CN106146412B - Quinazoline derivant and its preparation method and application - Google Patents

Quinazoline derivant and its preparation method and application Download PDF

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CN106146412B
CN106146412B CN201510149555.7A CN201510149555A CN106146412B CN 106146412 B CN106146412 B CN 106146412B CN 201510149555 A CN201510149555 A CN 201510149555A CN 106146412 B CN106146412 B CN 106146412B
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chloro
amino
fluorophenyl
acrylamide
propyl
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CN106146412A (en
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张健存
彭江灵
李宏
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Guangzhou Hengnuokang Pharmaceutical Technology Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Plural Heterocyclic Compounds (AREA)

Abstract

The present invention relates to a kind of quinazoline derivants and its preparation method and application, belong to field of pharmaceutical chemistry technology.The structure of the quinazoline derivant is shown in formula I, quinazoline derivant of the invention or its pharmaceutically acceptable salt, there is irreversible inhibiting effect to tyrosine kinase, and such compound can inhibit two kinds of tyrosine kinase of EGFR and HER2 simultaneously, also, such compound all has extraordinary inhibitory activity to kinds cancer cell line.

Description

Quinazoline derivative and preparation method and application thereof
Technical Field
The invention relates to the technical field of medicinal chemistry, in particular to a quinazoline derivative and a preparation method and application thereof.
Background
The Epidermal Growth Factor Receptor (EGFR) is a member of an ErbB protein family, and the other three subtypes are HER2(Neu, ErbB2), HER3(ErbB3) and HER4(ErbB4), which play important roles in the proliferation and differentiation processes of cells and are also one of the most deeply studied tyrosine receptor proteins at present. EGFR is widely present in normal epidermal tissues such as skin, hair follicles and gastrointestinal tract, and plays an important role in maintaining normal physiological activities. However, overexpression or sustained activation of EGFR can lead to a number of cancers, with EGFR abnormalities occurring in cancers including colorectal, lung, breast, and head and neck cancers.
In 2003-2004, the EGFR small-molecule inhibitors Gefitinib and Erlotinib are approved by the US FDA to be marketed for treating non-small cell lung cancer patients, and the drugs are particularly effective for the non-small cell lung cancer patients with activating mutation-carrying EGFR genotypes (accounting for 10-20% of the total number of the cancer patients). Unfortunately, highly sensitive patients often develop acquired resistance after about one year of drug administration. Among the acquired resistance mechanisms, the most common (50% of the total number of resistant patients) is the second mutation T790M of EGFR, i.e. threonine at position 790 is mutated to methionine, which can increase the binding capacity of EGFR to ATP, so that Gefitinib, these drug molecules, have difficulty to compete with ATP for binding to EGFR, thereby losing the drug effect.
Numerous studies have shown that the development of dual inhibitors targeting EGFR and HER2 tyrosine kinases has the following advantages: 1. the inhibition of two tyrosine kinases, namely EGFR and HER2, is easier to overcome drug resistance caused by cell growth signal redundancy caused by the up-regulation of other members of the EGFR family when a single tyrosine kinase inhibitor is used; 2. due to the highest activity of EGFR and HER2 heterodimers, dual inhibitors of EGFR and HER2 tyrosine kinase are effective in a greater number of cancer patients. 3. Compared with a single inhibitor, the dual inhibitor has a superimposed effect on the tumor cell inhibition effect. In vitro and in vivo experiments also showed that the anti-cancer effect of dual inhibition of EGFR and HER2 tyrosine kinase is greater than inhibition of a single receptor. In addition, compared with the simultaneous use of two drugs respectively acting on a single target point, the drug acting on the two target points is more convenient for patients to use, and the interaction between the drugs can be avoided.
Taken together, the development of dual irreversible inhibitors targeting EGFR and HER2 tyrosine kinases is a rational choice.
At present, irreversible dual tyrosine kinase inhibitors entering clinical research comprise Afatinib, HKI-272 and PF299804, and clinical experimental data show that the inhibitors have good development prospects.
Disclosure of Invention
Based on the above, there is a need for a quinazoline derivative with a new structure, which has an inhibitory effect on both EGFR and HER2 tyrosine kinases and has a good inhibitory activity on various cancer cells.
A quinazoline derivative represented by the formula I:
wherein,
R1is optionally selected from: phenyl, substituted phenyl, aryl containing fused rings, heteroaryl;
R2is optionally selected from: c1-C6Chain alkyl radical, C3-C8Cyclic alkyl radical, C containing a heteroatom of O, N, S, P1-C6Chain heteroalkyl, C containing O, N, S, P heteroatoms3-C8A cyclic heteroalkyl group;
R5is optionally selected from: hydrogen, halogen, cyano, C1-C6Chain alkyl radical, C3-C8A cyclic alkyl group;
R6is optionally selected from: hydrogen, C1-C6Chain alkyl radical, C3-C8A cyclic alkyl group;
R7is optionally selected from: hydrogen, halogen, cyano, C1-C6Chain alkyl radical, C3-C8Cyclic alkyl radical, C containing a heteroatom of O, N, S, P1-C6Chain heteroalkyl, C containing O, N, S, P heteroatoms3-C8A cyclic heteroalkyl group;
and, R5，R6，R7Any two substituents in the formula (I) can form a ring;
x is selected from: c, S ═ O;
y is selected from: C-CN, N;
w is selected from the following groups:
wherein: r3Is optionally selected from: hydrogen, C1-C3A chain alkyl group;
R4is optionally selected from: hydrogen, C1-C3A chain alkyl group.
The above quinazoline derivatives were developed to overcome the disadvantages of drug resistance and large dosage of early reversible inhibitors, and studies on irreversible inhibitors were carried out. By utilizing the characteristic that sulfydryl on Cys773 and Cys805 amino acid residues at the edge of an ATP binding area of EGFR and HER2 kinase has strong nucleophilicity, a Michael addition receptor is introduced into a drug molecule, so that the drug molecule can form covalent bond binding with the kinase to achieve the purpose of irreversible inhibition.
In some of these embodiments, R1Selected from the group consisting of:
wherein R is8Is optionally selected from: hydrogen, C1-C6Alkyl radical, C6-C10Substituted aralkyl, halogen, CF3，CHF2，CH2F，OR9，NR9R10，CN，CO2R9，CON R9R10，SO2R9，SO2N R9R10，NO2，NCON R9R10，NCO2R9，OCONR9R10，CSN R9R10，NCSNR9R10；
R9、R10Each is selected from: hydrogen, C1-C6Alkyl radical, C containing a heteroatom of O, N, S, P1-C6A chain heteroalkyl group;
z is selected from: c, N, O.
In some of these embodiments, R1Selected from the group consisting of:
wherein: r8Selected from: hydrogen, C1-C6Alkyl, halogen.
In some of these embodiments, R2Selected from the group consisting of:
wherein:
R11，R12each is selected from: hydrogen, C1-C6Chain alkyl radical, C containing a heteroatom of O, N, S, P1-C6A chain heteroalkyl group;
and, R11And R12Two substituents may form a ring;
n is selected from: 1-6.
In some of these embodiments, R7Selected from the group consisting of:
wherein:
R11，R12each is optionally: hydrogen, C1-C6Chain alkyl radical, C containing a heteroatom of O, N, S, P1-C6A chain heteroalkyl group;
and, R11And R12Two substituents may form a ring;
m is selected from: 1-6.
In some of these embodiments, R1Selected from the group consisting of:
wherein: r8Selected from: hydrogen, C1-C6Alkyl, halogen;
R2selected from the group consisting of:
wherein:
R11，R12each is selected from: hydrogen, C1-C6A chain alkyl group;
n is selected from: 1-2;
R5selected from: hydrogen, cyano;
R6selected from: hydrogen;
R7selected from the group consisting of:
wherein:
R11，R12each is optionally: hydrogen, C1-C6Chain alkyl radical, C containing a heteroatom of O, N, S, P1-C6A chain heteroalkyl group;
and, R11And R12Two substituents may form a ring;
m is selected from: 1-2;
x is selected from: c, S ═ O;
y is selected from: C-CN, N;
w is selected from the following groups:
wherein: r3Is optionally selected from: hydrogen;
R4is optionally selected from: and (3) hydrogen.
In some of these embodiments, the quinazoline derivative is selected from one of the following compounds:
n- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- (dimethylamino) ethoxy) quinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-morpholinoethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- (dimethylamino) ethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
(E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) butyl-2-enamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
(E) -N- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4- (dimethylamino) butyl-2-enamide;
n- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide;
n- (3- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
(E) -N- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) butyl-2-enamide;
n- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) ethenesulfonamide;
n- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -propyl-2-yn-1-yl) acrylamide;
(E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) propyl-2-yn-1-yl) -4- (dimethylamino) butyl-2-enamide;
(E) -N- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4-morpholinobutyl-2-enamide;
(E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) propyl-2-yn-1-yl) -4-morpholinobutyl-2 enamide;
n- ((4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) methyl) acrylamide;
4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazoline-6-carboxamide;
n- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -2-cyano-2-enamide;
n- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide.
The invention also discloses a preparation method of the quinazoline derivative or the pharmaceutically acceptable salt thereof, which adopts the following route for synthesis:
or synthesized by adopting the following route:
or synthesized by adopting the following route:
the invention also discloses application of the quinazoline derivative or pharmaceutically acceptable salt thereof in preparing antitumor drugs.
In some of these embodiments, the tumor comprises at least one of hemangioma, endometriosis, gastrointestinal tumor, histiocytic lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, nasopharyngeal cancer, leukemia.
Compared with the prior art, the invention has the following beneficial effects:
the quinazoline derivative or the pharmaceutically acceptable salt thereof has an irreversible inhibition effect on tyrosine kinases, and the compound can inhibit EGFR and HER2 tyrosine kinases simultaneously, so that the drug resistance caused by the up-regulation of other members of an EGFR family when a single tyrosine kinase irreversible inhibitor is used is overcome more easily. Moreover, when a substituent is introduced into the position 7 of quinazoline, the compound has the same enzyme activity as that of a positive control drug, but has better effect on a plurality of cancer cell lines than the positive control drug, which is probably related to the metabolism of drug molecules and the bioavailability of the drug molecules entering cells.
Detailed Description
The present invention is further illustrated by the following examples, which are not intended to limit the scope of the present invention in any way.
The compounds of the invention and their salts can also be prepared by methods known for the preparation of chemically related compounds, and the starting materials referred to in the examples can be obtained by analogous methods of the prior art.
"substituted" refers to the replacement of a hydrogen radical in a particular structure with a radical of a specified substituent. When more than one position in any particular structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at each position. As used herein, the term "substituted" is intended to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. A heteroatom such as nitrogen may have a hydrogen substituent and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatom.
"heteroaryl" refers to a 4n +2 aromatic ring system (e.g., sharing 6, 10, or 14 pi electrons in the cyclic orbital) containing 5-14 membered monocyclic or polycyclic (e.g., bicyclic or tricyclic) rings, and having a ring carbon atom and 1-4 ring heteroatoms, wherein each ring heteroatom is independently selected from nitrogen, oxygen, and sulfur ("5-14 membered heteroaryl"). Heteroaryl groups containing one or more nitrogen atoms, the point of attachment may be a carbon or nitrogen atom if valency permits. One or both rings of the polycyclic ring system of heteroaryl groups can be included at one or more heteroatoms. "heteroaryl" also includes heteroaryl ring systems as defined above fused with one or more carbocyclic or heterocyclic groups in which the point of attachment is on the heteroaryl ring, and in which case the number of ring members includes only the number of members on the heteroaryl ring system. "heteroaryl" also includes heteroaryl ring systems as defined above fused with one or more aryl groups, where the point of attachment may be on an aryl or heteroaryl ring, and in which case the number of ring members includes only the number of ring members in the fused polycyclic (aryl/heteroaryl) ring system. Polycyclic heteroaryl groups, wherein one of the rings does not contain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and the like), may have the point of attachment on either ring, that is, on the ring containing the heteroatom (e.g., 2-indolyl) or on the ring that does not contain the heteroatom (e.g., 5-indolyl). Exemplary 5-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, imidazole, pyrazole, oxazole, isoxazolyl, thiazolyl, and isothiazole. Exemplary 6-membered heteroaryl groups containing 1 heteroatom include, but are not limited to, pyridinyl. Exemplary 6-membered heteroaryl groups containing 2 heteroatoms include, but are not limited to, pyridazinyl, pyrimidinyl, and pyrazinyl.
"alkyl" refers to saturated or unsaturated alkyl groups, and "chain alkyl" refers to straight or branched chain alkyl groups, such as C1-C6Chain alkyl means saturated or unsaturated, straight chain or branched alkyl having 1 to 6 carbon atoms, wherein examples of saturated straight chain alkyl include, but are not limited to, ethyl, n-propyl, etc., examples of saturated branched alkyl include, but are not limited to, isopropyl, t-butyl, etc., examples of unsaturated straight chain alkyl include, but are not limited to, ethenyl, propenyl, etc., examples of unsaturated branched alkyl include, but are not limited to, 2-methylpropenyl, etc.; "Cyclic alkyl" refers to an alkyl group having a cyclic structure, such as C3-C8The cyclic alkyl group means a saturated or unsaturated alkyl group having a cyclic structure having 3 to 8 carbon atoms, wherein examples of the saturated cyclic alkyl group include, but are not limited to, cyclopropyl, cyclopentyl, ethyl-substituted cyclohexyl, etc., and examples of the unsaturated cyclic alkyl group include, but are not limited to, cyclopentene, etc. Unless otherwise indicated, an alkyl group can be unsubstituted (i.e., "unsubstituted alkyl") or substituted with one or more substituents (i.e., "substituted alkyl").
"heteroalkyl" refers to an alkyl group as defined herein wherein the backbone further comprises 1 or more heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus).
Example 1
Preparation of the compound 7-1, N- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- (dimethylamino) ethoxy) quinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide.
Synthesized according to the following line:
step (1) compound 2 (i.e. methyl 2-amino-4-fluoro-5-iodobenzoate) was prepared by the following method:
a250 mL clean two-neck round-bottom flask is taken, 50g of raw material 1(322.58mmol),100mL of tertiary butanol and 50mL of water are sequentially added, 44.g (161.29mmol) of elemental iodine is added in batches under stirring, then 40mL of 30% hydrogen peroxide is slowly added dropwise, and the mixture is heated to 50 ℃ in an oil bath and is kept warm for 2 h. The reaction was monitored by TLC. After the reaction, the system was cooled to room temperature, 50mL of a saturated aqueous solution of sodium bisulfite was added, and the mixture was extracted three times with 150mL of ethyl acetate, and the organic phases were combined, washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, and recrystallized to obtain the objective compound 2(59.61g, yield 66%). Step (2) compound 3 was prepared by the following method:
a50 mL clean single-neck round-bottom flask was charged with 1.8g of Compound 2, 1.36g of methyl orthoformate, 0.988g of ammonium acetate, and 20mL of acetonitrile in that order. Heat to reflux and monitor the reaction by TLC. After the reaction is finished, cooling the system to room temperature, adding 5mL of water, stirring, performing suction filtration, washing the filter cake twice with 5mL of water, performing suction drying, then washing twice with 5mL of diethyl ether, and performing vacuum drying to obtain a milky white solid, namely the compound 3(1.58g, yield 86%).
Step (3) Compound 4-1 was prepared as follows:
taking a clean two-mouth bottle, adding 50mL of dry DMF and 130mg of NaH (60%) (692mg, 34.6mmol), uniformly stirring the system at room temperature, then dropwise adding 2-dimethylethanolamine (1.3mL,26mmol), stirring the system for 30 minutes, then adding 5g of compound 3(17.3mmol), reacting at 90 ℃, monitoring the reaction by TLC, cooling to 0 ℃ after the reaction is completed, dropwise adding water to precipitate, filtering and drying to obtain a brown solid, namely the compound 4-1(5.35g, the yield is 98%).
Step (4) Compound 5-1 was prepared as follows:
a clean two-neck flask was charged with compound 4-1(3.15g, 10mmol), toluene 20mL and POCl3(5mL), Et is slowly added dropwise to the system after the system is stirred uniformly3N (2.69mL), after the addition is finished, heating to 75 ℃, stirring for 4 hours, monitoring the reaction by TLC, after the reaction of the raw materials is finished, dropwise adding 10mL of acetonitrile solution in which 8-1(1.6g) of the raw materials is dissolved into the system, continuously stirring for 2 hours at 75 ℃, monitoring the reaction by TLC, after the reaction is finished, cooling to room temperature, filtering, adding the filter cake into 75 mL of 1.2M sodium hydroxide aqueous solution, stirring the system for 2 hours, filtering, washing the filter cake with 10mL of water for 2 times, and drying to obtain a yellow solid, namely the compound 5-1(4.01g, 91%).
Step (5) Compound 7-1 was prepared as follows:
adding 50mg of compound 5-1 and Pd (Ph) into a clean two-mouth bottle3)2Cl28mg, CuI 2.3mg and 5mL of N, N-dimethylformamide, replacing the system with nitrogen for three times, and then adding 187mg of DIPEA (N, N-diisopropylethylamine) dropwise, stirring the system uniformlyThen, 24mg of compound 6-1 was added dropwise, the reaction system was stirred at room temperature, monitored by TLC (DCM: MeOH: 10:1), and after completion of the reaction, water was added to precipitate, which was filtered, and the filter cake was dried and purified by column chromatography to obtain a white solid, i.e., compound 7-1(30mg, 65%).
The characterization data for the target compound are:1H-NMR(400MHz，DMSO-d6):δ9.89(brs,1H),8.54(s,1H),8.29(s,1H),8.18-8.20(m,1H),7.81-7.85(m,1H),7.40-7.54(m,1H),7.21(s,1H),6.30(dd,J＝16Hz,8Hz,1H),6.11(dd,J＝12Hz,3Hz,1H),5.59(dd,J＝8Hz,3Hz,1H),4.24(t,J＝8Hz,1H),2.78(t,J＝8Hz,2H),2.25(s,6H),1.67(s,6H).
example 2
Preparation of the compound 7-2, N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-morpholinoethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide.
Referring to the preparation method of example 1, the target compound 7-2 is prepared by using N- (2-hydroxyethyl) morpholine as a raw material in the step (3) and using 6-2 as a raw material in the step 5) as in example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.84(s,1H),8.69(t,J＝5.6Hz,1H),8.63(s,1H),8.56(s,1H),8.19(dd,J＝6.9,2.6Hz,1H),7.82(ddd,J＝9.0,4.3,2.7Hz,1H),7.42(t,J＝9.1Hz,1H),7.23(s,1H),6.27(dd,J＝17.1,10.0Hz,1H),6.16(dd,J＝17.1,2.3Hz,1H),5.66(dd,J＝10.0,2.4Hz,1H),4.26-4.31(m,4H),3.60(q,J＝4.7Hz,4H),2.79-2.83(m,2H),2.57-2.62(m,4H).
example 3
Preparation of the compound 7-3, N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- (dimethylamino) ethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide.
Prepared according to the method of example 1, except that compound 6-2 is used as a starting material in step 5), the target compound 7-3 is prepared.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),8.78(t,J＝5.8Hz,1H),8.69(s,1H),8.56(s,1H),8.21(dd,J＝7.0,2.6Hz,1H),7.84(dt,J＝7.5,3.4Hz,1H),
7.42(t,J＝9.1Hz,1H),7.22(s,1H),6.29(dd,J＝17.1,10.1Hz,1H),6.16(d,J＝16.9Hz,1H),
5.66(dd,J＝10.0,2.4Hz,1H),4.21-4.29(m,4H),2.77(t,J＝5.4Hz,2H),2.31(s,6H).
example 4
Preparation of compound 7-4, (E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) butyl-2-enamide.
Referring to the preparation method of example 1, the target compound 7-4 is prepared by using 2-methoxyethanol as a raw material in the step (3) and using 6-3 as a raw material in the step 5) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.69-8.71(m,1H),8.64(s,1H),8.57(s,1H),8.19-8.20(m,1H),7.80-7.84(m,1H),7.44(t,J＝9.1Hz,1H),7.21(s,1H),6.27(dd,J＝16Hz,8Hz,1H),6.15(dd,J＝12Hz,3Hz,1H),5.65(dd,J＝8Hz,3Hz,1H),4.22-4.31(m,4H),1.41(t,J＝6.9Hz,3H).
example 5
Preparation of the compound 7-5, N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide.
Referring to the preparation of example 1, the target compound 7-5 was prepared by the procedure of example 1, step 5) using 6-2, except that ethanol was used as the starting material in step (3).
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.69-8.71(m,1H),8.64(s,1H),8.57(s,1H),8.19-8.20(m,1H),7.80-7.84(m,1H),7.44(t,J＝9.1Hz,1H),7.21(s,1H),6.27(dd,J＝16Hz,8Hz,1H),6.15(dd,J＝12Hz,3Hz,1H),5.65(dd,J＝8Hz,3Hz,1H),4.22-4.31(m,4H),1.41(t,J＝6.9Hz,3H).
example 6
Preparation of the compound 7-6, N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide.
Referring to the preparation method of example 1, the target compound 7-6 is prepared by using 2-methoxyethanol as a raw material in the step (3) and 6-2 as a raw material in the step 5) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.86(s,1H),8.69-8.71(m,1H),8.64(s,1H),8.57(s,1H),8.19-8.20(m,1H),7.80-7.84(m,1H),7.44(t,J＝9.1Hz,1H),7.24(s,1H),6.27(dd,J＝16Hz,8Hz,1H),6.15(dd,J＝12Hz,3Hz,1H),5.65(dd,J＝8Hz,3Hz,1H),4.23-4.33(m,4H),3.75-3.82(m,2H),3.38(s,3H).
example 7
Preparation of compound 7-7, (E) -N- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4- (dimethylamino) butyl-2-enamide.
Referring to the preparation method of example 1, the target compounds 7-7 are prepared by using 2-methoxyethanol as a raw material in the step (3) and using 6-4 as a raw material in the step 5) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.91(s,1H),8.56-8.57(m,2H),8.19-8.21(m,2H),7.83-7.85(m,1H),7.44(t,J＝9.1Hz,1H),7.20(s,1H),6.60(dt,J＝15.4,6.1Hz,1H),6.13(d,J＝15.5Hz,1H),4.28(dd,J＝5.6,3.2Hz,2H),3.77(dd,J＝5.3,3.2Hz,2H),3.34(s,3H),2.99(dd,J＝6.1,1.6Hz,2H),2.15(s,6H),1.67(s,6H).
example 8
Preparation of compound 7-8, (E) -N- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4- (dimethylamino) butyl-2-enamide.
Referring to the preparation of example 1, the target compounds 7-8 were prepared by the procedure of example 1, step 5) using 6-5 as the starting material except that ethanol was used as the starting material in step (3).
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.78(s,1H),8.61(dd,J＝5.0,1.6Hz,1H),8.53(d,J＝9.3Hz,2H),8.31(s,1H),8.05(d,J＝2.6Hz,1H),7.89(td,J＝7.7,1.8Hz,1H),7.80–7.66(m,2H),7.60(d,J＝7.8Hz,1H),7.38(dd,J＝7.5,4.9Hz,1H),7.26(d,J＝9.1Hz,1H),7.15(s,1H),6.61(dt,J＝15.5,6.4Hz,1H),6.19(d,J＝15.3Hz,1H),5.30(s,2H),4.30–4.14(m,2H),3.27-3.29(m,2H),2.35(s,6H),1.68(s,6H),1.42(t,J＝6.9Hz,3H).
example 9
Preparation of the compound 7-9, N- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide.
Referring to the preparation method of example 1, the target compound 7-9 is prepared by using ethanol as a raw material in step 3) and using 8-2 as a raw material in step 4) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.59(d,J＝4.3Hz,1H),8.52(s,1H),8.50(s,1H),8.29(s,1H),8.04(d,J＝2.6Hz,0H),7.88(td,J＝7.7,1.8Hz,1H),7.71(dd,J＝9.0,2.6Hz,1H),7.58(d,J＝7.9Hz,1H),7.48–7.30(m,1H),7.25(d,J＝9.0Hz,1H),7.14(s,1H),6.28(dd,J＝10.1Hz,2.3Hz,1H),5.59(dd,J＝10.1,2.3Hz,1H),5.60(dd,J＝8Hz,3Hz,1H),5.28(s,2H),4.19(q,J＝6.8Hz,2H),1.68(s,6H),1.41(t,J＝6.9Hz,3H).
example 10
Preparation of the compound 7-10, N- (3- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide.
Referring to the preparation method of the example 1, the target compound 7-10 is prepared by using ethanol as a raw material in the step 3), using the compound 8-2 as a raw material in the step 4) and using the compound 6-2 as a raw material in the step 5) as an operation method of the example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.70(t,J＝5.6Hz,1H),8.61(s,1H),8.59(d,J＝4.8Hz,1H),8.51(s,1H),8.04(d,J＝2.6Hz,1H),7.93–7.81(m,1H),7.70(dd,J＝8.9,2.6Hz,1H),7.58(d,J＝7.8Hz,1H),7.43–7.30(m,1H),7.25(d,J＝9.1Hz,1H),7.17(s,1H),6.27(dd,J＝17.1,10.0Hz,1H),6.15(dd,J＝17.1,2.3Hz,1H),5.66(dd,J＝10.0,2.3Hz,1H),5.28(s,2H),4.29(d,J＝5.6Hz,2H),4.24(q,J＝7.0Hz,2H),1.40(t,J＝7.0Hz,3H).
example 11
Preparation of the compound 7-11, N- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide.
Referring to the preparation method of example 1, the target compound 7-11 is prepared by using ethanol as a raw material in step 3), using the compound 8-3 as a raw material in step 4) and using the compound 6-2 as a raw material in step 5) as in example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.71(t,J＝5.6Hz,1H),8.62(s,1H),8.51(s,1H),8.03(d,J＝2.6Hz,1H),7.71(dd,J＝8.9,2.6Hz,1H),7.55–7.40(m,1H),7.29-7.33(m,2H),7.25(d,J＝9.0Hz,1H),7.22–7.10(m,2H),6.37–6.21(m,1H),6.16(dd,J＝17.1,2.3Hz,1H),5.66(dd,J＝10.0,2.3Hz,1H),5.24(s,2H),4.30(d,J＝5.6Hz,2H),4.24(q,J＝7.0Hz,2H),1.41(t,J＝7.0Hz,3H).
example 12
Preparation of compound 7-12, (E) -N- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) butyl-2-enamide.
Referring to the preparation method of the example 1, the target compounds 7-12 are prepared by using ethanol as a raw material in the step 3), using the compounds 8-3 as a raw material in the step 4) and using the compounds 6-3 as a raw material in the step 5) as in the example 1.
Characterization data for this compound are:1H NMR(400MHz,DMSO-d6)δ9.74(s,1H),8.61(s,1H),8.51(s,1H),8.48(t,J＝5.7Hz,1H),8.03(d,J＝2.6Hz,1H),7.71(dd,J＝9.0,2.6Hz,1H),7.55–7.41(m,1H),7.37–7.12(m,5H),6.69(dd,J＝15.2,6.9Hz,1H),5.95(dd,J＝15.3,1.8Hz,1H),5.24(s,2H),4.26(d,J＝5.5Hz,2H),4.10(q,J＝5.3Hz,2H),1.78-1.82(m,3H),1.41(t,J＝6.9Hz,3H).
example 13
Preparation of the compound 7-13, N- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide.
Referring to the preparation method of example 1, the target compounds 7-13 are prepared by using 2-methoxyethanol as a raw material in step 3), using the compounds 8-3 as a raw material in step 4) and using the compounds 6-2 as a raw material in step 5) as in example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.72(t,J＝5.6Hz,1H),8.64(s,1H),8.53(s,1H),8.05(d,J＝2.6Hz,1H),7.73(dd,J＝9.0,2.6Hz,1H),7.48(td,J＝8.1,6.1Hz,1H),7.40–7.11(m,5H),6.28(dd,J＝17.1,9.9Hz,1H),6.17(dd,J＝17.1,2.4Hz,1H),5.68(dd,J＝10.0,2.4Hz,1H),5.26(s,2H),4.30-4.33(m,4H),3.77(dd,J＝5.3,3.5Hz,2H),3.39(s,3H).
example 14
Preparation of compound 7-14, N- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) ethenesulfonamide.
Referring to the preparation method of example 1, the target compounds 7-14 are prepared by using ethanol as a raw material in step 3), and using compounds 8-3 as a raw material in step 4) and using compounds 6-6 as a raw material in step 5) in the same manner as in example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.75(s,1H),8.62(s,1H),8.52(s,1H),8.05–7.95(m,2H),7.71(dd,J＝8.9,2.6Hz,1H),7.50–7.42(m,1H),7.36–7.15(m,5H),6.86(dd,J＝16.5,10.0Hz,1H),6.14(d,J＝16.5Hz,1H),6.02(d,J＝10.0Hz,1H),5.25(s,2H),4.25(d,J＝6.9Hz,2H),4.05(q,7.0Hz,2H),1.42(t,J＝7.0Hz,3H).
example 15
Preparation of the compound 7-15, N- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide.
Referring to the preparation of example 1, the procedure of example 1 was followed except that methanol was used as a starting material in step 3) to prepare the objective compounds 7 to 15.
The characterization data for the target compound are:1H NMR(400MHz，DMSO-d6):δ9.91(s，1H)，8.56(d，J＝8.8Hz,1H),8.30(s,1H),8.17-8.22(m,1H),7.75-7.90(m,3H),7.43(t,J＝9.2Hz,1H),6.22-6.35(m,1H),6.05-6.15(m,1H),5.60(dd,J＝10,2Hz,1H),3.96(s,3H),1.69(s,6H).
example 16
Preparation of compound 7-16, N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -propyl-2-yn-1-yl) acrylamide.
Referring to the preparation method of example 1, the target compound 7-16 is prepared by using methanol as a raw material in step 3) and using 6-2 as a raw material in step 5) of example 1.
Characterization number of the CompoundAccording to the following steps:1H NMR(400MHz,DMSO-d6):δ9.86(s,1H),8.65-8.8(m,1H),8.65(s,1H),8.58(s,1H),8.30(s,1H),8.16-8.25(m,1H),7.75-7.90(m,1H),7.43(t,J＝9.2Hz,1H),6.22-6.35(m,1H),6.12-6.20(m,1H),5.65(dd,J＝10,1.2Hz,1H),4.31(d,J＝5.2Hz,2H),3.97(s,3H).
example 17
Preparation of compound 7-17, (E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) propyl-2-yn-1-yl) -4- (dimethylamino) butyl-2-enamide.
Referring to the preparation method of example 1, the target compounds 7-17 are prepared by using methanol as a raw material in step 3) and using 6-4 as a raw material in step 5) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6):δ9.87(s,1H),8.65-8.8(m,1H),8.65(s,1H),8.58(s,1H),8.16-8.25(m,1H),7.74-7.90(m,1H),7.43(t,J＝9.2Hz,1H),7.23(s,1H),6.60-6.70(m,1H),6.14(d,J＝15.2Hz,1H),4.30(d,J＝5.6Hz,2H),3.97(s,3H),3.21(d,J＝5.6Hz,2H),2.29(s,6H).
example 18
Preparation of compound 7-18, (E) -N- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4-morpholinobutyl-2-enamide.
Referring to the preparation method of example 1, the target compounds 7-18 are prepared by using methanol as a raw material in step 3) and using 6-7 as a raw material in step 5) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6):δ9.91(s,1H),8.64(s,1H),8.57(s,1H),8.21(s,1H),7.85-8.21(m,1H),7.78-7.86(m,1H),7.44(t,J＝9.2Hz,1H),7.21(s,1H),6.50-6.63(m,1H),6.14(d,J＝15.6Hz,1H),3.95(s,3H),3.58(m,4H),3.05(d,J＝5.6Hz,2H),2.36(m,4H),1.24(s,6H).
example 19
Preparation of compound 7-19, (E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) propyl-2-yn-1-yl) -4-morpholinobutyl-2 enamide.
Referring to the preparation method of example 1, the target compounds 7-19 are prepared by using methanol as a raw material in step 3) and using 6-8 as a raw material in step 5) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6):δ9.86(s,1H),8.58-8.65(m,2H),8.578(s,1H),8.15-8.25(m,1H),7.75-7.90(m,1H),7.44(t,J＝9.2Hz,1H),7.21(s,1H),6.55-6.68(m,1H),6.10(d,J＝15.6Hz,1H),4.28(d,J＝5.6Hz,1H),3.59(m,4H),3.07(d,J＝5.6Hz,2H),2.36(m,4H).
example 20
Preparation of compound 20, N-acryloyl-4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazoline-6-carboxamide.
Synthesized according to the following line:
step (1) compound 10 was prepared by the following method:
a dry and clean 500mL single-neck round-bottom flask was taken, and 9.9g of propylene dicyanide, 37.4mL of triethyl orthoformate and 35.4mL of acetic anhydride were added in sequence, and the temperature was raised to 140 ℃ for reaction for 6 h. After the reaction is finished, adding a small amount of activated carbon for continuing for 30min, stopping the reaction, filtering while the reaction is hot (adding kieselguhr), washing with ethanol, and spin-drying the filtrate (firstly spin-drying with a water pump and then pumping with an oil pump) to obtain a compound 10.
Step (2) Compound 11 was prepared as follows:
adding 300mL of ethanol into a 500mL single-neck round-bottom flask, standing at 0 deg.C, adding 1.9g of sodium (by shearing), heating to 10 deg.C, and stirring until the sodium is completely dissolved (or adding 2.218g C)2H5ONa) followed by 5.1mL of ethyl acetoacetate at room temperature for half an hour, 2g of compound 10 were added and reacted at 80 ℃ for half an hour and cooled to room temperature. After the reaction, spin-drying, adding 100mL of water, dropwise adding concentrated hydrochloric acid (pH is adjusted to 1-2) at 0 ℃, precipitating a large amount of solid, and filtering and drying (if drying is incomplete, the next reaction is inhibited) to obtain a compound 11.
Step (3) Compound 12 was prepared as follows:
a dry and clean 100mL single-neck flask was taken, and 2.06g of compound 11, 2mL of N, N-dimethylformamide dimethyl acetal, and 50mL of toluene were added in this order, heated to 105 ℃ and reacted for about 5 hours (water was generated in the reaction, and a water separator was added to divide the water). And after the reaction is finished, spin-drying, adding diethyl ether for spin-drying and curing, adding diethyl ether, stirring and filtering to obtain the compound 12.
Step (4) Compound 13 was prepared as follows:
a dry, clean 50mL single-neck round-bottom flask was taken, and 1.42g of Compound 12,0.831g of 3-chloro-4-fluoroaniline and 10mL of acetic acid were added in this order, and the mixture was heated to 125 ℃ for reflux reaction for 1.5 hours. After the reaction is finished, the solution is poured into 100mL of water to separate out a large amount of solid, the solid is filtered, washed by a large amount of water and washed by ethanol, and the compound 13 is obtained after drying.
Step (5) Compound 14 was prepared as follows:
taking a dry clean 25ml round-bottom flask, adding K2CO3(6mmol) was added to 5mL DMF followed by Compound 13(2.0mmol) and 2-bromoethyl methyl ether (3.3mmol), stirred overnight at 60 deg.C oil bath temperature and monitored by TLC for reaction. When the reaction of the raw materials is completed, 20ml of water is added to quench the reaction. The reaction mixture was extracted three times with ethyl acetate (3X 10mL), the organic phases were combined, washed once with brine (20mL), and then with Na2SO4And (5) drying. Filtering and evaporating the solvent to obtain the compound 14.
Step (6) Compound 15 was prepared as follows:
a clean dry round bottom flask was taken and Compound 14(1mmol) was dissolved in DMF (4mL) and 0.14mL formamide (3.5mmol) was added. The reaction was heated to 100 ℃ and a solution of NaOMe (30%) in methanol (0.33ml,1.8mmol) was added dropwise over 30 minutes. Monitoring the reaction by TLC, cooling the reaction system to room temperature after the raw materials are completely consumed, and adding CH into the reaction system2Cl2(30 ml). The reaction system was filtered through celite to obtain a filtrate. And removing the solvent to obtain a crude product. Passing through silica gel column to obtain pure compound 15.
Step (7) Compound 20 was prepared as follows:
compound 15(0.2mmol) was dissolved in 3mL dry THF under nitrogen. The reaction was cooled to 0 ℃. NaH (60%) (0.4mmol) was added to the reaction in portions. The reaction was stirred at 0 ℃ for 10 minutes, then warmed to room temperature and stirred for 45 minutes. The reaction was cooled to 0 ℃ and 1mL of dry THF in which acryloyl chloride (0.22mmol) was dissolved was added dropwise to the reaction. After the completion of the dropwise addition, the reaction system was stirred at 0 ℃ for 10 minutes and then at room temperature for 4 hours. The reaction was monitored by TLC, quenched with 1.5M HCl after completion and extracted with ethyl acetate. The organic phase was washed with a saturated cesium carbonate solution and a saturated brine, and dried over anhydrous magnesium sulfate. Evaporating to remove solvent, purifying with silica gel column to obtain pure compound 20.
The characterization data for the target compound are:1H NMR(400MHz,CDCl3)9.13(s,1H),8.84(s,1H),7.92(brs,1H),7.47(s,1H),7.42(d,J＝6.0Hz,1H),7.32(t,J＝9.2Hz,1H),7.21(t,J＝8.6Hz,1H),6.57(d,J＝16.4Hz,1H),6.19(dd,J＝16.4,10.4Hz),5.85(br s,1H),5.79(d,J＝10.4Hz,1H),4.44(t,J＝4.2Hz,2H),4.44(t,J＝4.2Hz,2H),3.88(t,J＝4.4Hz,2H),3.47(s,3H).
example 21
Preparation of the compound 21, N- ((4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) meth) acrylamide.
Synthesized according to the following line:
mixing LiAlH4(0.5mmol) was added to 25ml of dry THF and cooled to 0 ℃. A solution of compound 15(78mg,0.2mmol) in dry THF was slowly added dropwise to the reaction system. After the addition was complete, the mixture was stirred at 0 ℃ for 10 minutes and then heated to reflux. After the reaction was complete, the reaction was quenched with saturated sodium sulfate solution. Extracting twice with THF, combining organic phases, drying with anhydrous sodium sulfate, and evaporating to remove solvent to obtain the product 15-1.
Compound 15-1(0.14mmol) was dissolved in dichloromethane (10mL), triethylamine (0.14mmol) was added at 0 deg.C, and acryloyl chloride (0.17mmol) was slowly added dropwise. After the addition, the temperature was slowly raised to room temperature, and the mixture was stirred at room temperature for two hours. After the reaction was complete, saturated NaHCO was added3The reaction was quenched with aqueous solution. Extracting with dichloromethane for three times, mixing organic phases, washing with salt water, drying with anhydrous magnesium sulfate, and purifying with column to obtain pure compound21。
The characterization data for the target compound are:1H NMR(400MHz,CDCl3)8.68(s,1H),7.90(d,J＝6.4Hz,1H),7.87(s,1H),7.54-7.51(m,2H),7.23(s,1H),7.16(t,J＝8.6Hz,1H),6.48(d,J＝17.2Hz,1H),6.20(dd,J＝17.2,10.4Hz),5.89(d,J＝10.4Hz,1H),5.41(s,2H),4.29(t,J＝4Hz,2H),3.83(t,4Hz,2H),3.46(s,3H).
example 22
Preparation of compound 22, N- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -2-cyano-2-enamide.
Referring to the preparation method of example 1, the target compound 22 is prepared by using ethanol as a raw material in the step 3) and using 6 to 9 as a raw material in the step 4) of example 1.
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.76(s,1H),8.59(d,J＝4.3Hz,1H),8.52(s,1H),8.50(s,1H),8.29(s,1H),8.04(d,J＝2.6Hz,0H),7.88(td,J＝7.7,1.8Hz,1H),7.71(dd,J＝9.0,2.6Hz,1H),7.58(d,J＝7.9Hz,1H),7.48–7.30(m,2H),7.25(d,J＝9.0Hz,1H),7.14(s,1H),5.60(dd,J＝8Hz,3Hz,1H),5.28(s,2H),4.19(q,J＝6.8Hz,2H),4.23(d,J＝7.9Hz,3H),1.68(s,6H),1.41(t,J＝6.9Hz,3H).
example 23
Preparation of compound 23, N- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide. Synthesized according to the following line:
a two-neck bottle is added with 0.5 g of commercially available raw material 23-1, 15 ml of acetonitrile, 15 ml of water and 15 ml of acetic acid, 0.8 ml of sulfuric acid is slowly dripped into the system at zero ℃, 0.11 g of sodium nitrite is added when the solution becomes clear after stirring for 30 minutes, and after the solution is heated to room temperature and stirred for 30 minutes, 15 ml of aqueous solution of 0.70 g of potassium iodide is dripped. After the addition was completed, the temperature was raised to 50 ℃ and stirred for 30 minutes. Cooling the system, precipitating out, filtering, washing the filter cake with ice water, and drying to obtain brown solid, namely the compound 23-2(0.41 g, 66%).
Taking a clean two-mouth bottle, adding raw materials 23-280mg and Pd (Ph)3)2Cl28mg, CuI 2.3mg and 5mL of N, N-dimethylformamide, replacing the system with nitrogen for three times, then adding 187mg of DIPEA dropwise, stirring the system uniformly, adding 24mg of the raw material 6-1 dropwise, stirring the reaction system at room temperature, monitoring by TLC (DCM: MeOH ═ 10:1), adding water to precipitate after the reaction is completed, filtering, drying the filter cake, and purifying by a column to obtain a white solid, namely the compound 23(58mg, 65%).
The characterization data for the target compound are:1H NMR(400MHz,DMSO-d6)δ9.81(s,1H),8.60(d,J＝4.8Hz,1H),8.47(d,J＝3.1Hz,1H),8.30(s,1H),7.88(t,J＝7.7Hz,1H),7.59(d,J＝7.8Hz,1H),7.44(d,J＝2.2Hz,1H),7.38(dd,J＝7.5,4.9Hz,1H),7.34–7.19(m,2H),6.29(dd,J＝17.2,10.1Hz,1H),6.10(dd,J＝17.1,2.3Hz,1H),5.58(dd,J＝10.1,2.3Hz,1H),5.30(s,2H),4.21(q,J＝7.0Hz,2H),1.67(s,4H),1.42(t,J＝6.7Hz,3H).
comparative example
Reference is made to the following documents: the methods of PCT int.appl. (2014), WO 2014063631a120140501 and Nature chemical biology (2014),10(9), 760-:
examples of the experiments
In vitro enzyme inhibitory Activity
Enzyme inhibition activity was measured by enzyme-linked immunosorbent assay.
The compounds prepared in the above examples were assayed for enzyme inhibitory activity, and Z' -LYTE was used for the assay of EGFR and HER2 enzyme inhibitory activityTMKinase test kit (invitrogen, Z' -LYTE)TMThe Kinase assay kit-TYR6peptide, reference: nature,373, pp.536-9 (1995)).
The specific method comprises the following steps: according to Z' -LYTETMThe kinase test kit is configured with instructions for use of the reagents; adding enzyme and compound into 384-well plate at a certain ratio, mixing, and standing for 30 min; then adding ATP, mixing evenly and standing for 2 h; adding 5 μ L of Development reagent, mixing, standing at room temperature for 15min, 30min, and detecting with enzyme labeling instrument for 1 h; after 1h, 5 mu L of Stop regent is added, mixed evenly and detected by an enzyme-linked immunosorbent assay. Calculating the corresponding phosphorylation ratio, plotting the concentration of the drug and the corresponding kinase inhibition rate to obtain a dose-response curve, and determining the half Inhibitory Concentration (IC) of the drug50). The results are as follows:
TABLE 1 in vitro enzyme inhibitory Activity
Note: a is 0.1-10nM, b is 10-100nM, and c is 100-1000 nM.
From the data, the tyrosine kinase irreversible inhibitor provided by the invention has an inhibitory effect on both EGFR and HER2 tyrosine kinases, the half inhibitory concentration of the tyrosine kinase irreversible inhibitor is superior to or at least equal to that of a positive control WZ4002 and Afatinib, especially the compound 7-15 and the compound 7-16, the half inhibitory concentration of the tyrosine kinase irreversible inhibitor on both EGFR and HER2 tyrosine kinases is equal to that of the positive control, and the tyrosine kinase irreversible inhibitor has good enzyme inhibitory activity.
Second, in vitro cell inhibitory Activity
The above compounds showed high inhibitory activity against EGFR and HER2 tyrosine kinase, and their inhibitory activity against EGFR and HER 2-related tumor cells was further tested below.
We used MTT (thiazole blue) method to determine the inhibitory activity of the target compound on human non-small cell lung cancer cell line (Del19) Hcc827, epidermal cancer cell line A431, human non-small cell lung cancer cell line H1975, human breast cancer cell lines SK-BR-3, BT474 and MCF-7, and human gastric cancer cell line BCG-823.
The tumor cell inhibitory activity of the samples was examined by MTT (thiazole blue) method as follows. The tumor cells are: epidermal carcinoma cell line A431, EGFRWTOverexpression, human breast adenocarcinoma cell SK-BR-3, HER2 overexpression; human breast cancer cell lines BT-474, EGFR and HER2 overexpression; control human breast cancer cells, MCF-7, EGFR and HER2, were low expressed.
The experimental principle of MTT (thiazole blue) method.
Mitochondrial NADPH-related dehydrogenase in living cells can reduce yellow MTT into water-insoluble formazan in bluish purple, cell death, the enzyme is inactivated, and MTT is not reduced. The Optical Density (OD) values were measured at a wavelength of 570nm on a microplate reader. Thus, the ratio of active cells to apoptotic cells under the action of the drug was determined.
2. Experimental methods.
The inhibition rate of 5 mu M is screened on all target compounds, and then the compounds with high inhibition rate are selected for further determination of IC50。
MTT drug screening experimental process.
(1) Pancreatin digestion: the procedure of cell digestion by pancreatin was followed, and the digested cells were collected in a centrifuge tube.
(2) Calculating the cell concentration: the procedure of cell counting was followed.
(3) The cells were diluted with complete medium to a cell concentration of approximately 30000 cells/ml. 100 μ L of cell working solution was added to each well and 100 μ L of complete medium was added to the blank control wells.
(4) Dosing: the test drug was dissolved in DMSO to 10mM and stored at-20 ℃ until use. Thawing before experiment, and diluting to 100. mu.M with complete culture medium after cell adherence. Setting the concentration of the medicine: the highest final concentration was 100 μ M, 1: 5 equal ratio dilution to 20, 4, 0.8, 0.16, 0.032 u M, total 6 concentration gradient. The highest and second highest concentrations were diluted in complete medium, the remaining four concentrations were diluted in complete medium containing 2% DMSO. A drug concentration of 100. mu.L was added to the corresponding wells, and 6 replicates per concentration were made. Only 100. mu.L of complete medium containing 2% DMSO was added to the cell control wells.
(5) Co-culturing: at 37 ℃ 5% CO2Co-culture under conditions for 72 h.
(6) Adding MTT: carefully remove the supernatant, add 100. mu.L of MTT working solution diluted with medium at 0.5mg/ml per well, and incubate in the incubator for 4-5 h.
(7) Absorbance determination: after co-incubation, the supernatant was carefully aspirated, 100. mu.L DMSO was added to each well, the wells were placed on a shaker and dissolved for 10min with shaking, and the absorbance at 570nm was measured on a BioTeck microplate reader.
(8).IC50And (3) calculating: OD data were exported to Excel, cell viability was calculated at each concentration, and IC was calculated on GraphPadprism 4 software50。
Note: cell control wells-no drug was added, the deficient volume was supplemented with 2% DMSO medium, and the rest conditions were the same.
Blank-200. mu.L of medium added alone.
4. And (5) experimental results.
The specific experimental results are as follows:
TABLE 2 in vitro enzyme inhibitory Activity IC50
Note: a is 0.1-10nM, b is 10-100nM, and c is 100-1000 nM. NA means no detection.
As can be seen from the above results, the quinazoline derivatives of the present invention have inhibitory effects on a variety of cancer cell lines, and have IC effects on at least one type of cancer cell line50Less than positive control, especially Compound 7-9, Compound 7-10, Compound 7-13, Compound 7-16, IC against three cancer cell lines50IC between 0.1-10nM, compared to positive control50Three orders of magnitude smaller, with very good activity.
Furthermore, it can be seen from the above results that the results of enzyme activity and cell activity are not completely consistent, which may be caused by the fact that the cell activity test is influenced by the transport of drug molecules across cell membranes, the microenvironment in cells, and the intracellular metabolism.
According to the invention, a large number of compounds are designed and synthesized, and are screened to obtain the quinazoline derivative shown in the formula I, so that the quinazoline derivative has very good cell inhibition activity.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (9)

1. A quinazoline derivative represented by formula I or a pharmaceutically acceptable salt thereof:
w is selected fromWherein: r3Is hydrogen or C1-C3A chain alkyl group; r4Is hydrogen or C1-C3A chain alkyl group;
when W isWhen X is C or S ═ O, Y is N or C-CN;
R1selected from the group consisting of:
R2selected from the group consisting of:
when W isWhen X is C, Y is N, R1Is composed ofR2Is composed ofWherein: r8Selected from: hydrogen, C1-C6Alkyl, halogen;
R11，R12each is selected from: hydrogen, C1-C6Chain alkyl radical, C containing a heteroatom of O, N, S, P1-C6A chain heteroalkyl group; and, R11And R12Two substituents may form a ring; n is selected from: 1 to 6;
R5is optionally selected from: hydrogen, halogen, cyano, C1-C6Chain alkyl radical, C3-C8A cyclic alkyl group;
R6is optionally selected from: hydrogen, C1-C6Chain alkyl radical, C3-C8A cyclic alkyl group;
R7is optionally selected from: hydrogen, halogen, cyano, C1-C6Chain alkyl radical, C3-C8Cyclic alkyl radical, C containing a heteroatom of O, N, S, P1-C6Chain heteroalkyl, C containing O, N, S, P heteroatoms3-C8A cyclic heteroalkyl group;
and, R5，R6，R7Any two substituents may form a ring.
2. A quinazoline derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1Selected from the group consisting of:
R8selected from: hydrogen, halogen.
3. A quinazoline derivative according to claim 2, or a pharmaceutically acceptable salt thereof, wherein W is
4. A quinazoline derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R7Selected from the group consisting of:
H
wherein:
R11optionally selecting as follows: hydrogen, C1-C6Chain alkyl, or C containing O, N, S, P hetero atoms1-C6A chain heteroalkyl group;
R12optionally selecting as follows: c1-C6Chain alkyl, orC containing a heteroatom of O, N, S, P1-C6A chain heteroalkyl group;
and, R11And R12Two substituents may form a ring;
m is selected from: 1-6.
5. A quinazoline derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1Selected from the group consisting of:
R2selected from the group consisting of:
wherein:
R11，R12each is selected from: hydrogen, C1-C6A chain alkyl group;
n is selected from: 1-2;
R5selected from: hydrogen, cyano;
R6selected from: hydrogen;
R7selected from the group consisting of:
H
wherein:
R11optionally selecting as follows: hydrogen, C1-C6Chain alkyl, or C containing O, N, S, P hetero atoms1-C6A chain heteroalkyl group;
R12optionally selecting as follows: c1-C6Chain alkyl, or C containing O, N, S, P hetero atoms1-C6A chain heteroalkyl group;
and, R11And R12Two substituents may form a ring;
m is selected from: 1-2;
x is C; y is N; w is
6. A quinazoline derivative according to claim 1, or a pharmaceutically acceptable salt thereof, which is selected from one of the following compounds:
n- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- (dimethylamino) ethoxy) quinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-morpholinoethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2- (dimethylamino) ethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
(E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) butyl-2-enamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
(E) -N- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4- (dimethylamino) butyl-2-enamide
(E) -N- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4- (dimethylamino) butyl-2-enamide;
n- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide;
n- (3- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
(E) -N- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) butyl-2-enamide;
n- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) propyl-2-yn-1-yl) acrylamide;
n- (3- (4- ((3-chloro-4- ((3-fluorobenzyl) oxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) propyl-2-yn-1-yl) ethenesulfonamide;
n- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide;
n- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -propyl-2-yn-1-yl) acrylamide;
(E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) propyl-2-yn-1-yl) -4- (dimethylamino) butyl-2-enamide;
(E) -N- (4- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -4-morpholinobutyl-2-enamide;
(E) -N- (3- (4- ((3-chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl) propyl-2-yn-1-yl) -4-morpholinobutyl-2 enamide;
4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazoline-6-carboxamide;
n- ((4- ((3-chloro-4-fluorophenyl) amino) -7- (2-methoxyethoxy) quinazolin-6-yl) methyl) acrylamide;
n- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) -2-cyano-2-enamide;
n- (4- (4- ((3-chloro-4- (pyridin-2-ylmethoxy) phenyl) amino) -3-cyano-7-ethoxyquinazolin-6-yl) -2-methylbutyl-3-yn-2-yl) acrylamide.
7. A process for the preparation of a quinazoline derivative, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 6, which is synthesised according to the following route:
or synthesized by adopting the following route:
or synthesized by adopting the following route:
8. use of a quinazoline derivative according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, in the manufacture of an anti-tumour medicament.
9. The use of claim 8, wherein the tumor is at least one of hemangioma, endometriosis, gastrointestinal tumor, histiocytic lymphoma, non-small cell lung cancer, lung adenocarcinoma, lung squamous carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell cancer, nasopharyngeal cancer, leukemia.
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