A deuterated arylphosphooxide compound as an EGFR kinase inhibitor and its application

Abstract

This invention discloses a deuterated arylphosphooxide compound as an EGFR kinase inhibitor and its applications. The compound has the structures shown in formulas (I) and (II). The deuterated compound prepared by this invention can better target tumor sites, more effectively inhibit tumor cell proliferation and metastasis, and promote tumor cell apoptosis, showing promising application prospects in lung cancer drugs.

Description

Technical Field

[0001] This application relates to a compound and its pharmaceutical applications, specifically to a deuterated arylphosphooxide compound as an EGFR kinase inhibitor and its applications. Background Technology

[0002] Lung cancer is one of the most common malignant tumors, with approximately 1.6 million new cases of lung cancer diagnosed worldwide each year, and 1.4 million deaths caused by lung cancer annually.

[0003] EGFR (epidermal growth factor receptor)-TKI (tyrosine kinase inhibitor), as a small molecule inhibitor, regulates cell proliferation, survival, adhesion, migration, and differentiation. Approximately 62% of non-small cell lung cancer patients exhibit EGFR overexpression, and EGFR inhibition can significantly improve survival in some patients. This is achieved by utilizing endogenous ligands to competitively bind to EGFR, thereby inhibiting enzyme activation.

[0004] Osimertinib (AZD9291) is a third-generation EGFR-TKI targeted drug. Although it has a high response rate against resistance caused by the T790M mutation, patients can still develop resistance (Clin CancerRes; 21(17), 2015). In 2015, Nature Medicine, 21, 560-562, 2015, first reported an analysis of resistance in 15 patients with AZD9291. Among them, the acquisition of a third mutation, namely the EGFR C797S mutation, is one of the main mechanisms leading to resistance to the drug Osimertinib, accounting for about 40%. Meanwhile, various conferences also reported on AZD9291 resistance. For example, at the 2015 WCLC, Oxnard GR reported an analysis of resistance in 67 patients, with C797S accounting for approximately 22%; at the 2017 ASCO, Piotrowska also reported 23 cases, with C797S again accounting for approximately 22%; and at the 2017 ASCO, Zhou Caicun et al. reported an analysis of the resistance mechanism in 99 patients, with C797S accounting for approximately 22%. Therefore, overcoming AZD9291 resistance by targeting the C797S mutation and providing patients with safer and more effective fourth-generation EGFR C797S / T790M inhibitors is of significant research importance.

[0005] A 2016 article in *Nature*, 534, 129-132, 2016, reported a compound, EAI045, that could overcome the resistance of osimertinib to C797S. EAI045 is an allosteric inhibitor that, when combined with EGFR monoclonal antibodies such as cetuximab, showed good tumor-suppressive effects in a mouse model targeting the L858R / T790M / C797S mutation; however, this compound failed to enter clinical trials. A 2017 article in *Nature Communications* (8:14768, 2017) reported that the combination of brigatinib (AP26113) and EGFR monoclonal antibodies (such as cetuximab) could overcome resistance to the third-generation targeted drug osimertinib caused by the C797S mutation. In the PC9 (EGFR-C797S / T790M / del19) mouse model, the combination of brigatinib with panitumumab or cetuximab showed good antitumor efficacy. Currently, there is a lack of effective EGFR inhibitors for monotherapy against the novel mutation (C797S). Therefore, there is an urgent need for new types of highly selective EGFR inhibitors to address the drug resistance caused by the (EGFR) C797S point mutation. Summary of the Invention

[0006] Objective of the Invention: The objective of this invention is to provide a deuterated arylphosphooxide compound as an EGFR kinase inhibitor. Another objective of this invention is to provide the application of said compound in the treatment of lung cancer.

[0007] Technical solution: Compounds shown in formula (I) or (II):

[0008]

[0009] R1 and R2 are selected from either CH3- or CD3-, and at least one of R1 and R2 is CD3-;

[0010] R3 is selected from halogens;

[0011] R4 is selected from fused aromatic heterocyclic groups having 6-14 ring atoms;

[0012] R5, R6 and R7 are selected from either CH3- or CD3-, and at least one of R5, R6 and R7 is CD3-.

[0013] In the compound, R4 is selected from the following:

[0014]

[0015] In the compound, R3 is selected from halogens Br or Cl.

[0016] The compound is selected from:

[0017]

[0018]

[0019]

[0020]

[0021]

[0022] A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0023] The use of the compound or the pharmaceutical composition described herein in the preparation of EGFR kinase inhibitors.

[0024] The use of the compound or the pharmaceutical composition in the preparation of a cancer treatment drug.

[0025] The application described herein refers to lung cancer.

[0026] The use of the compound or the pharmaceutical composition described herein in combination with EGFR monoclonal antibody in the preparation of cancer treatment drugs.

[0027] The use of the compound or the pharmaceutical composition described herein in combination with EGFR monoclonal antibody in the preparation of drugs for treating lung cancer.

[0028] Beneficial effects: Compared with the prior art, the present invention has the following advantages: The deuterated compounds prepared by the present invention can better target tumor sites, more effectively inhibit the proliferation and metastasis of tumor cells and promote tumor cell apoptosis, and have good application prospects in lung cancer drugs. Detailed Implementation

[0029] To better understand the content of this application, further explanation will be provided below with reference to specific embodiments, but the specific implementation methods are not intended to limit the content of this application.

[0030] Example 1

[0031] The synthetic routes for compounds 9a, 9b, and 9c are as follows:

[0032]

[0033]

[0034] Compound 1a (100 mg), compound 2a (120 mg), and 23 mg K₂CO₃ were dissolved in 30 mL of acetonitrile. The reaction mixture was sealed in a tube and reacted at 80 °C for 24 h. The reaction solution was then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The solid was filtered, and the filter cake was washed with ethanol and ethyl acetate and dried in a vacuum drying oven at 50 °C to constant weight to obtain compound 3a.

[0035] Compound 1 (96 mg) was dissolved in 75 ml of DCM solution and reacted at room temperature for 8 h to obtain compound 2. 30 mg of compound 2 was taken, and TsOD3 and K2CO3 were added. Acetonitrile was used as the solvent, and the mixture was reacted at 80 °C for 9 h to obtain compound 3.

[0036] Compound 4 (10 mg) was dissolved in THF, cooled to 0°C, and NaH (12 mg) was added. The mixture was stirred at room temperature for 1 h, and TsOCD3 was added dropwise. The mixture was stirred at room temperature for another 12 h to obtain compound 5. Compound 5 (15 mg) was dissolved in TFA and DCM and reacted at room temperature for 12 h to obtain compound 6. Compound 6 (20 mg) was dissolved in 10 ml of THF and a small amount of formic acid and reacted at 110°C for 5 h to obtain compound 7.

[0037] Compound 3 (29 mg) and compound 7 (40 mg) were dissolved in DCM and reacted at 85 °C for 9 h. By changing the feed ratio of compound 3 and compound 7, compounds 8a, 8b, and 8c were obtained, respectively. Compounds 8a, 8b, and 8c (20 mg) were reacted with brominated or chlorinated compound 3a, methanesulfonic acid (90 mg), and butanol as solvents for 8 h. The reaction solution was then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated. The solid was filtered, and the filter cake was washed with ethanol and ethyl acetate and dried in a vacuum drying oven at 50 °C to constant weight to obtain compounds 9a-1, 9a-2, 9b-1, 9b-2, and 9c-1, 9c-2 (-1 is brominated, -2 is chlorinated).

[0038] 9a-1

[0039] 1H NMR(500MHz,Chloroform-d)δ9.16(s,1H),8.81(s,1H),8.56(s,1H),8.31(s,1H),8.07(dd,J=7.6,1.6Hz,1H),7.81(dd,J=7.6,1.5Hz,1H),7.70(td,J=7.4,1.5Hz,1H),7.52(td,J=7.4,1.6Hz,1H),7.06(s,1H),6.24(s,1H),3.55-3.42(m,4H),2.66(dd,J=7.4,6.8Hz,4H),2.48(s,1H),2.49-2.39(m,4H),2.30(s,2H),2.23(s,3H),2.08(d,J=13.0Hz,5H),1.83(qd,J=7.1,2.0Hz,4H).

[0040] 9a-2 1 H NMR(500MHz,Chloroform-d)δ9.32(s,1H),8.78(s,1H),8.56(s,1H),8.52(s,1H),8.03(dd,J=7.6,1.5Hz,1H),7.81(dd,J=7.6,1.5Hz,1H),7.70(td,J=7.5,1.6Hz,1H),7.52(td,J=7.4,1.6Hz,1H),7.06(s,1H),6.24(s,1H),3.55-3.42(m,4H),2.66(dd,J=7.4,6.8Hz,4H),2.48(s,1H),2.49-2.39(m,4H),2.30(s,2H),2.23(s,3H),2.08(d,J=13.0Hz,5H),1.83(qd,J=7.1,2.0Hz,4H).

[0041] 9b-1

[0042] 1H NMR(500MHz,Chloroform-d)δ9.16(s,1H),8.56(s,1H),8.31(s,1H),8.22(s,1H),8.07(dd,J=7.6,1.6Hz,1H),7.81(dd,J=7.6,1.5Hz,1H),7.70(td,J=7.4,1.5Hz,1H),7.52(td,J=7.4,1.6Hz,1H),7.06(s,1H),6.38(s,1H),3.84(s,3H),3.54-3.41(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.24(s,3H),2.08(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0043] 9b-2

[0044] 1 H NMR(500MHz,Chloroform-d)δ9.32(s,1H),8.56(s,1H),8.52(s,1H),8.18(s,1H),8.03(dd,J=7.6,1.5Hz,1H),7.81(dd,J=7.6,1.5Hz,1H),7.70(td,J=7.5,1.6Hz,1H),7.52(td,J=7.4,1.6Hz,1H),7.06(s,1H),6.38(s,1H),3.84(s,3H),3.54-3.41(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.24(s,3H),2.08(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0045] 9c-1

[0046] 1H NMR (500MHz, Chloroform-d) δ9.16 (s, 1H), 8.81 (s, 1H), 8.56 (s, 1H), 8.31 (s, 1H), 8.07 (dd, J=7.6, 1.5Hz, 1H), 7.81 (dd, J=7.5, 1.6Hz, 1H), 7.70 (td, J=7.4, 1.5Hz, 1H), 7.52 (td, J=7.4 , 1.6Hz, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55-3.42 (m, 4H), 2.84-2.77 (m, 4H), 2.76-2.70 (m, 4H), 2.48 (p, J=7.0Hz, 1H), 2.22 (s, 2H), 2.08 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.0, 1.2Hz, 4H).

[0047] 9c-2

[0048] 1 H NMR (500MHz, Chloroform-d) δ9.32 (s, 1H), 8.78 (s, 1H), 8.56 (s, 1H), 8.52 (s, 1H), 8.07 (dd, J=7.6, 1.5Hz, 1H), 7.81 (dd, J=7.6, 1.5Hz, 1H), 7.70 (td, J=7.4, 1.5Hz, 1H), 7.52 (td, J=7.4 , 1.6Hz, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55-3.42 (m, 4H), 2.84-2.77 (m, 4H), 2.76-2.70 (m, 4H), 2.48 (p, J=7.0Hz, 1H), 2.22 (s, 2H), 2.08 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.0, 1.2Hz, 4H).

[0049] Example 2

[0050] The synthetic routes for compounds 10a, 10b, and 10c are as follows:

[0051]

[0052] The synthetic routes for compounds 8a, 8b, and 8c are the same as in Example 1. Compound 1b (100 mg), compound 2a (120 mg), and 23 mg of K₂CO₃ are dissolved in 30 ml of acetonitrile. The reaction mixture is sealed in a tube and reacted at 80 °C for 24 h. The reaction solution is then cooled to room temperature. The reaction solution is poured into water, resulting in the precipitation of a large amount of solid. This solid is filtered, and the filter cake is washed with ethanol and ethyl acetate and dried in a vacuum oven at 50 °C to constant weight to obtain compound 3b. Compounds 8a, 8b, and 8c (20 mg each) are reacted with brominated or chlorinated compound 3b, methanesulfonic acid (90 mg), and butanol as solvents for 8 h. The reaction solution is then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with ethanol and ethyl acetate. It was then dried in a vacuum drying oven at 50°C to constant weight to obtain compounds 10a-1, 10a-2, 10b-1, 10b-2 and 10c-1, 10c-2 (-1 is brominated and -2 is chlorinated).

[0053] 10a-1

[0054] 1 H NMR (500MHz, Chloroform-d) δ9.52 (s, 1H), 9.04 (d, J=7.5Hz, 1H), 8.808.73 (m, 2H), 8.39 (s, 1H), 8.31 (s, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55-3.42 (m, 4H), 2.66 (dd, J=7.4, 6.8Hz, 4H), 2.48 (s, 1H), 2.492.39 (m, 4H), 2.30 (s, 2H), 2.23 (s, 3H), 2.14 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.1, 2.0Hz, 4H).

[0055] 10a-2

[0056] 1 H NMR (500MHz, Chloroform-d) δ9.68 (s, 1H), 9.04 (d, J=7.5Hz, 1H), 8.788.73 (m, 2H), 8.52 (s, 1H), 8.39 (s, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55-3.42 (m, 4H), 2.66 (dd, J=7.4, 6.8Hz, 4H), 2.48 (s, 1H), 2.49-2.39 (m, 4H), 2.30 (s, 2H), 2.23 (s, 3H), 2.14 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.1, 2.0Hz, 4H).

[0057] 10b-1

[0058] 1 H NMR(500MHz,Chloroform-d)δ9.52(s,1H),9.04(d,J=7.5Hz,1H),8.75(d,J=7.5Hz,1H),8.39(s,1H),8.31(s,1H),8.19(s,1H),7.06(s,1H),6.38(s,1H),3.84(s,3H),3.54-3.41(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.24(s,3H),2.14(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0059] 10b-2

[0060] 1 H NMR(500MHz,Chloroform-d)δ9.68(s,1H),9.04(d,J=7.5Hz,1H),8.75(d,J=7.5Hz,1H),8.49(s,1H),8.39(s,1H),8.15(s,1H),7.06(s,1H),6.38(s,1H),3.84(s,3H),3.54-3.41(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.24(s,3H),2.14(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0061] 10c-1

[0062] 1 H NMR(500MHz,Chloroform-d)δ9.52(s,1H),9.04(d,J=7.5Hz,1H),8.808.73(m,2H),8.39(s,1H),8.31(s,1H),7.06(s,1H),6.24(s,1H),3.55-3.42(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.22(s,3H),2.14(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0063] 10c-2

[0064] 1H NMR (500MHz, Chloroform-d) δ9.68 (s, 1H), 9.04 (d, J=7.5Hz, 1H), 8.788.73 (m, 2H), 8.52 (s, 1H), 8.39 (s, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55 -3.42 (m, 4H), 2.84-2.77 (m, 4H), 2.76-2.70 (m, 4H), 2.48 (p, J=7.0Hz, 1H), 2.22 (s, 2H), 2.14 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.0, 1.2Hz, 4H).

[0065] Example 3

[0066] The synthetic routes for compounds 11a, 11b, and 11c are as follows:

[0067]

[0068] The synthetic routes for compounds 8a, 8b, and 8c are the same as in Example 1. Compound 1c (100 mg), compound 2a (120 mg), and 23 mg of K₂CO₃ are dissolved in 30 ml of acetonitrile. The reaction mixture is sealed in a tube and reacted at 80 °C for 24 h. The reaction solution is then cooled to room temperature. The reaction solution is poured into water, resulting in the precipitation of a large amount of solid. This solid is filtered, and the filter cake is washed with ethanol and ethyl acetate and dried in a vacuum oven at 50 °C to constant weight to obtain compound 3c. Compounds 8a, 8b, and 8c (20 mg each) are reacted with the brominated or chlorinated compound 3c, methanesulfonic acid (90 mg), and butanol as solvents for 8 h. The reaction solution is then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with ethanol and ethyl acetate. The mixture was then dried in a vacuum drying oven at 50°C to constant weight to obtain compounds 11a-1, 11a-2, 11b-1, 11b-2 and 11c-1, 11c-2 (-1 is brominated and -2 is chlorinated).

[0069] 11a-1

[0070] 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),8.79(s,1H),8.59(d,J=1.3Hz,1H),8.30(s,1H),7.77-7.70(m,2H),7.55(td,J=7.5,1.5Hz,1H),7.45(td,J=7.4,1.5Hz,1H),7.06(s,1H),6.24(s,1H),3.55-3.42(m,4H),2.66(dd,J=7.4,6.8Hz,4H),2.48(s,1H),2.49-2.39(m,4H),2.30(s,2H),2.23(s,3H),2.14(d,J=13.0Hz,5H),1.83(qd,J=7.1,2.0Hz,4H).

[0071] 11a-2

[0072] 1 H NMR(500MHz,Chloroform-d)δ9.88(s,1H),8.75(s,1H),8.59(d,J=1.3Hz,1H),8.49(s,1H),7.77-7.70(m,2H),7.55(td,J=7.5,1.5Hz,1H),7.45(td,J=7.3,1.5Hz,1H),7.06(s,1H),6.24(s,1H),3.55-3.42(m,4H),2.66(dd,J=7.4,6.8Hz,4H),2.48(s,1H),2.49-2.39(m,4H),2.30(s,2H),2.23(s,3H),2.14(d,J=13.0Hz,5H),1.83(qd,J=7.1,2.0Hz,4H).

[0073] 11b-1

[0074] 1H NMR(500MHz,Chloroform-d)δ9.74(s,1H),8.59(d,J=1.3Hz,1H),8.34(s,1H),8.30(s,1H),7.77-7.70(m,2H),7.55(td,J=7.5,1.5Hz,1H),7.45(td,J=7.4,1.5Hz,1H),7.06(s,1H),6.38(s,1H),3.84(s,2H),3.54-3.41(m,4H),2.84-2.77(m,4H),2.76-2.70(m,4H),2.48(p,J=7.0Hz,1H),2.24(s,2H),2.14(d,J=13.0Hz,5H),1.83(qd,J=7.0,1.2Hz,4H).

[0075] 11b-2

[0076] 1 H NMR(500MHz,Chloroform-d)δ9.88(s,1H),8.59(d,J=1.3Hz,1H),8.49(s,1H),8.29(s,1H),7.77-7.70(m,2H),7.55(td,J=7.5,1.5Hz,1H),7.45(td,J=7.4,1.5Hz,1H),7.06(s,1H),6.38(s,1H),3.84(s,3H),3.54-3.41(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.24(s,3H),2.14(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0077] 11c-1

[0078] 1H NMR (500MHz, Chloroform-d) δ9.74 (s, 1H), 8.79 (s, 1H), 8.59 (d, J=1.3Hz, 1H), 8.3 0(s, 1H), 7.77-7.70(m, 2H), 7.55(td, J=7.5, 1.5Hz, 1H), 7.48-7.42(m, 1H), 7.06( s, 1H), 6.24 (s, 1H), 3.55-3.42 (m, 4H), 2.84-2.77 (m, 4H), 2.76-2.70 (m, 4H), 2.48 (p, J=7.0Hz, 1H), 2.22 (s, 2H), 2.14 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.0, 1.2Hz, 4H).

[0079] 11c-2

[0080] 1 H NMR (500MHz, Chloroform-d) δ9.88 (s, 1H), 8.75 (s, 1H), 8.59 (d, J=1.3Hz, 1H), 8.49 ( s, 1H), 7.77-7.70 (m, 2H), 7.55 (td, J=7.5, 1.5Hz, 1H), 7145 (td, J=7.4, 1.5Hz, 1H), 7 .06(s, 1H), 6.24(s, 1H), 3.55-3.42(m, 4H), 2.84-2.77(m, 4H), 2.76-2.70(m, 4H), 2. 48 (p, J=7.0Hz, 1H), 2.22 (s, 2H), 2.14 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.0, 1.2Hz, 4H).

[0081] Example 4

[0082] The synthetic routes for compounds 12a, 12b, and 12c are as follows:

[0083]

[0084] The synthetic routes for compounds 8a, 8b, and 8c are the same as in Example 1. Compound 1d (100 mg), compound 2a (120 mg), and 23 mg of K₂CO₃ are dissolved in 30 ml of acetonitrile. The reaction mixture is sealed in a tube and reacted at 80 °C for 24 h. The reaction solution is then cooled to room temperature. The reaction solution is poured into water, resulting in the precipitation of a large amount of solid. This solid is filtered, and the filter cake is washed with ethanol and ethyl acetate and dried in a vacuum oven at 50 °C to constant weight to obtain compound 3d. Compounds 8a, 8b, and 8c (20 mg each) are reacted with brominated or chlorinated compound 3d, methanesulfonic acid (90 mg), and butanol as solvents for 8 h. The reaction solution is then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with ethanol and ethyl acetate. It was then dried in a vacuum drying oven at 50°C to constant weight to obtain compounds 12a-1, 12a-2, 12b-1, 12b-2 and 12c-1, 12c-2 (-1 is brominated and -2 is chlorinated).

[0085] 12a-1

[0086] 1 H NMR (500MHz, Chloroform-d) δ9.05 (d, J=7.5Hz, 1H), 8.90 (s, 1H), 8.83-8.77 (m, 2H), 8.30 (s, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55-3.42 (m, 4H) ), 2.66 (dd, J=7.4, 6.8Hz, 4H), 2.48 (s, 1H), 2.49-2.39 (m, 4H), 2.30 (s, 2H), 2.23 (s, 3H), 2.16 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.1, 2.0Hz, 4H).

[0087] 12a-2

[0088] 1 H NMR (500MHz, Chloroform-d) δ9.05 (d, J=7.5Hz, 1H), 8.90 (s, 1H), 8.80 (d, J=7.5Hz, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55-3. 42 (m, 4H), 2.66 (dd, J=7.4, 6.8Hz, 4H), 2.48 (s, 1H), 2.49-2.39 (m, 4H), 2.3 0 (s, 2H), 2.23 (s, 3H), 2.16 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.1, 2.0Hz, 4H).

[0089] 12b-1

[0090] 1 H NMR(500MHz,Chloroform-d)δ9.05(d,J=7.5Hz,1H),8.90(s,1H),8.80(d,J=7.5Hz,1H),8.31(s,1H),8.22(s,1H),7.06(s,1H),6.38(s,1H),3.84(s,3H),3.54-3.41(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.24(s,3H),2.16(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0091] 12b-2

[0092] 1 H NMR(500MHz,Chloroform-d)δ9.05(d,J=7.5Hz,1H),8.90(s,1H),8.80(d,J=7.5Hz,1H),8.49(s,1H),8.18(s,1H),7.06(s,1H),6.38(s,1H),3.84(s,3H),3.54-3.41(m,5H),2.84-2.77(m,5H),2.76-2.70(m,5H),2.48(p,J=7.0Hz,1H),2.24(s,3H),2.16(d,J=13.0Hz,6H),1.83(qd,J=7.0,1.2Hz,5H).

[0093] 12c-1

[0094] 1 H NMR(500MHz,Chloroform-d)δ9.05(d,J=7.5Hz,1H),8.90(s,1H),8.83-8.77(m,2H),8.30(s,1H),7.06(s,1H),6.24(s,1H),3.55-3.42(m,4H),2.84-2.77(m,4H),2.76-2.70(m,4H),2.48(p,J=7.0Hz,1H),2.22(s,2H),2.16(d,J=13.0Hz,5H),1.83(qd,J=7.0,1.2Hz,4H).

[0095] 12c-2

[0096] 1H NMR (500MHz, Chloroform-d) δ9.05 (d, J=7.5Hz, 1H), 8.90 (s, 1H), 8.80 (d, J=7.5Hz, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3. 55-3.42(m, 4H), 2.84-2.77(m, 4H), 2.76-2.70(m, 4H), 2.48(p, J=7.0Hz , 1H), 2.22 (s, 2H), 2.16 (d, J=13.0Hz, 5H), 1.83 (qd, J=7.0, 1.2Hz, 4H).

[0097] Example 5

[0098] The synthetic routes for compounds 13a, 13b, and 13c are as follows:

[0099]

[0100] The synthetic routes for compounds 8a, 8b, and 8c are the same as in Example 1. Compound 1e (100 mg), compound 2a (120 mg), and 23 mg of K₂CO₃ are dissolved in 30 ml of acetonitrile. The reaction mixture is sealed in a tube and reacted at 80 °C for 24 h. The reaction solution is then cooled to room temperature. The reaction solution is poured into water, resulting in the precipitation of a large amount of solid. This solid is filtered, and the filter cake is washed with ethanol and ethyl acetate, then dried in a vacuum oven at 50 °C to constant weight to obtain compound 3e. Compounds 8a, 8b, and 8c (20 mg each) are reacted with brominated or chlorinated compound 3b, methanesulfonic acid (90 mg), and butanol as solvents for 8 h. The reaction solution is then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with ethanol and ethyl acetate. It was then dried in a vacuum drying oven at 50°C to constant weight to obtain compounds 13a-1, 13a-2, 13b-1, 13b-2 and 13c-1, 13c-2 (-1 is brominated, -2 is chlorinated).

[0101] 13a-1

[0102] 1H NMR(500MHz,Chloroform-d)δ8.62(s,1H),8.51(s,1H),8.27(s,1H),8.04-7.95(m,2H),7.58(dd,J=7.6,1.5Hz,1H),7.42(td,J=7.5,1.5Hz,1H),7.31(td,J=7.4,1.6Hz,1H),6.60(dd,J=7.5,1.5Hz,1H),6.25(d,J=1.5Hz,1H),3.56-3.40(m,4H),2.66(dd,J=7.4,6.8Hz,4H),2.50-2.44(m,4H),2.40(p,J=6.9Hz,1H),2.30(s,2H),1.82(qd,J=7.1,2.5Hz,5H).

[0103] 13a-2

[0104] 1 H NMR(500MHz,Chloroform-d)δ8.47(d,J=15.0Hz,2H),8.06-7.95(m,3H),7.58(dd,J=7.6,1.5Hz,1H),7.42(td,J=7.5,1.4Hz,1H),7.31(td,J=7.4,1.5Hz,1H),6.60(dd,J=7.5,1.5Hz,1H),6.25(d,J=1.5Hz,1H),3.56-3.49(m,1H),3.49(d,J=7.1Hz,1H),3.46(d,J=7.0Hz,1H),3.46-3.40(m,1H),2.66(dd,J=7.4,6.8Hz,4H),2.47(dd,J=7.4,6.7Hz,4H),2.39(p,J=6.9Hz,1H),2.30(s,2H),1.82(qd,J=7.1,2.5Hz,4H).

[0105] 13b-1

[0106] 1H NMR(500MHz,Chloroform-d)δ8.62(s,1H),8.26(d,J=1.8Hz,2H),7.98(dd,J=7.5,1.7Hz,1H),7.58(dd,J=7.6,1.5Hz,1H),7.42(td,J=7.5,1.5Hz,1H),7.31(td,J=7.4,1.5Hz,1H),7.12(d,J=7.5Hz,1H),6.76(dd,J=7.5,1.5Hz,1H),6.34(d,J=1.4Hz,1H),3.84(s,2H),3.56-3.49(m,1H),3.49(d,J=7.1Hz,1H),3.46(d,J=7.0Hz,1H),3.46-3.40(m,1H),2.84-2.77(m,4H),2.76-2.70(m,4H),2.46(p,J=7.0Hz,1H),1.82(qd,J=7.0,1.0Hz,4H).

[0107] 13b-2

[0108] 1 H NMR(500MHz,Chloroform-d)δ8.48(s,1H),8.22(s,1H),8.02-7.95(m,2H),7.58(dd,J=7.6,1.5Hz,1H),7.42(td,J=7.5,1.4Hz,1H),7.31(td,J=7.4,1.5Hz,1H),7.12(d,J=7.5Hz,1H),6.76(dd,J=7.5,1.5Hz,1H),6.34(d,J=1.4Hz,1H),3.84(s,2H),3.56-3.40(m,4H),2.84-2.77(m,4H),2.76-2.70(m,4H),2.44(p,J=7.1Hz,1H),1.82(qd,J=7.0,1.0Hz,4H).

[0109] 13c-1

[0110] 1H NMR (500MHz, Chloroform-d) δ8.62 (s, 1H), 8.51 (s, 1H), 8.27 (s, 1H), 8.05 (d, J=7.5Hz, 1H), 7.98 (dd, J= 7.5, 1.8Hz, 1H), 7.58 (dd, J=7.5, 1.5Hz, 1H), 7.43 (td, J=7.5, 1.6Hz, 1H), 7.31 (td, J=7.5, 1.6Hz, 1H), 6. 60 (dd, J=7.5, 1.5Hz, 1H), 6.25 (d, J=1.6Hz, 1H), 3.51 (dt, J=12.4, 7.1Hz, 2H), 3.46 (d, J=7.0Hz, 1H), 3.4 6-3.40 (m, 1H), 2.84-2.77 (m, 4H), 2.76-2.70 (m, 4H), 2.46 (p, J=7.0Hz, 1H), 1.82 (qd, J=7.0, 1.0Hz, 4H).

[0111] 13c-2

[0112] 1 H NMR (500MHz, Chloroform-d) δ8.47 (d, J=15.0Hz, 2H), 8.07 (d, J=7.5Hz, 1H), 8.02-7. 95 (m, 2H), 7.58 (dd, J=7.5, 1.5Hz, 1H), 7.43 (td, J=7.5, 1.6Hz, 1H), 7.31 (td, J=7.5, 1 .6Hz, 1H), 6.60 (dd, J=7.5, 1.5Hz, 1H), 6.25 (d, J=1.6Hz, 1H), 3.56-3.40 (m, 4H), 2.8 4-2.77 (m, 4H), 2.76-2.70 (m, 4H), 2.44 (p, J=7.1Hz, 1H), 1.82 (qd, J=7.0, 1.0Hz, 4H).

[0113] Example 6

[0114] The synthetic routes for compounds 14a, 14b, and 14c are as follows:

[0115]

[0116] The synthetic routes for compounds 8a, 8b, and 8c are the same as in Example 1. Compound 4f (100 mg), compound 2a (120 mg), and 23 mg of K₂CO₃ are dissolved in 30 ml of acetonitrile. The reaction mixture is sealed in a tube and reacted at 80 °C for 24 h. The reaction solution is then cooled to room temperature. The reaction solution is poured into water, resulting in the precipitation of a large amount of solid. This solid is filtered, and the filter cake is washed with ethanol and ethyl acetate and dried in a vacuum oven at 50 °C to constant weight to obtain compound 3f. Compounds 8a, 8b, and 8c (20 mg each) are reacted with the brominated or chlorinated compound 3f, methanesulfonic acid (90 mg), and butanol as solvents for 8 h. The reaction solution is then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with ethanol and ethyl acetate. The mixture was then dried in a vacuum drying oven at 50°C to constant weight to obtain compounds 14a-1, 14a-2, 14b-1, 14b-2 and 14c-1, 14c-2 (-1 is brominated, -2 is chlorinated).

[0117] 14a-1

[0118] 1 H NMR (500MHz, Chloroform-d) δ9.61 (s, 1H), 8.75 (s, 1H), 8.31 (s, 1H), 8.17 (dd, J=7.5, 1.5Hz, 1H), 7.99 (d, J =7.5Hz, 1H), 7.48 (td, J=7.5, 1.5Hz, 1H), 7.39 (dd, J=7.5, 1.7Hz, 1H), 7.32 (td, J=7.5, 1.6Hz, 1H), 6.60 (dd, J=7.5, 1.5Hz, 1H), 6.25 (d, J=1.6Hz, 1H), 3.51 (dt, J=12.4, 7.1Hz, 2H), 3.46 (d, J=7.0Hz, 1H), 3.46-3.40 (m , 1H), 2.71-2.62 (m, 6H), 2.50-2.41 (m, 4H), 2.39 (q, J=7.0Hz, 1H), 2.30 (s, 2H), 1.82 (qd, J=7.1, 2.5Hz, 4H).

[0119] 14a-2

[0120] 1H NMR(500MHz,Chloroform-d)δ9.63(s,1H),8.72(s,1H),8.52(s,1H),8.17(dd,J=7.6,1.5Hz,1H),8.01(d,J=7.5Hz,1H),7.47(td,J=7.4,1.5Hz,1H),7.42(dd,J=7.5,1.6Hz,1H),7.31(td,J=7.4,1.7Hz,1H),6.60(dd,J=7.5,1.5Hz,1H),6.25(d,J=1.6Hz,1H),3.56-3.40(m,4H),2.71-2.63(m,6H),2.47(dd,J=7.4,6.7Hz,4H),2.39(p,J=6.9Hz,1H),2.30(s,2H),1.82(qd,J=7.1,2.5Hz,4H).

[0121] 14b-1

[0122] 1 H NMR(500MHz,Chloroform-d)δ9.61(s,1H),8.32(d,J=10.6Hz,2H),8.17(dd,J=7.5,1.5Hz,1H),7.48(td,J=7.5,1.5Hz,1H),7.39(dd,J=7.5,1.7Hz,1H),7.32(td,J=7.5,1.6Hz,1H),7.12(d,J=7.5Hz,1H),6.76(dd,J=7.5,1.5Hz,1H),6.36(d,J=1.4Hz,1H),3.84(s,2H),3.56-3.49(m,1H),3.49(d,J=7.1Hz,1H),3.46(d,J=7.0Hz,1H),3.46-3.40(m,1H),2.84-2.77(m,4H),2.76-2.68(m,6H),2.46(p,J=7.0Hz,1H),1.82(qd,J=7.0,1.0Hz,4H).

[0123] 14b-2

[0124] 1H NMR(500MHz,Chloroform-d)δ9.63(s,1H),8.52(s,1H),8.29(s,1H),8.17(dd,J=7.5,1.5Hz,1H),7.47(td,J=7.4,1.5Hz,1H),7.42(dd,J=7.5,1.7Hz,1H),7.31(td,J=7.4,1.7Hz,1H),7.12(d,J=7.5Hz,1H),6.76(dd,J=7.5,1.5Hz,1H),6.38(d,J=1.4Hz,1H),3.84(s,2H),3.56-3.40(m,4H),2.84-2.77(m,4H),2.76-2.68(m,6H),2.44(p,J=7.1Hz,1H),1.82(qd,J=7.0,1.0Hz,4H).

[0125] 14c-1

[0126] 1 H NMR(500MHz,Chloroform-d)δ9.59(s,1H),8.75(s,1H),8.31(s,1H),8.17(dd,J=7.5,1.5Hz,1H),8.05(d,J=7.5Hz,1H),7.49(td,J=7.5,1.6Hz,1H),7.39(dd,J=7.5,1.6Hz,1H),7.34(td,J=7.5,1.6Hz,1H),6.60(dd,J=7.5,1.5Hz,1H),6.25(d,J=1.5Hz,1H),3.56-3.40(m,4H),2.84-2.77(m,4H),2.76-2.68(m,6H),2.46(p,J=7.0Hz,1H),1.82(qd,J=7.0,1.0Hz,4H).

[0127] 14c-2

[0128] 1H NMR (500MHz, Chloroform-d) δ9.49 (s, 1H), 8.72 (s, 1H), 8.52 (s, 1H), 8.17 (dd, J=7.5, 1.5H z, 1H), 8.07 (d, J=7.5Hz, 1H), 7.49 (td, J=7.5, 1.5Hz, 1H), 7.41 (dd, J=7.5, 1.7Hz, 1H), 7.31 (td, J=7.4, 1.5Hz, 1H), 6.60 (dd, J=7.5, 1.5Hz, 1H), 6.25 (d, J=1.5Hz, 1H), 3.56-3.40 (m, 4H ), 2.84-2.77(m, 4H), 2.76-2.68(m, 6H), 2.44(p, J=7.1Hz, 1H), 1.82(qd, J=7.0, 1.0Hz, 4H).

[0129] Example 7

[0130] The synthetic routes for compounds 15a, 15b, and 15c are as follows:

[0131]

[0132]

[0133] The synthetic routes for compounds 8a, 8b, and 8c are the same as in Example 1. 1 g (100 mg) of compound 2a, 120 mg of compound 2a, and 23 mg of K₂CO₃ are dissolved in 30 ml of acetonitrile. The reaction mixture is sealed in a tube and reacted at 80 °C for 24 h. The reaction solution is then cooled to room temperature. The reaction solution is poured into water, resulting in the precipitation of a large amount of solid. This solid is filtered, and the filter cake is washed with ethanol and ethyl acetate. The cake is then dried in a vacuum oven at 50 °C to constant weight, yielding 3 g of the compound. 20 mg of each of compounds 8a, 8b, and 8c, along with 3 g of the brominated or chlorinated compound, 90 mg of methanesulfonic acid, and butanol as solvents, are reacted for 8 h. The reaction solution is then cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with ethanol and ethyl acetate. The mixture was then dried in a vacuum drying oven at 50°C to constant weight to obtain compounds 15a-1, 15a-2, 15b-1, 15b-2 and 15c-1, 15c-2 (-1 is brominated and -2 is chlorinated).

[0134] 15a-1

[0135] 1H NMR(500MHz,Chloroform-d)δ9.60(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.79(s,1H),8.31(s,1H),8.03(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.06(s,1H),6.24(s,1H),3.553.42(m,4H),2.66(dd,J=7.4,6.8Hz,4H),2.48(s,1H),2.49-2.39(m,4H),2.31(s,2H),2.23(s,3H),2.14(d,J=13.0Hz,5H),1.83(q d,J=7.1,2.0Hz,4H).

[0136] 15a-2

[0137] 1 H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.75(s,1H),8.49(s,1H),8.03(d,J=7.5Hz,1H),7.50(d,J=7.5Hz,1H),7.06(s,1H),6.24(s,1H),3.55-3.42(m,4H),2.66(dd,J=7.4,6.8Hz,4H),2.48(s,1H),2.49-2.39(m,4H),2.31(s,2H),2.23(s,3H),2.14(d,J=13.0Hz,5H),1.83(q d,J=7.1,2.0Hz,4H).

[0138] 15b-1

[0139] 1H NMR(500MHz,Chloroform-d)δ9.60(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.31(s,1H),8.22(s,1H),8.03(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.06(s,1H),6.38(s,1H),3.84(s,2H),3.54-3.41(m,4H),2.84-2.77(m,4H),2.76-2.70(m,4H),2.48(p,J=7.0Hz,1H),2.24(s,2H),2.14(d,J=13.0Hz,5H),1.83(qd,J=7.0,1.2Hz,4H).

[0140] 15b-2

[0141] 1 H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.49(s,1H),8.18(s,1H),8.03(d,J=7.5Hz,1H),7.50(d,J=7.5Hz,1H),7.06(s,1H),6.38(s,1H),3.84(s,2H),3.54-3.41(m,4H),2.84-2.77(m,4H),2.76-2.70(m,4H),2.48(p,J=7.0Hz,1H),2.24(s,2H),2.14(d,J=13.0Hz,5H),1.83(qd,J=7.0,1.2Hz,4H).

[0142] 15c-1

[0143] 11H NMR (500 MHz, Chloroform-d) δ 9.60 (s, 1H), 9.34 (d, J = 7.5 Hz, 1H), 8.94 (d, J = 7.5 Hz, 1H), 8.79 (s, 1H), 8.31 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55 - 3.42 (m, 4H), 2.84 - 2.77 (m, 4H), 2.76 - 2.70 (m, 4H), 2.48 (p, J = 7.0 Hz, 1H), 2.22 (s, 2H), 2.14 (d, J = 13.0 Hz, 5H), 1.83 (qd, J = 7.0, 1.2 Hz, 4H).

[0144] 15c-2

[0145] 1 1H NMR (500 MHz, Chloroform-d) δ 9.63 (s, 1H), 9.34 (d, J = 7.5 Hz, 1H), 8.94 (d, J = 7.5 Hz, 1H), 8.75 (s, 1H), 8.49 (s, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.06 (s, 1H), 6.24 (s, 1H), 3.55 - 3.42 (m, 4H), 2.84 - 2.77 (m, 4H), 2.76 - 2.70 (m, 4H), 2.48 (p, J = 7.0 Hz, 1H), 2.22 (s, 2H), 2.14 (d, J = 13.0 Hz, 5H), 1.83 (qd, J = 7.0, 1.2 Hz, 4H).

[0146] Example 8

[0147]

[0148]

[0149] The synthetic route for compound 3 is the same as in Example 1, and the synthetic route for compound 3g is the same as in Example 7. Compound 3 (29 mg) and compound 16 (40 mg) were dissolved in DCM and reacted at 85°C for 9 hours. By changing the feed ratio of compound 3 and compound 16, compounds 18a, 18b, 18c, 18d, and 18e were obtained, respectively. Compounds 18a, 18b, 18c, 18d, and 18e (20 mg each) were reacted with 3g of a brominated or chlorinated compound, methanesulfonic acid (90 mg), and butanol as solvents for 8 hours, and the reaction solution was cooled to room temperature. The reaction solution was poured into water, and a large amount of solid precipitated out. The mixture was filtered, and the filter cake was washed with ethanol and ethyl acetate. The mixture was then dried in a vacuum drying oven at 50°C to constant weight to obtain compounds 19a-1, 19a-2, 19b-1, 19b-2, 19c-1, 19c-2, 19d-1, 19d-2, 19e-1, and 19e-2.

[0150] 19a-1

[0151] 1 H NMR (500MHz, Chloroform-d) δ9.60 (s, 1H), 9.34 (d, J=7.5Hz, 1H), 8.94 (d, J=7. 5Hz, 1H), 8.79 (s, 1H), 8131 (s, 1H), 8.04 (d, J = 7.5Hz, 1H), 7.52 (d, J = 7.5Hz, 1H) , 7.06 (s, 1H), 6.24 (s, 1H), 3.53-3.40 (m, 4H), 2.78 (dtdt, J=8.4, 7.0, 5.5, 1.5 Hz, 1H), 2.24-2.18 (m, 9H), 2.14 (d, J=13.0Hz, 5H), 1.84 (qd, J=7.1, 1.2Hz.4H).

[0152] 19a-2

[0153] 1 H NMR (500MHz, Chloroform-d) δ9.63 (s, 1H), 9.34 (d, J = 7.5Hz, 1H), 8.94 (d, J = 7.5Hz, 1H), 8.75 (s, 1H), 8149 (s, 1H), 8.03 (d, J = 7.5Hz, 1H), 7.50 (d, J = 7.5Hz, 1H), 7.06 (s , 1H), 6.24 (s, 1H), 3.53-3.40 (m, 4H), 2.78 (dtdt, J=8.4, 7.0, 5.5, 1.5Hz, 1H), 2.23 (s, 3H), 2.19 (d, J=1.4Hz, 6H), 2.14 (d, J=13.0Hz, 5H), 1.84 (qd, J=7.1, 1.2Hz, 4H).

[0154] 19b-1

[0155] 1 H NMR(500MHz,Chloroform-d)δ9.60(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.31(s,1H),8.22(s,1H),8.03(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.06(s,1H),6.38(s,1H),3.84(s,2H),3.54-3.40(m,4H),2.75(p,J=7.0Hz,1H),2.24(s,3H),2.14(d,J=13.0Hz,5H),1.92(qd,J=7.1,1.9Hz,4H).

[0156] 19b-2

[0157] 1 H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.49(s,

[0158] 1H),8.18(s,1H),8.01(d,J=7.3Hz,1H),7.50(d,J=7.5Hz,1H),7.06(s,1H),6.40(s,1H),3.84(s,2H),3.54-3.40(m,4H),2.84(p,J=6.9Hz,1H),2.24(s,3H),2.14(d,J=13.0Hz,5H),1.92(qd,J=7.1,1.4Hz,4H).

[0159] 19c-1

[0160] 1 H NMR(500MHz,Chloroform-d)δ9.60(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.79(s,1H),8.31(s,1H),8.03(d,J=7.5Hz,1H),7.54(d,J=7.3Hz,1H),7.06(s,1H),6.24(s,1H),3.54-3.41(m,4H),2.75(p,J=7.0Hz,1H),2.22(s,2H),2.14(d,J=13.0Hz,5H),1.89(qd,J=7.1,2.2Hz,4H).

[0161] 19c-2

[0162] 1 H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.75(s,1H),8.49(s,1H),8.01(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.06(s,1H),6.24(s,1H),3.54-3.41(m,4H),2.84(p,J=7.0Hz,1H),2.22(s,2H),2.14(d,J=13.0Hz,5H),1.91(qd,J=7.1,1.1Hz,4H).

[0163] 19d-1

[0164] 1 H NMR(500MHz,Chloroform-d)δ9.60(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.79(s,1H),8.31(s,1H),8.03(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.06(s,1H),6.24(s,1H),3.53-3.41(m,4H),2.72(dtdd,J=8.5,7.0,5.5,1.5Hz,1H),2.27(d,J=1.4Hz,3H),2.23(s,3H),2.14(d,J=13.0Hz,5H),1.92(qd,J=7.1,2.1Hz,4H).

[0165] 19d-2

[0166] 1H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.75(s,1H),8.49(s,1H),8.01(d,J=7.3Hz,1H),7.50(d,J=7.5Hz,1H),7.06(s,1H),6.24(s,1H),3.53-3.41(m,4H),2.73(dtdd,J=8.5,7.0,5.5,1.5Hz,1H),2.27(d,J=1.4Hz,3H),2.23(s,3H),2.14(d,J=13.0Hz,5H),1.92(qd,J=7.0,1.7Hz,4H).

[0167] 19e-1

[0168] 1 H NMR(500MHz,Chloroform-d)δ9.60(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.31(s,1H),8.22(s,1H),8.04(d,J=7.5Hz,1H),7.52(d,J=7.5Hz,1H),7.05(s,1H),6.38(s,1H),3.84(s,2H),3.53-3.40(m,4H),2.73(dtdd,J=8.5,7.0,5.5,1.5Hz,1H),2.29-2.22(m,6H),2.14(d,J=13.0Hz,5H),1.92(qd,J=7.1,1.7Hz,4H).

[0169] 19e-2

[0170] 1 H NMR(500MHz,Chloroform-d)δ9.63(s,1H),9.34(d,J=7.5Hz,1H),8.94(d,J=7.5Hz,1H),8.49(s,1H),8.18(s,1H),8.03(d,J=7.5Hz,1H),7.50(d,J=7.5Hz,1H),7.05(s,1H),6.40(s,1H),3.84(s,2H),3.53-3.40(m,4H),2.74(dtdd,J=8.4,7.0,5.5,1.5Hz,1H),2.29-2.22(m,6H),2.14(d,J=13.0Hz,5H),1.92(qd,J=7.0,1.6Hz,4H).

[0171] Example 9

[0172] The compounds of this invention exhibit excellent antiproliferative activity in EGFR Ba / F3(Δ19del / T790M / C797S) triple mutant cells and phosphorylation activity in EGFR Ba / F3(Δ19del / T790M / C797S) triple mutant cell models.

[0173] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0174] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the invention patent. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the protection scope of the present invention. Therefore, the protection scope of this invention patent should be determined by the appended claims.

[0175] In vivo pharmacodynamic studies of compound (9a) (1)

[0176] Experimental methods:

[0177] In vivo pharmacodynamic studies were conducted on BALB / c nude mice with subcutaneous implantation of Ba / F3 (△19del / T790M / C797S)-derived xenografts (CDX). Female BALB / c nude mice, 6-8 weeks old and weighing approximately 16-20 grams, were housed in an SPF-grade environment with individual ventilation in each cage (5 mice per cage). All animals had free access to standard certified commercial laboratory diets. A total of 48 mice purchased from Vital River Pharmaceuticals Beijing were used for the study. Cells were subcutaneously implanted in the right flank of each mouse to promote tumor growth. The experiment began when the average tumor volume reached approximately 80-120 cubic millimeters. The test compounds were administered orally daily, with compounds of formula (9a-1) administered at 5 mg / kg, 15 mg / kg, and 45 mg / kg for 13 consecutive days. Data are listed in Table 1. Tumor volume was measured twice weekly using calipers and expressed in cubic millimeters, calculated using the following formula: V = 0.5a × b 2Where a and b are the long and short diameters of the tumor, respectively. The antitumor efficacy was determined by dividing the average tumor increase volume in animals treated with the compound by the average tumor increase volume in untreated animals. TG1 (tumor inhibition value) was used to evaluate the inhibitory effect of the test drug on tumor growth in vivo. The TGI of the compound group (9a-1) (administered at 15 mg / kg) was 89.6%, and the TGI of the compound group (I) (administered at 45 mg / kg) was 107.44%.

[0178] On day 14 after administration in the pharmacodynamic experiments, plasma was collected from mice via submandibular blood collection before and 2 hours after the last administration, and at 1 hour, 4 hours, 8 hours, and 24 hours after administration. Approximately 100 μL of blood was collected each time, placed in anticoagulant tubes, centrifuged at 8000 rpm for 7 minutes to collect plasma, and stored at -80°C. Two hours after administration, lung and tumor tissues were collected simultaneously and stored at -80°C. The tumor tissue was divided into two aliquots (with the tumor weight for PD analysis not exceeding 100 mg) for detection and data analysis.

[0179] Experimental results: see Table 1 and Table 2.

[0180] Table 1

[0181]

[0182]

[0183] Table 2

[0184]

[0185] In vivo pharmacodynamic studies of compound (9a) (2)

[0186] Experimental methods:

[0187] 1. Cell Culture: Lung cancer PC-9 cells were cultured in vitro as a monolayer under the following conditions: RPMIL-1640 (cell culture medium) with 10% fetal bovine serum, 100 U / mL penicillin, and 100 μg / mL streptomycin, incubated at 37°C in a 5% CO2 incubator. Cells were passaged twice a week using trypsin-EDTA digestion. When cell saturation reached 80%-90% and the desired number was achieved, cells were harvested and counted. The density was 5 × 10⁶ cells / mL. 6 Each cell.

[0188] 2. Cell seeding: Place 0.2 ml (containing 5 × 10⁶ cells) into a container. 6PC-9 cell suspension (PBS:Matrigel = 1:1) was subcutaneously injected into the right posterior dorsal region of each mouse, for a total of 64 mice. On day 7 post-inoculation, the average tumor volume reached 169 mmHg. 3 At that time, the animals were randomly stratified and grouped for drug administration based on tumor volume and body weight. PBS was phosphate buffered saline, and Matrigel was the matrix gel.

[0189] 3. Administration: Dosage: 50 mg / kg for days 0-9, 25 mg / kg for days 10-21; oral administration; frequency: once daily for 3 weeks. Tumor measurements and laboratory indicators.

[0190] The tumor diameter was measured twice a week using calipers. The formula for calculating tumor volume is: V = 0.5 × b 2 , where a and b represent the long and short diameters of the tumor, respectively.

[0191] The antitumor efficacy of the compound was evaluated using TGI (%).

[0192] The relative tumor volume (RTV) is calculated based on the tumor measurement results. The formula is RT = V. t / Vo,

[0193] Where Vo is the tumor volume measured when the mice are grouped for drug administration (i.e., D0), Vt is the tumor volume of the corresponding mouse at a certain measurement, and TRTV and CRTV are data from the same day.

[0194] TGI (%) reflects the tumor growth inhibition rate. TGI (%) = [(1 - (mean tumor volume at the end of treatment - mean tumor volume at the start of treatment)) / (mean tumor volume at the end of treatment in the solvent control group - mean tumor volume at the start of treatment in the solvent control group)] × 100T%

[0195] Tumor weight will be measured and TGI (%) calculated after the experiment.

[0196] Experimental results: See Table 3. The TGI of compound (9a-1) was 100% on day 23.

[0197] Table 3

[0198]

[0199] Experimental Example 3: Inhibition of Wild-Type EGFR and Mutant EGFR Kinase Activity by EFGR Inhibitors

[0200] EGFR(WT) is the wild-type epidermal growth factor receptor (EGFR). EGFR(T790M) is an EGFR with a mutation at amino acid position 790, where threonine is replaced by methionine. EGFR(L858R) is an EGFR with a mutation at amino acid position 858, where leucine is replaced by arginine. EGFR(L861Q) is an EGFR with a mutation at amino acid position 861, where leucine is replaced by glutamine. EGFR(L858R / T790M) is a double-mutant EGFR with both amino acid positions 858 (leucine to glutamine) and 790 (threonine to methionine). EGFR(L858R / T790M / C797S) is a triple-mutant EGFR with amino acid positions 858 (leucine to glutamine), 790 (threonine to methionine), and 797 (cysteine ​​to serine).

[0201] The inhibitory effect of the compound on kinase activity was detected using enzyme-linked immunosorbent assay (ELISA). EGFR WT and EGFRT 790ML858R The kinase was purchased from Eurofins, EGFR 1790ML858R / C797SR The kinase was purchased from BPS Bioscience. The main experimental steps are as follows: The enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted to 20 μg / mL with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) and incubated at 37°C for 12-16 h to coat the microplate. ATP (final concentration 5 μM) diluted with reaction buffer (50 mM HEPES pH 7.4, 50 mM MgCl2, 0.5 mM MnCl2, 0.2 mM Na3VO4, 1 mM DTT) was added to each well, along with the test compound or solvent control. The kinase was then used to initiate the reaction, and the plate was incubated at 37°C with shaking for 1 h. The plate was washed three times with T-PBS, and antibody PY99 was added and incubated at 37°C with shaking for 0.5 h. After washing with T-PBS, horseradish peroxidase-labeled goat anti-mouse IgG was added, and the plate was incubated at 37°C with shaking for 0.5 h. After washing the plate again, add 2 mg / mL OPD chromogenic solution and incubate at 25°C in the dark for 1-10 min. Add 2 M H₂SO₄ to terminate the reaction. Detect using a SPECTRAMAX 190 microplate reader with adjustable wavelength at 492 nm. IC₂ 50 The value was obtained from the inhibition curve analysis.

[0202] Table 4 lists the compound numbers (corresponding to the compound numbers in the above examples) and the detection results of the inhibitory activity of the deuterated compounds on each kinase.

[0203] Table 4. Results of the inhibitory activity of various deuterated compounds on kinases.

[0204]

[0205]

[0206] As shown in Table 4, the deuterated compounds of this invention inhibit the growth of EGFR triple mutant proteases, thereby suppressing the growth of various tumor cells. The compounds of this invention are particularly effective in inhibiting EGFR protein kinase resistance mutants (such as EGFR...). T790M and EGFR T790MC797S The activity of ) can selectively act on EGFR L858R / T790M and EGFR L858R / T790MC797S Lung cancer cells can overcome the limitations of existing third-generation selective EGFR inhibitors. T790M Clinical drug resistance in patients with non-small cell lung cancer and other tumors induced by small molecule inhibitors such as Osimertinib (AZD9291), Olmutinib (HM6171), and Rociletinib (CO-1686).

Claims

1. A compound, characterized in that, selected from the group consisting of:

2. A pharmaceutical composition, characterized by, a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 for the manufacture of an EGFR kinase inhibitor.

4. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 for the manufacture of a medicament for treating cancer.

5. Use according to claim 4, characterized in that, the cancer is lung cancer.

6. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 in combination with an EGFR monoclonal antibody for the manufacture of a medicament for treating cancer.

7. Use of a compound of claim 1 or a pharmaceutical composition of claim 2 in combination with an EGFR monoclonal antibody for the manufacture of a medicament for treating lung cancer.

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