Therapeutic Pyrazolo[3,4-b]Pyridines and Indazoles

Abstract

The present invention provides for compounds of Formula I: wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, and L have any of the values defined in the specification, and pharmaceutically acceptable salts thereof, that are useful as agents in the treatment of central nervous disorders and conditions including attention deficit hyperactivity disorder, neuropathic pain, urinary incontinence, anxiety, depression, and schizophrenia and fibromyalgia. Also provided are pharmaceutical compositions comprising one or more compounds of Formula I.

1 . A compound of formula I: 
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof; wherein:
 X is N or C(R 4 ); 
 R 2  is 2-pyridinyl or phenyl, said 2-pyridinyl or said phenyl may be optionally substituted with one to three substituents independently selected from the group consisting of:
 hydrogen, halo, methyl, ethyl, CF 3 , methoxy, CH 2 F, CHF 2 , and CH 2 OH; 
 
 L is absent or methylene; 
 R 3  is selected from the group consisting of: 3-pyrrolidinyl, 4-piperidinyl, 3-piperidinyl, and 2-morpholinyl; and 
 R 4 , R 5 , R 6 , and R 7  are H; or three of R 4 , R 5 , R 6 , and R 7  are H and one of R 4 , R 5 , R 6 , and R 7  is selected from the group consisting of: halo, methoxy, and a C 1 -C 3  alkyl. 
 
   
   
       2 . The compound of  claim 1 , wherein X is C(R 4 ), R 2  is phenyl, and R 4 , R 5 , R 6 , and R 7  are H; or three of R 4 , R 5 , R 6 , and R 7  are H and one of R 4 , R 5 , R 6 , and R 7  is selected from the group consisting of: halo, methoxy, and a C 1 -C 3  alkyl. 
   
   
       3 . The compound of  claim 2 , wherein R 4 , R 5 , R 6 , and R 7  are H, and R 2  is optionally substituted with one or two substituents independently selected from the group consisting of: hydrogen and fluoro. 
   
   
       4 . The compound of  claim 3 , wherein R 3  is 3-pyrrolidinyl. 
   
   
       5 . The compound of  claim 4 , wherein said compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 
     (R)-1-(2,5-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole; 
     (R)-1-(2,4-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole; 
     (S)-1-(2,4-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole; 
     (S)-(−)-1-(2-fluorophenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole; 
     (S)-1-(2,6-difluoro-phenyl)-3-(pyrrolidin-3-ylmethoxy)-1H-indazole; 
     (R)-1-phenyl-3-(pyrrolidin-3-ylmethoxy)-1H-indazole; and 
     (S)-(−)-1-(2-fluorophenyl)-3-(pyrrolidin-2-yloxy)-1H-indazole. 
   
   
       6 . The compound of  claim 3 , wherein R 3  is 4-piperidinyl or 3-piperidinyl. 
   
   
       7 . The compound of  claim 6 , wherein said compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 
     (±)-1-(2,5-difluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole; 
     1-(3-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole; 
     1-phenyl-3-(piperidin-4-yloxy)-1H-indazole; 
     1-(2,6-difluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole; 
     1-(2,5-difluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole; 
     (±)-1-(3-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole; 
     (S)-(−)-1-(2-fluorophenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole; 
     (S)-1-(2,6-difluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole; and 
     (S)-(−)-1-phenyl-3-(piperidin-3-ylmethoxy)-1H-indazole. 
   
   
       8 . The compound of  claim 3 , wherein R 3  is 2-morpholinyl. 
   
   
       9 . The compound of  claim 8 , wherein -L-R 3  is: 
     
       
         
         
             
             
         
       
     
   
   
       10 . The compound of  claim 8 , wherein said compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 
     (S)-(+)-1-(2,5-difluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole; 
     (S)-1-(2,6-difluoro-phenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole; 
     (S)-(+)-1-(2,4-difluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole; 
     (S)-1-(3,4-difluoro-phenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole; 
     (S)-(+)-1-(2-fluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole; and 
     (S)-(+)-3-(morpholin-2-ylmethoxy)-1-phenyl-1H-indazole. 
   
   
       11 . The compound of  claim 2 , wherein R 6  is selected from the group consisting of: halo, methoxy, and a C 1 -C 3  alkyl; and
 R 2  is optionally substituted with one or two substituents independently selected from the group consisting of: hydrogen and fluoro.   
   
   
       12 . The compound of  claim 11 , wherein R 3  is 3-pyrrolidinyl. 
   
   
       13 . The compound of  claim 12 , wherein said compound or a pharmaceutically acceptable salt thereof is (R)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(pyrrolidin-3-ylmethoxy)-1H-indazole. 
   
   
       14 . The compound of  claim 11 , wherein R 3  is 4-piperidinyl or 3-piperidinyl. 
   
   
       15 . The compound of  claim 14 , wherein said compound or a pharmaceutically acceptable salt thereof is 1-(2,6-difluoro-phenyl)-5-fluoro-3-(piperidin-4-yloxy)-1H-indazole. 
   
   
       16 . The compound of  claim 11 , wherein R 3  is 2-morpholinyl. 
   
   
       17 . The compound of  claim 6 , wherein -L-R 3  is: 
     
       
         
         
             
             
         
       
     
   
   
       18 . The compound of  claim 16 , wherein said compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 
     (S)-1-(2,6-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole; 
     (S)-1-(2,5-difluoro-phenyl)-5-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole; and 
     (S)-(+)-5-fluoro-1-(2-fluorophenyl)-3-(morpholin-2-ylmethoxy)-1H-indazole. 
   
   
       19 . The compound of  claim 2 , wherein R 7  is selected from the group consisting of: halo, methoxy, and a C 1 -C 3  alkyl; and
 R 2  is optionally substituted with one or two substituents independently selected from the group consisting of: hydrogen and fluoro.   
   
   
       20 . The compound of  claim 17 , wherein R 3  is 4-piperidinyl or 3-piperidinyl. 
   
   
       21 . The compound of  claim 18 , wherein said compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of: 
     4-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-4-yloxy)-1H-indazole; 
     1-(2,5-difluoro-phenyl)-4-fluoro-3-(piperidin-4-yloxy)-1H-indazole; 
     1-(2,4-difluoro-phenyl)-4-fluoro-3-(piperidin-4-yloxy)-1H-indazole; 
     (S)-1-(2,5-difluoro-phenyl)-4-fluoro-3-(piperidin-3-ylmethoxy)-1H-indazole; and 
     (S)-4-fluoro-1-(2-fluoro-phenyl)-3-(piperidin-3-ylmethoxy)-1H-indazole. 
   
   
       22 . The compound of  claim 17 , wherein R 3  is 2-morpholinyl. 
   
   
       23 . The compound of  claim 20 , wherein said compound or a pharmaceutically acceptable salt thereof is (S)-1-(2,5-difluoro-phenyl)-4-fluoro-3-(morpholin-2-ylmethoxy)-1H-indazole. 
   
   
       24 . (canceled) 
   
   
       25 . (canceled) 
   
   
       26 . A method of treating attention deficit hyperactivity disorder (ADHD) comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 1 . 
   
   
       27 . A method of treating a disorder or condition selected from the group consisting of: neuropathic pain, stress urinary incontinence, anxiety, depression, and schizophrenia, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 1 . 
   
   
       28 . A method of treating fibromyalgia comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound according to  claim 1 . 
   
   
       29 . A method of treating fibromyalgia comprising administering to a mammal in need of such treatment a therapeutically effective amount of 1-(2-fluorophenyl)-3-(piperidin-4-yloxy)-1H-indazole, or a pharmaceutically acceptable salt thereof. 
   
   
       30 . A pharmaceutical composition comprising:
 a therapeutically effective amount of a compound of according to  claim 1  and a pharmaceutically acceptable carrier.   
   
   
       31 . (canceled) 
   
   
       32 . (canceled)