Pyrrolidine-derived beta 3 adrenergic receptor agonists

1. A compound of Formula I, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:

wherein

m is 0, 1, 2, 3, or 4;

n is 0, 1, 2, 3, 4, or 5;

p is 0, 1, or 2;

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

X is —CO— or —SO 2 —;

Y is selected from the group consisting of:

(1) C 1 -C 3 alkylene, optionally substituted with —NR 2 R 2 or hydroxy,

(2) —N(R 6 )—,

(3) —O—,

(4) a bond, and

(5) phenylene, optionally substituted with 1 to 3 groups independently selected from R 1 ;

Z is selected from the group consisting of:

(4) a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,

R 1 is selected from the group consisting of:

(1) C 1 -C 10 alkyl, optionally substituted with 1 to 5 groups selected from the group consisting of:

(a) hydroxy,

(b) halogen,

(c) cyano,

(d) QR 2 ,

(e) C 3 -C 8 cycloalkyl,

(f) Q′COR 3 ,

(g) —S(O) p —NR 2 R 2 ,

(h) —N(R 2 )SO 2 R 3 , and

(i) Q′CO 2 R 2 ,

(2) C 3 -C 8 cycloalkyl,

(3) oxo,

(4) halogen,

(5) cyano,

(6) QR 2 ,

(7) —S(O) p —NR 2 R 2 ,

(8) Q′COR 3 ,

(9) —N(R 2 )SO 2 R 3 ,

(10) Q′CO 2 R 2 , and

(11) Z, optionally substituted with 1 to 5 groups selected from the group consisting of:

(a) R 2 ,

(b) QR 2 ,

(e) halogen, and

(d) oxo;

R 2 is selected from the group consisting of

(1) hydrogen,

(2) C 1 -C 10 alkyl, optionally substituted with 1 to 5 groups selected from the group consisting of:

(a) hydroxy,

(b) halogen,

(c) —CO 2 R 4 ,

(d) —S(O) p —C 1 -C 10 alkyl,

(e) C 3 -C 8 cycloalkyl,

(f) C 1 -C 10 alkoxy, optionally substituted with 1 to 5 halogens, and

(g) Z, optionally substituted with 1 to 5 groups selected from the group consisting of halogen, trifluoromethyl, trifluoromethoxy, C 1 -C 10 alkyl and C 1 -C 10 alkoxy;

(3) C 3 -C 8 cycloalkyl,

(4) Z, optionally substituted with 1 to 5 groups selected from the group consisting of:

(a) halogen,

(b) nitro,

(c) oxo,

(d) —NR 4 R 4 ,

(e) C 1 -C 10 alkoxy, optionally substituted with 1 to 5 halogens,

(f) —S(O) p —C 1 -C 10 alkyl, and

(g) C 1 -C 10 alkyl, optionally substituted with 1 to 5 groups selected from hydroxy, halogen, trifluoromethyl, cyano, —CO 2 R 4 , C 3 -C 8 cycloalkyl, and QR 5 ;

R 3 is selected from the group consisting of:

(1) oxo,

(2) halogen,

(3) R 2 , and

(4) —NR 2 R 2 ;

R 4 is selected from the group consisting of:

(1) hydrogen, and

(2) C 1 -C 10 alkyl;

R 5 is selected from the group consisting of:

(1) Z, optionally substituted with 1 to 5 groups selected from the group consisting of halogen, trifluoromethyl, cyano, C 1 -C 10 alkyl, and C 1 -C 10 alkoxy, and

(2) C 1 -C 10 alkyl;

R 6 is selected from the group consisting of:

(1) hydrogen, and

(2) C 1 -C 10 alkyl;

Q is selected from the group consisting of:

(1) —N(R 2 )—,

(2) —O—, and

(3) —S(O) p —; and

Q′ is selected from the group consisting of:

(1) —N(R 2 )—,

(2) —O—, and

(3) a bond.

2. The compound of claim 1 , wherein m is 0 or 1; q is 0 or 1; and n is 0, 1 or 2.

3. The compound of claim 2 , wherein Y is methylene, —CH(CH 3 )— or a bond.

4. The compound of claim 2 wherein Z is selected from the group consisting of thiazolyl, oxazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrrolidinyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl and 1,2,5-oxadiazolyl.

5. The compound of claim 2 , wherein R 3 is selected from the group consisting of:

(1) C 1 -C 6 alkyl optionally substituted with 1 to 3 halogens,

(2) oxo,

(3) halogen,

(4) Z, optionally substituted with 1 to 3 groups selected from the group consisting of halogen, —NH 2 , C 1 -C6 alkyl, and trifluoromethyl, and

(5) —NH 2 .

6. The compound of claim 2 , wherein m is 0; q is 0; and n is 0 or 1.

7. A compound of Formula Ia, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:

wherein

n is 0, 1 or 2;

X is —CO— or —SO 2 —;

Y is selected from the group consisting of methylene, —CH(CH 3 )—, and a bond;

Z is selected from the group consisting of thiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, and pyrazoly; and

R 3 is selected from the group consisting of:

(1) C 1 -C6 alkyl, optionally substituted with 1 to 3 halogens,

(2) oxo,

(3) Z, optionally substituted with 1 to 3 groups selected from the group consisting of halogen, —NH 2 , C 1 -C6 alkyl, and trifluoromethyl, and

(4) —NR 2 R 2, wherein each occurrence of R 2 is independently hydrogen or C 1 -C6 alkyl.

8. The compound of claim 7 , wherein n is 0 or 1.

9. The compound of claim 7 , wherein Y is methylene or a bond.

10. The compound of claim 7 , wherein R 3 is selected from the group consisting of:

(1) methyl,

(2) oxo,

(3) —NH 2 , and

(4) —NH—C 1 -C6 alkyl.

11. A compound of claim 1 selected from the group consisting of:

or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

12. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.

13. A method for the treatment or prevention of a disease or disorder mediated by the activation of β3-adrenoceptor, wherein said method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 .

14. The method of claim 13 wherein the disease or disorder is selected from the group consisting of (1) overactive bladder, (2) urinary incontinence, (3) urge urinary incontinence, and (4) urinary urgency.

15. The method of claim 14 , wherein the method comprises administering to a patient in need thereof a therapeutically effective amount of a compound of claim 1 and one or more other active ingredients.