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 C 3-5 heteroarylene group selected from pyridylene, thienylene, pyrrolylene, and furylene; wherein the C 3-5 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, —OH, —C 1-5 alkyl, and —C 1-5 alkoxy;

t is 0, 1 or 2;

R 6 and R 7 are taken together to form:

optionally substituted with one to three —C 1-5 alkyl groups, or

where: d is 1 or 2; e is 0, 1 or 2; f is 0, 1, 2 or 3; R 8 is selected from —C 1-5 alkyl and ═O; R 9 is selected from —H, —C 1-5 alkyl, hydroxyphenyl, heteroaryl, and —X 9 R 9a ; where X 9 is selected from —C 1-5 alkylene, —C(O)—, —C 1-5 alkylene-C(O)—, —C(O)—C 1-5 alkylene, —S(O 2 )—, —C 1-5 alkylene-S(O 2 )—, and —S(O 2 )—C 1-5 alkylene; and R 9a is selected from —H, —OH, —C 1-5 alkyl, —C 1-5 alkoxy, aryl, heteroaryl, heterocyclyl, and —NR 9b R 9c , where R 9b and R 9c 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 , R 8 , R 9 , and R 9a-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 2,5-pyridylene, 2,5-thienylene, 2,4-pyrrolylene, 2,5-pyrrolylene, and 2,5-furylene.

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

8. The compound of claim 7 , wherein a, b, and c are 0; and Z is selected from —NHC(O)—, —N(CH 3 )C(O)—, and —C(O)NH—.

9. The compound of claim 1 , wherein R 6 and R 7 are taken together to form:

10. The compound of claim 1 , wherein R 6 and R 7 are taken together to form:

optionally substituted with two —C 1-5 alkyl groups.

11. The compound of claim 1 , wherein R 6 and R 7 are taken together to form:

where: d is 1; e is 0; f is 1; R 8 is ═O and R 9 is —H.

12. The compound of claim 1 , wherein R 6 and R 7 are taken together to form:

where: d is 1; e and f are 0; and R 9 is selected from —C 1-5 alkyl, hydroxyphenyl, heteroaryl, —C 1-5 alkylene-C 1-5 alkoxy, —C 1-5 alkyleneheteroaryl, —C(O)H, —C(O)—C 1-5 alkyl, —C(O)—C 1-5 alkoxy, —C(O)-heterocyclyl, —C(O)—NR 9b R 9c , —C 1-5 alkylene-C(O)-heterocyclyl, —C 1-5 alkylene-C(O)—NR 9b R 9c , and —S(O 2 )—C 1-5 alkyl; and wherein each alkyl and alkoxy group in R 9 and R 9b-c is optionally substituted with 1 to 5 fluoro substituents.

13. The compound of claim 1 , wherein R 6 and R 7 are taken together to form:

where: d is 2; e and f are 0; and R 9 is —C(O)—C 1-5 alkyl such as methyl; and wherein the alkyl group in R 9 is optionally substituted with 1 to 5 fluoro substituents.

14. The compound of claim 1 , wherein R 6 and R 7 are taken together to form:

where: d and e are 1; f is 0; and R 9 is selected from —H and —C 1-5 alkylenearyl; and wherein the alkyl group in R 9 is optionally substituted with 1 to 5 fluoro substituents.

15. The compound of claim 1 , selected from:

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

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

biphenyl-2-ylcarbamic acid 1-(2-{methyl-[5-(3-oxo-piperazin-1-ylmethyl)pyridine-2-carbonyl]amino}ethyl)piperidin-4-yl ester;

biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetyl-[1,4]diazepan-1-ylmethyl)pyridine-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

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

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

4-[6-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)pyridin-3-ylmethyl]piperazine-1-carboxylic acid methyl ester;

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

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

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

biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetyl-[1,4]diazepan-1-ylmethyl)thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

4-[5-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl) thiophen-2-ylmethyl]piperazine-1-carboxylic acid methyl ester;

biphenyl-2-ylcarbamic acid 1-(2-{[5-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl) thiophene-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

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

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

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

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

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

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

biphenyl-2-ylcarbamic acid 1-(2-{[5-(4-acetyl[1,4]diazepan-1-ylmethyl)furan-2-carbonyl]ethylamino}ethyl)piperidin-4-yl ester;

4-[5-({2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethyl}methylcarbamoyl)furan-2-ylmethyl]piperazine-1-carboxylic acid methyl ester;

biphenyl-2-ylcarbamic acid 1-(2-{[5-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)furan-2-carbonyl]methylamino}ethyl)piperidin-4-yl ester;

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

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

or a pharmaceutically acceptable salt thereof.

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

17. 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.

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