Pyrimidoindolones and methods for using same

Abstract

Novel pyrimidoindolone compounds are disclosed. Methods of using the pyrimidoindolone compounds and compositions containing the compounds in the treatment and/or prevention of disease and other conditions related to inflammation, neurodegeneration, osteoarthritis and apoptosis are also disclosed.

1 . A compound of formula II:  
     
       
         
         
             
             
         
       
       or a stereoisomer or pharmaceutically-acceptable salt thereof,  
       wherein:  
       R 1  and R 2  are independently hydrogen, halogen, alkyl, aryl, heteroaryl, or R 1  and R 2  together with the carbon atom to which they are attached, form a C 3 -C 7  carbocyclyl or a C 3 -C 7  heterocycle;  
       R 3  and R 17  are independently hydrogen or alkyl;  
       R 15  and R 16  are independently, hydrogen, alkyl, or aryl, provided that R 15  and R 16  are not both aryl;  
       R 4  is hydrogen, halogen, alkyl, nitro, nitrile, carboxyl, hydroxy, amino, R 7 R 8 N—, alkoxy, or perfluoroalkoxy;  
       X is nitro, cyano, alkyl, perfluoroalkoxy, halogen,  
       
         
           
           
               
               
           
         
       
       R 5  is alkyl, aryl, heteroaryl, heterocycle, or carbocyclyl;  
       R 6  is hydrogen or C 1 -C 3  alkyl;  
       R 7  and R 8  are independently hydrogen, alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, alkanoyl, perfluoroalkanoyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, or R 7  and R 8  together with the nitrogen to which they are attached form a 5 to 10 member optionally substituted monocyclic or bicyclic ring system, which may further contain heteroatoms selected from oxygen, nitrogen or sulfur, provided that no ring may contain more than 3 heteroatoms;  
       R 9  is hydrogen, alkyl, aryl, heteroaryl, aralkyl, C 4 -C 12  heteroaralkyl, or C 3 -C 12  carbocyclyl; and  
       n is an integer of 0 or 1.  
     
   
   
       2 . The compound according to  claim 1 , wherein the compound is: 
 8′-{[(2S)-2-(Methoxymethyl)pyrrolidinyl]sulfonyl}-3′,4′-dihydrospiro(1,3-dioxane-2,10′(2′H)-pyrimido(1,2-a)indole)    8′-{[(2S)-2-(Phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]   3′,3′-Dimethyl-8′-{[(2S)-2-(phenoxymethyl)pyrrolidin-1-yl]sulfonyl}-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole];    8′-{[(2R)-2-(Methoxymethyl)pyrrolidin-1-yl]sulfonyl}-3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′pyrimido[1,2-a]indole];    N-Benzyl-N-methyl-3′,4′-dihydrospiro[1,3-dioxane-2,10′(2′H)-pyrimido[1,2-alpha]-indole]-8′-sulfonamide;    8′-({(2S)-2-[(Benzyloxy)methyl]pyrrolidin-1-yl}sulfonyl)-3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole];    3′,3′-Dimethyl-8′-(pyrrolidin-1-ylsulfonyl)-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole];    3′,4′-Dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-amine;    N-3′,4′-Dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-ylbenzamide;    3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carbonitrile;    {(2S)-1-[(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methanol;    {(2S)-1-[(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)sulfonyl]pyrrolidin-2-yl}methyl 4-methylbenzenesulfonate;    3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′amine;    N-(3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indol]-8′-yl)benzenesulfonamide;    8′-Bromo-3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole];    3′,3′-Dimethyl-8′-vinyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole];    Methyl 3′,3′-dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carboxylate;    3′,3′-Dimethyl-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole]-8′-carboxylic acid;    2′-Methyl-8′-(pyrrolidin-1-ylsulfonyl)-3′,4′-dihydro-2′H-spiro[1,3-dioxane-2,10′-pyrimido[1,2-a]indole];    8′-{[(2S)-2-(methoxymethyl)pyrrolidin-1-yl]sulfonyl}spiro[cycloheptane-1,3′-pyrimido[1,2-a]indol]-10′(2′H)-one; 
 or pharmaceutically acceptable salts thereof.