Pyridinylaminopyrimidine derivatives, preparation process and use thereof

Abstract

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

What is claimed is: 
     
       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  trifluoroethyl; 
         R 4  is 
       
       
         
           
           
               
               
           
         
         each R 5  is dependently independently 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 pyrrolo[2,3-c]pyridinyl, pyrro[3,2-c]pyridinyl pyrrolo[3,2-c]pyridinyl, pyrro[2,3-b]pyridinyl pyrrolo[2,3-b]pyridinyl, pyrro[3,2-b]pyridinyl pyrrolo[3,2-b]pyridinyl, pyrro[2,3-b]pyrazinyl pyrrolo[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 independently 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 independently 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; and 
 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: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or 
       
         
           
           
               
               
           
         
         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  or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, excipient or diluent. 
     
     
       20. A method for selectively inhibiting an EGFR activating or resistant mutation over a wild-type EGFR, said method comprises contacting a biological sample with or administering to a lung cancer patient the compound represented by formula (I) of  claim 1  or a pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the same. 
     
     
       21. The method of  claim 19 , wherein the mammal is a human. 
     
     
       22. A compound, wherein said compound is 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 or a pharmaceutically acceptable salt thereof.