Pyrrolidine derived beta 3 adrenergic receptor agonists

1. A compound of Formula I, or an N-oxide thereof, 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, 4, or 5;

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

p is 0, 1, or 2;

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

Ar is phenyl or pyridyl;

X is selected from the group consisting of:

(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) —CO 2 R a ,

(d) —NR a R b , and

(e) C 3 -C 6 cycloalkyl;

Z is selected from the group consisting of:

(1) C 5 -C 10 carbocyclic ring,

(2) 4 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;

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

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

(2) C 3 -C 6 cycloalkyl,

(3) oxo,

(4) halogen,

(5) nitro,

(6) cyano,

(7) —C(O)R a ,

(8) —CO 2 R a ,

(9) —C(O)NR a R b ,

(10) —OR a ,

(11) —NR a R b , and

(12) Z optionally substituted with 1 to 5 halogen atoms;

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

(1) halogen,

(2) —OR a , and

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

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

(1) C 1 -C 6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen and —OR a ,

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

(3) oxo,

(4) halogen,

(5) cyano,

(6) —OR a ,

(7) —C(O)R a ,

(8) —CO 2 R a ,

(9) —C(O)NR a R b ,

(10) —NR a R b ,

(11) —C(O)NR a R b , and

(12) Z optionally substituted with 1 to 5 groups independently selected from

(a) C1-C6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, —OR a , oxo, cyano, CO 2 R a , and C 3 -C 6 cycloalkyl,

(b) C 3 -C 6 cycloalkyl,

(c) halogen,

(d) oxo,

(e)—OR a ,

(f) —NR a R b ,

(g) —C(O)NR a R b , and

(h) phenyl;

R 4 is selected from the group consisting of:

(1) hydrogen, and

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

(a) halogen,

(b)—OR a ,

(c) cyano,

(d) C 3 -C 6 cycloalkyl,

(e) Z optionally substituted with 1 to 5 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 5 halogen atoms, —OR a , oxo, cyano, CO 2 R a , and C 3 -C 6 cycloalkyl,

(g) —S(O) p —NR a R b , and

(h) —N(R a )SO 2 R b ;

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

(1) hydrogen,

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

(a) halogen,

(b) —OR b , and

(c) —CO 2 R b ,

(3) C 3 -C 6 cycloalkyl,

(4) Z optionally substituted with 1 to 5 halogen atoms; and

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

(1) hydrogen, and

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

2. The compound of claim 1 , wherein m is 0, q is 0 and R 4 is hydrogen or methyl.

3. The compound of claim 1 , wherein X is —CH 2 —, —CH 2 CH 2 —, —CH(CH 3 )—, or —CH(CH 3 )CH 2 —.

4. The compound of claim 1 , wherein Z is selected from the group consisting of:

(1) phenyl,

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

5. The compound of claim 4 wherein Z is a 5-membered heterocyclic ring having one nitrogen atom and 0 to 3 additional heteroatoms independently selected from N, O and S, or a 6-membered heterocycle having 1, 2 or 3 nitrogen atoms, or 1 nitrogen atom and one oxygen or sulfur atom.

6. The compound of claim 4 wherein Z is a 5- or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen fused to a C 5 -C 6 carbocyclic ring, and wherein said heterocyclic ring is a 5-membered heterocycle having one nitrogen ring atom and 0 to 3 additional heteroatoms independently selected from N, O and S, or a 6-membered heterocycle having 1, 2 or 3 ring nitrogen atoms, or 1 ring nitrogen atom and a ring oxygen or sulfur atom.

7. The compound of claim 4 wherein Z is a 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, wherein said fused ring has 2 to 5 heteroatoms, at least one of which is nitrogen.

8. The compound of claim 1 , wherein Z is selected from the group consisting of thiazolyl, oxazolyl, pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl, dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,

and r is 1 or 2.

9. The compound of claim 1 , wherein each occurrence of R 3 is independently selected from the group consisting of

(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) —OR a ,

(7) —C(O)R a ,

(8) —CO 2 R a ,

(9) —NR a R b ,

(11) —C(O)NR a R b , and

(12) Z optionally substituted with 1 to 5 groups independently selected from C 1 -C 6 alkyl and halogen.

10. The compound of claim 1 , wherein each occurrence of R a is independently selected from the group consisting of:

(1) hydrogen,

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

(3) C 3 -C 6 cycloalkyl.

11. A compound of Formula Ia, or an N-oxide thereof, 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, 4, or 5;

Ar is phenyl or pyridyl;

X is C 1 -C 6 alkanediyl;

Z is selected from the group consisting of:

(1) phenyl,

(2) 4 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 or a benzene 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;

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

(1) C 1 -C 6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen and —OR a ,

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

(3) oxo,

(4) halogen,

(5) —OR a ,

(7) —C(O)R a ,

(8) —CO 2 R a ,

(9) —NR a R b ,

(11) —C(O)NR a R b , and

(12) Z optionally substituted with 1 to 5 groups independently selected from C 1 -C 6 alkyl and halogen;

R 4 is hydrogen, methyl or ethyl;

R a is selected from the group consisting of:

(1) hydrogen,

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

(3) C 3 -C 6 cycloalkyl; and

R b is selected from the group consisting of:

(1) hydrogen, and

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

12. The compound of claim 11 , wherein each occurrence of R 3 is independently selected from the group consisting of:

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

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

(3) halogen,

(4) —OR a ,

(5) —CO 2 R a ,

(6) —NR a R b , and

(7) Z optionally substituted with 1 to 5 groups independently selected from C 1 -C 4 alkyl and halogen.

13. The compound of claim 1 sleeted from the group consisting of the compounds in Examples 1-137 of the specification.

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