Quinazoline derivatives

Abstract

A compound of the formula (I) or a pharmaceutically acceptable salt thereof, a hydrate thereof, a solvate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof has a superior tyrosine-specific protein kinase inhibitory activity and is useful as a pharmaceutical agent, particularly as an agent for the prophylaxis or treatment of various cancers, psoriasis or diseases caused by arteriosclerosis, and the like.

1 . A quinazoline derivative of the following formula (I)  
       
         
           
           
               
               
           
         
         wherein  
         n is an integer of 0-3,  
         R 1  is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a trifluoromethyl group, a C 1 -C 5  alkyl group, a C 1 -C 5  alkoxy group, 
 —S(O) f R 13  (wherein f is an integer of 0-2 and R 13  is a C 1 -C 5  alkyl group), —NR 14 R 15  (wherein R 14  and R 15  are each independently a hydrogen atom, a C 1 -C 5  alkyl group, a C 1 -C 5  alkanoyl group or a C 1 -C 5  alkylsulfonyl group), a C 2 -C 5  alkenyl group, a C 2 -C 5  alkynyl group or a C 1 -C 5  alkanoyl group,  
 
         one of R 2  and R 3  
 is R 27 SO 2 NH— (wherein R 27  is a C 1 -C 5  alkyl group optionally substituted by a morpholino group), (R 28 SO 2 ) 2 N— (wherein R 28  is a C 1 -C 5  alkyl group optionally substituted by a morpholino group), a C 1 -C 5  alkoxy group, CH 3 COCH 2 CONH—, CH 3 SCH 2 CH 2 CONH—, NCCH 2 CONH—,  
                     
 (wherein X is —C(O)— or SO 2 — and R 4 , R 5  and R 6  are each independently a hydrogen atom, a halogen atom, or a C 1 -C 5  alkyl group optionally substituted by a halogen atom, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or a di(C 1 -C 5  alkyl)amino group) or  
                     
 (wherein R 7  is a hydrogen atom, a C 1 -C 5  alkyl group optionally substituted by a halogen atom, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or di(C 1 -C 5  alkyl)amino group), and  
 
         the other of R 2  and R 3  is  
         
           
             
             
                 
                 
             
           
           wherein a) R 8  and R 9  are each independently a hydrogen atom, b) R 8  and R 9  are each independently, a C 1 -C 5  alkyl group optionally substituted by a hydroxyl group or a C 1 -C 5  alkoxy group, c) R 8  and R 9  are taken together to show C═O or d) R 8  and R 9  in combination form a ring to represent a C 3 -C 8  cycloalkylene optionally via —O—, —S— or —NR 10 — (wherein R 10  is a hydrogen atom or a C 1 -C 5  alkyl group), m is an integer of 0-3, R 11  and R 12  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, and  
           Y is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group, —N(R 16 )—(CO) u —(CR 17 R 18 ) v —(CO) j —R 19  (wherein R 16  is a) a hydrogen atom, or b) a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group, R 17  and R 18  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, u and j are each 0 or 1, v is an integer of 1-5 and R 19  is a hydrogen atom, a hydroxyl group, a cyano group, an amino group, a C 1 -C 5  alkoxy group, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or di(C 1 -C 5  alkyl)amino group,  
           provided that, (1) when u and j are simultaneously 0, then v is an integer of 2-5, or (2) when R 19  is a cyano group, then j=0),  
           
             
               
               
                   
                   
               
             
           
           wherein p and q are each independently an integer of 2 or 3, Z is —O— or —S(O) g — (wherein g is an integer of 0-2), a carbonyl group or —NR 20 — (wherein R 20  is a) a hydrogen atom, b) a C 1 -C 5  alkylsulfonyl group, c) a C 1 -C 5  alkanoyl group, d) a C 1 -C 5  alkoxycarbonyl group or e) a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group) or  
           
             
               
               
                   
                   
               
             
           
           wherein r and t are each independently an integer of 1-3, k is 0 or 1, W is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group, a carboxyl group, a cyano group, a di(C 1 -C 5  alkyl)amino group, a morpholino group, pyrrolidin-1-yl, piperidin-1-yl, 4-C 1 -C 5  alkylpiperazin-1-yl or CONR 21 R 22  (wherein R 21  and R 22  are each independently a hydrogen atom or a C 1 -C 5  alkyl group),  
         
         or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.  
       
     
     
         2 . The quinazoline derivative of  claim 1 , which is represented by the following formula (I)  
       
         
           
           
               
               
           
         
         wherein  
         n is an integer of 1 or 2,  
         R 1  is a halogen atom, a cyano group, a C 1 -C 5  alkyl group, a C 1 -C 5  alkoxy group, —S(O) f R 13  (wherein f is an integer of 0-2 and R 13  is a C 1 -C 5  alkyl group), —NR 14 R 15  (wherein R 14  and R 15  are each independently a hydrogen atom, a C 1 -C 5  alkyl group, a C 1 -C 5  alkanoyl group or a C 1 -C 5  alkylsulfonyl group), a C 2 -C 5  alkynyl group or a C 1 -C 5  alkanoyl group,  
         one of R 2  and R 3  
 is R 27 SO 2 NH— (wherein R 27  is a C 1 -C 5  alkyl group optionally substituted by a morpholino group), (R 28 SO 2 ) 2 N— (wherein R 28  is a C 1 -C 5  alkyl group optionally substituted by a morpholino group), a C 1 -C 5  alkoxy group, CH 3 COCH 2 CONH—, CH 3 SCH 2 CH 2 CONH—, NCCH 2 CONH—,  
                     
 wherein X is —C(O)— or SO 2 — and R 4 , R 5  and R 6  are each independently a hydrogen atom, a halogen atom, or a C 1 -C 5  alkyl group optionally substituted by a halogen atom, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or a di(C 1 -C 5  alkyl)amino group or  
                     
 wherein R 7  is a C 1 -C 5  alkyl group, and  
 
         the other of R 2  and R 3  is  
         
           
             
             
                 
                 
             
           
           wherein a) R 8  and R 9  are each independently a hydrogen atom, b) R 8  and R 9  are each independently a C 1 -C 5  alkyl group optionally substituted by C 1 -C 5  alkoxy group, m is an integer of 0-3, R 11  and R 12  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, and Y is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group, —N(R 16 )—(CO) u —(CR 17 R 18 ) v —(CO) j —R 19  (wherein R 16  is a hydrogen atom, or a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group, R 17  and R 18  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, u and j are each 0 or 1, v is an integer of 1-5 and R 19  is a hydrogen atom, a hydroxyl group, a cyano group, an amino group, a C 1 -C 5  alkoxy group, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or di(C 1 -C 5  alkyl)amino group,  
           provided that, (1) when u and j are simultaneously 0, then v is an integer of 2-5 or (2) when R 19  is cyano, then j is 0),  
           
             
               
               
                   
                   
               
             
           
           wherein p and q are each independently an integer of 2 or 3, Z is —O—, a carbonyl group or NR 20  (wherein R 20  is a hydrogen atom, a C 1 -C 5  alkylsulfonyl group, a C 1 -C 5  alkanoyl group, a C 1 -C 5  alkoxycarbonyl group or a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group) or  
           
             
               
               
                   
                   
               
             
           
           wherein r and t are each independently an integer of 1-3, k is 0 or 1, W is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group, a carboxyl group, a cyano group, a di(C 1 -C 5  alkyl)amino group, a morpholino group or CONR 21 R 22  (wherein R 21  and R 22  are each independently a hydrogen atom or a C 1 -C 5  alkyl group),  
         
         or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.  
       
     
     
         3 . The quinazoline derivative of  claim 1 , which is represented by the following formula (I)  
       
         
           
           
               
               
           
         
         wherein  
         n is an integer of 0-3,  
         R 1  is a hydrogen atom, a halogen atom, a hydroxyl group, a cyano group, a nitro group, a C 1 -C 5  alkyl group, a C 1 -C 5  alkoxy group, —S(O) f R 13  (wherein f is an integer of 0-2 and R 13  is a C 1 -C 5  alkyl group), —NR 14 R 15  (wherein R 14  and R 15  are each independently a hydrogen atom, a C 1 -C 5  alkyl group, a C 1 -C 5  alkanoyl group or a C 1 -C 5  alkylsulfonyl group), a C 2 -C 5  alkenyl group, a C 2 -C 5  alkynyl group or a C 1 -C 5  alkanoyl group,  
         R 2  is  
         
           
             
             
                 
                 
             
           
           wherein X is —C(O)— or SO 2 — and R 4 , R 5  and R 6  are each independently a hydrogen atom, a halogen atom or a C 1 -C 5  alkyl group optionally substituted by a halogen atom, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or di(C 1 -C 5  alkyl)amino group or  
           
             
               
               
                   
                   
               
             
           
           wherein R 7  is a C 1 -C 5  alkyl group optionally substituted by a halogen atom, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or di(C 1 -C 5  alkyl)amino group, and  
         
         R 3  is  
         
           
             
             
                 
                 
             
           
           wherein R 8  and R 9  are each independently a hydrogen atom, a C 1 -C 5  alkyl group optionally substituted by a hydroxyl group or a C 1 -C 5  alkoxy group, R 8  and R 9  are taken together to show C═O or R 8  and R 9  in combination form a ring to represent a C 3 -C 8  cycloalkylene optionally via —O—, —S— or —NR 10  (wherein R 10  is a hydrogen atom or a C 1 -C 5  alkyl group), m is an integer of 0-3, R 11  and R 12  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, and  
           Y is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group, —N(R 16 )—(CO) u —(CR 17 R 18 ) v —(CO) j —R 19  (wherein R 16  is a hydrogen atom, or a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group, R 17  and R 18  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, u and j are each 0 or 1, v is an integer of 1-5 and R 19  is a hydrogen atom, a hydroxyl group, a cyano group, an amino group, a C 1 -C 5  alkoxy group, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or di(C 1 -C 5  alkyl)amino group,  
           provided that (1) when u and j are simultaneously 0, then v is an integer of 2-5, and (2) when R 19  is a cyano group, then j is 0),  
           
             
               
               
                   
                   
               
             
           
           wherein p and q are each independently 2 or 3, Z is  
           —O— or —S(O) g — (wherein g is an integer of 0-2), a carbonyl group or —NR 20 — (wherein R 20  is a hydrogen atom, or a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group), or  
           
             
               
               
                   
                   
               
             
           
           wherein r and t are each independently an integer of 1-3, k is 0 or 1, W is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group, a carboxyl group, a cyano group, a di(C 1 -C 5  alkyl)amino group, a morpholino group, pyrrolidin-1-yl, piperidin-1-yl, 4-C 1 -C 5  alkylpiperazin-1-yl or —CONR 21 R 22  (wherein R 21  and R 22  are each independently a hydrogen atom or a C 1 -C 5  alkyl group),  
         
         or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.  
       
     
     
         4 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), n is 1 or 2, and 
 R 1  is a halogen atom, a cyano group, a C 1 -C 5  alkyl group, a C 1 -C 5  alkoxy group, —NR 14 R 15  (wherein R 14  and R 15  are each independently a hydrogen atom, a C 1 -C 5  alkyl group, a C 1 -C 5  alkanoyl group or a C 1 -C 5  alkylsulfonyl group), a C 2 -C 5  alkynyl group or a C 1 -C 5  alkanoyl group, or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         5 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), n is 1 or 2, and 
 R 1  is a halogen atom, a cyano group, a C 1 -C 5  alkyl group, a C 1 -C 5  alkoxy group, —NR 14 R 15  (wherein R 14  and R 15  is a C 1 -C 5  alkyl group), a C 2 -C 5  alkynyl group or a C 1 -C 5  alkanoyl group, or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         6 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), n is 2, and 
 R 1  is a halogen atom,    or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         7 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), n is 1, and 
 R 1  is a C 1 -C 5  alkoxy group, a C 2 -C 5  alkynyl group or a C 1 -C 5  alkanoyl group,    or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         8 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), 
 one of R 2  and R 3  is    R 27 SO 2 NH— (wherein R 27  is a C 1 -C 5  alkyl group optionally substituted by a morpholino group), (R 28 SO 2 ) 2 N— (wherein R 28  is a C 1 -C 5  alkyl group), a C 1 -C 5  alkoxy group, CH 3 COCH 2 CONH—, CH 3 SCH 2 CH 2 CONH—, NCCH 2 CONH—,                          wherein X is —C(O)— or SO 2 — and R 4 , R 5  and R 6  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, or                          wherein R 7  is a C 1 -C 5  alkyl group optionally substituted by a morpholino group, and the other of R 2  and R 3  is a substituent described in  claim 1 ,    or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         9 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), 
 one of R 2  and R 3  is    R 27 SO 2 NH—(wherein R 27  is a C 1 -C 5  alkyl group), a C 1 -C 5  alkoxy group or                          (wherein X is —C(O)— and R 4 , R 5  and R 6  are each a hydrogen atom), and    the other of R 2  and R 3  is a substituent described as the other of R 2  and R 3  in  claim 1 ,    or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         10 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), 
 one of R 2  and R 3  is a substituent described as any of R 2  and R 3  in  claim 1 , and    the other of R 2  and R 3  is                          wherein a) R 8  and R 9  are each independently a hydrogen atom, b) R 8  and R 9  are each independently a C 1 -C 5  alkyl group optionally substituted by a C 1 -C 5  alkoxy group, or d) R 8  and R 9  in combination form a ring to represent a C 3 -C 8  cycloalkylene optionally via —O— or —NR 10  (wherein R 10  is a hydrogen atom), m is 0 or 1, R 11  and R 12  are each independently a hydrogen atom and Y is a C 1 -C 5  alkoxy group, —N(R 16 )—(CO) u —(CR 17 R 18 ) v —(CO) j —R 19  (wherein R 16  is a) a hydrogen atom, or b) a C 1 -C 5  alkyl group optionally substituted by a C 1 -C 5  alkoxy group, R 17  and R 18  are each independently a hydrogen atom, u and j are 0 or 1, v is 2 and R 19  is a hydrogen atom, a cyano group, a C 1 -C 5  alkoxy group, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or di(C 1 -C 5  alkyl)amino group,    provided that (1) when u and j are simultaneously 0, then v is 2, and (2) when R 19  is a cyano group, then j is 0),                          wherein p and q are each independently 2 or 3, Z is —O— or —NR 20 — (wherein R 20  is a) a hydrogen atom, b) a C 1 -C 5  alkyl sulfonyl group, c) a C 1 -C 5  alkanoyl group, d) a C 1 -C 5  alkoxycarbonyl group or e) a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group), or                          wherein r and t are each independently 1 or 2, k is 0, W is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group or a carboxyl group,    or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         11 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), one of R 2  and R 3  is a substituent described in  claim 1  as one of R 2  and R 3 , and 
 the other of R 2  and R 3  is,                          wherein a) R 8  and R 9  are each independently a hydrogen atom, b) R 8  and R 9  are each independently a C 1 -C 5  alkyl group optionally substituted by a C 1 -C 5  alkoxy group, or d) R 8  and R 9  in combination form a ring to represent a C 3 -C 8  cycloalkylene optionally via —O— or —NR 10  (wherein R 10  is a hydrogen atom, m is 0 or 1, R 11  and R 12  are each independently a hydrogen atom), and Y is a C 1 -C 5  alkoxy group, —N(R 16 )—(CO) u —(CR 17 R 18 ) v —(CO) j —R 19  (wherein R 16  is a) a hydrogen atom or b) a C 1 -C 5  alkyl group optionally substituted by a C 1 -C 5  alkoxy group, R 17  and R 18  are each independently a hydrogen atom, u and j are each 0 or 1, v is 2 and R 19  is a hydrogen atom, a cyano group, a C 1 -C 5  alkoxy group, a morpholino group, 4-C 1 -C 5  alkylpiperazin-1-yl or a di(C 1 -C 5  alkyl)amino group,    provided that (1) when u and j are simultaneously 0, then v is 2, and (2) when R 19  is a cyano group, then j is 0),                          wherein p and q are each independently 2 or 3, Z is    —O— or NR 20 — (wherein R 20  is a) a hydrogen atom, b) a C 1 -C 5  alkylsulfonyl group, c) a C 1 -C 5  alkanoyl group, d) a C 1 -C 5  alkoxycarbonyl group or e) a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group), or                          wherein r and t are each independently 1 or 2, k is 0, W is a hydrogen atom, a hydroxyl group, a C 1 -C 5  alkoxy group, a C 1 -C 5  alkanoyloxy group or a carboxyl group,    or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         12 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), one of R 2  and R 3  is a substituent described in  claim 1  as one of R 2  and R 3 , and 
 the other of R 2  and R 3  is                          wherein a) R 8  and R 9  are each independently a hydrogen atom or b) R 8  and R 9  are each independently a C 1 -C 5  alkyl group optionally substituted by a C 1 -C 5  alkoxy group,    m is 0 or 1, R 11  and R 12  are each a hydrogen atom,    Y is                          wherein p and q are each 2, and    Z is —NR 20 — wherein R 20  is a C 1 -C 5  alkyl group optionally substituted by a cyano group or a C 1 -C 5  alkoxy group,    or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.    
     
     
         13 . The quinazoline derivative of  claim 1 , wherein, in the formula (I), n is 2, R 1  is a halogen atom, R 2  represents  
       
         
           
           
               
               
           
         
         wherein X is —C(O)— and R 4 , R 5  and R 6  are each a hydrogen atom,  
         R 3  is  
         
           
             
             
                 
                 
             
           
         
         wherein R 8  and R 9  are each independently a hydrogen atom or a C 1 -C 5  alkyl group, m is 0 or 1, and Y is —N(R 16 )—(CO) u —(CR 17 R 18 ) v —(CO) j —R 19  (wherein R 16  is a C 1 -C 5  alkyl group, R 17  and R 18  are each independently a hydrogen atom, u and j are each 0, v is 2 and R 19  is a di(C 1 -C 5  alkyl)amino group),  
         
           
             
             
                 
                 
             
           
         
         wherein p and q are each 2, and  
         Z is —NR 20 — (wherein R 20  is a hydrogen atom, —CO— or a C 1 -C 5  alkyl group),  
         or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.  
       
     
     
         14 - 20 . (canceled)  
     
     
         21 . The quinazoline derivative of  claim 1  which is represented by the following formula (1f)  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.  
       
     
     
         22 . A pharmaceutical composition comprising a quinazoline derivative of  claim 1  and a pharmaceutically acceptable carrier.  
     
     
         23 . A tyrosine-specific protein kinase inhibitor comprising a quinazoline derivative of  claim 1  as an active ingredient.  
     
     
         24 . The inhibitor of  claim 23 , wherein the tyrosine-specific protein kinase is EGF receptor tyrosine-specific protein kinase.  
     
     
         25 . The inhibitor of  claim 23 , wherein the tyrosine-specific protein kinase is EGF receptor tyrosine-specific protein kinase and HER2 tyrosine-specific protein kinase.  
     
     
         26 . A method for the treatment of a disease caused by potentiation of tyrosine-specific protein kinase activity, which comprises administering to a patient in need thereof a therapeutically effective amount of a quinazoline derivative of  claim 1  as an active ingredient.  
     
     
         27 . The method for the treatment of  claim 26 , wherein the disease is cancer, psoriasis, or a disease based on arteriosclerosis.  
     
     
         28 . The quinazoline derivative of  claim 1 , which is represented by the following formula (1f)  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, a hydrate thereof, an optically active compound thereof, a racemate thereof or a diastereomer mixture thereof.  
       
     
     
         29 . A method for the treatment and/or prophylaxis of a disease caused by potentiation of tyrosine-specific protein kinase activity, which comprises administering to a patient in need thereof a therapeutically effective amount of a quinazoline derivative of  claim 1  as an active ingredient.  
     
     
         30 . The method for the treatment or prophylaxis of  claim 29 , wherein the disease is cancer, psoriasis, or a disease based on arteriosclerosis.  
     
     
         31 . A method for inhibiting tyrosine-specific protein kinase, which comprises administering to a patient in need thereof a therapeutically effective amount of a quinazoline derivative of  claim 1 .  
     
     
         32 . The method of  claim 31 , wherein the tyrosine-specific protein kinase is EGF receptor tyrosine-specific protein kinase.  
     
     
         33 . The method of  claim 31 , wherein the tyrosine-specific protein kinase is EGF receptor tyrosine-specific protein kinase and HER2 tyrosine-specific protein kinase.