Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
View Patent ↗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:
a, b and c are all single bonds or all double bonds;
Y is selected from the group consisting of:
(1) —C(R 7 )(R 6 ),
(2) —N(R 6 ),
(3) C(O),
(4) oxygen,
(5) sulfur,
(6) S(O), and
(7) S(O) 2 ;
X is selected from the group consisting of:
(1) CH 2 ,
(2) —C(R 7 )(R 6 ),
(3) C(O),
(4) oxygen,
(5) N(R 6 ),
(6) sulfur,
(7) S(O), and
(8) S(O) 2 ;
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, and
(2) —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 3 and oxo;
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 three groups independently selected from R 8 ;
R 3 and R 4 are independently 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;
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 O, S, and —NC 1-4 alkyl;
each R 6 is independently selected from the group consisting of:
(1) —(CH 2 ) n C 2-7 heterocycloalkyl,
(2) C 1-6 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 -heteroaryl,
(7) —(CH 2 ) n C(O)R 5 ,
(8) —(CH 2 ) n C(O)OR 5 ,
(9) —(CH 2 ) n C(OH)R 5 ,
(10) —(CH 2 ) n C(O)(CH 2 ) n N(R 5 ) 2 ,
(11) —(CH 2 ) n C(O)(CH 2 ) n NR 7 R 8 ,
(12) —(CH 2 ) n —OR 5 ,
(13) —(CH 2 ) n —OC(O)R 5 ,
(14) —(CH 2 ) n —O—(CH 2 ) n —N(R 5 ) 2 ,
(15) —(CH 2 ) n CN,
(16) —(CH 2 ) n N(R 5 ) 2 ,
(17) —(CH 2 ) n N(R 5 )C(O)R 5 ,
(18) —(CH 2 ) n N(R 5 )C(O)OR 5 ,
(19) —(CH 2 ) n N(R 5 )C(O)(CH 2 ) n N(R 5 ) 2 ,
(20) —(CH 2 ) n N(R 5 )—S(O)—C 1-8 alkyl,
(21) —(CH 2 ) n N(R 5 )—S(O) 2 —C 1-8 alkyl,
(22) —(CH 2 ) n —S—R 5 ,
(23) —(CH 2 ) n —S(O)—R 5 , and
(24) —(CH 2 ) n —S(O) 2 —R 5 ,
wherein phenyl 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, and wherein any methylene (CH 2 ) in R 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or wherein two R 6 groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N,
wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R 3 and oxo;
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 1-4 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 5 ,
(9) —(CH 2 ) n N(R 5 ) 2 ,
(10) —(CH 2 ) n C═N,
(11) —(CH 2 ) n CO 2 R 5 ,
(12) —NO 2 ,
(13) —(CH 2 ) n NR 5 S(O) p R 5
(14) —(CH 2 ) n S(O) p N(R 5 ) 2 ,
(15) —(CH 2 ) n S(O) p R 5 ,
(16) —(CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 5 ) 2 ,
(18) —(CH 2 ) n NR 5 C(O)R 5 ,
(19) —(CH 2 ) n NR 5 CO 2 R 5 ,
(20) —(CH 2 ) n NR 5 C(O)-heteroaryl,
(21) —(CH 2 ) n C(O)NR 5 N(R 5 ) 2 ,
(22) —(CH 2 ) n C(O)NR 5 NR 5 C(O)R 5 ,
(23) —O(CH 2 ) n C(O)N(R 5 ) 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 1-4 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;
each R 9 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) —NR 5 ,
(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 ring;
r is l or 2;
s is 1 or 2;
n is 0, 1, 2, or 3; and
p is 0, 1, or 2.
2. The compound of claim 1 wherein a, b and c are double bonds,
and pharmaceutically acceptable salts thereof.
3. The compound of claim 2 wherein R 9 is hydrogen, and pharmaceutically acceptable salts thereof.
4. The compound of claim 3 wherein Y is selected from the group consisting of:
—C(R 7 )(R 6 ) and —N(R 6 ), and pharmaceutically acceptable salts thereof.
5. The compound of claim 3 wherein X is selected from the group consisting of: CH 2 , C(O), and oxygen, and pharmaceutically acceptable salts thereof.
6. The compound of claim 3 wherein R 2 is phenyl unsubstituted or substituted with one to three groups independently selected from R 8 , and pharmaceutically acceptable salts thereof.
7. The compound of claim 2 wherein R 4 is selected from the group consisting of: hydrogen, C 1-8 alkyl, and halogen, and pharmaceutically acceptable salts thereof.
8. The compound of claim 2 wherein Z is CH.
9. The compound of claim 6 wherein Z is N.
10. The compound of claim 2 wherein r is 1 or 2, 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
a, b and c are all single bonds or all double bonds;
Y is selected from the group consisting of:
(1) —C(R 7 )(R 6 ),
(2) —N(R 6 ),
(3) C(O),
(4) oxygen,
(5) sulfur,
(6) S(O), and
(7) S(O) 2 ;
X is selected from the group consisting of:
(1) CH 2 ,
(2) —C(R 7 )(R 6 ),
(3) C(O),
(4) oxygen,
(5) N(R 6 ),
(6) sulfur,
(7) S(O), and
(8) S(O) 2 ;
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, and
(2) —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 3 and oxo;
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 three groups independently selected from R 8 ;
R 3 and R 4 are independently 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;
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 O, S, and —NC 1-4 alkyl;
each R 6 is independently selected from the group consisting of:
(1) —(CH 2 ) n C 2-7 heterocycloalkyl,
(2) C 1-6 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 heteroaryl,
(7) —(CH 2 ) n C(O)R 5 ,
(8) —(CH 2 ) n C(O)OR 5 ,
(9) —(CH 2 ) n C(OH)R 5 ,
(10) —(CH 2 ) n C(O)(CH 2 ) n N(R 5 ) 2 ,
(11) —(CH 2 ) n C(O)(CH 2 ) n NR 7 R 8 ,
(12) —(CH 2 ) n —OR 5 ,
(13) —(CH 2 ) n —OC(O)R 5 ,
(14) —(CH 2 ) n —O—(CH 2 ) n —N(R 5 ) 2 ,
(15) —(CH 2 ) n CN,
(16) —(CH 2 ) n N(R 5 ) 2 ,
(17) —(CH 2 ) n N(R 5 )C(O)R 5 ,
(18) —(CH 2 ) n N(R 5 )C(O)OR 5 ,
(19) —(CH 2 ) n N(R 5 )C(O)(CH 2 ) n N(R 5 ) 2 ,
(20) —(CH 2 ) n N(R 5 )—S(O)—C 1-8 alkyl,
(21) —(CH 2 ) n N(R 5 )—S(O) 2 —C 1-8 alkyl,
(22) —(CH 2 ) n —S—R 5 ,
(23) —(CH 2 ) n —S(O)—R 5 , and
(24) —(CH 2 ) n —S(O) 2 —R 5 ,
wherein phenyl 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, and wherein any methylene (CH 2 ) in R 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or wherein two R 6 groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R 3 and oxo;
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 1-4 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 5 ,
(9) —(CH 2 ) n N(R 5 ) 2 ,
(10) —(CH 2 ) n C≡N,
(11) —(CH 2 ) n CO 2 R 5 ,
(12) —NO 2 ,
(13) —(CH 2 ) n NR 5 S(O) p R 5
(14) —(CH 2 ) n S(O) p N(R 5 ) 2 ,
(15) —(CH 2 ) n S(O) p R 5 ,
(16) —(CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,
(17) —(CH 2 ) n C(O)N(R 5 ) 2 ,
(18) —(CH 2 ) n NR 5 C(O)R 5 ,
(19) —(CH 2 ) n NR 5 CO 2 R 5 ,
(20) —(CH 2 ) n NR 5 C(O)-heteroaryl,
(21) —(CH 2 ) n C(O)NR 5 N(R 5 ) 2 ,
(22) —(CH 2 ) n C(O)NR 5 NR 5 C(O)R 53
(23) —O(CH 2 ) n C(O)N(R 5 ) 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 1-4 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;
each R 9 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) —NR 5 ,
(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 ring;
r is 1 or 2;
s is 1 or 2;
n is 0, 1, 2, or 3; and
p is 0, 1, or 2.
12. The compound of claim 1 of structural formula IIIa or IIIb of the indicated trans relative stereochemical configuration:
or a pharmaceutically acceptable salt thereof, wherein a, b and c are all single bonds or all double bonds;
Y is selected from the group consisting of:
(1) —C(R 7 )(R 6 ), and
(2) —N(R 6 );
X is selected from the group consisting of:
(1) CH 2 ,
(2) C(O),
(3) oxygen,
(4) sulfur,
(5) S(O), and
(6) S(O) 2 ;
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, and
(2) —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 3 and oxo;
each R 3 is independently selected from the group consisting of:
(1) C 1-8 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 5 ,
(9) —(CH 2 ) n N(R 5 ) 2 ,
(10) —(CH 2 ) n C≡N,
(11) —(CH 2 ) n C(O)OR 5 ,
(12) —(CH 2 ) n OC(O)R 5 ,
(13) —NO 2 ,
(14) —(CH 2 ) n NR 5 S(O) p R 5 ,
(15) —(CH 2 ) n N(S(O) p R 5 ) 2 ,
(16) —(CH 2 ) n S(O) p N(R 5 ) 2 ,
(17) —(CH 2 ) n S(O) p R 5 ,
(18) —(CH 2 ) n NR 5 C(O)N(R 5 ) 2 ,
(19) —(CH 2 ) n C(O)N(R 5 ) 2 ,
(20) —(CH 2 ) n NR 5 C(O)R 5 ,
(21) —(CH 2 ) n NR 5 CO 2 R 5 ,
(22) —(CH 2 ) n NR 5 C(O)-heteroaryl,
(23) —(CH 2 ) n C(O)NR 5 N(R 5 ) 2 ,
(24) —(CH 2 ) n C(O)NR 5 NR 5 C(O)R 5 ,
(25) —O(CH 2 ) n C(O)N(R 5 ) 2 ,
(26) —CF 3 ,
(27) —CH 2 CF 3 ,
(28) —OCF 3 , and
(29) —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;
each R 4 is independently selected from the group consisting of:
(1) hydrogen,
(2) C 1-8 alkyl,
(3) halogen,
(4) —OR 5 ,
(5) —(CH 2 ) n N(R 5 ) 2 ,
(6) —(CH 2 ) n C≡N,
(7) —NO 2 , and
(8) —CF 3 ,
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;
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 O, S, and —NC 1-4 alkyl;
each R 6 is independently selected from the group consisting of:
(1) C 1-6 alkyl,
(2) —(CH 2 ) n heteroaryl,
(3) —(CH 2 ) n C(O)(CH 2 ) n N(R 5 ) 2 ,
(4) —(CH 2 ) n C(O)(CH 2 ) n NR 7 R 8 ,
(5) —(CH 2 ) n CN,
(6) —(CH 2 ) n N(R 5 ) 2 ,
(7) —(CH 2 ) n N(R 5 )C(O)R 5 ,
(8) —(CH 2 ) n N(R 5 )C(O)OR 5 ,
(9) —(CH 2 ) n N(R 5 )—S(O)—C 1-8 alkyl, and
(10) —(CH 2 ) n N(R 5 )—S(O) 2 —C 1-8 alkyl,
wherein heteroaryl is unsubstituted or substituted with one to three groups independently selected from R 3 , and wherein alkyl is unsubstituted or substituted with one to three groups independently selected from R 3 and oxo, and wherein any methylene (CH 2 ) in R 6 is unsubstituted or substituted with one to two groups independently selected from halogen, hydroxy, and C 1-4 alkyl; or wherein two R 6 groups together with the atoms to which they are attached form a 3- to 7-membered monocyclic ring optionally containing an additional heteroatom selected from O, S, and N, wherein the monocyclic ring is unsubstituted or substituted on carbon or nitrogen with one to three groups independently selected from R 3 and oxo;
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 1-4 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 -heteroaryl,
(3) halogen,
(4) —OR 5 ,
(5) —NO 2 ,
(6) —SR 5 , and
(7) CF 3 ,
wherein heteroaryl 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 ) n 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;
r is 1 or 2;
s is 1 or 2;
n is 0, 1, 2, or 3; and
p is 0, 1, or 2.
13. The compound of claim 10 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 13 which is:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 13 which is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 13 which is:
or a pharmaceutically acceptable salt thereof.
17. The compound of claim 13 which is:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
19. The compound of claim 13 wherein the pharmaceutically acceptable salt thereof is the trifluoroacetic acid salt.