Compounds for the treatment of acute organ injury

Abstract

Disclosed herein are novel compounds and methods for the treatment of acute organ injury, including injuries resulting from ischemic events. The compounds may be used to treat organ including the brain, heart, or kidney, which have injured as a result of events such as stroke, cardiac arrest, traumatic brain injury, hemorrhagic shock, or subarachnoid hemorrhage.

What is claimed is: 
     
         1 . A method to reduce organ injury resulting from an ischemic event, comprising administering to a patient in need thereof a compound having the formula: 
       
         
           
           
               
               
           
         
       
       
         or a pharmaceutically acceptable salt thereof, 
         wherein 
         Ar 1  comprises an aryl or heteroaryl group; 
         L 1  is selected from null and C 1-6 alkyl; 
         R x1  is selected from hydrogen, C 1-6 alkyl; 
         X is O, NR N  or S; wherein R N  is selected from R N′ , OR N′ , N(R N′ ) 2 , SO 2 R N′ , SO 2 N(R N′ ) 2 , 
         C(O)R N′ ; C(O)OR N′ , OC(O)R N′ ; C(O)N(R N′ ) 2 , N(R N′ )C(O)R N′ , OC(O)N(R N′ ) 2 , 
         N(R N′ )C(O)N(R N′ ) 2 , wherein R N′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1 -sheterocyclyl; 
         R x2  is selected from hydrogen, C 1-6 alkyl; 
         L 2  is selected from null and C 1-6 alkyl; 
         Ar 2  is selected from an aryl and heteroaryl group; 
         wherein any two or more of Ar 1 , L 1 , R x1 , R N , R x2 , L 2  and Ar 2  may together form a ring. 
       
     
     
         2 . The method of  claim 1 , wherein Ar 1  is a heterocycle having the formula: 
       
         
           
           
               
               
           
         
       
       
         wherein X 1a  is selected from—N═CR x1a1 —; —CR x1a1 ═N—; O, S, and NR x1a ; 
         X 1b  is selected from N, CR x1b , —N═CR x1b1 —; and —CR x1b1 ═CR x1b2— ; 
         X 1c  is selected from N, CR x1c , —CR x1c1 ═CR x1c2 —; 
         wherein R 1a  is selected from L 1 , F, Cl, Br, I, NO 2 , CN, R 1a′ , OR 1a′ , N(R 1a′ ) 2 , SO 2 R 1a′ , SO 2 N(R 1a′ ) 2 , C(O)R 1a′ ; C(O)OR 1a′ , OC(O)R 1a′ ; C(O)N(R 1a′ ) 2,  N(R 1a′ )C(O)R 1a′ , OC(O)N(R 1a′ ) 2 , N(R 1a′ )C(O)N(R 1a′ ) 2 , wherein R 1a'  is in each case independently selected from hydrogen, C 1-  salkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R 1b  is selected from L 1 , R 1b′ , OR 1b′ , N(R 1b′ ) 2 , SO 2 R 1b′ , SO 2 N(R 1b′ ) 2 , C(O)R 1b′ ; C(O)OR 1b′ , OC(O)R 1b′ ; C(O)N(R 1b′ ) 2 , N(R 1b′ )C(O)R 1b′ , OC(O)N(R 1b′ ) 2 , N(R 1b′ )C(O)N(R 1b′ ) 2 , wherein R 1b′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-   8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R 1c  is selected from L 1 , R 1c′ , OR 1c′ , N(R 1c′ ) 2 , SO 2 R 1c′ , SO 2 N(R 1c′ ) 2 , C(O)R 1c′ ; C(O)OR 1c' , OC(O)R 1c′ ; C(O)N(R 1c′ ) 2 , N(R 1c′ )C(O)R 1c′ , OC(O)N(R 1c′ ) 2,  N(R 1c′ )C(O)N(R 1c′ ) 2 , wherein R 1c′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-   8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R 1d  is selected from L 1 , R 1d′ , OR 1d′ , N(R 1d′ ) 2 , SO 2 R 1d′ , SO 2 N(R 1d′ ) 2 , C(O)R 1d′ ; C(O)OR 1d′ , OC(O)R 1d′ ; C(O)N(R 1a′ ) 2 , N(R 1d′ )C(O)R 1d′ , OC(O)N(R 1d′ ) 2 , N(R 1d′ )C(O)N(R 1d′ ) 2 , wherein R 1d′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-   8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x1a  is selected from L 1 , R x1a′ , SO 2 R x1a′ , SO 2 N(R x1a′ ) 2 , C(O)R x1a′ ; C(O)OR x1a′ , C(O)N(R x1a′ ) 2 , wherein R x1a′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-  salkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x1b  is selected from L 1 , R x1b′ , OR x1b′ , N(R x1b′ ) 2 , SO 2 R x1b′ , SO 2 N(R x1b′ ) 2 , C(O)R x1b′ ; C(O)OR x1b′ , OC(O)R x1b′ ; C(O)N(R x1b′ ) 2 , N(R x1b′ )C(O)R x1b′ , OC(O)N(R x1b′ ) 2 , N(R x1b′ )C(O)N(R x1b′ ) 2 , wherein R x1b′  is in each case independently selected from hydrogen, C 1 -salkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x1b1  is selected from L 1 , R x1b1′ , OR x1b1′ , N(R x1b1′ ) 2 , SO 2 R x1b1′ , SO 2 N(R x1b1′ ) 2 , C(O)R x1b1′ ; C(O)OR x1b1′ , OC(O)R x1b1′ ; C(O)N(R x1b1′ ) 2 , N(R x1b1′ )C(O)R x1b1′ , OC(O)N(R x1b1′ ) 2 , N(R x1b1′ )C(O)N(R x1b1′ ) 2 , wherein R x1b1′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x1b2  is selected from L 1 , R x1b2′ , OR x1b2′ , N(R x1b2′ ) 2 , SO 2 R x1b2′ , SO 2 N(R x1b2′ ) 2 , C(O)R x1b2′ ; C(O)OR x1b2′ , OC(O)R x1b2′ ; C(O)N(R x1b2′ ) 2 , N(R x1b2′ )C(O)R x1b2′ , OC(O)N(R x1b2′ ) 2 , N(R x1b2′ )C(O)N(R x1b2′ ) 2 , wherein R x1b2′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x1c  is selected from L 1 , R x1c′ , OR x1c′ , N(R x1c′ ) 2 , SO 2 R x1c′ , SO 2 N(R x1c′ ) 2 , C(O)R x1c′ ; C(O)OR x1c′ , OC(O)R x1c′ ; C(O)N(R x1c′ ) 2 , N(R x1c′ )C(O)R x1c′ , OC(O)N(R x1c′ ) 2 , N(R x1c′ )C(O)N(R x1c′ ) 2 , wherein R x1c′  is in each case independently selected from hydrogen, C 1 -salkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x1c1  is selected from L 1 , R x1c1′ , OR x1c1′ , N(R x1c1′ ) 2 , SO 2 R x1c1′ , SO 2 N(R x1c1′ ) 2 , C(O)R x1c1′ ; C(O)OR x1c1′ , OC(O)R x1c1′ ; C(O)N(R x1c1′ ) 2 , N(R x1c1′ )C(O)R x1c1′ , OC(O)N(R x1c1′ ) 2 , N(R x1c1′ )C(O)N(R x1c1′ ) 2 , wherein R x1c1′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x1c2  is selected from L 1 , R x1e2′ , OR x1c2′ , N(R x1c2′ ) 2 , SO 2 R x1c2′ , SO 2 N(R x1c2′ ) 2 , C(O)R x1c2′ ; C(O)OR x1c2′ , OC(O)R x1c2′ ; C(O)N(R x1c2′ ) 2 , N(R x1c2′ )C(O)R x1c2′ , OC(O)N(R x1c2′ ) 2 , N(R x1c2′ )C(O)N(R x1c2′ ) 2 , wherein R x1e2′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein any two or more of R x1 , R n , R 1a  , R 1b  , R 1c , R 1d  , R x1a , R x1b , R x1b1 , R x1b2 , R x1c , R x1c1 , and R x1c2  may together form a ring; 
         wherein Ar 1  contains a single L 1  group. 
       
     
     
         3 . The method of  claim 2 , wherein Ar 1  is selected from heterocycle having the structure A-1, B-1, C-1, D-1, E-1, F-1, G-1, H-1, I-1, J-1, K-1, L-1, M-1, or N-1: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       . 
     
     
         4 . The method of  claim 3 , wherein Ar 1  is B-1. 
     
     
         5 . The method of  claim 2 , one of R 1a , R 1b , R 1c , and R 1d  is L 1 , and the other three are hydrogen. 
     
     
         6 . The method of  claim 3 , wherein X 1a  is NH, X 1b  is N, and X 1c  is CH. 
     
     
         7 . The method of  claim 3 , wherein Ar 2  is a heterocycle having the formula: 
       
         
           
           
               
               
           
         
       
       
         wherein X 2a  is selected from—N═CR x2a1 —; —CR x2a1 ═N—; O, S, and NR x2a ; 
         X 1b  is selected from N, CR x2b , —N═CR x2b1 —; and —CR x2b1 ═CR x1b2 —; 
         X 1c  is selected from N, CR x2c , —CR x2c1 ═CR x2c2 —; 
         wherein R 2a  is selected from L 2 , R 2a′ , OR 2a′ , N(R 2a′ ) 2 , SO 2 R 2a′ , SO 2 N(R 2a′ ) 2 , C(O)R 2a′ ; C(O)OR 2a′ , OC(O)R 2a′ ; C(O)N(R 2a′ ) 2 , N(R 2a′ )C(O)R 2a′ , OC(O)N(R 2a′ ) 2,  N(R 2a′ )C(O)N(R 2a′ ) 2 , wherein R 2a′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-  salkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R 2b  is selected from L 2 , R 2b′ , OR 2b′ , N(R 2b′ ) 2 , SO 2 R 2b′ , SO 2 N(R 2b′ ) 2 , C(O)R 2b′ ; C(O)OR 2b′ , OC(O)R 2b′ ; C(O)N(R 2b′ ) 2 , N(R 2b′ )C(O)R 2b′ , OC(O)N(R 2b′ ) 2 , N(R 2b′ )C(O)N(R 2b′ ) 2 , wherein R 2b′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-  salkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R 2c  is selected from L 2 , R 2c′ , OR 2c′ , N(R 2c′ ) 2 , SO 2 R 2c′ , SO 2 N(R 2c′ ) 2 , C(O)R 2c′ ; C(O)OR 2e′ , OC(O)R 2c′ ; C(O)N(R 2c′ ) 2 , N(R 2c′ )C(O)R 2c′ , OC(O)N(R 2c′ ) 2,  N(R 2c′ )C(O)N(R 2c′ ) 2 , wherein R 2c′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-  salkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R 2d  is selected from L 2 , R 2d′ , OR 2d′ , N(R 2d′ ) 2 , SO 2 R 2d′ , SO 2 N(R 2d′ ) 2 , C(O)R 2d′ ; C(O)OR 2d′ , OC(O)R 2d′ ; C(O)N(R 2d′ ) 2 , N(R 2d′ )C(O)R 2d′ , OC(O)N(R 2d′ ) 2 , N(R 2d′ )C(O)N(R 2d′ ) 2 , wherein R 2d′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-  salkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x2a1  is selected from L 2 , R x2a1′ , SO 2 R x2a1′ , SO 2 N(R x2a1′ ) 2 , C(O)R x2a1′ ; C(O)OR x2a1′ , C(O)N(R x2a1′ ) 2 , wherein R x2a1′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1 -sheterocyclyl; 
         wherein R x2b  is selected from L 2 , R x2b′ , OR x2b′ , N(R x2b′ ) 2 , SO 2 R x2b′ , SO 2 N(R x2b′ ) 2 , C(O)R x2b′ ; C(O)OR x2b   ' , OC(O)R x2b′ ; C(O)N(R x2b′ ) 2 , N(R x2b′ )C(O)R x2b′ , OC(O)N(R x2b′ ) 2 , N(R x2b′ )C(O)N(R x2b′ ) 2 , wherein R x2b′  is in each case independently selected from hydrogen, C 1 -salkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x2b1  is selected from L 2 , R x2b1′ , OR x2b1′ , N(R x2b1′ ) 2 , SO 2 R x2b1′ , SO 2 N(R x2b1′ ) 2 , C(O) R   x2b1′ ; C(O)O R   x2b1′ , OC(O)R x2b1′ ; C(O)N(R x2b1′ ) 2 , N(R x2b1′ )C(O)R x2b1′ , OC(O)N(R x2b1′ ) 2 , N(R x2b1′ )C(O)N(R x2b1′ ) 2 , wherein R x2b1′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x2b2  is selected from L 2 , R x2b2′ , OR x2b2′ , N(R x2b2′ ) 2 , SO 2 R x2b2′ , SO 2 N(R x2b2′ ) 2 , C(O)R x2b2′ ; C(O)OR x2b2′  , OC(O)R x2b2′ ; C(O)N(R x2b2′ ) 2 , N(R x2b2′ )C(O)R x2b2′ , OC(O)N(R x2b2′ ) 2 , N(R x2b2′ )C(O)N(R x2b2   ' ) 2 , wherein R x2b2′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x2c  is selected from L 2 , R x2c′ , OR x2c′ , N(R x2c′ ) 2 , SO 2 R x2c′ , SO 2 N(R x2c′ ) 2 , C(O)R x2c′ ; C(O)OR x2c′  OC(O)R x2c′ ; C(O)N(R x2c′ ) 2 , N(R x2c′ )C(O)R x2c′ , OC(O)N(R x2c′ ) 2 , N(R x2c′ )C(O)N(R x2c′ ) 2 , wherein R x2c′  is in each case independently selected from hydrogen, C 1-  salkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x2c1  is selected from L 2 , R x2c1′ , OR x2c1′ , N(R x2c1′ ) 2 , SO 2 R x2c1′ , SO 2 N(R x2c1′ ) 2 , C(O)R x2c1′ ; C(O)OR x2c1′ , OC(O)R x2c1′ ; C(O)N(R x2c1′ ) 2 , N(R x2c1′ )C(O)R x2c1′ , OC(O)N(R x2c1′ ) 2 , N(R x2c1′ )C(O)N(R x2c1′ ) 2 , wherein R x2c1′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein R x2c2  is selected from L 2 , R x2c2′ , OR x2c2′ , N(R x2c2′ ) 2 , SO 2 R x2c2′ , SO 2 N(R x2c2′ ) 2 , C(O)R  x2c2′ ; C(O)OR x2c2′ , OC(O)R x2c2′ ; C(O)N(R x2c2′ ) 2 , N(R x2c2′ )C(O)R x2c2’ , OC(O)N(R x2c2′ ) 2 , N(R x2c2′ )C(O)N(R x2c2′ ) 2 , wherein R x2c2′  is in each case independently selected from hydrogen, C 1-8 alkyl, C 2-8 alkenyl, C 2-8 alkynyl, aryl, C 1-8 heteroaryl, C 3-8 cycloalkyl, or C 1-8 heterocyclyl; 
         wherein any two or more of R x2 , R N , R 2a  , R 2b , R 2c , R 2d , R x2a , R x2b , R x2b1 , R x2b2 , R x2c , R x2c1 , and R x2c2  may together form a ring; 
         wherein Ar 2  contains a single L 2  group. 
       
     
     
         8 . The method of  claim 7 , wherein Ar 2  is selected from heterocycle having the structure A-2, B-2, C-2, D-2, E-2, F-2, G-2, H-2, 1-2, J-2, K-2, L-2, M-2, or N-2: 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
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         9 . The method of  claim 8 , wherein Ar 1  is B-1. 
     
     
         10 . The method of  claim 8 , wherein one of R 2a , R 2b , R 2c , and R 2d  is L 2 , and the other three are hydrogen. 
     
     
         11 . The method of  claim 7 , wherein X 2a  is NH, X 2b  is N, and X 2c  is CH. 
     
     
         12 . The method of  claim 8 , wherein when Ar 1  is A-1 and Ar 2  is A-2; Ar 1  is B-1 and Ar 2  is A-2; Ar 1  is C-1 and Ar 2  is A-2; Ar 1  is D-1 and Ar 2  is A-2; Ar 1  is E-1 and Ar 2  is A-2; Ar 1  is F-1 and Ar 2  is A-2; Ar 1  is G-1 and Ar 2  is A-2; Ar 1  is H-1 and Ar 2  is A-2; Ar 1  is I-1 and Ar 2  is A-2; Ar 1  is J-1 and Ar 2  is A-2; Ar 1  is K-1, and Ar 2  is A-2; Ar 1  is L-1 and Ar 2  is A-2; Ar 1  is M-1 and Ar 2  is A-2; Ar 1  is N-1 and Ar 2  is A-2; Ar 1  is A-1 and Ar 2  is B-2; Ar 1  is B-1 and Ar 2  is B-2; Ar 1  is C-1 and Ar 2  is B-2; Ar 1  is D-1 and Ar 2  is B-2; Ar 1  is E-1 and Ar 2  is B-2; Ar 1  is F-1 and Ar 2  is B-2; Ar 1  is G-1 and Ar 2  is B-2; Ar 1  is H-1 and Ar 2  is B-2; Ar 1  is I-1 and Ar 2  is B-2; Ar 1  is J-1 and Ar 2  is B-2; Ar 1  is K-1, and Ar 2  is B-2; Ar 1  is L-1 and Ar 2  is B-2; Ar 1  is M-1 and Ar 2  is B-2; Ar 1  is N-1 and Ar 2  is B-2; Ar 1  is A-1 and Ar 2  is C-2; Ar 1  is B-1 and Ar 2  is C-2; Ar 1  is C-1 and Ar 2  is C-2; Ar 1  is D-1 and Ar 2  is C-2; Ar 1  is E-1 and Ar 2  is C-2; Ar 1  is F-1 and Ar 2  is C-2; Ar 1  is G-1 and Ar 2  is C-2; Ar 1  is H-1 and Ar 2  is C-2; Ar 1  is I-1 and Ar 2  is C-2; Ar 1  is J-1 and Ar 2  is C-2; Ar 1  is K-1, and Ar 2  is C-2; Ar 1  is L-1 and Ar 2  is C-2; Ar 1  is M-1 and Ar 2  is C-2; Ar 1  is N-1 and Ar 2  is C-2; Ar 1  is A-1 and Ar 2  is D-2; Ar 1  is B-1 and Ar 2  is D-2; Ar 1  is C-1 and Ar 2  is D-2; Ar 1  is D-1 and Ar 2  is D-2; Ar 1  is E-1 and Ar 2  is D-2; Ar 1  is F-1 and Ar 2  is D-2; Ar 1  is G-1 and Ar 2  is D-2; Ar 1  is H-1 and Ar 2  is D-2; Ar 1  is I-1 and Ar 2  is D-2; Ar 1  is J-1 and Ar 2  is D-2; Ar 1  is K-1, and Ar 2  is D-2; Ar 1  is L-1 and Ar 2  is D-2; Ar 1  is M-1 and Ar 2  is D-2; Ar 1  is N-1 and Ar 2  is D-2; Ar 1  is A-1 and Ar 2  is E-2; Ar 1  is B-1 and Ar 2  is E-2; Ar 1  is C-1 and Ar 2  is E-2; Ar 1  is D-1 and Ar 2  is E-2; Ar 1  is E-1 and Ar 2  is E-2; Ar 1  is F-1 and Ar 2  is E-2; Ar 1  is G-1 and Ar 2  is E-2; Ar 1  is H-1 and Ar 2  is E-2; Ar 1  is I-1 and Ar 2  is E-2; Ar 1  is J-1 and Ar 2  is E-2; Ar 1  is K-1, and Ar 2  is E-2; Ar 1  is L-1 and Ar 2  is E-2; Ar 1  is M-1 and Ar 2  is E-2; Ar 1  is N-1 and Ar 2  is E-2; Ar 1  is A-1 and Ar 2  is F-2; Ar 1  is B-1 and Ar 2  is F-2; Ar 1  is C-1 and Ar 2  is F-2; Ar 1  is D-1 and Ar 2  is F-2; Ar 1  is E-1 and Ar 2  is F-2; Ar 1  is F-1 and Ar 2  is F-2; Ar 1  is G-1 and Ar 2  is F-2; Ar 1  is H-1 and Ar 2  is F-2; Ar 1  is I-1 and Ar 2  is F-2; Ar 1  is J-1 and Ar 2  is F-2; Ar 1  is K-1, and Ar 2  is F-2; Ar 1  is L-1 and Ar 2  is F-2; Ar 1  is M-1 and Ar 2  is F-2; Ar 1  is N-1 and Ar 2  is F-2; Ar 1  is A-1 and Ar 2  is G-2; Ar 1  is B-1 and Ar 2  is G-2; Ar 1  is C-1 and Ar 2  is G-2; Ar 1  is D-1 and Ar 2  is G-2; Ar 1  is E-1 and Ar 2  is G-2; Ar 1  is F-1 and Ar 2  is G-2; Ar 1  is G-1 and Ar 2  is G-2; Ar 1  is H-1 and Ar 2  is G-2; Ar 1  is I-1 and Ar 2  is G-2; Ar 1  is J-1 and Ar 2  is G-2; Ar 1  is K-1, and Ar 2  is G-2; Ar 1  is L-1 and Ar 2  is G-2; Ar 1  is M-1 and Ar 2  is G-2; Ar 1  is N-1 and Ar 2  is G-2; Ar 1  is A-1 and Ar 2  is H-2; Ar 1  is B-1 and Ar 2  is H-2; Ar 1  is C-1 and Ar 2  is H-2; Ar 1  is D-1 and Ar 2  is H-2; Ar 1  is E-1 and Ar 2  is H-2; Ar 1  is F-1 and Ar 2  is H-2; Ar 1  is G-1 and Ar 2  is H-2; Ar 1  is H-1 and Ar 2  is H-2; Ar 1  is I-1 and Ar 2  is H-2; Ar 1  is J-1 and Ar 2  is H-2; Ar 1  is K-1, and Ar 2  is H-2; Ar 1  is L-1 and Ar 2  is H-2; Ar 1  is M-1 and Ar 2  is H-2; Ar 1  is N-1 and Ar 2  is H-2; Ar 1  is A-1 and Ar 2  is I-2; Ar 1  is B-1 and Ar 2  is I-2; Ar 1  is C-1 and Ar 2  is I-2; Ar 1  is D-1 and Ar 2  is I-2; Ar 1  is E-1 and Ar 2  is I-2; Ar 1  is F-1 and Ar 2  is I-2; Ar 1  is G-1 and Ar 2  is I-2; Ar 1  is H-1 and Ar 2  is I-2; Ar 1  is I-1 and Ar 2  is I-2; Ar 1  is J-1 and Ar 2  is I-2; Ar 1  is K-1, and Ar 2  is I-2; Ar 1  is L-1 and Ar 2  is I-2; Ar 1  is M-1 and Ar 2  is I-2; Ar 1  is N-1 and Ar 2  is I-2; Ar 1  is A-1 and Ar 2  is J-2; Ar 1  is B-1 and Ar 2  is J-2; Ar 1  is C-1 and Ar 2  is J-2; Ar 1  is D-1 and Ar 2  is J-2; Ar 1  is E-1 and Ar 2  is J-2; Ar 1  is F-1 and Ar 2  is J-2; Ar 1  is G-1 and Ar 2  is J-2; Ar 1  is H-1 and Ar 2  is J-2; Ar 1  is I-1 and Ar 2  is J-2; Ar 1  is J-1 and Ar 2  is J-2; Ar 1  is K-1, and Ar 2  is J-2; Ar 1  is L-1 and Ar 2  is J-2; Ar 1  is M-1 and Ar 2  is J-2; Ar 1  is N-1 and Ar 2  is J-2; Ar 1  is A-1 and Ar 2  is K-2; Ar 1  is B-1 and Ar 2  is K-2; Ar 1  is C-1 and Ar 2  is K-2; Ar 1  is D-1 and Ar 2  is K-2; Ar 1  is E-1 and Ar 2  is K-2; Ar 1  is F-1 and Ar 2  is K-2; Ar 1  is G-1 and Ar 2  is K-2; Ar 1  is H-1 and Ar 2  is K-2; Ar 1  is I-1 and Ar 2  is K-2; Ar 1  is J-1 and Ar 2  is K-2; Ar 1  is K-1, and Ar 2  is K-2; Ar 1  is L-1 and Ar 2  is K-2; Ar 1  is M-1 and Ar 2  is K-2; Ar 1  is N-1 and Ar 2  is K-2; Ar 1  is A-1 and Ar 2  is L-2; Ar 1  is B-1 and Ar 2  is L-2; Ar 1  is C-1 and Ar 2  is L-2; Ar 1  is D-1 and Ar 2  is L-2; Ar 1  is E-1 and Ar 2  is L-2; Ar 1  is F-1 and Ar 2  is L-2; Ar 1  is G-1 and Ar 2  is L-2; Ar 1  is H-1 and Ar 2  is L-2; Ar 1  is I-1 and Ar 2  is L-2; Ar 1  is J-1 and Ar 2  is L-2; Ar 1  is K-1, and Ar 2  is L-2; Ar 1  is L-1 and Ar 2  is L-2; Ar 1  is M-1 and Ar 2  is L-2; Ar 1  is N-1 and Ar 2  is L-2; Ar 1  is A-1 and Ar 2  is M-2; Ar 1  is B-1 and Ar 2  is M-2; Ar 1  is C-1 and Ar 2  is M-2; Ar 1  is D-1 and Ar 2  is M-2; Ar 1  is E-1 and Ar 2  is M-2; Ar 1  is F-1 and Ar 2  is M-2; Ar 1  is G-1 and Ar 2  is M-2; Ar 1  is H-1 and Ar 2  is M-2; Ar 1  is I-1 and Ar 2  is M-2; Ar 1  is J-1 and Ar 2  is M-2; Ar 1  is K-1, and Ar 2  is M-2; Ar 1  is L-1 and Ar 2  is M-2; Ar 1  is M-1 and Ar 2  is M-2; Ar 1  is N-1 and Ar 2  is M-2; Ar 1  is A-1 and Ar 2  is N-2; Ar 1  is B-1 and Ar 2  is N-2; Ar 1  is C-1 and Ar 2  is N-2; Ar 1  is D-1 and Ar 2  is N-2; Ar 1  is E-1 and Ar 2  is N-2; Ar 1  is F-1 and Ar 2  is N-2; Ar 1  is G-1 and Ar 2  is N-2; Ar 1  is H-1 and Ar 2  is N-2; Ar 1  is I-1 and Ar 2  is N-2; Ar 1  is J-1 and Ar 2  is N-2; Ar 1  is K-1, and Ar 2  is N-2; Ar 1  is L-1 and Ar 2  is N-2; Ar 1  is M-1 and Ar 2  is N-2; or Ar 1  is N-1 and Ar 2  is N-2. 
     
     
         13 . The method of  claim 12 , wherein L 1  and L 2  are each null. 
     
     
         14 . The method of  claim 12 , wherein R 1a  is L 1  and R 2a  is L 2 ; R 1a  is L 1  and R 2b  is L 2 ; R 1a  is L 1  and R 2c  is L 2 ; R 1a  is L 1  and R 2d  is L 2 ; R 1b  is L 1  and R 2a  is L 2 ; R 1b  is L 1  and R 2b  is L 2 ; R 1b  is L 1  and R 2c  is L 2 ; R 1b  is L 1  and R 2d  is L 2 ; R 1c  is L 1  and R 2a  is L 2 ; R 1c  is L 1  and R 2b  is L 2 ; R 1c  is L 1  and R 2c  is L 2 ; R 1c  is L 1  and R 2d  is L 2 ; R 1d  is L 1  and R 2a  is L 2 ; R 1d  is L 1  and R 2b  is L 2 ; R 1d  is L 1  and R 2c  is L 2 ; or R 1d  is L 1  and R 2d  is L 2 . 
     
     
         15 . The method of  claim 13 , wherein R 1b  is L 1  and R 2b  is L 2 , R 1b  is L 1  and R 2c  is L 2 , or R 1c  is L 1  and R 2c  is L 2 . 
     
     
         16 . The method of  claim 12 , wherein Ar 1  is B-1 and Ar 2  is B-2. 
     
     
         17 . The method of  claim 14 , wherein R 1c  is L 1  and R 2c  is L 2 . And each of R 1a , R 1b , R 1d , R 2a , R 2b , and R 2d  are each hydrogen. 
     
     
         18 . The method of  claim 1 , wherein the injured organ is part of the central nervous system or cerebrovascular system. 
     
     
         19 . The method of  claim 1 , wherein the injured organ is the brain, heart, or kidney. 
     
     
         20 . The method of  claim 1 , wherein the injured organ is a result of stroke, cardiac arrest, traumatic brain injury, hemorrhagic shock, or subarachnoid hemorrhage.