CN102731485B - 4-(substituted benzene amino) quinazoline derivant and preparation method thereof, pharmaceutical composition and purposes - Google Patents

4-(substituted benzene amino) quinazoline derivant and preparation method thereof, pharmaceutical composition and purposes Download PDF

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CN102731485B
CN102731485B CN201110082288.8A CN201110082288A CN102731485B CN 102731485 B CN102731485 B CN 102731485B CN 201110082288 A CN201110082288 A CN 201110082288A CN 102731485 B CN102731485 B CN 102731485B
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amine
quinazolin
tetrahydrofuran
yloxy
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CN102731485A (en
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王晶翼
范传文
张龙
严守升
张明会
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QILU PHARMACEUTICAL (HAINAN) CO Ltd
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Qilu Pharmaceutical Co Ltd
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    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • C07—ORGANIC CHEMISTRY
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
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    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

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Abstract

The present invention relates to 4-(substituted benzene amino) quinazoline derivant and preparation method thereof, pharmaceutical composition and purposes. Specifically, the present invention relates to formula I compound or its pharmaceutically acceptable salt or solvate, wherein, R1、R2And R3Definition described in description and claims. The invention still further relates to the preparation method of formula I compound, comprise its pharmaceutical composition and their pharmaceutical applications. Formula I compound of the present invention is effective tyrosine kinase irreversible inhibitor.

Description

4- (substituted phenylamino) quinazoline derivative and preparation method, pharmaceutical composition and application thereof
Technical Field
The invention belongs to the field of pharmaceutical chemicals, and particularly relates to a novel 4- (substituted phenylamino) quinazoline derivative with anti-tumor activity and a preparation method thereof, and application of the 4- (substituted phenylamino) quinazoline derivative in the aspect of serving as a medicine for treating or assisting in treating tumors mediated by receptor tyrosine kinases of mammals (including human beings) or proliferating and migrating tumor cells driven by the receptor tyrosine kinases.
Background
Tumors are one of the major diseases that severely threaten human life and quality of life, and according to WHO statistics, about 690 million patients dying from tumors every year worldwide. Due to the change of living environment and life habit, the incidence and mortality of tumors are gradually increasing in recent years under the action of adverse environment and some adverse factors.
The existing tumor treatment is realized by finding and destroying tumors, with the continuous and deep research on cell signaling pathways, people know the oncogenes and the anticancer genes in tumor cells more and more deeply, and design of new antitumor drugs aiming at specific molecular targets of the tumors is more and more concerned, so that the method becomes a hot research field, and the targeted antitumor drugs are also applied to clinic as a new treatment method and are remarkably developed within a few years. It is now known that Protein Tyrosine Kinase (PTK) signaling pathways are closely related to tumor cell proliferation, differentiation, migration and apoptosis (LiSun, et., drug discovttoday, 2000, 5, 344-.
In recent years, efforts have been made to inhibit cell signal transduction pathways to develop novel target anti-tumor drugs. The signal transduction inhibitor can reduce the survival and proliferation signals of the tumor and promote apoptosis, but not through the cytotoxic effect, so that the selectivity is higher and the toxic and side effects are smaller. At present, more than ten kinds of signal transduction inhibitors are applied to clinical treatment of tumors, mainly tyrosine kinase inhibitor antitumor drugs, wherein the development of compounds with 4- (substituted phenylamino) quinazoline structure types is relatively mature, such as small molecule inhibitors of gefitinib (Iressa), erlotinib (Tarceva), Lapatinib (Lapatinib) and the like aiming at EGFR tyrosine kinase targets.
Gefitinib (Gefitinib), marketed under the trade name Iressa (Iressa), an EGFR tyrosine kinase inhibitor developed by AstraZeneca, which is the epidermal growth factor receptor tyrosine kinase inhibitor that first entered clinical studies, was marketed in japan in 2002 and in the united states the next year for the treatment of advanced or metastatic non-small cell lung cancer (NSCLC) that had previously received chemotherapy. Erlotinib (Erlotinib), tradename Tarceva (Tarceva), an EGFR tyrosine kinase inhibitor developed by OSI, assigned to Genentech and rotkish. Marketed in 2004 in the united states for the treatment of NSCLC and pancreatic cancer. Belongs to a first generation aniline quinazoline micromolecule inhibitor for treating NSCLC, is the only EGFR tyrosine kinase inhibitor which is proved to have survival advantage on advanced non-small cell lung cancer at present, is effective on various non-small cell lung cancer patients, has good tolerance, does not have bone marrow inhibition and neurotoxicity, can obviously prolong the life cycle, and improves the life quality of the patients. Lapatinib (Lapatinib), tradename Tycerb, is a dual inhibitor of EGFR and HER2 developed by GlaxoSmithKline, which has a stronger inhibitory effect on signaling of tumor proliferation and survival than single receptor inhibitors. FDA approved this product for marketing in the united states in 2007 for the indication of treatment with capecitabine in patients with advanced or metastatic breast cancer who overexpress HER2 and have previously received chemotherapy such as anthracyclines, taxanes and trastuzumab.
Furthermore, patent applications WO96/33977, WO97/30035, WO98/13354, WO00/55141, WO02/41882, WO03/82290 and EP837063 et al disclose certain quinazoline derivatives carrying a phenylamino substitution in the 4-position and a substituent in the 6-and/or 7-position, which have receptor tyrosine kinase activity.
However, with the emergence of kinase mutation and tumor resistance, a second generation of irreversible inhibitors against EGFR family targets has emerged. Irreversible inhibitors have many advantages, such as covalent bonding to the ATP binding site, and therefore, strong binding, no need to maintain high intracellular drug concentrations, reduced drug use, extended dosing time, reduced drug resistance, and the like. Irreversible inhibitors that are currently in clinical stage III are HKI-272 and BIBW-2992. As a second generation excellent variety in irreversible inhibitors aiming at EGFR targets, HKI-272 and BIBW-2992 have definite clinical curative effect, still have efficacy on drug-resistant tumors of first generation EGFR target inhibitors, have relatively small toxic and side effects (the maximum tolerated dose is 400mg/day and 90mg/day respectively), and are currently in clinical phase 3 research.
The small molecular tyrosine kinase inhibitor is used as a new targeted antitumor drug, opens a new window for treating and preventing tumors, has slight side effect and good tolerance. Although more than 10 small molecule tyrosine kinase inhibitors have contributed greatly to the clinical treatment of tumors, there is still a need to find additional compounds with better in vivo activity and/or improved pharmacological properties than the existing tyrosine kinase inhibitors, or to find strong or still effective inhibitors against variant kinases such as irreversible inhibitors and the like. Therefore, the development of new improved or more efficient tyrosine kinase inhibitors and the deeper understanding of the relationship between the drugs and known target proteins and the mechanism of the drugs for exerting antitumor effect have important significance for the clinical treatment of tumors.
Disclosure of Invention
The object of the present invention is to find new compounds with potent irreversible inhibition of tyrosine kinases. The present inventors have surprisingly found that 4- (substituted phenylamino) quinazoline derivatives having the structure of formula I have potent irreversible inhibition of tyrosine kinases and/or have good pharmacokinetic behavior in vivo. The present invention has been completed based on this finding.
To this end, a first aspect of the invention provides a compound of formula I:
or a pharmaceutically acceptable salt or solvate thereof,
wherein,
R1is selected from
R2Selected from hydrogen or N, N-dimethylaminomethyl;
R3selected from methoxyethyl, tetrahydrofuran-3-yl, (S) -tetrahydrofuran-3-yl or (R) -tetrahydrofuran-3-yl; and
each R4And R5Independently selected from one or more of hydrogen, halogen, alkyl, alkoxy, and haloalkyl;
if and only if R2Is hydrogen, R3When it is methoxyethyl, R1Is not that
If and only if R2Is N, N-dimethylaminomethyl, R3In the case of tetrahydrofuran-3-yl, (S) -tetrahydrofuran-3-yl or (R) -tetrahydrofuran-3-yl, R1Is not that
A compound of formula I according to a first aspect of the invention, wherein halogen is selected from fluorine, chlorine or bromine. In one embodiment, wherein said halogen is selected from fluorine or chlorine.
A compound of formula I according to a first aspect of the invention, wherein the alkyl is a straight or branched chain alkyl group, e.g. C1-C10Alkyl and C1-C6An alkyl group.
A compound of formula I according to a first aspect of the invention, wherein alkyl is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl and hexyl. In one embodiment, wherein said alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, and tert-butyl. In one embodiment, wherein said alkyl is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl.
A compound of formula I according to the first aspect of the invention, wherein the pharmaceutically acceptable salt is selected from the group consisting of hydrochloride, sulfate, mesylate, tosylate, fumarate, maleate and malate salts, or solvates, e.g. hydrates, of these salts.
A compound of formula I according to the first aspect of the invention, selected from:
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-amino-3-trifluoromethylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-amino-3-trifluoromethylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4-amino-3-trifluoromethylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (acrylamido) -3-trifluoromethylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4- (acrylamido) -3-trifluoromethylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (acrylamido) -3-trifluoromethylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-bromo-2-fluorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-fluoro-3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (2-methoxyethoxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (2-methoxyethoxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (2-methoxyethoxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
6- (acrylamido) -7- (2-methoxyethoxy) -N- (4-fluoro-3-cyanophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine;
6- (acrylamido) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonamido) -7- (2-methoxyethoxy) -N- (4- ((E) -4- (dimethylamino) crotonamido) -3-trifluoromethylphenyl) quinazolin-4-amine; and
6- (acrylamido) -7- (2-methoxyethoxy) -N- (4- (acrylamido) -3-trifluoromethylphenyl) quinazolin-4-amine;
or a pharmaceutically acceptable salt or solvate thereof.
In a second aspect, the present invention provides a process for the preparation of a compound of formula I according to the first aspect of the invention, which comprises the steps of:
a) synthesizing a corresponding intermediate II from the 6-nitro-7-fluoro-4-hydroxyquinazoline;
b) intermediate II with R in the presence of a suitable base3OH reacts to generate an intermediate III;
c) reacting the intermediate III with a suitable reducing agent to obtain an intermediate IV;
intermediate IV Synthesis of Compound I, two alternatives were chosen:
d) reacting the intermediate IV with corresponding acyl chloride to generate a compound I;
or
e) Reacting the intermediate IV with diethylphosphonoacetic acid by using a proper condensing agent to generate an intermediate, and reacting with corresponding aldehyde to generate a compound I;
wherein R is1、R2And R3Each group has the meaning as defined in any one of the embodiments of the first aspect of the invention.
The preparation method according to the second aspect of the invention, wherein 6-nitro-7-fluoro-4-hydroxyquinazoline in step a) is halogenated with a halogenating agent, and then reacted with the corresponding amine to obtain intermediate II, wherein the halogenating agent can be selected from thionyl chloride, phosphorus trichloride and phosphorus pentachloride. In one embodiment, the halogenating agent is thionyl chloride.
The process according to the second aspect of the invention, wherein the suitable base in step b) is selected from the group consisting of sodium hydride, potassium hydride and calcium hydride. In one embodiment, the suitable base is sodium hydride.
The preparation method according to the second aspect of the present invention, wherein the reducing agent in step c) is a reducing agent commonly used for nitro reduction and selected from SnCl2Concentrated hydrochloric acid, Zn powder acetic acid, Fe powder acetic acid, Pd-C catalytic hydrogenation and the like. In one embodiment, the reducing agent is SnCl2Concentrated hydrochloric acid. In another embodiment, the reducing agent is Zn powder acetic acid.
The preparation method according to the second aspect of the present invention, wherein the suitable condensing agent in step e) is a condensing agent commonly used for condensing amino group and carboxylic acid, and is selected from N, N' -Carbonyldiimidazole (CDI), kat condensing agent (BOP) or 4- (4, 6-dimethoxytriazine) -4-methylmorpholine hydrochloride (DMTMM), etc. In one embodiment, the condensing agent is CDI.
In the process of the second aspect of the invention, it is necessary, where necessary, to protect some groups (e.g., amino, hydroxyl, etc.) during the preparation of the compounds of formula I from undesired reactions and, at the same time, to remove the protecting groups when appropriate. These examples are not exhaustive and methods of using and deprotecting protecting groups not specifically mentioned are also within the scope of the invention.
A third aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula I according to any one of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
A fourth aspect of the present invention relates to the use of a compound of formula I as described in any one of the embodiments of the first aspect of the present invention in the manufacture of a medicament for the treatment and/or prophylaxis of a disease or condition associated with receptor tyrosine kinases in a mammal, including a human.
The fourth aspect of the present invention also relates to the use of a compound of formula I according to any one of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof for the manufacture of a medicament for the therapeutic or adjunctive treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven proliferation and migration of tumor cells in mammals, including humans.
It is expected that the compounds of the invention will be useful in the treatment of erbB receptor tyrosine kinase sensitive cancers such as EGFR or Her2 high expression and EGF driven tumors, including solid tumors such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, gastric, head and neck, liver, lung (especially non-small cell lung cancer), neuronal, esophageal, ovarian, pancreatic, prostate, kidney, skin, testicular, thyroid, uterine and vulva, etc., and non-solid tumors such as leukemia, multiple myeloma or lymphoma, etc. To this end, the tumors or cancers involved in the above-mentioned phrases "diseases or disorders associated with receptor tyrosine kinases" and "tumors mediated by receptor tyrosine kinases" or "proliferation and migration of tumor cells driven by receptor tyrosine kinases" of the present invention may include the erbB receptor tyrosine kinase sensitive cancers described above, such as EGFR or Her2 high expression and EGF driven tumors, including solid tumors such as cancers of the bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus, vulva, etc., and non-solid tumors such as leukemia, multiple myeloma or lymphoma, etc.
A fifth aspect of the present invention relates to a method for the treatment and/or prophylaxis of a disease or condition associated with receptor tyrosine kinases in a mammal in need thereof, which comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I as described in any one of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof.
The fifth aspect of the present invention also relates to a method for the treatment or co-treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven proliferation and migration of tumor cells in a mammal (including a human being) in need thereof, which comprises administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I according to any one of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof.
The fifth aspect of the present invention further relates to a method for the treatment and/or prophylaxis of tumors or cancers in a mammal, including a human, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound of formula I according to any one of the embodiments of the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof, said tumors or cancers comprising erbB receptor tyrosine kinase sensitive cancers, such as EGFR or Her2 high expression and EGF driven tumors, including solid tumors, such as bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and vulva, and non-solid tumors, such as leukemia, Multiple myeloma or lymphoma, etc.
A sixth aspect of the present invention relates to a pharmaceutical composition for the treatment and/or prophylaxis of a disease or condition associated with receptor tyrosine kinases, which comprises a compound of formula I as described in any one of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
The sixth aspect of the present invention also relates to a pharmaceutical composition for the therapeutic or adjuvant treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven tumor cell proliferation and migration in mammals, including humans, which comprises a compound of formula I as described in any of the embodiments of the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
The sixth aspect of the present invention further relates to a pharmaceutical composition for the treatment and/or prophylaxis of tumors or cancers in mammals (including humans) comprising a compound of formula I according to any of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof, optionally together with one or more pharmaceutically acceptable carriers or excipients, said tumors or cancers comprising erbB receptor tyrosine kinase sensitive cancers, such as EGFR or Her2 high expression and EGF driven tumors, including solid tumors, such as cancers of the bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and vulva, and non-solid tumors, such as leukemia, Multiple myeloma or lymphoma, etc.
A seventh aspect of the present invention relates to a compound of formula I according to any one of the embodiments of the first aspect of the present invention, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment and/or prevention of a disease or condition associated with receptor tyrosine kinases.
The seventh aspect of the present invention also relates to a compound of formula I according to any one of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the therapeutic or co-therapeutic treatment and/or prevention of receptor tyrosine kinase mediated proliferation and migration of tumors or receptor tyrosine kinase driven tumor cells in mammals, including humans.
The seventh aspect of the present invention further relates to a compound of formula I according to any one of the embodiments of the first aspect of the present invention or a pharmaceutically acceptable salt or solvate thereof for use in the treatment and/or prophylaxis of tumors or cancers in mammals, including humans, including erbB receptor tyrosine kinase sensitive cancers such as EGFR or Her2 high expression and EGF driven tumors, including solid tumors such as cancers of the bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, oesophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and vulva etc. and non-solid tumors such as leukemia, multiple myeloma or lymphoma etc.
Features of any aspect of the invention or any embodiment of that aspect are equally applicable to any other aspect or any embodiment of that other aspect, as long as they are not mutually inconsistent, although appropriate modifications to the respective features may be made, if applicable to each other.
The invention is further described below.
All documents cited herein are incorporated by reference in their entirety and to the extent such documents do not conform to the meaning of the present invention, the present invention shall control. Further, the various terms and phrases used herein have the ordinary meaning as is known to those skilled in the art, and even though such terms and phrases are intended to be described or explained in greater detail herein, reference is made to the term and phrase as being inconsistent with the known meaning and meaning as is accorded to such meaning throughout this disclosure.
In the compounds of formula I of the present invention, wherein the quinazoline rings may be numbered in the following illustrative order:
the term "halogen" or "halo" refers to fluorine, chlorine, bromine and iodine.
The terms "alkyl", "alkenyl" and "alkynyl" as used herein have the general meaning well known in the art, and are straight or branched chain hydrocarbyl groups such as, but not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, allyl, propenyl, propynyl, and the like, and may be collectively referred to as "hydrocarbyl" or "alkanyl".
In the process of the present invention for the synthesis of compounds of formula I, the various starting materials for the reaction are either prepared by methods known in the literature or are commercially available, as known to the person skilled in the art. The intermediates, starting materials, reagents, reaction conditions, etc. used in the above reaction schemes may be appropriately modified according to the knowledge of those skilled in the art. Alternatively, other compounds of formula I not specifically recited herein may also be synthesized by those skilled in the art according to the method of the second aspect of the invention.
The compound of formula I of the present invention may be used in combination with other pharmaceutically active ingredients as long as it does not produce other adverse effects, such as allergic reactions.
The active compound shown in the formula I can be independently used as an anti-cancer drug or can be used together with one or more other anti-tumor drugs. Combination therapy is achieved by administering the individual therapeutic components simultaneously, sequentially or separately.
The term "composition" as used herein means a product comprising the specified amounts of each of the specified ingredients, as well as any product which results, directly or indirectly, from combination of the specified amounts of each of the specified ingredients.
The compounds of the invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base functionality of the compounds of the invention with a suitable organic acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitate, pectate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Likewise, basic nitrogen-containing groups may be quaternized with: lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl sulfate, diethyl sulfate, dibutyl sulfate, and diamyl sulfate; long chain halides such as decyl, dodecyl, tetradecyl and octadecyl chlorides, bromides and iodides; arylalkyl halides such as benzyl bromide and phenethyl bromide and others. Thus obtaining a product that is soluble or dispersible in water or oil. Examples of acids which may be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric, hydrobromic, sulfuric and phosphoric acids, and organic acids such as oxalic, maleic, succinic and citric acids.
Base addition salts can be prepared in situ during the final isolation and purification of the compounds of the invention by reacting the carboxylic acid-containing moiety of the compounds of the invention with a suitable base, such as the hydroxide, carbonate and bicarbonate salts of a pharmaceutically acceptable metal cation, or ammonia or an organic primary, secondary or tertiary amine.
Pharmaceutically acceptable salts also include, but are not limited to, cations based on alkali or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like, as well as non-toxic quaternary ammonium and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium, and the like. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.
The compound of the formula I also comprises isomers, racemates, enantiomers, diastereomers, enantiomer enrichments, solvates and esters thereof, and the compound of the formula I and the isomers, racemates, enantiomers, diastereomers, enantiomer enrichments, solvates and esters thereof can also form solvates, such as hydrates, alcoholates and the like. The compounds may also be prodrugs or forms which release the active ingredient upon metabolic change in vivo. The selection and preparation of suitable prodrug derivatives is well known to those skilled in the art. In general, for the purposes of the present invention, the solvate forms are equivalent to the non-solvate forms with pharmaceutically acceptable solvents such as water, ethanol, and the like.
The actual dosage levels of each active ingredient in the pharmaceutical compositions of this invention can be varied so that the resulting amount of active compound is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration. Dosage levels will be selected with regard to the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is common practice in the art to start doses of the compounds at levels below those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
When used in the above-described treatment and/or prophylaxis or other treatment and/or prophylaxis, a therapeutically and/or prophylactically effective amount of one of the compounds of the present invention may be employed in pure form or, where present, in the form of a pharmaceutically acceptable ester or prodrug. Alternatively, the compounds may be administered in a pharmaceutical composition comprising the compound of interest together with one or more pharmaceutically acceptable excipients. The phrase "therapeutically and/or prophylactically effective amount" of a compound of the present invention refers to a sufficient amount of the compound to treat a disorder at a reasonable benefit/risk ratio applicable to any medical treatment and/or prophylaxis. It will be appreciated, however, that the total daily amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment. For any particular patient, the specific 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 treatment; drugs used in combination or concomitantly with the specific compound employed; and similar factors known in the medical arts. For example, it is common 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 dose until the desired effect is achieved. In general, the dosage of the compounds of formula I of the present invention for use in mammals, especially humans, may be between 0.001 to 1000mg/kg body weight/day, such as between 0.01 to 100mg/kg body weight/day, such as between 0.01 to 10mg/kg body weight/day.
Pharmaceutical compositions containing effective amounts of the compounds of the present invention may be prepared using pharmaceutical carriers well known to those skilled in the art. The invention therefore also provides pharmaceutical compositions comprising a compound of the invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specifically formulated for oral administration, for parenteral injection or for rectal administration in solid or liquid form.
The pharmaceutical compositions can be formulated in a variety of dosage forms for ease of administration, for example, oral formulations (e.g., tablets, capsules, solutions or suspensions); injectable formulations (e.g., injectable solutions or suspensions, or injectable dry powders, which are ready to use by the addition of water for injection prior to injection). The carrier in the pharmaceutical composition comprises: binders for oral formulations (e.g., starch, typically corn, wheat or rice starch, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone), diluents (e.g., lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and/or glycerol), lubricants (e.g., silicon dioxide, talc, stearic acid or salts thereof, typically magnesium or calcium stearate, and/or polyethylene glycol), and, if desired, disintegrating agents, such as starch, agar, alginic acid or salts thereof, typically sodium alginate, and/or effervescent mixtures, solubilizing agents, stabilizers, suspending agents, pigments, flavoring agents, and the like, preservatives for injectable formulations, solubilizers, stabilizers, and the like; bases for topical formulations, diluents, lubricants, preservatives, and the like. Pharmaceutical formulations may be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically), and if certain drugs are unstable under gastric conditions, they may be formulated as enteric coated tablets.
More specifically, the pharmaceutical compositions of the present invention may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (e.g., by powders, ointments, or drops), bucally to humans and other mammals, or as an oral or nasal spray. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Compositions suitable for parenteral injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol, and the like), vegetable oils (such as olive oil), injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
These compositions may also contain adjuvants such as preserving, wetting, emulsifying and dispersing agents. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example, sugars, sodium chloride and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of substances delaying absorption, for example, aluminum monostearate and gelatin.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
In some cases, to prolong the effect of a drug, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. Thus, the rate of absorption of the drug is dependent on its rate of dissolution, which in turn may be dependent on crystal size and crystal form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms can be prepared by forming a microcapsule matrix of the drug in a biodegradable polymer such as polylactide-polyglycolide. The rate of drug release can be controlled depending on the ratio of drug to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations may also be prepared by embedding the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial filter or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium immediately prior to use.
The compounds of the present invention or compositions thereof may be administered orally or parenterally. The oral administration can be tablet, capsule, coating agent, and intestinal tract external preparation such as injection and suppository. These formulations are prepared according to methods familiar to those skilled in the art. The adjuvants used for the manufacture of tablets, capsules, coatings are the customary adjuvants, such as starch, gelatin, gum arabic, silica, polyethylene glycol, solvents for liquid dosage forms, such as water, ethanol, propylene glycol, vegetable oils (e.g. corn oil, peanut oil, olive oil, etc.). The preparation containing the compound of the invention also comprises other auxiliary materials, such as a surfactant, a lubricant, a disintegrating agent, a preservative, a flavoring agent, a pigment and the like. The dosage of the compounds of formula I containing the present invention in tablets, capsules, coatings, injections and suppositories is calculated as the amount of compound present in the unit dosage form. The compound of formula I of the present invention is generally present in an amount of from 1 to 5000mg in a unit dosage form, preferably a unit dosage form containing from 10 to 500mg, more preferably a unit dosage form containing from 20 to 300 mg. In particular, the present invention may provide solid dosage forms for oral administration including capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound may be mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) humectants such as cetyl alcohol and glycerol monostearate; h) adsorbents such as kaolin and bentonite, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, buffers may also be included in the dosage forms.
Solid compositions of a similar type, using excipients such as lactose and high molecular weight polyethylene glycols and the like, can also be used as fillers in soft and hard capsules.
Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the art of pharmaceutical formulation. These solid dosage forms may optionally contain opacifying agents and may also be of such a composition that they release the active ingredient(s) only, or preferentially, at a site in the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. If appropriate, the active compounds can also be formulated in microencapsulated form with one or more of the abovementioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. Liquid dosage forms may contain, in addition to the active compound, inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Oral compositions may contain, in addition to inert diluents, adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.
Compositions for rectal or vaginal administration are preferably suppositories. Suppositories can be prepared by mixing the compounds of the invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at room temperature but liquid at body temperature and therefore melt in the rectal or vaginal cavity to release the active compound.
The compounds of the present invention and compositions thereof are also contemplated for topical administration. Dosage forms for topical administration of the compounds of the present invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any required preservatives, buffers, or propellants. Ophthalmic formulations, ocular ointments, powders, and solutions are also contemplated within the scope of the invention.
The compounds of the invention may also be administered in the form of liposomes. As is well known in the art, liposomes are typically made with phospholipids or other lipid materials. Liposomes are formed from single or multiple layers of hydrated liquid crystals dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions of the present invention in liposome form may contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are natural and synthetic phospholipids and phosphatidylcholines (lecithins), which may be used alone or together. Methods of forming liposomes are well known in the art.
The invention unexpectedly discovers that the quinazoline derivative shown in the structural formula I shows an inhibitory activity on EGFR and Her2 tyrosine kinases, and simultaneously has an inhibitory effect on cell strains with high expression of EGFR and Her2 tyrosine kinases, so that the quinazoline derivative can be used for diseases mediated by EGFR and Her2 receptor tyrosine kinases alone or partially, mainly through inhibiting one or more EGFR family tyrosine kinases and generating antiproliferative, anti-migration and pro-apoptosis through inhibiting the activity of the kinases. In particular, the compounds of the invention are useful in the prevention and treatment of tumors that are sensitive to one or more erbB receptor tyrosine kinases, particularly tumors that are highly expressed on EGFR or Her2 and EGF-driven, by the inhibition of EGFR and Her2 tyrosine kinases. Including solid tumors such as cancers of the bile duct, bone, bladder, brain/central nervous system, breast, colorectal, endometrial, stomach, head and neck, liver, lung (especially non-small cell lung cancer), neurons, esophagus, ovary, pancreas, prostate, kidney, skin, testis, thyroid, uterus and vulva, non-solid tumors such as leukemia, multiple myeloma or lymphoma.
Detailed Description
The invention is further illustrated by the following specific preparation examples and biological experiments, however, it should be understood that these examples and biological experiments are intended only for the purpose of more detailed description and are not to be construed as limiting the invention in any way.
Although many materials and methods of operation are known in the art for the purpose of carrying out the invention, the invention is nevertheless described herein in as detail as possible. It will be clear to those skilled in the art that, in the following, the materials used and the methods of operation are well known in the art, if not specifically stated.
In the present context, unless otherwise specified, wherein: (i) the temperature is expressed in degrees centigrade (DEG C), and the operation is carried out at room temperature or in a temperature environment; (ii) drying the organic solvent with anhydrous sodium sulfate, evaporating the solvent with a rotary evaporator under reduced pressure, and keeping the bath temperature not higher than 60 deg.C; (iii) the reaction process was followed by Thin Layer Chromatography (TLC); (iv) the final product has satisfactory proton NMR spectrum (1H-NMR) and Mass Spectrometry (MS) data.
Example 1: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quina-zoline Synthesis of oxazolin-4-amine (Compound 1)
Compound 1
a.N- (4-bromo-2-fluorophenyl) -6-nitro-7-fluoroquinazoline-4-amine synthesis
4-hydroxy-7-fluoro-6-nitroquinazoline (35.0g) was added to a 1000ml single-necked flask and 300ml of SOCl was added2And 5ml DMF, heated to reflux in an oil bath (T)Outer coverDissolving the raw materials clear after 2h at 95 ℃, reacting for 3 h-4 h under the condition of heat preservation, detecting the raw materials by TLC (developing agent PE: EA is 1: 1)Distilling off SOCl under reduced pressure2Adding dichloromethane into the residue to dissolve, distilling off dichloromethane under reduced pressure, repeating the above operation for 2 times, and evaporating the solvent under reduced pressure to obtain crude product of 4-chloro-6-nitro-7-fluoro-quinazoline.
Adding 4-chloro-6-nitro-7-fluoro-quinazoline (10mmol) into 300ml of acetonitrile, adding 4-bromo-2-fluoroaniline (8mmol) under mechanical stirring at room temperature, separating out a large amount of solids, heating in an oil bath to reflux, detecting by TLC (developing agent PE: EA ═ 1: 1 or EA) after 30min, completely supplementing 4-bromo-2-fluoroaniline (2mmol) if a small amount of B does not react, monitoring the raw material B by real-time TLC until the raw material B disappears, performing suction filtration, and washing with acetonitrile for several times to obtain the target product N- (4-bromo-2-fluorophenyl) -6-nitro-7-fluoro-quinazoline-4-amine (94% yield).
Synthesis of 6-nitro-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazolin-4-amine
NaH (40mmol) was added to a three-necked flask and mixed with 300ml THF uniformly, the temperature was lowered to 0 ℃ and a mixture of (S) -3-hydroxytetrahydrofuran (40mmol) in THF (25ml) was added dropwise with mechanical stirring, releasing a large amount of gas. After the dripping is finished, stirring is carried out for 2 hours at room temperature, and no gas is discharged. The temperature was reduced to-15 ℃ and a suspension of N- (4-bromo-2-fluorophenyl) -6-nitro-7-fluoroquinazolin-4-amine (5mmol) in THF (70ml) and DMF (5ml) was added dropwise. After the dropwise addition, the reaction was continued for 1.5 hours while maintaining the temperature, and naturally warmed to room temperature (28 ℃ C.), the reaction was continued for 2 hours, and the disappearance of the starting material C was detected by TLC (developer EA). Vacuum distilling at 30 deg.C, concentrating until no solution is distilled out. Diluting with appropriate amount of ice water (400ml), precipitating a large amount of solid, filtering, washing the filter cake with appropriate amount of water, and drying at low temperature to obtain 6-nitro-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazoline-4-amine (yield of 90%).
c.6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazoline-4- Amine (Compound)1) Synthesis of (2)
Compound 1
Taking 12mmol of SnCl2Completely dissolving (30ml) with a proper amount of concentrated hydrochloric acid, slowly dropwise adding into a reaction bottle filled with 6-nitro-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazoline-4-amine (4mmol) while stirring, heating to 50 ℃ for reaction for 2h, detecting by 3TLC (a developing agent EA: MeOH ═ 10: 1), completely reacting the raw materials, performing suction filtration, stirring a filter cake with absolute ethyl alcohol, performing suction filtration, and drying to obtain the hydrochloride of 6-amino-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazoline-4-amine (92% yield).
Suspending hydrochloride (3mmol) of 6-amino-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazoline-4-amine in a mixed solution of 80ml acetonitrile and 5ml N-methylpyrrolidone (NMP), cooling to below-5 ℃, dropwise adding an acetonitrile solution of acryloyl chloride, detecting by TLC (developing agent DCM: MeOH ═ 15: 1 or EA: MeOH ═ 10: 1) in real time until hydrochloride of raw material 6-amino-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-bromo-2-fluorophenyl) quinazoline-4-amine completely disappears, adding 2ml water for extraction, concentrating under reduced pressure at room temperature until no solvent is evaporated, diluting with 200ml of water, adjusting the pH value of an ice sodium hydroxide solution to 6-8, separating out a large amount of solid, filtering, extracting the filtrate for 3 times by using equal amount of ethyl acetate, drying, concentrating, combining with a filter cake, and performing column chromatography to obtain a target product, namely a light beige solid (49% yield).
1H-NM(600MHz，DMSO-d6，ppm)：9.78(s，1H)，9.53(s，1H)，8.95(s，1H)，8.40(s，H)，7.64(d，1H，J＝9.6Hz)，7.46(m，2H)，7.25(s，1H)，6.77(dd，1H，J＝10.2Hz，J＝17.2Hz)，6.32(d，1H，J＝17.2Hz)，5.83(d，1H，J＝10.2Hz)，5.31(d，1H，J＝3Hz)，4.02(s，1H)，3.95(m，2H)，3.79(m，2H)，2.35(m，1H)，2.16(m，1H)。
ESI-MS(m/z)：[M+H]+475.1。
Example 2: 6- (Acryloylamino) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-chlorophenyl) quina Synthesis of oxazolin-4-amine (Compound 2)
Compound 2
In a similar manner to the preparation of compound 1, starting from (R) -3-hydroxytetrahydrofuran and 4-fluoro-3-chloroaniline, compound 2 (55% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.83(s，1H)，9.56(s，1H)，8.95(s，1H)，8.54(d，1H，J＝4.2Hz)，8.14(dd，1H，J＝2.4Hz，J＝6.6Hz)，7.81(m，1H)，7.41(t，1H，J＝9.6Hz)，7.26(s，1H)，6.76(dd，1H，J＝10.8Hz，J＝17.2Hz)，6.33(dd，1H，J＝1.8Hz，J＝16.8Hz)，5.84(dd，1H，J＝1.2Hz，J＝9.6Hz)，5.31(t，1H，J＝1.8Hz)，4.01(m，2H)，3.94(dd，1H，J＝7.8Hz，J＝15.6Hz)，3.79(m，1H)，2.35(m，1H)，2.15(m，1H)。
ESI-MS(m/z)：[M+H]+429.3。
Example 3: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (tetrahydrofuran-3-yloxy) -N- (4- (pyridoxal) carbonyl Synthesis of pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine (Compound 3)
Compound 3
a.Synthesis of 4- (pyridin-2-ylmethoxy) -3-chlorophenylamino hydrochloride
2-Chloromethylpyridine hydrochloride 60g dissolved in 250ml DMF, add K2CO3(102g) When a large amount of gas is emitted, stirring at room temperature for reaction for 0.5h, adding 2-chloro-4-nitrophenol (65g) and KI (3.1g), heating to 60 ℃ for continuous reaction, monitoring by TLC in real time, adding 2000ml of ice water when the raw materials react completely, separating out a large amount of solid, performing suction filtration, washing a filter cake for multiple times, and drying to obtain a brown yellow solid. Adding the solid to SnCl2And (3eq) reacting in concentrated hydrochloric acid (150ml) solution at 50 ℃ for 4h, detecting by TLC that the raw materials completely react, filtering, and washing with absolute ethyl alcohol for a plurality of times to obtain the target product 4- (pyridin-2-ylmethoxy) -3-chloroanilino hydrochloride (yield 89%).
6-Nitro-7- (tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazol Synthesis of lin-4-amine
Adding 4-chloro-6-nitro-7-fluoro-quinazoline (10mmol) into 300ml acetonitrile, adding 4- (pyridine-2-ylmethoxy) -3-chloroaniline hydrochloride (10mmol) under mechanical stirring at room temperature, separating out a large amount of solid, heating in an oil bath to reflux, detecting by TLC after 30min until the raw material 4-chloro-6-nitro-7-fluoro-quinazoline disappears, and washing by suction filtration of acetonitrile for several times to obtain the target product 6-nitro-7-fluoro-N- (4- (pyridine-2-ylmethoxy) -3-chlorophenyl) quinazoline-4-amine.
NaH (20mmol) was added to a three-necked flask and mixed with 200ml THF, cooled to 0 deg.C, and a mixture of racemic 3-hydroxytetrahydrofuran (20mmol) in THF (25ml) was added dropwise with mechanical stirring, with a large amount of gas evolved. After the dripping is finished, stirring is carried out for 2 hours at room temperature, and no gas is discharged. The temperature was reduced to-15 ℃ and a suspension of 6-nitro-7-fluoro-N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine (10mmol) in THF (70ml) and DMF (5ml) was added dropwise. After the dripping is finished, the temperature is maintained for continuous reaction for 1.5h, the temperature is naturally raised to room temperature (28 ℃), the reaction is continued for 2h, and TLC detection is carried out. Vacuum concentrating at 30 deg.C until no solution is distilled off. Diluting with appropriate amount of ice water (400ml), precipitating a large amount of solid, filtering, washing filter cake with appropriate amount of water, and drying at low temperature to obtain 6-nitro-7- (-tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine.
c. (E) -6- (4- (dimethylamino) crotonylamino) -7- (tetrahydrofuran-3-yloxy) -N- (4- (pyridine-2-) Synthesis of methoxymethoxy) -3-chlorophenyl) quinazolin-4-amine (Compound 3)
Compound 3
Taking 12mmol of SnCl2Dissolving the intermediate in a proper amount of concentrated hydrochloric acid completely (30ml), slowly dropwise adding the solution into a reaction bottle filled with 6-nitro-7- (-tetrahydrofuran-3-yloxy) -N- (4- (pyridine-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine (4mmol) while stirring, heating to 50 ℃ for reaction for 2h, detecting by TLC that the raw material is completely reacted, performing suction filtration, stirring the filter cake with absolute ethanol, performing suction filtration, and drying to obtain the intermediate 6-nitro-7- (-tetrahydrofuran-3-yloxy) -N- (4- (pyridine-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine hydrochloride (98% yield).
Suspending hydrochloride (3mmol) of 6-nitro-7- (-tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine in a mixed solution of 80ml acetonitrile and 5ml NMP, cooling to below-5 ℃, dropwise adding acetonitrile solution of 4-N, N-dimethylamino crotonyl chloride, detecting by TLC in real time until the raw materials completely disappear, adding 2ml of water for quenching, concentrating at room temperature under reduced pressure until no solvent is evaporated, diluting with 200ml of water, adjusting pH to 6-8 by using an ice sodium hydroxide solution, separating out a large amount of solid, filtering, extracting the filtrate for 3 times by using ethyl acetate with the same amount, drying, concentrating, and combining the filtrate with a filter cake for column chromatography to obtain a target product, namely yellow granular crystals (38% yield).
1H-NM(600MHz，DMSO-d6，ppm)：9.69(s，1H)，9.44(s，1H)，8.93(s，1H)，8.60(d，1H，J＝4.8Hz)，8.48(s，1H)，7.98(d，1H，J＝2.4Hz)，7.89(m，1H)，7.70(dd，1H，J＝2.4Hz，J＝9Hz)，7.59(d，1H，J＝8.4Hz)，7.37(dd，1H，J＝4.8Hz，J＝6.6Hz)，7.24(t，1H，J＝9Hz)，7.19(s，1H)，6.81(m，1H)，6.59(d，1H，J＝15Hz)，5.29(s，3H)，4.00(d，2H，J＝3.6Hz)，3.93(dd，1H，J＝7.8Hz，J＝15.6Hz)，3.78(m，1H)，3.34(s，2H)，2.35(m，1H)，2.20(d，6H，J＝15Hz)，2.15(dd，2H，J＝6Hz，J＝13.2Hz)。
ESI-MS(m/z)：[M+H]+575.4。
Example 4: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) Synthesis of 3-chlorophenyl) -quinazolin-4-amine (Compound 4)
Compound 4
In a similar manner to the preparation of compound 3, starting from acryloyl chloride, compound 4 (46% yield) was obtained as a brownish yellow granular crystal.
1H-NM(600MHz，DMSO-d6，ppm)：9.71(s，1H)，9.55(s，1H)，8.91(s，1H)，8.60(d，1H，J＝3.6Hz)，8.49(s，1H)，7.99(s，1H)，7.89(t，1H，J＝7.2Hz)，7.69(d，1H，J＝8.4Hz)，7.59(d，1H，J＝7.8Hz)，7.37(t，1H，J＝5.4Hz)，7.25(t，2H，J＝9Hz)，6.75(dd，1H，J＝10.8Hz，J＝16.8Hz)，6.33(d，1H，J＝10.2Hz)，5.83(d，1H，J＝10.2Hz)，5.29(s，3H)，4.02(s，2H)，3.94(m，1H)，3.78(dd，1H，J＝7.2Hz，J＝12.6Hz)，2.35(m，1H)，2.14(t，1H，J＝6.6Hz)。
ESI-MS(m/z)：[M+H]+518.4。
Example 5: (E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (4- (3-fluorobenzyloxy) -3-chlorophenyl) quinazolin-4-amine (Compound 5)
Compound 5
a.4- (3-fluorobenzyloxy) -3-chlorophenylamino hydrochloride synthesis
Adding 2-chloro-4 nitrophenol (20mmol) and potassium carbonate (30mmol, 1.5eq) into a round-bottom flask, adding a proper amount of acetonitrile, slowly dropping 400ml of acetonitrile solution of 3-fluorobenzyl bromide (20mmol) through a constant pressure funnel, after the dropping is finished, slowly heating to 70 ℃, reacting for 18h, and detecting the completion of the raw material reaction by TLC. After cooling to room temperature, the reaction mixture was poured into an ice-water mixture, stirred well to precipitate a yellow solid, filtered, the resulting product was washed several times with ice-water, and dried under vacuum to give a yellow solid. Adding the yellow solid to SnCl2And (3eq) reacting in concentrated hydrochloric acid (70ml) at 50 ℃ for 4h, detecting by TLC that the raw materials completely react, filtering, and washing with absolute ethyl alcohol for several times to obtain the target product 4- (3-fluorobenzyloxy) -3-chlorophenylamino hydrochloride (yield 92%).
1H-NMR(300MHz，CDCl3，ppm)：7.37-7.30(m，1H)，7.22-7.17(m，2H)，7.03-6.97(m，1H)，6.79-9.75(m，2H)，6.52-6.48(m，1H)，5.03(s，2H)，3.49(b，2H)；
In a similar manner to the preparation of compound 3, starting from 4- (3-fluorobenzyloxy) -3-chlorophenylamino hydrochloride, compound 5 (28% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.70(s，1H)，9.45(s，1H)，8.93(s，1H)，8.55(s，1H)，8.03(s，1H)，7.70(d，1H，J＝7.2Hz)，7.47(dd，1H，J＝7.2Hz，J＝14.4Hz)，7.32(dd，3H，J＝7.8Hz，J＝18.6Hz)，7.21(m，4H)，6.80(m，1H)，6.60(d，1H，J＝15Hz)，5.29(s，2H)，5.25(s，3H)，4.00(d，3H，J＝2.4Hz)，3.93(dd，1H，J＝7.2Hz，J＝15Hz)，3.79(t，2H，J＝7.8Hz)，2.35(m，3H)，1.88(s，1H)。
ESI-MS(m/z)：[M+H]+592.5。
Example 6: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) -3- Synthesis of chlorophenyl) quinazolin-4-amine (Compound 6)
Compound 6
In a similar manner to the preparation of compound 5, starting from acryloyl chloride, compound 6 (37% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.70(s，1H)，9.45(s，1H)，8.90(s，1H)，8.49(s，1H)，7.97(d，1H，J＝2.4Hz)，7.69(dd，1H，J＝2.4Hz，J＝9Hz)，7.47(dd，1H，J＝7.8Hz，J＝14.4Hz)，7.33(t，2H，J＝7.8Hz)，7.25(d，1H，J＝8.4Hz)，7.23(s，1H)，7.19(dd，1H，J＝2.4Hz，J＝9Hz)，6.74(dd，1H，J＝10.2Hz，J＝16.8Hz)，6.32(dd，1H，J＝1.2Hz，J＝16.8Hz)，5.83(d，1H，J＝11.4Hz)，5.29(s，1H)，5.25(s，2H)，4.00(m，2H)，3.93(dd，1H，J＝7.8Hz，J＝16.2Hz)，3.78(m，1H)，2.35(m，1H)，2.14(m，1H)。
ESI-MS(m/z)：[M+H]+535.4。
Example 7: (E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (3-alkynylphenyl) quinazolin-4-amine (Compound 7)
Compound 7
In a similar manner to the preparation of Compound 1, starting from 3-alkynylaniline and 4-N, N' -dimethylaminocrotonyl chloride, Compound 7 (39% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.75(s，1H)，9.45(s，1H)，8.97(s，1H)，8.53(s，1H)，8.00(s，1H)，7.87(d，1H，J＝7.8Hz)，7.38(t，1H，J＝8.4Hz)，7.24(s，1H)，7.20(d，1H，J＝7.2Hz)，6.81(m，1H)，6.60(d，1H，J＝15.6Hz)，5.30(s，1H)，4.20(s，1H)，4.00(d，2H，J＝3.0Hz)，3.93(dd，1H，J＝7.2Hz，J＝15.6Hz)，3.79(m，1H)，3.09(d，2H，J＝6.0Hz)，2.34(m，1H)，2.16(m，8H)，1.19(t，2H，J＝10.8Hz)，1.10(dd，1H，J＝7.2Hz，J＝14.4Hz)。
ESI-MS(m/z)：[M+H]+458.4。
Example 8: 6- (Acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (3-alkynyl phenyl) quinazol Synthesis of lin-4-amine (Compound 8)
Compound 8
In a similar manner to the preparation of compound 1, starting from 3-alkynylaniline and acryloyl chloride, compound 8 (42% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.78(s，1H)，9.56(s，1H)，8.95(s，1H)，8.54(s，1H)，8.01(s，1H)，7.87(d，1H，J＝7.8Hz)，7.39(t，1H，J＝8.4Hz)，7.25(s，1H)，7.20(d，1H，J＝8.4Hz)，6.75(dd，1H，J＝10.2Hz，J＝17.2Hz)，6.33(dd，1H，J＝2.4Hz，J＝17.2Hz)，5.82(t，1H，J＝10.2Hz)，5.30(d，1H，J＝1.8Hz)，4.20(s，1H)，4.00(d，2H，J＝4.2Hz)，3.93(d，1H，J＝7.2Hz)，3.79(m，1H)，2.35(t，1H，J＝7.8Hz)，2.15(d，1H，J＝6.6Hz)。
MS(m/z)：[M+H]+401.3。
Example 9: (E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (4-chloro-3-trifluoromethylphenyl) quinazolin-4-amine (Compound 9)
Compound 9
In a similar manner to the preparation of compound 1, starting from 4-chloro-3-trifluoromethylaniline and 4-N, N' -dimethylaminocrotonyl chloride, compound 9 (33% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.71(s，1H)，9.55(s，1H)，8.92(s，1H)，8.61(s，1H)，8.60(d，1H，J＝4.2Hz)，8.49(s，1H)，7.99(d，1H，J＝2.4Hz)，7.89(m，1H)，7.70(dd，1H，J＝1.8Hz，J＝9Hz)，7.59(d，1H，J＝7.8Hz)，7.37(dd，1H，J＝4.8Hz，J＝7.2Hz)，7.25(d，1H，J＝8.4Hz)，7.23(s，1H)，6.75(dd，1H，J＝10.8Hz，J＝17.4Hz)，6.32(t，1H，J＝15Hz)，5.82(t，1H，J＝10.2Hz)，5.29(s，3H)，4.00(m，2H)，3.93(dd，1H，J＝7.8Hz，J＝15.6Hz)，3.79(m，1H)，3.38(dd，3H，J＝7.2Hz，J＝14.4Hz)，2.35(m，1H)，2.14(m，1H)。
ESI-MS(m/z)：[M+H]+536.4。
Example 10: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-chloro-3-trifluoromethyl) Synthesis of phenyl) quinazolin-4-amines (Compound 10)
Compound 10
In a similar manner to the preparation of compound 1, starting from acryloyl chloride, compound 10 (49% yield) was obtained as yellow, granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.58(s，1H)，8.99(s，1H)，8.59(s，1H)，8.41(d，1H，J＝2.4Hz)，8.29(dd，1H，J＝2.4Hz，J＝8.4Hz)，7.72(t，1H，J＝5.4Hz)，7.79(d，1H，J＝18.6Hz)，7.28(s，1H)，6.77(dd，1H，J＝10.2Hz，J＝17.4Hz)，6.33(t，1H，J＝16.8Hz)，5.84(d，1H，J＝11.4Hz)，5.32(d，1H，J＝2.4Hz)，4.00(dd，2H，J＝10.8Hz，J＝14.4Hz)，3.94(dd，1H，J＝7.8Hz，J＝15Hz)，3.79(m，1H)，2.36(m，1H)，2.16(m，1H)。
ESI-MS(m/z)：[M+H]+479.2。
Example 11: (E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (2-chloro-4-trifluoromethoxyphenyl) quinazolin-4-amine (Compound 11)
Compound 11
In a similar manner to the preparation of compound 1, starting from 2-chloro-4-trifluoromethoxyaniline, compound 11 (34% yield) was obtained as yellow granular crystals.
ESI-MS(m/z)：[M+H]+552.5，[M-H]-550.3。
Example 12: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (2-chloro-4-trifluoromethoxy) Synthesis of phenylphenyl) quinazolin-4-amines (Compound 12)
Compound 12
In a similar manner to the preparation of compound 1, starting from acryloyl chloride, compound 12 (40% yield) was obtained as yellow, granular crystals.
ESI-MS(m/z)：[M+H]+495.5，[M-H]-493.3。
Example 13: (E) -6- (4- (dimethylamino)Crotonamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (4-fluoro-3-cyanophenyl) quinazolin-4-amine (Compound 13)
Compound 13
In a similar manner to the preparation of compound 1, starting from 4-fluoro-3-cyanoaniline, compound 13 (25% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.96(s，1H)，9.46(s，1H)，8.98(s，1H)，8.55(s，1H)，8.38(d，1H，J＝2.4Hz)，8.15(t，1H，J＝4.2Hz)，7.55(t，1H，J＝9.0Hz)，7.26(s，1H)，6.82(m，1H)，6.61(d，1H，J＝15.6Hz)，5.31(s，1H)，4.00(d，2H，J＝14.4Hz)，3.94(dd，1H，J＝7.8Hz，J＝15.0Hz)，3.79(m，1H)，3.34(s，2H)，3.10(t，2H，J＝26.4Hz)，2.35(m，1H)，2.17(dd，7H，J＝12.0Hz，J＝19.2Hz)，1.23(s，2H)。
ESI-MS(m/z)：[M+H]+477.4，[M-H]-475.3。
Example 14: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-cyanophenyl) Synthesis of quinazolin-4-amines (Compound 14)
Compound 14
In a similar manner to the preparation of compound 1, starting from 4-fluoro-3-cyanoaniline, compound 14 (35% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.97(s，1H)，9.57(s，1H)，8.96(s，1H)，8.56(s，1H)，8.38(dd，1H，J＝3.0Hz，J＝6.0Hz)，8.15(m，1H)，7.55(t，1H，J＝9.0Hz)，7.27(s，1H)，6.76(dd，1H，J＝10.2Hz，J＝16.8Hz)，6.34(dd，1H，J＝1.8Hz，J＝17.4Hz)，5.84(dd，1H，J＝1.2Hz，J＝9.6Hz)，5.31(d，1H，J＝2.4Hz)，4.02(dd，2H，J＝4.2Hz，J＝15.0Hz)，3.94(m，1H)，3.79(m，1H)，2.36(m，1H)，2.15(m，1H)。
MS(m/z)：[M+H]+420.3。
Example 15: (E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine (Compound 15)
Compound 15
a.6-amino-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazoline- Synthesis of 4-amine hydrochloride
In a similar manner to the preparation of compound 3, starting from 4-nitrophenol, 6-amino-7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine hydrochloride can be obtained.
6- (Diethylphosphonoacetamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) Synthesis of Yl) phenyl) quinazolin-4-Amines
CDI(26.9g，6eq) is evenly mixed in 100ml acetonitrile, the temperature is reduced to 0, acetonitrile solution (50ml) of diethylphosphonoacetic acid (21.7g, 4eq) is added dropwise, the mixture naturally rises to room temperature after the dropping and is stirred for reaction for 1h, under the ice-water bath, mixed solution of acetonitrile (80ml) of 6-amino-7- ((S) -tetrahydrofuran-3-oxyl) -N- (4- (pyridine-2-yl methoxyl) phenyl) quinazoline-4-amine hydrochloride (12.6g, 1eq) and NMP (10ml) is added dropwise, after the complete dropping, the mixture is heated to room temperature and is continuously reacted for 4h, and the TLC detection reaction is complete. Concentrating under reduced pressure at room temperature until no liquid is evaporated, adding 400ml ice water, extracting with equal amount of ethyl acetate for 3 times, mixing ethyl acetate layers, and 400ml saturated NH4Back extracting with Cl aqueous solution for 1 time, and then adding ethyl acetate to saturated NH4And (3) extracting with a Cl aqueous solution for 2 times, combining ethyl acetate layers, drying with anhydrous sodium sulfate, and concentrating to obtain a target product 6- (diethylphosphonoacetamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine, wherein the target product is directly subjected to the next reaction without further purification.
(E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridoxal) Synthesis of pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine (Compound 13)
Compound 15
Dimethylamino acetaldehyde diethyl acetal (11g) is evenly mixed in 20ml of methanol, 50ml of saturated HCl/methanol solution is dripped into the mixture under ice water bath, the mixture naturally rises to room temperature after dripping, reaction is continued for 10 hours, and TLC detection shows that the reaction is complete (iodine color development) to obtain solution A.
Suspending 6- (diethylphosphonoacetamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine (16.5g) in 120ml THF, adding lithium chloride (2.3g), continuing to react at room temperature for 0.5h, cooling to 0, adding sodium methoxide (18g) in water (10ml), naturally raising to room temperature, continuing to react for 0.5h, cooling to 0 again, adding solution A, maintaining the reaction temperature, continuing to react for 1h, and detecting the reaction completion by TLC. Concentrated under reduced pressure at room temperature until no more liquid is distilled off, 600ml of ice water is added, extraction is carried out with ethyl acetate, and column chromatography is carried out to obtain compound 15 (30% yield).
1H-NM(600MHz，DMSO-d6，ppm)：9.65(d，1H，J＝18.6Hz)，9.48(s，1H)，8.90(s，1H)，8.59(d，1H，J＝4.2Hz)，8.42(t，1H，J＝26.4Hz)，7.85(t，1H，J＝7.8Hz)，7.66(t，2H，J＝18.6Hz)，7.55(d，1H，J＝13.8Hz)，7.36(t，1H，J＝4.8Hz)，7.19(d，1H，J＝12.6Hz)，7.04(d，3H，J＝8.4Hz)，6.79(m，1H)，6.59(t，1H，J＝15.0Hz)，5.27(s，1H)，5.19(s，3H)，3.99(s，3H)，3.93(dd，1H，J＝7.8Hz，J＝15.6Hz)，3.78(d，2H，J＝4.8Hz)，3.12(t，2H，J＝6.0Hz)，3.05(t，1H，J＝7.2Hz)，2.88(d，1H，J＝18.6Hz)，2.34(m，2H)，2.15(dd，9H，J＝22.8Hz，J＝35.4Hz)，1.90(s，5H)。
ESI-MS(m/z)：[M+H]+541.4。
Example 16: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) Synthesis of Yl) phenyl) quinazolin-4-amine (Compound 16)
Compound 16
Compound 16 (45% yield) was obtained as yellow granular crystals by a synthesis similar to compound 3 starting from 4-nitrophenol.
1H-NM(600MHz，DMSO-d6，ppm)：9.63(s，1H)，9.53(s，1H)，8.89(s，1H)，8.59(d，1H，J＝4.8Hz)，8.41(d，1H，J＝4.8Hz)，7.85(m，1H)，7.64(d，2H，J＝9.0Hz)，7.55(d，1H，J＝8.4Hz)，7.36(dd，1H，J＝5.4Hz，J＝7.2Hz)，7.20(s，1H)，7.04(d，2H，J＝9.0Hz)，6.73(t，1H，J＝6.0Hz)，6.31(dd，1H，J＝1.2Hz，J＝16.8Hz)，5.81(t，1H，J＝10.2Hz)，5.28(s，1H)，5.19(s，2H)，4.00(m，2H)，3.93(dd，1H，J＝7.8Hz，J＝15.6Hz)，3.78(m，1H)，2.33(m，1H)，2.13(m，1H)。
ESI-MS(m/z)：[M+H]+484.4。
Example 17: (E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (4- (3-fluorobenzyloxy) phenyl) quinazolin-4-amine (Compound 17)
Compound 17
In a similar manner to the preparation of compound 5, starting from 4-nitrophenol, compound 17 (41% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.63(d，1H，J＝13.2Hz)，9.44(s，1H)，8.89(d，1H，J＝24.0Hz)，8.42(d，1H，J＝8.4Hz)，7.65(t，3H，J＝9.0Hz)，7.45(t，2H，J＝6.6Hz)，7.31(t，3H，J＝7.2Hz)，7.18(dd，3H，J＝12.6Hz，J＝22.8Hz)，7.03(d，3H，J＝8.4Hz)，6.79(dd，1H，J＝9.6Hz，J＝15.6Hz)，6.59(d，1H，J＝16.2Hz)，5.27(s，2H)，5.15(s，3H)，4.22(t，1H，J＝6.6Hz)，3.99(s，3H)，3.93(d，2H，J＝7.8Hz)，3.78(d，2H，J＝4.8Hz)，3.10(d，2H，J＝5.4Hz)，2.34(m，2H)，2.15(m，7H)，1.90(s，2H)，1.37(d，1H，J＝7.2Hz)，1.23(s，1H)，0.91(t，1H，J＝7.8Hz)。
MS(m/z)：[M+H]+558.5。
Example 18: 6- (Acryloylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (3-fluorobenzyloxy) benzene Synthesis of Yl) quinazolin-4-amines (Compound 18)
Compound 18
In a similar manner to the preparation of compound 5, starting from 4-nitrophenol, compound 18 (50% yield) can be obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.62(s，1H)，9.53(s，1H)，8.89(s，1H)，8.42(s，1H)，7.65(d，1H，J＝9.6Hz)，7.45(dd，1H，J＝8.4Hz，J＝14.4Hz)，7.31(t，1H，J＝7.8Hz)，7.18(dd，1H，J＝9.0Hz，J＝18.0Hz)，7.03(d，1H，J＝8.4Hz)，6.73(dd，1H，J＝10.2Hz，J＝16.8Hz)，6.31(d，1H，J＝17.4Hz)，5.82(d，1H，J＝10.2Hz)，5.28(s，1H)，5.15(s，1H)，3.97(m，2H)，3.78(dd，1H，J＝8.4Hz，J＝12.6Hz)，2.33(m，1H)，2.13(t，1H，J＝7.2Hz)。
MS(m/z)：[M+H]+501.3。
Example 19: 6- (acrylamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (acrylamido) - Synthesis of 3-trifluoromethylphenyl) quinazolin-4-amine (Compound 19)
Compound 19
Compound 19 (62% yield) was obtained as yellow granular crystals in a similar synthetic procedure to compound 1 starting from 4-nitro-3-trifluoromethyl and acryloyl chloride.
1H-NM(600MHz，DMSO-d6，ppm)：9.97(s，1H)，9.57(s，1H)，8.96(s，1H)，8.56(s，1H)，8.38(dd，1H，J＝3.0Hz，J＝6.0Hz)，8.15(m，1H)，7.55(t，1H，J＝9.0Hz)，7.27(s，1H)，6.76(m，1H)，6.34(m，1H)，5.84(dd，1H，J＝1.2Hz，J＝9.6Hz)，5.31(d，1H，J＝2.4Hz)，4.02(dd，2H，J＝4.2Hz，J＝15.0Hz)，3.94(m，1H)，3.79(m，1H)，2.36(m，1H)，2.15(m，1H)。
MS(m/z)：[M+H]+514.3，[M-H]-512.3。
Example 20: (E) -6- (4- (dimethylamino) crotonylamino) -7- ((S) -tetrahydrofuran-3-yloxy) -N- Synthesis of (4-amino-3-trifluoromethylphenyl) quinazolin-4-amine (Compound 20)
Compound 20
Compound 20 (46% yield) was obtained as yellow granular crystals in a similar synthetic procedure to compound 1 starting from 4-nitro-3-trifluoromethyl and trans-4-N, N' -dimethylaminocrotonyl chloride.
1H-NM(600MHz，DMSO-d6，ppm)：9.96(s，1H)，9.46(s，1H)，8.98(s，1H)，8.55(s，1H)，8.38(d，1H，J＝2.4Hz)，8.15(t，1H，J＝4.2Hz)，7.55(t，1H，J＝9.0Hz)，7.26(s，1H)，6.82(m，1H)，6.61(d，1H，J＝15.6Hz)，5.31(s，1H)，4.00(d，2H，J＝14.4Hz)，3.94(m，1H)，3.79(m，1H)，3.10(d，2H，J＝6.0Hz)，2.35(m，1H)，2.17(s，12H)。
ESI-MS(m/z)：[M+H]+517.4，[M-H]-515.3。
Example 21: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-bromo-2-fluoro Synthesis of phenyl) quinazolin-4-amines (Compound 21)
Compound 21
Similar to the synthesis of compound 1, compound 21 was obtained (49% yield) using ethylene glycol monomethyl ether and trans-4-N, N-dimethylaminocrotonyl chloride as starting materials.
1H-NMR(600MHz，DMSO-d6，ppm)：9.75(s，1H)，9.51(s，1H)，8.92(s，1H)，8.39(s，1H)，7.64(m，1H)，7.47(m，2H)，7.31(d，J＝7.8Hz，1H)，6.79(m，1H)，6.58(d，J＝15.0Hz，1H)，4.37(t，J＝4.2Hz，2H)，3.81(t，J＝4.2Hz，2H)，3.35(s，3H)，3.09(d，J＝6.0Hz，2H)，2.19(s，6H)。
ESI-MS(m/z)：[M+H]+518.2。
Example 22: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-fluoro-3-chloro Synthesis of phenyl) quinazolin-4-amines (Compound 22)
Compound 22
In a similar manner to the preparation of compound 1, starting from 4-fluoro-3-chloroaniline, compound 22 (55% yield) was obtained as yellow granular crystals.
1H-NMR(600MHz，DMSO-d6，ppm)：9.75(s，1H)，9.53(s，1H)，8.93(s，1H)，8.53(s，1H)，8.01(s，1H)，7.64(d，J＝7.8Hz，1H)，7.38(t，J＝7.8Hz，1H)，7.20(s，1H)，6.80(m，1H)，6.57(d，J＝15.6Hz，1H)，4.37(m，2H)，3.81(t，J＝4.2Hz，2H)，3.35(s，3H)，3.09(d，J＝6Hz，2H)，2.19(s，6H)。
ESI-MS(m/z)：[M+H]+474.3。
Example 23: (E) -6- (4- (dimethylamino) crotonylamino) -7- (2-methoxyethoxy) -N- (4- (pyridine- Synthesis of 2-ylmethoxy) -3-chlorophenyl) quinazolin-4-amine (Compound 23)
Compound 23
In a similar manner to the preparation of compound 21 starting from 4- (pyridin-2-ylmethoxy) -3-chlorophenylamino hydrochloride, compound 23 (38% yield) was obtained as a brown yellow granular crystal.
1H-NMR(600MHz，DMSO-d6，ppm)：9.69(s，1H)，9.54(s，1H)，8.88(s，1H)，8.60(s，1H)，8.48(s，1H)，7.98(d，J＝2.4Hz，1H)，7.88(m，1H)，7.69(dd，J＝9.0Hz，J＝2.4Hz，1H)，7.59(d，J＝7.8Hz，1H)，7.37(t，J＝6.6，1H)，7.29(s，1H)，7.25(d，J＝9Hz，1H)，6.80(m，1H)，6.57(d，J＝15.6Hz，1H)，5.29(s，2H)，4.36(t，J＝4.8，2H)，3.80(t，J＝4.8，2H)，3.35(s，3H)，3.15(s，2H)，2.21(s，6H)。
ESI-MS(m/z)：[M+H]+563.5。
Examples24: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyl) Synthesis of oxy) -3-chlorophenyl) quinazolin-4-amine (Compound 24)
Compound 24
a.4- (3-fluorobenzyloxy) -3-chloroaniline hydrochloride synthesis
Adding 2-chloro-4 nitrophenol (20mmol) and potassium carbonate (30mmol, 1.5eq) into a round-bottom flask, adding a proper amount of acetonitrile, slowly dropping 400ml of acetonitrile solution of 3-fluorobenzyl bromide (20mmol) through a constant-pressure funnel, after the dropping is finished, slowly heating to 70 ℃, reacting for 18 hours, and detecting the completion of the raw material reaction by TLC. After cooling to room temperature, the reaction mixture was poured into an ice-water mixture, stirred well to precipitate a yellow solid, filtered, the resulting product was washed several times with ice-water, and dried under vacuum to give a yellow solid. Adding the yellow solid to SnCl2And (3eq) reacting in concentrated hydrochloric acid (70ml) at 50 ℃ for 4h, detecting by TLC that the raw materials completely react, filtering, and washing with absolute ethyl alcohol for several times to obtain the target product 4- (3-fluorobenzyloxy) -3-chloroaniline hydrochloride (yield 92%).
1H-NMR(300MHz，CDCl3，ppm)：7.37-7.30(m，1H)，7.22-7.17(m，2H)，7.03-6.97(m，1H)，6.79-9.75(m，2H)，6.52-6.48(m，1H)，5.03(s，2H)，3.49(b，2H)。
b. (E) -6- (4- (dimethylamino) crotonylamino) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyloxy) propanoic acid Synthesis of 3-chlorophenyl) quinazolin-4-amine
In a similar manner to the preparation of compound 21, starting from 4- (3-fluorobenzyloxy) -3-chloroaniline hydrochloride, compound 24 (43% yield) was obtained as brown yellow granular crystals.
1H-NMR(600MHz，DMSO-d6，ppm)：9.68(s，1H)，9.52(s，1H)，8.88(s，1H)，8.48(s，1H)，7.97(d，J＝3Hz，1H)，7.69(dd，J＝9.0Hz，J＝2.4Hz，1H)，7.47(m，1H)，7.33(m，2H)，7.29(m，1H)，7.24(d，J＝9.6Hz，1H)，7.18(m，1H)，6.80(m，1H)，6.56(d，J＝15Hz，1H)，5.25(s，2H)，4.36(t，J＝4.8，2H)，3.80(t，J＝4.8，2H)，3.35(s，3H)，3.10(d，J＝4.8Hz，2H)，2.19(s，6H)。
ESI-MS(m/z)：[M+H]+580.5。
Example 25: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (3-alkynylbenzene Synthesis of Yl) quinazolin-4-amines (Compound 25)
Compound 25
In a similar manner to the preparation of compound 21, starting from 3-alkynylaniline, compound 25 (51% yield) was obtained as yellow granular crystals.
1H-NMR(600MHz，DMSO-d6，ppm)：9.75(s，1H)，9.54(s，1H)，8.92(s，1H)，8.53(s，1H)，8.00(s，1H)，7.80(d，J＝7.8Hz，1H)，7.38(t，J＝7.8Hz，1H)，7.30(s，1H)，7.20(s，1H)，6.80(m，1H)，6.57(d，J＝15.0Hz，1H)，4.37(t，J＝4.2Hz，2H)，4.20(s，1H)，3.80(t，J＝4.2Hz，2H)，3.35(s，3H)，3.09(d，J＝6Hz，2H)，2.19(s，6H)。
ESI-MS(m/z)：[M+H]+446.4。
Example 26: 6- (Acryloylamino) -7- (2-methoxyethoxy) -N- (3-alkynylphenyl) quinazolin-4-amine Synthesis of Compound 26)
Compound 26
In a similar manner to the preparation of compound 21, starting from 3-alkynylaniline and acryloyl chloride, compound 26 (72% yield) was obtained as yellow particulate crystals.
1H-NMR(600MHz，DMSO-d6，ppm)：9.76(s，1H)，9.64(s，1H)，8.91(s，1H)，8.54(s，1H)，8.01(s，1H)，7.88(t，J＝8.4Hz，1H)，7.87(d，J＝1.2Hz，1H)，7.33(s，1H)，7.20(d，J＝7.8Hz，1H)，6.72(m，1H)，6.32(dd，J＝16.8Hz，J＝1.8Hz，1H)，5.83(dd，J＝16.2，J＝1.8Hz，1H)，4.38(t，J＝4.2Hz，2H)，4.19(s，1H)，3.80(t，J＝4.2Hz，2H)，3.36(s，3H)。
ESI-MS(m/z)：[M+H]+389.2。
Example 27: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-chloro-3-tris Synthesis of fluoromethylphenyl) quinazolin-4-amine (Compound 27)
Compound 27
In a similar manner to the preparation of compound 21, starting from 4-chloro-3-trifluoromethylaniline, compound 27 (41% yield) was obtained as yellow granular crystals.
1H-NMR(600MHz，DMSO-d6，ppm)：10.00(s，1H)，9.56(s，1H)，8.96(s，1H)，8.58(s，1H)，8.41(d，J＝2.4Hz，1H)，8.29(dd，J＝14.4，J＝1.8Hz，1H)，7.72(d，J＝9.0Hz，1H)，7.36(d，J＝10.2Hz，1H)，6.81(m，1H)，6.58(d，J＝15.6Hz，1H)，4.38(t，J＝4.2Hz，2H)，3.81(t，J＝4.2Hz，2H)，3.35(s，3H)，3.09(d，J＝6Hz，2H)，2.19(s，6H)。
MS(m/z)：[M+H]+524.40。
Example 28: 6- (Acryloylamino) -7- (2-methoxyethoxy) -N- (4-chloro-3-trifluoromethylphenyl) quinazol Synthesis of lin-4-amine (Compound 28)
Compound 28
In a similar manner to the preparation of compound 21, starting from 4-chloro-3-trifluoromethylaniline and acryloyl chloride, compound 28 (66% yield) was obtained as yellow granular crystals.
1H-NMR(600MHz，DMSO-d6，ppm)：10.0(s，1H)，9.69(s，1H)，8.95(s，1H)，8.59(s，1H)，8.42(d，J＝2.4Hz，1H)，8.30(dd，J＝8.4Hz，J＝2.4Hz，1H)，7.73(d，J＝8.4Hz，1H)，7.37(s，1H)，6.70(m，1H)，6.35(dd，J＝16.8Hz，J＝1.8Hz，1H)，5.83(m，1H)，4.40(t，J＝4.8Hz，2H)，3.81(t，J＝4.8Hz，2H)，3.35(s，3H)。
ESI-MS(m/z)：[M+H]+467.3。
Example 29: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy)) -N- (2-chloro-4-tris Synthesis of Fluoromethoxyphenyl) quinazolin-4-amine (Compound 29)
Compound 29
In a similar manner to the preparation of compound 21, starting from 2-chloro-4-trifluoromethoxyaniline, compound 29 was obtained (40% yield) as yellow granular crystals.
ESI-MS(m/z)：[M+H]+540.3，[M-H]-538.3。
Example 30: 6- (Acryloylamino) -7- (2-methoxyethoxy) -N- (2-chloro-4-trifluoromethoxyphenyl) quina Synthesis of oxazolin-4-amine (Compound 30)
Compound 30
In a similar manner to the preparation of compound 21, starting from 2-chloro-4-trifluoromethoxyaniline and acryloyl chloride, compound 30 (59% yield) was obtained as yellow, particulate crystals.
ESI-MS(m/z)：[M+H]+483.3，[M-H]-481.4。
Example 31: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-fluoro-3-cyano Synthesis of phenylphenyl) quinazolin-4-amines (Compound 31)
Compound 31
In a similar manner to the preparation of compound 21, starting from 4-fluoro-3-cyanoaniline, compound 31 (37% yield) was obtained as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.95(s，1H)，9.55(s，1H)，8.93(s，1H)，8.55(s，1H)，8.38(dd，1H，J＝1.8Hz，J＝6Hz)，8.15(dd，1H，J＝4.2Hz，J＝7.2Hz)，7.55(t，1H，J＝9Hz)，7.34(s，1H)，6.81(m，1H)，6.58(d，1H，J＝15Hz)，4.37(t，2H，J＝4.2Hz)，3.81(t，2H，J＝4.2Hz)，3.09(d，2H，J＝6Hz)，2.19(s，6H)。
ESI-MS(m/z)：[M+H]+465.4。
Example 32: 6- (Acryloylamino) -7- (2-methoxyethoxy) -N- (4-fluoro-3-cyanophenyl) quinazoline-4-carboxylic acid Synthesis of amine (Compound 32)
Compound 32
In a similar manner to the preparation of compound 21, starting from 4-fluoro-3-cyanoaniline and acryloyl chloride, compound 32 (59% yield) was obtained as yellow, granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.96(s，1H)，9.65(s，1H)，8.92(s，1H)，8.56(s，1H)，8.38(dd，1H，J＝3.0Hz，J＝6Hz)，8.15(m，1H)，7.56(t，1H，J＝3Hz)，7.345(s，1H)，6.74(dd，1H，J＝10.8Hz，J＝17.2Hz)，6.33(dd，1H，J＝1.8Hz，J＝16.2Hz)，5.83(dd，1H，J＝1.8Hz，J＝10.8Hz)，4.39(t，2H，J＝4.2Hz)，3.81(t，2H，J＝4.8Hz)，3.33(d，3H，J＝13.2Hz)。
ESI-MS(m/z)：[M+H]+408.2。
Example 33: (E) -6- (4- (dimethylamino) crotonylamino) -7- (2-methoxyethoxy) -N- (4- (pyridine- Synthesis of 2-ylmethoxy) phenyl) quinazolin-4-amine (Compound 33)
Compound 33
a 6-amino-7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine hydrochloride Synthesis of salts
In a similar manner to the preparation of compound 23, starting from 4-nitrophenol, 6-amino-7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine hydrochloride can be obtained.
b.6- (diethylphosphonoacetylamino) -7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quina Synthesis of azolin-4-amines
CDI (26.9g, 6eq) is uniformly mixed in 100ml of acetonitrile, the temperature is reduced to 0, acetonitrile solution (50ml) of diethylphosphonoacetic acid (21.7g, 4eq) is added dropwise, the mixture naturally rises to room temperature after the addition of the solution, the mixture is stirred and reacted for 1h, under ice-water bath, mixed solution of acetonitrile (80ml) of 6-amino-7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazoline-4-amine hydrochloride (12.5g, 1eq) and NMP (10ml) is added dropwise, and after the completion of the addition, the mixture is heated to room temperature and reacted for 4h continuously, and the reaction is detected completely by TLC. Concentrating under reduced pressure at room temperature until no liquid is evaporated, adding 400ml of ice water, extracting with equal amount of ethyl acetate for 3 times, combining ethyl acetate layers, drying with anhydrous sodium sulfate, and concentrating to obtain the target product, which is directly subjected to the next reaction without further purification.
c. (E) -6- (4- (dimethylamino) crotonylamino) -7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) Synthesis of Yl) phenyl) quinazolin-4-amine (Compound 33)
Compound 33
Dimethylamino acetaldehyde diethyl acetal (11g) is evenly mixed in 20ml of methanol, 50ml of saturated HCl/methanol solution is dripped into the mixture under ice water bath, the mixture naturally rises to room temperature after dripping, reaction is continued for 10 hours, and TLC detection shows that the reaction is complete (iodine color development) to obtain solution A.
Suspending 6- (diethylphosphonoacetamido) -7- (2-methoxyethoxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine (16.5g) in 120ml THF, adding lithium chloride (2.3g), continuing to react at room temperature for 0.5h, cooling to 0 ℃, adding sodium methoxide (18g) in water (10ml) dropwise, naturally increasing to room temperature, continuing to react for 0.5h, cooling to 0 ℃, adding solution A dropwise, maintaining the reaction temperature, continuing to react for 1h, and detecting the reaction completion by TLC. After concentration under reduced pressure at room temperature until no more liquid was distilled off, 600ml of ice water was added, extraction was performed with ethyl acetate, and column chromatography was performed to give compound 33 (31% yield).
1H-NM(600MHz，DMSO-d6，ppm)：8.86(s，1H)，8.59(d，1H，J＝4.8Hz)，8.41(s，1H)，7.85(m，1H)，7.65(d，2H，J＝9Hz)，7.54(d，1H，J＝7.8Hz)，7.36(dd，1H，J＝5.4Hz，J＝6.6Hz)，7.27(s，1H)，7.04(d，2H，J＝9Hz)，6.79(m，1H)，6.55(d，1H，J＝9Hz)，4.35(t，2H，J＝4.2Hz)，3.80(t，2H，J＝4.8Hz)，3.10(d，2H，J＝5.4Hz)，2.19(s，6H)。
MS(m/z)：[M+H]+529.5。
Example 34: (E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyl) Synthesis of oxy) phenyl) quinazolin-4-amine (Compound 34)
Compound 34
In a similar manner to the preparation of compound 24, starting from 4-hydroxynitrobenzene, compound 34 was obtained (50% yield) as yellow granular crystals.
1H-NM(600MHz，DMSO-d6，ppm)：9.62(s，2H)，8.85(s，1H)，8.42(s，1H)，7.65(d，2H，J＝8.4Hz)，7.45(dd，1H，J＝7.2Hz，J＝14.4Hz)，7.30(dd，3H，J＝7.8Hz，J＝18Hz)，7.17(dd，1H，J＝9.6Hz)，7.03(d，2H，J＝9Hz)，6.71(dd，2H，J＝10.2Hz，J＝16.8Hz)，6.31(d，1H，J＝17.4Hz)，5.82(d，1H，J＝10.2Hz)，5.15(s，2H)，4.36(t，2H，J＝4.2Hz)，3.79(t，2H，J＝4.2Hz)，3.34(d，9H，J＝1.2Hz)。
MS(m/z)：[M+H]+546.5，[M-H]-544.4。
Example 35: 6- (Acryloylamino) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) Synthesis of quinazolin-4-amine (Compound 35)
Compound 35
Compound 35 (47% yield) was obtained as yellow granular crystals by a similar synthesis method to compound 24 starting from acryloyl chloride.
1H-NMR(600MHz，DMSO-d6，ppm)：9.69(s，1H)，9.62(s，1H)，8.87(s，1H)，8.49(s，1H)，7.98(d，J＝2.4Hz，1H)，7.70(m，1H)，7.47(m，1H)，7.33(m，3H)，7.20(d，J＝1.8Hz，1H)，7.18(m，1H)，6.72(m，1H)，6.32(d，J＝11.4Hz，1H)，5.82(d，J＝10.2Hz，1H)，5.25(s，2H)，4.37(t，J＝4.8Hz，2H)，4.10(t，J＝4.8Hz，2H)，3.35(s，3H)。
MS(m/z)：[M-H]-521.3。
Example 36: (E) -6- (4- (dimethylamino) crotonylamino) -7- (2-methoxyethoxy) -N- (4- ((E) -4- Synthesis of (dimethylamino) crotonyl amido) -3-trifluoromethylphenyl) quinazolin-4-amine (Compound 36)
Compound 36
Compound 36 (51% yield) was obtained as yellow granular crystals by a synthesis similar to compound 21 starting from 4-nitro-3-trifluoromethyl.
1H-NMR(600MHz，DMSO-d6，ppm)：9.95(s，1H)，9.64(s，1H)，9.56(s，1H)，8.95(s，1H)，8.55(s，1H)，8.23(s，1H)，8.20(d，J＝7.8Hz，1H)，7.50(d，J＝8.0Hz，1H)，7.34(s，1H)，6.81(m，1H)，6.72(m，1H)，6.58(d，J＝15.0Hz，1H)，6.36(d，J＝15.0Hz，1H)，4.38(t，J＝4.2Hz，2H)，3.81(t，J＝4.2Hz，2H)，3.35(s，6H)，3.08(q，4H)，2.19(s，6H)，2.18(s，6H)。
MS(m/z)：[M+H]+616.5，[M-H]-614.4
Example 37: 6- (Acryloylamino) -7- (2-methoxyethoxy) -N- (4- (3-fluorobenzyloxy) -3-chlorophenyl) QuinazolesSynthesis of lin-4-amine (Compound 37)
Compound 37
Compound 37 (69% yield) was obtained as yellow granular crystals in a similar synthesis procedure to compound 21 starting from 4-nitro-3-trifluoromethyl and acryloyl chloride.
1H-NMR(600MHz，DMSO-d6，ppm)：9.97(s，1H)，9.74(s，1H)，9.67(s，1H)，8.94(s，1H)，8.56(s，1H)，8.25(s，1H)，8.22(d，J＝7.8Hz，1H)，7.51(d，J＝7.8Hz，1H)，7.35(s，1H)，6.74(m，1H)，6.53(m，1H)，6.34(d，J＝17.4Hz，1H)，6.25(d，J＝17.4Hz，1H)，5.83(dd，2H)，4.39(s，2H)，3.81(s，2H)，3.35(s，3H)。
MS(m/z)：[M+H]+502.4，[M-H]-500.3。
Biological experiments
The following assays can be used to determine the inhibitory effect of the compounds of the present invention on EGFR tyrosine kinase and the growth inhibitory effect in vivo on EGFR-highly expressed human squamous epidermal carcinoma a431 nude mouse graft tumor.
A)EGFR kinase Activity assay
In vitro kinase assays were detected using the HTScanEGFReceptorKinaseAssaykit (#7909) from CellSignaling technology. The method detects the inhibition effect of the compound to be detected on the phosphorylation of the EGFR receptor tyrosine kinase on the substrate peptide in vitro according to the kit instructions. Incubating ATP and substrate peptide and compound to be detected in kinase reaction buffer solution at room temperature, adding stop solution to stop reaction after a period of incubation, transferring the sample to a 96-well plate coated with streptavidin, washing the plate, and detecting phosphorylation on the substrate peptide by using HRP-labeled anti-substrate phosphorylation antibodyLevel, developed with TMB and quenched with 2M sulfuric acid. Detecting the absorption wavelength of 450nm, and calculating IC50Value (. mu.M). The results are shown in Table 1.
Table 1: inhibition of EGFR kinase Activity by Compounds of the invention
Test article IC50(μM)
Compound 1 0.121
Compound 2 0.006
Compound 3 0.008
Compound 4 0.135
Compound 5 0.510
Compound 6 0.560
Compound 7 0.001
Compound 8 0.032
Compound 9 2.350
Compound 10 0.105
Compound 11 0.054
Compound 12 0.093
Compound 13 0.147
Compound 14 0.167
Compound 15 0.009
Compound 16 0.100
Compound 17 0.134
Compound 18 0.072
Compound 19 1.023
Compound 20 1.056
Compound 21 0.003
Compound 22 0.001
Compound 23 0.005
Compound 24 1.72738 -->
Compound 25 0.001
Compound 26 0.002
Compound 27 0.574
Compound 28 2.729
Compound 29 0.105
Compound 30 1.321
Compound 31 1.002
Compound 32 0.196
Compound 33 0.010
Compound 34 0.091
Compound 35 0.102
Compound 36 0.102
Compound 37 0.115
B) Analysis of inhibitory Effect of the Compounds of the present invention on phosphorylation of EGFR on the surface of A431 cells
The human Epidermal Growth Factor Receptor (EGFR) phosphorylation assay employs the WesternBlot method, which detects the inhibitory effect of the compounds of the present invention on the activation of EGFR phosphorylation.
A431 in RPMI1640 medium containing 10% fetal bovine serum, 2mM glutamine and non-essential amino acids at 37 deg.C and 5% CO2Cells were cultured in a cell incubator and harvested from cell culture flasks using trypsin/ethylenediaminetetraacetic acid (EDTA). Cells were added to 24-well cell culture plates at 20000/well (1ml medium) at 37 ℃ with 5% CO2Culturing in cell culture box for 48 hr, changing fresh culture medium containing different concentrations of test compound with final concentration of DMSO of 0.25%, culturing at 37 deg.C with 5% CO2ConditionThe cells were lysed with 1 × SDS gel loading buffer (50mM Tris-HCl (pH6.8), 100mM DTT, 2% SDS, 10% glycerol, 0.1% bromophenol blue) and the cell lysates were heat denatured in a boiling water bath.
The supernatant was subjected to SDS-PAGE, and after completion of the electrophoresis, the protein was transferred to an NC membrane (Millipore, USA) using a semidry transfer membrane system, the NC membrane was placed in a blocking solution at 4 ℃ overnight, and then the membrane was reacted with I antibody and II antibody, respectively. After washing, ECL reagent is used for luminescence, tabletting and development, and the intensity of the band on the film shows that the inhibition effect on EGFR phosphorylation is strong and weak, and the result is shown in Table 2.
Table 2: analysis of inhibitory Effect of the Compounds of the present invention on EGFR phosphorylation on the cell surface of A431
Test article IC50
Compound 1 ++
Compound 2 ++++
Compound 3 ++++
Compound 4 ++
Compound 5 ++
Chemical combinationObject 6 ++
Compound 7 ++++
Compound 8 +++
Compound 9 +39 -->
Compound 10 ++
Compound 11 +++
Compound 12 +++
Compound 13 ++
Compound 14 ++
Compound 15 ++++
Compound 16 +++
Compound 17 ++
Compound 18 +++
Compound 19 +
Compound 20 +
Compound 21 ++++
Compound 22 ++++
Compound 23 ++++
Compound 24 +
Compound 25 ++++
Compound 26 ++++
Compound 27 ++
Compound 28 +
Compound 29 ++
Compound 30 +
Compound 31 +
Compound 32 ++
Compound 33 ++++
Compound 34 +++
Compound 35 +++
Compound 36 ++
Compound 37 ++
(IC50: the concentration of +++ is 1-10 nM; the concentration of +++ is 10-100 nM; , + represents a concentration of 100 to 1000 nM; + denotes a concentration > 1000nM)
As can be seen from the above experimental results, the compounds of the present invention have strong biological activity, and many compounds can effectively inhibit the activity of tyrosine kinase in nM.
C) Evaluation of in vivo drug efficacy
BALB/cA nude mice, female, 4-6 weeks old, weight 22 + -2 g, purchased from Beijing Huafukang Biotechnology GmbH, SPF-level environment.
A431 cells cultured in vitro are inoculated subcutaneously to the right armpit of a nude mouse, and each A431 cell is inoculated with 5 × 106Individual cells, passaged twice in vivo after tumorigenesis. Under aseptic condition, taking the vigorously growing tumor tissue and cutting into 1.5mm3The left and right tumor masses were inoculated to the right armpit of the nude mouse. Measuring the tumor diameter by using a vernier caliper until the tumor grows to 100-200 mm3Then, the animals are randomly grouped, the administration dose of the compounds 2, 3, 7, 15, 23, 25, 26 and 33 and a positive control is 20mg/kg, the intragastric administration is carried out, the administration is carried out once a day for 14 continuous days (d14), the control group is administered with an equal amount of solvent, the weight and the tumor diameter of the mice are measured 2-3 times per week in the administration period and the recovery period, the tumor volume and the relative tumor volume are calculated according to the measurement data, and the calculation formula of the Tumor Volume (TV) is that TV is 1/2 × a × b2Wherein a and b represent the major diameter and the minor diameter of the tumor, respectively. Calculating Relative Tumor Volume (RTV) according to the measured result, wherein the calculation formula is as follows: RTV is Vt/V0. Where V0 is the tumor volume at the start of the experiment and Vt is the tumor volume per measurement. The evaluation index of the antitumor activity is relative tumor proliferation rate T/C (%), and the calculation formula is as follows: T/C (%) ═ TRTV/CRTV×100％，TRTVRTV for treatment group; cRTVThe relative tumor growth inhibition rate (1-T/C) × 100% was determined as a negative control RTV, and the results are shown in table 3.
TABLE 3 therapeutic Effect of the Compounds of the present invention on A431 nude mouse transplantable tumors: (n＝8)
Note: (1) compared with the positive control group，＊P＜0.05，＊＊P＜0.01。
(2)d14: the end time of administration; d18: day 4 after the last dose.
(3) Positive control drug: n- [4- [ (3-chloro-4-fluorophenyl) amino ] -7- [ [ (3S) -tetrahydro-3-furanyl ] oxy ] -6-quinazolinyl ] -4- (dimethylamino) -2-butenamide.
The results show that: the tumor inhibition rates of compounds 2, 7, 15, 23, 25, 26 (95.8%, 96.1%, 95.4%, 86.1%, 97.5%, 94.3%, respectively, after 14 days of continuous administration) were better than that of the positive control (70.9%). All of the groups administered with compounds 2, 7, 15, 23, 25, 26 showed tumor regression, and only tumor regression was observed in the positive control group 2.
On day 4 after the last administration (d18), the tumor inhibition rates of the compounds reached the highest values, and the tumor inhibition rates of compounds 2, 7, 15, 23, 25 and 26 were 96.7%, 96.8%, 95.2%, 83.3%, 98.1% and 94.0%, respectively, which were better than the positive control (68.7%).
The results of in vivo experiments show that the compound has better tumor inhibition effect on tumors driven by tyrosine kinase.

Claims (6)

1. A compound selected from the group consisting of:
6- (acrylamido) -7- ((R) -tetrahydrofuran-3-yloxy) -N- (4-fluoro-3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonamido) -7- ((S) -tetrahydrofuran-3-yloxy) -N- (4- (pyridin-2-ylmethoxy) phenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-bromo-2-fluorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (4-fluoro-3-chlorophenyl) quinazolin-4-amine;
(E) -6- (4- (dimethylamino) crotonyl amido) -7- (2-methoxyethoxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
6- (acrylamido) -7- (2-methoxyethoxy) -N- (3-alkynylphenyl) quinazolin-4-amine;
or a pharmaceutically acceptable salt thereof.
2. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally one or more pharmaceutically acceptable carriers or excipients.
3. Use of a compound of claim 1 in the manufacture of a medicament for the treatment and/or prevention of a receptor tyrosine kinase-associated disease or disorder in a mammal.
4. The use of claim 3, wherein the mammal is a human.
5. The use of a compound according to claim 1 for the preparation of a medicament for the therapeutic or adjunctive treatment and/or prevention of receptor tyrosine kinase mediated tumor or receptor tyrosine kinase driven proliferation and migration of tumor cells in a mammal.
6. The use of claim 5, wherein the mammal is a human.
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