WO2011091152A1

WO2011091152A1 - Inhibitors of hepatitis c virus infection

Info

Publication number: WO2011091152A1
Application number: PCT/US2011/021889
Authority: WO
Inventors: Pablo Gastaminza; Francis V. Chisari; Suresh Mark Pitram; K. Barry Sharpless; Valery V. Fokin; Larissa B. Krasnova; Jiajia Dong
Original assignee: Pablo Gastaminza; Chisari Francis V; Suresh Mark Pitram; Sharpless K Barry; Fokin Valery V; Krasnova Larissa B; Jiajia Dong
Priority date: 2010-01-22
Filing date: 2011-01-20
Publication date: 2011-07-28

Abstract

Pharmaceutical compounds, compositions, combinations, and methods of treatment of Hepatitis C Virus infection are provided. Compounds of the invention are effective in killing, inhibiting, or blocking viral spread of a Hepatitis C Virus. Methods of preparation and methods of use are also provided.

Description

INHIBITORS OF HEPATITIS C VIRUS INFECTION

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Application Serial Number 61/297,313, filed January 22, 2010, which is incorporated by reference herein in its entirety.

STATEMENT OF GOVERNMENT SUPPORT

This invention was made with government support under Grant Nos.

5R01GM028384 and R01CA108304, awarded by the National Institutes of Health. The U.S. government has certain rights in the invention.

BACKGROUND

Hepatitis C virus (HCV) is a major human pathogen, infecting an estimated 170 million persons worldwide— roughly five times the number infected by human immunodeficiency virus type 1. A substantial fraction of these HCV infected individuals develop serious progressive liver disease, including cirrhosis and hepatocellular carcinoma.

Currently, the most effective HCV therapy employs a combination of a-interferon and ribavirin, leading to sustained efficacy in 40% of patients. Clinical results demonstrate that pegylated a-interferon is superior to unmodified a-interferon as monotherapy. However, even with experimental therapeutic regimens involving combinations of pegylated α-interferon and ribavirin, a substantial fraction of patients do not have a sustained reduction in viral load.

HCV is a positive-stranded RNA virus. Based on a comparison of the deduced amino acid sequence and the extensive similarity in the 5' untranslated region, HCV has been classified as a separate genus in the Flaviviridae family. All members of the Flaviviridae family have enveloped virions that contain a positive stranded RNA genome encoding all known virus-specific proteins via translation of a single, uninterrupted, open reading frame.

A great deal of heterogeneity is found within the nucleotide and encoded amino acid sequence throughout the HCV genome. At least six major genotypes have been characterized, and more than 50 subtypes have been described. The major genotypes of HCV differ in their distribution worldwide, and the clinical significance of the genetic heterogeneity of HCV remains elusive despite numerous studies of the possible effect of genotypes on pathogenesis and therapy.

The single strand HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF) encoding a single large polyprotein of about 3000 amino acids. In infected cells, this polyprotein is cleaved at multiple sites by cellular and viral proteases to produce the structural and non- structural (NS) proteins of the virus. In the case of HCV, the generation of mature nonstructural proteins is effected by two viral proteases. The viral genome also encodes a polymerase that catalyzes replication of viral RNA, in addition to other viral proteins, both functional and structural. SUMMARY

The present invention is directed to compounds and formulations that are effective for treatment of Hepatitis C virus (HCV) infections, such as in humans. In various embodiments, compounds of the invention "kill" the virus, i.e., interfere with viral functions necessary for replication and propagation of the virus in a mammalian host. In various embodiments, compounds of the invention inhibit viral spread, reducing the virulence of the viral strain infecting a population of host cells, such as liver cells in a human patient. The invention is also directed to methods of treatment using compounds of the invention.

In various embodiments the present invention provides a compound of formula (X):

( )

wherein:

X is a 1,2-ethylene or a 1,3-propylene group which can be unsubstituted or substituted;

a dotted line indicates an optional double bond;

Y is azido, NR, or 1,2,3-triazolyl, wherein R is hydrogen or (C₁-C₆)alkyl, provided that when Y is azido then R 7 , R 8 and R 9 are all absent;

Z 1 and Z 2 are each independently unsubstituted or substituted phenyl, wherein the phenyl group can be mono- or independently pluri- substituted with halo, haloalkyl, alkyl, alkenyl, alkynyl, azido, or (C₁-C₃)alkoxy; or Z 2 is NH₂ and Y, R 7 , R 8 , and R 9" are all absent;

R 1 and R 2" are independently at each occurrence hydrogen, (C₁-C₆)alkyl, (C₆- Cio)aryl, or 3-8 membered heterocyclyl, wherein any alkyl, aryl, or heterocyclyl group can be substituted or unsubstituted; or

R 1 , R 2 , and carbon atoms to which they are bonded, wherein the optional double bond is present, can form a fused (C₆-C₃o)aryl that can be substituted or unsubstituted;

R⁵ is absent, carbonyl, thiocarbonyl, or sulfonyl;

R⁶ is hydrogen, substituted or unsubstituted alkyl, cycloalkoxy, cycloalkylalkoxy, alkynyloxy, aralkoxy, heterocyclyloxy, cycloalkylamino, cycloalkylalkylamino, alkenylamino, arylamino, aralkylamino, heterocyclylamino, aroylamido, heteroaryl, or heteroarylalkyl;

or, R⁵ and R⁶ taken together can form a heterocyclyl;

R is absent, hydrogen, carbonyl, thiocarbonyl, sulfonyl, or (C₁-C₄)alkylene; R⁸ is absent, NH, or O; R⁹ is alkynyl, alkanoyl, carboxamido, cycloalkyl, aryl, aroyl, heterocyclyl, carboxy, or carboxy-alkyl, wherein any alkynyl, alkanoyl, carboxamido, cycloalkyl, aroyl, heterocyclyl, or carboxy-alkyl can be substituted;

or a dimer thereof of formula (XIA) or (XIB)

(XIB)

comprising two structures of formula (X) as defined above but wherein, for formula (XIA), R⁶ comprises a (C₁-C₁₂)alkylene diamine moiety bonded to two respective R⁵ groups, wherein R⁵ is carbonyl, thiocarbonyl, or sulfonyl; or, wherein for formula (XIB),

R 9 comprises a (C₁-C₁₂)alkylene diamine moiety bonded to two respective R 7 groups, wherein R 7 is carbonyl, thiocarbonyl, or sulfonyl, and R 8 is absent;

or a compound of formula (XX)

wherein

W is N or CH;

Q is OH or NHR²⁰;

20

R is hydrogen, alkylaminocarbonyl or arylaminocarbonyl wherein any alkyl or aryl can be substituted;

21

R is aralkyl or alkoxycarbonyl;

or a dimer thereof of formula (XXI)

wherein W and R²¹ are as defined above and wherein R²⁰ comprises an alkylene bis(aminocarbonyl) group;

or a compound of formula XXII)

( )

wherein W is N or CH and R²⁰ is hydrogen, alkylaminocarbonyl or

arylaminocarbonyl, and R²¹ is as defined above, wherein any alkyl or aryl can be substituted;

or a compound of formula (XXIII) II)

wherein R is hydrogen or (C₁-C6)alkyl;

or a compound of formula (X

XIV)

wherein R⁵ and R⁶ are as defined above;

or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof.

The present invention also provides a pharmaceutical composition. The pharmaceutical composition includes a pharmaceutically acceptable carrier; and a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.

In various embodiments, the pharmaceutical composition further includes one or more additional compounds having anti-Hepatitis C virus activity.

In various embodiments, the one or more additional compounds having anti-

Hepatitis C virus activity can be interferon, ribavirin, or a combination thereof.

In various embodiments, the one or more additional compounds can be an inhibitor of a HCV protease, or an inhibitor of a HCV polymerase.

In various embodiments, the interferon includes interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastoid interferon τ, or a combination thereof.

In various embodiments, the one or more additional compounds having anti- Hepatitis C virus activity includes interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, imiqimod, ribavirin, an inosine 5 '-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof.

In various embodiments, the present invention further provides a method of treating an animal inflicted with Hepatitis C Virus infection. The method includes administering to an animal in need of such treatment an effective amount of a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.

In various embodiments, the invention provides a method of treatment of an HCV infection in a host animal, such as a human patient, afflicted with an HCV strain that is resistant, or has developed resistance, to inhibitors of HCV viral protease or HCV viral polymerase. The protease(s) and polymerase(s) of viruses, such as HCV, are targeted by many varieties of medicinal compounds, and it is possible, or even likely, that resistance to these mechanisms of action may develop among viral populations. As it is believed by the inventors herein that the compounds of the invention target a viral component other than one of these enzyme systems, the inventors believe that cross-resistance is unlikely. Accordingly, the inventive compounds can be used in treatment of HCV strains that are already resistant, in treatment of HCV strains wherein development of protease or polymerase inhibitor resistant strains is of concern, and in combination therapy comprising use of a protease inhibitor, a polymerase inhibitor, or both, in conjunction with a compound of the invention.

In various embodiments, the compounds of the invention can also be used to prevent viral spread in a population of cells that has been exposed to an inoculum of HCV. In addition to blocking viral replication within a cell or a population, the compounds of the invention are believed to inhibit the transmission of the virus from an infected cell to an uninfected cell. Therefore, in various embodiments, a method of preventing viral spread is provided, comprising administering an effective amount of a compound of the invention to a patient exposed to an inoculum of HCV.

In various embodiments, the method further includes administering one or more additional compounds having anti-Hepatitis C virus activity prior to, after, or simultaneously with a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.

In one embodiment, the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof.

In various embodiments, the animal is a human.

In various embodiments, the present invention also provides a method of killing or inhibiting Hepatitis C Virus. The method includes contacting the Hepatitis C Virus with an effective amount of a compound of the formula (X), or a dimeric compound thereof of the formula (XIA) or (XIB), or a compound of the formula (XX) or a dimeric compound thereof of the formula (XXI), or a compound of the formula (XXII), or a compound of the formula (XXIII) or a compound of the formula (XXIV), or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite of any of the above formulas.

In various embodiments, the contacting is in vitro. In various embodiments, the contacting is in vivo.

DETAILED DESCRIPTION

Definitions

Reference will now be made in detail to certain claims of the disclosed subject matter, examples of which are illustrated in the accompanying structures and formulas. While the disclosed subject matter will be described in conjunction with the enumerated claims, it will be understood that they are not intended to limit the disclosed subject matter to those claims. On the contrary, the disclosed subject matter is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the presently disclosed subject matter as defined by the claims.

References in the specification to "one embodiment" indicate that the

embodiment described may include a particular feature, structure, or characteristic, but every embodiment may not necessarily include the particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to affect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.

When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other by a chemically feasible bonding configuration.

By "chemically feasible" is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim. The structures disclosed herein, in all of their embodiments are intended to include only "chemically feasible" structures, and any recited structures that are not chemically feasible, for example in a structure shown with variable atoms or groups, are not intended to be disclosed or claimed herein.

When a substituent is specified to be an atom or atoms of specified identity, "or a bond", a configuration is referred to when the substituent is "a bond" that the groups that are immediately adjacent to the specified substituent are directly connected to each other in a chemically feasible bonding configuration.

All chiral, diastereomeric, racemic forms of a structure are intended, unless a particular stereochemistry or isomeric form is specifically indicated. Compounds used in the present invention can include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or

diastereomeric partners, and these are all within the scope of the invention.

As used herein, the terms "stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated herein.

As to any of the groups described herein, which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non-feasible. In addition, the compounds of this disclosed subject matter include all stereochemical isomers arising from the substitution of these compounds.

Selected substituents within the compounds described herein are present to a recursive degree. In this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim. One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.

Recursive substituents are an intended aspect of the disclosed subject matter. One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in a claim of the disclosed subject matter, the total number should be determined as set forth above. The inclusion of an isotopic form of one or more atoms in a molecule that is different from the naturally occurring isotopic distribution of the atom in nature is referred to as an "isotopically labeled form" of the molecule. All isotopic forms of atoms are included as options in the composition of any molecule, unless a specific isotopic form of an atom is indicated. For example, any hydrogen atom or set thereof in a molecule can be any of the isotopic forms of hydrogen, i.e., protium ( 1 H), deuterium ( 2 H), or tritium ( H) in any combination. Similarly, any carbon atom or set thereof in a molecule can be any of the isotopic form of carbons, such as ^UC, ¹²C, ¹³C, or ¹⁴C, or any nitrogen atom or set thereof in a molecule can be any of the isotopic forms of nitrogen, such as ¹³N, ¹⁴N, or ¹⁵N. A molecule can include any combination of isotopic forms in the component atoms making up the molecule, the isotopic form of every atom forming the molecule being independently selected. In a multi-molecular sample of a compound, not every individual molecule necessarily has the same isotopic composition. For example, a sample of a compound can include molecules containing various different isotopic compositions, such as in a tritium or ¹⁴C radiolabeled sample where only some fraction of the set of molecules making up the macroscopic sample contains a radioactive atom. It is also understood that many elements that are not artificially isotopically enriched themselves are mixtures of naturally occurring isotopic forms, such as ¹⁴N and

15 N, 32 S and 34 S, and so forth. A molecule as recited herein is defined as including isotopic forms of all its constituent elements at each position in the molecule. As is well known in the art, isotopically labeled compounds can be prepared by the usual methods of chemical synthesis, except substituting an isotopically labeled precursor molecule. The isotopes, radiolabeled or stable, can be obtained by any method known in the art, such as generation by neutron absorption of a precursor nuclide in a nuclear reactor, by cyclotron reactions, or by isotopic separation such as by mass spectrometry. The isotopic forms are incorporated into precursors as required for use in any particular synthetic route. For example, ¹⁴C and ³H can be prepared using neutrons generated in a nuclear reactor. Following nuclear transformation, ¹⁴C and ³H are incorporated into precursor molecules, followed by further elaboration as needed.

The term "amino protecting group" or "N-protected" as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t- butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl,

o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,

3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,

4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,

3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)-1-methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, t- butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2- trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc), phenoxycarbonyl, 4- nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle. Typically, amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.

The term "hydroxyl protecting group" or "O-protected" as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used hydroxyl protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999). Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p- nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4- dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4- dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5- dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, l-(p-biphenylyl)- 1- methylethoxycarbonyl, a,a-dimethyl-3,5-dimethoxybenzyloxycarbonyl,

benzhydryloxycarbonyl, t-butyloxycarbonyl (Boc), diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethyloxycarbonyl (Teoc),

phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl (Fmoc), cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl,

phenylthiocarbonyl and the like; aralkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like. It is well within the skill of the ordinary artisan to select and use the appropriate hydroxyl protecting group for the synthetic task at hand.

In general, "substituted" refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, CI, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboxylate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines; and other heteroatoms in various other groups. Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, CI, Br, I, OR', OC(0)N(R')₂, CN, NO, N0₂, ON0₂, azido, CF₃, OCF₃, R', O (oxo), S (thiono), C(O), S(O), methylenedioxy, ethylenedioxy, N(R')₂, SR', SOR', S0₂R', S0₂N(R')₂, S0₃R', C(0)R', C(0)C(0)R', C(0)CH₂C(0)R', C(S)R', C(0)OR', OC(0)R', C(0)N(R')₂, OC(0)N(R')₂, C(S)N(R')₂, (CH₂)o-₂N(R')C(0)R', (CH₂)₀-₂N(R')N(R')₂, N(R')N(R')C(0)R', N(R')N(R')C(0)OR', N(R')N(R')CON(R')₂, N(R')S0₂R', N(R')S0₂N(R')₂, N(R')C(0)OR', N(R')C(0)R', N(R')C(S)R', N(R')C(0)N(R')₂, N(R')C(S)N(R')₂, N(COR')COR', N(OR')R',

C(=NH)N(R')₂, C(0)N(OR')R', or C(=NOR')R' wherein R' can be hydrogen or a carbon- based moiety, and wherein the carbon-based moiety can itself be further substituted.

When a substituent is monovalent, such as, for example, F or CI, it is bonded to the atom it is substituting by a single bond. When a substituent is more than monovalent, such as O, which is divalent, it can be bonded to the atom it is substituting by more than one bond, i.e., a divalent substituent is bonded by a double bond; for example, a C substituted with O forms a carbonyl group, C=0, which can also be written as "CO", "C(O)", or "C(=0)", wherein the C and the O are double bonded. When a carbon atom is substituted with a double-bonded oxygen (=0) group, the oxygen substituent is termed an "oxo" group. When a divalent substituent such as NR is double-bonded to a carbon atom, the resulting C(=NR) group is termed an "imino" group. When a divalent substituent such as S is double-bonded to a carbon atom, the results C(=S) grouip is termed a "thiocarbonyl" group.

Alternatively, a divalent substituent such as O, S, C(O), S(O), or S(0)₂ can be connected by two single bonds to two different carbon atoms. For example, O, a divalent substituent, can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group, termed an "oxy" group, between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]-oxabicyclo system. Further, any substituent can be bonded to a carbon or other atom by a linker, such as (CH₂)_n or (CR'₂)_n wherein n is 1, 2, 3, or more, and each R' is independently selected.

Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.

Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.

By a "ring system" as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic. By "spirocyclic" is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.

Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms. Examples of straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups. Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.

Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.

Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or 2,6- disubstituted cyclohexyl groups or mono-, di- or tri- substituted norbornyl or cycloheptyl groups, which can be substituted with, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups. The term "cycloalkenyl" alone or in combination denotes a cyclic alkenyl group.

The terms "carbocyclic," "carbocyclyl," and "carbocycle" denote a ring structure wherein the atoms of the ring are carbon, such as a cycloalkyl group or an aryl group. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other

embodiments the number of ring carbon atoms is 4, 5, 6, or 7. Unless specifically indicated to the contrary, the carbocyclic ring can be substituted with as many as N-l substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above. A carbocyclyl ring can be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring. A carbocyclyl can be monocyclic or polycyclic, and if polycyclic each ring can be independently be a cycloalkyl ring, a cycloalkenyl ring, or an aryl ring.

(Cycloalkyl) alkyl groups, also denoted cycloalkylalkyl, are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.

Alkenyl groups include straight and branched chain and cyclic alkyl groups as defined above, except that at least one double bond exists between two carbon atoms. Thus, alkenyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to vinyl, -CH=CH(CH₃), -CH=C(CH₃)₂, -C(CH₃)=CH₂, -C(CH₃)=CH(CH₃), -C(CH₂CH₃)=CH₂, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl, and hexadienyl among others.

Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons. Thus for example, cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups. Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring. Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.

(Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.

Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms. Examples include, but are not limited to -C≡CH, -C≡C(CH₃), -C≡C(CH₂CH₃), -CH₂C≡CH, -CH₂C≡C(CH₃), and -CH₂C≡C(CH₂CH₃) among others.

The term "heteroalkyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain alkyl group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may be optionally oxidized and the nitrogen heteroatom may be optionally quaternized. The heteroatom(s) may be placed at any position of the heteroalkyl group, including between the rest of the heteroalkyl group and the fragment to which it is attached, as well as attached to the most distal carbon atom in the heteroalkyl group. Examples include: -0-CH₂-CH₂-CH , -CH₂-CH₂CH₂-OH, -CH₂-CH₂-NH-CH₃, -CH₂-S-CH₂-CH₃, -CH₂CH₂-S(=0)-CH₃, and - CH₂CH₂-0-CH₂CH₂-0-CH₃. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃, or -CH₂-CH₂-S-S-CH₃.

A "cyclohetero alkyl" ring is a cycloalkyl ring containing at least one heteroatom. A cycloheteroalkyl ring can also be termed a "heterocyclyl," described below.

The term "heteroalkenyl" by itself or in combination with another term means, unless otherwise stated, a stable straight or branched chain monounsaturated or di-unsaturated hydrocarbon group consisting of the stated number of carbon atoms and one or two heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. Up to two heteroatoms may be placed consecutively. Examples include -CH=CH-0-CH₃, -CH=CH-CH₂-OH, -CH₂-CH=N-OCH₃,

-CH=CH-N(CH₃)-CH₃, -CH₂-CH=CH-CH₂-SH, and and -CH=CH-0-CH₂CH₂-0-CH₃.

Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.

Thus aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain about 6 to about 14 carbons in the ring portions of the groups. Aryl groups can be unsubstituted or substituted, as defined above. Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.

Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.

Representative aralkyl groups include benzyl and phenylethyl groups and fused

(cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl. Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.

Heterocyclyl groups or the term "heterocyclyl" includes aromatic and non- aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Thus a heterocyclyl can be a cycloheteroalkyl, or a heteroaryl, or if polycyclic, any combination thereof. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members. A heterocyclyl group designated as a C₂- heterocyclyl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C₄-heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. A heterocyclyl ring can also include one or more double bonds. A heteroaryl ring is an embodiment of a heterocyclyl group. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein. The phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above. Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.

Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members. A heteroaryl group is a variety of a heterocyclyl group that possesses an aromatic electronic structure. A heteroaryl group designated as a C₂-heteroaryl can be a 5-ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth. Likewise a C₄-heteroaryl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth. The number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl,

benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be unsubstituted, or can be substituted with groups as is discussed above. Representative substituted heteroaryl groups can be substituted one or more times with groups such as those listed above.

Additional examples of aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N-hydroxytetrazolyl, N- hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1-anthracenyl, 2-anthracenyl, 3- anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1- imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3- triazol-2-yl 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5- oxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl), pyridyl (2-pyridyl, 3-pyridyl, 4- pyridyl), pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3- pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1- isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8- isoquinolyl), benzo[b]furanyl (2-benzo[b]furanyl, 3-benzo[b]furanyl, 4-benzo[b]furanyl,

5- benzo[b]furanyl, 6-benzo[b]furanyl, 7-benzo[b]furanyl), 2,3-dihydro-benzo[b]furanyl (2-(2,3-dihydro-benzo[b]furanyl), 3-(2,3-dihydro-benzo[b]furanyl), 4-(2,3-dihydro- benzo[b]furanyl), 5-(2,3-dihydro-benzo[b]furanyl), 6-(2,3-dihydro-benzo[b]furanyl), 7- (2,3-dihydro-benzo[b]furanyl), benzo[b] thiophenyl (2-benzo[b] thiophenyl, 3- benzo[b] thiophenyl, 4-benzo[b] thiophenyl, 5-benzo[b]thiophenyl, 6-benzo[b]thiophenyl, 7-benzo[b]thiophenyl), 2,3-dihydro-benzo[b]thiophenyl, (2-(2,3-dihydro- benzo[b]thiophenyl), 3-(2,3-dihydro-benzo[b]thiophenyl), 4-(2,3-dihydro- benzo[b]thiophenyl), 5-(2,3-dihydro-benzo[b]thiophenyl), 6-(2,3-dihydro- benzo[b]thiophenyl), 7-(2,3-dihydro-benzo[b]thiophenyl), indolyl (1-indolyl, 2-indolyl,

3- indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), indazole (1-indazolyl, 3-indazolyl,

4- indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl,

7-benzimidazolyl, 8 -benzimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl,

6- benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz[b,f]azepine (5H-dibenz[b,f]azepin-1-yl, 5H-dibenz[b,f]azepine- 2-yl, 5H-dibenz[b,f]azepine-3-yl, 5H-dibenz[b,f]azepine-4-yl, 5H-dibenz[b,f]azepine-5- yl), 10,1 l-dihydro-5H-dibenz[b,f]azepine (10,1 l-dihydro-5H-dibenz[b,f]azepine-1-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-2-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-3-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-4-yl, 10,1 l-dihydro-5H-dibenz[b,f]azepine-5-yl), and the like.

Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above. Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.

Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.

The term "alkoxy" refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like. Examples of branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like. Examples of cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms. For example, an allyloxy group is an alkoxy group within the meaning herein. A methoxyethoxy group is also an alkoxy group within the meaning herein.

The terms "halo" or "halogen" or "halide" by themselves or as part of another substituent mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom, preferably, fluorine, chlorine, or bromine.

A "haloalkyl" group includes mono-halo alkyl groups, poly-halo alkyl groups wherein all halo atoms can be the same or different, and per-halo alkyl groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3-dibromo-3,3- difluoropropyl, perfluorobutyl, and the like.

A "haloalkoxy" group includes mono-halo alkoxy groups, poly-halo alkoxy groups wherein all halo atoms can be the same or different, and per-halo alkoxy groups, wherein all hydrogen atoms are replaced by halogen atoms, such as fluoro. Examples of haloalkoxy include trifluoromethoxy, 1,1-dichloroethoxy, 1,2-dichloroethoxy, 1,3- dibromo-3,3-difluoropropoxy, perfluorobutoxy, and the like.

The term "(C_x-C_y)perfluoroalkyl," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is -(C₁-C₆)perfluoroalkyl, more preferred is -(C₁-C3)perfluoroalkyl, most preferred is -CF₃.

The term "(C_x-C_y)perfluoroalkylene," wherein x < y, means an alkyl group with a minimum of x carbon atoms and a maximum of y carbon atoms, wherein all hydrogen atoms are replaced by fluorine atoms. Preferred is -(C₁-C₆)perfluoroalkylene, more preferred is -(C₁-C₃)perfluoroalkylene, most preferred is -CF₂-.

The terms "aryloxy" and "arylalkoxy" refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moiety. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.

An "acyl" group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom. The carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like. In the special case wherein the carbonyl carbon atom is bonded to a hydrogen, the group is a "formyl" group, an acyl group as the term is defined herein. An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group. An acyl group can include double or triple bonds within the meaning herein. An acryloyl group is an example of an acyl group. An acyl group can also include heteroatoms within the meaning here. A nicotinoyl group (pyridyl-3-carbonyl) group is an example of an acyl group within the meaning herein. Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like. When the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group. An example is a trifluoroacetyl group.

The term "amine" includes primary, secondary, and tertiary amines having, e.g., the formula N(group)₃ wherein each group can independently be H or non-H, such as alkyl, aryl, and the like. Amines include but are not limited to R-NH₂, for example, alkylamines, arylamines, alkylarylamines; R₂NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like. The term "amine" also includes ammonium ions as used herein.

An "amino" group is a substituent of the form -NH₂, -NHR, -NR₂, -NR₃ ⁺, wherein each R is independently selected, and protonated forms of each. Accordingly, any compound substituted with an amino group can be viewed as an amine. An "amino group" within the meaning herein can be a primary, secondary, tertiary or quaternary amino group. An "alkylamino" group includes a monoalkylamino, dialkylamino, and trialkylamino group.

An "ammonium" ion includes the unsubstituted ammonium ion NH₄ ⁺, but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.

The term "amide" (or "amido") includes C- and N-amide groups, i.e., -C(0)NR₂, and -NRC(0)R groups, respectively. Amide groups therefore include but are not limited to carbamoyl groups (-C(0)NH₂) and formamide groups (-NHC(O)H). A "carboxamido" group is a group of the formula C(0)NR₂, wherein R can be H, alkyl, aryl, etc.

The term "azido" refers to an N₃ group. An "azide" can be an organic azide or can be a salt of the azide (N₃ ^~) anion. The term "nitro" refers to an N0₂ group bonded to an organic moiety. The term "nitroso" refers to an NO group bonded to an organic moiety. The term nitrate refers to an ON0₂ group bonded to an organic moiety or to a salt of the nitrate (N0₃ ^~) anion.

The term "urethane" (or "carbamyl") includes N- and O-urethane groups, i.e.,

-NRC(0)OR and -OC(0)NR₂ groups, respectively. The term "sulfonamide" (or "sulfonamido") includes S- and N-sulfonamide groups, i.e., -SO₂NR₂ and -NRSO₂R groups, respectively. Sulfonamide groups therefore include but are not limited to sulfamoyl groups (-SO₂NH₂). An organosulfur structure represented by the formula -S(0)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.

The term "amidine" or "amidino" includes groups of the formula -C(NR)NR₂. Typically, an amidino group is -C(NH)NH₂.

The term "guanidine" or "guanidino" includes groups of the formula

-NRC(NR)NR₂. Typically, a guanidino group is -NHC(NH)NH₂.

A "salt" as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion. For example, acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH₄ ⁺ or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like. A "pharmaceutically acceptable" or "pharmacologically acceptable" salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt. A "zwitterion" is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form. A "zwitterion" is a salt within the meaning herein. The compounds of the present invention may take the form of salts. The term "salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be "pharmaceutically-acceptable salts." The term

"pharmaceutically- acceptable salt" refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention. Suitable pharmaceutically- acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include

hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),

methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic, galactaric and galacturonic acid. Examples of pharmaceutically unacceptable acid addition salts include, for example, perchlorates and tetrafluoroborates .

Suitable pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal and transition metal salts such as, for example, calcium, magnesium, potassium, sodium and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as, for example, N,A^-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine

(N-methylglucamine) and procaine. Examples of pharmaceutically unacceptable base addition salts include lithium salts and cyanate salts. Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of Formula (I) compounds, for example in their purification by recrystallization.. All of these salts may be prepared by conventional means from the corresponding compound according to Formula (I) by reacting, for example, the appropriate acid or base with the compound according to Formula (I). The term "pharmaceutically acceptable salts" refers to nontoxic inorganic or organic acid and/or base addition salts, see, for example, Lit et al., Salt Selection for Basic Drugs (1986), Int J. Pharm., 33, 201-217, incorporated by reference herein. Lists of many suitable salts are also found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, (1985), 1418, and the disclosure of which is incorporated herein by reference.

A "hydrate" is a compound that exists in a composition with water molecules. The composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form, i.e., a compound in water solution, while it may be hydrated, is not a hydrate as the term is used herein.

A "solvate" is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non- stoichiometric. As the term is used herein a "solvate" refers to a solid form, i.e., a compound in solution in a solvent, while it may be solvated, is not a solvate as the term is used herein.

A "prodrug" as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient. Examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985. As used herein, the term "prodrug" refers to any pharmaceutically acceptable form of compound of the invention which, upon administration to a patient, provides a compound of the invention . Pharmaceutically acceptable prodrugs refer to a compound that is metabolized, for example hydrolyzed or oxidized, in the host to form a compound of the invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on a functional moiety of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, dephosphorylated to produce the active compound. The compounds of the invention herein possess antiviral activity against HCV, or are metabolized to a compound that exhibits such activity. In addition, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group. For example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, claims for X being bromine and claims for X being bromine and chlorine are fully described. Moreover, where features or aspects of the invention are described in terms of Markush groups, those skilled in the art will recognize that the invention is also thereby described in terms of any combination of individual members or subgroups of members of Markush groups. Thus, for example, if X is described as selected from the group consisting of bromine, chlorine, and iodine, and Y is described as selected from the group consisting of methyl, ethyl, and propyl, claims for X being bromine and Y being methyl are fully described.

In various embodiments, the compound or set of compounds, such as are used in the inventive methods, can be any one of any of the combinations and/or sub- combinations of the above-listed embodiments.

The present invention further embraces isolated compounds according to the formulas specified herein. The expression "isolated compound" refers to a preparation of a compound of a specified formula, or a mixture of compounds, wherein the isolated compound has been separated from the reagents used, and/or byproducts formed, in the synthesis of the compound or compounds. "Isolated" does not mean that the preparation is technically pure (homogeneous), but it is sufficiently pure to compound in a form in which it can be used therapeutically. Preferably an "isolated compound" refers to a preparation of a compound or a mixture of compounds, which contains the named compound or mixture of compounds in an amount of at least 10 percent by weight of the total weight. Preferably the preparation contains the named compound or mixture of compounds in an amount of at least 50 percent by weight of the total weight; more preferably at least 80 percent by weight of the total weight; and most preferably at least 90 percent, at least 95 percent or at least 98 percent by weight of the total weight of the preparation.

The compounds of the invention and intermediates may be isolated from their reaction mixtures and purified by standard techniques such as filtration, liquid-liquid extraction, solid phase extraction, distillation, recrystallization or chromatography, including flash column chromatography, or HPLC.

Tautomerism

Within the present invention it is to be understood that a compound or a salt thereof may exhibit the phenomenon of tautomerism whereby two chemical compounds that are capable of facile interconversion by exchanging a hydrogen atom between two atoms, to either of which it forms a covalent bond. Since the tautomeric compounds exist in mobile equilibrium with each other they may be regarded as different isomeric forms of the same compound. It is to be understood that the formulae drawings within this specification can represent only one of the possible tautomeric forms. However, it is also to be understood that the invention encompasses any tautomeric form, and is not to be limited merely to any one tautomeric form utilized within the formulae drawings. The formulae drawings within this specification can represent only one of the possible tautomeric forms and it is to be understood that the specification encompasses all possible tautomeric forms of the compounds drawn not just those forms which it has been convenient to show graphically herein. For example, tautomerism may be exhibited by a pyrazolyl group bonded as indicated by the wavy line. While both substituents would be termed a 4-pyrazolyl group, it is evident that a different nitrogen atom bears the hydrogen atom in each structure.

Such tautomerism can also occur with substituted pyrazoles such as 3-methyl, 5- methyl, or 3,5-dimethylpyrazoles, and the like. Another example of tautomerism is amido-imido (lactam-lactim when cyclic) tautomerism, such as is seen in heterocyclic compounds bearing a ring oxygen atom adjacent to a ring nitrogen atom. For example, the equilibrium:

is an example of tautomerism. Accordingly, a structure depicted herein as one tautomer is intended to also include the other tautomer. Optical Isomerism

It will be understood that when compounds of the present invention contain one or more chiral centers, the compounds may exist in, and may be isolated as pure enantiomeric or diastereomeric forms or as racemic mixtures. The present invention therefore includes any possible enantiomers, diastereomers, racemates or mixtures thereof of the compounds of the invention.

The isomers resulting from the presence of a chiral center comprise a pair of non-superimposable isomers that are called "enantiomers." Single enantiomers of a pure compound are optically active, i.e., they are capable of rotating the plane of plane polarized light. Single enantiomers are designated according to the Cahn-Ingold-Prelog system. The priority of substituents is ranked based on atomic weights, a higher atomic weight, as determined by the systematic procedure, having a higher priority ranking. Once the priority ranking of the four groups is determined, the molecule is oriented so that the lowest ranking group is pointed away from the viewer. Then, if the descending rank order of the other groups proceeds clockwise, the molecule is designated (R) and if the descending rank of the other groups proceeds counterclockwise, the molecule is designated (S). The Cahn-Ingold-Prelog ranking is A > B > C > D. The lowest ranking atom, D is oriented away from the viewer.

The present invention is meant to encompass diastereomers as well as their racemic and resolved, diastereomerically and enantiomerically pure forms and salts thereof. Diastereomeric pairs may be resolved by known separation techniques including normal and reverse phase chromatography, and crystallization.

"Isolated optical isomer" means a compound which has been substantially purified from the corresponding optical isomer(s) of the same formula. Preferably, the isolated isomer is at least about 80%, more preferably at least 90% pure, even more preferably at least 98% pure, most preferably at least about 99% pure, by weight. Isolated optical isomers may be purified from racemic mixtures by well-known chiral separation techniques. According to one such method, a racemic mixture of a compound of the invention, or a chiral intermediate thereof, is separated into 99% wt.% pure optical isomers by HPLC using a suitable chiral column, such as a member of the series of DAICEL^® CHIRALPAK^® family of columns (Daicel Chemical Industries, Ltd., Tokyo, Japan). The column is operated according to the manufacturer's instructions. Rotational Isomerism

It is understood that due to chemical properties {i.e., resonance lending some double bond character to the C-N bond) of restricted rotation about the amide bond linkage (as illustrated below) it is possible to observe separate rotamer species and even, under some circumstances, to isolate such species (see below). It is further understood that certain structural elements, including steric bulk or substituents on the amide nitrogen, may enhance the stability of a rotamer to the extent that a compound may be isolated as, and exist indefinitely, as a single stable rotamer. The present invention therefore includes any possible stable ro tamers of formula (I) which are biologically active in the treatment of cancer or other proliferative disease states.

Regioisomerism

The preferred compounds of the present invention have a particular spatial arrangement of substituents on the aromatic rings, which is related to the structure activity relationship demonstrated by the compound class. Often such substitution arrangement is denoted by a numbering system; however, numbering systems are often not consistent between different ring systems. In six-membered aromatic systems, the spatial arrangements are specified by the common nomenclature "para" for

1,4-substitution, "meta" for 1,3 -substitution and "ortho" for 1,2- substitution as shown below.

Pharmaceutical Use

"Treating" or "treatment" within the meaning herein refers to an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder. As used herein, the terms "treating" or "treat" includes (i) preventing a pathologic condition from occurring (e.g., prophylaxis); (ii) inhibiting the pathologic condition or arresting its development; (iii) relieving the pathologic condition; and/or (iv) diminishing symptoms associated with the pathologic condition

Similarly, as used herein, an "effective amount" or a "therapeutically effective amount" of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition. In particular, a "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result . A therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects. As used herein, the term

"therapeutically effective amount" is intended to include an amount of a compound described herein, or an amount of the combination of compounds described herein, e.g., to treat or prevent the disease or disorder, or to treat the symptoms of the disease or disorder, in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme ReguL, 22:27 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased activity, or some other beneficial effect of the combination compared with the individual components.

As used herein, the term "infection" refers to the invasion of the host by germs including viruses that reproduce and multiply, causing disease by local cell injury, release of poisons, or germ-antibody reaction in the cells. The infection can be in a mammal (e.g., human).

As used herein, the term "metabolite" refers to any compound produced in vivo or in vitro from the parent drug of the invention, or any of its prodrugs that are converted biologically to a parent drug of the invention and then to a further biotransformation product of the parent drug.

As used herein, the term "patient" refers to a warm-blooded animal, and preferably a mammal, such as, for example, a cat, dog, horse, cow, pig, mouse, rat, or primate, including a human.

As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications commensurate with a reasonable benefit/risk ratio.

One diastereomer or one enantiomer of a compound disclosed herein may display superior biological activity compared with the other. When required, separation of the diastereomeric mixture or the racemic material can be achieved by HPLC, optionally using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Tucker et al., J. Med. Chem., 37, 2437 (1994), for the resolution of enantiomers. A chiral compound described herein may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g., Huffman et al., J. Org. Chem., 60: 1590 (1995). As used herein, "μβ" denotes microgram, "mg" denotes milligram, "g" denotes gram, "μΙ_/' denotes microliter, "mL" denotes milliliter, "L" denotes liter, "nM" denotes nanomolar, "μΜ" denotes micromolar, "mM" denotes millimolar, "M" denotes molar, and "nm" denotes nanometer.

Detailed Description

In various embodiments, the invention as disclosed herein provides a compound, a composition and a method for the treatment of hepatitis C in humans or other host animals, that includes administering an effective amount of a compound of the invention as described herein or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof, optionally in a pharmaceutically acceptable carrier as a pharmaceutical composition of the invention. The compounds of this invention either possess antiviral (i.e., anti-Hepatitis C virus) activity, or are metabolized to a compound that exhibits such activity.

In various embodiments, the invention provides a method of inhibiting an HCV protease enzyme comprising contacting the enzyme with an effective amount of a compound of the invention. In one embodiment, the contacting is in vitro. In one embodiment, the contacting is in vivo.

In various embodiments, the invention provides pharmaceutical combinations. In various embodiments, a combination of the invention further includes one or more additional compounds having anti-Hepatitis C virus activity. In one embodiment, the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof. In one embodiment, the interferon includes interferon a2b, pegylated interferon a, consensus interferon, interferon a2a,

lymphoblastoid interferon τ, or a combination thereof.

In various embodiments of a combination of the invention, the one or more additional compounds having anti-Hepatitis C virus activity includes interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof. In various embodiments of a combination of the invention, the one or more additional compounds having anti-Hepatitis C virus activity can be an inhibitor of a HCV protease, such as an inhibitor of the NS3 protease, or can be an inhibitor of a HCV polymerase, such as the NS5B polymerase.

The present invention also provides a method of treating an animal inflicted with

Hepatitis C Virus infection. The method includes administering to an animal in need of such treatment a compound of the invention and a pharmaceutically acceptable salt, a prodrug, or a metabolite thereof. The animal can be a human being.

In one embodiment, the method further includes administering one or more additional compounds having anti-Hepatitis C virus activity prior to, after, or

simultaneously with the compound of the invention or a pharmaceutically acceptable salt, a prodrug, or a metabolite thereof. In one embodiment, the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof. In one embodiment, the interferon includes interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastoid interferon τ, or a combination thereof. In one embodiment, the one or more additional compounds having anti-Hepatitis C virus activity includes interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof. In one embodiment, the animal is a human.

In various embodiments, the invention provides a method of treatment of an HCV infection in a host animal, such as a human patient, afflicted with an HCV strain that is resistant, or has developed resistance, to inhibitors of HCV viral protease or HCV viral polymerase. The protease(s) and polymerase(s) of viruses, such as HCV, are targeted by many varieties of medicinal compounds, and it is possible, or even likely, that resistance to these mechanisms of action may develop among viral populations. As it is believed by the inventors herein that the compounds of the invention target a viral component other than one of these enzyme systems, the inventors believe that cross-resistance is unlikely. Accordingly, the inventive compounds can be used in treatment of HCV strains that are already resistant, in treatment of HCV strains wherein development of protease or polymerase resistant strains is of concern, and in combination therapy comprising use of a protease inhibitor, a polymerase inhibitor, or both, in conjunction with a compound of the invention.

In various embodiment, the invention provides a compound of formula (X):

wherein:

a dotted line indicates an optional double bond;

Y is azido, NR, or 1,2,3-triazolyl, wherein R is hydrogen or (C₁-C6)alkyl, provided that when Y is azido then R 7 , R 8 and R 9 are all absent;

Z 1 and Z 2 are each independently unsubstituted or substituted phenyl, wherein the phenyl group can be mono- or independently pluri- substituted with halo, haloalkyl, alkyl, alkenyl, alkynyl, azido, or (C₁-C₃)alkoxy; or Z 2 is NH₂ and Y, R 7 , R 8 , and R 9" are all absent; R 1 and R 2" are independently at each occurrence hydrogen, (C₁-C6)alkyl, (C₆- C₁₀)aryl, or 3-8 membered heterocyclyl, wherein any alkyl, aryl, or heterocyclyl group can be substituted or unsubstituted; or

R 1 , R 2 , and carbon atoms to which they are bonded, wherein the optional double bond is present, can form a fused (C6-C₃₀)aryl that can be substituted or unsubstituted;

R⁵ is absent, carbonyl, thiocarbonyl, or sulfonyl;

or, R⁵ and R⁶ taken together can form a heterocyclyl;

R is absent, hydrogen, carbonyl, thiocarbonyl, sulfonyl, or (C₁-C₄)alkylene; R⁸ is absent, NH, or O;

R⁹ is alkynyl, alkanoyl, carboxamido, cycloalkyl, aryl, aroyl, heterocyclyl, carboxy, or carboxy-alkyl, wherein any alkynyl, alkanoyl, carboxamido, cycloalkyl, aryl, aroyl, heterocyclyl, or carboxy-alkyl can be substituted;

or a dimer thereof of formula (XIA) or (XIB)

comprising two structures of formula (X) as defined above but wherein, for formula (XIA), R⁶ comprises a (C₁-C₁2)alkylene diamine moiety bonded to two respective R⁵ groups, wherein R⁵ is carbonyl, thiocarbonyl, or sulfonyl; or, wherein for formula (XIB),

or a compound of formula (XX)

wherein

W is N or CH;

Q is OH or NHR²⁰;

R 20 is hydrogen, alkylaminocarbonyl or arylaminocarbonyl wherein any alkyl can be substituted;

R 21 is aralkyl or alkoxycarbonyl;

or a dimer thereof of formula (XXI)

wherein W and R are as defined above and wherein R²⁰ comprises an alkylene bis(aminocarbonyl) group;

or a compound of formula (XXII)

wherein W is N or CH and R²⁰ is hydrogen, alkylaminocarbonyl or

arylaminocarbonyl, and R 21 is as defined above, wherein any alkyl or aryl can be substituted;

or a compound of formula (XXIII)

( )

wherein R is hydrogen or (C₁-C₆)alkyl;

or a compound of formula (XXIV

wherein R⁵ and R⁶ are as defined above;

In various embodiments, for the compound of formula (X), R⁶ can be cycloalkoxy, cycloalkylalkoxy, alkynyloxy, , aralkoxy, or heterocyclyloxy. More specifically, the compound of formula (X) can be any of the following structures:

or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof. In various embodiments, for the formula (X), R⁶ can be cycloalkylamino or alkenylamino. More specifically, the compound of formula (X) can be any of the following structures:

In various embodiments, for the compound of formula (X), R⁶ can be arylamino, aralkylamino, or aroylamido. More specifically, the compound of formula (X) can be any of the following structures:

In various embodiments, for the compound of formula (X), R⁶ can be substituted or unsubstituted alkyl. More specifically, the compound of formula (X) can be any of the following structures:

In various embodiments, for a compound of formula (X) R⁶ can be substituted heteroarylalkyl. More specifically, a compound of formula (X) can be any of the following structures:

In various embodiments, for a compound of formula (X), R⁵ and R⁶ together can form a heterocyclyl. More specifically, a compound of formula (X) can be any of the following structures:

or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof. In various embodiments, for a compound of formula (X), R⁹ can be cycloalkyl. More specifically, a compound of formula (X) can be any of the following structures:

In various embodiments, for a compound of formula (X), R⁹ can be aroyl. More specifically, a compound of formula (X) can be any of the following structures:

In various embodiments, for a compound of formula (X), R9 can be alkynyl. More specifically, a compound of formula (X) can be any of the following structures:

In various embodiments, for a compound of formula (X), R⁹ can be aryl substituted with azido. More specifically, a compound of formula (X) can be any of the following structures:

In various embodiments, for a compound of formula (X,) R⁹ can be carboxyl, heteroaryl, or cycloalkyl. More specifically, a compound of formula (X) can be any of the following structures:

or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof. In various embodiments, for a compound of formula (X), R⁹ can be alkanoyl, carboxamido, aryl, or heterocyclyl. More specifically, a compound of formula (X) of claim 23 of any of the following structures:

In various embodiments, for a compound of formula (X), Z 1 , Z 2 , or both, can comprise an azidophenyl group. More specifically, a compound of formula (X) can be the following structure:

In various embodiments, for a compound of formula (X), Z 1 , Z 2 , or both, can comprise an alkynylphenyl. More specifically, a compound of formula (X) can be the following structure

In various embodiments, for a compound of formula (X), Y can be azido. More specifically, a compound of formula (X) can be any of the following structures:

In various embodiments, the inventive compound can be a dimer of formula (XIA) or (XIB)

(XIA)

More specifically, a dimer of formula (XI A) or (XIB) can be any of the following structures:

In various embodiments, a compound of the invention can be a compound of formula (XX). More specifically, a compound of formula (XX) can be any of the following structures:

In various embodiments, a compound of the invention can be a dimer of formula (XXI). More specifically, a compound of formula (XXI) can be any of the following formulas:

In various embodiments, a compound of the invention can be a compound of formula (XXII). More specifically, a compound of formula (XXII) can be of the following formula:

In various embodiments, a compound of the invention can be a compound of formula (XXIII). More specifically, a compound of formula (XXIII) can be of the following structure:

In various embodiments, a compound of the invention can be a compound of formula (XXIV). More specifically, a compound of formula (XXIV) can be of the following structure:

In various embodiments, the invention provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier; and a compound of the invention. The carrier can be any of those known in the art in which the compound of the invention has suitable stability for the use contemplated, as is discussed below.

In various embodiments, the invention provides a composition further comprising one or more additional compounds having anti-Hepatitis C virus activity. For example, the one or more additional compounds c anti-Hepatitis C virus activity can be an interferon, ribavirin, or a combination thereof. Or, the one or more additional compounds having anti-Hepatitis C virus activity can be an inhibitor of an HCV protease, or an inhibitor of an HCV polymerase, or both. More specifically, the interferon can be interferon a2b, pegylated interferon a, consensus interferon, interferon a2a,

lymphoblastoid interferon τ, or a combination thereof.

In various embodiments, the one or more additional compounds having anti- Hepatitis C virus activity can be interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, microRNA agonists or antagonists, or a combination thereof.

In various embodiments, the invention provides a method of treating an animal infected with Hepatitis C Virus, comprising administering to the animal an effective amount of a compound of the invention, or any pharmaceutically acceptable salt, solvate, hydrate, prodrug, or metabolite thereof. In various embodiments, the strain of the Hepatitis C Virus with which the animal is infected is resistant or is known to be capable of developing resistance to an anti-HCV therapy. For example, in various embodiments, treating can comprise inhibiting viral spread within the animal after exposure of the animal to an infectious inoculum of the virus. Or, treating can comprise inhibiting the Hepatitis C virus wherein the strain of the Hepatitis C virus infecting the animal is a strain that has developed resistance to an inhibitor of a Hepatitis C virus protease or of a Hepatitis C virus polymerase.

In various embodiments, a method of the invention can further comprise administering one or more additional compounds having anti-Hepatitis C virus activity prior to, after, or simultaneously with the compound of the invention, or a

pharmaceutically acceptable salt, solvate, hydrate, prodrug, or metabolite thereof. More specifically, the one or more additional compounds having anti-Hepatitis C virus activity can be an interferon, ribavirin, or a combination thereof. For example, the interferon can be interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastiod interferon τ, or a combination thereof. For example, the one or more additional compounds having anti-Hepatitis C virus activity can be interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof. In various embodiments of the method of the invention, the animal being treated for HCV infection is a human.

In various embodiments, the invention provides a method of killing, inhibiting, or blocking viral spread of a Hepatitis C Virus, comprising contacting the Hepatitis C Virus with an effective amount of a compound of claim 1, or any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or metabolite thereof sufficient to inhibit or kill, inhibit, or block viral spread of the Hepatitis C Virus. In various embodiments, the contacting is in vitro, as in experimental studies. In various embodiments, the contacting is in vivo, as in treatment of patients.

In various embodiments, the invention provides a use of a compound of the invention in preparation of a medicament for the treatment of Hepatitis C virus.

Preparation of Compounds of the Invention

Preparation of Exemplary Compounds

In general, syntheses were carried out analogously to those described in PCT patent application number PCT/US2009/052147, which is incorporated by reference herein in its entirety.

Solution percentages express a weight to volume relationship, and solution ratios express a volume to volume relationship, unless stated otherwise. Flash chromatography was carried out on silica gel (Si0₂) according to Still's flash chromatography technique (J. Org. Chem., 43, 2923, (1978).

The preparations of the compounds in the claims above were carried out using the methods outlined in PCT/US2009/052147 in conjunction with the knowledge of the person of ordinary skill in organic synthesis. The starting stilbenes are readily available from aldehydes (see, e.g., Chen et al., Organomet. Chem., 1984, 268, CI, (b) Pasqualiet al. J. Am. Chem. Soc. 1979, 101, 4740, and (c) Harris et al., J. Am. Chem. Soc. 1987, 109, 4739.) Suitable aldehydes include, for example, aromatic and hetero aromatic aldehydes.

Suitable aromatic aldehydes include, for example benzaldehyde,

benzeneacetaldehyde, 2-bromobenzaldehyde, 2-methoxybenzaldehyde, 2,3- dimethoxybenzaldehyde, benzeneacetaldehyde, 4-(methylthio)benzaldehyde, 1- naphthaldehyde, anthracene-9-carboxaldehyde, 1-pyrenecarboxaldehyde, 9H-fluorene-2- carboxaldehyde, 4-butoxybenzaldehyde, and the like, or combinations thereof.

Suitable heteroaromatic aldehydes include, for example, l-pyrrol-2-aldehyde, 1- pyrrol-3-aldehyde, furan-2-aldehyde, furan-3-aldehyde, thiophene-2-aldehyde, thiophene- 3-aldehyde, 4-pyridinecarboxaldehyde, 3-pyridinecarboxaldehyde, 2- pyridinecarboxaldehyde, 4,6-dimethyl-2-pyridinecarboxaldehyde, 4-methyl- pyridinecarboxaldehyde, pyrimidine-2-aldehyde, pyrimidine-4-aldehyde, 2-methyl- pyrimidine-4-aldehyde, 6-methylpyridine-2-aldehyde, pyrazine-2-aldehyde, pyridazine- 3-aldehyde, pyridazine-4-aldehyde, l-methylbenzimidazole-2-aldehyde, isoquinoline-4- aldehyde, 4-quinolinecarboxaldehyde, 3-quinolinecarboxaldehyde, 2- quinolinecarboxaldehyde, 2-chloro-3-quinolinecarboxaldehyde, 1 -methylindole-3- carboxaldehyde, l-acetyl-3-indolecarboxaldehyde, and the like, or combinations thereof.

All specific compounds cited in the present application have been synthesized and most have been tested for efficacy of inhibition of HCV protease bioactivity.

Compositions and Combinations

Another aspect of an embodiment of the invention provides compositions of the compounds of the invention, alone or in combination with another medicament. As set forth herein, compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, metabolites, pharmaceutically acceptable salts and mixtures thereof.

Compositions containing a compound of the invention can be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 19th Ed., 1995, incorporated by reference herein. The compositions can appear in

conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.

Typical compositions include a compound of the invention and a

pharmaceutically acceptable excipient which can be a carrier or a diluent. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which can be in the form of an ampoule, capsule, sachet, paper, or other container. When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it can be solid, semi- solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols,

polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents. The compositions can also be sterilized if desired.

The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.

If a solid carrier is used for oral administration, the preparation can be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge. If a liquid carrier is used, the preparation can be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or nonaqueous liquid suspension or solution.

Injectable dosage forms generally include aqueous suspensions or oil suspensions which can be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms can be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent. Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution. Alternatively, sterile oils can be employed as solvents or suspending agents. Preferably, the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the formulation can also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates. For injection, the formulations can optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these. The compounds can be formulated for parenteral administration by injection such as by bolus injection or continuous infusion. A unit dosage form for injection can be in ampoules or in multi-dose containers.

The formulations of the invention can be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art. Thus, the formulations can also be formulated for controlled release or for slow release.

Compositions contemplated by the present invention can include, for example, micelles or liposomes, or some other encapsulated form, or can be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations can be compressed into pellets or cylinders and implanted

intramuscularly or subcutaneously as depot injections. Such implants can employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide- polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) .

For nasal administration, the preparation can contain a compound of the invention, dissolved or suspended in a liquid carrier, preferably an aqueous carrier, for aerosol application. The carrier can contain additives such as solubilizing agents, e.g., propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabens.

For parenteral application, particularly suitable are injectable solutions or suspensions, preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil. Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application. Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch. A syrup or elixir can be used in cases where a sweetened vehicle can be employed.

A typical tablet that can be prepared by conventional tabletting techniques can contain:

Core:

Active compound (as free compound or salt thereof) 250 mg

Colloidal silicon dioxide (Aerosil)® 1.5 mg

Cellulose, microcryst. (Avicel)® 70 mg

Modified cellulose gum (Ac-Di-Sol)® 7.5 mg

Magnesium stearate Ad.

Coating:

HPMC approx. 9 mg

*Mywacett 9-40 T approx. 0.9 mg

*Acylated monoglyceride used as plasticizer for film coating.

A typical capsule for oral administration contains compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule. A typical injectable preparation is produced by aseptically placing 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.

The compounds of the invention can be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of a malcondition. Such mammals include also animals, both domestic animals, e.g.

household pets, farm animals, and non-domestic animals such as wildlife.

The compounds of the invention are effective over a wide dosage range. For example, in the treatment of adult humans, dosages from about 0.05 to about 5000 mg, preferably from about 1 to about 2000 mg, and more preferably between about 2 and about 2000 mg per day can be used. A typical dosage is about 10 mg to about 1000 mg per day. In choosing a regimen for patients it can frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.

Generally, the compounds of the invention are dispensed in unit dosage form including from about 0.05 mg to about 1000 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.

Usually, dosage forms suitable for oral, nasal, pulmonal or transdermal administration include from about 125 μg to about 1250 mg, preferably from about 250 μg to about 500 mg, and more preferably from about 2.5 mg to about 250 mg, of the compounds admixed with a pharmaceutically acceptable carrier or diluent.

Dosage forms can be administered daily, or more than once a day, such as twice or thrice daily. Alternatively dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician. Bioactivity Evaluation

It is within ordinary skill to evaluate any compound disclosed and claimed herein for effectiveness in inhibition of HCV protease and in the various cellular assays using the procedures described above and those found in the scientific literature. Accordingly, the person of ordinary skill can evaluate any of the claimed compounds for HCV protease inhibitory bioactivity without undue experimentation.

Any compound found to be an effective inhibitor of HCV protease can likewise be tested in animal models and in human clinical studies using the skill and experience of the investigator to guide the selection of dosages and treatment regimens. EXAMPLE 1

LIBRARY SCREENING PROCEDURE

Target cells were seeded the day before (10⁴ cells/well/ 96- well). The chemical library was provided in a 96- well format in DMSO solutions at lOmM concentration. The compounds were diluted to a final concentration of 20μΜ in complete medium (DMEM+10%FCS). A virus dilution containing -8.10³ HCV infectious units per ml (FFU/ml) of a cell culture adapted strain (D183, Zhong et al., J. Virology, 80, 11082-93 (2006)) was prepared in complete medium. Compound and virus dilutions were mixed 1: 1 and added to clone 2 cells, which were incubated in the presence of the virus (400 FFU/well) and compound (10μΜ) for 72 hours at 37°C. After this incubation period, the cells were fixed at room temperature (RT) with a 4% paraformaldehide solution in phosphate buffered saline (PBS, pH 7) for 20 minutes. The fixed cells were processed for colorimetric analysis as follows.

The procedure is a modification of the infectivity titration assay described in Zhong et al., Proc. Natl. Acad. Sci. USA, 102, 9294-9 (2005). Paraformaldehyde-fixed test wells are washed twice with 100 μΐ of PBS and incubated with 50 μΐ of blocking buffer (0.3% TritonXlOO, 3% bovine serum albumin -BSA-, 10% fetal calf serum-FCS and 5% hydrogen peroxide in PBS) for 1 hour at room temperature. A dilution (^g/ml) of a recombinant human IgG anti-E2 is added in incubation buffer (0.3% TritonXlOO, 3% bovine serum albumin (BSA) in PBS) for 1 hour at room temperature. The cells are washed four times with 200 μΐ of PBS and incubated with the appropriate dilution (1: 15000) of the secondary antibody conjugated to horseradish peroxidase (HRP, Goat anti-human IgG-HRP; Jackson Immunoresearch, Stanford, CA) for 1 hour at room temperature. The cells are washed again four times with 200 μΐ of PBS and the remaining peroxidase activity is evaluated by adding 3,3',5,5'-tetramethylbenzidine (TMB; Pierce, Rockford, IL) to the cells in the presence of hydrogen peroxide. The oxidation of TMB leads to the generation of a blue product that absorbs light at 650 nm. Before this colorimetric reaction reaches saturation levels, the reaction can be stopped by the addition of 1 volume of IN H₂SO₄, which generates a yellow product with an optimal absorbance of 450 nm. Each plate includes a standard curve with serial 2-fold dilutions of the virus to ensure appropriate colorimetric value transformation and negative controls (uninfected cells) to determine the background of the assay. Compounds with known antiviral capacity have been included in the process as quality controls of the assay and, as expected, their antiviral activity was also demonstrated using this technology. The signals above the background s in each well are expressed as percentage of the control after data transformation using the standard curve. Values below 20% of the control should be considered positive hits.

The screening technology described above does not discriminate between an antiviral compound and a false-positive result, as both should be associated with a reduced O.D.45o_nm signal. As for many cell-based assays, the readout relies on viable, proliferating cells. Since the virus requires actively dividing cells for efficient replication and viral antigen quantitation relies on the presence of similar amounts of cells in the well, a non-specific toxic effect of a given compound should lead to a false-positive readout. To avoid problem, the impact of the compounds on cell viability was evaluated. During the screening process, false -positive results were identified by measuring the cell biomass per well by staining the cells with crystal violet (1% solution in 50% ethanol- water) {see, e.g., Bernhardt et al. J. Cancer Res. Clin. Oncology, 118, 35-43 (1992)). The excess dye was extensively washed off with water and the bound dye was solubilized in 50 ml of a 1% SDS solution in water. The optical density was determined at 570 nm (biomass) and 690 nm (plate background). The difference between the O.D.57₀_690nm was used to calculate the relative biomass present in each well using vehicle-treated wells as a reference. This staining reflects the number of live cells in the well at the moment of fixation. Using this approach, it was possible to discriminate a positive hit from a false- positive for compounds that are toxic and whose antiviral activity cannot be evaluated using this system. The wells with biomass values below 75% of the positive control were considered false-positive and discarded for further analysis. Compounds for which antiviral activity in the absence of toxic effects was confirmed, were considered for further evaluation. See Gastaminza P, Whitten-Bauer C, Chisari FV. Unbiased probing of the entire hepatitis C virus life cycle identifies clinical compounds that target multiple aspects of the infection. Proc Natl Acad Sci U S A. 2010 Jan 5;107(l):291-6. Epub 2009 Dec 7. PubMed PMID: 19995961, incorporated by reference herein in its entirety. The candidate molecules selected after this primary screening were tested in a second round (counterscreening) using the same screening concentration. During this process, molecules with similar chemical structures were added to the collection in order to identify common structural features that confer antiviral activity against HCV. The hits obtained in this second round were tested in a third round of counterscreening to clearly identify inhibitory molecules.

Potency and Toxicity

It was desirable to define the measurable parameters to be used to evaluate the significance of the antiviral activity of a given compound. Compounds were generally ranked based on their potency, a parameter that is defined by the inhibitory concentration 50 (IC₅₀). The IC₅₀ is the concentration at which the compound inhibits the maximum value of the assay by 50%. This parameter is generally accompanied by the toxicity of the compound, provided as the lethal dose 50 (LD₅₀). The LD₅₀ is the concentration of compound that reduces cell viability by 50%. In general, candidates with a low IC₅₀ and a high LD₅₀ receive high priority, since the likelihood of the specificity of the observed antiviral effect increases as these two indices differ.

Potency (ICsn)

In order to determine the IC₅₀, serial dilutions of the different antiviral compounds were assayed using the colorimetric assay. Serial 2-fold dilutions of the compound were prepared. These solutions (50 ml) were mixed with 50 ml of an 8.10^J FFU/ml virus dilution in complete medium containing final compound concentrations starting at 50μΜ. The mixture was transferred into a 96- well plate containing 10⁴ clone 2 cells per well seeded the day prior to the experiment. The cultures were incubated for a period of 72 hours at 37°C, after which the cells were fixed and processed for colorimetric analysis as described above. IC₅₀ is defined as the compound concentration that should reduce HCV by 50%, based on the values obtained after O.D. transformation with the standard curve.

Toxicity (LDsn)

Our preliminary toxicity results ensure that the selected compounds are non-toxic at the screening concentration (10μΜ). However, in order to measure precisely the toxicity (LD₅₀) of the selected compounds, cell viability was measured in the presence of increasing concentrations of the antiviral compounds. Cell viability may be determined by measuring the mitochondrial metabolic capacity of the cells at any given time point. This may be achieved by culturing metabolically active cells with a modified soluble tetrazolium salt Thiazolyl Blue Tetrazolium Bromide also called MTT (Sigma- Aldrich, St.Louis, MO), which transforms MTT into formazan, a purple precipitate. This transformation, dependent on mitochondrial dehydrogenases, was quantified within 2-4 hours using a colorimetric assay that is read at 570 nm. The LD₅₀ of a particular compound was determined similarly to the IC₅₀. Serial dilutions of the compound (typically from 100 μΜ to 100 nanoM) in complete medium were added to the cells and incubated for 72 hours. Cell viability was analyzed by adding MTT (5μg/ml final concentration) and measuring the resulting formazan content, after resuspension in 100% DMSO, at 570 nm in a microplate spectrophotometer. LD₅₀ values were obtained by plotting the colorimetric values (O.D.57o_nm) versus the compound concentration and determining the concentration that rendered 50% of the activity observed in the control. This procedure is widely used for determination of cell viability because it is rapid, simple and yields highly reproducible results.

Compounds specifically defined herein were assigned the following compound ID #s, and most were tested for IC₅₀, IC₉₀, and LD₅₀ values as described above. Selected results are shown in Table 1, below.

Table 1 : Bioactivities of Selected Exemplary Compounds

IC₅₀ and IC₉₀ versus HCV protease bioactivity LD₅₀ versus cells A: < 0.1 μΜ concentration B: 0.1 < μΜ concentration < 1.0 μΜ

C: 1.0 < μΜ concentration < 10.0 μΜ

D: > 10.0 μΜ concentration

-: not tested

Remaining compounds that were tested exhibited:

ECso values of B and C except compound 211, 220, 221, 239, 240, 241, 246, 251, 258, 261, 285, 290, 291, 292, 296, 298, 305, 317, 318-322: = D;

EC₉₀ values (if determined) of C and D;

LD₅₀ values (if determined) of D except for compounds 171, 172 : = C. While the invention has been described and exemplified in sufficient detail for those skilled in this art to make and use it, various alternatives, modifications, and improvements will be apparent to those skilled in the art without departing from the spirit and scope of the claims.

All patents and publications referred to herein are incorporated by reference to the same extent as if each individual publication was specifically and individually indicated to be incorporated by reference.

The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the appended claims.

Claims

What is claimed is:

1. A compound of formula (X):

(X)

wherein:

a dotted line indicates an optional double bond;

R 1 and R 2" are independently at each occurrence hydrogen, (C₁-C₆)alkyl, (C₆- C₁₀)aryl, or 3-8 membered heterocyclyl, wherein any alkyl, aryl, or heterocyclyl group can be substituted or unsubstituted; or

R⁵ is absent, carbonyl, thiocarbonyl, or sulfonyl; R⁶ is hydrogen, substituted or unsubstituted alkyl, cycloalkoxy, cycloalkylalkoxy, alkynyloxy, aralkoxy, heterocyclyloxy, cycloalkylamino, cycloalkylalkylamino, alkenylamino, arylamino, aralkylamino, heterocyclylamino, aroylamido, heteroaryl, or heteroarylalkyl;

or, R⁵ and R⁶ taken together can form a heterocyclyl;

or a dimer thereof of formula (XIA) or (XIB)

(XIB) comprising two structures of formula (X) as defined above but wherein, for formula (XIA), R⁶ comprises a (C₁-C₁2)alkylene diamine moiety bonded to two respective R⁵ groups, wherein R⁵ is carbonyl, thiocarbonyl, or sulfonyl; or, wherein for formula (XIB),

R 9 comprises a (C₁-C 7

12)alkylene diamine moiety bonded to two respective R groups, wherein R 7 is carbonyl, thiocarbonyl, or sulfonyl, and R 8 is absent;

or a compound of formula (XX)

wherein

W is N or CH;

Q is OH or NHR²⁰;

R 21 is aralkyl or alkoxycarbonyl;

or a dimer thereof of formula (XXI)

wherein W and R are as defined above and wherein R comprises an alkylene bis(aminocarbonyl) group;

or a compound of formula (XXII)

wherein W is N or CH and R is hydrogen, alkylaminocarbonyl or arylaminocarbonyl, and R 21 is as defined above, wherein any alkyl or aryl can be substituted;

or a compound of formula (XXIII)

(XXIII)

wherein R is hydrogen or (Q-C^alkyl;

or a compound of formula (XXI

wherein R⁵ and R⁶ are as defined above;

2. The compound of formula (X) of claim 1 wherein R⁶ is cycloalkoxy, cycloalkylalkoxy, alkynyloxy, , aralkoxy, or heterocyclyloxy.

3. The compound of formula (X) of claim 2 of any of the following structures:

4. The compound of formula (X) of claim 1 wherein R⁶ is cycloalkylamino or alkenylamino.

5. The compound of formula (X) of claim 4 of any of the following structures:

The compound of formula (X) of claim 1 wherein R⁶ is arylamino, aralkylamino, ylamido.

The compound of formula (X) of claim 6 of any of the following structures:

8. The compound of formula (X) of claim 1 wherein R⁶ is substituted or unsubstituted alkyl.

9. The compound of formula (X) of claim 8 of any of the following structures:

10. The compound of formula (X) of claim 1 wherein R⁶ is substituted heteroarylalkyl.

1. The compound of formula (X) of claim 10 of any of the following structures:

12. The compound of formula (X) of claim 1 wherein R⁵ and R⁶ together form a heterocyclyl.

13. The compound of formula (X) of claim 12 of any of the following structures:

14. The compound of formula (X) of claim 1 wherein R⁹ is cycloalkyl.

15. The compound of formula (X) of claim 14 of any of the following structures:

16. The compound of formula (X) of claim 1 wherein R⁹ is aroyl.

17. The compound of formula (X) of claim 16 of any of the following structures:

18. The compound of formula (X) of claim 1 wherein R⁹ is alkynyl.

19. The compound of formula (X) of claim 18 of any of the following structures:

20. The compound of formula (X) of claim 1 wherein R⁹ is aryl substituted with azido.

21. The compound of formula (X) of claim 20 of any of the following structures:

22. The compound of formula (X) of claim 1 wherein R⁹ is carboxyl, heteroaryl, or cycloalkyl.

23. The compound of formula (X) of claim 22 of any of the following structures:

24. The compound of formula (X) of claim 1 wherein R⁹ is alkanoyl, carboxamido, aryl, or heterocyclyl.

The compound of formula (X) of claim 24 of any of the following structures:

26. The compound of formula (X) of claim 1 wherein Z¹, Z², or both, comprise an azidophenyl group.

27. The compound of formula (X) of claim 26 of the following structure:

28. The compound of formula (X) of claim 1 wherein Z¹, Z², or both, comprise an alkynylphenyl.

29. The compound of formula (X) of claim 28 of the following structure

30. The compound of formula (X) of claim 1 wherein Y is azido.

31. The compound of formula (X) of claim 30 of any of the following structures:

32. A dimer of formula (XIA) or (XIB)

(XIB). The dimer of formula (XI A) or (XIB) of any of the following structures:

or a pharmaceutically acceptable salt, a solvate or hydrate, a prodrug, or a metabolite thereof. A compound of formula (XX) of claim 1 of any of the following structures:

35. A dimer thereof of formula (XXI) of claim 1 of any of the following formulas:

36. A compound of formula (XXII) of claim 1 of the following formula:

37. A compound of formula (XXIII) of claim 1 of the following structure

A compound of formula (XXIV) of claim 1 of the following structure

39. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier; and a compound of claim 1.

40. The composition of claim 39, further comprising one or more additional compounds having anti-Hepatitis C virus activity.

41. The composition of claim 40, wherein the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof.

42. The composition of claim 40 wherein the one or more additional compounds having anti-Hepatitis C virus activity is an inhibitor of an HCV protease, or an inhibitor of an HCV polymerase, or both.

43. The composition of claim 41, wherein the interferon comprises interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastoid interferon τ, or a combination thereof.

44. The composition of claim 40, wherein the one or more additional compounds having anti-Hepatitis C virus activity comprises interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, microRNA agonists or antagonists, or a combination thereof.

45. A method of treating an animal infected with Hepatitis C Virus, comprising administering to the animal an effective amount of a compound of claim 1, or any pharmaceutically acceptable salt, solvate, hydrate, prodrug, or metabolite thereof.

46. The method of claim 45, wherein a strain of the Hepatitis C Virus with which the animal is infected is resistant or is known to be capable of developing resistance to an anti-HCV therapy.

47. The method of claim 46 wherein treating comprises inhibiting viral spread within the animal after exposure of the animal to an infectious inoculum of the virus.

48. The method of claim 47, wherein a strain of the Hepatitis C virus infecting the animal is a strain that has developed resistance to an inhibitor of a Hepatitis C virus protease or of a Hepatitis C virus polymerase.

49. The method of claim 45, further comprising administering one or more additional compounds having anti-Hepatitis C virus activity prior to, after, or simultaneously with the compound of claim 1 or a pharmaceutically acceptable salt, solvate, hydrate, prodrug, or metabolite thereof.

50. The method of claim 49, wherein the one or more additional compounds having anti-Hepatitis C virus activity are an interferon, ribavirin, or a combination thereof.

51. The method of claim 50, wherein the interferon comprises interferon a2b, pegylated interferon a, consensus interferon, interferon a2a, lymphoblastoid interferon x, or a combination thereof.

52. The method of claim 49, wherein the one or more additional compounds having anti-Hepatitis C virus activity comprises interleukin 2, interleukin 6, interleukin 12, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5'-monophospate dehydrogenase inhibitor, amantadine, rimantadine, or a combination thereof.

53. The method of claim 45, wherein the animal is a human.

54. A method of killing, inhibiting, or blocking viral spread of a Hepatitis C Virus, comprising contacting the Hepatitis C Virus with an effective amount of

a compound of claim 1, or any pharmaceutically acceptable salt, prodrug, solvate, hydrate, or metabolite thereof sufficient to inhibit or kill, inhibit, or block viral spread of the Hepatitis C Virus.

55. The method of claim 54, wherein the contacting is in vitro.

56. The method of claim 54, wherein the contacting is in vivo.

57. Use of a compound of claim 1 in preparation of a medicament for the treatment of Hepatitis C virus.