Biphenyl compounds useful as muscarinic receptor antagonists

1. A compound of formula I:

where:

a is 0 or 1; R 1 is halo;

b is 0 or 1; R 2 is halo;

A is selected from:

where m is 0 or 1; s is 0, 1 or 2; t is 0, 1 or 2; R 4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; and Ar 1 represents a phenylene group substituted with (R 5 ) q where q is 0 or an integer from 1 to 4 and each R 5 is independently selected from halo, hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

R 6 is selected from hydrogen and (1-4C)alkyl;

X 1 is selected from (1-3C)alkylene and —SO 2 —; where the alkylene is optionally substituted with 1 or 2 substituents independently selected from (1-4C)alkyl and —NR Xa R Xb ; wherein R Xa and R Xb independently selected from hydrogen and (1-4C)alkyl;

p is 0 or 1; R 7 is —OR 7a , where R 7a is (1-4C)alkyl or (3-6C)cycloalkyl; and

R 8 is selected from (1-4C)alkyl, (1-4C)alkyleneNR 8a R 8b , and phenyl, where each of R 8a and R 8b is independently hydrogen or (1-4C)alkyl; or R 8 is taken together with R 7 to form a ring having 1 to 2 oxygen atoms, where said ring is unsubstituted or substituted by 1 or 2 (1-4C)alkyl substituents;

wherein each alkyl and alkoxy group in R 7 , R 7a , R 8 , and R 8a-8b is optionally substituted with 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. The compound of claim 1 , wherein a and b each represent 0.

3. The compound of claim 1 , wherein p is 0.

4. The compound of claim 1 , wherein p is 1.

5. The compound of claim 1 , wherein the —OR 8 group is located at the para or meta position.

6. The compound of claim 1 , wherein R 8 is selected from methyl optionally substituted with 2 to 3 fluoro substituents, (1-4C)alkyleneNR 8a R 8b , and phenyl, each of R 8a and R 8b is independently methyl or ethyl.

7. The compound of claim 1 , wherein R 8 is taken together with R 7 to form a ring having 1 oxygen atom.

8. The compound of claim 7 , wherein R 8 is taken together with R 7 to form —(CH 2 ) 2 —C(CH 3 ) 2 — or —(CH 2 ) 2 —.

9. The compound of claim 1 , wherein R 8 is taken together with R 7 to form a ring having 2 oxygen atoms.

10. The compound of claim 8 , wherein R 8 is taken together with R 7 to form —O(CH 2 )— or —O(CH 2 ) 2 —.

11. The compound of claim 1 , wherein R 6 is hydrogen or methyl.

12. The compound of claim 1 , wherein A is

m is 0, s is 0, and t is 1.

13. The compound of claim 1 , wherein A is

m is 0, s is 0, t is 1, and R 4 is hydrogen or methyl.

14. The compound of claim 1 , having the formula:

15. The compound of claim 1 , selected from:

biphenyl-2-ylcarbamic acid 1-[2-(4-{[4-(3-dimethylaminopropoxy)benzylamino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{4-[(4-trifluoromethoxybenzylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{4-[(4-difluoromethoxybenzylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{4-[(3-cyclopentyloxy-4-methoxybenzylamino) methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{4-[(4-methoxybenzylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(4-{[(benzo[1,3]dioxol-5-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({4-[(4-methoxybenzylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester; and

biphenyl-2-ylcarbamic acid 1-[2-({4-[(2-methoxybenzylamino)methyl]benzoyl}methylamino)ethyl]piperidin-4-yl ester;

or a pharmaceutically acceptable salt or solvate thereof.

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

17. A compound of formula I:

or a pharmaceutically acceptable salt or stereoisomer thereof, prepared by the process comprising:

(a) reacting a compound of formula II:

or a salt thereof, with a compound of formula III:

wherein L 1 represents a leaving group; or

(b) coupling a compound of formula IVa:

or a reactive derivative thereof; with a compound of formula Va′ or Va″:

or coupling a compound of formula IVb:

with a compound of formula Vb′ or Vb″:

or a reactive derivative thereof; or

(c) reacting a compound of formula VI:

wherein L 5 represents a leaving group; with a compound of formula VII:

or

(d) reacting a compound of formula II with a compound of formula VIII:

(where “A” has one less carbon, i.e., m−1 instead of m) in the presence of a reducing agent; or

(e) reacting a compound of formula IX:

(where “A” has one less carbon, i.e., r−1 instead of r, or t−1 instead of t) with a compound of formula VII in the presence of a reducing agent; and

(f) removing any protecting groups that may be present to provide a compound of formula I; and

(g) optionally forming a pharmaceutically acceptable salt of the compound of formula I;

wherein:

a is 0 or 1; R 1 is halo;

b is 0 or 1; R 2 is halo;

A is selected from:

where m is 0 or 1; s is 0, 1 or 2; t is 0, 1 or 2; R 4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl; and Ar 1 represents a phenylene group substituted with (R 5 ) q , where q is 0 or an integer from 1 to 4, and each R 5 is independently selected from halo, hydroxy, (1-4C)alkyl and (1-4C)alkoxy;

R 6 is selected from hydrogen and (1-4C)alkyl;

X 1 is selected from (1-3C)alkylene and —SO 2 —; where the alkylene is optionally substituted with 1 or 2 substituents independently selected from (1-4C)alkyl and —NR Xa R Xb ; where R Xa and R Xb are independently selected from hydrogen and (1-4C)alkyl;

p is 0 or 1; R 7 represents —OR 7a where R 7a is (1-4C)alkyl or (3-6C)cycloalkyl; and

R 8 is selected from (1-4C)alkyl, (1-4C)alkyleneNR 8a R 8b , and phenyl, where each of R 8a and R 8b is independently hydrogen or (1-4C)alkyl; or R 8 is taken together with R 7 to form a ring having 1 to 2 oxygen atoms, where said ring is unsubstituted or substituted by 1 or 2 (1-4C)alkyl substituents;

wherein each alkyl and alkoxy group in R 7 , R 7 a, R 8 , and R 8a-8b is optionally substituted with 1 to 5 fluoro substituents.