CN113493419A - EGFR tyrosine kinase inhibitor and application thereof - Google Patents

EGFR tyrosine kinase inhibitor and application thereof Download PDF

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CN113493419A
CN113493419A CN202010192694.9A CN202010192694A CN113493419A CN 113493419 A CN113493419 A CN 113493419A CN 202010192694 A CN202010192694 A CN 202010192694A CN 113493419 A CN113493419 A CN 113493419A
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cancer
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compound
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amino
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陈弘道
胡佳琪
王心悟
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Nanjing Maisheng Technology Co.,Ltd.
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Pharmablock Sciences Nanjing Inc
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Priority to PCT/CN2021/081404 priority patent/WO2021185297A1/en
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Abstract

The invention provides a compound shown in formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and an application thereof in preparing a medicament for preventing or treating related diseases caused by EGFR mutation.

Description

EGFR tyrosine kinase inhibitor and application thereof
Technical Field
The invention belongs to the field of chemical medicine, and particularly relates to an EGFR tyrosine kinase inhibitor and application thereof.
Background
Lung cancer is one of the most common malignancies in the world, and is classified into Small Cell Lung Cancer (SCLC) and non-small cell lung cancer (NSCLC), including squamous cell carcinoma (squamous carcinoma), adenocarcinoma, and large cell carcinoma. NSCLC has cancer cells that grow and divide slower and spread metastases are relatively late compared to SCLC. NSCLC accounts for approximately 80% of all lung cancers, has a poor prognosis, and is found in the middle and advanced stages in approximately 75% of patients. Whereas overexpression and mutations of the Epidermal Growth Factor Receptor (EGFR) have been clearly demonstrated to lead to uncontrolled cell growth, associated with the progression of most cancer diseases, especially NSCLC (oncotarget.2016Jul 5; 7(27): 41691-.
EGFR is one of the epidermal growth factor receptor (HER) family members, which consists of EGFR (Erb-Bl), Erb-B2(HER-2/neu), Erb-B3, and Erb-B4. EGFR is a glycoprotein, a receptor of cell proliferation and signaling of Epidermal Growth Factor (EGF), belonging to the tyrosine kinase type, which is penetrated through the cell membrane and located on the surface of the cell membrane (Clin Cancer Res; 21 (3); February 1,2015, 526-.
In NSCLC patients, EGFR is not only overexpressed, but also has an aberrantly activating mutation in its tyrosine kinase domain for kinase activity independent of ligand binding. The most common kinase activity mutations are EGFR (Exon 19del E746-A750) and EGFR (Exon 21L 858R), the first generation of the marketed EGFR tyrosine kinase inhibitors (EGFR-TKI) gefitinib (gefitinib) and erlotinib (erlotinib) have been approved for the treatment of both, but the first generation of EGFR-TKI develops resistance during treatment, which is associated with a secondary mutation in which threonine at position 790 of EGFR is replaced with methionine (T790M). Second generation non-reversible covalent inhibitors such as Afatinib (Afatinib) are more effective in treating EGFR (delE746-a750) and EGFR (L858R) but are less effective in treating drug-resistant T790M mutant because they show dose-dependent toxicity (Biologics,2014,8: 183-. Third generation EGFR-TKIs have therefore been developed, such as AZD9291, CO-1686 and HM 61713. The third generation EGFR-TKI is a tyrosine kinase inhibitor with specific selectivity. Compared with the first generation and the second generation EGFR-TKI, the third generation EGFR-TKI reduces the inhibition of wild type EGFR, reduces the clinical toxic and side effects, and can obtain better curative effect by using higher clinical dose. (J Clin Oncol 2014; 32: abstr 8009; J Clin Oncol 2014; 32: abstr 8010).
Another EGFR mutation that is aberrantly activated to induce carcinogenesis is the exon20 insertion mutation (EGFR exon20ins), and previous studies have shown that this type of mutation accounts for 4% -10% of all EGFR mutant lung cancers (PLoS ONE 201510 (7): e 0133859). At present, no medicine can be clinically used for treatment (Mol Cancer ther.2013,12,220), such mutant patients are not sensitive to EGFR inhibitor medicines on the market at present, the current standard treatment scheme is cytotoxic chemotherapy, the prognosis effect is poor, the side effect is strong, and no targeted medicine is available at present. Candidate drugs Poziotinib and Ref-1 targeting EGFR exon20 insertion mutation have entered clinical research, but have very strong inhibition capability on wild type EGFR, and therefore, can bring about large toxic and side effects, such as skin toxicity and the like. The improvement of clinical dosage and clinical efficacy are severely limited. In addition, there are also the compounds CLN-081 and DZ9008, which have recently entered the clinic, and although their in vitro activity has been shown to reduce toxicity to wild type, their clinical effects have not been further demonstrated. In conclusion, compounds with higher activity and low toxicity have yet to be developed.
Disclosure of Invention
The invention discloses a compound capable of being used as an EGFR protein kinase inhibitor and application thereof in preparing a medicament for preventing or treating EGFR related diseases.
In one aspect, the present invention provides a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure BDA0002416483780000021
wherein R is1Is an aromatic ring, aromatic heterocycle or cycloalkane, optionally substituted with 0-2R1' substitution;
each R1' and R2Independently selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
R3selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
R4selected from hydrogen, C1-C6Alkyl or-NR5R6；
R5And R6Each independently selected from hydrogen, C1-C6Alkyl, -R7N(R8)(R9)；
R7、R8、R9Each independently selected from hydrogen or C1-C6An alkyl group;
n is 1 or 2;
Z1is C or N;
Z2is an alkylene group or a bond.
In some embodiments, formula (i) is formula (ia):
Figure BDA0002416483780000031
R1is an aromatic ring, aromatic heterocycle or cycloalkane, optionally substituted with 0-2R1' substitution;
each R1' and R2Independently selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
n is 1 or 2;
Z1is C or N;
Z2is methylene or a bond.
In other embodiments, formula (i) is formula (ib):
Figure BDA0002416483780000032
R1is an aromatic ring, aromatic heterocycle or cycloalkane, optionally substituted with 0-2R1' substitution;
each R1' and R2Independently selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
n is 1 or 2;
Z1is C or N.
In other embodimentsIn the scheme, R1Is optionally substituted by 0-2R1' substituted benzene ring, pyridine ring or cyclohexane.
In other embodiments, R1Selected from:
Figure BDA0002416483780000041
the aforementioned aryl groups, i.e., all-carbon monocyclic or fused-ring polycyclic aromatic groups having a conjugated pi-electron system. The aryl group may have 6 to 10 carbon atoms in one or more rings. Most commonly, the aryl group has 6 carbon atoms in the ring. For example, a C6-10 aryl group is an aromatic radical containing 6 to 10 carbon atoms, such as phenyl or naphthyl.
The aforementioned heteroaryl groups, i.e., monocyclic or fused ring polycyclic aromatic heterocyclic groups having in at least one ring one or more heteroatom ring members (ring-forming atoms) independently selected from O, S and N. Heteroaryl groups have 5 to 14 ring-forming atoms, including 1 to 13 carbon atoms and 1 to 8 heteroatoms selected from O, S and N. In some embodiments, heteroaryl groups have 5 to 10 ring-forming atoms, including one to four heteroatoms. Heteroaryl groups may also contain one to three oxo or thiono (i.e., ═ S) groups. In some embodiments, heteroaryl groups have 5 to 8 ring-forming atoms, including one, two, or three heteroatoms. For example, a 5-membered heteroaryl group is a monocyclic heteroaryl group as defined above, having 5 ring atoms in the monocyclic heteroaryl ring; a 6-membered heteroaryl is a monocyclic heteroaryl group as defined above, having 6 ring atoms in the monocyclic heteroaryl ring; a5-10 membered heteroaryl is a monocyclic or bicyclic heteroaryl group as defined above having 5, 6, 7, 8, 9 or 10 ring atoms in the monocyclic or bicyclic heteroaryl ring.
The aforementioned cycloalkyl groups, which may be saturated or unsaturated, non-aromatic, monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl or bicyclo [5.2.0] nonyl, decahydronaphthyl, and the like.) cycloalkyl groups have from 3 to 15 carbon atoms A monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl or cyclodecyl). The cycloalkyl group can be optionally substituted with 1 or more (e.g., 1 to 5) suitable substituents.
In other embodiments, the compound is selected from the group consisting of:
Figure BDA0002416483780000051
Figure BDA0002416483780000061
the compound can be used for preparing medicaments for preventing or treating receptor tyrosine kinase mutation, particularly EGFR mutation related diseases; the EGFR mutation-related diseases are cancers, particularly cancers related to EGFR mutation in exon20 domain, such as non-small cell lung cancer, breast cancer, brain cancer, ovarian cancer, pancreatic cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, bladder cancer, liver cancer, gastrointestinal tissue cancer, esophageal cancer, thyroid cancer, leukemia, lymphoma, multiple myeloma and the like.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, isomer thereof; a pharmaceutically acceptable carrier or excipient. The pharmaceutically acceptable carrier or excipient may comprise any conventional pharmaceutical carrier or excipient. Suitable pharmaceutical carriers include inert diluents or fillers, water, and various organic solvents such as hydrates and solvents. The pharmaceutical composition may contain additional ingredients such as flavoring agents, binders, excipients, and the like, if desired.
The pharmaceutical composition can also comprise other one or more anticancer drugs, and the anticancer drugs are small molecule drugs, monoclonal antibodies or fusion protein drugs.
The compound with EGFR tyrosine kinase inhibitory activity provided by the application has strong inhibitory capacity on EGFR (D770_ N771insNPG) insertion mutation kinase activity. The proliferation inhibition of wild type EGFR high expression mouse pro-B cell (BaF3) is low, and meanwhile, the proliferation of EGFR exon20 insertion mutation high expression BaF3 cell can be effectively inhibited. The selectivity of the inhibitory activity of mutant cells relative to wild-type cells is a more important and critical indicator as a clinical therapeutic window compared to the inhibitory activity of single, highly expressed tumor cells of mutant EGFR. Therefore, the compound provided by the application can be used in higher dose without obvious toxicity in clinical application, the curative effect is greatly improved, and a better prognostic effect is obtained. And has good inhibitory effect on the abnormal proliferation of common EGFR mutation, EGFR (delE746-A750), Her2 insertional mutation high expression tumor cells.
Detailed Description
Part of the intermediates involved in the invention can be prepared by reference to the following general methods:
the method A comprises the following steps:
Figure BDA0002416483780000081
the method B comprises the following steps:
Figure BDA0002416483780000082
the method C comprises the following steps:
Figure BDA0002416483780000091
example 1N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (2-phenoxyphenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000092
The method comprises the following steps:
Figure BDA0002416483780000093
compound 1.1(1g, 6.71mmol, 1eq.), compound 1.2(1g, 4.67mmol, 0.69eq.), tetratriphenylphosphine palladium (775.28mg, 670.91umol, 0.1eq.), and potassium carbonate (2.78g, 20.14mmol, 3eq.) were dissolved in dioxane (20mL) and water (4mL), replaced with nitrogen three times, warmed to 75 ℃, and reacted for 5 hours. EA (50mL) was added to the reaction solution to extract, and the organic phase was separated, dried over anhydrous magnesium sulfate, spin-dried, and subjected to column chromatography (n-heptane: ethyl acetate: 10: 1) to obtain a pale yellow oil (1.20g, yield: 63.23%).
Step two:
Figure BDA0002416483780000101
1.3(1.20g, 4.24mmol, 1eq.), 1.4(993.92mg, 6.37mmol, 1.5eq.), cesium carbonate (4.15g, 12.73mmol, 3eq.), xphos (404.68mg, 848.88umol, 0.2eq.), Pd2(dba)3(388.67mg, 424.44umol, 0.1eq.), dioxane (20mL), nitrogen substitution 3 times, temperature to 110 degrees, reaction for 3 hours. Dichloromethane (30mL) was added to the reaction solution, followed by filtration, spin-drying of the filtrate, and column chromatography to give a tan solid (1.50g, yield: 87.83%).
Step three:
Figure BDA0002416483780000102
compound 1.5(1.50g, 3.73mmol, 1eq.), N, N, N' -trimethylethylenediamine (1.14g, 11.18mmol, 3eq.) was dissolved in ACN (30mL), and the reaction was carried out at 80 ℃ for 12 hours. The reaction was spin-dried and column-chromatographed (DCM: MeOH ═ 30:1+ 5% aqueous ammonia) to give a brown gummy solid (600mg, yield: 33.22%).
Step four:
Figure BDA0002416483780000111
compound 1.6(400mg, 825.51umol, 1eq.), Fe (461.01mg, 8.26mmol, 10eq.) was dissolved in EtOH (10mL) and saturated NH4Aqueous Cl (5mL), warmed to 80 deg.C, stirred for 4h, cooled to room temperature, dichloromethane (100mL) added, filtered, the filtrate extracted with dichloromethane, the organic phases combined, dried over anhydrous magnesium sulfate, filtered, and spun dried. 400mg of black gum is obtained, and the crude product is directly subjected to the next reaction.
Step five:
Figure BDA0002416483780000112
under nitrogen protection, compound 1.7(400mg, 879.96umol, 1eq.), N-diethylethylamine (178.09mg, 1.76mmol, 2eq.) was dissolved in DCM (10mL), cooled to-10 ℃, compound 1.8(79.64mg, 879.96umol, 1eq.) was added and stirred for 30 min. Column chromatography (DCM: MeOH ═ 25:1) afforded a brown solid (68mg, yield: 15.19%).1H NMR(400MHz,DMSO-d6)(ppm):9.80(brs,1H),9.62(s,1H),8.63(s,1H),8.43(d,1H),8.19-8.21(d,1H),7.50-7.54(m,2H),7,31-7.40(m,3H),7.20-7.23(d,1H),7.10-7.14(t,1H),7.0-7.03(m,3H),6.30-6.35(dd,1H),5.77-5.78(d,1H),2.60-3.33(m,6H),2.59(s,3H)。LC-MS(m/z):510.19[M+H]+。
Example 2N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2-phenoxyphenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000121
Using a method similar to example 1, compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):9.85(brs,1H),8.90(s,1H),8.42-8.43(d,1H),8.20-8.30(m,1H),8.09(s,1H),7.49-7.54(m,1H),7.29-7.40(m,4H),7.11-7.14(t,1H),6.98-7.02(m,4H),6.30-6.35(dd,1H),5.76-5.79(d,1H),3.88(s,3H),3.0-3.29(m,2H),2.64(m,6H)。LC-MS(m/z):538.86[M+H]+。
Example 3N- (5- ((4- (2- (benzyloxy) phenyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenylamide
Figure BDA0002416483780000122
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (benzyloxy) phenyl) boronic acid to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.21(s,1H),9.55(s,1H),8.76(s,1H),8.42-8.43(d,1H),8.10-8.11(d,1H),7.44-7.50(m,4H),7.33-7.44(m,4H),7.22-7.27(t,2H),7.10-7.12(t,1H),6.37-6.40(d,1H),6.31-6.32(d,1H),5.78-5.81(dd,1H),5.26(d,2H),2.80-2.82(t,2H),2.65(s,3H),2.21-2.26(m,2H),2.20(s,6H)。LC-MS(m/z):524.09[M+H]+。
Example 4N- (5- ((4- (2- (benzyloxy) phenyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide
Figure BDA0002416483780000131
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (benzyloxy) phenyl) boronic acid and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.07(s,1H),8.40-8.42(d,1H),8.19-8.21(d,1H),8.03(s,1H),7.33-7.48(m,7H),7.24-7.26(d,1H),7.08-7,10(t,1H),7.0(s,1H),6.37-6.39(d,1H),6.30-6.31(d,1H),5.75-5.78(dd,1H),5.26(s,2H),3.86(s,3H),2.85-2.88(t,2H),2.70(s,3H),2.21-2.29(m,2H),2.20(s,6H)。LC-MS(m/z):554.06[M+H]+。
Example 5N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- (pyridin-2-ylmethoxy) phenyl) pyrimidin-2-yl) aminophenyl) acrylamide
Figure BDA0002416483780000132
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (pyridin-2-ylmethoxy) phenyl) boronic acid and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.08(s,1H),8.59-8.60(m,1H),8.44-8.45(d,1H),8.15-8.25(d,1H),8.05(s,1H),7.82-7.84(t,1H),7.50-7.53(m,3H),7.42-7.47(m,1H),7.20-7.24(d,1H),7.09-7.11(t,1H),7.01(s,1H),6.20-6.39(m,2H),5.75-5.78(d,1H),5.33(s,2H),3.86(s,3H),2.85-2.88(t,2H),2.70(s,3H),2.28-2.30(t,2H),2.20(s,6H)。LC-MS(m/z):554.98[M+H]+。
Example 6N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (2- (pyridin-2-ylmethoxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000141
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (pyridin-2-ylmethoxy) phenyl) boronic acid to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.21(s,1H),9.56(s,1H),8.76-8.77(d,1H),8.59-8.60(m,1H),8.45-8.47(d,1H),8.08-8.10(dd,1H),7.82-7.83(t,1H),7.43-7.52(m,4H),7.35(m,1H),7.22-7.24(d,2H),7.11-7.13(t,1H),6.31-6.44(m,2H),5.78-5.80(dd,1H),5.33(s,2H),2.79-2.82(t,2H),2.65(s,3H),2.19-2.25(m,8H)。LC-MS(m/z):524.98[M+H]+。
Example 7N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- (p-tolyloxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000142
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (p-tolyloxy) phenyl) boronic acid and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.13(s,1H),9.07(s,1H),8.42-8.43(d,1H),8.31-8.33(d,1H),8.09(s,1H),7.46-7.48(t,1H),7.34-7.35(d,1H),7.28-7.30(t,1H),7.17-7.19(d,2H),7.01(s,1H),6.90-7.0(m,3H),6.31-6.50(m,2H),5.76-5.79(dd,1H),3.86(s,3H),2.86-2.88(t,2H),2.86(s,3H),2.20-2.30(m,10H)。LC-MS(m/z):554.06[M+H]+。
Example 8N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- (pyridin-2-yloxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000151
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (pyridin-2-yloxy) phenyl) boronic acid and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.13(s,1H),9.05(s,1H),7.83-8,40(m,5H),6.90-7,37(m,5H),7.38-7.80(m,2H),6.35(m,2H),5.78(m,1H),3.84-3.87(m,3H),2.70-2.86(m,5H),2.10-2.22(m,7H)。LC-MS(m/z):541.30[M+H]+。
Example 9N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- (m-tolyloxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000152
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (m-tolyloxy) phenyl) boronic acid and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.13(s,1H),9.07(s,1H),8.42-8.43(d,1H),8.30-8.40(m,1H),8.09(s,1H),7.48-7.50(m,1H),7.23-7.34(m,3H),6.93-7.01(m,4H),6.85(s,1H),6.78-6.80(d,1H),6.25-6.45(m,2H),5.76-5.79(d,1H),3.86(s,1H),2.86-2.90(t,2H),2.71(s,3H),2.27-2.30(m,5H),2.20(s,6H)。LC-MS(m/z):553.92[M+H]+。
Example 10N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (4-methyl-2-phenoxyphenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000161
Using a method similar to example 1, compound 1.2 from step one was replaced with (4-methyl-2-phenoxyphenyl) pinacol boronate (prepared by method A above) and compound 1.4 from step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.14(s,1H),9.06(s,1H),8.38-8.39(d,1H),8.26-8.28(d,1H),8.05(s,1H),7.31-7.39(m,3H),7.09-7.14(m.2H),6.98-7.01(m,3H),6.83(s,1H),6.35-6.40(m,2H),5.76-5.79(dd,1H),3.85(s,3H),2.86-2.88(t,2H),2.71(s,3H),2.28-2.32(m,5H),2.21(s,6H)。LC-MS(m/z):553.94[M+H]+。
Example 11N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (3-methyl-2-phenoxyphenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000162
Using a method similar to that of example 1, Compound 1.2 of step one was replaced with (3-Methyl-2-phenoxyphenyl) pinacol boronic acid ester (prepared by the foregoing procedure a), compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):9.67(brs,1H),8.75(brs,1H),8.34-8.35(d,1H),8.03(s,2H),7.50-7.52(m,1H),7.34-7.36(t,1H),7.21-7.26(m,3H),6.92-6.96(m,3H),6.69-6.71(m,2H),6.30-6.34(m,2H),5.77-5.80(m,1H),3.85(s,3H),2.55-2.80(m,7H),2.13(s,3H)。LC-MS(m/z):553.98[M+H]+。
Example 12N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- (pyridin-3-yloxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000171
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (pyridin-3-yloxy) phenyl) pinacol boronate (prepared by method a above) and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.11(brs,1H),9.76(brs,1H),8.82(s,1H),8.33-8.44(m,3H),8.23-8.24(m,1H),8.09(s,1H),7.53-7.57(m,1H),7.29-7.39(m,4H),7.08-7.10(d,1H),6.96(s,2H),6.30-6.34(m,1H),5.74-5.77(m,1H),3.88(s,3H),3.10-3.33(m,3H),2.55-2.68(m,8H)。LC-MS(m/z):541.04[M+H]+。
Example 13N- (5- ((4- (2- (cyclohexyloxy) phenyl) pyrimidin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxyphenyl) acrylamide
Figure BDA0002416483780000172
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (cyclohexyloxy) phenyl) boronic acid and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.08(s,1H),8.44-8.45(d,1H),8.15-8.25(d,1H),8.00(s,1H),7.42-7.48(m,2H),7.17-7.19(d,1H),7.01-7.05(m,2H),6.25-6.45(m,2H),5.75-5.78(dd,1H),4.45-4.60(m,1H),3.86(s,3H),2.85-2.88(m,2H),2.70(s,3H),2.21-2.30(m,8H),1.90-1.91(m,2H),1.65-1.66(m,2H),1.50-1.54(m,4H),1.34-1.40(m,4H)。LC-MS(m/z):545.99[M+H]+。
Example 14N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- (3-methoxyphenoxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000181
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (3-methoxyphenoxy) phenyl) boronic acid and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.13(s,1H),9.06(s,1H),8.42-8.43(d,1H),8.30-8.40(d,1H),8.09(s,1H),7.49-7.51(m,1H),7.32-7.33(m,2H),7.24-7.27(t,1H),7.01-7.04(m,2H),6.69-6.71(m,1H),6.59-6.60(m,1H),6.49-6.52(m,1H),6.32-6.40(m,2H),5.76-5.79(d,1H),3.85(s,3H),3.73(s,3H),2.86-2.88(t,2H),2.71(s,3H),2,29(m,2H),2.21(s,6H)。LC-MS(m/z):569.91[M+H]+。
Example 15N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- (3- (trifluoromethyl) phenoxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000182
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- (3- (trifluoromethyl) phenoxy) phenyl) pinacol boronate (prepared by method a above) and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.10(s,1H),9.04(s,1H),8.41-8.43(d,1H),8.32-8.34(d,1H),8.07(s,1H),7.51-7.61(m,2H),7.46-7.48(m,1H),7.36-7,41(m,2H),7.29-7.30(d,1H),7.23-7.26(m,1H),7.11-7.13(dd,1H),7.00(s,1H),6.28-6.50(m,2H),5.76-5.79(d,1H),3.84(s,3H),2.86-2.87(t,2H),2.70(s,3H),2.30(m,2H),2.21(s,6H)。LC-MS(m/z):608.04[M+H]+。
Example 16N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (5-methyl-2- (m-tolyloxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000191
Using a method similar to example 1, compound 1.2 of step one was replaced with (5-methyl-2- (m-tolyloxy) phenyl) pinacol boronate (prepared by method a described above) and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.15(s,1H),9.07(s,1H),8.39-8.40(d,1H),8.06-8.09(m,2H),7.28-7.31(m,2H),7.19-7.23(t,1H),7.02(s,1H),6.89-6.92(m,2H),6.78(s,1H),6.71-6.74(m,1H),6.27-6.41(m,1H),6.22-6.23(d,1H),5.75-5.78(m,1H),3.85(s,1H),2.85-2.88(t,2H),2.71(s,3H),2.31(s,3H),2.26-2.30(m,6H),2.21(s,6H)。LC-MS(m/z):568.27[M+H]+。
Example 17N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (2- (3-isopropylphenoxy) phenyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide
Figure BDA0002416483780000192
Using a method similar to example 1, compound 1.2 from step one was replaced with (2- (3-isopropylphenoxy) phenyl) pinacol boronate (prepared by method A above) and compound 1.4 from step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):9.95(brs,1H),8.95(brs,1H),8.42-8.43(d,1H),8.20-8.30(m,1H),8.09(s,1H),7.47-7.55(m,1H),7.34-7.35(d,1H),7.26-7.30(m,3H),6.94-7.03(m,4H),6.76-6.78(m,1H),6.28-6.29(d,1H),5.75-5.78(m,1H),3.87(s,3H),3.04(m,3H),2.85-2.88(m2H),2.65(s,3H),1.16-1.18(d,6H)。LC-MS(m/z):582.24[M+H]+。
Example 18N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (2- (3-ethylphenoxy) phenyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide
Figure BDA0002416483780000201
Using a method similar to example 1, compound 1.2 from step one was replaced with (2- (3-ethylphenoxy) phenyl) pinacol boronate (prepared by method A above) and compound 1.4 from step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.07(s,1H),8.42-8.43(d,1H),8.30-8.34(m,1H),8.06(s,1H),7.48-7.52(t,1H),7.25-7.35(m,3H),6.97-7.01(m,3H),6.89(s,1H),6.77-6.80(dd,1H),6.32-6.38(m,2H),5.76-5.79(m,1H),3.86(s,3H),2.86-2.88(m,2H),2.70(s,3H),2.55-2.61(m,2H),2.30(m,2H),2.21(s,6H),1.13-1.16(t,3H)。LC-MS(m/z):567.86[M+H]+。
Example 19N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- ((5-methylpyridin-3-yloxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000202
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- ((5-methylpyridin-3-yloxy) phenyl) pinacol boronate (prepared by method a above) and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):9.67(s,1H),8.77(s,1H),8.43-8.44(d,1H),8.10-8.22(m,3H),7.52-7.56(t,1H),7.24-7.37(m,3H),7.05-7.08(d,1H),6.96(s,1H),6.82(m,1H),6.31-6.35(d,1H),5.77-5.75(d,1H),3.88(s,3H),3.10-3.30(m,2H),2.60-2.73(m,5H),2.26(s,6H)。LC-MS(m/z):554.64[M+H]+。
Example 20N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (4- (m-tolyloxy) pyridin-3-yl) pyrimidin-2-ylamino) phenyl) acrylamide
Figure BDA0002416483780000211
Using a method similar to example 1, compound 1.2 from step one was replaced with (3- (m-tolyloxy) pyridin-4-yl) pinacol boronate (prepared by method C above) and compound 1.4 from step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.02(s,1H),9.10(s,1H),8.83(s,1H),8.48-8.49(dd,2H),8.31(s,1H),7.36-7.41(m,2H),6.95-7.14(m,4H),6.74-6.76(d,1H),6.49(s,1H),6.23-6.28(m,1H),5.72-5.77(m,1H),3.85(s,3H),2.95(t,2H),2.68(s,3H),2.21-2.34(m,10H)。LC-MS(m/z):554.91[M+H]+。
Example 21N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- ((6-methylpyridin-2-yl) oxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000212
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- ((6-methylpyridin-2-yl) oxy) phenyl) pinacol boronate (prepared as described in method B above) and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.04(s,1H),8.36-8.37(d,1H),8.26-8.28(d,1H),8.04(s,1H),7.69-7.73(t,1H),7.51-7.55(t,1H),7.34-7.37(t,1H),7.14-7.19(m,2H),6.95-7.0(m,2H),6.79-6.81(d,1H),6.28-6.44(m,2H),5.76-5.78(d,1H),3.85(s,3H),2.87(m,2H),2.70(s,3H),2.20-2.30(m,11H)。LC-MS(m/z):555.35[M+H]+。
Example 22N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((4- (2- (3, 5-dimethylphenoxy) phenyl) pyrimidin-2-yl) amino) -4-methoxyphenyl) acrylamide
Figure BDA0002416483780000221
Using a method similar to example 1, compound 1.2 from step one was replaced with (2- (3, 5-dimethylphenoxy) phenyl) pinacol boronate (prepared by method A above) and compound 1.4 from step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.12(s,1H),9.08(s,1H),8.42-8.43(d,1H),8.33-8.35(d,1H),8.09(s,1H),7.47-7.51(m,1H),7.27-7.34(m,2H),6.96-7.01(m,2H),6.77(s,1H),6.63(s,2H),6.37-6.44(m,1H),6.27-6.32(m,1H),5.76-5.78(m,1H),3.86(s,3H),2.87(m,2H),2.70(s,3H),2.20-2.30(m,14H)。LC-MS(m/z):568.34[M+H]+。
Example 23N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((4- (2- ((4-methylpyridin-2-yl) oxy) phenyl) pyrimidin-2-yl) amino) phenyl) acrylamide
Figure BDA0002416483780000222
Using a method similar to example 1, compound 1.2 of step one was replaced with (2- ((4-methylpyridin-2-yl) oxy) phenyl) pinacol boronate (prepared by method B above) and compound 1.4 of step two was replaced with 4-fluoro-2-methoxy-5-nitroaniline to give the title compound.1H NMR(400MHz,DMSO-d6)(ppm):10.01(s,1H),9.73(s,1H),8.82(s,1H),8.36-8.38(d,1H),8.18-8.20(m,1H),8.05(s,1H),7.91-7.93(d,1H),7.51-7.55(m,1H),7.33-7.37(t,1H),7.14-7.18(t,2H),6.92-6.96(m,4H),6.30-6.35(m,1H),5.75-5.78(d,1H),3.88(s,3H),3.24(m,2H),2.71(m,5H),2.61(s,3H),2.32(s,3H)。LC-MS(m/z):555.22[M+H]+。
Experimental example 1 EGFR D770-N771 insNPG kinase Activity inhibition assay
EGFR D770-N771 insNPG kinase expressed in baculovirus expression system was purchased from Shanghai Yongwei (univ Biological Inc.). TK kinase HTRF Detection kit (#62TK0PEC) containing a biotin-labeled polypeptide Substrate TK Substrate-biotin, a Eu-labeled specific phosphorylated polypeptide Antibody TK Antibody-Cryptate, a HTRF fluorescence acceptor reagent Streptavidin-XL665, and a 5 Xkinase reaction buffer, Detection buffer was purchased from Cisbio Bioassays (Codolet, France). Dithiothreitol (DTT), magnesium chloride, manganese chloride, Adenosine Triphosphate (ATP), dimethyl sulfoxide (DMSO), and HEPES buffer were obtained from Sigma at the highest purity levels available.
General methods for EGFR kinase activity inhibition assay: the phosphorylation reaction buffer was composed of 1M HEPES (pH 7.0), 5mM MgCl2、1mM MnCl2Composition, 1mM DTT was added to the buffer immediately before the start of the experiment. Preparing a test compound DMSO storage mother liquor, and performing three-time concentration gradient dilution by using DMSO according to the experiment requirement. The obtained gradient diluted solution is further diluted by phosphorylation reaction buffer solution to obtain a working solution of the compound to be detected dissolved in the reaction buffer solution containing 5% DMSO. mu.L of the compound working solution and 4. mu.L of EGFR kinase solution diluted in reaction buffer were added to a white low volume 384-well microtiter plate, and 4. mu.L of a mixed solution of ATP and biotin-labeled polypeptide substrate in reaction buffer was added to start the phosphorylation reaction. In the WT EGFR assay, the final concentrations of WT kinase, polypeptide substrate, ATP and DMSO were 0.01ng/ul, 500nM, 4. mu.M and 1%, respectively, and in the EGFR D770_ N771insNPG assay, the final concentrations of kinase, polypeptide substrate, ATP and DMSO were 0.01ng/ul, 200nM, 4. mu.M and 1%, respectively. The reaction was carried out at room temperature for 60 minutes under protection from light. mu.L each of TK Antibody-Cryptate Antibody and Streptavidin-XL665 diluted in detection buffer was added thereto, and incubated at room temperature for 60 minutes. The final concentration of Streptavidin-XL665 in the WT EGFR kinase reaction system was 15.61nM, the final concentration of Streptavidin-XL665 in the EGFR D770_ N771insNPG kinase reaction system was 31.25nM, and the antibodies were diluted to the final concentrations provided by the supplier. Use of Tecan (
Figure BDA0002416483780000232
Figure BDA0002416483780000233
Switzerland) multifunctional microplate reader Spark to read the plate, and detect two groups of homogeneous time-resolved fluorescence intensities, wherein the excitation wavelength is 320nm, and the emission wavelengths are 665nm and 620nm respectively. Using Prism 7(La Jolla,15CA) to plot the ratio of 665nm/620nm fluorescence intensity against the inhibitor concentration, the resulting inhibition curves were normalized by a sigmoidal dose-dependent curve model, and the IC of the inhibitor was obtained50The value is obtained. EGFR D770-N771 insNPG kinase inhibitory Activity IC of a fraction of the Compound prepared according to the preceding examples50The results are shown in Table 1.
TABLE 1
Figure BDA0002416483780000231
Figure BDA0002416483780000241
Experimental results show that the compounds of the application can effectively inhibit EGFR D770_ N771insNPG kinase activity, wherein IC of example 250Less than 1 nM.
Experimental example 2 cell proliferation inhibition experiment
H358, HCC827 cells were purchased from cell bank of Chinese academy of sciences (Shanghai), BaF3 EGFR WT, BaF3 EGFR D770_ N771insSVD, BaF3 EGFR V769_ D770insASV, BaF3 ERBB2A775_ G776insYVMA cells were purchased from Beijing Congyuan Bochu, MDA-MB-231, SK-BR-3, BT474 were purchased from Nanjing Ke Bai Biotech Co. MEM medium, RPMI1640 medium, penicillin-streptomycin diabody, 0.5% pancreatin (10X) and epidermal growth factor EGF were purchased from ThermoFisher (Waltham, MA, USA). Certified Fetal Bovine Serum (FBS) was purchased from Biological Industries (Israel). Corning 96 and 384-well cell culture plates were purchased from corning (usa). Cell-Titer
Figure BDA0002416483780000242
Available from Promega Corporation (Madison, Wis., USA).
In order to evaluate the ability of the synthesized compounds to inhibit proliferation of lung cancer cells H358, HCC827 and BaF3 EGFR WT, BaF3 EGFR D770_ N771insSVD, BaF3 EGFR V769_ D770insASV, BaF3 ERBB2A775_ G776insYVMA cells, H358, HCC827, BaF3 EGFR D770_ N771insSVD, BaF3 EGFR V769_ D770insASV, BaF3 ERBB2A775_ G776insYVMA exponentially-increased cells were inoculated in an RPMI1640 medium containing 10% bovine serum and 1% penicillin-streptomycin double antibody, BaF3 exponentially-increased cells were inoculated in an RPMI1640 medium containing 10% bovine serum, 1% penicillin-streptomycin double antibody and 50ng/mL EGF, BaF 462A 775_ G775 YVMA was inoculated in medium containing 10% bovine serum, 1% penicillin-streptomycin double antibody, BaF 639/mL of HCC-W-E cells were placed at a density of 7500/mL, BaF 7500 density of H9/mL, BaF 759/mL of SAF 512-W/mL, and SAVE/mL cells were placed in a density of a 100000/mL, and a density of SAVE/K770,770,000 cells, and SAVE/mL, and SAC equivalent to obtain a density of SAVE/K equivalent to obtain a cell density of SAVE equivalent to obtain a cell density of SAVE equivalent of each of SAMP 770, 5% CO2Overnight in an incubator. Compounds were diluted to 12 points in DMSO, 3-fold gradient dilutions, starting at 2 mM. mu.L of DMSO solution from the compound stock plate was added to 99. mu.L of cell culture medium (final maximum concentration of compound in the assay was 10. mu.M, and final concentration of DMSO was 0.5%). mu.L of compound solution in culture medium was added to each well of the 384 plates according to a gradient. After addition of the compound solution, 384-well plates were placed at 37 ℃ in 5% CO2Incubate in incubator for 3 days. Cell viability was determined by quantifying the ATP present in the cell culture using the CellTiter-Glo assay kit from Promega (Madison, Wis., USA). After 20 minutes incubation, readings were taken under a chemiluminescent program using a SPARK multifunctional microplate reader from TECAN. Concentration of compound to inhibit cell viability by 50% (IC) was determined in Prism 7(LaJolla, CA) using a sigmoidal dose response model (variable slope, four parameters)50Value).
The drug-property controls Poziotinib, Osimertinib, Pyrotinib, TAS6417 and Neratinib used in the experiment are all obtained in a commercial mode, Ref-1 is prepared according to the preparation method described in WO2015195228A1, and the structure is as follows:
Figure BDA0002416483780000251
the results of the partial compounds prepared according to the preceding examples for the inhibition of BaF3 EGFR WT, BaF3 EGFR D770_ N771insSVD, BaF3 EGFR V769_ D770insASV cell proliferation are shown in table 2.
TABLE 2
Figure BDA0002416483780000252
Figure BDA0002416483780000261
The results show that the compounds of the invention have good selectivity for the cell proliferation inhibitory activity of BaF3 highly expressed by the two most extensive mutations D770_ N771insSVD and V769_ D770insASV in the insertions of WT EGFR and EGFR Exon20, as in example 12, wherein the values of BaF3 EGFR WT/BaF3 EGFR D770_ N771insSVD and BaF3 EGFR WT/BaF3 EGFR V769_ D770insASV are 2.15 and 2.38, respectively, showing good selectivity and clinical treatment space for the compounds of the invention.
The results of partial compounds prepared according to the previous examples on the inhibition of HCC827, H358 WT cell proliferation are shown in table 3.
TABLE 3
Figure BDA0002416483780000262
The results show that the partial compounds of the invention can inhibit the proliferation of H358 NSCLC cells expressing wild-type EGFR far less than Poziotinib.
The results of the partial compounds prepared according to the previous examples on the inhibition of cell proliferation by MDA-MB-231, SK-BR-3 and BT474 are shown in Table 4.
TABLE 4
Figure BDA0002416483780000263
Figure BDA0002416483780000271
The results show that the activity of partial compounds of the invention on breast cancer cell strains SK-BR-3 and BT474 is similar to that of Pyrotinib and Neratinib used clinically, but the activity of the partial compounds is better than that of the same type of EGFR inhibitor TAS6417 on breast cancer cells, and the partial compounds provide possibility for the application of the partial compounds on HER2 targets and breast cancer treatment.

Claims (13)

1. A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
Figure FDA0002416483770000011
wherein R is1Is an aromatic ring, aromatic heterocycle or cycloalkane, optionally substituted with 0-2R1' substitution;
each R1' and R2Independently selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
R3selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
R4selected from hydrogen, C1-C6Alkyl or-NR5R6；
R5And R6Each independently selected from hydrogen, C1-C6Alkyl, -R7N(R8)(R9)；
R7、R8、R9Each independently selected from hydrogen or C1-C6An alkyl group;
n is 1 or 2;
Z1is C or N;
Z2is an alkylene group or a bond.
2. A compound according to claim 1, a stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein formula (i) is formula (la):
Figure FDA0002416483770000012
R1is an aromatic ring, aromatic heterocycle or cycloalkane, optionally substituted with 0-2R1' substitution;
each R1' and R2Independently selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
n is 1 or 2;
Z1is C or N;
Z2is methylene or a bond.
3. A compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein formula (i) is formula (ib):
Figure FDA0002416483770000021
R1is an aromatic ring, aromatic heterocycle or cycloalkane, optionally substituted with 0-2R1' substitution;
each R1' and R2Independently selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
n is 1 or 2;
Z1is C or N.
4. A compound according to claim 1, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein:
R1is optionally substituted by 0-2R1' a substituted benzene ring, pyridine ring or cyclohexane;
each R1' and R2Independently selected from hydrogen, C1-C6Alkyl, halo C1-C6Alkyl, halogen, hydroxy, nitro, amino, cyano or alkoxy;
n is 1 or 2;
Z1is C or N;
Z2is methylene or a bond.
5. A compound, stereoisomer or pharmaceutically acceptable salt thereof according to claim 1, wherein R1Selected from:
Figure FDA0002416483770000022
Figure FDA0002416483770000031
6. the compound according to claim 1, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from the following compounds:
Figure FDA0002416483770000032
Figure FDA0002416483770000041
7. use of a compound according to any one of claims 1 to 6 for the preparation of a medicament for the prophylaxis or treatment of a disease associated with mutation of a receptor tyrosine kinase.
8. The use of claim 7, wherein the receptor tyrosine kinase mutation is an EGFR mutation.
9. The use of claim 8, wherein the related disease caused by EGFR mutation is cancer.
10. The use of claim 9, wherein the cancer is non-small cell lung cancer, breast cancer, brain cancer, ovarian cancer, pancreatic cancer, uterine cancer, cervical cancer, skin cancer, prostate cancer, bladder cancer, liver cancer, cancer of gastrointestinal tissue, esophageal cancer, thyroid cancer, leukemia, lymphoma, or multiple myeloma.
11. The use of claim 7, wherein the related disease caused by EGFR mutation is related cancer caused by a mutation in exon20 domain of EGFR.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of claims 1-6 and a pharmaceutically acceptable carrier or excipient.
13. The pharmaceutical composition of claim 12, further comprising an additional anti-cancer drug or drugs, said anti-cancer drug or drugs being small molecule drugs, monoclonal antibodies or fusion protein drugs.
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