Benzoxazines, benzothiazines, and related compounds having nos inhibitory activity

Abstract

The present invention features benzoxazines, benzothiazines, and related compounds that inhibit nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing various medical conditions.

What is claimed is: 
     
         1 . A compound having the formula: 
       
         
           
           
               
               
           
         
         wherein,
 Q is O—(CHR 6 ) 1-3  or S—(CHR 6 ) 1-3 ; 
 R 1  and each R 6  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 1-4  alkcycloalkyl, or —(CR 1A R 1B ) n NR 1C R 1D ; 
 R 1A  and R 1B  are, independently, H, hydroxy, halo, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkoxy, optionally substituted C 1-4  alkcycloalkyl, optionally substituted C 1-4  alkaryl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-4  alkheteroaryl, optionally substituted C 3-8  cycloalkyl, or optionally substituted C 2-9  heterocyclyl, or R 1A  and R 1B  combine to form ═O; 
 R 1C  and R 1D  are, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 1-6  alkoxy, optionally substituted C 1-4  alkcycloalkyl, optionally substituted C 1-4  alkaryl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-4  alkheteroaryl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 2-9  heterocyclyl, or an N-protecting group, or R 1C  and R 1D  combine to form an optionally substituted C 2-9  heterocyclyl or an N-protecting group; 
 n is an integer between 1-6; 
 each of R 2  and R 3  is, independently, H, hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-6  alkaryl, optionally substituted C 2-9  heterocyclyl, hydroxy, optionally substituted C 1-6  alkoxy, optionally substituted C 1-6  thioalkoxy, (CH 2 ) r2 NHC(NH)R 2A , or (CH 2 ) r2 NHC(S)NHR 2B , or optionally substituted C 1-4  alkheterocyclyl, 
 wherein r2 is an integer from 0 to 2, R 2A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6  thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, optionally substituted C 1-4  thioalkheterocyclyl, or substituted amino; and R 2B  is optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6  thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, optionally substituted C 1-4  thioalkheterocyclyl, or optionally substituted amino; 
 each of R 4  and R 5  is independently H, hal, (CH 2 ) r2 NHC(NH)R 2A , or (CH 2 ) r2 NHC(S)NHR 2B ; 
 wherein Y 1  and Y 2  are each H, or Y 1  and Y 2  together are ═O, or Y 1  and Y 2  are independently H, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-6  alkaryl, optionally substituted C 2-9  heterocyclyl, hydroxy, optionally substituted C 1-6  alkoxy, optionally substituted C 1-6  thioalkoxy, or optionally substituted C 1-4  alkheterocyclyl; 
 wherein one and only one of R 2 , R 3 , R 4 , and R 5  is (CH 2 ) r2 NHC(NH)R 2A  or (CH 2 ) r2 NHC(S)NHR 2B ; 
 or a pharmaceutically acceptable salt or prodrug thereof. 
 
       
     
     
         2 . The compound of  claim 1 , wherein
 Q is O—(CHR 6 ) 1-2  or S—(CHR 6 ) 1-2 ; and   R 1  and each R 6  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, optionally substituted C 1-4  alkheterocyclyl, or optionally substituted C 2-9  heterocyclyl.   
     
     
         3 . The compound of  claim 1 , wherein R 2 , R 3 , R 4 , or R 5  has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . The compound of  claim 3 , wherein R 2A  has the formula: 
       
         
           
           
               
               
           
         
         and 
         each of X 1 , X 2 , X 4 , and X 5  is independently selected from O, S, NR 7 , N, or CR 8 ; 
         X 3  is selected from N or C; 
         R 7  is H or optionally substituted C 1-6  alkyl; 
         R 8  is H, hal, optionally substituted C 1-6  alkyl, hydroxy, optionally substituted C 1-6  alkoxy, or optionally substituted C 1-6  thioalkoxy, 
         wherein at least one of X 1 , X 2 , X 4 , and X 5  is not CR 8 . 
       
     
     
         5 . The compound of  claim 4 , wherein R 2A  has the formula: 
       
         
           
           
               
               
           
         
         and 
         each of X 1  and X 2  is independently selected from O, S, NH, N, or CH; and 
         wherein at least one of X 1  and X 2  is not CH. 
       
     
     
         6 . The compound of  claim 1 , wherein said compound has a structure selected from 
       
         
           
           
               
               
           
         
         and 
         wherein one of R 4  and R 5  has the following structure: 
       
       
         
           
           
               
               
           
         
         wherein X 2  is O or S. 
       
     
     
         7 . The compound of  claim 1 , wherein Y 1  and Y 2  are each H or together are ═O, and Q is O—CHR 6 . 
     
     
         8 . The compound of  claim 1 , wherein Y 1  and Y 2  are each H or Y 1  and Y 2  together are ═O, and Q is O—(CHR 6 ) 2 , O—(CHR 6 ) 3 , S—(CHR 6 ) 2 , or S—(CHR 6 ) 3 . 
     
     
         9 . The compound of  claim 1 , wherein R 1  is optionally substituted C 1-6  alkyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl. 
     
     
         10 . The compound of  claim 9 , wherein R 1  is optionally substituted aminoC 1-6 alkyl or optionally substituted C 1-4  alkheterocyclyl, wherein said heterocyclyl is a 5- or 6-membered cyclic amine. 
     
     
         11 . The compound of  claim 10 , wherein said cyclic amine is substituted with a carboxyl, C 1-6  alkoxycarbonyl, or carbamoyl group. 
     
     
         12 . The compound of  claim 9 , wherein said heterocyclyl is optionally substituted pyrrolidinyl or optionally substituted piperidinyl. 
     
     
         13 . The compound of  claim 12 , wherein R 1  is 
       
         
           
           
               
               
           
         
         wherein R 9  is H, optionally substituted C 1-6  alkyl, or optionally substituted C 1-4  alkaryl. 
       
     
     
         14 . The compound of  claim 1 , wherein R 1  is an optionally substituted C 3 -C 8  cycloalkyl. 
     
     
         15 . The compound of  claim 14 , wherein said C 3 -C 8  cycloalkyl is substituted by an amino 
     
     
         16 . The compound of  claim 1 , wherein R 1  is (CR 1A R 1B ) n NR 1C R 1D . 
     
     
         17 . The compound of  claim 16 , wherein R 1A  and R 1B  are each H, and n is 2 or 3. 
     
     
         18 . The compound of  claim 16 , wherein R 1C  is H, and R 1D  is —CH 3 , —CH 2 CH 3 , —(CH 2 ) 2 OH, or —CH 2 CO 2 H; or R 1C  and R 1D  combine to form optionally substituted pyrrolidinyl or optionally substituted piperidinyl. 
     
     
         19 . The compound of  claim 16 , wherein R 1  is —CH 2 CH 2 N(CH 3 ) 2  or —CH 2 CH 2 NHCH 3 . 
     
     
         20 . The compound of  claim 1 , wherein one of R 4  or R 5  is H or F. 
     
     
         21 . A compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         22 . A pharmaceutical composition comprising the compound of  claim 1 , or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable excipient. 
     
     
         23 . A method of treating or preventing a condition in a mammal caused by the action of nitric oxide synthase (NOS), wherein said method comprises administering an effective amount of the compound of  claim 1 , or a pharmaceutically acceptable salt or prodrug thereof to said mammal. 
     
     
         24 . The method of  claim 23 , wherein said mammal is a human. 
     
     
         25 . The method of  claim 23 , wherein said condition is headache, neuropathic pain, chronic inflammatory pain, visceral pain, neuroinflammation, medication-induced hyperalgesia and/or allodynia, acute pain, chronic pain, bone cancer pain; chemical dependencies or addictions, CNS disorders, neurodegenerative diseases or nerve injury, cardiovascular related conditions, or gastrointestinal disorders. 
     
     
         26 . The method of  claim 25 , wherein said headache is migraine headache (with or without aura), chronic tension type headache (CTTH), migraine with allodynia, medication overuse headache, cluster headache, chronic headache, or transformed migraine. 
     
     
         27 . The method of  claim 25 , wherein said headache is a headache with an underlying mechanism of central sensitization. 
     
     
         28 . The method of  claim 25 , wherein said chronic pain has components of central sensitization. 
     
     
         29 . The method of  claim 25 , wherein said chronic pain is neuropathic pain.