2,3-dihydro-iminoisoindole derivatives

Abstract

A compound represented by the following general formula (1), or a salt thereof, has serine protease inhibiting activity, and particularly excellent inhibiting activity against clotting factor VIIa. This compound or a salt thereof is useful as therapeutic and/or prophylactic agents for diseases associated with thrombus formation. wherein R 1 represents hydrogen, R 2 represents optionally substituted phenyl, etc., R 3 represents optionally substituted C6-10 aryl, etc.

1 . A therapeutic or prophylactic agent for a disease selected from Group F1 below, which comprises a compound of formula (I), or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is 
 hydrogen; 
 R 2  is 
 a C6-10 aryl optionally substituted by 1-5 substituents selected from Group Al below or 
 a 9- to 12-membered benzene-fused cyclic group optionally substituted by 1-5 substituents selected from Group Al below; and 
 R 3  is 
 a C6-10 aryl optionally substituted by 1-5 substituents selected from Group Al below or 
 a 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group A1 below, 
 wherein Group A1 is selected from the group consisting of 
 hydroxyl, 
 halogen, 
 cyano, 
 nitro, 
 oxo, 
 C1-6 alkyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C3-8 cycloalkyl optionally substituted by 1-5 substituents selected from Group B1 below, 
 C2-6 alkenyl, 
 C2-6 alkynyl, 
 C1-6 alkoxy optionally substituted by 1-3 substituents selected from Group B1 below, 
 C3-8 cycloalkyloxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 C2-6 alkenyloxy, 
 C2-6 alkynyloxy, 
 C1-6 alkylthio, 
 C1-6 alkylsulfinyl, 
 C1-6 alkylsulfonyl, 
 C1-6 alkylsulfonyloxy, 
 C6-10 aryl optionally substituted by 1-5 substituents selected from Group B1 below, 
 C6-10 aryloxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group B1 below, 
 5- to 10-membered heteroaryloxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 a 5- or 6-membered non-aromatic heterocyclic group optionally substituted by 1-5 substituents selected from Group B1 below, 
 5- or 6-membered non-aromatic heterocyclooxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 a group of the formula —NR 1t — R 2t , and 
 a group of the formula —CO—R 3t ; 
 where R 1t  and R 2t  each independently is 
 hydrogen, 
 C1-6 alkyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C2-6 alkenyl, 
 C2-7 alkylcarbonyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C2-7 alkoxycarbonyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C1-6 alkylsulfonyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 carbamoyl, 
 aminosulfonyl, 
 C6-10 aryl optionally substituted by 1-5 substituents selected from Group B1 below, or 
 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group B1 below, and 
 R 3t  is 
 hydroxyl, 
 C1-6 alkyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C1-6 alkoxy optionally substituted by 1-3 substituents selected from Group B1 below, 
 amino, 
 mono(C1-6 alkyl)amino optionally substituted by 1-3 substituents selected from Group B1 below, or 
 di(C1-6 alkyl)amino optionally substituted by 1-3 substituents selected from Group B1 below, 
 wherein Group B1 is selected from the group consisting of 
 hydroxyl, 
 halogen, 
 cyano, 
 oxo, 
 C1-6 alkoxy optionally substituted by halogen, 
 C3-8 cycloalkyl, 
 amino, 
 mono(C1-6 alkyl)amino, 
 di(C1-6 alkyl)amino, 
 carbamoyl, 
 mono(C1-6 alkyl)aminocarbonyl, 
 di(C1-6 alkyl)aminocarbonyl, 
 C6-10 aryl optionally substituted by 1-5 substituents selected from Group C1 below, and 
 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group C1 below, 
 wherein Group C1 is selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy, 
 wherein Group F1 is selected from the group consisting of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis, disseminated intravascular coagulation syndrome and malignant tumor. 
 
   
   
       2 . A therapeutic or prophylactic agent for a disease selected from Group F2 below, which comprises a compound of formula (I), or a salt thereof: 
     
       
         
         
             
             
         
       
     
     wherein
 R 1  is 
 hydrogen; 
 R 2  is 
 a C6-10 aryl optionally substituted by 1-5 substituents selected from Group A 1 below or 
 a 9- to 12-membered benzene-fused cyclic group optionally substituted by 1-5 substituents selected from Group Al below; and 
 R 3  is 
 a C6-10 aryl optionally substituted by 1-5 substituents selected from Group Al below or 
 a 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group A1 below, 
 wherein Group A1 is selected from the group consisting of 
 hydroxyl, 
 halogen, 
 cyano, 
 nitro, 
 oxo, 
 C1-6 alkyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C3-8 cycloalkyl optionally substituted by 1-5 substituents selected from Group B1 below, 
 C2-6 alkenyl, 
 C2-6 alkynyl, 
 C1-6 alkoxy optionally substituted by 1-3 substituents selected from Group B1 below, 
 C3-8 cycloalkyloxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 C2-6 alkenyloxy, 
 C2-6 alkynyloxy, 
 C1-6 alkylthio, 
 C1-6 alkylsulfinyl, 
 C1-6 alkylsulfonyl, 
 C1-6 alkylsulfonyloxy, 
 C6-10 aryl optionally substituted by 1-5 substituents selected from Group B1 below, 
 C6-10 aryloxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group B1 below, 
 5- to 10-membered heteroaryloxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 a 5- or 6-membered non-aromatic heterocyclic group optionally substituted by 1-5 substituents selected from Group B1 below, 
 5- or 6-membered non-aromatic heterocyclooxy optionally substituted by 1-5 substituents selected from Group B1 below, 
 a group of the formula —NR 1t —R 2t , and 
 a group of the formula —CO—R 3t ; 
 where R 1t  and R 2t  each independently is 
 hydrogen, 
 C1-6 alkyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C2-6 alkenyl, 
 C2-7 alkylcarbonyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C2-7 alkoxycarbonyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C1-6 alkylsulfonyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 carbamoyl, 
 aminosulfonyl, 
 C6-10 aryl optionally substituted by 1-5 substituents selected from Group B1 below, or 
 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group B1 below, and 
 R 3t  is 
 hydroxyl, 
 C1-6 alkyl optionally substituted by 1-3 substituents selected from Group B1 below, 
 C1-6 alkoxy optionally substituted by 1-3 substituents selected from Group B1 below, 
 amino, 
 mono(C1-6 alkyl)amino optionally substituted by 1-3 substituents selected from Group B1 below, or 
 di(C1-6 alkyl)amino optionally substituted by 1-3 substituents selected from Group B1 below, 
 wherein Group B1 is selected from the group consisting of 
 hydroxyl, 
 halogen, 
 cyano, 
 oxo, 
 C1-6 alkoxy optionally substituted by halogen, 
 C3-8 cycloalkyl, 
 amino, 
 mono(C1-6 alkyl)amino, 
 di(C1-6 alkyl)amino, 
 carbamoyl, 
 mono(C1-6 alkyl)aminocarbonyl, 
 di(C1-6 alkyl)aminocarbonyl, 
 C6-10 aryl optionally substituted by 1-5 substituents selected from Group C1 below, and 
 5- to 10-membered heteroaryl group optionally substituted by 1-5 substituents selected from Group C1 below, 
 wherein Group C1 is selected from the group consisting of halogen, C1-6 alkyl, and C1-6 alkoxy, 
 wherein Group F2 is selected from the group consisting of thrombosis, deep vein thrombosis, pulmonary embolism, cerebral infarction, myocardial infarction, acute coronary syndrome, vascular restenosis and disseminated intravascular coagulation syndrome.