Substituted imidazoles as bombesin receptor subtype-3 modulators

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein

A is

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 5 ;

R 1 and R 2 are each independently selected from the group consisting of:

(1) —(CH 2 ) 4 F,

(2) —CH 2 F,

(3) Br,

(4) Cl,

(5) I,

(6) —(CH 2 ) 0-4 OH,

(7) —(CH 2 ) 2 C(CH 3 ) 2 OH,

(8) —(CH 2 ) 2 CN,

(9) —CH 2 C(CH 2 CH 3 ) 2 CN,

(10) —(CH 2 ) 2 CF 3 ,

(11) —(CH 2 ) 2-3 CCl 3 ,

(12) —(CH 2 ) 0-4 CH 3 ,

(13) —CH(CH 3 )CH 2 CH 3 ,

(14) —CH 2 CH(CH 3 )CH 2 CH 3 ,

(15) —CH 2 C(CH 3 ) 2 CH 2 CH 3 ,

(16) —CH 2 C(CH 3 )(CH 2 CH 3 )CH 2 CH 3 ,

(17) —(CH 2 ) 1-2 CH(CH 3 ) 2 ,

(18) —(CH 2 ) 1-2 CH(CH 2 CH 3 ) 2 ,

(19) —(CH 2 ) 1-2 C(CH 3 ) 3 ,

(20) —CH(CH 3 ) 3 ,

(21) —CH 2 C(CH 2 CH 3 ) 2 CH 2 CH 3 ,

(22) —CH 2 C(CH 2 F) 2 CH 2 CH 3 ,

(23) —CH═C(CH 3 ) 2 ,

(24) —CH═CH 2 ,

(25) —CH 2 C(CH 3 ) 2 CH 2 CH═CH 2 ,

(26) —CH 2 C(CH 3 ) 2 CH 2 CH═CHCH 3 ,

(27) —CH 2 C(CH 2 CH 3 ) 2 CH═CH 2 ,

(28) —(CH 2 ) 3 OCH 2 phenyl,

(29) —(CH 2 ) 0-2 cyclopropyl,

(30) —(CH 2 ) 0-2 cyclobutyl,

(31) —(CH 2 ) 0-2 cyclopentyl,

(32) —(CH 2 ) 0-2 cyclohexyl,

(33) —(CH 2 ) 0-2 cycloheptyl,

(34) —(CH 2 ) 0-2 cyclooctyl,

(35) —(CH 2 ) 0-2 adamantane,

(36) —(CH 2 ) 0-1 cyclopentene,

(37) —(CH 2 ) 0-1 cyclohexene,

(38) —CH 2 tetrahydrofuran,

(39) —CH 2 tetrahydropyran,

(40) —(CH 2 ) 1-2 phenyl,

(41) —CH 2 naphthalene,

(42) benzocyclobutene,

(43) —CH 2 benzodioxole,

(44) —(CH 2 ) 0-1 pyridine,

(45) —(CH 2 ) 3 thiophene,

(46) —C(CH 3 ) 2 CO 2 CH 3 ,

(47) —CH 2 C(CH 3 ) 2 C(O)CH 2 CH 3 ,

(48) —C(O)C(CH 3 ) 3 ,

(49) —CH 2 C(CH 3 ) 2 CH 2 CO 2 CH 3 , and

(50) —CH 2 cyclopentyl,

provided that R 1 and R 2 are not both hydrogen, wherein alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, and (CH 2 ) n are unsubstituted or substituted with 1 to 5 substituents selected from R 6 , and wherein two R 6 substituents together with the atom 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 , wherein the 3-6 membered cycloalkyl or cycloalkenyl ring is unsubstituted or substituted with 1 to 5 substituents selected from R 6 ;

R 3 is selected from the group consisting of:

(1) hydrogen,

(2) —C 1-6 alkyl, and

(3) —COC l-6 alkyl;

R 4 is selected from the group consisting of:

(1) —C 1-6 alkyl,

(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 CO 2 R 7 ,

(7) —(CH 2 ) n N(R 8 ) 2 ,

(8) —(CH 2 ) n NO 2 ,

(9) —(CH 2 ) n NR 7 COC 1-6 alkyl,

(10) —(CH 2 ) n NR 7 CO 2 C 1-6 alkyl,

(11) —(CH 2 ) n NR 7 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 5 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 R 8 ,

(8) —(CH 2 ) n CN,

(9) —(CH 2 ) n COR 7 ,

(10) —(CH 2 ) n CO 2 R 8 ,

(11) —(CH 2 ) n CONR 7 N(R 7 ) 2 ,

(12) —(CH 2 ) n O(CH 2 ) n CO 2 R 7 ,

(13) —(CH 2 ) n NO 2 ,

(14) —(CH 2 ) n CON(R 7 ) 2 ,

(15) —(CH 2 ) n N(R 8 ) 2 ,

(16) —(CH 2 ) n NR 7 (CH 2 ) n CO 2 R 7 ,

(17) —(CH 2 ) n NR 7 COC 1-6 alkyl,

(18) —(CH 2 ) n SO 2 N(R 7 ) 2 ,

(19) —(CH 2 ) n NR 7 SO 2 C 1-6 alkyl,

(20) —(CH 2 ) n SO 0-2 R 8 ,

(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 6 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 7 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 8 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 ) m phenyl, and

(6) —(CH 2 ) m heteroaryl,

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, 4, or 5;

each m is independently 1, 2, 3 or 4; and

q is 0, 1, 2, 3 or 4.

2. The compound of claim 1 wherein B is a mono- or bicyclic ring selected from the group consisting of: —C 3-8 cycloalkyl, —C 2-8 heterocycloalkyl, —C 2-8 heterocycloalkenyl, -aryl, and -heteroaryl, wherein cycloalkyl, heterocycloalkyl, heterocycloalkenyl, aryl, and heteroaryl are unsubstituted or substituted with 0 to 4 substituents selected from R 5 ; or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 wherein B is a ring selected from the group consisting of: cyclohexyl, piperidine, tetrahydropyrazolopyridine, oxodihydropyridine, tetrahydropyrazine, phenyl, pyrazole, imidazole, pyrazine, pyridazine, pyridine, pyrimidine, thiazole, isothiazole, thiadiazole, triazole, thiene, indazole, isoquinoline, triazolopyridine, pyrrolopyridine, imidazopyrazine, and pyrazolopyridine, wherein the ring is unsubstituted or substituted with 0 to 4 substituents selected from R 5 ; or a pharmaceutically acceptable salt thereof.

4. The compound of claim 1 wherein A is phenyl, wherein phenyl is unsubstituted or substituted with 0 to 4 substituents selected from R 4 ; or a pharmaceutically acceptable salt thereof.

5. The compound of claim 1 wherein A is unsubstituted phenyl; or a pharmaceutically acceptable salt thereof.

6. The compound of claim 1 wherein R 2 and R 3 are hydrogen; or a pharmaceutically acceptable salt thereof.

7. The compound of claim 1 wherein R 5 is selected from the group consisting of: —(CH 2 ) n halogen, —C 1-6 alkyl, —C 2-6 alkenyl, oxo, —(CH 2 ) n OR 8 , —CN, —COR 7 , —(CH 2 ) n CO 2 R 8 , —(CH 2 ) n O(CH 2 ) n CO 2 R 7 , —NO 2 , —(CH 2 ) n N(R 8 ) 2 , —NH(CH 2 ) n CO 2 R 7 , —NHCOC 1-6 alkyl, —SO 2 N(R 7 ) 2 , —CH═N—OH, —(CH 2 ) n heteroaryl, and —(CH 2 ) n O(CH 2 ) n heteroaryl, wherein alkyl, alkenyl, heteroaryl, and —(CH 2 ) n are unsubstituted or substituted with 1 to 3 halogens; or a pharmaceutically acceptable salt thereof.

8. The compound of claim 1 of formula IV:

or a pharmaceutically acceptable salt thereof; wherein

B is selected from the group consisting of:

(1) —C 3-8 cycloalkyl,

(2) -aryl, and

(3) -heteroaryl,

wherein cycloalkyl, aryl, and heteroaryl are unsubstituted or substituted with 0 to 4 substituents selected from R 5 ;

R 5 is selected from the group consisting of:

(1) halogen,

(2) —C 1-6 alkyl,

(3) —(CH 2 ) n O(CH 2 ) n heteroaryl, and

(4) —(CH 2 ) n CO 2 H;

R 6 is —C 1-6 alkyl, wherein alkyl is 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; and

each n is independently 0, 1, 2, 3 or 4.

9. The compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

10. The compound of claim 9 which is:

or a pharmaceutically acceptable salt thereof.

11. The compound of claim 9 which is:

or a pharmaceutically acceptable salt thereof.

12. The compound of claim 9 which is:

or a pharmaceutically acceptable salt thereof.

13. The compound of claim 9 which is:

or a pharmaceutically acceptable salt thereof.

14. The compound of claim 9 which is:

or a pharmaceutically acceptable salt thereof.

15. A composition which comprises a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.