,4, 8-triazaspiro [4.5] dec-1, 3-diene-8-carboxylic acid tert-butyl ester (230mg, 0.35mmol) and N, N-diisopropylethylamine (135mg, 1.04mmol) in dichloromethane (5 mL) was added p-toluenesulfonyl chloride (100mg, 0.52mmol), and the mixture was stirred at room temperature for 2 hours. TLC monitored the starting material mostly reacted out and quenched by addition of saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (15 mL. Times.3 times), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: petroleum ether to ethyl acetate) to give tert-butyl (E) -2- (4-bromophenyl) -3- (2- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1,3, 4-oxadiazol-2-yl) vinyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (152 mg). The product structure was not identified.
And 5: to a solution of tert-butyl (E) -2- (4-bromophenyl) -3- (2- (5- (1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1,3, 4-oxadiazol-2-yl) vinyl) -1,4, 8-triazaspiro [4.5] decane-1, 3-diene-8-carboxylate (152mg, 0.24mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.5 mL) and stirred at room temperature for 2 hours. TLC monitored most of the starting material for completion of the reaction and quenched by addition of saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure to give (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (5-1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1,3, 4-oxadiazole (150 mg, crude).
MS(ESI)M/Z:543.1[M+H+].
Step 6: to a solution of (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (5-1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1,3, 4-oxadiazole (150 mg, ca. 0.28 mmol) and triethylamine (84mg, 0.83mmol) in dichloromethane (5 mL) was added methanesulfonyl chloride (50mg, 0.44mmol), and the mixture was stirred at room temperature for 2 hours. TLC monitored the starting material for most of the reaction completion and quenched by the addition of water (10 mL). The mixture was extracted with dichloromethane (15 mL. Times.3), the organic phases were combined, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and finally concentrated under reduced pressure. The crude product was purified by preparative high performance liquid chromatography to give (E) -2- (2- (3- (4-bromophenyl) -8- (methylsulfonyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-dien-2-yl) vinyl) -5- (5-1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1,3, 4-oxadiazole (50.7 mg).
MS(ESI)M/Z:621.0[M+H+].
1H NMR(400MHz,CDCl3)δ9.10(d,J＝2.0Hz,1H),8.94(d,J＝2.0Hz,1H),8.59-8.56(m,1H),7.91(s,1H),7.83(s,1H),7.72-7.67(m,2H),7.65-7.57(m,4H),4.02(s,3H),3.76-3.67(m,4H),2.93(s,3H),2.06-1.97(m,4H)
Biological test evaluation:
test example 1: evaluation of proliferation inhibitory Effect of the Compound of the present invention on Ba/F3 cell line stably expressing triple mutant epidermal growth factor receptor
The experiment adopts a fluorescence method to measure the ATP content in cells to detect the proliferation inhibition effect of the compound on cell strains stably expressing the triple mutant epidermal growth factor receptors (EGFR triple mutants), and obtains the half inhibitory concentration IC of the compound on the proliferation inhibition of the cell strains of the triple mutant epidermal growth factor receptors (EGFR triple mutants)50。
1. Experimental materials
RPMI-1640 medium, fetal Bovine Serum (FBS), 100X Pen/Strep, glutaMAX-I Supplement was purchased from GIBCO. Cell Titer-Glo luminometer Cell viability assay reagents were purchased from Promega.
2. Experimental methods
1) Stably transfected Ba/F3 (DEL 19/T790M/C797S and L858R/T790M/C797S) cells were counted using a cytometer and plated at a density of 3000 cells per well in 96 well plates at 100. Mu.l per well. Placing in an incubator (37 ℃,5%2) And incubated overnight.
2) Day 0: to the plate cells, 500nL of test compound diluted in a gradient (starting concentration 30 μ M,10 concentrations, 12). Blank control was added 500nL of DMSO per well.
3) Day 3: add 100. Mu.L Cell Titer-Glo reagent to each well, shake for 2 min at 500rpm, centrifuge for 1 min at 1000rpm, incubate in dark for 10 min at room temperature to stabilize the luminescent signal.
4) The luminescence signal was detected with an Envision plate reader (PerkinElmer).
5) Data analysis was performed using GraphPad Prism 6 software to calculate the IC50 of the compound.
The compounds have good inhibition effect on cell proliferation of Ba/F3 Del19/T790M/C797S EGFR triple mutation cell lines and Ba/F3L858R/T790M/C797S EGFR triple mutation cell lines, and IC of the compounds50Values generally below 2. Mu.M; IC of a portion of the Compounds of the invention50Values lower than 1. Mu.M, more Excellent IC's of the compounds of the invention50Values below 0.5. Mu.M, even below 0.3. Mu.M. The results of the inhibition of three mutant epidermal growth factor receptor Ba/F3 cell lines by the partial compounds of the present invention are shown in Table 1.
TABLE 1 inhibition results of Ba/F3 cell lines stably expressing triple mutant epidermal growth factor receptor
Figure BDA0003618020270000381
Description of the drawings: a represents IC50Less than or equal to 0.5 mu M, B represents 0.5 mu M < IC50Less than or equal to 1 mu M, C represents 1 mu M < IC50Less than or equal to 2 mu M, D represents IC50More than 2 mu M; n.d. indicates not determined.

Claims (31)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0003618020260000011
wherein the content of the first and second substances,
R1is selected from C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -S (O)2Ra、-C(O)RbSubstituted or unsubstituted 4-6 membered heterocycloalkyl;
Rais selected from C1-6Alkyl, halo C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRaaRabOr C3-6Cycloalkyl, wherein RaaAnd RabEach independently selected from H and C1-4An alkyl group;
Rbis selected from C1-6Alkyl, halo C1-6Alkyl-, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRbaRbbOr C3-6Cycloalkyl radicals ofIn RbaAnd RbbEach independently selected from H, C1-4An alkyl group;
R2selected from optionally substituted by one or more RcSubstituted C5-10Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl-, phenyl-ethynyl-, RcCan be RcaOr Rcb，RcaSelected from halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl-, halo-C1-4Alkoxy-, -C1-6alkyl-OH or C1-4Alkyl-ethynyl-, RcbSelected from optionally substituted C1-4C substituted by alkyl3-6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R3is selected from H or C1-3An alkyl group;
n is selected from 0, 1, 2, 3 or 4;
a is selected from substituted or unsubstituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S or N;
b is selected optionally by one or more RdSubstituted 5-10 membered heteroaryl or C5-10Aryl radical, RdIs selected from C1-4Alkyl, halogen, C2-6Alkynyl, C1-4Alkoxy, -P (O) RdaRdb、-S(O)2RdcRddPhenyl, phenyloxy-, 5-6 membered heteroaryl; wherein R isdThe phenyloxy-, phenyl-, 5-6 membered heteroaryl group in (a) may further optionally be substituted by one or more C1-4Alkyl, halogen or C1-4Alkoxy substituted, RdaAnd RdbIs selected from C1-4Alkyl radical, RdcAnd RddIs selected from C1-4An alkyl group.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein,
R1is selected from C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -S (O)2Ra、-C(O)RbSubstituted or unsubstituted 4-6 membered heterocycloalkyl;
Rais selected from C1-6Alkyl, halo C1-6Alkyl radical, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRaaRabOr C3-6Cycloalkyl, wherein RaaAnd RabEach independently selected from H, C1-4An alkyl group;
Rbis selected from C1-6Alkyl, halo C1-6Alkyl-, C1-6alkyl-O-C1-6Alkyl-, -C1-6alkyl-OH, -C1-6alkyl-NRbaRbbOr C3-6Cycloalkyl, wherein RbaAnd RbbEach independently selected from H, C1-4An alkyl group;
R2selected from optionally substituted by one or more RcSubstituted C5-10Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl-, phenyl-ethynyl-, RcCan be RcaOr Rcb，RcaSelected from halogen, cyano, C1-4Alkyl radical, C1-4Alkoxy, halo C1-4Alkyl-, halo-C1-4Alkoxy-, -C1-6alkyl-OH or C1-4Alkyl-ethynyl-, RcbSelected from optionally substituted by C1-4C substituted by alkyl3-6Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R3is selected from H or C1-3An alkyl group;
n is selected from 0, 1, 2, 3 or 4;
a is selected from substituted or unsubstituted 5-6 membered heteroaryl, said 5-6 membered heteroaryl containing 1-3 heteroatoms selected from O, S or N;
b is selected from optionally substituted by one or more RdSubstituted 5-10 membered heteroaryl or C5-10Aryl radical, RdIs selected from C1-4Alkyl, halogen, C2-6Alkynyl, C1-4Alkoxy, -P (O) RdaRdb、-S(O)2RdcRddPhenyl, phenyloxy-; wherein R isdThe phenyloxy-phenyl group in (1) may further optionally be substituted by one or more C1-4Alkyl, halogen or C1-4Alkoxy substituted, RdaAnd RdbIs selected from C1-4Alkyl radical, RdcAnd RddIs selected from C1-4An alkyl group.
3. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1-2 wherein R isaSelected from methyl, ethyl, isopropyl, cyclopropyl, -CHF2、-CH2CH2OH、-CH2CH2OCH3、-CH2CH2N(CH3)2。
4. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 3 wherein R iscaSelected from F, br, cl, -CH3、-CHF2、-OCF3、-OCH3、CH3C≡C-、-C(CH3)2OH、-CN；RcbIs selected from
Figure FDA0003618020260000021
Figure FDA0003618020260000031
5. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4 wherein R is1Is selected from-CH3、
Figure FDA0003618020260000032
Figure FDA0003618020260000033
6. The compound of formula (I) as defined in any one of claims 1 to 4A compound or a pharmaceutically acceptable salt thereof, wherein R is1Is selected from-S (O)2Ra，RaAs defined in any one of claims 1 to 4.
7. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 6, wherein R is1Is selected from
Figure FDA0003618020260000034
8. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 7 wherein R is2Is selected from
Figure FDA0003618020260000035
Figure FDA0003618020260000036
Figure FDA0003618020260000037
RcaAnd RcbAs defined in any one of claims 1 to 7, m is selected from 0, 1, 2, 3 or 4.
9. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 8, wherein R is2Is selected from
Figure FDA0003618020260000041
Figure FDA0003618020260000042
10. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 9 wherein R is3Selected from H or methyl.
11. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-10 wherein a is selected from
Figure FDA0003618020260000043
Figure FDA0003618020260000044
a represents the end attached to the ethylenic bond and B represents the end attached to B.
12. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 11 wherein a is selected from
Figure FDA0003618020260000051
13. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1-12, wherein R isdIs selected from-CH3、-CH2CH3、-F、-C≡C、-P(O)(CH3)CH3、-S(O)2CH3A phenyl group,
Figure FDA0003618020260000052
14. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claims 1-13, wherein B is selected from
Figure FDA0003618020260000053
Figure FDA0003618020260000054
Figure FDA0003618020260000055
RdAs defined in any one of claims 1 to 13, p is selected from 01, 2, 3 or 4.
15. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 14, wherein B is selected from
Figure FDA0003618020260000056
Figure FDA0003618020260000057
Figure FDA0003618020260000061
16. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 15 wherein B is selected from
Figure FDA0003618020260000062
17. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 16, selected from formula (II),
Figure FDA0003618020260000063
wherein R is1、R2、R3B, n are as defined in any one of claims 1 to 17.
18. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 18 selected from formula (III) or (IV),
Figure FDA0003618020260000064
wherein R is1、R3、Rc、RdB, n are as defined in any one of claims 1 to 17, m is as defined in claim 8 and p is as defined in claim 14.
19. The compound of formula (I), or a pharmaceutically acceptable salt thereof, as claimed in claim 17, selected from formula (V),
Figure FDA0003618020260000071
wherein R is1、R3、Rc、m、n、RdP is as defined in claim 18.
20. A compound, or a pharmaceutically acceptable salt thereof, selected from,
Figure FDA0003618020260000072
Figure FDA0003618020260000081
Figure FDA0003618020260000091
Figure FDA0003618020260000101
Figure FDA0003618020260000111
21. a pharmaceutical composition comprising a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
22. A method of modulating EGFR and inducing EGFR degradation, comprising administering to a subject in need thereof an effective amount of a compound of any one of claims 1-20, or a pharmaceutically acceptable salt thereof.
23. Use of a compound of any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 20, in the manufacture of a medicament for the treatment of cancer.
24. The use according to claim 21, wherein the cancer is a cancer mediated by EGFR, including lymphoma, non-hodgkin's lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, melanoma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular cancer, gastric cancer, gastrointestinal stromal tumors (GIST), acute Myeloid Leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.
25. The use of claim 22, wherein the cancer is lung cancer.
26. An intermediate compound represented by the formulae (Z-1), (Z-2), (Z-3) and (Z-4) or a stereoisomer or a pharmaceutically acceptable salt thereof,
Figure FDA0003618020260000121
wherein R is2、R3B, n are as defined in any one of claims 1 to 20, PG is a commonly used amino protecting group.
27. The compound of formula (Z-1), (Z-2), (Z-3) and (Z-4) according to claim 26, or a stereoisomer, pharmaceutically acceptable salt thereof, which is selected from formula (Z-1 a), (Z-2 a), (Z-3 a) and (Z-4 a),
Figure FDA0003618020260000131
wherein R is3、RcB, m, n, as defined in any one of claims 1 to 20, PG as defined in claim 26.
28. A process for producing a compound of the formula (II), characterized in that a compound of the formula (Z-4) is obtained by deprotecting a compound of the formula (Z-3), and R is introduced1The compound shown in the formula (II) is prepared,
Figure FDA0003618020260000132
wherein PG and R2、R3B, n are as defined in claim 26, R1As defined in any one of claims 1 to 20.
29. A process for producing a compound of the formula (Z-3), characterized in that a compound of the formula (Z-2) is dehydrated to produce a compound of the formula (Z-3),
Figure FDA0003618020260000141
wherein PG and R2、R3B and n are as defined in claim 26.
30. A preparation method of a compound of a formula (Z-2), which is characterized in that the compound of the formula (Z-1) and a compound of a Z-5 are prepared to obtain the compound of the formula (Z-2) under the action of a condensing agent,
Figure FDA0003618020260000142
wherein PG and R2、R3B and n are as defined in claim 26.
31. The intermediate of claims 26-27 and the method of preparation of 28-30, wherein PG is selected from t-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl; (Z-1) preparation of (Z-2) using a condensing agent selected from 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride (DMTMM); (Z-2) preparation of (Z-3) the dehydrating agent used is selected from among Burgis' reagents.
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