IP Library › Granted Patent US 7,414,057

Granted Patent B2

US 7,414,057 · App. 10/526,178 · Granted Aug 19, 2008

Piperazine urea derivatives as melanocortin-4 receptor agonists

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Quick Facts

Patent No.: US 7,414,057
App. No.: 10/526,178
Granted: Aug 19, 2008
Kind: B2

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Abstract

Certain novel piperazine urea derivatives are agonists of the human melanocortin-4 receptor (MC-4R) and, in particular, are receptor-subtype selective agonists of MC-4R. They are useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity and diabetes.

Claims (296)

1. A compound of structural formula I:

or a pharmaceutically acceptable salt thereof; wherein

m is 1 or 2;

each p is independently 0, 1, or 2;

each n is independently 0, 1, or 2;

R 1 is 4-chlorobenzyl; 4-fluorobenzyl; 3,4-difluorobenzyl; 3,5-difluorobenzyl, 2-cyano-4-fluorobenzyl; or 4-methoxybenzyl;

R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently 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, and

(CH 2 ) n -heterocyclyl;

in which aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 11 ; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 11 and oxo;

or R 3 and R 5 and the carbon atoms to which they are attached form a 5- to 7-membered ring;

or R 3 and R 9 and the carbon atoms to which they are attached form a 5- to 7-membered ring;

or R 5 and R 7 and the carbon atoms to which they are attached form a 5- to 7-membered ring;

or R 7 and R 9 and the carbon atoms to which they are attached form a 5- to 7-membered ring;

R 2 is selected from the group consisting of

hydrogen,

C 2-6 alkenyl,

C 1-8 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n C 3-6 cycloalkyl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl,

(CH 2 ) 1-2 OR 12 ,

(CH 2 ) 1-2 CO 2 R 12 ,

(CH 2 ) 1-2 CONR 12 R 12 ,

CH 2 C≡CH, and

CH 2 CHF 2 ;

or R 2 and R 3 and the carbon atoms to which they are attached form a 5- to 7-membered ring;

or R 3 and R 4 and the carbon atom to which they are attached form a 3- to 6-membered spirocyclic ring;

R 11 is 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 12 ,

(CH 2 ) n N(R 12 ) 2 ,

(CH 2 ) n C≡N,

(CH 2 ) n CO 2 R 12 ,

NO 2 ,

(CH 2 ) n NR 12 SO 2 R 12 ,

(CH 2 ) n SO 2 N(R 12 ) 2 ,

(CH 2 ) n S(O) p R 12 ,

(CH 2 ) n NR 12 C(O)N(R 12 ) 2 ,

(CH 2 ) n C(O)N(R 12 ) 2 ,

(CH 2 ) n NR 12 C(O)R 12 ,

(CH 2 ) n NR 12 CO 2 R 12 ,

O(CH 2 ) n C(O)N(R 12 ) 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 11 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 12 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 any methylene (CH 2 ) carbon atom in R 12 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or two R 12 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 13 is independently selected from the group consisting of

hydrogen,

C 1-8 alkyl,

(CH 2 ) n -aryl,

(CH 2 ) n -heteroaryl,

(CH 2 ) n -heterocyclyl, and

(CH 2 ) n C 3-7 cycloalkyl;

wherein alkyl, aryl, heteroaryl, heterocyclyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, hydroxy, C 1-3 alkoxy, C 1-3 alkylthio, carboxy, C 1-4 alkyloxycarbonyl, amino, C 1-4 alkylamino, and di(C 1-4 alkylamino);

or two R 13 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 12 , 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 13 R 13 ),

(CH 2 ) n CO 2 R 13 ,

(CH 2 ) n COR 13 ,

(CH 2 ) n NR 13 C(O)R 13 ,

(CH 2 ) n NR 13 CO 2 R 13 ,

(CH 2 ) n NR 13 C(O)N(R 13 ) 2 ,

(CH 2 ) n NR 13 SO 2 R 13 ,

(CH 2 ) n S(O) p R 13 ,

(CH 2 ) n SO 2 N(R 13 )(R 13 ),

(CH 2 ) n OR 13 ,

(CH 2 ) n OC(O)R 13 ,

(CH 2 ) n OC(O)OR 13 ,

(CH 2 ) n OC(O)N(R 13 ) 2 ,

(CH 2 ) n N(R 13 )(R 13 ), and

(CH 2 ) n NR 13 SO 2 N(R 13 )(R 13 );

wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 11 ; alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 11 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 C 1-8 alkyl, (CH 2 ) n C 3-7 cycloalkyl, (CH 2 ) n -aryl, (CH 2 ) n -heterocyclyl, or (CH 2 ) n -heteroaryl; wherein aryl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 11 ; and (CH 2 ) n alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 11 and oxo.

2. The compound of claim 1 wherein R 2 is selected from the group consisting of

hydrogen,

C 1-8 alkyl,

CH 2 -aryl,

CH 2 -heteroaryl,

CH 2 -heterocyclyl,

CH 2 C 3-6 cycloalkyl,

CH 2 CO 2 R 12 ,

CH 2 CONR 12 R 12 ,

CH 2 OR 12 ,

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 11 ; and alkyl, cycloalkyl, and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 11 and oxo.

3. The compound of claim 2 wherein R 2 is hydrogen or C 1-4 alkyl.

4. The compound of claim 3 wherein R 2 is hydrogen.

5. The compound of claim 1 wherein X is selected from the group consisting of C 1-6 alkyl, (CH 2 ) n -phenyl, (CH 2 ) n -naphthyl, (CH 2 ) n -heteroaryl, (CH 2 ) n -heterocyclyl, (CH 2 ) n C(O)N(R 13 )(R 13 ), (CH 2 ) n CO 2 R 13 , (CH 2 ) n S(O) p R 13 , (CH 2 ) n OR 13 , (CH 2 ) n NR 13 C(O)R 13 , and (CH 2 ) n NR 13 SO 2 R 13 ; wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 11 ; alkyl and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 11 and oxo; and the (CH 2 ) n group is unsubstituted or substituted with one to three groups independently selected from R 12 , halogen, S(O) p R 12 , N(R 12 ) 2 , and OR 12 .

6. The compound of claim 5 wherein X is selected from the group consisting of C 1-6 alkyl, (CH 2 ) 0-1 -phenyl, (CH 2 ) 0-1 -heteroaryl, (CH 2 ) 0-1 -heterocyclyl, (CH 2 ) 0-1 NHC(O)R 13 , (CH 2 ) 0-1 CO 2 R 13 , and (CH 2 ) 0-1 C(O)N(R 13 )(R 13 ); wherein phenyl and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 11 ; and alkyl and heterocyclyl are unsubstituted or substituted with one to three groups independently selected from R 11 and oxo.

7. The compound of claim 6 wherein heteroaryl is selected from the group consisting of pyridyl, pyrazinyl, pyrimidinyl, triazolyl, tetrazolyl, thiadiazolyl, oxadiazolyl, pyrazolyl, and imidazolyl.

8. The compound of claim 1 wherein Y is C 3-6 cycloalkyl or C 1-6 alkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 11 and oxo.

9. The compound of claim 8 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 11 and oxo.

10. The compound of claim 1 wherein m is 1.

11. The compound of claim 1 wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each independently hydrogen or C 1-4 alkyl; or R 3 and R 5 and the carbon atoms to which they are attached form a 5- to 7-membered ring; or R 3 and R 9 and the carbon atoms to which they are attached form a 5- to 7-membered ring.

12. The compound of claim 11 wherein R 3 , R 4 , R 5 , and R 6 are each independently hydrogen or C 1-4 alkyl, and R 7 , R 8 , R 9 , and R 10 are hydrogen.

13. The compound of claim 12 wherein R 3 and R 5 are each independently hydrogen or C 1-4 alkyl; and R 4 and R 6 are hydrogen.

14. A compound of structural formula II:

wherein m is 1 or 2;

each R 11 is independently selected from the group consisting of

hydrogen,

halogen,

cyano,

C 1-4 alkyl,

C 1-4 alkoxy,

C 1-4 alkylthio,

trifluoromethyl, and

trifluoromethoxy;

R 2 is hydrogen or C 1-4 alkyl, unsubstituted or substituted with one to three groups independently selected from R 11 and oxo;

R 3 , R 5 , R 7 , and R 9 are each independently hydrogen or C 1-4 alkyl; or R 3 and R 5 and the carbon atoms to which they are attached form a 5- to 7-membered ring; or R 3 and R 9 and the carbon atoms to which they are attached form a 5- to 7-membered ring;

Y is C 5-7 cycloalkyl or C 1-6 alkyl, wherein alkyl and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 11 and oxo; and

X is selected from the group consisting of

15. The compound of claim 14 wherein the carbon atom marked with * has the R configuration.

16. The compound of claim 14 wherein m is 1.

17. The compound of claim 14 wherein R 3 and R 5 are each independently hydrogen or C 1-4 alkyl, and R 7 and R 9 are hydrogen.

18. The compound of claim 15 of structural formula III selected from the group consisting of:

(III)

R 3

R 5

R 7

R 9