US2016237089A1PendingUtilityA1

Substituted xanthines and methods of use thereof

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Assignee: HYDRA BIOSCIENCES INCPriority: Mar 15, 2013Filed: Apr 25, 2016Published: Aug 18, 2016
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
Inventors:Bertrand L. ChenardRandall J. Gallaschun
A61P 43/00A61P 25/18A61P 25/22A61P 25/24A61P 25/02A61P 25/08A61P 25/28A61P 25/00A61P 13/12C07D 487/04C07D 487/12C07D 473/06C07D 473/04
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Claims

Abstract

Compounds, compositions and methods are described for inhibiting the TRPC5 ion channel and disorders related to TRPC5.

Claims

exact text as granted — not AI-modified
We claim: 
     
         1 . A method of treating a TRPC5 mediated disorder in a subject, the method comprising administering to the subject a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1-4 R 5 ; 
 R 2  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, halo, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, C 3 -C 7  cycloalkyloxy, C 6 -C 10  aryl, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, —S—, —S—C 1 -C 6  alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, C 3 -C 7  cycloalkyloxy, C 6 -C 10  aryl, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, —S—, —S—C 1 -C 6  alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1-3 R 6 ; 
 R 3  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 3 -C 7  cycloalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 2 -C 6  hydroxyalkyl, or C 1 -C 6  alkoxy, each of which is optionally substituted with 1-4 R 7 ; 
 R 4  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1-4 R 8 ; 
 R 5 , R 6 , R 7 , and R 8  are each independently C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, halo, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 2 -C 12  dialkylamino, cyano, nitro, amido, C 1 -C 6  alkylamido, C 2 -C 12  dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, heterocycloalkyl, or heteroaryl, wherein each of C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 2 -C 12  dialkylamino, amido, C 1 -C 6  alkylamido, C 2 -C 12  dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 9 ; and 
 each R 9  is independently C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, heterocycloalkyl, C 6 -C 10  aryl, heteroaryl, C 4 -C 10  cycloalkylalkyl, heterocycloalkyl-C 1 -C 6  alkyl, C 7 -C 16  arylalkyl, heteroaryl-C 1 -C 6  alkyl, halo, hydroxyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, C 2 -C 8  alkoxyalkoxyl, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, C 1 -C 6  akyl-amino-C 1 -C 6  akyl, C 1 -C 6  akyl-amino-C 2 -C 12  dialkyl, —S—, —S—C 1 -C 6  alkyl, —S(O) 2 —C 1 -C 6  alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, —C(O)—C 6 -C 10  aryl, —NHC(O)—C 6 -C 10  aryl, —C(O)NH—C 6 -C 10  aryl, —C(O)OH, —C(O)O—C 1 -C 6  alkyl, —C(O)—C 1 -C 6  alkyl acyl, nitro, or cyano; to thereby treat the subject. 
 
     
     
         2 . The method of  claim 1 , wherein the TRPC5 mediated disorder is selected from the group consisting of: a neuropsychiatric disorder, a neurodegenerative disorder, nephropathy, and seizure disorder. 
     
     
         3 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is C 1 -C 6  alkyl. 
     
     
         4 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1  is C 1 -C 6  alkyl and R 5  is independently C 6 -C 10  aryl or heteroaryl. 
     
     
         5 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 6 -C 10  aryl, C 6 -C 10  aryloxy or heteroaryloxy. 
     
     
         6 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 6 -C 10  aryloxy. 
     
     
         7 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 1 -C 6  alkoxy. 
     
     
         8 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 1 -C 6  alkyl. 
     
     
         9 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is or C 1 -C 6  akylamino. 
     
     
         10 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is —S(O)— or —S(O) 2 —. 
     
     
         11 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is C 1 -C 6  alkyl, C 2 -C 6  hydroxyalkyl, or C 1 -C 6  alkoxy. 
     
     
         12 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3  is hydroxypropyl. 
     
     
         13 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4  is C 1 -C 6  alkyl. 
     
     
         14 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is independently C 6 -C 10  aryl, heteroaryl, C 3 -C 7  cycloalkyl, or heterocycloalkyl. 
     
     
         15 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is phenyl, pyridyl, thiazolyl, pyrimidinyl, or oxazolyl. 
     
     
         16 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is phenyl. 
     
     
         17 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is pyridyl. 
     
     
         18 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5  is thiazolyl. 
     
     
         19 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9  is independently C 1 -C 6  alkyl, C 1 -C 6  alkoxy, halo, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, or heterocycloalkyl. 
     
     
         20 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 6 -C 10  aryl or C 6 -C 10  aryloxy, and R 6  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  or haloalkoxy. 
     
     
         21 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 6 -C 10  aryloxy and R 6  is independently C 1 -C 6  haloalkyl or C 1 -C 6  or haloalkoxy. 
     
     
         22 . The method of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 6 -C 10  aryloxy and R 6  is —CF 3  or —OCF 3 . 
     
     
         23 . A compound of Formula I(a): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 1  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1-4 R 5 ; 
 R 2  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, halo, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, C 3 -C 7  cycloalkyloxy, C 6 -C 10  aryl, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, —S—, —S—C 1 -C 6  alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, C 3 -C 7  cycloalkyloxy, C 6 -C 10  aryl, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, —S—, —S—C 1 -C 6  alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1-3 R 6 ; 
 R 3  is C 2 -C 6  hydroxyalkyl or C 1 -C 6  heteroalkyl; 
 R 4  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1-4 R 8 ; 
 R 5 , R 6 , and R 8  are each independently C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, halo, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 2 -C 12  dialkylamino, cyano, nitro, amido, C 1 -C 6  alkylamido, C 2 -C 12  dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, heterocycloalkyl, or heteroaryl, each of C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 2 -C 12  dialkylamino, amido, C 1 -C 6  alkylamido, C 2 -C 12  dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 9 ; and 
 each R 9  is independently C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, heterocycloalkyl, C 6 -C 10  aryl, heteroaryl, C 4 -C 10  cycloalkylalkyl, heterocycloalkyl-C 1 -C 6  alkyl, C 7 -C 16  arylalkyl, heteroaryl-C 1 -C 6  alkyl, halo, hydroxyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, C 2 -C 8  alkoxyalkoxyl, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, C 1 -C 6  akyl-amino-C 1 -C 6  akyl, C 1 -C 6  akyl-amino-C 2 -C 12  dialkyl, —S—, —S—C 1 -C 6  alkyl, —S(O) 2 —C 1 -C 6  alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, —C(O)—C 6 -C 10  aryl, —NHC(O)—C 6 -C 10  aryl, —C(O)NH—C 6 -C 10  aryl, —C(O)OH, —C(O)O—C 1 -C 6  alkyl, —C(O)—C 1 -C 6  alkyl acyl, nitro, or cyano. 
 
     
     
         24 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 1  is C 1 -C 6  alkyl and R 5  is phenyl, pyridyl, thiazolyl, pyrimidinyl, or oxazolyl, e.g., phenyl, pyridiyl, or thiazolyl. 
     
     
         25 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 2  is C 6 -C 10  aryl or C 6 -C 10  aryloxy, and R 6  is independently C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, C 1 -C 6  or haloalkoxy. 
     
     
         26 . The compound of  claim 23 , or a pharmaceutically acceptable salt thereof, wherein R 3  is C 2 -C 6  hydroxyalkyl. 
     
     
         27 . A compound of Formula II: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 Ring A is phenyl, thiazolyl, pyrimidinyl, or oxazolyl; 
 R 2  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, halo, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, C 3 -C 7  cycloalkyloxy, C 6 -C 10  aryl, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, —S—, —S—C 1 -C 6  alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, nitro, cyano, wherein each of C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, C 3 -C 7  cycloalkyloxy, C 6 -C 10  aryl, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, —S—, —S—C 1 -C 6  alkyl, —S(O)—, —S(O) 2 —, heterocycloalkyl, heteroaryl, heteroaryloxy, sulfonamidyl, amido, urea, sulfonylurea, acyl, is optionally substituted with 1-3 R 6 ; 
 R 3  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 2 -C 6  hydroxyalkyl, or C 1 -C 6  alkoxy, each of which is optionally substituted with 1-4 R 7 ; 
 R 4  is C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 2 -C 6  alkenyl or C 2 -C 6  alkynyl, each of which is optionally substituted with 1-4 R 8 ; 
 R 6 , R 7 , and R 8  are each independently C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, halo, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 2 -C 12  dialkylamino, cyano, nitro, amido, C 1 -C 6  alkylamido, C 2 -C 12  dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, heterocycloalkyl, or heteroaryl, wherein each of C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, hydroxyl, C 1 -C 6  alkoxy, amino, C 1 -C 6  alkylamino, C 2 -C 12  dialkylamino, amido, C 1 -C 6  alkylamido, C 2 -C 12  dialkylamido, —S—, —S(O) 2 —, —C(O)O—, —C(O)—, —C(O)O—C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl, C 6 -C 10  aryl, heterocycloalkyl, or heteroaryl is optionally substituted with 1-3 R 9 ; 
 each R 9  is independently C 1 -C 6  alkyl, C 1 -C 6  heteroalkyl, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, heterocycloalkyl, C 6 -C 10  aryl, heteroaryl, C 4 -C 10  cycloalkylalkyl, heterocycloalkyl-C 1 -C 6  alkyl, C 7 -C 16  arylalkyl, heteroaryl-C 1 -C 6  alkyl, halo, hydroxyl, C 1 -C 6  alkoxy, C 6 -C 10  aryloxy, C 7 -C 16  arylalkoxy, C 2 -C 8  alkoxyalkoxyl, amino, C 1 -C 6  akylamino, C 2 -C 12  dialkylamino, C 1 -C 6  akyl-amino-C 1 -C 6  akyl, C 1 -C 6  akyl-amino-C 2 -C 12  dialkyl, —S—, —S—C 1 -C 6  alkyl, —S(O) 2 —C 1 -C 6  alkyl, sulfonamidyl, amido, urea, sulfonylurea, acyl, —C(O)—C 6 -C 10  aryl, —NHC(O)—C 6 -C 10  aryl, —C(O)NH—C 6 -C 10  aryl, —C(O)OH, —C(O)O—C 1 -C 6  alkyl, —C(O)—C 1 -C 6  alkyl acyl, nitro, or cyano; 
 each R a  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halo; 
 n is 1 or 2; and 
 m is 1, 2, or 3. 
 
     
     
         28 . The compound of  claim 27 , or a pharmaceutically acceptable salt thereof, wherein Ring A is phenyl or thiazolyl. 
     
     
         29 . The compound of  claim 27 , wherein R 3  is hydroxypropyl. 
     
     
         30 . A compound of Formula III: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein:
 R 2  is C 1 -C 6  alkoxy or C 6 -C 10  aryloxy substituted with 1-3 R 6 ; 
 R 3  is C 1 -C 6  heteroalkyl or C 2 -C 6  hydroxyalkyl; 
 R 4  is C 1 -C 6  alkyl; 
 R 6  is independently C 1 -C 6  alkyl, halo, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkoxy, or C 1 -C 6  alkoxy; 
 each R a  is C 1 -C 6  alkyl, C 1 -C 6  haloalkyl, halo; 
 n is 1 or 2; and 
 m is 1, 2, or 3. 
 
     
     
         31 . The compound of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein R 3  is hydroxypropyl. 
     
     
         32 . The compound of  claim 30 , or a pharmaceutically acceptable salt thereof, wherein R a  is independently chloro, fluoro, or methyl.

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