Pyridinylaminopyrimidine derivatives, preparation process and use thereof

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

wherein,

Ring A is aryl or heteroaryl;

R 1 is selected from a group consisting of hydrogen, halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 2 -C 5 alkenyl, C 2 -C 6 alkynyl or —CN;

R 2 is selected from a group consisting of C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 2 -C 6 alkenyl, —(CH 2 ) c OR 7 , —(CH 2 ) q NR 7 R 7 ′ or —(CH 2 ) C(O)R 7 ;

R 4 is

each R 5 is dependently halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, —OR 6 , —C(O)R 7 , —C(O)NR 7 R 7 ′, —OR 7 , —NR 7 R 7 ′, —CN or —NO 2 ;

R 3 is selected from a group consisting of

halogen, —CN, —NO 2 , C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —C(O)R 6 , —C(O)R 7 , —C(O)NR 7 R 7 ′, —OR 7 , —OR 6 , —NHR 7 , —NR 7 —(C 1 -C 4 alkyl), —NR 7 -(haloC 1 -C 4 alkyl), —NR 7 (CH 2 ) n C(O)R 6 , —NR 6 R 7 , —NR 7 -heterocycloalkyl, wherein said heterocycloalkyl is unsubstituted or substituted with 1-2 substituents selected from R 7 ,

or —NR 7 SO 2 R 7 ,

or heterocycloalkyl that is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —(CH 2 ) n OH, —NR 7 R 7 ′, —OR 7 or —C(O)R 7 ;

wherein, R 6 is —(CH 2 ) q OR 7 , —(CH 2 ) q NR 7 R 7 ′, —(CH 2 ) q NR 7 C(O)R 7 , —(CH 2 ) q C(O)R 7 or —(CH 2 ) q C(O)NR 7 R 7 ′;

R 7 and R 7 ′ are each independently hydrogen, C 1 -C 4 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl or haloC 1 -C 4 alkyl, or R 7 , R 7 ′ and the nitrogen atom attached thereto are cyclized together to form a heterocycloalkyl that is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —(CH 2 ) n OH, —NR 7 R 7 ′, —OR 7 or —C(O)R 7 ;

m is 1, 2 or 3;

n is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3 or 4.

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

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

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydrogen, halogen or haloC 1 -C 4 alkyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is C 1 -C 4 alkyl or haloC 1 -C 4 alkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 2 is C 2 -C 4 alkyl or haloC 2 -C 4 alkyl.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl or trifluoroethyl.

8. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is

R 7 and R 7 ′ are each independently hydrogen or C 1 -C 4 alkyl.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 4 is

R 7 is hydrogen.

10. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from a group consisting of

halogen, —CN, —NO 2 , C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —C(O)R 7 , —C(O)NR 7 R 7 ′, —OR 7 , —NHR 7 , —NR 7 —(C 1 -C 4 alkyl), —NR 7 (CH 2 ) n C(O)R 6 or —NR 6 R 7 ,

or heterocycloalkyl that is unsubstituted or substituted with 1-3 substituents selected from halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —(CH 2 ) n OH, —NR 7 R 7 ′, —OR 7 or —C(O)R 7 ;

wherein, R 6 is —(CH 2 ) q OR 7 , —(CH 2 ) q NR 7 R 7 ′, —(CH 2 ) q C(O)R 7 or —(CH 2 ) q C(O)NR 7 R 7 ′;

R 7 and R 7 ′ are each independently hydrogen, C 1 -C 4 alkyl or haloC 1 -C 4 alkyl, or R 7 , R 7 ′ and the nitrogen atom attached thereto are cyclized together to form a heterocycloalkyl;

n is 0, 1, 2, 3 or 4;

q is 0, 1, 2, 3 or 4.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 is —NR 6 R 7 , in which R 6 is —(CH 2 ) q NR 7 R 7 ′, R 7 and R 7 ′ are each independently hydrogen or C 1 -C 4 alkyl, q is 2.

12. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 is a heterocycloalkyl substituted by one substituent selected from halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl or —NR 7 R 7 ′, R 7 and R 7 ′ are each independently hydrogen or C 1 -C 4 alkyl.

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

14. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein each R 5 is dependently halogen, C 1 -C 4 alkyl, haloC 1 -C 4 alkyl, —OR 7 , —NR 7 R 7 ′, —CN or —NO 2 , R 7 and R 7 ′ are each independently hydrogen or C 1 -C 4 alkyl, m is 1, 2 or 3.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein each R 5 is dependently halogen, C 1 -C 4 alkyl, —OR 7 or —NR 7 R 7 ′, R 7 and R 7 ′ are each independently hydrogen or C 1 -C 4 alkyl, m is 1, 2 or 3.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

wherein ring A, R 1 , R 2 , R 3 , R 4 , R 5 and m are defined as in claim 1 ; L represents a leaving group, including hydrogen, halogen or

compounds (a) and (b) are used as starting material, and subjected to substitution under the catalysts to produce an Intermediate 2; the Intermediate 2 and an Intermediate 1 are subjected to substitution or coupling reaction to produce a compound (c), the nitro group of the compound (c) is reduced to produce a compound (d), the compound (d) is acylated to produce a compound (I); or the Intermediate 2 and an Intermediate 1′ are subjected to substitution or coupling reaction to directly produce a compound (I).

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

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

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

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