Indian Patents. 224319:UREA COMPOUNDS HAVING MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY

Title of Invention	UREA COMPOUNDS HAVING MUSCARINIC RECEPTOR ANTAGONIST ACTIVITY
Abstract	The invention relates to a compound of formula (Ia): that are muscarinic receptor antagonists and agonists and pharmaceutical compositions comprising such compounds.

Full Text	UREA COMPOUNDS HAVING MUSCAKIKIC RECEPTOR ANTAGOSIST ACTIVITY CROSS-REFERENCE TO RELATED APPLICATIONS: This appHcalion is a continuation-in-part of U.S. Patent Application Serial No. 09/456,170, filed December 7,1999. BACKGROUND OF THE INVENTION A receptor is a biological structure with one or more binding domains that reversJbJy complexes with one or more ligands, where that complexalion has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with thespaceoutsideof its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell. A ligand is a biifding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool. The super family of seven transmembrane proteins {7-rMs), also caUed G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell's boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like). Muscarinic receptors are members of the G-prolein coupled receptors that are composed of a family of five receptor sub-types (Mi.M,, M3, M4 and M,) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented (Bonner, T. I et al.. Science (Washington D.C.) 1987, 237, 527-532; Goyal, R. K., J. Med., 1989, 321, 1022; Hulme, E.G., et al., Annu. Rev. harmacolToxicol 1990, 30, 633; and Eglen, R. M. and Hegde, S. S., Drug News Perspect. 1997, 10(8), 462-469). For example, the smooth muscle is composed largely of Mj and M3 receptors, cardiac muscle is composed largely of Mj receptors, and salivary glands are largely composed of M3 receptors. It has been established thai the muscarinic receptors are involved in diseases such as chronic obstiuctive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher, A., Invest. Drugs, 1997, 6(10), 1395-1411;Martel, A.M., etal.. Drugs Future, 1997, 22(2), 135-137; Graui, A. and Castaner, J., Dns Future, 1996, 21(11), 1105-1108; and Graul, A., et al.. Drugs Future, 1997, 22(7), 733-737). A number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases. For example, oxybutynin is being used for the treatment of urinary urge incontinence and dicyclomine is being used for the treatment of irritable bowel syndrome. However, these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis. There is currently a need for novel muscarinic receptor antagonists. SUMMARY OF THE INVENTION The invention is directed to urea derivatives that are muscarinic receptor intagonists and agonists and that are useful in the treatment and prevention of 1 liseases mediated by muscarinic receptors (e.g. chronic obstmctive pulmonary lisease, chronic bronchitis, irritable bowei syndrome, urinary incontinence, and the ike). Accordingly, the invention provides a compound of the invention which is a :onipound of Formula (I): wherein: is an optional double bond; n, is an integer of from 1 to 4; n is an integer of from 1 to 3; V is -CH-, -0-, -S(0)n3- (where n is an integer of from 0 to 2), or -NR-(wherein R is hydrogen, alkyl, substituted alkyl, ary!, or heteroaryl); "Het" is a heteroaryl ring which optionally attaches (a) to a linker;- R' is hydrogen, alkyl, amino, substituted amino, -OR (where R is bydfogen, alkyl, or acyl), or a covalent bond altacbing (a) to a linker; R is hydrogen, alkyl, amino, substituted amino, -OR' (where R' is hydrogen or alkyi], aryl, araikyi, heleroaralkyl, or a covalent bond attaching (a) to a (inker; R, R', and R are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aikyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, aikylihio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker; K is a bond or an alkylene group; K" is a bond, -C(O)-,. -S(0)- (where n is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and B is heterocycioamino or heleroarylamino, which optionally attaches (a) to a linker; provided that at least one of the R R, R', R, "Het", heterocycloamino or heteroarylamino groups attaches (a) to a linker; X is a linker; Lj is a group selected from a group consisting of: (i) a group of formula (b): / wherein: D" is alkylene; D is -NR'R", -N'CRR'R") or-OR" where R', R\ and R" are, independently of each other, hydrogen, alkyl, or aralkyl; and R- and R' represent a covalent bond attaching (b) to a linker; R' is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkyisulfmyl, sulfonamido, alkylsulfonamido, carbamoyJ, (hiocarbamoyl, mono or dialkyjcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, aryithio, heteroaryl, heieraryloxy, heteroarylthio, heterocyciyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three subslituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, cart>oxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; R' and R' are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or one of R', R, R, or R together with the adjacent group forms a methylenedioxy or elhylenedioxy group; (ii) a group of formula (c): wherein; n I, is an integer of from I to 7; n 12 is 0 to 7; F is -NR'°-, -0-, -S-, or -CHR"- (wherein R'" and R" are, independently of each other, hydrogen, aiky!, or substituted alkyl); F' is a covaJent bond, 'OR'\ -NRR or -NR'RR" wherein R" is hydrogen or alkyl, R and R' are alkyl, and R is hydrogen, alkyl, or a covalent bond attaching (c) to a linker; R' is hydrogen, alkyi, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, tiio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamide, alkylsulfonamide, carbamoyl, thiocarbamoyi, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryi, heteraryloxy, heteroaryithio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino; I R' is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryi, heteraryloxy, heteroaryithio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents .elected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, jmino, or substituted amino; and R' is hydrogen, alkyl, hafo, hydroxy, alkoxy, or a covalent bond attaching ;he ligand to a linker provided that at least one of R and R' attaches (c) to a linker; R' is hydrogen, alky!, halo, hydroxy, alkoxy, or substituted alkyl; and (iii) a group of formula (d) or (e): wherein: R is alkyl, substituted alkyl, cycloalkyl. substituted cycloalkyi, or heterocycle; R" is alky!, substituted alkyl, aryi, acyl, heterocycle, or -COOR" where R" is alkyl; or R' and R' together with the nitrogen atom to which they are attached form beterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more (e.g. 1, 2, 3, or 4) alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl. R' is a covalent bond that attaches the (d) or the (e) to a linker; and R"' is alkyl; or a pharmaceuttcally acceptable salt; or prodrug thereof. Preferably X is a group of formula: -X'-Z-(Y=-Z)-Y'-Z-X'-wherein 7_ m is an integer of from 0 to 20; X at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(0)-, -C(0)0-. -C(0)NR-, -C(S)-, -C(S)0-. -C(S)NR- or a covaient bond where R is as defined below; Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynyfene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyciene, or a covaient bond; Y° and Y at each separate occurrence are selected from the group consisting of -0-, -C(0)-, -0C(0)-, -C(0)0-, -NR-, -SCO)n-, -C(0)NR'-, -NR' C(0)-, -NR' C(0)NR'-, -NR' C(S)NR'-. -C(=NR')-NR'-, -NR'-C(=NR')-, -OC{0)-NR'-, -NR'-C(0)-0-, -N=C(R'>NR'-, -NR'-C(R")=N-,-P(0)(OR')-0-, -0P(O)(0R')-, -S(0)„CR' R"-, -S(OVNR'-, -NR'-S(0)„-, -S-S-, and a covaient bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyi, substituted cycloaJkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aiyl, heteroaryi and heterocyclic (preferably, at least one of X% Y', Y or Z is not a covaient bond). The invention also provides a compound of the invention which Is a compound of formula (IV): wherein R, K", A, K, R', B", B, X, and I have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof. A preferred compound of the invention is a compound of formula (FVa); wherein X, and Lj have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof. The invention also provides a pharmaceutical composition comprising a pharmaceuticaily acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof. The in'ention also provides synthetic intermediates disclosed herein, as well as synthetic methods useful for preparing such intermediates, and synthetic methods useful for preparing compounds of the invention or salts thereof.' The invention also provides a method of treating diseases mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodmg thereof. The invention also provides a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof for use in medical therapy, as well as the use of a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment of a disease mediated by a muscarinic receptor in a mammal. Applicant has discovered that urea compounds of the present invention are metabolically more itaSle than compounds lacking such a urea functionality. Accordingly, compounds of the present invention have longer metabolic half-lives and/or longer duration of action in vivo, which can reduce the dose required for administration or can reduce (he likelihood of the generation of unwanted metabolites. DETAILED DESCRIPTION OF THE INVENTION The following terms have the following meanings unless otherwise indicated. Any imdefined terms have their art recognized meanings. The term "alkyl" refers lo a monoradica} branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-pwpyl, «-butyl, iso-butyl, «-hexyi, n-decyl, letradecyl, and the like. The term "substituted alkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -0-, -S(0)n- (where n is 0 lo 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyioxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted ihioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-aryl, -SOj-heteroaryl, and -NR'R wherein R' and R' may be the same or different and and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. This term is exemplified by groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the like. The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from I to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably I to 6 carbon atoms. This term is exemplified by groups such as melhylene (-CH-), ethylene (-CH2CH2-), the propylene isomers (eg-, -CHjCHCHr and -CH(CH3)CH;-) and the like. The term "substituted alkylene" refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyJoxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyciooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyI, -SO-substituted aikyi, -SO-aryi and -S02-heteroaryI. Additionaiiy, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures. The terra "alkylaminoalkyl", "alkyl aminoalkenyl" and "alkylaminoalkynyl" refers to the groups RNHR"- where R' is alkyl group as defined above and R" is alkylene, alkenylene or alkynylene group as defined above. Such groups are exemplified by 3-methylaminobutyl, 4-ethylamino-l,l-dimethylbutyn-l-yl, 4-ethylaminobutyn-1-yl, and the like. Te term "alkaryl" or "aralkyl" refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like. The term "alkoxy" refers to the groups aIkyl-0-, alkenyl-O-, cycloalkyl-O-, cycloaikenyl-O-, and alkynyi-O-, where alkyl, alkenyl, cycloalkyl, cycloalkenyi, and alkynyi are as defined herein. Preferred alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, /j-butoxy, rert-butoxy, i'ec-butoxy, n-penfoxy, «-hexoxy, 1,2-dimelhyibutoxy, and the like. The term "substituted alkoxy" refers to the groups substituted a!kyI-0-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl'O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyi and substituted alkynyi are as defined herein. The term "haloajkoxy" refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like. The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-0-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted aikyl, alkylene and substituted alkylene are as defined herein. Preferred alkylalkoxy groups are aIkylene-0-alkyl and include, by way of example, methylenemethoxy (-CH2OCH3), ethylenemethoxy (-CH2CH3OCH3), n-propylene-wo-propoxy (-CHCHiCHjOCHCCIj)), methylene-i-butoxy (-CHj-O-CCCH,),), and the like. The term "alkylthioalkoxy" refers to the group -alkylene-S-alkyl, a!kylene-S-substitt{ted alkyl, substituted alkyJene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example, methylenethiomethoxy (-CH2SCH3), ethylenethiomethoxy (-CHjCHjSCHj), n-propylene-ijo-thiopropoxy (-CHjCHjCHjSCHCCHj)!), methylene-Mhiobutoxy (-CHjSCCCHj)). and the like. The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl {-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-C(CH3)=CH2), and the like. The term "substituted alkenyl" refers to an alkenyl group as defined above having from I to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloaikenyl, substituted cycloaikenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxyiaikyi, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thjoalkoxy, aryl, aryloxy, heteroaryl, heleroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, aikoxyamino, nitre, -SO-alkyl, -SO-substituted alkyl, -SO-ary!, -SO-heteroaryl, -SOj-alkyl, -SO-substituted alkyl, -SO-aryl and -SOj-heteroaryl. The term "alkenylene" refers to a dlradicai of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to iO carbon Moms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH2CH=CH- orj-C(CH3)=CH-), and the like. The term "substituted alkenylene" refers to an alkenylene group as defined above having from 1 to 5 subslituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloaikenyl, substituted cycloaikenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxy!, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, aikoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyl, -SO-substituted alkyl, -SOj-aryl and -SO;-heteroaryl. Additionally, such substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycioalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group. The term "alkynyi" refers to a monoradica! of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms and having at Jeast 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyi groups include ethynyl (-CsCH), propargyl (-CHjCCH), and the like. The temj "substituted alkynyi" refers to an alkynyi group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycIoaJkenyl, substituted cycJoaJkenyJ, acyj, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxy!, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocycJooxy, thiol, thioalkoxy, substituted Ibioalkoxy, aryl, aiyioxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted aikyl, -SO-aiyl, -SO-heteroaryl, -SO-alkyl, -SOj-substituled alkyl, -SOj-aiyl, and ~SO-heteroaryl The term "alkynylene" refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at Jeast J and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynylene groups include ethynylene (-C=C-), propargylene (-CHjCC-), and the like. TTie term "substituted alkynylene" refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen. hydroxyl, keio, Ihioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, ihiohelerocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyI, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO;-alkyl, -SO-substituted alkyl, -SOj-aryl and -SO-heteroaryl. The term "acyl" refers to the groups HC(0)-, a!ky[-C(0)-, substituted aifcyi-C(0)-, cycl03lkyl-C(O>, substituted cycloalkyI-C{0)-, cycloalkenyKC(0>-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(0)- where alkyl. substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyi, substituted cycloalkenyi, aryl, heteroaryl, and heterocyclic are as defined herein. The term "acylamino" or "aminocarbonyl" refers to the group -C(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholjno) wherein alkyl, substitufed alkyl, aryl, heteroaryl, and heterocyclic are as defined herein. The term "aminoacyl" refers to the group -NRC(0)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, ary!, heteroaryl, and heterocyclic are as defined herein. The term "aminoacyloxy" or "alkoxycarbonylamino" refers to the group -NRC(0)OR where each R is independently hydrogen, alkyl, substituted alky], aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein. The term "acyloxy" refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, aryl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0- wherein alkyl, substituted alkyl. cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein. The term "ary!" refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substitueni, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyi, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacyiamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyI, -SO-substjtuted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyt, -SO-substituted alkyl, -S02-aryl, -SOj-heteroaryl and trihalomethyl. Preferred aryl substiluents include alkyl, alkoxy, halo, cyano, nitro, tnhalomethyl, and thioalkoxy. The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above. The term " arylene " refers to the diradical derived from aryl (including substituted aryl) as defined above and is exemplified by 1,2-phenyIene. 1,3- t phenyiene, 1,4-phenyIene, 1,2-naphthylene and the like. The term "amino" refers to the group -NHj. The terra "substituted amino" refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic provided that both R's are not hydrogen. The term "carboxyalkyl" or "alkoxycarbonyl" refers to the groups "-C(0)0-alkyl", "-C(0)0-substituted alkyl", "-C(0)0-cycloalkyl", "-C(0)0-substituted cycloalkyl", "-C(0)0-alkenyr', "-C(0)0-substituted alkenyl". "-C(0)0-aIkynyl" and "-C(O)0-substituted alkynyl" where alkyl, substituted alky], cycioalkyl, substituted cycloalkyi, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein. The term "cycloalkyi" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyi groups include, by way of example, single ring structures such as cyclopropyi, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like. The term "substituted cycloalkyi" refers to cycloalkyi groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, acyl, acyiamino, acyioxy, amino, substituted amino, am'moacyl, aminoacyJoxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, ihioheierocyclooxy, thiol, Ibioalkoxy, substituted thioalkoxy, aryJ, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitre, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyl, -SO-substituted alkyl, -SO-aryl and -SO-heteroaryl. The term "cyclyalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, and the like. The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from I to 5 substituents, and preferably 1 to 3 substituents. selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloalkenyl. substituted cycloalkenyl, acyl, acyiamino, acyioxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, caiboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy. heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-subslituted aikyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyl, -SOj-subslituted alkyl, -SOj-aryl and -SO-heteroaryl. The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo. The term "heteroaryj" refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with I to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl. alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyi, acylamino, alkaryl, ary], aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heleroaiyloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioaikoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO;-alkyI, -SOj-substituted alkyl, -SO-aryl, -SOj-heteroaryl and trihalomelhyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl. The term "heteroara!kyl" refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. Such heteroaralkyl groups are exemplified by pyridylmethyl, pyridylethyl, indolylmethyl, and the like. The term "heteroaryloxy" refers to the group heteroaryl-O-. The term " heteroarylene " refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6'pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-ben2ofuranyIene, 2,5-pyridnylene, 2,5-indolenyl, and the like. The term "heterocycle" or "heterocyclic" or refers to a monoradical saturated jnsaturated group having a single ring or multiple condensed rings, from I to 40 rarbon atoms and from I (o 10 hetero atoms, preferabJy I to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyiamino, acyioxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroary], -S02-a!kyl, -SOj-substiluled alkyl, ~SOj-aryl and -SO;-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morphoJino, piperidinyl, and the like. Examples of nitrogen heteroaryls and heterocycles include, but are not limited to, pyrrole, ibJophene, furan, imidazole, pyrazoJe, pyridine, pyrazine, pyrimidine, pyridazine indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, morpholine, tetrahydrofiiranyl, tetrahydrothiophene, and the like as well as N-alkoxy-nitrogen containing heterocycles. The term "heterocyclooxy" refers to the group heterocyclic-O-. The term "thioheterocyclooxy" refers to the group heterocyclic-S-. The term "heterocyclene" refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morphoJino and the like. "Heteroarylamino" means a 5 membered aromatic ring wherein one or two ring atoms are N, (he remaining ring atoms being C The heEerocycIoamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally subslituled with one or more subslifuenis, preferably one or iwo substifuents, selected from alkyl, substituted aikyl, cycloalkyl, aryl, aralkyl, heteroaryl, beteroaralky], halo, cyano, acyl, amino, substituted amino, acyJamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(0)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroary], aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, imidazole, pyrazole, benzimidazole and benzpyrazole. "Heterocycloamino" means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(0)n (where n is an integer om 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyi group. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(0)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, pyrroiidino, piperidino, morpholino, piperazJno, indolino, or thiomorpholino. The term heterocycloamino also includes, quinuclidine, l--a2abicyclo[2.2.1]h6ptyl, l-azabicyclo[3.2.iloctyl and the derivatives thereof. The term " oxyacylamino " or "aminocarbonyloxy" refers to the group -OC(0)NRR where each R is independently hydrogen, alkyi, substituted alkyl, atyl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein. The term " spiro-attached cycloaikyl group " refers lo a cycloalkyl group attached to another ring via one carbon atom common to both rings. The term "thiol" refers to the group -SH. The term "thioalkoxy" or "alkyithio" refers to the group -S-alkyl. The term "substituted thioalkoxy" refers to the group -S-substituted alkyl. The term "ihioaryloxy" refers lo the group aryl-S- wherein the aryJ group is as defined above including optionally substituted aryl groups also defined above. The term "thioheteroaiyloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above. As to any of the above groups which contain one or more substituents, it is understood, of course, t\|hat such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of Ibis invention include alJ stereochemical isomers arising from the substitution of these compounds. Unless specified otherwise, all ranges referred to herein include the stated end-point values. The term "pharmaceutically-acceptable salt" refers to salts which retain biological effectiveness and are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto. Phannaceti(icaI2y-accep(able base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of prirnary, secondary and tertiary amines, such as alkyl amines, dialkyj amines, irialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkeny! amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri{substituted alkenyl) amines, cycloalkyi amines, di(cyc!oaIkyl) amines, tri(cycIoaJkyI) amines, substituted cycloalkyi amines, disubstituted cycloalkyi amine, trisubstituted cycloalkyi amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloaikenyl) amities, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaiyl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together wth the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyi amine, diethyl amine, tri{wo-propyl) amine, tri(n-propyl) amine, ethanolamJne, 2-dimethy!aniinoethant)l, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpjperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyi carboxamides, dialkyl carboxan:iides, and the Uke. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and Che Jike. Salts derived from organic acids include acetic acid, propionic acid, glycoHc acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandeiic acid, methanesuifonic acid, elhanesuifonic acid, p-(oiuene-suIfonic acid, salicylic acid, and the like. The term " pharmaceuticaJly-acceptable cation " refers to the cation of a pharmaceuticaJly-acceptabie salt. The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, thiol, amino or caiboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylitiine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxy! functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzy! groups, and the like. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product. Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, butyl etc. which can be removed by mild conditions compatible with the nature of the product. The term "optional" or "optionally" means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. The term "inert organic solvent" or "inert organic solvent" means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methytethyl ketone, methanol, ethanol, propanol, isDpropanoE, f-bufanol, dioxane. pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert solvents. The term "treatment" refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes: (i) preventing the pathologic condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the disease condition; (ii) inhibiting the pathologic condition, i.e., arresting its development; (iii) relieving the pathologic condition, i.e., causing regression of the pathologic condition; or (iv) relieving the conditions mediated by the pathologic condition. The term "pathologic condition which is modulated by treatment with a ligand" covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the muscarinic receptors in general, and those disease states which have been found to be useftilly treated by a compound of the invention. Such disease states include, by way of example only, the treatment of a mammal afflicted with chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like. The term "therapeutically effective amount" refers to that amount of a :ompound which is sufficient to effect treatment, as defined above, when idministered to a mammal in need of such treatment. The therapeutically effective imount will vary depending upon Ihe subject and disease condition being treated, he weight and age of the subject, the severity of the disease condition, the manner )f administration and the like, which can readily be determined by one of ordinary ikill in the art. The term "linker", identified by the symbol 'X' refers to a group or groups hat covalently attaches L, and Lj. Additionally, the linker can be either a chiral or schiral molecule. The term "linker' does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the compounds of this invention can be attached to a solid support if desired. For sxample, such attachment to solid supports can be made for use in separation and purification processes and similar applications. "Pro-drugs" means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., NJS-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like. While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) may be preferred. Specific and preferred values listed herein for radicals, substituents, and ranges, are for 55 illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents A preferred value for A is phenyl or pyridine A preferred value for R' is hydrogen methyl, or ethyl. Another preferred value for R' is hydrogen. A preferred value for R is pyrrolyl, pyridinyl, or imidazolyl. Another preferred value for R is phenyl, A preferred value for V is -CH- or -NR"- (wherein R is hydrogen, alkyl, substituted alkyl, aryl, or heleroaryl). A preferred value for R is hydrogen or alkyl A preferred value for R is hydrogen, alkyf, aryl, aralkyi, heteroaralkyl, or a covalent bond attaching (a) to a linker Another preferred value for R is hydrogen, methyl, phenyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino, benzyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino. A preferred value for R, R', and R indepeiident of each other is hydrogen, alkyl, nitro, hydroxy, or amino. A preferred value for K is alkylene having from 1 to 10 carbon atoms. A preferred valine for K is alkylene having from I to 5 carbon atoms. A preferred value for K is a bond or a methylene group. A preferred value for K" is a bond. A preferred value for R, is hydrogen. A preferred value for B is a heterocycloamino group which attaches (a) to a linker. Another preferred value for B is a formula selected from a group consisting of formula (j), formula (k), and formula (1): A-herein: 11,3 and n,a are, independently of each other, an integer of from 0 to 4 provided that ni3+n,4 is an Integer of from 3 to 5; ni5 and n,-, are, independently of each other, an integer of from 0 to 4 provided that ni+n,, is an integer of from 3 to 5; 0,6 is an integer of from 0 to 3 provided that nj, + nj is an integer of from 3 to 5; n,j, n,, and njo are, independently of each other, an integer of from 0 to 3 provided that n\|g+ n,9 + njo is 2 or 3; nji is an integer of from 1 to 3; W" and W are, independently of each other: where: n22 isOor I; R and R" are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyi, aralkyl, or heterocyclylalkyl or a covalent bond attaching (a) to a linker; R" is alkyl, alkenyl or alkynyl; and W" is -N(0)n„ or -N-R where nj is 0 or 1, and R is aiky!, alkenyl, alkyiiyl, or aralkyl, or a covalent bond attaching (a) to a linker; provided that a carbon other than a bridge head carbon is bonded to B". Another preferred value for B is a ring represented by the following general wherein a carbon atom other than a bridge head carbon is bound to B"; and W is as defined above. A more preferred value for B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a iinker. Another more preferred value for B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker. Another more preferred value for B is piperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker. Another more preferred value for B is quinuclidine, i-azabicyclo[2.2.1 ]-heptyl, or 1 -azabicyclo[3.2.1 ]octyl attaching (a) to a linker, wherein a carbon other than a bridge head carbon is bound to B". A preferred value for D" is-(CH2)n43-where n3 is an integer of from I-IO, preferably 2-8, more preferably 2-4. Another preferred value for nj is an integer of from 3-10. A preferred value for D is -NR"R" or -N{R"RR")M- where R', R", and R are, independently of each other, hydrogen or methyl, and R and R" represent a covalent bond attaching (b) to a linker. More preferably R", R", and R" methyl, . and R and R represent a covalent bond attaching (b) to a linker. A preferred value for R is hydrogen. A preferred value for R' is hydrogen. A preferred value for R' and R independently is hydrogen; or one of R', R, R, or R together with the adjacent group forms a methylenedioxy or ethylenedioxy group. A preferred value forn,, is 1. A preferred value for n is 6. A preferred value for F is -0-. A preferred value for F' is a covalent bond, -OR", -NR"R" wherein R" is hydrogen or alkyl, or -NRRR') wherein R" and R are alkyl, and R" is a covalem bond attaching (c) to a linker. A preferred value for F" is -0-, -NH-, N(CH3)- or -N(CH,\- A more preferred value for F' is -NH-, NCCHj)- or -N(CH3)2- wherein the nitrogen atom attaches (c) to a linker. A preferred value for R is hydrogen. Preferably R" is ortho to the - Preferably is R is hydrogen. Preferably R' is hydrogen. Preferably L is a group of formula (d) wherein: R' is alkyl or substituted alkyl; R' is aJfcyl, substituted alkyl, or fjeterocyde; or R' and R" together with the nitrogen atom to which they are attached form heterocycle. Preferably, Lj is a group of formula A1-A241 as shown in the following table. Lj is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of Lj. 5 WE CLAIM: 1. A compound of formula (la): wherein: A is phenyl or pyridyl; B is -NH-; R is hydrogen; R2 is pyrrolyl, pyridinyl, imidazolyl or phenyl; K is a bond or a methylene group; K" is a bond; B is pyrrolidine, piperidine, or hexahydroazepine; R46 is alkyl, substituted alkyl, cycloalkyi, substituted cycloalkyl, or heterocycle; R'' is alkyl, substituted alkyl, aryl, acyl, heterocycle, or -COORo where Rso is alkyl; or R'* and R'" together with the nitrogen atom to which they are attached form heterocycle, which is optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acylojq, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboJQl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoj, substituted thioalkoxy, aryl, arylojo?, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, - SO-aryl, -SO-heteroaryl, -S02-alkyl, -SO2- substituted alkyl, -SOa-aryl -SOa-heteroartyl, alkyl, substituted alll, alkenyl, substituted alkenyl, alkynyl, and substituted aJkynyl; X is a group of formula: wherein mis an integer of from 0 to 20; Xa at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(0)-, -C(0)0-, -C(0)NR-, -C(S)-, -C(S)0-, -C(S)NR- or a covalent bond; Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloaJkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted aZlTiylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond; Y and Y at each separate occurrence are selected from the group consisting of-0-, -C(0)-, -0C(0)-, -C(0)0-, -NR-, -S(0)n-, -C(0)NR'-, -NR' C(0)-, -NR' C(0)NR'-, -NR'C(S}NR'-, -C(=NR')-NR'-, -NR'-C(=NRV, -OC(0)-NR'-, -NR'-C(0)-O-, -N=C(Xa)-NR'-, -NR'-C(XJ=N-, -P{0){ORyO~, -O-P(0)(OR')-, -S(0}nCR' R"-, -S(0)n-NR'-, -NR' 'S(0)n-, -S-S-, and a covalent bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, aikyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted aJkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaiy] and cieterocyclic; provided at least one of X», Y, Y or Z is not a covalent bond; Dr a pharmaceutically acceptable salt thereof. 2. The compound as claimed in claim 1, wherein A is phenyl, 3. The compound as claimed in claim 1, wherein the compound has the formula: 4. The compound as claimed in claims 1 to 3, wherein X is alkylene optionally substituted with one, two, or three hydroxy groups; alkylene wherein one, two or three carbon atoms have been replaced by an ojcygen atom; -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fLuoro groups. 5. The compound as claimed in claims 1 to 3, wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane 1,3-diyl, 2-hydroxypropane-l ,3-diyl, or 5-oxa-nonane-l ,9-diyI. 6. The compound as claimed in claims 1 to 5, wherein R"* is 3-piperidinyl, 4-piperidinyl or 3- pyrrolidinyl, which R'* is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloaikyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, jxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, hioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, ;ubstituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, dkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, ilkynyl, and substituted alkynyl. The compound as claimed in claims 1 to 5, wherein R"'* and R ogether with the nitrogen atom to which they are attached form a aiperidine or p3rrolidine ring which ring is optionally substituted with 1 :o 3 substituents independently selected from the group consisting of ilkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, :ycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acylojQ, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, tialogen, hydroxyl, keto, thioketo, carboxylalll, thioaryloxy, Lhioheteroaiyloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkojamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl. 8. The compound as claimed in claims 1 to 5, wherein R46 and R47 together with the nitrogen atom to which they are attached form an aza- crown ether. 9. The compound as claimed in claims 1 to 5, wherein R" and R*' together with the nitrogen atom to which they are attached form a group of the formula; 10. The compound as claimed in claims 1 to 5, wherein R46 and R47' together with the nitrogen atom to which they are attached form a group of the formula: 11. A pharmaceutical composition comprising a pharmaceuticaUy acceptable carrier and up to 20 weight percent of a compound as claimed in any of claims 1 to 10. 12. A compound substantially as herein described and exemplified.

Full Text

UREA COMPOUNDS HAVING MUSCAKIKIC RECEPTOR ANTAGOSIST ACTIVITY
CROSS-REFERENCE TO RELATED APPLICATIONS:
This appHcalion is a continuation-in-part of U.S. Patent Application Serial No. 09/456,170, filed December 7,1999.
BACKGROUND OF THE INVENTION
A receptor is a biological structure with one or more binding domains that reversJbJy complexes with one or more ligands, where that complexalion has biological consequences. Receptors can exist entirely outside the cell (extracellular receptors), within the cell membrane (but presenting sections of the receptor to the extracellular milieu and cytosol), or entirely within the cell (intracellular receptors). They may also function independently of a cell (e.g., clot formation). Receptors within the cell membrane allow a cell to communicate with thespaceoutsideof its boundaries (i.e., signaling) as well as to function in the transport of molecules and ions into and out of the cell.
A ligand is a biifding partner for a specific receptor or family of receptors. A ligand may be the endogenous ligand for the receptor or alternatively may be a synthetic ligand for the receptor such as a drug, a drug candidate or a pharmacological tool.
The super family of seven transmembrane proteins {7-rMs), also caUed G-protein coupled receptors (GPCRs), represents one of the most significant classes of membrane bound receptors that communicate changes that occur outside of the cell's boundaries to its interior, triggering a cellular response when appropriate. The G-proteins, when activated, affect a wide range of downstream effector systems both positively and negatively (e.g., ion channels, protein kinase cascades, transcription, transmigration of adhesion proteins, and the like).

Muscarinic receptors are members of the G-prolein coupled receptors that are composed of a family of five receptor sub-types (Mi.M,, M3, M4 and M,) and are activated by the neurotransmitter acetylcholine. These receptors are widely distributed on multiple organs and tissues and are critical to the maintenance of central and peripheral cholinergic neurotransmission. The regional distribution of these receptor subtypes in the brain and other organs has been documented (Bonner, T. I et al.. Science (Washington D.C.) 1987, 237, 527-532; Goyal, R. K., J. Med., 1989, 321, 1022; Hulme, E.G., et al., Annu. Rev. harmacolToxicol 1990, 30, 633; and Eglen, R. M. and Hegde, S. S., Drug News Perspect. 1997, 10(8), 462-469). For example, the smooth muscle is composed largely of Mj and M3 receptors, cardiac muscle is composed largely of Mj receptors, and salivary glands are largely composed of M3 receptors.
It has been established thai the muscarinic receptors are involved in diseases such as chronic obstiuctive pulmonary disease, asthma, irritable bowel syndrome, urinary incontinence, rhinitis, spasmodic colitis, chronic cystitis, and alzheimer,s disease, senile dementia, glaucoma, schizophrenia, gastroesophogeal reflux disease, cardiac arrhythmia, and hyper salvation syndromes (Fisher, A., Invest. Drugs, 1997, 6(10), 1395-1411;Martel, A.M., etal.. Drugs Future, 1997, 22(2), 135-137; Graui, A. and Castaner, J., Dns Future, 1996, 21(11), 1105-1108; and Graul, A., et al.. Drugs Future, 1997, 22(7), 733-737).
A number of compounds having muscarinic receptor antagonistic activities are being used to treat these diseases. For example, oxybutynin is being used for the treatment of urinary urge incontinence and dicyclomine is being used for the treatment of irritable bowel syndrome. However, these drugs have limited utility as they produce side effects such as dry mouth, blurred vision, and mydriasis.
There is currently a need for novel muscarinic receptor antagonists.

SUMMARY OF THE INVENTION
The invention is directed to urea derivatives that are muscarinic receptor intagonists and agonists and that are useful in the treatment and prevention of 1 liseases mediated by muscarinic receptors (e.g. chronic obstmctive pulmonary lisease, chronic bronchitis, irritable bowei syndrome, urinary incontinence, and the ike).
Accordingly, the invention provides a compound of the invention which is a :onipound of Formula (I):

wherein:
is an optional double bond;
n, is an integer of from 1 to 4;
n is an integer of from 1 to 3;
V is -CH-, -0-, -S(0)n3- (where n is an integer of from 0 to 2), or -NR-(wherein R is hydrogen, alkyl, substituted alkyl, ary!, or heteroaryl);
"Het" is a heteroaryl ring which optionally attaches (a) to a linker;-
R' is hydrogen, alkyl, amino, substituted amino, -OR (where R is bydfogen, alkyl, or acyl), or a covalent bond altacbing (a) to a linker;
R is hydrogen, alkyl, amino, substituted amino, -OR' (where R' is hydrogen or alkyi], aryl, araikyi, heleroaralkyl, or a covalent bond attaching (a) to a (inker;
R, R', and R are, independently of each other, hydrogen, halo, hydroxy, alkoxy, haloalkoxy, carboxy, alkoxycarbonyl, aikyl optionally substituted with one, two or three substituents selected from halo, hydroxy, carboxy, alkoxycarbonyl, aikylihio, alkylsulfonyl, amino, substituted amino, or a covalent bond attaching (a) to a linker;
K is a bond or an alkylene group;
K" is a bond, -C(O)-,. -S(0)- (where n is an integer of from 0 to 2), or an alkylene group optionally substituted with a hydroxyl group; and
B is heterocycioamino or heleroarylamino, which optionally attaches (a) to a linker;
provided that at least one of the R R, R', R, "Het", heterocycloamino or heteroarylamino groups attaches (a) to a linker;
X is a linker;
Lj is a group selected from a group consisting of: (i) a group of formula (b):

/
wherein:
D" is alkylene;
D is -NR'R", -N'CRR'R") or-OR" where R', R\ and R" are, independently of each other, hydrogen, alkyl, or aralkyl; and R- and R' represent a covalent bond attaching (b) to a linker;
R' is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy,
alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkyisulfmyl, sulfonamido,
alkylsulfonamido, carbamoyJ, (hiocarbamoyl, mono or dialkyjcarbamoyl, amino,
mono- or dialkylamino, aryl, aryloxy, aryithio, heteroaryl, heieraryloxy,
heteroarylthio, heterocyciyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl
optionally substituted with one, two or three subslituents selected from halo,
hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino;
R is hydrogen, halo, nitro, cyano, hydroxy, alkoxy, carboxy, alkoxycarbonyl, acyl, thio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamido, alkylsulfonamido, carbamoyl, thiocarbamoyl, mono or dialkylcarbamoyl, amino, mono- or dialkylamino, or alkyl optionally substituted with one, two, or three substituents selected from halo, hydroxy, cart>oxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted amino;
R' and R' are, independently of each other, hydrogen, alkyl, haloalkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl, acyl, thio, alkylthio, amino, mono- or dialkylamino; or

one of R', R, R, or R together with the adjacent group forms a methylenedioxy or elhylenedioxy group;
(ii) a group of formula (c):

wherein;
n I, is an integer of from I to 7;
n 12 is 0 to 7;
F is -NR'°-, -0-, -S-, or -CHR"- (wherein R'" and R" are, independently of each other, hydrogen, aiky!, or substituted alkyl);
F' is a covaJent bond, 'OR'\ -NRR or -NR'RR" wherein R" is hydrogen or alkyl, R and R' are alkyl, and R is hydrogen, alkyl, or a covalent bond attaching (c) to a linker;
R' is hydrogen, alkyi, halo, nitro, cyano, hydroxy, alkoxy, carboxy,
alkoxycarbonyl, acyl, tiio, alkylthio, alkylsulfonyl, alkylsulfinyl, sulfonamide,
alkylsulfonamide, carbamoyl, thiocarbamoyi, mono or dialkylcarbamoyl, amino,
mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryi, heteraryloxy,
heteroaryithio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl
optionally substituted with one, two or three substituents selected from halo,
hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, amino, or substituted
amino;
I R' is hydrogen, alkyl, halo, nitro, cyano, hydroxy, alkoxy, alkoxycarbonyl,
acyl, thio, alkylthio, amino, mono- or dialkylamino, aryl, aryloxy, arylthio, heteroaryi, heteraryloxy, heteroaryithio, heterocyclyl, heterocyclyloxy, aralkyl, heteroaralkyl, or alkyl optionally substituted with one, two or three substituents

.elected from halo, hydroxy, carboxy, alkoxycarbonyl, alkylthio, alkylsulfonyl, jmino, or substituted amino; and
R' is hydrogen, alkyl, hafo, hydroxy, alkoxy, or a covalent bond attaching ;he ligand to a linker provided that at least one of R and R' attaches (c) to a linker;
R' is hydrogen, alky!, halo, hydroxy, alkoxy, or substituted alkyl; and (iii) a group of formula (d) or (e):

wherein:
R is alkyl, substituted alkyl, cycloalkyl. substituted cycloalkyi, or heterocycle;
R" is alky!, substituted alkyl, aryi, acyl, heterocycle, or -COOR" where R" is alkyl; or
R' and R' together with the nitrogen atom to which they are attached form beterocycle, which heterocycle, in addition to optionally bearing the optional substituents defined hereinbelow for a heterocycle, can also optionally be substituted with one or more (e.g. 1, 2, 3, or 4) alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, or substituted alkynyl.
R' is a covalent bond that attaches the (d) or the (e) to a linker; and
R"' is alkyl;
or a pharmaceuttcally acceptable salt; or prodrug thereof.
Preferably X is a group of formula:
-X'-Z-(Y=-Z)-Y'-Z-X'-wherein
7_

m is an integer of from 0 to 20;
X at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(0)-, -C(0)0-. -C(0)NR-, -C(S)-, -C(S)0-. -C(S)NR- or a covaient bond where R is as defined below;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloalkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynyfene, substituted alkynylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyciene, or a covaient bond;
Y° and Y at each separate occurrence are selected from the group consisting of -0-, -C(0)-, -0C(0)-, -C(0)0-, -NR-, -SCO)n-, -C(0)NR'-, -NR' C(0)-, -NR' C(0)NR'-, -NR' C(S)NR'-. -C(=NR')-NR'-, -NR'-C(=NR')-, -OC{0)-NR'-, -NR'-C(0)-0-, -N=C(R'>NR'-, -NR'-C(R")=N-,-P(0)(OR')-0-, -0P(O)(0R')-, -S(0)„CR' R"-, -S(OVNR'-, -NR'-S(0)„-, -S-S-, and a covaient bond; where n is 0, 1 or 2; and R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyi, substituted cycloaJkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aiyl, heteroaryi and heterocyclic (preferably, at least one of X% Y', Y or Z is not a covaient bond).
The invention also provides a compound of the invention which Is a compound of formula (IV):

wherein R, K", A, K, R', B", B, X, and I have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof. A preferred compound of the invention is a compound of formula (FVa);

wherein X, and Lj have any of the values defined herein; or a pharmaceutically acceptable salt; or prodrug thereof.
The invention also provides a pharmaceutical composition comprising a pharmaceuticaily acceptable carrier and a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof.
The in'ention also provides synthetic intermediates disclosed herein, as well as synthetic methods useful for preparing such intermediates, and synthetic methods useful for preparing compounds of the invention or salts thereof.'
The invention also provides a method of treating diseases mediated by a muscarinic receptor in a mammal, comprising administering to said mammal a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt or prodmg thereof.
The invention also provides a compound of the invention or a pharmaceutically acceptable salt or prodrug thereof for use in medical therapy, as well as the use of a compound of Formula (I) or a pharmaceutically acceptable salt or prodrug thereof in the preparation of a medicament for the treatment of a disease mediated by a muscarinic receptor in a mammal.
Applicant has discovered that urea compounds of the present invention are metabolically more itaSle than compounds lacking such a urea functionality. Accordingly, compounds of the present invention have longer metabolic half-lives and/or longer duration of action in vivo, which can reduce the dose required for

administration or can reduce (he likelihood of the generation of unwanted metabolites.
DETAILED DESCRIPTION OF THE INVENTION
The following terms have the following meanings unless otherwise indicated. Any imdefined terms have their art recognized meanings.
The term "alkyl" refers lo a monoradica} branched or unbranched saturated hydrocarbon chain preferably having from 1 to 40 carbon atoms, more preferably 1 to 10 carbon atoms, and even more preferably 1 to 6 carbon atoms. This term is exemplified by groups such as methyl, ethyl, n-propyl, iso-pwpyl, «-butyl, iso-butyl, «-hexyi, n-decyl, letradecyl, and the like.
The term "substituted alkyl" refers to an alkyl group as defined above wherein one or more carbon atoms in the alkyl chain have been optionally replaced with a heteroatom such as -0-, -S(0)n- (where n is 0 lo 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyioxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted ihioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyl, -SO-aryl, -SOj-heteroaryl, and -NR'R wherein R' and R' may be the same or different and and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. This term is exemplified by groups such as hydroxymethyl, hydroxyethyl, hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-dimethylaminopropyl, 2-sulfonamidoethyl, 2-carboxyethyl, and the like.

The term "alkylene" refers to a diradical of a branched or unbranched saturated hydrocarbon chain, preferably having from I to 40 carbon atoms, more preferably 1 to 10 carbon atoms and even more preferably I to 6 carbon atoms. This term is exemplified by groups such as melhylene (-CH-), ethylene (-CH2CH2-), the propylene isomers (eg-, -CHjCHCHr and -CH(CH3)CH;-) and the like.
The term "substituted alkylene" refers to an alkylene group, as defined above, having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyJoxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyciooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyI, -SO-substituted aikyi, -SO-aryi and -S02-heteroaryI. Additionaiiy, such substituted alkylene groups include those where 2 substituents on the alkylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkylene group. Preferably such fused groups contain from 1 to 3 fused ring structures.
The terra "alkylaminoalkyl", "alkyl aminoalkenyl" and "alkylaminoalkynyl" refers to the groups RNHR"- where R' is alkyl group as defined above and R" is alkylene, alkenylene or alkynylene group as defined above. Such groups are exemplified by 3-methylaminobutyl, 4-ethylamino-l,l-dimethylbutyn-l-yl, 4-ethylaminobutyn-1-yl, and the like.
Te term "alkaryl" or "aralkyl" refers to the groups -alkylene-aryl and -substituted alkylene-aryl where alkylene, substituted alkylene and aryl are defined herein. Such alkaryl groups are exemplified by benzyl, phenethyl and the like.

The term "alkoxy" refers to the groups aIkyl-0-, alkenyl-O-, cycloalkyl-O-, cycloaikenyl-O-, and alkynyi-O-, where alkyl, alkenyl, cycloalkyl, cycloalkenyi, and alkynyi are as defined herein. Preferred alkoxy groups are alkyl-O- and include, by way of example, methoxy, ethoxy, n-propoxy, iso-propoxy, /j-butoxy, rert-butoxy, i'ec-butoxy, n-penfoxy, «-hexoxy, 1,2-dimelhyibutoxy, and the like.
The term "substituted alkoxy" refers to the groups substituted a!kyI-0-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl'O-, and substituted alkynyl-O- where substituted alkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyi and substituted alkynyi are as defined herein.
The term "haloajkoxy" refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.
The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-0-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted aikyl, alkylene and substituted alkylene are as defined herein. Preferred alkylalkoxy groups are aIkylene-0-alkyl and include, by way of example, methylenemethoxy (-CH2OCH3), ethylenemethoxy (-CH2CH3OCH3), n-propylene-wo-propoxy (-CHCHiCHjOCHCCIj)), methylene-i-butoxy (-CHj-O-CCCH,),), and the like.
The term "alkylthioalkoxy" refers to the group -alkylene-S-alkyl, a!kylene-S-substitt{ted alkyl, substituted alkyJene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein. Preferred alkylthioalkoxy groups are alkylene-S-alkyl and include, by way of example, methylenethiomethoxy (-CH2SCH3), ethylenethiomethoxy (-CHjCHjSCHj), n-propylene-ijo-thiopropoxy (-CHjCHjCHjSCHCCHj)!), methylene-Mhiobutoxy (-CHjSCCCHj)). and the like.
The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and

having at least 1 and preferably from 1-6 sites of vinyl unsaturation. Preferred alkenyl groups include ethenyl {-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-C(CH3)=CH2), and the like.
The term "substituted alkenyl" refers to an alkenyl group as defined above having from I to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloaikenyl, substituted cycloaikenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxyiaikyi, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thjoalkoxy, aryl, aryloxy, heteroaryl, heleroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, aikoxyamino, nitre, -SO-alkyl, -SO-substituted alkyl, -SO-ary!, -SO-heteroaryl, -SOj-alkyl, -SO-substituted alkyl, -SO-aryl and -SOj-heteroaryl.
The term "alkenylene" refers to a dlradicai of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to iO carbon Moms and even more preferably 2 to 6 carbon atoms and having at least 1 and preferably from 1-6 sites of vinyl unsaturation. This term is exemplified by groups such as ethenylene (-CH=CH-), the propenylene isomers (e.g., -CH2CH=CH- orj-C(CH3)=CH-), and the like.
The term "substituted alkenylene" refers to an alkenylene group as defined above having from 1 to 5 subslituents, and preferably from 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloaikenyl, substituted cycloaikenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxy!, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, aikoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyl, -SO-substituted alkyl, -SOj-aryl and -SO;-heteroaryl.

Additionally, such substituted alkenylene groups include those where 2 substituents on the alkenylene group are fused to form one or more cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycioalkenyl, aryl, heterocyclic or heteroaryl groups fused to the alkenylene group.
The term "alkynyi" refers to a monoradica! of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 20 carbon atoms and even more preferably 2 to 6 carbon atoms and having at Jeast 1 and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynyi groups include ethynyl (-CsCH), propargyl (-CHjCCH), and the like.
The temj "substituted alkynyi" refers to an alkynyi group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycIoaJkenyl, substituted cycJoaJkenyJ, acyj, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxy!, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocycJooxy, thiol, thioalkoxy, substituted Ibioalkoxy, aryl, aiyioxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted aikyl, -SO-aiyl, -SO-heteroaryl, -SO-alkyl, -SOj-substituled alkyl, -SOj-aiyl, and ~SO-heteroaryl
The term "alkynylene" refers to a diradical of an unsaturated hydrocarbon preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms and having at Jeast J and preferably from 1-6 sites of acetylene (triple bond) unsaturation. Preferred alkynylene groups include ethynylene (-C=C-), propargylene (-CHjCC-), and the like.
TTie term "substituted alkynylene" refers to an alkynylene group as defined above having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substimted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen.

hydroxyl, keio, Ihioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, ihiohelerocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyI, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO;-alkyl, -SO-substituted alkyl, -SOj-aryl and -SO-heteroaryl.
The term "acyl" refers to the groups HC(0)-, a!ky[-C(0)-, substituted aifcyi-C(0)-, cycl03lkyl-C(O>, substituted cycloalkyI-C{0)-, cycloalkenyKC(0>-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, heteroaryl-C(O)- and heterocyclic-C(0)- where alkyl. substituted alkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyi, substituted cycloalkenyi, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "acylamino" or "aminocarbonyl" refers to the group -C(0)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, heterocyclic or where both R groups are joined to form a heterocyclic group (e.g., morpholjno) wherein alkyl, substitufed alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "aminoacyl" refers to the group -NRC(0)R where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, ary!, heteroaryl, and heterocyclic are as defined herein.
The term "aminoacyloxy" or "alkoxycarbonylamino" refers to the group -NRC(0)OR where each R is independently hydrogen, alkyl, substituted alky], aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic are as defined herein.
The term "acyloxy" refers to the groups alkyl-C(0)0-, substituted alkyl-C(0)0-, cycloalkyl-C(0)0-, substituted cycloalkyl-C(0)0-, aryl-C(0)0-, heteroaryl-C(0)0-, and heterocyclic-C(0)0- wherein alkyl, substituted alkyl. cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclic are as defined herein.

The term "ary!" refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings (e.g., naphthyl or anthryl). Preferred aryls include phenyl, naphthyl and the like. Unless otherwise constrained by the definition for the aryl substitueni, such aryl groups can optionally be substituted with from 1 to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyi, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacyiamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyI, -SO-substjtuted alkyl, -SO-aryl, -SO-heteroaryl, -SO-alkyt, -SO-substituted alkyl, -S02-aryl, -SOj-heteroaryl and trihalomethyl. Preferred aryl substiluents include alkyl, alkoxy, halo, cyano, nitro, tnhalomethyl, and thioalkoxy.
The term "aryloxy" refers to the group aryl-O- wherein the aryl group is as defined above including optionally substituted aryl groups as also defined above.
The term " arylene " refers to the diradical derived from aryl (including
substituted aryl) as defined above and is exemplified by 1,2-phenyIene. 1,3-
t phenyiene, 1,4-phenyIene, 1,2-naphthylene and the like.
The term "amino" refers to the group -NHj.
The terra "substituted amino" refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclic provided that both R's are not hydrogen.
The term "carboxyalkyl" or "alkoxycarbonyl" refers to the groups "-C(0)0-alkyl", "-C(0)0-substituted alkyl", "-C(0)0-cycloalkyl", "-C(0)0-substituted cycloalkyl", "-C(0)0-alkenyr', "-C(0)0-substituted alkenyl".

"-C(0)0-aIkynyl" and "-C(O)0-substituted alkynyl" where alkyl, substituted alky], cycioalkyl, substituted cycloalkyi, alkenyl, substituted alkenyl, alkynyl and substituted alkynyl alkynyl are as defined herein.
The term "cycloalkyi" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyi groups include, by way of example, single ring structures such as cyclopropyi, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.
The term "substituted cycloalkyi" refers to cycloalkyi groups having from 1 to 5 substituents, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, acyl, acyiamino, acyioxy, amino, substituted amino, am'moacyl, aminoacyJoxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, ihioheierocyclooxy, thiol, Ibioalkoxy, substituted thioalkoxy, aryJ, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitre, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyl, -SO-substituted alkyl, -SO-aryl and -SO-heteroaryl.
The term "cyclyalkenyl" refers to cyclic alkenyl groups of from 4 to 20 carbon atoms having a single cyclic ring and at least one point of internal unsaturation. Examples of suitable cycloalkenyl groups include, for instance, cyclobut-2-enyl, cyclopent-3-enyl, cyclooct-3-enyl, and the like.
The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from I to 5 substituents, and preferably 1 to 3 substituents. selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyi, substituted cycloalkyi, cycloalkenyl. substituted cycloalkenyl, acyl, acyiamino, acyioxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, caiboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy.

heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-subslituted aikyl, -SO-aryl, -SO-heteroaryl, -SOj-alkyl, -SOj-subslituted alkyl, -SOj-aryl and -SO-heteroaryl.
The term "halo" or "halogen" refers to fluoro, chloro, bromo and iodo.
The term "heteroaryj" refers to an aromatic group of from 1 to 15 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen and sulfur within at least one ring (if there is more than one ring). Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with I to 5 substituents, preferably 1 to 3 substituents, selected from the group consisting of acyloxy, hydroxy, thiol, acyl. alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyi, acylamino, alkaryl, ary], aryloxy, azido, carboxyl, carboxylalkyl, cyano, halo, nitro, heteroaryl, heleroaiyloxy, heterocyclic, heterocyclooxy, aminoacyloxy, oxyacylamino, thioaikoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO;-alkyI, -SOj-substituted alkyl, -SO-aryl, -SOj-heteroaryl and trihalomelhyl. Preferred aryl substituents include alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy. Such heteroaryl groups can have a single ring (e.g., pyridyl or furyl) or multiple condensed rings (e.g., indolizinyl or benzothienyl). Preferred heteroaryls include pyridyl, pyrrolyl and furyl.
The term "heteroara!kyl" refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. Such heteroaralkyl groups are exemplified by pyridylmethyl, pyridylethyl, indolylmethyl, and the like.
The term "heteroaryloxy" refers to the group heteroaryl-O-.
The term " heteroarylene " refers to the diradical group derived from heteroaryl (including substituted heteroaryl), as defined above, and is exemplified by the groups 2,6'pyridylene, 2,4-pyridiylene, 1,2-quinolinylene, 1,8-quinolinylene, 1,4-ben2ofuranyIene, 2,5-pyridnylene, 2,5-indolenyl, and the like.

The term "heterocycle" or "heterocyclic" or refers to a monoradical saturated jnsaturated group having a single ring or multiple condensed rings, from I to 40 rarbon atoms and from I (o 10 hetero atoms, preferabJy I to 4 heteroatoms, selected from nitrogen, sulfur, phosphorus, and/or oxygen within the ring. Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acyiamino, acyioxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroary], -S02-a!kyl, -SOj-substiluled alkyl, ~SOj-aryl and -SO;-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred heterocyclics include morphoJino, piperidinyl, and the like.
Examples of nitrogen heteroaryls and heterocycles include, but are not limited to, pyrrole, ibJophene, furan, imidazole, pyrazoJe, pyridine, pyrazine, pyrimidine, pyridazine indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, pyrrolidine, piperidine, piperazine, indoline, morpholine, tetrahydrofiiranyl, tetrahydrothiophene, and the like as well as N-alkoxy-nitrogen containing heterocycles.
The term "heterocyclooxy" refers to the group heterocyclic-O-.
The term "thioheterocyclooxy" refers to the group heterocyclic-S-.

The term "heterocyclene" refers to the diradical group formed from a heterocycle, as defined herein, and is exemplified by the groups 2,6-morpholino, 2,5-morphoJino and the like.
"Heteroarylamino" means a 5 membered aromatic ring wherein one or two ring atoms are N, (he remaining ring atoms being C The heEerocycIoamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally subslituled with one or more subslifuenis, preferably one or iwo substifuents, selected from alkyl, substituted aikyl, cycloalkyl, aryl, aralkyl, heteroaryl, beteroaralky], halo, cyano, acyl, amino, substituted amino, acyJamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(0)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroary], aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, imidazole, pyrazole, benzimidazole and benzpyrazole.
"Heterocycloamino" means a saturated monovalent cyclic group of 4 to 8 ring atoms, wherein at least one ring atom is N and optionally contains one or two additional ring heteroatoms selected from the group consisting of N, O, or S(0)n (where n is an integer om 0 to 2), the remaining ring atoms being C, where one or two C atoms may optionally be replaced by a carbonyi group. The heterocycloamino ring may be fused to a cycloalkyl, aryl or heteroaryl ring, and it may be optionally substituted with one or more substituents, preferably one or two substituents, selected from alkyl, substituted alkyl, cycloalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, amino, substituted amino, acylamino, -OR (where R is hydrogen, alkyl, alkenyl, cycloalkyl, acyl, aryl, heteroaryl, aralkyl, or heteroaralkyl), or -S(0)nR [where n is an integer from 0 to 2 and R is hydrogen (provided that n is 0), alkyl, alkenyl, cycloalkyl, amino, heterocyclo, aryl, heteroaryl, aralkyl, or heteroaralkyl]. More specifically the term heterocycloamino includes, but is not limited to, pyrroiidino, piperidino, morpholino, piperazJno,

indolino, or thiomorpholino. The term heterocycloamino also includes, quinuclidine, l--a2abicyclo[2.2.1]h6ptyl, l-azabicyclo[3.2.iloctyl and the derivatives thereof.
The term " oxyacylamino " or "aminocarbonyloxy" refers to the group -OC(0)NRR where each R is independently hydrogen, alkyi, substituted alkyl, atyl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.
The term " spiro-attached cycloaikyl group " refers lo a cycloalkyl group attached to another ring via one carbon atom common to both rings.
The term "thiol" refers to the group -SH.
The term "thioalkoxy" or "alkyithio" refers to the group -S-alkyl.
The term "substituted thioalkoxy" refers to the group -S-substituted alkyl.
The term "ihioaryloxy" refers lo the group aryl-S- wherein the aryJ group is as defined above including optionally substituted aryl groups also defined above.
The term "thioheteroaiyloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined above including optionally substituted aryl groups as also defined above.
As to any of the above groups which contain one or more substituents, it is understood, of course, t|hat such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of Ibis invention include alJ stereochemical isomers arising from the substitution of these compounds.
Unless specified otherwise, all ranges referred to herein include the stated end-point values.
The term "pharmaceutically-acceptable salt" refers to salts which retain biological effectiveness and are not biologically or otherwise undesirable. In many cases, the compounds of this invention are capable of forming acid and/or base salts by virtue of the presence of amino and/or carboxyl groups or groups similar thereto.
Phannaceti(icaI2y-accep(able base addition salts can be prepared from

inorganic and organic bases. Salts derived from inorganic bases, include by way of example only, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of prirnary, secondary and tertiary amines, such as alkyl amines, dialkyj amines, irialkyl amines, substituted alkyl amines, di(substituted alkyl) amines, tri(substituted alkyl) amines, alkenyl amines, dialkeny! amines, trialkenyl amines, substituted alkenyl amines, di(substituted alkenyl) amines, tri{substituted alkenyl) amines, cycloalkyi amines, di(cyc!oaIkyl) amines, tri(cycIoaJkyI) amines, substituted cycloalkyi amines, disubstituted cycloalkyi amine, trisubstituted cycloalkyi amines, cycloalkenyl amines, di(cycloalkenyl) amines, tri(cycloaikenyl) amities, substituted cycloalkenyl amines, disubstituted cycloalkenyl amine, trisubstituted cycloalkenyl amines, aryl amines, diaryl amines, triaryl amines, heteroaryl amines, diheteroaiyl amines, triheteroaryl amines, heterocyclic amines, diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the substituents on the amine are different and are selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyi, substituted cycloalkyi, cycloalkenyl, substituted cycloalkenyl, aryl, heteroaryl, heterocyclic, and the like. Also included are amines where the two or three substituents, together wth the amino nitrogen, form a heterocyclic or heteroaryl group. Examples of suitable amines include, by way of example only, isopropylamine, trimethyi amine, diethyl amine, tri{wo-propyl) amine, tri(n-propyl) amine, ethanolamJne, 2-dimethy!aniinoethant)l, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N-alkylglucamines, theobromine, purines, piperazine, piperidine, morpholine, N-ethylpjperidine, and the like. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example, carboxylic acid amides, including carboxamides, lower alkyi carboxamides, dialkyl carboxan:iides, and the Uke.

Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and Che Jike. Salts derived from organic acids include acetic acid, propionic acid, glycoHc acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandeiic acid, methanesuifonic acid, elhanesuifonic acid, p-(oiuene-suIfonic acid, salicylic acid, and the like.
The term " pharmaceuticaJly-acceptable cation " refers to the cation of a pharmaceuticaJly-acceptabie salt.
The term "protecting group" or "blocking group" refers to any group which when bound to one or more hydroxyl, thiol, amino or caiboxyl groups of the compounds (including intermediates thereof) prevents reactions from occurring at these groups and which protecting group can be removed by conventional chemical or enzymatic steps to reestablish the hydroxyl, thiol, amino or carboxyl group. The particular removable blocking group employed is not critical and preferred removable hydroxyl blocking groups include conventional substituents such as allyl, benzyl, acetyl, chloroacetyl, thiobenzyl, benzylitiine, phenacyl, t-butyl-diphenylsilyl and any other group that can be introduced chemically onto a hydroxy! functionality and later selectively removed either by chemical or enzymatic methods in mild conditions compatible with the nature of the product. Preferred removable thiol blocking groups include disulfide groups, acyl groups, benzy! groups, and the like. Preferred removable amino blocking groups include conventional substituents such as t-butyoxycarbonyl (t-BOC), benzyloxycarbonyl (CBZ), fluorenylmethoxy-carbonyl (FMOC), allyloxycarbonyl (ALOC), and the like which can be removed by conventional conditions compatible with the nature of the product. Preferred carboxyl protecting groups include esters such as methyl, ethyl, propyl, butyl etc. which can be removed by mild conditions compatible with the nature of the product.

The term "optional" or "optionally" means that the subsequently described event, circumstance or substituent may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
The term "inert organic solvent" or "inert organic solvent" means a solvent which is inert under the conditions of the reaction being described in conjunction therewith including, by way of example only, benzene, toluene, acetonitrile, tetrahydrofuran, dimethylformamide, chloroform, methylene chloride, diethyl ether, ethyl acetate, acetone, methytethyl ketone, methanol, ethanol, propanol, isDpropanoE, f-bufanol, dioxane. pyridine, and the like. Unless specified to the contrary, the solvents used in the reactions described herein are inert solvents.
The term "treatment" refers to any treatment of a pathologic condition in a mammal, particularly a human, and includes:
(i) preventing the pathologic condition from occurring in a subject which may be predisposed to the condition but has not yet been diagnosed with the condition and, accordingly, the treatment constitutes prophylactic treatment for the disease condition;
(ii) inhibiting the pathologic condition, i.e., arresting its development;
(iii) relieving the pathologic condition, i.e., causing regression of the pathologic condition; or
(iv) relieving the conditions mediated by the pathologic condition.
The term "pathologic condition which is modulated by treatment with a ligand" covers all disease states (i.e., pathologic conditions) which are generally acknowledged in the art to be usefully treated with a ligand for the muscarinic receptors in general, and those disease states which have been found to be useftilly treated by a compound of the invention. Such disease states include, by way of example only, the treatment of a mammal afflicted with chronic obstructive pulmonary disease, chronic bronchitis, irritable bowel syndrome, urinary incontinence, and the like.

The term "therapeutically effective amount" refers to that amount of a :ompound which is sufficient to effect treatment, as defined above, when idministered to a mammal in need of such treatment. The therapeutically effective imount will vary depending upon Ihe subject and disease condition being treated, he weight and age of the subject, the severity of the disease condition, the manner )f administration and the like, which can readily be determined by one of ordinary ikill in the art.
The term "linker", identified by the symbol 'X' refers to a group or groups hat covalently attaches L, and Lj. Additionally, the linker can be either a chiral or schiral molecule. The term "linker' does not, however, extend to cover solid inert supports such as beads, glass particles, fibers, and the like. But it is understood that the compounds of this invention can be attached to a solid support if desired. For sxample, such attachment to solid supports can be made for use in separation and purification processes and similar applications.
"Pro-drugs" means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., NJS-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) may be preferred. Specific and preferred values listed herein for radicals, substituents, and ranges, are for

55

illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents
A preferred value for A is phenyl or pyridine
A preferred value for R' is hydrogen methyl, or ethyl.
Another preferred value for R' is hydrogen.
A preferred value for R is pyrrolyl, pyridinyl, or imidazolyl.
Another preferred value for R is phenyl,
A preferred value for V is -CH- or -NR"- (wherein R is hydrogen, alkyl, substituted alkyl, aryl, or heleroaryl).
A preferred value for R is hydrogen or alkyl
A preferred value for R is hydrogen, alkyf, aryl, aralkyi, heteroaralkyl, or a covalent bond attaching (a) to a linker
Another preferred value for R is hydrogen, methyl, phenyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino, benzyl optionally substituted with alkyl, alkoxy, halo, hydroxy, carboxy, or amino.
A preferred value for R, R', and R indepeiident of each other is hydrogen, alkyl, nitro, hydroxy, or amino.
A preferred value for K is alkylene having from 1 to 10 carbon atoms.
A preferred valine for K is alkylene having from I to 5 carbon atoms.
A preferred value for K is a bond or a methylene group.
A preferred value for K" is a bond.
A preferred value for R, is hydrogen.
A preferred value for B is a heterocycloamino group which attaches (a) to a linker.
Another preferred value for B is a formula selected from a group consisting of formula (j), formula (k), and formula (1):

A-herein:
11,3 and n,a are, independently of each other, an integer of from 0 to 4 provided that ni3+n,4 is an Integer of from 3 to 5;
ni5 and n,-, are, independently of each other, an integer of from 0 to 4 provided that ni+n,, is an integer of from 3 to 5;
0,6 is an integer of from 0 to 3 provided that nj, + nj is an integer of from 3 to 5;
n,j, n,, and njo are, independently of each other, an integer of from 0 to 3 provided that n|g+ n,9 + njo is 2 or 3;
nji is an integer of from 1 to 3;
W" and W are, independently of each other:

where:
n22 isOor I;
R and R" are, independently of each other, hydrogen, alkyl, alkenyl, alkynyl, cycloalkylalkyi, aralkyl, or heterocyclylalkyl or a covalent bond attaching (a) to a linker;
R" is alkyl, alkenyl or alkynyl; and

W" is -N(0)n„ or -N-R where nj is 0 or 1, and R is aiky!, alkenyl, alkyiiyl, or aralkyl, or a covalent bond attaching (a) to a linker;
provided that a carbon other than a bridge head carbon is bonded to B". Another preferred value for B is a ring represented by the following general

wherein a carbon atom other than a bridge head carbon is bound to B"; and W is as defined above.
A more preferred value for B is pyrrolidine, piperidine, or hexahydroazepine attaching (a) to a iinker.
Another more preferred value for B is piperidine wherein the nitrogen atom of said piperidine attaches (a) to a linker.
Another more preferred value for B is piperidin-4-yl wherein the nitrogen at the 1 position optionally attaches (a) to a linker.
Another more preferred value for B is quinuclidine, i-azabicyclo[2.2.1 ]-heptyl, or 1 -azabicyclo[3.2.1 ]octyl attaching (a) to a linker, wherein a carbon other than a bridge head carbon is bound to B".
A preferred value for D" is-(CH2)n43-where n3 is an integer of from I-IO, preferably 2-8, more preferably 2-4. Another preferred value for nj is an integer of from 3-10.
A preferred value for D is -NR"R" or -N{R"RR")M- where R', R", and R are, independently of each other, hydrogen or methyl, and R and R" represent a covalent bond attaching (b) to a linker. More preferably R", R", and R" methyl, . and R and R represent a covalent bond attaching (b) to a linker.
A preferred value for R is hydrogen.
A preferred value for R' is hydrogen.

A preferred value for R' and R independently is hydrogen; or one of R', R, R, or R together with the adjacent group forms a methylenedioxy or ethylenedioxy group.
A preferred value forn,, is 1.
A preferred value for n is 6.
A preferred value for F is -0-.
A preferred value for F' is a covalent bond, -OR", -NR"R" wherein R" is hydrogen or alkyl, or -NRRR') wherein R" and R are alkyl, and R" is a covalem bond attaching (c) to a linker.
A preferred value for F" is -0-, -NH-, N(CH3)- or -N(CH,\-
A more preferred value for F' is -NH-, NCCHj)- or -N(CH3)2- wherein the nitrogen atom attaches (c) to a linker.
A preferred value for R is hydrogen.
Preferably R" is ortho to the - Preferably is R is hydrogen.
Preferably R' is hydrogen.
Preferably L is a group of formula (d) wherein: R' is alkyl or substituted alkyl; R' is aJfcyl, substituted alkyl, or fjeterocyde; or R' and R" together with the nitrogen atom to which they are attached form heterocycle.
Preferably, Lj is a group of formula A1-A241 as shown in the following table. Lj is preferably linked to X through a non-aromatic nitrogen atom (e.g. a secondary amino nitrogen) of Lj.

5

WE CLAIM:
1. A compound of formula (la):

wherein:
A is phenyl or pyridyl;
B is -NH-;
R is hydrogen;
R2 is pyrrolyl, pyridinyl, imidazolyl or phenyl;
K is a bond or a methylene group;
K" is a bond;
B is pyrrolidine, piperidine, or hexahydroazepine;
R46 is alkyl, substituted alkyl, cycloalkyi, substituted cycloalkyl, or
heterocycle;
R'' is alkyl, substituted alkyl, aryl, acyl, heterocycle, or -COORo where
Rso is alkyl; or
R'* and R'" together with the nitrogen atom to which they are attached
form heterocycle, which is optionally substituted with 1 to 5 substituents
independently selected from the group consisting of alkoxy, substituted
alkoxy, cycloalkyi, substituted cycloalkyl, cycloalkenyl, substituted
cycloalkenyl, acyl, acylamino, acylojq, amino, substituted amino,
aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl,
keto, thioketo, carboJQl, carboxylalkyl, thioaryloxy, thioheteroaryloxy,
thioheterocyclooxy, thiol, thioalkoj, substituted thioalkoxy, aryl,
arylojo?, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy,
hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -

SO-aryl, -SO-heteroaryl, -S02-alkyl, -SO2- substituted alkyl, -SOa-aryl -SOa-heteroartyl, alkyl, substituted alll, alkenyl, substituted alkenyl, alkynyl, and substituted aJkynyl;
X is a group of formula:
wherein
mis an integer of from 0 to 20;
Xa at each separate occurrence is selected from the group consisting of -0-, -S-, -NR-, -C(0)-, -C(0)0-, -C(0)NR-, -C(S)-, -C(S)0-, -C(S)NR- or a covalent bond;
Z at each separate occurrence is selected from the group consisting of alkylene, substituted alkylene, cycloaJkylene, substituted cylcoalkylene, alkenylene, substituted alkenylene, alkynylene, substituted aZlTiylene, cycloalkenylene, substituted cycloalkenylene, arylene, heteroarylene, heterocyclene, or a covalent bond;
Y and Y at each separate occurrence are selected from the group consisting of-0-, -C(0)-, -0C(0)-, -C(0)0-, -NR-, -S(0)n-, -C(0)NR'-, -NR' C(0)-, -NR' C(0)NR'-, -NR'C(S}NR'-, -C(=NR')-NR'-, -NR'-C(=NRV, -OC(0)-NR'-, -NR'-C(0)-O-, -N=C(Xa)-NR'-, -NR'-C(XJ=N-, -P{0){ORyO~, -O-P(0)(OR')-, -S(0}nCR' R"-, -S(0)n-NR'-, -NR' 'S(0)n-, -S-S-, and a covalent bond; where n is 0, 1 or 2; and
R, R' and R" at each separate occurrence are selected from the group consisting of hydrogen, aikyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted aJkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaiy] and

cieterocyclic; provided at least one of X», Y, Y or Z is not a covalent bond;
Dr a pharmaceutically acceptable salt thereof.
2. The compound as claimed in claim 1, wherein A is phenyl,
3. The compound as claimed in claim 1, wherein the compound has the formula:

4. The compound as claimed in claims 1 to 3, wherein X is alkylene optionally substituted with one, two, or three hydroxy groups; alkylene wherein one, two or three carbon atoms have been replaced by an ojcygen atom; -alkylene-phenylene-alkylene- wherein the phenylene ring is optionally substituted with one or two chloro or fLuoro groups.
5. The compound as claimed in claims 1 to 3, wherein X is nonane-1,9-diyl, octane-1,8-diyl, propane 1,3-diyl, 2-hydroxypropane-l ,3-diyl, or 5-oxa-nonane-l ,9-diyI.
6. The compound as claimed in claims 1 to 5, wherein R"* is 3-piperidinyl, 4-piperidinyl or 3- pyrrolidinyl, which R'* is optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkoxy, substituted alkoxy, cycloaikyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy,

jxyaminoacyl, cyano, halogen, hydroxyl, keto, thioketo, carboxylalkyl, hioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, ;ubstituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, dkoxyamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, ilkynyl, and substituted alkynyl.
The compound as claimed in claims 1 to 5, wherein R"'* and R ogether with the nitrogen atom to which they are attached form a aiperidine or p3rrolidine ring which ring is optionally substituted with 1 :o 3 substituents independently selected from the group consisting of ilkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, :ycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acylojQ, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, cyano, tialogen, hydroxyl, keto, thioketo, carboxylalll, thioaryloxy, Lhioheteroaiyloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, heterocyclic, heterocyclooxy, hydroxyamino, alkojamino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl.
8. The compound as claimed in claims 1 to 5, wherein R46 and R47
together with the nitrogen atom to which they are attached form an aza-
crown ether.
9. The compound as claimed in claims 1 to 5, wherein R" and R*'
together with the nitrogen atom to which they are attached form a group
of the formula;

10. The compound as claimed in claims 1 to 5, wherein R46 and R47'
together with the nitrogen atom to which they are attached form a group
of the formula:

11. A pharmaceutical composition comprising a pharmaceuticaUy
acceptable carrier and up to 20 weight percent of a compound as claimed
in any of claims 1 to 10.
12. A compound substantially as herein described and exemplified.

Documents:

837-che.rtf

in-pct-2002-837-che abstract.pdf

in-pct-2002-837-che claims duplicate.pdf

in-pct-2002-837-che claims.pdf

in-pct-2002-837-che correspondence others.pdf

in-pct-2002-837-che correspondence po.pdf

in-pct-2002-837-che description (complete) duplicate-1.pdf

in-pct-2002-837-che description (complete) duplicate-2.pdf

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Patent Number

224319

Indian Patent Application Number

IN/PCT/2002/837/CHE

PG Journal Number

49/2008

Publication Date

05-Dec-2008

Grant Date

10-Oct-2008

Date of Filing

05-Jun-2002

Name of Patentee

THERAVANCE, INC

Applicant Address

901 GATEWAY BOULEVARD, SOUTH SAN FRANCISCO, CALIFORNIA 94080,

Inventors:

#	Inventor's Name	Inventor's Address
1	MATHAI MAMMEN	1852 VALPARAISO AVENUE, MENLO PARK, CA 94025,
2	DAVID OARE	1622 RALSTON AVENUE, BELMONT, CA 94002,

PCT International Classification Number

A61K31/4468

PCT International Application Number

PCT/US00/33155

PCT International Filing date

2000-12-07

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	09/456,170	1999-12-07	U.S.A.