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 and R 7 are taken together to form:

or

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 5 , 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 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 and R 7 are taken together to form:

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. The compound of claim 1 , selected from:

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

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

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

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

biphenyl-2-ylcarbamic acid 1-(2-{[4-(2,6-dimethylmorpholin-4-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester;

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

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

biphenyl-2-ylcarbamic acid 1-(2-{[4-(2,5-diaza-bicyclo[2.2.1]hept-2-ylmethyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester;

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

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

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

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

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

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

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

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

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

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

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

biphenyl-2-ylcarbamic acid 1-{2-[3-((1R,4R)-5-benzyl-2,5-diaza-bicyclo[2,2.1]hept-2-ylmethyl)benzylcarbamoyl]ethyl}piperidin-4-yl ester;

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

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

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

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

4-[4-(2-{2-[4-(biphenyl-2-ylcarbamoyloxy)piperidin-1-yl]ethylcarbamoyl}ethyl)benzyl]piperazine-1-carboxylic acid methyl ester;

biphenyl-2-ylcarbamic acid 1-(2-{3-[4-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)phenyl]propionylamino}ethyl)piperidin-4-yl ester;

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

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

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

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

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

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

biphenyl-2-ylcarbamic acid 1-{2-[2-methoxy-4-(3-oxopiperazin-1-ylmethyl)benzoylamino]ethyl}piperidin-4-yl ester;

or a pharmaceutically acceptable salt thereof.

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

18. 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.

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