Carbon monoxide releasing molecules and uses thereof

Abstract

Provided herein are novel carbon-monoxide releasing molecules (CO-RMs) of the Formula (I): and esters, amides, salts, solvates and hydrates thereof; wherein R 1 and R 2 are as described herein. Also provided are pharmaceutical compositions comprising these compounds, methods of their preparation, and their use in the treatment of liver disease and inflammation.

1 . A compound of the Formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 each instance of R 1  is independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with CO 2 R A1  or —C(═O)N(R A1 ) 2 , wherein each instance of R A1  is independently hydrogen or C 1-10 alkyl; 
 each instance of R 2  are independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with CO 2 R A2  or —C(═O)N(R A2 ) 2 , wherein each instance of R A2  is independently hydrogen or C 1-10 alkyl; 
 or R 1  and R 2  and the carbon to which they are both attached are independently joined to form a C 3-4  carbocyclyl; 
 provided that each instance of R 1  and R 2  attached to the same carbon are not both hydrogen. 
 
       
     
     
         2 - 5 . (canceled) 
     
     
         6 . The compound of  claim 1 , wherein the compound is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof. 
       
     
     
         7 . The compound of  claim 1 , wherein the compound is of the Formula (I-a): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof. 
       
     
     
         8 . The compound of  claim 1 , wherein the compound is of the Formula (I-b): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof; wherein each instance of m is independently 0, 1, or 2. 
       
     
     
         9 . The compound of  claim 8 , wherein the compound is of the Formula (I-c): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof. 
       
     
     
         10 . The compound of  claim 8 , wherein the compound is of the Formula (I-d): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof; wherein each instance of r is independently 0, 1, or 2. 
       
     
     
         11 . The compound of  claim 1 , wherein the compound is of the Formula (I-e): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof; wherein each instance of p is independently 1, 2, or 3. 
       
     
     
         12 . The compound of  claim 11 , wherein the compound is of the Formula (I-f): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof. 
       
     
     
         13 . The compound of  claim 1 , wherein the compound is of the Formula (I-g): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof wherein each instance of p is independently 1, 2, or 3. 
       
     
     
         14 . The compound of  claim 13 , wherein the compound is of the Formula (I-h): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof. 
       
     
     
         15 . The compound of  claim 1 , wherein the compound is of the Formula (I-i): 
       
         
           
           
               
               
           
         
         or a salt, ester, amide, solvate, or hydrate thereof, or a combination thereof; wherein each instance of q is independently 1 or 2. 
       
     
     
         16 . The compound of  claim 1 , wherein each instance of R 2  is hydrogen. 
     
     
         17 - 29 . (canceled) 
     
     
         30 . A method for treating liver disease in a subject in need thereof, the method comprising administering an effective amount of a compound of  claim 1  to treat the liver disease. 
     
     
         31 - 35 . (canceled) 
     
     
         36 . The method of  claim 30 , wherein the liver disease is selected from the group consisting of drug-induced liver injury, hepatitis, non-alcoholic fatty liver disease, alcohol-induced liver disease, liver cirrhosis, liver cancer, primary biliary cirrhosis, cholestatis, cystic disease of the liver, and primary sclerosing cholangitis. 
     
     
         37 - 42 . (canceled) 
     
     
         43 . A method for treating an inflammatory disease in a subject in need thereof, the method comprising administering an effective amount of a compound of  claim 1  to treat the inflammatory disease. 
     
     
         44 - 46 . (canceled) 
     
     
         47 . The method of  claim 43 , wherein the inflammatory disease is inflammation associated with a gastrointestinal disorder. 
     
     
         48 . The method of  claim 47 , wherein the gastrointestinal disorder is selected from peptic ulcers, regional enteritis, diverticulitis, gastrointestinal bleeding, eosinophilic gastrointestinal disorders, gastritis, diarrhea, gastroesophageal reflux disease, inflammatory bowel disease, Crohn's disease, Behcet's syndrome, colitis, and inflammatory bowel syndrome. 
     
     
         49 . A method of preparing a compound of  claim 1 , the method comprising reacting a molybdenum tri-CO complex with an isocyanide of the formula: 
       
         
           
           
               
               
           
         
         wherein:
 each instance of R 1  is independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with —CO 2 R A1  or —C(═O)N(R A1 ) 2 , wherein each instance of R A1  is independently hydrogen or C 1-10 alkyl; 
 each instance of R 2  are independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with —CO 2 R A2  or C(═O)N(R A2 ) 2 , wherein each instance of R A2  is independently hydrogen or C 1-10 alkyl; 
 or R 1  and R 2  and the carbon to which they are both attached are independently joined to form a C 3-4  carbocyclyl; and 
 each instance of R 3  is independently C 1-6 alkyl; 
 provided that each instance of R 1  and R 2  attached to the same carbon are not both hydrogen; 
 to provide a compound of the Formula (II): 
 
       
       
         
           
           
               
               
           
         
         or a solvate or hydrate thereof, or a combination thereof; 
         and hydrolyzing the compound of Formula (II) to provide a compound of the Formula (I): 
       
       
         
           
           
               
               
           
         
         or a salt, solvate, or hydrate, or a combination thereof. 
       
     
     
         50 - 55 . (canceled) 
     
     
         56 . A compound of the Formula (II): 
       
         
           
           
               
               
           
         
         or a salt, solvate or hydrate thereof, or a combination thereof; 
         wherein:
 each instance of R 1  is independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with —CO 2 R A1  or —C(═O)N(R A1 ) 2 , wherein each instance of R A1  is independently hydrogen or C 1-10 alkyl; 
 each instance of R 2  are independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with —CO 2 R A2  or —C(═O)N(R A2 ) 2 , wherein each instance of R A2  is independently hydrogen or C 1-10  alkyl; 
 or R 1  and R 2  and the carbon to which they are both attached are independently joined to form a C 3-4  carbocyclyl; and 
 each instance of R 3  is independently C 1-6 alkyl; 
 provided that each instance of R 1  and R 2  attached to the same carbon are not both hydrogen. 
 
       
     
     
         57 . A compound of the Formula (III): 
       
         
           
           
               
               
           
         
         or a salt, solvate or hydrate thereof, or a combination thereof; 
         wherein:
 each instance of R 1  is independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with —CO 2 R A1  or —C(═O)N(R A1 ) 2 , wherein each instance of R A1  is independently hydrogen or C 1-10 alkyl; 
 each instance of R 2  are independently hydrogen, an unsubstituted C 1-3 alkyl, or a C 1-3 alkyl substituted with —CO 2 R A2  Or —C(═O)N(R A2 ) 2 , wherein each instance of R A2  is independently hydrogen or C 1-10 alkyl; 
 or R 1  and R 2  and the carbon to which they are both attached are independently joined to form a C 3-4  carbocyclyl; and 
 each instance of R 4  is independently hydrogen or C 1-6 alkyl; 
 provided that each instance of R 1  and R 2  attached to the same carbon are not both hydrogen.