Pyrrolidine derived β3 adrenergic receptor agonists

1. 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

m is 0, 1, 2, or 3;

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

p is 0, 1, or 2;

q is 0 or 1;

X is selected from the group consisting of:

(1) a bond,

(2) C 1 -C 4 alkanediyl, C 2 -C 4 alkenediyl, and C 2 -C 4 alkynediyl, wherein each of alkanediyl, alkenediyl and alkynediyl is optionally substituted with 1 to 3 groups independently selected from (a) halogen, and (b) —OR a , and

(3) absent;

or V is a carbonyl group and W is 3-azabicyclo[3.1.0]hex-3-yl;

Z is tetrazolyl;

each occurrence of R 1 is independently selected from the group consisting of:

(1) C 1 -C 4 alkyl optionally substituted with 1 to 3 halogen atoms, and

(2) halogen;

each occurrence of R 2 is independently selected from the group consisting of:

(1) halogen, and

(2) methyl;

each occurrence of R 3 is independently selected from the group consisting of:

(1) halogen,

(2) —OR a ,

(3) oxo,

(4) —CO 2 R a , and

(5) C 1 -C 4 alkyl optionally substituted with 1 to 3 groups independently selected from halogen, —OR a , and —CO 2 R a ;

each occurrence of R a is independently selected from the group consisting of:

(1) hydrogen, and

(2) C 1 -C 4 alkyl optionally substituted with 1 to 3 halogen atoms; and

each occurrence of R b is independently selected from the group consisting of:

(1) hydrogen, and

(2) C 1 -C 4 alkyl optionally substituted with 1 to 3 groups independently selected from the group consisting of:

(a) hydroxy, and

(b) halogen.

2. The compound of claim 1 , wherein m is 0, n is 0, 1, 2, or 3, and p is 0, and wherein each occurrence of R 3 is independently selected from the group consisting of:

(1) halogen,

(2) —OH,

(3) oxo,

(4) —CO 2 H,

(5) methyl optionally substituted with 1 to 3 groups selected from halogen, and hydroxyl, and

(6) ethyl optionally substituted with 1 to 3 groups selected from halogen, and hydroxyl.

3. The compound of claim 1 having Formula (Ib) or a pharmaceutically acceptable salt thereof:

wherein

n is 0, 1, 2 or 3;

q is 0 or 1;

X is selected from the group consisting of:

(1) a bond,

(2) C 1 -C 4 alkanediyl, optionally substituted with 1 to 3 halogen atoms, and

(3) absent; and

V is a carbonyl group and W is 3-azabicyclo[3.1.0]hex-3-yl, wherein W is substituted with 1 to 3 R 3 groups;

Z is selected from the group consisting of tetrazolyl; and

each occurrence of R 3 is independently selected from the group consisting of:

(1) halogen,

(2) —OH,

(3) oxo,

(4) —CO 2 H,

(5) methyl optionally substituted with 1 to 3 groups selected from halogen and hydroxyl,

(6) ethyl optionally substituted with 1 to 3 groups selected from halogen and hydroxyl.

4. A compound selected from the group consisting of:

(R)-phenyl[(2R,5S)-5-[(6-{[(1R,5S,6s)-6-(1H-tetrazol-1-yl)-3-azabicyclo[3.1.0]hex-3yl]carbonyl}pyridin-3-yl)methyl]pyrrolidine-2-yl]methanol;

(R)-{(2R,5S)-5-[(6-{[6-(1-methyl-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}pyridin-3-yl)methyl]pyrrolidin-2-yl)(phenyl)methanol; and

(R)-{(2R,5S)-5-[(6-{[6-(2,2,2-trifluoroethyl)-1H-tetrazol-5-yl)-3-azabicyclo[3.1.0]hex-3-yl]carbonyl}pyridin-3-yl)methyl]pyrrolidin-2-yl)(phenyl)methanol;

or a pharmaceutically acceptable salt thereof.

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

6. A pharmaceutical composition comprising a compound of claim 4 and a pharmaceutically acceptable carrier.