EGFR Inhibitor, Composition, and Preparation Method Therefor

Abstract

The present invention relates to compounds of Formula I, methods of using the compounds as EGFR inhibitors, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.

##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, ##STR00115## wherein, R.sub.1 and R.sub.2 are independently selected from halogens, CN, NH.sub.2, —C.sub.1-6 alkyl, —C.sub.1-6 alkoxy and —C.sub.3-5 cycloalkyl, respectively; the NH.sub.2, —C.sub.1-6 alkyl, —C.sub.1-6 alkoxy and —-C.sub.3-5 cycloalkyl are optionally substituted with halogens and —C.sub.1-4 alkyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form phenyl, —C.sub.5-6 heteroaryl, —C.sub.5-7 heterocyclyl or —C.sub.5-6 cycloalkyl; the phenyl, —C.sub.5-6 heteroaryl, —C.sub.5-7 heterocyclyl or —C.sub.5-6 cycloalkyl are optionally substituted with halogen, CN, NH.sub.2, —C.sub.1-6 alkyl; R.sub.3 is selected from hydrogen, halogen and —C.sub.1-6 alkyl; R.sub.4 is selected from hydrogen, halogen, —C.sub.1-6 alkyl, —C.sub.1-6 alkoxy and —C.sub.1-6 haloalkyl; R.sub.5 is selected from —C.sub.5-6 heterocyclyl, ##STR00116## the —C.sub.5-6 heterocyclyl is optionally substituted with —C.sub.4-6 cycloalkyl, —C.sub.4-6 heterocyclyl and —NR.sub.7R.sub.8; R.sub.6, R.sub.7, R.sub.8, R.sub.12, R.sub.13, R.sub.14 and R.sub.15 are independently selected from hydrogen, —C.sub.1-6 alkyl and —C.sub.1-6 halogenated alkyl, respectively; X is selected from CH and N; m, n, m′, n′, and s are independently selected from 1 and 2, respectively.

2. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.1 and R.sub.2 are independently selected from —C.sub.1-6 alkyl and —C.sub.3-5 cycloalkyl.

3. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.1 and R.sub.2 are independently selected from —CH.sub.3 and ##STR00117##

4. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.1 and R.sub.2, together with the atoms to which they are attached form —C.sub.5-6 heteroaryl; the —C.sub.5-6 heteroaryl is optionally substituted with hydrogen, halogen, CN, —NH.sub.2, —C.sub.1-3 alkyl, and —C.sub.3-5 cycloalkyl.

5. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.1 and R.sub.2 together with the atoms to which they are attached form ##STR00118##

6. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.1 and R.sub.2 together with the atoms to which they are attached form ##STR00119##

7. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.3 is selected form halogen.

8. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.3 is selected form Cl or Br.

9. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.4 is selected from —C.sub.1-6 alkoxy.

10. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.4 is selected form —O—CH.sub.3.

11. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.5 is selected from —C.sub.5-6 heterocyclyl.

12. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.5 is selected from ##STR00120##

13. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.6 is selected from hydrogen, —C.sub.1-3 alkyl and —C.sub.1-3 halogenated alkyl.

14. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein R.sub.6 is selected from H, CH.sub.3, CH.sub.2CH.sub.3 and CHF.sub.2.

15. The compound of claim 1, or a stereoisomer, tautomer, deuterated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, wherein the compound is: 1) (6-(5-Chloro-2-((2-methoxy-5-(1-methyl-1hydro-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 2) (6-((5-Chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 3) (6-((5-Chloro-2-((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-(1H-pyrazol-4-yl) benzene)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 4) (6-((5-Chloro-2((4-(4-(dimethylamino)piperidin-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 5) (6-((2-((4-([1,4′-Dipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) Phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 6) (6-((5-Chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(pyrrol-1-yl) piperidine-1-yl)phenyl)amino)pyrimidin-4-yl)yl)-2,3-dimethylphenyl)dimethylphosphine oxide; 7) (6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-4-(2-methyl-2,7-diazaspiro[3.5]nonyl-7-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 8) (R)-(6-((5-chloro-2-((2-methoxy-5-methyl-1H-pyrazol-4-yl)-4-(octahydro-2hydro-Pyridine [1,2-a]pyrazine-2-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 9) (6-((5-chloro-2-(2-methoxy-5-(1-methyl-1hydro-pyrazole)-4-morpholinephenyl)amino) pyrimidine-4-amino)quinoxalin-5-dimethylphosphine oxide; 10) (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 11) (6-((2((4-([1,4′-Bipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)-5-bromopyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 12) (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-3-cyclopropyl-2-methyl)dimethylphosphine oxide; 13) (6-((2-((4-([1,4′-Bipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)-5-bromopyrimidine-4-yl)amino)-3-cyclopropyl-2-methylphenyl)dimethylphosphine oxide; 14) (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1h-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 15) (6-((2-((4-([1,4′-Bipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)-5-bromopyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 16) (6-((2-((4-([1,4′-Bipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)-5-bromopyrimidine-4-yl)amino)-3-cyclopropyl-2-methylphenyl)dimethylphosphine oxide; 17) (6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1h-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 18) (R)-(6-((5-Chloro-2-((2-methoxy-5-([1-methyl-1hydro-pyrazol-4-yl]-4-(octahydro-2hydro-pyrazol[1,2-a]pyrazine-2-yl) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 19) (6-((5-Bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 20) (6-((2-((4-([1,4′-Bipiperidine]-1′-yl)-5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl) amino)-5-bromopyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 21) (6-((5-Chloro-2-((5-(1-methyl-1hydro-pyrazol-4-yl)-2-methoxy-4-morpholinophenyl) amino)pyrimidine-4-Amino)2,3-dimethylphenyl)-dimethylphosphine oxide; 22) (6-((5-Bromo-2-((5-(1-ethyl-1h-pyrazol-4-yl)-2-methoxy-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 23) (6-(2-(5-((1-Ethyl-1hydro-pyrazol-4-yl)-2-methoxy-4-morpholinophenyl)amino) pyrimidine-4-amino)-2,3 dimethylphenyl)dimethylphosphine oxide; 24) (6-((5-Bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-4-morpholinophenyl) amino)pyrimidine-4-Amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine oxide; 25) (6-((5-Bromo-2-((4-(4-cyclopentylpiperazine-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide; 26) (6-((5-Bromo-2-((4-(4-cyclopentylpiperazine-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide; 27) (6-((5-Bromo-2-((4-(4-cyclopentylpiperazine-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-Yl) phenyl)amino)pyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine oxide; or 28) (6-((5-Chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidine-1-yl)phenyl)amino)pyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine, oxide).

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

17. A method of inhibiting various different forms of EGFR, including L858R, Δ19del, T790M, C797S and any combination of them, said method comprising administering to a patient a compound of claim 1, or a pharmaceutically acceptable salt thereof.

18. A method of treating EGFR-driven cancer, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1, or a pharmaceutically acceptable salt thereof.

19. The method of claim 18, wherein EGFR-driven cancer characterized by the presence of one or more mutations selected from, but not limited to: (i) C797S, (ii) L858R and C797S, (iii) C797S and T790M, (iv) L858R, T790M, and C797S, or (v) Δ19del , T790M and C797S.

20. The method of claim 18, wherein EGFR-driven cancers involve colon cancer, stomach cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, brain cancer, kidney cancer, prostate cancer, ovarian cancer, or breast cancer.

21. The method of claim 20, wherein lung cancer is non-small cell lung cancer caused by EGFR.sup.L858R/T790M/C797S or EGFR.sup.Δ19del/T790M/C797S mutant.

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)

Description

EXAMPLES

[0103] It should be understood that the preceding general descriptions and the detailed descriptions below are exemplary and illustrative only and are not a restriction on any subject requiring protection. Unless expressly stated otherwise, all portions and percentages are by weight, and all temperature units are in degrees Celsius. The compounds described herein can be obtained from commercial sources or synthesized by conventional methods as shown below using commercially available raw materials and reagents.

[0104] The following abbreviations have been used in embodiments:

[0105] AcOH: acetic acid;

[0106] DIEA: N,N-diisopropylethylamine;

[0107] DMF: N,N-dimethylformamide;

[0108] DMSO: dimethyl sulfoxide;

[0109] EA: ethyl acetate;

[0110] HEPES: 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid;

[0111] LCMS: Liquid Chromatography-Mass Spectrometry;

[0112] h or hrs: hours;

[0113] Pd/C: Palladium on active carbon;

[0114] MeOH: methanol;

[0115] n-BuOH: n-butanol

[0116] DME: 1,2-Dimethoxyethane

[0117] 1,4-dioxane: 1,4-dioxane

[0118] p-TsOH: p-toluenesulfonic acid

[0119] K.sub.2CO.sub.3: Potassium carbonate

[0120] K.sub.3PO.sub.4: Potassium phosphate

[0121] NMP: N-methyl-2-pyrrolidone;

[0122] TLC: Thin Layer Chromatography;

[0123] Ra/Ni: Raney Nickel

[0124] Pd(OAc).sub.2: Palladium acetate

[0125] Pd(PPh.sub.3).sub.4: Tetrakis(triphenylphosphine) palladium(0)

[0126] Pd(dppt).sub.2Cl.sub.2CH.sub.2Cl.sub.2: 1,1′-Bis(diphenylphosphino)ferroceue-palladium(II)dichloride dichloromethane complex

[0127] Xantphos: 4,5-bis-diphenylphosphanyl-9,9-dimethyl-9h-xanthene.

Example 1 Synthesis of Compound 1

(6-((5-Chloro-2-((2-methoxy-5-(1-methyl-1hydro-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0128] ##STR00008##

Step 1: Synthesis of Compound 1-2

[0129] ##STR00009##

[0130] Under nitrogen gas protection, add 1-1 (500 mg) and N-methylpyrazoleboronic acid (450 mg) into a 50 mL single-neck flask, dissolve them in 10 mL dioxane and 2 mL water, and then add Pd(dppf).sub.2C.sub.12CH.sub.2C.sub.12 (160 mg) and K.sub.2CO.sub.3 (560 mg) into the flask, then replace nitrogen gas for three times, and keep them for chemical reaction overnight in an oil bath at 100° C. Cool down. Pour the reaction solution into water, extract it with ethyl acetate for three times, and merge, dry and concentrate the organic phase. The obtained crude is slurried with petroleum ether to get 400 mg product 1-2, MS: 252 [M+H]+

Step 2: Synthesis of Compound 1-3

[0131] ##STR00010##

[0132] Add 1-2 (400 mg) and 1-methyl-4-(4-piperidinyl)piperazine (146 mg) into a 50 mL single-neck flask, dissolve them in 10 mL DMSO, and then add K.sub.2CO.sub.3 (440 mg) into the flask, and keep them for chemical reaction overnight in an oil bath at 100° C., then process them by the way of cooling down, diluting, washing with water, washing with saturated sodium chloride, drying the organic phase, spinning dry, column chromatography (petroleum ether: ethyl acetate=4:1) to get the product (compound 1-3) 600 mg, MS: 415 [M+H]+

Step 3: Synthesis of Compound 1-4

[0133] ##STR00011##

[0134] Add 1-3 (200 mg) to a 25 single-neck flask, dissolve them in 5 mL methanol, and then add Raney nickel (20 mg) into the flask, then replace nitrogen gas for three times, and keep them for chemical reaction at 25° C. for 2 h, then filter them and spin them dry to obtain the product (Compound 1-4) 100 mg, proceed to the next reaction directly, MS: 385 [M+H]+

Step 4: Synthesis of Compound 1-6

[0135] ##STR00012##

[0136] Add 1-5 (2.5 g) to a 200 mL single-neck flask, dissolve them in 75 mL AcOH, add iodine chloride (dissolve iodine chloride in 25 mL AcOH) dropwise into the flask at room temperature, keep them fir chemical react at room temperature for 1 h, concentrate them, then add 100 mL ethyl acetate, and use saturated sodium bicarbonate solution to adjust the pH to 9, then wash it with water, sodium thiosulfate aqueous solution and saturated brine, then process them by the way of drying, filtering, spinning dry to get crude product, then the crude product is slurried with ether to obtain 4 g of a brown-red product, which is directly proceeded to the next reaction, MS: 272 [M+H]+

Step 5: Synthesis of Compound 1-7

[0137] ##STR00013##

[0138] Add compound 1-6 (3.0 g), dimethylphosphine oxide (1.29 g), K.sub.3PO.sub.4 (5.49 g), Pd(OAc).sub.2 (243.10 mg), Xantphos (1.25 g), and dioxane (20 mL) into a 100 mL reaction flask, raise the temperature to 100° C. under N.sub.2 protection, and then heat and stir for 12 h. Stop the reaction when LCMS monitors the end of the reaction. Add water (50 mL) to the reaction solution to extract it with dichloromethane (3×50 mL), wash the organic phase with saturated brine (3×30 mL), and then dry it with anhydrous sodium sulfate, then separate and purify it with column chromatography (dichloromethane: Methanol=15:1), and then remove the solvent to get the target product 1-6 (2.0 g) as a brown solid, MS: 222 [M+H].sup.+

Step 6: Synthesis of Compound 1-9

[0139] ##STR00014##

[0140] Add compounds 1-7 (1 g), 1-8 (1.64 g), DIEA (1.16 g), and n-BuOH (20 mL) to the reaction flask in sequence, raise the temperature to 120° C., heat and stir for 12 h. Stop the reaction when LCMS monitor the end of the reaction. Add water (50 mL) to the reaction solution to extract it with dichloromethane (3×50 mL), wash the organic phase with saturated brine (3×30 mL), and then dry and concentrate it with anhydrous sodium sulfate, then separate and purify it with Column chromatography (dichloromethane: Methanol=15:1), and then remove the solvent to get the target product 1-9(0.6 g) as a yellow solid. MS:368 [+H].sup.+

Step 7: Synthesis of Compound 1

[0141] ##STR00015##

[0142] Add 1-4 (100 mg), 1-5 (105 mg) to a 5 mL microwave tube, dissolve them in NMP (1 mL), and then add p-TsOH (95 mg) for chemical react at 140° C. for 1 h, and the system was directly purified with Flash purification system to get the 64.4 mg of product (CH.sub.3CN:H.sub.2O=5%˜50%). MS: 716 [M+H].sup.+

Example 2 Synthesis of Compound 2

(6-((5-Chloro-2-((4-(4-dimethylamino)piperidine-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0143] ##STR00016##

Step 1: Synthesis of Compound 2-2

[0144] ##STR00017##

[0145] Prepare compound 2-2 as the method described for compound 1-3 using compound 2-1 instead of compound 1-2, N,N-Dimethylpiperidin-4-amine instead of 1-methyl-4-(4-piperidinyl)piperazine. MS: 358 [M+H].sup.+

Step 2: Synthesis of Compound 2-3

[0146] ##STR00018##

[0147] Prepare compound 2-3 as the method described for compound 1-4 using compound 2-2 instead of compound 1-3. MS: 328 [M+H].sup.+

Step 3: Synthesis of Compound 2-4

[0148] ##STR00019##

[0149] Prepare compound 2-4 as the method described for compound 1-2 using compound 2-3 instead of compound 1-1, MS: 330 [M+H].sup.+

Step 4: Synthesis of Compound 2

[0150] ##STR00020##

[0151] Prepare compound 2 as the method described for compound 1 using compound 2-4 instead of compound 1-4. MS: 661 [M+H]+

Example 3 Synthesis of Compound 3

(dimethylamino)piperidine-1-yl)-2-methoxy-5-(1H-pyrazol-4-yl) phenyl)amino)pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0152] ##STR00021##

Step 1: Synthesis of Compound 3-2

[0153] ##STR00022##

[0154] Prepare compound 3-2 as the method described for compound 1-2 using compound 3-1 instead of compound 1-1, compound 1-Boc-4-pyrazole boronic acid instead of compound N-methylpyrazole boronic acid. MS: 416 [M+H]+

Step 2: Synthesis of Compound 3

[0155] ##STR00023##

[0156] Prepare compound 3 as the method described for compound 1 using compound 3-2 instead of compound 1-4. MS:647 [M+H].sup.+

Example 4 Synthesis of Compound 4

(6-((5-Chloro-2-((4-(4-(dimethylamino)piperidine-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

[0157] ##STR00024##

Step 1: Synthesis of Compound 4-1

[0158] ##STR00025##

[0159] Add compound 4-1 (2.0 g), HCl (10 mL) to the reaction flask, and add NaNO.sub.2 (996.53 mg) aqueous solution (5 mL) dropwise into the reaction flask at 0° C., and continue stirring for 1 h, then add KI (3.00 g) aqueous solution (10 mL), keep it return to room temperature naturally and continue stirring for 1 h. Stop the reaction as TLC monitoring the end of the reaction. Add water (20 mL) to the reaction solution to extract the organic phase with ethyl acetate (3×20 mL), and wash the organic phase with Na.sub.2S.sub.2O.sub.3 (3×20 mL), saturated brine (3×20 mL), and dry it with anhydrous sodium sulfate, then separate and purify it with Column chromatography (n-hexane: ethyl acetate=8:1), and then remove the solvent to get the target compound 4-2 (3.0 g) as a yellow solid.

Step 2: Synthesis of Compound 4-3

[0160] ##STR00026##

[0161] Add compound 4-2 (3.0 g), dimethylphosphine oxide (1.27 g), K.sub.3PO.sub.4 (4.60 g), Pd(OAc) 2 (243.10 mg), Xantphos (1.25 g), dioxane (20 mL) to the reaction flask in sequence, under the protection of N2, raise the temperature to 100° C., and then heat and stir for 12 h. Stop the reaction when LCMS monitoring the end of the reaction. Add water (50 mL) to the reaction solution to extract it with dichloromethane (3×50 mL), then wash the organic phase with saturated brine (3×30 mL), and dry it with anhydrous sodium sulfate, then separate and purify it with Column chromatography (dichloromethane: Methanol=15:1), and then remove the solvent to get the target product 4-3 (2.0 g) as a brown solid. MS: 228 [M+H].sup.+

Step 3: Synthesis of Compound 4-4

[0162] ##STR00027##

[0163] Add compound 4-3 (2.0 g), Pd/C (500 mg), and. MeOH (30 mL) to the reaction flask in sequence, then inject H.sub.2 into it, and stir the reaction solution at room temperature for 3 h. Stop the reaction when LCMS monitoring the end of the reaction. Filter it by suction, rinse with methanol (20 mL), collect the organic phase, then remove the solvent to get the target product 4-4 (1.2 g) as a light brown solid. MS: 198 [M+H].sup.+

Step 4: Synthesis of Compound 4-5

[0164] ##STR00028##

[0165] Add compound 4-4 (1 g), 1-8 (1.40 g), K.sub.2CO.sub.3 (1.40 g), and DMF (20 mL) to the reaction flask in sequence, raise the temperature to 100° C., and then heat and stir for 12 h. Stop the reaction when LCMS monitoring the end of the reaction. Pour the reaction solution into water (50 mL) and extract it with dichloromethane (3×50 mL), then tWash the organic phase with saturated brine (3×30 mL), then dry it with anhydrous sodium sulfate, then separate and purify it with Column chromatography (dichloromethane: Methanol=15:1), and then remove the solvent to get the target compound 4-5 (1.5 g) as a yellow solid. MS:344 [M+H].sup.+

Step 5: Synthesis of Compound 4

[0166] ##STR00029##

[0167] Prepare compound 5 as the method described for compound 1 using compound 2-4 instead of compound 1-4, compound 4-5 instead of compound 1-9. MS: 637 [M+H].sup.+

Example 5 Synthesis of Compound 5 (36560)

(6-((2-((4-([1,4′-Dipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0168] ##STR00030##

Step 1: Synthesis of Compound 5-1

[0169] ##STR00031##

[0170] Prepare compound 6-1 as the method described for compound 1-3 using compound 1,4′-bipiperidine instead of compound 1-methyl-4-(4-piperidinyl)piperazine, MS: 400 [M+H].sup.+

Step 2: Synthesis of Compound 5-2

[0171] ##STR00032##

[0172] Prepare compound 5-2 as the method described for compound 1-4 using compound 5-1 instead of compound 1-3. MS: 370 [M+H].sup.+

Step 3: Synthesis of Compound 5

[0173] ##STR00033##

[0174] Prepare compound 5 as the method described for compound 1 using compound 5-2 instead of compound 1-4. MS: 701 [M+H].sup.+

Example 6 Synthesis of Compound 6

(6-((5-Chloro-2-(((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(pyrrol-1-yl) piperidine-1-yl) phenyl)amino) pyrimidine-4-yl) amino)-2,3-dimethylphenyl)dimethylphosphine oxide

[0175] ##STR00034##

Step 1: Synthesis of Compound 6-1

[0176] ##STR00035##

[0177] Prepare compound 6-1 as the method described for compound 1-3 using compound 4-pyrrolidine-1-yl-piperidine instead of compound 1-methyl-4-(4-piperidinyl)piperazine. MS: 386 [M+H].sup.+

Step 2: Synthesis of Compound 6-2

[0178] ##STR00036##

[0179] Preapre compound 6-2 as the method described for compound 1-4 using compound 6-1 instead of compound 1-3, MS: 356 [M+H].sup.+

Step 3: Synthesis of Compound 6

[0180] ##STR00037##

[0181] Prepare compound 6 as the method described for compound 4 using compound 6-2 instead of compound 2-4. MS: 663 [M+H].sup.+

Example 7 Synthesis of Compound 7

(6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-4-(2,7-diaza-spiro[3.5]nonyl-7-yl)phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)phosphine oxide

[0182] ##STR00038##

Step 1: Synthesis of Compound 7-1

[0183] ##STR00039##

[0184] Prepare compound 6-1 as the method described for compound 1-3 using compound 2-methyl-2,7-diaza-spiro[3.5]nonane instead of compound 1-methyl-4-(4-piperidinyl)piperazine, MS: 372 [M+H].sup.+

Step 2: Synthesis of Compound 7-2

[0185] ##STR00040##

[0186] Prepare compound 7-2 as the method described for compound 1-4 using compound 7-1 instead of compound 1-3. MS: 342 [M+H].sup.+

Step 3: Synthesis of Compound 6

[0187] ##STR00041##

[0188] Prepare compound 7 as the method described for compound 4 using compound 7-2 instead of compound 2-4. MS: 649 [M+H].sup.+

Example 8 Synthesis of Compound 8

(R)-(6-((5-chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(octahydro-2hydro-Pyridine[1,2-a]pyrazine-2-yl)phenyl)amino)pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

[0189] ##STR00042##

Step 1: Synthesis of Compound 8-1

[0190] ##STR00043##

[0191] Prepare compound 8-1 as the method described for compound 1-3 using compound (R)-Octahydro-1H-pyrido[1,2-a]pyrazine instead of compound 1-methyl-4-(4-piperidinyl)piperazine. MS: 372[M+H].sup.+

Step 2: Synthesis of Compound 8-2

[0192] ##STR00044##

[0193] Prepare compound 8-2 as the method described for compound 1-4 using compound 8-1 instead of compound 1-3. MS: 342 [M+H].sup.+

Step 3: Synthesis of Compound 8

[0194] ##STR00045##

[0195] Prepare compound 8 as the method described for compound 4 using compound 8-2 instead of compound 2-4. MS: 649 [M+H].sup.+

Example 9 Synthesis of Compound 9

(6-((5-chloro-2-((2-methoxy-5-(1-methyl-1hydra-pyrazole)-4-morpholinephenyl) amino)pyrimidine-4-amino)quinoxaline-5-dimethylphosphine oxide

[0196] ##STR00046##

Step 1: Synthesis of Compound 9-2

[0197] ##STR00047##

[0198] Add 9-1 (0.4 g) and N-methylpyrazole boronic acid (399 mg) to a flask with stirring nitrogen protection, dissolve them in 10 mL dioxane and 2 mL water, and then add Pd(dppf) to it Cl.sub.2 (130 mg) and K.sub.2CO.sub.3 (265 mg) into the flask, then replace nitrogen gas for three times and transfer them into an oil bath at 100° C. to have chemical reaction overnight. when the raw materials for chemical reaction are exhausted and the main peak was the product under LCMS monitoring, stop the chemical reaction and lower the temperature of reaction solution to room temperature. Pour the reaction solution into 50 mL of water, then extractit with 30 mL of ethyl acetate for three times, and the organic phases were merged, dried, and concentrated. The crude product was purified by the mixing with a silica gel column (petroleum ether: ethyl acetate from 0 to 80%) to obtain 400 mg of product. MS: 252 [M+H].sup.+

Step 2: Synthesis of Compound 9-3

[0199] ##STR00048##

[0200] Add 9-2 (0.4 g) and morpholine (278 mg) to a flask with stirring nitrogen protection, dissolve them in 10 mL DMSO, then add K.sub.2CO.sub.3 (441 mg) to the flask, then replace nitrogen gas for three times and transfer them into an oil bath at 90° C. to have chemical reaction overnight. When LCMS monitored that the raw materials for chemical reaction were exhausted and the main peak was the product, stop the chemical reaction and lower the temperature of reaction solution to room temperature. Pour the reaction solution into 60 mL of water, then extractit with 40 mL of ethyl acetate for three times, and the organic phases were merged, dried, and concentrated.

[0201] The crude product was purified by the mixing with a silica gel column (petroleum ether: ethyl acetate from 0 to 100%) to obtain 400 mg of product. MS: 319 [M+H].sup.+

Step 3: Synthesis of Compound 9-4

[0202] ##STR00049##

[0203] Add compound 9-3 (400 mg) into 15 mL of tetrahydrofuran and 5 ml of methanol in a round bottom flask with a stirring device, and then add 0.25 g of Raney Ni into flask, then replace nitrogen gas for three times, and keept them for chemical reaction at room temperature for 3 hours. When LCMS monitored that the raw materials for chemical reaction were exhausted and the main peak was the product, stop the chemical reaction and filter the reaction solution by adding diatomaceous earth, and then the filtrate was concentrated and dried by rotary evaporation. The crude product was not subjected to further purification treatment, and was directly used in the next reaction to obtain 300 mg of crude compound 9-4. MS: 289 [M+H].sup.+

Step 4: Synthesis of Compound 9

[0204] ##STR00050##

[0205] Add compounds 9-4 (78 mg) and 1-9 (100 mg) into 10 mL of n-butanol in the sealed tube with magneton, and then add 28 mg of p-toluenesulfonic acid, and keep them for chemical reaction in an oil bath for 16 hours at 110° C., When LCMS monitored that the raw materials for chemical reaction were exhausted and the main peak was the product, stop the chemical reaction and lower the temperature of reaction solution to room temperature. Concentrate the reaction solution, and then separate it with 0-30% H.sub.2O: MeOH in reverse phase to obtain 60 mg of product. MS: 620 [M+H].sup.+

[0206] Compound 9: .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.49 (s, 1H), 11.32 (s, 1H), 8.93 (s, 1H), 8.87 (d, 2H), 8.31 (s, 1H), 8.10 (s, 1H), 7.80 (s, 1H), 7.59 (s, 1H), 6.87 (s, 1H), 3.83 (s, 6H), 3.77 (m, 4H), 2.88 (s, 3H), 2.02-2.88 (m, 8H).

Example 10 Synthesis of Compound 10

(6-((5-Bromo-2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0207] ##STR00051##

Step 1: Synthesis of Compound 10-2

[0208] ##STR00052##

[0209] Prepare compound 10-2 as the method described for compound 1-9 using compound 10-1 instead of compound 1-8. MS: 412 [M+H].sup.+

Step 2: Synthesis of Compound 10

[0210] ##STR00053##

[0211] Prepare compound 10 as the 1 method described for compound 1 using compound 10-2 instead of compound 1-9. MS: 760 [M+H].sup.+

Example 11 Synthesis of Compound 11

(6-((2-((4-([1,4′-Bipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0212] ##STR00054##

Step 1: Synthesis of Compound 11

[0213] ##STR00055##

[0214] Prepare compound 11 as the method described for compound 10 using compound 52-instead of compound 1-4. MS: 745 [M+H].sup.+

Example 12 Synthesis of Compound 12

(6-((5-Bromo-2-methoxy-5-(1-methyl-1H-pyrozol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)-3-cyclopropyl-2-methyl)dimethylphosphine oxide

[0215] ##STR00056##

Step 1: Synthesis of Compound 12-2

[0216] ##STR00057##

[0217] Under nitrogen protection, add 12-1 (5 g) and cyclopropylboronic acid (2.8 g) into a 500 mL single-neck bottle, and then dissolve them in 100 mL ethylene glycol dimethyl ether and 20 mL water, and then add Pd(PPh.sub.3).sub.4 (2.5 g) and Na.sub.2CO.sub.3 (4.6 g) into the bottle, then replace nitrogen gas for three times, and keep them for chemical reaction in an oil bath at 100° C. for 2 hours. Cool down. Pour the reaction solution into water to extract it with ethyl acetate for three times, then process the organic phases by the way of merging, drying, concentrating and column chromatography (petroleum ether: ethyl acetate=3:1) to get 3.5 g of product. MS: 193 [M+H].sup.+

Step 2: Synthesis of Compound 12-3

[0218] ##STR00058##

[0219] Add compound 12-2 (2.0 g), HCl (10 mL) to a 100 mL three-neck flask, slowly add NaNO.sub.2 (0.86 g) aqueous solution (5 mL) to the reaction flask under 0° C., and continue to stir for 1 h. Add KI (2.59 g) aqueous solution (10 mL), make the temperature rise up naturally and continue stirring for 1 h. Stop the reaction when TLC monitored the end of the reaction. Add water (20 mL) to the reaction solution to extract it with ethyl acetate (3×20 mL), and wash the organic phase with Na.sub.2S.sub.2O.sub.3 (3×20 mL), saturated. brine (3×20 mL) in sequence, and then dry it with anhydrous sodium sulfate, then separate and purify it with Column chromatography (n-hexane: ethyl acetate=8:1), and then remove the solvent to get the target compound 12-3 (2.5 g) as a yellow solid.

Step 3: Synthesis of Compound 12-4

[0220] ##STR00059##

[0221] Prepare compound 12-4 as the method described for compound 1-7 using compound 12-4 instead of compound 1-6. MS: 254 [M+H].sup.+

Step 4: Synthesis of Compound 12-5

[0222] ##STR00060##

[0223] Add 12-4 (1 g) to a 100 mL single-neck flask, and then dissolve it in 50 mL methanol, add Pd/C (200 mg) into the flask, replace hydrogen gas for three times, keep them for chemical reaction at 25° C. for 2 h, then filter and spin them dry to obtain 0.8 g of product which was directly used for the next reaction. MS: 224 [M+H].sup.+

Step 5: Synthesis of Compound 12-6

[0224] ##STR00061##

[0225] Prepare compound 12-6 as the method described for compound 10-2 using compound 12-5 instead of compound 1-7. MS: 414 [M+H].sup.+

Step 6: Synthesis of Compound 12

[0226] ##STR00062##

[0227] Prepare compound 12 as the method described for compound 1 using compound 12 instead of compound 1-9. MS: 762 [M+H]+

Example 13 Synthesis of Compound 13

(6-((2-((4-([1,4′-Bromopyrimidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrozole-4-yl) phenyl)amino)-5-bromopyrimidin-4-yl)amino)-3-cyclopropyl-2-methylphenyl) dimethylphosphine oxide

[0228] ##STR00063##

Step 1: Synthesis of Compound 13

[0229] ##STR00064##

[0230] Prepare compound 13 as the method described for compound 10 using compound 12-6 instead of compound 1-4. MS: 747 [M+H].sup.+

Example 14 Synthesis of Compound 14

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1h-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl) piperidine-1-yl)phenyl)amino)pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

[0231] ##STR00065##

Step 1: Synthesis of Compound 14-1

[0232] ##STR00066##

[0233] Prepare compound 14-1 as the method described for compound 10-2 using compound 4-4 instead of compound 1-7. MS: 388 [M+H].sup.+

Step 2: Synthesis of Compound 14

[0234] ##STR00067##

[0235] Prepare compound 14 as the method described for compound 1 using compound 14-1 instead of compound 1-9. MS: 736 [M+H].sup.+

Example 15 Synthesis of Compound 15

(6-((2-((4-([1,4′-Bipiperidine]-1′-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)-5-bromopyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

[0236] ##STR00068##

Step 1: Synthesis of Compound 15

[0237] ##STR00069##

[0238] Prepare compound 15 as the method described for compound 14 using compound 5-2 instead of compound 1-4. MS: 721 [M+H].sup.+

Example 16 Synthesis of Compound 16

(6-((5-Bromo-2-((2-methoxy-5-(1-methyl-1hydro-pyrazole)-4-morpholinephenyl) amino)pyrimidine-4-amino)quinoxaline-5-dimethylphosphine oxide

[0239] ##STR00070##

Synthesis of Compound 16

[0240] ##STR00071##

[0241] Prepare compound 16 as the method described for compound 9 using compound 10-2 instead of compound 1-9. MS: 664 [M+H].sup.+

Example 17 Synthesis of Compound 17

(6-((5-Bromo-2-((5-(1-(difluoroethyl)-1hydro-pyrozole-4)-2-methoxy-4-(4-(4-methyl Piperidine-1)piperidine-1-piperidine-1-)phenyl)amino)pyrimidine-4-)amino)quinoxaline-5-dimethylphosphine oxide

[0242] ##STR00072##

Step 1: Synthesis of Compound 17-1

[0243] ##STR00073##

[0244] Prepare compound 17-1 as the method described for compound 1-2 using compound N-difluoromethyl pyrazole boronic acid instead of compound N-methylpyrazole boronic acid. MS: 288 [M+H].sup.+

Step 2: Synthesis of Compound 17-2

[0245] ##STR00074##

[0246] Prepare compound 17-2 as the method described for compound 1-3 using compound 17-1 instead of compound 1-2, MS: 451 [M+H].sup.+

Step 3: Synthesis of Compound 17-3

[0247] ##STR00075##

[0248] Prepare compound 17-3 as the method described for compound 1-4 using compound 17-2 instead of compound 1-3, MS: 421 [M+H].sup.+

Step 4: Synthesis of Compound 17

[0249] ##STR00076##

[0250] Prepare compound 17 as the method described for compound 1 using compound 17-3 instead of compound 1-4, compound 10-2 instead of compound 1-9, MS: 796 [M+H].sup.+

Example 18 Synthesis of Compound 18

(R)-(6-((5-Chloro-2-((2-methoxy-5-([1-methyl-1hydro-pyrazol-4-yl]-4-(octahydro-2hydro-pyrozol [1,2-a]pyrazine-2-yl) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0251] ##STR00077##

Synthesis of Compound 18

[0252] ##STR00078##

[0253] Prepare compound 18 as the method described for compound 1 using compound 8-2 instead of compound 1-4, MS: 673 [M+H].sup.+

Example 19 Synthesis of Compound 19

(6-((5-Bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy)-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0254] ##STR00079##

Step 1: Synthesis of Compound 19-1

[0255] ##STR00080##

[0256] Prepare compound 19-1 as the method described for compound 1-2 using compound N-ethylpyrazol boronic acid instead of N-methylpyrazole boronic acid, MS: 266 [M+H].sup.+

Step 2: Synthesis of Compound 19-2

[0257] ##STR00081##

[0258] Prepare compound 19-2 as the method described for compound 1-3 using compound 19-1 instead of compound 1-2, MS: 429 [M+H].sup.+

Step 3: Synthesis of Compound 19-3

[0259] ##STR00082##

[0260] Prepare compound 19-3 as the method described for compound 1-4 using compound 19-2 instead of compound 1-3, MS: 399 [M+H].sup.+

Step 4: Synthesis of Compound 19

[0261] ##STR00083##

[0262] Prepare compound 19 as the method described for compound 1 using compound 19-3 instead of compound 1-4, compound 10-2 instead of compound 1-9- MS: 776 [M+H].sup.+

Example 20 Synthesis of Compound 20

(6-((2-((4-([1,4′-Bipiperidine]-5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxyphenyl) amino)-5-bromopyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

[0263] ##STR00084##

Step 1: Synthesis of Compound 20-1

[0264] ##STR00085##

[0265] Prepare compound 20-1 as the method described for compound 19-2 using 4-piperidinopiperidine instead of 1-methyl-4(4-piperidinyl)piperazine, MS: 414 [M+H].sup.+

Step 2: Synthesis of Compound 20-2

[0266] ##STR00086##

[0267] Prepare compound 20-2 as the method described for compound 1-4 using compound 20-1 instead of compound 1-3, MS: 384 [M+H].sup.+

Step 3: Synthesis of Compound 20

[0268] ##STR00087##

[0269] Prepare compound 20 as the method described for compound 1 using compound 20-2 instead of compound 1-4, compound 14-1 instead of compound 1-9, MS: 735 [M+H].sup.+

Example 21 Synthesis of Compound 21

(6-((5-Chloro-2-((5-(1-methyl-1hydro-pyrazol-4-yl)-2-methoxy-4-morpholinophenyl) amino)pyrimidine-4-Amino)2,3-dimethylphenyl)-dimethylphosphine oxide

[0270] ##STR00088##

Step 1: Synthesis of Compound 21-1

[0271] ##STR00089##

[0272] Preapare compound 21-1 as the method described for compound 19-2 using morpholine instead of compound 1-methyl-4-(4-piperidinyl)piperazine, MS:333 [M+H].sup.+

Step 2: Synthesis of Compound 21-2

[0273] ##STR00090##

[0274] Prepare compound 21-2 as the method described for compound 1-4 using compound 21-1 instead of compound 1-3, MS: 303 [M+H].sup.+

Step 3: Synthesis of Compound 21

[0275] ##STR00091##

[0276] Prepare compound 21 as the method described for compound 1 using compound 21-1 instead of compound 1-4, compound 14-1 instead of compound 1-9. MS: 656 [M+H].sup.+

Example 22 Synthesis of Compound 22

(6-((5-Bromo-2-((5-(1-ethyl-1h-pyrazol-4-yl)-2methoxy-4-(4-(4-methylpiperazine-1-yl) piperidin-1-yl)phenyl)amino)pyrimidine-4-yl)amino)-2,3-dimethylphenyl)dimethylphosphine oxide

Synthesis of Compound 22

[0277] ##STR00092##

[0278] Prepare compound 22 as the method described for compound 1 using compound 19-3 instead of compound 1-4, compound 14-1 instead of compound 1-9, MS: 750 [M+H].sup.+

Example 23 Synthesis of Compound 23

(6-(2-(5-((1-Ethyl-1hydro-pyrazol-4-yl)-2-methoxy-4-morpholinophenyl) amino)pyrimidine-4-amino)-2,3dimethylphenyl) dimethylphosphine oxide

[0279] ##STR00093##

Step 1: Synthesis of Compound 23-1

[0280] ##STR00094##

[0281] Prepare compound 23-2 as the method described for compound 4-5 using compound 23-1 instead of compound 1-8, MS: 310 [M+H].sup.+

Step 2: Synthesis of Compound 23

[0282] ##STR00095##

[0283] Prepare compound 23 as the method described for compound 24 using compound 23-2 instead of compound 14-1, MS: 576 [M+H].sup.+

Example 24: Synthesis of Compound 24

(6-((5-Bromo-2-((5-(1-ethyl-1H-pyrazol-4-yl)-2-methoxy-4-morpholinophenyl) amino)pyrimidine-4-Amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine oxide

[0284] ##STR00096##

Step 1: Synthesis of Compound 24-2

[0285] ##STR00097##

[0286] In a 100 ml single-neck flask, dissolve compound 24-1 (25 g, 172.23 mmol) in concentrated sulfuric acid (100 mL), and then add concentrated nitric acid (16.28 g, 258.34 mmol) dropwise into it at 0° C., and then stir for 2 h at room temperature. Complete reaction of the raw materials under TLC monitoring. Pour the reaction solution slowly into 2 L of ice water to quench, precipitate a light yellow solid, stir for 1 h, and be filtered; the filter cake was rinsed with 1 L of water, then collect the filter cake, and dried it to obtain compound 24-2 (24.5 g, 128.84 mmol), yield rate: 74.81%), MS: 191 [M+H].sup.+

Step 2: Synthesis of Compound 24-3

[0287] ##STR00098##

[0288] In a 500 ml single-neck flask, dissolve compound 24-2 (24.5 g, 128.84 mmol) in phosphine oxychloride (200 mL), heat to 100° C. and stir overnight. LCMS monitored the complete reaction of the raw materials. The reaction solution was cooled down to room temperature, and concentrated; the residue was poured into 1 L of ice water, stirred for 0.5 h, filtered, and the filter cake was rinsed with 1 L of water. The filter cake was collected and dried to obtain compound 24-3 (25 g, 119.85 mmol, yield rate: 93.02%).

Step 3: Synthesis of Compound 24-4

[0289] ##STR00099##

[0290] In a 500 ml single-neck flask, dissolve compound 24-3 (25 g, 119.85 mmol) in 150 mL ethanol, add 30 mL H.sub.2O, and then add iron powder (33.47 g, 599.23 mmol), ammonium chloride (32.05 g, 599.23 mmol), heat the reaction solution to 90° C. and stir for 3 h. The reaction solution was cooled down to room temperature, and filtered with celite; the filter cake was rinsed with ethanol several times, and the filtrate was collected and concentrated. The residue was purified by Flash silica gel column (A: DCM, B: MeOH; methanol from 0-5%, running for 20 min) to obtain compound 24-4 (16.9 g, 94.62 mmol, yield rate: 78.95%). MS: 179 [M+H].sup.+

Step 4: Synthesis of Compound 24-5

[0291] ##STR00100##

[0292] In a 250 ml single-neck flask, dissolve compound 24-4 (16.9 g, 94.62 mmol) in glacial acetic acid (320 mL), add a solution of iodine chloride (18.43 g, 113.54 mmol) dropwise in acetic acid (80 mL) at room temperature, then stir at room temperature for 2 h. Complete reaction of the raw materials under LCMS monitoring. Adding 500 ml of n-hexane to the reaction liquid to dilute, and solids were precipitated out and then filtered: rinse the filter cake with n-hexane, and drain. The filter cake was dissolved in a mixed solvent of DCM:MeOH=10:1, washed with saturated sodium carbonate solution twice, saturated sodium thiosulfate solution twice, saturated sodium chloride washed once, dried, filtered, and concentrated. The residue was purified by Flash silica gel column (A:DCM, B:MeOH; MeOH from 0-5%, 20 min) to obtain compound 24-5 (22.23 g, 73.00 mmol, yield rate: 77.16%). MS: 305 [M+H].sup.+

Step 5: Synthesis of Compound 24-6

[0293] ##STR00101##

[0294] In a 250 ml single-neck flask, dissolve compound 24-5 (10.00 g, 32.84 mmol), dimethyl phosphine oxide (2.69 g, 34.48 mmol), Xantphos (3.80 g, 6.57 mmol), palladium acetate (737.27 mg, 3.28 mmol) and anhydrous potassium phosphate (13.94 g, 65.68 mmol) into 1,4-dioxane (100 mL), treat the solution with nitrogen displacement 3 times, heat it to 100° C. and be stifled overnight. The temperature was lowered, the reaction solution was filtered, and the filtrate was concentrated; the residue was purified by Flash silica gel column, first with petroleum ether/ethyl acetate (ethyl acetate from 0-50%, running for 10 mins), and then with dichloromethartelmethanol (methanol 0-6%, 20 min) to obtain compound 24-6 (6.18 g, 24.27 mmol, yield rate: 73.90%). MS: 255 [M+H].sup.+

Step 6: Synthesis of Compound 24-7

[0295] ##STR00102##

[0296] Add compound 24-6 (4 g, 15.71 mmol), cyclopropylboronic acid (5.40 g, 62.83 mmol), palladium acetate (352.65 mg, 1.57 mmol), triphenylphosphine (0.82 g, 3.14 mmol), Cs.sub.2CO.sub.3 (15.35 g, 47.12 mmol) into the mixed solvent of toluene (60 mL) and H.sub.2O (10 mL), heat to 100° C. under nitrogen protection, and stir for 12 h. Complete reaction under LCMS monitoring, and cool down to room temperature. Add 40 mL of water, separate the layers, take the organic phase, extract the aqueous phase with ethyl acetate (3×30 mL), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography (dichloromethane: methanol=15:1). The yellow solid, compound 24-7 (2.2 g, 8.45 mmol, yield rate: 53.81%) was obtained. MS: 261 [M+H].sup.+

Step 7: Synthesis of Compound 24-8

[0297] ##STR00103##

[0298] Add compound 24-7 (2.2 g, 8.45 mmol), 5-bromo-2,4-dichloropyrimidine (3.85 g, 16.91 mmol), DIEA (3.28 g, 25.36 mmol, 4.42 mL), n-BuOH (40 mL) successively into the reaction flask, heat to 120° C. and stir for 10 h. LCMS monitored the completion of the reaction. Cool down the reaction to room temperature; filter the solution, and dry the filter cake to obtain a pale yellow solid, the compound 24-8 (2.4 g, 5.31 mmol, yield rate: 62.86%). MS: 451 [M+H].sup.+

Step 8: Synthesis of Compound 24

[0299] ##STR00104##

[0300] Prepare compound 24 as the method described for compound 21 using compound 24-8 instead of compound 14-1. MS: 717 [M+H].sup.+

Example 25 Synthesis of Compound 25

(6-((5-Bromo-2-((4-(4-cyclopentylpiperazine-1yl)-2-methoxy-5-(1-methyl-1H-pyrozole-4-yl) phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl) dimethylphosphine oxide

[0301] ##STR00105##

Step 1: Synthesis of Compound 25-1

[0302] ##STR00106##

[0303] Prepare compound 6-1 as the method described for compound 6-1 using compound 4-cyclopentylpiperidine instead of compound 4-pyrrolidine-1-piperidine. MS: 386 [M+H].sup.+

Step 2: Synthesis of Compound 25-2

[0304] ##STR00107##

[0305] Prepare compound 25-2 as the method described for compound 6-2 using compound 25-2 instead of compound 6-1. MS: 356 [M+H].sup.+

Step 3: Synthesis of Compound 25

[0306] ##STR00108##

[0307] Prepare compound 25 as the method described for compound 6 using compound 25-2 instead of compound 6-2, compound 10-2 instead of compound 4-5. MS: 731 [M+H].sup.+

Example 26 Synthesis of Compound 26

(6-((5-Bromo-2-((4-(4-cyclopentylpiperazine-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-yl) phenyl)amino)pyrimidin-4-yl)amino)-2,3-dimethylphenyl)dimethylphoshine oxide;

[0308] ##STR00109##

Synthesis of Compound 26

[0309] ##STR00110##

[0310] Prepare compound 26 as the method described for compound 14 using compound 25-2 instead of compound 1-4. MS: 707 [M+H].sup.+

Example 27 Synthesis of Compound 27

(6-((5-Bromo-2-((4-(4-cyclopentylpiperazine-1-yl)-2-methoxy-5-(1-methyl-1H-pyrazole-4-Yl) phenyl)amino)pyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine oxide;

[0311] ##STR00111##

Synthesis of Compound 27

[0312] ##STR00112##

[0313] Prepare compound 27 as the method described for compound 25 using compound 24-8 instead of compound 25-5. MS: 770[M+H].sup.+

Example 28 Synthesis of Compound 28

[0314] Compound 28 (6-((5-Chloro-2-((2-methoxy-5-(1-methyl-1H-pyrazol-4-yl)-4-(4-(4-methylpiperazine-1-yl)piperidine-1-yl) phenyl)amino)pyrimidin-4-yl)amino)-2-cyclopropylquinolin-5-yl)dimethylphosphine oxide)

##STR00113##

[0315] Add 1-4 (100 mg) and 24-8 (105 mg) into a 10 mL single-neck bottle, dissolve them in n-BuOH (4 mL), and then add p-TsOH (112 mg) into the bottle, keep them for chemical reaction at 110° C. for 4 h, complete reaction under LCMS and cool down to room temperature, followed by adding 10 mL dichloroinethane to dilute, washing with aqueous sodium bicarbonate and then with water, concentration and FLASH depuration (CH.sub.3CN:H.sub.2O=5%˜50%) to get the 92 mg product. MS: 755 [M+H].sup.+

Comparative Compound A

[0316] Prepare comparative compound A by the method described in Example 40 according WO2019015655.

##STR00114##

PHARMACOLOGICAL TESTING

Test 1 EGFR A19de1 IT790M/C797S kinase test

[0317] Mobility variation analysis was performed to determine the affinity of the compound for EGFRΔ19del/T790M/C797S. The enzymatic reaction scheme is as follows:

[0318] 1. Prepare 1* kinase buffer as follows:

TABLE-US-00001 Final 1* kinase buffer concentration HEPES PH7.5 (mM) 50 Brij-35 0.0150% DTT (mM)  2 Mgcl.sub.2, Mncl.sub.2 (mM) 10

[0319] 2. Preparation of compound concentration gradient: The test compound was tested with an initial concentration of 3000 nM or 100 nM, diluted in a 384 source plate to a 100% DMSO solution with 100-fold final concentration, and the compound is 3-fold diluted with Precision to 10 concentrations. A dispenser Echo 550 was used to transfer 250 nL 100-fold final concentration of the compound to the target plate OptiPlate-384F.

[0320] 3. Prepare 2.5-fold final concentration of kinase solution with 1×Kinase buffer;

[0321] 4. 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.

[0322] 5. Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate for well mixation, and then incubate at room temperature for 10 minutes.

[0323] 6. Prepare a mixture of ATP and Kinase substrate at 5/3-fold final concentration with 1×Kinase buffer.

[0324] 7. Add 15 μL mixture of 5/3-fold final concentration of ATP and substrate to start reaction.

[0325] 8. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, shake it well and then incubate it at room temperature for corresponding time.

[0326] 9. Add 30 μL of stop detection solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, shake it well.

[0327] 10. Read conversion rate with Caliper EZ Reader.

[0328] 11. Calculation formula

% Inhibition=((Conversion%_max−Conversion%_sample)/(Conversion%_max−Conversion%_.sub.min))*100

[0329] Wherein: Conversion%_sample is the sample conversion rate reading; Conversion%_min: Mean value of negative control wells, representing the conversion rate reading of wells without enzymatic activity; Conversion%_max: Mean value of positive control wells, representing the conversion rate reading of wells without compound inhibition.

[0330] The dose-effect curve was fitted with concentration log value as X-axis and percentage inhibition rate as Y-axis. Log (inhibitor) vs. Response—Variable Slope of GraphPad Prism 5 was used to fit the dose-effect curve to obtain IC50 value of enzymatic activity for each compound.

[0331] The calculation formula is as Y=Bottom (Top−Bottom)/(1+10{circumflex over ( )}((LogIC.sub.50−X)*HillSlope)).

[0332] The results are expressed as IC50 values, as shown in Table 1. As illustrated in examples, IC.sub.50 value is within the following range for the compound of the present invention: “A” represents “IC.sub.50≤1nM”; “B” represents “1 nM<IC.sub.50≤100nM”.

TABLE-US-00002 TABLE 1 EGFR Δ19del/T790M/C797S No. IC.sub.50 (nM) 1 0.3 2 0.2 3 0.3 4 A 5 A 6 A 7 B 8 A 9 0.3 10 A 11 A 12 A 13 A 14 A 15 A 16 A 17 0.3 18 0.2 19 0.3 20 0.2 21 0.3 22 4.2 23 1.4 24 17 25 0.3 26 0.2 27 1.3 28 0.31

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

[0333] 1. Cell Culture

[0334] Cell line: Ba/F3 cells with stable overexpression of Δ19del/T790M/C797S or L858R/T790M/C797S mutant genes, named Ba/F3-Δ19del/T790M/C797S and Ba/F3-L858R/T790M/C797S, and A431 EGFR wild-type cell line.

[0335] A. Culture Medium

[0336] RPMI 1640 and 10% FBS and 1% PS; _EM, 10% PBS and 1% PS

[0337] B. Cell Recovery

[0338] a) Preheat the medium in a 37° C. water bath;

[0339] b) Remove the cryotube from the liquid nitrogen tank, quickly put it in a 37° C. water bath for completely melting within 1 minute.

[0340] c) Transfer the cell suspension to a 15 mL centrifuge tube containing 8 mL of medium, and centrifuge at 1000 rpm for 5 minutes.

[0341] d) Discard the supernatant, resuspend the cells in 1 mL culture medium, transfer it to a 75 cm2 culture flask containing 15 mL of culture medium, and culture in a incubator with 5% CO.sub.2 at 37° C.;

[0342] C. Cellpassage

[0343] a) Preheat the medium in a 37° C. water bath;

[0344] b) Collect the cells in a 15 mL centrifuge tube and centrifuge at 1000 rpm for 5 minutes. 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% CO.sub.2 at 37° C.

[0345] 2. Compound Preparation

[0346] 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);

[0347] b) Dilute compound solution thereof to 1:100 in medium to prepare 10-fold working solution;

[0348] 3. Cell Plate Culture

[0349] 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;

[0350] b) Inoculate the cells into a 96-well cell culture plate with a density of 2000 cells/well;

[0351] 4. Compound Treatment

[0352] a) The compound prepared in Step 2 was added to a cell plate with 15 μL per well at final concentrations of 1000, 333, 111.1, 37, 12.3, 4.1, 1.4, 0.5, 0.2, and 0 nM. The final concentration of DMSO was 0.1%. The blank control well is with medium (0.1% DMSO).

[0353] b) Incubate cells in an incubatorother 72 hours;

[0354] 5. Assay

[0355] a) Take out the 96-well cell culture plate and add 50 μl CTG reagent (CellTiter Glo kit, promega, Cat #G7573);

[0356] b) Shake the plate for 2 minutes and let cool at room temperature for 10 minutes,

[0357] c) Read luminous signal value with Perkin Elmer reader.

Analysis of Experimental Data

[0358] The data were analyzed by GraphPad Prism 6.0 software to obtain the fitting curve of compound activity.

[0359] Fining compound IC.sub.50 from nonlinear regression equation:

Y=Min+(Max−Min)/(1+10{circumflex over ( )}((LogIC.sub.50−X)*slope));

X: Logarithm of compound concentration; Y: luminous signal

[0360] The result of cell proliferation assay is expressed by IC.sub.50, as shown in Table 2. As illustrated in examples, IC.sub.50 value is within the following range for the compound of the present invention: “A” represents “IC.sub.50≤50 nM”; “B” represents “50 nM<IC.sub.50<100 nM”.

TABLE-US-00003 TABLE 2 BaF3 BaF3 A431 L858R/T790M/C Δ19del/T790M/C797S EGFR WT No. 797S IC.sub.50 (nM) IC.sub.50 (nM) IC.sub.50 (nM) 1 2.1 2.1 112 2 18.3 6.5 109.9 3 60.4 60.4 571 4 14.9 10.2 191.9 5 6.5 3.0 114.1 6 A A / 7 B B / 8 A A / 9 16.8 8.0 251.8 10 A A / 11 A A / 12 A A / 13 A A / 14 A A / 15 A A / 16 A A / 17 3.8 3.5 120.5 18 8.2 6.7 111.5 19 1.3 1.0 135.3 20 0.4 0.7 151.7 21 3.6 0.7 465.0 22 31.1 24.6 3258 25 4.0 2.5 107 26 2.8 4.6 241 27 8.7 12.4 1174 28 6.6 1.0 201 Comparative 16.7 22 375 compound A Note: ″/” stands for “not tested”.

Test 3 Liver Microsomal Clearance Test

[0361] 1. Prepare 0.5 mg/mL liver microsome diluent containing K-butter and MgCl.sub.2:

TABLE-US-00004 Concentration Volume Final Reagent of stock solution added concentration MgCl.sub.2 solution  50 mM  40 μL  5 mM K-buffer 100 mM 306 μL 87 mM Liver microsome 20 mg/mL  10 μL 0.5 mg/mL

[0362] 2. Plate incubation:

[0363] 2.1 Take 356 μL of the liver microsome diluent prepared above and add it to the preset wells of the incubation plate, the number of multiple wells n=1, mark it as the incubation plate.

[0364] 2.2 Take 4 μL of the positive control compound Verapamil (50 μM) and the working solution of the test compound (200 μM) into the above incubation plate containing 356 μL of liver microsome diluent, and mix well (The dilution solvent from the stock solution to the working solution is a mixed solvent of acetonitrile: methanol: water=1:1:2, and the final concentration of DMSO is ≤0.5%),

[0365] 2.3 Place the incubation plate in a 37° C. thermostatic oscillator (at shaking speed of 100 rpm) for pre-incubation with 10 min.

[0366] 2.4 Add 40 μL of 10 mM NADPH (add 40 μL of K-buffer to the wells without NADPH) to each reaction well to start the reaction and start timing.

[0367] 3. Sample collection and treatment:

[0368] 3.1 After adding NADPH to start the reaction, immediately take out 50 μL of the sample and add it to the precipitation plate pre-added with 400 μL of stop solution, and shake on an oscillator at 600 rpm for 5 min at room temperature as a 0 min sample.

[0369] 3.2 At the predetermined time points of 5 min, 15 min and 45 min, take out 50 μL of sample from the incubation plate and add it to the precipitation plate. The subsequent steps were the same as the treatment of 0 min sample. 3.3 After balancing, centrifuge above precipitation plate at 3200 rpm for 10 min at 4° C.

[0370] 3.4 Take 50 μL of the supernatant after centrifugation and add it to pre-added 20% acetonitrile water at appropriate proportion, shake on an oscillator at 600 rpm for 2 min at room temperature, mix well, and put it into the LC-MS/MS sampler for sample injection.

Analysis of Experimental Data

[0371] 1. Respectively measure peak area of analyte in the sample and peak area of the internal standard at different time points, use the ratio of the peak area of the analyte to the peak area. of the internal standard at non-zero time point, and the ratio of peak area of the analyte in 0 min sample to the peak area of internal standard to calculate residual percentage of active drug; use the natural logarithmic value of the residual percentage as the ordinate, and the incubation time as the abscissa to plot, fit the straight line, and calculate the slope.

[0372] 2. Calculation formula is as follows:

[0373] Elimination rate constant (K)=−slope;

[0374] Half-life period (T.sub.1/2)=0.693/K;

[0375] Intrinsic clearance (CL.sub.int, in vitro)=K/C.sub.protein;

[0376] Note: C.sub.protein represents the concentration of liver microsomal protein in the final incubation system.

[0377] The CL.sub.int data measured are shown in Table 3.

TABLE-US-00005 TABLE 3 Instrinsic clearance of liver microsomal protein, CL.sub.int (μL/min/mg proteins) No. Human Monkey Dog Rat Mice Comparative 17.4 65.4 15.6 22 16.4 compound 1 1  2.4 38.8 1 4 6.6 5 15.4 43.2 25.8 0.8 11.2

Test 4 hERG IC.SUB.50 .Test

[0378] 1. Thaw hERG kits (Tracer, E-4031 and Membranes) at room temperature;

[0379] 2. Add 10 μL of positive compound E-4031 and 10 μL of test compound (10 mM) to 384 well plate (Corning, Art. No. 3658);

[0380] 3. E-4031 is sequentially 5-fold diluted by pure water (10 concentration points in total), and the test compound is sequentially 5-fold diluted by DMSO (10 concentration points in total).

[0381] 4. Take 1 μL of all gradient concentrations and add them in parallel to the wells containing 24 μL Assay buffer, and dilute 25 times (take 3 μL of the maximum concentration of E-4031 and add it to 72 μL Assay buffer).

[0382] 5. Add 10 μL Membranes to another black 384-well plate (Coming, Art.4511).

[0383] 6. Take 5 μL of 25-fold diluted working solution of positive and test compounds, and add it to above-mentioned plate with 10 μL Membranes, 2 copies at each concentration.

[0384] 7. Negative control: Add 5 μL Assay buffer to the well with 10 μL Membranes, 8 copies in parallel;

[0385] 8. Positive control: Add 5 μL E-4031 (120 μM) to the well with 10 μL Membranes, 8 copies in parallel;

[0386] 9. Dilute a certain amount of Tracer solution at the ratio of 1:61,5, and then add 5 μL to all the wells pre-added positive compound, test compound, negative control and positive control.

[0387] 10. Before measuring the fluorescence polarization, cover the analysis plate to protect the reagents from light and evaporation, and incubate at room temperature (20-25° C.) for 2 hours.

[0388] 11. Read fluorescence polarization in PerkinElmer EnVision® Multilabel after incubation;

[0389] 12. Calculation formula:

Y=100/(1+10{circumflex over ( )}((LogIC.sub.50−X)*HillSlope))

[0390] Wherein, X is concentration of test article (Log μM), Y is relative residual activity (%), HillSlope is slope, IC.sub.50 and 95% confidence interval are calculated by Prism software. The assay results are shown in Table 4.

TABLE-US-00006 TABLE 4 IC.sub.50 results of hERG protein to compound No. IC.sub.50 (μM) Comparative 13.5 compound 1 1 >30