EGFR INHIBITORS, COMPOSITIONS AND METHODS THERE OF

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, ##STR00231## wherein, R.sub.1 and R.sub.2 are each independently selected from is H, halogen, CN, —C.sub.1-6 alkyl or —C.sub.1-6 alkoxyl; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form a 5- to 6-membered heteroaryl ring optionally comprising for 2 hetero atoms independently selected from N, S, or O; or R.sub.1 and R.sub.2 together with the atoms to which they are attached form an aryl ring; R.sub.3 is H, halogen, —C.sub.1-6 alkyl; R.sub.4 is H, halogen, —C.sub.1-6 alkyl or —C.sub.1-6 alkoxyl; R.sub.5 is —OR.sub.7, —O(CH.sub.2).sub.t—NR.sub.8R.sub.9, —NR.sub.8R.sub.9, ##STR00232## R.sub.6 is H, —C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl; wherein —C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl optionally substituted with one or more substituents independently selected from halogen, —C.sub.1-6 alkyl, —C.sub.1-4 haloalkyl or —NR.sub.16R.sub.17; R.sub.7 is C.sub.1-6 alkyl, C.sub.3-10 heteocyclyl, or C.sub.3-10 heteroaryl; R.sub.8 and R.sub.9 are each independently selected from —C.sub.1-6 alkyl, or —C.sub.1-6 alkylene-NR.sub.10R.sub.11, wherein R.sub.10 and R.sub.11 are each independently selected from H or —C.sub.1-6 alkyl; or R.sub.10 and R.sub.11 together with the atoms to which they are attached form a 5- to 6-membered heterocyclic ring; or R.sub.8 and R.sub.9 together with the atoms to which they are attached form a 5- to 6-membered heterocyclic ring; R.sub.12, R.sub.13, R.sub.14 and R.sub.15 are each independently selected from H or —C.sub.1-6 alkyl; R.sub.12 and R.sub.13 together with the atoms to which they are attached form a 4- to 6-membered ring; L is a bond, NR.sub.18 or (CH.sub.2).sub.t; R.sub.16, R.sub.17 and R.sub.18 are each independently selected from H, or —C.sub.1-6 alkyl. X is CH or N; m, n, m′, n′ are each independently selected from 1 or 2; s and t are each independently selected from 1, 2 or 3, or a stereoisomer, tautomer, deuterinated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof.

2. The compound of claim 1, wherein R.sub.1 and R.sub.2 are each independently selected from is H, CN, and —CH.sub.3.

3. The compound of claim 1, wherein R.sub.1 and R.sub.2 together with the atoms to which they are attached form ##STR00233##

4. The compound of claim 1, wherein R.sub.3 is selected from H, F, Cl, Br, and CH.sub.3.

5. The compound of claim 1, wherein R.sub.4 is selected from H, —CH.sub.3, and —OCH.sub.3.

6. The compound of claim 1, wherein R.sub.5 is selected from ##STR00234##

7. The compound of claim 1, wherein L is selected from —NH—, and —NCH.sub.3—.

8. The compound of claim 1, wherein R.sub.6 is selected from ##STR00235##

9. The compound of claim 1, wherein the compound is Formula II, or a stereoisomer, tautomer, deuterinated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, ##STR00236## wherein, R.sub.3 is H, halogen, —C.sub.1-6 alkyl; R.sub.4 is H, halogen, —C.sub.1-6 alkyl or —C.sub.1-6 alkoxyl; R.sub.5 is —OR.sub.7, —O(CH.sub.2).sub.t—NR.sub.8R.sub.9, —NR.sub.8R.sub.9, ##STR00237## R.sub.7 is C.sub.1-6 alkyl, C.sub.3-10 heteocyclyl, or C.sub.3-10 heteroaryl; R.sub.8 and R.sub.9 are each independently selected from —C.sub.1-6 alkyl, or —C.sub.1-6 alkylene-NR.sub.10R.sub.11, wherein R.sub.10 and R.sub.11 are each independently selected from H or —C.sub.1-6 alkyl; or R.sub.10 and R.sub.11 together with the atoms to which they are attached form a 5- to 6-membered heterocyclic ring; or R.sub.8 and R.sub.9 together with the atoms to which they are attached form a 5- to 6-membered heterocyclic ring; R.sub.12, R.sub.13, R.sub.14 and R.sub.15 are each independently selected from H or —C.sub.1-6 alkyl; R.sub.12 and R.sub.13 together with the atoms to which they are attached form a 4- to 6-membered ring; X is CH or N; m, n, m′, n′ are each independently selected from 1 or 2; s and t are each independently selected from 1, 2 or 3.

10. The compound of claim 9, wherein R.sub.3 is selected from H, F, Cl, and CH.sub.3.

11. The compound of claim 9, wherein R.sub.4 is selected from H, and —OCH.sub.3.

12. The compound of claim 9, wherein R.sub.5 is selected from —OR.sub.7, —NR.sub.8R.sub.9, ##STR00238##

13. The compound of claim 9, wherein R.sub.7 is C.sub.3-10 heteocyclyl.

14. (canceled)

15. (canceled)

16. (canceled)

17. The compound of claim 1, wherein the compound is Formula II, or a stereoisomer, tautomer, deuterinated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, ##STR00239## wherein, R.sub.3 is H, halogen, or C.sub.1-6 alkyl; R.sub.4 is H, halogen, C.sub.1-6 alkyl or C.sub.1-6 alkoxyl; R.sub.5 is ##STR00240## R.sub.12, R.sub.13, R.sub.14 are each independently selected from H or C.sub.1-6 alkyl; R.sub.12 and R.sub.13 together with the atoms to which they are attached form a 4- to 6-membered ring; m, n, m′, n′ are each independently selected from 1 or 2.

18. (canceled)

19. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)

26. The compound of claim 1, wherein the compound is Formula IV, or a stereoisomer, tautomer, deuterinated compound, pharmaceutically acceptable salt, prodrug, chelate, non-covalent complex, or solvate thereof, ##STR00241## wherein, Ring A is selected from aryl ring or 5- to 6-membered heteroaryl ring optionally comprising for 2 hetero atoms independently selected from N, S, or O; R.sub.3 is H, halogen, or —C.sub.1-6 alkyl; R.sub.4 is H, halogen, —C.sub.1-6 alkyl or —C.sub.1-6 alkoxyl; R.sub.5 is —OR.sub.7, —O(CH.sub.2).sub.t—NR.sub.8R.sub.9, —NR.sub.8R.sub.9, ##STR00242## R.sub.7 is C.sub.1-6 alkyl, C.sub.3-10 heteocyclyl, or C.sub.3-10 heteroaryl; R.sub.8 and R.sub.9 are each independently selected from —C.sub.1-6 alkyl, or —C.sub.1-6 alkyl-NR.sub.10R.sub.11, wherein R.sub.10 and R.sub.11 are each independently selected from H or —C.sub.1-6 alkyl; or R.sub.10 and R.sub.11 together with the atoms to which they are attached form a 5- to 6-membered heterocyclic ring; or R.sub.8 and R.sub.9 together with the atoms to which they are attached form a 5- to 6-membered heterocyclic ring; R.sub.12, R.sub.13, R.sub.14 and R.sub.15 are each independently selected from H or —C.sub.1-6 alkyl; R.sub.12 and R.sub.13 together with the atoms to which they are attached form a 4- to 6-membered ring; m, n, m′, n′ are each independently selected from 1 or 2; s and t are each independently selected from 1, 2 or 3.

27. (canceled)

28. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)

35. (canceled)

36. (canceled)

37. The compound of claim 1, wherein the compound is 1) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dim ethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide; 2) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dim ethylamino)-2-azaspiro[3.5]nonan-2-yl)phenyl)acrylamide; 3) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(6-(dim ethylamino)-2-azaspiro[3.3]heptan-2-yl)phenyl)acrylamide; 4) N-(2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide; 5) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dim ethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide; 6) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dim ethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-N-methylacrylamid; 7) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dim ethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)methacrylamide; 8) (E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-4-(dimethylamino)but-2-enamide; 9) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dim ethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-fluoroacrylamide; 10) N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide; 11) N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide; 12) N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 13) N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 14) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt; 15) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide; 16) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 17) (S)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)acrylamide; 18) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide; 19) N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)acrylamide hydrochloric acid salt; 20) N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 21) N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide; 22) N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 23) N-(5-((5-chloro-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt; 24) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 25) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(di methylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide; 26) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dim ethylamino)-2-azaspiro[3.5]nonan-2-yl)-4-methoxyphenyl)acrylamide; 27) N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide; 28) N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 29) N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(4-(4-m ethylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 30) N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide; 31) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dim ethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methylphenyl)acrylamide; 32) N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-ylamino)phenyl)acrylamide; 33) N-(5-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-2-(9-(dimeth ylamino)-3-azaspiro[5.5]undecan-3-yl)-4-methoxyphenyl)acrylamide; 34) N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide; 35) N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide; 36) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dim ethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide; 37) N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide; 38) N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 39) N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide; 40) N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide; 41) N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((l-methylpiperidin-4-yl)oxy)phenyl)acrylamide.

38. 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.

39. (canceled)

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

41. The method of claim 40, wherein the EGFR-driven cancer is characterized by the presence of one or more mutations selected from: (i) C797S, (ii) both L858R and C797S, (iii) both C797S and T790M, (iv) L858R, T790M, and C797S, and (v) Δ19del, T790M and C797S.

42. The method of claim 40, wherein the EGFR-driven cancer is colon cancer, gastric cancer, thyroid cancer, lung cancer, leukemia, pancreatic cancer, melanoma, multiple melanoma, brain cancer, renal cancer, prostate cancer, ovarian cancer or breast cancer.

43. (canceled)

44. (canceled)

45. (canceled)

46. (canceled)

Description

EXAMPLES

[0168] It is to be understood that the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of any subject matter claimed. All parts and percentages are by weight and all temperatures are degrees Celsius, unless explicitly stated otherwise. The compounds described herein can be obtained from commercial sources or synthesized by conventional methods as shown below using commercially available starting materials and reagents.

[0169] The following abbreviations have been used in the examples: [0170] AcOH or HOAc: Acetic acid; [0171] DCM: Dichloromethane; [0172] DIEA: N,N-Diisopropylethylamine; [0173] DMF: Dimethylformamide; [0174] DMSO: Dimethyl sulfoxide; [0175] EA or EtOAc: Ethyl acetate; [0176] Et.sub.2O: Diethyl ether; [0177] HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; [0178] LCMS: Liquid chromatography-mass spectrometry; [0179] h or hrs: hour or hours; [0180] Pd/C: Palladium on carbon; [0181] PE: Petroleum ether; [0182] MeOH: Methanol; [0183] min: minute; [0184] NMP: N-Methyl-2-pyrrolidone [0185] rt or r.t.: room temperature; [0186] TFA: Trifluoroacetic acid; [0187] THF: Tetrahydrofuran; [0188] TLC: Preparative thin layer chromatography; [0189] NaOtBu: Sodium tert-butoxide; [0190] Xantphos: 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene; [0191] t-BuXPhos Pd(II): Methanesulfonato(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II).

Example 1 Synthesis of Compound 1

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide

[0192] ##STR00017##

Step 1: Synthesis of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0193] ##STR00018##

[0194] To a mixture of (2-aminophenyl)dimethylphosphine oxide (2.50 g) in DMF (30 mL), 2,4,5-trichloropyrimidine (3.52 g) and potassium carbonate (4.08 g) was added under stirring. The mixture was heated 60° C. for about 8 h. The mixture solution was poured into water and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was recrystallized by hexane/ethyl acetate (10:1, 10 mL). After filtration, the solid was dried to obtain (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (3.00 g) as white solid. MS: 316 [M+H].sup.+.

Step 2: Synthesis of (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0195] ##STR00019##

[0196] To a solution of 4-fluoro-3-nitroaniline (2.5 g) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (5.05 g) dissolved in n-BuOH (50 mL) was added TsOH (4.1 g). The reaction mixture was stirred at 100° C. for 2 h. The reaction mixture was cooled down to room temperature and diluted with EtOAc (150 mL). The resulting solution was washed with water and NaCl saturated aqueous solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from PE to obtain 5.3 g (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide as a yellow solid. MS: 436 [M+H].sup.+.

Step 3: Synthesis of 3-azaspiro[5.5]undecan-9-one trifluoroacetate

[0197] ##STR00020##

[0198] To a stirred solution of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate (0.5 g) in DCM (6 mL) was added TFA (2 mL). The reaction mixture was stirred at room temperature for 2 h. After completion of the reaction (monitored by TLC), the reaction mixture was evaporated under reduced pressure to obtain 3-azaspiro[5.5]undecan-9-one trifluoroacetate (0.9 g, crude) as a yellow oil.

Step 4: Synthesis of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one

[0199] ##STR00021##

[0200] To a solution of 3-azaspiro[5.5]undecan-9-one trifluoroacetate (0.9 g, crude) and (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (0.5 g) dissolved in DMSO (10 mL) was added K.sub.2CO.sub.3 (2 g). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled down to room temperature and diluted with DCM (50 mL). The resulting solution was washed with water and NaCl saturated aqueous solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from Et.sub.2O to obtained 0.68 g of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one as a red solid. MS: 583 [M+H].sup.+.

Step 5: Synthesis of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0201] ##STR00022##

[0202] To a solution of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one (380 mg) in DCM (6 mL) was added dimethylamine (1.63 mL, 2N in THF) and AcOH (39 mg). The mixture was stirred at 90° C. After 1 h, sodium triacetoxyborohydride (413 mg) was added and the mixture was further stirred at room temperature for 1 h. After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (30 mL). The resulting solution was washed with 10% NaHCO.sub.3 aqueous solution and NaCl saturated aqueous solution. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum. The crude product was re-crystallized from Et.sub.2O to obtained 370 mg of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide as a red solid. MS: 612 [M+H].sup.+.

Step 6: Synthesis of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0203] ##STR00023##

[0204] To a solution of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (370 mg) dissolved in MeOH (10 mL) was added Raney Ni (200 mg). H.sub.2 gas was connected via a needle to the reaction mixture which was stirred at room temperature for 3 h. The solution was filtered through diatomite to remove the Raney Ni. The solution was evaporated to give 260 mg of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 582 [M+H].sup.+

Step 7: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide (Compound 1)

[0205] ##STR00024##

[0206] To a solution of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (260 mg) in DCM (10 mL) was added DIEA (70 mg) at 0° C. This was followed by the addition of acryloyl chloride (44 mg, dissolved in 1 mL DCM), in portions at 0° C. The resulting solution was stirred for 2 h at 0° C. The reaction was then quenched by the addition of 10 mL of 10% NaHCO.sub.3 aqueous solution. The resulting solution was extracted with 2*20 mL DCM and the organic layer combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel with DCM/MeOH (8:1) to obtain 25 mg N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide (Compound 1). MS: 636 [M+H].sup.+.

[0207] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.23 (s, 1H), 9.37 (s, 1H), 9.06 (s, 1H), 8.69 (s, 1H), 8.17 (d, J=7.2 Hz, 2H), 7.57 (ddd, J=14.0, 7.7, 1.6 Hz, 1H), 7.47 (t, J=8.5 Hz, 2H), 7.14 (m, 2H), 6.67 (dd, J=16.9, 10.3 Hz, 1H), 6.22 (dd, J=17.0, 1.9 Hz, 1H), 5.76 (dd, J=10.2, 1.8 Hz, 1H), 3.08 (s, 1H), 2.72 (m, 10H), 1.88 (t, J=15.7 Hz, 4H), 1.78 (d, J=13.6 Hz, 6H), 1.71 (m, 2H), 1.67-1.55 (m, 2H), 1.52 (m, 2H), 1.21-1.12 (m, 2H).

Example 2 Synthesis of Compound 2

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)phenyl)acrylamide

[0208] ##STR00025##

Step 1: Synthesis of 2-azaspiro[3.5]nonan-7-one trifluoroacetate

[0209] ##STR00026##

[0210] Following the same procedure as 3-azaspiro[5.5]undecan-9-one trifluoroacetate using tert-butyl 7-oxo-2-azaspiro[3.5]nonane-2-carboxylate instead of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate to obtain 2-azaspiro[3.5]nonan-7-one trifluoroacetate.

Step 2: Synthesis of 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2-azaspiro[3.5]nonan-7-one

[0211] ##STR00027##

[0212] Following the same procedure as 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one using 2-azaspiro[3.5]nonan-7-one trifluoroacetate instead of 3-azaspiro[5.5]undecan-9-one trifluoroacetate to obtain 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2-azaspiro[3.5]nonan-7-one. MS: 555 [M+H].sup.+.

Step 3: Synthesis of (2-((5-chloro-2-((4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0213] ##STR00028##

[0214] Following the same procedure as (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2-azaspiro[3.5]nonan-7-one instead of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one to obtain (2-((5-chloro-2-((4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 584 [M+H].sup.+.

Step 4: Synthesis of (2-((2-((3-amino-4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0215] ##STR00029##

[0216] Following the same procedure as (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 554 [M+H].sup.+.

Step 5: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)phenyl)acrylamide (Compound 2)

[0217] ##STR00030##

[0218] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (2-((2-((3-amino-4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)phenyl)acrylamide (Compound 2). MS: 608 [M+H].sup.+.

Example 3 Synthesis of Compound 3

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)phenyl)acrylamide

[0219] ##STR00031##

Step 1: Synthesis of 2-azaspiro[3.3]heptan-6-one trifluoroacetate

[0220] ##STR00032##

[0221] Following the same procedure as 3-azaspiro[5.5]undecan-9-one trifluoroacetate using tert-butyl 6-oxo-2-azaspiro[3.3]heptane-2-carboxylate instead of tert-butyl 9-oxo-3-azaspiro[5.5]undecane-3-carboxylate to obtain 2-azaspiro[3.3]heptan-6-one trifluoroacetate.

Step 2: Synthesis of 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2-azaspiro[3.3]heptan-6-one

[0222] ##STR00033##

[0223] Following the same procedure as 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one using 2-azaspiro[3.3]heptan-6-one trifluoroacetate instead of 3-azaspiro[5.5]undecan-9-one trifluoroacetate to obtain 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2-azaspiro[3.3]heptan-6-one. MS: 527 [M+H].sup.+.

Step 3: Synthesis of (2-((5-chloro-2-((4-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0224] ##STR00034##

[0225] Following the same procedure as (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2-azaspiro[3.3]heptan-6-one instead of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one to obtain (2-((5-chloro-2-((4-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 556 [M+H].sup.+.

Step 4: Synthesis of (2-((2-((3-amino-4-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0226] ##STR00035##

[0227] Following the same procedure as (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 526 [M+H].sup.+.

Step 5: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)phenyl)acrylamide (Compound 3)

[0228] ##STR00036##

[0229] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (2-((2-((3-amino-4-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(6-(dimethylamino)-2-azaspiro[3.3]heptan-2-yl)phenyl)acrylamide (Compound 3). MS: 580 [M+H].sup.+.

Example 4 Synthesis of Compound 4

N-(2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide

[0230] ##STR00037##

Step 1: Synthesis of (2-((2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0231] ##STR00038##

[0232] To a mixture of (2-aminophenyl)dimethylphosphine oxide (5.0 g) in n-BuOH (50 mL), 2,4-dichloropyrimidine (4.4 g) and DIEA (5.73 g) was added under stirring. The mixture was heated 120° C. overnight. The mixture solution was poured into water and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was recrystallized by Et.sub.2O. After filtration, the solid was dried to obtain (2-((2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (4.9 g) as off-white solid. MS: 282 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0233] ##STR00039##

[0234] Following the same procedure as (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 402 [M+H].sup.+.

Step 3: Synthesis of 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0235] ##STR00040##

[0236] To a solution of 7-azaspiro[3.5]nonan-2-one hydrogen chloride salt (262 mg) and (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) dissolved in DMSO (10 mL) was added K.sub.2CO.sub.3 (518 mg). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled down to room temperature and diluted with DCM (50 mL). The resulting solution was washed with water and NaCl saturated aqueous solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was re-crystallized from Et.sub.2O to obtained 0.66 g of 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one as a red solid. MS: 555 [M+H].sup.+.

Step 4: Synthesis of (2-((2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0237] ##STR00041##

[0238] Following the same procedure as (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one instead of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one to obtain (2-((2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 584 [M+H].sup.+.

Step 5: Synthesis of (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0239] ##STR00042##

[0240] Following the same procedure as (2-((2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 520 [M+H].sup.+.

Step 6: Synthesis of N-(2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 4)

[0241] ##STR00043##

[0242] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (Compound 4). MS: 574 [M+H].sup.+.

Example 5 Synthesis of Compound 5

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide

[0243] ##STR00044##

Step 1: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide

[0244] ##STR00045##

[0245] Following the same procedure as (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-amino-5-fluoro-4-nitrophenoxy)methylium instead of 4-fluoro-3-nitroaniline to obtain (2-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 466 [M+H].sup.+.

Step 2: Synthesis of 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0246] ##STR00046##

[0247] Following the same procedure as 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one using (2-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one. MS: 551 [M+H].sup.+.

Step 3: Synthesis of (2-((5-chloro-2-((4-(2-(dimethylamino)spiro[3.5]nonan-7-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0248] ##STR00047##

[0249] Following the same procedure as (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one instead of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one to obtain (2-((5-chloro-2-((4-(2-(dimethylamino)spiro[3.5]nonan-7-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 614 [M+H].sup.+.

Step 4: Synthesis of (2-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0250] ##STR00048##

[0251] Following the same procedure as (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(2-(dimethylamino)spiro[3.5]nonan-7-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 584 [M+H].sup.+.

Step 5: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide (Compound 5)

[0252] ##STR00049##

[0253] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (2-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide. (Compound 5). MS: 604 [M+H].sup.+.

[0254] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.21 (s, 1H), 8.97 (s, 1H), 8.45 (s, 1H), 8.27 (s, 1H), 8.10 (d, J=6.1 Hz, 2H), 7.51 (dd, J=14.3, 7.6 Hz, 1H), 7.30 (t, J=8.2 Hz, 1H), 7.05 (t, J=7.5 Hz, 1H), 6.82 (s, 1H), 6.64 (dd, J=17.0, 10.2 Hz, 1H), 6.17 (dd, J=17.0, 2.0 Hz, 1H), 5.70 (dd, J=10.1, 2.0 Hz, 1H), 3.77 (s, 3H), 2.80-2.74 (m, 2H), 2.74-2.68 (m, 2H), 2.59 (m, 1H), 2.03 (m, 8H), 1.76 (m, 8H), 1.69 (d, J=5.3 Hz, 2H), 1.57 (d, J=19.1 Hz, 2H).

Example 6 Synthesis of Compound 6

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-N-methylacrylamide

[0255] ##STR00050##

Step 1: Synthesis of (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-(methylamino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0256] ##STR00051##

[0257] To a solution of (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) in MeOH (4 mL) was added paraformaldehyde (50 mg), K.sub.2CO.sub.3 (100 mg) and sodium cyanoborohydride (50 mg). The mixture is stirred at room temperature for 1 h. The reaction mixture was diluted with DCM (50 mL). The resulting solution was washed with H.sub.2O and NaCl saturated aqueous solution. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel with DCM/MeOH (8:1). This obtained 80 mg (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-(methyl amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 568 [M+H].sup.+.

Step 2: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-N-methylacrylamid

[0258] ##STR00052##

[0259] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-(methylamino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-N-methylacrylamid. MS: 622 [M+H].sup.+.

Example 7 Synthesis of Compound 7

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)methacrylamide

[0260] ##STR00053##

Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)methacrylamide

[0261] ##STR00054##

[0262] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-N-methylacrylamid using methacryloyl chloride instead of acryloyl chloride to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)methacrylamide. MS: 622 [M+H].sup.+.

[0263] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.25 (s, 1H), 9.41 (s, 1H), 9.16 (s, 1H), 8.71 (s, 1H), 8.38 (d, J=2.5 Hz, 1H), 8.17 (s, 1H), 7.57-7.47 (m, 1H), 7.50-7.41 (m, 2H), 7.18-7.10 (m, 2H), 5.86 (s, 1H), 5.58-5.53 (m, 1H), 3.57 (s, 1H), 2.74-2.64 (m, 2H), 2.67-2.57 (m, 2H), 2.57 (s, 6H), 2.18-2.08 (m, 4H), 2.03-1.93 (m, 3H), 1.79-1.69 (m, 2H), 1.71-1.61 (m, 2H).

Example 8 Synthesis of Compound 8

(E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-4-(dimethylamino)but-2-enamide

[0264] ##STR00055##

Synthesis of (E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-4-(dimethylamino)but-2-enamide

[0265] ##STR00056##

[0266] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-N-methylacrylamid (Compound 6) using (E)-4-(dimethylamino)but-2-enoyl chloride instead of acryloyl chloride to obtain (E)-N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-4-(dimethylamino)but-2-enamide. MS: 665 [M+H].sup.+.

Example 9 Synthesis of Compound 9

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-fluoroacrylamide

[0267] ##STR00057##

Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-fluoroacrylamide

[0268] ##STR00058##

[0269] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-N-methylacrylamid using 2-fluoroacryloyl chloride instead of acryloyl chloride to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)-2-fluoroacrylamide. MS: 626 [M+H].sup.+.

Example 10 Synthesis of Compound 10

N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0270] ##STR00059##

Step 1: Synthesis of (6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0271] ##STR00060##

[0272] To a mixture of (6-aminoquinoxalin-5-yl)dimethylphosphine oxide (1 g) in n-BuOH (20 mL), 2,4,5-trichloropyrimidine (0.99 g) and DIEA (1.17 g) was added under stirring. The mixture was heated 120° C. for about 48 h. The mixture solution was poured into water and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was recrystallized by hexane/ethyl acetate (10:1, 10 mL). After filtration, the solid was dried to obtain (6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide (760 mg). MS: 368 [M+H].sup.+.

Step 2: Synthesis of (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0273] ##STR00061##

[0274] Following the same procedure as (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (6-((2,5-dichloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 488 [M+H].sup.+.

Step 3: Synthesis of 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0275] ##STR00062##

[0276] Following the same procedure as 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one using (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one. MS: 607 [M+H].sup.+

Step 4: Synthesis of (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0277] ##STR00063##

[0278] Following the same procedure as (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one instead of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one to obtain (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 636 [M+H].sup.+.

Step 5: Synthesis of (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0279] ##STR00064##

[0280] Following the same procedure as (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 606 [M+H].sup.+.

Step 6: Synthesis of N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0281] ##STR00065##

[0282] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide. MS: 660 [M+H].sup.+.

[0283] .sup.1H NMR (500 MHz, DMSO-d6) δ 12.94 (s, 1H), 9.49 (s, 1H), 9.22 (s, 1H), 9.03 (s, 1H), 8.87-8.86 (m, 2H), 8.28 (d, J=12.3 Hz, 2H), 8.04 (d, J=9.5 Hz, 1H), 7.41 (d, J=8.6 Hz, 1H), 7.10 (d, J=8.7 Hz, 1H), 6.61-6.60 (m, 1H), 6.10-6.09 (m, 1H), 5.66 (d, J=10.4 Hz, 1H), 3.60-6.59 (m, 1H), 2.96-2.95 (m, 2H), 2.74-2.68 (m, 2H), 2.66-2.64 (m, 2H), 2.60 (s, 6H), 2.17-2.07 (m, 2H), 2.15-2.05 (m, 2H), 1.91-1.90 (m, 2H).

Example 11 Synthesis of Compound 11

N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide

[0284] ##STR00066##

Step 1: Synthesis of (6-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0285] ##STR00067##

[0286] Following the same procedure as (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide using 4-fluoro-2-methoxy-5-nitroaniline oxide instead of 4-fluoro-3-nitroaniline to obtain (6-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 518 [M+H].sup.+.

Step 2: Synthesis of 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0287] ##STR00068##

[0288] Following the same procedure as 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one using (6-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one. MS: 637 [M+H].sup.+.

Step 3: Synthesis of (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0289] ##STR00069##

[0290] Following the same procedure as (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one instead of 3-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one to obtain (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 666 [M+H].sup.+.

Step 4: Synthesis of (6-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0291] ##STR00070##

[0292] Following the same procedure as (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (6-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 636 [M+H].sup.+.

Step 5: Synthesis of N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide

[0293] ##STR00071##

[0294] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (6-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methoxyphenyl)acrylamide. MS: 690 [M+H].sup.+.

Example 12 Synthesis of Compound 12

N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0295] ##STR00072##

Step 1: Synthesis of (6-((5-bromo-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0296] ##STR00073##

[0297] Following the same procedure as (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (6-((5-bromo-2-chloropyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (6-((5-bromo-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 532 [M+H].sup.+.

Step 2: Synthesis of (6-((5-bromo-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0298] ##STR00074##

[0299] Following the same procedure as 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one using (6-((5-bromo-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide, using 1-methyl-4-(piperidin-4-yl)piperazine instead of 7-azaspiro[3.5]nonan-2-one hydrogen chloride salt to obtain (6-((5-bromo-2-((4-(4-(4-methyl piperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 695 [M+H].sup.+.

Step 3: Synthesis of (6-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0300] ##STR00075##

[0301] Following the same procedure as (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (6-((5-bromo-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (6-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 665 [M+H].sup.+.

Step 4: Synthesis of N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0302] ##STR00076##

[0303] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(9-(di methyl amino)-3-azaspiro[5.5]undecan-3-yl)phenyl)acrylamide using (6-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide. MS: 719 [M+H].sup.+.

[0304] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.70 (s, 1H), 9.48 (s, 1H), 9.00 (s, 2H), 8.87-8.77 (m, 2H), 8.34 (s, 1H), 8.28 (s, 1H), 8.02 (d, J=9.5 Hz, 1H), 7.37 (s, 1H), 7.08 (d, J=8.7 Hz, 1H), 6.59 (dd, J=16.8, 10.3 Hz, 1H), 6.07 (d, J=17.0 Hz, 1H), 5.64 (d, J=10.3 Hz, 1H), 3.61 (s, 1H), 2.97-2.87 (m, 3H), 2.64-2.58 (m, 4H), 2.05-1.95 (m, 7H), 1.82-1.72 (m, 4H), 1.26-1.16 (m, 1H).

Example 13 Synthesis of Compound 13

N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0305] ##STR00077##

Step 1: Synthesis of (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0306] ##STR00078##

[0307] Following the same procedure as (6-((5-bromo-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide using 4-fluoro-2-methoxy-5-nitroaniline oxide instead of 4-fluoro-3-nitroaniline to obtain (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 562 [M+H].sup.+.

Step 2: Synthesis of (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0308] ##STR00079##

[0309] Following the same procedure as (6-((5-bromo-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide using (6-((5-bromo-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (6-((5-bromo-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide to obtain (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 725 [M+H].sup.+.

Step 3: Synthesis of (6-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0310] ##STR00080##

[0311] Following the same procedure as (6-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide using (6-((5-bromo-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (6-((5-bromo-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide to obtain (6-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 695 [M+H].sup.+.

Step 4: Synthesis of N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0312] ##STR00081##

[0313] Following the same procedure as N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide using (6-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of (6-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide to obtain N-(5-((5-bromo-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide. MS: 719 [M+H].sup.+.

[0314] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 12.68 (s, 1H), 8.95 (s, 1H), 8.84-8.74 (m, 3H), 8.46 (s, 1H), 8.28 (s, 1H), 8.14 (s, 1H), 7.86 (d, J=9.4 Hz, 1H), 6.88 (s, 1H), 6.59 (dd, J=17.0, 10.2 Hz, 1H), 6.11-6.01 (m, 1H), 5.61 (d, J=10.4 Hz, 1H), 3.79 (s, 3H), 3.06-2.96 (m, 3H), 2.71-2.61 (m, 4H), 2.02-1.92 (m, 6H), 1.85-1.75 (m, 4H), 1.25-1.15 (m, 3H).

Example 14 Synthesis of Compound 14

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt

[0315] ##STR00082##

Step 1: Synthesis of tert-butyl 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate

[0316] ##STR00083##

[0317] To a mixture of (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) in DMSO (5 mL), tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (312 mg) and potassium carbonate (317 mg) was added under stirring. The mixture was heated 90° C. for about 8 h. The mixture solution was poured into water and extracted with ethyl acetate (50 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the tert-butyl 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (600 mg) as red solid. MS: 642 [M+H].sup.+.

Step 2: Synthesis of (2-((5-chloro-2-((3-nitro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide trifluoroacetic acid salt

[0318] ##STR00084##

[0319] To a solution of tert-butyl 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (600 mg) in DCM (5 mL) was added TFA (5 mL). The mixture was stirred 5 h at room temperature. The mixture was concentrated under reduced pressure to afford the (2-((5-chloro-2-((3-nitro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide trifluoroacetic acid salt (600 mg) as red semi-solid. MS: 542 [M+H].sup.+.

Step 3: Synthesis of (2-((5-chloro-2-((4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0320] ##STR00085##

[0321] To a solution of (2-((5-chloro-2-((3-nitro-4-(2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide trifluoroacetic acid salt (600 mg) in methanol (10 mL) was added HCHO (1 mL). The mixture was stirred 30 min at room temperature. Then the reaction mixture was added Na(OAc).sub.3BH (970 mg), and stirred another 2 h. The mixture solution was poured into water and extracted with DCM (15 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure to afford the (2-((5-chloro-2-((4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) as red solid. MS: 556 [M+H].sup.+.

Step 4: Synthesis of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0322] ##STR00086##

[0323] To a solution of (2-((5-chloro-2-((4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) in methanol/H.sub.2O (20 mL, 5:1) was added Fe (250 mg) and ammonium chloride (96 mg). The mixture was heated at 80° C. for 5 h. The mixture was then filtered through diatomaceous earth and washed with methanol; the filtrate was then concentrated under reduced pressure and purified by silica gel column chromatography using DCM/methanol (95:5) as the eluent, and to obtain (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (400 mg) as off-white solid. MS: 526 [M+H].sup.+.

Step 5: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt

[0324] ##STR00087##

[0325] To a solution of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) in DCM/H.sub.2O (10 mL, 5:1) was added NaHCO.sub.3 (100 mg). The mixture was added acryloyl chloride (34 mg) dropwise at 0° C., and stirred another 2 h. The mixture solution was poured into water and extracted with DCM (15 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure, purified by C18 silica gel column chromatography using H.sub.2O (0.5% HCO/methanol (20%-30%) as the eluent to afford N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt (40 mg) as yellow solid. MS: 580 [M+H].sup.+.

[0326] .sup.1H NMR (500 MHz, Methanol-d.sub.4) δ 8.24 (m, 1H), 8.18 (m, 1H), 7.79 (s, 1H), 7.69-7.68 (m, 2H), 7.54-7.53 (m, 1H), 7.41-7.40 (m, 2H), 6.62 (dd, J=17.0, 8.0 Hz, 1H), 6.53 (dd, J=17.0, 8.0 Hz, 1H), 5.99-5.98 (m, 1H), 4.55-4.30 (m, 2H), 4.03-3.82 (m, 2H), 3.60-3.45 (m, 2H), 3.20-2.97 (m, 2H), 2.30 (s, 3H), 1.88-1.31 (m, 4H).

Example 15 Synthesis of Compound 15

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide

[0327] ##STR00088##

Step 1: Synthesis of (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0328] ##STR00089##

[0329] Following the same procedure as using N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine instead of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 518 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0330] ##STR00090##

[0331] Following the same procedure as (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 488 [M+H].sup.+.

Step 3: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide (Compound 15)

[0332] ##STR00091##

[0333] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide (Compound 15). MS: 542 [M+H].sup.+.

[0334] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.24 (s, 1H), 10.26 (s, 1H), 9.88 (s, 1H), 9.41 (s, 1H), 8.67 (s, 1H), 8.30 (s, 1H), 8.17 (s, 1H), 7.57-7.56 (m, 1H), 7.46-7.45 (m, 2H), 7.19 (d, J=8.7 Hz, 1H), 7.15-7.09 (m, 1H), 6.25 (dd, J=16.9, 2.0 Hz, 1H), 5.75 (dd, J=16.9, 2.0 Hz, 1H), 3.34 (s, 3H), 2.64-2.60 (m, 4H), 1.78 (s, 6H).

Example 16 Synthesis of Compound 16

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0335] ##STR00092##

Step 1: Synthesis of (2-((5-chloro-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0336] ##STR00093##

[0337] Following the same procedure as 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate using 1-methyl-4-(piperidin-4-yl)piperazine instead of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain (2-((5-chloro-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 599 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0338] ##STR00094##

[0339] Following the same procedure as (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 569 [M+H].sup.+.

Step 3: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0340] ##STR00095##

[0341] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((3-amino-4-(4-(4-methyl piperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide. MS: 623 [M+H]+.

[0342] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.23 (s, 1H), 9.38 (s, 1H), 9.06 (s, 1H), 8.68 (d, J=7.5 Hz, 1H), 8.17 (d, J=11.8 Hz, 2H), 7.57-5.56 (m, 1H), 7.46-7.45 (m, 2H), 7.21-7.04 (m, 2H), 6.69-6.68 (m, 1H), 6.23-6.22 (m, 1H), 5.79-5.73 (m, 1H), 3.34 (s, 3H), 2.98-2.48 (m, 12H), 1.85-1.15 (m, 5H).

Example 17 Synthesis of Compound 17

(S)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)acrylamide

[0343] ##STR00096##

Step 1: Synthesis of (S)-(2-((5-chloro-2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0344] ##STR00097##

[0345] Following the same procedure as tert-butyl 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate using (S)-octahydropyrrolo[1,2-a]pyrazine instead of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain (S)-(2-((5-chloro-2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 542 [M+H].sup.+.

Step 2: Synthesis of (S)-(2-((2-((3-amino-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0346] ##STR00098##

[0347] Following the same procedure as (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (S)-(2-((5-chloro-2-((4-(hexahydropyrrolo[1,2-a]pyrazin-2 (1H)-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (S)-(2-((2-((3-amino-4-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 512 [M+H].sup.+.

Step 3: Synthesis of (S)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)acrylamide

[0348] ##STR00099##

[0349] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (S)-(2-((2-((3-amino-4-(hexahydropyrrolo[1,2-a]pyrazin-2 (1H)-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (S)—N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(hexahydropyrrolo[1,2-a]pyrazin-2(1H)-yl)phenyl)acrylamide. MS: 566 [M+H].sup.+.

Example 18 Synthesis of Compound 18

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide

[0350] ##STR00100##

Step 1: Synthesis of (2-((5-chloro-2-((4-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0351] ##STR00101##

[0352] Following the same procedure as tert-butyl 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate using N-methyl-2-(pyrrolidin-1-yl)ethanamine instead of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate to obtain (2-((5-chloro-2-((4-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 544 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((3-amino-4-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0353] ##STR00102##

[0354] Following the same procedure as (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 514 [M+H].sup.+.

Step 3: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide (Compound 18)

[0355] ##STR00103##

[0356] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((3-amino-4-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(methyl(2-(pyrrolidin-1-yl)ethyl)amino)phenyl)acrylamide (Compound 18). MS: 568 [M+H].sup.+.

Example 19 Synthesis of Compound 19

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)acrylamide hydrochloric acid salt

[0357] ##STR00104##

Step 1: Synthesis of (2-((2-chloro-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0358] ##STR00105##

[0359] To a mixture of (2-aminophenyl)dimethylphosphine oxide (5.00 g) in NMP (50 mL), 2,4-dichloro-5-methylpyrimidine (5.78 g) and potassium carbonate (11.46 g) was added under stirring. The mixture was heated 130° C. for about 12 h. The mixture solution was poured into water and extracted with DCM (50 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 a and concentrated to give crude product, which was purified by silica gel column chromatography using DCM/MeOH (5%-6%) as the eluent, and to obtain (2-((2-chloro-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (5.00 g) as brown solid. MS: 296 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((4-fluoro-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0360] ##STR00106##

[0361] Following the same procedure as (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-chloro-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((4-fluoro-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 415 [M+H].sup.+.

Step 3: Synthesis of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0362] ##STR00107##

[0363] Following the same procedure as (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-((4-fluoro-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 544 [M+H].sup.+.

Step 4: Synthesis of (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0364] ##STR00108##

[0365] To a solution of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) in methanol (20 mL) was added 10% palladium on carbon (100 mg) and the mixture hydrogenated (hydrogen balloon) at room temperature for 5 h. The mixture was then filtered through diatomaceous earth and washed with methanol; the filtrate was then concentrated under reduced pressure to afford the (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) as white solid. MS: 468 [M+H].sup.+.

Step 5: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)acrylamide hydrochloric acid salt

[0366] ##STR00109##

[0367] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)phenyl)acrylamide hydrochloric acid salt. MS: 522 [M+H].sup.+.

Example 20 Synthesis of Compound 20

N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0368] ##STR00110##

Step 1: Synthesis of dimethyl(2-((5-methyl-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0369] ##STR00111##

[0370] Following the same procedure as (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 1-methyl-4-(piperidin-4-yl)piperazine instead of N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine to obtain dimethyl(2-((5-methyl-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphine oxide. MS: 579 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0371] ##STR00112##

[0372] Following the same procedure as (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using dimethyl(2-((5-methyl-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphine oxide instead of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 549 [M+H].sup.+.

Step 3: Synthesis of N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0373] ##STR00113##

[0374] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide. MS: 603[M+H].sup.+.

Example 21 Synthesis of Compound 21

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0375] ##STR00114##

Step 1: Synthesis of (2-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0376] ##STR00115##

[0377] Following the same procedure as (2-((2-((4-fluoro-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 4-fluoro-2-methoxy-5-nitroaniline instead of 4-fluoro-3-nitroaniline to obtain (2-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 445 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0378] ##STR00116##

[0379] Following the same procedure as (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 528 [M+H].sup.+.

Step 3: Synthesis of (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0380] ##STR00117##

[0381] Following the same procedure as (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 498 [M+H].sup.+.

Step 4: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 21)

[0382] ##STR00118##

[0383] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (Compound 21). MS: 552 [M+H].sup.+.

Example 22 Synthesis of Compound 22

N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0384] ##STR00119##

Step 1: Synthesis of (2-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0385] ##STR00120##

[0386] Following the same procedure as (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 1-methyl-4-(piperidin-4-yl)piperazine instead of N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine to obtain (2-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 609 [M+H]+.

Step 2: Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0387] ##STR00121##

[0388] Following the same procedure as (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 579 [M+H].sup.+.

Step 3: Synthesis of N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0389] ##STR00122##

[0390] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-methylpyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide. MS: 633 [M+H].sup.+.

Example 23 Synthesis of Compound 23

N-(5-((5-chloro-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt

[0391] ##STR00123##

Step 1: Synthesis of 1-iodonaphthalen-2-amine

[0392] ##STR00124##

[0393] At the N.sub.2 atmosphere benzyltrimethylammonium dichloroiodate was added to a mixture of naphthalen-2-amine (4.00 g) in DCM (120 mL) and MeOH (40 mL). The mixture was stirred 2 h at room temperature. The mixture solution was poured into sodium bicarbonate solution and DCM (50 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure, purified by silica gel column chromatography using DCM/methanol (95:5) as the eluent to obtain 1-iodonaphthalen-2-amine (7.02 g) as brown oil. MS: 269 [M+H].sup.+.

Step 2: Synthesis of (2-aminonaphthalen-1-yl)dimethylphosphine oxide

[0394] ##STR00125##

[0395] At the N.sub.2 atmosphere, to a mixture of 1-iodonaphthalen-2-amine (2.00 g) in dioxane (20 mL), dimethylphosphine oxide (580 mg), Xnatphos (860 mg), Pd(OAc).sub.2 (167 mg) and K.sub.3PO.sub.4 (3.16 g) was added under stirring. The mixture was heated 100° C. for about 10 h. The mixture solution was poured into water and extracted with DCM (50 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced, purified by silica gel column chromatography using DCM/methanol (95:5) as the eluent to obtain (2-aminonaphthalen-1-yl)dimethylphosphine oxide (1.60 g) as brown solid. MS: 219 [M+H].sup.+.

Step 3: Synthesis of (2-((2,5-dichloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide

[0396] ##STR00126##

[0397] To a mixture of (2-aminonaphthalen-1-yl)dimethylphosphine oxide (1.0 g) in n-BuOH (20 mL), 2,4,5-trichloropyrimidine (1.67 g), DIEA (1.18 g), was added under stirring. The mixture was heated 120° C. for about 8 h. The mixture was then filtered through diatomaceous earth and washed with n-BuOH; the filter cake was then concentrated under reduced pressure to obtain (2-((2,5-dichloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide (1.30 g) as white solid. MS: 366 [M+H].sup.+.

Step 4: Synthesis of 7-(4-amino-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0398] ##STR00127##

[0399] Following the same procedure as 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one using 4-fluoro-3-nitroaniline instead of (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide to obtain 7-(4-amino-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one. MS: 276 [M+H]+.

Step 5: Synthesis of 7-(4-amino-2-nitrophenyl)-N,N-dimethyl-7-azaspiro[3.5]nonan-2-amine

[0400] ##STR00128##

[0401] Following the same procedure as (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide using 7-(4-amino-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one instead of 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinoxalin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one to obtain 7-(4-amino-2-nitrophenyl)-N,N-dimethyl-7-azaspiro[3.5]nonan-2-amine. MS: 305 [M+H]+.

Step 6: Synthesis of (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide

[0402] ##STR00129##

[0403] Following the same procedure as (2-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2,5-dichloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide instead of (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide and using 7-(4-amino-2-nitrophenyl)-N,N-dimethyl-7-azaspiro[3.5]nonan-2-amine instead of 4-fluoro-3-nitroaniline to obtain (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide. MS: 634 [M+H].sup.+.

Step 7: Synthesis of (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide

[0404] ##STR00130##

[0405] Following the same procedure as (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide instead of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)-5-methylpyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide. MS: 604 [M+H].sup.+.

Step 8: Synthesis of N-(5-((5-chloro-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt

[0406] ##STR00131##

[0407] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt using (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)naphthalen-1-yl)dimethylphosphine oxide instead of (2-((2-((3-amino-4-(2-methyl-2,7-diazaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((1-(dimethylphosphoryl)naphthalen-2-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide hydrochloric acid salt. MS: 658 [M+H].sup.+.

Example 24 Synthesis of Compound 24

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0408] ##STR00132##

Step 1: Synthesis of (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0409] ##STR00133##

[0410] To a solution of 1-methyl-4-(4-piperidyl)piperazine (141.66 mg) and 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-(4-fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2,4-diamine (300 mg) dissolved in DMSO (10 mL) was added K.sub.2CO.sub.3 (267.03 mg). The reaction mixture was stirred at 90° C. overnight. The reaction mixture was cooled down to room temperature and diluted with DCM (20 mL). The resulting solution was washed with water and NaCl saturated aqueous solution. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to obtained 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]-5-nitro-phenyl]pyrimidine-2,4-diamine (430 mg) as a yellow solid. MS: 629 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0411] ##STR00134##

[0412] To a solution of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]-5-nitro-phenyl]pyrimidine-2,4-diamine (430 mg) dissolved in MeOH (20 mL) and H.sub.2O (2 mL), was added Fe (190.88 mg, 3.42 mmol) and NH.sub.4Cl (182.81 mg, 3.42 mmol). The reaction mixture was stirred at 90° C. for 5 hrs. The resulting solution was filtered and collect the filtrate. The filtrate was concentrated under vacuum. The crude product was purified by silica gel column chromatography using DCM/methanol (0-10%, 20 mins) as the eluent to obtained (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (260 mg). MS: 599 [M+H].sup.+.

Step 3: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0413] ##STR00135##

[0414] To a solution of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (130 mg) in DCM (10 mL) and H.sub.2O (5 mL), was dropwise added prop-2-enoyl chloride (22 mg) in DCM (1 ml) at 0-10° C. The resulting solution was stirred for 0.5 h at 0-10° C. The reaction was concentrated by vacuum. The residue was purified by column chromatography over silica gel with DCM/MeOH (8:1). This obtained N-(5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (33.8 mg) MS: 653 [M+H].sup.+.

Example 25 Synthesis of Compound 25

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0415] ##STR00136##

Step 1: Synthesis of (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0416] ##STR00137##

[0417] Following the same procedure as (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine instead of 1-methyl-4-(4-piperidyl)piperazine to obtain (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 534 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)amino)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0418] ##STR00138##

[0419] Following the same procedure as Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-((2-(dimethylamino)ethyl)amino)-2-methoxy-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]-5-nitro-phenyl]pyrimidine-2,4-diamine to obtain (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)amino)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 504 [M+H].sup.+.

Step 3: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide

[0420] ##STR00139##

[0421] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acryl amide using (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)amino)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of N2-[5-amino-2-methoxy-4-[4-(4-methyl piperazin-1-yl)-1-piperidyl]phenyl]-5-chloro-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxyphenyl)acrylamide. MS: 572 [M+H].sup.+.

[0422] .sup.1H NMR (500 MHz, DMSO-d6) δ 11.22 (s, 1H), 8.45 (m, 1H), 8.32 (s, 1H), 8.12 (s, 1H), 7.54 (m, 1H), 7.30 (s, 1H), 7.05 (m, 2H), 6.24 (m, 1H), 5.76 (m, 1H), 3.87 (m, 3H), 3.25 (s, 3H), 2.89 (m, 6H) 2.36 (m, 4H), 1.79 (s, 6H).

Example 26 Synthesis of Compound 26

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-4-methoxyphenyl)acrylamide

[0423] ##STR00140##

Step 1: Synthesis of 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-2-azaspiro[3.5]nonan-7-one

[0424] ##STR00141##

[0425] Following the same procedure as (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using 2-azaspiro[3.5]nonan-7-one trifluoroacetate instead of 1-methyl-4-(4-piperidyl)piperazine to obtain 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-2-azaspiro[3.5]nonan-7-one. MS: 585 [M+H].sup.+.

Step 2: Synthesis of (2-((5-chloro-2-((4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0426] ##STR00142##

[0427] To a solution of 2-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methoxy-2-nitrophenyl)-2-azaspiro[3.5]nonan-7-one (700 mg) in MeOH (20 mL), was added N-methylmethanamine (2 M, 2.99 mL) and AcOH (143 mg). The mixture was stirred at 60° C. for 1 h. To the resulting solution, was added Na(CN)BH.sub.3 (226 mg). The reaction mixture was stirred for 1 hr at r.t. The resulting mixture was concentrated under vacuum. The crude product was purificated by gel column using DCM/MeOH (0-10%, 20 mins) to obtain (2-((5-chloro-2-((4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (255 mg) as a red solid. MS: 614 [M+H].sup.+.

Step 4: Synthesis of (2-((2-((5-amino-4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0428] ##STR00143##

[0429] Following the same procedure as Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]-5-nitro-phenyl]pyrimidine-2,4-diamine to obtain (2-((2-((5-amino-4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 584 [M+H].sup.+.

Step 5: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-4-methoxyphenyl)acrylamide

[0430] ##STR00144##

[0431] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide using (2-((2-((5-amino-4-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-2-methoxyphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of N2-[5-amino-2-methoxy-4-[4-(4-methyl piperazin-1-yl)-1-piperidyl]phenyl]-5-chloro-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(7-(dimethylamino)-2-azaspiro[3.5]nonan-2-yl)-4-methoxyphenyl)acrylamide MS: 638[M+H].sup.+.

Example 27 Synthesis of Compound 27

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0432] ##STR00145##

Step 1: Synthesis of (2-((5-fluoro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0433] ##STR00146##

[0434] Following the same procedure as (2-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidin-4-amine to obtained (2-((5-fluoro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 450 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0435] ##STR00147##

[0436] Following the same procedure as (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-fluoro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-(4-fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2,4-diamine to obtain (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 532 [M+H].sup.+.

Step 3: Synthesis of (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0437] ##STR00148##

[0438] Following the same procedure as Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)-N4-(2-(dimethylphosphanyl)phenyl)-5-fluoropyrimidine-2,4-diamine instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]-5-nitro-phenyl]pyrimidine-2,4-diamine to obtain (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 502 [M+H].sup.+.

Step 4: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0439] ##STR00149##

[0440] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide using (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of N2-[5-amino-2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]phenyl]-5-chloro-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine to obtain N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide. MS: 556 [M+H].sup.+.

Example 28 Synthesis of Compound 28

N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0441] ##STR00150##

Step 1: Synthesis of (2-((5-fluoro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0442] ##STR00151##

[0443] Following the same procedure as (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-fluoro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-(4-fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2,4-diamine to obtain (2-((5-fluoro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 613 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0444] ##STR00152##

[0445] Following the same procedure as Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-fluoro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]-5-nitro-phenyl]pyrimidine-2,4-diamine to obtain (2-((2-((5-amino-2-methoxy-4-(4-(4-methyl piperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 583 [M+H].sup.+.

Step 3: Synthesis of N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0446] ##STR00153##

[0447] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide using (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of N2-[5-amino-2-methoxy-4-[4-(4-methyl piperazin-1-yl)-1-piperidyl]phenyl]-5-chloro-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine to obtain N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide. MS: 637 [M+H].sup.+.

[0448] .sup.1H NMR (500 MHz, DMSO-d6) δ 11.55 (s, 1H), 9.03 (s, 1H), 8.61 (m, 1H), 8.22 (s, 1H), 8.07 (m, 2H), 7.56 (m, 1H), 7.38 (m, 1H), 7.06 (m, 1H), 6.82 (s, 1H), 6.70 (m, 1H), 6.19 (m, 1H), 5.72 (m, 1H), 3.79 (s, 3H), 3.17 (s, 2H), 2.70 (m, 8H) 2.43 (m, 6H), 1.85 (m, 9H).

Example 29 Synthesis of Compound 29

N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0449] ##STR00154##

Step 1: Synthesis of (2-((5-fluoro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0450] ##STR00155##

[0451] Following the same procedure as (2-((5-chloro-2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 2,5-dichloro-N-(2-dimethylphosphorylphenyl)pyrimidin-4-amine and using 4-fluoro-3-nitroaniline instead of 4-fluoro-2-methoxy-5-nitro-aniline to obtain (2-((5-fluoro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 420 [M+H].sup.+.

Step 2: Synthesis of (2-((5-fluoro-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0452] ##STR00156##

[0453] Following the same procedure as (2-((5-chloro-2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-fluoro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-(4-fluoro-2-methoxy-5-nitro-phenyl)pyrimidine-2,4-diamine to obtain (2-((5-fluoro-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 583 [M+H].sup.+.

Step 3: Synthesis of (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0454] ##STR00157##

[0455] Following the same procedure as Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide using (2-((5-fluoro-2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of 5-chloro-N4-(2-dimethylphosphorylphenyl)-N2-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]-5-nitro-phenyl]pyrimidine-2,4-diamine to obtain (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 553 [M+H].sup.+.

Step 4: Synthesis of N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0456] ##STR00158##

[0457] Following the same procedure as N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide using (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)-5-fluoropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of N2-[5-amino-2-methoxy-4-[4-(4-methylpiperazin-1-yl)-1-piperidyl]phenyl]-5-chloro-N4-(2-dimethylphosphorylphenyl)pyrimidine-2,4-diamine to obtain N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)-5-fluoropyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide. MS: 607 [M+H].sup.+.

Example 30 Synthesis of Compound 30

N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0458] ##STR00159##

Step 1: Synthesis of 5-iodoquinolin-6-amine

[0459] ##STR00160##

[0460] To a solution of quinolin-6-amine (2.50 g) in acetic acid (30 mL), was added a solution of ICl (4.08 g) in 10 ml of acetic acid at 10-15° C. The reaction solution was stirred at 20° C. for 1 hour. The reaction mixture was concentrated under vacuum. The residue was washed with ethyl acetate (50 ml), and then was filtered by a suction funnel. The solid was collected to obtain 5-iodoquinolin-6-amine (5.20 g). MS: 271 [M+H].sup.+.

Step 2: Synthesis of (6-aminoquinolin-5-yl)dimethylphosphine oxide

[0461] ##STR00161##

[0462] To a solution of 5-iodoquinolin-6-amine (4.70 g) in DMF/H2O (100 mL/20 ml), was added methylphosphonoylmethane (1.80 g), Xantphos (1.77 g), Pd(OAc).sub.2 (344 mg) and K.sub.3PO.sub.4 (9.76 g) at r.t. The reaction solution was stirred at 120° C. overnight. The reaction mixture was concentrated under vacuum. The residue was purificated by silica gel column (MeOH was changed from 0 to 10%, 20 mins) to obtained (6-aminoquinolin-5-yl)dimethylphosphine oxide (2.50 g). MS: 221 [M+H].sup.+.

Step 3: (6-((2,5-dichloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide

[0463] ##STR00162##

[0464] To a solution of 2,4,5-trichloropyrimidine (1.67 g, 9.08 mmol) in n-Butanol (15 ml), was added (6-aminoquinolin-5-yl)dimethylphosphine oxide (1.00 g) and DIEA (1.76 g, 13.62 mmol, 2.37 mL) at r.t. The reaction solution was stirred at 120° C. for 4 hours. The reaction mixture was cooled to room temperature. The reaction mixture was filtered by a suction funnel and the solid was collected to obtained (6-((2,5-dichloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (0.90 g, 2.45 mmol, 53.98% yield). MS: 367 [M+H].sup.+.

Step 4: Synthesis of (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide

[0465] ##STR00163##

[0466] To a solution of (6-((2,5-dichloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (1.60 g) in 2-butyl alcohol (15 mL), was added 4-fluoro-3-nitro-aniline (680 mg) and TsOH (1.13 g). The reaction solution was stirred at 100° C. for overnight. The reaction mixture was cooled down to room temperature and was filtered by by a suction funnel. The solid was collected and dried to obtained (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide. MS: 487 [M+H].sup.+.

Step 5: Synthesis of 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0467] ##STR00164##

[0468] To a solution of (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (1.60 g) in DMSO (20 mL), was added 7-azaspiro[3.5]nonan-2-one hydrochloride (693 mg) and anhydrous potassium carbonate (1.36 g). The reaction solution was stirred at 90° C. for overnight. The reaction mixture was cooled to room temperature and diluted with water (50 mL). The resulting mixture was extracted with dichloromethane for two times. The organic layers was dried over anhydrous sodium sulfate and concentrated under vacuum to obtained 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one (1.00 g) as a yellow solid. MS: 606 [M+H].sup.+.

Step 6: Synthesis of (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide

[0469] ##STR00165##

[0470] To a solution of 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one (1.00 g) in MeOH (20 mL), was added dimethylamine solution (372 mg) and AcOH (99 mg). The reaction mixture was stirred at 60° C. for 0.5 h. Then Na(CN)BH.sub.3 (311 mg) was added to the resulting solution. The resulting mixture was stirred at r.t for 2 h. The resulting mixture was concentrated under vacuum. The crude product was purificated by flash silica gel column (MeOH from 0-10%, 20 mins) to obtained (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (0.95 g). MS: 635 [M+H].sup.+.

Step 7: Synthesis of (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide

[0471] ##STR00166##

[0472] To a solution of (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (1.00 g) in MeOH (20 ml), was added Pd/C (200 mg). The reaction solution was stirred under hydrogen pressure for 2 hours. The reaction mixture is filtered by a a suction funnel. The filtrate was collected and concentrated to obtained (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (380 mg) as a yellow solid. MS: 605 [M+H].sup.+.

Step 8: Synthesis of N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0473] ##STR00167##

[0474] To a solution of (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (120 mg) NaHCO.sub.3 (50 mg) in DCM (5 mL) and H.sub.2O (5 mL), was dropwise added prop-2-enoyl chloride (22 mg) in DCM (0.5 ml) at 0-10° C. The resulting solution was stirred for 0.5 h at 0-10° C. The reaction was concentrated by vacuum. The residue was purified by column chromatography over silica gel with DCM/MeOH (8:1) to obtain Compound 30 N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide (27.6 mg) MS: 659 [M+H].sup.+.

[0475] .sup.1H NMR (500 MHz, DMSO-d6) δ 12.45 (s, 1H), 11.03 (s, 1H), 9.383 (d, J=7.5 Hz, 1H), 9.01 (s, 1H), 8.85 (m, 2H), 8.57 (d, J=8.5 Hz, 1H), 8.21 (m, 2H), 8.05 (d, J=9.5 Hz, 1H), 7.56 (m, 1H), 7.37 (d, J=7.0 Hz, 1H), 6.97 (d, J=8.5 Hz, 1H), 6.64 (m, 1H), 6.17 (m, 1H), 5.76 (m, 1H), 2.67 (m, 2H), 2.62 (m, 2H), 2.48 (s, 6H), 2.14 (s, 2H) 2.06-1.96 (m, 8H), 1.75 (m, 4H).

Example 31 Synthesis of Compound 31

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methylphenyl)acrylamide

[0476] ##STR00168##

Step 1: Synthesis of 4-fluoro-2-methyl-5-nitroaniline

[0477] ##STR00169##

[0478] To a solution of 4-fluoro-2-methylaniline (5.25 g) in H.sub.2SO.sub.4 (45 mL), was dropwise added a solution of fuming nitric acid (3.17 g) in H.sub.2SO.sub.4 (5 mL) at 0-10° C. The resulting solution was stirred for 2 h at 0-10° C. Pour the reaction solution into ice water, then adjust pH to 9-10 with a aqueous solution of 8 N NaOH and a yellow solid was separated out. The solid was filtered by a suction funnel. The filter cake was dried to obtained 4-fluoro-2-methyl-5-nitroaniline (6.30 g). MS: 171 [M+14].sup.+.

Step 2: Synthesis of (2-((5-chloro-2-((4-fluoro-2-methyl-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0479] ##STR00170##

[0480] Following the same procedure as (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide using 4-fluoro-2-methyl-5-nitro aniline instead of 4-fluoro-3-nitro-aniline and using (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (6-((2,5-dichloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide (1.60 g) to obtain (2-((5-chloro-2-((4-fluoro-2-methyl-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 450 [M+H].sup.+.

Step 3: Synthesis of 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0481] ##STR00171##

[0482] Following the same procedure as 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one using (2-((5-chloro-2-((4-fluoro-2-methyl-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (6-((5-chloro-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide to obtain 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one. MS: 569 [M+H].sup.+.

Step 4: Synthesis of (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methyl-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0483] ##STR00172##

[0484] Following the same procedure as (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide using 7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-5-methyl-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one instead of 7-(4-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one to obtain (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methyl-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 598 [M+H].sup.+

Step 5: Synthesis of (2-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0485] ##STR00173##

[0486] Following the same procedure as Synthesis of (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide using (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methyl-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (6-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide to obtain (2-((2-((5-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-2-methylphenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide. MS: 568 [M+H].sup.+.

Step 6: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methylphenyl)acrylamide

[0487] ##STR00174##

[0488] Following the same procedure as N-(5-((5-chloro-4-((5-(dimethylphosphoryl)quinolin-6-yl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide using (2-((2-((5-amino-2-methyl-4-(2-(methyl amino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide instead of (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)quinolin-5-yl)dimethylphosphine oxide to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-4-methylphenyl)acrylamide. MS: 622 [M+H].sup.+.

[0489] .sup.1H NMR (500 MHz, DMSO-d.sub.6) δ 11.25 (s, 1H), 10.49 (s, 1H), 9.01 (s, 1H), 8.76 (s, 1H), 8.44 (s, 1H), 8.08 (s, 2H), 7.52 (m, 1H), 7.17 (s, 1H), 7.04 (m, 2H), 6.71 (m, 1H), 6.20 (m, 1H), 5.73 (d, J=11.5 Hz, 1H) 2.75 (m, 2H), 2.70 (m, 2H), 2.55 (s, 6H) 2.17 (m, 2H), 2.13 (s, 3H), 2.00 (m, 2H), 1.77 (m, 10H).

Example 32 Synthesis of Compound 32

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-ylamino)phenyl)acrylamide

[0490] ##STR00175##

Step 1: Synthesis of 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)-5-fluoropyrimidine-2,4-diamine

[0491] ##STR00176##

[0492] To a solution of N.sup.4-(2-(dimethylphosphoryl)phenyl)-5-fluoro-N.sup.2-(4-fluoro-3-nitrophenyl)pyrimidine-2,4-diamine (500 mg) in DMSO (5 mL) was added K.sub.2CO.sub.3 (330 mg), this was followed by addition of N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine (183 mg), The reaction mixture was stirred at 90° C. overnight, The reaction mixture was cooled down to room temperature and diluted with DCM (50 mL). The resulting solution was washed with water and NaCl saturated aqueous solution respectively, the organic phase was concentrated under vacuum, The crude product was re-crystallized from Et.sub.2O to obtain 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)-5-fluoropyrimidine-2,4-diamine (520 mg) as yellow solid MS: 502 [M+14].sup.+

Step 2: Synthesis of N1-(2-(dimethylamino)ethyl)-N4-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-yl)-N1-methylbenzene-1,2,4-triamine

[0493] ##STR00177##

[0494] To a solution of 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)-5-fluoropyrimidine-2,4-diamine (520 mg) in MeOH (10 mL), was added Pd/C (100 mg), the mixture was stirred under H.sub.2 atmosphere at 25° C. for 2 hrs, The solution was filtered through diatomite to remove the Pd/C, The solution was evaporated to give N1-(2-(dimethylamino)ethyl)-N4-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-yl)-N1-methylbenzene-1,2,4-triamine (400 mg) as grey solid. MS: 472[M+H].sup.+

Step 3: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-ylamino)phenyl)acrylamide

[0495] ##STR00178##

[0496] To a solution of N1-(2-(dimethylamino)ethyl)-N4-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-yl)-N1-methylbenzene-1,2,4-triamine (400 mg) in DCM/H.sub.2O (5 mL:5 mL), was added NaHCO.sub.3 (160 mg), this was followed by addition of acryloyl chloride (80 mg) below 0° C., the mixture was stirred at 25° C. for 30 minutes, The resulting solution was extracted with 2*20 mL of DCM and the organic layers combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel with DCM/MeOH (8:1) to obtained N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-ylamino)phenyl)acrylamide (186 mg) as off-white solid. MS: 526[M+H].sup.+.

Example 33 Synthesis of Compound 33

N-(5-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-4-methoxyphenyl)acrylamide

[0497] ##STR00179##

Step 1: Synthesis of 3-(4-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-5-methoxy-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one

[0498] ##STR00180##

[0499] Following the same procedure as 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)-5-fluoropyrimidine-2,4-diamine, using 5-chloro-N4-(2-(dimethylphosphoryl)phenyl)-N2-(4-fluoro-2-methoxy-5-nitrophenyl)pyrimidine-2,4-diamine instead of N4-(2-(dimethylphosphoryl)phenyl)-5-fluoro-N2-(4-fluoro-3-nitrophenyl)pyrimidine-2,4-diamine, using 3-azaspiro[5.5]undecan-9-one trifluoroacetate instead of N.sup.1,N.sup.1,N.sup.2-trimethyl ethane-1,2-di amine to obtain 3-(4-(5-chloro 4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-5-methoxy-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one. MS: 613[M+H].sup.+

Step 2: Synthesis of 5-chloro-N2-(4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-2-methoxy-5-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)pyrimidine-2,4-diamine

[0500] ##STR00181##

[0501] To a solution of 3-(4-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-5-methoxy-2-nitrophenyl)-3-azaspiro[5.5]undecan-9-one (200 mg) in DCM/MeOH (5 mL:5 mL), this was followed by addition of HOAc (50 mg), then added dimethylamine (2 mL 2N in THF), the mixture was stirred at 65° C. for 1 hr, NaBH.sub.3CN (200 mg) was added and the mixture was further stirred at room temperature for 16 hrs, After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (30 mL). The resulting solution was washed with 10% NaHCO.sub.3 aqueous solution and NaCl saturated aqueous solution. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum, The crude product was re-crystallized from Et.sub.2O to obtained 100 mg of 5-chloro-N2-(4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-2-methoxy-5-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)pyrimidine-2,4-diamine. MS: 642 [M+H].sup.+

Step 3: synthesis of N2-(5-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-2-methoxyphenyl)-5-chloro-N4-(2-(dimethylphosphoryl)phenyl)pyrimidine-2,4-diamine

[0502] ##STR00182##

[0503] Following the same procedure as N1-(2-(dimethylamino)ethyl)-N4-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-yl)-N1-methylbenzene-1,2,4-triamine, using 5-chloro-N2-(4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-2-methoxy-5-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)pyrimidine-2,4-diamine instead of 2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(2-(dimethylphosphoryl)phenyl)-5-fluoropyrimidine-2,4-diamine to obtain N2-(5-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-2-methoxyphenyl)-5-chloro-N4-(2-(dimethylphosphoryl)phenyl)pyrimidine-2,4-diamine. MS: 612 [M+H].sup.+

Step 4: synthesis of N-(5-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-4-methoxyphenyl)acrylamide

[0504] ##STR00183##

[0505] Following the same procedure as N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-ylamino)phenyl)acrylamide, using N2-(5-amino-4-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-2-methoxyphenyl)-5-chloro-N4-(2-(dimethylphosphoryl)phenyl)pyrimidine-2,4-diamine instead of N1-(2-(dimethylamino)ethyl)-N4-(4-(2-(dimethylphosphoryl)phenylamino)-5-fluoropyrimidin-2-yl)-N1-methyl benzene-1,2,4-triamine to obtain N-(5-(5-chloro-4-(2-(dimethylphosphoryl)phenylamino)pyrimidin-2-ylamino)-2-(9-(dimethylamino)-3-azaspiro[5.5]undecan-3-yl)-4-methoxy phenyl)acrylamide. MS: 666 [M+H].sup.+

Example 34 Synthesis of Compound 34

N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide

[0506] ##STR00184##

Step 1: synthesis of 5-iodoquinoxalin-6-amine

[0507] ##STR00185##

[0508] To a solution of quinoxalin-6-amine (7.5 g) in HOAc (150 mL), was added ICl (10 g), The reaction mixture was stirred at 25° C. 2 hrs, the mixture was poured into hexane, then filtered, got 5-iodoquinoxalin-6-amine (12 g). MS: 272[M+H].sup.+

Step 2: synthesis of 5-(dimethylphosphoryl)quinoxalin-6-amine

[0509] ##STR00186##

[0510] To a solution of 5-iodoquinoxalin-6-amine (12 g) in dioxane (120 mL), was added Dimethylphosphine oxide (5.2 g), it was followed by addition of Xantphos (2.6 g), Pd(OAc).sub.2 (990 mg), K.sub.3PO.sub.4 (2.4 g), The reaction mixture was stirred at 100° C. overnight, the organic phase was concentrated under vacuum, the mixture diluted with EA (500 mL). The resulting solution was washed with water and NaCl saturated aqueous solution respectively, the organic phase was concentrated under vacuum, The residue was purified by column chromatography over silica gel with DCM/MeOH (20:1) to obtained 5-(dimethylphosphoryl)quinoxalin-6-amine (6 g) MS: 222[M+H].sup.+

Step 3: Synthesis of N-(5-bromo-2-chloropyrimidin-4-yl)-5-(dimethylphosphoryl)quinoxalin-6-amine

[0511] ##STR00187##

[0512] To a solution of 5-(dimethylphosphoryl)quinoxalin-6-amine (6 g) in n-BuOH (60 mL), was added DIEA (7 g), this was followed by 5-bromo-2,4-dichloro-pyrimidine (12 g), The reaction mixture was stirred at 140° C. for 48 hrs, cooled to 25° C., filtered, got N-(5-bromo-2-chloropyrimidin-4-yl)-5-(dimethylphosphoryl)quinoxalin-6-amine (1.7 g), MS: 414[M+H].sup.+

Step 4: Synthesis of 5-bromo-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)-N2-(4-fluoro-3-nitrophenyl)pyrimidine-2,4-diamine

[0513] ##STR00188##

[0514] To a solution of N-(5-bromo-2-chloropyrimidin-4-yl)-5-(dimethylphosphoryl)quinoxalin-6-amine (600 mg) in n-BuOH (20 mL), was added 4-fluoro-3-nitroaniline (272 mg), this was followed by addition of p-TsOH (375 mg), The reaction mixture was stirred at 120° C. for 2 hrs, the mixture diluted with DCM (100 mL). The resulting solution was washed with water and NaCl saturated aqueous solution respectively, the organic phase was concentrated under vacuum, The residue was purified by column chromatography over silica gel with DCM/MeOH (20:1) to obtained 5-bromo-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)-N2-(4-fluoro-3-nitrophenyl)pyrimidine-2,4-diamine (400 mg). MS: 532[M+H].sup.+

Step 5: Synthesis of 5-bromo-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine

[0515] ##STR00189##

[0516] To a solution of 5-bromo-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)-N2-(4-fluoro-3-nitrophenyl)pyrimidine-2,4-diamine (400 mg) in DMSO (10 mL), was added K.sub.2CO.sub.3 (210 mg), this was followed by addition of N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine (153 mg), The reaction mixture was stirred at 100° C. overnight, The reaction mixture was cooled down to room temperature and diluted with DCM (50 mL). The resulting solution was washed with water and NaCl saturated aqueous solution respectively, the organic phase was concentrated under vacuum, The crude product was re-crystallized from Et.sub.2O to obtained 5-bromo-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine (200 mg) as yellow solid. MS: 614[M+H].sup.+

Step 6: Synthesis of N4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,2,4-triamine

[0517] ##STR00190##

[0518] To a solution of 5-bromo-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine (200 mg) in EtOH/H.sub.2O (10 mL/10 mL), was added Fe powder (180 mg), this was followed by addition of NH.sub.4Cl (180 mg), the mixture was stirred at 80° C. for 2 hrs, The solution was filtered, the organic phase was concentrated under vacuum, The residue was purified by column chromatography over silica gel with DCM/MeOH (10:1) to obtained N4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-yl amino)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,2,4-triamine (150 mg) MS: 586[M+14].sup.+

Step 7: synthesis of N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide

[0519] ##STR00191##

[0520] To a solution of N4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,2,4-triamine (150 mg) in DCM/H.sub.2O (5 mL:5 mL), was added NaHCO.sub.3 (160 mg), this was followed by addition of acryloyl chloride (23 mg) below 5° C., the mixture was stirred at 25° C. for 30 minutes, The resulting solution was extracted with 2*20 mL DCM and the organic layers combined. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography over silica gel with DCM/MeOH (8:1) to obtained N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide (33.2 mg) as off-white solid. MS: 624 [M+H].sup.+

Example 35 Synthesis of Compound 35

N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0521] ##STR00192##

Step 1: synthesis of 7-(4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one

[0522] ##STR00193##

[0523] Following the same procedure as 5-bromo-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine, using (6-((5-bromo-2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of 5-bromo-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)-N2-(4-fluoro-3-nitrophenyl)pyrimidine-2,4-diamine, using 7-azaspiro[3.5]nonan-2-one hydrogen chloride salt instead of N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine to obtain 7-(4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one. MS 651 [M+H].sup.+

Step 2: synthesis of 5-bromo-N2-(4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine

[0524] ##STR00194##

[0525] To a solution of 7-(4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-one (200 mg) in DCM/MeOH (5 mL:5 mL), this was followed by addition of HOAc (50 mg), then added dimethylamine (2 mL 2N in THF), the mixture was stirred at 65° C. for 1 hr, NaBH.sub.3CN (200 mg) was added and the mixture was further stirred at room temperature for 16 hrs, After completion of the reaction (monitored by TLC), the reaction mixture was diluted with DCM (30 mL). The resulting solution was washed with 10% NaHCO.sub.3 aqueous solution and NaCl saturated aqueous solution. The mixture was dried over anhydrous magnesium sulfate and concentrated under vacuum, The crude product was re-crystallized from Et.sub.2O to obtained 100 mg 5-bromo-N2-(4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine. MS: 680 [M+H].sup.+

Step 3: Synthesis of (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0526] ##STR00195##

[0527] Following the same procedure as N4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,2,4-triamine, using 5-bromo-N2-(4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine instead of 5-bromo-N2-(4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)-N4-(5-(dimethylphosphoryl)quinoxalin-6-yl)pyrimidine-2,4-diamine to obtain (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide. MS: 650 [M+H].sup.+

Step 4: synthesis of N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0528] ##STR00196##

[0529] Following the same procedure as N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)acrylamide, using (6-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-bromopyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide instead of N4-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-yl)-N1-(2-(dimethylamino)ethyl)-N1-methylbenzene-1,2,4-triamine to obtain N-(5-(5-bromo-4-(5-(dimethylphosphoryl)quinoxalin-6-ylamino)pyrimidin-2-ylamino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide. MS: 704 [M+H].sup.+

Example 36 Synthesis of Compound 36

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0530] ##STR00197##

Step 1: Synthesis of tert-butyl (7-(4-amino-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-yl)carbamate

[0531] ##STR00198##

[0532] To a solution of 4-fluoro-3-nitroaniline (2.0 g) in DMSO (20 mL) was added K.sub.2CO.sub.3 (3.5 g) at room temperature, then tert-butyl (7-azaspiro[3.5]nonan-2-yl)carbamate (3.3 g) was added into the mixture in portions. The mixture was heated to 90° C. overnight. TLC showed the reaction was completed. The solution was poured into water and extracted with ethyl acetate (30 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by column chromatography (hexane/ethyl acetate from 0 to 20%). After concentration, the solid was dried to obtain tert-butyl (7-(4-amino-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (2.1 g) as yellow solid. MS: 376.46 [M+H].sup.+.

Step 2: Synthesis of tert-butyl (7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-yl)carbamate

[0533] ##STR00199##

[0534] To a mixture of tert-butyl (7-(4-amino-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.5 g) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.26 g) in Dioxane (20 mL) was added Methanesulfonato(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (633 mg) and NaOtBu (765 mg) at room temperature under nitrogen atmosphere. Then the mixture was heated to 110° C. overnight. LCMS showed the reaction was completed. The solution was diluted with EtOAc (20 mL) and then filtrated under reduced pressure. The filtrate was concentrated by vacuum. The crude product was purified by column chromatography (hexane/ethyl acetate from 1:0 to 0:1). After concentration, the solid was dried to obtain tert-butyl (7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.3 g) as brown solid. MS: 656.12 [M+H].sup.+.

Step 3: Synthesis of (2-((2-((4-(2-amino-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0535] ##STR00200##

[0536] To a solution of tert-butyl (7-(4-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-nitrophenyl)-7-azaspiro[3.5]nonan-2-yl)carbamate (1.3 g) in DCM (30 mL) was added 2,2,2-trifluoroacetic acid (10 mL) at room temperature under nitrogen atmosphere. Then the mixture was stirred at room temperature for 2 hours. LCMS showed the reaction was completed. The solution was concentrated by vacuum. The crude product was without further purification and applied to the next step directly. After concentration, the solid was dried to obtain (2-((2-((4-(2-amino-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.2 g) as colorless oil. MS: 556.00 [M+H].sup.+.

Step 4: Synthesis of (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0537] ##STR00201##

[0538] To a solution of (2-((2-((4-(2-amino-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (600 mg) in MeOH (30 mL) was added K.sub.2CO.sub.3 that adjusted pH to 8, then Paraformaldehyde was added. After stirred for 10 min, NaBH.sub.3CN was added in portions. Then the mixture was stirred at room temperature for 1 hour. LCMS showed the reaction was completed. The solution was poured into water and extracted with DCM (30 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM/MeOH=10:1). After concentration, the solid was dried to obtain (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) as yellow solid. MS: 584.06 [M+H].sup.+.

Step 5: Synthesis of (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0539] ##STR00202##

[0540] To a solution of (2-((5-chloro-2-((4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) in i-PrOH (20 mL) was added Pd/C in one portion. Then the mixture was stirred under H.sub.2 (balloon, 15 psi) at room temperature overnight. LCMS showed the reaction was completed. The solution was filtrated and the filtrate was concentrated by vacuum. The crude product was without further purification and applied to the next step directly. After concentration, the solid was dried to obtain (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (240 mg) as gray solid. MS: 554.08 [M+H].sup.+.

Step 6: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide

[0541] ##STR00203##

[0542] To a solution of (2-((2-((3-amino-4-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (300 mg) in DCM (5 mL) and H.sub.2O (5 mL) was added NaHCO.sub.3 (68.23 mg) in one portion at 0° C. Then acryloyl chloride (54 mg) was added in dropwise. The mixture was stirred at this temperature for 10 min. LCMS showed the reaction was completed. The reaction mixture was quenched by MeOH and then concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O=30%). After concentration, the solid was dried to obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(2-(dimethylamino)-7-azaspiro[3.5]nonan-7-yl)phenyl)acrylamide (170 mg) as off-white solid. MS: 608.54 [M+H].sup.+.

Example 37 Synthesis of Compound 37

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide

[0543] ##STR00204##

Step 1: Synthesis of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0544] ##STR00205##

[0545] To a mixture of (2-((2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.0 g) and 4-fluoro-3-nitroaniline (609 mg) in n-BuOH (20 mL) was added p-TsOH (917 mg) in one portion at room temperature. Then the mixture was heated to 110° C. and stirred at this temperature for 1 hour. LCMS showed the reaction was completed. The reaction mixture was concentrated by vacuum. The crude product was purified by column chromatography (MeOH:DCM=10%). After concentration, the solid was dried to obtain (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.0 g) as gray solid. MS: 401.34 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0546] ##STR00206##

[0547] To a mixture of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (300 mg) and N.sup.1,N.sup.1,N.sup.2-trimethylethane-1,2-diamine (114 mg) in DMSO (10 mL) was added K.sub.2CO.sub.3 (206 mg) in one portion at room temperature. Then the mixture was heated to 90° C. and stirred at this temperature for 16 h. LCMS showed the reaction was completed. The solution was poured into water and extracted with ethyl acetate (30 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH from 0 to 30%). After concentration, the solid was dried to obtain (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) as red solid. MS: 483.51 [M+H].sup.+.

Step 3: Synthesis of (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0548] ##STR00207##

[0549] To a solution of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) in MeOH (5 mL) and H.sub.2O (5 mL) was added Fe (115 mg) and NH.sub.4Cl (44 mg) in one portion. Then the mixture was heated to 90° C. and stirred for 2 hours. LCMS showed the reaction was completed and the desired MS was detected. The solution was filtrated and the filtrate was concentrated by vacuum. The crude product was without further purification and applied to the next step directly. After concentration, the solid was dried to obtain (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg) as red solid. MS: 453.53 [M+H].sup.+.

Step 4: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide

[0550] ##STR00208##

[0551] To a solution of (2-((2-((3-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg) in DCM (5 mL) and H.sub.2O (5 mL) was added NaHCO.sub.3 (37 mg) in one portion at 0° C. Then acryloyl chloride (24 mg) was added in dropwise. The mixture was stirred at this temperature for 10 min. LCMS showed the reaction was completed. The reaction mixture was quenched by MeOH and then concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O=50%). After concentration, the obtained product was adjusted pH to 9 and then extracted by EtOAc (5 mL*3) and the combined organic phase were further purified by prep-TLC and obtain N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)phenyl)acrylamide (6 mg) as yellow solid. MS: 508.97 [M+H].sup.+.

Example 38 Synthesis of Compound 38

N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0552] ##STR00209##

Step 1: Synthesis of dimethyl(2-((2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphine oxide

[0553] ##STR00210##

[0554] To a mixture of (2-((2-((4-fluoro-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) and 1-methyl-4-(piperidin-4-yl)piperazine (342 mg) in DMSO (10 mL) was added K.sub.2CO.sub.3 (344 mg) in one portion at room temperature. Then the mixture was heated to 90° C. and stirred at this temperature for 16 hours. LCMS showed the reaction was completed. The solution was poured into water and extracted with ethyl acetate (30 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was purified by column chromatography (DCM:MeOH from 0 to 15%). After concentration, the solid was dried to obtain dimethyl(2-((2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphine oxide (260 mg) as red solid. MS: 564.63 [M+H].sup.+.

Step 2: Synthesis of (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0555] ##STR00211##

[0556] To a solution of dimethyl(2-((2-((4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)phosphine oxide (260 mg) in MeOH (5 mL) and H.sub.2O (5 mL) was added Fe (128 mg) and NH.sub.4Cl (50 mg) in one portion. Then the mixture was heated to 90° C. and stirred for 2 hours. LCMS showed the reaction was completed and the desired MS was detected. The solution was filtrated and the filtrate was concentrated by vacuum. The crude product was without further purification and applied to the next step directly. After concentration, the solid was dried to obtain (2-((2-((3-amino-4-(4-(4-methyl piperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg, crude) as red solid.

Step 3: Synthesis of N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0557] ##STR00212##

[0558] To a solution of (2-((2-((3-amino-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (100 mg) in DCM (5 mL) and H.sub.2O (5 mL) was added NaHCO.sub.3 (24 mg) in one portion at 0° C. Then acryloyl chloride (21 mg) was added in dropwise. The mixture was stirred at this temperature for 10 min. LCMS showed the reaction was completed. The reaction mixture was quenched by MeOH and then concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O=30%). After concentration, the obtained product was adjusted pH to 9 and then extracted by EtOAc (5 mL*3) and the combined organic phase were adjusted to HCl salt obtain N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (8 mg) as yellow solid. MS: 588.68 [M+H].sup.+.

Example 39 Synthesis of Compound 39

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0559] ##STR00213##

Step 1: Synthesis of (2-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0560] ##STR00214##

[0561] To a mixture of (2-((2-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.0 g) and 4-fluoro-3-nitroaniline (727 mg) in n-BuOH (20 mL) was added p-TsOH (917 mg) in one portion at room temperature. Then the mixture was heated to 110° C. and stirred at this temperature for 1 hour. LCMS showed the reaction was completed. The reaction mixture was concentrated by vacuum. The crude product was washed by H.sub.2O and EtOAc and then filtrated. The filtrate cake was concentrated under reduced pressure, the solid was dried to obtain (2-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (1.3 g, crude) as yellow solid.

Step 2: Synthesis of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0562] ##STR00215##

[0563] To a mixture of (2-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) and N1,N1,N2-trimethylethane-1,2-diamine (177 mg) in DMSO (10 mL) was added K.sub.2CO.sub.3 (320 mg) in one portion at room temperature. Then the mixture was heated to 90° C. and stirred at this temperature for 16 hours. LCMS showed the reaction was completed. The solution was poured into water and extracted with DCM:MeOH=10:1 (30 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was without further purification and applied to the next step directly. After concentration, the solid was dried to obtain (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg, crude) as red solid.

Step 3: Synthesis of (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0564] ##STR00216##

[0565] To a solution of (2-((2-((4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) in MeOH (5 mL) was added Pd/C (200 mg) in one portion. Then the mixture was stirred under H.sub.2 balloon for 2 hours. LCMS showed the reaction was completed and the desired MS was detected. The solution was filtrated and the filtrate was concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O from 0 to 30%). After concentration, the solid was dried to obtain (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) as gray solid. MS: 483.56 [M+H].sup.+.

Step 4: Synthesis of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide

[0566] ##STR00217##

[0567] To a solution of (2-((2-((5-amino-4-((2-(dimethylamino)ethyl)(methyl)amino)-2-methoxyphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (150 mg) in DCM (5 mL) and H.sub.2O (5 mL) was added NaHCO.sub.3 (39 mg) in one portion at 0° C. Then acryloyl chloride (34 mg) was added in dropwise. The mixture was stirred at this temperature for 10 min. LCMS showed the reaction was completed. The reaction mixture was quenched by MeOH and then concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O=30%). After concentration, the obtained product was adjusted pH to 9 and then extracted by EtOAc (5 mL*3) and the combined organic phase were adjusted to HCl salt obtain N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxyphenyl)acrylamide (20 mg) as white solid. MS: 539.00 [M+H].sup.+.

Example 40 Synthesis of Compound 40

N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0568] ##STR00218##

Step 1: Synthesis of (2-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0569] ##STR00219##

[0570] To a mixture of (2-((2-((4-fluoro-2-methoxy-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) and 1-methyl-4-(piperidin-4-yl)piperazine (318 mg) in DMSO (10 mL) was added K.sub.2CO.sub.3 (320 mg) in one portion at room temperature. Then the mixture was heated to 90° C. and stirred at this temperature for 16 hours. LCMS showed the reaction was completed. The solution was poured into water and extracted with DCM:MeOH=10:1 (30 mL*3). The combined organic layer was washed with saturated sodium chloride aqueous solution (50 mL*2), dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The crude product was without further purification and applied to the next step directly. After concentration, the solid was dried to obtain (2-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg, crude) as red solid.

Step 3: Synthesis of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0571] ##STR00220##

[0572] To a solution of (2-((2-((2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)-5-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (500 mg) in MeOH (5 mL) was added Pd/C (200 mg) in one portion. Then the mixture was stirred under H.sub.2 balloon for 2 hours. LCMS showed the reaction was completed and the desired MS was detected. The solution was filtrated and the filtrate was concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O from 0 to 30%). After concentration, the solid was dried to obtain (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) as gray solid.

Step 4: Synthesis of N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide

[0573] ##STR00221##

[0574] To a solution of (2-((2-((5-amino-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (150 mg) in DCM (5 mL) and H.sub.2O (5 mL) was added NaHCO.sub.3 (34 mg) in one portion at 0° C. Then acryloyl chloride (29 mg) was added in dropwise. The mixture was stirred at this temperature for 10 min. LCMS showed the reaction was completed. The reaction mixture was quenched by MeOH and then concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O=30%). After concentration, obtain N-(5-((4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-4-methoxy-2-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)acrylamide (26 mg) as pink solid. MS: 620.03 [M+H].sup.+.

Example 41 Synthesis of Compound 41

N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-methylpiperidin-4-yl)oxy)phenyl)acrylamide

[0575] ##STR00222##

Step 1: 4-((1-methylpiperidin-4-yl)oxy)-3-nitroaniline

[0576] ##STR00223##

[0577] To a mixture of 1-methylpiperidin-4-ol (1.48 g) in DMF (20 mL) was added NaH (338 mg) in one portion at room temperature. Then 4-fluoro-3-nitroaniline (2.0 g) was added in portions. The mixture was stirred at this temperature for 16 hours. LCMS showed the reaction was completed. The reaction mixture was poured into water (50 mL) and extracted by EtOAc (30 mL*3). The combined organic phase was dried by Na.sub.2SO.sub.4, then filtered and concentrated in vacuum. The residue was purified by silica gel chromatography PE:EA from 0 to 80% to obtain 4-((1-methylpiperidin-4-yl)oxy)-3-nitroaniline (1.0 g, crude) as black solid. MS: 251.29 [M+H].sup.+

Step 2: Synthesis of (2-((5-chloro-2-((4-((1-methylpiperidin-4-yl)oxy)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0578] ##STR00224##

[0579] To a mixture of 4-((1-methylpiperidin-4-yl)oxy)-3-nitroaniline (300 mg) and (2-((2,5-dichloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (415 mg) in Dioxane (10 mL) was added Methanesulfonato(2-di-t-butylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)(2′-amino-1,1′-biphenyl-2-yl)palladium(II) (189.92 mg) and tert-butoxysodium (114.73 mg) in one portion at room temperature. Then the mixture was reacted under microwave 110° C. for 1.5 hours. LCMS showed the reaction was completed. The solution was concentrated under reduced pressure. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O from 0 to 50%). After concentration, the solid was dried to obtain (2-((5-chloro-2-((4-((1-methylpiperidin-4-yl)oxy)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (300 mg) as yellow solid. MS: 530.95 [M+H].sup.+

Step 3: Synthesis of (2-((2-((3-amino-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0580] ##STR00225##

[0581] To a solution of (2-((5-chloro-2-((4-((l-methylpiperidin-4-yl)oxy)-3-nitrophenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (300 mg) in MeOH (5 mL) and H.sub.2O (10 mL) was added Fe (157.77 mg) and NH.sub.4Cl (60.45 mg) in one portion. Then the mixture was heated to 90° C. and stirred for 2 hours. LCMS showed the reaction was completed and the desired MS was detected. The solution was filtrated and the filtrate was concentrated by vacuum. The crude product was without further purification and applied to the next step directly. After concentration, the solid was dried to obtain (2-((2-((3-amino-4-((1-methylpiperidin-4-yl)oxy)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (300 mg) as yellow solid.

Step 4: Synthesis of N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-methylpiperidin-4-yl)oxy)phenyl)acrylamide

[0582] ##STR00226##

[0583] To a solution of (2-((2-((3-amino-4-((l-methylpiperidin-4-yl)oxy)phenyl)amino)-5-chloropyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide (200 mg) in DCM (5 mL) and H.sub.2O (5 mL) was added NaHCO.sub.3 (50 mg) in one portion at 0° C. Then acryloyl chloride (90 mg) was added in dropwise. The mixture was stirred at this temperature for 10 min. LCMS showed the reaction was completed. The reaction mixture was quenched by MeOH and then concentrated by vacuum. The crude product was purified by reversed phase chromatography (MeOH:H.sub.2O=50%). After concentration, obtain N-(5-((5-chloro-4-((2-(dimethylphosphoryl)phenyl)amino)pyrimidin-2-yl)amino)-2-((1-methylpiperidin-4-yl)oxy)phenyl)acrylamide (40 mg) as pink solid. MS: 555.40 [M+H].sup.+.

Comparative Compound A

(2-((5-chloro-2-((4-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)-3-methylphenyl)amino)pyrimidin-4-yl)amino)phenyl)dimethylphosphine oxide

[0584] Prepare the following Comparative compound A as described for Example 36 in WO2018108064.

##STR00227##

Comparative Compound B

N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-54(4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide

[0585] ##STR00228##

Comparative Compound C

(6-((5-bromo-2-((2-methoxy-5-methyl-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0586] Prepare the following Comparative compound C as described for Example 34 in WO2019015655.

##STR00229##

Comparative Compound D

(6-((5-bromo-2-((5-ethyl-2-methoxy-4-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)phenyl)amino)pyrimidin-4-yl)amino)quinoxalin-5-yl)dimethylphosphine oxide

[0587] Prepare the following Comparative compound D as described for Example 41 in WO2019015655.

##STR00230##

Pharmacological Testing

[0588] Test 1 Kinase Assay for EGFR Δ19del/T790M/C797S, EGFR T790M/L858R and EGFR L858R

[0589] Mobility shift assay was performed to determine that the compounds exhibit affinity for EGFR Δ19del/T790M/C797S, EGFR T790M/L858R and EGFR L858R. Enzyme reaction protocol are as followed:

[0590] 1. Preparing 1* Kinase buffer as followed.

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

[0591] 2. Preparing Compound Concentration Gradient: Compounds were tested at a concentration of 300 nM, diluted to 100-fold final concentration in 100% DMSO solution in 96-well plates, and compounds were diluted 3 times with Precision, 10 concentrations. Each concentration of the compound was then further diluted to a 5-fold final concentration of the intermediate dilution solution using 1* Kinase buffer.

[0592] 3. 5 μL of each of the prepared intermediate dilution compounds was separately added to the compound wells of the 384-well plate, and each concentration was tested for duplicate wells; 5 μL of 5% DMSO was added to the negative control wells and the positive control wells, respectively.

[0593] 4. 2.5-fold final concentration of the kinase solution was prepared using 1*Kinase buffer.

[0594] 5. Add 10 μL of 2.5-fold final concentration of kinase solution to the compound well and positive control well; add 10 μL of 1*Kinase buffer to the negative control well.

[0595] 6. Centrifuge at 1000 rpm for 30 seconds, shake the reaction plate and incubate for 10 minutes at room temperature.

[0596] 7. A mixed solution of 2.5 times the final concentration of ATP and Kinase substrate (5-FAM-EEPLYWSFPAKKK-CONH2) was prepared using 1*Kinase buffer.

[0597] 8. 10 μL of a 2.5-fold final concentration of a mixed solution of ATP and a substrate was added to initiate the reaction.

[0598] 9. Centrifuge the 384-well plate at 1000 rpm for 30 seconds, mix by shaking, and incubate at room temperature for the corresponding time.

[0599] 10. Add 30 μL of the stop solution to stop the kinase reaction, centrifuge at 1000 rpm for 30 seconds, and mix by shaking.

[0600] 11. Read the conversion rate with Caliper EZ Reader.

[0601] Convert conversion values to inhibition values:

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

[0602] “max” stands for the mean value of the positive control well ratio; “min” stands for the mean value of the negative control well; conversion % sample: sample conversion reading.

[0603] Fit the data in log(inhibitor) vs. response Variable slope of GraphPad Prism 5 to obtain IC50 values.

[0604] Equation used is: Y=Bottom+(Top−Bottom)/(1+(IC50/X)*HillSlope)

[0605] The result is expressed with IC50, shown as Table 1, Compounds of the present disclosure, as exemplified in the Examples, showed IC50 values in the following ranges: “A” stands for “IC50≤10 nM”; “B” stands for “10 nM<IC.sub.50≤100 nM”; “C” stands for “IC.sub.50>100 nM”.

TABLE-US-00002 TABLE 1 EGFR Δ 19del/ EGFR EGFR T790M/C797S L858R T790M/L858R IC.sub.50 IC.sub.50 IC.sub.50 No. (nm) (nm) (nm)  1 A B A  2 A B A  3 A B A  4 A B A  5 A B A  6 A — —  7 A — —  8 A — —  9 A — — 10 A — — 11 A — — 12 — — — 13 — — — 14 A A A 15 A A A 16 A A A 17 A A A 18 A A A 19 A A A 20 A A A 21 B A A 22 A B A 23 A — — 24 A B A 25 B A A 26 A B A 27 B A A 28 B B B 29 A B A 30 A — — 31 — — — 32 B A A 33 A B A 34 A — — 35 A — — 36 A A A 37 B A A 38 B B B 39 C A A 40 B B B 41 A B A Note: “—” stands for “not tested”

[0606] Test 2 Ba/F3-Δ19del/T790M/C797S and Ba/F3-L858R/T790M/C797S Cells Proliferation Assay

[0607] 1. Cell culture

Cell line: Ba/F3 cells with Δ19del/T790M/C797S or L858R/T790M/C797S mutation gene stably overexpressed named Ba/F3-Δ19del/T790M/C797S and Ba/F3-L858R/T790M/C797S.

[0608] A. Culture medium

[0609] RPMI 1640 and 10% FBS and 1% PS.

[0610] B. Cell recovery

[0611] a) The medium was preheated in a 37 water bath in advance.

[0612] b) Remove the cryogenic vials from the liquid nitrogen tank, quickly put it into a 37° C. water bath, and completely melt it in 1 min.

[0613] c) Transfer the cell suspension to a 15 mL centrifuge tube containing 8 mL medium, centrifuge 1000 rpm, 5 min,

[0614] d) Discard the supernatant, resuspend the cells in 1 mL medium, and transfer to a 75 cm.sup.2 flask containing 15 mL medium, culture the cells in an incubator at 37° C., 5% CO.sub.2.

[0615] C. Cell passage

[0616] a) The medium was preheated in a 37° C.; water bath in advance.

[0617] b) Collect cell to a 15 mL centrifuged tube, centrifuge at 1000 rpm for 5 min. Discard the supernatant, count, and make the cell density at 1×10.sup.4 cells/mL, then place it in a 37° C., 5% CO.sub.2 incubator.

[0618] 2. Compound preparation

[0619] a) The test compound (20 mM stock solution) was diluted to 200 uM with 100% DMSO as starting concentration then 3-fold serial diluted with “9+0” concentrations. in a 96-well dilution plate (Cat #P-05525, Labcyte);

[0620] b) The above compound solution was diluted 1:20 times with culture medium to prepare a 10 fold working solution;

[0621] 3. Cell plating

[0622] a) Take cells in log phase growth, centrifuge at 1000 rpm for 5 min, then resuspend the cells with culture medium, then count cells;

[0623] b) Cells were seeded to 96-well cell culture plate with density at 2000 cells/well;

[0624] 4. Compound treatment

[0625] a) Compounds prepared at step 2 were added to cell plate with 15 μL per well, the final concentrations were 1000,333, 111.1, 37,12.3, 4.1, 1.4, 0.5, 0.2 and 0 nM, and the final concentration of DMSO was 0.5%. The blank control well was a culture medium (0.5% DMSO);

[0626] b) The cells were incubated for an additional 72 h in the incubator.

[0627] 5. Detection

[0628] a) Remove the 96-well cell culture plate and add 50 μl of CTG reagent (CellTiter Glo kit, promega, Cat #G7573).

[0629] b) Plate was shaked for 2 min and then let it cool for 10 min at room temperature.

[0630] c) The Luminescence signal value was read using a PerkinElmer reader.

[0631] Experimental Data Analysis

[0632] Data were analyzed using GraphPad Prism 6.0 software to obtain a fitted curve of compound activity.

[0633] Fit the Compound IC50 from non-linear regression equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*Hill Slope));

[0634] X: The log of the concentration of the compound; Y: Luminescence value.

[0635] Test 3 H1975 and HCC827 Cells Proliferation Assay

[0636] 1. Cell culture

[0637] Cell line: H1975(L858R/T790M) and HCC827(Δ19del)

[0638] A. Culture medium

[0639] RPMI 1640 and 10% FBS and 1% PS.

[0640] B. Cell recovery

[0641] a) The medium was preheated in a 37° C. water bath in advance.

[0642] b) Remove the cryogenic vials from the liquid nitrogen tank, quickly put it into a 37° C. water bath, and completely melt it in 1 min.

[0643] c) Transfer the cell suspension to a 15 mL centrifuge tube containing 8 mL medium, centrifuge 1000 rpm, 5 min.

[0644] d) Discard the supernatant, resuspend the cells in 1 mL medium, and transfer to a 75 cm.sup.2 flask containing 15 mL medium, culture the cells in an incubator at 37° C., 5% CO.sub.2.

[0645] C. Cell passage

[0646] a) The medium was preheated in a 37° C. water bath in advance.

[0647] b) Collect cell to a 15 mL centrifuged tube, centrifuge at 1000 rpm for 5 min. Discard the supernatant, count, and make the cell density at 1×10.sup.4 cells/mL, then place it in a 37° C., 5% CO.sub.2 incubator.

[0648] 2. Compound preparation

[0649] a) The test compound (20 mM stock solution) was diluted to 2 mM with 100% DMSO as starting concentration then 3-fold serial diluted with “9+0” concentrations. in a 96-well dilution plate (Cat #P-05525, Labcyte);

[0650] b) The above compound solution was diluted 1:20 times with culture medium to prepare a 10 fold working solution;

[0651] 3. Cell plating

[0652] a) Take cells in log phase growth, centrifuge at 1000 rpm for 5 min, then resuspend the cells with culture medium, then count cells;

[0653] b) Cells were seeded to 96-well cell culture plate with density at 2000 cells/well (suitable for H1975 cell) and at 2500 cells/well (suitable for HCC827 cell);

[0654] 4. Compound treatment

[0655] a) Compounds prepared at step 2 were added to cell plate with 15 μL per well, the final concentrations were 10000, 3333,1111.1, 370.4, 123.5, 41.2, 13.7, 4.6, 1.5 and 0 nM, and the final concentration of DMSO was 0.5%. The blank control well was a culture medium (0.5% DMSO);

[0656] b) The cells were incubated for an additional 72 h in the incubator.

[0657] 5. Detection

[0658] a) Remove the 96-well cell culture plate and add 50 μl of CTG reagent (CellTiter Glo kit, promega, Cat #G7573).

[0659] b) Plate was shaked for 2 min and then let it cool for 10 min at room temperature.

[0660] c) The Luminescence signal value was read using a PerkinElmer reader.

[0661] Experimental Data Analysis

[0662] Data were analyzed using GraphPad Prism 6.0 software to obtain a fitted curve of compound activity.

[0663] Fit the Compound IC50 from non-linear regression equation:

Y=Bottom+(Top−Bottom)/(1+10{circumflex over ( )}((Log IC50−X)*HillSlope));

[0664] X: The log of the concentration of the compound; Y: Luminescence value.

[0665] The cells proliferation assay results are expressed with IC50, shown as Table 2. Compounds of the present disclosure, as exemplified in the Examples, showed IC50 values in the following ranges: “A” stands for “IC.sub.50≤10 nM”; “B” stands for “10 nM<IC.sub.50<50 nM”; “C” stands for “IC.sub.50≥50 nM”.

TABLE-US-00003 TABLE 2 BaF3 BaF3 Δ 19del/ L858R/T790M/C797S T790M/C797S H1975 HCC827 IC.sub.50 IC.sub.50 IC.sub.50 IC.sub.50 No. (nm) (nm) (nm) (nm)  1 A A A A  2 — — — —  3 — — — —  4 — — — —  5 — — A B  6 — B — —  7 B B — B  8 B B B B  9 B B — — 10 A A A B 11 — B B B 12 B B B B 13 — — B B 14 — — B B 15 B B A A 16 B B A B 17 B B B B 18 B B A A 19 — B B A 20 — B B A 21 — — B A 22 — — — A 23 A A B B 24 — — — B 25 — — — A 26 — — — — 27 — — A A 28 — — — B 29 — B — B 30 B A B B 31 — — B B 32 — — B A 33 — — B B 34 A A A A 35 A A A A 36 A A A A 37 — — B A 38 — — — — 39 — — B A 40 — — — — 41 — — B B Comparative A A 61.7 89.5 compound A Comparative C C A A compound B Comparative 16.8 9.6 71.4 — compound C Comparative 12.9 5.7 83.58 — compound D Note: “—” stands for “not tested”

[0666] As shown in the Table 2, we can see Comparative compound A disclosed in WO2018108064, Comparative compound C and D disclosed in WO2019015655 have higher inhibition of triple mutant (L858R/T790M/C797S or Δ19del/T790M/C797S), while at the same time having relatively low inhibition of double mutant (L858R/T790M) and single mutant (L858R). Additionally, We can see Comparative compound B (also known as AZD 9291) have higher inhibition of double mutant (L858R/T790M) and single mutant (L858R), while at the same time having relatively low inhibition of triple mutant (L858R/T790M/C797S or Δ19del/T790M/C797S). However, the exemplified compounds of this invention display high inhibition of triple mutant (L858R/T790M/C797S or 19del/T790M/C797S), double mutant (L858R/T790M) and single mutant (L858R).