Modulators of Aldehyde Dehydrogenase and Methods of Use Thereof

Abstract

The present disclosure provides compounds that function as modulators of aldehyde dehydrogenase (ALDH) enzymatic activity, as well as compositions and formulations comprising the compounds. The present disclosure provides therapeutic methods involving administering a subject compound, or a subject pharmaceutical composition.

1 .- 76 . (canceled) 
     
     
         77 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently H, CH 2 , CH 3 , NH, NH 2 , O, or a halogen; 
         n is the integer 0 or 1; 
         y is the integer 0 or 1; 
            (dotted line) is an optional bond; 
         z is the integer 0, 1, or 2; 
         R 1  to R 7  are each independently selected from H, a halo, a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; 
         X b  is C, N, O, or S, wherein b is the integer 0 or 1; 
         X c  is C, N, O, or S, wherein c is the integer 0 or 1; and 
         R 8  is selected from a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted bicyclic group, a substituted or unsubstituted hetero bicyclic group, a substituted or unsubstituted polycyclic group, and a substituted or unsubstituted hetero polycyclic group. 
       
     
     
         78 . The compound of  claim 77 , wherein R 8  is a substituted pyrrolidin-2-one group, a substituted pyrrolo[2,3-d]pyrimidine group, a substituted pyrazolo[3,4-d]pyrimidine group, a substituted pyrazin-2-one group, or a substituted 4,5,6,7-tetrahydro-tetrazolo[1,5-a]pyrimidine group;
 or R 8  is a substituted pyridine oxide.   
     
     
         79 . The compound of  claim 77 , having Formula (IIa): 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently H, CH 2 , CH 3 , NH, NH 2 , O, or a halogen; 
         n is the integer 0 or 1; 
         y is the integer 0 or 1; 
            (dotted line) is an optional bond; 
         z is the integer 0, 1, or 2, with the provisos that: 1) z=0 when X=halogen and   is not a bond; and 2) when z=0, X═O,   is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group; and 
         R8 is selected from a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, and an unsubstituted heteroaryl group. 
       
     
     
         80 . The compound of  claim 77 , having Formula (IIb): 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently H, CH 2 , CH 3 , NH, NH 2 , O, or a halogen; 
         n is the integer 0 or 1; 
         y is the integer 0 or 1; 
            (dotted line) is an optional bond; 
         z is the integer 0, 1, or 2, with the provisos that: 1) z=0 when X=halogen and   is not a bond; and 2) when z=0, X═O,   is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group; 
         R 1  is selected from H, a halo, an aliphatic group, an alkyl group, a substituted alkyl group, a substituted or unsubstituted alkenyl group, and a substituted or unsubstituted alkynyl group; and 
         R 8  is selected from a substituted cyclic group, an unsubstituted cyclic group, a substituted heterocyclic group, and an unsubstituted heterocyclic group. 
       
     
     
         81 . The compound of  claim 77 , having Formula (IIc): 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently H, CH 2 , CH 3 , NH, NH 2 , O, or a halogen; 
         n is the integer 0 or 1; 
         y is the integer 0 or 1; 
            (dotted line) is an optional bond; 
         z is the integer 0, 1, or 2, with the provisos that: 1) z=0 when X=halogen and   is not a bond; and 2) when z=0, X═O,   is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group; 
         R 1  is selected from H, a halo, an aliphatic group, an alkyl group, a substituted alkyl group, a substituted or unsubstituted alkenyl group, and a substituted or unsubstituted alkynyl group; and 
         R 8  is selected from a substituted bicyclic group, an unsubstituted bicyclic group, a substituted hetero bicyclic group, and an unsubstituted hetero bicyclic group. 
       
     
     
         82 . The compound of  claim 77 , having Formula (IId): 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently H, CH 2 , CH 3 , NH, NH 2 , O, or a halogen; 
         n is the integer 0 or 1; 
         y is the integer 0 or 1; 
            (dotted line) is an optional bond; 
         z is the integer 0, 1, or 2, with the provisos that: 1) z=0 when X=halogen and   is not a bond; and 2) when z=0, X═O,   is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group; and 
         R 8  is selected from a substituted aryl group, an unsubstituted aryl group, a substituted heteroaryl group, and an unsubstituted heteroaryl group. 
       
     
     
         83 . The compound of  claim 77 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         84 . A compound of Formula III: 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently C, N, O, or S; 
         n is the integer 0, 1 or 2; 
         y is the integer 0, 1 or 2; 
            is an optional double bond; 
         each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7  and R 8  is independently selected from H, C, N, O, a halo, a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; 
         A is C or S, wherein a=1 when A=C, and a=2 when A=S; 
         X c  is CH 2 , NH, 0, or S, wherein c is the integer 0 or 1; and 
         Ar is selected from a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted bicyclic group, a substituted or unsubstituted hetero bicyclic group, a substituted or unsubstituted polycyclic group, and a substituted or unsubstituted hetero polycyclic group. 
       
     
     
         85 . The compound of  claim 84 , wherein the compound has the structure: 
       
         
           
           
               
               
           
         
       
     
     
         86 . A compound of Formula IV: 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently CH 2 , CH 3 , NH, NH 2 , O, or S; 
         n is the integer 0, 1 or 2; 
         y is the integer 0, 1 or 2; 
            (dotted line) is an optional bond; 
         z is the integer 0 or 1, with the provisos that: 1) z=0 when X=halogen and   is not a bond; and 2) when z=0, X═O,   is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group; 
         w is the integer 0 or 1, with the provisos that: 1) w=0 when X=halogen and   is not a bond; and 2) when w=0, X═O,   is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group; 
         each of R 1 , R 2 , R 3 , R 4 , and R 5  is independently selected from H, C, N, O, a halo, a substituted or unsubstituted alkoxyl group, a substituted or unsubstituted amine group, a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; 
         X b  is C, N, O, or S, where b is the integer 0 or 1; and 
         R 6  is selected from a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted bicyclic group, a substituted or unsubstituted hetero bicyclic group, a substituted or unsubstituted polycyclic group, and a substituted or unsubstituted hetero polycyclic group. 
       
     
     
         87 . A compound of Formula V: 
       
         
           
           
               
               
           
         
         or a pro-drug, a pharmaceutically acceptable salt, an analog, or a derivative thereof, 
         wherein: 
         X n  and X y  are each independently CH 2 , CH 3 , NH, NH 2 , O, or S; 
         n is the integer 0, 1 or 2; 
         y is the integer 0, 1 or 2; 
            (dotted line) is an optional bond; 
         z is the integer 0 or 1, with the provisos that: 1) z=0 when X=halogen and   is not a bond; and 2) when z=0, X═O,   is not a bond, and one or more oxygen atoms (X) are present, oxygen is attached to a methyl group; 
         each of R 1 , R 2  and R 3  is independently selected from H, C, N, O, a halo, a substituted or unsubstituted alkoxyl group, a substituted or unsubstituted amine group, a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, and a substituted or unsubstituted heteroaryl group; 
         m is an integer from 1 to 10; 
         A is C or S, wherein a=1 when A=C, and a=2 when A=S; 
         b is the integer 0 or 1; and 
         R 4  is selected from a hydroxyl group, a substituted or unsubstituted phenyl group, an aliphatic group, an alkyl group, a substituted alkyl group, an alkenyl group, an alkynyl group, a substituted or unsubstituted cyclic group, a substituted or unsubstituted heterocyclic group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a substituted or unsubstituted bicyclic group, a substituted or unsubstituted hetero bicyclic group, a substituted or unsubstituted polycyclic group, and a substituted or unsubstituted hetero polycyclic group. 
       
     
     
         88 . The compound of  claim 87 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         89 . A pharmaceutical composition comprising:
 a) a compound of  claim 77 ; and   b) a pharmaceutically acceptable excipient.   
     
     
         90 . A method of reducing a level of an aldehyde present at a toxic level in an individual to below the toxic level, the method comprising administering to the individual an effective amount of the pharmaceutical composition of  claim 89 , wherein the aldehyde is a biogenic aldehyde or a xenogenic aldehyde. 
     
     
         91 . A method of treating alcohol intolerance, alcohol addiction, or an alcohol abuse disorder, the method comprising administering to an individual who has alcohol intolerance, alcohol addiction, or an alcohol abuse disorder an effective amount of the pharmaceutical composition of  claim 89 . 
     
     
         92 . A method of treating an acute or a chronic free-radical associated disease in an individual in need thereof, the method comprising administering to the individual an effective amount of the pharmaceutical composition of  claim 89 . 
     
     
         93 . A method of treating an ocular disorder in an individual, the method comprising administering to the individual an effective amount of the pharmaceutical composition of  claim 89 . 
     
     
         94 . A method of treating radiation-induced damage to epithelial cells in an individual, the method comprising administering to the individual an effective amount of the pharmaceutical composition of  claim 89 . 
     
     
         95 . A method of reducing the likelihood that an individual will develop head and neck cancer, the method comprising administering to the individual an effective amount of the pharmaceutical composition of  claim 89 . 
     
     
         96 . A method of treating cancer in an individual, the method comprising administering:
 a) the pharmaceutical composition of  claim 89 ; and   b) a cancer chemotherapeutic agent or ionizing radiation,   wherein the pharmaceutical composition and the cancer chemotherapeutic agent, or the pharmaceutical composition and the ionizing radiation, are administered in combined effective amounts to treat the cancer.   
     
     
         97 . A method of reducing the likelihood that an individual will develop oral cancer or lung cancer, the method comprising administering to the individual an effective amount of the pharmaceutical composition of  claim 89 .