CROSS REFERENCE TO RELATED APPLICATION

This application claims the priority of U.S. provisional application Ser. No. 61/756,557 filed Jan. 25, 2013 which is herein incorporated by reference.

FIELD OF THE INVENTION

The invention relates to novel compounds of Formula I, including pharmaceutically acceptable salts thereof, which have activity against hepatitis C virus (HCV), and are useful in treating those infected with HCV. The invention also relates to compositions and methods of using these compounds.

BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) chronically infects an estimated 170 million people worldwide, with 3 to 4 million infected individuals in the United States alone (Boyer, N. and Marcellin, P. J. Hepatology. 2000, 32:98-112; Alter, M. J., et al. Engl. J. Med. 1999, 341:556-562). Prior to the mid 1990s, transfusion with infected blood products was the main route of HCV transmission. Following the introduction of blood screening methods, transmission via injection drug use became the primary risk factor. Chronic infection often leads to the development of severe liver complications, including fibrosis, cirrhosis, and hepatocellular carcinoma. HCV infection is also the leading cause of orthotopic liver transplantation in the United States. The degree to which disease progression is related to viral and cellular factors is not completely understood.

Considerable heterogeneity is found within the nucleotide and encoded amino acid sequence of the HCV genome (Simmonds, P. J. Gen. Virology. 2004, 85:3173-3188). Based on this sequence diversity, six major genotypes and multiple associated subtypes have been described. The genotypes of HCV differ in their worldwide distribution, 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.

Medical treatment for HCV is limited by the lack of a vaccine or approved therapies that specifically target the virus. Currently, patients undergo treatment with a combination of parenterally administered pegylated alpha-interferon and oral ribavirin. Genotype 1 HCV is the most difficult to treat and elimination of the virus (sustained virologic response) is achieved for only approximately 50% of patients (Fried, M. W. et al. N. Engl. J. Med. 2002, 347:975-982; Zeumzem, S. Nature Clinical Practice. 2008, 5:610-622). This poor treatment response, combined with often severe side effects induced by therapy, highlight a need for improved antiviral drugs with better efficacy and safety profiles.

HCV is a member of the Flaviviridae family of viruses with a single-stranded positive-sense RNA genome. Following infection of host cells, the 9.6 Kb genome is translated into a polyprotein precursor of approximately 3,000 amino acids (reviewed in Lindenbach, B. D. and Rice, C. M. Nature. 2005, 436:933-938; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463). Post-translational processing by both cellular and viral proteases results in the generation of at least 10 separate viral proteins. The structural proteins (which by definition are found in mature virions) include core, E1, E2, and possibly p7, and originate from the amino-terminal region of the polyprotein. The core protein assembles into the viral nucleocapsid. The E1 and E2 glycoproteins form heterodimers that are found within the lipid envelope surrounding the viral particles, and mediate host cell receptor binding and entry of the virus into cells. It is unclear if p7 is a structural protein, and its role in replication has yet to be defined. However p7 is believed to form an ion channel in cellular membranes, preventing acidification of intracellular compartments in which virions are assembled, and it has been shown to be essential for viral replication and assembly. The nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A, and NS5B are produced through maturational cleavages of the carboxy-terminal region of the polyprotein. NS2 along with the amino terminus of NS3 form the NS2-3 metalloprotease which cleaves at the NS2-NS3 junction. Additionally, NS2 is involved in assembly and egress of nascent virions. The NS3 protein contains both a serine protease in its amino-terminal region, and a nucleotide-dependent RNA helicase in its carboxy-terminal region. NS3 forms a heterodimer with the NS4A protein, constituting the active protease which mediates cleavages of the polyprotein downstream of NS3, both in cis, at the NS3-NS4A cleavage site, and in trans, for the remaining NS4A-NS4B, NS4B-NS5A, NS5A-NS5B sites. The complex formation of the NS3 protein with NS4A seems necessary to the processing events, enhancing the proteolytic efficiency at all of the sites. The NS3 protein also exhibits nucleoside triphosphatase and RNA helicase activities. The NS4B protein has been shown to be important for localization of HCV proteins into replication complexes in altered membranous structures within the cell. NS5B encodes an RNA-dependent RNA polymerase that is involved in the replication of HCV.

Subgenomic HCV replicons, containing the untranslated regions 5â€² and 3â€² to the coding sequence fused to the nonstructural proteins or the full-length polyprotein, are competent for translation, viral protein expression, and replication within cultured cells (Lohmann, V. et al. Science. 1999, 285:110-113; Moradpour, D, Penin, F., and Rice, C. M. Nature Reviews. 2007, 5:453-463). The replicon system has proven valuable for the identification of inhibitors targeting the nonstructural proteins associated with these functions. However, only limited subsets of HCV genotypes have been used to generate functional replicons.

Other systems have been used to study the biology of the HCV structural proteins that mediate the entry into host cells. For example, virus-like-particles made in recombinant baculovirus-infected cells with the HCV core, E1 and E2 proteins have also been used to study the function of the HCV E1 and E2 proteins (Barth, H., et al. J. Biol. Chem. 2003, 278:41003-41012). In addition, pseudotyping systems where the E1 and E2 glycoproteins are used to functionally replace the glycoproteins of retroviruses have been developed (Bartosch, B., Dubuisson, J. and Cosset, F.-L. J. Exp. Med. 2003, 197:633-642; Hsu, M. et al. Proc. Natl. Acad. Sci. USA. 2003, 100:7271-7276). These systems yield HCV pseudoparticles that bind to and enter host cells in a manner which is believed to be analogous to the natural virus, thus making them a convenient tool to study the viral entry steps as well as to identify inhibitors block this process.

Recently, a full-length genotype 2a HCV clone, JFH1, was isolated and demonstrated the ability to replicate in vitro. Through repeated passage and adaptation in cell culture increased titers of infectious virus were produced (Lindenbach, B. D., et al. Science. 2005, 309:623-626; Wakita, T. et al. Nature Med. 2005, 11:791-796). In contrast to the HCV replicon or pseudotyping systems, the infectious virus is useful for studying the complete HCV replication cycle, including identifying inhibitors of not only the replication proteins, but those involved in early steps in virus infection (entry and uncoating) and production of progeny viruses (genome packaging, nucleocapsid assembly, virion envelopment and egress).

Triazines have been disclosed. See WO 2009/091388 and US 2009/0286778.

The invention provides technical advantages, for example, the compounds are novel and are effective against hepatitis C. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

SUMMARY OF THE INVENTION

One aspect of the invention is a compound of Formula I, including pharmaceutically acceptable salts thereof:

[Image Omitted]

wherein

a, b and c are nitrogen;
or a and b are nitrogen, while c is â€”CH;
or b and c are nitrogen, while a is â€”CH;
or a and c are nitrogen, while b is â€”CH;
R¹is selected from alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, haloalkyl, alkoxy, and haloalkoxy;
R²is selected from alkyl, cycloalkyl, (Ar²)alkyl, (Ar²)cycloalkyl, ((Ar²)cycloalkyl)alkyl, ((Ar²)alkyl)cycloalkyl, and (((Ar²)alkyl)cycloalkyl)alkyl;
R³is hydrogen, alkyl or cycloalkyl;
R⁴is hydrogen, alkyl or cycloalkyl;
R⁵is

[Image Omitted]

wherein ring A is a 4 to 7 membered alkylene ring substituted with L;

R⁶is selected from hydrogen, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, and haloalkoxy;
R⁷is hydroxy, alkyloxy, phenoxy, SO₂R⁹, SO₂N(R¹⁰)(R¹¹), CN, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl,
((alkyl))cycloalkyl)alkyl, or bridged bicycloalkyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ether, cyclicether, benzocyclicether, bicyclicether, CO₂R⁹, NR⁹CO₂R¹¹, N(R¹⁰)(R¹¹), CON(R¹⁰)(R¹¹), NR⁹CON(R¹⁰)(R¹¹), SO₂N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³;
or R⁷is hydrogen, N-alkoxycarbonylpiperidinyl, piperidinonyl, or Ar⁴;
R⁸is hydrogen, alkyl, or cycloalkyl, and alkyl or cycloalkyl is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, fused bicyclic alkyl, bridged bicyclic alkyl, spiro bicyclic alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R⁹, N(R¹⁰)(R¹¹) tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³;
or R⁷and R⁸taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
R⁹is hydrogen, Ar³, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, or ((alkoxy)alkoxy)alkoxy;
R¹⁰is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶;
R¹¹is hydrogen, alkyl, cycloalkyl, or Ar⁶;
or R¹⁰and R¹¹taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
R¹²is hydrogen, alkyl, cycloalkyl, or Ar⁶;
R¹³is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹⁵)(R¹⁶), and alkylCO;
R¹⁴is hydrogen, alkyl, cycloalkyl, or Ar⁶;
or R¹³and R¹⁴taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
R¹⁵is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl;
R¹⁶is hydrogen, alkyl, or cycloalkyl;
or R¹⁵and R¹⁶taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
L is selected from the group of alkylene, cycloalkylene, (cycloalkyl)alkyl, (alkyl)cycloalkyl, and alkyl(cycloalkyl)alkyl, and is substituted with 0-1CO₂R¹²or CONR¹³R¹⁴;
Ar¹is phenyl or pyridyl or pyrimidinyl or pyrazolyl, substituted with 1CON(R⁵)(R⁶), OR⁵, N(R⁵)(R⁶) or R⁵, or with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar²is phenyl substituted with 0-3 substituents selected from halo, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, and haloalkoxy;
Ar³is phenyl, biphenyl, terphenyl, naphthalenyl, furanyl, benzofuranyl, fluorenyl, fluorenonyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzoisothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, indolinyl, chromenonyl, or dibenzofuranyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl,) CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, Ar⁵, OAr⁵, NR¹³, Ar⁵, N(R¹³)COAr⁵, N(R¹³)SO₂Ar⁵, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, and PhCONHSO₂; and said alkyl, alkenyl, cycloalkyl, alkynyl or Ar⁵is further substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, aryoxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, PhCONHSO₂and Ar⁶;
or Ar³is phenyl substituted with 1 substituents selected from benzyl, phenoxy, pyridyloxy, pyrimidyloxy, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, dimethoxypyrimdinyl, indolyl, indolinyl, and isoindolinyl;

Ar⁴is phenyl, indanyl, tetrahydronaphthyl, isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹³)(R¹⁴), and alkylCO;

Ar⁵is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, OAr⁶, NR¹³Ar⁶, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴) amidine, urea, ketone, sulfone and sulfamide;
Ar⁶is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, phenyl, hydroxy, alkoxy, aryloxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, ester, ketone, amidine, urea, ketone, sulfone and sulfamide;

The invention also relates to pharmaceutical compositions comprising a compound of Formula 1, including a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In addition, the invention provides one or more methods of treating hepatitis C infection comprising administering a therapeutically effective amount of a compound of Formula I to a patient.

Also provided as part of the invention are one or more methods for making the compounds of Formula I.

The present invention is directed to these, as well as other important ends, hereinafter described.

DETAILED DESCRIPTION OF THE EMBODIMENTS

Unless otherwise specifically set forth elsewhere in the application, these terms have the following meanings. â€œHâ€ refers to hydrogen, including its isotopes, such as deuterium. â€œHaloâ€ means fluoro, chloro, bromo, or iodo. â€œAlkylâ€ means a straight or branched alkyl group composed of 1 to 6 carbons. â€œAlkenylâ€ means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond. â€œCycloalkylâ€ means a monocyclic ring system composed of 3 to 8 carbons. â€œAlkyleneâ€ means a straight or branched divalent alkyl group. â€œAlkenyleneâ€ means a straight or branched divalent alkyl group with at least one double bond. â€œCycloalkyleneâ€ means a divalent cycloalkane moiety composed of 3 to 7 carbons and includes gem-divalency (for example 1,1-cyclopropanediyl) as well as non-gem-divalency (for example, 1,4-cyclohexanediyl). â€œAlkylidinylâ€ means a divalent alkene substituent where the divalency occurs on the same carbon of the alkene. â€œHydroxyalkyl,â€ â€œalkoxyâ€ and other terms with a substituted alkyl moiety include straight and branched isomers composed of 1 to 6 carbon atoms for the alkyl moiety. â€œHaloalkylâ€ and â€œhaloalkoxyâ€ include all halogenated isomers from monohalo substituted alkyl to perhalo substituted alkyl. â€œArylâ€ includes carbocyclic and heterocyclic aromatic substituents. Phenylene is a divalent benzene ring. â€œ1,4-Phenyleneâ€ means 1,4-benzenediyl with respect to regiochemistry for the divalent moiety. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.

The substituents described above may be attached at any suitable point of attachment unless otherwise specified. However, it is understood that the compounds encompassed by the present invention are those that are chemically stable as understood by those skilled in the art. Additionally, the compounds encompassed by the present disclosure are those that are suitably stable for use as a pharmaceutical agent.

As set forth above, the invention includes all pharmaceutically acceptable salt forms of the compounds. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, camsylate, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.

Some of the compounds of the invention possess asymmetric carbon atoms (see, for example, the structures below). The invention includes all stereoisomeric forms, including enantiomers and diastereomers as well as mixtures of stereoisomers such as racemates. Some stereoisomers can be made using methods known in the art. Stereoisomeric mixtures of the compounds and related intermediates can be separated into individual isomers according to methods commonly known in the art. The use of wedges or hashes in the depictions of molecular structures in the following schemes and tables is intended only to indicate relative stereochemistry, and should not be interpreted as implying absolute stereochemical assignments.

The invention is intended to include all isotopes of atoms occurring in the present 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 deuterium and tritium. Isotopes of carbon include ¹³C and ¹⁴C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.

As set forth above, the invention is directed to compounds of Formula I, including pharmaceutically acceptable salts thereof:

[Image Omitted]

wherein

a, b and c are nitrogen;
or a and b are nitrogen, while c is â€”CH;
or b and c are nitrogen, while a is â€”CH;
or a and c are nitrogen, while b is â€”CH;
R¹is selected from alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, hydroxycycloalkyl, alkoxycycloalkyl, halocycloalkyl, cycloalkenyl, indanyl, alkylcarbonyl, and benzyl, wherein the benzyl moiety is substituted with 0-3 substituents selected from halo, alkyl, cycloalkyl, alkenyl, alkynyl, hydroxyl, cyano, haloalkyl, alkoxy, and haloalkoxy;
R²is selected from alkyl, cycloalkyl, (Ar²)alkyl, (Ar²)cycloalkyl, ((Ar²)cycloalkyl)alkyl, ((Ar²)alkyl)cycloalkyl, and (((Ar²)alkyl)cycloalkyl)alkyl;
R³is hydrogen, alkyl or cycloalkyl;
R⁴is hydrogen, alkyl or cycloalkyl;
R⁵is or

[Image Omitted]

wherein ring A is a 4 to 7 membered alkylene ring substituted with L;

- R⁶is selected from hydrogen, halo, alkyl, cycloalkyl, haloalkyl, halocycloalkyl, alkoxy, and haloalkoxy;
- R⁷is hydroxy, alkyloxy, phenoxy, SO₂R⁹, SO₂N(R¹⁰)(R¹¹), CN, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, (cycloalkyl)alkyl, (alkyl)cycloalkyl, ((alkyl))cycloalkyl)alkyl, or bridged bicycloalkyl, and is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, benzocycloalkyl, bicyclicalkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, ether, cyclicether, benzocyclicether, bicyclicether, CO₂R⁹, NR⁹CO₂R¹¹, N(R¹⁰)(R¹¹), CON(R¹⁰)(R¹¹), NR⁹CON(R¹⁰)(R¹¹), SO₂N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³;
or R⁷is hydrogen, N-alkoxycarbonylpiperidinyl, piperidinonyl, or Ar⁴;
R⁸is hydrogen, alkyl, or cycloalkyl, and alkyl or cycloalkyl is substituted with 0-4 substituents selected from the group consisting of halo, alkyl, cycloalkyl, fused bicyclic alkyl, bridged bicyclic alkyl, spiro bicyclic alkyl, hydroxyalkyl, alkoxyalkyl, hydroxy, alkoxy, benzyloxy, CO₂R⁹, N(R¹⁰)(R¹¹), tetrahydrofuranyl, tetrahydropyranyl, Ar³, OAr³, NR¹³Ar³, N(R¹³)COAr³, and N(R¹³)SO₂Ar³;
or R⁷and R⁸taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
R⁹is hydrogen, Ar³, alkyl, cycloalkyl, hydroxyalkyl, alkoxyalkyl, ((hydroxyalkyl)alkoxy)alkoxy, or ((alkoxy)alkoxy)alkoxy;
R¹⁰is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶;
R¹¹is hydrogen, alkyl, cycloalkyl, or Ar⁶;
or R¹⁰and R¹¹taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
R¹²is hydrogen, alkyl, cycloalkyl, or Ar⁶;
R¹³is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, alkoxycarbonyl, or Ar⁶, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹⁵)(R¹⁶), and alkylCO;
R¹⁴is hydrogen, alkyl, cycloalkyl, or Ar⁶;
or R¹³and R¹⁴taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
R¹⁵is hydrogen, alkyl, cycloalkyl, alkylcarbonyl, or alkoxycarbonyl;
R¹⁶is hydrogen, alkyl, or cycloalkyl;
or R¹⁵and R¹⁶taken together with the nitrogen to which they are attached is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiomorpholine 1,1-dioxide, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolinyl, or isoindolinyl, and is substituted with 0-2 substituents selected from alkyl, (aryl)aklyl, alkylcarbonyl, and alkoxycarbonyl;
L is selected from the group of alkylene, cycloalkylene, (cycloalkyl)alkyl, (alkyl)cycloalkyl, and alkyl(cycloalkyl)alkyl, and is substituted with 0-1CO₂R¹²or CONR¹³R¹⁴;
Ar¹is phenyl or pyridyl or pyrimidinyl or pyrazolyl, substituted with 1CON(R⁵)(R⁶), OR⁵, N(R⁵)(R⁶) or R⁵, or with 0-3 substituents selected from halo, alkyl, haloalkyl, alkoxy, and haloalkoxy;
Ar²is phenyl substituted with 0-3 substituents selected from halo, hydroxy, cyano, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, alkoxy, and haloalkoxy;
Ar³is phenyl, biphenyl, terphenyl, naphthalenyl, furanyl, benzofuranyl, fluorenyl, fluorenonyl, thiophenyl, benzothiophenyl, pyrrolyl, indolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzoisothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, indolinyl, chromenonyl, or dibenzofuranyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, Ar⁵, OAr⁵, NR¹³Ar⁵, N(R¹³)COAr⁵, N(R¹³)SO₂Ar⁵, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, and PhCONHSO₂; and said alkyl, alkenyl, cycloalkyl, alkynyl or Ar⁵is further substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, aryoxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone, sulfamide, PhCONHSO₂and Ar⁶;
or Ar³is phenyl substituted with 1 substituent selected from benzyl, phenoxy, pyridyloxy, pyrimidyloxy, tetrazolyloxy, thiazolyl, phenylpyrazolyl, methyloxadiazolyl, thiadiazolyl, triazolyl, methyltriazolyl, tetrazolyl, pyridinyl, dimethoxypyrimdinyl, indolyl, indolinyl, and isoindolinyl;
Ar⁴is phenyl, indanyl, tetrahydronaphthyl, isochromanyl, benzodioxolyl, pyridinyl, pyrazolyl, imidazolyl, or triazolyl, and is substituted with 0-3 substituents selected from cyano, halo, alkyl, alkyenyl, haloalkyl, alkoxy, and haloalkoxy, N(R¹³)(R¹⁴), and alkylCO;
Ar⁵is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, (CO₂R¹²)alkyl, (CO₂R¹²)alkenyl, (CON(R¹³)(R¹⁴))alkyl, phenyl, hydroxy, alkoxy, OAr⁶, NR¹³Ar⁶, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, CO₂R¹², COR¹², SO₂R¹², CON(R¹³)(R¹⁴), SO₂N(R¹³)(R¹⁴), N(R¹³)(R¹⁴), amidine, urea, ketone, sulfone and sulfamide;
Ar⁶is phenyl, naphthalenyl, furanyl, benzofuranyl, azabenzofuranyl, thiophenyl, benzothiophenyl, azabenzothiophenyl, pyrrolyl, indolyl, azaindolyl, indanyl, pyridinyl, quinolinyl, azaquinolinyl, isoquinolinyl, azaisoquinolinyl, quinoxalinyl, azaquinoxalinyl, pyrimidinyl, quinazolinyl, azaquinazolinyl, pyrazolyl, indazolyl, azaindazolyl, oxazolyl, benzoxazolyl, azabenzoxazolyl, isoxazolyl, benzoisoxazolyl, azabenzoisoxazolyl, imidazolyl, benzoimidazolyl, azabenzoimidazolyl, thiazolyl, benzothiazolyl, azabenzothiazolyl, isothiazolyl, benzoisothiazolyl, azabenzothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, benzotriazolyl, azabenzotriazolyl, tetrazolyl, or indolinyl, and is substituted with 0-5 substituents selected from cyano, halo, alkyl, cycloalkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, phenyl, hydroxy, alkoxy, aryloxy, alkylthio, haloalkoxy, haloalkylthio, alkylcarbonyl, ester, ketone, amidine, urea, ketone, sulfone and sulfamide;

More preferred compounds, including pharmaceutically acceptable salts thereof, are selected from the group of

[Image Omitted]

In addition, other preferred compounds, including pharmaceutically acceptable salts thereof, are selected from the group of

[Image Omitted]

Pharmaceutical Compositions and Methods of Treatment

The compounds demonstrate activity against HCV NS5B and can be useful in treating HCV and HCV infection. Therefore, another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

Another aspect of the invention is a composition further comprising a compound having anti-HCV activity.

Another aspect of the invention is a composition where the compound having anti-HCV activity is an interferon or a ribavirin. Another aspect of the invention is where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, interferon lambda, and lymphoblastoid interferon tau.

Another aspect of the invention is a composition where the compound having anti-HCV activity is a cyclosporin. Another aspect of the invention is where the cyclosporin is cyclosporin A.

Another aspect of the invention is a composition where the compound having anti-HCV activity is selected from the group consisting of interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5â€²-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is a composition where the compound having anti-HCV activity is effective to inhibit the function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is a composition comprising a compound, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier, an interferon and ribavirin.

Another aspect of the invention is a method of inhibiting the function of the HCV replicon comprising contacting the HCV replicon with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of inhibiting the function of the HCV NS5B protein comprising contacting the HCV NS5B protein with a compound or a pharmaceutically acceptable salt thereof.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof. In another embodiment the compound is effective to inhibit the function of the HCV replicon. In another embodiment the compound is effective to inhibit the function of the HCV NS5B protein.

Another aspect of the invention is a method of treating an HCV infection in a patient comprising administering to the patient a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt thereof, in conjunction with (prior to, after, or concurrently) another compound having anti-HCV activity.

Another aspect of the invention is the method where the other compound having anti-HCV activity is an interferon or a ribavirin.

Another aspect of the invention is the method where the interferon is selected from interferon alpha 2B, pegylated interferon alpha, consensus interferon, interferon alpha 2A, interferon lambda, and lymphoblastoid interferon tau.

Another aspect of the invention is the method where the other compound having anti-HCV activity is a cyclosporin.

Another aspect of the invention is the method where the cyclosporin is cyclosporin A.

Another aspect of the invention is the method where the other compound having anti-HCV activity is selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, interfering RNA, anti-sense RNA, Imiqimod, ribavirin, an inosine 5â€²-monophospate dehydrogenase inhibitor, amantadine, and rimantadine.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of a target selected from the group consisting of HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, IMPDH, and a nucleoside analog for the treatment of an HCV infection.

Another aspect of the invention is the method where the other compound having anti-HCV activity is effective to inhibit the function of target in the HCV life cycle other than the HCV NS5B protein.

â€œTherapeutically effectiveâ€ means the amount of agent required to provide a meaningful patient benefit as understood by practitioners in the field of hepatitis and HCV infection.

â€œPatientâ€ means a person infected with the HCV virus and suitable for therapy as understood by practitioners in the field of hepatitis and HCV infection.

â€œTreatment,â€ â€œtherapy,â€ â€œregimen,â€ â€œHCV infection,â€ and related terms are used as understood by practitioners in the field of hepatitis and HCV infection.

The compounds of this invention are generally given as pharmaceutical compositions comprised of a therapeutically effective amount of a compound or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier and may contain conventional excipients. Pharmaceutically acceptable carriers are those conventionally known carriers having acceptable safety profiles. Compositions encompass all common solid and liquid forms including for example capsules, tablets, lozenges, and powders as well as liquid suspensions, syrups, elixirs, and solutions. Compositions are made using common formulation techniques, and conventional excipients (such as binding and wetting agents) and vehicles (such as water and alcohols) are generally used for compositions. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 17th edition, 1985.

Solid compositions are normally formulated in dosage units and compositions providing from about 1 to 1000 mg of the active ingredient per dose are preferred. Some examples of dosages are 1 mg, 10 mg, 100 mg, 250 mg, 500 mg, and 1000 mg. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is 0.25-1000 mg/unit.

Liquid compositions are usually in dosage unit ranges. Generally, the liquid composition will be in a unit dosage range of about 1-100 mg/mL. Some examples of dosages are 1 mg/mL, 10 mg/mL, 25 mg/mL, 50 mg/mL, and 100 mg/mL. Generally, other agents will be present in a unit range similar to agents of that class used clinically. Typically, this is about 1-100 mg/mL.

The invention encompasses all conventional modes of administration; oral and parenteral methods are preferred. Generally, the dosing regimen will be similar to other agents used clinically. Typically, the daily dose will be about 1-100 mg/kg body weight daily. Generally, more compound is required orally and less parenterally. The specific dosing regimen, however, will be determined by a physician using sound medical judgment.

The invention also encompasses methods where the compound is given in combination therapy. That is, the compound can be used in conjunction with, but separately from, other agents useful in treating hepatitis and HCV infection. In these combination methods, the compound will generally be given in a daily dose of about 1-100 mg/kg body weight daily in conjunction with other agents. The other agents generally will be given in the amounts used therapeutically. The specific dosing regimen, however, will be determined by a physician using sound medical judgment.

Some examples of compounds suitable for compositions and methods are listed in Table 1.

TABLE 1Type of Inhibitor orBrand NamePhysiological ClassTargetSource CompanyNIM811Cyclophilin InhibitorNovartisZadaxinImmuno-modulatorScicloneSuvusMethylene blueBioenvisionActilonTLR9 agonistColey(CPG10101)Batabulin (T67)AnticancerÎ²-tubulin inhibitorTularik Inc., SouthSan Francisco, CAISIS 14803AntiviralantisenseISISPharmaceuticals Inc,Carlsbad, CA/ElanPhamaceuticals Inc.,New York, NYSummetrelAntiviralantiviralEndoPharmaceuticalsHoldings Inc.,Chadds Ford, PAGS-9132 (ACH-AntiviralHCV InhibitorAchillion/Gilead806)PyrazolopyrimidineAntiviralHCV InhibitorsArrow Therapeuticscompounds andLtd.saltsFrom WO-200504728826 May 2005LevovirinAntiviralIMPDH inhibitorRibapharm Inc.,Costa Mesa, CAMerimepodibAntiviralIMPDH inhibitorVertex(VX-497)PharmaceuticalsInc., Cambridge,MAXTL-6865 (XTL-Antiviralmonoclonal antibodyXTL002)BiopharmaceuticalsLtd., Rehovot, IsrealTelaprevirAntiviralNS3 serine proteaseVertex(VX-950, LY-inhibitorPharmaceuticals570310)Inc., Cambridge,MA/Eli Lilly andCo. Inc.,Indianapolis, INHCV-796AntiviralNS5B ReplicaseWyeth/ViropharmaInhibitorNM-283AntiviralNS5B ReplicaseIdenix/NovartisInhibitorGL-59728AntiviralNS5B ReplicaseGene Labs/InhibitorNovartisGL-60667AntiviralNS5B ReplicaseGene Labs/InhibitorNovartis2â€²C MeAAntiviralNS5B ReplicaseGileadInhibitorPSI 6130AntiviralNS5B ReplicaseRocheInhibitorR1626AntiviralNS5B ReplicaseRocheInhibitor2â€²C MethylAntiviralNS5B ReplicaseMerckadenosineInhibitorJTK-003AntiviralRdRp inhibitorJapan Tobacco Inc.,Tokyo, JapanLevovirinAntiviralribavirinICNPharmaceuticals,Costa Mesa, CARibavirinAntiviralribavirinSchering-PloughCorporation,Kenilworth, NJViramidineAntiviralRibavirin ProdrugRibapharm Inc.,Costa Mesa, CAHeptazymeAntiviralribozymeRibozymePharmaceuticalsInc., Boulder, COBILN-2061Antiviralserine proteaseBoehringerinhibitorIngelheim PharmaKG, Ingelheim,GermanySCH 503034Antiviralserine proteaseSchering PloughinhibitorZadazimImmune modulatorImmune modulatorSciClonePharmaceuticalsInc., San Mateo, CACepleneImmunomodulatorimmune modulatorMaximPharmaceuticalsInc., San Diego, CACellCeptImmunosuppressantHCV IgG immuno-F. Hoffmann-LasuppressantRoche LTD, Basel,SwitzerlandCivacirImmunosuppressantHCV IgG immuno-NabisuppressantBiopharmaceuticalsInc., Boca Raton, FLAlbuferon-Î±Interferonalbumin IFN-Î±2bHuman GenomeSciences Inc.,Rockville, MDInfergen AInterferonIFNInterMunealfacon-1PharmaceuticalsInc., Brisbane, CAOmega IFNInterferonIFN-Ï‰Intarcia TherapeuticsIFN-Î² and EMZ701InterferonIFN-Î² and EMZ701TransitionTherapeutics Inc.,Ontario, CanadaRebifInterferonIFN-Î²1aSerono, Geneva,SwitzerlandRoferon AInterferonIFN-Î±2aF. Hoffmann-LaRoche LTD, Basel,SwitzerlandIntron AInterferonIFN-Î±2bSchering-PloughCorporation,Kenilworth, NJIntron A andInterferonIFN-Î±2b/Î±1-thymosinRegeneRxZadaxinBiopharma. Inc.,Bethesda, MD/SciClonePharmaceuticals Inc,San Mateo, CARebetronInterferonIFN-Î±2b/ribavirinSchering-PloughCorporation,Kenilworth, NJActimmuneInterferonINF-Î³InterMune Inc.,Brisbane, CAInterferon-Î²InterferonInterferon-Î²-1aSeronoMultiferonInterferonLong lasting IFNViragen/ValentisWellferonInterferonLympho-blastoid IFN-GlaxoSmithKlineÎ±n1plc, Uxbridge, UKOmniferonInterferonnatural IFN-Î±Viragen Inc.,Plantation, FLPegasysInterferonPEGylated IFN-Î±2aF. Hoffmann-LaRoche LTD, Basel,SwitzerlandPegasys andInterferonPEGylated IFN-Î±2a/MaximCepleneimmune modulatorPharmaceuticalsInc., San Diego, CAPegasys andInterferonPEGylated IFN-F. Hoffmann-LaRibavirinÎ±2a/ribavirinRoche LTD, Basel,SwitzerlandPEG-IntronInterferonPEGylated IFN-Î±2bSchering-PloughCorporation,Kenilworth, NJPEG-Intron/InterferonPEGylated IFN-Schering-PloughRibavirinÎ±2b/ribavirinCorporation,Kenilworth, NJIP-501Liver protectionantifibroticIndevusPharmaceuticalsInc., Lexington, MAIDN-6556Liver protectioncaspase inhibitorIdunPharmaceuticalsInc., San Diego, CAITMN-191 (R-7227)Antiviralserine proteaseInterMuneinhibitorPharmaceuticalsInc., Brisbane, CAGL-59728AntiviralNS5B ReplicaseGenelabsInhibitorANA-971AntiviralTLR-7 agonistAnadysBoceprevirAntiviralserine proteaseSchering PloughinhibitorTMS-435Antiviralserine proteaseTibotec BVBA,inhibitorMechelen, BelgiumBI-201335Antiviralserine proteaseBoehringerinhibitorIngelheim PharmaKG, Ingelheim,GermanyMK-7009Antiviralserine proteaseMerckinhibitorPF-00868554Antiviralreplicase inhibitorPfizerANA598AntiviralNon-NucleosideAnadysNS5B PolymerasePharmaceuticals,InhibitorInc., San Diego, CA,USAIDX375AntiviralNon-NucleosideIdenixReplicase InhibitorPharmaceuticals,Cambridge, MA,USABILB 1941AntiviralNS5B PolymeraseBoehringerInhibitorIngelheim CanadaLtd R&D, Laval,QC, CanadaPSI-7851AntiviralNucleosidePharmasset,Polymerase InhibitorPrinceton, NJ, USAPSI-7977AntiviralNucleotide NS5BPharmasset,Polymerase InhibitorPrinceton, NJ, USAVCH-759AntiviralNS5B PolymeraseViroChem PharmaInhibitorVCH-916AntiviralNS5B PolymeraseViroChem PharmaInhibitorGS-9190AntiviralNS5B PolymeraseGileadInhibitorPeg-interferonAntiviralInterferonZymoGenetics/Bristol-lamdaMyers Squibb

Synthetic Methods

The compounds may be made by methods available in the art, as well as those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials. The variables (e.g. numbered â€œRâ€ substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention.

Abbreviations used in the schemes generally follow conventions used in the art. Chemical abbreviations used in the specification and examples are defined as follows: â€œNaHMDSâ€ for sodium bis(trimethylsilyl)amide; â€œDMFâ€ for N,N-dimethylformamide; â€œMeOHâ€ for methanol; â€œNBSâ€ for N-bromosuccinimide; â€œArâ€ for aryl; â€œTFAâ€ for trifluoroacetic acid; â€œLAHâ€ for lithium aluminum hydride; â€œBOCâ€ , â€œDMSOâ€ for dimethylsulfoxide; â€œhâ€ for hours; â€œrtâ€ for room temperature or retention time (context will dictate); â€œminâ€ for minutes; â€œEtOAcâ€ for ethyl acetate; â€œTHFâ€ for tetrahydrofuran; â€œEDTAâ€ for ethylenediaminetetraacetic acid; â€œEt₂Oâ€ for diethyl ether; â€œDMAPâ€ for 4-dimethylaminopyridine; â€œDCEâ€ for 1,2-dichloroethane; â€œACNâ€ for acetonitrile; â€œDMEâ€ for 1,2-dimethoxyethane; â€œHOBtâ€ for 1-hydroxybenzotriazole hydrate; â€œDIEAâ€ for diisopropylethylamine, â€œNfâ€ for CF₃(CF₂)₃SO₂â€”; and â€œTMOFâ€ for trimethylorthoformate.

Abbreviations are defined as follows: â€œ1Ã—â€ for once, â€œ2Ã—â€ for twice, â€œ3Ã—â€ for thrice, â€œÂ° C.â€ for degrees Celsius, â€œeqâ€ for equivalent or equivalents, â€œgâ€ for gram or grams, â€œmgâ€ for milligram or milligrams, â€œLâ€ for liter or liters, â€œmLâ€ for milliliter or milliliters, â€œÎ¼Lâ€ for microliter or microliters, â€œNâ€ for normal, â€œMâ€ for molar, â€œmmolâ€ for millimole or millimoles, â€œminâ€ for minute or minutes, â€œhâ€ for hour or hours, â€œrtâ€ for room temperature, â€œRTâ€ for retention time, â€œatmâ€ for atmosphere, â€œpsiâ€ for pounds per square inch, â€œconc.â€ for concentrate, â€œsatâ€ or â€œsat'dâ€ for saturated, â€œMWâ€ for molecular weight, â€œmpâ€ for melting point, â€œccâ€ for enantiomeric excess, â€œMSâ€ or â€œMass Specâ€ for mass spectrometry, â€œESIâ€ for electrospray ionization mass spectroscopy, â€œHRâ€ for high resolution, â€œHRMSâ€ for high resolution mass spectrometry, â€œLCMSâ€ for liquid chromatography mass spectrometry, â€œHPLCâ€ for high pressure liquid chromatography, â€œRP HPLCâ€ for reverse phase HPLC, â€œTLCâ€ or â€œtlcâ€ for thin layer chromatography, â€œNMRâ€ for nuclear magnetic resonance spectroscopy, â€œ¹Hâ€ for proton, â€œÎ´â€ for delta, â€œsâ€ for singlet, â€œdâ€ for doublet, â€œtâ€ for triplet, â€œqâ€ for quartet, â€œmâ€ for multiplet, â€œbrâ€ for broad, â€œHzâ€ for hertz, and â€œÎ±â€ , â€œÎ²â€ , â€œRâ€ , â€œSâ€ , â€œEâ€ , and â€œZâ€ are stereochemical designations familiar to one skilled in the art.

Chemistry Experimental

LC/MS Method (i.e., Compound Identification)

All Liquid Chromatography (LC) data were recorded on a Shimadzu LC-10AS or LC-20AS liquid chromotograph using a SPD-10AV or SPD-20A UV-Vis detector and Mass Spectrometry (MS) data were determined with a Micromass Platform for LC in electrospray mode.

HPLC Method (i.e., Compound Isolation)

Compounds purified by preparative HPLC were diluted in methanol (1.2 mL) and purified using a Shimadzu LC-8A or LC-10A automated preparative HPLC system.

Syntheses of Intermediates:

Preparation of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid

[Image Omitted]

Step 1: To a solution of 2,4,6-trichloro-1,3,5-triazine (15 g) in THF (300 mL) was added 2,2,2-trifluoroethanol (8.14 g) and Hunig'sBase (15.63 mL). The resulting mixture was stirred for 16 hours. After removal of most THF and precipitate through a plug washing with THF, the filtrate was concentrate to give a crude that will be used as it is.

Step 2: To a solution of the product in Step 1 above (10 g) in THF (100 mL) was added tert-butyl 4-aminobenzoate (7.79 g) and Hunig'sBase (7.04 mL). The resulting mixture was stirred for 16 h. The precipitate was filtered and washed with Et₂O, dried, then washed with water and dried to give 10.6 g of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.

tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoateMS (M + H)⁺ Calcd.405.1MS (M + H)⁺ Observ.405.0LC ConditionSolvent A100% Water-0.1% TFASolvent B100% ACN-0.1% TFAStart % B2Final % B98Gradient Time1.6 minStop Time1.8 minFlow Rate0.8 mL/minWavelength220Solvent PairACN-H₂0-0.1% TFAColumnAquity UPLC BEH C18 1.7 um

Step 3: To a slurry of tert-butyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (3.6 g) and 1-(4-chlorophenyl)cyclopropanamine (1.49 g) in THF (50 mL) was stirred for 5 hours at 80Â° C. The precipitate was filtrated through a plug washing with THF to give a crude product that was purified by Biotage eluting with 4/1-hexane/ethyl acetate to give 1.8 g of tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate as a solid.

tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoateMS (M + H)⁺ Calcd.536.2MS (M + H)⁺ Observ.536.0LC ConditionSolvent A100% Water-0.1% TFASolvent B100% ACN-0.1% TFAStart % B2Final % B98Gradient Time1.6 minStop Time1.8 minFlow Rate0.8 mL/minWavelength220Solvent PairACN-H₂0-0.1% TFAColumnAquity UPLC BEH C18 1.7 um

Step 4: A solution of above tert-butyl 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (4 g) and HCl in dioxane (7.46 ml, 4M) was stirred for 4 hours. Concentration gave 3.58 g of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid as a solid.

4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acidMS (M + H)⁺ Calcd.480.1MS (M + H)⁺ Observ.480.1LC ConditionSolvent A100% Water-0.1% TFASolvent B100% ACN-0.1% TFAStart % B2Final % B98Gradient Time1.6 minStop Time1.8 minFlow Rate0.8 mL/minWavelength220Solvent PairACN-H₂0-0.1% TFAColumnAquity UPLC BEH C18 1.7 um

Preparation of (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate

[Image Omitted]

To a solution of 4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoic acid (50 mg) in DMF (2 mL) was added O-(benzotriazol-1-yl-N,N,Nâ€²,Nâ€²-tetramethyluronium tetrafluoroborate (23.82 mg) and (S)-methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride (18.90 mg) and iPr₂NEt (0.052 ml). After stirring at rt for 4 h, the mixture was purified by preparative HPLC to give (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate.

(S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoateMS (M + H)⁺ Calcd.680.2MS (M + H)⁺ Observ.680.3Retention Time3.44 minLC ConditionSolvent A5% ACN:95% Water:10 mMAmmonium ActetateSolvent B95% ACN:5% Water:10 mMAmmonium ActetateStart % B0Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairACN:Water:Ammonium ActetateColumnPhenomenex Luna C18, 50 Ã— 2, 3u

Preparation of (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate

[Image Omitted]

To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (1 g) in CH₂Cl₂(10 mL) was added TFA (3 mL). The mixture was stirred at room temperature for 16 hours. All the solvents were removed under vacuum to give (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (0.8 g).

(S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoateMS (M + H)⁺ Calcd.580.2MS (M + H)⁺ Observ.580.0Retention Time1.35 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Syntheses of Claim I:

Synthesis of Compound 1001, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)propanoate

[Image Omitted]

A mixture of (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (20 mg) and 3,4-diethoxycyclobut-3-ene-1,2-dione (7.35 mg) in methanol (2 mL) was heated at 100Â° C. for 16 hours. After cooling to room temperature, the mixture was purified by preparative HPLC to give (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-methoxy-3,4-dioxocyclobut-1-enylamino)propanoate (4 mg).

Compound 1001MS (M + H)⁺ Calcd.690.2MS (M + H)⁺ Observ.690.1Retention Time3.01 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1002, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)propanoate and Compound 1003, (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-hydroxy-3,4-dioxocyclobut-1-enylamino)propanoate

[Image Omitted]

A mixture of (S)-methyl 3-amino-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)propanoate (50 mg) and 3,4-diethoxycyclobut-3-ene-1,2-dione (22.01 mg) in ethanol (2 mL) was heated at 100Â° C. for 16 hours. After cooling to room temperature, the mixture was purified by preparative HPLC to give (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-hydroxy-3,4-dioxocyclobut-1-enylamino)propanoate (8 mg) and (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)propanoate (12 mg).

Compound 1002MS (M + H)⁺ Calcd.704.2MS (M + H)⁺ Observ.704.1Retention Time3.15 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Compound 1003MS (M + H)⁺ Calcd.676.2MS (M + H)⁺ Observ.676.1Retention Time2.90 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B50Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1004, (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)propanoic acid

[Image Omitted]

A mixture of (S)-methyl 2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)propanoate (10 mg) and K₂CO₃(7.85 mg, 0.057 mmol) in acetone-water (2 mL, 1:1 by volume) was heated at 100Â° C. for 3 hours. All the solvents were removed under vacuum and the residue was purified by preparative HPLC to give (S)-2-(4-(4-(1-(4-chlorophenyl)cyclopropylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzamido)-3-(2-ethoxy-3,4-dioxocyclobut-1-enylamino)propanoic acid (3.8 mg).

Compound 1004MS (M + H)⁺ Calcd.690.2MS (M + H)⁺ Observ.690.1Retention Time3.60 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B30Final % B100Gradient Time4 minFlow Rate0.8 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 50 mm 3 um

Synthesis of Compound 1005, 4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(3-((2-ethoxy-3,4-dioxocyclobut-1-en-1-yl)amino)-2,2-dimethylpropyl)benzamide

[Image Omitted]

Compound 1005 was made using the same procedure preparing Compound 1002, using N-(3-amino-2,2-dimethylpropyl)-4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamide as the starting material.

Compound 1005MS (M + H)⁺ Calcd.688.2MS (M + H)⁺ Observ.688.4Retention Time1.87 minLC ConditionSolvent A5% ACN:95% Water:10 mMAmmonium ActetateSolvent B95% ACN:5% Water:10 mMAmmonium ActetateStart % B30Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN:Water:Ammonium ActetateColumnPhenomenex LUNA C18, 30 Ã— 2, 3u

Synthesis of Compound 1006, 4-((4(1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)-N-(3-((2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)amino)-2,2-dimethylpropyl)benzamide

[Image Omitted]

K₂CO₃(5.2 mg) was added into the solution of Compound 1005 (25 mg) in EtOH (2 mL) and water (2 mL). The reaction was carried out at room temperature for 16 hours. All the solvents were removed under vacuum and the residue was purified by preparative HPLC to give Compound 1006.

Compound 1006MS (M + H)⁺ Calcd.660.2MS (M + H)⁺ Observ.660.2Retention Time2.28 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

General Procedure to Prepare Claim I from Compound 1005:

iPr₂NEt oe Et₃N (1-20 eq.) and amine was added into a solution of Compound 1005 were combined in MeOH, EtOH, THF or DMF. The mixture was stirred at room temperature or 115Â° C. for 17 hours. The solvents were removed via evaporation at reduced pressure and the residue was purified by preparative HPLC system.

[Image Omitted]

Compound 1007 [Image Omitted]

MS (M + H)⁺ Calcd.713.2MS (M + H)⁺ Observ.713.3Retention Time2.37 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % Bâ€ƒ0Final % B100Gradient Timeâ€ƒâ€‰2 minFlow Rateâ€ƒâ€‰1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1008 [Image Omitted]

MS (M + H)⁺Calcd.785.2MS (M + H)⁺Observ.785.3Retention Time2.40 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1009 [Image Omitted]

MS (M + H)⁺ Calcd.755.3MS (M + H)⁺ Observ.755.3Retention Time2.48 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1010 [Image Omitted]

MS (M + H)⁺Calcd.796.3MS (M + H)⁺Observ.796.5Retention Time2.11 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1013 [Image Omitted]

MS (M + H)⁺Calcd.735.2MS (M + H)⁺Observ.735.3Retention Time2.43 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

General procedure to prepare Claim I from (S)-methyl 4-amino-2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoate

[Image Omitted]

A mixture of (S)-methyl 4-amino-2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoate (1 eq.) and 3,4-diethoxycyclobut-3-ene-1,2-dione or 3,4-dimethoxycyclobut-3-ene-1,2-dione (1-2 eq.) in ethanol was heated at 100Â° C. to 130Â° C. for 16 hours. Then, amine (10-20 eq.) and iPr₂NEt (20 eq.) were added and the resulting mixture was heated to 100Â° C. to 130Â° C. for 1-16 hours. The mixture was purified by preparative HPLC system.

Compound 1011 [Image Omitted]

MS (M + H)⁺Calcd.782.3MS (M + H)⁺Observ.782.4Retention Time2.29 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1014 [Image Omitted]

MS (M + H)⁺Calcd.826.2MS (M + H)⁺Observ.826.4Retention Time2.56 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1018 [Image Omitted]

MS (M + H)⁺Calcd.866.4MS (M + H)⁺Observ.866.5Retention Time2.57 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1019 [Image Omitted]

MS (M + H)⁺Calcd.862.3MS (M + H)⁺Observ.862.5Retention Time2.51 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1020 [Image Omitted]

MS (M + H)⁺Calcd.926.2MS (M + H)⁺Observ.926.6Retention Time1.91 minLC ConditionSolvent A5% ACN:95% Water:10 mM Ammonium ActetateSolvent B95% ACN:5% Water:10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN:Water:Ammonium ActetateColumnPhenomenex LUNA C18, 30 Ã— 2, 3 u

General procedure to prepare Claim I from (S)-methyl 4-amino-2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoate

[Image Omitted]

A mixture of (S)-methyl 4-amino-2-(4-((4-((1-(4-chlorophenyl)cyclopropyl)amino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-yl)amino)benzamido)butanoate (1 eq.) and 3,4-diethoxycyclobut-3-ene-1,2-dione or 3,4-dimethoxycyclobut-3-ene-1,2-dione (1-2 eq.) in ethanol was heated at 100Â° C. to 130Â° C. for 16 hours. Then, amine (10-20 eq.) and iPr₂NEt (20 eq.) were added and the resulting mixture was stirred at room temperature for 16-72 hours. The mixture was purified by preparative HPLC system.

Compound 1022 [Image Omitted]

MS (M + H)⁺Calcd.799.3MS (M + H)⁺Observ.799.4Retention Time2.43 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

General Procedure to Prepare Claim I from Esters:

[Image Omitted]

K₂CO₃(2 eq.) was added into a solution of methyl ester derivative and/or ethyl ester derivative (1 eq.) in EtOH and water. The reaction was stirred at room temperature for 16 hours before solid was removed via filtration. The filtrate was purified by preparative HPLC system.

Compound 1012 [Image Omitted]

MS (M + H)⁺Calcd.785.3MS (M + H)⁺Observ.785.3Retention Time2.45 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1015 [Image Omitted]

MS (M + H)⁺Calcd.809.3MS (M + H)⁺Observ.809.4Retention Time2.04 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1016 [Image Omitted]

MS (M + H)⁺Calcd.751.2MS (M + H)⁺Observ.751.3Retention Time2.29 minLC ConditionSolvent A90% Water-10% Methanol-0.1% TFASolvent B10% Water-90% Methanol-0.1% TFAStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairWater-Methanol-TFAColumnPHENOMENEX-LUNA 2.0 Ã— 30 mm 3 um

Compound 1017 [Image Omitted]

MS (M + H)⁺Calcd.769.2MS (M + H)⁺Observ.769.5Retention Time1.53 minLC ConditionSolvent A5% ACN:95% Water:10 mM Ammonium ActetateSolvent B95% ACN:5% Water:10 mM Ammonium ActetateStart % B0Final % B100Gradient Time2 minFlow Rate1 mL/minWavelength220Solvent PairACN:Water:Ammonium ActetateColumnPhenomenex LUNA C18, 30 Ã— 2, 3 u

Biological Methods

Infection assays. HCV pseudoparticles, produced using standardized methodology (Bartosch, B., Dubuisson, J. and Cosset, F.-L. J. Exp. Med. 2003, 197:633-642) were made via a liposome-based transfection procedure of 293T cells with plasmids expressing the murine leukemia virus capsid and polymerase proteins, an MLV genome encoding the luciferase reporter gene, and envelope glycoproteins from either HCV or vesicular stomatitis virus (VSV). The genotype 1a HCV E1 and E2 envelope coding sequences were derived from the H77C isolate (GenBank accession number AF009606). Media containing pseudoparticles was collected 3 days following transfection, filtered, and stored at âˆ’20Â° C. as a viral stock. Infections were performed in 384-well plates by mixing pseudovirus with 1Ã—10⁴Huh7 cells/well in the presence or absence of test inhibitors, followed by incubation at 37Â° C. Luciferase activity, reflecting the degree of entry of the pseudoparticles into host cells, was measured 2 days after infection. The specificity of the compounds for inhibiting HCV was determined by evaluating inhibition of VSV pseudoparticle infection.

Compounds and data analysis. Test compounds were serially diluted 3-fold in dimethyl sulfoxide (DMSO) to give a final concentration range in the assay of 50.0 Î¼M to 0.04 pM. Maximum activity (100% of control) and background were derived from control wells containing DMSO but no inhibitor or from uninfected wells, respectively. The individual signals in each of the compound test wells were then divided by the averaged control values after background subtraction and multiplied by 100% to determine percent activity. Assays were performed in duplicate and average EC₅₀values (reflecting the concentration at which 50% inhibition of virus replication was achieved) were calculated. Compound EC₅₀data is expressed as A=0.01â‰¦10 nM; B=10-1000 nM. Representative data for compounds are reported in Table 2.

TABLE 2EC₅₀EC₅₀Compd #Structure(1a, nM)(1a, nM)1001 [Image Omitted]

117.20â€‚B 1002 [Image Omitted]

B 1003

47.00B 1004 [Image Omitted]

B 1005

A 1006

â€‚0.52A 1007 [Image Omitted]

A 1008

â€ƒ0.050A 1009 [Image Omitted]

A 1010

A 1011

â€‚5.98A 1012 [Image Omitted]

A 1013

A 1014

B 1015

â€‚6.55A 1016 [Image Omitted]

A 1017

A 1018

A 1019

B 1020

A 1021

â€‚1.24A

It will be evident to one skilled in the art that the present disclosure is not limited to the foregoing illustrative examples, and that it can be embodied in other specific forms without departing from the essential attributes thereof. It is therefore desired that the examples be considered in all respects as illustrative and not restrictive, reference being made to the appended claims, rather than to the foregoing examples, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.