Substituted imidazoles as bombesin receptor subtype-3 modulators
View Patent ↗Certain novel substituted imidazoles are ligands of the human bombesin receptor and, in particular, are selective ligands of the human bombesin receptor subtype-3 (BRS-3). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the modulation of BRS-3, such as obesity, and diabetes.
1. A compound of formula I:
or a pharmaceutically acceptable salt thereof; wherein
A is aryl,
wherein aryl is unsubstituted or substituted with 0 to 4 substituents selected from R 6 ;
B is a mono- or bicyclic ring selected from the group consisting of:
(1) —C 3-8 cycloalkyl,
(2) —C 3-8 cycloalkenyl,
(3) —C 2-8 heterocycloalkyl,
(4) —C 2-8 heterocycloalkenyl,
(5) -aryl, and
(6) -heteroaryl,
wherein cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl are unsubstituted or substituted with 0 to 4 substituents selected from R 7 ;
X is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —(CH 2 ) n C 3-7 cycloalkyl,
(6) —(CH 2 ) n C 2-7 heterocycloalkyl,
(7) —(CH 2 ) n aryl,
(8) —(CH 2 ) n heteroaryl,
(9) —CF 3 ,
(10) halogen,
(11) —OR 11 ,
(12) —OCF 3 ,
(13) —COR 9 ,
(14) —CO 2 R 11 ,
(15) —CON(R 9 ) 2 ,
(16) —CN,
(17) —N(R 11 ) 2 ,
(18) —N(R 9 )C(O)C 1-6 alkyl,
(19) —N(R 9 )CO 2 R 11 ,
(20) —N(R 9 )SO 2 C 1-6 alkyl,
(21) —N(R 9 )SO 2 N(R 9 ) 2 ,
(22) —SH,
(23) —S(O) 0-2 C 1-6 alkyl, and
(24) —SO 2 N(R 11 ) 2 ,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and —(CH 2 ) n are unsubstituted or substituted with one to five substituents selected from R 8 , and wherein X and R 4 together with the atoms to which they are attached may form a 3-6 membered cycloalkyl ring containing 0-3 heteroatoms independently selected from oxygen, sulfur, and NR 9 , and wherein the 3-6 membered cycloalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from R 8 , provided that at least one of X, Y, R 4 and R 5 is not hydrogen;
Y is independently selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 2-8 alkenyl,
(4) —C 2-8 alkynyl,
(5) —(CH 2 ) n C 3-7 cycloalkyl,
(6) —(CH 2 ) n C 2-7 heterocycloalkyl,
(7) —(CH 2 ) n aryl,
(8) —(CH 2 ) n heteroaryl, and
(9) —CF 3 ,
wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl and —(CH 2 ) n are unsubstituted or substituted with one to five substituents selected from R 8 , and wherein X and Y or Y and R 6 together with the atoms to which they are attached may form a 3-6 membered cycloalkyl ring containing 0-3 heteroatoms independently selected from oxygen, sulfur, and NR 9 , and wherein the 3-6 membered cycloalkyl ring is unsubstituted or substituted with 1 to 4 substituents selected from R 8 ;
R 1 and R 2 are each independently selected from the group consisting of:
(1) hydrogen,
(2) —(CH 2 ) n halogen,
(3) —(CH 2 ) n OR 8 ,
(4) —(CH 2 ) n CN,
(5) —(CH 2 ) n CF 3 ,
(6) —(CH 2 ) n CHF 2 ,
(7) —(CH 2 ) n CH 2 F,
(8) —(CH 2 ) n CCl 3 ,
(9) —C 1-8 alkyl,
(10) —(CH 2 ) n C 2-8 alkene,
(11) —(CH 2 ) n C 2-8 alkyne,
(12) —(CH 2 ) n C 3-10 cycloalkyl,
(13) —(CH 2 ) n C 3-10 cycloalkenyl,
(14) —(CH 2 ) n C 2-12 heterocycloalkyl,
(15) —SC 1-8 alkyl,
(16) —SC 3-8 cycloalkyl,
(17) —(CH 2 ) n aryl,
(18) —(CH 2 ) n heteroaryl,
(19) —(CH 2 ) n CO 2 R 7 , and
(20) —(CH 2 ) n COC 1-8 alkyl,
provided that R 1 and R 2 are not both hydrogen, wherein alkyl, alkene, alkyne, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with 1 to 5 substituents selected from R 10 , and wherein two R 10 substituents together with the atoms to which they are attached may form a 3-6 membered cycloalkyl or cycloalkenyl ring containing 0 to 3 heteroatoms independently selected from oxygen, sulfur, and NR 7 , and wherein the 3-6 membered cycloalkyl or cycloalkenyl ring is unsubstituted or substituted with 1 to 4 substituents selected from R 10 ;
R 3 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl, and
(3) —COC l-6 alkyl;
R 4 and R 5 are each independently selected from the group consisting of:
(1) hydrogen,
(2) halogen,
(3) —C 1-6 alkyl,
(4) —(CH 2 ) n C 3-8 cycloalkyl,
(5) —(CH 2 ) n C 2-8 heterocycloalkyl,
(6) —C 1-6 alkoxy,
(7) —OH,
(8) —CH 2 F,
(9) —CHF 2 ,
(10) —CF 3 ,
(11) —CN,
(12) —SR ,
(13) —SC 1-6 alkyl,
(14) aryl, and
(15) heteroaryl,
wherein alkyl, alkoxy, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with one to five substituents selected from R 8 ;
R 6 is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —(CH 2 ) n halogen,
(3) —(CH 2 ) n OR 11 ,
(4) —(CH 2 ) n CN,
(5) —(CH 2 ) n CF 3 ,
(6) —(CH 2 ) n CO 2 R 9 ,
(7) —(CH 2 ) n N(R 11 ) 2 ,
(8) —(CH 2 ) n NO 2 ,
(9) —(CH 2 ) n NR 9 COC 1-6 alkyl,
(10) —(CH 2 ) n NR 9 CO 2 C 1-6 alkyl,
(11) —(CH 2 ) n NR 9 SO 2 C 1-6 alkyl, and
(12) —(CH 2 ) n SO 0-2 C 1-6 alkyl,
wherein alkyl is substituted with 1 to 3 halogens;
R 7 is selected from the group consisting of:
(1) —(CH 2 ) n halogen,
(2) —C 1-6 alkyl,
(3) —C 2-6 alkenyl,
(4) —(CH 2 ) n C 3-8 cycloalkyl,
(5) —(CH 2 ) n heterocycloalkyl,
(6) oxo,
(7) —(CH 2 ) n OR 11 ,
(8) —(CH 2 ) n CN,
(9) —(CH 2 ) n COR 9 ,
(10) —(CH 2 ) n CO 2 R 11 ,
(11) —(CH 2 ) n CONR 9 N(R 9 ) 2 ,
(12) —(CH 2 ) n O(CH 2 ) n CO 2 R 9 ,
(13) —(CH 2 ) n NO 2 ,
(14) —(CH 2 ) n CON(R 9 ) 2 ,
(15) —(CH 2 ) n N(R 11 ) 2 ,
(16) —(CH 2 ) n NR 9 (CH 2 ) n CO 2 R 9 ,
(17) —(CH 2 ) n NR 9 COC 1-6 alkyl,
(18) —(CH 2 ) n SO 2 N(R 9 ) 2 ,
(19) —(CH 2 ) n NR 9 SO 2 C 1-6 alkyl,
(20) —(CH 2 ) n SO 0-2 R 11 ,
(21) —(CH 2 ) n OP(O) 2 OH,
(22) —CH=N—OH,
(23) —(CH 2 ) n aryl,
(24) —(CH 2 ) n heteroaryl, and
(25) —(CH 2 ) n O(CH 2 ) n heteroaryl,
wherein alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and —(CH 2 ) n are unsubstituted or substituted with 1 to 3 halogens;
R 8 is selected from the group consisting of:
(1) oxo,
(2) —OH,
(3) halogen,
(4) —CN,
(5) —CF 3 ,
(6) —CHF 2 ,
(7) —CH 2 F,
(8) —C 1-8 alkyl,
(9) —C 1-8 alkoxy,
(10) —COC 1-8 alkyl,
(11) —CO 2 C 1-8 alkyl, and
(12) —CO 2 H,
wherein each alkyl and alkoxy carbon is unsubstituted or substituted with 1 to 3 halogen substituents;
R 9 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen and —OH;
R 10 is independently selected from the group consisting of:
(1) halogen,
(2) —OH,
(3) oxo,
(4) —CN,
(5) —CCl 3 ,
(6) —CF 3 ,
(7) —CHF 2 ,
(8) —CH 2 F,
(9) —SO 2 C 1-6 alkyl,
(10) —COC l-8 alkyl,
(11) —CO 2 C 1-8 alkyl,
(12) —CO 2 H,
(13) —C 1-8 alkyl, and
(14) —C 1-8 alkoxy,
wherein alkyl and alkoxy are unsubstituted or substituted with 1 to 4 substituents selected from —C 1-6 alkyl and halogen, and wherein the —C 1-6 alkyl substituent is unsubstituted or substituted with 1 to 3 halogens;
R 11 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —C 3-8 cycloalkyl,
(4) —C 2-7 heterocycloalkyl,
(5) —(CH 2 )mphenyl, and
(6) —(CH 2 )mheteroaryl,
wherein alkyl, cycloalkyl, and heterocycloalkyl are unsubstituted or substituted with 1 to 3 halogens or —OH, and wherein phenyl and heteroaryl are unsubstituted or substituted with 1 to 3 halogens;
each n is independently 0, 1, 2, 3 or 4; and
each m is independently 1, 2, 3 or 4.
2. The compound of claim 1 wherein A is phenyl, wherein phenyl is unsubstituted or substituted with 0 to 4 substituents selected from R 6 ; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 wherein B is a ring selected from the group consisting of: phenyl, pyridine, pyrazole, isothiazole, and (1,4,5,6)tetrahydro-7H-pyrazolo-{3,4-b}-pyridine-7yl, wherein B is unsubstituted or substituted with 0 to 4 substituents selected from R 7 ; or a pharmaceutically acceptable salt thereof.
4. The compound of claim 1 wherein R 2 and R 3 are hydrogen; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 wherein R 1 is selected from the group consisting of: hydrogen, —C 1-8 alkyl, and —(CH 2 ) n C 2-8 alkene, provided that both R 1 and R 2 are not hydrogen, wherein alkyl, alkene, and (CH 2 ) n are unsubstituted or substituted with 1 to 4 substituents selected from R 10 ; or a pharmaceutically acceptable salt thereof.
6. The compound of claim 1 wherein X is selected from the group consisting of: —C 1-6 alkyl, —(CH 2 ) n aryl, halogen, —OH, —OC 1-6 alkyl, —N(R 11 ) 2 , —N(R 9 )C(O)C 1-6 alkyl, —N(R 9 )CO 2 R 11 , and —N(R 9 )SO 2 C 1-6 alkyl, wherein alkyl, aryl and —(CH 2 ) n are unsubstituted or substituted with one to five substituents selected from R 8 ; or a pharmaceutically acceptable salt thereof.
7. The compound of claim 6 wherein X is selected from the group consisting of: fluorine, —OH, —OCH 2 CH(CH 3 ) 2 , —OCH 3 , —NH 2 , NHCH 3 , N(CH 3 ) 2 , NHCH 2 CH 3 , —NHCH 2 phenyl, —N(CH 3 )C(O)CH 3 , —NHC(O)CH 3 , —NHC(O)CH 2 C(CH 3 ) 3 , —NHCO 2 CH 2 phenyl, —NHCO 2 CH 3 , and —NHSO 2 CH 3 ; or a pharmaceutically acceptable salt thereof.
8. The compound of claim 1 wherein R 4 is selected from the group consisting of: hydrogen, halogen, —C 1-6 alkyl, and —OH, wherein alkyl is unsubstituted or substituted with one to five substituents selected from R 8 ; or a pharmaceutically acceptable salt thereof.
9. The compound of claim 1 wherein R 5 is hydrogen, and Y is hydrogen or methyl, provided that both X and Y are not hydrogen; or a pharmaceutically acceptable salt thereof.
10. The compound of claim 1 of formula III:
or a pharmaceutically acceptable salt thereof; wherein
B is a mono- or bicyclic ring selected from the group consisting of:
(1) -aryl, and
(2) -heteroaryl,
wherein aryl and heteroaryl are unsubstituted or substituted with 0 to 4 substituents selected from R 7 ;
X is independently selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) —OH,
(3) —N(R 11 ) 2 , and
(4) —N(R 9 )C(O)C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to five substituents selected from R 8 , and
wherein X and R 4 together with the atoms to which they are attached may form a 3-6 membered cycloalkyl ring containing 0-3 heteroatoms independently selected from oxygen, sulfur, and NR 9 , and
wherein the 3-6 membered ring is unsubstituted or substituted with 1 to 4 substituents selected from R 8 ;
Y and R 5 are hydrogen;
R 1 is —C 1-8 alkyl, wherein alkyl is unsubstituted or substituted with 1 to 4 substituents selected from R 10 ;
R 4 is independently selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with one to five substituents selected from R 8 ;
R 6 is selected from the group consisting of:
(1) —C 1-6 alkyl,
(2) halogen,
(3) —OR 9 ,
(4) —CN,
(5) —N(R 9 ) 2 ,
(6) —NHCOC 1-6 alkyl,
(7) —NHCO 2 C 1-6 alkyl, and
(8) —SO 0-2 C 1-6 alkyl;
R 7 is selected from the group consisting of:
(1) halogen,
(2) —C 1-6 alkyl,
(3) —OR 11 ,
(4) —CN,
(5) —COC l-6 alkyl,
(6) —CO 2 R 11 ,
(7) —CON(R 9 ) 2 ,
(8) —CO 2 N(R 9 ) 2 ,
(9) —N(R 11 ) 2 ,
(10) —NHCO 2 C 1-6 alkyl,
(11) —SOC 1-6 alkyl,
(12) —SO 2 R 9 , and
(13) —SO 2 N(R 9 ) 2 ,
wherein alkyl is unsubstituted or substituted with 1 to 3 halogens;
R 8 is selected from the group consisting of:
(1) oxo,
(2) —OH,
(3) halogen,
(4) —CN,
(5) —CF 3 ,
(6) —CHF 2 ,
(7) —CH 2 F,
(8) —C 1-8 alkyl,
(9) —C 1-8 alkoxy,
(10) —COC l-8 alkyl,
(11) —CO 2 C 1-8 alkyl, and
(12) —CO 2 H,
wherein each alkyl and alkoxy carbon is unsubstituted or substituted with 1 to 3 halogen substituents;
R 9 is selected from the group consisting of:
(1) hydrogen, and
(2) —C 1-6 alkyl,
wherein alkyl is unsubstituted or substituted with 1 to 3 substituents selected from halogen and —OH;
R 10 is independently selected from the group consisting of:
(1) halogen,
(2) —OH,
(3) oxo,
(4) —CN,
(5) —CF 3 ,
(6) —SO 2 C 1-6 alkyl,
(7) —CHF 2 , and
(8) —C 1-6 alkyl;
R 11 is selected from the group consisting of:
(1) hydrogen,
(2) —C 1-6 alkyl,
(3) —(CH 2 ) m phenyl, and
(4) —(CH 2 ) m heteroaryl,
wherein each alkyl carbon is unsubstituted or substituted with 1 to 3 halogens and each phenyl and heteroaryl carbon is unsubstituted or substituted with one halogen;
each n is independently 0, 1, 2, 3 or 4;
each m is independently 1, 2, 3 or 4; and
each q is independently 0, 1, 2, 3 or 4.
11. The compound of claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 which is:
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 11 which is:
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 11 which is:
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 11 which is:
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 11 which is:
or a pharmaceutically acceptable salt thereof.
17. A composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.