US2013184258A1PendingUtilityA1

Compositions Useful as Inhibitors of Voltage-Gated Sodium Channels

Assignee: VERTEX PHARMAPriority: Aug 8, 2003Filed: Oct 26, 2012Published: Jul 18, 2013
Est. expiryAug 8, 2023(expired)· nominal 20-yr term from priority
A61P 31/22A61P 43/00A61P 9/06A61P 3/10A61P 25/00A61P 25/04A61P 25/22A61P 25/28A61P 25/02A61P 25/14A61P 25/06A61P 29/00A61P 25/24A61P 25/08A61P 25/18A61P 25/12A61P 25/10A61P 1/00A61P 1/02A61P 1/04A61P 13/02A61P 19/02C07D 213/76C07D 239/545C07D 237/22C07D 513/04C07C 2601/08C07D 285/135C07D 239/69C07D 239/52C07C 311/46C07C 311/51C07D 409/12C07D 231/38C07D 417/14C07D 405/14C07D 231/42C07D 417/12C07C 2601/14C07D 295/26C07D 403/12C07D 401/12C07D 263/50C07D 413/12C07D 261/16C07D 239/47C04B 35/632C07D 241/22C07D 405/12C07D 237/20C07D 277/52C07D 209/80C07D 407/12C07D 209/92C07D 285/125C07D 277/82C07D 239/42C07C 2601/02
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Claims

Abstract

The present invention relates to compounds useful as inhibitors of voltage-gated sodium channels. The invention also provides pharmaceutically acceptable compositions comprising the compounds of the invention and methods of using the compositions in the treatment of various disorders.

Claims

exact text as granted — not AI-modified
1 . A compound selected from the following table: 
       
         
           
                 
                 
               
                     
                 
                   # 
                   Compound 
                 
                     
                 
                     
                 
                 
                 
               
                   3 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   4 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   6 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   7 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   9 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   16 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   17 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   18 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   22 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   23 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   24 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   26 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   27 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   28 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   29 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   33 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   36 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   38 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   43 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   47 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   50 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   51 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   55 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   58 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   61 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   66 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   67 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   68 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   71 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   74 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   75 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   81 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   88 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   89 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   90 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   91 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   92 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   93 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   94 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   95 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   96 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   103 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   104 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   109 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   110 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   112 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   117 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   118 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   121 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   123 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   124 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   127 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   129 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   131 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   132 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   134 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   135 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   137 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   138 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   139 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   140 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   141 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   143 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   148 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   149 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   151 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   158 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   161 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   162 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   163 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   164 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   165 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   166 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   167 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   168 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   170 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   171 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   172 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   173 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   174 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   175 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   177 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   182 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   186 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   250 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   258 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   273 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   278 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   279 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   294 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   302 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   303 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   312 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   313 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   314 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   315 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   316 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   317 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   339 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   342 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   345 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   350 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   353 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   356 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   357 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   360 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   361 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   364 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   365 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   368 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   370 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   373 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   375 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   376 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   380 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   383 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   388 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   391 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   393 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   395 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   398 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   399 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   400 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   403 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   406 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   409 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   410 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   411 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   412 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   413 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   414 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   415 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   416 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   417 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   418 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   419 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   420 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   421 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   423 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   424 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   425 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   426 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   427 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   428 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   429 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   430 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   431 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   432 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   433 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   434 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   435 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   436 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   437 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   438 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   439 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   440 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   441 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   442 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   443 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   444 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   445 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   446 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   447 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   448 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   449 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   450 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   451 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   452 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   453 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   454 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   455 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   456 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   457 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   458 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   459 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   460 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   461 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   462 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   463 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   464 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   465 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   466 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   467 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   468 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   469 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   470 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   471 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   472 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   473 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   474 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   475 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   476 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   477 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   478 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   479 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   480 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   481 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   482 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   483 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   484 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   485 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   486 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   488 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   489 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   490 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   491 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   492 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   495 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   497 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   498 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   500 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   501 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   502 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   503 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   504 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   505 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   506 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   507 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   508 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   509 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   510 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   511 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   512 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   513 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   514 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   515 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   516 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   517 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   518 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   519 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   520 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   521 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   522 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   523 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   524 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   525 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   526 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   527 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   528 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   529 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   530 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   531 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   532 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   533 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   534 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   535 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   536 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   537 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   539 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   542 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   543 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   544 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
                   545 
                   
                     
                       
                       
                           
                           
                       
                     
                   
                 
                     
                 
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         or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 - 75 . (canceled) 
     
     
         76 . A pharmaceutical composition comprising a compound according to  claim 1 , and a pharmaceutically acceptable adjuvant or carrier. 
     
     
         77 - 116 . (canceled)

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