Substituted diphenyl heterocycles useful for treating HCV infection Number:7,153,880 from the United States Patent and Trademark Office (PTO) owispatent The present invention relates to substituted diphenyl heterocycle compounds and pharmaceutical compositions thereof that inhibit replication of HCV virus. The present invention also relates to the use of the compounds and/or compositions to inhibit HCV replication and/or proliferation and to treat or prevent HCV infections.<H heterocycles, Substituted, Substituted, dip, 7153880.html, Patent, pto, 7153880

Title: Substituted diphenyl heterocycles useful for treating HCV infection

Abstract: The present invention relates to substituted diphenyl heterocycle compounds and pharmaceutical compositions thereof that inhibit replication of HCV virus. The present invention also relates to the use of the compounds and/or compositions to inhibit HCV replication and/or proliferation and to treat or prevent HCV infections.

Patent Number: 7,153,880 Issued on 12/26/2006 to Singh, et al.

Inventors: Singh; Rajinder (Belmont, CA), Goff; Dane (Redwood, CA), Lu; Henry (Foster City, CA), Issakani; Sarkiz D. (San Jose, CA), Sun; Thomas (Fremont, CA)
Assignee: Rigel Pharmaceuticals, Inc. (South San Francisco, CA)

Appl. No.: 10/873,914

Filed: June 22, 2004

Related U.S. Patent Documents


Application Number	Filing Date	Patent Number	Issue Date
10286017	Nov., 2002	6759538
60405472	Aug., 2002
60350107	Nov., 2001

Current U.S. Class: 514/378 ; 514/236.8; 544/137; 546/208; 548/240

Current International Class: A61K 31/415 (20060101); A61P 43/00 (20060101); C07D 207/02 (20060101)

Field of Search: 548/240 514/378

References Cited [Referenced By]

U.S. Patent Documents


2852503	September 1958	Edward et al.
3189447	June 1965	Neugebauer et al.
3257203	June 1966	Klupfel et al.
3335149	August 1967	Preston
3910942	October 1975	Narayanan et al.
3964896	June 1976	Neidermyer et al.
4087409	May 1978	Preston
4405793	September 1983	Fuchs et al.
4743521	May 1988	Hoffmann et al.
4752324	June 1988	Thomas et al.
4777258	October 1988	Sitzmann
5151441	September 1992	Mueller et al.
5256666	October 1993	Mueller et al.
5463071	October 1995	Himmelsbach et al.
5814627	September 1998	Schwab et al.
6355669	March 2002	Yamauchi et al.
6759538	July 2004	Singh et al.
2002/0035156	March 2002	Roniker et al.
2002/0049213	April 2002	Weidner-Wells et al.
2004/0142985	July 2004	Singh et al.

Foreign Patent Documents


392520	Oct., 1965	CH
559 195	Feb., 1975	CH
21 37 719	Feb., 1973	DE
27 21 955	Nov., 1978	DE
100 32 874	Jan., 2002	DE
563 686	Mar., 1993	EP
0 776 894	Jun., 1997	EP
0 927 992	Jul., 1999	EP
1 459 375	Apr., 1966	FR
02-146048	Jun., 1990	JP
03-122652	May., 1991	JP
04124178	Apr., 1992	JP
WO 93/17671	Sep., 1993	WO
WO 94/17059	Jun., 1994	WO
WO 95/24397	Sep., 1995	WO
WO 98/17652	Apr., 1998	WO
WO 98/47509	Oct., 1998	WO
WO 99/04390	Jan., 1999	WO
WO 99/20309	Apr., 1999	WO
WO 00/45799	Jan., 2000	WO
WO 00/40242	Jul., 2000	WO
WO 00/78726	Dec., 2000	WO
WO 02/20436	Mar., 2002	WO
WO 02/055025	Jul., 2002	WO
WO 03/040112	May., 2003	WO
WO 04/018463	Mar., 2004	WO
WO 04/103366	Dec., 2004	WO

Other References

Roth, et al., "Zur Kondensation von Chalkonoxyden mit Hydroxylamin," Arch. Pharm. 294, 769-774 (1961). cited by other .
Kazimierz Samula, "Oksymowanic Azachalkonow," Roczniki Chemll, Ann. Soc. Chim. Polonorum 45, 2063 (1971). cited by other .
Kazimierz Samula, "Cyclization of Azachalcones and .beta.-Hydroxyketones Oximes," Roczniki Chemll, Ann. Soc. Chim. Polonorum 48, 959-964 (1974). cited by other .
Robert K. Howe et al., "Nitrile Oxide Cycloaddition Routes to 2-(Isoxazol)-benzoates and 2-(1,2,4-Oxadiazol-3-yl)benzoates," Heterocycl. Chem. 19(4), 721-726 (1982). cited by other .
Elena Belgodere et al., "Studies on Isomeric Pyridylisoxazoles," Heterocycles, 20(3), 501-504 (1983). cited by other .
Sandor Batori et al., "Photoinduced Ring Transformation of Pyrido-[1,2-b]pyridazinium-4-olate," Tetrahedron, 50(16), 4699-4708 (1994). cited by other .
Takaki Kanbara et al., "Preparation of Soluble and Fluorescent Poly(arylene)s by 1,3-Dipolar Polycycloaddition and Properties of the Polymers," Polymer Bulleting, 36, 673-679 (1996). cited by other .
Yi-Yin Ku et al., "Use of Iodoacetylene as a Dipolarphilc in the Synthesis of 5-Iodoisxazole Derivatives," Organic Letters, 3(26), 4185-4187 (2001). cited by other .
Maybridge, plc, Trevillett, Tintagel, Catalog N. RF01996, Cornwall PL34 OHW, England. cited by other .
Maybridge, plc, Trevillett, Tintagel, Catalog N. RF01972, Cornwall PL34 OWH, England. cited by other .
Gatta et al. Synthesis of [1,2,4] Triazoloquinazoline and [1,2,4] Triazolo- 1,4-benzodiazepine derivatives. Journal of Heterocyclic Chemistry. (1993), vol. 30, pp. 11-16. cited by other .
Database Chemcats Online! 1999m XP-002310049, Databased accession No. RN 247059-16-1. cited by other .
Maybridge Hts, Order No. BTB 09742; RN 247059-16-1 Maybridge PLC, Trevillett, Tintagel, Cornwall, PL340HW, UK, Jan. 8, 2004 XP002297442. cited by other .
STN File CA, Abstract 135:46129 & V.M. Barot et al, Asian Journal of Chemistry (2001), 13(1), pp. 341-343. cited by other .
STN File CA, Abstract 132:265141 & S.V. Damle et al, Indian Journal of Heterocyclic Chemistry (1999), 9(2), pp. 81-86. cited by other .
STN File CA, Abstract 132:180505 & V.R. Naik et al, Asian Journal of Chemistry (2000), 12(1), pp. 305-307. cited by other .
STN File CA, Abstract 129:216539 & S.M. Naik et al, Oriental Journal of Chemistry (1998), 14(1), pp. 167-168. cited by other .
STN File CA, Abstract 126:74789 & M. Shah et al, Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry (1996), 35B(12), pp. 1282-1286. cited by other .
STN File CA, Abstract 122:81186 & S.R. Modi et al, Oriental Journal of Chemistry (1994), 10(1), pp. 85-86. cited by other .
STN File CA, Abstract 118:191597 & T. Bandiera et al, Journal of Heterocyclic Chemistry (1992), 29(6), pp. 1423-1428. cited by other.

Primary Examiner: Saeed; Kamal A.
Attorney, Agent or Firm: McDonnell Boehnen Hulbert & Berghoff LLP

Parent Case Text

1. CROSS-REFERENCES TO RELATED APPLICATIONS

This application claims benefit under 35 U.S.C. .sctn. 119(e) to U.S. Provisional Application Ser. No. 60/350,107, filed Nov. 2, 2001 and U.S. Provisional Application Ser. No. 60/405,472, filed Aug. 23, 2002 and is a divisional application of U.S. Ser. No. 10/286,017, filed Nov. 1, 2002 now U.S. Pat. No. 6,759,538.

Claims

What is claimed is:

1. An intermediate compound useful for synthesizing substituted diphenyl heterocycle compounds, said intermediate compound having a structure defined by structural formula (II): ##STR00035## including the pharmaceutically acceptable salts, hydrates, solvates, N-oxides and prodrugs thereof, wherein: X and Y are each, independently of one another, N or O , provided that X and Y are not both O and are not both N; Z is --CH; R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are each, independently of one another, selected from the group consisting of hydrogen, --OH, --SH, --CN, --NO.sub.2, halo, fluoro, chloro, bromo, iodo, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, lower haloalkyl, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, lower alkylthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, methoxy, substituted methoxy, lower heteroalkoxy, substituted lower heteroalkoxy, cycloalkoxy, substituted cycloalkoxy, lower haloalkoxy, monohalomethoxy, dihalomethoxy, trihalomethoxy, trifluoromethoxy, amino, lower di- or monoalkylamino, substituted lower di- or monoalkylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, phenoxy, substituted phenoxy, arylalkyl, substituted arylalkyl, arylalkyloxy, substituted arylalkyloxy, benzyl, benzyloxy, carboxyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, carbamate, substituted carbamate, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl and a group of the formula -L-R.sup.4, where "L" is a linker and R.sup.14 is cycloalkyl, substituted cycloalkyl, provided that at least one of R.sup.2 or R.sup.6 is other than hydrogen; R.sup.6 is selected from the group consisting of hydrogen, --OH, --SR, --CN, --NO.sub.2 halo, fluoro, chloro, bromo, iodo, lower alkyl, substituted lower alkyl, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, lower haloalkyl, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, lower alkylthio, substituted lower alkylthio, lower alkoxy, substituted lower alkoxy, methoxy, substituted methoxy, lower heteroalkoxy, substituted lower heteroalkoxy, cycloalkoxy, substituted cycloalkoxy, cycloheteroalkoxy, substituted cycloheteroalkoxy, lower haloalkoxy, monohalomethoxy, dihalomethoxy, trihalomethoxy, trifluoromethoxy, amino, lower di- or monoalkylamino, substituted lower di- or monoalkylamino, aryl, substituted and, aryloxy, substituted aryloxy, phenoxy, substituted phenoxy, arylalkyl, substituted arylalkyl, arylalkyloxy, substituted arylalkyloxy, benzyl, benzyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylalkyl, substituted heteroarylalkyl, heteroarylalkyloxy, substituted heteroarylalkyloxy, carboxyl, lower alkoxycarbonyl, substituted lower alkoxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, arylalkyloxycarbonyl, substituted arylalkyloxycarbonyl, carbamate, substituted carbamate, carbamoyl, substituted carbamoyl, sulfamoyl, substituted sulfamoyl and a group of the formula -L-R.sup.14', where "L" is a linker and R.sup.14' is cycloalkyl, substituted cycloalkyl, cycloheteroalkyl or substituted cycloheteroalkyl; and R.sup.15 is NO.sub.2 or NHR, where R is hydrogen, lower alkyl or a protecting group, or a protected analog of the compound of structural formula (II).

2. The compound of claim 1 in which X is O and Y is N.

3. The compound of claim 1 in which X is N and Y is O.

4. The compound of any one of claims 1, and 2 3 in which R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are each hydrogen.

5. The compound of any one of claims 1, and 2 3 in which R.sup.3 and R.sup.5 are each hydrogen.

6. The compound of claim 5 in which R.sup.4 is -L-R.sup.14.

7. The compound of claim 6 in which L is --O--(CH.sub.2).sub.1-3.

8. The compound of any one of claims 1, and 2 3 in which R.sup.3, R.sup.4 and R.sup.5 are each hydrogen.

9. The compound of claim 8 in which R.sup.6 is selected from the group consisting of --OH, --NO.sub.2, halo, fluoro, chloro, bromo, iodo, lower alkyl, methyl, lower heteroalkyl, (C3 C6) cycloalkyl, 5- or 6-membered cycloheteroalkyl, N-morpholinyl, N-methyl-N-piperazinyl, N-piperadinyl, substituted N-piperadinyl, 4-(N-piperadinyl)-N-piperadinyl, 4-amino-N-piperadinyl, lower alkoxy, methoxy, ethoxy, lower alkylthio, methylthio, lower haloalkyl, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, lower haloalkyloxy, monohalomethoxy, dihalomethoxy, trihalomethoxy, trifluoromethoxy, aryl, phenyl, arylalkyl, benzyl, aryloxy, phenoxy, arylalkyloxy, benzyloxy, 5- or 6-membered heteroaryl, lower alkyloxycarbonyl, sulfamoyl and -L-R.sup.14', where L is --(CH.sub.2).sub.1-3-- or --O--(CH.sub.2).sub.1-3-- and R.sup.14' is a 5- or 6-membered cycloheteroalkyl or N-morpholinyl.

10. The compound of claim 1 in which R.sup.2 is selected from the group consisting of Cl, F, Me, --CF.sub.3, --OCHF.sub.2, I, Br, --OEt, -iPr, --OCF.sub.3, --C(O)OMe, --O-iPr, Ph, ##STR00036## and COOH; R.sup.3 is selected from the group consisting of H, Cl, Me, --C(O)OMe, and COOH; R.sup.4 is selected from the group consisting of H, Cl, --N(Me.sub.2, Me and; R.sup.5 is selected from the group consisting of H, Me, Cl, F and --CF.sub.3; R.sup.6 is selected from the group consisting of H, Cl, ##STR00037## --SMe, ##STR00038## F, Me, OH, iPr, --OMe, ##STR00039## R.sup.8 is selected from the group consisting of F, H, Me, and --OMe; R.sup.9 is H; R.sup.10 is selected from the group consisting of H, F, and --OMe; and R.sup.13 is selected from the group consisting of H and Me.

11. The compound of claim 10 in which the heterocyclic "B" ring is a isoxazole analog or regioisomer thereof.

12. A composition comprising a pharmaceutically acceptable vehicle and a compound according to claim 1.

13. The composition of claim 12 which is a liposome suspension.

14. The composition of claim 13 which comprises from about 0.5 30 mg/ml of the compound and about 100 200 mg/ml of a phospholipid in water.

15. The composition of claim 14 which further includes about 5 mg/ml of cholesterol.

Description

2. FIELD OF INVENTION

The present invention relates to substituted diphenyl heterocycles and compositions thereof useful for treating or preventing Hepatitis C virus (HCV) infections. In particular, the present invention relates to substituted diphenyl isoxazole, pyrazole and oxadiazole compounds, compositions comprising the compounds and the use of such compounds and compositions to inhibit HCV replication and/or proliferation as a therapeutic approach towards the treatment and/or prevention of HCV infections in humans and animals.

3. BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) infection is a global human health problem with approximately 150,000 new reported cases each year in the United States alone. HCV is a single stranded RNA virus, which is the etiological agent identified in most cases of non-A, non-B post-transfusion and post-transplant hepatitis and is a common cause of acute sporadic hepatitis (Choo et al., Science 244:359, 1989; Kuo et al., Science 244:362, 1989; and Alter et al., in Current Perspective in Hepatology, p. 83, 1989). It is estimated that more than 50% of patients infected with HCV become chronically infected and 20% of those develop cirrhosis of the liver within 20 years (Davis et al., New Engl. J. Med. 321:1501, 1989; Alter et al., in Current Perspective in Hepatology, p. 83, 1989; Alter et al., New Engl. J. Med. 327:1899, 1992; and Dienstag Gastroenterology 85:430, 1983). Moreover, the only therapy available for treatment of HCV infection is interferon-.alpha. (INTRON.RTM. A, PEG-INTRON.RTM. A, Schering-Plough; ROFERON-A.RTM., PEGASys.RTM., Roche). Most patients are unresponsive, however, and among the responders, there is a high recurrence rate within 6 12 months after cessation of treatment (Liang et al., J. Med. Virol. 40:69, 1993). Ribavirin, a guanosine analog with broad spectrum activity against many RNA and DNA viruses, has been shown in clinical trials to be effective against chronic HCV infection when used in combination with interferon-.alpha. (see, e.g., Poynard et al., Lancet 352:1426 1432, 1998; Reichard et al., Lancet 351:83 87, 1998), and this combination therapy has been recently approved (REBETRON, Schering-Plough; see also Fried et al., 2002, N. Engl. J. Med. 347:975 982). However, the response rate is still at or below 50%. Therefore, additional compounds for treatment and prevention of HCV infection are needed.

4. SUMMARY OF THE INVENTION

In one aspect, the present invention provides substituted diphenyl heterocycles that are potent inhibitors of Hepatitis C virus ("HCV") replication and/or proliferation. In one embodiment, the compounds are substituted diphenyl isoxazole, pyrazole and/or oxadiazole compounds according to structural formula (I):

##STR00001## where Z is CH (isoxazoles, or pyrazoles) or N (oxadiazoles) and X and Y are each, independently of one another, O and N, provided that: (i) X and Y are not both O and (ii) when X and Y are each N, then Z is CH. The "A" phenyl ring includes at least one, and in many instances two, substituents positioned ortho to the point of attachment (R.sup.2 and/or R.sup.6) and optionally from 1 to 4 additional substituents, which may be the same or different. Although the "A" ring may include a single ortho (R.sup.2 or R.sup.6) substituent, compounds which include two ortho substituents (R.sup.2 and R.sup.6) are particularly active and useful. It is preferable that at least one of the substituent groups at positions R.sup.2 and/or R.sup.6 provide some steric bulk. For example, it is preferable that the R.sup.2 and/or R.sup.6 substituent be larger than a fluoro group.

The nature of the R.sup.2 and/or R.sup.6 substituents, as well as the optional substituents at positions R.sup.3, R.sup.4 and R.sup.5, can vary widely. As a consequence, the "A" phenyl ring may be substituted with virtually any substituent groups, provided that at least one of R.sup.2 or R.sup.6 is other than hydrogen. When the "A" phenyl ring includes more than one substituent, the substituents may be the same or different. Typical substituent groups useful for substituting the "A" ring include, but are not limited to, branched, straight-chain or cyclic alkyls, mono- or polycyclic aryls, branched, straight-chain or cyclic heteroalkyls, mono- or polycyclic heteroaryls, halos, branched, straight-chain or cyclic haloalkyls, hydroxyls, oxos, thioxos, branched, straight-chain or cyclic alkoxys, branched, straight-chain or cyclic haloalkoxys, trifluoromethoxys, mono- or polycyclic aryloxys, mono- or polycyclic heteroaryloxys, ethers, alcohols, sulfides, thioethers, sulfanyls (thiols), imines, azos, azides, amines (primary, secondary and tertiary), nitriles (any isomer), cyanates (any isomer), thiocyanates (any isomer), nitrosos, nitros, diazos, sulfoxides, sulfonyls, sulfonic acids, sulfamides, sulfonamides, sulfamic esters, aldehydes, ketones, carboxylic acids, esters, amides, amidines, formadines, amino acids, acetylenes, carbamates, lactones, lactams, glucosides, gluconurides, sulfones, ketals, acetals, thioketals, oximes, oxamic acids, oxamic esters, etc., and combinations of these groups.

These substituent groups may be further substituted at one or more available carbon or heteroatoms with the same or different additional substituents, which may be selected from the substituents described above. Any reactive functionalities in the groups used to substituted the "A" phenyl ring may be masked with a protecting group or a progroup, as is well-known in the art.

The substituent groups may be attached directly to the phenyl ring, or they may be spaced away from the ring by way of a linker. The nature of the linker can vary widely, and can include virtually any combination of atoms or groups useful for spacing one molecular moiety from another. For example, the linker may be an acyclic hydrocarbon bridge (e.g, a saturated or unsaturated alkyleno such as methano, ethano, etheno, propano, prop[1]eno, butano, but[1]eno, but[2]eno, buta[1,3]dieno, and the like), a monocyclic or polycyclic hydrocarbon bridge (e.g., [1,2]benzeno, [2,3]naphthaleno, and the like), a simple acyclic heteroatomic or heteroalkyldiyl bridge (e.g., --O--, --S--, --S--O--, --NH--, --PH--, --C(O)--, --C(O)NH--, --S(O)--, --S(O).sub.2--, --S(O)NH--, --S(O).sub.2NH--, --O--CH.sub.2--, --CH.sub.2--O--CH.sub.2--, --O--CH.dbd.CH--CH.sub.2--, and the like), a monocyclic or polycyclic heteroaryl bridge (e.g., [3,4]furano, pyridino, thiopheno, piperidino, piperazino, pyrizidino, pyrrolidino, and the like) or combinations of such bridges. In one embodiment, the "A" ring is substituted at both R.sup.2 and R.sup.6 with the same or different halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, methoxy, haloalkyl, trifluoromethyl, 5 6 membered cycloheteroalkyl or substituted 5 6 membered cycloheteroalkyl group.

The "C" ring is substituted at the meta position with a group of the formula --NR.sup.11C(O)R.sup.12, where R.sup.11 is hydrogen or lower alkyl and R.sup.12 is monohalomethyl or dihalomethyl. The "C" ring may optionally include from 1 to 4 additional substituents (R.sup.8, R.sup.9, R.sup.10 and/or R.sup.13), which may be the same or different. As for the "A" phenyl ring, the nature of the optional R.sup.8, R.sup.9, R.sup.10 and R.sup.13 substituents can vary broadly. Groups useful for substituting the "C" phenyl ring are the same as those described for the "A" phenyl ring, supra. In one embodiment, the "C" ring does not include optional substituents, such that R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are each hydrogen.

As will be recognized by skilled artisans, the actual electron distribution or double bonding pattern of the "B" ring will depend upon the identities of substituents X and Y. As illustrated, structural formula (I) is specifically intended to include at least the following six structures:

##STR00002## ##STR00003##

In another aspect, the invention provides starting and intermediate compounds useful for synthesizing the compounds of the invention. Representative starting and intermediate compounds useful for synthesizing isoxazole and pyrazole compounds of the invention include compounds 201, 203, 205, 207, 209, 223, 225, 227, 229, 231, 245, 247, 248a, 248b, 249, 257 and 259 as depicted in FIGS. 1 7. Representative starting and intermediate compounds useful for synthesizing oxadiazole compounds of the invention include compounds 265, 267, 269, 271, 285, 287 and 289 as depicted in FIGS. 1 7.

In one embodiment, the intermediates are compounds according to structural formula (II):

##STR00004## wherein R.sup.15 is NO.sub.2 or NHR, where R is hydrogen, lower alkyl or a protecting group and X, Y, Z, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.8, R.sup.9, R.sup.10 and R.sup.13 are as previously defined for structural formula (I) and subject to the same provisos. Like the compounds of structural formula (I), in the compounds of structural formula (II) the double bonding pattern will depend upon the identities of substituents X and Y.

In another aspect, the invention provides methods of making the substituted diphenyl heterocycle compounds of structural formula (I) or (II). Specific exemplary embodiments of the methods are illustrated in FIGS. 1 7. In one embodiment, the method for synthesizing compounds according to structural formula (I) comprises optionally alkylating a compound according to structural formula (II) in which R.sup.15 is NHR with an alkylating agent (e.g., R.sup.11-halide) followed by optional deprotection and acylation with an acylating agent of the formula LG-C(O)--R.sup.12, where "LG" represents a leaving group or an activating group and R.sup.12 is as previously defined in connection with the compounds of formula (I).

In another aspect, the present invention provides compositions comprising the compounds of the invention. The compositions generally comprise a substituted diphenyl isoxazole, pyrazole or oxadiazole of the invention, or a salt, hydrate, solvate, N-oxide or prodrug thereof and a suitable excipient, carrier or diluent. The composition may be formulated for veterinary uses or for use in humans.

The compounds of the invention are potent inhibitors of HCV replication and/or proliferation. Accordingly, in still another aspect, the present invention provides methods of inhibiting HCV replication and/or proliferation, comprising contacting a Hepatitis C virion with an amount of a compound or composition of the invention effective to inhibit its replication or proliferation. The methods may be practiced either in vitro or in vivo, and may be used as a therapeutic approach towards the treatment and/or prevention of HCV infections.

In a final aspect, the present invention provides methods of treating and/or preventing HCV infections. The methods generally involve administering to a subject that has an HCV infection or that is at risk of developing an HCV infection an amount of a compound or composition of the invention effective to treat or prevent the HCV infection. The method may be practiced in animals in veterinary contexts or in humans.

5. BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 7 provide exemplary synthetic schemes for synthesizing the compounds of the invention.

6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

6.1 Definitions

As used herein, the following terms are intended to have the following meanings:

"Alkyl," by itself or as part of another substituent, refers to a saturated or unsaturated, branched, straight-chain or cyclic monovalent hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane, alkene or alkyne. Typical alkyl groups include, but are not limited to, methyl; ethyls such as ethanyl, ethenyl, ethynyl; propyls such as propan-1-yl, propan-2-yl, cyclopropan-1-yl, prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), cycloprop-1-en-1-yl; cycloprop-2-en-1-yl, prop-1-yn-1-yl , prop-2-yn-1-yl, etc.; butyls such as butan-1-yl, butan-2-yl, 2-methyl-propan-1-yl, 2-methyl-propan-2-yl, cyclobutan-1-yl, but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1 ,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

The term "alkyl" is specifically intended to include groups having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions "alkanyl," "alkenyl," and "alkynyl" are used. Preferably, an alkyl group comprises from 1 to 15 carbon atoms (C.sub.1 C.sub.15 alkyl), more preferably from 1 to 10 carbon atoms (C.sub.1 C.sub.10 alkyl) and even more preferably from 1 to 6 carbon atoms (C.sub.1 C.sub.6 alkyl or lower alkyl).

"Alkanyl," by itself or as part of another substituent, refers to a saturated branched, straight-chain or cyclic alkyl radical derived by the removal of one hydrogen atom from a single carbon atom of a parent alkane. Typical alkanyl groups include, but are not limited to, methanyl; ethanyl; propanyls such as propan-1-yl, propan-2-yl (isopropyl), cyclopropan-1-yl, etc.; butanyls such as butan-1-yl, butan-2-yl (sec-butyl), 2-methyl-propan-1-yl (isobutyl), 2-methyl-propan-2-yl (t-butyl), cyclobutan-1-yl, etc.; and the like.

"Alkenyl," by itself or as part of another substituent, refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon double bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkene. The group may be in either the cis or trans conformation about the double bond(s). Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl, cycloprop-1-en-1-yl; cycloprop-2-en-1-yl ; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl, cyclobut-1-en-1-yl, cyclobut-1-en-3-yl, cyclobuta-1,3-dien-1-yl, etc.; and the like.

"Alkynyl," by itself or as part of another substituent refers to an unsaturated branched, straight-chain or cyclic alkyl radical having at least one carbon-carbon triple bond derived by the removal of one hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl, etc.; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl, etc.; and the like.

"Alkyldiyl" by itself or as part of another substituent refers to a saturated or unsaturated, branched, straight-chain or cyclic divalent hydrocarbon group derived by the removal of one hydrogen atom from each of two different carbon atoms of a parent alkane, alkene or alkyne, or by the removal of two hydrogen atoms from a single carbon atom of a parent alkane, alkene or alkyne. The two monovalent radical centers or each valency of the divalent radical center can form bonds with the same or different atoms. Typical alkyldiyl groups include, but are not limited to, methandiyl; ethyldiyls such as ethan-1,1-diyl, ethan-1,2-diyl, ethen-1,1-diyl, ethen-1,2-diyl; propyldiyls such as propan-1,1-diyl, propan-1,2-diyl, propan-2,2-diyl, propan-1,3-diyl, cyclopropan-1,1-diyl, cyclopropan-1,2-diyl, prop-1-en-1,1-diyl, prop-1-en-1,2-diyl, prop-2-en-1,2-diyl, prop-1-en-1,3-diyl, cycloprop-1-en-1,2-diyl, cycloprop-2-en-1,2-diyl, cycloprop-2-en-1,1-diyl, prop-1-yn-1,3-diyl, etc.; butyldiyls such as, butan-1,1-diyl, butan-1,2-diyl, butan-1,3-diyl, butan-1,4-diyl, butan-2,2-diyl, 2-methyl-propan-1,1-diyl, 2-methyl-propan-1,2-diyl, cyclobutan-1,1-diyl; cyclobutan-1,2-diyl, cyclobutan-1,3-diyl, but-1-en-1,1-diyl, but-1-en-1,2-diyl, but-1-en-1,3-diyl, but-1-en-1,4-diyl, 2-methyl-prop-1-en-1,1-diyl, 2-methanylidene-propan-1,1-diyl, buta-1,3-dien-1,1-diyl, buta-1,3-dien-1,2-diyl, buta-1,3-dien-1,3-diyl, buta-1,3-dien-1,4-diyl, cyclobut-1en-1,2-diyl, cyclobut-1-en-1,3-diyl, cyclobut-2-en-1,2-diyl, cyclobuta-1,3-dien-1,2-diyl, cyclobuta-1,3-dien-1,3-diyl, but-1-yn-1,3-diyl, but-1-yn-1,4-diyl, buta-1,3-diyn-1,4-diyl, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkanyldiyl, alkenyldiyl and/or alkynyldiyl is used. Where it is specifically intended that the two valencies are on the same carbon atom, the nomenclature "alkylidene" is used. In preferred embodiments, the alkyldiyl group comprises from 1 to 6 carbon atoms (C1 C6 alkyldiyl). Also preferred are saturated acyclic alkanyldiyl groups in which the radical centers are at the terminal carbons, e.g., methandiyl (methano); ethan-1,2-diyl (ethano); propan-1,3-diyl (propano); butan-1,4-diyl (butano); and the like (also referred to as alkylenos, defined infra).

"Alkyleno," by itself or as part of another substituent, refers to a straight-chain saturated or unsaturated alkyldiyl group having two terminal monovalent radical centers derived by the removal of one hydrogen atom from each of the two terminal carbon atoms of straight-chain parent alkane, alkene or alkyne. The locant of a double bond or triple bond, if present, in a particular alkyleno is indicated in square brackets. Typical alkyleno groups include, but are not limited to, methano; ethylenos such as ethano, etheno, ethyno; propylenos such as propano, prop[1]eno, propa[1,2]dieno, prop[1]yno, etc.; butylenos such as butano, but[1]eno, but[2]eno, buta[1,3]dieno, but[1]yno, but[2]yno, buta[1,3]diyno, etc.; and the like. Where specific levels of saturation are intended, the nomenclature alkano, alkeno and/or alkyno is used. In preferred embodiments, the alkyleno group is (C1 C6) or (C1 C3) alkyleno. Also preferred are straight-chain saturated alkano groups, e.g., methano, ethano, propano, butano, and the like.

"Alkoxy," by itself or as part of another substituent, refers to a radical of the formula --OR, where R is an alkyl or cycloalkyl group as defined herein. Representative examples alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy and the like.

"Alkoxycarbonyl," by itself or as part of another substituent, refers to a radical of the formula --C(O)-alkoxy, where alkoxy is as defined herein.

"Alkylthio," by itself or as part of another substituent, refers to a radical of the formula --SR, where R is an alkyl or cycloalkyl group as defined herein. Representative examples of Alkylthio groups include, but are not limited to, methylthio, ethylthio, propylthio, isopropylthio, butylthio tert-butylthio, cyclopropylthio, cyclopentylthio, cyclohexylthio, and the like.

"Aryl," by itself or as part of another substituent, refers to a monovalent aromatic hydrocarbon group derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system, as defined herein. Typical aryl groups include, but are not limited to, groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like. Preferably, an aryl group comprises from 6 to 20 carbon atoms (C.sub.6 C.sub.20 aryl), more preferably from 6 to 15 carbon atoms (C.sub.6 C.sub.15 aryl) and even more preferably from 6 to 10 carbon atoms (C.sub.6 C.sub.10 aryl).

"Arylalkyl," by itself or as part of another substituent, refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp.sup.3 carbon atom, is replaced with an aryl group as, as defined herein. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, 2-phenylethen-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, 2-naphthylethen-1-yl, naphthobenzyl, 2-naphthophenylethan-1-yl and the like. Where specific alkyl moieties are intended, the nomenclature arylalkanyl, arylalkenyl and/or arylalkynyl is used. Preferably, an arylalkyl group is (C.sub.6 C.sub.30) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C.sub.1 C.sub.10) alkyl and the aryl moiety is (C.sub.6 C.sub.20) aryl, more preferably, an arylalkyl group is (C.sub.6 C.sub.20) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C.sub.1 C.sub.8) alkyl and the aryl moiety is (C.sub.6 C.sub.12) aryl, and even more preferably, an arylalkyl group is (C.sub.6 C.sub.15) arylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the arylalkyl group is (C.sub.1 C.sub.5) alkyl and the aryl moiety is (C.sub.6 C.sub.10) aryl.

"Aryloxy," by itself or as part of another substituent, refers to a radical of the formula --O-aryl, where aryl is as defined herein.

"Arylalkyloxy, by itself or as part of another substituent, refers to a radical of the formula --O-arylalkyl, where arylalkyl is as defined herein.

"Aryloxycarbonyl," by itself or as part of another substituent, refers to a radical of the formula --C(O)--O-aryl, where aryl is as defined herein.

"Carbamoyl," by itself or as part of another substituent, refers to a radical of the formula --C(O)NR'R'', where R' and R'' are each, independently of one another, selected from the group consisting of hydrogen, alkyl and cycloalkyl as defined herein, or alternatively, R' and R'', taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered cycloheteroalkyl ring as defined herein, which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, S and N.

"Compounds of the invention" refers to compounds encompassed by the various descriptions and structural formulae disclosed herein. The compounds of the invention may be identified by either their chemical structure and/or chemical name. When the chemical structure and chemical name conflict, the chemical structure is determinative of the identity of the compound. The compounds of the invention may contain one or more chiral centers and/or double bonds and therefore may exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), rotamers, enantiomers or diastereomers. Accordingly, when stereochemistry at chiral centers is not specified, the chemical structures depicted herein encompass all possible configurations at those chiral centers including the stereoisomerically pure form (e.g., geometrically pure, enantiomerically pure or diastereomerically pure) and enantiomeric and stereoisomeric mixtures. Enantiomeric and stereoisomeric mixtures can be resolved into their component enantiomers or stereoisomers using separation techniques or chiral synthesis techniques well known to the skilled artisan. The compounds of the invention may also exist in several tautomeric forms including the enol form, the keto form and mixtures thereof. Accordingly, the chemical structures depicted herein encompass all possible tautomeric forms of the illustrated compounds. The compounds of the invention may also include isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass conventionally found in nature. Examples of isotopes that may be incorporated into the compounds of the invention include, but are not limited to, .sup.2H, .sup.3H, .sup.11C, .sup.13C, .sup.14C, .sup.15N, .sup.18O, .sup.17O, .sup.31P, .sup.32P, .sup.35S, .sup.18F and .sup.36Cl. Compounds of the invention may exist in unsolvated forms as well as solvated forms, including hydrated forms and as N-oxides. In general, the hydrated, solvated and N-oxide forms are within the scope of the present invention. Certain compounds of the present invention may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.

"Cycloalkyl," by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical, as defined herein. Where a specific level of saturation is intended, the nomenclature "cycloalkanyl" or "cycloalkenyl" is used. Typical cycloalkyl groups include, but are not limited to, groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. Preferably, the cycloalkyl group comprises from 3 to 10 ring atoms (C.sub.3 C.sub.10 cycloalkyl) and more preferably from 3 to 7 ring atoms (C.sub.3 C.sub.7 cycloalkyl).

"Cycloheteroalkyl," by itself or as part of another substituent, refers to a saturated or unsaturated cyclic alkyl radical in which one or more carbon atoms (and optionally any associated hydrogen atoms) are independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atom(s) include, but are not limited to, N, P, O, S, Si, etc. Where a specific level of saturation is intended, the nomenclature "cycloheteroalkanyl" or "cycloheteroalkenyl" is used. Typical cycloheteroalkyl groups include, but are not limited to, groups derived from epoxides, azirines, thiiranes, imidazolidine, morpholine, piperazine, piperidine, pyrazolidine, pyrrolidone, quinuclidine, and the like. Preferably, the cycloheteroalkyl group comprises from 3 to 10 ring atoms (3 10 membered cycloheteroalkyl) and more preferably from 5 to 7 ring atoms (5 7 membered cycloheteroalkyl).

A cycloheteroalkyl group may be substituted at a heteroatom, for example, a nitrogen atom, with a lower alkyl group. As specific examples, N-methyl-imidazolidinyl, N-methyl-morpholinyl, N-methyl-piperazinyl, N-methyl-piperidinyl, N-methyl-pyrazolidinyl and N-methyl-pyrrolidinyl are included within the definition of "cycloheteroalkyl." A cycloheteralkyl group may be attached to the remainder of the molecule via a ring carbon atom or a ring heteroatom.

"Dialkylamino" or "Monoalkylamino," by themselves or as part of other substituents, refer to radicals of the formula --NRR and --NHR, respectively, where each R is independently selected from the group consisting of alkyl and cycloalkyl, as defined herein. Representative examples of dialkylamino groups include, but are not limited to, dimethylamino, methylethylamino, di-(1-methylethyl)amino, (cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino, (cyclohexyl)(propyl)amino and the like. Representative examples of monalkylamino groups include, but are not limited to, methylamino, ethylamino, propylamino, isopropylamino, cyclohexylamino, and the like.

"Halogen" or "Halo," by themselves or as part of another substituent, refer to a fluoro, chloro, bromo and/or iodo radical.

"Haloalkyl," by itself or as part of another substituent, refers to an alkyl group as defined herein in which one or more of the hydrogen atoms is replaced with a halo group. The term "haloalkyl" is specifically meant to include monohaloalkyls, dihaloalkyls, trihaloalkyls, etc. up to perhaloalkyls. The halo groups substituting a haloalkyl can be the same, or they can be different. For example, the expression "(C.sub.1 C.sub.2) haloalkyl" includes 1-fluoromethyl, 1-fluoro-2-chloroethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl, etc.

"Haloalkyloxy," by itself or as part of another substituent, refers to a group of the formula --O-haloalkyl, where haloalkyl is as defined herein.

"Heteroalkyl," "Heteroalkanyl," "Heteroalkenyl," "Heteroalkynyl," "Heteroalkyldiyl" and "Heteroalkyleno," by themselves or as part of other substituents, refer to alkyl, alkanyl, alkenyl, alkynyl, alkyldiyl and alkyleno groups, respectively, in which one or more of the carbon atoms (and optionally any associated hydrogen atoms), are each, independently of one another, replaced with the same or different heteroatoms or heteroatomic groups. Typical heteroatoms or heteroatomic groups which can replace the carbon atoms include, but are not limited to, O, S, N, Si, --NH--, --S(O)--, --S(O).sub.2--, --S(O)NH--, --S(O).sub.2NH-- and the like and combinations thereof. The heteroatoms or heteroatomic groups may be placed at any interior position of the alkyl, alkenyl or alkynyl groups. Examples of such heteroalkyl, heteroalkanyl, heteroalkenyl and/or heteroalkynyl groups include --CH.sub.2--CH.sub.2--O--CH.sub.3, --CH.sub.2--CH.sub.2--NH--CH.sub.3, --CH.sub.2--CH.sub.2--N(CH.sub.3)--CH.sub.3, --CH.sub.2--S--CH.sub.2,--CH.sub.3, --CH.sub.2--CH.sub.2--S(O)--CH.sub.3, --CH.sub.2--CH.sub.2--S(O).sub.2--CH.sub.3, --CH.dbd.CH--O--CH.sub.3, --CH.sub.2--CH.dbd.N--O--CH.sub.3, and --CH.sub.2--CH.sub.2--O--C.dbd.CH. For heteroalkyldiyl and heteroalkyleno groups, the heteratom or heteratomic group can also occupy either or both chain termini. For such groups, no orientation of the group is implied.

"Heteroaryl," by itself or as part of another substituent, refers to a monovalent heteroaromatic radical derived by the removal of one hydrogen atom from a single atom of a parent heteroaromatic ring systems, as defined herein. Typical heteroaryl groups include, but are not limited to, groups derived from acridine, .beta.-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene, and the like. Preferably, the heteroaryl group comprises from 5 to 20 ring atoms (5 20 membered heteroaryl), more preferably from 5 to 10 ring atoms (5 10 membered heteroaryl). Preferred heteroaryl groups are those derived from furan, thiophene, pyrrole, benzothiophene, benzofuran, benzimidazole, indole, pyridine, pyrazole, quinoline, imidazole, oxazole, isoxazole and pyrazine.

"Heteroarylalkyl" by itself or as part of another substituent refers to an acyclic alkyl group in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp.sup.3 carbon atom, is replaced with a heteroaryl group. Where specific alkyl moieties are intended, the nomenclature heteroarylalkanyl, heteroarylakenyl and/or heteroarylalkynyl is used. In preferred embodiments, the heteroarylalkyl group is a 6 21 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety of the heteroarylalkyl is (C1 C6) alkyl and the heteroaryl moiety is a 5 15-membered heteroaryl. In particularly preferred embodiments, the heteroarylalkyl is a 6 13 membered heteroarylalkyl, e.g., the alkanyl, alkenyl or alkynyl moiety is (C1 C3) alkyl and the heteroaryl moiety is a 5 10 membered heteroaryl.

"Parent Aromatic Ring System" refers to an unsaturated cyclic or polycyclic ring system having a conjugated .pi. electron system. Specifically included within the definition of "parent aromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, fluorene, indane, indene, phenalene, etc. Typical parent aromatic ring systems include, but are not limited to, aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene and the like.

"Parent Heteroaromatic Ring System" refers to a parent aromatic ring system in which one or more carbon atoms (and optionally any associated hydrogen atoms) are each independently replaced with the same or different heteroatom. Typical heteroatoms to replace the carbon atoms include, but are not limited to, N, P, O, S, Si, etc. Specifically included within the definition of "parent heteroaromatic ring system" are fused ring systems in which one or more of the rings are aromatic and one or more of the rings are saturated or unsaturated, such as, for example, benzodioxan, benzofuran, chromane, chromene, indole, indoline, xanthene, etc. Typical parent heteroaromatic ring systems include, but are not limited to, arsindole, carbazole, .beta.-carboline, chromane, chromene, cinnoline, furan, imidazole, indazole, indole, indoline, indolizine, isobenzofuran, isochromene, isoindole, isoindoline, isoquinoline, isothiazole, isoxazole, naphthyridine, oxadiazole, oxazole, perimidine, phenanthridine, phenanthroline, phenazine, phthalazine, pteridine, purine, pyran, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolizine, quinazoline, quinoline, quinolizine, quinoxaline, tetrazole, thiadiazole, thiazole, thiophene, triazole, xanthene and the like.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is made with counterions understood in the art to be generally acceptable for pharmaceutical uses and which possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid and the like; or (2) salts formed when an acidic proton present in the parent compound is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, N-methylglucamine, morpholine, piperidine, dimethylamine, diethylamine and the like. Also included are salts of amino acids such as arginates and the like, and salts of organic acids like glucurmic or galactunoric acids and the like (see, e.g., Berge et al., 1977, J. Pharm. Sci. 66:1 19).

"Pharmaceutically acceptable vehicle" refers to a diluent, adjuvant, excipient or carrier with which a compound of the invention is administered.

"Protecting group" refers to a group of atoms that, when attached to a reactive functional group in a molecule, mask, reduce or prevent the reactivity of the functional group. Typically, a protecting group may be selectively removed as desired during the course of a synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3.sup.rd Ed., 1999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1 8, 1971 1996, John Wiley & Sons, NY. Representative amino protecting groups include, but are not limited to, formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl ("CBZ"), tert-butoxycarbonyl ("Boc"), trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl ("SES"), trityl and substituted trityl groups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl ("FMOC"), nitro-veratryloxycarbonyl ("NVOC") and the like. Representative hydroxyl protecting groups include, but are not limited to, those where the hydroxyl group is either acylated (e.g., methyl and ethyl esters, acetate or propionate groups or glycol esters) or alkylated such as benzyl and trityl ethers, as well as alkyl ethers, tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPS groups) and allyl ethers.

"Prodrug" refers to a derivative of an active compound (drug) that undergoes a transformation under the conditions of use, such as within the body, to release an active drug. Prodrugs are frequently, but not necessarily, pharmacologically inactive until converted into the active drug. Prodrugs are typically obtained by masking a functional group in the drug believed to be in part required for activity with a progroup (defined below) to form a promoiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug. The cleavage of the promoiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a physical or environrnental parameter, such as a change of temperature. The agent may be endogenous to the conditions of use, such as an enzyme present in the cells to which the prodrug is administered or the acidic conditions of the stomach, or it may be supplied exogenously.

A wide variety of progroups, as well as the resultant promoieties, suitable for masking functional groups in active compounds to yield prodrugs are well-known in the art. For example, a hydroxyl functional group may be masked as a sulfonate, ester or carbonate promoiety, which may be hydrolyzed in vitro to provide the hydroxyl group. An amino functional group may be masked as an amide, imine, phosphinyl, phosphonyl, phosphoryl or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group. A carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide promoiety, which may be hydrolyzed in vivo to provide the carboxyl group. Other specific examples of suitable progroups and their respective promoieties will be apparent to those of skill in the art.

"Progroup" refers to a type of protecting group that, when used to mask a functional group within an active drug to form a promoiety, converts the drug into a prodrug. Progroups are typically attached to the functional group of the drug via bonds that are cleavable under specified conditions of use. Thus, a progroup is that portion of a promoiety that cleaves to release the functional group under the specified conditions of use. As a specific example, an amide promoiety of the formula --NH--C(O)CH.sub.3 comprises the progroup --C(O)CH.sub.3.

"Substituted," when used to modify a specified group or radical, means that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent(s). Substituent groups useful for substituting saturated carbon atoms in the specified group or radical include, but are not limited to --R.sup.a, halo, --O.sup.-, .dbd.O, --OR.sup.b, --SR.sup.b, --S.sub.-, .dbd.S, --NR.sup.cR.sup.c, .dbd.NR.sup.b, .dbd.N--OR.sup.b, trihalomethyl, --CF.sub.3, --CN, --OCN, --SCN, --NO, --NO.sub.2, .dbd.N.sub.2, --N.sub.3, --S(O).sub.2R.sup.b, --S(O).sub.2O.sup.-, --S(O).sub.2OR.sup.b, --OS(O).sub.2R.sup.b, --OS(O).sub.2O.sup.-, --OS(O).sub.2OR.sup.b, --P(O)(O.sup.31).sub.2, --P(O)(OR.sup.b)(O.sup.-), --P(O)(OR.sup.b)(OR.sup.b), --C(O)R.sup.b, --C(S)R.sup.b, --C(NR.sup.b)R.sup.b, --C(O)O.sup.-, --C(O)OR.sup.b, --C(S)OR.sup.b, --C(O)NR.sup.cR.sup.c, --C(NR.sup.b)NR.sup.cR.sup.c, --OC(O)R.sup.b, --OC(S)R.sup.b, --OC(O)O.sup.-, --OC(O)OR.sup.b, --OC(S)OR.sup.b, --NR.sup.bC(O)R.sup.b, --NR.sup.bC(S)R.sup.b, --NR.sup.bC(O)O.sup.-, --NR.sup.bC(O)OR.sup.b, --NR.sup.bC(S)OR.sup.b, --NR.sup.bC(O)NR.sup.cR.sup.c, --NR.sup.bC(NR.sup.b)R.sup.b and --NR.sup.bC(NR.sup.b)NR.sup.cR.sup.c, where R.sup.a is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each R.sup.b is independently hydrogen or R.sup.a; and each R.sup.c is independently R.sup.b or alternatively, the two R.sup.cs are taken together with the nitrogen atom to which they are bonded form a 5-, 6- or