Acylated piperidine derivatives as melanocortin-4 receptor modulators
Certain novel N-acylated spiropiperidine derivatives are ligands of the human melanocortin receptor(s) and, in particular, are selective ligands of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of MC-4R, such as obesity, diabetes, nicotine addiction, alcoholism, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.
1 . A compound of structural formula I:
or a pharmaceutically acceptable salt thereof; wherein
X is selected from the group consisting of:
(1) —C 1-8 alkyl,
(2) —(CH 2 ) n C 3-8 cycloalkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -naphthyl,
(5) —(CH 2 ) n -heteroaryl,
(6) —(CH 2 ) n heterocycloalkyl,
(7) —(CH 2 ) n C≡N,
(8) —(CH 2 ) n CON(R 5 ) 2 ,
(9) —(CH 2 ) n CO 2 R 5 ,
(10) —(CH 2 ) n COR 5 ,
(11) —(CH 2 ) n NR 5 C(O)R 5 ,
(12) —(CH 2 ) n NR 5 CO 2 R 5 ,
(13) —(CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,
(14) —(CH 2 ) n NR 5 SO 2 R 5 ,
(15) —(CH 2 ) n S(O) p R 5 ,
(16) —(CH 2 ) n SO 2 N(R 5 ) 2 ,
(17) —(CH 2 ) n OR 5 ,
(18) —(CH 2 ) n OC(O)R 5 ,
(19) —(CH 2 ) n OC(O)OR 5 ,
(20) —(CH 2 ) n OC(O)N(R 5 ) 2 ,
(21) —(CH 2 ) n N(R 5 ) 2 , and
(22) —(CH 2 ) n NR 5 SO 2 N(R 5 ) 2 ,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 4 , and alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 4 and oxo, and wherein any (CH 2 ) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl;
Y is selected from the group consisting of:
(1) hydrogen,
(2)-C 1-8 alkyl,
(3) —C 2-6 alkenyl,
(4) —(CH 2 ) n C 3-8 cycloalkyl,
(5) —(CH 2 ) n -phenyl,
(6) —(CH 2 ) n -naphthyl,
(7) —(CH 2 ) n -heteroaryl, and
(8) —(CH 2 ) n -heterocycloalkyl,
wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 4 , and alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three groups independently selected from R 4 and oxo, and wherein any (CH 2 ) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl;
Z is selected from the group consisting of:
(1) —CH—, and
(2) —N—;
R 1 is selected from the group consisting of:
(1) —(CH 2 ) n C 2-7 heterocycloalkyl,
(2) —(CH 2 ) n bridgedC 2-7 heterocycloalkyl, and
(3) —N(R 7 )C 2-7 heterocycloalkyl,
wherein heterocycloalkyl and (CH 2 ) n are unsubstituted or substituted with one to three groups independently selected from R 9 and oxo, provided that Z and R 1 are not attached via a N—N bond;
R 2 is selected from the group consisting of:
(1) phenyl,
(2) naphthyl, and
(3) heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to four groups independently selected from R 8 ;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) —C 1-8 alkyl,
(4) —OC 1-8 alkyl,
(5) halogen,
(6) —N(R 5 ) 2 ,
(7) —SR 5 , and
(8) —CF 3 ,
wherein two C 1-8 alkyl substituents along with the atoms to which they are attached can form a 4- to 8-membered cycloalkyl or heterocycloalkyl ring, and provided that when Z is —N—, Y is H or —OH, X is phenyl substituted with one to three R 4 substituents and at least one R 4 is —C 1-4 alkyl, —(CH 2 ) 0-2 C 3-5 cycloalkyl, halogen, —(CH 2 ) 0-3 OR a , CN, CO 2 R b , —(CH 2 ) 0-2 NR b SO 2 R c C, CF 3 , CH 2 CF 3 , OCF 3 , or OCH 2 CF 3 , wherein R a , R b and R c C are —H, —CH 3 , or —CH 2 CH 3 , then both R 3 substituents are not methyl;
each R 4 is independently selected from the group consisting of:
(1) —C 1-8 alkyl,
(2) —C 2-8 alkenyl,
(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) —(CH 2 ) n -halogen,
(9) —(CH 2 ) n —OR 6 ,
(10) —(CH 2 ) n —OSi(C 1-6 alkyl) 3 ,
(11) —(CH 2 ) n C(O)R 6 ,
(12) —(CH 2 ) n OC(O)R 6 ,
(13) —(CH 2 ) n C(O)OR 6 ,
(14) —(CH 2 ) n C≡N,
(15) —NO 2 ,
(16) —(CH 2 ) n N(R 6 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 6 ) 2 ,
(18) —(CH 2 ) n NR 6 C(O)R 6 ,
(19) —(CH 2 ) n NR 6 C(O)OR 6 ,
(20) —(CH 2 ) n NR 6 C(O)-heteroaryl,
(21) —(CH 2 ) n NR 6 C(O)N(R 6 ) 2 ,
(22) —(CH 2 ) n C(O)NR 6 N(R 6 ) 2 ,
(23) —(CH 2 ) n C(O)NR 6 NR 6 C(O)R 6 ,
(24) —(CH 2 ) n NR 6 S(O) p R 6 ,
(25) —(CH 2 ) n S(O) p N(R 6 ) 2 ,
(26) —(CH 2 ) n S(O) p R 6 ,
(27) —O(CH 2 ) n C(O)N(R 6 ) 2 ,
(28) —CF 3 ,
(29) —CH 2 CF 3 ,
(30) —OCF 3 , and
(31) —OCH 2 CF 3 ,
wherein alkenyl, phenyl, naphthyl, heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, —CO 2 C 1-6 alkyl, and —CO 2 H, and wherein any alkyl, cycloalkyl, and heterocycloalkyl in R 4 is unsubstituted or substituted with one or two groups independently selected from halogen, hydroxy, oxo, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, —CO 2 C 1-6 alkyl, and —CO 2 H, or two R 4 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
R 5 is independently selected from the group consisting of
(1) hydrogen,
(2) —C 1-8 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —C 1-8 alkoxy,
(6) —(CH 2 ) n C 3-7 cycloalkyl,
(7) —(CH 2 ) n C 2-7 heterocycloalkyl,
(8) —(CH 2 ) n -phenyl,
(9) —(CH 2 ) n -naphthyl,
(10) —(CH 2 ) n -heteroaryl, and
(11) —(CH 2 ) n C 3-7 bicycloalkyl,
wherein alkenyl, alkynyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 4 , and alkyl, alkoxy, cycloalkyl, heterocycloalkyl, and bicycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 4 and oxo, and wherein any (CH 2 ) in R 5 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl, or two R 5 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 6 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n -naphthyl,
(6) —(CH 2 ) n -heterocycloalkyl,
(7) —(CH 2 ) n C 3-7 cycloalkyl,
(8) —(CH 2 ) n C 3-7 bicycloalkyl,
(9) —(CH 2 ) n CF 3 , and
(10) —(CH 2 ) n CHF 2 ,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy, or two R 6 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 O, S, and NC 1-4 alkyl;
each R 7 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-8 alkyl,
wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy;
each R 8 is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —(CH 2 ) n phenyl,
(3) —(CH 2 ) n naphthyl,
(4) —(CH 2 ) n heteroaryl,
(5) —(CH 2 ) n C 2-7 heterocycloalkyl,
(6) —(CH 2 ) n C 3-7 cycloalkyl,
(7) halogen,
(8) —OR 6 ,
(9) —(CH 2 ) n N(R 6 ) 2 ,
(10) —(CH 2 ) n C≡N,
(11) —(CH 2 ) n CO 2 R 6 ,
(12) —NO 2 ,
(13) —(CH 2 ) n NR 6 S(O) p R 6 ,
(14) —(CH 2 ) n S(O) p N(R 6 ) 2 ,
(15) —(CH 2 ) n S(O) p R 6 ,
(16) —(CH 2 ) n NR 6 C(O)N(R 6 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 6 ) 2 ,
(18) —(CH 2 ) n NR 6 C(O)R 6 ,
(19) —(CH 2 ) n NR 6 CO 2 R 6 ,
(20) —(CH 2 ) n NR 6 C(O)-heteroaryl,
(21) —(CH 2 ) n C(O)NR 6 N(R 6 ) 2 ,
(22) —(CH 2 ) n C(O)NR 6 NR 6 C(O)R 6 ,
(23) —O(CH 2 ) n C(O)N(R 6 ) 2 ,
(24) —CF 3 ,
(25) —CH 2 CF 3 ,
(26) —OCF 3 , and
(27) —OCH 2 CF 3 ,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, —C 1-6 alkyl, trifluoromethyl, and C 1-4 alkoxy, and wherein alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, oxo, —C 1-6 alkyl, trifluoromethyl, and C 1-4 alkoxy;
each R 9 is independently selected from the group consisting of:
(1) —(CH 2 ) n -halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n —CO 2 R 6 ,
(4) —(CH 2 ) n —OR 6 ,
(5) —(CH 2 ) n -phenyl,
(6) —(CH 2 ) n -heteroaryl,
(7) —(CH 2 ) n -naphthyl,
(8) —(CH 2 ) n -heterocycloalkyl,
(9)-(CH 2 ) n C 3-7 cycloalkyl,
(10) —(CH 2 ) n C 3-7 bicycloalkyl,
(11) —(CH 2 ) n CF 3 , and
(12) —(CH 2 ) n CHF 2 ,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy, or two R 6 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 O, S, and NC 1-4 alkyl;
r is 1 or 2;
s is 0, 1, or 2;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, or 2.
2 . The compound of claim 1 wherein each R 3 is hydrogen; or a pharmaceutically acceptable salt thereof.
3 . The compound of claim 1 wherein R 2 is phenyl substituted with one to four groups independently selected from R 8 ; or a pharmaceutically acceptable salt thereof.
4 . The compound of claim 1 wherein X is selected from the group consisting of: -phenyl, -pyridyl and —(CH 2 ) n CON(R 5 ) 2 , wherein phenyl and pyridyl are unsubstituted or substituted with one to three groups independently selected from R 4 , and any (CH 2 ) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
5 . The compound of claim 1 wherein R 4 is independently selected from the group consisting of: —C 1-8 alkyl, —(CH 2 ) n -heteroaryl, —(CH 2 ) n -halogen, —(CH 2 ) n NR 6 C(O)R 6 , and —(CH 2 ) n NR 6 S(O) p R 6 , wherein heteroaryl is unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, —CO 2 C 1-6 alkyl, and —CO 2 H, and wherein any alkyl in R 4 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, oxo, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, —CO 2 C 1-6 alkyl; or a pharmaceutically acceptable salt thereof.
6 . The compound of claim 1 wherein Y is hydrogen, and X is phenyl or pyridyl, wherein phenyl and pyridyl are substituted with one to three groups independently selected from R 4 ; or a pharmaceutically acceptable salt thereof.
7 . The compound of claim 1 , wherein Y is cyclohexane and X is —C(O)NHC(CH 3 ) 3 ; or a pharmaceutically acceptable salt thereof.
8 . The compound of claim 1 wherein Z is —CH—; or a pharmaceutically acceptable salt thereof.
9 . The compound of claim 1 wherein Z is —N—; or a pharmaceutically acceptable salt thereof.
10 . The compound of claim 1 wherein r is 1 and s is 1.
11 . The compound of claim 1 of structural formula IIa or IIb of the indicated trans relative stereochemical configuration:
or a pharmaceutically acceptable salt thereof; wherein
X is selected from the group consisting of
(1) —C 1-8 alkyl,
(2) —(CH 2 ) n C 3-8 cycloalkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -naphthyl,
(5) —(CH 2 ) n -heteroaryl,
(6) —(CH 2 ) n heterocycloalkyl,
(7) —(CH 2 ) n C≡N,
(8) —(CH 2 ) n CON(R 5 ) 2 ,
(9) —(CH 2 ) n CO 2 R 5 ,
(10) —(CH 2 ) n COR 5 ,
(11) —(CH 2 ) n NR 5 C(O)R 5 ,
(12) —(CH 2 ) n NR 5 CO 2 R 5 ,
(13) —(CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,
(14) —(CH 2 ) n NR 5 SO 2 R 5 ,
(15) —(CH 2 ) n S(O) p R 5 ,
(16) —(CH 2 ) n SO 2 N(R 5 ) 2 ,
(17) —(CH 2 ) n OR 5 ,
(18) —(CH 2 ) n OC(O)R 5 ,
(19) —(CH 2 ) n OC(O)OR 5 ,
(20) —(CH 2 ) n OC(O)N(R 5 ) 2 ,
(21) —(CH 2 ) n N(R 5 ) 2 , and
(22) —(CH 2 ) n NR 5 SO 2 N(R 5 ) 2 ,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 4 , and alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 4 and oxo, and wherein any (CH 2 ) in X is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl;
Y is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-8 alkyl,
(3) —C 2-6 alkenyl,
(4) —(CH 2 ) n C 3-8 cycloalkyl,
(5) —(CH 2 ) n -phenyl,
(6) —(CH 2 ) n -naphthyl,
(7) —(CH 2 ) n -heteroaryl, and
(8) —(CH 2 ) n -heterocycloalkyl,
wherein alkenyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 4 , alkyl, cycloalkyl, and heterocycloalkyl are optionally substituted with one to three groups independently selected from R 4 and oxo, and wherein any (CH 2 ) in Y is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl;
Z is selected from the group consisting of:
(1) —CH—, and
(2) —N—;
R 1 is selected from the group consisting of:
(1) —(CH 2 ) n C 2-7 heterocycloalkyl,
(2) —(CH 2 ) n bridgedC 2-7 heterocycloalkyl, and
(3) —N(R 7 )C 2-7 heterocycloalkyl,
wherein heterocycloalkyl and (CH 2 ) n are unsubstituted or substituted with one to three groups independently selected from R 9 and oxo, provided that Z and R 1 are not attached via a N—N bond;
R 2 is selected from the group consisting of:
(1) phenyl,
(2) naphthyl, and
(3) heteroaryl,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to four groups independently selected from R 8 ;
each R 3 is independently selected from the group consisting of:
(1) hydrogen,
(2) —OH,
(3) —C 1-8 alkyl,
(4) —OC 1-8 alkyl,
(5) halogen,
(6) —N(R 5 ) 2 ,
(7) —SR 5 , and
(8) —CF 3 ,
wherein two C 1-8 alkyl substituents along with the atoms to which they are attached can form a 4- to 8-membered cycloalkyl or heterocycloalkyl ring, and provided that when Z is —N—, Y is H or —OH, X is phenyl substituted with one to three R 4 substituents and at least one R 4 is C 1-4 alkyl, —(CH 2 ) 0-2 C 3-5 cycloalkyl, halogen, —(CH 2 ) 0-3 OR a , CN, CO 2 R b , —(CH 2 ) 0-2 NR b SO 2 R c , CF 3 , CH 2 CF 3 , OCF 3 , or OCH 2 CF 3 , wherein R a , R b and R c are —H, —CH 3 , or —CH 2 CH 3 , then both R 3 substituents are not methyl;
each R 4 is independently selected from the group consisting of:
(1)-C 1-8 alkyl,
(2) —C 2-8 alkenyl,
(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) —(CH 2 ) n -halogen,
(9) —(CH 2 ) n —OR 6 ,
(10) —(CH 2 ) n —OSi(C 1-6 alkyl) 3 ,
(11) —(CH 2 ) n C(O)R 6 ,
(12) —(CH 2 ) n OC(O)R 6 ,
(13) —(CH 2 ) n C(O)OR 6 ,
(14) —(CH 2 ) n C═N,
(15) —NO 2 ,
(16) —(CH 2 ) n N(R 6 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 6 ) 2 ,
(18) —(CH 2 ) n NR 6 C(O)R 6 ,
(19) —(CH 2 ) n NR 6 C(O)OR 6 ,
(20) —(CH 2 ) n NR 6 C(O)-heteroaryl,
(21) —(CH 2 ) n NR 6 C(O)N(R 6 ) 2 ,
(22) —(CH 2 ) n C(O)NR 6 N(R 6 ) 2 ,
(23) —(CH 2 ) n C(O)NR 6 NR 6 C(O)R 6 ,
(24) —(CH 2 ) n NR 6 S(O) p R 6 ,
(25) —(CH 2 ) n S(O) p N(R 6 ) 2 ,
(26) —(CH 2 ) n S(O) p R 6 ,
(27) —O(CH 2 ) n C(O)N(R 6 ) 2 ,
(28) —CF 3 ,
(29) —CH 2 CF 3 ,
(30) —OCF 3 , and
(31) —OCH 2 CF 3 ,
wherein alkenyl, phenyl, naphthyl, heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, —CO 2 C 1-6 alkyl, and —CO 2 H, and wherein any alkyl, cycloalkyl, and heterocycloalkyl in R 4 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, oxo, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, —CO 2 C 1-6 alkyl, and —CO 2 H, or two R 4 substituents on the same carbon atom are taken together with the carbon atom to form a cyclopropyl group;
R 5 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-8 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —C 1-8 alkoxy,
(6) —(CH 2 ) n C 3-7 cycloalkyl,
(7) —(CH 2 ) n C 2-7 heterocycloalkyl,
(8) —(CH 2 ) n -phenyl,
(9) —(CH 2 ) n -naphthyl,
(10) —(CH 2 ) n -heteroaryl, and
(11) —(CH 2 ) n C 3-7 bicycloalkyl,
wherein alkenyl, alkynyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 4 , and alkyl, alkoxy, cycloalkyl, heterocycloalkyl, and bicycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 4 and oxo, and wherein any (CH 2 ) in R 5 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl, or two R 5 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 6 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n -naphthyl,
(6) —(CH 2 ) n -heterocycloalkyl,
(7) —(CH 2 ) n C 3-7 cycloalkyl,
(8) —(CH 2 ) n C 3-7 bicycloalkyl,
(9) —(CH 2 ) n CF 3 , and
(10) —(CH 2 ) n CHF 2 ,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy, or two R 6 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 O, S, and NC 1-4 alkyl;
each R 7 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-8 alkyl,
wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy;
each R 8 is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —(CH 2 ) n phenyl,
(3) —(CH 2 ) n naphthyl,
(4) —(CH 2 ) n heteroaryl,
(5) —(CH 2 ) n C 2-7 heterocycloalkyl,
(6) —(CH 2 ) n C 3-7 cycloalkyl,
(7) halogen,
(8) —OR 6 ,
(9) —(CH 2 ) n N(R 6 ) 2 ,
(10) —(CH 2 ) n C═N,
(11) —(CH 2 ) n CO 2 R 6 ,
(12) —NO 2 ,
(13) —(CH 2 ) n NR 6 S(O) p R 6 ,
(14) —(CH 2 ) n S(O) p N(R 6 ) 2 ,
(15) —(CH 2 ) n S(O) p R 6 ,
(16) —(CH 2 ) n NR 6 C(O)N(R 6 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 6 ) 2 ,
(18) —(CH 2 ) n NR 6c (O)R 6 ,
(19) —(CH 2 ) n NR 6c O 2 R 6 ,
(20) —(CH 2 ) n NR 6 C(O)-heteroaryl,
(21) —(CH 2 ) n C(O)NR 6 N(R 6 ) 2 ,
(22) —(CH 2 ) n C(O)NR 6 NR 6 C(O)R 6 ,
(23) —O(CH 2 ) n C(O)N(R 6 ) 2 ,
(24) —CF 3 ,
(25) —CH 2 CF 3 ,
(26) —OCF 3 , and
(27) —OCH 2 CF 3 ,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, —C 1-6 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 1-6 alkyl, trifluoromethyl, and C 1-4 alkoxy;
each R 9 is independently selected from the group consisting of:
(1) —(CH 2 ) n -halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n —CO 2 R 6 ,
(4) —(CH 2 ) n —OR 6 ,
(5) —(CH 2 ) n -phenyl,
(6) —(CH 2 ) n -heteroaryl,
(7) —(CH 2 ) n -naphthyl,
(8) —(CH 2 ) n -heterocycloalkyl,
(9) —(CH 2 ) n C 3-7 cycloalkyl,
(10) —(CH 2 ) n C 3-7 bicycloalkyl,
(11) —(CH 2 ) n CF 3 , and
(12) —(CH 2 ) n CHF 2 ,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy, or two R 6 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 O, S, and NC 1-4 alkyl;
r is 1 or 2;
s is 0, 1, or 2;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, or 2.
12 . The compound of claim 1 of the following structural formula IIa and IIb with the indicated trans relative stereochemical configuration:
or a pharmaceutically acceptable salt thereof; wherein
X is selected from the group consisting of:
(1) phenyl, and
(2) pyridyl,
wherein phenyl and pyridyl are unsubstituted or substituted with one to three groups independently selected from R 4 ;
Y is hydrogen;
Z is selected from the group consisting of:
(1) —CH—, and
(2) —N—;
R 1 is selected from the group consisting of:
(1) tetrahydropyran,
(2) pyrrolidine,
(3) 2-oxa-5-azabicyclo[2.2.1]heptane, and
(4) —N(CH 3 )-tetrahydropyran,
wherein R 1 is unsubstituted or substituted with one to three groups independently selected from R 4 and oxo wherein heterocycloalkyl and (CH 2 ) n are unsubstituted or substituted with one to three groups independently selected from R 9 and oxo, provided that Z and R 1 are not attached via a N—N bond.
R 2 is 2,4-difluorophenyl;
each R 3 is hydrogen;
each R 4 is independently selected from the group consisting of:
(1) —C 1-8 alkyl,
(2) —(CH 2 ) n -heteroaryl,
(3) —(CH 2 ) n -halogen,
(4) —(CH 2 ) n NR 6 C(O)R 6 , and
(5) —(CH 2 ) n NR 6 S(O) p R 6 ,
wherein heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, —CO 2 C 1-6 alkyl, and —CO 2 H, and wherein any alkyl in R 4 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, oxo, —C 1-6 alkyl, trifluoromethyl, —C 1-6 alkoxy, and —CO 2 C 1-6 alkyl;
R 5 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-8 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —C 1-8 alkoxy,
(6) —(CH 2 ) n C 3-7 cycloalkyl,
(7) —(CH 2 ) n C 2-7 heterocycloalkyl,
(8) —(CH 2 ) n -phenyl,
(9) —(CH 2 ) n -naphthyl,
(10) —(CH 2 ) n -heteroaryl, and
(11) —(CH 2 ) n C 3-7 bicycloalkyl,
wherein alkenyl, alkynyl, phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three groups independently selected from R 4 , and alkyl, alkoxy, cycloalkyl, heterocycloalkyl, and bicycloalkyl are unsubstituted or substituted with one to three groups independently selected from R 4 and oxo, and wherein any (CH 2 ) in R 5 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and —C 1-6 alkyl, or two R 5 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 6 is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n -phenyl,
(4) —(CH 2 ) n -heteroaryl,
(5) —(CH 2 ) n -naphthyl,
(6) —(CH 2 ) n -heterocycloalkyl,
(7) —(CH 2 ) n C 3-7 cycloalkyl,
(8) —(CH 2 ) n C 3-7 bicycloalkyl,
(9) —(CH 2 ) n CF 3 , and
(10) —(CH 2 ) n CHF 2 ,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy, or two R 6 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 O, S, and NC 1-4 alkyl;
each R 7 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-8 alkyl,
wherein alkyl is unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy;
each R 8 is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —(CH 2 ) n phenyl,
(3) —(CH 2 ) n naphthyl,
(4) —(CH 2 ) n heteroaryl,
(5) —(CH 2 ) n C 2-7 heterocycloalkyl,
(6) —(CH 2 ) n C 3-7 cycloalkyl,
(7) halogen,
(8) —OR 6 ,
(9) —(CH 2 ) n N(R 6 ) 2 ,
(10) —(CH 2 ) n C═N,
(11) —(CH 2 ) n CO 2 R 6 ,
(12) —NO 2 ,
(13) —(CH 2 ) n NR 6 S(O) p R 6 ,
(14) —(CH 2 ) n S(O) p N(R 6 ) 2 ,
(15) —(CH 2 ) n S(O) p R 6 ,
(16) —(CH 2 ) n NR 6 C(O)N(R 6 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 6 ) 2 ,
(18) —(CH 2 ) n NR 6 C(O)R 6 ,
(19) —(CH 2 ) n NR 6 CO 2 R 6 ,
(20) —(CH 2 ) n NR 6 C(O)-heteroaryl,
(21) —(CH 2 ) n C(O)NR 6 N(R 6 ) 2 ,
(22) —(CH 2 ) n C(O)NR 6 NR 6 C(O)R 6 ,
(23) —O(CH 2 ) n C(O)N(R 6 ) 2 ,
(24) —CF 3 ,
(25) —CH 2 CF 3 ,
(26) —OCF 3 , and
(27) —OCH 2 CF 3 ,
wherein phenyl, naphthyl, and heteroaryl are unsubstituted or substituted with one to three substituents independently selected from halogen, hydroxy, —C 1-6 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 1-6 alkyl, trifluoromethyl, and C 1-4 alkoxy;
each R 9 is independently selected from the group consisting of:
(1) —(CH 2 ) n -halogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) n —CO 2 R 6 ,
(4) —(CH 2 ) n —OR 6 ,
(5) —(CH 2 ) n -phenyl,
(6) —(CH 2 ) n -heteroaryl,
(7) —(CH 2 ) n -naphthyl,
(8) —(CH 2 ) n -heterocycloalkyl,
(9) —(CH 2 ) n C 3-7 cycloalkyl,
(10) —(CH 2 ) n C 3-7 bicycloalkyl,
(11)-(CH 2 ) n CF 3 , and
(12) —(CH 2 ) n CHF 2 ,
wherein alkyl, phenyl, heteroaryl, heterocycloalkyl, and cycloalkyl are unsubstituted or substituted with one to three groups independently selected from halogen, —C 1-6 alkyl, hydroxy, and C 1-4 alkoxy, or two R 6 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 O, S, and NC 1-4 alkyl;
r is 1 or 2;
s is 0, 1, or 2;
n is 0, 1, 2, 3, or 4; and
p is 0, 1, or 2.
13 . The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14 . A composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
15 . (canceled)
16 . A method of treating diseases mediated by the melanocortin-4 receptor in a subject in need thereof by administering a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
17 . The method according to claim 16 wherein the disease mediated by the melanocortin-4 receptor is selected from the group consisting of: obesity, diabetes mellitus, male erectile dysfunction and an obesity-related disorder.