Biphenyl compounds useful as muscarinic receptor antagonists Number:7,521,041 from the United States Patent and Trademark Office (PTO) owispatent

Title: Biphenyl compounds useful as muscarinic receptor antagonists

Abstract: This invention provides compounds of formula I: ##STR00001## wherein a, b, c, d, m, n, p, s, t, W, Ar.sup.1, R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.6, R.sup.7, and R.sup.8 are as defined in the specification. The compounds of formula I are muscarinic receptor antagonists. The invention also provides pharmaceutical compositions containing such compounds, processes and intermediates for preparing such compounds and methods of using such compounds to treat pulmonary disorders.

Patent Number: 7,521,041 Issued on 04/21/2009 to Mammen,   et al.

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Inventors:	Mammen; Mathai (Redwood Shores, CA), Ji; Yu-Hua (Redwood City, CA), Mu; YongQi (Los Altos, CA), Husfeld; Craig (Redwood City, CA), Li; Li (Sunnyvale, CA)
Assignee:	Theravance, Inc. (South San Francisco, CA)
Appl. No.:	11/974,318
Filed:	October 12, 2007

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Related U.S. Patent Documents

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	Application Number	Filing Date	Patent Number	Issue Date
	11077433	Mar., 2005	7288657
	60552443	Mar., 2004

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Current U.S. Class:	424/9.1 ; 435/7.1; 514/316; 514/326
Current International Class:	A61K 49/00 (20060101); A61K 31/44 (20060101); G01N 33/53 (20060101)
Field of Search:	424/9.1 435/7.1 514/316,326

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References Cited [Referenced By]

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U.S. Patent Documents

6617325	September 2003	Lehman-Lintz et al.
6635764	October 2003	Mammen et al.
6656694	December 2003	Mammen
6693202	February 2004	Aggen et al.
7141671	November 2006	Mammen et al.
7262205	August 2007	Mammen et al.
7265133	September 2007	Mammen et al.
2003/0018019	January 2003	Meade et al.
2004/0209860	October 2004	Mammen et al.
2004/0209915	October 2004	Mammen et al.
2005/0113417	May 2005	Mammen et al.
2005/0203083	September 2005	Mammen et al.
2005/0203132	September 2005	Mammen et al.
2005/0203134	September 2005	Mammen et al.
2005/0203137	September 2005	Mammen et al.
2005/0203139	September 2005	Mammen et al.
2006/0205775	September 2006	Ji et al.
2006/0205784	September 2006	Mu et al.
2006/0205946	September 2006	Ji et al.

Foreign Patent Documents

	0 747 355		Dec., 1996		EP
	WO 95/06635		Mar., 1995		WO
	WO 99/64043		Dec., 1999		WO
	WO 01/42212		Jun., 2001		WO
	WO 02/051841		Jul., 2002		WO
	WO 2004/012684		Feb., 2004		WO

Other References

Broadley et al., "Muscarinic Receptor Agonists and Antagonists", Molecules, 6, pp. 142-193 (2001). cited by other . Eglen et al., "Muscarinic Receptor Subtypes:Pharmacology and Therapeutic Potential", DN&P, 10(8), pp. 462-469 (1997). cited by other . Zlotos et al., "Muscarinic receptor agonists and antagonists", Exp. Opin. Ther. Patents, 9(8), pp. 1029-1053 (1999). cited by other . Naito et al., "Selective Muscarinic Antagonist. II. .sup.1) Synthesis and Antimuscarinic Properties of Biphenylylcarbamate Derivatives", Chem. Pharm. Bull. , vol. 46, No. 8, pp. 1286-1294 (1998). cited by other . Ziedalski et at., "Advances in the Management of Chronic Obstructive Pulmonary Disease", Expert Opin,. Pharmacother. 4(7):1063-1082 (2003). cited by other . Hcaplus 129:58129a, "Selective muscarinic antagonists. II Synthesis and antimuscarinic properties of biphenylcarbamate derivatives", Naito et al. cited by other.

Primary Examiner: Seaman; D. Margaret
Assistant Examiner: Chandrakumar; Nizal S
Attorney, Agent or Firm: Hagenah; Jeffrey A. Eberle; Shelley

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Parent Case Text

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CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of U.S. Ser. No. 11/077,433, filed Mar. 10, 2005, which now U.S. Pat. No. 7,288,657 claims the benefit of U.S. Provisional Application No. 60/552,443, filed on Mar. 11, 2004; the entire disclosures of which are incorporated herein by reference in their entirety.

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Claims

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What is claimed is:

1. A method of determining the effect of antagonizing a muscarinic receptor on a biological system or sample comprising a muscarinic receptor, the method comprising: (a) contacting a first sample of the biological system or sample with a muscarinic agonist; (b) measuring the amount of cyclic adenosine monophosphate (cAMP) produced in the first sample; (c) contacting a second sample of the biological system or sample with the muscarinic agonist and a muscarinic receptor-antagonizing amount of a compound; (d) measuring the amount of cAMP produced in the second sample; and (e) comparing the amount of cAMP in step (b) with the amount in step (d); wherein the compound in step (c) has the formula: ##STR00037## wherein: a is 0 or 1; R.sup.1 is halo; b is 0 or 1; R.sup.2 is halo; m is 0 or 1; R.sup.4 is selected from hydrogen and (1-4C)alkyl; s is 0, 1 or 2; Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is independently selected from halo, hydroxy, (1-4C)alkyl and (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; p is 0 or 1; and R.sup.7 and R.sup.8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl group in R.sup.7 and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof.

2. A method for antagonizing a muscarinic receptor in a mammal which comprises administering to the mammal, a therapeutically effective amount of the compound having the formula: ##STR00038## wherein: a is 0 or 1; R.sup.1 is halo; b is 0 or 1; R.sup.2 is halo; m is 0 or 1; R.sup.4 is selected from hydrogen and (1-4C)alkyl; s is 0, 1 or 2; Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is independently selected from halo, hydroxy, (1-4C)alkyl and (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; p is 0 or 1; and R.sup.7 and R.sup.8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl group in and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof.

3. A method of determining the effect of antagonizing a muscarinic receptor on a biological system or sample comprising a muscarinic receptor, the method comprising: (a) contacting a first sample of the biological system or sample with a muscarinic agonist and guanosine 5'-O-(.gamma.-thio)triphosphate (GTP.gamma.S); (b) measuring the amount of GTP.gamma.S binding in the first sample; (c) contacting a second sample of the biological system or sample with the muscarinic agonist, GTP.gamma.S, and a muscarinic receptor-antagonizing amount of a compound; (d) measuring the amount of GTP.gamma.S binding in the second sample; and (e) comparing the amount of GTP.gamma.S binding in step (b) with the amount in step (d); wherein the compound in step (c) has the formula: ##STR00039## wherein: a is 0 or 1; R.sup.1 is halo; b is 0 or 1; R.sup.2 is halo; m is 0 or 1; R.sup.4 is selected from hydrogen and (1-4C)alkyl; s is 0, 1 or 2; Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is independently selected from halo, hydroxy, (1-4C)alkyl and (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; p is 0 or 1; and R.sup.7 and R.sup.8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl group in R.sup.7 and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof.

4. A method of determining the effect of antagonizing a muscarinic receptor on a biological system or sample comprising a muscarinic receptor, the method comprising: (a) contacting a first sample of the biological system or sample with a muscarinic agonist; (b) measuring the amount of calcium released in the first sample; (c) contacting a second sample of the biological system or sample with the muscarinic agonist and a muscarinic receptor-antagonizing amount of a compound; (d) measuring the amount of calcium released in the second sample; and (e) comparing the amount of calcium released in step (b) with the amount in step (d); wherein the compound in step (c) has the formula: ##STR00040## wherein: a is 0 or 1; R.sup.1 is halo; b is 0 or 1; R.sup.2 is halo; m is 0 or 1; R.sup.4 is selected from hydrogen and (1-4C)alkyl; s is 0, 1 or 2; Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is independently selected from halo, hydroxy, (1-4C)alkyl and (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; p is 0 or 1; and R.sup.7 and R.sup.8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl group in R.sup.7 and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof.

5. A method of determining the effect of antagonizing a muscarinic receptor on a mammal, the method comprising: (a) administering a muscarinic receptor-antagonizing amount of a compound to the mammal; (b) inducing bronchoconstriction in the mammal; (c) measuring pulmonary resistance; wherein the compound in step (b) has the formula: ##STR00041## wherein: a is 0 or 1; R.sup.1 is halo; b is 0 or 1; R.sup.2 is halo; m is 0 or 1; R.sup.4 is selected from hydrogen and (1-4C)alkyl; s is 0, 1 or 2; Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen and sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is independently selected from halo, hydroxy, (1-4C)alkyl and (1-4C)alkoxy; t is 0, 1 or 2; n is 0 or an integer from 1 to 3; p is 0 or 1; and R.sup.7 and R.sup.8 are independently hydrogen or (1-4C)alkyl; wherein each alkyl group in R.sup.7 and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or stereoisomer thereof.

6. The method of claim 1, 3, or 4, wherein the biological system or sample is selected from cells, cellular extracts, plasma membranes, tissue samples, and mammals.

7. The method of claim 1, which further comprises contacting a third sample of the biological system or sample with a test compound; measuring the amount of cAMP produced in the third sample; and comparing the amount of cAMP produced in the third sample with the amount of cAMP in step (b) and step (d).

8. The method of claim 7, wherein the comparison is used to identify test compounds having about equal or superior blockade of agonist-mediated inhibition of cAMP accumulation than the compound of step (c).

9. The method of claim 1, wherein the muscarinic agonist is selected from oxotremorine, acetylcholine, pilocarpine, and methacholine.

10. The method of claim 3, wherein the muscarinic agonist is selected from oxotremorine, acetylcholine, pilocarpine, and methacholine.

11. The method of claim 3, which further comprises contacting a third sample of the biological system or sample with a test compound; measuring the amount of GTP.gamma.S binding in the third sample; and comparing the amount of GTP.gamma.S binding in the third sample with the amount of GTP.gamma.S binding in step (b) and step (d).

12. The method of claim 11, wherein the comparison is used to identify test compounds having about equal or superior blockade of agonist-mediated GTP.gamma.S binding than the compound of step (c).

13. The method of claim 4, wherein the muscarinic agonist is selected from oxotremorine, acetylcholine, pilocarpine, and methacholine.

14. The method of claim 4, which further comprises contacting a third sample of the biological system or sample with a test compound; measuring the amount of calcium released in the third sample; and comparing the amount of calcium released in the third sample with the amount of calcium released in step (b) and step (d).

15. The method of claim 14, wherein the comparison is used to identify test compounds having about equal or superior blockade of agonist-mediated calcium release than the compound of step (c).

16. The method of claim 5, wherein bronchoconstriction is induced by administering acetylcholine to the mammal.

17. The method of claim 1, 2, 3, 4, or 5, wherein a and b each represent 0.

18. The method of claim 1, 2, 3, 4, or 5, wherein m is 0, is 0 and t is 1.

19. The method of claim 1, 2, 3, 4, or 5, wherein the --CONR.sup.7R.sup.8 group is in the para position, and n is 2.

20. The method of claim 1, 2, 3, 4, or 5, wherein Ar.sup.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.sup.5 substituents.

21. The method of claim 1, 2, 3, 4, or 5, wherein a and b each represent 0; m is 0; s is 0; t is 1; Ar.sup.1 represents phen-1,4-ylene optionally substituted with one or two R.sup.5 substituents; n is 2 and the --CONR.sup.7R.sup.8 group is in the para position; and R.sup.8 is hydrogen.

22. The method of claim 1, 2, 3, 4, or 5, wherein the compound is biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester or a pharmaceutically acceptable salt thereof.

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Description

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BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel biphenyl compounds having muscarinic receptor antagonist or anticholinergic activity. This invention also relates to pharmaceutical compositions comprising such biphenyl compounds, processes and intermediates for preparing such biphenyl compounds and methods of using such biphenyl compounds to treat pulmonary disorders.

2. State of the Art

Pulmonary or respiratory disorders, such as chronic obstructive pulmonary disease (COPD) and asthma, afflict many millions of people worldwide and such disorders are a leading cause of morbidity and mortality.

Muscarinic receptor antagonists are known to provide bronchoprotective effects and therefore, such compounds are useful for treating respiratory disorders, such as COPD and asthma. When used to treat such disorders, muscarinic receptor antagonists are typically administered by inhalation. However, even when administered by inhalation, a significant amount of the muscarinic receptor antagonist is often absorbed into the systemic circulation resulting in systemic side effects, such as dry mouth, mydriasis and cardiovascular side effects.

Additionally, many inhaled muscarinic receptor antagonists have a relatively short duration of action requiring that they be administered several times per day. Such a multiple-daily dosing regime is not only inconvenient but also creates a significant risk of inadequate treatment due to patient non-compliance with the required frequent dosing schedule.

Accordingly, a need exists for new muscarinic receptor antagonists. In particular, a need exists for new muscarinic receptor antagonists that having high potency and reduced systemic side effects when administered by inhalation. Additionally, a need exists for inhaled muscarinic receptor antagonists having a long duration of action thereby allowing for once-daily or even once-weekly dosing. Such compounds are expected to be particularly effective for treating pulmonary disorders, such as COPD and asthma, while reducing or eliminating side effects, such as dry-mouth and constipation.

SUMMARY OF THE INVENTION

The present invention provides novel biphenyl compounds having muscarinic receptor antagonist or anticholinergic activity. Among other properties, compounds of this invention have been found to possess high potency and reduced systemic side effects when administered by inhalation and to have a long duration of action.

Accordingly, in one of its composition aspects, this invention provides a compound of formula I:

##STR00002## wherein:

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

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

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

c is 0 or an integer from 1 to 5;

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

m is 0 or 1;

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

s is 0, 1 or 2;

Ar.sup.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.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.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.sup.6 independently represents fluoro or (1-4C)alkyl;

p is 0 or 1; and

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

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

or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

In another of its composition aspects, this invention is directed to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. Such pharmaceutical compositions may optionally contain other therapeutic agents. Accordingly, in one embodiment, this invention is directed to such a pharmaceutical composition wherein the composition further comprises a therapeutically effective amount of a steroidal anti-inflammatory agent, such as a corticosteroid; a .beta..sub.2 adrenergic receptor agonist; a phosphodiesterase-4 inhibitor; or a combination thereof.

Compounds of this invention possess muscarinic receptor antagonist activity. Accordingly, compounds of formula I are expected to be useful for treating pulmonary disorders, such as chronic obstructive pulmonary disease and asthma.

Accordingly, in one of its method aspects, this invention is directed to a method for treating a pulmonary disorder, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

Additionally, in another of its method aspects, this invention is directed to a method of producing bronchodilation in a patient, the method comprising administering to a patient a bronchodilation-producing amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

This invention is also directed to a method of treating chronic obstructive pulmonary disease or asthma, the method comprising administering to a patient a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

In another one of its method aspects, this invention is directed to a method for antagonizing a muscarinic receptor in a mammal comprising administering to the mammal, a therapeutically effective amount of the compound of formula I.

Since compounds of this invention possess muscarinic receptor antagonist activity, such compounds are also useful as research tools. Accordingly, in yet another of its method aspects, this invention is directed to a method for using a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof as a research tool for studying a biological system or sample, or for discovering new chemical compounds having muscarinic receptor antagonist activity.

This invention is also directed to processes and novel intermediates useful for preparing compounds of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. Accordingly, in another of its method aspects, this invention is directed to a process of preparing a compound of formula I, the process comprising: (a) reacting a compound of formula II with a compound of formula III; or (b) coupling a compound of formula IV with a compound of formula V; or (c) reacting a compound of formula VI 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; or (f) reacting a compound of formula XVIII with a compound of formula XIX; and then removing any protecting groups, if necessary, to provide a compound of formula I; wherein compounds of formula I-IX, XVIII and XIX, are as defined herein.

In one embodiment, the above process further comprises the step of forming a pharmaceutically acceptable salt of a compound of formula I. In other embodiments, this invention is directed to the other processes described herein; and to the product prepared by any of the processes described herein.

This invention is also directed to a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, for use in therapy or as a medicament.

Additionally, this invention is directed to the use of a compound of formula I or a pharmaceutically acceptable salt or solvate or stereoisomer thereof, for the manufacture of a medicament; especially for the manufacture of a medicament for the treatment of a pulmonary disorder or for antagonizing a muscarinic receptor in a mammal.

DETAILED DESCRIPTION OF THE INVENTION

In one of its composition aspects, this invention is directed to novel biphenyl compounds of formula I or pharmaceutically acceptable salts or solvates or stereoisomers thereof. These compounds may contain one or more chiral centers and therefore, this invention is directed to racemic mixtures; pure stereoisomers (i.e., enantiomers or diastereomers); stereoisomer-enriched mixtures and the like unless otherwise indicated. When a particular stereoisomer is shown or named herein, it will be understood by those skilled in the art that minor amounts of other stereoisomers may be present in the compositions of this invention unless otherwise indicated, provided that the desired utility of the composition as a whole is not eliminated by the presence of such other isomers.

The compounds of formula I also contain several basic groups (e.g., amino groups) and therefore, the compounds of formula I can exist as the free base or in various salt forms. All such salt forms are included within the scope of this invention. Furthermore, solvates of compounds of formula I or salts thereof are included within the scope of this invention.

Additionally, where applicable, all cis-trans or E/Z isomers (geometric isomers), tautomeric forms and topoisomeric forms of the compounds of formula I are included within the scope of this invention unless otherwise specified.

The compounds of formula I, as well as those compounds used in its synthesis, may also include isotopically-labeled compounds, i.e., where one or more atoms have been enriched with atoms having an atomic mass different from the atomic mass predominately found in nature. Examples of isotopes that may be incorporated into the compounds of Formula (I) include, but are not limited to, .sup.2H, .sup.3H, .sup.13C, .sup.14C, .sup.15N, .sup.18O and .sup.17O.

The nomenclature used herein to name the compounds of this invention is illustrated in the Examples herein. This nomenclature has been derived using the commercially-available AutoNom software (MDL, San Leandro, Calif.). For example, compounds of formula I wherein W is O have typically been named as ester derivatives of biphenyl-2-ylcarbamic acid.

REPRESENTATIVE EMBODIMENTS

The following substituents and values are intended to provide representative examples of various aspects and embodiments of this invention. These representative values are intended to further define and illustrate such aspects and embodiments and are not intended to exclude other embodiments or to limit the scope of this invention. In this regard, the representation that a particular value or substituent is preferred is not intended in any way to exclude other values or substituents from this invention unless specifically indicated.

The value for a is 0, 1, 2, 3, 4 or 5; particularly 0, 1 or 2, and even more particularly 0 or 1. The value for b is 0, 1, 2, 3 or 4; particularly 0, 1 or 2, and even more particularly 0 or 1. In one embodiment, both a and b are 0.

When present, each R.sup.1 may be at the 2, 3, 4, 5 or 6-position of the phenyl ring to which it is attached. Each R.sup.1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.1a, --C(O)OR.sup.1b, --SR.sup.1c, --S(O)R.sup.1d, --S(O).sub.2R.sup.1e, --NR.sup.1fR.sub.1g, --NR.sub.1hS(O).sub.2R.sup.1i, and --NR.sup.1jC(O)R.sup.1k, examples of which include methyl, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, dimethylamino and the like. Particular values for R.sup.1 are fluoro or chloro.

When present, each R.sup.2 may be at the 3, 4, 5 or 6-position on the phenylene ring to which it is attached (where the carbon atom on the phenylene ring attached to the nitrogen atom is position 1). Each R.sup.2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.2a, --C(O)OR.sup.2b, --SR.sup.2c, --S(O)R.sup.2d, --S(O).sub.2R.sup.2e, --NR.sup.2fR.sup.2g, --NR.sup.2hS(O).sub.2R.sup.2i, and --NR.sup.2jC(O)R.sup.2k, examples of which include methyl, fluoro, chloro, bromo, hydroxy, methoxy, amino, methylamino, dimethylamino and the like. Particular values for R.sup.2 are fluoro or chloro.

Each R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1e, R.sup.1f, R.sup.1g, R.sup.1h, R.sup.1i, R.sup.1j, and R.sub.1k and R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.2f, R.sup.2g, R.sup.2h, R.sup.2i, R.sup.2j, and R.sup.2k as used in R.sup.1 and R.sup.2, respectively, is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl, examples of which include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl or benzyl. In one embodiment, these groups are independently hydrogen or (1-3C)alkyl. In another embodiment, these groups are independently hydrogen, methyl or ethyl. In addition, each alkyl and alkoxy group in R.sup.1, R.sup.1a-1k, R.sup.2, and R.sup.2a-2k is optionally substituted with 1 to 5 fluoro substituents.

In one embodiment of this invention, W is O. In another embodiment, W is NW.sup.a. Generally, it has been found that compounds in which W represents O exhibit particularly high affinity for muscarinic receptors. Accordingly, in a particular embodiment of this invention, W represents O.

When W is NW.sup.a, W.sup.a is hydrogen or (1-4C)alkyl, examples of which include hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, W.sup.a is hydrogen or (1-3C)alkyl. In another embodiment, W.sup.a is hydrogen, methyl or ethyl, particularly hydrogen or methyl. In yet another embodiment, W.sup.a is hydrogen and NW.sup.a is NH.

The value for c is 0, 1, 2, 3, 4, or 5; particularly 0, 1, or 2; and more particularly 0 or 1. In one particular embodiment, c is 0. In another embodiment, c is 2.

Each R.sup.3 independently represents (1-4C)alkyl or two R.sup.3 groups that are joined to form (1-3C)alkylene, (2-3C)alkenylene or oxiran-2,3-diyl. In one embodiment, each R.sup.3 is independently (1-4C)alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In addition, each alkyl group in R.sup.3 is optionally substituted with 1 to 5 fluoro substituents. In one embodiment, each R.sup.3 is independently (1-3C)alkyl, and in another embodiment, each R.sup.3 is independently methyl or ethyl.

In one embodiment, each R.sup.3 is at the 3, 4 or 5-position on the piperidine ring (where the nitrogen atom of the piperidine ring is position 1). In a particular embodiment, R.sup.3 is at the 4-position on the piperidine ring. In another embodiment, R.sup.3 is at the 1-position of the piperidine ring, i.e., on the nitrogen atom of the piperidine ring thus forming a quaternary amine salt.

In yet another embodiment, two R.sup.3 groups are joined to form a (1-3C)alkylene or (2-3C)alkenylene group. For example, two R.sup.3 groups at the 2 and 6-positions on the piperidine ring can be joined to form an ethylene bridge (i.e., the piperidine ring and the R.sup.3 groups form an 8-azabicyclo[3.2.1]octane ring); or two R.sup.3 groups at the 1 and 4-positions on the piperidine ring can be joined to form an ethylene bridge (i.e., the piperidine ring and the R.sup.3 groups form an 1-azabicyclo[2.2.2]octane ring). In this embodiment, other R.sup.3 groups as defined herein may also be present.

In still another embodiment, two R.sup.3 groups are joined to form a oxiran-2,3-diyl group. For example, two R.sup.3 groups at the 2 and 6-positions on the piperidine ring can be joined to form a 3-oxatricyclo[3.3.1.0.sup.2,4]nonane ring). In this embodiment, other R.sup.3 groups as defined herein may also be present.

The value for m is 0 or 1. In one embodiment, m is 0.

R.sup.4 represents hydrogen, (1-4C)alkyl, or (3-4C)cycloalkyl. Examples of (1-4C)alkyl include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. Examples of (3-4C)cycloalkyl groups include cyclopropyl and cyclobutyl. In one embodiment R.sup.4 represents hydrogen or (1-3C)alkyl, in particular hydrogen, methyl or ethyl. In another embodiment, R.sup.4 is hydrogen.

The value for s is 0, 1 or 2. A particular value for s is 0 or 1. In one embodiment, s is 0. In another embodiment, s is 2.

Ar.sup.1 is a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur. The phenylene or heteroarylene group may be unsubstituted (q is 0) or substituted with 1, 2, 3, or 4 (q is 1, 2, 3, or 4) R.sup.5 substituents, which are independently selected from halo, hydroxy, (1-4C)alkyl or (1-4C)alkoxy. In addition, each alkyl and alkoxy group in R.sup.5 is optionally substituted with 1 to 5 fluoro substituents. The value for q is 0, 1, 2, 3, or 4, particularly 0, 1, 2 or 3. In one embodiment, q is 0, 1 or 2. The point of attachment for Ar.sup.1 is at any available carbon or heteroatom ring atom. In certain embodiments, Ar.sup.1 is a phenylene group attached at the meta or para position.

In one embodiment Ar.sup.1 is phen-1,3-ylene or phen-1,4-ylene wherein the phenylene group is unsubstituted or substituted with 1, 2 or 3 R.sup.5 substituents. Representative R.sup.5 substituents include fluoro, chloro, bromo, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and trifluoromethoxy. Particular examples of Ar.sup.1 groups in this embodiment include 2-fluorophen-1,4-ylene, 3-fluorophen-1,4-ylene, 2-chlorophen-1,4-ylene, 3-chlorophen-1,4-ylene, 2-methylphen-1,4-ylene, 3-methylphen-1,4-ylene, 2-methoxyphen-1,4-ylene, 3-methoxyphen-1,4-ylene, 2-trifluoromethoxyphen-1,4-ylene, 3-trifluoromethoxyphen-1,4-ylene, 2,3-difluorophen-1,4-ylene, 2,5-difluorophen-1,4-ylene, 2,6-difluorophen-1,4-ylene, 2,3-dichlorophen-1,4-ylene, 2,5-dichlorophen-1,4-ylene, 2,6-dichlorophen-1,4-ylene, 2-chloro-5-methoxyphen-1,4-ylene, 2-chloro-6-methoxyphen-1,4-ylene, 2-chloro-5-trifluoromethoxyphen-1,4-ylene, 2-chloro-6-trifluoromethoxyphen-1,4-ylene, and 2,5-dibromophen-1,4-ylene.

In another embodiment, Ar.sup.1 is a (3-5C)heteroarylene group containing 1 or 2 heteroatoms independently selected from oxygen, nitrogen or sulfur; wherein the heteroarylene group is unsubstituted or substituted with 1 or 2 R.sup.5 substituents. Representative heteroarylene groups include divalent species of pyrrole, imidazole, thiazole, oxazole, furan, thiophene, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine and pyrimidine, where the point of attachment is at any available carbon or nitrogen ring atom. More specific examples of such Ar.sup.1 groups include 2,5-furylene, 2,4-thienylene, 2,5-thienylene, 2,5-pyridylene, 2,6-pyridylene, and 2,5-pyrrolylene. Representative R.sup.5 substituents include fluoro, chloro, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, methoxy, ethoxy, isopropoxy, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and trifluoromethoxy. Particular examples of substituted Ar.sup.1 groups include 3-fluoro-2,5-thienylene, 3-chloro-2,5-thienylene, 3-methyl-2,5-thienylene, 3-methoxy-2,5-thienylene, and 3-methoxy-6-chloro-2,5-pyridylene.

In one particular embodiment, Ar.sup.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 1 or 2 R.sup.5 substituents. In another particular embodiment, Ar.sup.1 represents phen-1,4-ylene or 2,4-thienylene optionally substituted with 1 or 2 R.sup.5 substituents.

The value for t is 0, 1 or 2. A particular value for t is 1.

The value for n is 0, 1, 2, or 3. Particular values for n are 1 or 2. In one embodiment, n is 2.

The value for d is 0, 1, 2, 3, or 4. Particular values for d are 0, 1 or 2. In one embodiment, d is 0.

Each R.sup.6 independently represents fluoro or (1-4C)alkyl, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In addition, each alkyl and alkoxy group in R.sup.6 is optionally substituted with 1 to 5 fluoro substituents. In one embodiment, each R.sup.6 independently represents fluoro or (1-3C)alkyl, and in another embodiment, each R.sup.6 is independently selected from fluoro, methyl, ethyl or trifluoromethyl.

The value for p is 0 or 1. In one particular embodiment, p is 0.

R.sup.7 and R.sup.8 each independently represent hydrogen or (1-4C)alkyl, examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. In one embodiment, R.sup.7 and R.sup.8 each independently represent hydrogen or (1-3C)alkyl. In a particular embodiment, R.sup.7 is hydrogen, methyl, ethyl, n-propyl or isopropyl, and R.sup.8 is hydrogen. In another particular embodiment, R.sup.7 and R.sup.8 are both hydrogen or both ethyl. In addition, each alkyl and alkoxy group in R.sup.7 and R.sup.8 is optionally substituted with 1 to 5 fluoro substituents.

As noted in formula I, the --CONR.sup.7R.sup.8 group can be located at any carbon atom on the ring. For example, when n is 2, the --CONR.sup.7R.sup.8 group can be located at the ortho, meta or para position. In one embodiment, the --CONR.sup.7R.sup.8 group is located at the meta or para position; and in a particular embodiment, the --CONR.sup.7R.sup.8 group is located at the para position.

A particular group of compounds of interest are compounds of formula I wherein a, b, c and d are 0; n is 2; and R.sup.4 is hydrogen, methyl or ethyl.

Another particular group of compounds of interest are compounds of formula I wherein a, b, c and d are 0; R.sup.4 is hydrogen, methyl or ethyl; and R.sup.7 is hydrogen.

Another particular group of compounds of interest are compounds of formula I wherein a, b, c and d are 0; R.sup.4 is hydrogen, methyl or ethyl; R.sup.7 is hydrogen, methyl, ethyl, n-propyl or isopropyl, and R.sup.8 is hydrogen.

Another particular group of compounds of interest are compounds of formula I wherein a, b, c and d are 0; R.sup.4 is hydrogen, methyl or ethyl; and R.sup.7 and R.sup.8 are ethyl.

Another particular group of compounds of interest are compounds of formula I wherein a, b, c and d are 0; R.sup.4 is hydrogen, methyl or ethyl; R.sup.7 and R.sup.8 are hydrogen; and s is 0.

Another particular group of compounds of interest are compounds of formula I wherein a, b, c and d are 0; R.sup.4 is hydrogen, methyl or ethyl; R.sup.7 and R.sup.8 are hydrogen; s is 0; and t is 1.

Another particular group of compounds of interest are compounds of formula I wherein a, b, c and d are 0; R.sup.4 is hydrogen, methyl or ethyl; R.sup.7 and R.sup.8 are hydrogen; s is 0; t is 1; and m is 0.

Representative Subgeneric Groupings

The following subgeneric formulae and groupings are intended to provide representative examples of various aspects and embodiments of this invention and as such, they are not intended to exclude other embodiments or to limit the scope of this invention unless otherwise indicated.

A particular group of compounds of formula I are those disclosed in U.S. Provisional Application No. 60/552,443, filed on Mar. 11, 2004. This group includes compounds of formula Ia:

##STR00003## wherein:

a is 0 or an integer of from 1 to 3; each R.sup.1 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.1a, --C(O)OR.sup.1b, --SR.sup.1c, --S(O)R.sup.1d, --S(O).sub.2R.sup.1e and --NR.sup.1fR.sup.1g; each of R.sup.1a, R.sup.1b, R.sup.1c, R.sup.1d, R.sup.1e, R.sup.1f and R.sup.1g is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

b is 0 or an integer of from 1 to 3; each R.sup.2 is independently selected from (1-4C)alkyl, (2-4C)alkenyl, (2-4C)alkynyl, (3-6C)cycloalkyl, cyano, halo, --OR.sup.2a, --C(O)OR.sup.2b, --SR.sup.2c, --S(O)R.sup.2d, --S(O).sub.2R.sup.2e and --NR.sup.2fR.sup.2g; each of R.sup.2a, R.sup.2b, R.sup.2c, R.sup.2d, R.sup.2e, R.sup.2f and R.sup.2g is independently hydrogen, (1-4C)alkyl or phenyl(1-4C)alkyl;

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

c is 0 or an integer from 1 to 4; each R.sup.3 independently represents (1-4C)alkyl;

m is 0 or 1;

R.sup.4 is hydrogen or (1-4C)alkyl;

s is 0 or 1;

Ar.sup.1 represents a phenylene group or a (3-5C)heteroarylene group containing 1 or 2 heteroatoms selected independently from oxygen, nitrogen or sulfur; wherein the phenylene or heteroarylene group is substituted with (R.sup.5).sub.q where q is 0 or an integer from 1 to 4 and each R.sup.5 is selected independently from halo, hydroxy, (1-4C)alkyl or (1-4C)alkoxy;

t is 0 or 1;

n is 0, 1 or 2;

d is 0 or an integer from 1 to 4; each R.sup.6 independently represents fluoro or (1-4C)alkyl; and

R.sup.7 is hydrogen or (1-4C)alkyl;

wherein each alkyl and alkoxy group in R.sup.1, R.sup.1a-1g, R.sup.2, R.sup.2a-2g, R.sup.3, R.sup.5, R.sup.6 or R.sup.7 is optionally substituted with 1 to 5 fluoro substituents; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof.

This group also includes compounds of formula Ib:

##STR00004## wherein: R.sup.4, q, R.sup.5 and R.sup.7 are as defined for formula Ia; or a pharmaceutically acceptable salt or solvate or stereoisomer thereof. A particular embodiment includes compounds of formula Ib, where q is 0, 1 or 2, and R.sup.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.

In addition, particular compounds of formula I that are of interest include: biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethyl)piper- idin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl]ethylamino}ethyl)piperi- din-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{methyl-[4-(4-methylcarbamoylpiperidin-1-ylmethyl)benzoyl]amino}ethy- l)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}ethy- l)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-isopropylcarbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}et- hyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-carbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]ethyl}pipe- ridin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[2,5-d]bromo-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}et- hyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-{2-[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoylamino]eth- yl}piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)-2-fluorobenzoyl]methyla- mino}ethyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-diethylcarbamoylpiperidin-1-ylmethyl)benzoyl]methylamino}ethy- l)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)pipe- ridin-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]methylamin- o}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}ethy- l)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)-1H-pyrrole-2-carbon- yl]methylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)-1H-pyrrole-2-carbonyl]methylam- ino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]met- hylamino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-diethylcarbamoyl-piperidin-1-ylmethyl)furan-2-carbonyl]methyl- amino}ethyl)piperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-(4-carbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]-amino}ethyl)p- iperidin-4-yl ester; biphenyl-2-yl-carbamic acid 1-(2-{[5-((R)-3-diethylcarbamoylpiperidin-1-ylmethyl)furan-2-carbonyl]ami- no}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)p- iperidin-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-y- l ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-benzoyl]methylamino}e- thyl)piperidin-4-yl ester; biphenyl-2-ylcarbamic acid 1-(2-{[4-(4-carbamoylpiperidin-1-ylmethyl)-2-chloro-5-methoxybenzoyl]meth- ylamino}ethyl)piperidin-4-yl ester; and biphenyl-2-ylcarbamic acid 1-[2-({2-[4-(4-carbamoylpiperidin-1-ylmethyl)phenyl]acetyl}methylamino)et- hyl]piperidin-4-yl ester;

or a pharmaceutically acceptable salt or solvate thereof.

Definitions

When describing the compounds, compositions, methods and processes of this invention, the following terms have the following meanings unless otherwise indicated.

The term "alkyl" means a monovalent saturated hydrocarbon group which may be linear or branched. Unless otherwise defined, such alkyl groups typically contain from 1 to 10 carbon atoms. Representative alkyl groups include, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like.

The term "alkylene" means a divalent saturated hydrocarbon group which may be linear or branched. Unless otherwise defined, such alkylene groups typically contain from 1 to 10 carbon atoms. Representative alkylene groups include, by way of example, methylene, ethane-1,2-diyl ("ethylene"), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl, pentane-1,5-diyl and the like.

The term "alkoxy" means a monovalent group of the formula (alkyl)-O--, where alkyl is as defined herein. Representative alkoxy groups include, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, tert-butoxy and the like.

The term "alkenyl" means a monovalent unsaturated hydrocarbon group which may be linear or branched and which has at least one, and typically 1, 2 or 3, carbon-carbon double bonds. Unless otherwise defined, such alkenyl groups typically contain from 2 to 10 carbon atoms. Representative alkenyl groups include, by way of example, ethenyl, n-propenyl, isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like. The term "alkenylene" means a divalent alkenyl group.

The term "alkynyl" means a monovalent unsaturated hydrocarbon group which may be linear or branched and which has at least one, and typically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwise defined, such alkynyl groups typically contain from 2 to 10 carbon atoms. Representative alkynyl groups include, by way of example, ethynyl, n-propynyl, n-but-2-ynyl, n-hex-3-ynyl and the like. The term "alkynylene" means a divalent alkynyl group.

The term "aryl" means a monovalent aromatic hydrocarbon having a single ring (i.e., phenyl) or fused rings (i.e., naphthalene). Unless otherwise defined, such aryl groups typically contain from 6 to 10 carbon ring atoms. Representative aryl groups include, by way of example, phenyl and naphthalene-1-yl, naphthalene-2-yl, and the like. The term "arylene" means a divalent aryl group.

The term "azacycloalkyl" means a monovalent heterocyclic ring containing one nitrogen atom, i.e., a cycloalkyl group in which one carbon atom has been replaced with a nitrogen atom. Unless otherwise defined, such azacycloalkyl groups typically contain from 2 to 9 carbon atoms. Representative examples of an azacycloalkyl group are pyrrolidinyl and piperidinyl groups. The term "azacycloalkylene" means a divalent azacycloalkyl group. Representative examples of an azacycloalkylene group are pyrrolidinylene and piperidinylene groups.

The term "cycloalkyl" means a monovalent saturated carbocyclic hydrocarbon group. Unless otherwise defined, such cycloalkyl groups typically contain from 3 to 10 carbon atoms. Representative cycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like. The term "cycloalkylene" means a divalent cycloalkyl group.

The term "halo" means fluoro, chloro, bromo and iodo.

The term "heteroaryl" means a monovalent aromatic group having a single ring or two fused rings and containing in the ring at least one heteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur. Unless otherwise defined, such heteroaryl groups typically contain from 5 to 10 total ring atoms. Representative heteroaryl groups include, by way of example, monovalent species of pyrrole, imidazole, thiazole, oxazole, furan, thiophene, triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine, pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene, benzimidazole, benzthiazole, quinoline, isoquinoline, quinazoline, quinoxaline and the like, where the point of attachment is at any available carbon or nitrogen ring atom. The term "heteroarylene" means a divalent heteroaryl group.

The term "heterocyclyl" or "heterocyclic" means a monovalent saturated or unsaturated (non-aromatic) group having a single ring or multiple condensed rings and containing in the ring at least one heteroatom (typically 1 to 3 heteroatoms) selected from nitrogen, oxygen or sulfur. Unless otherwise defined, such heterocyclic groups typically contain from 2 to 9 total ring carbon atoms. Representative heterocyclic groups include, by way of example, monovalent species of pyrrolidine, imidazolidine, pyrazolidine, piperidine, 1,4-dioxane, morpholine, thiomorpholine, piperazine, 3-pyrroline and the like, where the point of attachment is at any available carbon or nitrogen ring atom. The term "heterocyclene" means a divalent heterocyclyl or heterocyclic group.

When a specific number of carbon atoms is intended for a particular term used herein, the number of carbon atoms is shown in parentheses preceding the term. For example, the term "(1-4C)alkyl" means an alkyl group having from 1 to 4 carbon atoms.

The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (e.g., salts having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. Salts derived from pharmaceutically acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc and the like. Particularly preferred are ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic bases include salts of primary, secondary and tertiary amines, including substituted amines, cyclic amines, naturally-occurring amines and the like, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like. Salts derived from pharmaceutically acceptable acids include acetic, ascorbic, benzenesulfonic, benzoic, camphosulfonic, citric, ethanesulfonic, edisylic, fumaric, gentisic, gluconic, glucoronic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, lactobionic, maleic, malic, mandelic, methanesulfonic, mucic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, nicotinic, nitric, orotic, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, xinafoic and the like. Particularly preferred are citric, hydrobromic, hydrochloric, isethionic, maleic, naphthalene-1,5-disulfonic, phosphoric, sulfuric and tartaric acids.

The term "salt thereof" means a compound formed when the hydrogen of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Preferably, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient.

The term "solvate" means a complex or aggregate formed by one or more molecules of a solute, i.e. a compound of formula I or a pharmaceutically acceptable salt thereof, and one or more molecules of a solvent. Such solvates are typically crystalline solids having a substantially fixed molar ratio of solute and solvent. Representative solvents include, by way of example, water, methanol, ethanol, isopropanol, acetic acid and the like. When the solvent is water, the solvate formed is a hydrate.

It will be appreciated that the term "or a pharmaceutically acceptable salt or solvate or stereoisomer thereof" is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of a compound of formula I.

The term "therapeutically effective amount" means an amount sufficient to effect treatment when administered to a patient in need of treatment.

The term "treating" or "treatment" as used herein means the treating or treatment of a disease or medical condition (such as COPD) in a patient, such as a mammal (particularly a human) that includes: (a) preventing the disease or medical condition from occurring, i.e., prophylactic treatment of a patient; (b) ameliorating the disease or medical condition, i.e., eliminating or causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, i.e., slowing or arresting the development of the disease or medical condition in a patient; or (d) alleviating the symptoms of the disease or medical condition in a patient.

The term "leaving group" means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. By way of example, representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.

The term "protected derivatives thereof" means a derivative of the specified compound in which one or more functional groups of the compound are protected from undesired reactions with a protecting or blocking group. Functional groups which may be protected include, by way of example, carboxylic acid groups, amino groups, hydroxyl groups, thiol groups, carbonyl groups and the like. Representative protecting groups for carboxylic acids include esters (such as a p-methoxybenzyl ester), amides and hydrazides; for amino groups, carbamates (such as tert-butoxycarbonyl) and amides; for hydroxyl groups, ethers and esters; for thiol groups, thioethers and thioesters; for carbonyl groups, acetals and ketals; and the like. Such protecting groups are well-known to those skilled in the art and are described, for example, in T. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York, 1999, and references cited therein.

The term "amino-protecting group" means a protecting group suitable for preventing undesired reactions at an amino group. Representative