Thiazole compounds and methods of use   

Abstract: wherein the variables Ar1, R2, R3, R4, r, q, and t are defined herein. Certain compounds of Formula I described herein possess potent antiviral activity. The invention also provides compounds of Formula I that are potent and/or selective inhibitors of Hepatitis C virus replication. Certain compounds described herein inhibit assembly of the HCV replication complex. The invention also provides pharmaceutical compositions containing one or more compounds of Formula I, or a salt, solvate, or acylated prodrug of such compounds, and one or more pharmaceutically acceptable carriers, excipients, or diluents. The invention further comprises methods of treating patients suffering from certain infectious diseases by administering to such patients an amount of a compound of Formula I effective to reduce signs or symptoms of the disease. These infectious diseases include viral infections, particularly HCV infections. The invention is particularly includes methods of treating human patients suffering from an infectious disease, but also encompasses methods of treating other animals, including livestock and domesticated companion animals, suffering from an infectious disease. Methods of treatment include administering a compound of Formula I as a single active agent or administering a compound of Formula I in combination with on or more other therapeutic agent. The present invention provides compounds, salts and hydrates of Formula I,

This application claims priority from U.S. Provisional Application Ser. No. 60/679,133, filed May 9, 2005, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to thiazole compounds and the preparation of such compounds. The present invention further relates to methods for use of such compounds, including for the treatment of hepatitis C virus.

BACKGROUND OF THE INVENTION

Hepatitis C Virus (HCV) is one of the most prevalent causes of chronic liver disease in the United States, reportedly accounting for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. It has been estimated that almost 4 million Americans, or about 1.8 percent of the U.S. population, have antibodies to HCV (i.e., anti-HCV antibodies), indicating previous or ongoing infection with the virus. Hepatitis C causes an estimated 8,000 to 10,000 deaths annually in the United States. While the acute phase of HCV infection is usually associated with mild symptoms, some evidence suggests that only about 15% to 20% of infected people will clear HCV.

It has been reported that HCV is an enveloped, single-stranded RNA virus that contains a positive-stranded genome of about 9.6 kb. HCV is classified as a member of the Hepacivirus genus of the family Flaviviridae.

The HCV lifecycle includes entry into host cells; translation of the HCV genome, polyprotein processing, and replicase complex assembly; RNA replication, and virion assembly and release. Translation of the HCV RNA genome yields a more than 3000 amino acid long polyprotein that is processed by at least two cellular and two viral proteases. The HCV polyprotein is:

NH2—C-E1-E2-p7-NS2-NS3-NS4A-NS4B—NS5A-NS5B—COOH.

The cellular signal peptidase and signal peptide peptidase have been reported to be responsible for cleavage of the N-terminal third of the polyprotein (C-E1-E2-p7) from the nonstructural proteins (NS2-NS3-NS4A-NS4B—NS5A-NS5B). The NS2-NS3 protease mediates a first cis cleavage at the NS2-NS3 site. The NS3-NS4A protease then mediates a second cis-cleavage at the NS3-NS4A junction. The NS3-NS4A complex then cleaves at 3 downstream sites to separate the remaining nonstructural proteins. Accurate processing of the polyprotein is asserted to be essential for forming an active HCV replicase complex.

Once the polyprotein has been cleaved, the replicase complex comprising at least the NS3-NS5B nonstructural proteins assembles. The replicase complex is cytoplasmic and membrane-associated. Major enzymatic activities in the replicase complex include serine protease activity and NTPase helicase activity in NS3, and RNA-dependent RNA polymerase activity of NS5B. In the RNA replication process, a complementary negative strand copy of the genomic RNA is produced. The negative strand copy is used as a template to synthesize additional positive strand genomic RNAs that may participate in translation, replication, packaging, or any combination thereof to produce progeny virus. Assembly of a functional replicase complex has been described as a component of the HCV replication mechanism. Provisional application docket no. A&P 18477.047, “Pharmaceutical compositions for and Methods of Inhibiting HCV Replication,” inventor Mingjun Huang, filed Apr. 11, 2005 is hereby incorporated by reference for in its entirety for its disclosure related to assembly of the replicase complex.

While previously known HCV inhibitors are suitable for their intended purposes, there nonetheless remains a need for additional HCV inhibitors. In addition, there remains a need for additional methods of treatment for HCV patients. Thus, there remains a need to develop, characterize and optimize molecules for the development of anti-hepatitis C drugs. Accordingly, it is an object of the present invention to provide such compounds, compositions and methods of treatment.

SUMMARY

In accordance with the present invention, compounds that inhibit hepatitis C virus replication have been identified, and methods for use of such compounds are provided.

In one aspect, the present invention includes and provides compounds of Formulas (I) and pharmaceutically acceptable salts thereof, which compounds are useful in the inhibition of hepatitis C virus replication and the treatment of hepatitis C viral infection. Within this aspect, the invention includes compounds of Formula I

and pharmaceutically acceptable salt or hydrate thereof, wherein the variables Ar1, R2, R3, R4, q, r, and t carry definitions set forth below.

Ar1 is fluorenyl, or Ar1 is phenyl, naphthyl, a 5- or 6-membered monocyclic heteroaryl group, or a 9- or 10-membered bicyclic heteroaryl group, wherein Ar1 is substituted with R and R1.

R is 0 or one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

R1 is one or two substituents independently chosen from (a) and (b), where (a) is halogen, hydroxyl, amino, cyano, nitro, —COOH, —SO2NH2C1-C2haloalkyl, and C1-C2haloalkoxy, and (b) C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10alkanoyl, C2-C10alkylester, C1-C10 alkoxy, mono- or di-C1-C10alkylcarboxamide, or a group —YZ.

Y is bond, or Y is C1-C10alkyl, a C2C10alkenyl, or C2-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain.

Z is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkenyl, heterocycloalkyl, phenyl, naphthyl, indanyl, (C3-C7cycloalkyl)C0-C10alkoxy, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy;

Any R and R1 which are covalently bound to adjacent carbon atoms may be joined to form an aromatic or partially saturated carbocyclic ring system having 1 or 2 rings, each ring having 5 or 6 ring carbon atoms.

R2 is halogen, —COOH, —CONH2, —C(O)OCH3, —C(O)CH3, —NHC(O)OH, or amino, or

R2 is —CH2Ra, —NH—S(O)2Ra, —CH2—NH—S(O)2Ra, —S(O)2Ra, —C(O)—NH—Ra, —C(O)—NH—CH2Ra, —NH—C(O)—Ra, —NH—C(O)—Rb, —C(O)O—Ra, —C(O)—O—Rb, —ORa, —C(O)—Ra, or —C(O)—Rb, each of which is substituted with 0 or one or more substituents independently chosen from (c), (d), and (e), or

R2 is C1-C6alkyl, phenyl, a 5- to 6-membered heteroaryl, phenyl fused to a 5 or 6 membered cycloalkyl or heterocycloalkyl ring, or a bicyclic 8- to 10-membered heteroaryl, each of which is substituted with 0 or one or more substituents independently chosen from (c), (d), and (e); where

(c) is halogen, hydroxyl, oxo, cyano, amino, nitro, —C(O)NH2, —C(O)OH, —S(O)NH2, C1-C2haloalkyl, and C1-C2haloalkoxy,

(d) is C1-C4alkyl, C1-C4alkoxy, C2-C4alkenyl, mono- and di-C1-C6alkylamino, mono- and di-(C1-C4alkyl)carboxamide, mono- or di(C1-C4alkyl)sulfonamide, C1C4alkylester, each of which is substituted with 0 or one or more substituents independently chosen from oxo, halogen, hydroxyl, oxo, cyano, amino, nitro, —C(O)NH2, —C(O)OH, —S(O)NH2, C1-C4alkoxy, mono- and di-C1-C6alkylamino, mono- and di-(C1-C4alkyl)carboxamide, mono- or di(C1-C4alkyl)sulfonamide, C1C4alkylester C1-C2haloalkyl, and C1-C2haloalkoxy; and

(e) (C3-C7cycloalkyl)C0-C4alkyl, (heterocycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, each of which is substituted with oxo, halogen, hydroxyl, oxo, cyano, amino, nitro, —C(O)NH2, —C(O)OH, —S(O)NH2, C1-C2haloalkyl, and C1-C2haloalkoxy.

R2 and R4 are taken together with the carbon atoms of the thiazole ring to which they are attached to form a C5-C7 carbocyclic ring, which is aromatic or partially unsaturated;

R3 is hydrogen, C1-C4alkyl, or —C(O)—Rd.

R4 is hydrogen, halogen, hydroxyl, amino, cyano, nitro, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy or phenyl; or R4 is taken together with R2 to form a ring;

Ra is independently chosen at each occurrence from: heterocycloalkyl, phenyl, and 5- and 6-membered heteroaryl, each of which is substituted with 0 or one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C1-C4 alkyl, and C1-C4 alkoxy.

Rb is C1-C6 alkyl, wherein the alkyl is optionally substituted with a halogen, hydroxyl, —C(O)OH, phenyl, or 4-(NH2S(O)2)-phenyl.

Rd is C1-C6alkyl, phenyl, or 5- to 6-membered heteroaryl; r is 0, 1, or 2; q is 0 or 1; t is 0 or 1; and q and t are not both 1.

In another aspect, the present invention includes and provides pharmaceutical compositions comprising compounds of the present invention.

In another aspect, the present invention includes and provides methods for the inhibition of hepatitis C virus replication using compounds of the present invention.

In a further aspect, the present invention includes and provides methods for the treatment or prevention of hepatitis C viral infection.

In an aspect, the present invention includes and provides a method for treating or preventing hepatitis C virus in a subject in need thereof, said method comprising: administering to the subject an amount of a compound of formula (I), including compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), and (I-g), or a pharmaceutically acceptable salt, hydrate, prodrug or metabolite thereof, where hepatitis C virus is treated or prevented. The compound of formula I may be administered to the subject alone or may be administered to the subject in combination with one or more other active agents, such as one or more other anti-viral agents.

These and other aspects of the invention will be more clearly understood with reference to the following detailed description, examples and claims.

DETAILED DESCRIPTION

Prior to setting forth the invention in detail, it may be helpful to provide definitions of certain terms to be used herein. Compounds of the present invention are described using standard nomenclature. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

Formula I includes all subformulae thereof. For example Formula I includes compounds of Formulas (I-a), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), and (I-i) and the pharmaceutically acceptable salts, prodrugs, hydrates, polymorphs, and thereof.

The term Formula I encompasses all compounds that satisfy Formula I, including any enantiomers, racemates and stereoisomers, as well as all pharmaceutically acceptable salts of such compounds. The phrase “a compound of Formula I” includes all forms of such compounds, including salts and hydrates, unless clearly contraindicated by the context in which this phrase is used.

The terms “a” and “an” do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item. The term “or” means “and/or”. The terms “comprising”, “having”, “including”, and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to”). Recitation of ranges of values are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. The endpoints of all ranges are included within the range and independently combinable. All methods described herein can be performed in a suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”), is intended merely to better illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention as used herein. Unless defined otherwise, technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs.

In certain situations, the compounds of Formula I may contain one or more asymmetric elements such as stereogenic centers, including chiral centers, stereogenic axes and the like, e.g. asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. For compounds with two or more asymmetric elements, these compounds can additionally be mixtures of diastereomers. For compounds having asymmetric centers, it should be understood that all of the optical isomers and mixtures thereof are encompassed. In addition, compounds with carbon-carbon double bonds may occur in Z- and E-forms, with all isomeric forms of the compounds being included in the present invention.

The term “chiral” refers to molecules, which have the property of non-superimposability of the mirror image partner.

The term “stereoisomers” refers to compounds, which have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

“Diastereomer” refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high resolution analytical procedures such as electrophoresis, crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.

“Enantiomers” refer to two stereoisomers of a compound, which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with (−) or 1 meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms “racemic mixture” and “racemate” refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers, but rather includes all tautomeric forms.

The invention includes compounds of Formula I having all possible isotopes of atoms occurring in the compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example, and without limitation, isotopes of hydrogen include tritium and deuterium and isotopes of carbon include 11C, 13C, and 14C.

Certain compounds are described herein using a general formula that includes variables, e.g. R, R1, R2, R3, R4, t, q, and r. Unless otherwise specified, each variable within such a Formula I is defined independently of other variables. Thus, if a group is said to be substituted, e.g. with 0-2 R*, then said group may be substituted with up to two R* groups and R* at each occurrence is selected independently from the definition of R*. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.

The term “substituted”, as used herein, means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom\'s normal valence is not exceeded. When the substituent is oxo (i.e., ═O), then 2 hydrogens on the atom are replaced. When aromatic moieties are substituted by an oxo group, the aromatic ring is replaced by the corresponding partially unsaturated ring. For example a pyridyl group substituted by oxo is a pyridone. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation into an effective therapeutic agent.

A dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —(CH2)C3-C8cycloalkyl is attached through carbon of the methylene (CH2) group.

“Alkanoyl” indicates an alkyl group as defined herein, attached through a keto (—(C═O)—) bridge. Alkanoyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms. For example a C2alkanoyl group is an acetyl group having the formula CH3(C═O)—.

As used herein, the term “alkyl” includes both branched and straight chain saturated aliphatic hydrocarbon groups, having the specified number of carbon atoms, generally from 1 to about 18 carbon atoms, though in some embodiments alkyl groups having from 1 to 10, 1 to 8, 1 to 6, 1 to 4, or 1 to 2 carbon atoms are preferred.

“Alkenyl” as used herein, includes straight and branched hydrocarbon chains comprising one or more unsaturated carbon-carbon bonds, which may occur in any stable point along the chain. Alkenyl groups described herein typically have from 2 to about 12 carbons atoms. Preferred alkenyl groups are lower alkenyl groups, those alkenyl groups having from 2 to about 8 carbon atoms, e.g. C2-C8, C2-C6, and C2-C4 alkenyl groups. Examples of alkenyl groups include ethenyl, propenyl, and butenyl groups.

“Alkynyl” as used herein, includes straight or branched hydrocarbon chain comprising one or more triple carbon-carbon bonds that may occur in any stable point along the chain, such as ethynyl and propynyl. Alkynyl groups described herein typically have from 2 to about 12 carbons atoms. Preferred alkynyl groups are lower alkynyl groups, those alkynyl groups having from 2 to about 8 carbon atoms, e.g. C2-C10, C2-C6, and C2-C4 alkynyl groups.

The term “alkylester” indicates an alkyl group as defined herein attached through an ester linkage. The ester linkage may be in either orientation, e.g. a group of the formula —O(C═O)alkyl or a group of the formula —(C═O)Oalkyl.

“Alkoxy” indicates an alkyl group as defined above with the indicated number of carbon atoms attached through an oxygen bridge (—O—). Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, 2-butoxy, t-butoxy, n-pentoxy, 2-pentoxy, 3-pentoxy, isopentoxy, neopentoxy, n-hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. C4-C10alkoxy group

As used herein, the term “aryl” includes radicals of an aromatic group obtained by removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system and containing only carbon in the aromatic ring or rings. Aromatic rings have 4n+2 p electrons in a cyclic arrangement. Such aromatic groups may be further substituted with carbon or non-carbon atoms or groups. Typical aryl groups contain 1 or 2 separate, fused, or pendant rings and from 6 to about 12 ring atoms, without heteroatoms as ring members. Where indicated aryl groups may be substituted. Such substitution may include fusion to a 5 to 7-membered saturated cyclic group that optionally contains 1 or 2 heteroatoms independently chosen from N, O, and S, to form, for example, a 3,4-methylenedioxy-phenyl group. Aryl groups include, for example, phenyl, naphthyl, including 1-naphthyl and 2-naphthyl, and bi-phenyl.

A “carbocyclic ring” may have 1 to 3 fused, pendant, or spiro rings, containing only carbon ring members. Typically, a carbocyclic ring comprises contains from 3 to 8 ring members (rings having from 4 or 5 to 7 ring members are recited in certain embodiments) and carbocycles comprising fused, pendant, or spiro rings typically contain from 9 to 14 ring members. Unless otherwise specified, a carbocycle may be a cycloalkyl group (i.e., each ring is saturated), a partially saturated group, or an aryl group (i.e., at least one ring within the group is aromatic). A carbocyclic group may generally be linked via any ring or substituent atom, provided that a stable compound results. When indicated carbocylic groups, such as 4- to 7-membered or 5- to 7-membered groups, may be substituted. Representative aromatic carbocycles are phenyl, naphthyl and biphenyl. In certain embodiments preferred carbocycles are carbocycles having a single ring, such as phenyl and 3- to 7-membered cycloalkyl groups.

“Cycloalkyl” as used herein, includes a monocyclic saturated hydrocarbon ring group, having the specified number of carbon atoms. Monocyclic cycloalkyl groups typically have from 3 to about 8 carbon ring atoms or from 3 to about 7 carbon ring atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

In the term “(cycloalkyl)alkyl”, cycloalkyl and alkyl are as defined above, and the point of attachment is on the alkyl group. This term encompasses, but is not limited to, cyclopropylmethyl, cyclohexylmethyl, and cyclohexylmethyl. (Cycloalkyl)C0-C2alkyl″ indicates a cycloalkyl group that is directly attached via a single covalent bond (i.e. (cycloalkyl)C0alkyl) or attached through an alkyl group having from 1 to about 2 carbon atoms. Similarly in the term “(cycloalkyl)alkoxy”, cycloalkyl and alkoxy are as defined above, and the point of attachment the oxygen of the alkoxy. “(Cycloalkyl)C0alkoxy is a cycloalkyl group that is attached through an oxygen linker.

As used herein the term “mono- and/or di-alkylcarboxamide” includes groups of formula (alkyl1)—NH—(C═O)— and (alkyl1)(alkyl2)—N—(C═O)— in which the alkyl1 and alkyl2 groups are independently chosen alkyl groups as defined above having the indicated number of carbon atoms.

As used herein “Haloalkyl” indicates both branched and straight-chain alkyl groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms, generally up to the maximum allowable number of halogen atoms. Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.

“Haloalkoxy” indicates a haloalkyl group as defined above attached through an oxygen bridge.

“Halogen” as used herein includes fluorine, chlorine, bromine, and iodine. In the context of the present invention, a substituent may be a halogen or may be substituted with a halogen.

“Heteroaryl” as used herein includes an aryl group, wherein one or more carbon atoms has been replaced with another atom. For example, in an embodiment, “heteroaryl” includes an aryl group as defined herein, wherein one or more carbon atoms has been replaced with oxygen, nitrogen, or sulfur. Heteroaryl includes stable 5- to 7-membered monocyclic aromatic rings which contains from 1 to 4, or preferably from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. Heteroaryl also includes stable bicyclic or tricyclic systems containing at least one 5- to 7-membered aromatic ring which contains from 1 to 3, or preferably from 1 to 2, heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon. When the total number of S and O atoms in the heteroaryl group exceeds 1, these heteroatoms are not adjacent to one another. It is preferred that the total number of S and O atoms in the heteroaryl group is not more than 2. It is particularly preferred that the total number of S and O atoms in the aromatic heterocycle is not more than 1.

The term “heterocycloalkyl” includes a saturated monocyclic group containing from 1 to about 3 heteroatoms chosen from N, O, and S, with remaining ring atoms being carbon, or a saturated bicyclic ring system having at least one N, O, or S ring atom with remaining atoms being carbon. Monocyclic heterocycloalkyl groups have from 4 to about 8 ring atoms, and more typically have from 5 to 7 ring atoms. Examples of heterocycloalkyl groups include morpholinyl, piperazinyl, piperidinyl, and pyrrolidinyl groups.

“Heterocycle” as used herein includes by way of example and not limitation these heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention “heterocycle” includes a “cyclic alkyl” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have been replaced with a heteroatom (e.g. O, N, or S).

Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

By way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, or 4 of a pyridine, position 3 or 4 of a pyridazine, position 2, 4, or 5 of a pyrimidine, position 2 or 3 of a pyrazine, position 2 or 3 of a furan, tetrahydrofuran, thiofuran, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 2-pyrazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

As used herein, the term “mono- and/or di-alkylamino” includes secondary or tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. The alkyl groups are independently chosen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino. “Mono- and/or dialkylaminoalkyl” groups are mono- and/or di-alkylamino groups attached through an alkyl linker having the specified number of carbon atoms, for example a di-methylaminoethyl group. Tertiary amino substituents may by designated by nomenclature of the form N—R—N—R′, indicating that the groups R and R′ are both attached to a single nitrogen atom.

“Phenoxy” means a conjugate base of a phenyl alcohol. “(Phenyl)alkyl is a phenyl group covalently bound to an alkyl radical as described above. Similarly “(phenyl)alkoxy” refers to a phenyl group covalently bound to an alkoxy radical as described above. Non-limiting exemplary phenoxy radicals include:

The term “treatment” or “treating,” to the extent it relates to a disease or condition includes preventing the disease or condition from occurring, inhibiting the disease or condition, eliminating the disease or condition, and/or relieving one or more symptoms of the disease or condition.

“Pharmaceutically acceptable salts” includes derivatives of the disclosed compounds wherein the parent compound is modified by making non-toxic acid or base salts thereof, and further refers to pharmaceutically acceptable solvates of such compounds and such salts. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts and the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, conventional non-toxic acid salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, mesylic, esylic, besylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, HOOC—(CH2)n—COOH where n is 0-4, and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound, a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred, where practicable. Lists of additional suitable salts may be found, e.g., in Remington\'s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa.

The term “pharmaceutically acceptable excipient” refers to an excipient for administration of a pharmaceutical agent, such as the compounds of the present invention. The term refers to any pharmaceutical excipient that may be administered without undue toxicity. Pharmaceutically acceptable excipients are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there exist a wide variety of suitable pharmaceutical formulations of the present invention. The formulations may be prepared by any of the methods known in the art of pharmacy. For example, exemplary techniques and formulations are found in Remington\'s Pharmaceutical Sciences (Mack Publishing Co., Easton, Pa.). In a preferred aspect, formulations of the present invention are prepared by uniformly and intimately bringing into association the active ingredient, e.g., a compound of the present invention, with liquid carriers or finely divided solid carriers or both, and then, optionally shaping the product.

The term “prodrugs” includes any compounds that become compounds of Formula I when administered to a mammalian subject, e.g., upon metabolic processing of the prodrug. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I.

The term “therapeutically effective amount” of a compound of this invention means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as an amelioration of symptoms, e.g., an amount effective to decrease the symptoms of a viral infection, and preferably an amount sufficient to reduce the symptoms of an HCV infection. In certain circumstances a patient suffering from a viral infection may not present symptoms of being infected. Thus a therapeutically effective amount of a compound is also an amount sufficient to prevent a significant increase or significantly reduce the detectable level of virus or viral antibodies in the patient\'s blood, serum, or tissues. A significant increase or reduction in the detectable level of virus or viral antibodies is any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student\'s T-test, where p<0.05.

A “replicon” as used herein includes any genetic element, for example, a plasmid, cosmid, bacmid, phage or virus, that is capable of replication largely under its own control. A replicon may be either RNA or DNA and may be single or double stranded.

“Nucleic acid” or a “nucleic acid molecule” as used herein refers to any DNA or RNA molecule, either single or double stranded and, if single stranded, the molecule of its complementary sequence in either linear or circular form. In discussing nucleic acid molecules, a sequence or structure of a particular nucleic acid molecule can be described herein according to the normal convention of providing the sequence in the 5′ to 3′ direction.

By “viral inhibitory amount” it is meant an amount sufficient to inhibit viral replication or infectivity. Optionally, the pharmaceutical formulations of the invention may comprise a combination of compounds of the present invention, or may include a second active ingredient useful in the treatment of viral infections, such as anti-viral agents that include, but are not limited to: pegylated alpha interferon; un-pegylated alpha interferon; ribavirin; protease inhibitors; polyermase inhibitors; p7 inhibitors; entry inhibitors, including fusion inhibitors such as Fuzeon™ (Trimeris); helicase inhibitors; anti-fibrotics; drugs that target IMPDH (inosine monophosphate dehydrogenase inhibitors), such as Merimepadib™ (Vertex Pharmaceuticals Inc.); synthetic thymosin alpha 1 (ZADAXIN™, SciClone Pharmaceuticals Inc.); therapeutic viral vaccines, such as those produced by Chiron and Immunogenics; and immunomodulators, such as histamine.

In accordance with the present invention, compounds that inhibit HCV replication have been identified and methods of using these compounds for preventing or treating HCV infection are provided. Without being limited to a particular theory, it is believed that the compounds of the present invention act as replicase complex defect inducers, inhibiting the formation of a functional replicase complex.

In an aspect of the present invention, compounds are provided that are useful for treating or preventing hepatitis C virus infection. In another aspect of the present invention, compounds are provided that are useful for inhibiting replication of hepatitis C virus.

The invention includes methods of treatment using compounds of the Formula (I-a)

or pharmaceutically acceptable salt, hydrate or prodrug thereof.

Within formula (I-a) the variables Ar1, R2, R3, R4, t, q, and r, carry the values set forth below, wherein:

Ar1 is fluorenyl.

Or, Ar1 is phenyl, naphthyl, a 5- or 6-membered monocyclic heteroaryl group, or a 9- or 10-membered bicyclic heteroaryl group, wherein Ar1 is substituted with R and R1.

R is 0 or one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

R1 is one or two substituents independently chosen from (a) and (b)

(a) halogen, hydroxyl, amino, cyano, nitro, —COOH, —SO2NH2C1-C2haloalkyl, and C1-C2haloalkoxy, and

(b) C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10alkanoyl, C2-C10alkylester, C1-C10 alkoxy, mono- or di-C1-C10alkylcarboxamide, or a group —YZ,

where Y is bond, or Y is C1-C10alkyl, a C2C10alkenyl, or C2-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain; and

Z is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkenyl, heterocycloalkyl, phenyl, naphthyl, indanyl, (C3-C7cycloalkyl)C0-C10alkoxy, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) other than hydrogen, is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

Any R and R1 which are covalently bound to adjacent carbon atoms may be joined to form an aromatic or partially saturated carbocyclic ring system having 1 or 2 rings, each ring having 5 or 6 ring carbon atoms.

R2 is halogen, —COOH, —CONH2, —C(O)OCH3, —C(O)CH3, —NHC(O)OH, or amino.

Or, R2 is —CH2Ra, —NH—S(O)2Ra, —CH2—NH—S(O)2Ra, —S(O)2Ra, —C(O)—NH—Ra, —C(O)—NH—CH2Ra, —NH—C(O)—Ra, —NH—C(O)—Rb, —C(O)O—Ra, —C(O)—O—Rb, —ORa, —C(O)—Ra, or —C(O)—Rb, each of which is substituted with 0 or one or more substituents independently chosen from (c), (d), and (e).

Or, R2 is C1-C6alkyl, phenyl, a 5- to 6-membered heteroaryl, phenyl fused to a 5 or 6 membered cycloalkyl or heterocycloalkyl ring, or a bicyclic 8- to 10-membered heteroaryl, each of which is substituted with 0 or one or more substituents independently chosen from (c), (d), and (e);

(c) halogen, hydroxyl, oxo, cyano, amino, nitro, —C(O)NH2, —C(O)OH, —S(O)NH2, C1-C2haloalkyl, and C1-C2haloalkoxy,

(d) C1-C4alkyl, C1-C4alkoxy, C2-C4alkenyl, mono- and di-C1-C6alkylamino, mono- and di-(C1-C4alkyl)carboxamide, mono- or di(C1-C4alkyl)sulfonamide, C1C4alkylester, each of which is substituted with 0 or one or more substituents independently chosen from oxo, halogen, hydroxyl, oxo, cyano, amino, nitro, —C(O)NH2, —C(O)OH, —S(O)NH2, C1-C4alkoxy, mono- and di-C1-C6alkylamino, mono- and di-(C1-C4alkyl)carboxamide, mono- or di(C1-C4alkyl)sulfonamide, C1C4alkylester C1-C2haloalkyl, and C1-C2haloalkoxy

(e) (C3-C7cycloalkyl)C0-C4alkyl, (heterocycloalkyl)C0-C4alkyl, (phenyl)C0-C4alkyl, each of which is substituted with oxo, halogen, hydroxyl, oxo, cyano, amino, nitro, —C(O)NH2, —C(O)OH, —S(O)NH2, C1-C2haloalkyl, and C1-C2haloalkoxy.

R2 and R4 may be taken together with the carbon atoms of the thiazole ring to which they are attached to form a C5-C7 carbocyclic ring, which is aromatic or partially unsaturated.

R3 is hydrogen, C1-C4alkyl, or —C(O)—Rd.

R4 is hydrogen, halogen, hydroxyl, amino, cyano, nitro, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy or phenyl; or R4 is taken together with R2 to form a ring.

Ra is heterocycloalkyl, phenyl, or 5- or 6-membered heteroaryl, each of which is substituted with 0 or one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, C1-C4 alkyl, and C1-C4 alkoxy.

Rb is C1-C6 alkyl, wherein the alkyl is optionally substituted with a halogen, hydroxyl, —C(O)OH, phenyl, or 4-(NH2S(O)2)-phenyl.

Rd is C1-C6alkyl, phenyl, or 5- to 6-membered heteroaryl.

And r is 0, 1, or 2.

q is 0 or 1;

t is 0 or 1; and q and t are not both 1;

Wherein at least one of the following conditions are met:

(i) R4 is not hydrogen; or

(ii) at least one R1 is other than halogen, unsubstituted alkyl, unsubstituted alkoxy, amino, —C(O)NH2, —S(O)2NH2, unsubstituted alkanoyl, unsubstituted alkylester, or —S(O)2NH(heteroaryl); or

(iii) R2 is other than aryl or heteroaryl; or

(iv) R2 is aryl or heteroaryl, substituted with at least one group other than halogen, unsubstituted alkyl, unsubstituted alkoxy, amino, —C(O)NH2, —S(O)2NH2, unsubstituted alkanoyl, unsubstituted alkylester, or —S(O)2NH(heteroaryl).

The invention includes compounds, salts and hydrates of Formula I-a, in which one or more of the following conditions are met. The invention includes compounds of Formula I in which the variables Ar1, R1, R2, R3, R4, t, q, carry any combination of the definitions set forth below for these variables that results in a stable compound.

(a) t is 0, e.g the invention provides compounds and salts of Formula (I-b).

(b) q is 0, e.g. the invention provides compounds, salts, and hydrates of formula (I-c).

(c) r is 0, i.e. the invention provides compounds and salts of Formula (I-d).

(d) r is 0 and t is 1, i.e. the invention provides compounds and salts of Formula (I-e)

(e) t and q are 0 and r is 1 or 2, e.g. the invention provides compounds and salts of Formula (I-f).

(f) t, q, and r are all 0, e.g. the invention provides compounds and salts of Formula (I-g).

(a) Ar1 is phenyl substituted with R and R1.

(b) Ar1 is pyridyl substituted with R and R1.

(c) Ar1 is phenyl, pyridyl, benzofuranyl, benzimidazolyl, benzothiazolyl, furanyl, imidazolyl, isoxazolyl, pyrrolyl, thienyl, thiazolyl, or tetrahydroisoquinolinyl, each substituted with R and R1.

(d) Ar1 is fluorenyl.

(e) Ar1 is phenyl or pyridyl, each substituted with R and R1; and t, q, and r are all 0.

(f) t and q are both 0 and r is 0 or 1; and

Ar1 is phenyl, naphthyl, a 5- or 6-membered monocyclic heteroaryl group, or a 9- or 10-membered bicyclic heteroaryl group, wherein Ar1 is substituted with R and R1.

R is 0 or one or more substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

R1 is one or two substituents independently chosen from (a) and (b); (a) halogen, hydroxyl, amino, cyano, nitro, —COOH, —SO2NH2C1-C2haloalkyl, and C1-C2haloalkoxy, and (b) C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10alkanoyl, C2-C10alkylester, C1-C10 alkoxy, mono- or di-C1-C10alkylcarboxamide, or a group —YZ.

Where Y is bond, or Y is C1-C10alkyl, a C2C10alkenyl, or C2-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain; and Z is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkenyl, heterocycloalkyl, phenyl, naphthyl, indanyl, (C3-C7cycloalkyl)C0-C10alkoxy, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) other than hydrogen, is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

For certain compounds of this embodiment Ar1 is phenyl or a 6-membered heteroaryl group substituted with an R1 in the meta position.

In certain other compounds of this embodiment Ar1 is phenyl or a 6-membered heteroaryl group substituted with an R1 in the para position.

(g) Ar1 is phenyl or a 6-membered heteroaryl group substituted with independently chosen R1 substituents in the meta and para positions.

(h) Ar1 is phenyl or a 6-membered heteroaryl group substituted with independently chosen R1 substituents in the meta and para positions and R is 0 substituents.

(i) Ar1 is phenyl or a 6-membered heteroaryl group substituted with an R1 substituent in either the meta and para positions; and at least one R1 is C4-C10 alkyl, C4-C10 alkenyl, C4-C10 alkynyl, C4-C10alkanoyl, C4-C10alkylester, C4-C10 alkoxy, mono- or di-C4-C10alkylcarboxamide, or a group —YZ. Where Y is bond, or Y is C4-C10alkyl, a C4C10alkenyl, or C4-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain; and Z is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkenyl, heterocycloalkyl, phenyl, naphthyl, indanyl, (C3-C7cycloalkyl)C0-C10alkoxy, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) other than hydrogen, is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

In certain compounds of this embodiment a second R1 is halogen, trifluoromethyl, or trifluoromethoxy.

(j) Ar1 is phenyl or a 6-membered heteroaryl group substituted with R1 substituents in either the meta and para positions; and one R1 is C4-C10 alkyl, C4-C10 alkenyl, C4-C10 alkynyl, C4-C10alkanoyl, C4-C10alkylester, C4-C10 alkoxy, mono- or di-C4-C10alkylcarboxamide, or a group —YZ. Where Y is bond, or Y is C4-C10alkyl, a C4C10alkenyl, or C4-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain; and Z is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkenyl, heterocycloalkyl, phenyl, naphthyl, indanyl, (C3-C7cycloalkyl)C0-C10alkoxy, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) other than hydrogen, is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; and the other R1 is halogen, trifluormethyl, or trifluoromethoxy.

(k) Ar1 is phenyl or a 6-membered heteroaryl group substituted with R1 substituents in either the meta and para positions; and one R1 is a group —YZ. Where Y is bond, or Y is C4-C10alkyl, a C4-C10alkenyl, or C4-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain; and Z is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkenyl, heterocycloalkyl, phenyl, naphthyl, indanyl, (C3-C7cycloalkyl)C0-C10alkoxy, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) other than hydrogen, is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; and the other R1 is halogen, trifluormethyl, or trifluoromethoxy.

(l) Ar1 is phenyl or a 6-membered heteroaryl group substituted with R1 substituents in either the meta and para positions; and one R1 is a group —YZ. Where Y is C6-C10alkyl, a C6C10alkenyl, or C6-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain; and Z is C3-C7cycloalkyl, heterocycloalkyl, phenyl, naphthyl, indanyl, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) other than hydrogen, is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy; and the other R1 is halogen, trifluormethyl, or trifluoromethoxy.

(a) R is 1 or 2 substituents independently chosen from halogen, hydroxyl, amino, cyano, nitro, C1-C2alkyl, C1-C2alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

(b) R is 1 or 2 substituents independently chosen from hydroxyl, cyano, C1-C2alkyl, C1-C2alkoxy, trifluoromethyl, and trifluoromethoxy.

(c) R is one or more substituents independently chosen from halogen, phenyl, and cyano.

(d) R is one or more substituents independently chosen from fluorine and chlorine.

(e) At least one R1 is C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C2-C10alkanoyl, C2-C10alkylester, C1-C10 alkoxy, mono- or di-C1-C10alkylcarboxamide, or a group —YZ. Where Y is bond, or Y is C1-C10alkyl, a C2C10alkenyl, or C2-C10alkynyl, each optionally having 1 or 2 oxygen or nitrogen atoms within the alkyl, alkenyl, or alkynyl chain; and Z is hydrogen, C3-C7cycloalkyl, C3-C7cycloalkenyl, heterocycloalkyl, phenyl, naphthyl, indanyl, (C3-C7cycloalkyl)C0-C10alkoxy, or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, wherein each (b) other than hydrogen, is substituted with 0 or one or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, oxo, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, and C1-C2haloalkoxy.

(f) At least one R1 is:

(g) R1 is one or two substituents independently chosen from (a) and (b), (a) halogen, hydroxyl, amino, cyano, nitro, C1-C2haloalkyl, and C1-C2haloalkoxy, and (b) C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C1-C10alkoxy, (C3-C7cycloalkyl)C0-C2alkyl, (C3-C7cycloalkyl)C0-C2alkoxy, mono- and di-C1-C6alkylamino, (phenyl)C0-C2alkyl, (phenyl)C0-C2alkoxy, (indanyl)C0-C2alkyl, (indanyl)C0-C2alkoxy, and (heterocycloalkyl)C0-C2alkyl, wherein each (b) is substituted with 0 or more substituents independently chosen from: halogen, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, and phenyl.

(h) At least one R1 is (a) halogen, hydroxyl, amino, cyano, nitro, C1-C2haloalkyl, C1-C2haloalkoxy, (b) C1-C8 alkyl, C1-C10 alkoxy, or (phenyl)C0-C2alkoxy, each of which is substituted with 0 or more substituents independently chosen from: halogen, hydroxyl, cyano, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethoxy, and phenyl.

(i) At least one R1 is t-butyl, trifluoromethyl, n-pentoxy, benzyloxy, or para-chlorophenoxy.

(j) At least one R1 is n-butoxy, trifluomethoxy, phenoxy, n-butyl, or phenyl.

(k) At least one R1 is C1-C10 alkyl, C1-C10 alkoxy, (phenyl)C0-C2alkyl, indanyl-oxy, or phenoxy, each of which is substituted with 0 or 1 or more independently chosen halogen substituents.

(l) At least one R1 is C1-C10alkoxy, phenyl, indanyloxy, or phenoxy, each of which is substituted with 0 or 1 or more independently chosen halogen substituents.

(m) At least one R1 is methoxy, phenoxy, n-butoxy, n-pentyloxy, n-hexyloxy, n-heptanyloxy, n-octanyloxy, phenyl(CH)2O— benzyloxy, cycloalkylmethyloxy, indanyloxy, or trifluoromethoxy.

(n) At least one R1 is an independently chosen C1-C10alkoxy substituent, substituted with 0 or one or more fluorine substituents.

(O) At least one R1 is an independently chosen C1-C10alkoxy substituent, which is substituted with 0 or one or more substituents independently chosen from phenyl, indanyl, and naphthyl.

(p) At least one R1 is a C1-C10alkoxy substituent, substituted with a phenyl substituent or C3-C7cycloalkyl substituent.

(q) At least one R1 is a C1-C10 alkyl, substituted with 0 or one or more substituents independently chosen from halogen, phenyl, C3-C7cycloalkyl, and 5- to 6-membered heterocyloalkyl.

(r) At least one R1 is methyl, n-butyl, n-pentyl, t-butyl, benzyl, trifluoromethyl, or piperidin-1-ylmethyl.

(s) At least one R1 is heterocycloalkyl or 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, each of which is substituted with 0 or more substituents independently chosen from: halogen, hydroxyl, amino, cyano, nitro, C1-C4alkyl, C1-C4alkoxy, C1-C2haloalkyl, C1-C2haloalkoxy, phenyl, and naphthyl.

(t) At least one R1 is morpholin-1-yl, 4-phenyl-piperidin-1-yl, 1,2,3-thiazol-4-yl, or 2-methylpyrimidin-6-yl.

(u) At least one R1 is C1-C2haloalkyl, C1-C8alkyl, (phenyl)C1-C2alkyl, or (heterocycloalkyl)C1-C2alkyl.

(v) At least one R1 is (5- and 6-membered heterocycloalkyl)C0-C10alkoxy, each of which is substituted with 0 or one or more substituents independently chosen from C1-C4 alkyl and phenyl. In certain compounds of this embodiment the 5- and 6-membered heterocycloalkyl, comprise nitrogen or oxygen or both.

(w) R1 is morpholinyl or piperidinyl.

(x) R1 is a 5- to 6-membered heterocycloalkyl, substituted with a phenyl.

(y) At least one R1 is 5- to 6-membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently chosen from N, O, and S, substituted with 0 or one or more substituents independently chosen from C1-C4alkyl and phenyl.

(z) R1 is thiadiazolyl.

(aa) R1 is 4-methyl-1,2,3 thiadiazolyl.

(bb) R1 is pyrimidinyl.

(cc) R1 is 4-methyl-pyrimidinyl.

(dd) R1 is a C1-C10 alkoxy.

(ee) R is halogen or trifluoromethyl, t, q, and r are all 0 and R4 is hydrogen, halogen, methyl, or phenyl.

(a) R3 is hydrogen.

(a) The invention includes compounds Formula (I-h) and (I-i) in which the positions of R2 and R4 are fixed. Compounds of Formula (I-h) and (I-i) in which q ant t are 0 and r is 0 or are preferred. The invention includes:

(b) The invention includes compounds of formula (I-h) or (I-i) in which t and q are 0 and r is 0 or 1.

(c) For compounds of formula (I-h) or (I-i) in which t and q are 0 and r is 0.

(d) R2 is phenyl, substituted with 0 or 1 or more independently chosen halogen substituents.

(e) R2 is phenyl substituted with one or more chlorine or fluorine substituents.

(f) R2 is phenyl substituted with fluoro at the para position.

(g) R2 is a 5- to 6-membered heteroaryl.

(h) R2 is a 6-membered heteroaryl.

(i) R2 is a 5- to 6-membered heteroaryl comprising nitrogen.