EGFR INHIBITOR, COMPOSITION, AND METHOD FOR PREPARATION THEREOF

Abstract

Provided are the compounds of Formula I, a method for using these compounds as an EGFR inhibitor, and a pharmaceutical composition comprising the compounds. The compound is used for treatment, prevention or amelioration of diseases or conditions such as cancer or infection.

##STR00001##

Claims

1. A compound of Formula I, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex or solvate thereof, ##STR00058## wherein, R.sub.1 is halogen, —C.sub.1-6 alkyl or —C.sub.1-6 alkoxy; R.sub.2 is selected from H, —C.sub.1-6 alkyl, halogen or —C.sub.5-6 heteroaryl, wherein the heteroatom of —C.sub.5-6 heteroaryl consists of one or two N, O, S atoms, and can be substituted with —C.sub.1-6 alkyl; ring A is selected from —C.sub.3-6 saturated carbocycle or —C.sub.3-6 saturated heterocycle, wherein the heteroatom of —C.sub.3-6 saturated heterocycle consists of one or two N, O, S atoms.

2. The compound of claim 1, wherein R.sub.1 is selected from Cl, Br or —OCH.sub.3.

3. The compound of claim 2, wherein R.sub.1 is selected from Cl or Br.

4. The compound of claim 1, wherein R.sub.2 is selected from H, —CH.sub.3, —CH.sub.2CH.sub.3, ##STR00059##

5. The compound of claim 4, wherein R.sub.2 is selected from —CH.sub.2CH.sub.3 or ##STR00060##

6. The compound of claim 1, wherein R.sub.1 is Br, and R.sub.2 is —CH.sub.2CH.sub.3.

7. The compound of claim 1, wherein ring A is a —C.sub.3-6 saturated carbocycle.

8. The compound of claim 7, wherein ring A is selected from ##STR00061##

9. The compound of claim 1, wherein ring A is a —C.sub.3-6 saturated heterocycle.

10. The compound of claim 9, wherein ring A is selected from ##STR00062##

11. The compound of claim 1, wherein the compound is: 1) (2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide; 2) (2-((5-bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide; 3) (5-cyclopropyl-2-((2-((5-(1-ethyl-1H-pyrazol -4-yl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methoxypyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide; 4) (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide; 5) (5-propyl-2-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methoxypyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide; 6) (2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)phenyl)dimethylphosphine oxide; 7) (2-((5-chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopentylphenyl)dimethylphosphine oxide; 8) (2-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino-5-morpholinyl)dimethylphosphine oxide; 9) (2-((5-bromo-2-((2-methoxy-5-(1-methyl-1H-pyrrol-3-yl)-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-amino)-5-cyclopropylphenyl)dimethylphosphine oxide; or 10) (2-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide.

12. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt or stereoisomer thereof, and at least one pharmaceutically acceptable carrier or adjuvant.

13. A method for inhibiting various forms of EGFR, wherein the various forms of EGFR are mutant forms of EGFR, including L858R, Δ19del, T790M and C797S, and any combinations thereof, said method comprising administering to a patient a compound of claim 1, or a pharmaceutically acceptable salt thereof.

14. A method for treating EGFR-driven cancer, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1, or pharmaceutically acceptable salts thereof.

15. The method of claim 14, wherein the EGFR-driven cancer is characterized by the presence of one or more mutations selected from: (i) C797S, (ii) L858R and C797S, (iii) C797S and T790M, (iv) L858R, T790M and C797S, or (v) Δ19del, T790M and C797S.

16. The method of claim 14, wherein the EGFR-driven cancer comprises colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.

17. The method of claim 16, wherein the lung cancer is a non-small cell lung cancer caused by EGFR.sup.L858R/T790M/C797S or EGFR.sup.Δ19del/T790M/C797S mutant.

18. (canceled)

19. (canceled)

20. (canceled)

21. (canceled)

Description

EXAMPLE 1

Synthesis of Compound 1

(2-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide

[0090] ##STR00007##

Step 1: Synthesis of Compound 1-3

[0091] ##STR00008##

[0092] Add 1-1 (3.00 g), 1-2 (4.14 g), K.sub.2CO.sub.3 (6.24 g) and DMSO (30 mL) successively to the reaction flask, raise temperature to 90° C. and stir with heating for 12 hr. The reaction was complete as monitored by LCMS, and then stopped. The reaction solution was poured into water (100 mL) and filtered with suction. The filter cake was washed with water, and dried to obtain the yellow solid of desired product 1-3 (4.20 g), MS: 363 [M+H].sup.+

Step 2: Synthesis of Compound 1-4

[0093] ##STR00009##

[0094] Add compound 1-3 (4.20 g), Pd/C (1.00 g) and MeOH (60 mL) successively to the reaction flask, introduce H.sub.2. The reaction solution was stirred at room temperature for 3 hr. The reaction was complete as monitored by LCMS, and then stopped. The solution was filtered with suction and rinsed with methanol (20 mL); the organic phase was collected, and the solvent was removed to obtain the reddish-brown liquid of desired compound 1-4 (3.5 g), MS: 333[M+H].sup.+

Step 3: Synthesis of Compound 1-6

[0095] ##STR00010##

[0096] Add compound 1-5 (3.0 g), dimethylphosphine oxide (865 mg), K.sub.3PO.sub.4 (6.41 g), Pd(OAc).sub.2 (226 mg), Xantphos (1.75 g), 1,4-Dioxane (60 mL) successively to the reaction flask, heat to 100° C. under nitrogen protection, stir with heating for 4 hr. The reaction was complete as monitored by LCMS, and then stopped. The water was added to the reaction solution, and which was extracted with dichloromethane (3×50 mL), the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, separated and dried by column chromatography (dichloromethane:methanol=15:1); the solvent was removed to obtain the yellow solid of desired product 1-6 (2.0 g), MS: 248[M+H].sup.+

Step 4: Synthesis of Compound 1-8

[0097] ##STR00011##

[0098] Add compounds 1-6 (2.20 g), 1-7 (1.52 g), K.sub.3PO.sub.4 (5.65 g), Pd(dppf)Cl.sub.2 (649 mg), 1,4-dioxane (30 mL) and water (3 mL) successively to the reaction flask, heat to 100° C. under nitrogen protection, stir with heating for 12 hr. The reaction was complete as monitored by LCMS, and then stopped. The water (50 mL) was added to the reaction solution, and which was extracted with dichloromethane (3×50 mL), the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, separated and dried by column chromatography (dichloromethane:methanol=10:1); the solvent was removed to obtain the brown solid of desired product 1-8 (1.20 g), MS: 210[M+H].sup.+

Step 5: Synthesis of Compound 1-10

[0099] ##STR00012##

[0100] Add compounds 1-8 (364 mg), 1-9 (794 mg), K.sub.2CO.sub.3 (721 mg) and DMF (10 mL) successively to the reaction flask, heat to 100° C., stir with heating for 12 hr. The reaction was complete as monitored by LCMS, and then stopped. The water (50 mL) was added to the reaction solution, and which was extracted with dichloromethane (3×50 mL), the organic phase was washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate, separated and dried by column chromatography (dichloromethane:methanol=13:1); the solvent was removed to obtain the yellowish solid of desired product 1-10 (330 mg), MS: 400 [M+H].sup.+

Step 6: Synthesis of Compound 1

[0101] ##STR00013##

[0102] Add compounds 1-10 (80 mg), 1-4 (80 mg), p-toluenesulfonic acid (52 mg) and n-butanol (2 mL) successively to the reaction flask, heat to 100° C., stir with heating for 12 hr. The reaction was complete as monitored by LCMS, and then stopped. The reaction solution was poured into 2N sodium carbonate solution (30 mL), extracted with mixed solvent of dichloromethane/methanol=10/1 (3×30 mL), combined with organic phase, washed with saturated brine (3×30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was separated and purified by thick preparative plate (dichloromethane:methanol=12:1), and the eluted product was concentrated to obtain the off-white solid compound 1 (25.5 mg). MS: 696[M+H].sup.+, .sup.1H NMR (500 MHz, DMSO) δ 10.708(s, 1H), 8.186-8.176(m, 1H), 8.143-8.111(m, 1H,), 8.030(s, 1H), 7.407 (s, 1H), 7.281 (d, 1H, J=14), 6.920 (d, 1H, J=9), 6.768 (s, 1H), 3.7463 (s, 3H), 3.013 (m, 2H), 2.715 (m, 2H), 2.603 (m, 1H), 2.362 (m, 8H), 2.178 (s, 3H), 1.904 (m, 3H), 1.755 (d, 6H, J=13), 1.592 (m, 2H), 1.235 (s, 2H), 1.037(m, 3H), 0.959 (m, 2H), 0.651 (m, 2H).

EXAMPLE 2

Synthesis of Compound 2

2-((5-Bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide

[0103] ##STR00014##

Step 1: Synthesis of Compound 2-3

[0104] ##STR00015##

[0105] Dissolve compound 2-1 (1.50 g) in 1,4-dioxane (10 ml) and water (2 ml) in a 50 ml stand-up bottle, and then add compound 2-2 (1.60 g), Pd (dppf)Cl.sub.2 (489.94 mg) and anhydrous potassium carbonate (995.03 mg). The reaction system was heated to 100° C. under nitrogen protection and stirred overnight. It was naturally cooled down to room temperature. Add ethyl acetate/water (30 ml/30 ml) for layering, collect organic phase and concentrate. The residue mixed with silica gel, and purified by flash silica gel column (Phase A: n-hexane, phase B: ethyl acetate; B%: 0-100%, 20 min); the product eluent was collected and concentrated to obtain the compound 2-3 (1.20 g) MS: 266 [M+H].sup.+

Step 2: Synthesis of Compound 2-4

[0106] ##STR00016##

[0107] The compound 2-4 was synthesized as the method described for compound 1-3 using compound 2-3 instead of raw compound 1-1. For compound 2-4, MS: 429[M+H].sup.+

Step 3: Synthesis of Compound 2-5

[0108] ##STR00017##

[0109] The compound 2-5 was synthesized as the method described for compound 1-4 using compound 2-4 instead of raw compound 1-3. For compound 2-5, MS: 399[M+H].sup.+

Step 4: Synthesis of Compound 2

[0110] ##STR00018##

[0111] The compound 2 was synthesized as the method described for compound 1 using compound 2-5 instead of raw compound 1-4. For compound 2, MS: 762[M+H].sup.+

EXAMPLE 3

Synthesis of Compound 3

(5-Cyclopropyl-2-((2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methoxypyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0112] ##STR00019##

Step 1: Synthesis of Compound 3-2

[0113] ##STR00020##

[0114] The compound 3-2 was synthesized as the method described for compound 1-10 using compound 3-1 instead of raw compound 1-9. For compound 3-2, MS: 352[M+H].sup.+

Step 2: Synthesis of Compound 3

[0115] ##STR00021##

[0116] The compound 3 was synthesized as the method described for compound 1 using compound 3-2 instead of raw compound 1-10, compound 2-5 instead of raw compound 1-4. For compound 3, MS:714 [M+1-1].sup.+

EXAMPLE 4

Synthesis of Compound 4

(2-((5-Chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperazin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide

[0117] ##STR00022##

Step 1: Synthesis of Compound 4-2

[0118] ##STR00023##

[0119] The compound 4-2 was synthesized as the method described for compound 1-3 using compound 4-1 instead of compound 1-1. For compound 4-2, MS: 335[M+H].sup.+

Step 2: Synthesis of Compound 4-3

[0120] ##STR00024##

[0121] The compound 4-3 was synthesized as the method described for compound 1-4 using compound 4-2 instead of compound 1-3. For compound 4-3, MS: 305[M+H].sup.+

Step 3: Synthesis of Compound 4-5

[0122] ##STR00025##

[0123] The compound 4-5 was synthesized as the method described for compound 1-10 using compound 4-4 instead of raw compound 1-9. For compound 4-5, MS: 356[M+H].sup.+

Step 3: Synthesis of Compound 4

[0124] ##STR00026##

[0125] The compound 4 was synthesized as the method described for compound 1 using compound 4-5 instead of raw compound 1-10, compound 4-3 instead of raw compound 1-4. For compound 4, MS: 624 [M+H].sup.+

EXAMPLE 5

Synthesis of Compound 5

(5-propyl-2-((2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methoxypyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0126] ##STR00027##

Step 1: Synthesis of Compound 5

[0127] ##STR00028##

[0128] The compound 5 was synthesized as the method described for compound 1 using compound 2-2 instead of raw compound 1-10. For compound 5, MS: 648 [M+H].sup.+

EXAMPLE 6: Synthesis of Compound 6

(2-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-(tetrahydro-2H-pyran-4-yl)phenyl)dimethylphosphine oxide

[0129] ##STR00029##

Step 1: Synthesis of Compound 6-1

[0130] ##STR00030##

[0131] Dissolve compound 6-a (400 mg) in 15 mL of methanol, add palladium/carbon (100 mg, 20%); the gas in the reactor was replaced with H.sub.2 for three times, and the reaction was carried out for 2 hr at room temperature. After filtering, the solvent was removed to obtain the yellow solid 6-1 (300 mg), MS: 254 [M+H].sup.+

Step 2: Synthesis of Compound 6-2

[0132] ##STR00031##

[0133] The compound 6-2 was synthesized as the method described for compound 1-10 using compound 6-1 instead of raw compound 1-8. For compound 6-2, MS: 444 [M+H].sup.+

Step 3: Synthesis of Compound 6

[0134] ##STR00032##

[0135] The compound 6 was synthesized as the method described for compound 1 using compound 6-2 instead of raw compound 1-10. For compound 6, MS: 740 [M+H].sup.+

EXAMPLE 7

Synthesis of Compound 7

(2-((5-Chloro-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-5-cyclopentylphenyl)dimethylphosphine oxide

[0136] ##STR00033##

Step 1: Synthesis of Compound 7-2

[0137] ##STR00034##

[0138] The compound 7-2 was synthesized as the method described for compound 1-8 using compound 7-1 instead of raw compound 1-7. For compound 7-2, MS: 236 [M+H].sup.+

Step 2: Synthesis of Compound 7-3

[0139] ##STR00035##

[0140] The compound 7-3 was synthesized as the method described for compound 6-1 using compound 7-2 instead of raw compound 6-a. For compound 7-3, MS: 238 [M+H].sup.+

Step 3: Synthesis of Compound 7-4

[0141] ##STR00036##

[0142] The compound 7-4 was synthesized as the method described for compound 1-10 using compound 7-3 instead of raw compound 1-8, compound 4-4 instead of raw compound 1-9. For compound 7-4, MS: MS: 384 [M+H].sup.+

Step 4: Synthesis of Compound 7

[0143] ##STR00037##

[0144] The compound 7 was synthesized as the method described for compound 1 using compound 7-4 instead of raw compound 1-10. For compound 7, MS: 680 [M+H].sup.+

EXAMPLE 8

Synthesis of Compound 8

(2-((5-Bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino-5-morpholinyl)dimethylphosphine oxide

[0145] ##STR00038##

Step 1: Synthesis of Compound 8-3

[0146] ##STR00039##

[0147] Dissolve 8-1 (267 mg), 8-2 (105 mg) and anhydrous potassium carbonate (415 mg) in DMF (5 mL) in a 50 mL stand-up bottle; the reaction solution was heated to 100° C. and stirred for 2 hr, cooled down to room temperature, diluted with water (30 ml), extracted twice with ethyl acetate (30 ml*2), combined with organic phase, washed three times with water (50 ml*3), dried and concentrated, and then separated and purified by column chromatography (dichloromethane:methanol=15:1) to obtain the compound 8-3 (313 mg), MS: 335 [M+H].sup.+

Step 2: Synthesis of Compound 8-4

[0148] ##STR00040##

[0149] Dissolve 8-3 (313 mg) in absolute ethyl alcohol (10 mL) /H.sub.2O (2 mL) in a 50 ml stand-up bottle, add iron powder (523 mg) and ammonium chloride (501 mg); the reaction solution was heated to 90° C. and stirred for 2 hr. After complete reaction, the reaction solution was cooled down to room temperature, and filtered by suction bottle with diatomite; the filter cake was rinsed with 50 ml of absolute ethyl alcohol; the filtrate was collected and concentrated; the residue was dissolved in DCM/H.sub.2O (30 ml/30 ml); the organic phase was collected, dried over anhydrous sodium sulfate, filtered and concentrated to get 8-4 (224 mg), MS: 305 [M+H].sup.+

Step 3: Synthesis of Compound 8-5

[0150] ##STR00041##

[0151] The compound 8-5 was synthesized as the method described for compound 1-6 using compound 8-4 instead of raw compound 1-5. For compound 8-5, MS:255 [M+H].sup.+

Step 4: Synthesis of Compound 8-6

[0152] ##STR00042##

[0153] The compound 8-6 was synthesized as the method described for compound 1-10 using compound 8-5 instead of raw compound 1-8. For compound 8-6, MS:445 [M+H].sup.+

Step 5: Synthesis of Compound 8

[0154] ##STR00043##

[0155] The compound 8 was synthesized as the method described for compound 1 using compound 8-6 instead of raw compound 1-10. For compound 8, MS:741 [M+H].sup.+

EXAMPLE 9

Synthesis of Compound 9

(2-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrrol-3-yl)-4-(4-(4-methylpiperazine-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)-amino)-5-cyclopropylphenyl)dimethylphosphine oxide

[0156] ##STR00044##

Step 1: Synthesis of Compound 9-2

[0157] ##STR00045##

[0158] The compound 9-2 was synthesized as the method described for compound 2-3 using compound 9-1 instead of raw compound 2-2. For compound 9-2, MS: 251[M+H].sup.+

Step 2: Synthesis of Compound 10-3

[0159] ##STR00046##

[0160] The compound 9-3 was synthesized as the method described for compound 1-3 using compound 9-2 instead of raw compound 1-1. For compound 9-3, MS: 414[M+H].sup.+

Step 3: Synthesis of Compound 9-4

[0161] ##STR00047##

[0162] The compound 9-4 was synthesized as the method described for compound 1-4 using compound 9-3 instead of raw compound 1-3. For compound 9-4, MS: 384[M+H].sup.+

Step 4: Synthesis of Compound 9

[0163] ##STR00048##

[0164] The compound 9 was synthesized as the method described for compound 1 using compound 9-4 instead of raw compound 1-4. For compound 9, MS: 747[M+H].sup.+

EXAMPLE 10

Synthesis of Compound 10

(2-((5-Bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)Amino)pyrimidin-4-yl)amino)-5-cyclopropylphenyl)dimethylphosphine oxide

[0165] ##STR00049##

Step 1: Synthesis of Compound 10-2

[0166] ##STR00050##

[0167] The compound 10-2 was synthesized as the method described for compound 1-3 using compound 10-1 instead of raw compound 1-1. For compound 10-2, MS: 349[M+H].sup.+

Step 2: Synthesis of Compound 10-3

[0168] ##STR00051##

[0169] The compound 10-3 was synthesized as the method described for compound 1-4 using compound 10-2 instead of raw compound 1-3. For compound 10-3, MS: 319[M+H].sup.+

Step 3: Synthesis of Compound 11

[0170] ##STR00052##

[0171] The compound 10 was synthesized as the method described for compound 1 using compound 10-4 instead of raw compound 1-4. For compound 10, MS: 682[M+H].sup.+

CONTROL EXAMPLE 1

[0172] WO2009143389 disclosed on Page 216 of the control example 1, but did not give any preparation method and effect data. This application provides a preparation method for control example 1 as follows:

##STR00053##

CONTROL EXAMPLE 1

Step 1: Synthesis of Compound 1-3

[0173] ##STR00054##

[0174] Add compounds 1-1 (1.00 g), 1-2 (1.29 g), K.sub.2CO.sub.3 (1.62 g) and DMSO (10 mL) successively to the reaction flask, heat to 90° C., and stir with heating for 12 hr. The reaction was complete as monitored by LCMS, and then stopped. The reaction solution was poured into water (50 mL), and extracted with DCM (2×30 mL); the organic phase was washed with water (3×20 mL) and saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The resulting crude product was slurried with ether (20 mL) to obtain the yellow solid of desired product 1-3 (1.60 g), MS: 335 [M+H].sup.+

Step 2: Synthesis of Compound 1-3

[0175] ##STR00055##

[0176] Add compound 1-3 (1.60 g), raney nickel (0.50 g) and MeOH (20 mL) successively to the reaction flask, introduce Hz; the reaction solution was stirred at room temperature for 3 hr. The reaction was complete as monitored by LCMS, and then stopped. The reaction solution was filtered with suction, and rinsed with methanol (20 mL); the organic phase was collected, and the solvent was removed to obtain the gray solid of desired product 1-4 (1.45 g), MS: 305 [M+H].sup.+

Step 3: Synthesis of Compound 1-7

[0177] ##STR00056##

[0178] Add compounds 1-5 (0.5 g), 1-6 (0.5 g), DIEA (1.06 g) and n-butanol (5 mL) successively to the reaction flask, heat to 100° C., and stir for 3 hr. The reaction was complete as monitored by LCMS, and then stopped. The reaction solution was concentrated, separated and purified by column chromatography (dichloromethane:methanol=20:1), and the solvent was removed to obtain the white solid of desired product compound 1-7 (600 mg), MS: 330 [M+H].sup.+

Step 4: Synthesis of Control Example 1

[0179] ##STR00057##

[0180] Add compounds 1-7 (100 mg), 1-4 (92 mg), p-toluenesulfonic acid (104 mg) and n-butanol (6 mL) successively to the reaction flask, heat to 100° C., and stir for 5 hr. The reaction was complete as monitored by LCMS, and then stopped. The reaction solution was poured into sodium carbonate solution (15 mL), and extracted with dichloromethane (2×15 mL); the organic phase was washed with saturated brine (3×10 mL), dried over anhydrous sodium sulfate, separated and purified by column chromatography (dichloromethane:methanol=10:1), and then concentrated to obtain off-white solid of control example 1 (63 mg), MS: 598 [M+H].sup.+

Pharmacological Test

[0181] Test 1 EGFR Δ19del/T790M/C797S Kinase Test

[0182] Mobility variation analysis was performed to determine the affinity of the compound for EGFRΔ19del/T790M/C797S. The enzymatic reaction scheme is as follows:

[0183] 1. Prepare 1*kinase buffer as follows.

TABLE-US-00001 1*kinase buffer Final concentration HEPES PH 7.5(mM) 50 Brij-35 0.0150% DTT(mM) 2 Mgcl.sub.2, Mncl.sub.2 (mM) 10

[0184] 2. Prepare compound concentration gradient: The test compound was tested at concentration of 300 nM, diluted with 100% DMSO solution in a 96-well plate to 100-fold final concentration, and then diluted to 3-fold concentration with Precision.10. Compound at each concentration was further diluted to 5-fold final concentration of intermediate dilution.

[0185] 3. Add 5 μL of each prepared intermediate dilution compounds to the compound wells of 384-well plate respectively, and test the repeated wells of each concentration; add 5 μL of 5% DMSO into the negative control well and the positive control well respectively.

[0186] 4. Prepare 2.5-fold final concentration of kinase solution with 1×Kinase buffer.

[0187] 5. Add 10 μL of 2.5-fold final concentration of kinase solution to the compound well and the positive control well; add 10 μL of 1×Kinase buffer to the negative control well.

[0188] 6. Centrifuge at 1000 rpm for 30 s, shake the reaction plate for well mixing, and then incubate at room temperature for 10 minutes.

[0189] 7. Prepare a mixture of ATP and Kinase substrate (5-FAM-EEPLYWSFPAKKK-CONH.sub.2) at 2.5-fold final concentration with 1×Kinase buffer.

[0190] 8. Add 10 μL mixture of ATP and substrate at 2.5-fold final concentration to start reaction.

[0191] 9. Centrifuge the 384-well plate at 1000 rpm for 30 s, shake it well and then incubate it at room temperature for corresponding time.

[0192] 10. Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 s, and shake it well.

[0193] 11. Read conversion rate with Caliper EZ Reader.

[0194] Convert the conversion rate to inhibition rate:

inhibition %=(max−conversion % sample)/(max−min)*100.

[0195] “max”: Mean value of negative control wells; “min”: Mean value of positive control wells; conversion % sample: Sample conversion reading.

[0196] GraphPad Prism 5 was used for % inhibition curve fitting to obtain the IC.sub.50 value.

[0197] The calculation formula: Y=inhibition %_min+(inhibition %_max−inhibition %_min)/(1+(IC.sub.50/X){circumflex over ( )}slope). wherein, Y is inhibition %; X is concentration of compound to be tested.

[0198] The results are expressed as IC.sub.50 values, as shown in Table 1.

TABLE-US-00002 TABLE 1 EGFR No. Δ19del/T790M/C797S IC.sub.50(nM) Control example 1 2.7 1 0.3 2 0.4 3 0.4 4 1.2 5 1.6 6 0.7 7 1.1 8 0.3 9 0.3 10 0.3

Test 2 Ba/F3-Δ19del/T790M/C797S and Ba/F3-L858R/T790M/C797S Cell

Proliferation Assay

[0199] 1. Cell Culture

[0200] Cell line: Ba/F3 cells with Δ19del/T790M/C797S or L858R/T790M/C797S mutation gene stably over-expressed named Ba/F3-Δ19del/T790M/C797S and Ba/F3-L858R/T790M/C797S, and A431 wild-type cell line.

[0201] A. Culture Medium

[0202] RPMI 1640, 10% FBS and 1% PS; DMEM, 10% FBS and 1% PS

[0203] B. Cell Recovery

[0204] a) The medium was preheated in a 37° C. water bath in advance.

[0205] b) Remove the cryogenic vials from the liquid nitrogen tank, quickly put it into a 37° C. water bath, and completely melt it in 1 min.

[0206] c) Transfer the cell suspension to a 15 mL centrifuge tube containing 8 mL of medium, and centrifuge at 1000 rpm for 5 min.

[0207] d) Discard the supernatant, resuspend the cells in 1 mL of culture medium, transfer it to a 75 cm.sup.2 flask containing 15 mL of culture medium, and culture the cells in a incubator with 5% CO.sub.2 at 37° C.

[0208] C. Cell Passage

[0209] a) The medium was preheated in a 37° C. water bath in advance.

[0210] b) Collect the cells in a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 min. Discard the supernatant, count to make the cell density at 1×10.sup.4 cells/mL, and then place it in a incubator with 5% CO2 at 37° C.

[0211] 2. Compound Preparation

[0212] a) Dilute the test compound (20 mM stock solution) to 10 mM with 100% DMSO as the starting concentration, and then serially dilute 3 times with a “9+0” concentration in 96-well dilution plate (Cat #P-05525, Labcyte);

[0213] b) Dilute compound solution thereof to 1:100 in medium to prepare 10-fold working solution.

[0214] 3. Cell Plate Culture

[0215] a) Centrifuge the growth cells in logarithmic phase at 1000 rpm for 5 minutes, resuspend the cells in culture medium, and then count the cells;

[0216] b) Inoculate the cells into a 96-well cell culture plate with a density of 2000 cells/well;

[0217] 4. Compound Treatment

[0218] a) 15 μl of compounds prepared at step 2 were added to cell plate, the final concentrations were 1000, 333, 111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5 and 0 nM, and the final concentration of DMSO was 0.1%. The blank control well was a culture medium (0.1% DMSO);

[0219] b) Incubate cells in an incubator for another 72 hours;

[0220] 5. Assay

[0221] a) Take out the 96-well cell culture plate and add 50 μl of CTG reagent (CellTiter Glo kit, promega, Cat#G7573);

[0222] b) Shake the plate for 2 minutes and let cool at room temperature for 10 minutes;

[0223] c) Read luminous signal value with PerkinElmer reader.

[0224] Analysis of Test Data

[0225] The data were analyzed by GraphPad Prism 6.0 software to obtain the fitting curve of compound activity.

[0226] Fitting compound IC.sub.50 from nonlinear regression equation:

Y=Min+(Max−Min)/(1+10{circumflex over ( )}((Log IC50−X)*slope));

[0227] X: Logarithm of compound concentration; Y: luminous signal value.

[0228] The result of cell proliferation assay is expressed by IC50, as shown in Table 2.

TABLE-US-00003 TABLE 2 BaF3 A431 No. Δ19del/T790M/C797SIC.sub.50(nM) IC.sub.50(nM) Control example 1 49.9 597.5 1 1.2 681.8 2 7.2 267.7 3 55.4 830 4 / / 5 302 / 6 15.6 674.4 7 38.3 1405 8 30.4 886 9 5.2 604 10 9.7 543.2 Notes: “—” stands for “not tested”.

Test 3 Pharmacokinetic Experiment

[0229] Male SD rats (3 rats in each group) were administered orally, and fasted overnight from at least 12 hours before administration to 4 hours after administration before the experiment. Blood was taken from the orbital vein. The time points of blood collection for oral administration were: 15 min, 30 min, 1 hr, 2 hr, 4 hr, 7 hr and 24 hr, the dosage of administration was 5 mpk, and the blood collection volume was 300 μL. After anticoagulant treatment with 2.0% EDTA, the blood was centrifuged at 4000 rpm for 5 min, and then about 100 μL was taken and placed for testing at −20° C. Plasma samples were analyzed by liquid chromatography tandem mass spectrometry (LC-MS/MS). The plasma concentration-time data of individual animals were analyzed by the non-compartment model of WinNonlin (V4.1, Pharsight) software, and the pharmacokinetic parameters of the compounds tested were calculated. The PK characteristics of compounds in rats are shown in Table 3.

TABLE-US-00004 TABLE 3 C.sub.max AUC.sub.last Compound t.sub.½ (h) (ng/mL) (h .Math. ng/mL) 1 9.1 2100 32921