Bridged piperidine derivatives as melanocortin receptor agonists

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof;

wherein m is 1 or 2;

each n is independently 0, 1, or 2;

each p is independently 0, 1 or 2;

q is 1 or 2;

R 1 is selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CHR 7 ) n —C 3-6 cycloalkyl,

(CHR 7 ) q —O(CHR 7 )aryl,

(CHR 7 ) n -aryl, and

(CHR 7 ) n -heteroaryl;

wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; and alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo;

R 2 is selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CH 2 ) n C 3-6 cycloalkyl, and

(CH 2 ) n -aryl;

R 3 and R 4 are each independently selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CH 2 ) n C 3-6 cycloalkyl,

(CH 2 ) n -aryl,

hydroxy,

halogen, and

amino;

R 5 is selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n C 3-6 cycloalkyl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

COC(R 7 ) 2 NH 2 ,

COR 7 ,

(CH 2 ) n OR 7 ,

(CH 2 ) n CO 2 R 7 ,

(CH 2 ) n CONR 7 R 7 ,

CH 2 C≡CH,

CO 2 R 7 ,

CH 2 CHF 2 ,

CONR 7 R 7 , and

SO 2 R 7 ;

wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo;

each R 6 is independently selected from the group consisting of

hydrogen,

C 1-6 alkyl,

(CH 2 ) n -phenyl,

(CH 2 ) n -naphthyl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

(CH 2 ) n C 3-7 cycloalkyl,

halogen,

OR 7 ,

(CH 2 ) n N(R 7 ) 2 ,

(CH 2 ) n C≡N,

(CH 2 ) n CO 2 R 7 ,

NO 2 ,

(CH 2 ) n NR 7 SO 2 R 7 ,

(CH 2 ) n SO 2 N(R 7 ) 2 ,

(CH 2 ) n S(O) p R 7 ,

(CH 2 ) n NR 7 C(O)N(R 7 ) 2 ,

(CH 2 ) n C(O)N(R 7 ) 2 ,

(CH 2 ) n NR 7 C(O)R 7 ,

(CH 2 ) n NR 7 CO 2 R 7 ,

O(CH 2 ) n C(O)N(R 7 ) 2 ,

CF 3 ,

CH 2 CF 3 ,

OCF 3 , and

OCH 2 CF 3 ;

wherein phenyl, naphthyl, heteroaryl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy; and wherein any methylene (CH 2 ) carbon atom in R 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

each R 7 is independently selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CH 2 ) n -phenyl,

(CH 2 ) n -naphthyl,

(CH 2 ) n -heteroaryl, and

(CH 2 ) n C 3-7 cycloalkyl;

wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo; and wherein any methylene (CH 2 ) carbon atom in R 7 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two R 7 groups together with the atom to which they are attached form a 5- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from O, S, and NC 1-4 alkyl;

each R 8 is independently selected from the group consisting of

hydrogen,

(CH 2 ) n C 1-7 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl, and

(CH 2 ) n C 3-7 cycloalkyl;

wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; and alkyl, cycloalkyl, heterocyclyl, and (CH 2 ) n are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo; or two substituents when on the same methylene (CH 2 ) carbon atom are taken together with the carbon atom to which they are attached to form a cyclopropyl group;

or two R 8 groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR 7 , NBoc, and NCbz;

X is selected from the group consisting of

C 1-8 alkyl,

(CH 2 ) n C 3-8 cycloalkyl,

(CH 2 ) n -phenyl,

(CH 2 ) n -naphthyl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n heterocyclyl,

(CH 2 ) n C≡N,

(CH 2 ) n CON(R 8 R 8 ),

(CH 2 ) n CO 2 R 8 ,

(CH 2 ) n COR 8 ,

(CH 2 ) n NR 8 C(O)R 8 ,

(CH 2 ) n NR 8 CO 2 R 8 ,

(CH 2 ) n NR 8 C(O)N(R 8 ) 2 ,

(CH 2 ) n NR 8 SO 2 R 8 ,

(CH 2 ) n S(O) p R 8 ,

(CH 2 ) n SO 2 N(R 8 )(R 8 ),

(CH 2 ) n OR 8 ,

(CH 2 ) n OC(O)R 8 ,

(CH 2 ) n OC(O)OR 8 ,

(CH 2 ) n OC(O)N(R 8 ) 2 ,

(CH 2 ) n N(R 8 )(R 8 ), and

(CH 2 ) n NR 8 SO 2 N(R 8 )(R 8 );

wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo; and

wherein any methylene (CH 2 ) carbon atom in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; and

Y is selected from the group consisting of

hydrogen,

C 1-8 alkyl,

C 2-6 alkenyl,

(CH 2 ) n C 3-8 cycloalkyl,

(CH 2 ) n -phenyl,

(CH 2 ) n -naphthyl,

(CH 2 ) n -heteroaryl, and

(CH 2 ) n -heterocyclyl;

wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R 6 and oxo; and wherein any methylene (CH 2 ) carbon atom in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl.

2. The compound of claim 1 wherein R 1 is CHR 7 -aryl, CHR 7 OCHR 7 -aryl, or CHR 7 -heteroaryl wherein aryl and heteroaryl are unsubstituted or substituted with one to two groups independently selected from R 6 .

3. The compound of claim 2 wherein R 1 is benzyl optionally substituted with one or two groups independently selected from halogen, C 1-4 alkyl, C 1-4 alkoxy, CN, CF 3 , and OCF 3 .

4. The compound of claim 3 wherein R 1 is 4-chlorobenzyl; 4-fluorobenzyl; 3,4-difluorobenzyl; 3,5-difluorobenzyl; 2-cyano-4-fluorobenzyl; or 4-methoxybenzyl.

5. The compound of claim 1 wherein R 2 is hydrogen or methyl.

6. The compound of claim 1 wherein R 5 is selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

(CH 2 ) n C 3-6 cycloalkyl,

(CH 2 ) n CO 2 R 7 ,

(CH 2 ) n CONR 7 R 7 ,

(CH 2 ) n OR 7 ,

COC(R 7 )NH 2 ,

CH 2 C≡CH, and

CH 2 CHF 2 ;

wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo.

7. The compound of claim 6 wherein X is selected from the group consisting of

C 1-6 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

(CH 2 ) n C(O)N(R 8 )(R 8 ),

(CH 2 ) n CO 2 R 8 ,

(CH 2 ) n OR 8 ,

(CH 2 ) n S(O) 0-2 R 8 ,

(CH 2 ) n NHC(O)R 8 ,

(CH 2 ) n OC(O)NR 8 R 8 , and

(CH 2 ) n NR 8 SO 2 R 8 ;

wherein aryl and heteroaryl are optionally substituted with one to three groups independently selected from R 6 ; heterocyclyl is optionally substituted with one to three groups independently selected from R 6 and oxo; the (CH 2 ) n group is optionally substituted with one to three groups independently selected from R 7 , halogen, S(O) 0-2 R 7 , N(R 7 ) 2 , and OR 7 ; and each R 8 is independently selected from H, C 1-8 alkyl, and C 3-6 cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R 6 and oxo; or two R 8 groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR 7 , NBoc, and NCbz.

8. The compound of claim 7 wherein X is selected from the group consisting of

C 1-6 alkyl,

(CH 2 ) 0-1 -heteroaryl,

CH 2 -heterocyclyl,

CO 2 R 8 ,

CH 2 OR 8 ,

CH 2 S(O) 0-2 R 8 ,

NHC(O)R 8 ,

CH 2 NR 8 SO 2 R 8 ,

CH 2 OC(O)NR 8 R 8 ,

CH 2 NR 8 SO 2 R 8 , and

C(O)N(R 8 )(R 8 );

wherein heteroaryl is optionally substituted with one to three groups independently selected from R 6 ; heterocyclyl is optionally substituted with one to three groups independently selected from R 6 and oxo; and each R 8 is independently selected from H, C 1-8 alkyl, and C 3-6 cycloalkyl, wherein alkyl and cycloalkyl are optionally substituted with one to three groups independently selected from R 6 and oxo; or two R 8 groups together with the atoms to which they are attached form a 5- to 8-membered mono- or bi-cyclic ring system optionally containing an additional heteroatom selected from O, S, NR 7 , NBoc, and NCbz.

9. The compound of claim 1 wherein Y is selected from the group consisting of

C 1-8 alkyl,

(CH 2 ) n C 3-7 cycloalkyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heterocyclyl, and

(CH 2 ) n -heteroaryl;

wherein aryl and heteroaryl are optionally substituted with one to three groups independently selected from R 6 ; and (CH 2 ) n , alkyl, cycloalkyl, and heterocyclyl are optionally substituted with one to three groups independently selected from R 6 and oxo.

10. The compound of claim 9 wherein Y is

cyclohexyl,

cycloheptyl,

cyclopentyl, or

C 1-6 alkyl;

wherein alkyl and cycloalkyl groups are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo.

11. The compound of claim 10 wherein Y is cyclohexyl or C 1-6 alkyl; wherein the cyclohexyl and alkyl groups are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo.

12. The compound of claim 1 of formula II:

wherein m is 1 or 2;

each n is independently 0, 1, or 2;

R 2 is hydrogen or methyl;

R 3 is hydrogen, fluoro, or hydroxy;

each R 6 is independently selected from the group consisting of

hydrogen,

halogen,

cyano,

C 1-4 alkyl,

C 1-4 alkoxy,

trifluoromethyl, and

trifluoromethoxy;

R 5 is selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

(CH 2 ) n C 3-6 cycloalkyl,

(CH 2 ) n CO 2 R 7 ,

(CH 2 ) n CONR 7 R 7 ,

(CH 2 ) n OR 7 ,

COC(R 7 )NH 2 ,

CH 2 C≡CH, and

CH 2 CHF 2 ;

wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 6 ; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo;

Y is selected from the group consisting of

C 5-7 cycloalkyl and

C 1-6 alkyl;

wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 6 and oxo; and

X is selected from the group consisting of

—NHC(O)tBu; —C(O)NHCH(Et) 2 ; —C(O)NHCH 2 tBu;

 —CH 2 SCH(CH 3 ) 2 ; —CH 2 S(O)CH(CH 3 ) 2 ; —CH 2 S(O) 2 CH(CH 3 ) 2 ; —C(O)NHCH 2 CH 2 N(CH 3 ) 2 ; C(O)CH(CH 3 ) 2 ; —CH 2 NHCOtBu; —CH 2 OC(O)NMe 2 ; —CH 2 C(O)NEt 2 ; —CH 2 OC(Me) 2 CO 2 H; —C(O)NHC(Me) 2 CO 2 Me; —C(O)NHC(Me) 2 CO 2 H; —CH 2 N(CH 3 )COtBu; —CH 2 N(iPr)COMe; —CH 2 N(iPr)SO 2 Me; C(O)NHC(Me) 2 CH 2 OMe; C(O)NHC(Me) 2 CH 2 OH; —CH 2 CH 2 C(Me) 2 OH;

13. The compound of claim 12 wherein the carbon atom marked with an * has the R configuration.

14. The compound of claim 13 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

16. A method for the treatment of obesity in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound according to claim 1 .

17. A method for the treatment of diabetes mellitus in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .

18. A method for the treatment of male or female sexual dysfunction in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .

19. A method for the treatment of erectile dysfunction in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .