Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor Number:7,074,805 from the United States Patent and Trademark Office (PTO) owispatent The isoquinoline compounds of formula (I) ##STR00001## are VR1 antagonists that are useful in treating pain, inflammation, thermal hyperalgesia, urinary incontinence and bladder over activity. The "R", "Z" and "L" variables are defined in the disclosure and the "X" variables are defined as follows: X.sub.1 is CR.sub.1; X.sub.2 is selected from the group consisting of N and CR.sub.2; X.sub.3 is selected from the group consisting of N and CR.sub.3; X.sub.4 is CR.sub.4; and X.sub.5 is selected from the group consisting of N and C.<H azabicyclic, vanilloid, Fused, azabicycl, 7074805.html, Patent, pto, 7074805

Title: Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor

Abstract: The isoquinoline compounds of formula (I) ##STR00001## are VR1 antagonists that are useful in treating pain, inflammation, thermal hyperalgesia, urinary incontinence and bladder over activity. The "R", "Z" and "L" variables are defined in the disclosure and the "X" variables are defined as follows: X.sub.1 is CR.sub.1; X.sub.2 is selected from the group consisting of N and CR.sub.2; X.sub.3 is selected from the group consisting of N and CR.sub.3; X.sub.4 is CR.sub.4; and X.sub.5 is selected from the group consisting of N and C.

Patent Number: 7,074,805 Issued on 07/11/2006 to Lee, et al.

Inventors: Lee; Chih-Hung (Vernon Hills, IL); Bayburt; Erol K. (Gurene, IL); DiDomenico, Jr.; Stanley (Richmond, IL); Drizin; Irene (Wadsworth, IL); Gomtsyan; Arthur R. (Vernon Hills, IL); Koenig; John R. (Chicago, IL); Perner; Richard J. (Gurnee, IL); Schmidt, Jr.; Robert G. (Waukegan, IL); Turner; Sean C. (Evanston, IL); White; Tammie K. (Gurnee, IL); Zheng; Guo Zhu (Lake Bluff, IL)
Assignee: Abbott Laboratories (Abbott Park, IL)

Appl. No.: 364210

Filed: February 11, 2003

Current U.S. Class: 514/307 ; 546/143

Current International Class: A61K 31/47 (20060101); C07D 217/00 (20060101)

Field of Search: 514/307 546/143

References Cited [Referenced By]

U.S. Patent Documents


3647819	March 1972	Kirchner
3711610	January 1973	Kirchner
3814711	June 1974	Eloy et al.
4958026	September 1990	Schoellkopf et al.
5362878	November 1994	Chang et al.
5444038	August 1995	James et al.
5656634	August 1997	Chang et al.
5760246	June 1998	Biller et al.
6291476	September 2001	Kordik et al.
6472414	October 2002	Biller et al.
6511998	January 2003	Kordik et al.
6555539	April 2003	Reich et al.

Foreign Patent Documents


0418071	Mar., 1991	EP
0609960	Aug., 1994	EP
1 403 255	Mar., 2004	EP
1 344 579	Oct., 1963	FR
2020280	Nov., 1979	GB
WO91/13874	Sep., 1991	WO
97/26240	Jul., 1997	WO
00/50387	Aug., 2000	WO
02/08221	Jan., 2002	WO
WO03/14064	Feb., 2003	WO
03/014064	Feb., 2003	WO
WO03/22809	Mar., 2003	WO
03/22809	Mar., 2003	WO
WO03/80578	Oct., 2003	WO

Other References

Berge, et al., "Pharmaceutical Salts," Journal of Pharmaceutical Sciences 66:1-19 (1977) (Jan., 1977). cited by other .
Caterina, et al., "Impaired Nociception and pain sensation in mice lacking the capsaicin receptor," Science 288:306-313 (2000) (Apr. 14, 2000). cite- d by other .
Caterina, et al., "The capsaicin receptor: a heat-activated ion channel in the pain pathway," Nature 389:816-824 (1997) (Oct. 23, 1997). cited by other .
Caterina, et al., "The Vanilloid Receptor: A Molecular gateway to the pain pathway," Annual Review of Neuroscience 24:487-517 (2001). cited by other .
Collier, et al., Br. J. Pharmacol. Chemother. 32:295-310 (1968). cited by other .
Davis, et al., "Vanilloid receptor-1 is essential for inflammatory thermal hyperalgesia," Nature 405:183-187 (2000) (May 11, 2000). cited by other .
Fowler, "Intravesical treatment of overactive bladder," Urology 55(Supp 5A):60-64 (2000) (May, 2000). cited by other .
Hayes, et al., "Cloning and functional expression of a human orthologue of rat vanilloid receptor-1," Pain 88:205-215 (2000). cited by other .
Nolano, et al., "Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation," Pain 81:135-145 (1999). cited by other .
Poste , et al., Methods in Cell Biology, Academic Press, New York, N.Y. vol. 14:33-71 (1976). cited by other .
Adams et al., "Dialkylaminoalkyquinolines," J. Chem. Soc. 3066-3071 (1957). cited by other .
Cannon et al., "Synthesis of N-alkyl derivatives of 4-(2'-aminothyl)indole," J. Heterocyclic Chemistry 19:1195-1199 (1982) (Sep.-Oct., 1982). cited by other .
Craig et al., "Derivatives of aminoisoquinolines," J. Am. Chem. Soc. 64:783-784 (1942) (Nov., 1942). cited by other .
Fieser et al., "A comparison of heterocyclic systems with benzene. VI. Quinines of the quinoline and isoquinoline series," J. Amer. Chem. Soc. 57:1840-1844 (1935) (Oct. , 1935). cited by other .
Forbes et al., "N-(1-methyl-5-indolyl)-N'-(3-pyridyl)urea hydrochloride: the first selective 5-HT.sub.1C receptor antagonist," J. Med. Chem. 36:1104-1107 (1993). cited by other .
Gall et al., "171. On a few derivatives of heterocyclic carbonic acids IV. Metal ions and biological action, 36.sup.th report," Helv. Chim. Acta 38(171):1421-1423 (1955) with translation. cited by other .
Honma et al., "Structure-based generation of a new class of potent Cdk4 inhibitors: New de Novo design strategy and library design," J. Med. Chem. 44:4615-4627 (2001). cited by other .
Kawasaki et al., "A new approach to 4-(2-aminoethyl)indoles via Claisen ortho-amide rearrangement of 3-hydroxy-2-methoxyindolines," J. Chem. Soc. Chem. Commun. 10:781-782 (1990). cited by other .
Kumar et al. "Antiparasitic agents: Part XV--Synthesis of 2-substituted 1(3)H-imidazo[4,5-f]isoquinolines as anthelmintic agents," Indian Journal of Chemistry 31B:177-182 (1992) (Mar., 1992). cited by other .
Mooney et al., "Potential antitumor agens, 10. Synthesis and biochemical properties of 5-N-alkylamino-,N,N-dialkylamino-, and N-alkylacetamido-1-formylisoquinoline thiosemicarbazones," Journal of Medicinal Chemistry 17(11):1145-1150 (1974). cited by other .
Naruto et al., "Photo-induced Friedel-Crafts reactions. IV>Indoleacetic acids," Chemical and Pharmaceutical Bulletin, Tokyo, JP 20(10):2163-2171 (1972). cited by other .
Prijs et al. "9. On a few derivatives of heterocyclic carbonic acids I . . . Metal ions and biological action, 16.sup.th report," Helv. Chim. Acta 37:90-94 (1954) with translation. cited by other .
Sato et al., "Construction of optically pure tryptophans from serine derived aziridine-2-carboxylates," Tetrahedron Letters 30(31):4073-4076 (1989). cited by other .
Taurins et al., "Thiazoloisoquinolines. IV. The synthesis and spectra of thiazolo[4,5-h]-and thiazolo[5,4-f]isoquinolines. The ultraviolet and proton magnetic resonance spectra of some substituted isoquinolines," Canadian Journal of Chemistry 49(24):4054-4061 (1971). cited by other .
Warpehoski et al., "Stereoelectronic factors influencing the biological activity and DNA intereaction of synthetic antitumor agents modeled on CC-1065," J. Med. Chem. 31:590-603 (1988) (Issue No. 3). cited by other .
Lichtenthaler et al., "Nucleosides. 44. Benzo-separated Pyrazolopyrimidines: Expeditions Synthesis of [3,4-g] and [3,4-h]-linked Pyrazoloquinazolinones" Tetrahedron Letters 22(44) :4397-4400 (1981). cit- ed by other .
Nunn et al., "Semmler-Wolf Aromatization and Abnormal Beckmann and Schmidt Reactions of 3-Alkyl-4Oxo-1-phenyl-4,5,6,7,-tetrahydroindazoles and their oximes in polyphosphoric acid" J. Chem. Soc. Perkin Transactions 1, 1973 No. 22:2697-2703 (1973). cited by other .
R. Gall: Uber Einige Derivative Heterocyclischer Carbonsauren, Helv. Chim. Acta, vol. 37 (1954), pp. 90-94 (English translation summary-last page). cited by other.

Primary Examiner: Crane; L. E.
Attorney, Agent or Firm: Gabryleda Ferari-Dileo

Claims

What is claimed is:

1. A compound of formula (I) ##STR00016## or a pharmaceutically acceptable salt or prodrug thereof, wherein - - - is absent or is a single bond; X.sub.1 is CR.sub.1; X.sub.2 is selected from the group consisting of N and CR.sub.2; X.sub.3 is selected from the group consisting of N and CR.sub.3; X.sub.4 is CR.sub.4; X.sub.5 is selected from the group consisting of N and C; provided that only one of X.sub.2, and X.sub.3 is N; Z.sub.1 is O; Z.sub.2 is a bond or selected from the group consisting of NH and O; L is selected from the group consisting of alkenylene, alkylene, cycloalkylene, ##STR00017## --(CH.sub.2).sub.mO(CH.sub.2).sub.n--, and N(R.sub.Y), wherein the left end of --(CH.sub.2).sub.mO(CH.sub.2).sub.n-- is attached to Z.sub.2 and the right end is attached to R.sub.9; m and n are each independently 1-6; R.sub.Y is selected from the group consisting of hydrogen and alkyl; R.sub.1, R.sub.3, R.sub.5, R.sub.6, and R.sub.7 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylcarbonyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, --NR.sub.AS(O).sub.2R.sub.B, --S(O).sub.2R.sub.B, --NZ.sub.AZ.sub.B, (NZ.sub.AZ.sub.B)alkyl, (NZ.sub.AZ.sub.B)carbonylalkyl and (NZ.sub.AZ.sub.B)sulfonyl, wherein Z.sub.A and Z.sub.B are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, and arylalkyl; R.sub.2 and R.sub.4 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, --NR.sub.AS(O).sub.2R.sub.B, --S(O).sub.2OR.sub.A, --S(O).sub.2R.sub.B, --NZ.sub.AZ.sub.B, (NZ.sub.AZ.sub.B)alkyl, (NZ.sub.AZ.sub.B)alkylcarbonyl, (NZ.sub.AZ.sub.B)carbonyl, (NZ.sub.AZ.sub.B)carbonylalkyl, and (NZ.sub.AZ.sub.B)sulfonyl; R.sub.A is selected from the group consisting of hydrogen and alkyl; R.sub.B is selected from the group consisting of alkyl, aryl, and arylalkyl; R.sub.8a is selected from the group consisting of hydrogen and alkyl; R.sub.8b is absent when X.sub.5 is N or R.sub.8b is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, and hydroxy when X.sub.5 is C; and R.sub.9 is selected from the group consisting of hydrogen, aryl, cycloalkyl, and heterocycle.

2. The compound according to claim 1 wherein - - - is a single bond; X.sub.1 is CR.sub.1; X.sub.2 is CR.sub.2; X.sub.3 is N; and X.sub.4 is CR.sub.4.

3. The compound according to claim 2 wherein X.sub.5 is N; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is aryl.

4. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.6 and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.A, Z.sub.B, Z.sub.C, and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

5. The compound according to claim 4 selected from the group consisting of N-[2-(3-fluorophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-[2-(3-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-[4-(trifluoromethyl)benzyl]urea; N-[3-fluoro-5-(trifluoromethyl)benzyl]-N'-isoquinolin-5-ylurea; N-(2,5-dichlorobenzyl)-N'-isoquinolin-5-ylurea; N-(1,3-benzodioxol-5-ylmethyl)-N'-isoquinolin-5-ylurea; N-[2-(4-fluorophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-(3-bromobenzyl)-N'-isoquinolin-5-ylurea; N-[2-(3,4-dimethylphenyl)ethyl]-N'-isoquinolin-5-ylurea; N-[1-(4-bromophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-[4-(trifluoromethoxy)benzyl]urea; N-isoquinolin-5-yl-N'-(4-methylbenzyl)urea; N-(4-fluorobenzyl)-N'-isoquinolin-5-ylurea; N-[2-(3,4-dichlorophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-[2-(3,5-dimethoxyphenyl)ethyl]-N'-isoquinolin-5-ylurea; N-(4-chlorobenzyl)-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-{2-[3-(trifluoromethyl)phenyl]ethyl}urea; N-[2-(2,6-dichlorophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-[2-(2,3-dichlorophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-[3-(trifluoromethoxy)benzyl]urea; N-[2-(4-ethoxy-3-methoxyphenyl)ethyl]-N'-isoquinolin-5-ylurea; N-[2-(2,4-dichlorophenyl)ethyl]-N'-isoquinolin-5-ylurea; N-(3-bromo-4-fluorobenzyl)-N'-isoquinolin-5-ylurea; N-(3,4-dimethylbenzyl)-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-(3-phenylpropyl)urea; N-(3,5-dichlorobenzyl)-N'-isoquinolin-5-ylurea; N-(3-chloro-4-methylbenzyl)-N'-isoquinolin-5-ylurea; N-(3,4-dichlorobenzyl)-N'-isoquinolin-5-ylurea; N-(3-fluorobenzyl)-N'-isoquinolin-5-ylurea; N-(4-tert-butylbenzyl)-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-[2-(3-methylphenyl)ethyl]urea; N-isoquinolin-5-yl-N'-[2-(4-methylphenyl)ethyl]urea; N-[2-(2,4-dimethylphenyl)ethyl]-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-[2-(2-methylphenyl)ethyl]urea; N-isoquinolin-5-yl-N'-{4-[(trifluoromethyl)thio]benzyl}urea; N-isoquinolin-5-yl-N'-[3-(trifluoromethyl)benzyl]urea; N-[4-chloro-3-(trifluoromethyl)benzyl]-N'-isoquinolin-5-ylurea; N-(3,5-dimethylbenzyl)-N'-isoquinolin-5-ylurea; N-(3,5-difluorobenzyl)-N'-isoquinolin-5-ylurea; N-(4-bromobenzyl)-N'-isoquinolin-5-ylurea; N-(3,5-dimethoxybenzyl)-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-(3,4,5-trimethoxybenzyl)urea; N-isoquinolin-5-yl-N'-[4-(methylsulfonyl)benzyl]urea; N-(3,4-dimethoxybenzyl)-N'-isoquinolin-5-ylurea; N-isoquinolin-5-yl-N'-(1-naphthylmethyl)urea; N-(2,4-dimethylbenzyl)-N'-isoquinolin-5-ylurea; N-[4-(dimethylamino)benzyl]-N'-isoquinolin-5-ylurea; N-(4-bromobenzyl)-N'-(3-chloroisoquinolin-5-yl)urea; N-[(4-cyanophenyl)methyl]-N'-isoquinolin-5-ylurea; N-[(4-bromophenyl)methyl]-N'-(3-methylisoquinolin-5-yl)urea; N-[(4-bromophenyl)methyl]-N'-(1-chloroisoquinolin-5-yl)urea; N-[(4-bromophenyl)methyl]-N'-(1-methylisoquinolin-5-yl)urea; N-isoquinolin-5-yl-N'-[(4-morpholin-4-ylphenyl)methyl]urea; N-{[4-(2,6-dimethylmorpholin-4-yl)phenyl]methyl}-N'isoquinolin-5ylurea N-isoquinolin-5-yl-N'-[(4-thiomorpholin-4-ylphenyl)methyl]urea; methyl 5-({[(4-bromobenzyl)amino]carbonyl}amino)isoquinoline-3-carboxylate; methyl 5-({[(2,4-dichlorobenzyl)amino]carbonyl}amino)isoquinoline-3-carbo- xylate; N-(8-bromoisoquinolin-5-yl)-N'-(2,4-dichlorobenzyl)urea; N-(8-bromoisoquinolin-5-yl)-N'-(4-fluorobenzyl)urea; N-(8-bromoisoquinolin-5-yl)-N'-(3-fluorobenzyl)urea; N-[1-(4-chlorophenyl)-1-methylethyl]-N'-isoquinolin-5-ylurea; N-(1,1'-biphenyl-4-ylmethyl)-N'-5-isoquinolinylurea; N-[3-fluoro-4-(trifluoromethyl)benzyl]-N'-5-isoquinolinylurea; N-5-isoquinolinyl-N'-(3-methylbenzyl)urea; N-[4-fluoro-3-(trifluoromethyl)benzyl]-N'-5-isoquinolinylurea; N-(3-chloro-4-fluorobenzyl)-N'-5-isoquinolinylurea; N-5-isoquinolinyl-N'-[4-(1-pyrrolidinyl)benzyl]urea; N-[4-(1-azepanyl)benzyl]-N'-5-isoquinolinylurea; N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N'-5-isoquinolinylurea; N-[4-(1-azepanyl)-3-fluorobenzyl]-N'-5-isoquinolinylurea; N-[4-(1-azocanyl)benzyl]-N'-5-isoquinolinylurea; N-benzhydryl-N'-5-isoquinolinylurea; N-[(1S)-1-(4-bromophenyl)ethyl]-N'-5-isoquinolinylurea; N-[(1R)-1-(4-bromophenyl)ethyl]-N'-5-isoquinolinylurea; N-5-isoquinolinyl-N'-{1-[4-(trifluoromethyl)phenyl]ethyl}urea; (-) N-5-isoquinolinyl-N'-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}urea; (+) N-5-isoquinolinyl-N'-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}urea; N-[1-(4-tert-butylphenyl)ethyl]-N'-5-isoquinolinylurea; N-{cyclopropyl[4-(trifluoromethyl)phenyl]methyl}-N'-5-isoquinolinylurea; N-(3-fluorobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(4-bromo-3-fluorobenzyl)-N'-5-isoquinolinylurea; N-(3-amino-5-isoquinolinyl)-N'-[4-(1-piperidinyl)benzyl]urea; N-(3-amino-5-isoquinolinyl)-N'-[4-(1-azepanyl)benzyl]urea; N-(1,1'-biphenyl-3-ylmethyl)-N'-5-isoquinolinylurea; N-5-isoquinolinyl-N'-[4-(2-pyridinyl)benzyl]urea; N-(4-bromo-3-fluorobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-[3-fluoro-4-(4-methyl-1-piperidinyl)benzyl]-N'-(3-methyl-5-isoqinolinyl- )urea; N-(3-methyl-5-isoquinolinyl)-N'-[4-(4-methyl-1-piperidinyl)benzyl]- urea; N-[3-fluoro-4-(1-piperidinyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)u- rea; N-(3-methyl-5-isoquinolinyl)-N'-[4-(1-piperidinyl)benzyl]urea; N-[4-(1-azepanyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-(3-methyl-5-isoquinolinyl)-N'-[4-(1-pyrrolidinyl)benzyl]urea; N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-[4-(1-azepanyl)-3-fluorobenzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-[4-(1-azocanyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-[4-(1-azocanyl)-3-fluorobenzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-[(1S)-1-(4-bromophenyl)ethyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-{(1S)-1-[4-(1-azepanyl)phenyl]ethyl}-N'-(3-methyl-5-isoquinolinyl)urea; N-benzyl-N'-(3-chloro-5-isoquinolinyl)urea; N-(4-bromobenzyl)-N'-(1-chloro-5-isoquinolinyl)urea; N-(4-cyanobenzyl)-N'-5-isoquinolinylurea; N-(4-bromobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(4-bromobenzyl)-N'-(1-methyl-5-isoquinolinyl)urea; N-5-isoquinolinyl-N'-[4-(4-morpholinyl)benzyl]urea; N-[4-(2,6-dimethyl-4-morpholinyl)benzyl]-N'-5-isoquinolinylurea; N-5-isoquinolinyl-N'-[4-(4-thiomorpholinyl)benzyl]urea; N-(4-bromobenzyl)-N'-(3-fluoro-5-isoquinolinyl)urea; N-(3-chloro-5-isoquinolinyl)-N'-[4-(4-morpholinyl)benzyl]urea; N-[3,5-difluoro-4-(4-morpholinyl)benzyl]-N'-5-isoquinolinylurea; N-(4-bromobenzyl)-N'-(1,3-dimethyl-5-isoquinolinyl)urea; N-(3,4-dimethylbenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-[3,5-bis(trifluoromethyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-(3-amino-5-isoquinolinyl)-N'-(4-bromobenzyl)urea; N-(3-methyl-5-isoquinolinyl)-N'-[4-(trifluoromethyl)benzyl]urea; N-(4-tert-butylbenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(4-tert-butylbenzyl)-N'-(1,3-dimethyl-5-isoquinolinyl)urea; N-(4-tert-butylbenzyl)-N'-(1,3-dimethyl-5-isoquinolinyl)urea; N-[3-fluoro-4-(trifluoromethyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-[1-(4-bromophenyl)ethyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-(3,4-dichlorobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(2,4-dichlorobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(3-chlorobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(3-methyl-5-isoquinolinyl)-N'-[4-(trifluoromethoxy)benzyl]urea; N-[2-(3,4-dichlorophenyl)ethyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-(4-ethylbenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(3-methyl-5-isoquinolinyl)-N'-{2-[4-(trifluoromethyl)phenyl]ethyl}urea; N-(3-methyl-5-isoquinolinyl)-N'-{4-[(trifluoromethyl)thio]benzyl}urea; N-(4-chlorobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(2,4-difluorobenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-(1,3-dimethyl-5-isoquinolinyl)-N'-[3-fluoro-4-(trifluoromethyl)benzyl]u- rea; N-(4-isopropylbenzyl)-N'-(3-methyl-5-isoquinolinyl)urea; N-[4-fluoro-3-(trifluoromethyl)benzyl]-N'-(3-methyl-5-isoquinolinyl)urea; N-(3-amino-5-isoquinolinyl)-N'-{1-[4-(trifluoromethyl)phenyl]ethyl}urea; N-(3-amino-5-isoquinolinyl)-N'-[3-fluoro-4-(trifluoromethyl)benzyl]urea; N-(5-bromo-2-fluorobenzyl)-N'-5-isoquinolinylurea; N-(4-chloro-2-fluorobenzyl)-N'-5-isoquinolinylurea; N-(4-tert-butylbenzyl)-N'-5-isoquinolinylurea; N-(3,4-difluorobenzyl)-N'-5-isoquinolinylurea; N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-N'-5-isoquinolinylurea; N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]propyl}-N'-5-isoquinolinylurea; N-(8-bromo-5-isoquinolinyl)-N'-(2,4-dichlorobenzyl)urea; N-(8-bromo-5-isoquinolinyl)-N'-(4-fluorobenzyl)urea; N-(8-bromo-5-isoquinolinyl)-N'-(3-fluorobenzyl)urea; N-[1-(4-chlorophenyl)-1-methylethyl]-N'-5-isoquinolinylurea; N-(4-bromo-3-methylbenzyl)-N'-5-isoquinolinylurea; N-[2-fluoro-4-(trifluoromethyl)benzyl]-N'-5-isoquinolinylurea; N-(4-bromobenzyl)-N'-(3-hydroxy-5-isoquinolinyl)urea; N-[3-bromo-4-(trifluoromethyl)benzyl]-N'-5-isoquinolinylurea; N-[2,4-bis(trifluoromethyl)benzyl]-N'-5-isoquinolinylurea; N-[2,3-difluoro-4-(trifluoromethyl)benzyl]-N'-5-isoquinolinylurea; N-[2-chloro-4-(trifluoromethyl)benzyl]-N'-5-isoquinolinylurea; N-5-isoquinolinyl-N'-{1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}urea; and N-[2-(4-bromophenyl)-2-hydroxyethyl]-N'-5-isoquinolinylurea.

6. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is aryl wherein said aryl is substituted with aryloxy.

7. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with aryloxy wherein said aryloxy is phenoxy substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

8. The compound according to claim 7 selected from the group consisting of N-isoquinolin-5-yl-N'-(4-phenoxybenzyl)urea; and N-isoquinolin-5-yl-N'-(3-phenoxybenzyl)urea.

9. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is aryl wherein said aryl is napthyl.

10. The compound according to claim 9 that is N-isoquinolin-5-yl-N'-(1-naphthylmethyl)urea.

11. The compound according to claim 2 wherein X.sub.5 is N; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is cycloalkyl.

12. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.6 and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and alkyl; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is cycloalkyl wherein said cycloalkyl is selected from the group consisting of adamantyl, bicyclo[3.1.1]heptyl, and cyclohexyl, wherein the cycloalkyl is substituted with 0, 1 or 2 alkyl groups; and Z.sub.A and Z.sub.B are independently selected from the group consisting of hydrogen and alkyl.

13. The compound according to claim 12 selected from the group consisting of N-(1-adamantylmethyl)-N'-5-isoquinolinylurea; N-(cyclohexylmethyl)-N'-5-isoquinolinylurea; N-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-N'-5-isoquinolinylurea; N-[(4-tert-butylcyclohexyl)methyl]-N'-5-isoquinolinylurea; and N-5-isoquinolinyl-N'-{[4-(trifluoromethyl)cyclohexyl]methyl}urea.

14. The compound according to claim 2 wherein X.sub.5 is N; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is heterocycle.

15. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.6 and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is heterocycle wherein said heterocycle is pyridinyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.A, Z.sub.B, Z.sub.C, and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

16. The compound according to claim 15 that is N-5-isoquinolinyl-N'-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea.

17. The compound according to claim 2 wherein X.sub.5 is N; Z.sub.1 is O; Z.sub.2 is NH; R.sub.8b is absent; and R.sub.9 is hydrogen.

18. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is hydrogen.

19. The compound according to claim 18 selected from the group consisting of N-hexyl-N'-isoquinolin-5-ylurea; N-5-isoquinolinyl-N'-pentylurea; and N-5-isoquinolinyl-N'-octylurea.

20. The compound according to claim 2 wherein X.sub.5 is N; Z.sub.1 is O; Z.sub.2 is NH; L is cycloalkylene; R.sub.8b is absent; and R.sub.9 is aryl.

21. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is cycloalkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

22. The compound according to claim 21 that is N-isoquinolin-5-yl-N'-[(trans)-2-phenylcyclopropyl]urea.

23. The compound according to claim 2 wherein X.sub.5 is N; Z.sub.1 is O; Z.sub.2 is a bond; L is cycloalkylene; R.sub.8b is absent; and R.sub.9 is aryl.

24. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is a bond; L is cycloalkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

25. The compound according to claim 24 that is N-5-isoquinolinyl-2-phenylcyclopropanecarboxamide.

26. The compound according to claim 2 wherein X.sub.5 is N; Z.sub.1 is O; Z.sub.2 is NH; L is --(CH.sub.2).sub.mO(CH.sub.2).sub.n-- wherein the left end is attached to Z.sub.2 and the right end is attached to R.sub.9; R.sub.8b is absent; and R.sub.9 is aryl.

27. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8a are each hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is --(CH.sub.2).sub.mO(CH.sub.2).sub.n-- wherein the left end is attached to Z.sub.2 and the right end is attached to R.sub.9; m is 1-2; n is 0-2; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

28. The compound according to claim 27 selected from the group consisting of N-isoquinolin-5-yl-N'-(2-phenoxyethyl)urea; and N-[(2,4-dichlorobenzyl)oxy]-N'-5-isoquinolinylurea.

29. The compound according to claim 2 wherein X.sub.5 is N; Z.sub.1 is O; Z.sub.2 is NH; L is N(R.sub.Y); R.sub.8b is absent; and R.sub.9 is aryl.

30. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8a are each hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is N(R.sub.Y); m is 2-4; n is 0; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

31. The compound according to claim 30 that is N-5-isoquinolinyl-2-[4-(trifluoromethyl)phenyl]hydrazinecarboxamide.

32. The compound according to claim 2 wherein X.sub.5 is N; Z.sub.1 is O; Z.sub.2 is a bond; ##STR00018## R.sub.8b is absent; and R.sub.9 is aryl.

33. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.5, R.sub.6, R.sub.7, and R.sub.8a are each hydrogen; R.sub.8b is absent; R.sub.2 is selected from the group consisting of hydrogen and alkyl; Z.sub.1 is O; Z.sub.2 is a bond; ##STR00019## R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

34. The compound according to claim 33 that is selected from the group consisting of 4-(3,4-dichlorophenyl)-N-isoquinolin-5-ylpiperazine-1-carboxamide; 4-(3-chlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide; 4-(3,4-dimethylphenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide; 4-(4-chlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide; N-5-isoquinolinyl-3-methyl-4-(4-methylphenyl)-1-piperazinecarboxamide; 4-(2,3-dimethylphenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide; 4-(2,3-dichlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide; 4-(3,4-dichlorophenyl)-N-(3-methyl-5-isoquinolinyl)-1-piperazinecarboxami- de; N-5-isoquinolinyl-4-[3-(trifluoromethyl)phenyl]-1-piperazinecarboxami- de; and 4-(4-bromophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide.

35. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5 and R.sub.6 are each hydrogen; R.sub.7 is (CF.sub.3).sub.2(HO)C--; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

36. The compound according to claim 35 that is N-(4-bromobenzyl)-N'-{6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)eth- yl]isoquinolin-5-yl}urea.

37. The compound according to claim 2 wherein X.sub.5 is N; Z.sub.1 is O; Z.sub.2 is O; L is alkylene; R.sub.8b is absent; and R.sub.9 is aryl.

38. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6, R.sub.7, and R.sub.8a are each hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is O; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

39. The compound according to claim 38 selected from the group consisting of 4-(trifluoromethyl)benzyl isoquinolin-5-ylcarbamate; 2-(3-bromophenyl)ethyl isoquinolin-5-ylcarbamate; 4-cyanobenzyl isoquinolin-5-ylcarbamate; 4-methylbenzyl 5-isoquinolinylcarbamate; 4-bromobenzyl 5-isoquinolinylcarbamate; 2-(4-chlorophenyl)ethyl 5-isoquinolinylcarbamate; and 2-[2-(trifluoromethyl)phenyl]ethyl 5-isoquinolinylcarbamate.

40. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.2, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; Z.sub.1 is O; Z.sub.2 is O; L is alkylene; R.sub.8b is absent; and R.sub.9 is aryl wherein said aryl is naphthyl.

41. The compound according to claim 40 that is 1-naphthylmethyl isoquinolin-5-ylcarbamate.

42. The compound according to claim 2 wherein X.sub.5 is N; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is a bond; L is alkenylene; and R.sub.9 is aryl.

43. The compound according to claim 2 wherein X.sub.5 is N; R.sub.1, R.sub.6 and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is a bond; L is alkenylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.A, Z.sub.B, Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

44. The compound according to claim 43 that is selected from the group consisting of (2E)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamide; N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-3-butenamide; (2Z)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamide; (2E)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinyl-2-butenamid- e; 3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinyl-3-butenamide; (2E)-N-5-isoquinolinyl-3-[4-(1-piperidinyl)phenyl]-2-butenamide; N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]acrylamide; N-5-isoquinolinyl-3-[3-(trifluoromethyl)phenyl]acrylamide; 3-(4-isopropylphenyl)-N-5-isoquinolinylacrylamide; 3-(3,4-dichlorophenyl)-N-5-isoquinolinylacrylamide; 3-(1,1'-biphenyl-4-yl)-N-5-isoquinolinylacrylamide; 3-(3-bromo-4-fluorophenyl)-N-5-isoquinolinylacrylamide; 3-(4-tert-butylphenyl)-N-5-isoquinolinylacrylamide; and 3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinylacrylamide.

45. The compound according to claim 2 wherein X.sub.5 is C; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is heterocycle.

46. The compound according to claim 2 wherein X.sub.5 is C; R.sub.1, R.sub.6 and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is hydrogen; R.sub.8b is hydrogen; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is heterocycle wherein said heterocycle is selected from the group consisting of imidazolyl, pyridinyl, pyrrolidinyl, and thienyl, wherein the heterocycle is substituted with 0, 1 or 2 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, oxo, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.A, Z.sub.B, Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

47. The compound according to claim 46 selected from the group consisting of 2-(5-isoquinolinyl)-N-[2-(2-thienyl)ethyl]acetamide; N-[3-(1H-imidazol-1-yl)propyl]-2-(5-isoquinolinyl)acetamide; 2-(5-isoquinolinyl)-N-[3-(2-oxo-1-pyrrolidinyl)propyl]acetamide; and 2-(5-isoquinolinyl)-N-[2-(3-pyridinyl)ethyl]acetamide.

48. The compound according to claim 2 wherein X.sub.5 is C; Z.sub.1 is O; Z.sub.2 is NH; L is --(CH.sub.2).sub.mO(CH.sub.2).sub.n-- wherein the left end is attached to Z.sub.2 and the right end is attached to R.sub.9; and R.sub.9 is hydrogen.

49. The compound according to claim 2 wherein X.sub.5 is C; R.sub.1, R.sub.6 and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is hydrogen; R.sub.8b is hydrogen; Z.sub.1 is O; Z.sub.2 is NH; L is --(CH.sub.2).sub.mO(CH.sub.2).sub.n-- wherein the left end is attached to Z.sub.2 and the right end is attached to R.sub.9; m is 1-4; n is 0-4; R.sub.9 is hydrogen; and Z.sub.A and Z.sub.B are independently selected from the group consisting of hydrogen and alkyl.

50. The compound according to claim 49 that is N-(3-butoxypropyl)-2-(5-isoquinolinyl)acetamide.

51. The compound according to claim 2 wherein X.sub.5 is C; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is aryl.

52. The compound according to claim 2 wherein X.sub.5 is C; R.sub.1, R.sub.6, R.sub.7, R.sub.8a and R.sub.8b are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.A, Z.sub.B, Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

53. The compound according to claim 52 selected from the group consisting of 2-isoquinolin-5-yl-N-[4-(trifluoromethyl)benzyl]acetamide; N-(4-bromobenzyl)-2-(3-methyl-5-isoquinolinyl)acetamide; N-(4-bromobenzyl)-2-(5-isoquinolinyl)acetamide; N-[1-(4-bromophenyl)ethyl]-2-(5-isoquinolinyl)acetamide; N-[1-(4-bromophenyl)ethyl]-2-(3-methyl-5-isoquinolinyl)acetamide; 2-(5-isoquinolinyl)-N-[4-(trifluoromethoxy)benzyl]acetamide; N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)acetamide; N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide; N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-2-(5-isoquinolinyl)acetam- ide; N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]propyl}-2-(5-isoquinolinyl)- acetamide; 2-(3-methyl-5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]acetamide; N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(3-methyl-5-isoquinolinyl)acetam- ide; 2-(5-isoquinolinyl)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}acetamide; N-(3,3-diphenylpropyl)-2-(5-isoquinolinyl)acetamide; 2-(5-isoquinolinyl)-N-(3-phenylpropyl)acetamide; N-(2,2-diphenylethyl)-2-(5-isoquinolinyl)acetamide; N-benzyl-2-(5-isoquinolinyl)acetamide; 2-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}acetamide; 2-(5-isoquinolinyl)-N-(2-phenylethyl)acetamide; N-[3-bromo-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide; N-(4-bromo-3-methylbenzyl)-2-(5-isoquinolinyl)acetamide; N-[2,4-bis(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide; N-[2-chloro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide; N-[2,3-difluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide; and N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)acetamide.

54. The compound according to claim 2 wherein X.sub.5 is C; R.sub.1, R.sub.6, and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is selected from the group consisting of hydrogen and alkyl; R.sub.8b is alkyl; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.A, Z.sub.B, Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

55. The compound according to claim 54 selected from the group consisting of N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)propanamide; 2-(5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]propanamide; 2-(5-isoquinolinyl)-N-[3-(trifluoromethyl)benzyl]propanamide; 2-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}propanamide; N-(4-bromobenzyl)-2-(5-isoquinolinyl)propanamide; N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)propanamide; N-[3-fluoro-5-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)propanamide; 2-(5-isoquinolinyl)-N-[4-(trifluoromethoxy)benzyl]propanamide; 2-(5-isoquinolinyl)-N-[3-(trifluoromethoxy)benzyl]propanamide; N-(2,4-dimethylbenzyl)-2-(5-isoquinolinyl)propanamide; N-(2,5-dimethylbenzyl)-2-(5-isoquinolinyl)propanamide; N-(2,3-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide; N-(2,4-dichlorobenzyl)-2-(5-isoqinolinyl)propanamide; N-(2,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide; N-(3,4-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide; N-(3,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide; N-[4-(1-azepanyl)benzyl]-2-(5-isoquinolinyl)propanamide; N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)propanamide; N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)butanamide; 2-(5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]butanamide; N-(4-bromobenzyl)-2-(5-isoquinolinyl)butanamide; 2-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}butanamide; N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)butanamide; and 2-(5-isoquinolinyl)-2-methyl-N-{4-[(trifluoromethyl)thio]benzyl}propanami- de.

56. The compound according to claim 2 wherein X.sub.5 is C; R.sub.1, R.sub.6, and R.sub.7 and are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is hydrogen; R.sub.8b is selected from the group consisting of alkoxy, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, halogen, and hydroxy; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.A, Z.sub.B, Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

57. The compound according to claim 56 selected from the group consisting of N-(4-tert-butylbenzyl)-2-hydroxy-2-(5-isoquinolinyl)acetamide; N-(4-tert-butyl-3-fluorobenzyl)-2-hydroxy-2-(5-isoquinolinyl)acetamide; tert-butyl 4-[(4-tert-butylbenzyl)amino]-3-(5-isoquinolinyl)-4-oxobutanoate; 2-[(4-tert-butylbenzyl)amino]-1-(5-isoquinolinyl)-2-oxoethyl acetate; 2-[(4-tert-butylbenzyl)amino]-1-(5-isoquinolinyl)-2-oxoethyl methanesulfonate; N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)-2-methoxyacetamide; and N-(4-tert-butylbenzyl)-2-chloro-2-(5-isoquinolinyl)acetamide.

58. The compound according to claim 2 wherein X.sub.5 is C; R.sub.1, R.sub.6, R.sub.7, and R.sub.7 are each hydrogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and --NZ.sub.AZ.sub.B; R.sub.5 is selected from the group consisting of hydrogen and halogen; R.sub.8a is selected from the group consisting of hydrogen and alkyl; R.sub.8b is selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, and hydroxy; Z.sub.1 is O; Z.sub.2 is O; L is alkylene; R.sub.9 is hydrogen; and Z.sub.A and Z.sub.B are independently selected from the group consisting of hydrogen and alkyl.

59. The compound according to claim 58 selected from the group consisting of ethyl 5-isoquinolinylacetate; ethyl 2-(5-isoquinolinyl)propanoate; ethyl 2-(5-isoquinolinyl)butanoate; ethyl 2-(5-isoquinolinyl)-2-methylpropanoate; ethyl hydroxy(5-isoquinolinyl)acetate; and 4-tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate.

60. The compound according to claim 1 wherein - - - is a single bond; X.sub.1 is CR.sub.1; X.sub.2 is N; X.sub.3 is CR.sub.3; and X.sub.4 is CR.sub.4.

61. The compound according to claim 60 wherein X.sub.5 is N; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; and R.sub.9 is aryl.

62. The compound according to claim 60, wherein X.sub.5 is N; R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are each hydrogen; R.sub.8b is absent; Z.sub.1 is O; Z.sub.2 is NH; L is alkylene; R.sub.9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and --NZ.sub.CZ.sub.D; and Z.sub.C and Z.sub.D are independently selected from the group consisting of hydrogen and alkyl.

63. The compound according to claim 62 selected from the group consisting of N-isoquinolin-8-yl-N'-[4-(trifluoromethyl)benzyl]urea; and N-(4-bromobenzyl)-N'-isoquinolin-8-ylurea.

64. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

65. A method of treating a disorder wherein the disorder is ameliorated by inhibiting vanilloid receptor subtype 1 (VR1) receptor, and wherein the disorder is selected from the group comprising pain, bladder overactivity, urinary incontinence and inflammatory thermal hyperalgesia in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

66. A method of treating bladder overactivity in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

67. A method of treating urinary incontinence in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

68. A method of treating pain in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

69. A method of treating inflammatory thermal hyperalgesia in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof.

Description

TECHNICAL BACKGROUND

The present invention relates to compounds of formula (I), which are useful for treating disorders caused by exacerbated by or vanilloid receptor activity, pharmaceutical compositions containing compounds of formula (I) and are useful in treating pain, bladder overactivity, and urinary incontinence.

BACKGROUND OF INVENTION

Nociceptors are primary sensory afferent (C and A.delta. fibers) neurons that are activated by a wide variety of noxious stimuli including chemical, mechanical, thermal, and proton (pH <6) modalities. The lipophillic vanilloid, capsaicin, activates primary sensory fibers via a specific cell surface capsaicin receptor, cloned as VR1. The intradermal administration of capsaicin is characterized by an initial burning or hot sensation followed by a prolonged period of analgesia. The analgesic component of VR1 receptor activation is thought to be mediated by a capsaicin-induced desensitization of the primary sensory afferent terminal. Thus, the long lasting anti-nociceptive effects of capsaicin has prompted the clinical use of capsaicin analogs as analgesic agents. Further, capsazepine, a capsaicin receptor antagonist can reduce inflammation-induced hyperalgesia in animal models. VR1 receptors are also localized on sensory afferents which innervate the bladder. Capsaicin or resiniferatoxin has been shown to ameliorate incontinence symptoms upon injection into the bladder.

The VR1 receptor has been called a "polymodal detector" of noxious stimuli since it can be activated in several ways. The receptor channel is activated by capsaicin and other vanilloids and thus is classified as a ligand-gated ion channel. VR1 receptor activation by capsaicin can be blocked by the competitive VR1 receptor antagonist, capsazepine. The channel can also be activated by protons. Under mildly acidic conditions (pH 6-7), the affinity of capsaicin for the receptor is increased, whereas the pH <6, direct activation of the channel occurs. In addition, when membrane temperature reaches 43.degree. C., the channel is opened. Thus heat can directly gate the channel in the absence of ligand. The capsaicin analog, capsazepine, which is a competitive antagonist of capsaicin, blocks activation of the channel in response to capsaicin, acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodium and calcium enter through the channel pore, resulting in cell membrane depolarization. This depolarization increases neuronal excitability, leading to action potential firing and transmission of a noxious nerve impulse to the spinal cord. In addition, depolarization of the peripheral terminal can lead to release of inflammatory peptides such as, but not limited to, substance P and CGRP, leading to enhanced peripheral sensitization of tissue.

Recently, two groups have reported the generation of a "knock-out" mouse lacking the VR1 receptor. Electrophysiological studies of sensory neurons (dorsal root ganglia) from these animals revealed a marked absence of responses evoked by noxious stimuli including capsaicin, heat, and reduced pH. These animals did not display any overt signs of behavioral impairment and showed no differences in responses to acute non-noxious thermal and mechanical stimulation relative to wild-type mice. The VR1 (-l-) mice also did not show reduced sensitivity to nerve injury-induced mechanical or thermal nociceptin. However, the VR1 knock-out mice were insensitive to the noxious effects of intradermal capsaicin, exposure to intense heat (50-55.degree. C.), and failed to develop thermal hyperalgesia following the intradermal administration of carrageenan.

The compounds of the present invention are novel VR1 antagonists and have utility in treating pain, bladder overactivity, and urinary incontinence.

SUMMARY OF THE PRESENT INVENTION

The present invention discloses fused azabicyclic compounds, a method for inhibiting the VR1 receptor in mammals using these compounds, a method for controlling pain in mammals, and pharmaceutical compositions including those compounds. More particularly, the present invention is directed to compounds of formula (I) ##STR00002## or a pharmaceutically acceptable salt or prodrug thereof, wherein -- is absent or a single bond; X.sub.1 is selected from the group consisting of N and CR.sub.1; X.sub.2 is selected from the group consisting of N and CR.sub.2; X.sub.3 is selected from the group consisting of N, NR.sub.3, and CR.sub.3; X.sub.4 is a bond or selected from the group consisting of N and CR.sub.4; X.sub.5 is selected from the group consisting of N and C; provided that at least one of X.sub.1, X.sub.2, X.sub.3, and X.sub.4 is N; and provided that when X.sub.4 is a bond, one of X.sub.1, X.sub.2, or X.sub.3 must be N--H; Z.sub.1 is selected from the group consisting of OH, NH, and S; Z.sub.2 is a bond or selected from the group consisting of NH and O; L is selected from the group consisting of alkenylene, alkylene, alkynylene, ##STR00003## --(CH.sub.2).sub.mO(CH.sub.2).sub.n--, --N(H)O--, and --NHNH-- wherein the left end of --(CH.sub.2).sub.mO(CH.sub.2).sub.n-- and --N(H)O-- is attached to Z.sub.2 and the right end is attached to R.sub.9; provided that when Z.sub.2 is NH or O then L is other than --N(H)O-- or --NHNH--; m and n are each independently 1-6; R.sub.1, R.sub.3, R.sub.5, R.sub.6 and R.sub.7 are each independently selected from hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro, (CF.sub.3).sub.2(HO)C--, --NR.sub.AS(O).sub.2R.sub.B, --S(O).sub.2OR.sub.A, --S(O).sub.2R.sub.B, --NZ.sub.A.sub.Z.sub.B, (NZ.sub.AZ.sub.B)alkyl, (NZ.sub.AZ.sub.B)carbonyl, (NZ.sub.AZ.sub.B)carbonylalkyl and (NZ.sub.AZ.sub.B)sulfonyl, wherein Z.sub.A and Z.sub.B are each independently selected from hydrogen, alkyl, alkylcarbonyl, formyl, aryl and arylalkyl; R.sub.2 and R.sub.4 are each independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, alkylthio, alkynyl, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, ethylenedioxy, formyl, formylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, methylenedioxy, mercapto, mercaptoalkyl, nitro, (CF.sub.3).sub.2(HO)C--, --NR.sub.AS(O).sub.2R.sub.B, --S(O).sub.2OR.sub.A, --S(O).sub.2R.sub.B, --NZ.sub.AZ.sub.B, (NZ.sub.AZ.sub.B)alkyl, (NZ.sub.AZ.sub.B)alkylcarbonyl, (NZ.sub.AZ.sub.B)carbonyl, (NZ.sub.AZ.sub.B)carbonylalkyl, (NZ.sub.AZ.sub.B)sulfonyl, (NZ.sub.AZ.sub.B)C(.dbd.NH)--, (NZ.sub.AZ.sub.B)C(.dbd.NCN)NH--, and (NZ.sub.AZ.sub.B)C(.dbd.NH)NH--; R.sub.A is selected from hydrogen and alkyl; R.sub.B is selected from alkyl, aryl and arylalkyl; R.sub.8 is absent or selected from hydrogen and alkyl; provided that R.sub.8 is absent when X.sub.5 is CH.sub.2 and R.sub.8 is selected from hydrogen and alkyl when X.sub.5 is N; and R.sub.9 is selected from hydrogen, aryl and heterocycle.

DETAILED DESCRIPTION OF THE PRESENT INVENTION

In the principle embodiment, compounds of formula (I) are disclosed ##STR00004## or a pharmaceutically acceptable salt or prodrug thereof, wherein -- is absent or a covalent bond; X.sub.1 is selected from the group consisting of N and CR.sub.1; X.sub.2 is selected from the group consisting of N and CR.sub.2; X.sub.3 is selected from the group consisting of N, NR.sub.3, and CR.sub.3; X.sub.4 is a bond or selected from the group consisting of N and CR.sub.4; X.sub.5 is selected from the group consisting of N and C; provided that at least one of X.sub.1, X.sub.2, X.sub.3, and X.sub.4 is N; and provided that when X.sub.4 is a bond, one of X.sub.1, X.sub.2, or X.sub.3 must be N--H; Z.sub.1 is selected from the group consisting of O, NH, and S; Z.sub.2 is a bond or selected from the group consisting of NH and O; L is selected from the group consisting of alkenylene, alkylene, alkynylene, ##STR00005## --(CH.sub.2).sub.mO(CH.sub.2).sub.n--, --N(H)O--, and --NHNH-- wherein the left end of --(CH.sub.2).sub.mO(CH.sub.2).sub.n-- and --N(H)O-- is attached to Z.sub.2 and the right end is attached