Pyrazole derivatives as cannabinoid receptor 1 antagonists

1. A compound according to the structure:

wherein:

each R 1 and R 2 is a substituent independently selected from the group consisting of Cl, F, Br, OH, optionally substituted C1-10 alkyl, optionally substituted C1-10 alkoxy, optionally substituted C2-4 alkenyl, optionally substituted C2-4 alkynyl, NR 10 R 11 , NHCOR 10 , NHCO 2 R 10 , CH 2 OR 10 , CONR 10 R 11 , CO 2 R 10 , CN, CF 3 , NO 2 , N 3 , C1-3 alkylthio, R 10 SO, R 10 SO 2 , CF 3 S, and CF 3 SO 2 ;

R 3 is H or C1-3 alkyl;

R 4 and R 5 taken together form a piperidine ring with the N to which they are attached, which is substituted at the 4 position with at least one substituent selected from the group consisting of NR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NHCONR 10 R 11 , NR 10 COOR 11 ; and

CONR 10 R 11 ,

R 10 and R 11 are independently selected from H and C1-10 alkyl;

and a and b are each independently integers from 0 to 5

or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or stereoisomer thereof.

2. The compound of claim 1 , wherein a is 1 and the R 1 substituent is at the para position and b is 2 and the R 2 substituents are at the ortho and para positions.

3. The compound of claim 2 , wherein R 1 and both R 2 substituents are Cl.

4. The compound of claim 1 , wherein R 3 is CH 3 .

5. The compound of claim 1 , wherein the compound comprises one or more chiral centers.

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

1-{[5-4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide;

1-{[5-4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-(ethylamino)piperidine-4-carboxamide;

1-{[5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide;

tert-Butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)carbamate;

1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-amine;

N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)acetamide;

N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)methanesulfonamide;

3-tert-butyl-1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)urea;

1-N-tert-butyl-4-C-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-piperidine-1,4-diamido;

tert-butyl N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-yl)carbamate;

1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-amine;

1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-yl)-3-(propan-2-yl)urea;

1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-yl)-3-propylurea;

3-butyl-1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-yl)urea;

N-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}piperidin-4-yl)methanesulfonamide;

1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)-3-hexylurea;

1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)-3-(propan-2-yl)urea;

1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)-3-ethylurea;

1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)-3-propylurea;

3-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)-1-cyclohexylurea;

3-butyl-1-(1-{[5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl]carbonyl}-4-phenylpiperidin-4-yl)urea;

4-C-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-piperidine-1,4-diamido;

4-C-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-1-N-ethylpiperidine-1,4-diamido;

4-C-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-1-N-(propan-2-yl)piperidine-1,4-diamido;

4-C-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-1-N-propylpiperidine-1,4-diamido;

1-N-butyl-4-C-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-piperidine-1,4-diamido;

N-(tert-butyl)-1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carbonyl)-4-phenylpiperidine-4-carboxamide;

or a pharmaceutically acceptable ester, amide, salt, solvate, prodrug, or stereoisomer thereof.

7. A method for treating or delaying the progression of disorders that are alleviated by antagonizing the CB1 receptor, the method comprising administering a compound according to claim 1 , wherein the disorder is selected from the group consisting of obesity, liver diseases, diabetes, pain, inflammation, and dyslipidemia.

8. A pharmaceutical composition, comprising the compound of claim 1 and one or more pharmaceutically acceptable carriers.