Quinazoline derivatives, compositions, and uses related thereto

Abstract

The disclosure relates to quinazoline derivatives, compositions, and methods related thereto. In certain embodiments, the disclosure relates to inhibitors of NADPH-oxidases (Nox enzymes) and/or myeloperoxidase.

1 . A pharmaceutical composition comprising a compound comprising formula I, 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt or prodrug thereof, wherein; 
         X is —(CR 14 R 15 ) n —Y or NH 2 ; 
         n is 1, 2, 3, 4, 5, or 6; 
         Y is hydrogen, alkyl, or an aromatic heterocyclcyl optionally substituted with one or more, the same or different, R 10 ; 
         R 2  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 10 ; 
         R 3  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3  is optionally substituted with one or more, the same or different, R 10 ; 
         R 4  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4  is optionally substituted with one or more, the same or different, R 10 ; 
         R 5  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5  is optionally substituted with one or more, the same or different, R 10 ; 
         R 10  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 11 ; 
         R 11  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11  is optionally substituted with one or more, the same or different, R 12 ; 
         R 12  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 12  is optionally substituted with one or more, the same or different, R 13 ; 
         R 13  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; 
         R 14  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14  is optionally substituted with one or more, the same or different, R 16 ; 
         R 15  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15  is optionally substituted with one or more, the same or different, R 16 ; and 
         R 16  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. 
       
     
     
         2 . A pharmaceutical composition of  claim 1  comprising a compound of formula IA, 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt or prodrug thereof, wherein; 
         A is a five or six membered aromatic heterocyclic ring optionally substituted with one or more, the same or different, R 10 ; the dotted line represents a double or single bond; 
         n is 1, 2, 3, 4, 5, or 6; 
         R 2  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 10 ; 
         R 3  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3  is optionally substituted with one or more, the same or different, R 10 ; 
         R 4  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4  is optionally substituted with one or more, the same or different, R 10 ; or R 3  and R 4  form a heterocyclic ring. 
         R 5  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5  is optionally substituted with one or more, the same or different, R 10 ; 
         R 10  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 11 ; 
         R 11  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11  is optionally substituted with one or more, the same or different, R 12 ; 
         R 12  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 12  is optionally substituted with one or more, the same or different, R 13 ; and 
         R 13  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. 
       
     
     
         3 . A pharmaceutical composition of  claim 1  comprising a compound of formula II 
       
         
           
           
               
               
           
         
         or pharmaceutically acceptable salt or prodrug thereof, wherein; 
         Q is N or C—R 5 ; 
         G is N or C—R 4 ; 
         K is N or C—R 3 ; 
         L is N or C—R 2 ; 
         X is —NH-(A) n -, or —NH 2  where Y is absent optionally substituted with one or more, the same or different, R 10 ; 
         n is 1, 2, 3, 4, 5, 6, 7, or 8; 
         A is the same or different at each occurrence O, NH, S, CR 14 R 15 , or C═O; 
         Y is OR 6 , SR 6 , NR 6 R 7 , or  + NR 6 R 7 R 17 ; 
         R 1  is alkyl optionally substituted with one or more, the same or different, R 10 ; 
         R 2  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 2  is optionally substituted with one or more, the same or different, R 10 ; 
         R 3  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 3  is optionally substituted with one or more, the same or different, R 10 ; 
         R 4  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 4  is optionally substituted with one or more, the same or different, R 10 ; 
         R 5  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 5  is optionally substituted with one or more, the same or different, R 10 ; 
         R 6  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 6  is optionally substituted with one or more, the same or different, R 16 ; 
         R 7  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 7  is optionally substituted with one or more, the same or different, R 16 ; or 
         R 6  and R 7  and the nitrogen to which they bond form a 3 to 8 membered heterocyclyl optionally substituted with one or more, the same or different, R 16 ; 
         R 10  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 10  is optionally substituted with one or more, the same or different, R 11 ; 
         R 11  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 11  is optionally substituted with one or more, the same or different, R 12 ; 
         R 12  is alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 12  is optionally substituted with one or more, the same or different, R 13 ; 
         R 13  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; 
         R 14  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 14  is optionally substituted with one or more, the same or different, R 16 ; 
         R 15  is hydrogen, alkyl, halogen, nitro, cyano, hydroxy, amino, mercapto, formyl, carboxy, carbamoyl, alkoxy, alkylthio, alkylamino, (alkyl) 2 amino, alkylsulfinyl, alkylsulfonyl, arylsulfonyl, carbocyclyl, aryl, or heterocyclyl, wherein R 15  is optionally substituted with one or more, the same or different, R 16 ; 
         R 16  is halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl; and 
         R 17  is alkyl optionally substituted with one or more R 18  selected from halogen, nitro, cyano, hydroxy, trifluoromethoxy, trifluoromethyl, amino, formyl, carboxy, carbamoyl, mercapto, sulfamoyl, methyl, ethyl, methoxy, ethoxy, acetyl, acetoxy, methylamino, ethylamino, dimethylamino, diethylamino, N-methyl-N-ethylamino, acetylamino, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, methylthio, ethylthio, methylsulfinyl, ethylsulfinyl, mesyl, ethylsulfonyl, methoxycarbonyl, ethoxycarbonyl, N-methylsulfamoyl, N-ethylsulfamoyl, N,N-dimethylsulfamoyl, N,N-diethylsulfamoyl, N-methyl-N-ethylsulfamoyl, carbocyclyl, aryl, or heterocyclyl. 
       
     
     
         4 . The pharmaceutical composition of  claim 1 , wherein R 4  is halogen and R 3  is hydrogen. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein R 4  is halogen and R 3  is halogen. 
     
     
         6 . The pharmaceutical composition of  claim 1 , wherein R 3  is alkoxy and R 4  is alkoxy, or R 3  and R 4  form a heterocyclic ring from —OCH 2 O— or —OCH 2 CH 2 O—. 
     
     
         7 . The composition of  claim 1 , wherein the compound is selected from:
 3-(3-(1H-imidazol-4-yl)propyl)-2-thioxo-2,3-dihydroquinazolin-4-one;   3-(3-(pyridin-2-yl)propyl)-2-thioxo-2,3-dihydroquinazolin-4-one;   3-(4-(dimethylamino)butyl)-6,7-dimethoxy-2-thioxo-2,3-dihydroquinazolin-4-one;   3-isopropyl-6,7-dimethoxy-2-thioxo-2,3-dihydroquinazolin-4-one;   6,7-difluoro-3-isopropyl-2-thioxo-2,3-dihydroquinazolin-4-one;   3-ethyl-6-fluoro-2-thioxo-2,3-dihydroquinazolin-4-one; and   3-amino-6-fluoro-2-thioxo-2,3-dihydroquinazolin-4(1H)-one.   
     
     
         8 . The compound of  claim 3 , which is 3-amino-6-fluoro-2-methylquinazolin-4(3H)-one. 
     
     
         9 . A method of treating a NOX- or MPO-related disease comprising administering a pharmaceutical composition of  claim 1 , to a subject in need thereof. 
     
     
         10 . The method of  claim 9 , wherein the NOX- or MPO-related disease is selected from hypertension, ischemia/reperfusion injury, stroke, myocardial infarction, diabetes, atherosclerosis, Alzheimer's disease, chronic obstructive pulmonary disease, asthma, inflammatory bowel disease, cystic fibrosis, schizophrenia, asbestos lung injury, multiple sclerosis, chronic heart failure, rheumatoid arthritis, glomerulonephritis, various cancers, acute respiratory distress syndrome, acute lung inflammation, Parkinson's disease, pulmonary fibrosis, liver fibrosis, cardiac hypertrophy, diabetic nephropathy, diabetic neuropathy, scar formation, skin aging and damage, and psoriasis. 
     
     
         11 . The use of a compound as described in  claim 1 , in the production of a medicament for the treatment of a NOX- or MPO-related disease. 
     
     
         12 . A method of preventing aging, sunburn, or scar formation comprising administering a composition comprising a compound of  claim 1 , to a subject in need thereof. 
     
     
         13 . A method of preventing tissue injury comprising administering a composition comprising a compound of  claim 1 , to subject before, during or after and organ transplant. 
     
     
         14 . An aqueous biological storage medium comprising a compound of  claim 1 . 
     
     
         15 . The biological storage medium of  claim 14 , further comprising a salt, an amino acid, a saccharide, a vitamin, or adenosine triphosphate.