Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same

Abstract

Compounds having the formula (I), and pharmaceutically-acceptable salts, hydrates and prodrugs thereof, in which E is X is N or CH, W is —NR 16 R 17 , —NR 16 C(═O)R 22 , —NR 16 CO 2 R 22 , —OR 23 , or a heteroaryl or heterocyclo group as defined in the specification, and R 1 through R 12 , R 16 , R 17 , R 22 , R 23 , x, y, and z are as defined in the specification, are useful as modulaters of melanocortin receptors, particularly MC-1R and MC-4R.

1 . A compound according to formula (I),  
     
       
         
         
             
             
         
       
       or a pharmaceutically-acceptable salt, hydrate or prodrug thereof,  
       in which  
       E is  
       
         
           
           
               
               
           
         
       
       X is N or CH;  
       R 1  is hydrogen or C 1-6 alkyl or is taken together with R 2  or R 3  to form a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or heterocycle;  
       R 2  is hydrogen, aryl, cycloalkyl, heteroaryl, heterocyclo; or C 1-6 alkyl or C 2-6 alkenyl optionally substituted with one to three of hydroxy, alkoxy, halogen, cyano, nitro, trifluoromethyl, amino, alkylamino, aryl, cycloalkyl, heteroaryl, and/or heterocyclo; or R 2  is taken together with R 1  or R 3  to form a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or heterocycle;  
       R 3  is hydrogen or C 1-6 alkyl or is taken together with R 1  or R 2  to form a monocyclic or bicyclic aryl, cycloalkyl, heteroaryl or heterocycle;  
       R 4 , R 5 , R 5a  R 5b , R 6 , R 6a , R 6b , and R 7  are independently selected from hydrogen, alkyl, substituted alkyl, halogen, hydroxy, alkoxy, keto, aryl, heteroaryl, cycloalkyl, and heterocyclo, or R 5a  and/or R 5b , R 6a  and/or R 6b , are taken together with R 8  or R 9  to form a fused carbocyclic, heterocyclic or heteroaryl ring;  
       R 8  and R 9  are independently hydrogen, halogen, cyano, alkyl, substituted alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclo, aryl, heteroaryl, —OR 13 , —NR 13 R 14 , —SR 13 —S(O) p R 14 , —C(═O)R 13 , —OC(═O)R 13 , —CO 2 R 13 , —C(═O)NR 13 R 14 , —NR 13 C(═O)R 14 , —OC(═O)NR 13 R 14 , —NR 13 CO 2 R 14 , —NR 13 C(═O)NR 14 R 15  or —NR 13 SO 2 R 14 ; or R 8  and R 9  taken together form a monocyclic or bicyclic cycloalkyl or heterocyclo joined in a spiro fashion to ring E at C*, provided that R 8  and R 9  are not both hydrogen, and provided further that when R 8  is —OR 13 , —(CH 2 ) k -aryl or —(CH 2 ) k -heteroaryl, then R 9  is not —C(═O)NR 18 R 19 , —CO 2 R 19 , —(CH 2 ) m NR 18 SO 2 R 20 , —(CH 2 ) m NR 18 C(═O)R 20 , —(CH 2 ) m OR 19 , (CH 2 ) m O(C═O)R 20 , —CH(R 18 )R 19 , or (CH 2 ) m NR 18 (C═O)NR 19 R 21 ;  
       R 11  and R 12  are selected independently of each other from hydrogen, alkyl, halogen, hydroxy, hydroxyalkyl, haloalkyl, amino, aminoalkyl, alkylamino, arylalkyl, cycloalkylalkyl, heteroarylalkyl, aryl, and cycloalkyl, and where y is at least 1, then R 11  and R 12  may be heterocyclo or heterocycloalkyl, or R 11  and R 12 , when attached to the same carbon atom, may join to form a spirocycloalkyl ring;  
       R 13 , R 14  and R 15  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, heterocyclo, or heteroaryl; or R 13  and R 14 , or R 14  and R 15  may join together to form a heterocyclo or heteroaryl, except R 14  is not hydrogen when joined to a sulfonyl group as in —S(O) p R 14  or —NR 13 SO 2 R 14 ;  
       W is selected from: 
 1) —NR 16 R 17 , —NR 16 C(═O)R 22 , —NR 16 CO 2 R 22 , —OR 23 , amidino, and guanidino;  
 2) heteroaryl or heterocyclo groups selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, isoxazolyl, thiazolyl, isothiazolyl, 3-azaisothiazolyl, pyridyl, pyrazinyl, pyridazinyl, 1,2-dihydropyridazinyl, and pyranyl, wherein said heteroaryl and heterocyclo groups may be substituted or unsubstituted and may have an optionally-substituted carbocyclic, heterocyclic or heteraryl ring fused thereto; or  
 3) a ring selected from:  
                     
 and where at least one of x and/or y is at least 1, W may be  
                     
 wherein B is N, O or S;  
 
       R 16  and R 17  are selected from hydrogen, alkyl and substituted alkyl;  
       R 18 , R 19  and R 21  are independently hydrogen or C 16 alkyl optionally substituted with halogen;  
       R 20  is C 1-6 alkyl, aryl, or heteroaryl;  
       R 22  and R 23  are independently selected from hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, and heterocyclo;  
       R 24  and R 25  at each occurrence are attached to any available carbon or nitrogen atom of W and at each occurrence are selected from hydrogen, C 1-6 alkyl, halogen, substituted C 1-6 alkyl, amino, alkylamino, cyano, nitro, trifluoromethoxy, —C(═O)R 26 , —CO 2 R 26 , —SO 2 R 26 , —OR 26 , aryl, heteroaryl, heterocyclo, and cycloalkyl, and/or two R 25  attached to two adjacent carbon atoms or adjacent carbon and nitrogen or carbon atoms may join to form a fused optionally-substituted heteroaryl, heterocyclo or cycloalkyl ring, and/or two R 24  or two R 25  when attached to the same carbon atom may form keto (═O);  
       R 26  is hydrogen, alkyl, substituted alkyl, aryl, heterocyclo, cycloalkyl, or heteroaryl, except when joined to a sulphonyl group as in SO 2 R 26 , then R 26  is not hydrogen;  
       k and m are independently 0, 1, 2 or 3;  
       p is 1, 2, or 3;  
       r is 0 or 1;  
       s is 0 or 1;  
       u and v are 0, 1, 2, or 3;  
       w is 0, 1, or 2;  
       x and y are 0, 1, 2, 3, or 4; and  
       z is 0 or 2.  
     
   
   
       2 . (canceled)  
   
   
       3 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which 
 W is —NR 16 R 17 , —NHC(═O)R 22 , —NHCO 2 alkyl, OR 23 , or azetidinyl;    R 16  and R 17  are independently selected from hydrogen, C 1-8 alkyl, and (CH 2 ) q -J, wherein J is selected from napthyl, furanyl, indolyl, imidazolyl, pyrimidinyl, benzothienyl, pyridinyl, pyrrolyl, pyrrolidinyl, thienyl, and C 3-7 cycloalkyl, wherein the alkyl, alkylene, and/or J groups of R 16  and/or R 17  are optionally substituted with up to three R 32 ;    R 22  is selected from C 1-6 alkyl, trifluoromethyl, alkoxyalkyl, furylalkyl, alkylaminoethyl, phenyl, pyrollylalkyl, piperidinyl, and piperidinylalkyl, wherein R 22  in turn is optionally substituted with one to two C 1-4 alkyl and/or —CO 2 (C 1-4 alkyl);    R 23  is hydrogen or phenyl;    R 32  is selected from C 1-6 alkyl, hydroxy, C 1-4 alkoxy, amino, C 1-4 alkylamino, aminoC 1-4 alkyl, trifluoromethyl, halogen, phenyl, benzyl, phenyloxy, benzyloxy, —C(═O)(CH 2 )NH 2 , —CO 2 (C 1-4 alkyl), —SO 2 (C 1-4 alkyl), tetrazolyl, piperidinyl, pyridinyl, and indolyl, wherein when R 32  is a ring, said ring in turn is optionally substituted with one to two C 1-4 alkyl, hydroxy, methoxy, and/or halogen; and    q is 0, 1, 2 or 3.    
   
   
       4 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which 
 W is a ring selected from:                          and where at least one of x and/or y is at least 1, W may be                          wherein B is N, O or S;    R 24  is selected from keto (═O), C 1-6 alkyl, halogen, amino, aminoalkyl, alkylamino, hydroxy, C 1-4 alkoxy, hydroxyC 1-4 alkyl, —C(═O)alkyl, —C(═O)aminoalkyl, —C(═O)phenyl, —C(═O)benzyl, —CO 2 alkyl, —CO 2 phenyl, —CO 2 benzyl, —SO 2 alkyl, —SO 2 aminoalkyl, —SO 2 phenyl, —SO 2 benzyl, phenyl, benzyl, phenyloxy, benzyloxy, pyrrolyl, pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, and tetrazolyl, and each R 24  in turn is optionally substituted with one to two R 31 ;    R 25  at each occurrence is attached to any available carbon or nitrogen atom of W and is selected from C 1-6 alkyl, halogen, amino, aminoalkyl, alkylamino, hydroxy, C 1-4 alkoxy, hydroxyC 1-4 alkyl, —C(═O)alkyl, —C(═O)aminoalkyl, —C(═O)phenyl, —C(═O)benzyl, —CO 2 alkyl, —CO 2 phenyl, —CO 2 benzyl, —SO 2 alkyl, —SO 2 aminoalkyl, —SO 2 phenyl, —SO 2 benzyl, phenyl, benzyl, phenyloxy, benzyloxy, pyrrolyl, pyrazolyl, piperidinyl, pyridinyl, pyrimidinyl, and tetrazolyl, and/or two R 25  when attached to adjacent carbon atoms may be taken together to form a fused benzo or pyrazolyl ring, and/or two R 25  when attached to the same carbon atom (in the case of a non-aromatic ring) may form keto (═O), and each R 25  in turn is optionally substituted with up to two R 31 ;    R 31  is selected from halogen, trifluoromethyl, C 1-4 alkyl, hydroxy, and C 1-4 alkoxy;    w is selected from 0, 1, or 2; and    u and v are selected from 0, 1, and 2.    
   
   
       5 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which 
 R 8  and R 9  are selected independently from hydrogen, alkyl, —(CH 2 ) j —C(═O)alkyl, —(CH 2 ) j -phenyl, —(CH 2 ) j -napthyl, —(CH 2 ) j —C 4-7 cycloalkyl, —(CH 2 ) j -heterocyclo, and —(CH 2 ) j — heteroaryl, or R 8  and R 9  together form a spirocycloalkyl or spiroheterocyclic ring; and    j is selected from 0, 1, 2 and 3.    
   
   
       6 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which 
 E is                          
   
   
       7 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt thereof, in which 
 R 11  and R 12  are (i) at each occasion independently selected from: 
 a) hydrogen,  
 b) C 1-6 alkyl,  
 c) C 1-6 alkyl substituted with up to two of hydroxy, alkoxy, amino, alkylamino, imidazolyl, pyrazolyl, phenyl, napthyl, pyridinyl, indolyl, pyrimidyl, furyl, thiazolyl, and thienyl, wherein said ringed substituents in turn are optionally substituted with one to three R 33  and/or have a benzene ring fused thereto optionally substituted with one to two R 33 ;  
 d) C 3-7 cycloalkyl optionally substituted with up to two R 33  and/or having a benzene ring fused thereto, wherein said fused benzene ring is optionally substituted with up to two R 33 ;  
 e) phenyl optionally substituted with up to three R 33 ;  
 f) where y is at least one, R 11  and R 12  may also be selected from piperidinyl, pyrrolidinyl, piperidinylalkyl, and pyrrolidinylalkyl, in turn optionally substituted with up to three R 33 ; or  
   ii) alternatively, one of R 11  and one of R 12  attached to the same carbon atom may be taken together to form a spirocycloalkyl ring;    R 33  is selected from C 1-6 alkyl, hydroxy, C 1-6 alkoxy, halogen, nitro, phenyl, benzyl, phenyloxy, benzyloxy, —C(═O)phenyl, amino, alkylamino, and aminoalkyl, wherein when R 33  includes a phenyl group said phenyl group in turn is optionally substituted with one to two of halogen, nitro, cyano, C 1-4  alkyl, and/or C 1-4  alkoxy.    
   
   
       8 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt thereof, in which 
 R 2  is selected from hydrogen, C 1-6 alkyl, C 2-6 alkenyl, biphenyl, C 2-6 alkenylene-K, and —(CH 2 ) g —K;    K is selected from phenyl, napthyl, thienyl, thiazolyl, pyridinyl, pyrimidinyl, and C 5-6 cycloalkyl, wherein each group K in turn is optionally substituted with one to three R 30  or has a benzene ring fused thereto, which also may be substituted with one to three R 30 ;    R 30  is selected from C 1-4 alkyl, hydroxy, alkoxy, halogen, nitro, cyano, amino, alkylamino, phenyl, and acylphenyl; and    g is 0, 1, 2 or 3.    
   
   
       9 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which —X(R 1 )—CH(R 2 )—CH(R 3 ) r —(CH 2 ) s —, taken together are selected from C 1-4 alkylene,  
     
       
         
         
             
             
         
       
     
   
   
       10 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt thereof, in which 
 X is N;    R 1  is hydrogen or C 1-4 alkyl;    r is 0; and    s is 0.    
   
   
       11 . A compound according to  claim 10 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which 
 W is                          —NR 16 R 17 , NR 16 C(═O)R 22 , OH, or imidazolyl;    R 16  and R 17  are selected from hydrogen and C 1-4 alkyl;    R 22  is C 1-4 alkyl, phenyl or piperidinylC 1-4 alkyl;    R 24  is C 1-4 alkyl; and    u is 0 or 1.    
   
   
       12 . A compound according to  claim 11 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which 
 R 11  is hydrogen, C 1-4 alkyl, or imidazolylC 1-4 alkyl; and    R 12  is hydrogen or C 1-4 alkyl.    
   
   
       13 . A compound according to  claim 1 , or a pharmaceutically-acceptable salt hydrate, or prodrug thereof, in which R 16  and R 17  are independently selected from hydrogen, C 1-8 alkyl, and C 1-8 substituted alkyl, except R 16  and R 17  are not alkyl substituted with pyridiyl, imidazolyl, thiazolyl, pyrimidinyl, or piperazinyl, and W is not morpholinyl.  
   
   
       14 . (canceled)  
   
   
       15 . (canceled)  
   
   
       16 . (canceled)  
   
   
       17 . (canceled)  
   
   
       18 . A pharmaceutical composition comprising at least one compound according to  claim 1  or a pharmaceutically-acceptable salt hydrate, or prodrug thereof; and a pharmaceutically-acceptable carrier or diluent.  
   
   
       19 . A pharmaceutical composition comprising (i) at least one compound according to  claim 1  or a pharmaceutically-acceptable salt hydrate, or prodrug thereof; (ii) at least one second compound effective for treating an inflammatory or immune disease, a cardiovascular disease, or neurodegenerative disorder; and (iii) a pharmaceutically-acceptable carrier or diluent.  
   
   
       20 . The pharmaceutical composition according to  claim 19  in which the at least one second compound comprises a phosphodiesterase inhibitor.  
   
   
       21 . A method of treating a melanocortin-receptor associated condition, the method comprising administering to a warm-blooded species in need of such treatment a therapeutically-effective amount of at least one compound according to  claim 1 .  
   
   
       22 . The method of  claim 21  in which the melanocortin-receptor associated condition is an MC-1R or MC-4R associated condition.