Hydroxymethyl pyrrolidines as 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;

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

X is —CO— or —SO 2 —;

Y is selected from the group consisting of:

(1) C 1 -C 5 alkanediyl, C 2 -C 5 alkenediyl, and C 2 -C 5 alkynediyl, wherein each of alkanediyl, alkenediyl and alkynediyl is optionally substituted with one to three groups independently selected from halogen, —ORa, —S(O) p —C 1 -C 3 alkyl;

(2) —(CR a R a ) j -Q-(CR a R a ) k , wherein j and k are integers independently selected from 0, 1 and 2,

(3) a bond, and

(4) phenylene optionally substituted with one to three groups independently selected from R 1 ;

Z is selected from the group consisting of:

(1) 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, and

(2) 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 10 carbocyclic ring;

R 1 is selected from the group consisting of:

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

(2) C 3 -C 6 cycloalkyl,

(3) halogen,

(4) nitro,

(5) cyano,

(6) —C(O)R a ,

(7) —C(O) 2 R a ,

(8) —C(O)NR a R b , and

(9) -QR b ;

R 2 is selected from the group consisting of halogen and C 1 -C 5 alkyl;

R 3 is selected from the group consisting of:

(1) C 1 -C 6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, —ORa, —CO 2 R a , and —CONR a R b ,

(2) —(CH 2 ) t -phenyl or —(CH 2 ) t —O-phenyl, and wherein said phenyl in each is optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 5 alkyl optionally substituted with 1 to 5 halogen atoms, and —OR a ,

(3) oxo,

(4) thioxo,

(5) halogen,

(6) —CN,

(7) C 3 -C 6 cycloalkyl,

(8) —(CH 2 ) t -heterocyclic ring or —(CH 2 ) t —O-heterocyclic ring, and wherein the heterocyclic ring in each is a 5- or 6-membered ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, and wherein said heterocyclic ring is optionally ortho-fused to a benzene ring, and optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 5 alkyl optionally substituted with 1 to 5 halogen atoms, and —OR a ,

(9) —OR a ,

(10) —C(O)ORa,

(11) —C(O)Ra,

(12) —C(O)NR a R b ,

(12) —NR a R b ,

(13) —NR a C(O)R b ,

(14) —NR a C(O)OR b , and

(15) —NR a C(O)NR a R b ;

R a is selected from the group consisting of hydrogen and C 1 -C 6 alkyl optionally substituted with 1 to 5 halogen atoms;

R b is selected from the group consisting of:

(1) hydrogen,

(2) C 1 -C 6 alkyl optionally substituted with 1 to 5 groups selected from the group consisting of:

(a) hydroxy,

(b) halogen,

(c) —CO 2 R a ,

(d) —S(O) p —C 1 -C 3 alkyl;

(e) C 3 -C 8 cycloalkyl,

(f) C 1 -C 6 alkoxy optionally substituted with 1 to 5 halogens, and

(g) phenyl optionally substituted with 1 to 5 groups independently selected from the group consisting of halogen, nitro, —NR a R a , trifluoromethyl, trifluoromethoxy, C 1 -C 5 alkyl and —OR a ,

(3) C 3 -C 8 cycloalkyl, and

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

(a) halogen,

(b) nitro,

(c) —NR a R a ,

(d) —OH,

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

(f) —S(O) p —C 1 -C 6 alkyl; and

(g) C 1 -C 6 alkyl optionally substituted with up to 5 groups selected from hydroxy, halogen, trifluoromethyl, cyano, —CO 2 R a , C 3 -C 8 cycloalkyl, and -QR c ;

R c is selected from the group consisting of:

(1) Z optionally substituted with up to 5 groups selected from halogen, trifluoromethyl, cyano, C 1 -C 5 alkyl and C 1 -C 5 alkoxy, and

(2) C 1 -C 6 alkyl; and

Q is selected from the group consisting of:

(1) —N(R a )—,

(2) —O—, and

(3) —S(O) p —.

2. The compound of claim 1 wherein Y is methylene, —CH(CH 3 )— or a bond.

3. The compound of claim 1 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.

4. The compound of claim 1 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.

5. The compound of claim 1 having Formula Ia, or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt of the stereoisomer thereof:

wherein Y, Z, R 3 and n are as defined in claim 1 .

6. The compound of claim 5 wherein Y is methylene, —CH(CH 3 )— or a bond.

7. The compound of claim 5 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.

8. The compound of claim 5 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.

9. The compound of claim 8 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, and wherein the fused ring has 2 to 4 nitrogen atoms and no other heteroatoms.

10. The compound of claim 5 wherein Z is selected from the group consisting of:

wherein r is 1 or 2.

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

(1) C 1 -C 6 alkyl optionally substituted with halogen or —OR a ,

(2) oxo,

(3) halogen,

(4) —OR a ,

(5) —C(O)NR a R b , and

(6) —NR a R b ;

wherein R a and R b is as defined in claim 1 .