CN107674059B - Benzaheteroaromatic ring compound and preparation method and application thereof - Google Patents

Benzaheteroaromatic ring compound and preparation method and application thereof Download PDF

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CN107674059B
CN107674059B CN201710792397.6A CN201710792397A CN107674059B CN 107674059 B CN107674059 B CN 107674059B CN 201710792397 A CN201710792397 A CN 201710792397A CN 107674059 B CN107674059 B CN 107674059B
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methoxyquinazolin
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CN107674059A (en
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蒋晟
涂正超
郝海平
姚毅武
邱亚涛
姚和权
强磊
陈东
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China Pharmaceutical University
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The invention belongs to the field of chemical medicine, and discloses a benzazepine aromatic ring compound shown in formula I or pharmaceutically acceptable salt, stereoisomer, racemate, prodrug or solvate thereof. The invention also discloses application of the benzazepine aromatic ring compound in preparing a medicament for treating diseases caused by abnormal activity of protein kinase and/or nicotinamide phosphoribosyl transferase. The benzazepine aromatic ring compound shown in the formula I or the salt thereof has the double inhibition effect of tyrosine kinase and Nampt, can be used as an effective component for treating or preventing tumors, and has the advantages of good curative effect and small toxic and side effect.

Description

Benzaheteroaromatic ring compound and preparation method and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and relates to a benzoazepine aromatic ring compound, a preparation method and application thereof, and a pharmaceutical composition containing the compound and application thereof.
Background
Some malignant tumors such as lung cancer, liver cancer, rectal cancer and leukemia have become one of the most important factors seriously harming the life happiness of people and influencing the health index of residents due to difficult early discovery, early diagnosis and early treatment. In the case of the current state of cancer treatment, the overall therapeutic effect is poor. Therefore, the development of targeted therapeutic drugs with pertinence is a scientific research problem which needs to be solved urgently by scientific researchers. In recent years, although some novel targeted new drugs such as tyrosine protein kinase inhibitors are developed and marketed, the new drugs are far from meeting the increasing demand.
Approximately half of the 520 protein kinases in humans are Protein Tyrosine Kinases (PTKs). Protein tyrosine kinase occupies a very important position in signal transduction pathways in cells, and regulates a series of biochemical processes such as growth, differentiation, death and the like in cells. The dysfunction of protein tyrosine kinase can cause a series of diseases in organisms. Studies have shown that activation of more than half of the proto-oncogenes and oncogenes is associated with protein tyrosine kinases. Abnormal expression of protein tyrosine kinases can lead to disturbed regulation of cell proliferation, which in turn leads to tumorigenesis. In addition, the abnormal expression of protein tyrosine kinase is closely related to the metastasis of tumor, the generation of tumor new blood vessel and the chemotherapy resistance of tumor. The research and development of the anti-tumor drugs by taking the protein tyrosine kinase as a target point become an international hot spot.
The great success of the small-molecule protein tyrosine kinase inhibitor in the clinical tumor treatment further proves that the protein tyrosine kinase is a key therapeutic target, and simultaneously indicates the importance of the protein tyrosine kinase in the tumorigenesis. To date, dozens of small molecule inhibitors and antibodies of protein tyrosine kinases have entered clinical trials. Some of them have been marketed and have achieved better therapeutic effects, such as inhibitors of Epidermal Growth Factor Receptor (EGFR), i.e., Iressa and Tarceva, etc., and successful cancer treatment is a milestone in cancer treatment.
However, with the wide clinical application of Iressa and Tarceva, the problem of drug resistance is increasingly prominent. Some patients are naturally resistant to it, while others develop acquired resistance during the course of medication. Clinically, disease progression occurs in most patients after 9-13 months of first-line treatment with EGFR-TKI. Scientists found that the T790M gene mutation occurred in most drug resistant patients. The accepted mechanism of tolerance is now secondary mutations in the kinase domain of the target gene expression product, and patients with these mutations are prone to relapse and have a poor prognosis. How to overcome the drug resistance of Iressa and Tarceva is an important subject of tumor medicine at present, and the search for novel tyrosine kinase small-molecule inhibitors is an important approach for overcoming the drug resistance of Iressa and Tarceva. The recently marketed small molecule inhibitor of tyrosine kinases, ocitinib (AZD9291) from asikang, uk, was effective in some cases of Iressa resistance.
Nicotinamide phosphoribosyltransferase (Nampt) is the rate-limiting enzyme in the mammalian Nicotinamide Adenine Dinucleotide (NAD) synthesis pathway, regulating intracellular NAD levels. NAD is a coenzyme for many enzymes in the living body and plays an important role in many cellular physiological processes. Tumor cells require more energy, more NAD-dependent enzymes, in order to maintain a high proliferation rate. Therefore, tumor cells need to synthesize and replenish more NAD, which is more dependent on intracellular NAD levels than normal cells. Additional studies have shown that Nampt also has pro-angiogenic activity, supporting the growth of some tumor cells. These studies have made Nampt a very attractive target for anticancer drug research in recent years, and Nampt inhibitors can be used for tumor chemotherapy. Three Nampt inhibitors are currently in clinical research, FK866, CHS828 and GMX 1777. Clinical tests show that the adverse reactions of the three medicines are similar, and are mainly manifested as thrombocytopenia and gastrointestinal toxicity reaction. The three compounds are all cytotoxic compounds in nanomolar level, and have better antitumor activity in vitro and in vivo experiments.
Therefore, a new low-toxicity and high-efficiency tyrosine kinase small-molecule inhibitor is necessary and urgent in the aspect of tumor treatment.
Disclosure of Invention
The invention aims to provide a novel benzazepine aromatic ring compound which is used as a dual inhibitor of tyrosine kinase and Nampt and is used for solving the problems of low curative effect, easy tolerance and the like of the existing tyrosine kinase drug aiming at the defects in the prior art.
The invention also aims to provide a preparation method of the benzazepine aromatic ring compound.
The invention also provides the pharmaceutical application of the benzazepine aromatic ring compound or the pharmaceutically acceptable salt thereof.
The purpose of the invention is realized by the following technical scheme:
benzazepine aromatic ring compounds shown in formula (I) or pharmaceutically acceptable salts, stereoisomers, racemes, prodrugs or solvates thereof:
Figure BDA0001399549830000021
one of the substituents of R and R' is selected from
Figure BDA0001399549830000022
The other substituent is selected from hydrogen, methoxy, methoxyethoxy, methoxy, ethoxy,
Figure BDA0001399549830000023
R' is substituted or unsubstituted phenyl, and the substituent of the phenyl is selected from halogen, -NO2、-CN、-OH、R1R2N-, (3-fluorophenyl) methoxy group, Cl-6Alkyl, halogen substituted Cl-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, Cl-6Alkoxy, halogen substituted Cl-6Alkoxy radical, C3-6A cycloalkoxy group; r1、R2Each independently represents H, C1-6An alkyl group;
wherein Q is selected from
Figure BDA0001399549830000031
L1Is selected from C2-8Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, and L1Hydrogen in the hydrogen can be converted into S1Substitution;
A1selected from-O-, -NH-, S (═ O)mAn amide bond, an ester bond (-COO-), a thioester bond (-COS-), a disulfide bond, a nitrogen-nitrogen double bond, a nitrogen-oxygen bond or a covalent bond, and A1Hydrogen in the hydrogen can be converted into S2Substitution;
L2is represented by C2-8Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl or covalent bond, and L2Hydrogen in the hydrogen can be converted into S3Substitution;
A2represents-O-, -NH-, S (═ O)m、Cl-6Alkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-6Cycloalkyl radical, and A2Hydrogen in the hydrogen can be converted into S4Substitution;
m is 0, 1 or 2;
S1、S2、S3and S4Each independently selected from-CN, -CF3、-CO2H. Halogen, Cl-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6Alkynyl, R3O-、R3R4N-、R3S(＝O)m-、R3R4NS(＝O)m-、R3R4NC(＝O)-、R3R4NC(＝O)O-、R3OC(＝O)-、R5C(＝O)-、R5C(＝O)O-、R5C(＝O)NR3-、R3R4NC(＝O)NR6-、R3OC(＝O)NR6-、R3S(＝O)mNR6-、R3R4NS(＝O)mNR6-、R3R4NC(＝NR7)NR6-、R3R4NC(＝CHNO2)NR6-、R3R4NC(＝N-CN)NR6-、R3R4NC(＝NR7)-、R3S(＝O)(＝NR7)NR6-or R3R4NS(＝O)(＝NR7)-；
R3、R4、R5、R6And R7Each independently represents H, C1-6Alkyl radical, C3-6Cycloalkyl radical, C2-6Alkenyl radical, C2-6An alkynyl group; when R is3And R4When attached to the same nitrogen atom, may form a C together with the nitrogen atom3-12A heteroalicyclic ring, this C3-12The heteroalicyclic may comprise O, N, S (═ O)mA heteroatom; and R is3、R4、R5、R6And R7The hydrogen in the hydrogen can be substituted by halogen, CN, Cl-6Alkyl or C3-6Cycloalkyl is substituted.
Preferably, one of the substituents R and R' is selected from
Figure BDA0001399549830000032
The other substituent is selected from hydrogen, methoxy, methoxyethoxy, methoxy, ethoxy,
Figure BDA0001399549830000033
R' is substituted or unsubstituted phenyl, and the substituent of the phenyl is selected from ethynyl, F, Cl, Br, (3-fluorophenyl) methoxy and-NH2、-N(CH3)2；
Wherein Q is selected from
Figure BDA0001399549830000034
L1Is selected from- (CH)2)t-, t is an integer from 2 to 8;
A1hydrogen from the group consisting of-O-, -NH-may be replaced by Cl-6Alkyl substitution, -S-, -SO2-or a covalent bond;
L2is selected from- (CH)2)n-n is an integer from 0 to 8;
A2selected from-O-, -NH-, -S-, -SO2-。
Further preferably, one of the substituents R and R' is selected from
Figure BDA0001399549830000041
The other substituent is selected from hydrogen, methoxy,
Figure BDA0001399549830000042
R' is substituted or unsubstituted phenyl, the substituent of the phenyl is selected from ethynyl, F, Cl, Br and (3-fluorophenyl) methoxy, and the phenyl can be monosubstituted or polysubstituted;
wherein Q is selected from
Figure BDA0001399549830000043
L1Is selected from- (CH)2)t-, t is an integer from 2 to 7;
A1hydrogen from the group consisting of-O-, -NH-may be replaced by Cl-3Alkyl substitution or covalent bonding;
L2is selected from- (CH)2)n-n is an integer from 0 to 2;
A2selected from-O-, -NH-, -S-, -SO2-。
Most preferably, one of the substituents R and R' is selected from
Figure BDA0001399549830000044
The other substituent is selected from hydrogen, methoxy,
Figure BDA0001399549830000045
R' is substituted or unsubstituted phenyl, the substituted phenyl is selected from 3-ethynylphenyl, 3-chloro-4 fluorophenyl, 3-bromophenyl, 3-chloro-4- ((3 fluorobenzyl) oxy) phenyl;
wherein Q is selected from
Figure BDA0001399549830000046
L1Is- (CH)2)t-, t is an integer from 4 to 7, A1Is a covalent bond, L2Is a covalent bond, A2is-O-, -NH-, -S-; or L1Is- (CH)2)t-, t is an integer from 2 to 5, A1is-O-or-NH-, L2Is- (CH)2) n-, n is 2, A2is-O-, -NH-, -S-.
In the invention
Figure BDA0001399549830000047
Represents a 2-, 3-or 4-substituted pyridyl group.
The benzazepine aromatic ring compound is selected from the following compounds:
(E) -N- (2- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (3- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) propyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (4- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) butyl) -3- (pyridine-3-substituted) acrylamide.
(E) -N- (5- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- (2- ((4- ((3-phenylethyl) amino) -7-methoxyquinazolin-6-substitution)) ethoxy) yl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- ((2- ((4- ((3-phenylethyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) amino) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- (ethyl (2- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) amino) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- ((2- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) (isopropyl) amino) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) oxy) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) amino) pentyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) amino) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) mercapto) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) mercapto) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) sulfonyl) pentyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) sulfonyl) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) hexyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) hexyl) -3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridine-3-substituted) guanidine;
(E) -N- (5- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-bromophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((7-methoxy-4- (phenylamino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((4-chlorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((2-fluorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -1- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-substituted) oxy) pentyl) -2-cyano-3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substitution) oxy) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) hexyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) hexyl) -3- (pyridine-4-substituted) guanidine;
(E) -N- (5- ((6-acrylamido-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- (2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazoline-6-substituted) acrylamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((5- ((E) -3- (pyridine-3-substituted) acrylamido) pentyl) oxy) quinazolin-6-substituted) -4- (dimethylamino) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- ((E) -2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazolin-6-substituted) -4- (dimethylamino) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((5- ((E) -3- (pyridine-3-substituted) acrylamido) pentyl) oxy) quinazolin-6-substituted) -4- (pyridine-1-substituted) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- ((E) -2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazolin-6-substituted) -4- (pyridin-1-substituted) but-2-enamide;
(E) -N- (2- (2- ((6-acrylamido-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-7-substituted) oxy) ethoxy) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- ((3- (2-cyano-3- (pyridin-4-substituted) guanidino) propyl) amino) ethoxy) quinazolin-6-substituted) acrylamide.
"alkyl" means straight or branched chain, C1-6The alkyl group means a straight chain or branched alkyl group having 1 to 6 carbon atoms, and it should be noted that, when the number of carbon atoms is not particularly limited, it refers only to the number of carbon atoms of the alkyl moiety, and does not include the number of carbon atoms of the substituent of the alkyl group.
"cycloalkyl" refers to a monocyclic saturated cycloalkyl group having a specified number of carbon atoms, including cyclopropyl, methyl-cyclopropyl, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, and the like.
The invention includes the free form of formula I, as well as pharmaceutically acceptable salts or stereoisomers. Some specific exemplary compounds herein are protonated salts of amine-based compounds.
"free form" refers to the amine compound in non-salt form.
"pharmaceutically acceptable salt" refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of mammals, especially humans, without excessive toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula (I). The free form of a particular salt of the compound may be isolated using techniques known in the art. For example, the free form is regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous sodium hydroxide, sodium carbonate, dilute aqueous ammonia, and potassium bicarbonate. The free forms differ somewhat from their respective salt forms in certain physical properties, such as solubility in polar solvents, but for the purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms. Pharmaceutically acceptable salts of the invention can be synthesized from compounds of the invention containing a basic or acidic moiety by conventional chemical methods. In general, salts of basic compounds are prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric amount or excess of an inorganic or organic acid in the form of the desired salt in an appropriate solvent or combination of solvents. Similarly, salts of the compounds are formed by reaction with a suitable inorganic or organic base. Thus, pharmaceutically acceptable salts of the compounds of the present invention include the conventional non-toxic salts formed by the reaction of a basic compound of the present invention with inorganic or organic acids, including salts with inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, sulfamic acid, phosphoric acid, nitric acid and the like, as well as salts prepared with organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, acetic acid, stearic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, sulfanilic acid, fumaric acid, 2-acetoxy-benzoic acid, fumaric acid, p-toluenesulfonic acid, methanesulfonic acid, ethane disulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid and the like. If the compounds of the present invention are acidic, suitable "pharmaceutically acceptable salts" refer to salts prepared by pharmaceutically acceptable non-toxic bases including inorganic and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc, and the like. Salts of organic non-toxic bases of the compounds of the invention include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as arginine, β, caffeine, choline, N' -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, methylglucamine, histidine, lysine, isopropylamine, morpholine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
"isomers" refers to two or more compounds that are identical in molecular composition but differ in structure and properties.
"racemic" refers to an equimolar mixture of a chiral molecule and its enantiomer having optical activity, which is formed by mixing equal amounts of molecules having opposite optical rotation directions and the same optical activity, and whose optical activity is offset by the interaction between these molecules, and thus is optically inactive.
"solvate" refers to a mixture of a compound and a solvent, e.g., a crystal is a solvate.
"prodrug" refers to a compound that is rapidly converted in vivo by hydrolysis in blood to yield the parent compound having the above formula.
The invention also provides a preparation method of the benzazepine aromatic ring compound shown in the formula I, wherein when one substituent in R and R' is selected from
Figure BDA0001399549830000091
The other substituent is selected from hydrogen, methoxy, methoxyethoxy, A2is-O-, L2Is a covalent bond, A1Is a covalent bond, L1Is- (CH)2)nAnd when n is an integer of 2 to 8, the method comprises the following steps:
(1) compound 1 or compound 2 in SOCl2Under the action of (1), carrying out chlorination reaction in an organic solvent dichloromethane to obtain a compound 3;
(2) compound 3 with aromatic amine H2Reacting N-R' in an organic solvent dichloromethane to obtain a compound 5;
(3) reacting the compound 5 in an organic solvent dichloromethane under the action of alkali (triethylamine) to obtain a compound 6;
(4) compound 6 with BocHN- (CH)2)nReacting LG in an organic solvent dichloromethane under the action of a base (triethylamine), and then obtaining a compound 8 under the action of an acid (trifluoroacetic acid); wherein n is an integer of 2-8, LG is a common leaving group in organic chemistry, and is F, Cl, Br, I, OMs, OTs, OTf;
(5) reacting the compound 8 in an organic solvent under the action of a condensing agent (EDCI) to obtain a compound 10, or reacting the compound 8 in the organic solvent under the action of a base (triethylamine or pyridine) to obtain a compound 13 or a compound 14.
Figure BDA0001399549830000092
When A is2is-O-, -NS2-，L2Is- (CH)2)nN is an integer of 2 to 8, A1is-O-, L1Is- (CH)2)t-when t is an integer from 2 to 8, comprising the steps of:
(1) compound 6 is reacted with BocHN- (CH) in the presence of base (DIPEA)2)t-O-(CH2)n-LG is reacted in an organic solvent and then, under the action of an acid (trifluoroacetic acid), to compound 16;
(2) compound 16 is reacted in an organic solvent under the action of a condensing agent (EDCI) to give compound 17, or reacted in an organic solvent under the action of a base to give compound 18 or compound 19.
Figure BDA0001399549830000101
When one substituent in R and R' is selected from
Figure BDA0001399549830000102
Another substituent is selected from
Figure BDA0001399549830000103
Figure BDA0001399549830000104
A2is-O-, L2Is a covalent bond, A1Is a covalent bond, L1Is- (CH)2)nAnd when n is an integer of 2 to 8, the method comprises the following steps:
(1) compound 25 with SOCl2Carrying out chlorination reaction in an organic solvent to obtain a compound 26;
(2) compound 26 and aromatic amine H2Reacting N-R' in an organic solvent to obtain a compound 27;
(3) compound 27 with TBSO- (CH)2)n-OH reacts in an organic solvent (dichloromethane) under the action of a base (DIPEA, triethylamine) to obtain a compound 29;
(4) reacting the compound 29 in an organic solvent under the action of a reducing agent (sodium borohydride and the like) to obtain a compound 30;
(5) compound 30 is subjected to condensation agent (EDCI) to give compound 32;
(6) the compound shown in the formula 32 reacts in an organic solvent dichloromethane under the action of a fluorine-containing reagent tetrabutylammonium fluoride, and then reacts with MsCl to obtain a compound 33;
(7) compound 33 in NaN3Under the action, reacting in an organic solvent to obtain a compound 34;
(8) compound 34 is reacted in the organic solvent dichloromethane with the action of a condensing agent (EDCI) to give compound 35, or reacted in the organic solvent dichloromethane with the action of a base (triethylamine or pyridine) to give compound 36 or compound 37.
Figure BDA0001399549830000111
When A is2is-O-, L2Is- (CH)2)nN is an integer of 2 to 8, A1is-O-, L1Is- (CH)2)t-when t is an integer from 2 to 8, comprising the steps of:
(1) reacting compound 32 in an organic solvent (tetrahydrofuran, dichloromethane) under the action of a fluorine-containing reagent such as tetrabutylammonium fluoride to obtain compound 38;
(2) compound 38 is reacted with BocHN- (CH) in the presence of base (DIPEA, triethylamine)2)t-LG is reacted in an organic solvent (dichloromethane) and then reacted under the action of an acid (trifluoroacetic acid) to give compound 39;
(3) reacting the compound 39 in an organic solvent under the action of a condensing agent (EDCI) to obtain a compound 40;
Figure BDA0001399549830000121
when A is2is-NH-, L2Is- (CH)2)nN is an integer of 2 to 8, A1is-NH-, -NS2-，L1Is- (CH)2)t-when t is an integer from 2 to 8, comprising the steps of:
(1) compound 34 is reacted with BocHN- (CH) under the action of base2)t-LG is reacted in an organic solvent and then reacted under the action of an acid to obtain a compound 41;
(2) the compound 41 is reacted in an organic solvent under the action of a condensing agent to give a compound 42, and the compound 42 is further reacted in an organic solvent under the action of a base to give a compound 43.
Figure BDA0001399549830000122
In-vitro biological activity determination experiments show that the benzazepine aromatic ring compound shown in the formula I or the salt thereof has the dual inhibition effects of tyrosine kinase and Nampt, can be used as an effective component for treating or preventing tumors, and has the advantages of good curative effect and small toxic and side effects.
The application of the benzazepine aromatic ring compound or the pharmaceutically acceptable salt, stereoisomer, raceme, prodrug or solvate thereof in preparing the medicine for treating diseases caused by abnormal activity of protein kinase and/or nicotinamide phosphoribosyl transferase.
The diseases caused by the abnormal activity of the protein kinase and/or the nicotinamide phosphoribosyl transferase are tumors, including solid tumors and liquid tumors; in particular lung cancer, bone cancer, membrane adenocarcinoma, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, carcinoma of the esophagus, carcinoma of the small intestine, carcinoma of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, carcinoma of the prostate, chronic or acute leukemia, carcinoma of the bladder, carcinoma of the kidney or ureter, carcinoma of the kidney, neoplasms of the central nervous system, spinal axis tumors, pituitary adenomas, gastrointestinal stromal tumors, colorectal cancer, non-small cell lung cancer, mastocytosis, glioma.
The protein kinase is ALK, AXL, BT, CDKll, c-Met, KDR, VEGFR2, RET, PDGFR- α, PDGFR- β, c-KIT, Flt3, MEK1, MEK2, CSF1R, EPHA2, MKNK2, TIE2, TRKA, SRC, PLK40, RON, EGF1R, HER2, HER3, HER4, PDGFR- α, c-fms, FLT1, SRC, Frk, Btk, Csk, Abl, Fes, Fps, Fak, AcK, Yes, Fyn, Lyn, Lck, Fgr, Yrk, PDK1, TAK1, Tie-1, YSK 686K 9, TRKB, TRKC, SLK, PKN2, PKT 1, MSMAP 86K or DDR 8427.
A medicine for treating diseases caused by abnormal activity of protein kinase and/or nicotinamide phosphoribosyl transferase is prepared from benzoazepine aromatic ring compound or its pharmaceutically acceptable salt, stereoisomer, racemate, prodrug or solvate, and one or more pharmaceutically acceptable auxiliary materials.
The medicine is oral liquid, injection, anal suppository, nasal inhalant, eye drop or skin patch. Oral agents include, but are not limited to, tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or tinctures. Compositions intended for oral administration may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents.
The compounds of the present invention may be administered to a mammal, preferably a human, either alone or in pharmaceutical compositions in combination with a pharmaceutically acceptable recipient, adjuvant or diluent, in accordance with standard pharmaceutical techniques. The compounds can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally, and topically, ocularly, pulmonarily, nasally, parenterally.
In one embodiment, the compounds of formula (I) are used to treat or control cancer in a patient in need thereof at a dosage of 0.1 to 500 mg/day/kg body weight orally. Suitable modes of administration are single daily administration or multiple administrations of two, three, four etc. times daily administration or administration using sustained release techniques. For large mammals, the preferred dosage range is 0.1-1500 mg/day/kg body weight. The dosage of the composition is 1-500 mg for patients with the average weight of 70 kg. For some particularly highly active compounds, the daily dose for adult patients may be as low as 0.1 mg/day.
In one embodiment, the compounds of formula (I) are used to treat or control cancer in a patient in a dosage range of 0.1 to 500 mg/day/kg body weight by intravenous injection. Suitable modes of administration are single daily administration or multiple administrations of two, three, four etc. times daily administration or administration using sustained release techniques. For large mammals, the preferred dosage range is 0.1-1500 mg/day/kg body weight. The dosage of the composition is 1-500 mg for patients with the average weight of 70 kg. For some particularly highly active compounds, the daily dose for adult patients may be as low as 0.1 mg/day.
Detailed Description
The technical scheme of the invention is carried out by combining the specific examplesThe following is a description, but the scope of the invention is not limited by the examples. It should be noted that in the following examples, the conventional post-treatment method is: after the reaction is finished, adding a proper amount of water into the reaction solution, separating an organic phase from a water phase, and combining the organic phases; if desired, the organic phase is again treated with 5% HCl solution and/or saturated Na2SO4Drying, filtering, decompressing, spin-drying to obtain a crude product, and separating and purifying by column chromatography to obtain a final product.
Example 1
Figure BDA0001399549830000141
Step 1, 4-chloro-7-methoxyquinazolin-6-ol acetate
Placing 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate (4g,17.1mmol) in a 100mL conical flask, adding 40mL thionyl chloride and 1 drop of DMF at room temperature, and heating and refluxing for 24 hours; most of the thionyl chloride was distilled off, ice water was added, filtered and dried to give 4-chloro-7-methoxyquinazolin-6-ol acetate (4.07g) in 94% yield.
1H-NMR(400MHz,CDCl3)：δ8.95(s,1H),7.90(s,1H),7.44(s,1H),4.02(s,3H),2.39(s,3H).
Step 2, 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol acetate
4-chloro-7-methoxyquinazolin-6-ol acetate (4.07g,16.1mmol) and 3-aminophenylacetylene (3.77g,21.3mmol) were placed in 140mL isopropanol and heated at reflux for 12 h, cooled, and filtered to give 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol acetate (4.59g) in 85% yield.
1H-NMR(400MHz,DMSO-d6)：δ11.48(s,1H),8.94(s,1H),8.80(s,1H),7.90(s,1H),7.77(d,J＝8.4Hz,1H),7.54(s,1H),7.49(t,J＝7.8Hz,1H),7.41(d,J＝7.7Hz,1H),4.29(s,1H),4.01(s,3H),2.39(s,3H).
Step 3,4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol
4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol acetate (1g) was placed in 30mL of methanol, 1.2mL of ammonia (28% by mass) was added, and the mixture was refluxed for 2 hours, cooled, filtered, and dried to give 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol (0.6g) with a yield of 70%.
1H-NMR(400MHz,CDCl3)：δ9.70(s,1H),9.41(s,1H),8.47(s,1H),8.07(s,1H),7.90(d,J＝8.2Hz,1H),7.79(s,1H),7.36(t,J＝8.0Hz,1H),7.20(s,1H),7.17(d,J＝7.6Hz,1H),4.17(s,1H),3.97(s,3H).
Step 4, 6- (2- (tert-butoxycarbonyl) aminoethoxy) -N- (3-ethynylphenyl) -7-methoxyquinazolin-4-amino
Putting 4- ((3-ethynylphenyl) amino) -7-methoxyquinazoline-6-alcohol (1eq), 2- (tert-butoxycarbonylamino) ethyl iodide (1.1eq) and anhydrous potassium carbonate (2.4eq) in a DMF solution, reacting at 50 ℃, monitoring the reaction by TLC, adding ice water after the reaction is completed, separating out a solid, filtering and drying to obtain a target compound which is identified as 6- (2- (tert-butoxycarbonyl) aminoethoxy) -N- (3-ethynylphenyl) -7-methoxyquinazoline-4-amino.
1H-NMR(400MHz,DMSO-d6)：δ11.26(s,1H),8.87(s,1H),8.24(s,1H),7.85(s,1H),7.75(d,J＝8.0Hz,1H),7.51(t,J＝7.9Hz,1H),7.42(d,J＝7.7Hz,1H),7.35(s,1H),7.14(t,J＝5.3Hz,1H),4.29(s,1H),4.25–4.17(m,2H),3.99(s,3H),3.42(d,J＝5.7Hz,2H),2.50(s,3H),1.38(s,9H).13C NMR(125MHz,DMSO)δ158.5,156.9,156.1,155.5,149.7,149.3,137.6,136.2,129.8,129.6,128.0,125.7,122.5,107.7,104.8,100.4,83.3,81.8,78.3,68.5,56.9,28.6.
Step 5, (E) -N- (2- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) ethyl) -3- (pyridine-3-substituted) acrylamide
Placing the compound obtained in the step 4 into dichloromethane, adding trifluoroacetic acid (dichloromethane: trifluoroacetic acid v/v ═ 1:5), reacting at room temperature for 1h, adding saturated sodium bicarbonate solution, spin-drying the organic layer, adding dichloromethane again, adding the freshly prepared compounds trans-3 (3-pyridyl) allylic (2eq), EDCI (2eq), and DIPEA (3eq), reacting at room temperature for 2 h, adding 1M sodium hydroxide, stirring for 10 min, separating to obtain an organic layer, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, and performing silica gel column chromatography (eluent: dichloromethane/methanol ═ 20/1) to obtain the compound 1-1, (E) -N- (2- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) ethyl) -3- (pyridine-3-substituted) acrylamide .
MS(EI,m/z):466(M++1).1H-NMR(400MHz,CDCl3)：δ8.87(s,1H),8.76(s,1H),8.70(s,1H),8.60–8.52(m,3H),8.36(s,1H),7.90–7.79(m,2H),7.68(d,J＝7.7Hz,1H),7.51(t,J＝7.8Hz,1H),7.30(dd,J＝7.6,4.8Hz,1H),7.25(s,1H),6.65(t,J＝6.3Hz,1H),6.58(d,J＝15.7Hz,1H),4.40(t,J＝7.4Hz,2H),4.01(s,3H),3.89–3.79(m,2H),2.63(s,3H).13C NMR(125MHz,CDCl3)δ198.1,166.7,156.6,154.4,153.7,150.6,149.3,147.4,147.2,140.3,139.0,137.7,134.6,130.4,129.0,125.7,123.7,123.5,121.7,120.3,109.5,107.8,102.4,66.1,56.2,37.2,26.8.
Example 2
Figure BDA0001399549830000161
The procedure in step 4 of example 1 was repeated except for replacing 2- (tert-butoxycarbonylamino) ethyl iodide with 3- (tert-butoxycarbonylamino) propyl bromide to obtain the compound 1-2, (E) -N- (3- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) propyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):480(M++1).1H-NMR(400MHz,CDCl3)：δ8.62(s,1H),8.59(s,2H),8.51(d,J＝4.7Hz,1H),7.93(s,1H),7.83(d,J＝8.0Hz,1H),7.61(d,J＝8.0Hz,1H),7.51(d,J＝15.7Hz,1H),7.47(s,1H),7.34–7.18(m,4H),7.14(s,1H),6.52(d,J＝15.7Hz,1H),4.09(t,J＝6.1Hz,2H),3.91(s,3H),3.60(q,J＝6.0Hz,2H),3.02(s,1H),2.11–2.05(m,6.0Hz,2H).13C NMR(125MHz,CDCl3)δ165.8,156.7,154.9,153.6,150.4,148.9,148.0,147.4,139.1,137.6,134.4,130.5,128.9,127.7,125.5,123.7,122.8,122.7,122.6,109.3,107.6,103.2,83.4,77.4,67.9,56.1,37.5,28.6.
Example 3
Figure BDA0001399549830000162
The procedure in step 4 of example 1 was repeated except for replacing 2- (tert-butoxycarbonylamino) ethyl iodide with 4- (tert-butoxycarbonylamino) butyl bromide to give compound 1-3, (E) -N- (4- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) butyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):494(M++1).1H-NMR(400MHz,CDCl3)：δ8.60(s,1H),8.56(s,2H),8.49(d,J＝4.7Hz,1H),7.91(s,1H),7.81(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.49(d,J＝15.7Hz,1H),7.45(s,1H),7.31–7.15(m,4H),7.12(s,1H),6.50(d,J＝15.7Hz,1H),4.06(t,J＝6.1Hz,2H),3.88(s,3H),3.60(q,J＝6.0Hz,2H),3.02(s,1H),2.13–2.07(m,4H).13C NMR(125MHz,CDCl3)δ165.3,156.3,154.6,153.3,150.1,148.6,148.0,147.2,139.0,137.3,134.2,130.3,128.7,127.5,125.3,123.5,122.7,122.6,109.2,107.5,103.1,83.2,77.3,67.8,56.0,37.6,29.7,28.7.
Example 4
Figure BDA0001399549830000171
The procedure in step 4 of example 1 was repeated except for replacing 2- (tert-butoxycarbonylamino) ethyl iodide with 5- (tert-butoxycarbonylamino) pentyl bromide to give the compound 1-4, (E) -N- (5- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):508(M++1).1H-NMR(400MHz,CDCl3)：δ9.20(s,1H),8.63(s,1H),8.57(s,1H),8.51(d,J＝4.8Hz,1H),7.82(s,1H),7.75(d,J＝8.3Hz,1H),7.68(s,1H),7.57(d,J＝7.9Hz,1H),7.44(d,J＝15.7Hz,1H),7.29–7.12(m,4H),6.54(t,J＝6.7Hz,1H),6.49(d,J＝15.7Hz,1H),4.02(t,J＝7.4Hz,2H),3.93(s,3H),3.43(q,J＝6.5Hz,2H),2.97(s,1H),1.88(m,2H),1.57(m,2H),1.37(m,2H).13C NMR(125MHz,CDCl3)δ166.0,157.0,154.9,153.4,150.2,148.8,148.5,147.2,139.3,137.4,134.4,130.5,128.7,127.6,126.0,123.7,123.3,122.8,122.5,109.7,107.3,102.4,83.5,77.2,69.0,56.0,38.9,29.1,27.4,22.2.
Example 5
Figure BDA0001399549830000172
The 2- (tert-butoxycarbonylamino) ethyl iodide in step 4 of example 1 was replaced with (2- (tert-butoxycarbonylamino) ethoxy) ethyl bromide, and the rest was the same as in example 1 to give a compound of 1-5, (E) -N- (2- (2- ((4- ((3-phenethyl) amino) -7-methoxyquinazolin-6-substitution)) ethoxy) yl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):510(M++1).1H-NMR(400MHz,CDCl3)：δ8.84(s,1H),8.63(s,1H),8.55(d,J＝2.32Hz,1H),8.48(dd,J＝1.59,4.90Hz,1H),7.86(d,J＝1.81Hz,1H),7.81–7.70(m,1H),7.58(s,1H),7.54(d,J＝8.03Hz,1H),7.47(d,J＝15.71Hz,1H),7.30–7.13(m,4H),6.90(t,J＝5.57Hz,1H),6.44(d,J＝15.74Hz,1H),4.12(d,J＝5.86Hz,2H),3.86(s,3H),3.83–3.74(m,2H),3.64–3.51(m,4H),3.01(s,1H).13C NMR(125MHz,CDCl3)δ165.8,156.8,155.0,153.7,150.3,148.9,148.3,147.6,139.2,137.5,134.3,130.4,128.8,127.7,125.5,123.6,122.7,122.6,122.6,109.4,107.7,103.3,83.4,69.8,68.8,68.5,56.0,39.3.
Example 6
Figure BDA0001399549830000181
The substitution of 2- (tert-butoxycarbonylamino) ethyl iodide in step 4 of example 1 with (2- (tert-butoxycarbonylamino) ethylamino) ethyl bromide, and the rest was the same as in example 1, gave compounds 1-6, identified as (E) -N- (2- ((2- ((4- ((3-phenethyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) amino) ethyl) -3- (pyridin-3-substituted) acrylamide.
MS(EI,m/z):509(M++1).1H-NMR(400MHz,MeOD)：δ8.61(d,J＝2.22Hz,1H),8.47(dd,J＝1.55,4.93Hz,1H),8.37(s,1H),7.97–7.87(m,2H),7.80–7.71(m,1H),7.65(s,1H),7.47(d,J＝15.89Hz,1H),7.40(dd,J＝4.88,8.01Hz,1H),7.33(t,J＝7.91Hz,1H),7.22(d,J＝7.57Hz,1H),7.04(s,1H),6.67(d,J＝15.84Hz,1H),4.27(t,J＝5.02Hz,2H),3.92(s,3H),3.53(t,J＝6.30Hz,2H),3.33–3.28(m,1H),3.15(t,J＝5.08Hz,2H),2.96(t,J＝6.20Hz,2H).13CNMR(125MHz,CDCl3)δ170.6,160.8,159.1,156.5,153.2,152.5,152.1,150.2,143.1,140.1,138.6,135.1,132.3,131.2,129.5,129.4,127.9,127.0,126.7,126.6,113.0,109.9,106.5,86.9,81.2,71.9,59.1,42.6.
Example 7
Figure BDA0001399549830000182
The substitution of 2- (tert-butoxycarbonylamino) ethyl iodide in step 4 of example 1 with (2- (tert-butoxycarbonylamino) -N-ethyl-ethylamino) ethyl bromide, and the rest were the same as in example 1, affording compounds 1-7, identified as (E) -N- (2- (ethyl (2- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) amino) ethyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):537(M++1).1H-NMR(400MHz,MeOD)：δ8.62(d,J＝2.22Hz,1H),8.46(dd,J＝1.55,4.93Hz,1H),8.36(s,1H),7.97–7.87(m,2H),7.81–7.70(m,1H),7.64(s,1H),7.46(d,J＝15.89Hz,1H),7.40(dd,J＝4.88,8.01Hz,1H),7.33(t,J＝7.91Hz,1H),7.22(d,J＝7.57Hz,1H),7.04(s,1H),6.67(d,J＝15.84Hz,1H),4.27(t,J＝5.02Hz,2H),3.92(s,3H),3.53(t,J＝6.30Hz,2H),3.33–3.28(m,1H),3.15(t,J＝5.08Hz,2H),2.96(t,J＝6.20Hz,2H),2.03(q,J＝7.4Hz,2H),1.03(t,J＝7.4Hz,3H).13C NMR(125MHz,CDCl3)δ170.4,160.3,159.2,156.6,153.3,152.6,152.0,150.1,143.1,140.2,138.5,135.1,132.2,131.3,129.6,129.3,127.8,127.1,126.6,126.5,113.1,110.0,106.5,86.7,81.4,71.8,59.2,49.9,42.6,13.3.
Example 8
Figure BDA0001399549830000191
The substitution of 2- (tert-butoxycarbonylamino) ethyl iodide in step 4 of example 1 with (2- (tert-butoxycarbonylamino) -N-isopropyl-ethylamino) ethyl bromide, and the rest was the same as in example 1, gave compounds 1-8, identified as (E) -N- (2- ((2- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) (isopropyl) amino) ethyl) -3- (pyridin-3-substituted) acrylamide.
MS(EI,m/z):551(M++1).1H-NMR(400MHz,MeOD)：δ8.62(d,J＝2.22Hz,1H),8.46(dd,J＝1.55,4.93Hz,1H),8.36(s,1H),7.97–7.87(m,2H),7.81–7.70(m,1H),7.64(s,1H),7.46(d,J＝15.89Hz,1H),7.40(dd,J＝4.88,8.01Hz,1H),7.33(t,J＝7.91Hz,1H),7.22(d,J＝7.57Hz,1H),7.04(s,1H),6.67(d,J＝15.84Hz,1H),4.27(t,J＝5.02Hz,2H),3.92(s,3H),3.53(t,J＝6.30Hz,2H),3.33–3.28(m,1H),3.15(t,J＝5.08Hz,2H),2.96(t,J＝6.20Hz,2H),2.69(m,1H),1.05(d J＝6.8Hz,3H),1.02(d J＝6.8Hz,3H).13C NMR(125MHz,CDCl3)δ170.4,160.3,159.2,156.6,153.3,152.6,152.0,150.1,143.1,140.2,138.5,135.1,132.2,131.3,129.6,129.3,127.8,127.1,126.6,126.5,113.1,110.0,106.5,86.7,81.4,71.8,59.2,49.9,42.6,13.3.
Example 9
Figure BDA0001399549830000192
The procedure in step 4 of example 1 was repeated except for replacing 2- (tert-butoxycarbonylamino) ethyl iodide with 6- (tert-butoxycarbonylamino) hexyl bromide to obtain the compound 1-9, (E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) hexyl) -3- (pyridin-3-substituted) acrylamide.
MS(EI,m/z):522(M++1).1H-NMR(400MHz,CDCl3)：δ9.45(s,1H),8.69(d,J＝2.3Hz,2H),8.54(d,J＝4.8Hz,1H),7.97(d,J＝2.4Hz,1H),7.82(d,J＝8.1Hz,1H),7.70(d,J＝8.5Hz,2H),7.61(d,J＝15.7Hz,1H),7.27(d,J＝7.3Hz,2H),7.21(d,J＝7.4Hz,2H),6.60–6.48(m,2H),3.90(s,3H),3.80(t,J＝7.0Hz,2H),3.35(q,J＝7.0Hz,2H),3.00(s,1H),1.76-1.72(m,2H),1.59–1.41(m,2H),1.34-1.17(m,4H).13C NMR(125MHz,CDCl3)δ165.6,156.9,154.9,153.5,150.4,149.0,148.9,147.2,139.4,137.6,134.3,130.5,128.8,127.5,125.5,123.7,122.8,122.6,122.6,109.7,107.3,102.2,83.6,68.9,56.1,39.5,29.5,28.7,26.1,24.8.
Example 10
Figure BDA0001399549830000201
The procedure in step 4 of example 1 was repeated except for replacing 2- (tert-butoxycarbonylamino) ethyl iodide with 7- (tert-butoxycarbonylamino) heptyl bromide to give a compound of 1-10, (E) -N- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridin-3-substituted) acrylamide.
MS(EI,m/z):536(M++1).1H-NMR(400MHz,CDCl3)：δ9.45(s,1H),8.69(d,J＝2.3Hz,2H),8.54(d,J＝4.8Hz,1H),7.97(d,J＝2.4Hz,1H),7.82(d,J＝8.1Hz,1H),7.70(d,J＝8.5Hz,2H),7.61(d,J＝15.7Hz,1H),7.27(d,J＝7.3Hz,2H),7.21(d,J＝7.4Hz,2H),6.60–6.48(m,2H),3.90(s,3H),3.80(t,J＝7.0Hz,2H),3.35(q,J＝7.0Hz,2H),3.00(s,1H),1.76-1.72(m,2H),1.64–1.29(m,8H).13C NMR(125MHz,CDCl3)δ165.6,156.9,154.9,153.5,150.4,149.0,148.9,147.2,139.4,137.6,134.3,130.5,128.8,127.5,125.5,123.7,122.8,122.6,122.6,109.7,107.3,102.2,83.6,68.9,56.1,42.0,28.8,28.6,28.5,26.2,25.6.
Example 11
Figure BDA0001399549830000202
The synthesis of 4- ((3-ethynylphenyl) amino) -6-amino-7-methoxyquinazoline was carried out using a literature procedure (j.med.chem.,2010,53, 2000-2009). Target compounds 1-11, identified as (E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-yl) amino) pentyl) -3- (pyridine-3-substituted) acrylamide, were synthesized by substituting 4- ((3-ethynylphenyl) amino) -6-amino-7-methoxyquinazoline for 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol in example 4, and using the same procedures as in steps 4 and 5 of example 4.
MS(EI,m/z):507(M++1).1H-NMR(400MHz,MeOD)：δ8.53(d,J＝4.8Hz,1H),7.84(s,1H),7.77(d,J＝8.3Hz,1H),7.70(s,1H),7.58(d,J＝7.9Hz,1H),7.42(d,J＝15.7Hz,1H),7.28(d,J＝8.8Hz,2H),7.12(d,J＝8.8Hz,2H),6.54(t,J＝6.7Hz,1H),6.49(d,J＝15.7Hz,1H),3.93(s,3H),3.43(q,J＝6.5Hz,2H),3.38q,J＝6.8Hz,2H),2.97(s,1H),1.90(m,2H),1.59(m,2H),1.38(m,2H).13C NMR(125MHz,MeOD)δ166.1 157.1,154.7,153.2,150.4,148.9,148.6,147.2,139.3,137.4,134.4,130.5,128.7,127.6,126.0,123.7,123.3,122.8,122.5,109.7,107.3,102.4,83.5,77.2,59.0,56.1,38.8,28.9,27.5,20.3.
Example 12
Figure BDA0001399549830000211
The synthesis of 4- ((3-ethynylphenyl) amino) -6-amino-7-methoxyquinazoline was carried out using a literature procedure (j.med.chem.,2010,53, 2000-2009). Target compounds 1-12, identified as (E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-yl) amino) hexyl) -3- (pyridine-3-substituted) acrylamide, were synthesized using 4- ((3-ethynylphenyl) amino) -6-amino-7-methoxyquinazoline instead of 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol in example 9, and otherwise identical to steps 4 and 5 of example 9.
MS(EI,m/z):521(M++1).1H-NMR(400MHz,MeOD)：δ9.45(s,1H),8.69(d,J＝2.3Hz,2H),8.54(d,J＝4.8Hz,1H),7.97(d,J＝2.4Hz,1H),7.82(d,J＝8.1Hz,1H),7.70(d,J＝8.5Hz,2H),7.61(d,J＝15.7Hz,1H),7.27(d,J＝7.3Hz,2H),7.21(d,J＝7.4Hz,2H),6.60–6.48(m,2H),3.90(s,3H),3.38(q,J＝7.0Hz,2H),3.35(q,J＝7.0Hz,2H),3.00(s,1H),1.76-1.72(m,2H),1.59–1.41(m,2H),1.34-1.17(m,4H).13C NMR(125MHz,MeOD)δ165.6,156.9,154.9,153.5,150.4,149.0,148.9,147.2,139.4,137.6,134.3,130.5,128.8,127.5,125.5,123.7,122.8,122.6,122.6,109.7,107.3,102.2,83.6,68.9,40.1,39.6,29.4,28.8,26.3,23.4.
Example 13
Figure BDA0001399549830000212
The synthesis of 4- ((3-ethynylphenyl) amino) -6-phenylacetylthio-7-methoxyquinazoline was carried out using a well-known literature method (j.med.chem.,2010,53, 2000-2009). Compounds 1-13, identified as (E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) mercapto) pentyl) -3- (pyridine-3-substituted) acrylamide, were synthesized by substituting 4- ((3-ethynylphenyl) amino) -6-phenylacetylthio-7-methoxyquinazoline for 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol in example 4, and using the same procedures as in steps 4 and 5 of example 4.
MS(EI,m/z):524(M++1).1H-NMR(400MHz,CDCl3)：δ9.21(s,1H),8.59(s,1H),8.53(s,1H),8.52(d,J＝4.8Hz,1H),7.83(s,1H),7.75(d,J＝8.3Hz,1H),7.63(s,1H),7.54(d,J＝7.9Hz,1H),7.48(d,J＝15.7Hz,1H),7.28–7.14(m,4H),6.54(t,J＝6.7Hz,1H),6.49(d,J＝15.7Hz,1H),3.93(s,3H),3.43(q,J＝6.5Hz,2H),2.97(s,1H),2.89(t,J＝7.4Hz,2H),1.88(m,2H),1.57(m,2H),1.37(m,2H).13C NMR(125MHz,CDCl3)δ165.9,156.8,154.6,153.2,150.1,148.8,148.5,147.2,139.3,137.4,134.4,130.5,128.8,127.6,126.1,123.7,123.1,122.6,122.5,109.8,107.4,102.3,83.5,77.3,69.0,38.9,37.0,29.1,27.4,22.2.
Example 14
Figure BDA0001399549830000221
The synthesis of 4- ((3-ethynylphenyl) amino) -6-phenylacetylthio-7-methoxyquinazoline was carried out using a well-known literature method (j.med.chem.,2010,53, 2000-2009). Target compounds 1-14, identified as (E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) mercapto) hexyl) -3- (pyridine-3-substituted) acrylamide, were synthesized using 4- ((3-ethynylphenyl) amino) -6-phenylacetylthio-7-methoxyquinazoline in place of the 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol of example 9, and the procedures were otherwise the same as in steps 4 and 5 of example 9.
MS(EI,m/z):538(M++1).1H-NMR(400MHz,CDCl3)：δ9.45(s,1H),8.69(d,J＝2.3Hz,2H),8.54(d,J＝4.8Hz,1H),7.97(d,J＝2.4Hz,1H),7.82(d,J＝8.1Hz,1H),7.70(d,J＝8.5Hz,2H),7.61(d,J＝15.7Hz,1H),7.27(d,J＝7.3Hz,2H),7.21(d,J＝7.4Hz,2H),6.60–6.48(m,2H),3.90(s,3H),3.80(t,J＝7.0Hz,2H),3.35(q,J＝7.0Hz,2H),3.00(s,1H),1.76-1.72(m,2H),1.59–1.41(m,2H),1.34-1.17(m,4H).13C NMR(125MHz,CDCl3)δ165.8,156.9,154.5,153.7,150.6,149.0,148.7,147.3,139.4,137.8,134.3,130.4,128.8,127.3,125.5,123.8,122.8,122.8,122.6,109.3,107.2,102.5,83.7,68.8,39.5,37.1,29.5,28.7,26.0,24.5.
Example 15
Figure BDA0001399549830000222
Compound 1-13(1eq) was dissolved in a mixed solution of acetonitrile and water (v/v ═ 1:2), potassium permanganate (4eq) was added, the mixture was reacted at 60 ℃ for two hours, then cooled to room temperature, the solvent was evaporated under reduced pressure, ethyl acetate and water were added, the mixture was stirred for ten minutes and separated to obtain an organic phase, which was dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure and separated by silica gel column chromatography (eluent: dichloromethane/methanol ═ 20/1) to obtain the objective compound 1-15, which was identified as (E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) sulfonyl) pentyl) -3- (pyridine-3-substituted) acrylamide, with a yield of 20%.
MS(EI,m/z):524(M++1).1H-NMR(400MHz,CDCl3)：δ9.21(s,1H),8.61(s,1H),8.53(s,1H),8.52(d,J＝4.8Hz,1H),7.98(s,1H),7.80(d,J＝8.3Hz,1H),7.71(s,1H),7.60(d,J＝7.9Hz,1H),7.52(d,J＝15.7Hz,1H),7.40(d,J＝8.3Hz,1H),7.32(t,J＝7.8Hz,1H),7.20(d,J＝15.6Hz,2H),6.54(t,J＝6.7Hz,1H),6.49(d,J＝15.7Hz,1H),3.93(s,3H),3.43(q,J＝6.5Hz,2H),3.11(t,J＝7.4Hz,2H),2.97(s,1H),1.88(m,2H),1.57(m,2H),1.37(m,2H).13C NMR(125MHz,CDCl3)δ166.0,157.0,154.9,153.4,150.2,148.8,148.5,147.2,139.3,137.4,134.4,130.5,128.7,127.6,126.0,123.7,123.3,122.8,122.5,109.7,107.3,102.4,83.5,77.2,69.0,62.2,38.9,29.1,27.4,22.2.
Example 16
Compound 1-14(1eq) was dissolved in a mixed solution of acetonitrile and water (v/v ═ 1:2), potassium permanganate (4eq) is added, the mixture is reacted for two hours at 60 ℃, then cooled to room temperature, the solvent is evaporated under reduced pressure, ethyl acetate and water are added, the mixture is stirred for ten minutes and then separated to obtain an organic phase, the organic phase is dried by anhydrous sodium sulfate, filtered, the solvent is evaporated under reduced pressure and then separated by silica gel column chromatography (eluent: dichloromethane/methanol ═ 20/1) to obtain the target compound 1-14 which is identified as (E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazoline-6-substituted) sulfonyl) hexyl) -3- (pyridine-3-substituted) acrylamide with the yield of 25%.
Figure BDA0001399549830000231
MS(EI,m/z):570(M++1).1H-NMR(400MHz,CDCl3)：δ9.22(s,1H),8.61(s,1H),8.53(s,1H),8.52(d,J＝4.8Hz,1H),7.98(s,1H),7.80(d,J＝8.3Hz,1H),7.71(s,1H),7.60(d,J＝7.9Hz,1H),7.52(d,J＝15.7Hz,1H),7.40(d,J＝8.3Hz,1H),7.31(t,J＝7.8Hz,1H),7.20(d,J＝15.6Hz,2H),6.54(t,J＝6.7Hz,1H),6.49(d,J＝15.7Hz,1H),3.93(s,3H),3.43(q,J＝6.5Hz,2H),3.11(t,J＝7.4Hz,2H),2.97(s,1H),1.76-1.72(m,2H),1.59–1.41(m,2H),1.34-1.17(m,4H).13C NMR(125MHz,CDCl3)δ166.0,157.0,154.9,153.4,150.2,148.8,148.5,147.2,139.3,137.4,134.4,130.5,128.7,127.6,126.0,123.7,123.3,122.8,122.5,109.7,107.3,102.4,83.5,77.2,69.0,62.2,37.1,29.5,28.7,26.0,24.5.
Example 17
Substituting 2- (tert-butoxycarbonylamino) ethyl iodide in step 4 of example 1 with 5- (tert-butoxycarbonylamino) pentyl bromide, reacting with 4- ((3-ethynylphenyl) amino) -7-methoxyquinazolin-6-ol to give 6- (5-tert-butoxycarbonylaminopentyloxy) -N- (3-ethynylphenyl) -7-methoxyquinazolin-4-amino, 6- (5-tert-butoxycarbonylaminopentyloxy) -N- (3-ethynylphenyl) -7-methoxyquinazolin-4-amino (1eq) dissolved in pyridine, adding methyl-N' -cyano-N- (pyridine-4-substituted) thiocarbamoylamino (1eq) and triethylamine (1eq), the mixture was reacted at 50 ℃ overnight, the solvent was evaporated under reduced pressure, and the crude product was directly isolated by silica gel column chromatography (eluent: dichloromethane/methanol-20/1) to give the title compound 1-17, which was identified as (E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridin-4-substituted) guanidine.
Figure BDA0001399549830000241
MS(EI,m/z):521(M++1).1H-NMR(400MHz,DMSO-d6)：δ9.47(s,1H),9.38(s,1H),8.49(s,1H),8.37(s,2H),7.98(s,1H),7.89(d,J＝8.2Hz,2H),7.82(s,1H),7.40(t,J＝7.9Hz,1H),7.21(d,J＝9.2Hz,4H),4.18(s,1H),4.15(d,J＝6.9Hz,2H),3.93(s,3H),3.33(d,J＝8.2Hz,2H),1.94–1.77(m,2H),1.74–1.58(m,2H),1.53-1.52(m,2H).13C NMR(125MHz,DMSO-d6)δ156.5,154.9,153.1,150.6,150.0,148.8,147.4,146.2,140.2,129.3,126.8,125.2,123.0,122.1,116.9,115.1,109.3,107.7,103.0,83.9,80.9,69.1,56.3,42.1,29.0,28.7,23.4.
Example 18
Figure BDA0001399549830000242
The 2- (tert-butoxycarbonylamino) ethyl iodide in step 4 of example 1 was replaced with 6- (tert-butoxycarbonylamino) hexyl bromide, synthesized by the method of the first four steps of example 1, 6- (5-tert-butoxycarbonylaminohexyloxy) -N- (3-ethynylphenyl) -7-methoxyquinazoline-4-amino (1eq) was dissolved in pyridine, methyl-N' -cyano-N- (pyridine-3-substituted) thiocarbamoylamino (1eq) and triethylamine (1eq) were added, the mixture was reacted at 50 ℃ overnight, the solvent was evaporated under reduced pressure, and the resulting crude product was directly separated by silica gel column chromatography (eluent: dichloromethane/methanol-20/1) to give the objective compound 1-18, identified as (E) -2-cyano-1- (6- ((4-) (1eq) (3-phenylethynyl) amino) -7-methoxyquinazoline-6-substituted) oxy) hexyl) -3- (pyridine-3-substituted) guanidine.
MS(EI,m/z):535(M++1).1H-NMR(500MHz,DMSO-d6)：δ9.50(s,1H),9.20(s,1H),8.49(s,1H),8.46(d,J＝2.6Hz,1H),8.31(d,J＝4.7Hz,1H),7.99(t,J＝1.9Hz,1H),7.89(dd,J＝8.2,2.2Hz,1H),7.83(s,1H),7.66(d,J＝8.2Hz,1H),7.54(t,J＝5.7Hz,1H),7.39(t,J＝7.9Hz,1H),7.35(dd,J＝8.3,4.7Hz,1H),7.20(d,J＝11.4Hz,2H),4.18(s,1H),4.14(t,J＝6.6Hz,2H),3.93(s,3H),3.26(q,J＝6.7Hz,2H),1.84(d,J＝12.1Hz,2H),1.62–1.53(m,2H),1.53–1.45(m,2H),1.41–1.39(m,2H).13C NMR(125MHz,DMSO-d6)δ158.4,156.5,154.9,153.1,148.8,147.3,145.7,145.2,140.2,135.1,131.2,129.3,126.7,125.2,124.0,123.0,122.1,117.4,109.3,107.7,102.9,83.9,80.9,69.2,56.3,42.0,29.2,29.0,26.4,25.7.
Example 19
Figure BDA0001399549830000251
Substituting methyl-N '-cyano-N- (pyridine-3-substituted) thiocarbamoylamino group in example 18 with methyl-N' -cyano-N- (pyridine-4-substituted) thiocarbamoylamino group as in example 18 gave compounds 1-19, identified as (E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) hexyl) -3- (pyridine-4-substituted) guanidine.
MS(EI,m/z):535(M++1).1H-NMR(400MHz,DMSO-d6)：δ9.56(s,1H),8.50(s,1H),8.38(d,J＝5.6Hz,2H),7.99(s,2H),7.89(d,J＝8.3Hz,1H),7.84(s,1H),7.40(t,J＝7.9Hz,1H),7.31–6.99(m,4H),4.19(s,1H),4.15(t,J＝6.5Hz,2H),3.93(s,3H),3.35–3.30(m,2H),1.91–1.76(m,2H),1.64–1.54(m,2H),1.55–1.33(m,4H).13C NMR(125MHz,DMSO-d6)δ156.6,155.0,152.9,149.6,148.8,146.9,140.1,129.3,126.8,125.3,123.1,122.1,116.8,114.9,109.3,107.4,103.0,83.9,80.9,69.2,56.3,42.2,29.0,29.0,26.4,25.7.
Example 20
Figure BDA0001399549830000252
Substituting methyl-N '-cyano-N- (pyridine-substituted 4-substituted) thiocarbamoylamino group in example 17 with methyl-N' -cyano-N- (pyridine-3-substituted) thiocarbamoylamino group as in example 17 gave compounds 1-20, identified as (E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) guanidine.
MS(EI,m/z):521(M++1).1H-NMR(400MHz,MeOD)：δ8.47(s,0H),8.41(s,1H),8.32(d,J＝4.8Hz,1H),7.89(s,1H),7.81–7.70(m,2H),7.66(s,1H),7.39(dd,J＝8.4,4.9Hz,1H),7.34(t,J＝7.9Hz,1H),7.24(d,J＝7.6Hz,1H),7.08(s,1H),4.16(t,J＝6.2Hz,2H),3.95(s,3H),3.50(s,1H),3.38(t,J＝7.0Hz,2H),1.94-1.91(m,2H),1.74-1.72(m,2H),1.62-1.60(m,2H).13CNMR(125MHz,MeOD)δ157.0,155.5,151.8,149.3,145.3,144.5,138.9,134.8,132.2,128.4,127.4,125.7,124.0,123.0,122.7,108.9,105.0,102.0,82.8,77.3,68.9,55.2,41.6,28.6,28.3,23.0.
Example 21
Figure BDA0001399549830000261
Substituting 5- (tert-butoxycarbonylamino) pentyl bromide in step 4 of example 17 with 7- (tert-butoxycarbonylamino) heptyl bromide as described in example 17 gave compounds 1-21, identified as (E) -2-cyano-1- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridin-4-substituted) guanidine.
MS(EI,m/z):549(M++1).1H-NMR(400MHz,DMSO-d6)：δ9.47(s,1H),8.49(s,1H),8.37(d,J＝5.7Hz,2H),7.99(s,2H),7.89(d,J＝8.2Hz,1H),7.80(s,1H),7.39(t,J＝7.9Hz,1H),7.28–7.08(m,4H),4.18(s,1H),4.12(t,J＝6.5Hz,2H),3.93(s,3H),3.29(s,2H),1.81(q,J＝7.2,6.6Hz,2H),1.64–1.29(m,8H).13C NMR(125MHz,MeOD)δ156.8,155.3,152.2,149.2,149.0,147.0,145.9,139.2,128.4,127.2,125.5,122.8,122.6,116.5,114.9,109.1,105.6,101.8,82.9,77.3,68.9,55.1,42.0,28.8,28.6,28.5,26.2,25.6.
Example 22
Figure BDA0001399549830000262
Substituting methyl-N '-cyano-N- (pyridine-4-substituted) thiocarbamoylamino group in example 21 with methyl-N' -cyano-N- (pyridine-3-substituted) thiocarbamoylamino group as in example 17 gave compounds 1-22, identified as (E) -2-cyano-1- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridine-3-substituted) guanidine.
MS(EI,m/z):549(M++1).1H-NMR(400MHz,MeOD)：δ8.50–8.43(m,1H),8.40(d,J＝1.8Hz,1H),8.33(d,J＝4.8Hz,1H),7.89(d,J＝2.3Hz,1H),7.76(t,J＝8.9Hz,2H),7.67(d,J＝1.9Hz,1H),7.41(dd,J＝8.3,5.0Hz,1H),7.34(t,J＝7.9Hz,1H),7.24(d,J＝7.6Hz,1H),7.11(s,1H),4.15(t,J＝6.0Hz,2H),3.96(s,3H),3.49(s,1H),3.33(d,J＝7.3Hz,2H),1.91-1.87(m,2H),1.64-1.55(m,4H),1.44-1.41(m,4H).13C NMR(125MHz,MeOD)δ158.6,157.0,155.4,152.3,149.3,146.1,145.4,144.5,139.2,134.8,132.2,128.4,127.2,125.6,124.0,122.9,122.7,117.2,109.2,105.7,101.9,82.9,77.2,69.0,55.1,41.7,28.8,28.6,28.6,26.2,25.7.
Example 23
Figure BDA0001399549830000271
The procedure of example 4 was followed using 3-chloro-4-fluoroaniline instead of 3-aminophenylacetylene in step 2 of example 4 to give compounds 1-23, identified as (E) -N- (5- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):536(M++1).1H-NMR(500MHz,CDCl3)：δ9.21(s,1H),8.62(s,1H),8.58(s,1H),8.54(d,J＝4.1Hz,1H),7.80(dd,J＝6.6,2.7Hz,1H),7.69(s,1H),7.64–7.55(m,2H),7.43(d,J＝15.7Hz,1H),7.27(d,J＝6.6Hz,1H),7.22(s,1H),7.04(t,J＝8.8Hz,1H),6.50(d,J＝15.7Hz,1H),6.41(t,J＝6.3Hz,1H),4.07(t,J＝7.5Hz,2H),3.95(s,3H),3.48(q,J＝6.6Hz,2H),1.99–1.84(m,2H),1.66–1.54(m,2H),1.44–1.34(m,2H).13C NMR(125MHz,CDCl3)δ166.1,156.9,155.5,155.0,153.6,153.4,150.6,148.7(d,J＝46.34Hz,1C),147.3,138.0,135.9(d,J＝3.53Hz,1C),134.3,130.2,124.8,123.7,122.5(d,J＝6.66Hz,1C),122.3,120.6(d,J＝18.50Hz,1C),116.3(d,J＝21.90Hz,1C),109.5,107.6,102.2,69.1,56.1,38.5,29.2,26.9,21.6.
Example 24
Figure BDA0001399549830000272
Example 4 was repeated using 3-bromoaniline instead of 3-aminophenylacetylene in step 2 of example 4 to give compounds 1-24, identified as (E) -N- (5- ((4- ((3-bromophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):562(M++1).1H-NMR(400MHz,CDCl3)：δ9.21(s,1H),8.62(s,1H),8.58(s,1H),8.54(d,J＝4.1Hz,1H),7.80(d,J＝6.6Hz,1H),7.69(s,1H),7.67(d,J＝6.6Hz,1H),7.64–7.55(m,2H),7.43(d,J＝15.7Hz,1H),7.27(t,J＝6.6Hz,1H),7.22(s,1H),7.04(t,J＝8.8Hz,1H),6.50(d,J＝15.7Hz,1H),6.41(t,J＝6.3Hz,1H),4.07(t,J＝7.5Hz,2H),3.95(s,3H),3.48(q,J＝6.6Hz,2H),1.99–1.84(m,2H),1.66–1.54(m,2H),1.44–1.34(m,2H).
Example 25
Figure BDA0001399549830000281
Synthesis procedure as in example 4 was followed using aniline in place of 3-aminophenylacetylene in step 2 of example 4 to give compounds 1-25, identified as (E) -N- (5- ((7-methoxy-4- (phenylamino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):484(M++1).1H-NMR(400MHz,CDCl3)：δ9.22(s,1H),8.63(s,1H),8.59(s,1H),8.55(d,J＝4.1Hz,1H),7.80(d,J＝6.6Hz,2H),7.63–7.54(m,5H),7.22(s,1H),7.04(t,J＝8.8Hz,1H),6.50(d,J＝15.7Hz,1H),6.42(t,J＝6.3Hz,1H),4.08(t,J＝7.5Hz,2H),3.96(s,3H),3.47(q,J＝6.6Hz,2H),2.01–1.83(m,2H),1.65–1.58(m,2H),1.45–1.33(m,2H).
Example 26
Figure BDA0001399549830000282
Synthesis procedure as in example 4 was followed using 4-chloroaniline instead of 3-aminophenylacetylene in step 2 of example 4 to give compounds 1-26, identified as (E) -N- (5- ((4- ((4-chlorophenyl) amino) -7-methoxyquinazoline-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):518(M++1).1H-NMR(400MHz,CDCl3)：δ9.22(s,1H),8.65(s,1H),8.61(s,1H),8.57(s,1H),7.80(d,J＝6.6Hz,2H),7.66(d,J＝7.8Hz,2H),7.43(d,J＝15.7Hz,1H),7.39(d,J＝7.8Hz,2H),7.22(s,1H),7.04(t,J＝8.8Hz,1H),6.50(d,J＝15.7Hz,1H),6.42(t,J＝6.3Hz,1H),4.08(t,J＝7.5Hz,2H),3.96(s,3H),3.47(q,J＝6.6Hz,2H),2.01–1.83(m,2H),1.65–1.58(m,2H),1.45–1.33(m,2H).
Example 27
Figure BDA0001399549830000283
Synthesis of example 4 using 3-chloro-4- ((3-fluorobenzyl) oxy) aniline instead of 3-aminophenylacetylene in step 2 of example 4 gave compounds 1-27, identified as (E) -N- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):642(M++1).1H-NMR(400MHz,CDCl3)：δ9.05(s,1H),8.60(s,1H),8.54(s,1H),8.51(d,J＝4.5Hz,1H),7.67(d,J＝12.5Hz,2H),7.57(d,J＝9.4Hz,1H),7.38(d,J＝15.7Hz,1H),7.31(q,J＝7.4Hz,1H),7.27–7.20(m,2H),7.18–7.08(m,2H),6.99(t,J＝8.5Hz,1H),6.86(d,J＝8.8Hz,1H),6.46(d,J＝15.7Hz,1H),6.24(t,J＝6.4Hz,1H),4.99(s,2H),4.13(t,J＝7.5Hz,2H),3.97(s,3H),3.50(q,J＝6.5Hz,2H),2.03–1.91(m,2H),1.65-1.61(m,2H),1.44-1.41(m,2H).13C NMR(125MHz,CDCl3)δ166.1,163.9,162.9(d,J＝246.2Hz),154.9,153.6,150.7,150.5,149.0,148.4,147.2,139.2(d,J＝7.6Hz),138.1,134.2,133.3,130.2,130.0(d,J＝8.2Hz),125.4,123.6,123.2,122.7,122.3(d,J＝2.9Hz),122.1,114.8(d,J＝21.2Hz),114.3,113.9(d,J＝22.1Hz),109.4,107.6,102.2,70.4,69.1,56.1,38.4,29.2,26.8,21.5.
Example 28
Figure BDA0001399549830000291
Example 4 was repeated as described for example 4, using 2-fluoroaniline instead of 3-aminophenylacetylene in step 2 of example 4 to give compounds 1-28, which were identified as (E) -N- (5- ((4- ((2-fluorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):502(M++1).1H-NMR(400MHz,CDCl3)：δ9.21(s,1H),8.62(s,1H),8.59(s,1H),8.52(d,J＝4.8Hz,1H),7.83(s,1H),7.77(d,J＝8.3Hz,1H),7.65(d,J＝7.8Hz,1H),7.57(t,J＝7.9Hz,1H),7.44(d,J＝15.7Hz,1H),7.29–7.12(m,4H),6.54(t,J＝6.7Hz,1H),6.49(d,J＝15.7Hz,1H),4.03(t,J＝7.4Hz,2H),3.94(s,3H),3.45(q,J＝6.5Hz,2H),1.87(m,2H),1.58(m,2H),1.37(m,2H).
Example 29
Figure BDA0001399549830000292
The procedure is as in example 27, replacing the starting material, 3, 4-dihydro-7-methoxy-4-oxoquinazolin-6-ol acetate, with 4-oxo-1, 4-dihydroquinazolin-6-yl acetate. Compounds 1-29 were obtained and identified as (E) -N- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):612(M++1).1H-NMR(500MHz,CDCl3)：δ9.21(s,1H),8.62(s,1H),8.58(s,1H),8.54(d,J＝4.1Hz,1H),7.80(d,J＝6.6Hz,1H),7.69(d,J＝6.8Hz,1H),7.64–7.55(m,2H),7.43(d,J＝15.7Hz,1H),7.27(d,J＝6.6Hz,1H),7.25(d,J＝6.8Hz,1H),7.23(s,1H),7.02(t,J＝8.8Hz,1H),6.49(d,J＝15.7Hz,1H),6.40(t,J＝6.3Hz,1H),4.05(t,J＝7.5Hz,2H),3.47(q,J＝6.6Hz,2H),1.98–1.83(m,2H),1.68–1.56(m,2H),1.45–1.35(m,2H).
Example 30
Figure BDA0001399549830000301
The procedure is as in example 4, replacing the starting material with 4-oxo-1, 4-dihydroquinazolin-6-yl acetate. Compounds 1-30 were obtained and identified as (E) -N- (5- ((4- ((3-phenylethynyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):478(M++1).1H-NMR(400MHz,CDCl3)：δ9.20(s,1H),8.63(s,1H),8.57(s,1H),8.51(d,J＝4.8Hz,1H),8.15(d,J＝8.8Hz,1H),7.82(s,1H),7.75(d,J＝8.3Hz,1H),7.57(d,J＝7.9Hz,1H),7.45(d,J＝8.8Hz,1H),7.44(d,J＝15.7Hz,1H),7.29–7.12(m,4H),6.54(t,J＝6.7Hz,1H),6.49(d,J＝15.7Hz,1H),4.02(t,J＝7.4Hz,2H),3.43(q,J＝6.5Hz,2H),1.88(m,2H),1.57(m,2H),1.37(m,2H).
Example 31
Figure BDA0001399549830000302
The procedure is as in example 17, replacing the starting material with 4-oxo-1, 4-dihydroquinazolin-6-yl acetate and 3-aminophenylacetylene in step 2 with 3-chloro-4- ((3-fluorobenzyl) oxy) aniline. Compounds 1-31 were obtained and identified as (E) -1- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-substituted) oxy) pentyl) -2-cyano-3- (pyridin-4-substituted) guanidine.
MS(EI,m/z):625(M++1).1H-NMR(400MHz,CDCl3)：δ9.05(s,1H),8.60(s,1H),8.54(s,1H),8.51(d,J＝4.5Hz,1H),8.15(d,J＝8.8Hz,1H),7.98(s,1H),7.89(d,J＝8.2Hz,2H),7.75(d,J＝8.3Hz,1H),7.57(d,J＝9.4Hz,1H),7.31(q,J＝7.4Hz,1H),7.27–7.20(m,2H),7.18–7.08(m,2H),6.99(t,J＝8.5Hz,1H),6.86(d,J＝8.8Hz,1H),6.24(t,J＝6.4Hz,1H),4.99(s,2H),4.13(t,J＝7.5Hz,2H),3.97(s,3H),3.50(q,J＝6.5Hz,2H),2.03–1.91(m,2H),1.65-1.61(m,2H),1.44-1.41(m,2H).
Example 32
Figure BDA0001399549830000311
Synthesis procedure as in example 17, the starting material was replaced by 4-oxo-1, 4-dihydroquinazolin-6-yl acetate. Compounds 1-31 were obtained and identified as (E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine.
MS(EI,m/z):491(M++1).1H-NMR(400MHz,DMSO-d6)：δ9.47(s,1H),9.38(s,1H),8.49(s,1H),8.37(s,2H),8.15(d,J＝8.8Hz,1H),7.98(s,1H),7.89(d,J＝8.2Hz,2H),7.75(d,J＝8.3Hz,1H),7.40(t,J＝7.9Hz,1H),7.21(d,J＝9.2Hz,4H),4.18(s,1H),4.15(d,J＝6.9Hz,2H),3.33(d,J＝8.2Hz,2H),1.94–1.77(m,2H),1.74–1.58(m,2H),1.53-1.52(m,2H).
Example 33
Figure BDA0001399549830000312
The procedure is as in example 4, replacing the starting material with 3, 4-dihydro-6-methoxy-4-oxoquinazolin-7-ol acetate. Compounds 1-33 were obtained and identified as (E) -N- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):508(M++1).1H-NMR(400MHz,DMSO-d6)：δ9.49(s,1H),8.74(d,J＝2.32Hz,1H),8.53(dd,J＝1.58,4.85Hz,1H),8.48(s,1H),8.22(t,J＝5.69Hz,1H),8.04–7.85(m,3H),7.81(s,1H),7.51–7.33(m,3H),7.26–7.12(m,2H),6.73(d,J＝15.86Hz,1H),4.17(s,1H),4.13(t,J＝6.51Hz,2H),3.95(s,3H),3.23(q,J＝6.33Hz,2H),1.82(t,J＝7.13Hz,2H),1.63–1.41(m,4H).13C NMR(125MHz,DMSO-d6)δ164.9,156.5,154.1,153.1,150.4,149.5,149.4,147.4,140.2,135.5,134.3,131.1,129.3,126.7,125.1,124.7,124.3,123.0,122.1,109.2,108.1,102.2,83.9,80.9,68.7,56.6,39.0,29.2,28.6,23.5.
Example 34
Figure BDA0001399549830000321
The procedure is as in example 17, replacing the starting material with 3, 4-dihydro-6-methoxy-4-oxoquinazolin-7-ol acetate. Compounds 1-34 were obtained and identified as (E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine.
MS(EI,m/z):521(M++1).1H-NMR(500MHz,DMSO-d6)：δ9.55(s,1H),8.50(s,1H),8.45–8.31(m,2H),8.04–7.78(m,4H),7.41(t,J＝7.93Hz,1H),7.33–7.10(m,4H),4.19(s,1H),4.15(t,J＝6.43Hz,2H),3.96(s,3H),3.35–3.32(m,2H),1.89–1.78(m,2H),1.70–1.57(m,2H),1.56–1.42(m,2H).13C NMR(125MHz,CDCl3)δ161.3,158.9,154.3,151.9,144.9,134.1,130.0,127.6,126.9,121.6,119.8,113.9,112.8,107.1,88.7,85.7,73.5,61.5,46.9,38.3,33.6,33.2,28.5,28.0.
Example 35
Figure BDA0001399549830000322
The procedure is as in example 9, replacing the starting material with 3, 4-dihydro-6-methoxy-4-oxoquinazolin-7-ol acetate. Compound 2-1 was obtained and identified as (E) -N- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) hexyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):522(M++1).1H-NMR(400MHz,DMSO-d6)δ9.51(s,1H),8.75(d,J＝2.32Hz,1H),8.54(dd,J＝1.58,4.85Hz,1H),8.47(s,1H),8.21(t,J＝5.69Hz,1H),8.03–7.86(m,3H),7.82(s,1H),7.50–7.34(m,3H),7.25–7.13(m,2H),6.76(d,J＝15.86Hz,1H),4.19(s,1H),4.15(t,J＝6.51Hz,2H),3.96(s,3H),3.24(q,J＝6.33Hz,2H),1.84(t,J＝7.13Hz,2H),1.65–1.42(m,6H).
Example 36
Figure BDA0001399549830000331
The procedure is as in example 18, replacing the starting material with 3, 4-dihydro-6-methoxy-4-oxoquinazolin-7-ol acetate. Compound 2-2 was obtained and identified as (E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) hexyl) -3- (pyridine-3-substituted) guanidine.
MS(EI,m/z):535(M++1).
Example 37
Figure BDA0001399549830000332
The procedure is as in example 20, replacing the starting material with 3, 4-dihydro-6-methoxy-4-oxoquinazolin-7-ol acetate. Compound 2-3 was obtained and identified as (E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) guanidine.
MS(EI,m/z):521(M++1).
Example 38
Figure BDA0001399549830000333
The procedure is as in example 19, replacing the starting material with 3, 4-dihydro-6-methoxy-4-oxoquinazolin-7-ol acetate. Compound 2-4 was obtained and identified as (E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) hexyl) -3- (pyridine-4-substituted) guanidine.
MS(EI,m/z):535(M++1).1H-NMR(500MHz,DMSO-d6)：δ9.56(s,1H),8.51(s,1H),8.46–8.32(m,2H),8.03–7.79(m,4H),7.43(t,J＝7.93Hz,1H),7.33–7.10(m,4H),4.18(s,1H),4.16(t,J＝6.43Hz,2H),3.95(s,3H),3.34–3.31(m,2H),1.88–1.75(m,2H),1.71–1.58(m,2H),1.56–1.42(m,4H).
Example 39
Figure BDA0001399549830000341
Step 1.4-chloro-6-nitro-7-chloroquinazoline
3, 4-dihydro-6-nitro-7-chloro-4-oxoquinazoline (2g) was placed in a 100ml Erlenmeyer flaskAfter 40ml of thionyl chloride and 1 drop of DMF were added at room temperature, the mixture was refluxed for 24 hours, distilled to remove most of thionyl chloride, ice water was added, filtered and dried to give 4-chloro-6-nitro-7-chloroquinazoline (2.05g) with a yield of 95%.1H-NMR(DMSO-d6)：δ9.56(s,1H),8.71(s,1H),8.28(s,1H).
Step 2.4- ((3-chloro-4-fluorophenyl) amino) -6-nitro-7-chloroquinazoline
4-chloro-6-nitro-7-chloroquinazoline (2.05g), 3-chloro-4-fluoroaniline (1.5g) were placed in 80 ml of isopropanol and heated under reflux for 12 hours, cooled and filtered to give 4- ((3-chloro-4-fluorophenyl) amino) -6-nitro-7-chloroquinazoline (2.7g) in 90% yield.
1H-NMR(DMSO-d6)：δ11.6(s,1H),9.55(s,1H),8.71(s,1H),8.28(s,1H),8.08(dd,J＝6.6,2.4Hz,1H),7.76(m,1H)，7.55(t,J＝9.3Hz,1H).
Step 3.7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -N- (3-chloro-4-fluoroaniline) -6-nitroquinazolin-4-amine
Dissolving 4- ((3-chloro-4-fluorophenyl) amino) -6-nitro-7-chloroquinazoline (2.7g) in anhydrous THF, adding potassium tert-butoxide (1.3g) and mono tert-butyldimethylsilyl-protected pentanediol (1.9g) under ice bath, slowly raising the temperature to room temperature to react for 12 hours, placing the mixture under ice bath, slowly adding saturated aqueous ammonium chloride solution, then adding ethyl acetate, raising the temperature to room temperature and stirring for ten minutes, separating to obtain an organic layer, drying with anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain 7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -N- (3-chloro-4-fluoroaniline) -6-nitroquinazolin-4-amine (3.3g) with the yield of 80%.
1H-NMR(CDCl3)δ9.56(s,1H),8.78(s,1H),8.51(s,1H),7.97(dd,J＝6.6,2.4Hz,1H),7.67(m,1H)，7.54(s,1H),7.51(t,J＝9.3Hz,1H),4.11(t,J＝7.8Hz,2H),3.77(t,J＝7.2Hz,2H),1.84-1.80(m,2H),1.65-1.58(m,2H),1.43-1.38(m,2H),0.98(s,9H),0.21(s,6H).
Step 4.7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -N- (3-chloro-4-fluoroaniline) -6-aminoquinazolin-4-amine
7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -N- (3-chloro-4-fluoroaniline) -6-nitroquinazolin-4-amine (3.3g) was dissolved in ethanol, 10% palladium on charcoal (0.3g) was added, and after the air in the reaction flask was replaced with hydrogen three times, the mixture was stirred at room temperature overnight. Filtration and evaporation of the solvent under reduced pressure gave the amino compound (3.1g) in 100% yield.
MS(EI,m/z):506(M++1).
Step 5N- (7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-substituted) acrylamide
The amino compound (1eq) obtained in the previous step was dissolved in DMF, acrylic acid (1.5eq), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (3eq) and N, N-diisopropylethylamine (3eq) were added in this order under ice-cooling, and after stirring at room temperature overnight, the solvent was distilled off under reduced pressure, added with ethyl acetate to redissolve, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and subjected to silica gel column chromatography (eluent: dichloromethane/methanol ═ 20/1) after the solvent was distilled off under reduced pressure to give N- (7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-substituted) acrylamide in 52% yield.
MS(EI,m/z):559(M++1).1H-NMR(CDCl3)：δ10.29(s,1H),9.56(s,1H),8.78(s,1H),8.09(s,1H),7.96(dd,J＝6.6,2.4Hz,1H),7.73(s,1H),7.65(m,1H)，7.51(t,J＝9.3Hz,1H),6.48(dd,J＝15.8,6.8Hz,1H),6.09(d,J＝6.8Hz,1H),5.74(dd,J＝15.8Hz,1H),4.11(t,J＝7.8Hz,2H),3.77(t,J＝7.2Hz,2H),1.85-1.81(m,2H),1.64-1.57(m,2H),1.44-1.37(m,2H),0.97(s,9H),0.19(s,6H).
Step 6.5- ((6-acrylamido-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-7-substituted) oxy) pentyl methanesulfonate
Dissolving N- (7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazoline-6-substituted) acrylamide (1eq) in anhydrous tetrahydrofuran, adding a tetrahydrofuran solution (1eq) of tetrabutylammonium fluoride, reacting at room temperature for one hour, adding a saturated aqueous amine chloride solution and ethyl acetate, separating to obtain an organic layer, drying over anhydrous sodium sulfate, filtering, and evaporating the solvent under reduced pressure to obtain a brown compound. Dissolving the compound in anhydrous dichloromethane, sequentially adding triethylamine (1.2eq) and methylsulfonyl chloride (1.1eq) in an ice bath, heating to room temperature for reaction for three hours, adding saturated aqueous solution of amine chloride and ethyl acetate, separating to obtain an organic layer, drying with anhydrous sodium sulfate, filtering, and evaporating under reduced pressure to remove the solvent to obtain a brown crude compound.
MS(EI,m/z):523(M++1).
Step 7N- (7- ((5-aminopentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-substituted) acrylamide
Dissolving the brown compound obtained in the step 6 in DMF, adding sodium azide (1.5eq), reacting for three hours at room temperature, then decompressing and distilling to remove the solvent, adding ethyl acetate and water, separating to obtain an organic layer, extracting with saturated saline solution, drying with anhydrous sodium sulfate, filtering, decompressing and distilling to remove the solvent to obtain the brown compound. The compound was dissolved in tetrahydrofuran, triphenylphosphine (1.1eq) and water (5eq) were added, the reaction was allowed to proceed overnight at room temperature, the solvent was evaporated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (eluent: dichloromethane/methanol ═ 20/1) to give N- (7- ((5-aminopentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-substituted) acrylamide in a yield of 60% based on N- (7- ((5- ((tert-butyldimethylsilyl) oxy) pentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-substituted) acrylamide.
MS(EI,m/z):444(M++1).1H-NMR(MeOD)：δ8.48(s,1H),8.07(s,1H),7.70(s,1H),7.4(dd,J＝6.6,2.4Hz,1H),7.28(s,1H)，7.21(t,J＝9.2Hz,1H),6.48(dd,J＝15.8,6.8Hz,1H),6.09(d,J＝6.8Hz,1H),5.74(dd,J＝15.8Hz,1H),4.11(t,J＝7.8Hz,2H),2.69(t,J＝7.2Hz,2H),1.85-1.81(m,2H),1.64-1.57(m,2H),1.44-1.37(m,2H).
(E) -N- (5- ((6-acrylamido-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide
Trans-3- (3-pyridyl) enepropionic acid (compound 9, 1eq) was placed in a dichloromethane solution, EDCI (1eq) and DIPEA (1.5eq) were added, and stirred for 2 hours. And (3) dissolving the compound prepared in the step (7) in dichloromethane, adding the reaction solution, reacting for 10 hours at room temperature, adding a saturated amine chloride solution, stirring for 10 minutes, separating to obtain an organic layer, drying with anhydrous sodium sulfate, removing the solvent under reduced pressure, and performing column chromatography to obtain the compound 2-5.
MS(EI,m/z):575(M++1).1H-NMR(MeOD)：δ8.51(d,J＝4.8Hz,1H),8.48(s,1H),8.07(s,1H),7.70(s,1H),7.68(s,1H),7.57(d,J＝7.9Hz,1H),7.4(dd,J＝6.6,2.4Hz,1H),7.44(d,J＝15.7Hz,1H),7.28(s,1H)，7.21(t,J＝9.2Hz,1H),6.54(t,J＝6.7Hz,1H),6.51-6.47(m,2H),6.08(d,J＝6.8Hz,1H),5.73(dd,J＝15.8Hz,1H),4.10(t,J＝7.8Hz,2H),2.66(t,J＝7.2Hz,2H),1.84-1.81(m,2H),1.63-1.56(m,2H),1.45-1.38(m,2H).
Example 40
Figure BDA0001399549830000361
Substituting mono-tert-butyldimethylsilyl-protected pentanediol in step 3 of example 39 with mono-tert-butyldimethylsilyl-protected hexanediol, preparing the compound N- (7- ((5-aminopentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-substituted) acrylamide, prepared according to example 39, dissolving N- (7- ((5-aminopentyl) oxy) -4- ((3-chloro-4-fluorophenyl) amino) quinazolin-6-substituted) acrylamide (1eq) in pyridine, adding methyl-N' -cyano-N- (pyridin-4-substituted) thiocarbamoylamino (1eq) and triethylamine (1eq), reacting the mixture at 50 ℃ overnight, the solvent was evaporated under reduced pressure and the crude product was directly separated by column chromatography on silica gel (eluent: dichloromethane/methanol-20/1) to give the title compound 2-6, which was identified as (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- (2-cyano-3- (pyridine-4-substituted) guanidino) hexyl) oxy) quinazolin-6-substituted) acrylamide.
MS(EI,m/z):602(M++1).1H-NMR(MeOD)：δ8.51(s,1H),8.46(d,J＝7.6Hz,1H),8.07(s,1H),7.71(s,1H),7.41(dd,J＝6.6,2.4Hz,1H),7.31(s,1H)，7.26(d,J＝7.6Hz,1H),7.21(t,J＝9.2Hz,1H),6.48(dd,J＝15.8,6.8Hz,1H),6.09(d,J＝6.8Hz,1H),5.74(dd,J＝15.8Hz,1H),4.11(t,J＝7.8Hz,2H),2.69(t,J＝7.2Hz,2H),1.85-1.81(m,2H),1.64-1.57(m,2H),1.44-1.37(m,2H).
EXAMPLE 41
Figure BDA0001399549830000371
Compound 2-7, identified as (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((5- ((E) -3- (pyridine-3-substituted) acrylamido) pentyl) oxy) quinazolin-6-substituted) -4- (dimethylamino) but-2-enamide, was prepared as in example 39 by replacing the acrylic acid in step 5 of example 39 with 4- (dimethylamino) but-2-enoic acid.
1H NMR(MeOD)δ8.51(s,1H),8.48(s,1H),8.07(s,1H),7.70(s,1H),7.68(s,1H),7.57(d,J＝7.9Hz,1H),7.4(dd,J＝6.6,2.4Hz,1H),7.44(d,J＝15.7Hz,1H),7.28(s,1H)，7.21(t,J＝9.2Hz,1H),6.75(d,J＝15.8Hz,1H),6.54(t,J＝6.7Hz,1H),6.51-6.47(m,2H),6.38(d,J＝15.8Hz,1H),4.10(t,J＝7.8Hz,2H),3.02(d,J＝8.6Hz,2H),2.77(s,3H),2.74(s,3H),2.66(t,J＝7.2Hz,2H),1.84-1.79(m,2H),1.63-1.56(m,2H),1.45-1.38(m,2H).MS(EI,m/z):632(M++1).
Example 42
Example 40 was repeated using 4- (dimethylamino) but-2-enoic acid instead of acrylic acid to give compounds 2-8, identified as (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- ((E) -2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazolin-6-substituted) -4- (dimethylamino) but-2-enamide.
MS(EI,m/z):659(M++1).1H-NMR(MeOD)：δ8.51(s,1H),8.46(d,J＝7.6Hz,1H),8.07(s,1H),7.71(s,1H),7.41(dd,J＝6.6,2.4Hz,1H),7.31(s,1H)，7.26(d,J＝7.6Hz,1H),7.21(t,J＝9.2Hz,1H),6.75(d,J＝15.8Hz,1H),6.38(dd,J＝15.8Hz,1H),4.11(t,J＝7.8Hz,2H),2.69(t,J＝7.2Hz,2H),3.02(d,J＝8.6Hz,2H),2.77(s,3H),2.74(s,3H),1.85-1.81(m,2H),1.64-1.57(m,2H),1.44-1.37(m,2H).
Figure BDA0001399549830000381
Example 43
Figure BDA0001399549830000382
Compound 2-9, identified as (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((5- ((E) -3- (pyridine-3-substituted) acrylamido) pentyl) oxy) quinazolin-6-substituted) -4- (pyridine-1-substituted) but-2-enamide, was prepared as in example 39 by replacing the acrylic acid in step 5 of example 39 with 4- (pyridine-1-substituted) but-2-enoic acid.
MS(EI,m/z):672(M++1).1H-NMR(MeOD)δ8.51(s,1H),8.48(s,1H),8.07(s,1H),7.70(s,1H),7.68(s,1H),7.57(d,J＝7.9Hz,1H),7.4(dd,J＝6.6,2.4Hz,1H),7.44(d,J＝15.7Hz,1H),7.28(s,1H)，7.21(t,J＝9.2Hz,1H),6.75(d,J＝15.8Hz,1H),6.54(t,J＝6.7Hz,1H),6.51-6.47(m,2H),6.38(d,J＝15.8Hz,1H),4.10(t,J＝7.8Hz,2H),3.02(d,J＝8.6Hz,2H),2.66(t,J＝7.2Hz,2H),2.51(t,J＝6.8Hz,3H),2.48(t,J＝6.8Hz,3H),1.85-1.82(m,2H),1.64-1.57(m,6H),1.46-1.37(m,4H).
Example 44
Figure BDA0001399549830000383
Example 40 was repeated using 4- (pyridin-1-substituted) but-2-enoic acid in place of acrylic acid to give compounds 2-10, identified as (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- ((E) -2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazolin-6-substituted) -4- (pyridin-1-substituted) but-2-enamide.
MS(EI,m/z):699(M++1).1H-NMR(MeOD)：δ8.51(s,1H),8.46(d,J＝7.6Hz,1H),8.07(s,1H),7.71(s,1H),7.41(dd,J＝6.6,2.4Hz,1H),7.31(s,1H)，7.26(d,J＝7.6Hz,1H),7.21(t,J＝9.2Hz,1H),6.75(d,J＝15.8Hz,1H),6.38(dd,J＝15.8Hz,1H),4.12(t,J＝7.8Hz,2H),3.03(d,J＝8.6Hz,2H),2.67(t,J＝7.2Hz,2H),2.52(t,J＝6.8Hz,3H),2.49(t,J＝6.8Hz,3H),1.86-1.83(m,2H),1.65-1.58(m,6H),1.47-1.38(m,4H).
Example 45
Figure BDA0001399549830000391
The mono-tert-butyldimethylsilyl-protected pentanediol in step 3 of example 39 was replaced with tert-butoxycarbonylamino mono-substituted ethylene glycol as in example 39. Compounds 2-11 were obtained and identified as (E) -N- (2- (2- ((6-acrylamido-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-7-substituted) oxy) ethoxy) ethyl) -3- (pyridine-3-substituted) acrylamide.
MS(EI,m/z):577(M++1).1H-NMR(MeOD)：δ8.51(d,J＝4.8Hz,1H),8.48(s,1H),8.07(s,1H),7.70(s,1H),7.68(s,1H),7.57(d,J＝7.9Hz,1H),7.4(dd,J＝6.6,2.4Hz,1H),7.44(d,J＝15.7Hz,1H),7.28(s,1H)，7.21(t,J＝9.2Hz,1H),6.54(t,J＝6.7Hz,1H),6.51-6.47(m,2H),6.08(d,J＝6.8Hz,1H),5.73(dd,J＝15.8Hz,1H),4.21–4.12(m,2H),3.78(t,J＝4.93Hz,2H),3.58–3.48(m,2H),3.29(q,J＝5.0Hz,2H).
Example 46
The synthesis was performed as in example 40, substituting mono-tert-butyldimethylsilyl-protected 3-aminohexanediol for the mono-tert-butyldimethylsilyl-protected hexanediol in step 3 of example 40. Compounds 2-12 were obtained and identified as (E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- ((3- (2-cyano-3- (pyridine-4-substituted) guanidino) propyl) amino) ethoxy) quinazoline-6-substituted) acrylamide.
MS(EI,m/z):603(M++1).1H-NMR(MeOD)δ8.50(s,1H),8.47(d,J＝7.6Hz,1H),8.06(s,1H),7.70(s,1H),7.40(dd,J＝6.6,2.4Hz,1H),7.31(s,1H)，7.26(d,J＝7.6Hz,1H),7.22(t,J＝9.2Hz,1H),6.49(dd,J＝15.8,6.8Hz,1H),6.10(d,J＝6.8Hz,1H),5.74(dd,J＝15.8Hz,1H),4.29(t,J＝5.15Hz,2H),3.26(t,J＝6.26Hz,2H),3.14(t,J＝5.14Hz,2H),2.86(t,J＝6.25Hz,2H).
Figure BDA0001399549830000401
EXAMPLE 47 in vitro Biochemical Activity assay
(1) Method for measuring activity of EGFR (epidermal growth factor receptor) and variant thereof
Diluting EGFR substrate to 200M (reaction concentration is 20M) by using reaction buffer solution, diluting EGFR enzyme to appropriate concentration, adding compounds to be detected with different concentrations, reacting for 30 minutes at 37 ℃, then adding substrate development solution (developer) with 2 times concentration of the same volume, incubating for 15 minutes at room temperature, finally measuring reading by using a microplate reader, wherein the exciting light is 360nm, the emitting light is 460nm, and the data is processed by Prime 4 software.
(2) NAMPT enzyme activity determination method
Nicotinamide phosphoribosyltransferase catalyzes the substrates nicotinamide (nicotinamide) and 5-phosphoribosyl-1-pyrophosphate (PRPP) to Nicotinamide Mononucleotide (NMN). NMN can be converted into Nicotinamide Adenine Dinucleotide (NAD) under the action of nicotinamide mononucleotide adenylyltransferase (Nicotinamide adenine transferase 1, NMNAT1)+) Product NAD+The amount of (b) reflects the level of activity of the NAMPT enzyme. NAD (nicotinamide adenine dinucleotide)+The amount of the compound is detected by converting water-soluble tetrazolium salt (WST-1) into WST-1 formazan through an enzyme cycling reaction by using Alcohol Dehydrogenase (ADH) and diaphorase (diaphorase). The method comprises the following specific steps:
1) formulation buffer 1, comprising: 10 μ L of 10XNAMPT aqueous solution, 10 μ L of 10 XNicotinamide, 10 XPRPP 10 μ L, 10 XATP 10 μ L, 2 μ L of NMNAT1 enzyme, and dH2O (deionized water) 48. mu.L brought the volume to 90. mu.L.
2) And preparing a buffer solution 2, which comprises: 50 XWST-12. mu.L, 50 XADH 2. mu.L, 50 XDiaphorase 2. mu.L, 10XEtOH 10. mu.L, plus dH2O4. mu.L brought the volume to 20. mu.L.
3) mu.L of buffer 1 was added to each well of the plate, followed by 2. mu.L of compound (0.1mM), 2. mu.L of DMSO was added to the blank control, and 2. mu.L of Iressa (1mM) was added to the positive control.
4) Adding 2 mu L of recombinant NAMPT into each hole for initial enzyme reaction, fully mixing uniformly, and incubating for 60min at 30 ℃.
5) And after the reaction is finished, adding 20 mu L of buffer solution 2 for color development, and dynamically detecting the absorption value at 450nm for 5-35min of the reaction.
The results of measurement of the inhibitory activity of the EGFR enzyme and the mutant thereof and the inhibitory activity of NAMPT enzyme of each compound are shown in table 1.
D：IC50>1μM；C：IC50＝100nM-1μM；B：IC50＝1nM-100nM；A：IC50<1nM。IC50Refers to the concentration of inhibitor at which half of the inhibition occurs (50% inhibition concentration).
TABLE 1 EGFR enzyme and its variants and NAMPT enzyme inhibitory Activity assay results
Figure BDA0001399549830000411
From the results in table 1 it can be seen that: compared with positive control (Iressa), the compound has remarkable activity of inhibiting EGFR enzyme and variant thereof and NAMPT enzyme.
EXAMPLE 48 assay for detecting Compounds Activity on cancer cells
1. The experimental principle is as follows: the MTT method is used for detecting the cancer cell growth inhibition activity of the compound. The principle of the MTT method is as follows: the yellow thiazole blue can penetrate a cell membrane to enter a cell, amber dehydrogenase in mitochondria of a living cell can reduce exogenous MTT into bluish purple needle-shaped Formazan crystals which are difficult to dissolve in water and deposit the crystals in the cell, the crystals can be dissolved by dimethyl sulfoxide (DMSO), an enzyme linked immunosorbent detector is used for detecting the light absorption value at 490nm/570nm wavelength, and the cell number can be indirectly reflected.
2. Experimental materials: the cancer cell lines used were A549 (human lung cancer cell), MCF-7 (human breast cancer cell), U937 (human leukemia cell), PANC-1 (human pancreatic cancer cell), MOLT-4 (human acute lymphoblastic leukemia cell); all cells were from the us cell bank. Culturing with DMEM + 10% FBS culture medium or 1640+ 10% FBS culture medium respectively.
3. Experimental methods and analysis of results:
experimental groups: 190 μ L of cell suspension +10 μ L of different concentrations of drug (final concentration 10)-8M)。
Blank control group: 200 μ L PBS buffer.
Negative control group: 190. mu.L of cell suspension + 10. mu.L of DMSO solution (final DMSO concentration is 0.1%).
Positive control group: 190. mu.L cell suspension + 10. mu.L different concentrations (10)-6M) Iressa.
a)、Cells were seeded in 96-well plates at 1500/well, 190. mu.L/well, 5% CO at 37 ℃2Culturing in an incubator overnight;
b) adding 10 mu L of drugs with different concentrations into each hole the next day, wherein the final concentration of the drugs is 10-8M, arranging three parallel holes; 37 ℃ and 5% CO2Incubating in an incubator for 72 hours;
c) 20 μ L of 5mg/mL MTT, 5% CO at 37 ℃2Incubating in an incubator for 4 hours;
d) discarding the supernatant, adding 100 mu L DMSO into each well, and oscillating;
e) 570nm, calculating cell viability, calculating IC from the results50The following table is obtained.
D：IC50＝1μM-10μM；C：IC50＝100nM-1μM；B：IC50＝10nM-100nM；A：IC50＝0.1nM-10nM。IC50The concentration of drug required for 50% growth inhibition of the cells (50% growth inhibition) is indicated.
TABLE 2 cellular Activity (IC) of Compounds50)
Figure BDA0001399549830000421
Figure BDA0001399549830000431
From the results in table 2 it can be seen that: the compounds have significant activity in inhibiting the growth of the listed tumor cells compared to the positive control (Iressa).

Claims (10)

1. The benzazepine aromatic ring compound shown in the formula I or pharmaceutically acceptable salt, stereoisomer and racemate thereof:
Figure FDA0002287302540000011
one of the substituents of R and R' is selected from
Figure FDA0002287302540000012
The other substituent is selected from hydrogen, methoxy,
Figure FDA0002287302540000013
R' is substituted or unsubstituted phenyl, the substituent of the phenyl is selected from ethynyl, F, Cl, Br and (3-fluorophenyl) methoxy, and the phenyl can be monosubstituted or polysubstituted;
wherein Q is selected from
Figure FDA0002287302540000014
L1Is selected from- (CH)2)t-, t is an integer from 2 to 7;
A1hydrogen from the group consisting of-O-, -NH-may be replaced by Cl-3Alkyl substitution or covalent bonding;
L2is selected from- (CH)2)n-n is an integer from 0 to 2;
A2selected from-O-, -NH-, -S-, -SO2-。
2. Benzazepine aromatic rings compounds according to claim 1, wherein one of the substituents R and R' is selected from
Figure FDA0002287302540000015
The other substituent is selected from hydrogen, methoxy,
Figure FDA0002287302540000016
R' is substituted or unsubstituted phenyl, the substituted phenyl is selected from 3-ethynylphenyl, 3-chloro-4 fluorophenyl, 3-bromophenyl, 3-chloro-4- ((3 fluorobenzyl) oxy) phenyl;
wherein Q is selected from
Figure FDA0002287302540000017
L1Is- (CH)2)t-, t is an integer from 4 to 7, A1Is a covalent bond and is a non-covalent bond,L2is a covalent bond, A2is-O-, -NH-, -S-; or L1Is- (CH)2)t-, t is an integer from 2 to 5, A1is-O-or-NH-, L2Is- (CH)2) n-, n is 2, A2is-O-, -NH-, -S-.
3. Benzazepine aromatic ring compounds according to claim 1, characterized in that said benzazepine aromatic ring compounds are selected from the following compounds:
(E) -N- (2- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (3- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) propyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (4- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) butyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- (4- (3-ethynylphenylamino) -7-methoxyquinazolin-6-oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- (2- ((4- ((3-phenylethyl) amino) -7-methoxyquinazolin-6-substitution)) ethoxy) yl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- ((2- ((4- ((3-phenylethyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) amino) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- (ethyl (2- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) amino) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (2- ((2- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) ethyl) (isopropyl) amino) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) oxy) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) amino) pentyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) amino) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) mercapto) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) mercapto) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) sulfonyl) pentyl) -3- (pyridine-3-substitution) acrylamide;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substitution) sulfonyl) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) hexyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) hexyl) -3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (7- ((4- ((3-phenylethynyl) amino) -7-methoxyquinazolin-6-substituted) oxy) heptyl) -3- (pyridine-3-substituted) guanidine;
(E) -N- (5- ((4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-bromophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((7-methoxy-4- (phenylamino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((4-chlorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((2-fluorophenyl) amino) -7-methoxyquinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -1- (5- ((4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) quinazolin-6-substituted) oxy) pentyl) -2-cyano-3- (pyridine-4-substituted) guanidine;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) quinazolin-6-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine;
(E) -N- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-4-substituted) guanidine;
(E) -N- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substitution) oxy) hexyl) -3- (pyridine-3-substitution) acrylamide;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) hexyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (5- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) guanidine;
(E) -2-cyano-1- (6- ((4- ((3-phenylethynyl) amino) -6-methoxyquinazolin-7-substituted) oxy) hexyl) -3- (pyridine-4-substituted) guanidine;
(E) -N- (5- ((6-acrylamido-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-7-substituted) oxy) pentyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- (2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazoline-6-substituted) acrylamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((5- ((E) -3- (pyridine-3-substituted) acrylamido) pentyl) oxy) quinazolin-6-substituted) -4- (dimethylamino) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- ((E) -2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazolin-6-substituted) -4- (dimethylamino) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((5- ((E) -3- (pyridine-3-substituted) acrylamido) pentyl) oxy) quinazolin-6-substituted) -4- (pyridine-1-substituted) but-2-enamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- ((6- ((E) -2-cyano-3- (pyridin-4-substituted) guanidino) hexyl) oxy) quinazolin-6-substituted) -4- (pyridin-1-substituted) but-2-enamide;
(E) -N- (2- (2- ((6-acrylamido-4- ((3-chloro-4-fluorophenyl) amino) quinazolin-7-substituted) oxy) ethoxy) ethyl) -3- (pyridine-3-substituted) acrylamide;
(E) -N- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- ((3- (2-cyano-3- (pyridin-4-substituted) guanidino) propyl) amino) ethoxy) quinazolin-6-substituted) acrylamide.
4. Use of a benzazepine aromatic ring compound of any one of claims 1 to 3 or a pharmaceutically acceptable salt, stereoisomer, or racemate thereof for the manufacture of a medicament for the treatment of a disease caused by abnormal activity of a protein kinase and/or nicotinamide phosphoribosyl transferase; wherein the protein kinase is a protein tyrosine kinase.
5. The use according to claim 4, wherein said disease caused by abnormal activity of protein kinase and/or nicotinamide phosphoribosyltransferase is a tumor, and said tumor is a solid tumor or a liquid tumor.
6. The use according to claim 5, wherein the neoplasm is lung cancer, bone cancer, membrane adenocarcinoma, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's disease, carcinoma of the esophagus, carcinoma of the small intestine, carcinoma of the endocrine system, carcinoma of the thyroid gland, carcinoma of the parathyroid gland, sarcoma of soft tissue, carcinoma of the urethra, carcinoma of the penis, carcinoma of the prostate, chronic or acute leukemia, carcinoma of the bladder, carcinoma of the ureter, carcinoma of the kidney, neoplasms of the central nervous system, spinal axis tumors, pituitary adenomas, gastrointestinal stromal tumors, mastocytosis, gliomas, sarcomas, lymphomas.
7. The use according to claim 6, wherein the lung cancer is non-small cell lung cancer or small cell lung cancer.
8. The use according to claim 4, wherein the protein kinase is ALK, AXL, BT, CDKll, c-Met, KDR, VEGFR2, RET, PDGFR- α, PDGFR- β, c-KIT, Flt3, MEK1, MEK2, CSF1R, EPHA2, MKNK2, TIE2, TRKA, SRC, PLK40, RON, EGF1R, HER2, HER3, HER4, PDGFR- α, c-fms, FLT1, SRC, Frk, Btk, Csk, Abl, Fes, Fps, Fak, AcK, Yes, Fyn, Lyn, Lck, Fgr, Yrk, PDK1, TAK1, Tie-1, YSK 9, 686, TRK, PKN2, MST 86K, or DDR 86K.
9. A medicament for treating diseases caused by abnormal activity of protein kinase and/or nicotinamide phosphoribosyltransferase, which takes the benzazepine aromatic ring compound or the pharmaceutically acceptable salt, stereoisomer or racemate thereof according to any one of claims 1 to 3 as an active ingredient and also comprises one or more pharmaceutically acceptable auxiliary materials.
10. The medicament according to claim 9, wherein the medicament is an oral formulation, an injection, an anal suppository, a nasal inhalant, an eye drop or a skin patch.
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