Biphenyl compounds useful as muscarinic receptor antagonists

1. A compound of formula I:

wherein:

a is 0 or 1;

R 1 is -halo;

b is 0 or 1;

R 2 is -halo;

W is —O—;

c is 0;

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 C 3-5 heteroarylene group selected from pyridylene, thienylene, pyrrolylene, and furylene;

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, and aryl optionally substituted with 1-2-C 1-5 alkyl or halo groups;

wherein each alkyl and alkoxy group in R 6 , R 6a , 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 and b each represent 0.

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

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

5. The compound of claim 1 , wherein Ar is selected from 2,5-pyridylene, 2,5-thienylene, 2,4-pyrrolylene, 2,5-pyrrolylene, and 2,5-furylene.

6. The compound of claim 1 , wherein a and b are 0; and Z is selected from —NHC(O)—, —N(CH 3 )C(O)—, and —C(O)NH—.

7. 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.

8. 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.

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

10. 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.

11. The compound of claim 1 , selected from:

biphenyl-2-ylcarbamic acid 1-{2-[methyl(5-methylaminomethylpyridine-2-carbonyl)amino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-diethylaminomethylpyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethylamino)methyl]pyridine-2-carbonyl]methylamino)ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}pyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[bis-(2-hydroxyethyl)amino]methyl}pyridine-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[methyl-(5-methylaminomethylthiophene-2-carbonyl)amino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-diethylaminomethylthiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethylamino)methyl]thiophene-2-carbonyl}methylamino)ethyl]piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[(furan-2-ylmethyl)amino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[bis-(2-hydroxy-ethyl)amino]methyl}thiophene-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-methylaminomethylthiophene-2-carbonyl)amino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethylamino)methyl]thiophene-2-carbonyl}amino)ethyl]piperidin-4-yl ester;

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

biphenyl-2-ylcarbamic acid 1-{2-[methyl-(5-methylaminomethyl-1H-pyrrole-2-carbonyl)amino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[methyl(5-methylaminomethylfuran-2-carbonyl)amino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-{2-[(5-diethylaminomethylfuran-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethylamino)methyl]furan-2-carbonyl]methylamino)ethyl}piperidin-4-yl ester;

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

biphenyl-2-ylcarbamic acid 1-{2-[(5-{[bis-(2-hydroxyethyl)amino]methyl}furan-2-carbonyl)methylamino]ethyl}piperidin-4-yl ester;

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

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

biphenyl-2-ylcarbamic acid 1-[2-({5-[(2-hydroxyethylamino)methyl]furan-2-carbonyl}amino)ethyl]piperidin-4-yl ester;

or a pharmaceutically acceptable salt thereof.

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

13. 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.

14. The compound of claim 13 , prepared by the process which further comprises forming a pharmaceutically acceptable salt of the compound of formula I.