Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators

1. A compound of structural formula IIIa or IIIb of the indicated trans relative stereochemical configuration:

or a pharmaceutically acceptable salt thereof; wherein

X is oxygen or CH 2 ;

Y is C(R 6 ) 2 or C═C(R 6 ) 2 ;

Z is independently selected from the group consisting of:

(1) CH, and

(2) N,

provided that when Z is N, R 1 is not —NR 7 C 2-7 heterocycloalkyl;

R 1 is selected from the group consisting of

(1) C 1-6 alkyl,

(2) —N(R 7 )C 2-7 heterocycloalkyl,

(3) —(CH 2 ) n C 2-7 heterocycloalkyl,

(4) —C(O)C 1-6 alkyl,

(5) —C(O)heteroaryl,

wherein heteroaryl is unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;

R 3 is selected from the group consisting of:

(1) hydrogen,

(2) C 1-8 alkyl,

(3) —(CH 2 ) n -phenyl,

(4) —(CH 2 ) n -naphthyl,

(5) —(CH 2 ) n -heteroaryl,

(6) —(CH 2 ) n C 2-7 heterocycloalkyl,

(7) —(CH 2 ) n C 3-7 cycloalkyl,

(8) halogen,

(9) OR 5 ,

(10) —(CH 2 ) n N(R 5 ) 2 ,

(11) —(CH 2 ) n C≡N,

(12) —(CH 2 ) n C(O)OR 5 ,

(13) —(CH 2 ) n OC(O)R 5 ,

(14) NO 2 ,

(15) —(CH 2 ) n NR 5 S(O) p R 5 ,

(16) —(CH 2 ) n N(S(O) p R 5 ) 2 ,

(17) —(CH 2 ) n S(O) p N(R 5 ) 2 ,

(18) —(CH 2 ) n S(O) p R 5 ,

(19) —(CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,

(20) —(CH 2 ) n C(O)N(R 5 ) 2 ,

(21) —(CH 2 ) n NR 5 C(O)R 5 ,

(22) —(CH 2 ) n NR 5 CO 2 R 5 ,

(23) —(CH 2 ) n NR 5 C(O)-heteroaryl,

(24) —(CH 2 ) n C(O)NR 5 N(R 5 ) 2 ,

(25) —(CH 2 ) n C(O)NR 5 NR 5 C(O)R 5 ,

(26) O(CH 2 ) n C(O)N(R 5 ) 2 ,

(27) CF 3 ,

(28) CH 2 CF 3 ,

(29) OCF 3 , and

(30) OCH 2 CF 3 ,

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

R 4a and R 4b are independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-8 alkyl,

(3) halogen,

(4) CF 3 ,

wherein alkyl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, C 1-4 alkyl, trifluoromethyl, and C 1-4 alkoxy;

each R 5 is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-8 alkyl,

(3) —(CH 2 ) n C 3-7 cycloalkyl,

(4) —(CH 2 ) n C 2-7 heterocycloalkyl,

(5) —(CH 2 ) n -phenyl,

(6) —(CH 2 ) n -naphthyl,

(7) —(CH 2 ) n -heteroaryl, and

(8) —(CH 2 ) n C 3-7 bicycloalkyl,

wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, naphthyl, cycloalkyl, bicycloalkyl and (CH 2 ) are unsubstituted or substituted with one to three groups independently selected from halogen, C 1-4 alkyl, hydroxy, and C 1-4 alkoxy, or wherein two R 5 groups together with the atom to which they are attached form a 4- to 8-membered mono- or bicyclic ring system optionally containing an additional heteroatom selected from 0, S, and —NC 1-4 alkyl;

each R 6 is independently selected from the group consisting of: hydrogen,

(2) —(CH 2 ) n -heteroaryl,

(3) —(CH 2 ) n C(O)N(R 5 ) 2 ,

(4) —(CH 2 ) n C(O)N(R 5 )N(R 5 )C(O)R 5 ,

(5) —(CH 2 ) n CN,

(6) —(CH 2 ) n N(R 5 ) 2 ,

(7) —(CH 2 ) n N(R 5 )C(O)R 5 ,

wherein heteroaryl is unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein any methylene carbon (CH 2 ) in R 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl;

each R 7 and R 8 is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) C 3-7 cycloalkyl,

(4) C 2-7 heterocycloalkyl,

(5) phenyl,

(6) naphthyl, and

(7) heteroaryl,

wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 3 and oxo;

each R 10 is independently selected from the group consisting of:

(1) hydrogen,

(2) C 1-6 alkyl,

(3) (CH 2 ) n phenyl,

(4) halogen,

(5) —OR 5 ,

(6) (CH 2 ) n CN,

(7) CF 3 ,

(8) CH 2 CF 3 ,

(9) OCF 3 , and

(10) OCH 2 CF 3 ,

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

each R 11 is hydrogen;

r is 2;

s is 1;

n is 0, 1, 2, or 3; and

p is 0, 1, or 2.

2. A compound of claim 1 which is

or a pharmaceutically acceptable salt thereof.

3. A compound of claim 2 which is:

or a pharmaceutically acceptable salt thereof.

4. A compound of claim 2 which is:

or a pharmaceutically acceptable salt thereof.

5. A compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. A pharmaceutical composition which comprises a compound of claim 1 and a pharmaceutically acceptable carrier.

7. A compound of claim 2 wherein the pharmaceutically acceptable salt thereof is the bis trifluoroacetic acid salt.