Heterocyclic egfr mutation inhibitors and uses thereof

Abstract

The application discloses a heterocyclic EGFR mutation inhibitor in the field of pharmaceutical chemistry, which is a heterocyclic compound shown in general formula I or a stereoisomer or optical isomer thereof or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, R5, R6, p, X, Y, Z, W, Cy1 and Cy2 are as defined in the claims. The main effect of the heterocyclic EGFR mutation inhibitor is to exert an antitumor effect by inhibiting a mutant EGFR.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a heterocyclic EGFR mutant inhibitor and application thereof. BACKGROUND

[0002] Epidermal growth factor receptor (EGFR) is a transmembrane tyrosine kinase receptor. After binding with a ligand, it forms a dimer, and its intracellular tyrosine kinase region binds with ATP to cause phosphorylation, thereby starting the downstream RAS / RAF / MAPK, STAT and PI3K / AKT / mTOR signaling pathways and regulating various physiological activities of normal cells. In addition, abnormal activation of EGFR can regulate various functions of tumor cells, such as growth, differentiation, invasion, metastasis and angiogenesis. Studies have shown that the formation of cancers including breast cancer and lung cancer is related to abnormal regulation of EGFR. Given the important role of EGFR in the occurrence and development of lung cancer, EGFR has become one of the important targets for treating lung cancer. More and more small molecule EGFR inhibitors have been developed and applied in clinical trials and treatment of lung cancer and other cancers, and the curative effect is obviously better than that of standard chemotherapeutic drugs such as platinum alkylating agents, and the median survival of patients has been significantly improved. However, primary or acquired drug resistance often occurs during the use of such inhibitors, thereby limiting their further application in clinical practice. It has been reported that the main cause of such drug resistance is drug resistance mutations, such as exon 19 deletion (Del19), L858R mutation, T790M mutation, C797S mutation and C797G mutation.

[0003] First-generation EGFR inhibitors, represented by Gefitinib and Icotinib containing an aromatic aminoquinazoline structure, can reversibly bind to EGFR, competitively inhibiting the binding of ATP to EGFR, thereby blocking the signaling pathways of tumor cell proliferation and anti-apoptosis, and inhibiting tumor cell growth. Second-generation EGFR inhibitors, represented by Afatinib containing an aromatic aminoquinazoline structure, can irreversibly bind to EGFR, increasing the drug's occupancy of the ATP binding site through covalent linkage, inhibiting phosphorylation, and blocking the signaling pathways of tumor cell growth and metastasis. These inhibitors have poor selectivity for mutant and wild-type EGFR, a narrow therapeutic window, and significant toxic side effects, limiting their application. Third-generation EGFR inhibitors, represented by pyrimidine derivatives such as Osimertinib, benzimidazole derivatives such as Nazartinib, and pyrimidopyrrole derivatives such as Avitinib, are mainly developed for EGFR with T790M resistance mutations. They can potently, irreversibly, and selectively covalently bind to cysteine ​​residues (Cys797) in the ATP-binding domain, inhibiting EGFR phosphorylation. In 2015, the U.S. FDA granted accelerated approval to Osimertinib for the treatment of metastatic EGFR. T790M Patients with mutation-positive NSCLCs.

[0004] Although third-generation EGFR inhibitors can reduce EGFR T790M The mutation offered a glimmer of hope for patients, but with the use of these drugs, the Cys797 mutation emerged, rendering third-generation inhibitors ineffective. This is especially true for EGFR. L858R / T790M / C797S and EGFR Del19 / T790M / C797S The emergence of drug-resistant variants with three mutations has left patients with this type of lung cancer facing a situation where no treatment is available. Therefore, there is an urgent clinical need for a treatment for cancers caused by these mutations. Summary of the Invention

[0005] The purpose of this invention is to design and synthesize a class of heterocyclic compounds or their stereoisomers or optical isomers, or their pharmaceutically acceptable salts, and pharmaceutical compositions containing said compounds. Their main function is to exert their antitumor effect by inhibiting mutant EGFR. Mutation types include, but are not limited to, single mutations such as T790M, L718Q, L844V, V948R, L858R, C797S, C797G, and Del19, or combined mutations such as Del19 / L718Q, Del19 / T790M, L858R / L718Q, L858R / T790M, Del19 / T790M / C797S, Del19 / T790M / C797G, L858R / T790M / C797S, and L858R / T790M / I941R.

[0006] The heterocyclic EGFR mutation inhibitors in this scheme are heterocyclic compounds represented by general formula I, or their stereoisomers or optical isomers, or their pharmaceutically acceptable salts.

[0007]

[0008] In the formula, X is O, NH, NHCH2, NHNHCO or NHNH;

[0009] Y is either none, CH2, NH, or CONH;

[0010] It can be a single bond or a double bond;

[0011] Z represents CO or N;

[0012] W is either CH or N;

[0013] p is 0, 1, or 2;

[0014] R1 is hydrogen, halogen atom, phenylamino, amino, -(C1-C3 amide), -(C1-C3 alkyl), -(C1-C3 alkylamino), -(C1-C3 alkoxy), -(C1-C2 haloalkyl), or -(C1-C2 haloalkoxy).

[0015] R2 and R3 may be the same or different, and are both selected from hydrogen, halogen atom, cyano, -(C1-C3 alkyl), -(C1-C3 alkoxy), -(C1-C2 haloalkyl) or -(C1-C2 haloalkoxy);

[0016] R4 is hydrogen, a 6-10 aryl group, a 5-10 aryl heterocyclic group, or a 3-10 heterocyclic alkyl group, wherein the heterocycle contains 1-3 identical or different nitrogen, sulfur, or oxygen atoms, and the heterocycle is unsubstituent or substituted by 1-3 identical or different groups selected from the following: -(C1-C3 alkyl), -(C1-C3 alkoxy), cyano, halogen atom, -(C1-C3 haloalkyl), -(C1-C3 haloalkoxy), amino, -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, or hydroxyl-substituted.

[0017] R6 is hydrogen, hydroxyl, halogen atom, -(C1-C2 acyl) or -(C1-C3 alkyl);

[0018] Cy1 is either non-existent, has a benzene ring, or has a pyridine ring;

[0019] Cy2 is none, thiophene, pyrrole, pyrazole, imidazole or The above heterocycles are unsubstituted or substituted by 1-2 groups selected from the same or different groups: halogen atom, -(C1-C3 alkyl), -(C1-C3 alkoxy) or -(C1-C2 haloalkyl);

[0020] R9 and R 10 Each group is independently selected from hydrogen, substituted or unsubstituted C1-C3 alkoxy groups, substituted or unsubstituted piperazine (C1-C3 alkoxy), substituted or unsubstituted piperidinyl (C1-C3 alkoxy), substituted or unsubstituted morpholino (C1-C3 alkoxy), and substituted or unsubstituted tetrahydropyranyl (C1-C3 alkoxy), wherein the substitution means that 1-3 hydrogen atoms in the above groups are replaced by the same or different groups selected from the group consisting of: halogen, -(C1-C3 alkyl), -(C1-C3 alkoxy);

[0021] R5 is

[0022] Where m is 0 or 1;

[0023] n is 1, 2, or 3;

[0024] Cy3 is a 6-10 aryl, a 5-6 aryl heterocyclic or a 5-7 heterocyclic, wherein the heterocycle contains 1-3 identical or different nitrogen, sulfur or oxygen atoms.

[0025] R7 is a hydrogen atom, -(C1-C3 alkyl), -(C1-C3 alkoxy), halogen atom, -(C1-C3 haloalkyl), or -(C1-C3 haloalkoxy);

[0026] R8 represents a hydrogen atom, -(C1-C3 haloalkyl), or -(CH2). 0-3 -OH, -CONH(C1-C3 alkyl)N(C1-C3 alkyl) 0-2 -CONH (C1-C3 alkyl) (5-8 membered heterocyclic group), -(C1-C3 alkyl)N (C1-C3 alkyl) 0-2 -N (C1-C3 alkyl) 0-2 -(C1-C3 alkyl)N(C1-C3 alkyl) 0-1 (5-6 membered cycloalkyl), -CO (5-8 membered heterocyclic), -(CH2) 0-3 -(4-8 membered heterocyclic group), -O(CH2) 0-3 -(5-6 membered heterocyclic group), wherein the heterocyclic group may contain 1-3 identical or different nitrogen, sulfur or oxygen atoms, and the heterocycle is unsubstituent or substituted by 1-3 identical or different groups selected from the following: -(C1-C6 alkyl), -(C1-C6 alkoxy), -(C1-C6 haloalkyl), halogen atom, -(C1-C3 alkylamino), -(CH2) 0-3-(5-6 membered heterocyclic group), -CO(C1-C3 alkyl)OH, -CO(C1-C3 alkyl), -(C1-C3 alkyl)O(C1-C3 alkyl), -O(CH2) 1-3 -OH, -CON (C1-C6 alkyl) 0-2 -O(C1-C3 alkyl)N(C1-C3 alkyl) 0-2 -(C1-C3 alkyl)NH(C1-C3 alkyl), -(C1-C3 alkyl)N(C1-C3 alkyl)2, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, -(CH2) 0-3 -OH, amino, or hydroxyl groups.

[0027] In another preferred embodiment, the heterocyclic EGFR mutation inhibitor is any one of the following compounds:

[0028]

[0029]

[0030]

[0031]

[0032]

[0033]

[0034]

[0035]

[0036]

[0037]

[0038]

[0039]

[0040] The present invention also provides a pharmaceutical composition comprising a compound of any structure of the heterocyclic EGFR mutation inhibitors described in this application, or a stereoisomer or optical isomer thereof, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0041] This invention also provides the use of any of the heterocyclic EGFR mutation inhibitors described in this application, or their stereoisomers or optical isomers, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the treatment or prevention of proliferative diseases or EGFR-mediated diseases or for inhibiting EGFR.

[0042] In another preferred embodiment, the EGFR-mediated disease is cancer.

[0043] In another preferred embodiment, the cancer is selected from the group consisting of: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, gastric cancer, multiple myeloma, and solid tumors.

[0044] According to some common methods in the field to which this invention pertains, compounds of any structure among the heterocyclic EGFR mutation inhibitors of general formula I of this invention can react with acids to form pharmaceutically acceptable salts. Pharmaceutically acceptable addition salts include addition salts of inorganic and organic acids, with salts reacting with the following acids being particularly preferred: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid, etc.

[0045] In this invention, "halogen" refers to fluorine, chlorine, or bromine; "alkyl" refers to a straight-chain or branched alkyl group; and "cycle" refers to a monocyclic or fused-cycle ring.

[0046] The active compounds of the present invention, or their pharmaceutically acceptable salts and solvates, can be used alone as the sole antitumor drug, or in combination with already marketed antitumor drugs (such as osimertinib, cisplatin, irinotecan, cetuximab, dacomitinib, saprotinib, and canenatinib). Combination therapy is achieved by administering the various therapeutic components simultaneously, sequentially, or separately. Detailed Implementation

[0047] The examples and preparation methods provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation methods does not limit the scope of the present invention in any way.

[0048] The following synthetic route (Route 1) summarizes and describes the preparation of the Formula I derivatives of the present invention. All starting materials are prepared by the methods described in these illustrations, by methods well known to those skilled in the art of organic chemistry, or are commercially available. All final derivatives of the present invention are prepared by the methods described in these illustrations or by similar methods well known to those skilled in the art of organic chemistry. All variable factors used in these illustrations are as defined below or as defined in the claims.

[0049]

[0050] Preparation of compound I in route 1

[0051] According to the present invention, all compounds of Formula I can be prepared by condensation of amine 1 and acid 2 under the action of HATU and DIEA according to method 1. Wherein, R1, R2, R3, R4, R5, R6, p, X, Y, Z, W, Cy1, and Cy2 in Formula I are as defined in the claims.

[0052] More specifically, when Z is CO, the compound of formula II can be prepared using the method of route 2:

[0053]

[0054] Preparation of compound II via route 2

[0055] More specifically, when Z is N, the compound of formula Ш can be prepared using the method described in route 3:

[0056]

[0057] Preparation of compound Ш via route 3

[0058] More specifically, when R5 is Compound II-1 can be prepared via route 4, and compound Ш-1 can be prepared via route 5:

[0059]

[0060] Preparation of compound II-1 via route 4

[0061]

[0062] Preparation of compound Ш-1 via route 5

[0063] More specifically, when R5 is Compound II-2 can be prepared via route 6, and compound Ш-2 can be prepared via route 7.

[0064]

[0065] Preparation of compound II-2 in route 6

[0066]

[0067] Preparation of compound Ш-2 according to route 7

[0068] The examples are intended to illustrate, and not limit, the scope of the invention. The proton NMR spectra of the compounds were determined using a Bruker ARX-600, and high-resolution mass spectrometry was performed using a quadrupole liquid chromatography-mass spectrometry (LC-MS) system; all reagents used were commercially available analytical grade or chemically pure.

[0069] Example 1: Synthesis of N-(4-((6-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide (target compound)

[0070] (1) Synthesis of methyl 2-(5-bromo-1-oxoisoindoline-2-yl)-2-phenylacetate

[0071] At 0 °C, methyl 4-bromo-2-bromomethylbenzoate (6.00 g, 19.5 mmol) was dissolved in 45 mL of DMF, and methyl 2-amino-2-phenylacetic acid hydrochloride (6.46 g, 21.3 mmol) and DIEA (7.63 g, 58.8 mmol) were added. The mixture was stirred until completely dissolved, and then reacted at 110 °C for 14 h. The reaction solution was cooled to room temperature, poured into 150 mL of ice water, and filtered to obtain 9.80 g of yellow solid, which was purified by column chromatography to obtain 7.23 g of pale yellow solid.

[0072] (2) Synthesis of 2-(5-(4-(4-Boc-1-piperazinyl)phenyl)-1-oxoisoindol-2-yl)-2-phenylacetic acid

[0073] 2-(5-bromo-1-oxoisoindoline-2-yl)-2-phenylacetic acid methyl ester (7.00 g, 19.4 mmol) was dissolved in 150 mL of 1,4-dioxane, followed by the addition of 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester (11.32 g, 29.2 mmol) and 45 mL of sodium carbonate aqueous solution (2 mol / L). The mixture was degassed by sonication for 1 min, preheated at 100 °C for 20 min, and then PdCl₂(dppf)₂ (0.78 g, 1.1 mmol) and X-phos (0.86 g, 1.8 mmol) were added sequentially. The reaction was continued for 12 h. The reaction solution was cooled to room temperature, filtered, and the solid was dissolved in water. The pH was adjusted to 4 with dilute hydrochloric acid, and the mixture was filtered again to obtain a brown solid. 7.35 g of light brown solid was purified by column chromatography.

[0074] (3N) 4 Synthesis of 2,4-(4-nitrophenyl)pyrimidine-2,4-diamine

[0075] At room temperature, 6.50 g (0.05 mol) of 4-chloro-2-aminopyrimidine and 13.81 g (0.1 mol) of p-nitroaniline were added to 65 mL of isopropanol, and 3 drops of concentrated hydrochloric acid were added dropwise. The mixture was refluxed for 2 h. The reaction solution was cooled to room temperature and filtered to obtain 12.84 g of yellow solid.

[0076] ⑷N 4 -(4-aminophenyl)pyrimidin-2,4-diamine

[0077] N 4 10.00 g (0.04 mol) of 4-nitrophenyl)pyrimidine-2,4-diamine was dissolved in 120 mL of 90% ethanol, and iron powder (11.20 g, 0.20 mol) and 1 drop of concentrated hydrochloric acid were added. The mixture was refluxed for 4 h. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 6.21 g of light brown solid.

[0078] (5) Synthesis of N-(4-((6-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0079] N 4 0.20 g (1.0 mmol) of 4-nitrophenyl)pyrimidine-2,4-diamine and 0.58 g (1.1 mmol) of 2-(5-(4-(4-Boc-1-piperazinyl)phenyl)-1-oxoisoindol-2-yl)-2-phenylacetic acid (0.1 mmol) were dissolved in 4 mL of DMF. HATU (1.3 mmol) and DIEA (2.0 mmol) were added sequentially, and the mixture was reacted at room temperature for 2 h. The reaction solution was poured into 15 mL of ice water and filtered to obtain 0.45 g of tert-butyl 4-(4-(2-(2-((4-((6-aminopyrimidine-4-yl)amino)phenyl)amino)-2-oxo-1-phenylethyl)-1-oxo-5-yl)phenyl)piperazin-1-carboxylic acid. The ester was added to 5 mL of dichloromethane, followed by 2 mL of trifluoroacetic acid, and the mixture was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure to obtain a brown viscous substance, which was dissolved in an appropriate amount of dichloromethane. The pH was then adjusted to 8-9 with a saturated sodium bicarbonate aqueous solution. The mixture was filtered, and the crude product was purified by column chromatography to obtain 0.24 g of the target compound. 1H NMR(600MHz,DMSO-d6)δ10.44(s,1H),8.80(s,1H),8.01(s,1H),7.79(s,1H),7.7 2-7.77(m,2H),7.60(m,2H),7.52(m,2H),7.44-7.47(m,4H),7.41(m,3H),7.05(m ,2H),6.25(s,2H),6.24(s,1H),5.74(s,1H),4.88(d,J=18.0Hz,1H),4.00(d,J=1 8.0Hz,1H),3.23(m,4H),2.97(m,4H),1.23(s,1H); HRMS(ESI)m / z:611.3748[M+H] + .

[0080] Example 2 Synthesis of 2-(5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)acetamide (target compound)

[0081] (1) Synthesis of methyl 2-(5-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenylacetate

[0082] Methyl 2-(5-bromo-1-oxoisoindolin-2-yl)-2-phenylacetate (1.80 g, 5.0 mmol) and 4-ethynylbenzaldehyde (0.98 g, 7.5 mmol) were added to 36 mL of DMF, followed by triethylamine (15.0 mmol), PdCl₂(PPh₃)₂ (0.25 mmol), PPh₃ (0.5 mmol), and CuI (0.25 mmol). The reaction mixture was reacted at 80 °C for 5 h. The reaction solution was poured into 100 mL of water, extracted twice with ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give a brown liquid. The target compound was purified by column chromatography to obtain 1.42 g of the compound.

[0083] (2) Synthesis of methyl 2-(5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-isoindoline-2-yl)-2-phenylacetate

[0084] Methyl 2-(5-((4-formylphenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenylacetate (1.23 g, 3.0 mmol) was dissolved in 30 mL of dichloromethane at room temperature, followed by the addition of 0.45 mmol of 1-methylpiperazine and 0.45 mmol of sodium triacetoxyborohydride. The reaction mixture was then reacted at room temperature for 15 h. The reaction solution was poured into 20 mL of water, extracted twice with dichloromethane, and the combined dichloromethane layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a brown oily substance.

[0085] (3) Synthesis of 2-(5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenylacetic acid

[0086] Methyl 2-(5-((4-(((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-isoindoline-2-yl)-2-phenylacetic acid (0.8 g, 1.6 mmol) was added to 20 mL and 10 mL of methanol, followed by the addition of sodium hydroxide (0.2 g). The mixture was reacted at 50 °C for 2 h. The methanol was removed by vacuum concentration, and 10 mL of water was added. The pH was adjusted to 4 with dilute hydrochloric acid, and the mixture was filtered to obtain 2-(5-((4-(((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenylacetic acid.

[0087] (4) Synthesis of 2-(5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)acetamide

[0088] N 1 -(quinazolin-4-yl)phenyl-1,4-diamine (0.10 g, 0.4 mmol) and 2-(5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenylacetic acid (0.24 g, 0.5 mmol) were dissolved in 3 mL of LMF, and HATU (0.52 mmol) and DIEA (0.8 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 2 h. The reaction solution was poured into 10 mL of ice water and filtered to give 0.13 g of the target compound. HRMS (ESI) m / z: 698.3295 [M+H] + .

[0089] Example 3 2-(5-((6-aminopyridin-3-yl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)acetamide

[0090] HRMS(ESI) m / z: 602.2375 [M+H] +.

[0091] Example 4: N-(4-((6-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0092] 1 H NMR(600MHz,DMSO-d6)δ10.44(s,1H),8.80(s,1H),8.01(s,1H),7.90(s,1H),7.84(m,1H),7.60(m,3H),7.52(m,2H),7.39-7.48(m, 7H),7.05(m,2H),6.25(s,3H),5.74(s,1H),4.88(d,J=18.0Hz,1H),3.98(d,J=18.0Hz,1H),3.24(m,4H),3.00(m,4H),1.23(s,1H).

[0093] Example 5: N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0094] 1 H NMR(600MHz,DMSO-d6)δ10.44(s,1H),9.04(s,1H),7.78(m,2H),7.75(m,1H),7.7 3(m,1H),7.65(m,2H),7.57(m,2H),7.55(m,2H),7.46(m,2H),7.41(m,3H),7.00(m ,2H),6.24(s,1H),6.12(s,2H),5.96(d,1H),4.88(d,J=18.0Hz,1H),4.00(d,J=1 8.0Hz,1H),3.10(m,4H),2.83(m,4H),1.23(s,1H); HRMS(ESI)m / z:611.3835[M+H] + .

[0095] Example 6 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(pyrimidin-4-ylamino)phenyl)acetyl

[0096] 1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.55(s,1H),8.57(s,1H),8.22(d,1H),7. 78(s,1H),7.73(m,2H),7.57-7.60(m,6H),7.47(m,2H),7.41(m,3H),7.02(s,1H ),7.00(s,1H),6.75(d,1H),6.25(s,1H),4.87(d,J=18.0Hz,1H),4.00(d,J=18. 0Hz,1H),3.12(m,4H),2.84(m,4H),1.23(s,1H); HRMS(ESI)m / z:596.3500[M+H] + .

[0097] Example 7: N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0098] 1 H NMR(600MHz,DMSO-d6)δ10.43(s,1H),9.03(s,1H),7.89(s,1H),7.84(m,1H),7.77(m ,1H),7.64(m,2H),7.59(m,3H),7.53(m,2H),7.46(m,3H),7.41(m,3H),7.02(s,1H), 7.00(s,1H),6.25(s,1H),6.12(s,1H),5.96(d,1H),4.86(d,J=18.0Hz,1H),3.98(d, J=18.0Hz,1H),3.11(m,4H),2.84(m,4H),1.23(s,1H); HRMS(ESI)m / z:611.3661[M+H] + .

[0099] Example 8: N-(4-((2-aminopyrimidin-4-yl)amino)-3-chlorophenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0100] 1H NMR(600MHz,DMSO-d6)δ10.68(s,1H),8.47(s,1H),7.93(s,1H),7.72-7.7 8(m,5H),7.57(m,2H),7.46(m,2H),7.42(m,4H),7.01(m,2H),6.21(s,1H) ,6.04(s,2H),5.96(d,1H),4.83(d,J=18.0Hz,1H),4.00(d,J=18.0Hz,1H) ,3.13(br,4H),2.86(br,4H),1.23(s,1H); HRMS(ESI)m / z:645.3501[M+H] + .

[0101] Example 9: N-(4-((2-aminopyrimidin-4-yl)amino)-2-fluorophenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0102] 1 H NMR(600MHz,DMSO-d6)δ10.20(s,1H),9.35(s,1H),7.93(s,1H),8.02(m,1H),7.82(d,1H),7. 77(s,1H),7.71-7.76(m,2H),7.61(m,1H),7.58(m,2H),7.47(m,2H),7.42(m,3H),7.28(m,1H ),7.01(s,1H),7.00(s,1H),6.39(s,1H),6.27(s,2H),6.01(d,1H),4.84(d,J=18.0Hz,1H),3 .97(d,J=18.0Hz,1H),3.11(m,4H),2.83(m,4H),1.23(s,1H); HRMS(ESI)m / z:629.3812[M+H] + .

[0103] Example 10N-(3-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0104] 1H NMR(600MHz,DMSO-d6)δ10.48(s,1H),9.11(s,1H),7.84(s,1H),7.78(m,2H),7.73(m ,2H),7.65(m,1H),7.57(d,2H),7.47(m,2H),7.41(m,3H),7.22(m,2H),7.02(s,1H), 7.01(s,1H),6.27(s,1H),6.08(s,2H),6.02(d,1H),4.87(d,J=18.0Hz,1H),4.00(d, J=18.0Hz,1H),3.14(m,4H),2.87(m,4H),1.23(s,1H); HRMS(ESI)m / z:611.3487[M+H] + .

[0105] Example 11: N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(diethylamino)phenyl)-1-oxoisoindololin-2-yl)-2-phenylacetamide

[0106] 1 H NMR(600MHz,DMSO-d6)δ10.44(s,1H),9.05(s,1H),7.78(m,1H),7.69-7.74( m,3H),7.65(m,2H),7.53(m,4H),7.46(m,2H),7.41(m,3H),6.74(m,2H),6.2 4(s,1H),6.12(s,2H),5.97(d,1H),4.87(d,J=18.0Hz,1H),3.99(d,J=18.0H z,1H),3.37(m,4H),1.23(s,1H),1.10(t,6H); HRMS(ESI)m / z:598.3621[M+H] + .

[0107] Example 1: 2N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-morpholinophenyl)-1-oxoisoindoline-2-yl)-2-phenylacetamide

[0108] 1H NMR(600MHz,DMSO-d6)δ10.50(s,1H),9.20(s,1H),7.79(s,1H),7.73-7.77( m,3H),7.67(m,2H),7.59(m,2H),7.54(m,2H),7.46(m,2H),7.40(m,3H),7.0 4(m,2H),6.25(s,1H),6.18(s,2H),6.01(d,1H),4.88(d,J=18.0Hz,1H),4.0 0(d,J=18.0Hz,1H),3.75(m,4H),3.17(m,4H); HRMS(ESI)m / z:612.3494[M+H] + .

[0109] Example 13 (S)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindoline-2-yl)-2-phenylacetamide

[0110] 1 H NMR(600MHz,DMSO-d6)δ10.44(s,1H),9.04(s,1H),7.72-7.78(m,4H),7.65(m,2H) ,7.57(m,2H),7.53(m,2H),7.46(m,2H),7.41(m,3H),7.03(s,1H),7.02(s,1H),6.2 4(s,1H),6.12(s,2H),5.96(d,1H),4.88(d,J=18.0Hz,1H),4.00(d,J=18.0Hz,1H), 3.17(m,4H),2.45(m,4H),2.22(s,3H),1.23(s,1H); HRMS(ESI)m / z:625.3983[M+H] + .

[0111] Example 14 (R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindoline-2-yl)-2-phenylacetamide

[0112] 1H NMR(600MHz,DMSO-d6)δ10.43(s,1H),9.03(s,1H),7.72-7.78(m,4H),7.66(m,2H) ,7.57(m,2H),7.53(m,2H),7.46(m,2H),7.41(m,3H),7.03(s,1H),7.02(s,1H),6.2 4(s,1H),6.12(s,2H),5.96(d,1H),4.88(d,J=18.0Hz,1H),4.00(d,J=18.0Hz,1H), 3.20(m,4H),2.45(m,4H),2.22(s,3H),1.23(s,1H); HRMS(ESI)m / z:625.3718[M+H] + .

[0113] Example 15N-(4-((2-methylpiperazin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0114] 1 H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.43(s,1H),8.12(d,1H),7.79(s,1H ),7.73(m,2H),7.58(m,6H),7.47(m,2H),7.41(m,3H),7.02(d,2H),6.56(d ,1H),6.25(s,1H),4.90(d,J=18.0Hz,1H),4.02(d,J=18.0Hz,1H),3.12(m, 4H),2.84(m,4H),2.42(s,3H),1.23(s,1H); HRMS(ESI)m / z:610.3749[M+H] + .

[0115] Example 16 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)acetamide

[0116] 1H NMR(600MHz,DMSO-d6)δ10.60(s,1H),9.82(s,1H),8.56(m,2H),7.85(m,1H ),7.80(m,3H),7.75(m,3H),7.67(m,2H),7.61(m,3H),7.48(m,2H),7.42(m ,3H),7.05(d,2H),6.27(s,1H),4.92(d,J=18.0Hz,1H),4.04(d,J=18.0Hz, 1H),3.22(m,4H),2.97(m,4H),1.23(s,1H); HRMS(ESI)m / z:646.3693[M+H] + .

[0117] Example 17 N-(4-((5-chloro-2-methylpyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0118] 1 H NMR(600MHz,DMSO-d6)δ10.58(s,1H),8.95(s,1H),8.29(s,1H),7.80(s,1H),7.74(m,2H),7.60(m,6H),7.47(m,2H),7.42(m,3H),7.03(d,2H), 6.26(s,1H),4.90(d,J=18.0Hz,1H),4.03(d,J=18.0Hz,1H),3.21(m,4H ),2.94(m,4H),2.38(s,3H),1.23(s,1H); HRMS(ESI)m / z:644.3585[M+H] + .

[0119] Example 18 N-(4-((2-methylpyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0120] 1H NMR(600MHz,DMSO-d6)δ10.51(s,1H),9.59(s,1H),8.05(d,1H),7.79(s,1H ),7.73(m,2H),7.60(m,6H),7.47(m,2H),7.41(m,3H),7.02(d,2H),6.40(d ,1H),6.25(s,1H),4.90(d,J=18.0Hz,1H),4.02(d,J=18.0Hz,1H),3.83(s, 3H),3.13(m,4H),2.86(m,4H),1.23(s,1H); HRMS(ESI)m / z:626.3576[M+H] + .

[0121] Example 19 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(pyridin-4-ylamino)phenyl)acetamide

[0122] 1 H NMR(600MHz,DMSO-d6)δ10.55(s,1H),8,74(s,1H),8.15(d,2H),7.79(s,1H ),7.76(m,2H),7.61(m,4H),7.47(m,2H),7.42(m,3H),7.17(d,2H),7.04(d ,2H),6.84(d,2H),6.25(s,1H),4.90(d,J=18.0Hz,1H),4.03(d,J=18.0Hz, 1H),3.25(m,4H),2.99(m,4H),1.23(s,1H); HRMS(ESI)m / z:595.3367[M+H] + .

[0123] Example 20: N-(4-((6-acetamidopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0124] 1H NMR(600MHz,DMSO-d6)δ10.50(s,1H),10.46(s,1H),9.56(s,1H),8.35(s,1H), 7.79(s,1H),7.73(m,2H),7.59(m,6H),7.51(s,1H),7.45(m,2H),7.41(m,3H), 7.01(d,2H),6.25(s,1H),4.90(d,J=18.0Hz,1H),4.02(d,J=18.0Hz,1H),3.16 (m,4H),2.89(m,4H),2.09(s,3H),1.23(s,1H); HRMS(ESI)m / z:653.3736[M+H] + .

[0125] Example 21 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(thiophene[3,2-d]pyrimidin-4-ylamino)phenyl)acetamide

[0126] 1 H NMR(600MHz,DMSO-d6)δ10.58(s,1H),9.68(s,1H),8.54(s,1H),8.19(s,1H),7.70-7.79(m,5H),7.58(m,4H),7.47(m, 6H), 7.02 (m, 2H), 6.25 (s, 1H), 4.91 (d, J = 18.0Hz, 1H), 4.03 (d, J = 18.0Hz, 1H), 3.12 (m, 4H), 2.84 (m, 4H), 1.23 (s, 1H).

[0127] Example 22N-(4-((6,7-dimethoxyquinazoline-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0128] 1H NMR(600MHz,DMSO-d6)δ10.58(s,1H),9.49(s,1H),8.42(s,1H),7.86(s,1H),7.80(s ,1H),7.75(m,4H),7.66(m,2H),7.60(m,2H),7.48(m,2H),7.42(m,3H),7.17(s,1H), 7.04(d,2H),6.27(s,1H),4.91(d,J=18.0Hz,1H),4.04(d,J=18.0Hz,1H),3.96(s,3H ),3.93(s,3H),3.18(m,4H),2.92(m,4H),1.23(s,1H); HRMS(ESI)m / z:706.4026[M+H] + .

[0129] Example 23: N-(4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0130] 1 H NMR(600MHz,DMSO-d6)δ11.72(s,1H),10.51(s,1H),9.30(s,1H),8.24(s,1H ),7.73-7.84(m,5H),7.59(m,4H),7.47(m,2H),7.43(m,3H),7.21(s,1H),7.0 2(m,2H),6.76(s,1H),6.26(s,1H),4.92(d,J=18.0Hz,1H),4.03(d,J=18.0H z,1H),3.11(m,4H),2.83(m,4H),1.23(s,1H); HRMS(ESI)m / z:635.3705[M+H] + .

[0131] Example 24: N-(4-((9-methyl-9H-purin-6-yl)amino)phenyl)-2-(1-oxo5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide

[0132] 1H NMR(600MHz,DMSO-d6)δ10.52(s,1H),9.80(s,1H),8.39(s,1H),8.26(s,1H),7.9 0(s,1H),7.88(s,1H),7.79(s,1H),7.73(m,2H),7.58(m,4H),7.47(m,2H),7.41(m ,3H),7.02(m,2H),6.26(s,1H),4.88(d,J=18.0Hz,1H),4.00(d,J=18.0Hz,1H),3 .78(s,3H),3.11(m,4H),2.83(m,4H),1.23(s,1H); HRMS(ESI)m / z:650.3825[M+H] + .

[0133] Example 25 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)propylamine

[0134] HRMS(ESI) m / z: 584.2812 [M+H] + .

[0135] Example 26 2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-3-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)propionamide

[0136] HRMS(ESI) m / z: 660.3114 [M+H] + .

[0137] Example 27 Synthesis of 2-phenyl-2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)acetamide (target compound)

[0138] (1) Synthesis of methyl 2-(6-bromo-2H-indazol-2-yl)-2-phenylacetate

[0139] At room temperature, methyl 2-bromo-2-phenylacetate (11.40 g, 50.0 mmol) and 6-bromoindazole (10.80 g, 55.0 mmol) were added to 250 mL of acetonitrile, followed by cesium carbonate (19.50 g, 60.0 mmol). The reaction mixture was reacted at room temperature for 2 h. The reaction solution was poured into 300 mL of water, extracted three times with ethyl acetate, and the combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain the target compound.

[0140] (2) Synthesis of 2-(5-(4-(4-(tert-butyloxycarbonyl)piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-phenylacetic acid

[0141] 2-(6-bromo-2H-indazole-2-yl)-2-phenylacetic acid methyl ester (6.88 g, 20.0 mmol) was dissolved in 130 mL of 1,4-dioxane, followed by the addition of 4-(4-Boc-1-piperazinyl)phenylboronic acid pinacol ester (10.00 g, 26.0 mmol) and 40 mL of sodium carbonate aqueous solution (2 mol / L). The mixture was degassed by sonication for 1 min, preheated at 100 °C for 20 min, and then PdCl₂(dppf)₂ (0.78 g, 1.1 mmol) and X-phos (0.86 g, 1.8 mmol) were added sequentially. The reaction was continued for 12 h. The reaction solution was cooled to room temperature, filtered, and the solid was dissolved in water. The pH was adjusted to 4 with dilute hydrochloric acid, filtered again, and a brown solid was obtained. The solid was purified by column chromatography to yield 6.85 g of the target compound.

[0142] (3) Synthesis of N-(4-nitrophenyl)quinazoline-4-amine

[0143] At room temperature, 8.20 g (0.05 mol) of 4-chloroquinazoline and 9.66 g (0.07 mol) of p-nitroaniline were added to 120 mL of isopropanol, and 4 drops of concentrated hydrochloric acid were added dropwise. The mixture was refluxed for 4 h. The reaction solution was cooled to room temperature and filtered to obtain 11.23 g of yellow solid.

[0144] ⑷N 1 -(quinazolin-4-yl)phenyl-1,4-diamine

[0145] N-(4-nitrophenyl)quinazolin-4-amine (10.00 g, 37.5 mmol) was dissolved in 120 mL of 90% ethanol, and iron powder (8.40 g, 0.15 mol) and 1 drop of concentrated hydrochloric acid were added. The mixture was refluxed for 3 h. The mixture was filtered while hot, and the filtrate was concentrated under reduced pressure and purified by column chromatography to obtain 5.87 g of a light brown solid.

[0146] (5) Synthesis of 2-phenyl-2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)acetamide

[0147] N 1-(quinazolin-4-yl)phenyl-1,4-diamine (0.24 g, 1.0 mmol) and 2-(5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2H-indazol-2-yl)-2-phenylacetic acid (0.56 g, 1.1 mmol) were dissolved in 4 mL of DMF, and HATU (1.3 mmol) and DIEA (2.0 mmol) were added sequentially. The reaction mixture was reacted at room temperature for 3 h. The reaction mixture was poured into 15 mL of ice water, filtered, and the solid was added to 5 mL of dichloromethane, followed by 2 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain a brown viscous substance, which was dissolved in an appropriate amount of dichloromethane. The pH was then adjusted to 8–9 with a saturated sodium bicarbonate aqueous solution, filtered, and the crude product was purified by column chromatography to obtain 0.14 g of the target compound. 1 H NMR(600MHz,DMSO-d6)δ10.66(s,1H),9.81(s,1H),8.56(s,1H),8.54(m,1 H),8.17(s,1H),7.94(m,1H),7.86(m,1H),7.80(m,2H),7.77(m,1H),7.66( m,2H),7.63(m,1H),7.57(m,1H),7.53(m,2H),7.41-7.45(m,5H),7.37-7.4 0(m,1H),7.00(m,2H),6.82(s,1H),3.12(m,4H),2.89(m,4H),1.23(s,1H).

[0148] Example 28 2-Phenylacetamide-2-(6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)acetamide

[0149] 1 H NMR(600MHz,DMSO-d6)δ10.62(s,1H),9.81(s,1H),8.56(s,1H),8.54(m,1H),8.14(s,1H),7.85(m,1H),7.77-7.82(m,4H),7.6 5(m,2H),7.62(m,2H),7.48(m,4H),7.42(m,3H),7.38(m,1H),7.01(m,2H),6.89(s,1H),3.11(m,4H),2.85(m,4H),1.23(s,1H).

[0150] Example 29 N-(2-fluoro-4-(quinazolin-4-ylamino)phenyl)-2-phenyl-2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)acetamide

[0151] 1 H NMR(600MHz,DMSO-d6)δ10.38(s,1H),9.93(s,1H),8.66(s,1H),8.55(m,1H),8.19(s, 1H),8.09(m,1H),7.94(m,1H),7.85(m,1H),7.87-7.90(m,2H),7.80(m,1H),7.64-7.6 7(m,2H),7.59(m,1H),7.53(m,2H),7.47(m,3H),7.42(m,2H),7.38(m,1H),7.00(m,2H ),6.98(s,1H),3.08(m,4H),2.84(m,4H),1.23(s,1H); HRMS(ESI)m / z:649.3602[M+H] + .

[0152] Example 30 2-Phenylacetamide-2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-((4-(quinazolin-4-ylamino)benzyl)carbamoyl)acetamide

[0153] 1 H NMR(600MHz,DMSO-d6)δ9.83(s,1H),8.85(m,1H),8.57(m,2H),8.15(s,1H),7.91(s,1H),7.86(m,1H),7.79(m,3H),7.63(m,1H),7.56(m,1H), 7.52(m,3H),7.42(m,2H),7.33-7.38(m,3H),7.29(d,2H),6.95(m,2H), 6.70(s,1H),4.34-4.42(m,2H),3.07(m,4H),2.84(m,4H),1.23(s,1H).

[0154] Example 31 2-Phenyl-2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-(4-(quinazolin-4-yloxy)phenyl)acetamide

[0155] HRMS(ESI) m / z: 632.2812 [M+H] + .

[0156] Example 32 Synthesis of 2-phenyl-2-(5-(phenylamino)-2H-indazol-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)acetamide (target compound)

[0157] (1) Synthesis of methyl 2-phenyl-2-(5-(phenylamino)-2H-indazol-2-yl)acetate

[0158] 2-Phenylacetic-2-(5-(phenylamino)-2H-indazol-2-yl)methyl acetate (1.72 g, 5.0 mmol), aniline (0.93 g, 10.0 mmol), and potassium carbonate (2.07 g, 15.0 mmol) were added to 40 mL of 2-butanol, degassed, and heated to 100 °C. Pd₂(dba)₃ (0.46 g, 0.5 mmol) and Xphos (3.58 g, 7.5 mmol) were added, and the reaction was continued for 6 h. After cooling to room temperature, 50 mL of water was added to the reaction mixture, and the mixture was extracted twice with dichloromethane. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a light brown liquid.

[0159] (2) Synthesis of 2-phenyl-2-(5-(phenylamino)-2H-indazol-2-yl)acetic acid

[0160] 2-Phenylacetic acid methyl ester (0.71 g, 2.0 mmol) was added to 15 mL of methanol and 10 mL of water, followed by sodium hydroxide (0.24 g). The mixture was reacted at 50 °C for 2 h. The methanol was removed by concentration under reduced pressure, and then 10 mL of water was added. The pH was adjusted to 4 with dilute hydrochloric acid, and the mixture was filtered to obtain the target compound.

[0161] (3) Synthesis of 2-phenyl-2-(5-(phenylamino)-2H-indazol-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)acetamide

[0162] N 1 1,4-(quinazolin-4-yl)phenyl-1,4-diamine (0.10 g, 0.4 mmol) and 2-phenyl-2-(5-(phenylamino)-2H-indazol-2-yl)acetic acid (0.17 g, 0.5 mmol) were dissolved in 3 mL of DMF, and HATU (0.52 mmol) and DIEA (0.8 mmol) were added sequentially. The reaction mixture was allowed to react at room temperature for 2 h. The reaction solution was poured into 10 mL of ice water and filtered to give 86.3 mg of the target compound. HRMS (ESI) m / z: 562.2402 [M+H] + .

[0163] Bioevaluation methods

[0164] Add 3000 log-growth phase NCI-H1975-EGFR to each well. L858R / T790M / C797S After cell culture for 24 hours and cell adhesion, 50 μL of culture medium was aspirated from each well, and 40 μL of culture medium was added, followed by 10 μL of the prepared compound solution. The cells were then incubated at 37°C and 5% CO2 for 72 hours. 50 μL of the compound solution was added to each well. Mix well, incubate at room temperature for 10 min, measure absorbance values, fit the inhibition curve, and calculate IC50.50 The values ​​are shown in the table below.

[0165]

[0166] The above experimental results clearly show that the compound of general formula I to be protected by this invention has good in vitro antitumor activity, which is equivalent to or superior to the marketed anti-lung cancer drug Osimertinib.

[0167] In this invention, compounds of general formula I can be administered alone, but are usually given in mixture with a pharmaceutical carrier. The choice of the pharmaceutical carrier depends on the desired route of administration and standard pharmaceutical practice. The following describes the new applications of this type of compound in the pharmaceutical field using various pharmaceutical dosage forms, such as tablets, capsules, injections, aerosols, suppositories, films, drops, liniments, and ointments.

[0168] Example 33: Tablets

[0169] 10.0g of a compound containing the compound of claim 1 (taking the compound of Example 12 as an example) was mixed with 20.0g of excipients according to the general pharmaceutical tableting method and then compressed into 100 tablets, each weighing 300mg.

[0170] Example 34: Capsules

[0171] Using 10.0g of the compound of claim 1 (taking the compound of Example 27 as an example), and 20.0g of excipients mixed in accordance with the requirements for pharmaceutical capsules, the mixture is filled into empty capsules, each weighing 300mg.

[0172] Example 35: Injection

[0173] Using 10.0 g of the compound of claim 1 (taking the compound of Example 1 as an example), the compound was adsorbed onto activated carbon according to conventional pharmaceutical methods, filtered through a 0.65 μm microporous membrane, and then filled into a nitrogen tank to prepare an aqueous injection preparation. Each injection contained 2 mL, and a total of 100 bottles were filled.

[0174] Example 36: Aerosol

[0175] The compound containing 10.0 g of the compound of claim 1 (taking the compound of Example 22 as an example) is dissolved in an appropriate amount of propylene glycol, and then distilled water and other excipients are added to prepare a 500 mL clear solution.

[0176] Example 37: Suppositories

[0177] 10.0 g of a compound containing the compound of claim 1 (taking the compound of Example 19 as an example) was finely ground, and an appropriate amount of glycerin was added. After grinding evenly, melted glycerin gelatin was added, and the mixture was ground evenly. The mixture was then poured into a mold coated with lubricant to prepare 50 suppositories.

[0178] Example 38: Film Formulation

[0179] Using 10.0 g of the compound of claim 1 (taking the compound of Example 30 as an example), polyvinyl alcohol, pharmaceutical glycerin, water, etc. are stirred and expanded, then heated and dissolved. The mixture is filtered through an 80-mesh sieve, and the compound of Example 30 is added to the filtrate and stirred and dissolved. 100 films are then made by coating the film.

[0180] Example 39: Droplets

[0181] 10.0g of a compound containing the compound of claim 1 (taking the compound of Example 17 as an example) was heated and melted with 50.0g of a matrix such as gelatin and mixed evenly. The mixture was then dropped into low-temperature liquid paraffin to prepare 1000 pills.

[0182] Example 40: Topical lotion

[0183] The compound containing 10.0 g of the compound of claim 1 (taking the compound of Example 29 as an example) was mixed and ground with 2.5 g of excipients such as emulsifiers according to conventional pharmaceutical methods, and then distilled water was added to 200 mL to obtain the product.

[0184] Example 41: Ointment

[0185] The compound containing 10.0g of the compound of claim 1 (taking the compound of Example 15 as an example) was finely ground and then mixed with 500g of an oily matrix such as petrolatum.

[0186] Although the invention has been described with reference to specific embodiments, modifications and equivalent variations will be apparent to those skilled in the art, and are all included within the scope of the invention.

Claims

1. A heterocyclic EGFR mutation inhibitor, characterized in that: The heterocyclic EGFR mutation inhibitors include any one of the following compounds or pharmaceutically acceptable salts of said compounds: 2-(5-((4-((4-methylpiperazin-1-yl)methyl)phenyl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)acetamide; 2-(5-((6-aminopyridin-3-yl)ethynyl)-1-oxoisoindoline-2-yl)-2-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)acetamide; N-(4-((6-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(pyrimidin-4-ylamino)phenyl)acetamide; N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(4-((2-aminopyrimidin-4-yl)amino)-3-chlorophenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(4-((2-aminopyrimidin-4-yl)amino)-2-fluorophenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(3-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(diethylamino)phenyl)-1-oxoisoindololin-2-yl)-2-phenylacetamide; N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-morpholinylphenyl)-1-oxoisoindololin-2-yl)-2-phenylacetamide; (S)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindoline-2-yl)-2-phenylacetamide; (R)-N-(4-((2-aminopyrimidin-4-yl)amino)phenyl)-2-(5-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxoisoindoline-2-yl)-2-phenylacetamide; N-(4-((2-methylpiperazin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)acetamide; N-(4-((5-chloro-2-methylpyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(4-((2-methylpyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(pyridin-4-ylamino)phenyl)acetamide; N-(4-((6-acetaminopyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; 2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenyl-N-(4-(thiophene[3,2-d]pyrimidin-4-ylamino)phenyl)acetamide; N-(4-((6,7-dimethoxyquinazolin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(4-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; N-(4-((9-methyl-9H-purin-6-yl)amino)phenyl)-2-(1-oxo-5-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-2-phenylacetamide; 2-(1-oxo-6-(4-(piperazin-1-yl)phenyl)isoindoline-2-yl)-3-phenyl-N-(4-(quinazolin-4-ylamino)phenyl)propionamide; 2-Phenylacetamide, 2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)acetamide; 2-Phenylacetamide, 2-(6-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-(4-(quinazolin-4-ylamino)phenyl)acetamide; N-(2-fluoro-4-(quinazolin-4-ylamino)phenyl)-2-phenyl-2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)acetamide; 2-Phenylacetyl-2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-((4-(quinazolin-4-ylamino)benzyl)carbamoyl)acetamide; 2-Phenylacetamide, 2-(5-(4-(piperazin-1-yl)phenyl)-2H-indazol-2-yl)-N-(4-(quinazolin-4-yloxy)phenyl)acetamide; The EGFR mutations include one or more of the L858R mutation, T790M mutation, and C797S mutation.

2. A pharmaceutical composition, characterized in that, A compound comprising any one of the heterocyclic EGFR mutation inhibitors of claim 1, or a pharmaceutically acceptable salt thereof, as an active ingredient and a pharmaceutically acceptable excipient.

3. The use of any compound of the heterocyclic EGFR mutation inhibitors according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of medicaments for the treatment and / or prevention of proliferative diseases.

4. The use of any compound of the heterocyclic EGFR mutation inhibitors according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the preparation of medicaments for treating and / or preventing EGFR-mediated diseases or inhibiting EGFR.

5. The application as described in claim 4, characterized in that: The EGFR-mediated disease is cancer.

6. The application as described in claim 5, characterized in that: The cancers mentioned are: non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, glioma, ovarian cancer, head and neck squamous cell carcinoma, cervical cancer, esophageal cancer, liver cancer, kidney cancer, pancreatic cancer, colon cancer, skin cancer, lymphoma, stomach cancer, and multiple myeloma.

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