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, 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;

Y is a ring system selected from the group consisting of:

wherein R 5 , R 6 , R 7 , R 8 , R 9 , and R 10 are each a hydrogen;

or two R 5 groups, two R 6 groups, or two R 7 groups, together with the carbon atom to which they are attached, form a 3- to 6-membered ring containing 0, 1, 2, or 3 hetero atoms independently selected from oxygen, sulfur, and nitrogen; wherein the 3- to 6-membered ring is optionally fused to a phenyl or a 4- to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen to form a fused ring; and wherein the 3- to 6-membered ring or the fused ring is optionally substituted with 1 to 5 R 3 groups;

or R 5 and R 6 , R 6 and R 7 , or R 5 and R 9 , together with the nitrogen or carbon atoms to which they are attached, form a 5- to 6-membered ring containing 0, 1, 2, or 3 hetero atoms independently selected from oxygen and nitrogen; wherein the 5- to 6-membered ring is optionally fused to a phenyl or a 4- to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen to form a fused ring; and wherein the 5- to 6-membered ring or the fused ring is optionally substituted with 1 to 5 R 3 groups;

or R 6 and R 9 form a direct bond;

or R 6 and R 8 form a C 1 -C 4 alkylene bridge; and wherein the alkylene bridge is optionally substituted with 1 to 3 R 3 groups;

or R 6 and R 9 form a C 1 -C 4 alkylene bridge; and wherein the alkylene bridge is optionally substituted with 1 to 3 R 3 groups;

or R 7 and R 8 form a C 1 -C 4 alkylene bridge; and wherein the alkylene bridge is optionally substituted with 1 to 3 R 3 groups;

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) halogen,

(4) —OR a ,

(5) oxo,

(6) cyano,

(7) —C(O)R a ,

(8) —C(O)NR a R b ,

(9) —NR a R b ,

(10) —S(O)P—C 1 -C 6 alkyl, and

(11) 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:

(a) halogen,

(b) oxo,

(c) cyano,

(d) —OR a ,

(e) —C(O)R a ,

(f) —CO 2 R a ,

(g) —C(O)R C ,

(h) —C(O)NR a R b ,

(i) —NR a R b ,

(j) —N(R a )C(O)R a ,

(k) —S(O)p-C 1 -C 6 alkyl,

(l) C 3 -C 6 cycloalkyl 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 , and oxo, and

(m) 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, oxo, cyano, —OR a , —CO 2 R a , C 3 -C 6 cycloalkyl, and Z,

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

(3) halogen,

(4) oxo,

(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) —N(R a )C(O)R a ,

(12) —N(R a )CO 2 R a ,

(13) —N(R a )C(O)NR a R b ,

(14)═N—OR a ,

(15) —S(O) p —R a , and

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

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

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

(c) halogen,

(d) nitro,

(e) oxo,

(f) cyano,

(g) —OR a ,

(h) —C(O)R a ,

(i) —CO 2 R a ,

(j) —C(O)NR a R b ,

(k) —NR a R b ,

(l) —S(O)p-C 1 -C 6 alkyl, and

(m) 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, oxo, cyano, —OR a , —CO 2 R a , and C 3 -C 6 cycloalkyl;

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) cyano,

(c) —OR b ,

(d) —C(O)R b ,

(e) —CO 2 R b ,

(f) —C(O)NR b R b ,

(g) —S(O) p —C 1 -C 6 alkyl;

(h) C 3 -C 6 cycloalkyl optionally substituted with 1 to 5 groups independently selected from C 1 -C 6 alkyl and —OR b , and

(i) 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, oxo, cyano, —OR b , —CO 2 R b , C 3 -C 6 cycloalkyl, and Z,

(3) C 3 -C 6 cycloalkyl optionally substituted with 1 to 5 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, oxo, —OR b , and Z, and

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

(a) halogen,

(b) nitro,

(c) cyano,

(d) oxo,

(e) —OR b ,

(f) —C(O)R b ,

(g) —CO 2 R b ,

(h) —C(O)NR b R b ,

(i) —NR b R b ,

(j) —S(O) p —C 1 -C 6 alkyl,

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

(l) C 3 -C 6 cycloalkyl, and

(m) 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, oxo, cyano, —OR b , —CO 2 R b , and C 3 -C 6 cycloalkyl;

each occurrence of R b 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 halogen, C 1 -C 6 alkyl optionally substituted with 1 to 5 groups independently selected from halogen, oxo, cyano, hydroxy, C 1 -C 6 alkoxy, —C(O)NH 2 , —CO 2 H, C 3 -C 6 cycloalkyl optionally substituted with 1 to 5 groups independently selected from hydroxy and C 1 -C 6 alkyl, and Z optionally substituted with 1 to 5 groups independently selected from halogen, hydroxy, oxo, and C 1 -C 6 alkyl,

(3) C 3 -C 6 cycloalkyl optionally substituted with 1 to 5 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 5 halogen atoms, hydroxy, C 1 -C 6 alkoxy, and oxo, and

(4) Z optionally substituted with 1 to 5 groups independently selected from halogen, trifluoromethyl, C 1 -C 6 alkyl, oxo, hydroxy, and C 1 -C 6 alkoxy; and

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

wherein R d and R e are each hydrogen or C 1 -C 6 alkyl; or two R d groups or two R e groups together with the carbon atom to which they are attached form a 3- to 6-membered ring containing 0 or 1 hetero atom selected from oxygen and nitrogen; and wherein the 3- to 6-membered ring is optionally substituted with 1 to 5 R 3 groups;

wherein R f and R g are each hydrogen or C 1 -C 6 alkyl; or R f and R g form a C 1 -C 4 alkylene bridge;

wherein R h and R i are each hydrogen or C 1 -C 6 alkyl; or R h and R i form a C 1 -C 4 alkylene bridge; and

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

3. The compound of claim 2 , 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.

4. The compound of claim 3 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.

5. The compound of claim 3 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 the 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 1 ring oxygen or sulfur atom.

6. The compound of claim 3 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 the fused ring has 2 to 5 heteroatoms, at least one of which is nitrogen.

7. The compound of claim 3 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.

8. 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 3 groups independently selected from:

(a) halogen,

(b) oxo,

(c) —OR a ,

(d) —C(O)R a ,

(e) —CO 2 R a ,

(f) —C(O)NR a R b ,

(g) —NR a R b ,

(h) —N(R a )C(O)R a ,

(i) —S(O)p-C 1 -C 6 alkyl,

(j) C 3 -C 6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 3 halogen atoms, and —OR a ,

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

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

(3) halogen,

(4) oxo,

(5) —OR a ,

(6) —C(O)R a ,

(7) —CO 2 R a ,

(8) —C(O)NR a R b ,

(9) —NR a R b ,

(10) —N(R a )C(O)R a ,

(11) —S(O)p-R a , and

(12) Z optionally substituted with 1 to 3 groups independently selected from

(a) C 1 -C 6 alkyl optionally substituted with 1 to 3 groups independently selected from halogen, oxo, —OR a , C 3 -C 6 cycloalkyl, and Z,

(b) C 3 -C 6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 3 halogen atoms, —OR a , and Z,

(c) halogen,

(d) oxo,

(e) —OR a ,

(f) —C(O)R a ,

(g) —CO 2 R a ,

(h) —C(O)NR a R b ,

(i) —NR a R b ,

(j) —S(O)p-C 1 -C 6 alkyl, and

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

9. 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 3 groups independently selected from:

(a) halogen,

(b) —OR b ,

(c) —C(O)R b ,

(d) —C(O)NR b R b ,

(e) —S(O) p —C 1 -C 6 alkyl;

(f) C 3 -C 6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from C 1 -C 6 alkyl and —OR b , and

(g) Z optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 3 halogen atoms, oxo, —OR b , C 3 -C 6 cycloalkyl, and Z,

(3) C 3 -C 6 cycloalkyl optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 3 groups independently selected from halogen, —OR b , and Z, and

(4) Z optionally substituted with 1 to 3 groups independently selected from:

(a) halogen,

(b) oxo,

(c) —OR b ,

(d) —C(O)R b ,

(e) —NR b R b ,

(f) —S(O) p —C 1 -C 6 alkyl,

(g) C 1 -C 6 alkyl optionally substituted with 1 to 3 groups independently selected from halogen, oxo, —OR b , C 3 -C 6 cycloalkyl, and Z,

(h) C 3 -C 6 cycloalkyl, and

(i) Z optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 6 alkyl optionally substituted with 1 to 3 halogen atoms, oxo, —OR b , and C 3 -C 6 cycloalkyl.

10. The compound of claim 1 having Formula Ib:

wherein R 5 and R 6 are each a hydrogen;

or two R 5 groups, together with the carbon atom to which they are attached, form a 5-membered ring containing 0 or 1 hetero atom selected from oxygen and nitrogen; and wherein the 5-membered ring is optionally substituted with 1 to 3 R 3 groups;

or R 5 and R 6 , together with the carbon atoms to which they are attached, form a 5- to 6-membered ring containing 0, 1, 2, or 3 hetero atoms independently selected from oxygen and nitrogen; and wherein the 5- to 6-membered ring is optionally substituted with 1 to 3 R 3 groups.

11. The compound of claim 1 having Formula Ic:

wherein R 5 , R 6 , and R 9 are each a hydrogen;

or two R 5 groups, together with the carbon atom to which they are attached, form a 4- to 6-membered ring containing 0, 1, 2, or 3 hetero atoms selected from oxygen, sulfur, and nitrogen; wherein the 4- to 6-membered ring is optionally fused to a phenyl or a 5- to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen to form a fused ring; and wherein the 4- to 6-membered ring or the fused ring is optionally substituted with 1 to 3 R 3 groups;

or two R 6 groups, together with the carbon atom to which they are attached, form a 4- to 6-membered ring containing 0, 1, 2, or 3 hetero atoms selected from oxygen, sulfur, and nitrogen; wherein the 4- to 6-membered ring is optionally fused to a phenyl or a 5- to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen to form a fused ring; and wherein the 4- to 6-membered ring or the fused ring is optionally substituted with 1 to 3 R 3 groups;

or R 5 and R 6 , together with the carbon atoms to which they are attached, form a 5- to 6-membered ring containing 0, 1, 2, or 3 hetero atoms independently selected from oxygen and nitrogen; wherein the 5- to 6-membered ring is optionally fused to a phenyl or a 5- to 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen to form a fused ring; and wherein the 5- to 6-membered ring or the fused ring is optionally substituted with 1 to 3 R 3 groups;

or R 6 and R 9 form a direct bond;

or R 6 and R 9 form a C 1 -C 4 alkylene bridge, and wherein the alkylene bridge is optionally substituted with 1 to 2 R 3 groups.

12. The compound of claim 1 having Formula Id:

wherein R 5 , R 6 , R 7 , R 8 , and R 9 are each a hydrogen;

or R 5 and R 6 , together with the carbon and nitrogen atoms to which they are attached, form a 5-to 6-membered ring containing 0, 1, 2, or 3 hetero atoms independently selected from oxygen and nitrogen; and wherein the 5- to 6-membered ring is optionally substituted with 1 to 3 R 3 groups;

or R 6 and R 8 form a C 1 -C 4 alkylene bridge, and wherein the alkylene bridge is optionally substituted with 1 to 2 R 3 groups;

or R 6 and R 9 form a C 1 -C 4 alkylene bridge, and wherein the alkylene bridge is optionally substituted with 1 to 2 R 3 groups;

or R 7 and R 8 form a C 1 -C 4 alkylene bridge, and wherein the alkylene bridge is optionally substituted with 1 to 2 R 3 groups.

13. A compound having Formula II:

wherein m is 0, 1, 2, 3, 4, or 5;

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

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,

(2) C 3 -C 6 cycloalkyl,

(3) —OR a ,

(4) —NR a R b , and

(5) halogen;

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; and

A and R are as defined in the following table:

A

R

CH

H

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

N

CH

N

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

CH

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