Biphenyl compounds useful as muscarinic receptor antagonists

1. A compound of formula I:

wherein:

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

each R 1 is independently selected from —C 1-5 alkyl, —C 2-5 alkenyl, —C 2-5 alkynyl, —C 3-6 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-1k is independently —H, —C 1-5 alkyl or phenyl-C 1-5 alkyl;

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

each R 2 is independently selected from —C 1-5 alkyl, —C 2-5 alkenyl, —C 2-5 alkynyl, —C 3-6 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-2k is independently —H, —C 1-5 alkyl or -phenyl-C 1-5 alkyl;

W is —O— or —NW a —, where W a is —H or —C 1-5 alkyl;

c is 0 or an integer from 1 to 5;

each R 3 independently is —C 1-5 alkyl or two R 3 groups are joined to form C 1-3 alkylene, C 2-3 alkenylene or oxiran-2,3-diyl;

m is 0 or 1;

Z is selected from —C(O)N(R 4 )— and —N(R 4 )C(O)—, where R 4 is selected from —H, —C 1-5 alkyl, and —C 3-5 cycloalkyl;

s is 0, 1 or 2;

Ar is a phenylene 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, —OH, —C 1-5 alkyl, and —C 1-5 alkoxy;

t is 0, 1 or 2;

R 6 is selected from —H, —C 1-5 alkyl, and —X 6 R 6a ; where X 6 is —C 1-5 alkylene and R 6a is selected from —OH, —C 1-5 alkoxy and -heteroaryl; and

R 7 is selected from —H, —C 1-5 alkyl, —C 3-6 cycloalkyl, and —X 7 R 7a ; where X 7 is selected from —C 1-5 alkylene, —C(O)—, —C 1-5 alkylene-C(O)—, —S(O 2 )—, —C 1-5 alkylene-S(O 2 )—, and —S(O 2 )—C 1-5 alkylene; and R 7a is selected from —OH, —C 1-5 alkyl, —C 3-6 cycloalkyl, —C 1-5 alkoxy, heteroaryl, —NR 7b R 7c , where R 7b and R 7c are independently —H or —C 1-5 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 7a-c 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, b and c each represent 0.

3. The compound of claim 1 , wherein W is —O—.

4. The compound of claim 1 , wherein m is 0 and t is 1.

5. The compound of claim 1 , wherein Z is selected from —NHC(O)—, —N(CH 3 )C(O)—, and —C(O)NH—.

6. The compound of claim 1 , wherein Ar is selected from phenylene and phenylene substituted with methoxy.

7. The compound of claim 6 , wherein Ar is selected from phen-1,3-ylene, phen-1,4-ylene, and 2-methoxyphen-1,4-ylene.

8. The compound of claim 3 , wherein m is 0 and t is 1.

9. The compound of claim 8 , wherein a, b, and c are 0; Z is selected from —NHC(O)—, —N(CH 3 )C(O)—, and —C(O)NH—; and Ar is selected from phenylene and phenylene substituted with methoxy.

10. The compound of claim 1 , wherein R 6 is —H and R 7 is selected from —H, —C 1-5 alkyl, —C 3-6 cycloalkyl, —C 1-5 alkylene-OH, —C 1-5 alkylene-C 3-6 cycloalkyl, —C 1-5 alkylene-C 1-5 alkoxy, —C 1-5 alkyleneheteroaryl, —C(O)—C 1-5 alkyl, —C(O)—C 3-6 cycloalkyl, —C(O)-heteroaryl, —C 1-5 alkylene-C(O)—NR 7b R 7c , —S(O 2 )—C 1-5 alkyl, —S(O 2 )-heteroaryl, —S(O 2 )-aryl, and —S(O 2 )—C 1-5 alkylene-NR 7b R 7c ; where the aryl is optionally substituted with 1-2-C 1-5 alkyl or halo groups, and wherein each alkyl and alkoxy group in R 7 and R 7b-c is optionally substituted with 1 to 5 fluoro substituents.

11. The compound of claim 1 , wherein R 6 is —C 1-5 alkyl and R 7 is selected from —C 1-5 alkylene-OH, —C 1-5 alkyleneheteroaryl, —C 1-5 alkylene-C(O)OH, and —C 1-5 alkylene-S(O 2 )—C 1-5 alkyl; and wherein each alkyl group in R 7 is optionally substituted with 1 to 5 fluoro substituents.

12. The compound of claim 1 , wherein R 6 and R 7 are different —C 1-5 alkyl groups.

13. The compound of claim 1 , wherein R 6 and R 7 are the same, and are selected from: —C 1-5 alkyl, —C 1-5 alkylene-OH, and —C 1-5 alkylene-C 1-5 alkoxy.

14. The compound of claim 1 , selected from:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

biphenyl-2-ylcarbamic acid 1-[2-(methyl-{4-[(methylpyridin-3-ylmethylamino) methyl]benzoyl}amino)ethyl]piperidin-4-yl ester;

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

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

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

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

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

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

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

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

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

biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylbenzoylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-aminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-{[(pyridin-4-ylmethyl)amino]methyl}benzylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{3-[(furan-2-ylmethylmethylamino)methyl]benzylcarbamoyl}ethyl)piperidin-4-yl ester;

{[3-({3-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]propionylamino}methyl)benzyl]methylamino}acetic acid;

biphenyl-2-ylcarbamic acid 1-[2-(3-cyclobutylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-cyclopropylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-methylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-dimethylaminomethylbenzylcarbamoyl)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{methyl-[3-(4-methylaminomethylphenyl)propionyl]amino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{[3-(4-ethylaminomethylphenyl)propionyl]methylamino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(4-aminomethylphenylcarbamoyl)ethyl]piperidin-4-yl ester;

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

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

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

biphenyl-2-ylcarbamic acid 1-(2-{4-[(quinoline-8-sulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester;

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

biphenyl-2-ylcarbamic acid 1-(2-{4-[(2,6-dichlorobenzenesulfonylamino)methyl]phenylcarbamoyl}ethyl)piperidin-4-yl ester;

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

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

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

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

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

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

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

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

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

biphenyl-2-ylcarbamic acid 1-[2-(4-{[(pyridin-4-ylmethyl)amino]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-{[(1H-indol-7-ylmethyl)amino]methyl}phenylcarbamoyl)ethyl]piperidin-4-yl ester;

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

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

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

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

biphenyl-2-ylcarbamic acid 1-{2-[3-(4-methylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[3-(4-ethylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester;

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

biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopropylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(cyclopropylmethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[3-(4-cyclopentylaminomethylphenyl)propionylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(2-hydroxyethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(2-methoxyethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(3-{4-[(carbamoylmethylamino)methyl]phenyl}propionylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[3-(4-{[bis-(2-hydroxyethyl)amino]methyl}phenyl)propionylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[2-(4-methylaminomethylphenyl)acetylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[2-(4-ethylaminomethylphenyl)acetylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(2-hydroxyethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(2-methoxyethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-(2-{4-[(carbamoylmethylamino)methyl]phenyl}acetylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(2-methoxy-4-methylaminomethylbenzoyl)methylamino]ethyl}piperidin-4-yl ester;

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

biphenyl-2-ylcarbamic acid 1-[2-(2-methoxy-4-methylaminomethylbenzoylamino) ethyl]piperidin-4-yl ester; and

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

or a pharmaceutically acceptable salt thereof.

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

16. The compound of claim 1 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 coupling a compound of formula IVb:

 with a compound of formula Vb:

 or a reactive derivative thereof; or

(c) reacting a compound of formula VI:

 wherein L 2 represents a leaving group, with a compound of formula VII:

 or

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

 in the presence of a reducing agent; or

(e) reacting a compound of formula IX:

 with a compound of formula VII in the presence of a reducing agent; and then

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

17. The compound of claim 16 , prepared by the process which further comprises forming a pharmaceutically acceptable salt of the compound of formula I.