Biphenyl compounds useful as muscarinic receptor antagonists

1. A method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound having the formula:

wherein:

a is 0 or an integer of from 1 to 5;

each R 1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 1a , —C(O)OR 1b , —SR 1c , —S(O)R 1d , —S(O) 2 R 1e , —NR 1f R 1g , —NR 1h S(O) 2 R 1i , and —NR 1j C(O)R 1k ; where each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 1i , R 1j , and R 1k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is0 or an integer of from 1 to 4;

each R 2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 2a , —C(O)OR 2b , —SR 2c , —S(O)R 2d , —S(O) 2 R 2e , —NR 2f R 2g , —NR 2h S(O) 2 R 2i , and —NR 2j C(O)R 2k ; where each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , R 2j , and R 2k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW a , where W a is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R 3 independently represents (1-4C)alkyl or two R 3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

R 4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

s is 0, 1 or 2;

Ar 1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein the phenylene or heteroarylene group is 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 or (1-4C)alkoxy;

t is 0, 1 or 2;

n is 0 or an integer from 1 to 3;

d is 0 or an integer from 1 to 4;

each R 6 independently represents fluoro or (1-4C)alkyl;

p is 0 or 1; and

R 7 and R 8 are independently hydrogen or (1-4C)alkyl;

wherein each alkyl and alkoxy group in R 1 , R 1a-1k , R 2 , R 2a-2k , R 3 , R 5 , R 6 , R 7 , and R 8 is optionally substituted with 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient a therapeutically effective amount of a compound having the formula:

wherein:

a is 0 or an integer of from 1 to 5;

each R 1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 1a , —C(O)OR 1b , —SR 1c , —S(O)R 1d , —S(O) 2 R 1e , —NR 1f R 1g , —NR 1h S(O) 2 R 1i , and —NR 1j C(O)R 1k ; where each of R 1a , R 1b , R 1c , R 1d , R 1e , R 1f , R 1g , R 1h , R 1i , R 1j , and R 1k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 4;

each R 2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, —OR 2a , —C(O)OR 2b , —SR 2c , —S(O)R 2d , —S(O) 2 R 2e , —NR 2f R 2g , —NR 2h S(O) 2 R 2i , and —NR 2j C(O)R 2k ; where each of R 2a , R 2b , R 2c , R 2d , R 2e , R 2f , R 2g , R 2h , R 2i , R 2j , and R 2k is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

W represents O or NW a , where W a is hydrogen or (1-4C)alkyl;

c is 0 or an integer from 1 to 5;

each R 3 independently represents (1-4C)alkyl or two R 3 groups are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

R 4 is selected from hydrogen, (1-4C)alkyl, and (3-4C)cycloalkyl;

s is 0, 1 or 2;

Ar 1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein the phenylene or heteroarylene group is 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 or (1-4C)alkoxy;

t is 0, 1 or 2;

n is 0 or an integer from 1 to 3;

d is 0 or an integer from 1 to 4;

each R 6 independently represents fluoro or (1-4C)alkyl;

p is 0 or 1; and

R 7 and R 8 are independently hydrogen or (1-4C)alkyl;

wherein each alkyl and alkoxy group in R 1 , R 1a-1k , R 2 , R 2a-2k , R 3 , R 5 , R 6 , R 7 , and R 8 is optionally substituted with 1 to 5 fluoro substituents;

or a pharmaceutically acceptable salt or stereoisomer thereof.

3. The method of claims 1 or 2 , wherein the compound is administered by inhalation.

4. The method of claim 3 , wherein the compound is administered in the form of an aerosol.

5. The method of claim 3 , wherein the compound is administered in the form of a powder.

6. The method of claim 3 , wherein the compound is administered in the form of a solution.

7. The method of claim 3 , wherein the compound is administered using a nebulizer inhaler.

8. The method of claim 3 , wherein the compound is administered using a metered-dose inhaler.

9. The method of claim 3 , wherein the compound is administered using a dry powder inhaler.

10. The method of claims 1 or 2 , wherein a, b and c each represent 0.

11. The method of claims 1 or 2 , wherein W represents O.

12. The method of claims 1 or 2 , wherein m is 0, s is 0 and t is 1.

13. The method of claims 1 or 2 , wherein the —CONR 7 R 8 group is in the para position, d is 0 and n is 2.

14. The method of claims 1 or 2 , wherein Ar 1 represents phen-1,3-ylene, phen-1, 4-ylene, 2,4-thienylene or 2,5-thienylene; wherein the phenylene or thienylene group is optionally substituted with one or two R 5 substituents.

15. The method of claim 14 , wherein Ar 1 represents phen-1, 4-ylene or 2,4-thienylene, optionally substituted with one or two R 5 substituents.

16. The method of claims 1 or 2 , wherein R 4 selected from hydrogen, methyl and ethyl.

17. The method of claims 1 or 2 , wherein R 7 is selected from hydrogen, methyl, ethyl, n-propyl and isopropyl; and R 8 is hydrogen.

18. The method of claims 1 or 2 , wherein R 7 and R 8 are ethyl.

19. The method of claims 1 or 2 , wherein a, b and c each represent 0; W represents O; m is 0; s is 0; t is 1; Ar 1 represents phen-1,4-ylene optionally substituted with one or two R 5 substituents; d is 0; n is 2, the —CONR 7 R 8 group is in the para position; and R 8 is hydrogen.

20. The method of claim 19 , wherein R 5 is independently selected from halo, (1-4C)alkyl or (1-4C)alkoxy, wherein each alkyl and alkoxy group is optionally substituted with from 1 to 3 fluoro substituents.

21. The method of claims 1 or 2 , wherein the compound is selected from:

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

biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]ethylamino}ethyl)piperidin-4-yl ester;

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

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

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

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

biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{[2,5-dibromo-4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-fluorobenzoyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoyl]methylamino}ethyl)piperidin-4-yl ester;

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

biphenyl-2-ylcarbamic acid 1-(2-{[4-(3-(S)-diethylcarbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[4-(2-carbamoyl-piperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[4-(4-carbamoyl-piperidin-1-ylmethyl)-2-methoxybenzoyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]amino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)thiophene-2-carbonyl]amino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)-1H -pyrrole-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)-1H-pyrrole-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-diethylcarbamoyl-piperidin-1-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]-amino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]amino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-[2-({3-[4-(3-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-[2-({3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-yl-carbamic acid 1-(2-{3-[4-(3-diethylcarbamoylpiperidin-1-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl) benzoylamino]ethyl}piperidin-4-yl ester;

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

biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-5-methoxyberizoyl]methylamino}ethyl)piperidin-4-yl ester; and

biphenyl-2-ylcarbamic acid 1-[2-({2-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]acetyl}methylamino)ethyl]piperidin-4-yl ester;

or a pharmaceutically acceptable salt thereof.

22. The method of claim 21 , wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl) benzoyl]methylamino}ethyl)piperidin-4-yl ester or a pharmaceutically acceptable salt thereof.

23. The method of claims 1 or 2 , which further comprises administering a therapeutically effective amount of an agent selected from β 2 adrenergic receptor agonists, steroidal anti-inflammatory agents, phosphodiesterase-4 inhibitors, and combinations thereof.

24. The method of claim 23 , wherein a β 2 adrenergic receptor agonist and a steroidal anti-inflammatory agent are administered.