Dibenzo [b,f] [1,4]oxazapine compounds

Abstract

The present invention relates to 11-(piperazin-1-yl)dibenzo[b,f][1,4]oxazapine compounds of the formula: where the variables are as defined herein, their salts and pharmaceutically acceptable compositions thereof. Methods of preparing these compounds are also described. These compounds may be used in the treatment of disorders such as schizophrenia, treatment resistant schizophrenia, bipolar disorder, psychotic depression, treatment resistant depression, schizophrenia-associated depression, treatment resistant OCD, autism, senile psychosis, psychotic dementia, L-DOPA induced psychosis, psychogenic polydipsia, psychotic symptoms of neurological disorders, sleep disorders.

1 . A compound having the structure 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, 
       wherein
 R 1  and R 2  are independently —Cl, —F, —Br, —I or —H; 
 R 3  is —R (nonoptionally substituted in this single instance at R 3 ), —(C 0 -C 6  alk)C(O)OR e , —(C 0 -C 6  alk)C(O)NR a   2 , —(C 0 -C 6  alk)C(O)NR a R 19 , —(C 0 -C 6  alk)C(O)NR 19   2 , —(C 0 -C 6  alk)-C(O)NR 20 , —(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)-O—(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)-OR, —(C 0 -C 6  alk)C(O)R k , or —(C 0 -C 6  alk)-N R a R 19 ; 
 R 4  is —H or —R; 
 each R 5 , R 6  and R 7  is independently —R, —(C 0 -C 6  alk)-OR, —(C 0 -C 6  alk)-NR a R 19 , —NO 2 , -halogen, —CN, —OH, —OOCR, —(C 0 -C 6  alk)COOR e , —(C 0 -C 6  alk)C(O)NR a R 19 , —(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)-O—(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)Het, —(C 0 -C 6  alk)-O—(C 0 -C 6  alk)Het, —(C 0 -C 6  alk)Hca, —(C 0 -C 6  alk)-O—(C 0 -C 6  alk)Hca, —(C 0 -C 6  alk)Cak, —(C 0 -C 6  alk)-O—(C 0 -C 6  alk)Cak, —(C 0 -C 6  alk)C(O)Hca, —(C 0 -C 6  alk)C(O)Ar, —(C 0 -C 6  alk)C(O)Het, or —(C 0 -C 6  alk)C(O)Cak; 
 w is 0, 1, 2 or 3; 
 x is 0, 1, 2 or 3; and 
 y is 0, 1, 2 or 3; 
 in which
 each R e  is independently —H, —R, —(C 1 -C 6  alk)C(O)Hca, —(C 1 -C 6  alk) C(O)Cak, —(C 1 -C 6  alk)C(O)Het, —(C 1 -C 6  alk)C(O)Ar, —(C 1 -C 6  alk)C(O)O-Hca, —(C 1 -C 6  alk)C(O)O-Cak, —(C 1 -C 6  alk)C(O)O-Het, —(C 1 -C 6  alk)C(O)O—Ar, —(C 0 -C 6  alk)Hca, —(C 0 -C 6  alk)Het, —(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)Cak, —(C 1 -C 6  alk)C(O)OR, —(C 1 -C 6  alk)C(O)NR 19   2 , —(C 0 -C 6  alk)-OR, or —(C 0 -C 6  alk)-OH; 
 each R a  is independently —H, —R, —(C 1 -C 6  alk)-OR, —(C 1 -C 6  alk)-OH, —(C 0 -C 6  alk)C(O)OR, —(C 1 -C 6  alk)-NR 19   2 , —(C 0 -C 6  alk)Hca, —(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)Het, or —(C 0 -C 6  alk)Cak; 
 each R k  is independently —H, —R, —(C 1 -C 6  alk)C(O)Hca, —(C 1 -C 6  alk)C(O)Cak, —(C 1 -C 6  alk)C(O)Het, —(C 1 -C 6  alk)C(O)Ar, —(C 1 -C 6  alk)Hca, —(C 0 -C 6  alk)Het, —(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)Cak, —(C 1 -C 6  alk)C(O)OR, or —(C 1 -C 6  alk)C(O)NR 19   2 ; 
 each Cak is a cycloalkyl or cycloalkenyl group, optionally substituted with 1, 2 or 3 substituents independently selected from —R, —(C 0 -C 6  alk)C(O)OR, ═O, —OH, —CN, —(C 0 -C 6  alk)OR, —OCH 2 CH 2 —O—, —OCH 2 —O—, —SO 2 —R, —SO 2 —(C 1 -C 6  haloalkyl), —(C 0 -C 6  alk)C(O)NR 19   2 , —(C 0 -C 6  alk)Het, —SO 2 (C 0 -C 6  alk)-Hca, —(C 0 -C 6  alk)Ar, —(C 0 -C 6  alk)Het, —(C 0 -C 6  alk)Hca, —(C 0 -C 6  alk)C(O)R, —SO 2 (C 0 -C 6  alk)Ar, —SO 2 (C 0 -C 6  alk)Het, and —SO 2 (C 0 -C 6  alk)cycloalk, 
 each Ar is an aryl group, optionally substituted with 1, 2 or 3 substituents independently selected from —R, —OR, —(C 0 -C 6  alk)NR 19   2 , —NO 2 , —Cl, —F, —Br, —I, —CN, —(C 0 -C 6  alk)OH, —(C 0 -C 6  alk)C(O)OR, —(C 0 -C 6  alk)C(O)OH, —(C 1 -C 6  haloalkyl), —O(C 1 -C 6  haloalkyl), —(C 0 -C 6  alkyl)heterocycloalk, —SO 2 R, —(C 0 -C 6  alk)-C)(O)-heterocycloalk, —(C 0 -C 6  alk)-C(O)-cycloalk, —(C 0 -C 6  alkyl)-C(O)-heteroaryl, —(C 0 -C 6  alk)-C(O)-aryl, —(C 0 -C 6  alkyl)-C(O)O-heterocycloalk, —(C 0 -C 6  alk)-C(O)O-cycloalk, —(C 0 -C 6  alkyl)-C(O)O-heteroaryl, —(C 0 -C 6  alk)-C(O)O-aryl, —(C 0 -C 6  alk)-heterocycloalkyl, —(C 0 -C 6  alk)-heteroaryl, —(C 0 -C 6  alk)-aryl, and —(C 0 -C 6  alk)-cycloalk; 
 each Het is a heteroaryl group, optionally substituted with 1, 2 or 3 groups independently selected from —R, —OR, —(C 0 -C 6  alk)NR 19   2 , —NO 2 , —Cl, —F, —Br, —I, —CN, —(C 0 -C 6  alk)OH, —(C 0 -C 6  alk)CO 2 R, —(C 0 -C 6  alk)C(O)OH, —(C 1 -C 6  haloalkyl), —O(C 1 -C 6  haloalkyl), —(C 0 -C 6  alkyl)heterocycloalk, —SO 2 R, —(C 0 -C 6  alk)-C(O)-heterocycloalk, —(C 0 -C 6  alk)-C(O)-cycloalk, —(C 0 -C 6  alk)-C(O)-heteroaryl, —(C 0 -C 6  alk)-C(O)-aryl, —(C 0 -C 6  alk)-C(O)O-heterocycloalk, —(C 0 -C 6  alk)-C(O)O-cycloalk, —(C 0 -C 6  alk)-C(O)O-heteroaryl, —(C 0 -C 6  alk)-C(O)O-aryl, —(C 0 -C 6  alk)-heterocycloalkyl, —(C 0 -C 6  alk)-heteroaryl, —(C 0 -C 6  alk)-aryl, and —(C 0 -C 6  alk)-cycloalk; 
 each Hca is a heterocycloalk group, optionally substituted with 1, 2 or 3 substituents independently selected from —R, —(C 1 -C 6  haloalkyl), —O(C 1 -C 6  haloalkyl), —(C 0 -C 6  alk)-C(O)OR, —(C 0 -C 6  alk)-C(O)R, ═O, —OH, —CN, —(C 0 -C 6  alk)OR, —OCH 2 CH 2 —O—, —OCH 2 O—, —SO 2 R, —SO 2 —(C 1 -C 6  haloalkyl), —(C 0 -C 6  alk)C(O)NR 19   2 , —(C 0 -C 6  alk)-heterocycloalk, —(C 0 -C 6  alk)-aryl, —(C 0 -C 6  alk)-heterocycloalk, —(C 0 -C 6  alk)-cycloalk, —SO 2 (C 0 -C 6  alk)-heterocycloalk, —SO 2 (C 0 -C 6  alk)-aryl, —SO 2 (C 0 -C 6  alk)-heteroaryl —SO 2 (C 0 -C 6  alkyl)heteroaryl, —SO 2 (C 0 -C 6  alk)-cycloalk; 
 each R 10  and R 11  is independently —H or —R; 
 each R 19  is independently selected from —H, —OH and —R in which any (C 1 -C 8  alk) or —(C 1 -C 8  haloalkyl) groups are optionally substituted with 1, 2 or 3 substituents independently selected from ═O, —(C 1 -C 6  alkoxy), —OH, or -halogen; —(C 1 -C 6  haloalkyl), wherein the —(C 1 -C 6  haloalkyl)may be substituted with from 1 to 6 halogens, —SO 2 —(C 1 -C 6  alk), and —C(O)—(C 1 -C 6  alk); 
 each R 20  is a Hca or Het ring wherein that N from the —(C 0 -C 6  alk)-C(O)NR 20 , is a heteroatom in the Hca or Het ring, the ring optionally substituted with 1 or 2 substituents independently selected from ═O, —(C 1 -C 6  alkoxy), —OH, or -halogen; —(C 1 -C 6  haloalkyl), —SO 2 —(C 1 -C 6  alk), and —C(O)—(C 1 -C 6  alk), 
 each R is independently —(C 1 -C 8  alk), —(C 3 -C 8  cycloalk), —(C 3 -C 12  heterocycloalk), —(C 1 -C 8  haloalkyl), or —(C 3 -C 8  halocycloalk), optionally substituted with 1, 2 or 3 substituents independently selected from —(C 1 -C 6  alkoxy), —(C 1 -C 6  hydroxyalkyoxy), —(C 1 -C 6  hydroxyalkyl), acetoxyalkyl, —C(O)O(C 1 -C 6  alkyl), —OH, ═O, —N(C 1 -C 6  alkyl) 2 , —NH(C 1 -C 6 alk), —NH 2 , —OC(O)(C 0 -C 6  alk), —SO 2 —(C 1 -C 6  alk), and —CO—(C 0 -C 6  alk); and 
 each (C 0 -C 6  alk), (C 1 -C 6  alk), and —(C 1 -C 8  alk) is independently optionally substituted with 1, 2, 3 or 4 substitutents selected independently from —(C 1 -C 4  alkyl), —(C 1 -C 4  alkoxy), —OH, ═O, -halogen, —C(O)O(C 1 -C 3  alkyl) and —C(O)(C 1 -C 3  alkyl); and is optionally halogenated. 
 
 
     
     
         2 .- 32 . (canceled) 
     
     
         33 . A method of treating schizophrenia, treatment-resistant schizophrenia, bipolar disorder, psychotic depression, treatment-resistant depression, obsessive-compulsive disorder (OCD), autism, senile psychosis, psychotic dementia, L-DOPA induced psychosis, psychogenic polydipsia, psychotic symptoms associated with neurological disorders, sleep disorders, depressed states associated with schizophrenia, the method comprising administering a compound or salt according to  claim 1  to a patient in need of such treatment. 
     
     
         34 .- 35 . (canceled) 
     
     
         36 . The method of  claim 33  wherein the compound or salt according to  claim 1  is administered to a patient in need of such treatment is administered in combination with one or more antipsychotics, antidepressants, anti-anxiety agents, or nicotine. 
     
     
         37 .- 39 . (canceled)