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:

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

X is selected from:

(1) a bond, and

(2) C 1 -C 6 alkanediyl optionally substituted with 1 to 5 groups independently selected from:

(a) halogen,

(b) —OR a ,

(c) aryl, and

(d) heteroaryl;

Z is selected from:

(1) a bond,

(2) 5 to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,

(3) benzene ring fused to a C 5 -C 10 carbocyclic ring,

(4) 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C 5 -C 10 carbocyclic ring, and

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

R 1 is selected from:

(1) C 1 -C 6 alkyl,

(2) —(C 1-10 alkyl)OH,

(3) —(C 1-10 alkyl)oxy(C 1-10 alkyl),

(4) hydroxy, and

(5) —O(C 1-10 alkyl);

each occurrence of R 2 is independently selected from:

(1) C 1 -C 6 alkyl optionally substituted with 1 to 5 halogen atoms,

(2) C 3 -C 6 cycloalkyl, optionally substituted with 1 to 5 halogen atoms,

(3) oxo,

(4) halogen,

(5) cyano,

(6) —OH,

(7) —C 0 -C 6 alkyloxyC 1 -C 6 alkyl,

(8) —CO 2 R a ,

(9) —(C═O) C 1 -C 6 alkyl,

(10) 5 to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen,

wherein the C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, —C 0 -C 6 alkyloxyC 1 -C 6 alkyl, and —(C═O) C 1 -C 6 alkyl groups of R 2 are optionally substituted with 0, 1, 2, or 3 R 3 substituents selected from:

(1) C 1 -C 6 alkyl optionally substituted with 1 to 5 halogens,

(2) halogen,

(3) —OH, and

(4) —CO 2 H;

each occurrence of R a is independently selected from:

(1) hydrogen,

(2) C 3 -C 6 cycloalkyl;

(3) C 1 -C 6 alkyl optionally substituted with 1 to 5 groups independently selected from:

(a) halogen,

(b) hydroxy,

(c) —CO(C 1 -C 6 alkyl),

(d) —CO 2 (C 1 -C 6 alkyl), and

(e) —CO 2 H, and

provided that when n is 1, X is —CH 2 —, R 1 is —CH 3 , and R 2 is —CH 3 or F, then Z is other than pyridinyl, pyrazolyl, or [1,2,4]triazolo[4,3-a]pyridinyl.

2. The compound of claim 1 , wherein n is 0, 1, 2, or 3.

3. The compound of claim 1 , wherein X is a bond, —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, —CH(CH(CH 3 ) 2 )—, —CH 2 CHCH 3 —, —CH(CH 2 CH 3 )—, —CH 2 CHCH 3 —, —CH 2 CH(CH 3 ) 2 —, or —CH(CH 3 )CH 2 — and X is optionally substituted with one to three groups selected from —OR a , and aryl.

4. The compound of claim 3 , wherein X is optionally substituted with one to three groups selected from —OCH 3 , —OCHCH 3 , —OCH(CH 3 ) 2 and phenyl.

5. The compound of claim 4 wherein Z is thiazolyl, oxazolyl, pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, pyridinyl, dihydropyridinyl, dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, 2,3-dihydro-1,3,4-oxadiazolyl, oxadiazolyl, dihydro-oxadiazolyl, 4,5-dihydro-1,3,4-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,

6. The compound of claim 5 wherein R 1 is selected from: C 1 -C 6 alkyl, —(C 1-10 alkyl)OH, —(C 1-10 alkyl)oxy(C 1-10 alkyl), hydroxy, and —O(C 1-10 alkyl).

7. The compound of claim 5 wherein Z is selected from dihydropyrazinyl, pyrazolyl,

dihydro-oxadiazolyl, 4,5-dihydro-1,3,4-oxadiazolyl, dihydropyridinyl, pyridinyl, pyrazinyl, and pyridazinyl.

8. The compound of claim 7 , wherein R 1 is selected from: —C 1 -C 4 alkyl, —(C 1-4 alkyl)OH, —(C 1-4 alkyl)oxy(C 1-4 alkyl), hydroxy, and —O(C 1-4 alkyl).

9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, selected from:

4-(((2S,5R)-5-((R)-(4-chlorophenyl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(2-methoxyethyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(2-methoxypropyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(2-methoxy-2-(6-oxo-1,6-dihydropyridin-2-yl)ethyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)propyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)-2-phenylethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-isopropyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-cyclopropyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-(methoxymethyl)-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2 S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-ethoxy-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-ethyl-4-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl)methyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((4,5,6,7-tetrahydro-1H-indazol-3-yl)methyl)benzamide;

4-(((2 S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((4-hydroxy-5-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((4-methoxy-5-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

N-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N—((R)-1-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(-2-methyl-1-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl) benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((6-oxo-1,6-dihydropyridin-2-yl)methyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(pyridin-3-ylmethyl)benzamide,

4-(((2 S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-ethyl-N-(pyridin-3-ylmethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(pyridin-3-yl)ethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-(6,7-dihydro-5H-cyclopenta[b]pyridin-5-yl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((2-methoxypyridin-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((2-fluoropyridin-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((2-fluoropyridin-3-yl)methyl)-N-(2-hydroxyethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((6-oxo-1,6-dihydropyridin-3-yl)methyl)benzamide,

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((6-methoxypyridin-3-yl)methyl)-N-methylbenzamide,

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((6-chloropyridin-3-yl)methyl)-N-methylbenzamide,

(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-(1-hydroxyethyl)pyridin-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-(2-hydroxypropan-2-yl)pyridin-3-yl)methyl)-N-methylbenzamide;

5-((4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methylbenzamido)methyl)nicotinic acid;

Methyl 5-((4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl) methyl)-N-methylbenzamido)methyl)nicotinate;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-cyanopyridin-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((5-(5-methyl-1,3,4-oxadiazol-2-yl)pyridin-3-yl)methyl)benzamide;

N-((5-(1H-tetrazol-5-yl)pyridin-3-yl)methyl)-4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((6-fluoro-5-methylpyridin-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(pyrazin-2-ylmethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(pyrazin-2-yl)ethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(pyridazin-4-ylmethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)methyl)benzamide; and

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((3-methyl-4-oxo-3,4-dihydroquinazolin-2-yl)methyl)benzamide.

10. A compound of claim 1 or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof, selected from:

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl) pyrrolidin-2-yl)methyl)-N-methyl-N-((5-methyl-1H-pyrazol-3-yl)methyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)propyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(1-(5-methyl-1H-pyrazol-3-yl)-2-phenylethyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-isopropyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-cyclopropyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-(methoxymethyl)-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-((5-(trifluoromethyl)-1H-pyrazol-3-yl)methyl)benzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-ethoxy-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((5-ethyl-4-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((4-hydroxy-5-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide;

4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-((4-methoxy-5-methyl-1H-pyrazol-3-yl)methyl)-N-methylbenzamide; and

N-((4-chloro-5-methyl-1H-pyrazol-3-yl)methyl)-4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methylbenzamide.

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

12. A method for activation of β3-adrenoreceptor in subject comprising administering to said subject a compound of claim 1 .

13. 4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N—((R)-1-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)ethyl)benzamide, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.

14. 4-(((2S,5R)-5-((R)-(6-chloropyridin-3-yl)(hydroxy)methyl)pyrrolidin-2-yl)methyl)-N-methyl-N-(-2-methyl-1-(4-methyl-5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)benzamide or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof.