CN111777599A - Quinazoline, pyridopyrimidine or bipyrimidine bi-aromatic ring derivative EGFR inhibitor and preparation method and application thereof - Google Patents

Quinazoline, pyridopyrimidine or bipyrimidine bi-aromatic ring derivative EGFR inhibitor and preparation method and application thereof Download PDF

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CN111777599A
CN111777599A CN201910265046.9A CN201910265046A CN111777599A CN 111777599 A CN111777599 A CN 111777599A CN 201910265046 A CN201910265046 A CN 201910265046A CN 111777599 A CN111777599 A CN 111777599A
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radical
quinazoline
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growth factor
epidermal growth
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梁永宏
曾兆森
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Yaoya Technology Shanghai Co ltd
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    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Abstract

The invention discloses a selective inhibitor of a clinical mutant of EGFR protein tyrosine kinase, which has a structure shown in formula (I), is a double aromatic ring template compound containing quinazoline, pyridopyrimidine or bipyrimidine, and simultaneously discloses a preparation method of the compound and the application of the compound as EGFR protein tyrosine kinaseUse of selective inhibitors of clinical mutants of kinases, in particular of the epidermal growth factor receptor EGFR of the T790M variant, and in the treatment of diseases associated with the overexpression of the epidermal growth factor receptor EGFR, such as kidney, lung, prostate, pancreatic, breast and glioma

Description

Quinazoline, pyridopyrimidine or bipyrimidine bi-aromatic ring derivative EGFR inhibitor and preparation method and application thereof
Technical Field
The present invention relates to quinazoline, pyridopyrimidine or bispyrimidine bisaromatic ring derivatives.
Prospect techniques
The epidermal growth factor EGFR (epidermal growth factor receptor) is a 170kDa transmembrane glycoprotein receptor tyrosine kinase, which is activated by epidermal growth factors and influences the growth and differentiation of cells. Binding of EGF or TGF α to EGFR activates receptor tyrosine kinase activity. Tyrosine residues Tyr 1068, Tyr 1148, and Tyr1173 at the carboxyl terminal of EGFR are the main sites for autophosphorylation to occur after EGF binding. Once activated, phosphorylated tyrosine residues at positions 1068 and 1173 of EGFR mediate the binding of Grb2 to EGFR. In addition, the tyrosine residue phosphorylated at position 1173 is the primary binding site for SHC on EGFR. EGFR is widely distributed in many normal and malignant epithelial cells, and its overexpression and self-activation may be associated with the development of many tumors. At present, the method is mainly used for researching various epitheliogenic malignant tumors including head and neck squamous cell carcinoma, lung cancer, breast cancer, bladder cancer and the like.
Protein Tyrosine Kinases (PTKs) are a class of kinases that catalyze the transfer of gamma-phosphate on ATP to protein tyrosine residues. It is believed that the growth factor receptor proteins, including epidermal growth factor receptor, function by phosphorylation, and that epidermal growth factor receptor EGFR tyrosine kinase phosphorylates the epidermal growth factor receptor. Clinically, EGFR tyrosine kinase inhibitors have been used in the treatment of cancer, the first generation reversible EGFR tyrosine kinase inhibitors gefitinib and erlotinib. Significant clinical response (50-80%) was shown in humans with these specific activating mutations. However, patients who develop secondary mutations to these drugs suffer recurrence of cancer within months. Second generation EGFR tyrosine kinase inhibitors include neratinib, dacatinib, afatinib, all of which contain electrophilic groups Michael receptors in their structures. Among them, in the case of afatinib as a representative drug, the allylamide structure plays a crucial role in the antitumor activity of afatinib, and it acts as a Michael acceptor to undergo a Michael addition reaction with the catalytic site (new nuclear thiol group) of a cysteine residue (Cys797) on EGFR, thereby inactivating the kinase, irreversibly inhibiting the activity of tyrosine kinase, and thus having good tolerance. Researchers have completely demonstrated the presence of these covalent bonds at the molecular level by growing crystals of inhibitors and receptors, and have found that afatinib strongly inhibits these enzymes by interacting with Cys 805 of HER2 with Cys 803 of HER 4. In vitro tests on wild-type EGFR show that afatinib has better effects on the inhibition of the wild-type EGFR and the L858R/T790M double mutant compared with gefitinib, erlotinib and lapatinib. In addition, afatinib inhibited DER4 more than lapatinib by 30 times. The inhibition effect of the third generation EGFR tyrosine kinase inhibitor oxitinib on the L858R/T790M/C797S three mutant reaches nanomolar. By taking oxitinib as a lead, an EGFR tyrosine kinase inhibitor with strong inhibition effect on mutant type is further developed, and meanwhile, the research and development of a novel high-efficiency and low-toxicity antitumor drug with drug resistance is very important in the current drug research and development field.
Disclosure of Invention
The invention designs a series of inhibitor small seeds for inhibiting T790M variant EGFR tyrosine kinase, finds out a compound with high inhibitory activity to T790M variant EGFR, and the compound has obvious inhibitory action to cancer cells, wherein the compound is a compound containing a double aromatic ring of quinazoline, pyridopyrimidine or bipyrimidine and an alpha, beta-unsaturated carboxylic acid amide structure. The compound can realize high-activity inhibition on T790M/L858R variant EGFR, can inhibit or kill EGFRT790M variant tumor cells, and has high inhibition activity on wild type EGFR.
The invention provides a compound of quinazoline, pyridopyrimidine or bi-pyrimidine bi-aromatic ring derivatives shown in formula (I), or a stereoisomer thereof, or pharmaceutically acceptable salt thereof, wherein the compound contains bi-aromatic ring and alpha, beta-unsaturated carboxylic acid amide structure, and can be used as an irreversible EGFR inhibitor,
Figure BDA0002016511580000021
wherein:
x represents CH or N; y represents CH or N;
a can be selected from any one of the following
Figure BDA0002016511580000022
X1Can select N or CR6；
R1Can be selected from H, halogen, CN, NO2，CF3，CHF2，C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynylalkyl radical, C1-C6Oxyalkyl radical, C1-C6An aminoalkyl group;
R2can be selected from H and C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynylalkyl radical, C1-C6Oxyalkyl radical, C1-C6Aminoalkyl radical, C1-C6Alkylcarbonyl group, C1-C6An alkenylcarbonyl group;
R3can be selected from H, CN, NO2，CF3，CHF2，C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynylalkyl radical, C1-C6Oxyalkyl radical, C1-C6An aminoalkyl group or a substituted aminoalkyl group,
R4can be selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6Alkoxy, CF3, CHF2；
R5Can select C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6An oxyalkyl group;
R6can be selected from H and C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6Alkoxy radical, C1-C6An aminoalkyl group;
preferably, the compounds include compounds having the structure as shown in table 1:
TABLE 1 Compounds of the general structural formula (I) include one of the compounds with the numbers 301-308
Figure BDA0002016511580000023
Figure BDA0002016511580000031
The invention also provides a preparation method of the EGFR protein tyrosine kinase selective inhibitor, which is shown in Scheme 1. The method comprises the following steps: the intermediate II-1 is obtained by the coupling reaction of the initial raw material, and the compound shown in the general formula (I) is obtained by the intermediate II-1 through two steps of nucleophilic substitution (shown in Scheme 1).
Synthesis and preparation of Scheme 1 compound of general formula I
Figure RE-GDA0002122447160000032
The invention also provides application of the compound or the stereoisomer or the pharmaceutically acceptable salt thereof in preparing antitumor drugs and EFGR kinase inhibitors.
The pharmaceutical composition is in the form of tablets, capsules, granules, sprays or injections.
The pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder and a lubricant. Including, but not limited to, any and all solvents, dispersion media, coatings, absorption delaying agents, and the like, such media and agents for pharmaceutically active substances are well known in the art.
The invention also provides the quinazoline, pyridopyrimidine or bipyrimidine bi-aromatic ring epidermal growth factor inhibitor and the application of pharmaceutically acceptable salts thereof as protein tyrosine kinase inhibitors;
further, the protein tyrosine kinase inhibitor is an epidermal growth factor receptor inhibitor;
more preferably, the epidermal growth factor receptor inhibitor is an inhibitor of the epidermal growth factor receptor of the T790M variant.
The application of quinazoline, pyridopyrimidine or bipyrimidine bi-aromatic ring epidermal growth factor inhibitor and pharmaceutically acceptable salt or pharmaceutical composition thereof in preparing medicines for treating diseases related to epidermal growth factor receptor overexpression.
Further, the tumor is liver cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer, and astrocytoma.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The above-described aspects of the present invention will be described in further detail below with reference to specific embodiments of embodiments. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above-mentioned contents of the invention belong to the scope of the invention.
Detailed Description
The invention is further illustrated by the following specific examples.
The compound shown in the general formula (I) is obtained by synthesizing and preparing the initial raw material of the compound shown in the general formula (I) and performing coupling reaction on the initial raw material to obtain an intermediate II-1, and sequentially performing nucleophilic substitution, hydrogenation reduction ring closing, nucleophilic substitution, reduction and acylation on the intermediate II-1. It is to be noted that the compounds of the general formula (I) include, but are not limited to, the compounds listed below.
Example 1: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (1 "-methyl-1H-3" -indole) quinazoline
Figure BDA0002016511580000041
Preparation of 2-chloro-4- (1 '-methyl-1H-3' -indole) quinazoline:
Figure BDA0002016511580000042
2, 4-dichloroquinazoline (0.8g, 4mmol) was dissolved in ethylene glycol dimethyl ether (20mL), stirred in an ice bath, ferric trichloride (0.77g,4.59mmol) was added in portions, and then the reaction was stirred at room temperature for 15 minutes. N-methylindole (0.683, 5.2mmol) was then added dropwise, after which the reaction was heated to 60 ℃ and stirred for 24 hours. The reaction was stopped, cooled to 0 deg.C, 3.5mL of methanol and 9mL of water were added, and the reaction was stirred at room temperature for 3 hours. A large amount of solid precipitated, filtered, the filter cake washed with methanol and dried to give a yellow solid, 0.8g, yield: 68 percent. LC/MS (ESI): m/z 294(M + H)+。
Preparation of tert-butyl 4-fluoro-2-methoxy-5-nitroanilide:
Figure BDA0002016511580000043
4-fluoro-2-methoxy-5-nitroaniline (50g,0.269mol), Boc anhydride (58.62g, 0.269mol) were dissolved in acetonitrile (1L), warmed to 55 ℃ for reaction for 7 hours, the acetonitrile was evaporated off under reduced pressure, ethyl acetate (500mL) was added for dissolution, petroleum ether (100mL) was added dropwise with stirring to precipitate a solid, which was filtered to give 61.5g of a yellow solid, yield: 81 percent of
Preparation of ethyl N- (2-dimethylaminoethyl) glycolate:
Figure BDA0002016511580000051
glyoxylic acid hydrate (60g, 0.652mol) was dissolved in methanol (500mL), stirred at room temperature for 30 minutes, then cooled to 0 ℃, N-dimethylethylenediamine (57g,0.646mol) was added dropwise, and after stirring for 30 minutes, 10% Pd/C (8.2g) was added, followed by replacement with hydrogen gas three times with methanol (10mL), and the reaction was stirred at room temperature for 24 hours. Stopping reaction, filtering to remove palladium-carbon, washing filter cake with a little methanol, and concentrating filtrate under reduced pressure to obtain crude product N- (2-bis)Methylaminoethyl) glycine. The resulting crude N- (2-dimethylaminoethyl) glycine was dissolved in ethanol (500mL), concentrated sulfuric acid (8mL) was added with stirring at room temperature, refluxed for 16 hours, the ethanol was evaporated under reduced pressure, ethyl acetate (500mL) was added to dissolve, 250mL of water was then added, Ph was adjusted to 11 with 15% NaOH solution, layer-by-layer extraction was performed, the aqueous layer was extracted with ethyl acetate (2 × 50mL), then washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 102.2g of a brown yellow oil, yield: 90 percent. LC/MS (ESI): m/z 175(M + H)+。
Preparation of tert-butyl 4- (N, N-dimethyl-N' -ethyl acetate ethylenediamine) -2-methoxy-5-nitroanilide:
Figure BDA0002016511580000052
tert-butyl 4-fluoro-2-methoxy-5-nitroanilide (40g, 0.14mol) was dissolved in DMAC (600mL), stirred at room temperature, added with N- (2-dimethylaminoethyl) glycine ethyl ester (26.7g,12mmol) and DIPEA (23.4g,0.18mol), heated to 60 ℃ and stirred for 6 hours. The reaction was complete by TLC. Stopping the reaction, cooling to room temperature, slowly pouring the reaction solution into stirred ice water, precipitating a large amount of solid, performing suction filtration, and drying a filter cake to obtain a light yellow solid 54.2g, wherein the yield is as follows: 88 percent. LC/MS (ESI): m/z 440(M + H)+。
Preparation of 1- (N, N-dimethylaminoethyl) -3-oxo-4-boc amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline
Figure BDA0002016511580000053
Tert-butyl 4- (N, N-dimethyl-N' -acetate-ethylenediamine) -2-methoxy-5-nitroanilide (44g, 0.1mol) was dissolved in methanol (600mL), and 5% Pd/C (0.15g) was added and replaced with hydrogen gas three times, after which the reaction was stirred under 40Psi of hydrogen gas atmospheric pressure for 3 hours. The reaction was complete by TLC. Stopping the reaction, filtering the palladium-carbon, washing a filter cake by a small amount of methanol, concentrating the filtrate under reduced pressure, and separating by a quick column to obtain 24.4g of yellow solid with the yield: 67%. LC/MS (ES)I)：m/z 365(M+H)+。
Preparation of 1- (N, N-dimethylaminoethyl) -3-oxo-4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline
Figure BDA0002016511580000054
1- (N, N-dimethylaminoethyl) -3-oxo-4-boc amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (21.6, 59.2mmol) was dissolved in 1, 4-dioxane (600mL), stirred at room temperature, 4N HCl (160mL) was added, and the reaction was stirred for 10 hours. The reaction was complete by TLC. The reaction was stopped. With saturated Na2Adjusting the pH of the CO3 solution to 7-9, extracting with dichloromethane (500mL), drying, and concentrating under reduced pressure to obtain 14.37g of yellow solid, wherein the yield is as follows: 92 percent. LC/MS (ESI): m/z 265(M + H)+。
Preparation of 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline:
Figure BDA0002016511580000061
1- (N, N-dimethylaminoethyl) -3-oxo-4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (13.2g, 50mmol) is dissolved in THF (20mL), stirred at 0 deg.C and LiAlH is added4Subsequently, the reaction was stirred at 0 ℃ for 30 minutes, then heated to 80 ℃ and stirred for 4 hours. The reaction was complete by TLC. The reaction was stopped. Cooling to 0 ℃, dripping water (0.5mL) to quench the reaction, then adding concentrated hydrochloric acid (6mL) and water (20mL), stirring for 30 minutes, separating out a solid, performing suction filtration, drying a filter cake, and performing quick column separation on the obtained crude product to obtain 8.53g of a brown yellow solid, wherein the yield is as follows: 68 percent. LC/MS (ESI): m/z 251.1(M + H)+。
Preparation of 2- [ 4' -fluoro-5 ' -nitro-2 ' -methoxy ] anilino-4- (1 "-methyl-1H-3" -indole) quinazoline:
Figure BDA0002016511580000062
2-chloro-4- (1-methyl-1H-3-indole) quinazoline (293mg,1mmol) was dissolved in 20mL dioxane, and 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (215mg,1.1mmol) were added with stirring at room temperature, followed by heating to 85 ℃ and stirring for reaction for 7 hours. LCMS check reaction complete. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 5mL of water and 40% NaOH. Filtration, washing of the filter cake with methanol and drying gave 467mg of yellow solid, yield: 92 percent. LC/MS (ESI): m/z 508(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (1 "-methyl-1H-3" -indole) quinazoline (compound 301):
Figure BDA0002016511580000063
2- [1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline]-4- (1 "-methyl-1H-3" -indole) quinazoline (193mg, 0.38mmol) and DIPEA (0.073mL,0.42mmol) were dissolved in dichloromethane (5mL), stirred at 0 deg.C, then a solution of acryloyl chloride (34.5mg,0.38mmol) in DCM (1mL) was added dropwise, after which the reaction was stirred for 2 hours. The reaction was complete by TLC. The reaction was stopped, DCM (25mL) was added, followed by 50mL of saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 25mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 98mg of yellow solid, yield: 46 percent.1H NMR(400MHz,DMSO)2.21(6H,s),2.30(2H,t),3.13-3.56(4H,m),3.75(2H,t),3.86(3H,s),3.92(3H,s),5.77(1H,dd),6.27(1H,dd),6.43(1H,dd),7.04(1H,s),7.20(1H, m),7.28(1H,m),7.35(1H,m),7.56-7.58(1H,d),7.64-7.66(1H,d),7.79(1H,m),8.09(1H,s), 8.14-8.16(1H,d),8.28-8.31(2H,m),9.35(1H,s)。LC/MS(ESI)：m/z 562(M+H)+。
Example 2: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (1 '-methyl-4-aza-3' -indole) quinazoline
Figure BDA0002016511580000071
Preparation of 2-chloro-4- (1 ' -methyl-7 ' -aza-1H-3 ' -indole) quinazoline:
Figure BDA0002016511580000072
1-methyl-3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrrolo [2,3-B]Pyridine (0.74g, 2.87mmol) and 2, 4-dichloroquinazoline (0.684g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL), followed by the addition of dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) (0.31g, 0.19mmol), 2M sodium carbonate solvent (3.2mL, 6.3mmol) with stirring and heating to 80 ℃ under nitrogen for 4 hours. The reaction was complete by TLC. The reaction was stopped and diluted with water (1 mL). Ethyl acetate (25mL) was extracted 2 times with anhydrous MgSO4Drying, concentration and flash column separation of the crude product afforded 527mg of a yellow solid, yield: 62 percent. LC/MS (ESI): m/z 296(M + H)+。
Preparation of 2- [1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline ] -4- (1 "-methyl-7" -aza-1H-3 "-indole) quinazoline:
Figure BDA0002016511580000073
2-chloro-4- (1-methyl-7-aza-1H-3-indole) quinazoline (296mg,1mmol) was dissolved in 20mL dioxane, 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (215mg,1.1mmol) were added with stirring at room temperature, followed by heating to 85 ℃ and stirring for 7 hours. LCMS check reaction complete. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 5mL of water and 40% NaOH solution. Filtration, washing of the filter cake with methanol and drying gave 467mg of yellow solid, yield: 89 percent. LC/MS (ESI): m/z 509(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (1 "-methyl-7" -aza-1H-3 "-indole) quinazoline (compound 302):
Figure BDA0002016511580000081
2- [1' -N, N-dimethylamine aminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline]-4- (1 "-methyl-7" -aza-1H-3 "-indole) quinazoline (386mg, 0.76mmol) and DIPEA (0.146mL,0.42mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, then acryloyl chloride (69mg,0.76mmol) was dissolved in DCM (2mL) dropwise, followed by stirring for 2 hours. The reaction was complete by TLC. The reaction was stopped, DCM (50mL) was added, followed by 100mL saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 50mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product afforded 231mg of a yellow solid in yield: 54 percent.1H NMR(400MHz,DMSO,25℃)2.22(6H,s),2.30(2H, t),3.12(2H,t),3.58(2H,m),3.78(2H,m),3.74(3H,s),3.92(3H,s),5.68(1H,dd),6.29(1H,dd),6.37 (1H,dd),7.05(1H,s),7.14-7.28(3H,m),7.53-7.63(2H,m),7.69-7.74(2H,m),7.84(1H,d),7.92(1H, s),8.24(1H,d),8.65(1H,s),9.79(1H,s)。LC/MS(ESI)：m/z 563(M+H)+。
Example 3: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (3 "-pyrazolo [1,5-a ] pyridine) quinazoline
Figure BDA0002016511580000082
Preparation of 2-chloro-4- (3' -pyrazolo [1,5-a ] pyridine) quinazoline:
Figure BDA0002016511580000083
pyrazolopyridine (1, 5-A) -3-boronate (0.7g, 0.287mmol) and 2, 4-dichloroquinazoline (0.684g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL) and dichlorobis (methylene chloride) was added with stirringTert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) (0.13g, 0.19mmol), 2M sodium carbonate solvent (32mL, 6.3mmol) was heated to 80 ℃ with stirring under nitrogen for 4 hours. The reaction was complete by TLC. The reaction was stopped and diluted with water (2 mL). Ethyl acetate (25mL) was extracted 2 times with anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 458mg of a yellow solid, yield: 57 percent. LC/MS (ESI): m/z 281(M + H)+。
Preparation of 2- [1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline ] -4- (3 "-pyrazolo [1,5-a ] pyridine) pyrimidine:
Figure BDA0002016511580000091
2-chloro-4- (3' -pyrazole [1,5-a ]]Pyridine) quinazoline (281mg,1mmol) was dissolved in 20mL dioxane, and 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (0.22g,1.13mmol) were added at room temperature with stirring, followed by heating to 85 ℃ and stirring for 7 hours. The reaction was complete by TLC. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 5mL of water and 40% NaOH. Filtration, washing of the filter cake with methanol and drying gave a yellow solid, 416mg, yield: 84 percent. LC/MS (ESI): m/z 495(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (3 "-pyrazolo [1,5-a ] pyridine) quinazoline (compound 303):
Figure BDA0002016511580000092
2- [1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline]-4- (3' -pyrazolo [1, 5-a)]Pyridine) quinazoline (375mg, 0.76mmol) and DIPEA (0.146mL,0.42mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, then acryloyl chloride (69mg,0.76mmol) was dissolved in DCM (2mL) dropwise, after which the reaction was stirred for 2 hours. The reaction was completed by TLC detection. The reaction was stopped, DCM (50mL) was added, followed by 100mL saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 50mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 191mg of a yellow solid in yield: 46 percent.1H NMR(400MHz,DMSO,25℃)2.21(6H,s),2.31(2H,t),3.14(2H, t),3.56(2H,m),3.75(2H,m),3.82(3H,s),5.73(1H,dd),6.19(1H,dd),6.41(1H,dd),7.02-7.06(2H, m),7.20(1H,m),7.29-7.34(1H,m),7.53-7.63(2H,m),7.69-7.75(2H,m),7.6(1H,d),8.17(1H,s), 8.44(1H,d),8.75-8.79(2H,m),9.19(1H,s)。LC/MS(ESI)：m/z 549(M+H)+。
Example 4: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- [ 4'- (4' -methylpiperazinyl) phenyl ] quinazoline
Figure BDA0002016511580000093
Preparation of 2-chloro-4- [ 4' - (4 "-methylpiperazinyl) phenyl ] quinazoline:
Figure BDA0002016511580000101
4- (4' -methylpiperazinyl) phenylboronic acid (0.631g, 0.287mmol) and 2, 4-dichloroquinazoline (0.684g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL) under nitrogen blanket, followed by the addition of tetrakis (triphenylphosphine) palladium (II) (0.13g, 0.185mmol), 2M sodium carbonate solvent (32mL, 6.31mmol) with stirring. Then heated to 80 ℃ with stirring for 4 hours. The reaction was complete by TLC. The reaction was stopped and diluted with water (2 mL). Ethyl acetate (25mL) was extracted 2 times with anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 516mg of a yellow solid in yield: 53 percent. LC/MS (ESI): m/z 340(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-7' -methoxy-1 ', 2', 3 ', 4' -tetrahydro-6 '-quinoxaline } -4- [4 "- (4"' -methylpiperazinyl) phenyl ] quinazoline:
Figure BDA0002016511580000102
2-chloro-4- [ 4'- (4' -methylpiperazinyl) phenyl]Quinazoline (340mg,1mmol) was dissolved in 100mL dioxane, and 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (0.21g,1.1mmol) were added at room temperature with stirring, followed by heating to 85 ℃ and stirring for 7 hours. LCMS check reaction complete. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 10mL of water and 40% NaOH. Filtration, washing of the filter cake with methanol and drying gave a yellow solid, 464mg, yield: 84 percent. LC/MS (ESI): m/z 553(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- [4 "- (4-methylpiperazinyl) phenyl ] quinazoline (compound 304):
Figure BDA0002016511580000103
2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [ 4' - (4 ' -methylpiperazinyl) phenyl]Quinazoline (420mg, 0.76mmol) and DIPEA (0.146mL,0.42mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, then acryloyl chloride (69mg,0.76mmol) was dissolved in DCM (2mL) dropwise, after which the reaction was stirred for 2 hours. The reaction was complete by TLC. The reaction was stopped, DCM (50mL) was added, followed by 100mL saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 50mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 211mg of a yellow solid in yield: 46 percent.1H NMR(400MHz,DMSO,25℃)2.20(9H,m),2.30-2.50(6H, m),2.90-3.45(10H,m),3.86(3H,s),5.77(1H,dd),6.27(1H,dd),6.43(1H,dd),6.93(2H,d),7.05 (1H,s),7.20(1H,m),7.53-7.64(4H,m),7.69-7.74(2H,m),7.84(1H,d),7.92(1H,s),9.35(1H,s)。LC/MS(ESI)：m/z 607(M+H)+。
Example 5: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- [4 "- (4 '-methylpiperazinyl) -2' -methoxyphenyl ] quinazoline
Figure BDA0002016511580000111
Preparation of 2-chloro-4- [2 ' -methoxy-4 ' - (4 ' -methylpiperazinyl) phenyl ] quinazoline:
Figure BDA0002016511580000112
4- (4' -methylpiperazinyl) -2-methoxyphenylboronic acid (0.72g, 2.87mmol) and 2, 4-dichloroquinazoline (0.684g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL) under nitrogen blanket, followed by the addition of dichloro-di-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) (0.13g, 1.85mmol), 2M sodium carbonate solvent (32mL, 6.31mmol) with stirring. Then heated to 80 ℃ with stirring for 5 hours. The reaction was complete by TLC. The reaction was stopped and diluted with water (2 mL). Ethyl acetate (25mL) was extracted 2 times with anhydrous MgSO4Drying, concentration and flash column separation of the crude product afforded 510mg of a yellow solid in yield: 48 percent. LC/MS (ESI): m/z 370(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-7' -methoxy-1 ', 2', 3 ', 4' -tetrahydro-6 '-quinoxaline } -4- [2 "-methoxy-4" - (4 "' -methylpiperazinyl) phenyl ] quinazoline:
Figure BDA0002016511580000113
2-chloro-4- [ 4'- (4' -methylpiperazinyl) phenyl]Quinazoline (0.37g,1mmol) was dissolved in 20mL dioxane, and 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (0.21g,1.1mmol) were added at room temperature with stirring, after which the reaction was heated to 85 ℃ and stirred for 7 hours. LCMS check reaction complete. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 10mL of water and 40% NaOH. Filtration, washing of the filter cake with methanol and drying gave a yellow solid, 490mg, yield: 84 percent. LC/MS (ESI): m/z 583(M + H)+。
Preparation of 2- {1' -N, N-dimethylaminoethyl-4 ' -acrylamido-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [4 "- (4 '" -methylpiperazinyl) -2 "-methoxyphenyl ] quinazoline (compound 305):
Figure BDA0002016511580000121
2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [ 4' - (4 ' -methylpiperazinyl) phenyl]Quinazoline (442mg, 0.76mmol) and DIPEA (0.146mL,0.42mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, then acryloyl chloride (69mg,0.76mmol) was dissolved in DCM (2mL) dropwise, after which the reaction was stirred for 2 hours. The reaction was complete by TLC. The reaction was stopped, DCM (50mL) was added, followed by 100mL saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 50mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 237mg of yellow solid, yield: 49 percent.1H NMR(400MHz,DMSO,25℃)2.20(6H,s),2.30(2H,t), 2.38(3H,s),3.11-3.23(6H,m),3.61(4H,m),3.81(3H,s),3.88(3H,s),5.78(1H,dd),6.14-6.46(4H, m),7.08(2H,m),7.21(1H,m),7.53-7.58(2H,m),7.69-7.75(2H,m),7.84(1H,d),7.92(1H,s), 9.23(1H,s)。LC/MS(ESI)：m/z 637(M+H)+。
Example 6: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (4 "-morpholinylphenyl) quinazoline
Figure BDA0002016511580000122
Preparation of 2-chloro-4- [ 4' -morpholinylphenyl ] quinazoline:
Figure BDA0002016511580000123
4-Morpholinylphenylboronic acid (0.6g, 2.87mmol) and 2, 4-dichloroquinazoline (0.684g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL) and dichlorobis was added with stirringTert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) (0.13g, 0.185mmol), 2M sodium carbonate solvent (32mL, 6.31 mmol). Then heated to 80 ℃ with stirring for 5 hours. The reaction was complete by TLC. The reaction was stopped and diluted with water (2 mL). Ethyl acetate (25mL) was extracted 2 times with anhydrous MgSO4Drying, concentration and flash column separation of the crude product afforded 497mg as a yellow solid, yield: 53 percent. LC/MS (ESI): m/z 327(M + H)+。
Preparation of 2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [4 "-morpholinylphenyl ] quinazoline:
Figure BDA0002016511580000131
2-chloro-4- [ 4'- (4' -methylpiperazinyl) phenyl]Quinazoline (275mg,1mmol) was dissolved in 100mL dioxane, and 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (0.21g,1.1mmol) were added at room temperature with stirring, after which the reaction was heated to 85 ℃ and stirred for 7 hours. LCMS check reaction complete. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 10mL of water and 40% NaOH. Filtration, washing of the filter cake with methanol and drying gave a yellow solid, 398mg, yield: 74 percent. LC/MS (ESI): m/z 540(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (4 "-morpholinylphenyl) quinazoline (compound 306):
Figure BDA0002016511580000132
2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [ 4' - (4 ' -methylpiperazinyl) phenyl]Quinazoline (371mg, 0.76mmol) and DIPEA (0.146mL,0.42mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, then acryloyl chloride (69mg,0.76mmol) was dissolved in DCM (2mL) dropwise, after which the reaction was stirred for 2 hours. The reaction was complete by TLC. The reaction is stopped, and the reaction mixture is stirred,DCM (50mL) was added followed by 100mL saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 50mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product afforded 194mg of a yellow solid in yield: and 43 percent.1H NMR(400MHz,DMSO,25℃)2.22(6H,s),2.30(2H,t), 3.12-3.45(10H,m),3.81(4H,m),3.85(3H,s),5.77(1H,dd),6.27(1H,dd),6.43(1H,dd),7.05(3H, m),7.21(1H,m),7.55-7.63(2H,m),7.69-7.74(2H,m),7.84(1H,d),7.92(1H,s),8.04(2H,d), 9.45(1H,s)。LC/MS(ESI)：m/z 594(M+H)+。
Example 7: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (1 "-naphthyl) pyrimidine
Figure BDA0002016511580000133
Preparation of 2-chloro-4- [1' -naphthyl ] quinazoline:
Figure BDA0002016511580000141
1-Naphthaleneboronic acid (0.49g, 2.87mmol) and 2, 4-dichloroquinazoline (0.684g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL) and dichlorodi-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) (0.13g, 0.185mmol), 2M sodium carbonate solvent (32mL, 6.31mmol) were added with stirring. Then heated to 80 ℃ with stirring for 5 hours. The reaction was complete by TLC. The reaction was stopped and diluted with water (2 mL). Ethyl acetate (25mL) was extracted 2 times with anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 444mg of yellow solid, yield: 53 percent. LC/MS (ESI): m/z 292(M + H)+。
Preparation of 2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [1 "-naphthyl ] quinazoline:
Figure BDA0002016511580000142
2-chloro-4- [ 4'- (4' -methylpiperazinyl) phenyl]Quinazoline (a)240mg,1mmol) was dissolved in 20mL dioxane, and 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (0.21g,1.1mmol) were added at room temperature with stirring, after which the reaction was heated to 85 ℃ and stirred for 7 hours. LCMS check reaction complete. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 10mL of water and 40% NaOH. Filtration, washing of the filter cake with methanol and drying gave a yellow solid, 444mg, yield: 88 percent. LC/MS (ESI): m/z 505(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (1 "-naphthyl) quinazoline (compound 307):
Figure BDA0002016511580000143
2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [ 4' - (4 ' -methylpiperazinyl) phenyl]Quinazoline (345mg, 0.76mmol) and DIPEA (0.146mL,0.42mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, then acryloyl chloride (69mg,0.76mmol) was dissolved in DCM (2mL) dropwise, after which the reaction was stirred for 2 hours. The reaction was complete by TLC. The reaction was stopped, DCM (50mL) was added, followed by 100mL saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 50mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product afforded 161mg of a yellow solid in yield: 38 percent.1H NMR(400MHz,DMSO,25℃)2.20(6H,s),2.30(2H,t),3.13 (2H,t),3.23(2H,m),3.45(2H,m),3.86(3H,s),5.77(1H,dd),6.27(1H,dd),6.43(1H,dd),7.04(1H,s),7.20(1H,m),7.49-7.74(10H,m),,7.84(1H,d),8.07(2H,dd),9.28(1H,s)。LC/MS(ESI)： m/z 559(M+H)+。
Example 8: 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (2 "-naphthyl) quinazoline
Figure BDA0002016511580000151
Preparation of 2-chloro-4- [ 2' -naphthyl ] quinazoline:
Figure BDA0002016511580000152
2-Naphthaleneboronic acid (0.49g, 2.87mmol) and 2, 4-dichloroquinazoline (0.684g, 3.44mmol) were dissolved in ethylene glycol dimethyl ether (20mL) and dichlorodi-tert-butyl- (4-dimethylaminophenyl) phosphine palladium (II) (0.13g, 0.185mmol), 2M sodium carbonate solvent (32mL, 6.31mmol) were added with stirring. Then heated to 80 ℃ with stirring for 5 hours. The reaction was complete by TLC. The reaction was stopped and diluted with water (2 mL). Ethyl acetate (25mL) was extracted 2 times with anhydrous MgSO4Drying, concentration and flash column separation of the crude product afforded 385mg of a yellow solid, yield: 46 percent. LC/MS (ESI): m/z 292(M + H)+。
Preparation of 2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [2 "-naphthyl ] quinazoline:
Figure BDA0002016511580000153
2-chloro-4- [ 4'- (4' -methylpiperazinyl) phenyl]Quinazoline (240mg,1mmol) was dissolved in 20mL dioxane, and 1- (N, N-dimethylaminoethyl) -4-amino-7-methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline (275mg,1.1mmol) and p-toluenesulfonic acid (0.21g,1.1mmol) were added at room temperature with stirring, followed by heating to 85 ℃ and stirring for 7 hours. LCMS check reaction complete. The reaction was stopped, cooled to room temperature, and adjusted to Ph 9 by the addition of 10mL of water and 40% NaOH. Filtration, washing of the filter cake with methanol and drying gave a yellow solid, 394mg, yield: 78 percent. LC/MS (ESI): m/z 505(M + H)+。
Preparation of 2- {1'-N, N-dimethylaminoethyl-4' -acrylamido-7 '-methoxy-1', 2 ', 3', 4 '-tetrahydro-6' -quinoxaline } -4- (2 "-naphthyl) pyrimidine (compound 308):
Figure BDA0002016511580000154
2- {1' -N, N-dimethylaminoethyl-7 ' -methoxy-1 ', 2 ', 3 ', 4' -tetrahydro-6 ' -quinoxaline } -4- [ 4' - (4 ' -methylpiperazinyl) phenyl]Quinazoline (345mg, 0.76mmol) and DIPEA (0.146mL,0.42mmol) were dissolved in dichloromethane (10mL), stirred at 0 deg.C, then acryloyl chloride (69mg,0.76mmol) was dissolved in DCM (2mL) dropwise, after which the reaction was stirred for 2 hours. The reaction was complete by TLC. The reaction was stopped, DCM (50mL) was added, followed by 100mL saturated NaHCO3Washed with water, the aqueous layer was extracted with DCM (2X 50mL), anhydrous MgSO4Drying, concentration and flash column separation of the crude product gave 203mg of a yellow solid in yield: 48 percent.1H NMR(400MHz,DMSO,25℃)2.22(6H,s),2.31(2H,t), 3.10-3.23(4H,m),3.45(2H,m),3.92(3H,s),5.77(1H,dd),6.27(1H,dd),6.43(1H,dd),7.04(1H,s), 7.20(1H,m),7.54-7.74(6H,m),7.82(2H,m),7.92(1H,s),8.00(1H,dd),8.04(1H,dd),8.04(1H, d),8.19(1H,s),9.34(1H,s)。LC/MS(ESI)：m/z 559(M+H)+。
Example 16 measurement of ALK kinase inhibitory Activity and binding Rate to related mutation sites
For the compounds 501-515 prepared in examples 1-15, the FRET technique was used for the procurement of the ALK kinase inhibitory activity of the compounds, and IC was used for the inhibitory activity50This indicator represents, IC50I.e., the concentration of the compound at which the activity of ALK kinase is inhibited by 50%.
The simultaneous procurement of TR-FRET technique for the inhibition of EGFR-T790M kinase activity of compounds 201-213 prepared in examples 1-15 of the compounds of the present invention, and IC for procurement50This index pair is expressed. Procurement Lifetechnologies Z' -LYTETMThe Kinase Assay kit (PV3193) was used and the EGFR-T790M Kinase solution from Tyrosine 4Peptide was used for the activity Assay. The results are shown in Table 2
Table 1 measurement of ALK inhibitory activity and ALK T790M binding rate of example compounds
ALK ALKT790M
Sample numbering IC50(nM) IC50(nM)
301 18.6 0.8
302 16.5 1.5
303 27.2 2.5
304 67.7 14.4
305 76.5 53.5
306 78.9 62.6
307 83.8 74.6
308 92.4 77.8
Example 17: measurement of inhibitory Activity of the Compound on cancer cell line (MTT method assay)
Cell lines: human non-small cell lung cancer adenocarcinoma cell line NCI-H1975 (highly expressed EGFR-T790M) and human non-small cell lung cell line A549 (highly expressed EFGR).
The method comprises the following steps: cell lines NCI-H1975 and A549 were cultured in 20% FBS (fetal bovine serum) (Gibco) +1640+ 1% double antibody. Then NCI-H1975 cells with good growth state are taken, 5000 cells/well are respectively inoculated on a 96-well cell plate, and the cell plate is placed in an incubator at 37 ℃ and containing 5% CO2 for incubation for 24 hours to ensure that the cells are completely attached to the wall. Discarding old culture solution, sequentially adding 100 μ L culture solution containing 0.3, 1,3, 10, 30, 100, 300, 1000, 3000 and 10000nmol/L compounds to be tested into each well, adding 100 μ L culture solution containing 0.1% DMSO into each well of solvent control group, repeating 3 wells for each group, discarding old culture solution after 72 hr, adding 100 μ L culture solution containing 0.5 mg/mL into each well under dark condition-1And (3) placing the MTT culture solution in a cell culture box, continuously incubating for 4h, removing the supernatant, adding 100 mu LDMSO into each hole, oscillating, and measuring the absorbance value of each hole by using a microplate reader at the wavelength of 492 nm. The inhibition rate of each compound on the growth of the prepared cells is converted to obtain the IC in the following table50(nM)。
TABLE 3 Effect of Compounds on Lung cancer cell lines
Figure BDA0002016511580000161
Figure BDA0002016511580000171

Claims (10)

1. Quinazoline, pyridopyrimidine or bipyrimidine bi-aromatic ring epidermal growth factor inhibitor with structural general formula (I) and pharmaceutically acceptable salt
Figure FDA0002016511570000011
Wherein:
x represents CH or N; y represents CH or N;
a can be selected from any one of the following
Figure FDA0002016511570000012
X1Can select N or CR6；
R1Can be selected from H, halogen, CN, NO2，CF3，CHF2，C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynylalkyl radical, C1-C6Oxyalkyl radical, C1-C6An aminoalkyl group;
R2can be selected from H and C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynylalkyl radical, C1-C6Oxyalkyl radical, C1-C6Aminoalkyl radical, C1-C6Alkylcarbonyl group, C1-C6An alkenylcarbonyl group;
R3can be selected from H, CN, NO2，CF3，CHF2，C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynylalkyl radical, C1-C6Oxyalkyl radical, C1-C6An aminoalkyl group or a substituted aminoalkyl group,
R4can be selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6Alkoxy, CF3, CHF2；
R5Can select C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6An oxyalkyl group;
R6can be selected from H and C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6Alkoxy radical, C1-C6An aminoalkyl group.
2. The quinazoline, pyridopyrimidine or bisaromatic ring epidermal growth factor inhibitor and pharmaceutically acceptable salt according to claim 1, wherein the compound of the general structural formula (I) comprises one of compounds No 201-213
Figure FDA0002016511570000013
Figure FDA0002016511570000021
3. A process for preparing a quinazoline, pyridopyrimidine or bis-pyrimidine bis-aromatic ring epidermal growth factor inhibitor and pharmaceutically acceptable salts according to claim 1 or 2. The method is characterized by comprising the following steps:
(1) the compound I-1 and the compound I-2 are subjected to coupling reaction to obtain a compound II-1:
Figure FDA0002016511570000022
wherein: a can be selected from any one of the following
Figure FDA0002016511570000023
X1Can select N or CR6；
R4Can be selected from H, halogen, CN, C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6Alkoxy, CF3, CHF2；
R5Can select C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6An oxyalkyl group;
R6can be selected from H and C1-C6Alkyl radical, C1-C6Cycloalkyl radical, C1-C6Alkenyl radical, C1-C6Alkynyl, C1-C6Alkoxy radical, C1-C6An aminoalkyl group;
(2) the compounds II-1 and II-2 are subjected to substitution reaction to obtain a compound III-1:
Figure FDA0002016511570000031
(3) the compounds III-1 and III-2 are subjected to nucleophilic reaction to obtain a compound I
Figure FDA0002016511570000032
4. A pharmaceutical composition comprising the quinazoline, pyridopyrimidine, or bis-pyrimidine bis-aromatic ring epidermal growth factor inhibitor of claim 1 or 2, a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
5. The pharmaceutical composition according to claim 4, wherein the pharmaceutical composition is in the form of a tablet, capsule, granule, spray or injection.
6. The pharmaceutical composition of claim 4, wherein the pharmaceutically acceptable carrier is selected from one or more of a filler, a disintegrant, a binder, and a lubricant.
7. Use of the quinazoline, pyridopyrimidine or bispyrimidine bisaromatic ring epidermal growth factor inhibitor and pharmaceutically acceptable salts according to claims 1 and 2 as protein tyrosine kinase inhibitors.
8. Use according to claim 7, characterized in that: the protein tyrosine kinase inhibitor is an epidermal growth factor receptor inhibitor.
9. Use of a quinazoline, pyridopyrimidine or bispyrimididine bis-aromatic ring epidermal growth factor inhibitor and a pharmaceutically acceptable salt according to claim 1 or 2 or a pharmaceutical composition according to any one of claims 4 to 6 for the preparation of a medicament for the treatment of a disease associated with epidermal growth factor receptor overexpression.
10. Use according to claim 9, characterized in that: the diseases related to the overexpression of the epidermal growth factor receptor are selected from one or more of renal cancer, lung cancer, prostatic cancer, pancreatic cancer, breast cancer and glioma.
CN201910265046.9A 2019-04-03 2019-04-03 Quinazoline, pyridopyrimidine or bipyrimidine bi-aromatic ring derivative EGFR inhibitor and preparation method and application thereof Pending CN111777599A (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101208332A (en) * 2005-04-29 2008-06-25 阿斯利康(瑞典)有限公司 Quinazoline derivatives as inhibitors of egf and/or erbb2 receptor tyrosine kinase
CN105001208A (en) * 2015-08-06 2015-10-28 南京雷科星生物技术有限公司 EGFR inhibitor and preparing method and application thereof
CN107793413A (en) * 2016-09-05 2018-03-13 天津滨江药物研发有限公司 Pyrimidine heterocyclic compound and its preparation method and application

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101208332A (en) * 2005-04-29 2008-06-25 阿斯利康(瑞典)有限公司 Quinazoline derivatives as inhibitors of egf and/or erbb2 receptor tyrosine kinase
CN105001208A (en) * 2015-08-06 2015-10-28 南京雷科星生物技术有限公司 EGFR inhibitor and preparing method and application thereof
CN107793413A (en) * 2016-09-05 2018-03-13 天津滨江药物研发有限公司 Pyrimidine heterocyclic compound and its preparation method and application

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