Benzazepine derivatives

Abstract

The present invention provides novel benzazepine compounds of Formula (1), or salts thereof, having vasopressin V 1a and V 2 antagonisms, and medical uses thereof. In the formula, R 1 is optionally substituted C 1-6 alkyl, etc.; L is —C(═O)—NH—, etc.; Ring A 1 is a hydrocarbon ring, etc.; Ring A 2 is a hydrocarbon ring, etc.; and each of Rings A 1 and A 2 may have at least one substituent.

1 . A benzazepine compound of Formula (1): 
       
         
           
           
               
               
           
         
         wherein R 1  is deuterium, OH, COOH, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyl-O—CO—, or optionally substituted C 2-6  alkenyl;
 L is a direct bond or —C(═O)—NH—; 
 Ring A 1  is a hydrocarbon ring or heterocycle; 
 Ring A 2  is a hydrocarbon ring or heterocycle; and 
 each of Rings A 1  and A 2  may have at least one substituent, 
 
         or a salt thereof. 
       
     
     
         2 . The compound according to  claim 1 , wherein Ring A 1  is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, or a saturated or unsaturated 3- to 15-membered monocyclic, bicyclic, or tricyclic heterocycle comprising as the ring member 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur,
 Ring A 2  is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, or a saturated or unsaturated 3- to 15-membered monocyclic, bicyclic, or tricyclic heterocycle comprising as the ring member 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and   each of Rings A 1  and A 2  may have at least one substituent,   
       or a salt thereof. 
     
     
         3 . The compound according to  claim 1 , or a salt thereof, wherein Ring A 1  is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 to 4 nitrogen atoms, a saturated or unsaturated 7- to 15-membered heterobicycle comprising as the ring heteroatom 1 to 5 nitrogen atoms, a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 or 2 oxygen atoms and at least one nitrogen atom, or a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 or 2 sulfur atoms and at least one nitrogen atom,
 Ring A 2  is a saturated or unsaturated 3- to 8-membered monocyclic hydrocarbon ring, a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 to 4 nitrogen atoms, a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 or 2 oxygen atoms, a saturated or unsaturated 7- to 12-membered heterobicycle comprising as the ring heteroatom 1 to 3 oxygen atoms, a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 or 2 sulfur atoms, a saturated or unsaturated 7- to 15-membered heterobicycle comprising as the ring heteroatom 1 to 5 nitrogen atoms, a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 or 2 oxygen atoms and at least one nitrogen atom, or a saturated or unsaturated 5- or 6-membered heteromonocycle comprising as the ring heteroatom 1 or 2 sulfur atoms and at least one nitrogen atom, and   each of Rings A 1  and A 2  may have at least one substituent,   
       or a salt thereof. 
     
     
         4 . The compound according to  claim 1 , wherein Ring A 1  is benzene, pyridine, pyrazine, or tetrahydroisoquinoline and Ring A 1  may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyl-O—, halogen, and oxo;
 Ring A 2  is benzene, pyridine, furan, thiophene, or tetrahydroisoquinoline and Ring A 2  may have 1 to 4 substituents independently selected from the group consisting of optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkyl-O—, optionally substituted C 3-6  cycloalkyl, halogen, oxo, optionally substituted phenyl, and optionally substituted pyridyl, 
 provided that when Ring A 2  has multiple substituents on its ring carbon atoms, then the substituents may combine together with the carbon atoms to form C 3-6  cycloalkyl; or a salt thereof. 
 
     
     
         5 . The compound according to  claim 4 , wherein, in Ring A 1 , a substituent of the optionally substituted C 1-6  alkyl or optionally substituted C 1-6  alkyl-O— is each independently the same or different 1 to 3 groups selected from the group consisting of halogen and C 1-6  alkyl-O—,
 in Ring A 2 , a substituent of the optionally substituted C 1-6  alkyl or optionally substituted C 1-6  alkyl-O— is each independently the same or different 1 to 3 halogen, a substituent of the optionally substituted C 3-6  cycloalkyl is the same or different 1 to 3 halogen, a substituent of the optionally substituted phenyl is 1 to 3 groups independently selected from the group consisting of halogen, C 1-6  alkyl, and C 1-6  alkyl-O—, and a substituent of the optionally substituted pyridyl is the same or different 1 to 3 halogen, or a salt thereof. 
 
     
     
         6 . The compound according to  claim 1 , wherein R 1  is deuterium; OH; COOH; C 1-6  alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of optionally substituted amino, optionally substituted C 1-6  alkyl-O—, optionally substituted C 1-6  alkyl-SO 2 —O—, optionally substituted silyl-O—, OH, optionally substituted C 1-6  alkyl-COO—, tetrahydropyranyl-O—, thiazolyl, and pyridyl; optionally substituted C 1-6  alkyl-O—CO—; or optionally substituted C 2-6  alkenyl,
 the optionally substituted amino is amino optionally substituted with 1 or 2 groups independently selected from the group consisting of C 1-6  alkyl optionally substituted with OH, optionally substituted C 1-6  alkyl-SO 2 —, optionally substituted C 1-6  alkyl-O—CO—, and benzyl-O—CO—, 
 the optionally substituted C 1-6  alkyl in the optionally substituted C 1-6  alkyl-O—, optionally substituted C 1-6  alkyl-SO 2 —, optionally substituted C 1-6  alkyl-SO 2 —O—, optionally substituted C 1-6  alkyl-COO—, and optionally substituted C 1-6  alkyl-O—CO— is C 1-6  alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, C 1-6  alkyl-O—, optionally substituted phenyl, optionally substituted phenyl-SO 2 —NH—, and naphthalenyl-SO 2 —NH—, the optionally substituted phenyl being phenyl optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, C 1-6  alkyl, and NO 2 , 
 the optionally substituted silyl-O— is silyl-O— optionally substituted with the same or different 1 to 3 C 1-6  alkyl, and 
 the optionally substituted C 2-6  alkenyl is C 2-6  alkenyl optionally substituted with the same or different 1 to 3 halogen, or a salt thereof. 
 
     
     
         7 . The compound according to  claim 1 , wherein R 1  is deuterium; OH; or C 1-6  alkyl optionally substituted with optionally substituted amino, optionally substituted C 1-6  alkyl-O—, or OH,
 the optionally substituted amino is amino optionally substituted with C 1-6  alkyl optionally substituted with OH, and 
 the optionally substituted C 1-6  alkyl-O— is C 1-6  alkyl-O— optionally substituted with the same or different 1 to 3 halogen, or a salt thereof. 
 
     
     
         8 . The compound according to  claim 1 , wherein R 1  is C 1-6  alkyl substituted with OH, or a salt thereof. 
     
     
         9 . The compound according to  claim 1 , wherein Ring A 1  is benzene optionally substituted with halogen, C 1-6  alkyl, halo-C 1-6  alkyl, C 1-6  alkyl-O—, halo-C 1-6  alkyl-O—, C 1-6  alkyl-O—C 1-6  alkyl-O—, halo-C 1-6  alkyl-O—C 1-6  alkyl-O—, C 1-6  alkyl-O-halo-C 1-6  alkyl-O—, or halo-C 1-6  alkyl-O-halo-C 1-6  alkyl-O—; pyridine optionally substituted with halogen; pyrazine; or tetrahydroisoquinoline optionally substituted with oxo; and
 Ring A 2  is benzene optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, C 1-6  alkyl, halo-C 1-6  alkyl, C 1-6  alkyl-O—, halo-C 1-6  alkyl-O—, C 3-6  cycloalkyl, optionally substituted phenyl, and pyridyl, the optionally substituted phenyl being phenyl optionally substituted with halogen, C 1-6  alkyl, halo-C 1-6  alkyl, C 1-6  alkyl-O—, or halo-C 1-6  alkyl-O—; pyridine optionally substituted with C 1-6  alkyl, halo-C 1-6  alkyl, or phenyl; furan optionally substituted with C 1-6  alkyl; thiophene optionally substituted with C 1-6  alkyl; or tetrahydroisoquinoline optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, C 1-6  alkyl, and oxo, provided that when tetrahydroisoquinoline has multiple C 1-6  alkyl groups on its ring carbon atoms, then the C 1-6  alkyl groups may combine together with the carbon atoms to form C 3-6  cycloalkyl, or a salt thereof. 
 
     
     
         10 . The compound according to  claim 1 , wherein R 1  is C 1-6  alkyl substituted with OH, Ring A 1  is benzene optionally substituted with halogen, C 1-6  alkyl, C 1-6  alkyl-O—, or C 1-6  alkyl-O—C 1-6  alkyl-O—; or pyridine optionally substituted with halogen, and
 Ring A 2  is benzene optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, C 1-6  alkyl, halo-C 1-6  alkyl, C 1-6  alkyl-O—, halo-C 1-6  alkyl-O—, C 3-6  cycloalkyl, optionally substituted phenyl, and pyridyl, the optionally substituted phenyl being phenyl optionally substituted with halogen, C 1-6  alkyl, halo-C 1-6  alkyl, C 1-6  alkyl-O—, or halo-C 1-6  alkyl-O—, or a salt thereof. 
 
     
     
         11 . The compound according to  claim 1 , wherein R 1  is C 1-6  alkyl substituted with OH,
 Ring A 1  is benzene optionally substituted with halogen, C 1-6  alkyl-O—, or halo-C 1-6  alkyl-O—; or pyridine, and   Ring A 2  is benzene optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen, C 1-6  alkyl, halo-C 1-6  alkyl, and phenyl optionally substituted with halogen; pyridine optionally substituted with phenyl or halo-C 1-6  alkyl; or tetrahydroisoquinoline optionally substituted with 1 to 3 groups independently selected from the group consisting of halogen and oxo, or a salt thereof.   
     
     
         12 . The compound according to  claim 1 , wherein L is —C(═O)—NH—, or a salt thereof. 
     
     
         13 . A compound, or a salt thereof, selected from the following compound group: