Pyridinylaminopyrimidine derivatives, preparation process and use thereof

Abstract

The present invention relates to pyridinylaminopyrimidine derivatives represented by the following formula (I), and pharmaceutically acceptable salts, preparation process and use thereof, wherein R₁, R₂, R₃, R₄, R₅, m and A are defined as in the description. Pyridinylaminopyrimidine derivatives of the present invention can selectively inhibit the activity of mutant-type epidermal growth factor receptor (egfr), have a good inhibition for the cancer cell proliferation, and therefore can be used as a therapeutic agent for treating tumors and relevant diseases.

##STR00001##

Description

RELATED APPLICATIONS

This application is a

Blank control OD: the OD value of the well of normally growed cells without the action of a drug.

Inhibitor OD: the OD value of the well of cells with the action of the added compounds to be screened.

The median inhibitory concentration (IC₅₀) value is obtained by the software GraphPad Prism 5.0 by the 4-parameter logistic curve fit calculation. Each experiment is repeated three times, and the average IC₅₀ value for three experiments is used as the final index for the inhibitory ability.

The pharmacodynamic action of the compound of the present invention in terms of inhibiting the growth of transplanted tumors in animal may be assayed by conventional methods. One preferable evaluation method of which is the inhibitory effect on the growth of subcutaneously transplanted tumors of human lung cancer H1975-bearing nude mice. The experimental method is as follows: human lung cancer H1975 cell strain (5×10⁶/each mouse) is inoculated to nude mice subcutaneously at the right side of the back thereof. After the tumors grow to 100-150 mm³ on average, the animals are divided into groups randomly according to the tumor size and the animal weight. The test compounds are administered by intragastric administration in a certain dosages, and solvent control groups are administered with equal amount of solvent by intragastric administration, wherein the administration is performed once per day for a continuous period of 12 days. During the entire experimental process, the animal weight and the tumor size are measured twice per week, so as to observe whether or not the toxic reaction occurs. The tumor volume is calculated as follows:
Tumor volume (mm³)=0.5×(Tumor major diameterx Tumor minor diameter²)

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the tumor volume curve for subcutaneously transplanted tumors of human lung cancer H1975-bearing nude mice at the administration dosage of 25 mg/kg of the compound of Example 3 and AZD9291.

FIG. 2 is the body weight curve for human lung cancer H1975-bearing nude mice at the administration dosage of 25 mg/kg of the compound of Example 3 and AZD9291.

The present invention will be further illustrated hereinafter in connection with specific Examples. It should be understood that these Examples are only used to illustrate the present invention by the way of examples without limiting the scope thereof. In the following Examples, the experimental methods without specifying conditions are generally performed according to conventional conditions or based on the conditions recommended by the manufacturer. The parts and percentages are the parts and percentages by weight respectively, unless otherwise specified.

DETAILED DESCRIPTION OF THE INVENTION

1. Preparation Examples of the Compounds of the Present Invention

Intermediate 1a: N²-methyl-N²-[2-(dimethylamino)ethyl]-6-methoxy-3-nitropyridin-2,5-diamine hydrochloride

##STR00017##

Step 1: Synthesis of 6-chloro-2-methoxy-3-nitropyridine

##STR00018##

To a 250 mL three-necked flask were added 2,6-dichloro-3-nitropyridine (11.58 g, 60 mmol), 150 ml tetrahydrofuranand methanol (1.92 g, 60 mmol). The mixture was cooled to 0° C. To the mixture was added in batch 60% sodium hydride (2.4 g, 60 mmol). The resulting mixture was stirred at 0° C. for 1 hour, warmed up slowly to room temperature, and continued to stir for 1 hour. To the reaction mixture was added 100 ml ethyl acetate. The reaction mixture was washed successively with water (50 ml×2) and saturated brine (50 ml). The organic phase was dried with anhydrous sodium sulfate, filtered, evaporated under a reduced pressure to remove the solvent, purified by silica gel column chromatography (petroleum ether:ethyl acetate=30:1) to produce 7.3 g of a product with a yield of 64%.

¹H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=8.3 Hz, 1H), 7.07 (d, J=8.3 Hz, 1H), 4.15 (s, 3H).

Step 2: Synthesis of 6-chloro-2-methoxypyridin-3-amine

##STR00019##

To a 100 mL single-necked flask were added 6-chloro-2-methoxy-3-nitropyridine (2.0 g, 10.6 mmol), ammonia chloride (2.8 g, 53.0 mmol) and 80 ml of a mixed solvent of ethanol and water (volume ratio=3:1). To the mixture was added in batch a reduced iron powders (3.0 g, 53.0 mmol). The mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature, and filtered through diatomite. 150 ml ethyl acetate and 120 ml saturated sodium chloride were added to the filtrate. An organic layer was separated and dried with anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under a reduced pressure to produce a brown solid (1.6 g) with a yield of 95%. MS m/z: 159 [M+1].

Step 3: Synthesis of N-(6-chloro-2-methoxypyridin-3-yl)acetamide

##STR00020##

To a 250 mL single-necked flask were added 6-chloro-2-methoxypyridin-3-amine (1.6 g, 10.1 mmol), diisopropylethylamine (2.6 ml, 15.1 mmol) and 100 ml dichloromethane. The mixture was cooled to 5° C. in an ice bath. Acetyl chloride (0.86 ml, 12.1 mmol) was added. The reaction continued for 1.25 hours. The reaction mixture was washed successively with 80 ml water, 80 ml 1N hydrochloric acid and 80 ml saturated sodium chloride solution, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness under a reduced pressure to produce 1.9 g of a brown solid with a yield of 94%. MS m/z: 201 [M+1].

Step 4: Synthesis of N-(6-chloro-2-methoxy-5-nitropyridin-3-yl)acetamide

##STR00021##

To a 100 mL single-necked flask were added N-(6-chloro-2-methoxypyridin-3-yl)acetamide (1.9 g, 9.47 mmol) and 20 ml trifluoroacetic anhydride. The mixture was cooled in an ice-salt bath to −10° C. Fuming nitric acid (0.4 ml, 9.47 mmol) was dropwisely added while the temperature was controlled to below −5° C. After the completion of dropwise addition, the reaction continued in an ice-salt bath for 1.25 hours. The reaction mixture was slowly added to crushed ice. A solid precipitated and was filtered. The resulting crude product was dried at 60° C., and added to ethyl acetate to form a slurry. 1.5 g of an beige solid was obtained with a yield of 65%. MS m/z: 244 [M−1].

¹H NMR (400 MHz, DMSO-d6) δ 9.90 (s, 1H), 9.17 (s, 1H), 4.06 (s, 3H), 2.17 (s, 3H).

Step 5: Synthesis of N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-nitropyridin-3-yl}acetamide hydrochloride

##STR00022##

To a 100 mL single-necked flask were added N-(6-chloro-2-methoxy-5-nitropyridin-3-yl)acetamide (1.0 g, 4.1 mmol), 30 ml acetonitrile and N,N,N′-trimethylethylenediamine (0.6 g, 6.1 mmol). The mixture was reacted at 80° C. for 3 hours. The reaction mixture was concentrated under a reduced pressure to about ⅓ of the original volume. 50 ml ethyl acetate was added. The mixture was stirred for several minutes, a solid precipitated and was filtered to produce 1.1 g of an beige solid with a yield of 87%.

¹H NMR (400 MHz, DMSO-d6) δ 11.13 (s, 1H), 9.53 (s, 1H), 8.73 (s, 1H), 4.05 (s, 5H), 3.41 3.36 (m, 2H), 2.83 (s, 3H), 2.80 (s, 6H), 2.07 (s, 3H).

Step 6: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-methoxy-3-nitropyridin-2,5-diamine hydrochloride

##STR00023##

To a 50 mL single-necked flask were added N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-methoxy-5-nitropyridin-3-yl}acetamide (600 mg, 1.93 mmol), 15 ml methanol and 0.3 ml concentrated hydrochloric acid. The mixture was reacted at 60° C. overnight. The reaction mixture was evaporated to dryness under a reduced pressure. 100 ml dichloromethane and 80 ml saturated sodium bicarbonate were added. The resulting mixture was stirred until no bubble produced. An organic layer was separated and dried with anhydrous sodium sulfate, filtered, and concentrated under a reduced pressure. The residue was purified by silica gel column chromatography (dichloromelhanemethanol=10:1) to produce 400 mg of a brown solid. MS m/z: 270 [M+1].

¹H NMR (400 MHz, DMSO-d6) δ 11.20 (s, 1H), 8.16 (s, 1H), 4.06-4.02 (m, 5H), 3.38 (br s, 2H), 2.83 (s, 3H), 2.80 (s, 3H), 2.79 (s, 3H).

Intermediate 1b: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-isopropyloxy-3-nitropyridin-2,5-diamine

##STR00024##

Step 1: Synthesis of 6-chloro-2-isopropyloxy-3-nitropyridine

##STR00025##

The compound was synthesized in the same manner as those in Step 1 of Intermediate 1a.

¹H NMR (400 MHz, CDCl₃) δ 8.22 (d, J=8.3 Hz, 1H), 6.98 (d, J=8.3 Hz, 1H), 5.50 (kept, J=6.2 Hz, 1H), 1.43 (d, J=6.2 Hz, 6H).

Step 2: Synthesis of 6-chloro-2-isopropyloxypyridin-3-amine

##STR00026##

The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 74%. MS m/z: 187 [M+1], 189.

Step 3: Synthesis of N-(6-chloro-2-isopropyloxypyridin-3-yl)acetamide

##STR00027##

The compound was synthesized in the same manner as those in Step 3 of Intermediate 1a with a yield of 83%. MS m/z: 229 [M+1], 231.

Step 4: Synthesis of N-(6-chloro-2-isopropyloxy-5-nitropyridin-3-yl)acetamide

##STR00028##

The compound was synthesized in the same manner as those in Step 4 of Intermediate 1a with a yield of 33%. MS m/z: 272 [M−1].

Step 5: Synthesis of N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide

##STR00029##

To a 500 mL single-necked flask were added N-(6-chloro-2-isopropyloxy-5-nitropyridin-3-yl)acetamide (15 g, 54.8 mmol), 150 ml acetonitrile, N,N,N′-trimethylethylenediamine (7.28 g, 71.3 mmol) and potassium carbonate (15.15 g, 110 mmol). The mixture was reacted at 80° C. overnight. The reaction mixture was cooled to room temperature, and filtered. The filtrate was evaporated to dryness under a reduced pressure to produce 18.6 g of a product with a yield of 100%.

MS m/z: 340 [M+1].

Step 6: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-isopropyloxy-3-nitropyridin-2,5-diamine

##STR00030##

The compound was synthesized in the same manner as those in Step 6 of Intermediate 1a with a yield of 38%. MS m/z: 298 [M+1].

Intermediate 1c: N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-3-nitropyridin-2,5-diamine

##STR00031##

Step 1: Synthesis of 6-chloro-2-(2,2,2-trifluoroethoxyl)-3-nitropyridine

##STR00032##

The compound was synthesized in the same manner as those in Step 1 of Intermediate 1a with a yield of 80%.

Step 2: Synthesis of 6-chloro-2-(2,2,2-trifluoroethoxyl)pyridin-3-amine

##STR00033##

The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 83%.

Step 3: Synthesis of N-[6-chloro-2-(2,2,2-trifuoroethoxyl)pyridin-3-yl]acetamide

##STR00034##

The compound was synthesized in the same manner as those in Step 3 of Intermediate 1a with a yield of 71%. MS m/z: 269 [M+1], 271.

Step 4: Synthesis of N-[6-chloro-2-(2,2,2-trifluoroethoxyl)-5-nitropyridin-3-yl]acetamide

##STR00035##

The compound was synthesized in the same manner as those in Step 4 of Intermediate 1a with a yield of 53%. MS m/z: 314 [M+1], 316.

¹H NMR (400 MHz, CDCl₃) δ 9.37 (s, 1H), 7.63 (s, 1H), 4.93 (q, J=8.2 Hz, 2H), 2.30 (s, 3H).

Step 5: Synthesis of N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-(2,2,2-trifluoroethoxyl)-5-nitropyridin-3-yl}acetamide

##STR00036##

To a 25 mL single-necked flask were added N-[6-chloro-2-(2,2,2-trifluoroethoxyl)]-5-nitropyridin-3-ypacetamide (626 mg, 2 mmol), 10 ml acetonitrile, N,N,N′-trimethylethylenediamine (224 mg, 2.2 mmol) and potassium carbonate (138 mg, 4 mmol). The mixture was stirred at room temperature overnight. To the reaction mixture was added 100 ml ethyl acetate. The resulting mixture was washed with 20 ml water, dried with anhydrous sodium sulfate, and evaporated under a reduced pressure to remove the solvent to produce 710 mg of a product with a yield of 94%. MS m/z: 380 [M+1].

Step 6: Synthesis of N²-methyl-N²-[2-(dimethylamino)ethyl]-6-(2,2,2-trifluoroethoxyl)-3-nitropyridin-2,5-diamine

##STR00037##

The compound was synthesized in the same manner as those in Step 6 of Intermediate 1a with a yield of 100%. MS m/z: 338 [M+1].

Intermediate 1d: tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}carbamate

##STR00038##

Step 1: Synthesis of N-tert-butoxycarbonyl-N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide

##STR00039##

To a 500 mL single-necked flask were added N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide (18.6 g, 54.8 mmol), 4-dimethylaminopyridine (0.67 g, 5.48 mmol), 150 ml acetonitrile and di-tert-butyl dicarbonate (59.8 g, 274 mmol). The mixture was reacted at 80° C. for 2.5 hours. The reaction mixture was cooled to room temperature, was evaporated to dryness under a reduced pressure, and purified by silica gel column chromatography (dichloromethane methanol=10:1) to produce 24 g of a product with a yield of 100%.

Step 2: Synthesis of tert-butyl {6-({[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}carbamate

##STR00040##

To a 500 mL single-necked flask were added N-tertbutoxycarbonyl-N-{6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxy-5-nitropyridin-3-yl}acetamide (24 g, 54.6 mmol) and 240 ml methanol. The mixture was cooled to 0° C. Sodium methoxide (2.95 g, 54.6 nunol) was added. The mixture was slowly warmed up to room temperature and reacted overnight. The reaction mixture was concentrated under a reduced pressure. The residue was dissolved in 300 ml ethyl acetate, and washed with 100 ml water. The organic phase was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness under a reduced pressure to produce 18 g of a product with a yield of 83%.

Step 3: Synthesis of tert-butyl {5-amino-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}carbamate

##STR00041##

The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 97%.

MS m/z: 368 [M+1].

¹H NMR (400 MHz, DMSO-d6) δ 7.61 (s, 1H), 7.44 (s, 1H), 6.74 (br s, 2H), 5.09-4.96 (m, 1H), 3.29 (t, J=5.8 Hz, 2H), 3.19 (t, J=5.7 Hz, 2H), 2.70 (s, 6H), 2.56 (s, 3H), 1.45 (s, 9H), 1.26 (d, J=6.2 Hz, 6H).

Step 4: Synthesis of tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}-carbamate

##STR00042##

To a 500 ml three-necked flask were added tert-butyl {5-amino-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-isopropyloxypyridin-3-yl}carbamate (9 g, 24.49 mmol), trimethylamine (6.83 ml, 49.0 mmol) and 250 ml dichloromethane. The reaction mixture was cooled in an ice-water bath to below 5° C. Acryloyl chloride (2.1 ml, 25.7 mmol) was dropwisely added. The resulting mixture was continued to react for 1 hour. The reaction mixture was washed successively with 150 ml saturated sodium bicarbonate solution and 150 ml saturated brine, dried with anhydrous sodium sulfate, and filtered. The filtrate was evaporated to dryness under a reduced pressure to produce 5 g of a product with a yield of 48%. MS m/z: 422 [M+1].

¹H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1H), 8.16 (s, 1H), 7.88 (s, 1H), 6.44 (dd, J=17.0, 10.1 Hz, 1H), 6.22 (dd, J=17.0, 1.9 Hz, IH), 5.74 (dd, J=10.1, 1.9 Hz, 1H), 5.22-5.13 (m, 1H), 3.09 (t, J=6.5 Hz, 2H), 2.77 (s, 3H), 2.41 (t, J=6.5 Hz, 2H), 2.18 (s, 6H), 1.45 (s, 9H), 1.31 (d, J=6.2 Hz, 6H).

Intermediate 1e: tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-(2,2,2-trifluoroethoxyl)pyridin-3-yl}carbamate

##STR00043##

The compound was synthesized in the same manner as those in Step 1 of Intermediate 1d with a yield of 99%. MS m/z: 480 [M+1].

Step 2: Synthesis of tert-butyl {6- f[2-(dimethylamino)ethyl](methypamino}-2-(2,2,2-trifluoroethoxyl)-5-nitropyridin-3-ylIcarbamate

##STR00044##

The compound was synthesized in the same manner as those in Step 2 of Intermediate 1d with a yield of 88%. MS m/z: 438 [M+1].

Step 3: Synthesis of tert-butyl {5-amino-6-{[2-(dimethylamino)ethyl](methyl)amino}-2-(2,2,2-trifluoroethoxyl)pyridin-3-yl}carbamate

##STR00045##

The compound was synthesized in the same manner as those in Step 2 of Intermediate 1a with a yield of 76%. MS m/z: 408 [M+1].

Step 4: Synthesis of tert-butyl {5-acrylamide-6-{[2-(dimethylamino)ethyl](methyl0amino}-2-(2,2,2-trifluoroethoxyl)pyridin-3-yl}carbamate

##STR00046##

The compound was synthesized in the same manner as those in Step 4 of Intermediate 1d with a yield of 62%. MS m/z: 462 [M+1].

¹H NMR (400 MHz, CDCl₃) δ 10.11 (s, 1H), 9.35 (s, 1H), 6.61 (s, 1H), 6.46 (dd, J=16.9, 1.7 Hz, 1H), 6.39-6.25 (m, 1H), 5.70 (dd, J=10.0, 1.8 Hz, 1H), 4.76 (q, J=8.5 Hz, 2H), 2.96 (s, 2H), 2.71 (s, 3H), 2.42 (s, 2H), 2.34 (s, 6H), 1.53 (s, 9H).

Intermediate 2a: 3-(2-chloropyrimidin-4-yl)-1-methyl-1H-indole

##STR00047##

To a 500 mL single-necked flask were added 2,4-dichloropyrimidine (14.9 g, 100 mmol), 1-methyl-1H-indole (13 g, 100 mmol), 200 ml 1,2-diclaloroethane and aluminium chloride (13.9 g, 120 mmol). The mixture was stirred at 80° C. for 1.5 hours. The reaction mixture was cooled to room temperature in an ice bath. 120 ml methanol and 400 ml water were added to quench the reaction. A solid precipitated and was filtered. The filter cake was washed with methanol, and dried in vacuum to produce 17.2 g of a product with a yield of 71%. MS m/z: 244 [M+1], 246.

¹H NMR (400 MHz, DMSO-d6) δ 8.53 (d, J=5.5 Hz, 1H), 8.49 (s, 1H), 8.42 (dd, J=7.0, 1.5 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.56 (dd, J=7.0, 1.2 Hz, 1H), 7.33-7.26 (m, 2H), 3.90 (d, J=5.2 Hz, 3-H).

Intermediate 2b: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-indole

##STR00048##

The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 87%. MS m/z: 278[M+1], 279, 280.

¹H NMR (400 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.74 (s, 1H), 8.56 (dd, J=7.3, 1.2 Hz, 1H), 7.62 (d, J=7.6 Hz, 1H), 7.39-7.34 (m, 1H), 7.34-7.29 (m, 1H), 3.97 (s, 3H).

Intermediate 2c: 3-(2-chloropyrimidin-4-yl)-1-methyl-5-fluoro-1H-indole

##STR00049##

The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 29%. MS m/z: 262 [M+1], 264.

¹H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 8.53 (d, J=5.5 Hz, 1H), 8.10 (dd, J=10.3, 2.5 Hz, 1H), 7.80 (d, J=5.5 Hz, 1H), 7.60 (dd, J=8.9, 4.6 Hz, 1H), 7.17 (td, J=9.1, 2.6 Hz, 1H), 3.90 (s, 3H).

Intermediate 2d: 3-(2-chloropyrimidin-4-yl)-1-methyl-6-fluoro-1H-indole

##STR00050##

The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 262 [M+1], 264.

¹H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J=5.5 Hz, 1H), 8.49 (s, 1H), 8.39 (dd, J=8.8, 5.6 Hz, 1H), 7.81 (d, J=5.5 Hz, 1H), 7.47 (dd, J=9.9, 2.3 Hz, 1H), 7.14 (td, J=9.6, 2.4 Hz, 1H), 3.86 (s, 3H).

Intermediate 2e: 3-(2-chloropyrimidin-4-yl)-1-methyl-5,6-difluoro-1H-indole

##STR00051##

The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 280 [M+1], 282.

¹H NMR (400 MHz, DMSO-d6) δ 8.54 (d, J=5.5 Hz, 1H), 8.52 (s, 1H), 8.22 (dd, J=11.7, 8.2 Hz, 1H), 7.79 (d, J=5.5 Hz, 1H), 7.73 (dd, J=11.2, 7.0 Hz, 1H), 3.86 (s, 3H).

Intermediate 2f: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-6-fluoro-1H-indole

##STR00052##

The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 296 [M+1], 297, 298.

¹H NMR (400 MHz, CDCl₃) δ 8.69 (dd, J=8.9, 5.5 Hz, 1H), 8.50 (s, 1H), 8.41 (s, 1H), 7.17 7.07 (m, 2H), 3.90 (s, 3H).

Intermediate 2g: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-5,6-difluoro-1H-indole

##STR00053##

The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 314 [M+1], 315, 316.

¹H NMR (400 MHz, DMSO-d6) δ 8.85 (s, 1H), 8.77 (s, 1H), 8.39 (dd, J=12.1, 8.3 Hz, 1H), 7.83 (dd, J=11.0, 7.1 Hz, 1H), 3.94 (s, 3H).

Intennediate 2h: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-5-fluoro-1H-indole

##STR00054##

The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 296 [M+1], 297, 298.

¹H NMR (400 MHz, CDCl₃) δ 8.49 (s, 1H), 8.46 (s, 1H), 8.46-8.42 (m, 1H), 7.34 (dd, J=8.9, 4.4 Hz, 1H), 7.14 (td, J=8.9, 2.6 Hz, 1H), 3.94 (s, 3H).

Intermediate 2i: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-1H-indole

##STR00055##

The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 73%. MS m/z: 262 [M+1], 264.

¹H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J=3.7 Hz, 1H), 8.54 (dd, J=7.2, 1.2 Hz, 1H), 8.39 (d, J=3.0 Hz, 1H), 7.62 (d, J=7.5 Hz, 1H), 7.41-7.30 (m, 2H), 3.96 (s, 3H).

Intermediate 2j: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-5-fluoro-1H-indole

##STR00056##

The compound was synthesized in the same manner as those in Intermediate 2a with a yield of 77%. MS m/z: 280 [M+1], 282.

¹H NMR (400 MHz, DMSO-d6) δ 8.71 (d, J=3.5 Hz, 1H), 8.45 (d, J=2.8 Hz, 1H), 8.20 (dd, J=10.3, 2.5 Hz, 1H), 7.66 (dd, J=8.9, 4.5 Hz, 1H), 7.30-7.16 (m, 1H), 3.96 (s, 3H).

Intermediate 2k: 3-(2-chloro-5-fluoropyrimidin-4-yl)-1-methyl-5,6-difluoro-1H-indole

##STR00057##

The compound was synthesized in the same manner as those in Intermediate 2a. MS m/z: 298 [M+1], 300.

¹H NMR (400 MHz, CDCl₃) δ 8.56 (dd, J=11.4, 8.1 Hz, 1H), 8.36 (d, J=3.3 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.19 (dd, J=10.1, 6.6 Hz, 1H), 3.90 (s, 3H).

Intermediate 2l: 3-(2,5-dichloropyrimidin-4-yl)-1-methyl-1H-

The tumor growth curves of three experimental groups are shown in FIG. 1, and the mice's weight growth curves are shown in FIG. 2. The results show that the compounds of the present invention have a good inhibition effect on the growth of subcutaneously transplanted tumors of human lung cancer H1975-bearing nude mice, while having little effect on the weights of nude mice, and showing a good safety.

All of the literatures mentioned herein are incorporated into the present application by reference. It should be also noted that, upon reading the above mentioned contents of the present application, a person skilled in the art can modify, change or amend the present invention without departing from the spirits of the present invention, and these equivalents are also within the scope as defined by the claims appended in the present application.

Claims

1. A compound represented by the following general formula (I), or a pharmaceutically acceptable salt thereof,

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein Ring A is heteroaryl.

3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein Ring A is indolyl, indazolyl, pyrro[2,3-c]pyridinyl, pyrro[3,2-c]pyridinyl, pyrro[2,3-b]pyridinyl, pyrro[3,2-b]pyridinyl, pyrro[2,3-b]pyrazinyl, indolin-2-onyl, pyridinyl, pyrazolyl or pyrimidinyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R₁ is hydrogen, halogen or haloC₁-C₄alkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R₂ is C₁-C₄alkyl or haloC₁-C₄alkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R₂ is C₂-C₄alkyl or haloC₂-C₄alkyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R₂ is isopropyl or trifluoroethyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R₄ is

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R₄ is

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R₃ is selected from a group consisting of

halogen, —CN, —NO₂, C₁-C₄alkyl, haloC₁-C₄alkyl, —C(O)R₇, —C(O)NR₇R₇′, —OR₇, —NHR₇, —NR₇—(C₁-C₄alkyl), —NR₇(CH₂)_nC(O)R₆, or —NR₆R₇,

or heterocycloalkyl that is unsubstituted or substituted with 1-3 substituents selected from halogen, C₁-C₄alkyl, haloC₁-C₄alkyl, —(CH₂)_nOH, —NR₇R₇′, —OR₇ or —C(O)R₇;

wherein, R₆ is —(CH₂)OR₇, —(CH₂)_qNR₇R₇′, —(CH₂)_qC(O)R₇ or —(CH₂)_qC(O)NR₇R₇′;

R₇ and R₇′ are each independently hydrogen, C₁-C₄alkyl or haloC₁-C₄alkyl, or R₇, R₇′ and the nitrogen atom attached thereto are cyclized together together to form a heterocycloalkyl;

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R₃ is —NR₆R₇, in which R₆ is —(CH₂)_qNR₇R₇′, R₇ and R₇′ are each independently hydrogen or C₁-C₄alkyl, q is 2.

12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R₃ is a heterocycloalkyl substituted by one substituent selected from halogen, C₁-C₄alkyl, haloC₁C₄alkyl or —NR₇R₇′, R₇ and R₇′ are each independently hydrogen or C₁-C₄alkyl.

13. The compound according to claim 12 or a pharmaceutically acceptable salt thereof, wherein said heterocycloalkyl is pyrrolidinyl.

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R₅ is dependently halogen, C₁-C₄alkyl, haloC₁-C₄alkyl, —OR₇, —NR₇R₇′, —CN or —N_O2, R₇ and R₇′ are each independently hydrogen or C₁-C₄alkyl, m is 1, 2 or 3.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein each R₅ is dependently halogen, C₁-C₄alkyl, —OR₇ or NR₇R₇′, R₇ and R₇′ are each independently hydrogen or C₁-C₄alkyl, m is 1, 2 or 3.

16. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein said compound is selected from a group consisting of:

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino)pyridin-3-yl}acrylamide;

N-(2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro[4-(1-methyl-6-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-fluoro-[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-fluoro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-fluoro[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-6-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{5-fluoro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-(2,2,2-trifluoroethoxyl)-5-{[4-(1-methyl-5-fluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide methanesulfonate;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{5-chloro-[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide methanesulfonate;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[4-(1-methyl-5,6-difluoro-1H-indol-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide methanesulfonate;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[5-chloro-4-(1-methyl-1H-pyrro[2,3-b]pyridin-3-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[5-chloro-4-(1-methyl-1H-pyrro[2,3-b]pyridin-5-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[5-chloro-4-(1-methyl-1H-pyrazol-4-yl)pyrimidin-2-yl]amino}pyridin-3-yl}acrylamide;

N-{2-{[2-(dimethylamino)ethyl](methy)amino}-6-isopropyloxy-5-{[5-choro-2′-methoxy-(4,5′-bipyrimidine)-2-yl]amino}pyridin-3-yl}acrylamide; and

N-{2-{[2-(dimethylamino)ethyl](methyl)amino}-6-isopropyloxy-5-{[5-chloro-2′amino-(4,5′-bipyrimidine)-2-yl]amino}pyridin-3-yl}acrylamide.

17. A process for preparing the compound represented by the general formula (I) of claim 1, comprising the steps of:

18. A pharmaceutical composition, comprising the compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent.

19. A method for treating an egfr activating or resistant mutation mediated lung cancer in a mammal, said method comprises administering to a mammal the compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a therapeutically effective amount of a compound represented by formula (I) of claim 1 and a pharmaor ceutically acceptable carrier, excipient or diluent.

20. A method for selectively inhibiting an egfr activating or resistant mutation over a egfr, said method comprises contacting a biological sample with or administering to a lung cancer patient the compound represented by formula (I) of claim 1 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same.

21. The method of claim 19, wherein the mammal is a human.

22. A pharmaceutical composition comprising a compound having the structure:

23. A pharmaceutical composition comprising a compound having the structure:

24. A method for treating an egfr activating or resistant mutation-mediated lung cancer in a mammal, said method comprises administering to the mammal a compound having the structure:

25. A method for treating an egfr activating or resistant mutation-mediated lung cancer in a mammal, said method comprises administering to the mammal a compound having the structure: