US2014051687A1PendingUtilityA1

Substituted indole compounds having nos inhibitory activity

58
Assignee: NEURAXON INCPriority: Apr 13, 2005Filed: Oct 21, 2013Published: Feb 20, 2014
Est. expiryApr 13, 2025(expired)· nominal 20-yr term from priority
A61P 9/00A61P 3/10A61P 43/00A61P 9/10A61P 25/00A61P 25/06A61P 25/14A61P 25/24A61P 29/00A61P 25/30A61P 25/08A61P 25/18A61P 25/16A61P 25/04A61P 25/36A61P 25/28A61P 25/22A61P 25/32A61P 25/02A61P 13/12A61P 21/02C07D 409/14C07D 409/12C07D 471/08C07D 451/02C07D 401/04C07D 471/04C07D 413/14C07D 405/14C07D 209/08C07D 453/02C07D 405/12C07D 209/04
58
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Claims

Abstract

The present invention features inhibitors of nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing conditions such as, for example, stroke, reperfusion injury, neurodegeneration, head trauma, CABG, migraine headache with and without aura, migraine with allodynia, central post-stroke pain (CPSP), neuropathic pain, morphine/opioid induced tolerance and hyperalgesia.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . (canceled) 
     
     
         2 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 R 2  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 4-8  cycloalkenyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
 R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5B NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; R 5B  is optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and 
 R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6B NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; R 6B  is optionally substituted C 6-10  aryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
 wherein one, but not both, of R 5  and R 6  is H. 
 
     
     
         3 . The pharmaceutical composition of  claim 2 , wherein,
 R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, or optionally substituted C 1-4  alkheterocyclyl;   each of R 2  and R 3  is, independently, H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl;   each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy;   R 5  is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and   R 6  is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl.   
     
     
         4 . The pharmaceutical composition of  claim 2 , wherein R 5  is R 5A C(NH)NH(CH 2 ) r5 , and R 5A  is thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, thio-t-butyloxy, phenyl, benzyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, or 4-isothiazole. 
     
     
         5 . The pharmaceutical composition of  claim 2 , wherein R 6  is R 6A C(NH)NH(CH 2 ) r6 , and R 6A  is methyl, fluoromethyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, thio-t-butyloxy, phenyl, benzyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, or 4-isothiazole. 
     
     
         6 . The pharmaceutical composition of  claim 2 , wherein one or more of R 1 , R 2 , and R 3  is not H. 
     
     
         7 . The pharmaceutical composition of  claim 2 , wherein R 1  is (CH 2 ) m1 X 1 , wherein X 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 1A  and R 1B  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 1C  and R 1D  is, independently, H, OH, CO 2 R 1E , or NR 1F R 1G , wherein each of R 1E , R 1F , and R 1G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 1C  and R 1D  together with the carbon they are bonded to are C═O; 
 Z 1  is NR 1H , NC(O)R 1H , NC(O)OR 1H , NC(O)NHR 1H , NC(S)R 1H , NC(S)NHR 1H , NS(O) 2 R 1H , O, S, S(O), or S(O) 2 , wherein R 1H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m1 is an integer of 2 to 6; 
 n1 is an integer of 1 to 4; 
 p1 is an integer of 0 to 2; and 
 q1 is an integer of 0 to 5. 
 
     
     
         8 . The pharmaceutical composition of  claim 2 , wherein R 3  is (CH 2 ) m3 X 3 , wherein X 3  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 3A  and R 3B  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 3D  and R 3D  is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 3C  and R 3D  together with the carbon they are bonded to are C═O; 
 Z 3  is NR 3H , NC(O)R 3H , NC(O)OR 3H , NC(O)NHR 3H , NC(S)R 3H , NC(S)NHR 3H , NS(O) 2 R 3H , O, S, S(O), or S(O) 2 , wherein R 3H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m3 is an integer of 2 to 6; 
 n3 is an integer of 1 to 4; 
 p3 is an integer of 0 to 2; and 
 q3 is an integer of 0 to 5. 
 
     
     
         9 . The pharmaceutical composition of  claim 2 , wherein said compound selectively inhibits neuronal nitric oxide synthase (nNOS) over endothelial nitric oxide synthase (eNOS) or inducible nitric oxide synthase (iNOS). 
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein said compound selectively inhibits nNOS over both eNOS and iNOS. 
     
     
         11 . The pharmaceutical composition of  claim 2 , wherein R 5  is R 5B NHC(S)NH(CH 2 ) r5 , and R 5B  is thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, or thio-t-butyloxy. 
     
     
         12 . The pharmaceutical composition of  claim 2 , wherein R 6  is R 6B NHC(S)NH(CH 2 ) r6 , and R 6B  is thiomethoxy, thioethoxy, thio-n-propyloxy, thio-i-propyloxy, thio-n-butyloxy, thio-i-butyloxy, thio-t-butyloxy, phenyl, 2-thienyl, 3-thienyl, 2-furanyl, 3-furanyl, 2-oxazole, 4-oxazole, 5-oxazole, 2-thiazole, 4-thiazole, 5-thiazole, 2-isoxazole, 3-isoxazole, 4-isoxazole, 2-isothiazole, 3-isothiazole, or 4-isothiazole. 
     
     
         13 . The pharmaceutical composition of  claim 2 , wherein R 1  or R 3  is optionally substituted C 2-9  heterocyclyl or optionally substituted C 1-4  alkheterocyclyl, wherein the heterocyclyl moiety is a bicyclic, nitrogen containing heterocyclyl. 
     
     
         14 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, or optionally substituted C 1-4  alkheterocyclyl; 
 R 2  is (CH 2 ) m2 X 2 , wherein X 2  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 2A  and R 2B  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 2C  and R 2D  is, independently, H, OH, CO 2 R 2E , or NR 2F R 2G , wherein each of R 2E , R 2F , and R 2G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 2C  and R 2D  together with the carbon they are bonded to are C═O; 
 Z 2  is NR 2H , NC(O)R 2H , NC(O)OR 2H , NC(O)NHR 2H , NC(S)R 2H , NC(S)NHR 2H , NS(O) 2 R 2H , O, S, S(O), or S(O) 2 , wherein R 2H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m2 is an integer of 0 to 6; 
 n2 is an integer of 1 to 4; 
 p2 is an integer of 0 to 2; 
 q2 is an integer of 0 to 5; 
 R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
 R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; and 
 R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
 wherein one, but not both, of R 5  and R 6  is H. 
 
     
     
         15 . The pharmaceutical composition of  claim 14 , wherein
 R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl;   R 5  is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and   R 6  is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl.   
     
     
         16 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein, R 1  is (CH 2 ) m3 X 1 , wherein X 1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein
 each of R 3C  and R 3D  is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 3C  and R 3D  together with the carbon they are bonded to are C═O; 
 Z 3  is NC(NH)R 3H , wherein R 3H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m3 is an integer of 0 to 6; 
 n3 is an integer of 1 to 4; 
 p3 is an integer of 0 to 2; 
 q3 is an integer of 0 to 5; 
 each of R 2  and R 3  is, independently, H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
 R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; and 
 R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
 wherein one, but not both, of R 5  and R 6  is H. 
 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein
 each of R 2  and R 3  is, independently, H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl;   R 5  is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and   R 6  is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl.   
     
     
         18 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, or optionally substituted C 1-4  alkheterocyclyl; 
 R 2  is (CH 2 ) m3 X 2 , wherein X 2  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 3C  and R 3D  is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 3C  and R 3D  together with the carbon they are bonded to are C═O; 
 Z 3  is NC(NH)R 3H , wherein R 3H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m3 is an integer of 0 to 6; 
 n3 is an integer of 1 to 4; 
 p3 is an integer of 0 to 2; 
 q3 is an integer of 0 to 5; 
 R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
 R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; and 
 R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
 wherein one, but not both, of R 5  and R 6  is H. 
 
     
     
         19 . The pharmaceutical composition of  claim 18 , wherein
 R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl;   R 5  is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and   R 6  is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl.   
     
     
         20 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, or optionally substituted C 1-4  alkheterocyclyl; 
 R 2  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 R 3  is (CH 2 ) m3 X 3 , wherein X 3  is selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 3C  and R 3D  is, independently, H, OH, CO 2 R 3E , or NR 3F R 3G , wherein each of R 3E , R 3F , and R 3G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 3C  and R 3D  together with the carbon they are bonded to are C═O; 
 Z 3  is NC(NH)R 3H , wherein R 3H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m3 is an integer of 0 to 6; 
 n3 is an integer of 1 to 4; 
 p3 is an integer of 0 to 2; 
 q3 is an integer of 0 to 5; 
 each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
 R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; and 
 R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
 wherein one, but not both, of R 5  and R 6  is H. 
 
     
     
         21 . The pharmaceutical composition of  claim 20 , wherein
 R 2  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl;   R 5  is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and   R 6  is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl.   
     
     
         22 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein, R 1  is (CH 2 ) m1 X 1 , wherein X 1  is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
       
       wherein
 each of R 1A  and R 1B  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 1C  and R 1D  is, independently, H, OH, CO 2 R 1E , or NR 1F R 1G , wherein each of R 1E , R 1F , and R 1G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 1C  and R 1D  together with the carbon they are bonded to are C═O; 
 Z 1  is NR 1H , NC(O)R 1H , NC(O)OR 1H , NC(O)NHR 1H , NC(S)R 1H , NC(S)NHR 1H , NS(O) 2 R 1H , O, S, S(O), or S(O) 2 , wherein R 1H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m1 is an integer of 2 to 6; 
 n1 is an integer of 1 to 4; 
 p1 is an integer of 0 to 2; 
 q1 is an integer of 0 to 5; 
 R 2  is 
 
       
         
           
           
               
               
           
         
         wherein each of R 2J2 ,R 2J3 , R 2J4 ,R 2J5 , and R 2J6  is, independently, H, C 1-6  alkyl; OH; C 1-6 alkoxy; SH; C 1-6 thioalkoxy; Halo; NO 2 ; CN; CF 3 ; OCF 3 ; NR 2Ja R 2Jb , where each of R 2Ja  and R 2JB  is, independently, H or C 1-6  alkyl; C(O)R 2Jc , where R 2Jc  is H or C 1-6 alkyl; CO 2 R 2Jd , where R 2Jd  is H or C 1-6  alkyl; tetrazolyl; C(O)NR 2Je R 2Jf , where each of R 2Je  and R 2Jf  is, independently, H or C 1-6  alkyl; OC(O)R 2Jg , where R 2Jg  is C 1-6  alkyl; NHC(O)R 2Jh , where R 2Jh  is H or C 1-6 alkyl; SO 3 H; S(O) 2 NR 2Ji R 2Jj , where each of R 2Ji  and R 2Jj  is, independently, H or C 1-6  alkyl; S(O)R 2Jk , where R 2Jk  is C 1-6  alkyl; or S(O) 2 R 2Jl , where R 2Jl  is C 1-6  alkyl; 
         R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
         each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
         R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; and 
         R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
         wherein one, but not both, of R 5  and R 6  is H. 
       
     
     
         23 . The pharmaceutical composition of  claim 22 , wherein
 R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl;   R 5  is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and   R 6  is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl.   
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein, R 1  is (CH 2 ) m1 X 1 , wherein X 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
       
       wherein
 each of R 1A  and R 1B  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 1C  and R 1D  is, independently, H, OH, CO 2 R 1E , or NR 1F R 1G , wherein each of R 1E , R 1F , and R 1G  is, independently, H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl, or R 1C  and R 1D  together with the carbon they are bonded to are C═O; 
 Z 1  is NR 1H , NC(O)R 1H , NC(O)OR 1H , NC(O)NHR 1H , NC(S)R 1H , NC(S)NHR 1H , NS(O) 2 R 1H , O, S, S(O), or S(O) 2 , wherein R 1H  is H, optionally substituted C 1-6  alkyl, optionally substituted C 3-8  cycloalkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 m1 is an integer of 2 to 6; 
 n1 is an integer of 1 to 4; 
 p1 is an integer of 0 to 2; 
 q1 is an integer of 0 to 5; 
 R 2  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
 R 3  is 
 
       
         
           
           
               
               
           
         
         wherein each of R 3J2 ,R 3J3 , R 3J4 ,R 3J5 , and R 3J6  is, independently, H, C 1-6  alkyl; OH; C 1-6  alkoxy; SH; C 1-6 thioalkoxy; Halo; NO 2 ; CN; CF 3 ; OCF 3 ; NR 3Ja R 3Jb , where each of R 3Ja  and R 3J3  is, independently, H or C 1-6  alkyl; C(O)R 3Jc , where R 3Jc  is H or C 1-6 alkyl; CO 2 R 3Jd , where R 3Jd  is H or C 1-6  alkyl; tetrazolyl; C(O)NR 3Je R 3Jf , where each of R 3Je  and R 3Jf  is, independently, H or C 1-6  alkyl; OC(O)R 3Jg , where R 3Jg  is C 1-6  alkyl; NHC(O)R 3Jh , where R 3Jh  is H or C 1-6 alkyl; SO 3 H; S(O) 2 NR 3Ji R 3Jj , where each of R 3Ji  and R 3Jj  is, independently, H or C 1-6  alkyl; S(O)R 3Jk , where R 3Jk  is C 1-6  alkyl; or S(O) 2 R 3Jk , where R 3Jl  is C 1-6  alkyl; 
         each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
         R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; and 
         R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
         wherein one, but not both, of R 5  and R 6  is H. 
       
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein
 R 2  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl;   R 5  is H or R 5A C(NH)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl; and   R 6  is H or R 6A C(NH)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, or optionally substituted C 1-4  thioalkheterocyclyl.   
     
     
         26 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the group consisting of: 2-ethyl-1-(1H-indol-5-yl)-isothiourea; N-(1H-indol-5-yl)-thiophene-2-carboxamidine; N-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-thiophene-2-carboxamidine; N-{1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-indol-6-yl}-thiophene-2-carboxamidine; 1-[1-(2-dimethylamino-ethyl)-1H-indol-6-yl]-2-ethyl-isothiourea; N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indol-6-yl]-thiophene-2-carboxamidine; N-(1-phenethyl-1H-indol-6-yl)-thiophene-2-carboxamidine; N-[3-(2-dimethylamino-ethyl)-1H-indol-5-yl]-thiophene-2-carboxamidine; N-(1-{2-[2-(4-bromo-phenyl)-ethylamino]-ethyl}-1H-indol-6-yl)-thiophene-2-carboxamidine; (+)-N-{1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-indol-6-yl}-thiophene-2-carboxamidine; (−)-N-{1-[2-(1-methyl-pyrrolidin-2-yl)-ethyl]-1H-indol-6-yl}-thiophene-2-carboxamidine; N-[1-(1-methyl-azepan-4-yl)-1H-indol-6-yl]-thiophene-2-carboxamidine; and N-[1-(2-piperidin-1-yl-ethyl)-1H-indol-6-yl]-thiophene-2-carboxamidine, or a pharmaceutically acceptable salt thereof. 
     
     
         27 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 R 1  or R 3  is 
 
       
         
           
           
               
               
           
         
         wherein Z is NR X , R X  is H or C 1-6  alkyl, o is an integer from 0-3, p is an integer from 1 to 2, q is an integer from 0 to 2, r is an integer from 0 to 1, s is an integer from 1 to 3, u is an integer from 0 to 1, and t is an integer from 5 to 7, and wherein said R 1  or R 3  substituent includes 0 to 6 carbon-carbon double bonds or 0 or 1 carbon-nitrogen double bonds; 
         R 2  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; 
         each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy; 
         R 5  is H, R 5A C(NH)NH(CH 2 ) r5  or R 5A NHC(S)NH(CH 2 ) r5 , wherein r5 is an integer from 0 to 2, R 5A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
         R 6  is H or R 6A C(NH)NH(CH 2 ) r6  or R 6A NHC(S)NH(CH 2 ) r6 , wherein r6 is an integer from 0 to 2, R 6A  is optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, optionally substituted C 1-4  alkheterocyclyl, optionally substituted C 1-6 thioalkoxy, optionally substituted C 1-4  thioalkaryl, optionally substituted aryloyl, or optionally substituted C 1-4  thioalkheterocyclyl; 
         wherein one, but not both, of R 5  and R 6  is H; and 
         when R 1  or R 3  is not 
       
       
         
           
           
               
               
           
         
         R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, or optionally substituted C 1-4  alkheterocyclyl; and 
         R 3  is H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl. 
       
     
     
         28 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 X is O or S; 
 R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 2  and R 3  is, independently, H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; and 
 each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy. 
 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein X is S. 
     
     
         30 . The pharmaceutical composition of  claim 28 , wherein
 each of R 2  and R 3  is, independently, H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl.   
     
     
         31 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, wherein,
 X is O or S; 
 R 1  is H, optionally substituted C 1-6  alkyl, optionally substituted C 1-4  alkaryl, or optionally substituted C 1-4  alkheterocyclyl; 
 each of R 2  and R 3  is, independently, H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  bridged heterocyclyl, optionally substituted C 1-4  bridged alkheterocyclyl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl; and 
 each of R 4  and R 7  is, independently, H, F, C 1-6  alkyl, or C 1-6  alkoxy. 
 
     
     
         32 . The pharmaceutical composition of  claim 31 , wherein X is S. 
     
     
         33 . The pharmaceutical composition of  claim 31 , wherein
 each of R 2  and R 3  is, independently, H, Hal, optionally substituted C 1-6  alkyl, optionally substituted C 6-10  aryl, optionally substituted C 1-4  alkaryl, optionally substituted C 2-9  heterocyclyl, or optionally substituted C 1-4  alkheterocyclyl.   
     
     
         34 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         35 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         36 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a compound having the formula: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof.

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