CN115260194B - Novel EGFR degradation agent - Google Patents

Novel EGFR degradation agent Download PDF

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CN115260194B
CN115260194B CN202210449444.8A CN202210449444A CN115260194B CN 115260194 B CN115260194 B CN 115260194B CN 202210449444 A CN202210449444 A CN 202210449444A CN 115260194 B CN115260194 B CN 115260194B
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CN115260194A (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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Abstract

The present invention provides a novel class of compounds that degrade the EGFR protein, pharmaceutical compositions containing the compounds, useful intermediates for preparing the 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 present invention is in the field of pharmaceutical chemistry, and in particular relates to a novel class of compounds that degrade EGFR proteins, pharmaceutical compositions containing the compounds, useful intermediates for preparing the compounds, and methods of treating cell proliferative disorders, such as cancer, using the compounds of the present invention.
Background
EGFR, the EGFR 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 cell growth, proliferation and differentiation. EGFR mutations are also one of the most common types of mutations in NSCLC patients, and can account for 40% to 50% of Asian populations in particular. EGFR has therefore been one of the hottest targets in the field of drug development.
Currently, EGFR inhibitors on the market are divided into the first, second and third generation. The first generation is reversible targeted drugs such as gefitinib, erlotinib, and icotinib. The second generation is irreversible targeted drugs such as afatinib and dacatinib. Although the first and second generation targeting drugs have remarkable curative effects, most patients can have drug resistance after using the drugs for 1-2 years. Of the EGFR inhibitor resistant patients, 50% were associated with the T790M mutation. The third generation EGFR targeting drug, namely the Ornitinib, can overcome tumor 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 reason for drug resistance is mainly C797S mutation. The C797S mutation is manifested as a mutation of a cysteine residue to serine, which disrupts EGFR protein binding to third generation targeting drugs, thereby failing to prevent EGFR protein phosphorylation and downstream signaling pathway activation. At present, no mature treatment means exists for the treatment of the Ornitinib drug 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 medicines for treating cancers.
The invention provides a compound shown as a formula (I-A) or pharmaceutically acceptable salt thereof,
Figure BDA0003618020270000021
wherein,,
R 1 selected from C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -S (O) 2 R a 、-C(O)R b Substituted or unsubstituted 4-6 membered heterocycloalkyl;
R a selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR aa R ab 、C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein R aa R is R ab Each independently selected from H, C 1-4 Alkyl, phenyl or 5-6 membered heteroaryl optionally substituted with one or more C 1-4 Alkyl, halogenated C 1-4 Alkyl-, C 1-4 Alkoxy, halogen substituted;
R b selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl-, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR ba R bb 、C 3-6 Cycloalkyl, phenyl or 5-6 membered heteroaryl, wherein R ba R is R bb Each independently selected from H, C 1-4 Alkyl, phenyl or 5-6 membered heteroaryl optionally substituted with one or more C 1-4 Alkyl, halogenated C 1-4 Alkyl-, C 1-4 Alkoxy, halogen substituted;
R 2 selected from optionally one or more R c Substituted C 5-10 Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl-, phenyl-ethynyl-, R c Can be R ca Or R is cb ，R ca Selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl-, halo C 1-4 Alkoxy-, -C 1-6 alkyl-OH or C 1-4 Alkyl-ethynyl-, R cb Selected from optionally covered by C 1-4 C substituted by alkyl 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R 3 selected from H or C 1-3 Alkyl, 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 one or more R d Substituted 5-to 10-membered heteroaryl or C 5-10 Aryl, R d Selected from C 1-4 Alkyl, halogen, C 2-6 Alkynyl, C 1-4 Alkoxy, -P (O) R da R db 、-S(O) 2 R dc R dd Phenyl, phenyloxy-, 5-6 membered heteroaryl; wherein R is d The phenyloxy-, phenyl, 5-6 membered heteroaryl groups of (C) may further optionally be substituted with one or more C 1-4 Alkyl, halogen or C 1-4 Substituted by alkoxy, R da And R is db Selected from C 1-4 Alkyl, R dc And R is dd Selected from C 1-4 An alkyl group;
L 1 is a bond or is selected from C 1-4 Alkylene group, wherein the C 1-4 The carbon atoms in the alkylene groups may be further optionally substituted by one or more U groups selected from O, S, NH or NR ua Wherein R is ua Selected from C 1-4 An alkyl group;
L 2 is a bond or is selected from C 1-4 Alkylene group, wherein the C 1-4 The carbon atoms in the alkylene groups may be further optionally substituted by one or more Q groups selected from C.ident. C, O, S, NH, NR qa -NHC (O) -or-C (O) NH-, wherein R qa Selected from C 1-4 An alkyl group.
The invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof,
Figure BDA0003618020270000031
wherein,,
R 1 selected from C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -S (O) 2 R a 、-C(O)R b Substituted or unsubstituted 4-6 membered heterocycloalkyl;
R a selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR aa R ab 、C 3-6 Cycloalkyl, wherein R is aa R is R ab Each independently selected from H, C 1-4 An alkyl group;
R b selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl-, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR ba R bb 、C 3-6 Cycloalkyl, wherein R is ba R is R bb Each independently selected from H, C 1-4 An alkyl group;
R 2 selected from optionally one or more R c Substituted C 5-10 Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl-, phenyl-ethynyl-, R c Can be R ca Or R is cb ，R ca Selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl-, halo C 1-4 Alkoxy-, -C 1-6 alkyl-OH or C 1-4 Alkyl-ethynyl-, R cb Selected from optionally covered by C 1-4 C substituted by alkyl 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R 3 selected from H or C 1-3 Alkyl, n is selected from 0, 1, 2, 3 or 4;
a is selected from a substituted or unsubstituted 5-6 membered heteroaryl group, said 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from O, S or N;
b is selected from optionally one or more R d Substituted 5-to 10-membered heteroaryl or C 5-10 Aryl, R d Selected from C 1-4 Alkyl, halogen, C 2-6 Alkynyl, C 1-4 Alkoxy, -P (O) R da R db 、-S(O) 2 R dc R dd Phenyl, phenyloxy-, 5-6 membered heteroaryl; wherein R is d The phenyloxy-, phenyl, 5-6 membered heteroaryl groups of (C) may further optionally be substituted with one or more C 1-4 Alkyl, halogen or C 1-4 Substituted by alkoxy, R da And R is db Selected from C 1-4 Alkyl, R dc And R is dd Selected from C 1-4 An alkyl group.
The invention provides a compound shown as a formula (I) or pharmaceutically acceptable salt thereof, wherein,
R 1 selected from C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -S (O) 2 R a 、-C(O)R b Substituted or unsubstituted 4-6 membered heterocycloalkyl;
R a selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR aa R ab 、C 3-6 Cycloalkyl, wherein R is aa R is R ab Each independently selected from H, C 1-4 An alkyl group;
R b selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl-, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR ba R bb 、C 3-6 Cycloalkyl, wherein R is ba R is R bb Each independently selected from H, C 1-4 An alkyl group;
R 2 selected from optionally one or more R c Substituted C 5-10 Aryl, 5-10 membered heteroaryl-, 5-6 membered heterocycloalkyl-, 5-6 membered heterocycloalkenyl-, phenyl-ethynyl-, R c Can be R ca Or R is cb ，R ca Selected from halogen, cyano, C 1-4 Alkyl, C 1-4 Alkoxy, halo C 1-4 Alkyl-, halo C 1-4 Alkoxy-, -C 1-6 alkyl-OH or C 1-4 Alkyl-ethynyl-, R cb Selected from optionally covered by C 1-4 C substituted by alkyl 3-6 Cycloalkyl, 4-6 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, phenyl-O-;
R 3 selected from H or C 1-3 Alkyl, n is selected from 0, 1, 2, 3 or 4;
a is selected from a substituted or unsubstituted 5-6 membered heteroaryl group, said 5-6 membered heteroaryl group containing 1-3 heteroatoms selected from O, S or N;
b is selected from optionally one or more R d Substituted 5-to 10-membered heteroaryl or C 5-10 Aryl, R d Selected from C 1-4 Alkyl, halogen, C 2-6 Alkynyl, C 1-4 Alkoxy, -P (O) R da R db 、-S(O) 2 R dc R dd Phenyl, phenyloxy-; wherein R is d The phenyl groups of (a) may further optionally be substituted with one or more C 1-4 Alkyl, halogen or C 1-4 Substituted by alkoxy, R da And R is db Selected from C 1-4 Alkyl, R dc And R is dd Selected from C 1-4 An alkyl group.
In some embodiments of the present invention, L in the compound represented by the above formula (I-A) or a pharmaceutically acceptable salt thereof 1 Is a bond or is selected from-CH 2 -、-CH 2 CH 2 -、-CH 2 NH-。
In some embodiments of the present invention, L in the compound represented by the above formula (I-A) or a pharmaceutically acceptable salt thereof 2 Is a bond or is selected from-CH 2 -、-CH 2 CH 2 -、-NHCH 2 -、-CH 2 NH-、-NH-、-NHC(O)-。
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof a Selected from methyl, ethyl, isopropyl, cyclopropyl, -CHF 2 、-CH 2 CH 2 OH、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 N(CH 3 ) 2 。
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof ca Selected from F, br, cl, -CH 3 、-CHF 2 、-OCF 3 、-OCH 3 、CH 3 C≡C-、-C(CH 3 ) 2 OH、-CN；R cb Selected from the group consisting of
Figure BDA0003618020270000051
Figure BDA0003618020270000052
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof 1 Selected from-CH 3 、
Figure BDA0003618020270000053
Figure BDA0003618020270000054
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof 1 Selected from-S (O) 2 R a ，R a As defined above.
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof 1 Selected from the group consisting of
Figure BDA0003618020270000055
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof 2 Selected from the group consisting of
Figure BDA0003618020270000061
Figure BDA0003618020270000062
Figure BDA0003618020270000063
R ca And R is R cb As defined above, m is selected from 0, 1, 2, 3 or 4.
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof 2 Selected from the group consisting of
Figure BDA0003618020270000064
Figure BDA0003618020270000065
Figure BDA0003618020270000071
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof 2 Selected from the group consisting of
Figure BDA0003618020270000072
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof 3 Selected from H or methyl.
In some embodiments of the present invention, in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof, A is selected from
Figure BDA0003618020270000073
Figure BDA0003618020270000074
a represents an ethylenic linkage, and B represents a B linkage.
In some embodiments of the present invention, in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof, A is selected from
Figure BDA0003618020270000075
In some embodiments of the present invention, R in the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof d Selected from-CH 3 、-CH 2 CH 3 、-F、-C≡C、-P(O)(CH 3 )CH 3 、-S(O) 2 CH 3 Phenyl group,
Figure BDA0003618020270000076
In some embodiments of the present invention, B is selected from the group consisting of the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof
Figure BDA0003618020270000077
Figure BDA0003618020270000078
Figure BDA0003618020270000081
R d As defined above, p is selected from 0, 1, 2, 3 or 4.
In some embodiments of the present invention, the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof, wherein B is selected from
Figure BDA0003618020270000082
Figure BDA0003618020270000083
In some embodiments of the present invention, the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof, wherein B is selected from the group consisting of,
Figure BDA0003618020270000084
In some embodiments of the present invention, the compounds represented by the above formulas (I-A) and (I) or pharmaceutically acceptable salts thereof, wherein B is selected from
Figure BDA0003618020270000085
In some embodiments of the present invention, the compounds of formulas (I-A) and (I) above, or pharmaceutically acceptable salts thereof, are selected from formula (II),
Figure BDA0003618020270000091
wherein R is 1 、R 2 、R 3 B, n are as defined above.
In some embodiments of the present invention, the compounds of formulas (I-A) and (I) above, or pharmaceutically acceptable salts thereof, are selected from formulas (III) or (IV),
Figure BDA0003618020270000092
wherein R is 1 、R 3 、R c 、R d B, n, m, p are as defined above.
In some embodiments of the present invention, the compounds of formulas (I-A) and (I) above, or pharmaceutically acceptable salts thereof, are selected from formula (V),
Figure BDA0003618020270000093
wherein R is 1 、R 3 、R c 、m、n、R d P is as defined above.
The present invention also provides a compound selected from the group consisting of,
Figure BDA0003618020270000101
Figure BDA0003618020270000111
Figure BDA0003618020270000121
/>
Figure BDA0003618020270000131
/>
Figure BDA0003618020270000141
the invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the above compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The pharmaceutical compositions can be formulated for particular routes of administration, such as oral, parenteral, rectal, and the like. Oral administration, such as 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; is taken orally; parenteral, e.g., by subcutaneous, intravenous, intramuscular, or intrasternal injection, or infusion techniques (e.g., as a sterile injectable aqueous or nonaqueous solution or suspension); transnasal, including administration to the nasal mucosa, e.g., by inhalation spray; topical, for example in the form of a cream or ointment; or rectally, for example in the form of suppositories. They may be administered alone, but will typically 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 invention may 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 nature and extent of concurrent therapy, the frequency of treatment, the route of administration, the renal and hepatic function of the patient, and the desired effect. The therapeutically effective dose of the compound, pharmaceutical composition or combination thereof will depend on the type, 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 of the active ingredients required to prevent, treat or inhibit the progress of the condition or disorder.
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 a compound as described above, or a pharmaceutically acceptable salt thereof.
The invention also provides application of the compound or pharmaceutically acceptable salt thereof or the pharmaceutical composition in preparing a medicament for treating cancer.
Such 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 carcinoma, gastric cancer, gastrointestinal stromal tumor (GIST), acute Myelogenous Leukemia (AML), cholangiocarcinoma, renal cancer, thyroid cancer, anaplastic large cell lymphoma, mesothelioma, multiple myeloma, melanoma.
The invention also provides a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof or a pharmaceutical composition as described above. Such 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 carcinoma, 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 aspects of the invention, the cancer is lung cancer.
The invention also provides intermediate compounds shown in the formulas (Z-1), (Z-2), (Z-3) and (Z-4), wherein the intermediate compounds or stereoisomers and pharmaceutically acceptable salts thereof are used for preparing the compounds:
Figure BDA0003618020270000161
wherein R is 2 、R 3 B, n PG is a protecting group commonly used for amino groups, and PG may be selected from t-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl.
In some embodiments of the present invention, the intermediate compounds of formulas (Z-1), (Z-2), (Z-3) and (Z-4) may be selected from formulas (Z-1 a), (Z-2 a), (Z-3 a) and (Z-4 a), respectively,
Figure BDA0003618020270000162
Wherein PG, R c 、R 3 And B, m, n are as defined above.
In one aspect of the inventionIn some embodiments, the compound of formula (II) is deprotected from a compound of formula (Z-3) to provide a compound of formula (Z-4), and R is introduced 1 Preparing a compound shown in a formula (II),
Figure BDA0003618020270000171
wherein R is 1 、PG、R 2 、R 3 B, n are as defined above.
In some embodiments of the present invention, the compound of formula (Z-3) is prepared by dehydration of a compound of formula (Z-2),
Figure BDA0003618020270000172
wherein the dehydrating agent can be a primary Gibbs reagent, PG, R 2 、R 3 B, n are as defined above.
In some embodiments of the present invention, the compound of formula (Z-2) is obtained by reacting a compound of 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-dimethoxy triazine) -4-methylmorpholine hydrochloride), PG, R 2 、R 3 B, n are as defined above.
The invention also provides a preparation method of the compound or the pharmaceutically acceptable salt thereof, and a representative preparation route is shown in the following scheme:
Figure BDA0003618020270000181
wherein R is 1 、PG、R 2 、R 3 B, n are as defined above.
The intermediate compound Z-1 with the amino protected by PG group reacts with the Z-5 compound under the action of condensing agent to obtain an intermediate compound Z-2. Wherein PG is a commonly used amino protecting group including, but not limited to, t-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl, benzyloxycarbonyl, p-methoxybenzyl, benzyl, trityl, and the like. Among them, condensing agents are commonly used agents for promoting the reaction of carboxyl groups with amino groups to form amides, including, but not limited to, 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride (DMTMM), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 2- (7-azabenzotriazol) -N, N, N ', N' -tetramethylurea Hexafluorophosphate (HATU), and the like.
Cyclizing the Z-2 compound under the action of a dehydrating agent to obtain an intermediate Z-3 compound, wherein commonly used dehydrating agents include, but are not limited to, a Buerger reagent and the like.
The Z-3 compounds are generally deprotected under acidic or basic action to give Z-4. Common acids include, but are not limited to, hydrochloric acid, acetic acid, trifluoroacetic acid, hydrobromic acid and the like.
Introduction of R on the amino group of Z-4 Compounds 1 A group to give a compound of formula (II), R 1 The groups may be introduced by nucleophilic substitution reactions, e.g. using R 1 X is halogen as a reactant, including but not limited to introduction of 2-methoxyethyl by using 1-iodo-2 methoxyethane, introduction of methanesulfonyl chloride into methanesulfonyl, introduction of methyl iodide into methyl, and the like. The methyl group may be introduced by using an aqueous formaldehyde solution and reducing the aqueous formaldehyde solution with sodium borohydride acetate or the like.
In some embodiments of the invention, PG is selected from t-butoxycarbonyl; (Z-1) the condensing agent used in the preparation of (Z-2) is selected from 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride (DMTMM); (Z-2) the dehydrating agent used in the preparation (Z-3) is selected from the group consisting of the Buerger's reagent.
In some embodiments of the present invention, the compounds of formula (I-A), formula (I), (III), (IV) and formula (V) may be prepared by the synthetic methods described above.
The technical effects are as follows:
the compound has good inhibition effect on the cell proliferation of Ba/F3 Del19/T790M/C797S EGFR tri-mutant cell line and Ba/F3L858R/T790M/C797S EGFR tri-mutant cell line.
Definition and description
The following terms and phrases used herein are intended to have the following meanings unless otherwise indicated. A particular term or phrase, unless otherwise specifically defined, should not be construed as being ambiguous or otherwise clear, but rather should be construed in a generic sense.
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 prepared with relatively non-toxic acids or bases. These salts may be prepared during synthesis, isolation, purification of the compound, or the purified compound may be used alone in free form to react with a suitable acid or base. When the compound contains relatively acidic functional groups, reaction with alkali metal, alkaline earth metal hydroxides or organic amines yields base addition salts, including cations based on alkali metals and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations, and the like. When the compound contains a relatively basic functional group, it is reacted with an organic acid or an inorganic acid to give 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 "diastereoisomer" refers to a stereoisomer of a molecule having two or more chiral centers and having 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 a ring-forming carbon atom in a molecule cannot rotate freely.
Unless otherwise indicated, with solid wedge bonds
Figure BDA0003618020270000201
And wedge-shaped dotted bond->
Figure BDA0003618020270000202
Representing the absolute configuration of a solid centre, using straight solid keys +.>
Figure BDA0003618020270000203
And straight dotted bond->
Figure BDA0003618020270000204
Indicating the relative configuration of the stereogenic centers.
Stereoisomers of the compounds of the invention may be prepared by chiral syntheses or chiral reagents or other conventional techniques. For example, one enantiomer of a compound of the invention may be prepared by asymmetric catalytic techniques or chiral auxiliary derivatization techniques. Or by chiral resolution techniques, a single configuration of the compound is obtained from the mixture. Or directly prepared by chiral starting materials. The separation of the optically pure compounds in the invention is usually accomplished by using preparative chromatography, and chiral chromatographic columns are used to achieve the purpose of separating chiral compounds.
The term "pharmaceutically acceptable carrier" refers to a medium commonly accepted in the art for delivery of biologically active agents to animals, particularly mammals, and includes, for example, adjuvants, excipients or vehicles, such as diluents, preservatives, fillers, flow modifiers, disintegrants, wetting agents, emulsifying agents, suspending agents, sweetening, flavoring, perfuming, antibacterial, antifungal, lubricating and dispersing agents, depending on the mode of administration and nature of the dosage form. Pharmaceutically acceptable carriers are formulated within the purview of one of ordinary skill in the art according to a number of factors. Including but 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 therapeutic indication of interest. Pharmaceutically acceptable carriers include both aqueous and nonaqueous media and 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 included in the formulation for a variety of reasons (e.g., stabilizing the active agent, adhesive, etc.) are well known to those of ordinary skill in the art.
The term "excipient" generally refers to the carrier, diluent, and/or medium required to make an effective pharmaceutical composition.
The term "prophylactically or therapeutically effective 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 effect/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated that the total daily amount of the compounds of formula I or pharmaceutically acceptable salts and compositions of the present invention will be determined by the physician within the scope of sound medical judgment. For any particular patient, the particular therapeutically effective dose level will depend on 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; 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; duration of treatment; a medicament for use in combination with or simultaneously with the particular compound employed; and similar factors well known in the medical arts. For example, it is common in the art to start doses of the compound at levels below that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. In general, the compounds of formula I or pharmaceutically acceptable salts thereof of the present invention may be administered to a mammal, particularly a human, at a dosage of from about 0.001 to 1000mg/kg body weight/day, for example from about 0.01 to 100mg/kg body weight/day, for example from about 0.01 to 10mg/kg body weight/day.
The term "optionally substituted" or "optionally" means that the type and number of substituents, which may or may not be substituted, unless otherwise specified, may be chemically substantialMay be any on the basis of what is now described, e.g. the term "optionally substituted with one or more R 2 Substituted "means that it may be substituted by one or more R 2 Substituted or not by R 2 And (3) substitution.
When any variable (e.g. R 2 ) Where the composition or structure of a compound occurs more than once, its definition is independent in each case. For example, if a group is substituted with 0-2R 2 Substituted, the radicals may optionally be substituted by up to two R 2 Substituted, and R in each case 2 There are independent options.
When the number of one linking group is 0, such as-O (CH) 2 ) n CH 3 N=0 means that the linking group is a single bond, i.e. -OCH 3 。
When L in the structural unit A-L-B is defined as a "bond", it means that L is absent and that the A group is directly linked to the B group as a structure of A-B.
Where a bond of a substituent may cross-connect to two atoms on a ring, the substituent may be bonded to any atom on the ring. For example, structural units
Figure BDA0003618020270000211
Represents a substituent R 1 Substitution may occur at any position on the phenyl ring.
Unless otherwise specified, structural units appearing herein
Figure BDA0003618020270000212
Represents a substituent R d The 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 none of the listed substituents indicates through which atom it is attached to a compound included in the chemical structural formula but not specifically mentioned, such substituents may be bonded through any of their atoms. For example, pyrazole as a substituent means that any one of the carbon atoms of the pyrazole ring is attached to the substituted group; when out of the structureAt present
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 that the N atom on the morpholine ring is a bonding atom.
Unless otherwise specified, "ring" refers to saturated, partially saturated or unsaturated monocyclic and polycyclic, 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" refers to substituted or unsubstituted heteroatoms, typically selected from N, O, S, and oxidized forms of heteroatoms, typically including NO, SO, S (O) 2 The nitrogen atom may be substituted, i.e., NR (R is H or other substituent as defined herein); the number of atoms in the ring is generally defined as the number of ring elements, e.g., "3-6 membered heterocycloalkyl" means a ring of 3-6 atoms arranged around, each ring optionally containing 1 to 3 heteroatoms, i.e., N, O, S, NO, SO, S (O) 2 Or 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 aromaticity, which may be a single ring or multiple rings fused together. Preferably C 5-10 Aryl, more preferably C 5-8 Aryl, most preferably monocyclic C 5-6 An 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) 2 Or NR). Preferably a 5-or 6-membered monocyclic heteroaryl group. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, thienyl, pyridyl, pyrimidinyl.
The term "alkyl" is used to denote a straight or branched saturated hydrocarbon group unless otherwise specified. Preferably C 1-6 More preferably C 1-3 Examples 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 having one or more carbon atoms replaced with a heteroatom selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and 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, -OCH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 、-OCH(CH 3 ) 2 、-N(CH 3 ) 2 、-CH 2 -CH 2 -O-CH 3 、-CH 2 -CH 2 -NH-CH 3 、-CH 2 -CH 2 -N(CH 3 )-CH 3 、-CH 2 -S-CH 2 -CH 3 、-CH 2 -CH 2 、-S(O)-CH 3 、-S(O) 2 -CH 3 、-CH 2 -CH 2 -S(O) 2 -CH 3 Etc.
Unless otherwise specified, "alkenyl" refers to an alkyl group having one or more carbon-carbon double bonds. Preferably C 2-8 Examples 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 C 2-8 Alkynyl, examples of alkynyl include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and the like.
The term "halogen" means 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 halogen atoms, unless otherwise specified. Preferably halogenated C 1-6 Alkyl, more preferably halogenated C 1-3 Examples 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 obtained by substituting a hydrogen atom in a hydroxyl group with an alkyl group. Preferably C 1-6 Alkoxy, more preferably C 1-3 An alkoxy group. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, neopentoxy, n-hexyloxy.
Unless otherwise specified, "cycloalkyl" refers to a saturated monocyclic or polycyclic hydrocarbon group. Cycloalkyl is preferably 3-8 membered monocycloalkyl, more preferably 3-6 membered monocycloalkyl, examples of which include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl.
Unless otherwise specified, "heterocycloalkyl" refers to mono-and polyheterocyclic alkyl groups containing a number of heteroatoms in the ring, said heteroatoms generally being selected from N, O, S, NO, SO, S (O) 2 And NR. Heterocyclyl is preferably a 3-8 membered mono-heterocycloalkyl, more preferably a 3-6 membered mono-heterocycloalkyl, examples of which include, but are not limited to, oxiranyl, tetrahydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, 1, 3-dioxolane, 1, 4-dioxane, and the like.
Unless otherwise specified, "heterocycloalkenyl" refers to a heteroatom-containing cyclic monoolefin, including 3-10 membered heterocycloalkenyl, preferably 3-6 membered heterocycloalkenyl, most preferably 5-6 membered heterocycloalkenyl, examples of heterocycloalkenyl include, but are not limited to
Figure BDA0003618020270000231
Etc.
It is specifically stated that combinations of all substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
The concentration unit M herein, unless otherwise specified, represents mol/L, e.g., 1M NaOH solution is 1mol/L NaOH solution.
In the examples of the present invention, the title compound is named after the compound structure is converted by Chemdraw. If the compound name is inconsistent with the compound structure, the compound name can be determined in an auxiliary way by combining the related information and the reaction route; cannot be confirmed by other methods, and the structural formula of the given compound is subject to.
The preparation method of some compounds in the present invention refers to the preparation method of the aforementioned analogous compounds. It will be appreciated 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 using or referring to the preparation method to which they are applied.
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 set forth below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternatives well known to those skilled in the art, preferred embodiments including but not limited to the examples of the present invention.
Abbreviations used in the examples of the present invention and their corresponding chemical names are as follows:
abbreviations (abbreviations) Description of the invention
DMTMM 4- (4, 6-Dimethoxytriazine) -4-methylmorpholine hydrochloride
Prague reagent N- (triethylammonium sulfonyl) carbamic acid methyl ester
Detailed Description
The structure of the compounds of the present invention is determined by Nuclear Magnetic Resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts (δ) are given in parts per million (ppm). NMR measurements were performed using Bruker Neo 400M or Bruker Assend 400 nuclear magnetic instruments with deuterated dimethyl sulfoxide (DMSO-d 6) and deuterated methanol (CD) 3 OD) and/or deuterated chloroform (CDCl 3), the internal standard being Tetramethylsilane (TMS).
LC-MS was performed using an Agilent 1260-6125B single quadrupole mass spectrometer or a Waters H-Class SQD2 mass spectrometer (electrospray ionization as the ion source). HPLC determinations used Waters e2695-2998 or Waters ARC and Agilent 1260 or Agilent Poroshell HPH high performance liquid chromatography.
The HPLC was performed using Waters 2555-2489 (10 μm, ODS 250 cm. Times.5 cm) or GILSON Trilution LC, and the column was a Welch XB-C18 column (5 um, 21.2. Times.150 mm).
The thin layer chromatography silica gel plate uses smoke table Jiang You silica gel to develop a GF254 silica gel plate of a limited company or a GF254 silica gel plate of a new material limited company on the market of the nissan, the specification adopted by TLC is 0.15-0.20 mm, the preparation size is 20x20cm, and column chromatography is generally used for forming 200-300 mesh silica gel 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 invention were carried out under continuous magnetic stirring under dry nitrogen or argon atmosphere, with the solvent being a dry solvent and the reaction temperature being in degrees celsius, without specific description.
Example 1:
(E) -2- (2- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (compound 1)
Figure BDA0003618020270000251
The reaction flow is as follows:
Figure BDA0003618020270000252
the reaction steps are as follows:
step 1: compound (E) -3- (3- (4-bromophenyl) -8- (t-butoxycarbonyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) acrylic acid (800 mg,1.7 mmol) and quinoline-3-carbohydrazide (390 mg,2.1 mmol) were dissolved in tetrahydrofuran (30 mL) and methanol (10 mL), DMTMM (577 mg,2.1 mmol) was added and stirred at room temperature for 2 hours. Saturated aqueous sodium bicarbonate (40 mL) was added and extracted with ethyl acetate (30 mL. Times.3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/2) to give 320mg of tert-butyl (E) -2- (4-bromophenyl) -3- (3-oxo-3- (2- (quinoline-3-carbonyl) hydrazino) propyl-1-en-1-yl) -1,4, 8-triazaspiro [4.5] decan-1, 3-diene-8-carboxylate.
MS(ESI)M/Z:631.1[M+H] + .
Step 2: to a microwave tube were 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] decan-1, 3-diene-8-carboxylate (25 mg,0.04 mmol) and tetrahydrofuran (3 mL), followed by the addition of the Bojis reagent (30 mg,0.12 mmol). The microwave tube is sealed well and heated to 100 ℃ for reaction for 5 hours. 8 reactions were dosed in parallel. Cooled to room temperature, 8 reactions were combined and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=1/1) to give 100mg of (E) -2- (4-bromophenyl) -3- (2- (5- (quinolin-3-yl) -1,3, 4-oxadiazol-2-yl) vinyl) -1,4, 8-triazaspiro [4.5] decan-1, 3-diene-8-carboxylic acid tert-butyl ester.
MS(ESI)M/Z:613.2[M+H] + .
1 H NMR(400MHz,CDCl 3 ):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).
Step 3: to a solution of (E) -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-carboxylic acid tert-butyl ester (100 mg,0.16 mmol) 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 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 concentrated under reduced pressure to give 100mg of crude (E) -2- (2- (3- (4-bromophenyl) -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:513.2[M+H] + .
Step 4: (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (100 mg, crude), 36% aqueous formaldehyde (41 mg,0.49 mmol) and acetic acid (20 mg,0.33 mmol) were dissolved in tetrahydrofuran (5 mL), and sodium borohydride acetate (104 mg,0.49 mmol) 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 organic phases were combined, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by high performance liquid chromatography to give 37.7mg of the final product (E) -2- (2- (3- (4-bromophenyl) -8-methyl-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:526.6[M+H] + .
1 H 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] dec-1, 3-dien-2-yl) vinyl) -5- (5-ethynylpyridin-3-yl) -1,3, 4-oxadiazole (compound 2)
Figure BDA0003618020270000271
The reaction flow is as follows:
Figure BDA0003618020270000281
the reaction steps are as follows:
step 1: methyl 5-bromonicotinate (1.5 g,7.0 mmol), trimethylsilylacetylene (2.0 g,20.4 mmol), cuprous iodide (66 mg,0.35 mmol) and bis (triphenylphosphine) palladium dichloride (243 mg,0.35 mmol) were added to triethylamine (20 mL), nitrogen was displaced 3 times, and the temperature was raised to 80℃for 1 hour. Cooled to room temperature, and the reaction was poured into water (100 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3), and the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product obtained was used directly in the next step.
MS(ESI)M/Z:234.7[M+H] + .
Step 2: the crude product of the previous step was dissolved in methanol (20 mL), potassium carbonate (2.4 g,17.4 mmol) was added and stirred at room temperature for 1 hour. The TLC detection raw materials are mostly reacted, and the reaction solution is concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether/ethyl acetate=5/1) to give 620mg of methyl 5-ethynylnicotinate.
MS(ESI)M/Z:162.1[M+H] + .
1 H NMR(400MHz,CDCl 3 ):δ9.17(s,1H),8.87(s,1H),8.38(t,J＝2.0Hz,1H),3.97(s,3H),3.29(s,1H).
Step 3: methyl 5-ethynylnicotinate (620 mg,3.9 mmol) was dissolved in methanol (15 mL), hydrazine hydrate (962mg, 19.2 mmol) was added and heated at reflux overnight. TLC detection of the completion of the reaction of the starting material was carried out, and the reaction solution was concentrated to dryness under reduced pressure to give 5-ethynyl nicotinic acid hydrazide (600 mg, yield 97%).
MS(ESI)M/Z:162.0[M+H] + .
3.7 mg of the final product (E) -2- (2- (3- (4-bromophenyl) -8-methyl-1, 4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) vinyl) -5- (5-acetylenepyridin-3-yl) -1,3, 4-oxadiazole was prepared starting from 5-ethynylnicotinic acid hydrazide by the synthetic procedure of example 1.
MS(ESI)M/Z:501.1[M+H] + .
1 H NMR(400MHz,CDCl 3 ):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] dec-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (compound 3)
Figure BDA0003618020270000291
The reaction flow is as follows:
Figure BDA0003618020270000292
the reaction steps are as follows:
step 1: (E) -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-carboxylic acid tert-butyl ester (90 mg,0.15 mmol) was dissolved in ethyl acetate (5 mL), and a 6M hydrochloric acid gas/ethyl acetate solution (0.15 mL,0.90 mmol) was added and stirred at room temperature for 1 hour. TLC detection showed that the starting material disappeared, and the reaction solution was concentrated under reduced pressure to give 87.2mg of (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] dec-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] dec-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole dihydrochloride (87.2 mg, crude product) was dissolved in N, N-dimethylformamide (5 mL), and 1-iodo-2 methoxyethane (27.3 mg,0.15 mmol) and potassium carbonate (82.8 mg,0.60 mmol) were sequentially added. Stir at room temperature overnight. TLC detection showed the starting material disappeared and the reaction system was quenched by addition of water (20 mL). The mixture was extracted with ethyl acetate (30 mL. Times.2), and 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 high performance liquid chromatography 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] + .
1 H NMR(400MHz,CDCl 3 ):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] dec-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole (compound 4)
Figure BDA0003618020270000301
The reaction flow is as follows:
Figure BDA0003618020270000311
the reaction steps are as follows:
(E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) vinyl) -5- (quinolin-3-yl) -1,3, 4-oxadiazole dihydrochloride (76 mg,0.13 mmol) was dissolved in dichloromethane (5 mL) and methanesulfonyl chloride (15.8 mg,0.14 mmol) and triethylamine (42 mg,0.42 mmol) were added sequentially. Stir at room temperature overnight. TLC detection showed the starting material disappeared and the reaction system was quenched by addition of water (20 mL). The mixture was extracted with dichloromethane (20 mL. Times.2), and 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 high performance liquid chromatography to give 13.9mg of (E) -2- (2- (3- (4-bromophenyl) -8- (methylsulfonyl) -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:590.9[M+H] + .
1 H NMR(400MHz,CDCl 3 ):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 by the synthetic method of reference example 4:
Figure BDA0003618020270000312
Figure BDA0003618020270000321
/>
Figure BDA0003618020270000331
example 15:
(E) -2- (2- (3- (4-bromophenyl) -8- (methylsulfonyl) -1,4, 8-triazaspiro [4.5] dec-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 flow is as follows:
Figure BDA0003618020270000342
the reaction steps are as follows:
step 1: to a mixed solution of methyl 5-bromonicotinate (5.0 g,23.1 mmol), 1-methyl-4- (4, 5-tetramethyl-1, 3, 2-dioxapentaborane-2-yl) -1H-pyrazole (5.3 g,27.7 mmol) and potassium carbonate (7.99 g,57.9 mmol) in 1, 4-dioxane/water (50 mL/10 mL) was added bis- (triphenylphosphine) -palladium dichloride (800 mg,1.14 mmol), nitrogen substitution 3 times, and stirred at 100℃for 12 hours. TLC monitored that the starting material was mostly complete, the reaction was cooled to room temperature and quenched by the addition of water (50 mL). The mixture was extracted with ethyl acetate (50 mL. Times.3), 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).
1 H NMR(400MHz,CDCl 3 )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).
Step 2: 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 warmed to 90℃and refluxed for 2 days. TLC monitoring the reaction of most of the starting material was completed, the reaction solution was cooled to room temperature, solid precipitated, filtered, and the cake was dried to give 5- (1-methyl-1H-pyrazol-4-yl) nicotinic hydrazide (2.5 g).
1 H NMR(400MHz,DMSO-d 6 )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).
Step 3: (E) -3- (3- (4-bromophenyl) -8- (t-butoxycarbonyl) -1,4, 8-triazaspiro [4.5] dec-1, 3-dien-2-yl) acrylic acid (200 mg,0.43 mmol), 5- (1-methyl-1H-pyrazol-4-yl) nicotinic hydrazide (100 mg,0.46 mmol), triethylamine (130 mg,1.29 mmol) and 2- (7-azobenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (250 mg,0.65 mg) were dissolved in dichloromethane (5 mL), and stirred at room temperature for 12 hours. TLC monitored that the starting material was mostly complete and quenched by addition of saturated sodium bicarbonate solution (10 mL). The mixture was extracted with dichloromethane (15 ml×3 times), the organic phases were combined, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: dichloromethane-dichloromethane/methanol=10:1) to give (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] decan-1, 3-diene-8-carboxylic acid tert-butyl ester (230 mg).
MS(ESI)M/Z:661.1[M+H + ].
Step 4: to a solution of (E) -2- (4-bromophenyl) -3- (3- (2- (5- (1-methyl-1H-pyrazol-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 (230 mg,0.35 mmol) and N, N-diisopropylethylamine (135 mg,1.04 mmol) in dichloromethane (5 mL) was added p-toluenesulfonyl chloride (100 mg,0.52 mmol), and the mixture was stirred at room temperature for 2 hours. TLC monitored that the starting material was mostly complete and quenched by addition of saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (15 mL. Times.3), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (eluent: petroleum ether-ethyl acetate) to give (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] decan-1, 3-diene-8-carboxylic acid tert-butyl ester (152 mg). The product structure was not identified.
Step 5: to a solution of (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-carboxylic acid tert-butyl ester (152 mg,0.24 mmol) in dichloromethane (2.5 mL) was added trifluoroacetic acid (0.5 mL), and the mixture was stirred at room temperature for 2 hours. TLC monitored that the starting material was mostly complete and quenched by addition of saturated sodium bicarbonate solution (10 mL). The mixture was extracted with ethyl acetate (10 ml×3 times), and the organic phases were combined, washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give (E) -2- (2- (3- (4-bromophenyl) -1,4, 8-triazaspiro [4.5] dec-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] dec-1, 3-dien-2-yl) vinyl) -5- (5-1-methyl-1H-pyrazol-4-yl) pyridin-3-yl) -1,3, 4-oxadiazole (150 mg, about 0.28 mmol) and triethylamine (84 mg,0.83 mmol) in methylene chloride (5 mL) was added methylsulfonyl chloride (50 mg,0.44 mmol), and the mixture was stirred at room temperature for 2 hours. TLC monitored that the starting material was mostly reacted and quenched by addition of water (10 mL) to the reaction. The mixture was extracted with dichloromethane (15 ml×3 times), the organic phases were combined, washed with water (15 mL), dried over anhydrous sodium sulfate, filtered, and 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] dec-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 + ].
1 H NMR(400MHz,CDCl 3 )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 inhibition effect of the Compounds of the present invention on Ba/F3 cell lines stably expressing triple mutant EGFR
The experiment adopts a fluorescence method to measure the ATP content in cells to detect the proliferation inhibition effect of the compound on cell lines stably expressing the triple mutant EGFR (EGFR triple mutants), and obtains half inhibition concentration IC of the compound on proliferation inhibition of the cell lines of the triple mutant EGFR (EGFR triple mutants) 50 。
1. Experimental materials
RPMI-1640 medium, fetal Bovine Serum (FBS), 100 XPen/Strep, glutaMAX-I supply was purchased from GIBCO corporation. Cell Titer-Glo luminescence Cell viability assay reagents were purchased from Promega corporation.
2. Experimental method
1) Stably transfected Ba/F3 (DEL 19/T790M/C797S and L858R/T790M/C797S) cells were counted by a cytometer per wellA density of 3000 cells were seeded into 96 well plates at 100 μl per well. Placing in incubator (37 ℃,5% CO) 2 ) Incubate overnight.
2) Day 0: 500nL of a gradient diluted test compound (initial concentration of 30. Mu.M, 10 concentrations, 1:3 dilution) was added to the cells of the plates using D300e (TECAN) and the final DMSO concentration was 0.5%, and the plates were incubated in a cell incubator for 72 hours (37 ℃,5% CO) 2 ). Blank control was added to 500nL of DMSO per well.
3) Day 3: mu.L of Cell Titer-Glo reagent was added to each well, and the mixture was shaken at 500rpm for 2 minutes, centrifuged at 1000rpm for 1 minute, and incubated at room temperature for 10 minutes under dark conditions to stabilize the luminescence signal.
4) The luminescence signal was detected by an Envision enzyme-labeled instrument (PerkinElmer).
5) Data analysis was performed using GraphPad Prism 6 software to calculate IC50 of compounds.
Proved by measurement, the compound has good inhibition effect on the cell proliferation of the Ba/F3 Del19/T790M/C797S EGFR tri-mutant cell line and the Ba/F3L 858R/T790M/C797S EGFR tri-mutant cell line, and the IC thereof 50 Values are typically below 2 μm; IC of part of the Compounds of the invention 50 IC of the compound of the present invention having a value of less than 1. Mu.M, more excellent 50 Values below 0.5 μm and even below 0.3 μm. The results of inhibition of the Ba/F3 cell lines of the triple mutant epidermal growth factor receptor by some compounds of the present invention are shown in table 1.
TABLE 1 inhibition of Ba/F3 cell lines stably expressing triple mutant EGFR receptors
Figure BDA0003618020270000381
Description: a represents IC 50 Less than or equal to 0.5 mu M, B represents 0.5 mu M < IC 50 C represents 1 mu M < IC 50 Less than or equal to 2 mu M, D represents IC 50 > 2. Mu.M; n.d. represents not measured.

Claims (27)

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure FDA0004271512990000011
Wherein,,
R 1 selected from C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -S (O) 2 R a 、-C(O)R b ；
R a Selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR aa R ab Or C 3-6 Cycloalkyl, wherein R is aa R is R ab Each independently selected from H, C 1-4 An alkyl group;
R b selected from C 1-6 Alkyl, halogenated C 1-6 Alkyl-, C 1-6 alkyl-O-C 1-6 Alkyl-, -C 1-6 alkyl-OH, -C 1-6 alkyl-NR ba R bb Or C 3-6 Cycloalkyl, wherein R is ba R is R bb Each independently selected from H, C 1-4 An alkyl group; r is R 2 Selected from optionally one or more R c Substituted phenyl, R c Is R ca ，R ca Selected from halogen;
R 3 selected from H;
a is selected from
Figure FDA0004271512990000012
B is selected from
Figure FDA0004271512990000013
R d Selected from C 1-4 Alkyl, C 2-6 Alkynyl, p is selected from 0, 1, 2, 3 or 4.
2. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in any one of claim 1, wherein R a Selected from methyl, ethyl, isopropyl, cyclopropane, -CHF 2 、-CH 2 CH 2 OH、-CH 2 CH 2 OCH 3 、-CH 2 CH 2 N(CH 3 ) 2 。
3. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ca Selected from F, br, cl.
4. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from-CH 3 、
Figure FDA0004271512990000014
Figure FDA0004271512990000021
5. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 1 Selected from-S (O) 2 R a ，R a As defined in claim 1.
6. The compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 5, wherein R 1 Selected from the group consisting of
Figure FDA0004271512990000022
7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R 2 Selected from the group consisting of
Figure FDA0004271512990000023
R ca As defined in claim 1, m is selected from 0, 1, 2, 3 or 4.
8. As claimed inA compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 7, wherein R 2 Selected from the group consisting of
Figure FDA0004271512990000024
9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein R d Selected from-CH 3 、-CH 2 CH 3 、-C≡C。
10. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein B is selected from
Figure FDA0004271512990000025
Figure FDA0004271512990000026
11. A compound of formula (I) or a pharmaceutically acceptable salt thereof as claimed in claim 10 wherein B is selected from
Figure FDA0004271512990000031
12. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, selected from formula (II),
Figure FDA0004271512990000032
wherein R is 1 、R 2 、R 3 B, n are as defined in claim 1.
13. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of formula (III) and (IV),
Figure FDA0004271512990000033
Wherein R is 1 、R 3 、R c 、R d B, n, p are as defined in claim 1 and m is as defined in claim 7.
14. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 13, wherein the compound is selected from formula (V),
Figure FDA0004271512990000034
wherein R is 1 、R 3 、R c 、m、n、R d P is as defined in claim 13.
15. A compound, or a pharmaceutically acceptable salt thereof, selected from,
Figure FDA0004271512990000041
Figure FDA0004271512990000051
16. a pharmaceutical composition comprising a compound of any one of claims 1-15, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
17. Use of a compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 16, in the manufacture of a medicament for the treatment of cancer.
18. The use of claim 17, wherein the cancer is an EGFR-mediated cancer, including lymphoma, ovarian cancer, cervical cancer, prostate cancer, colorectal cancer, breast cancer, pancreatic cancer, glioma, leukemia, gastric cancer, endometrial cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, cholangiocarcinoma, renal cancer, thyroid cancer, mesothelioma, multiple myeloma, melanoma.
19. The use of claim 18, wherein the cancer is lung cancer.
20. An intermediate compound represented by the formula (Z-4) or a stereoisomer, a pharmaceutically acceptable salt thereof,
Figure FDA0004271512990000061
wherein R is 2 、R 3 B, n are as defined in any one of claims 1 to 14.
21. The compound of formula (Z-4) or a stereoisomer, pharmaceutically acceptable salt thereof according to claim 20, which is independently selected from formula (Z-4 a),
Figure FDA0004271512990000062
wherein R is 3 、R c B, m, n are as defined in claim 20.
22. A process for the preparation of a compound of formula (II), characterized in that a compound of formula (Z-4) is obtained by deprotecting a compound of formula (Z-3), and R is introduced 1 Preparing a compound shown in a formula (II),
Figure FDA0004271512990000063
wherein R is 2 、R 3 、B、n、R 1 PG is a commonly used amino protecting group as defined in any of claims 1-14.
23. The process for preparing a compound of formula (II) according to claim 22, wherein the compound of formula (Z-3) is prepared by dehydration of a compound of formula (Z-2),
Figure FDA0004271512990000071
wherein PG, R 2 、R 3 B, n are as defined in claim 22.
24. The process for preparing a compound of formula (II) according to claim 23, wherein the compound of formula (Z-1) is reacted with a Z-5 compound under the action of a condensing agent to prepare a compound of formula (Z-2),
Figure FDA0004271512990000072
wherein PG, R 2 、R 3 B, n are as defined in claim 23.
25. The process according to any one of claims 22 to 24, wherein PG is selected from t-butoxycarbonyl, benzyloxycarbonyl, p-toluenesulfonyl.
26. The process according to claim 23 or 24, wherein the dehydrating agent is selected from the group consisting of the bergs reagent.
27. The process of claim 24, wherein the condensing agent is selected from the group consisting of 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride.
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