Imidazole derivatives

Abstract

The invention provides compounds of formula 1 wherein R 1 , R 2 , R 3 , and R 4 are as defined, and their pharmaceutically acceptable salts. Compounds of formula 1 are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula 1 for treating and preventing diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions and methods comprising compounds of formula 1 for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.

1 . A compound of the formula  
     
       
         
         
             
             
         
       
     
     wherein R 1  is (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, (3-8 membered) heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, or (C 7 -C 11 )bicycloalkenyl, and wherein R 1  is optionally substituted with from one to six substituents R 5  independently selected from F, Cl, Br, I, nitro, cyano, —CF 3 , —NR 7 R 8 , —NR 7 C(═O)R 8 , —NR 7 C(═O)OR 8 , —NR 7 C(═O)NR 8 R 9 , —NR 7 S(═O) 2 R 8 , —NR 7 S(═O) 2 NR 8 R 9 , OR 7 , —OC(═O)R 7 , —OC(═O)OR 7 , —C(═O)OR 7 , —C(═O)R 7 , —C(═O)NR 7 R 8 , —OC(═O)NR 7 R 8 , —OC(═O)SR 7 , —SR 7 , —S(═O)R 7 , —S(═O) 2 R 7 , —S(═O) 2 NR 7 R 8 , —O—S(═O) 2 R 7 , —N 3 , and R 7 ; 
 R 2  is H, F, —CH 3 , —CN, or —C(═O)OR 7 ;  
 R 3  is —C(═O)NR 9 —, —C(═O)O—, —C(═O)(CR 10 R 11 ) n —, or —(CR 10 R 11 ) n —;  
 R 4  is a straight chain or a branched (C 1 -C 8 )alkyl, a straight chain or a branched (C 2 -C 8 )alkenyl, a straight chain or branched (C 2 -C 8  alkynyl), (3-8 membered) heterocycloalkyl, (5-11 membered) heterobicycloalkyl, or (5-14 membered) heteroaryl; and wherein R 4  is optionally substituted with from one to three substitutents R 6  independently selected from F, Cl, Br, I, nitro, cyano, —CF 3 , —NR 7 R 8 , —NR 7 C(═O)R 8 , —NR 7 C(═O)OR 8 , —NR 7 C(═O)NR 8 R 9 , —NR 7 S(═O) 2 R 8 , —NR 7 S(═O) 2 NR 8 R 9 , —OR 7 , —OC(═O)R 7 , —OC(═O)OR 7 , —C(═O)OR 7 , —C(═O)R 7 , —C(═O)NR 7 R 8 , —OC(═O)NR 7 R 8 , —OC(═O)SR 7 , —SR 7 , —S(═O)R 7 , —S(═O) 2 R 7 , —S(═O) 2 NR 7 R 8 , or R 7 ;  
 each R 7 , R 8 , and R 9  is independently selected from H, straight chain or branched (C 1 -C 8 )alkyl, straight chain or branched (C 2 -C 8 )alkenyl, straight chain or branched (C 2 -C 8  alkynyl), (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, (3-8 membered) heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C 7 -C 11 )bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C 6 -C 14 )aryl, and (5-14 membered) heteroaryl, wherein R 7 , R 8 , and R 9  are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, NO 2 , —CN, —CF 3 , —NR 10 R 11 , —NR 10 C(═O)R 11 , —NR 10 C(═O)OR 11 , —NR 10 C(═O)NR 10 R 12 , —NR 10 S(═O) 2 R 11 , —NR 10 S(═O) 2 NR 11 R 12 , —OR 10 , —OC(═O)R 10 , —OC(═O)OR 10 , —OC(═O)NR 10 R 11 , —OC(═O)SR 10 , —SR 10 , —S(═O)R 10 , —S(═O) 2 R 10 , —S(═O) 2 NR 10 R 11 , —C(═O)R 10 , —C(═O)OR 10 , —C(═O)NR 10 R 11 , and R 10 ;  
 or, when R 7  and R 8  are as in NR 7 R 8 , they may instead optionally be connected to form with the nitrogen of NR 7 R 8  to which they are attached a heterocycloalkyl moiety of from three to seven ring members, said heterocycloalkyl moiety optionally comprising one or two further heteroatoms independently selected from N, O, and S;  
 each R 10 , R 11 , and R 12  is independently selected from H, straight chain or branched (C 1 -C 8 )alkyl, straight chain or branched (C 2 -C 8 )alkenyl, straight chain or branched (C 2 -C 8  alkynyl), (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, (3-8 membered) heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C 7 -C 11 )bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C 6 -C 14 )aryl, and (5-14 membered) heteroaryl, wherein R 10 , R 11 , and R 12  are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, —NO 2 , —CN, —CF 3 , —NR 13 R 14 , —NR 13 C(═O)R 14 , —NR 13 C(═O)OR 14 , —NR 13 C(═O)NR 14 R 15 , —NR 13 S(═O) 2 R 14 , —NR 13 S(═O) 2 NR 14 R 15 , —OR 13 , —OC(═O)R 13 , —OC(═O)OR 13 , —OC(═O)NR 13 R 14 , —OC(═O)SR 13 , —SR 13 , —S(═O)R 13 , —S(═O) 2 R 13 , —S(═O) 2 NR 13 R 14 , —C(═O)R 13 , —C(═O)OR 13 , —C(═O)NR 13 R 14 , and R 13 ;  
 each R 13 , R 14 , and R 15  is independently selected from H, straight chain or branched (C 1 -C 8 )alkyl, straight chain or branched (C 2 -C 8 )alkenyl, straight chain or branched (C 2 -C 8  alkynyl), (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, (3-8 membered) heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C 7 -C 11 )bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C 6 -C 14 )aryl, and (5-14 membered) heteroaryl, wherein R 13 , R 14 , and R 15  are each independently optionally substituted with from one to six substituents independently selected from F, Cl, Br, I, —NO 2 , —CN, —CF 3 , —NR 16 R 17 , —NR 16 C(═O)R 17 , —NR 16 C(═O)OR 17 , —NR 16 C(═O)NR 17 R 18 , —NR 16 S(═O) 2 R 17 , —NR 16 S(═O) 2 NR 17 R 18 , —OR 16 , —OC(═O)R 16 , —OC(═O)OR 16 , —OC(═O)NR 16 R 17 , —OC(═O)SR 16 , —SR 16 , —S(═O)R 16 , —S(═O) 2 R 16 , —S(═O) 2 NR 16 R 17 , —C(═O)R 16 , —C(═O)OR 16 , —C(═O)NR 16 R 17 , and  
 each R 16 , R 17 , and R 18  is independently selected from H, straight chain or branched (C 1 -C 8 )alkyl, straight chain or branched (C 2 -C 8 )alkenyl, straight chain or branched (C 2 -C 8  alkynyl), (C 3 -C 8 )cycloalkyl, (C 4 -C 8 )cycloalkenyl, (3-8 membered) heterocycloalkyl, (C 5 -C 11 )bicycloalkyl, (C 7 -C 11 )bicycloalkenyl, (5-11 membered) heterobicycloalkyl, (C 6 -C 13 )aryl, and (5-12 membered) heteroaryl;  
 n is 0, 1, 2, or 3;  
 wherein R 10  and R 11  in —C(═O)(CR 10 R 11 ) n — and —(CR 10 R 11 ) n — are for each iteration of n defined independently as recited above;  
 or a pharmaceutically acceptable salt thereof.  
 
   
   
       2 . A compound according to  claim 1 , wherein R 3  is —C(═O)NH— or —C(═O)(CR 10 R 11 ) n —.  
   
   
       3 . A compound according to  claim 2 , wherein R 10  and R 11  are at each iteration of n both hydrogen.  
   
   
       4 . A compound according to  claim 1 , wherein R 1  is optionally substituted (C 3 -C 8 )cycloalkyl or optionally substituted (C 5 -C 11 ) bicycloalkyl.  
   
   
       5 . A compound according to  claim 4 , wherein R 1  is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or norbornyl, each optionally substituted.  
   
   
       6 . A compound according to  claim 5 , wherein R 1  is optionally substituted with from one to three substituents independently selected from F, Cl, Br, I, nitro, cyano, —CF 3 , —NR 7 R 8 , —NR 7 C(═O)R 8 , —OR 7 , —C(═O)OR 7 , —C(═O)R 7 , and R 7 .  
   
   
       7 . A compound according to  claim 4 , wherein R 1  is optionally substituted bicyclo-[3.1.0]-hexyl.  
   
   
       8 . A compound of  claim 1 , wherein R 4  is an (optionally substituted 5-14 membered) heteroaryl.  
   
   
       9 . A compound according to  claim 8 , wherein R 4  is an optionally substituted pyridyl.  
   
   
       10 . A compound according to  claim 8 , wherein R 4  is quinolyl, or isoquinolyl, each optionally substituted.  
   
   
       11 . A compound according to  claim 10 , wherein R 4  is unsubstituted.  
   
   
       12 . A compound according to  claim 1 , wherein R 2  is hydrogen.  
   
   
       13 . A compound of  claim 1 , selected from the group consisting of: 
 N-(1-cyclobutyl-1H-imidazol-4-yl)-2-quinolin-6-yl-acetamide;    N-[1-(cis-3-phenyl-cyclobutyl)-1H-imidazol-4-yl]-2-quinolin-6-yl-acetamide;    1-(1-cyclobutyl-1H-imidazol-4-yl)-3-isoquinolin-5-yl-urea;    6-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    1H-imidazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    6-hydroxy-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    3-methyl-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    2-pyridin-3-yl-thiazole-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    6-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutylcarbamoyl}-nicotinic acid methyl ester;    pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    5-methyl-pyrazine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    6-chloro-pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    quinoline-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    1H-pyrrole-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    N-{cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-2-m-tolyl-acetamide;    pyridine-2-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide;    piperidine-4-carboxylic acid {cis-3-[4-(2-naphthalen-1-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide hydrochloride;    N-{cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-benzamide; and    pyridine-2-carboxylic acid {cis-3-[4-(2-isoquinolin-5-yl-acetylamino)-imidazol-1-yl]-cyclobutyl}-amide; and 
 pharmaceutically acceptable salts of the foregoing compounds.  
   
   
   
       14 . A pharmaceutical composition for treating a) a disease or condition comprising abnormal cell growth; b) a neurodegenerative disease or condition; or c) a disease or condition the treatment of which can be effected or facilitated by inhibiting GSK-3, in a mammal comprising a compound of  claim 1  in an amount effective in treating said disease or condition, and a pharmaceutically acceptable carrier.