Pyrrolidine derived β3 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 or 1;

n is 0, 1, or 2;

q is 0 or 1;

A is —CH═ or —N═;

B 1 is —CH 2 — or —NH—;

R 6 and R 9 are each a hydrogen;

or R 6 and R 9 form a direct bond;

each occurrence of R 1 and R 2 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 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:

(a) halogen,

(b) —OR a , and

(c) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms, optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 4 alkyl optionally substituted with 1 to 3 halogen atoms,

(2) halogen,

(3) —OR a ,

(4) —NR a R b , and

(5) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms, optionally substituted with 1 to 3 groups independently selected from

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

(b) halogen,

(c) —OR a , and

(d) —NR a R b ; and

each occurrence of R a and 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 halogen atoms.

2. The compound of claim 1 , wherein:

m is 0;

n is 0, 1, or 2;

q is 0;

A is —CH═;

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:

(a) halogen,

(b) —OR a , and

(c) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms, optionally substituted with 1 to 3 groups independently selected from halogen, C 1 -C 4 alkyl optionally substituted with 1 to 3 halogen atoms,

(2) halogen, and

(3) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms, optionally substituted with 1 to 3 groups independently selected from

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

(b) halogen,

(c) —OR a , and

(d) —NR a R b ; and

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

(1) hydrogen,

(2) methyl, and

(3) ethyl.

3. The compound of claim 2 , wherein:

n is 0 or 1;

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

(1) C 1 -C 4 alkyl optionally substituted with 1 to 2 groups independently selected from:

(a) halogen, and

(b) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms selected from the group consisting of pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, wherein said 5- to6-membered heterocyclic ring is optionally substituted with 1 to 3 groups independently selected from halogen and C 1 -C 4 alkyl,

(2) halogen, and

(3) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms selected from the group consisting of pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl,pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl; wherein said 5- to6-membered heterocyclic ring is optionally substituted with 1 to 3 groups independently selected from

(a) C 1 -C 4 alkyl, and

(b) halogen.

4. The compound of claim 3 , wherein

R 3 is selected from the group consisting of:

(1) C 1 -C 4 alkyl optionally substituted with 1 to 2 5- to 6 -membered heterocyclic ring with 1 to 4 nitrogen atoms, and

(2) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms selected from the group consisting of pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, wherein said 5- to6-membered heterocyclic ring is optionally substituted with 1 to 2 C 1 -C 4 alkyl groups.

5. The compound of claim 1 having Formula I a:

wherein B 2 is —CH— or —N—;

R 6 and R 9 are each a hydrogen;

or R 6 and R 9 form a direct bond; and

R 3 is selected from the group consisting of:

(1) methyl optionally substituted with 1 to 2 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms,

(2) ethyl optionally substituted with 1 to 2 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms; and

(3) a 5- to 6-membered heterocyclic ring with 1 to 4 nitrogen atoms selected from the group consisting of pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, pyridazinyl dihydropyridazinyl, pyrrolidinyl, imidazolyl, pyrazolyl, wherein said 5-to6-membered heterocyclic ring is optionally substituted with 1 to 2 groups independently selected from methyl, ethyl, propyl and halogen.

6. The compound of claim 5 , wherein:

B 2 is —CH—; and

R 3 is selected from the group consisting of pyridyl, dihydropyridyl, 1,2,4-triazolyl, 1,2,3triazolyl, tetrazolyl, pyrimidinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, pyrazinyl, dihydropyrazinyl, and pyridazinyl, wherein R 3 is optionally substituted with 1 to 2 groups independently selected from methyl, ethyl, propyl and halogen.

7. A compound of Formula (Ib), or a pharmaceutically acceptable salt thereof, wherein R is selected from the following table:

(Ib)

Compound #

R

1

2

3

4

5

6

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