Substituted imidazole 4-carboxamides as cholecystokinin-1 receptor modulators

1. A method of treating diabetes mellitus or obesity, which method comprises administering to a mammalian patient in need of such treatment a therapeutically effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof; wherein

X is N or CR 16 ;

R 1 , R 2 , R 3 and R 4 are each selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —OH,

(4) —C 1-6 alkyl, and

(5) —C 1-6 alkoxy,

wherein alkyl and alkoxy are unsubstituted or substituted with one to five substituents selected from halogen, OH, C 1-6 alkyl, and C 1-6 alkoxy, and R 2 and R 3 or R 3 and R 4 together with the atoms to which they are attached form a 4-8 membered ring containing 0-2 heteroatoms independently selected from oxygen, and wherein the 4-8 membered ring is unsubstituted or substituted with a substituent selected from OH, halogen, C 1-6 alkyl, and C 1-6 alkoxy;

R 5 , R 6 and R 7 are each independently selected from the group consisting of:

(1) hydrogen,

(2) halogen,

(3) —C 1-6 alkyl, and

(4) —C 1-6 alkoxy,

wherein alkyl and alkoxy are unsubstituted or substituted with one to five substituents selected from halogen, OH, C 1-6 alkyl, and C 1-6 alkoxy;

R 8 is hydrogen;

R 9 is hydrogen;

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

(1) Cl,

(2) —CH═CHCO 2 H,

(3) —C(O)morpholine,

(4) —C(O)pyrrolidine,

(5) —C(O)piperidine,

(6) —CO 2 H,

(7) —CO 2 CH 2 phenyl,

(8) —CO 2 CH 3 ,

(9) —(CH 2 ) 2 CO 2 H,

(10) —CO 2 tetrahydropyran,

(11) —CONH 2 ,

(12) —CONHCH 3 ,

(13) —CONHCH 2 CH 3 ,

(14) —CON(CH 2 CH 3 ) 2 ,

(15) —CON(CH 3 ) 2 ,

(16) —CONHCH(CH 3 ) 2 ,

(17) —CONHcyclopropyl,

(18) —CONHphenyl,

(19) —C(O)NHcyclopentyl,

(20) —C(O)NH(CH 2 ) 1-6 OH,

(21) —C(O)NHtetrahydropyran,

(22) —CONHCH 2 CO 2 H,

(23) —CON(CH 3 )CH 2 CO 2 H,

(24) —CONHCOC(CH 3 ) 3 ,

(25) —C(O)NHCH(CO 2 CH 2 phenyl) 2 ,

(26) —C(O)NHCH(CO 2 CH 2 CH 3 ) 2 , and

(27) tetrazole,

wherein the alkyl, alkene, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl substituents and —(CH 2 ) n as described in the above R 10 substituents are unsubstituted or substituted with one to eight substituents selected from —C 1-6 alkyl, oxo, halogen, —C 1-6 alkoxy, —(CH 2 ) n OH, —(CH 2 ) n CN, —(CH 2 ) n CF 3 , —(CH 2 ) n SO 3 H, —(CH 2 ) n CO 2 H, —(CH 2 ) n CO 2 C 1-6 alkyl, and —(CH 2 ) n CO 2 C 2-6 alkene, and alkyl and alkoxy are unsubstituted or substituted with one to five substituents independently selected from halogen, —OH, —SO 3 H, —CO 2 H, and —CO 2 C 1-6 alkyl;

R 16 is selected from the group consisting of: hydrogen, —OH, —C 1-6 alkyl unsubstituted or substituted with —OH or phenyl, and —C 1-6 alkoxy;

each n is independently 0, 1, 2, 3, 4, 5, 6, 7 or 8; and

m is 1 and p is 0, and

a therapeutically effective amount of a second agent selected from the group consisting of an insulin-sensitizer, a cholesterol lowering agent, and an anti-obesity agent.

2. The method of claim 1 , wherein the second agent is an insulin-sensitizer.

3. The method of claim 2 , wherein the insulin-sensitizer is selected from the group consisting of a PPARγ antagonist, a dipeptidyl peptidase 4 inhibitor, a glucagon like peptide 1 agonist, and a biguanidine.

4. The method of claim 3 , wherein the dipeptidyl peptidase 4 inhibitor is sitagliptin.

5. The method of claim 3 , wherein the biguandine is selected from the group consisting of metformin and phenformin.

6. The method of claim 1 , wherein the second agent is a cholesterol lowering agent.

7. The method of claim 6 , wherein the cholesterol lowering agent is selected from the group consisting of a HMG-CoA reductase inhibitor, a PPARα agonist, and a cholesterol absorption inhibitor.

8. The method of claim 7 , wherein the HMG-CoA reductase inhibitor is selected from the group consisting of atorvastatin, itavastatin, fluvastatin, lovastatin, pravastatin, rivastatin, rosuvastatin, and simvastatin.

9. The method of claim 7 , wherein the cholesterol absorption inhibitor is ezetimibe.

10. The method of claim 7 , wherein the PPARα agonist is selected from the group consisting of beclofibrate, benzafibrate, ciprofibrate, clofibrate, etofibrate, fenofibrate, and gemfibrozil.

11. The method of claim 1 , wherein the second agent is an anti-obesity agent.

12. The method of claim 11 , wherein the anti-obesity agent is selected from the group consisting of a neuropeptide Y1 antagonist, a neuropeptide Y2 agonist, a neuropeptide Y5 antagonist, a pancreatic lipase inhibitor, a cannabinoid CB1 receptor antagonist or inverse agonist, a melanin-concentrating hormone receptor antagonist, a melanocortin 4 receptor agonist, a ghrelin receptor antagonists, a neurokinin-1 receptor antagonists, a peptide YY analog, a serotonergic agent, a 5HT2c agonist, and a bombesin receptor subtype 3 agonist.

13. The method of claim 12 , wherein the serotonergic agent is selected from phentermine.