Therapeutic Aryl-Amido-Aryl Compounds and Their Use

Abstract

The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain aryl-amido-aryl compounds of the following formula (for convenience, collectively referred to herein as “AAA compounds”), which, inter alia, are (selective) retinoic acid receptor α (RARα) agonists. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to (selectively) activate RARα, and in the treatment of diseases and conditions that are mediated by RARα, that are ameliorated by the activation of RARα, etc., including cognitive disorders, memory impairment, memory deficit, senile dementia, Alzheimer's disease, early stage Alzheimer's disease, intermediate stage Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, and mild cognitive impairment.

1 - 154 . (canceled) 
     
     
         155 . A compound of the following formula, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         —R 1  is independently —X, —R X , —O—R X , —O—R A , —O—R C , —O-L-R C , —O—R AR , or —O-L-R AR ; 
         —R 2  is independently —X, —R X , —O—R X , —O—R A , —O—R C , —O-L-R C , —O—R AR , or —O-L-R AR ; 
         —R 3  is independently —X, —R X , —O—R X , —O—R A , —O—R C , —O-L-R C , —O—R AR , or —O-L-R AR ; 
         with the proviso that —R 1 , —R 2 , and —R 3  are not all —O—R A ; 
         wherein: 
         each —X is independently —F, —Cl, —Br, or —I; 
         each —R A  is saturated aliphatic C 1-6 alkyl; 
         each —R X  is saturated aliphatic C 1-6 haloalkyl; 
         each —R C  is saturated C 3-7 cycloalkyl; 
         each —R AR  is phenyl or C 5-6 heteroaryl; 
         each -L- is saturated aliphatic C 1-3 alkylene; 
         and wherein: 
         -J- is —C(═O)—NR N —; 
         —R N  is independently —H or —H or —R NN ; 
         —R NN  is saturated aliphatic C 1-4 alkyl; 
         ═Y— is ═CR Y — and —Z═ is —CR Z ═; 
         —R Y  is —H; 
         —R Z  is independently —H or —R ZZ ; 
         —R ZZ  is independently —F, —Cl, —Br, —I, —OH, saturated aliphatic C 1-4 alkoxy, saturated aliphatic C 1-4 alkyl, or saturated aliphatic C 1-4 haloalkyl; 
         ═W— is ═CR W —; 
         —R W  is —H; 
         —R O  is independently —OH, —OR E , —NH 2 , —NHR T1 , —NR T1 R T1  or —NR T2 R T3 ; 
         —R E  is saturated aliphatic C 1-6 alkyl; 
         each —R T1  is saturated aliphatic C 1-6 alkyl; 
         —NR T2 R T3  is independently azetidino, pyrrolidino, piperidino, piperizino, N—(C 1-3 alkyl) piperizino, or morpholino; 
         with the proviso that the compound is not a compound selected from the following compounds, and salts, hydrates, and solvates thereof:
 4-(3,5-dichloro-4-ethoxy-benzoylamino)-benzoic acid (PP-02); and 
 4-(3,5-dichloro-4-methoxy-benzoylamino)-benzoic acid (PP-03). 
 
       
     
     
         156 . A compound according to  claim 155 , wherein:
 —R 1  is independently —X, —R X , —O—R X , —O—R A , —O—R C , or —O-L-R C ;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is independently —X, —R X , —O—R X , —O—R A , —O—R C , or —O-L-R C ;   with the proviso that —R 1 , —R 2 , and —R 3  are not all —O—R A .   
     
     
         157 . A compound according to  claim 155 , wherein:
 —R 1  is independently —X, —R X , —O—R A , —O—R C , or —O-L-R C ;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is independently —X, —R X , —O—R A , —O—R C , or —O-L-R C ;   with the proviso that —R 1 , —R 2 , and —R 3  are not all —O—R A .   
     
     
         158 . A compound according to  claim 155 , wherein:
 —R 1  is independently —X or —R X ;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is independently —X or —R X .   
     
     
         159 . A compound according to  claim 155 , wherein:
 —R 1  is —X;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is —X.   
     
     
         160 . A compound according to  claim 155 , wherein:
 —R 1  is —X;   —R 2  is independently —O—R A  or —O—R C ; and   —R 3  is —X.   
     
     
         161 . A compound according to  claim 155 , wherein:
 —R 1  is independently —O—R A , —O—R C , or —O-L-R C ;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is independently —X or —R X ;   or:   —R 1  is independently —X or —R X ;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is independently —O—R A , —O—R C , or —O-L-R C .   
     
     
         162 . A compound according to  claim 155 , wherein:
 —R 1  is independently —O—R A  or —O—R C ;   —R 2  is independently —O—R A  or —O—R C ; and   —R 3  is independently —X or —R X ;   or:   —R 1  is independently —X or —R X ;   —R 2  is independently —O—R A  or —O—R C ; and   —R 3  is independently —O—R A  or —O—R C .   
     
     
         163 . A compound according to  claim 155 , wherein:
 —R 1  is —O—R A ;   —R 2  is —O—R A ; and   —R 3  is independently —X or —R X ;   or:   —R 1  is independently —X or —R X ;   —R 2  is —O—R A ; and   —R 3  is —O—R A .   
     
     
         164 . A compound according to  claim 155 , wherein:
 —R 1  is independently —O—R A , —O—R C , or —O-L-R C ;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is —X;   or:   —R 1  is —X;   —R 2  is independently —O—R A , —O—R C , or —O-L-R C ; and   —R 3  is independently —O—R A , —O—R C , or —O-L-R C .   
     
     
         165 . A compound according to  claim 155 , wherein:
 —R 1  is independently —O—R A  or —O—R C ;   —R 2  is independently —O—R A  or —O—R C ; and   —R 3  is —X;   or:   —R 1  is —X;   —R 2  is independently —O—R A  or —O—R C ; and   —R 3  is independently —O—R A  or —O—R C .   
     
     
         166 . A compound according to  claim 155 , wherein:
 —R 1  is independently —O—R A ;   —R 2  is independently —O—R A ; and   —R 3  is —X;   or:   —R 1  is —X;   —R 2  is independently —O—R A ; and   —R 3  is independently —O—R A .   
     
     
         167 . A compound according to  claim 155 , wherein:
 each —X is independently —F, —Cl, or —Br;   each —R A  is saturated aliphatic C 1-4 alkyl;   each —R X  is —CF 3 ;   each —R C  is independently cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl;   each —R AR  is independently phenyl, pyridinyl, pyrimidinyl, or pyridizinyl; and   each -L- is independently —CH 2 — or —CH 2 CH 2 —.   
     
     
         168 . A compound according to  claim 155 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         169 . A compound according to  claim 156 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         170 . A compound according to  claim 157 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         171 . A compound according to  claim 158 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         172 . A compound according to  claim 159 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         173 . A compound according to  claim 160 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         174 . A compound according to  claim 161 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         175 . A compound according to  claim 162 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         176 . A compound according to  claim 163 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         177 . A compound according to  claim 164 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         178 . A compound according to  claim 165 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         179 . A compound according to  claim 166 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         180 . A compound according to  claim 167 , wherein:
 —R ZZ  is independently —F, —Cl, —OH, or -Me;   —R N  is —H; and   —R O  is —OH.   
     
     
         181 . A compound according to  claim 155 , which is selected from the following compounds, or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         182 . A composition comprising a compound according to  claim 155 , and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         183 . A method of preparing a composition comprising admixing a compound according to  claim 155  and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         184 . A method of treatment of a cognitive disorder, memory impairment, memory deficit, senile dementia, Alzheimer's disease, early stage Alzheimer's disease, intermediate stage Alzheimer's disease, late stage Alzheimer's disease, cognitive impairment, or mild cognitive impairment comprising administering to a subject in need of treatment a therapeutically-effective amount of a compound according to  claim 155 .