Heterocyclic substituted-3-heteroarylidenyl-2-indolinone derivative

Abstract

Disclosed is a compound represented by formula (1) or a pharmacologically acceptable salt thereof. (In the formula, R 1 is optionally substituted heteroaryl etc.; R 2 is hydrogen etc.; R 3 and R 4 are each independently hydrogen etc., R 5 is the following group: (wherein Y is optionally substituted five membered heteroaryl etc., R 9a is optionally substituted aryl etc., R 9b and R 9c are each dependently hydrogen etc., and m is the integral 0 etc.) etc.; R 6 is hydrogen etc.; and R 7 is hydrogen etc.

1 . A compound of formula 1: 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt thereof, 
         R 1  is optionally substituted heteroaryl, or optionally substituted heteroalicyclic; 
         R 2  is hydrogen, optionally substituted alkyl, optionally substituted alkylcarbonyl, optionally substituted alkoxycarbonyl, or optionally substituted aminocarbonyl; 
         R 3  and R 4  are each independently hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted aminocarbonyl, or the following group: 
       
       
         
           
           
               
               
           
         
         (wherein 
         X is optionally substituted five membered heteroaryl or optionally substituted heteroalicyclic, 
         R 8a  is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroalicyclic, 
         R 8b  and R 8c  are each independently hydrogen, alkyl, halogen, cyano, amino, nitro, hydroxy, trifluoromethyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroalicyclic, and 
         n is the integral 0 to 2), 
         R 5  is hydrogen, halogen, cyano, nitro, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, optionally substituted aminocarbonyl, or the following group: 
       
       
         
           
           
               
               
           
         
         (wherein 
         Y is optionally substituted five membered heteroaryl (provided that the five membered heteroaryl is not the following group: 
       
       
         
           
           
               
               
           
         
         wherein R 9a  is same as the above definition), 
         R 9a  is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heteroalicyclic, 
         R 9b  and R 9c  are each dependently hydrogen, alkyl, halogen, cyano, amino, nitro, hydroxy, trifluoromethyl, and 
         m is the integral 0 to 2), and 
         at least one of R 3 , R 4  and R 5  is the following group: 
       
       
         
           
           
               
               
           
         
         (X, R 8a , R 8b , R 8c  and n are same as the above definition), or the following group: 
       
       
         
           
           
               
               
           
         
         (Y, R 9a , R 9b , R 9c  and m are same as the above definition); 
         R 6  is hydrogen, halogen, cyano, nitro, hydroxy, amino, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted alkyl carbonyl, or optionally substituted aminocarbonyl; and 
         R 7  is hydrogen, optionally substituted alkyl, or optionally substituted cycloalkyl. 
       
     
     
         2 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 R 1  is optionally substituted heteroaryl, or optionally substituted heteroalicyclic, wherein the heteroaryl is selected from the group consisting of pyrrole, furan, thiophene, pyridine, pyrimidine, pyrazine, pyridazine, indole, and pyrrolopyridinone, and heteroalicyclic is selected from the group consisting of pyridone, pyrrolidine, and piperidine.   
     
     
         3 . The compound according to  claim 2 , or pharmaceutically acceptable salt thereof,
 R 1  is optionally substituted heteroaryl, or optionally substituted heteroalicyclic, wherein heteroaryl is pyrrole, or pyrrolopyridinone, and heteroalicyclic is pyridone.   
     
     
         4 . The compound according to anyone of  claims 1 - 3 , or pharmaceutically acceptable salt thereof,
 the substituent of optionally substituted heteroaryl and optionally substituted heteroalicyclic in R 1  is one or more substituent(s) selected from the group consisting of halogen, alkyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted alkoxy carbonyl, optionally substituted alkylcarbonyl, or optionally substituted aminocarbonyl.   
     
     
         5 . The compound according to anyone of  claims 1 - 4 , or pharmaceutically acceptable salt thereof,
 R 1  is one of the group selected from the following group:   
       
         
           
           
               
               
           
         
         (wherein R 10  is hydroxy, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted amino). 
       
     
     
         6 . The compound according to  claim 5 , or pharmaceutically acceptable salt thereof,
 R 10  is hydroxy, mono-substituted alkyl amino (said alkyl is substituted by di-substituted alkyl amino, or heteroalicyclic), piperazynyl, homopiperazynyl or morphorinyl.   
     
     
         7 . The compound according to  claim 6 , or pharmaceutically acceptable salt thereof,
 R 10  is hydroxy, ethyl amino (said ethyl is substituted by di-ethyl amino, 1-pyrrolidino), or 4-piperazinyl (said piperazinyl is substituted with alkyl).   
     
     
         8 . The compound according to  claim 7 , or pharmaceutically acceptable salt thereof,
 R 10  is hydroxy, 2-(di-ethyl amino)ethyl amino, 2-pyrrolidino ethyl amino, 4-methyl piperazinyl or morpholino.   
     
     
         9 . The compound according to anyone of  claims 1 - 8 , or pharmaceutically acceptable salt thereof,
 R 2  is hydrogen, or optionally substituted alkoxy carbonyl.   
     
     
         10 . The compound according to  claim 9 , or pharmaceutically acceptable salt thereof,
 R 2  is hydrogen.   
     
     
         11 . The compound according to anyone of  claims 1 - 10 , or pharmaceutically salt thereof,
 R 3  and R 4  are each independently
 1: hydrogen, 
 2: halogen, 
 3: cyano, 
 4: nitro, 
 5: hydroxy, 
 6: alkyl. 
 7: alkoxy, 
 8: amino, 
 9: alkylcarbonyl, 
 10: alkoxycarbonyl, 
 11: aminocarbonyl, and 
 12: the following group: 
   
       
         
           
           
               
               
           
         
         (wherein X, R 8a , R 8b , R 8c , and n are same as the above definition), 
         wherein said alkyl, alkoxy, amino, alkylcarbonyl, alkoxycarbonyl, and aminocarbonyl are optionally substituted with one or more substitutent(s) selected from the group consisting of
 (a) alkyl, 
 (b) alkenyl, 
 (c) alkynyl, 
 (d) hydroxy, 
 (e) amino, 
 (f) nitro, 
 (g) cyano, 
 (h) halogen, 
 (i) alkoxy, 
 (j) alkylcarbonyl, 
 (k) alkoxycarbonyl, 
 (l) aminocarbonyl, 
 (m) aryl, 
 (n) heteroaryl, 
 (o) cycloalkyl, and 
 (p) heteroalicyclic). 
 
       
     
     
         12 . The compound according to  claim 11 , or pharmaceutically acceptable salt thereof,
 R 3  and R 4  are each independently
 1: hydrogen, 
 2: halogen, 
 3: alkyl(said alkyl is optionally substituted with one or more substituent(s) selected from the group consisting of 
   (a) alkyl,   (b) alkenyl,   (c) alkynyl,   (d) hydroxy,   (e) amino,   (f) nitro,   (g) cyano,   (h) halogen,   (i) alkoxy,   (j) alkylcarbonyl,   (k) alkoxycarbonyl,   (l) aminocarbonyl,   (m) aryl,   (n) heteroaryl,   (o) cycloalkyl, and   (p) heteroalicyclic)
 4: the following group: 
   
       
         
           
           
               
               
           
         
         (wherein X, R 8a , R 8b , R 8c , and n are same as the above definition). 
       
     
     
         13 . The compound according to  claim 12 , or pharmaceutically acceptable salt thereof,
 R 3  and R 4  are each independently hydrogen, or the following group:   
       
         
           
           
               
               
           
         
         (wherein X, R 8a , R 8b , R 8c , and n are same as the above definition). 
       
     
     
         14 . The compound according to anyone of  claims 1 - 13 , or pharmaceutically acceptable salt thereof,
 X is pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole, oxadiazole, pyrrolidine, piperidine, azepane, tetrahydrofuran, oxane, or oxepane.   
     
     
         15 . The compound according to  claim 14 , or pharmaceutically acceptable salt thereof,
 X is pyrrole, furan, thiophene, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, triazole, thiadiazole, or oxadiazole.   
     
     
         16 . The compound according to  claim 15 , or pharmaceutically acceptable salt thereof,
 X is thiophene, pyrazole, oxazole, thiazole, thiadiazole, or oxadiazole.   
     
     
         17 . The compound according to  claim 16 , or pharmaceutically acceptable salt thereof,
 X is pyrazole, thiazole, or oxazole.   
     
     
         18 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 R 8a , R 8b  and R 8c  are each independently hydrogen, alkyl, halogen, cyano, amino, nitro, hydroxy, trifluoromethyl, phenyl, or pyridyl.   
     
     
         19 . The compound according to  claim 18 , or pharmaceutically acceptable salt thereof,
 R 8a , R 8b  and R 8c  are each dependently hydrogen, alkyl, phenyl, or pyridyl.   
     
     
         20 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 n is the integra 0.   
     
     
         21 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 X is selected from the group consisting of the following group:   
       
         
           
           
               
               
           
         
         R 8a  is piperidinyl, pyranyl, phenyl, thiophenyl, pyrazinyl, pyrimidinyl, pyridazinyl, or pyridyl (said piperidinyl, pyranyl, phenyl, thiophenyl pyrazinyl, pyrimidinyl, pyridazinyl, or pyridyl are optionally substituted with halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, or aminocarbonyl), and 
         R 8b  is alkyl. 
       
     
     
         22 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 R 3  and R 4  are hydrogen.   
     
     
         23 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 R 5  is selected from the group consisting of the following group:   
       
         
           
           
               
               
           
         
         R 9a  piperidinyl, pyranyl, phenyl, thiophenyl, pyrazinyl, pyrimidinyl, pyridazinyl, or pyridyl (said piperidinyl, pyranyl, phenyl, thiophenyl, pyrazinyl, pyrimidinyl, pyridazinyl, or pyridyl are optionally substituted with halogen, hydroxy, cyano, amino, nitro, alkyl, alkoxy, alkoxycarbonyl, alkylcarbonyl, or aminocarbonyl). and 
         R 9b  is alkyl. 
       
     
     
         24 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 R 6  is hydrogen, halogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, optionally substituted alkoxy, optionally substituted amino, optionally substituted alkoxycarbonyl, optionally substituted alkylcarbonyl, or optionally substituted aminocarbonyl.   
     
     
         25 . The compound according to  claim 1 , or pharmaceutically acceptable salt thereof,
 R 7  is hydrogen, methyl, ethyl, n-propyl, or isopropyl.   
     
     
         26 . A pharmaceutical composition comprising the compound of  claim 1 , or pharmaceutically acceptable salt thereof.