Use of small molecule inhibitors targeting eya tyrosine phosphatase

Abstract

Inhibitors of EYA tyrosine phosphatase are provided herein, as well as pharmaceutical compositions and methods relating thereto.

1 . A method of treating an ocular disorder in an individual, comprising:
 selecting or identifying an individual suffering from an ocular disorder selected from the group consisting of proliferative retinopathy, retinopathy of prematurity, diabetic retinopathy, age related macular degeneration, retinal vasculitis, exudative vitreoretinopathy, tumor angiogenesis, hemangiomas or tumor metastasis; and   administering to the individual a compound selected from the group of compounds having the structure of Formula I:   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof, 
           wherein: 
           R 1  is selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, C-amido, N-amido, S-sulfonamido, and N-sulfonamido, said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, and (cyclolalkyl)alkyl are each optionally substituted with one or more R 1A ; 
           each R 1A  is independently selected from the group consisting of hydroxy, halo, cyano, nitro, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, and amino; 
           R 2  is selected from the group consisting of H (hydrogen), halo, hydroxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, and C 1-6  alkyl substituted with one or more hydroxy; 
           R 3  is selected from the group consisting of halo, hydroxy, O-carbamyl, N-carbamyl, C-amido, S-sulfonamido, N-sulfonamido, C-carboxy, amino, and C 1-6  alkyl substituted with one or more hydroxy; 
           R 4  is selected from the group consisting of H (hydrogen), halo, C 1-6  alkyl optionally substituted with up to 5 fluoro and C 1-6  alkoxy optionally substituted with up to 5 fluoro; 
           R 5  and R 6  are each independently selected from the group consisting of H (hydrogen), halo, cyano, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, and amino, said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, and (cyclolalkyl)alkyl each optionally substituted with one or more R 1A ; 
           X 1  is [C(R 2A ) 2 ] n , O (oxygen), or NR 2A , or X 1  is absent; 
           X 2  is [C(R 2A ) 2 ] n , O (oxygen), or NR 2A , or X 2  is absent; 
           each R 2A  is independently selected from the group consisting of H (hydrogen), halo, hydroxy, O-carbamyl, N-carbamyl, C-amido, S-sulfonamido, N-sulfonamido, C-carboxy, amino, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, C 1-6  alkyl substituted with one or more hydroxyl, and C 1-6  alkyl optionally substituted with up to 5 fluoro; 
           each n is independently 1 or 2; 
           Y 1  is O (oxygen), S (sulfur), or NR 2A ; and 
           each Z is independently selected from the group consisting CR 2A , and N (nitrogen), 
           wherein the compound is administered to the individual in an amount effective to inhibit an EYA tyrosine phosphatase but below the level effective to inhibit a cysteine catalysis-based tyrosine phosphatase. 
         
       
     
     
         2 . A method of treating an ocular disorder in an individual, comprising:
 selecting or identifying an individual suffering from an ocular disorder selected from the group consisting of proliferative retinopathy, retinopathy of prematurity, diabetic retinopathy, age related macular degeneration, retinal vasculitis, exudative vitreoretinopathy, tumor angiogenesis, hemangiomas or tumor metastasis;   administering to the individual a tyrosine phosphatase inhibitor in an amount effective to specifically inhibit an EYA tyrosine phosphatase without inhibiting PTP-1B tyrosine phosphatase, wherein the tyrosine phosphatase inhibitor is a compound selected from the group of compounds having the structure of Formula I:   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof, 
           wherein: 
           R 1  is selected from the group consisting of C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, C-amido, N-amido, S-sulfonamido, and N-sulfonamido, said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, and (cyclolalkyl)alkyl are each optionally substituted with one or more R 1A ; 
           each R 1A  is independently selected from the group consisting of hydroxy, halo, cyano, nitro, (C 1 -C 6 )alkyl optionally substituted with up to 5 fluoro, C 1-6  alkoxy optionally substituted with up to 5 fluoro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, and amino; 
           R 2  is selected from the group consisting of H (hydrogen), halo, hydroxy, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, and C 1-6  alkyl substituted with one or more hydroxy; 
           R 3  is selected from the group consisting of halo, hydroxy, O-carbamyl, N-carbamyl, C-amido, S-sulfonamido, N-sulfonamido, C-carboxy, amino, and C 1-6  alkyl substituted with one or more hydroxy; 
           R 4  is selected from the group consisting of H (hydrogen), halo, C 1-6  alkyl optionally substituted with up to 5 fluoro and C 1-6  alkoxy optionally substituted with up to 5 fluoro; 
           R 5  and R 6  are each independently selected from the group consisting of H (hydrogen), halo, cyano, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, and amino, said C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, and (cyclolalkyl)alkyl each optionally substituted with one or more R 1A ; 
           X 1  is [C(R 2A ) 2 ] n , O (oxygen), or NR 2A , or X 1  is absent; 
           X 2  is [C(R 2A ) 2 ] n , O (oxygen), or NR 2A , or X 2  is absent; 
           each R 2A  is independently selected from the group consisting of H (hydrogen), halo, hydroxy, O-carbamyl, N-carbamyl, C-amido, S-sulfonamido, N-sulfonamido, C-carboxy, amino, C 2-6  alkenyl, C 2-6  alkynyl, aryl, heteroaryl, heterocyclyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl, cycloalkyl, cycloalkenyl, (cyclolalkyl)alkyl, C 1-6  alkyl substituted with one or more hydroxyl, and C 1-6  alkyl optionally substituted with up to 5 fluoro; 
           each n is independently 1 or 2; 
           Y 1  is O (oxygen), S (sulfur), or NR 2A ; and 
           each Z is independently selected from the group consisting CR 2A , and N (nitrogen). 
         
       
     
     
         3 . The method of  claim 2 , wherein the amount effective to specifically inhibit an EYA tyrosine phosphatase without inhibiting PTP-1B tyrosine phosphatase is 17 μM or less.