COMBINATION TREATMENTS FOR HEPATITIS C

CROSS-REFERENCE TO RELATED PATENTS AND PATENT APPLICATIONS

This is a Patent Cooperation Treaty application and claims the benefit of US Provisional Application No. 61/524,606, filed August 17, 2011 and US Provisional Application No. 61/526,790, filed August 24, 201 1 , both of which are hereby incorporated by reference in their entireties.

FIELD OF THE INVENTION

The present invention relates to methods for the treatment of viral infections mediated by a member of the Flavivi dae family of viruses such as Hepatitis C virus

(HCV), and to compositions for such treatment, and more particularly to methods for the treatment of Hepatitis C in subjects needing such treatment comprising administering to the subject any benzofuran NS5B polymerase inhibitor described herein (Formulas (I!) and (MB)) in combination with any NS5a inhibitor described herein (Formulas (I), (Mi}, (Π Β), and (MIC)) and to compositions and pharmaceutical compositions comprising an benzofuran NS5B polymerase inhibitor in combination with an NSoa inhibitor.

BACKGROUND OF THE INVENTION

Chronic infection with HCV is a major health problem associated with increased risk for chronic liver disease, cirrhosis, hepatocellular carcinoma, and liver failure. HCV is a hepacivirus member of the Flaviviridae family of RNA viruses that affect animals and humans. The genome is a single ~9.6-kilobase strand of RNA, and consists of one open reading frame that encodes for a polyprotein of -3000 amino acids flanked by untranslated regions at both 5' and 3' ends (5'- and 3'-UTR). The polyprotein serves as the precursor to at least 10 separate viral proteins critical for replication and assembly of progeny viral particles. The organization of structural and non-structural proteins in the HCV polyprotein is as follows: C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. Because the replicative cycle of HCV does not involve any DNA intermediate and the virus is not integrated into the host genome, HCV infection can theoretically be cured. While the pathology of HCV infection affects mainly the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes.

HCV is the major causative agent for post-transfusion and for sporadic hepatitis. Infection by HCV is insidious in a high proportion of chronically infected (and infectious) carriers who may not experience clinical symptoms for many years. An estimated 170 million chronic carriers worldwide are at risk of developing liver disease. See, for example, Szabo, et al., Pathol.Oncol.Res. 2003, 9:215-221 , and Hoofnagle JH,

Hepatology 1997 ^' , 26: 15S-20S. In the United States alone 2.7 million are chronically infected with HCV, and the number of HCV-related deaths in 2000 was estimated between 8,000 and 10,000, a number that is expected to increase significantly over the next years.

Historically, the standard treatment for chronic HCV was interferon alpha (IFN- alpha), particularly, pegylated interferon (PEG-IFN) alpha, in combination with ribavirin, which required six to twelve months of treatment. This combination regimen included 48 weekly injections of interferon and daily doses of oral ribavirin HCV patients infected with the genotype 1 virus.

IFN-alpha belongs to a family of naturally occurring small proteins with

characteristic biological effects such as antiviral, immunoregulatory, and antitumoral activities. Interferons are produced and secreted by most animal nucleated cells in response to several diseases, in particular viral infections. IFN-alpha is an important regulator of growth and differentiation affecting cellular communication and immunological control. Treatment of HCV with interferon has frequently been associated with adverse side effects such as fatigue, fever, chills, headache, myalgias, arthralgias, mild alopecia, psychiatric effects and associated disorders, autoimmune phenomena and associated disorders and thyroid dysfunction.

Ribavirin, an inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), enhances the efficacy of IFN-alpha in the treatment of HCV. Despite the introduction of ribavirin, more than 50% of the patients do not eliminate the virus with the current standard therapy of interferon-alpha (IFN) and ribavirin. Also, a number of patients still have significant side effects related to ribavirin. Ribavirin causes significant hemolysis in 10-20% of patients treated at currently recommended doses, and the drug is both teratogenic and embryotoxic.

A number of additional approaches are being pursued to combat the virus. These include, for example, application of antisense oligonucleotides or ribozymes for inhibiting HCV replication. Furthermore, low-molecular weight compounds that directly inhibit HCV proteins and interfere with viral replication are considered as attractive strategies to control HCV infection. Among the viral targets, the NS3/4A protease/helicase, the NS5B RNA-dependent RNA polymerase, and the non-structural NS5A protein, are considered the most promising HCV viral targets for new drugs. Indeed, compounds said to be useful for treating HCV infections are disclosed, for example, in WO2005/051318 (Chunduru, et al.) and WO2009/023179 (Schmitz, et al.). These references disclose methods for preparing the compounds, compositions comprising the compounds, compositions comprising the compounds and additional compounds, and methods of treating HCV. Recently, two HCV therapeutic drugs have been approved in the US; each used as

3-way combination therapies in conjunction with pegylated interferon and ribavirin. These are Vertex's and Johnson and Johnson's NS3/4A protease inhibitor, Incivek® (telaprevir) and Merck's NS3/4A protease inhibitor, Victrelis® (boceprevir). The older 2-way pegylated interferon and ribavirin treatment regimen for HCV only cured about 40% of genotype 1 infected patients. Adding Victrelis® to that regimen shortens treatment duration for some and improves cure rates to more than 60%. Likewise, adding Incivek® to that regimen shortens treatment and boosts cure rates to as high as 80%.

Unfortunately, neither Victrelis® nor Incivek® can be used alone without also including the pegylated interferon and ribavirin regimen, which brings along their concomitant unfavorable side effect profiles. These protease inhibitors also are associated with additional side effects such as rash and increased neutropenia. Such single active agent drugs also increase the risk of selecting for particular HCV mutations within the patient's body, which are resistant to these protease inhibitors.

Even with these recent improvements, a substantial fraction of patients do not respond with a sustained reduction in viral load and there is a clearly a need for more effective antiviral therapy of HCV infection. Therefore, what is needed is a combination therapy strategy to combat the HCV virus without having to include the problematic pegylated interferon and ribavirin therapeutics. Multiple combination therapies that include Direct-acting antivirals (DAA) targeted to more than one particular type of HCV protein could reduce the incidence of side effects. Just as importantly, DAAs could reduce the virus's ability to mutate within the patient's body, which can lead to a resurgence of HCV viral titer.

In view of the worldwide epidemic level of HCV, the limited treatment options available, and the need to expand access to all oral DAA regimens, there is a an ever growing need for new effective drugs for treating chronic HCV infections.

SUMMARY OF THE INVENTION

In accordance with one embodiment of the present invention, there is provided a method for the treatment of Hepatitis C in a human in need thereof comprising administering to the human a first compound having a structure according to Formula (I):

wherein each R is independently -CH(R ¹ )-NH-C(0)-OR ² ;

wherein each R ¹ is independently -CH(OH)-CH ₃ or -CH(OCH ₃ )-CH ₃ ; and each R ² is independently Ci_ ₃ alkyl;

or a pharmaceutically acceptable salt thereof,

in combination with a second rding to Formula (II);

wherein:

R is independently selected from the group consisting of halogen, Ci_ ₆ alkyl, alkoxy, -CN, -CF ₃ , -O- C ₆ - ioaryl optionally substituted by halogen, and -O-heteroaryl optionally substituted by halogen;

R ¹ is -C(0)OH, -C(0)NHR ⁵ or heterocyclyl;

R ² is C^alkyl, C ₃ . ₆ cycloalkyl, -C(H)F ₂ , -CF ₃ , or -OR ⁶ ;

R ³ is -S(0) ₂ R ⁷ or -C(0)R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyi; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyi, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ i ₀ aryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyi; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyi, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl; or (c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-ealkoxy, -C(H)F ₂ , -CF ₃ , C-i-ealkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is hydrogen, Ci_ ₆ alkyl, hydroxy, or -OR ⁶ ;

R ⁶ is Ci. ₆ alkyl or C ₃ - ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl, or aminoalkyl;

R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ or R ⁸ , R ⁹ , and R ¹² together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ),

N(R ¹⁰ )(R ¹¹ ), and C ₃ . ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(0)OH, C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci-ealkyl;

R ¹³ is alkoxy;

X is alkylene or -O-alkylene _, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_

₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ and C ₃ _ ecycloalkyl;

m is 1 , 2, or 3;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF REPRESENTATIVE EMBODIMENTS

Throughout this application, references are made to various embodiments relating to compounds, compositions, and methods. The various embodiments described are meant to provide a variety of illustrative examples and should not be construed as descriptions of alternative species. Rather it should be noted that the descriptions of various embodiments provided herein may be of overlapping scope. The embodiments discussed herein are merely illustrative and are not meant to limit the scope of the present invention.

It is to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of the present invention. In this specification and in the claims that follow, reference will be made to a number of terms that shall be defined to have the following meanings.

The term "alkyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms. For example, Ci_ ₆ alkyl means a straight or branched alkyl containing at least 1 , and at most 6, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, f-butyl, n-pentyl, 1 ,1-dimethylpropyl, and n-hexyl.

As used herein, the term "alkylene" refers to a straight or branched chain divalent hydrocarbon radical, preferably having from one to six carbon atoms, unless specified otherwise. Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, n-propylene, n-butylene, and the like.

The term "alkoxy" refers to an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom. For example, Ci_ ₆ alkoxy refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 6 carbon atoms attached through an oxygen linking atom. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, prop-1-oxy, prop-2-oxy, but-1-oxy, but-2- oxy, 2-methylprop-1-oxy, 2-methylprop-2-oxy, pentoxy and hexyloxy.

The term "halogen" or "halo" refers to a fluorine (fluoro, F), chlorine (chloro, CI), bromine (bromo, Br) or iodine (iodo, I) atom.

The terms "hydroxy" or "hydroxyl" refer to a radical or substituent of the formula

OH.

The term "cycloalkyl" refers to a saturated cyclic group containing 3 to 6 carbon ring-atoms (unless otherwise specified). Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term "aryl" refers to a carbocyclic aromatic moiety (such as phenyl or naphthyl) containing the specified number of carbon atoms, particularly from 6-10 carbon atoms. Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, indenyl, azulenyl, fluorenyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl, indanyl,

phenanthridinyl and the like. Unless otherwise indicated, the term "aryl" also includes each possible positional isomer of an aromatic hydrocarbon radical, such as in 1-naphthyl, 2-naphthyl, 5-tetrahydronaphthyl, 6-tetrahydronaphthyl, 1-phenanthridinyl,

2-phenanthridinyl, 3-phenanthridinyl, 4-phenanthridinyl, 7-phenanthridinyl,

8-phenanthridinyl, 9-phenanthridinyl and 10-phenanthridinyl.

The term "heteroaryl" refers to a group or moiety comprising an aromatic monovalent monocyclic or bicyclic radical, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. This term also encompasses bicyclic heterocyclic-aryl compounds containing an aryl ring moiety fused to a heterocycloalkyi ring moiety, containing 5 to 10 ring atoms, including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryls useful in the present invention include, but are not limited to, furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, triazinyl, benzofuranyl, isobenzofuryl, 2,3-dihydrobenzofuryl, 1 ,3-benzodioxolyl,

dihydrobenzodioxinyl, benzothienyl, indolizinyl, indolyl, isoindolyl, dihydroindolyl, benzimidazolyl, dihydrobenzimidazolyl, benzoxazolyl, dihydrobenzoxazolyl, benzthiazolyl, benzoisothiazolyl, dihydrobenzoisothiazolyl, indazolyl, imidazopyridinyl, pyrazolopyridinyl, benzotriazolyl, triazolopyridinyl, purinyl, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl,

1 ,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1 ,8-naphthyridinyl, and pteridinyl. All isomers of the above heteroaryl groups are within the scope of this invention. Each heteroaryl group may be attached at any ring carbon or may be attached through nitrogen when the nitrogen is part of a 5-membered ring.

Generally, the heteroaryl groups present in the compounds of this invention are 5-membered and/or 6-memebred monocyclic heteroaryl groups. Selected 5-membered heteroaryl groups contain one nitrogen, oxygen, or sulfur ring heteroatom, and optionally contain 1 , 2, or 3 additional nitrogen ring atoms. Selected 6-membered heteroaryl groups contain 1 , 2, or 3 nitrogen ring heteroatoms. Illustrative examples of 5- or 6-membered heteroaryl groups useful in the present invention include, but are not limited to furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, and triazinyl.

The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen, such as N(O) {N ⁺ -0 ^~ } and sulfur such as S(O) and S(0) ₂ , and the quaternized form of any basic nitrogen.

The term "heterocyclyl" refers to a 3- to 7-membered monocyclic heterocyclic ring which is saturated, partially saturated, or unsaturated. Each heterocyclyl consists of one or more carbon atoms and one or more oxygen, nitrogen, or sulfur atoms. The

heterocyclyl may be attached at any carbon or nitrogen atom, provided that the attachment results in the creation of a stable structure. When the heterocyclyl has substituents, it is understood that the substituents may be attached to any atom in the ring, provided that a stable chemical structure results.

The present invention provides combinations of therapeutic compounds as compositions and pharmaceutical compositions and also as methods for treating Hepatitis C in a subject in need of Hepatitis C treatment.

As such, the present invention provides in certain embodiments, a composition comprising a first co (I):

wherein each R is independently -CH(R ¹ )-NH-C(0)-OR ² ;

wherein each R ¹ is independently -CH(OH)-CH ₃ or -CH(OCH ₃ )-CH ₃ ; and each R ² is independently Ci _-3 alkyl;

or a pharmaceutically acceptable salt thereof,

in combination with a second rding to Formula (II);

wherein:

R is independently selected from the group consisting of halogen, Ci_ ₆ alkyl, alkoxy, -CN, -CF ₃ , -O- C ₆ _ ioaryl optionally substituted by halogen, and -O-heteroaryl optionally substituted by halogen;

R ¹ is -C(0)OH, -C(0)NHR ⁵ or heterocyclyl;

R ² is Ci _-6 alkyl, C ₃ . ₆ cycloalkyl, -C(H)F ₂ , -CF ₃ , or -OR ⁶ ;

R ³ is -S(0) ₂ R ⁷ or -C(0)R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyi; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-ealkoxy, -C(H)F ₂ , -CF ₃ , C-i-ealkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ i ₀ aryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is hydrogen, Ci_ ₆ alkyl, hydroxy, or -OR ⁶ ;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci-ealkyl, hydroxyalkyl, or aminoalkyl;

R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ or R ⁸ , R ⁹ , and R ¹² together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ),

N(R ¹⁰ )(R ¹¹ ), and C ₃ . ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(0)OH, C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -O-alkylene _, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ and C ₃ - ecycloalkyl;

m is 1 , 2, or 3;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a composition comprising a first compound having a structure according to Formula I:

wherein each R is independently -CH(R ¹ )-NH-C(0)-OR ² ;

wherein each R ¹ is independently -CH(OH)-CH ₃ or -CH(OCH ₃ )-CH ₃ ; and each R ² is independently Ci_ ₃ alkyl;

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

(MB)

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C ₃ . ₆ cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C^alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl; (b) C ₆ _ ₁₀ aryl substituted with B(R ^S )( R ⁹ ), or XB(R ^S )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, d- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is Ci_ ₆ alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl or aminoalkyl;

R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of C-i-ealkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ _ ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci-ealkoxy, -C(H)F ₂ , -CF ₃ , C-i-ealkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -

C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a composition comprising a first compound having the structure: , or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a composition compri

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a pharmaceutical composition comprisi to Formula I:

wherein each R is independently -CH(R ¹ )-NH-C(0)-OR ² ;

wherein each R ¹ is independently -CH(OH)-CH ₃ or -CH(OCH ₃ )-CH ₃ ; and each R ² is independently Ci_ ₃ alkyl;

or a pharmaceutically acceptable salt thereof,

in combination with a second rding to Formula (II);

wherein:

R is independently selected from the group consisting of halogen, C-i-ealkyl, alkoxy, -CN, -CF ₃ , -O- C ₆ _ ioaryl optionally substituted by halogen, and -O-heteroaryl optionally substituted by halogen;

R ¹ is -C(0)OH, -C(0)NHR ⁵ or heterocyclyl;

R ² is C^alkyl, C ₃ . ₆ cycloalkyl, -C(H)F ₂ , -CF ₃ , or -OR ⁶ ;

R ³ is -S(0) ₂ R ⁷ or -C(0)R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyi; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-ealkoxy, -C(H)F ₂ , -CF ₃ , C-i-ealkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ i ₀ aryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is hydrogen, Ci_ ₆ alkyl, hydroxy, or -OR ⁶ ;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci-ealkyl, hydroxyalkyl, or aminoalkyl;

R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ or R ⁸ , R ⁹ , and R ¹² together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ),

N(R ¹⁰ )(R ¹¹ ), and C ₃ . ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(0)OH, C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -O-alkylene _, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ and C ₃ - ecycloalkyl;

m is 1 , 2, or 3;

or a pharmaceutically acceptable salt thereof,

and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a pharmaceutical composition comprising a first compound having a structure according to Formula I:

wherein each R is independently -CH(R ¹ )-NH-C(0)-OR ² ;

wherein each R ¹ is independently -CH(OH)-CH ₃ or -CH(OCH ₃ )-CH ₃ ; and each R ² is independently Ci_ ₃ alkyl;

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

(MB)

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C ₃ . ₆ cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, C^alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ^6, -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is C^alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl or aminoalkyl;

R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ - ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , - C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ . ecycloalkyl;

or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a pharmaceutical compo the structure:

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a pharmaceutical compo tructure:

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first compound having a

wherein each R is independently -CH(R ¹ )-NH-C(0)-OR ² ;

wherein each R ¹ is independently -CH(OH)-CH ₃ or -CH(OCH ₃ )-CH ₃ ; and each R ² is independently Ci_ ₃ alkyl;

or a pharmaceutically acceptable salt thereof,

in combination with a second rding to Formula (II);

wherein:

R is independently selected from the group consisting of halogen, Ci_ ₆ alkyl, alkoxy, -CN, -CF ₃ , -O- C ₆ - ioaryl optionally substituted by halogen, and -O-heteroaryl optionally substituted by halogen;

R ¹ is -C(0)OH, -C(0)NHR ⁵ or heterocyclyl;

R ² is C^alkyl, C ₃ . ₆ cycloalkyl, -C(H)F ₂ , -CF ₃ , or -OR ⁶ ;

R ³ is -S(0) ₂ R ⁷ or -C(0)R ⁷ ;

R ⁴ is (a) heteroaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )(

R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ i ₀ aryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is hydrogen, C-i-ealkyl, hydroxy, or -OR ⁶ ;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl, or aminoalkyl;

R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and

R ⁹ or R ⁸ , R ⁹ , and R ¹² together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ),

N(R ¹⁰ )(R ¹¹ ), and C ₃ . ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(0)OH, C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy; X is alkylene or -O-alkylene _, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ and C ₃ _ ecycloalkyl;

m is 1 , 2, or 3;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first compound having a structure according to Formula I:

wherein each R is independently -CH(R ¹ )-NH-C(0)-OR ² ;

wherein each R ¹ is independently -CH(OH)-CH ₃ or -CH(OCH ₃ )-CH ₃ ; and each R ² is independently Ci_ ₃ alkyl;

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

(MB)

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C ₃ . ₆ cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, d- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ . ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is C^alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl or aminoalkyl;

R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ _ ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or C-i-ealkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci-ealkoxy, -C(H)F ₂ , -CF ₃ , C-i-ealkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , - C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl; or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first compound having the structure:

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides aA method of treating Hepatitis C in a human in need thereof comprising administering to the human a first

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure: , or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a composition comprising a first comp

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci_ ₃ alkyl;

on each carbon to which there are R ³ groups, either both R ³ s are H or the R ³ groups together with the carbon to which they are bonded form a 4-, 5-, or 6- membered saturated spiro ring with the proviso that there is no more than 1 spiro ring on each saturated nitrogen-containing ring;

each saturated spiro formed from R ³ groups is independently cycloalkyl, or may contain 1 or 2 oxygen atoms, or 1 or 2 sulfur atoms, or 1 S0 ₂ , or 1 NR ⁴ ;

each R ⁴ is independently H, CiOJOC^alkyl, CiOJd^alkyl, CiC NC^alkyl, S0 ₂ C^ 4alkyl; and each spiro ring may optionally be substituted with deuterium, fluorine, or 1-2 methyl groups;

or a pharmaceutically acceptable salt thereof,

in combination with a second rding to Formula (II);

wherein:

R is independently selected from the group consisting of halogen, Ci_ ₆ alkyl, alkoxy, -CN, -CF ₃ , -O- C ₆ _ ioaryl optionally substituted by halogen, and -O-heteroaryl optionally substituted by halogen;

R ¹ is -C(0)OH, -C(0)NHR ⁵ or heterocyclyl;

R ² is C^alkyl, C ₃ - ₆ cycloalkyl, -C(H)F ₂ , -CF ₃ , or -OR ⁶ ;

R ³ is -S(0) ₂ R ⁷ or -C(0)R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ i ₀ aryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )(

R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci-ealkoxy, -C(H)F ₂ , -CF ₃ , C-i-ealkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is hydrogen, Ci_ ₆ alkyl, hydroxy, or -OR ⁶ ;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci-ealkyl, hydroxyalkyl, or aminoalkyl;

R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ or R ⁸ , R ⁹ , and R ¹² together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ),

N(R ¹⁰ )(R ¹¹ ), and C ₃ . ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(0)OH, C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -O-alkylene, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ and C ₃ _ ecycloalkyl;

m is 1 , 2, or 3;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a composition comprising a first compound having a structure according to Formula NIB:

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci_ ₃ alkyl;

each X is independently CRR, O, or S;

each n is independently 2 or 3; and

each R is independently methyl, hydrogen, or deuterium,

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C _3-6 cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ . ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is d_ ₆ alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl or aminoalkyl; R and R are each independently hydroxy, alkoxy, or aminoalkyl; or R and R together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of C _-6 alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ - ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci-ealkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , - C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ^6, -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a composition comprising a first compound having a structure according to Formula NIC:

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci _-3 alkyl;

each X is independently CRR, O or S;

n is 2 or 3; and

each R is independently methyl, hydrogen, or deuterium,

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C _3-6 cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ . ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is d_ ₆ alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl or aminoalkyl; R and R are each independently hydroxy, alkoxy, or aminoalkyl; or R and R together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of C _-6 alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ - ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci-ealkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , - C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ^6, -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a composition compris

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof. In certain embodiments, the present invention also provides a composition compri

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a pharmaceutical composition comprisin ormula III:

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci _-3 alkyl;

on each carbon to which there are R ³ groups, either both R ³ s are H or the R ³ groups together with the carbon to which they are bonded form a 4-, 5-, or 6- membered saturated spiro ring with the proviso that there is no more than 1 spiro ring on each saturated nitrogen-containing ring; each saturated spiro formed from R ³ groups is independently cycloalkyl, or may contain 1 or 2 oxygen atoms, or 1 or 2 sulfur atoms, or 1 SO ₂ , or 1 NR ⁴ ;

each R ⁴ is independently H, C(0)OCi_ ₄ alkyl, C(0)Ci_ ₄ alkyl, C(0)NCi_ ₄ alkyl, S0 ₂ d_ 4alkyl; and each spiro ring may optionally be substituted with deuterium, fluorine, or 1-2 methyl groups;

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (II);

wherein:

R is independently selected from the group consisting of halogen, Ci_ ₆ alkyl, alkoxy,

-CN, -CF ₃ , -O- C ₆ _ ioaryl optionally substituted by halogen, and -O-heteroaryl optionally substituted by halogen;

R ¹ is -C(0)OH, -C(0)NHR ⁵ or heterocyclyl;

R ² is Ci _-6 alkyl, C ₃ - ₆ cycloalkyl, -C(H)F ₂ , -CF ₃ , or -OR ⁶ ;

R ³ is -S(0) ₂ R ⁷ or -C(0)R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyi; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyi, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ i ₀ aryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyi; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyi, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is hydrogen, Ci_ ₆ alkyl, hydroxy, or -OR ⁶ ;

R ⁶ is Ci- ₆ alkyl or C ₃ - ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl, or aminoalkyl;

R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ or R ⁸ , R ⁹ , and R ¹² together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ),

N(R ¹⁰ )(R ¹¹ ), and C ₃ . ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(0)OH, C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -O-alkylene, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_

6alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ and C ₃ . ecycloalkyl;

m is 1 , 2, or 3;

or a pharmaceutically acceptable salt thereof,

and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a pharmaceutical composition comprising a first compound having a structure according to Formula NIB:

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci _-3 alkyl;

each X is independently CRR, O, or S;

each n is independently 2 or 3; and

each R is independently methyl, hydrogen, or deuterium,

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

(MB)

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C ₃ - ₆ cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, C^alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is d_ ₆ alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl or aminoalkyl;

R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of C^alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ _ ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or C-i-ealkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , - C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl;

or a pharmaceutically acceptable salt thereof,

and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a pharmaceutical composition comprising a first compound having a structure according to Formula NIC:

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci _-3 alkyl;

each X is independently CRR, O or S;

n is 2 or 3; and

each R is independently methyl, hydrogen, or deuterium,

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C ₃ - ₆ cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, C^alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is d_ ₆ alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ . ₆ cycloalkyl;

R ⁷ is Ci- ₆ alkyl, hydroxyalkyl or aminoalkyl;

R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of C^alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ _ ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or C-i-ealkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , - C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl;

or a pharmaceutically acceptable salt thereof,

and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a pharmaceutical composition comprising a first compound having the structure: , or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a pharmaceutical composition comprising a first compound having the structure:

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof;

and a pharmaceutically acceptable carrier.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first compound having a str

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci_ ₃ alkyl;

on each carbon to which there are R ³ groups, either both R ³ s are H or the R ³ groups together with the carbon to which they are bonded form a 4-, 5-, or 6- membered saturated spiro ring with the proviso that there is no more than 1 spiro ring on each saturated nitrogen-containing ring;

each saturated spiro formed from R ³ groups is independently cycloalkyl, or may contain 1 or 2 oxygen atoms, or 1 or 2 sulfur atoms, or 1 S0 ₂ , or 1 NR ⁴ ;

each R ⁴ is independently H, CiOJOC^alkyl, CiOJd^alkyl, CiC NC^alkyl, S0 ₂ C^ 4alkyl; and each spiro ring may optionally be substituted with deuterium, fluorine, or 1-2 methyl groups;

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (II); wherein:

R is independently selected from the group consisting of halogen, Ci _-6 alkyl, alkoxy, -CN, -CF ₃ , -O- C ₆ _ ioaryl optionally substituted by halogen, and -O-heteroaryl optionally substituted by halogen;

R ¹ is -C(0)OH, -C(0)NHR ⁵ or heterocyclyl;

R ² is Ci _-6 alkyl, C ₃ - ₆ cycloalkyl, -C(H)F ₂ , -CF ₃ , or -OR ⁶ ;

R ³ is -S(0) ₂ R ⁷ or -C(0)R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )(

R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ - ioaryl substituted with B(R ⁸ )( R ⁹ ), X B(R ⁸ )(R ⁹ ), OXB(R ⁸ (R ⁹ ), B (R ⁸ )( R ⁹ )(R ¹² ), XB(R ⁸ )R ⁹ )(R ¹² ) or Het optionally substituted with hydroxy or hydroxyalkyl; and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms; R ⁵ is hydrogen, Ci_ ₆ alkyl, hydroxy, or -OR ⁶ ;

R ⁶ is Ci. ₆ alkyl or C ₃ - ₆ cycloalkyl;

R ⁷ is Ci_ ₆ alkyl, hydroxyalkyl, or aminoalkyl;

R ⁸ , R ⁹ , and R ¹² are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ or R ⁸ , R ⁹ , and R ¹² together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ),

N(R ¹⁰ )(R ¹¹ ), and C3- ₆ Cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, C(0)OH, C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -O-alkylene _, wherein alkylene is optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_

₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ , -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ and C ₃ - ecycloalkyl;

m is 1 , 2, or 3;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first compound ha

wherein each R ¹ is independently H or Ci

each R ² is independently Ci_ ₃ alkyl;

each X is independently CRR, O, or S;

each n is independently 2 or 3; and each R is independently methyl, hydrogen, or deuterium,

or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

(MB)

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C ₃ - ₆ cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, d- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ . ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, C^alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -

OCF ₃ , -OR ^D ' -NR ^lu R" , -NHC(0)R ^IU , C ₃ - ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms; R ⁵ is d_ ₆ alkyl;

R ⁶ is Ci. ₆ alkyl or C ₃ - ₆ cycloalkyl;

R ⁷ is Ci_ ₆ alkyl, hydroxyalkyl or aminoalkyl;

R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ - ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -

C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ^6, -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first compound havin a structure according to Formula NIC:

wherein each R ¹ is independently H or Ci_ ₃ alkyl;

each R ² is independently Ci_ ₃ alkyl;

each X is independently CRR, O or S;

n is 2 or 3; and

each R is independently methyl, hydrogen, or deuterium, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having a structure according to Formula (MB);

(MB)

wherein:

R is F or CI;

R ¹ is -C(0)NHR ⁵ ;

R ² is C ₃ - ₆ cycloalkyl;

R ³ is -S(0) ₂ R ⁷ ;

R ⁴ is

(a) heteroaryl substituted with B(R ⁸ )( R ⁹ ) or X B(R ⁸ )( R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ - NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ - ₆ cycloalkyl, and heterocyclyl;

(b) C ₆ _ ₁₀ aryl substituted with B(R ⁸ )( R ⁹ ), or XB(R ⁸ )(R ⁹ ), and optionally substituted with one or more substituents independently selected from the group consisting of halogen, d- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ . ₆ cycloalkyl, and heterocyclyl; or

(c) Het optionally substituted with one or more substituents independently selected from the group consisting of halogen, Ci_ ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , -C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, - OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ₆ cycloalkyl, and heterocyclyl;

Het is a 5 or 6-membered monocyclic heterocyclic ring or 8- to 1 1- membered bicyclic heterocyclic ring system any ring of which is either saturated, partially saturated or unsaturated, which may be optionally benzofused if monocyclic or which may be optionally spiro-fused, and wherein each Het consists of one or more carbon atoms and one boron atom and one or more oxygen atoms; one boron atom, one oxygen atom, and one nitrogen atom; or one boron atom and one or more nitrogen atoms;

R ⁵ is C^alkyl; R ⁶ is Ci. ₆ alkyl or C ₃ - ₆ cycloalkyl;

R ⁷ is Ci-ealkyl, hydroxyalkyl or aminoalkyl;

R ⁸ and R ⁹ are each independently hydroxy, alkoxy, or aminoalkyl; or R ⁸ and R ⁹ together with the boron atom to which they are attached form a 5 to 14-membered ring, said ring comprising carbon atoms and optionally one or more heteroatoms which can be N or O; said ring may be optionally substituted with one or more substituents

independently selected from the group consisting of Ci_ ₆ alkyl, hydroxyalkyl, aminoalkyl, amino, oxo, C(0)OH, C(0)OXOR ¹³ , C(O)N(R ¹⁰ )(R ¹¹ ), N(R ¹⁰ )(R ¹¹ ), and C ₃ - ₆ cycloalkyl each of which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxy, amino, halogen, and C(0)OH,

C(O)N(R ¹⁰ )(R ¹¹ ), and N(R ¹⁰ )(R ¹¹ );

R ¹⁰ and R ¹¹ are each independently hydrogen or Ci_ ₆ alkyl;

R ¹³ is alkoxy;

X is alkylene or -Oalkylene _, wherein alkylene is optionally substituted with halogen, Ci- ₆ alkoxy, -C(H)F ₂ , -CF ₃ , Ci_ ₆ alkyl, hydroxy, hydroxyalkyl, aminoalkyl, -C(0)NH ₂ , - C(0)OH, -C(0)NHR ⁵ , -S(0) ₂ R ⁶ , -S(0) ₂ NH ₂ , -CN, -OCF ₃ , -OR ⁶ ' -NR ¹⁰ R ¹¹ , -NHC(0)R ¹⁰ , C ₃ _ ecycloalkyl;

or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a method of treating Hepatitis C in a human in need thereof comprising administering to the human a first

, or a pharmaceutically acceptable salt thereof,

in combination with a second compound having the structure:

, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the present invention also provides a compound of Formula (II), wherein the compound of Formula (II) is selected from the group consisting of:

(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylca rbamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)boronic acid;

(2-Chloro-4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylca rbamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)boronic acid; 4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)be nzofuran-6- yl)methylsulfonamido)phenylboronic acid;

3- (N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benz ofuran-6- yl)methylsulfonamido)phenylboronic acid;

4- (N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benz ofuran-6- yl)methylsulfonamido)-2-fluorophenylboronic acid;

4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)be nzofuran-6- yl)methylsulfonamido)-3-fluorophenylboronic acid;

4- (N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)benz ofuran-6- yl)methylsulfonamido)-2-fluorophenylboronic acid;

6-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl )benzofuran-6- yl)methylsulfonamido)pyridin-3-ylboronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2-(trifluoromethyl)phenyl)boronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2,6-difluorophenyl)boronic acid;

(2-cyano-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcar bamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)boronic acid;

6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chl orophenyl)-5- cyclopropylbenzofuran-3-carboxylic acid;

(4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofura n-6-yl)methylsulfonamido)- 2-chlorophenyl)boronic acid;

6-(N-(7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5-yl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2-(methylsulfonyl)phenyl)boronic acid;

1-(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methyl carbamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)-4-methyl-2,67-trioxa-1-borabicy clo[2.2.2]octan-1-uide; ((4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl) benzofuran-6- yl)methylsulfonamido)phenoxy)methyl)boronic acid;

((2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylc arbamoyl)benzofuran-6- yl)methylsulfonamido)phenoxy)methyl)boronic acid;

5- Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide; (4-(N-(2-(4-Chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2-cyanophenyl)boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-( 4^,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carb oxamide;

(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methy lcarbamoyl)benzofuran-6- yl)methylsulfonamido)phenethyl)boronic acid;

5- Cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran- 3-carboxamide;

6- (N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-4-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide;

(3-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoy l)benzofuran-6- yl)methylsulfonamido)phenethyl)boronic acid;

6-(N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide;

6-(N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide, enantiomer 1 ;

6-(N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide, enantiomer 2;

5- Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihydro-1 H-benzo[c][1 ,2]oxaborinin-

6- yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

and pharmaceutically acceptable salts thereof.

In certain embodiments, the present invention also provides a compound of Formula (I), wherein the compound of Formula (I) is selected from the group consisting of: dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(bip henylene-2,6- diyl)bis(1 H-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]pyrrole-2,1 (2H)-diyl))bis(3- hydroxy-1 -oxobutane-2, 1 -diyl))dicarbamate, dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(bip henylene-2,6- diyl)bis(1 H-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]pyrrole-2,1 (2H)-diyl))bis(3- methoxy-1 -oxobutane-2, 1-diyl))dicarbamate,

methyl [(1 S,2R)-1-{[(2S,3aS,6aS)-2-[4-(6-{2-[(2S,3aS,6aS)-1-((2S,3R)-3 -hydroxy-2-

{[(methyloxy)carbonyl]amino}butanoyl)octahydrocyclopenta[ it)]pyrrol-2-yl]-1 /-/-imidazol-4- yl}-2-biphenylenyl)-1 /-/-imidazol-2-yl]hexahydrocyclopenta[it)]pyrrol-1 (2/-/)-yl]carbonyl}-2- (methyloxy)propyl]carbamate,

dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(9H- fluorene-2,7- diyl)bis(1 H-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]pyrrole-2,1 (2H)-diyl))bis(3- methoxy-1-oxobutane-2,1-diyl))dicarbamate, dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(9,1 0-dihydroanthracene-

2.6- diyl)bis(1 H-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]pyrrole-2, 1 (2H)-diyl))bis(3- methoxy-1-oxobutane-2,1-diyl))dicarbamate, dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(9,1 0- dihydrophenanthrene-2,7-diyl)bis(1 H-imidazole-5,2- diyl))bis(hexahydrocyclopenta[b]pyrrole-2, 1 (2H)-diyl))bis(3-methoxy-1 -oxobutane-2, 1 - diyl))dicarbamate, dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(9-m ethyl-9H-carbazole-

2.7- diyl)bis(1 H-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]pyrrole-2, 1 (2H)-diyl))bis(3- methoxy-1 -oxobutane-2, 1-diyl))dicarbamate, dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(9,9 - difluoro-9H-fluorene-2,7-diyl)bis(1 H-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]pyrrole- 2,1 (2H)-diyl))bis(3-methoxy-1 -oxobutane-2, 1 -diyl))dicarbamate, dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(5,5 - dioxidodibenzo[b,d]thiophene-3,7-diyl)bis(1 H-imidazole-5,2- diyl))bis(hexahydrocyclopenta[b]pyrrole-2, 1 (2H)-diyl))bis(3-methoxy-1 -oxobutane-2, 1 - diyl))dicarbamate, dimethyl ((2S,2'S,3R,3'R)-((2S,2'S,3aS,3a'S,6aS,6a'S)-2,2'-(5,5'-(dib enzo[b,e][1 ,4]dioxine- 2,7-diyl)bis(1 H-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]pyrrole-2, 1 (2H)-diyl))bis(3- methoxy-1 -oxobutane-2, 1-diyl))dicarbamate, and pharmaceutically acceptable salts thereof.

In certain embodiments, the present invention also provides a compound of Formula (III), wherein the compound of Formula (III) is selected from the group consisting of: methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[(3S,7S,9S)-7,9-dimethyl-2-((2S)-3-m ethyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-6, 10-dioxa-2-azaspiro[4.5]dec-3-yl]-1 /-/-imidazol-4- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, methyl [( 1 S)-2-methyl-1 -({(2S)-2-[4-(4'-{2-[(8S)-7-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-1 ,4-dioxa-7-azaspiro[4.4]non-8-yl]-1 /-/-imidazol-4- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, dimethyl (4,4'-biphenyldiylbis{1 /-/-imidazole-4,2-diyl[(3S,7S,9S)-7,9-dimethyl-6,10-dioxa-2- azaspiro[4.5]decane-3,2-diyl][(2S)-3-methyl-1 -oxo-1 , 2-butanediyl]})biscarbamate, dimethyl (4,4'-biphenyldiylbis{1 /-/-imidazole-4,2-diyl(8S)-1 ,4-dioxa-7-azaspiro[4.4]nonane- 8,7-diyl[(2S)-3-methyl-1-oxo-1 ,2-butanediyl]})biscarbamate, methyl ((1 S)-1-methyl-2-{(3S)-3-[4-(4'-{2-[(2S)-1-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1 /-/-imidazol-4-yl}-4-biphenylyl)-1 /-/- imidazol-2-yl]-6,10-dioxa-2-azaspiro[4.5]dec-2-yl}-2-oxoethy l)carbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[(3S)-2-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-6, 10-dioxa-2-azaspiro[4.5]dec-3-yl]-1 H-imidazol-4- yl}-4-biphenylyl)-1 H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[(3S)-8,8-dimethyl-2-((2S)-3-methyl- 2- {[(methyloxy)carbonyl]amino}butanoyl)-6, 10-dioxa-2-azaspiro[4.5]dec-3-yl]-1 /-/-imidazol-4- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[(3S)-2-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-6, 10-dioxa-2-azaspiro[4.5]dec-3-yl]-1 /-/-imidazol-4- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate- c 6, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[(8S)-7-((2S)-3-methyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-1 ,4-dioxa-7-azaspiro[4.4]non-8-yl]-1 /-/-imidazol-4- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate- c4, methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[(2R,3R,8S)-2,3-dimethyl-7-((2S)-3-m ethyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-1 ,4-dioxa-7-azaspiro[4.4]non-8-yl]-1 /-/-imidazol-5- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[(2S,3S,8S)-2,3-dimethyl-7-((2S)-3-m ethyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-1 ,4-dioxa-7-azaspiro[4.4]non-8-yl]-1 /-/-imidazol-5- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[(8S)-7-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-1 ,4-dithia-7-azaspiro[4.4]non-8-yl]-1 /-/-imidazol-4- yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl[(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[(8S)-7-((2S)-2-{[(methylox y)

carbonyl]amino}butanoyl)-1 ,4-dithia-7-azaspiro[4.4]non-8-yl]-1 H-imidazol-4-yl}-4- biphenylyl)-1 H-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[(8S)-7-({[(methyloxy)carbo nyl] amino}acetyl)- 1 ,4-dithia-7-azaspiro[4.4]non-8-yl]-1 /-/-imidazol-4-yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1 - pyrrolidinyl}carbonyl)propyl] carbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[2-((2S)-3-methyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-8-oxa-2-azaspiro[4. 5]dec-3-yl]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[2-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-8,8-dioxido-8-thia-2-a zaspiro[4.5]dec-3-yl]-1 /-/- imidazol-4-yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[8,8-difluoro-2-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-2-azaspiro[4.5]dec-3-y l]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, dimethyl (4,4'-biphenyldiylbis{1 /-/-imidazole-4,2-diyl(3S)-8-oxa-2-azaspiro[4.5]decane-3,2- diyl[(2S)-3-methyl-1 -oxo-1 ,2-butanediyl]})biscarbamate, 1 ,1-dimethylethyl 2-{N-[(methyloxy)carbonyl]-L-valyl}-3-(4-{4'-[2-((2S)-1-{N- [(methyloxy)carbonyl]-L-valyl}-2-pyrrolidiny^

2-yl)-2,8-diazaspiro[4.5]decane-8-carboxylate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[2-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-2,8-diazaspiro[4.5]dec -3-yl]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[8-acetyl-2-((2S)-3-methyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-2,8-diazaspiro[4.5] dec-3-yl]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, methyl 2-{/V-[(methyloxy)carbonyl]-L-valyl}-3-(4-{4'-[2-((2S)-1-{/V -[(methyloxy)carbonyl]-L- valyl}-2-pyrrolidinyl)-1/-/-imidazol-4-yl]-4-biphenylyl}-1 /-/-imidazol-2-yl)-2,8- diazaspiro[4.5]decane-8-carboxylate,

1 ,1-dimethylethyl 6-{N-[(methyloxy)carbonyl]-L-valyl}-7-(4-{4'-[2-((2S)-1-{N-

[(methyloxy)carbonyl]-L-valyl}-2-pyrrolidinyl)-^

2-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[6-((2S)-3-methyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4] oct-7-yl]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate , methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[2-acetyl-6-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4]oct -7-yl]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, methyl 6-{/V-[(methyloxy)carbonyl]-L-valyl}-7-(4-{4'-[2-((2S)-1-{/V -[(methyloxy)carbonyl]-L- valyl}-2-pyrrolidinyl)-1/-/-imidazol-4-yl]-4-biphenylyl}-1 /-/-imidazol-2-yl)-2,6- diazaspiro[3.4]octane-2-carboxylate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[2-[(methylamino)carbonyl]- 6-((2S)-3-methyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-2,6-diazaspiro[3.4] oct-7-yl]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[6-((2S)-3-methyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-2-(methylsulfonyl)- 2,6-diazaspiro[3.4]oct-7-yl]-1 /-/- imidazol-4-yl}-4-biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[(7S)-2,2-difluoro-6-((2S)-3-methyl- 2- {[(methyloxy)carbonyl]amino}butanoyl)-6-azaspiro[3.4]oct-7-y l]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]c arbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[1-((2S)-3-methyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-8-oxa-1-azaspiro[4. 5]dec-2-yl]-1 /-/-imidazol-4-yl}-4- biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate, methyl ((1 S)-1-{[(2S)-2-(4-{4'-[2-(1-acetyl-8-oxa-1-azaspiro[4.5]dec-2 -yl)-1 H-imidazol-4-yl]- 4-biphenylyl}-1 /-/-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}-2-methylpropyl)c arbamate, methyl [(1 S)-1-({(2S)-2-[4-(4'-{2-[8,8-difluoro-1-((2S)-3-methyl-2-{[( methyloxy)

carbonyl]amino}butanoyl)-1-azaspiro[4.5]dec-2-yl]-1 /-/-imidazol-4-yl}-4-biphenylyl)-1 /-/- imidazol-2-yl]-1-pyrrolidinyl}carbonyl)-2-methylpropyl]carba mate, methyl [(1 S)-1-({8,8-difluoro-2-[4-(4'-{2-[(2S)-1-((2S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1 /-/-imidazol-4-yl}-4-biphenylyl)-1 /-/- imidazol-2-yl]-1-azaspiro[4.5]dec-1-yl}carbonyl)propyl] carbamate, methyl ((1 S)-2-{8,8-difluoro-2-[4-(4'-{2-[(2S)-1-((2S)-3-methyl-2-{[(m ethyloxy)

carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1 H-imidazol-4-yl}-4-biphenylyl)-1 H-imidaz 1 -azaspiro[4.5]dec-1 -yl}-1 -methyl-2-oxoethyl)carbamate, methyl [(1 S)-1-({8,8-difluoro-2-[4-(4'-{2-[(2S)-1-((2S)-3-methyl-2-{[( methyloxy)

carbonyl]amino}butanoyl)-2-pyrrolidinyl]-1 H-imidazol-4-yl}-4-biphenylyl)-1 H-imidaz 1 -azaspiro[4.5]dec-1 -yl}carbonyl)-3-methylbutyl]carbamate, methyl ((1 S)-1-{[(2S)-2-(4-{4'-[2-(1-acetyl-8,8-difluoro-1-azaspiro[4. 5]dec-2-yl)-1 H- imidazol-4-yl]-4-biphenylyl}-1 /-/-imidazol-2-yl)-1-pyrrolidinyl]carbonyl}-2- methylpropyl)carbamate, methyl [(1 S)-2-methyl-1-({(2S)-2-[4-(4'-{2-[1-((2S)-3-methyl-2-{[(meth yloxy)

carbonyl]amino}butanoyl)-8,8-dioxido-8-thia-1-azaspiro[4. 5]dec-2-yl]-1 H-imidazol-4-yl}-4^ biphenylyl)-1 /-/-imidazol-2-yl]-1-pyrrolidinyl}carbonyl)propyl]carbamate,

and pharmaceutically acceptable salts thereof.

In certain embodiments, the present invention also provides a compound of Formula (II), wherein the compound of Formula (II) is selected from the group consisting of:

(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylca rbamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)boronic acid;

(2-Chloro-4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylca rbamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)boronic acid;

4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)be nzofuran-6- yl)methylsulfonamido)phenylboronic acid;

3- (N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benz ofuran-6- yl)methylsulfonamido)phenylboronic acid;

4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl )benzofuran-6- yl)methylsulfonamido)-2-fluorophenylboronic acid;

4- (N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benz ofuran-6- yl)methylsulfonamido)-3-fluorophenylboronic acid;

4-(N-(2-(4-chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl )benzofuran-6- yl)methylsulfonamido)-2-fluorophenylboronic acid;

6-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)be nzofuran-6- yl)methylsulfonamido)pyridin-3-ylboronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2-(difluoromethyl)phenyl)boronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoy l)benzofuran-6- yl)methylsulfonamido)-2-(trifluoromethyl)phenyl)boronic acid;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2,6-difluorophenyl)boronic acid;

(2-cyano-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcar bamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)boronic acid;

6-(N-(4-borono-3-chlorophenyl)methylsulfonamido)-2-(4-chloro phenyl)-5- cyclopropylbenzofuran-3-carboxylic acid;

(4-(N-(3-carbamoyl-2-(4-chlorophenyl)-5-cyclopropylbenzofura n-6-yl)methylsulfonamido)- 2-chlorophenyl)boronic acid; 6-(N-(7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5-yl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide;

(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2-(methylsulfonyl)phenyl)boronic acid;

1-(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methyl carbamoyl)benzofuran-6- yl)methylsulfonamido)phenyl)-4-methyl-2,6,7-trioxa-1 -borabicyclo[2.2.2]octan-1 -uide; ((4-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl) benzofuran-6- yl)methylsulfonamido)phenoxy)methyl)boronic acid;

((2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylc arbamoyl)benzofuran-6- yl)methylsulfonamido)phenoxy)methyl)boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

(4-(N-(2-(4-Chlorophenyl)-5-cyclopropyl-3-(methylcarbamoyl)b enzofuran-6- yl)methylsulfonamido)-2-cyanophenyl)boronic acid;

5-Cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(3-methyl-4-( 4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl)methylsulfonamido)benzofuran-3-carb oxamide;

(2-Chloro-4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylca rbamoyl)benzofuran-6- yl)methylsulfonamido)phenethyl)boronic acid;

5- Cyclopropyl-6-(N-(7-fluoro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran- 3-carboxamide;

6-(N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-4-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide;

(3-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoy l)benzofuran-6- yl)methylsulfonamido)phenethyl)boronic acid;

6- (N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide;

6-(N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide, enantiomer 1 ;

6-(N-(3-Chloro-4-(2-hydroxy-1 ,2-oxaborolan-5-yl)phenyl)methylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide, enantiomer 2;

5-Cyclopropyl-2-(4-fluorophenyl)-6-(N-(1-hydroxy-3,4-dihy dro-1 H-benzo[c][1 ,2]oxaborinin- 6-yl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide;

and pharmaceutically acceptable salts thereof.

The present invention also provides a method for the treatment of Hepatitis C in a human in need thereof comprising administering to the human a first compound of Formulas (II) or (MB), or a pharmaceutically acceptable salt thereof, in combination with a second compound having a structure of Formulas (I), (III), (1MB), or (NIC), or a pharmaceutically acceptable salt thereof, and optionally in combination with one or more of the following therapeutic Hepatitis C treatment agents: an HCV NS2 protease inhibitor, an HCV NS3/4A protease inhibitor, an HCV NS3 helicase inhibitor, an HCV NS4B replication factor inhibitor, an HCV NS5A replication factor inhibitor, an HCV NS5B polymerase inhibitor, an HCV entry inhibitor, an HCV internal ribosome entry site (IRES) inhibitor, a microsomal triglyceride transfer protein (MTP) inhibitor, an a-glucosidase inhibitor, a caspase inhibitor, a cyclophilin inhibitor, an immunomodulator, a metabolic pathway inhibitor, an interferon, and a nucleoside analogue, which are administered in effective amounts as is known in the art.

Examples of suitable HCV NS3/4A protease inhibitors include boceprevir (such as Victrelis™), telaprevir (such as Incivek™), simeprevir (also known as TMC-435350), danoprevir (also known as RG7227 or ITMN-191 ), BI-201335, narlaprevir (also known as SCH 900518), vaniprevir (also known as MK-7009), asunaprevir (also known as BMS- 650032), GS 9256, GS 9451 , ACH-0141625, VX-985, ABT-450, PHX1766, IDX320, MK-5172, GNS-227, AVL-192, ACH-2684, and ACH-1095.

Examples of suitable HCV NS4B inhibitors include clemizole.

Examples of suitable HCV NS5A inhibitors include ABT-267, BMS-790052, BMS- 824393, BMS-766, AZD7295, CF102, GS 5885, PPI-461 , PPI-1301 , PPI-437, PPI-668, PPI-833, ACH-2928, EDP-239, IDX380, and IDX719.

Examples of suitable HCV NS5B polymerase inhibitors include silibinin sodium hemisuccinate, tegobuvir (also known as GS-9190), filibuvir (also known as

PF-00868554), VX-222, VX-759, ANA598, BMS-791325, ABT-333, ABT-072, Bl 207127, IDX375, mericitabine (also known as RG7128 ), RG7348 (also known as MB-1 1362), RG7432, PSI-7977, PSI-7851 , PSI-352938, PSI-661 , TMC 649128, IDX184, INX-08189, JTK-853, VCH-916, BILB 1941 , GS-6620, and GS-9669.

Examples of suitable HCV entry inhibitors include PRO-206, ITX-5061 , ITX4520, REP 9C, SP-30, and JTK-652.

Examples of suitable microsomal triglyceride transfer protein (MTP) inhibitors include BMS-201038 and CP-346086.

Examples of suitable a-glucosidase inhibitors include celgosovir (also known as MX-3253 or MBI-3253) and castanospermine.

Examples of suitable caspase inhibitors include IDN-6556.

Examples of suitable cyclophilin inhibitors include alisporivir (also known as DEBIO-025), NIM81 1 (also known as N-methyl-4-isoleucine cyclosporine), and SCY-635 (also known as [(R)-2-(N,N-dimethylamino)ethylthio-Sar] ³ -[4'-hydroxy-MeLeu] ⁴ -cyclosporin A).

Examples of suitable immunomodulators include Alloferon, IMN-6001 , NOV-205, ME-3738, interleukin-7 (such as CYT 107), ANA-773, IMO-2125, and GS 9620.

Examples of suitable metabolic pathway inhibitors include ritonavir (such as Norvir ^® ).

Examples of suitable interferons include interferon alfa-2a (such as Roferon-A ^® , Veldona ^® , or LBSI5535), peginterferon alfa-2a (such as Pegasys ^® ), interferon alfa-2b (such as Intron A ^® or Locteron ^® ), peginterferon alfa-2b (such as PEG Intron ^® or P1 101 ), interferon alfa-2b analogues (such as Hanferon™), interferon alpha-2b XL, interferon alfacon-1 (such as Infergen ^® ), interferon alfa-n1 (such as Wellferon ^® ), interferon omega (such as Biomed 510), HDV-interferon, peginterferon beta (such as TRK-560), peginterferon lambda (such as BMS-914143), and interferon-alpha 5.

Examples of suitable nucleoside analogues include ribavirin (such as Copegus ^® , Ravanex ^® , Rebetol ^® , RibaPak™, Ribasphere ^® , Vilona ^® , and Virazole ^® ), taribavirin (also known as viramidine), and isatoribine (also known as ANA245) and its prodrugs ANA971 and ANA975.

When a first compound of Formulas (II) or (MB), or pharmaceutically acceptable salt thereof is used in combination with a second compound having a structure of Formulas (I), (III), (NIB), or (NIC), the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician.

The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical compositions by any convenient route. When administration is sequential, either the first compound of Formulas (II) or (MB), or the second compound of Formulas (I), (III), (NIB), or (NIC), may be administered first. When administration is simultaneous, the combination may be administered either in the same or a different pharmaceutical composition.

The present invention further provides a pharmaceutical composition comprising a first compound of Formulas (II) or (MB), or a pharmaceutically acceptable salt thereof, and a second compound of Formulas (I), (III), (NIB), or (NIC), or a pharmaceutically acceptable salt thereof. When combined in the same formulation it will be appreciated that the two compounds should be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

Certain compounds of the present invention may exist in the present combination treatment in stereoisomeric forms (e.g., they may contain one or more asymmetric carbon atoms). The individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. The invention also extends to conformational isomers of compounds of the present invention and any geometric (c/s and/or trans) isomers of said compounds.

It is understood that compounds of the present invention may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present invention.

It will also be appreciated that compounds of the invention which exist as polymorphs, and mixtures thereof, are within the scope of the present invention.

The present invention also features a compound of Formula (I), (II), (MB), (III), (1MB), or (NIC), or a pharmaceutically acceptable salt thereof. As used herein, the term "pharmaceutically acceptable salts" refers to salts that retain the desired biological activity of the subject compound and exhibit minimal undesired toxicological effects. For a review on suitable salts see Berge et al, J. Pharm. Sci., 1977, 66, 1 -19. The term

"pharmaceutically acceptable salts" includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

In certain embodiments, compounds of Formula (I), (II), (MB), (III), (NIB), or (NIC), may contain an acidic functional group and may therefore be capable of forming pharmaceutically acceptable base addition salts by treatment with a suitable base.

Pharmaceutically acceptable base salts include ammonium salts (for example ammonium or tetraalkylammonium), metal salts, for example alkali-metal or alkaline-earth-metal salts (such as hydroxides, sodium, potassium, calcium or magnesium), organic amines (such as tris [also known as tromethamine or tris(hydroxymethyl)aminomethane], ethanolamine, diethylamine, triethanolamine, choline, isopropylamine, dicyclohexylamine or N-methyl-D- glucamine), cationic amino acids (such as arginine, lysine or histidine) or bases for insoluble salts (such as procaine or benzathine).

In certain embodiments, compounds according to Formula (I), (II), (MB), (III), (NIB), or (NIC), may contain a basic functional group and may therefore be capable of forming pharmaceutically acceptable acid addition salts by treatment with a suitable acid. A pharmaceutically acceptable acid addition salt may be formed by reaction of a compound of Formula (I), (II), (MB), (III), (NIB), or (NIC), with a suitable strong inorganic acid (such as hydrobromic, hydrochloric, sulfuric, nitric, phosphoric or perchloric) or a suitable strong organic acid, for example, sulfonic acids [such as p-toluenesulfonic, benzenesulfonic, methanesulfonic, ethanesulfonic, 2-hydroxyethanesulfonic, naphthalenesulfonic (e.g. 2- naphthalenesulfonic)], carboxylic acids (such as acetic, propionic, fumaric, maleic, benzoic, salicylic or succinic), anionic amino acids (such as glutamaic or aspartic), hydroxyl acids (such as citric, lactic, tartaric or glycolic), fatty acids (such as caproic, caprylic, decanoic, oleic or stearic) or acids for insoluble salts (such as pamoic or resinic [e.g. polystyrene sulfonate]), optionally in a suitable solvent such as an organic solvent, to give salt which is usually isolated for example by crystallisation and filtration. In one embodiment, a pharmaceutically acceptable acid addition salt of a compound of Formula (I), (II), (MB), (III), (1MB), or (NIC), is a salt of a strong acid, for example a hydrobromide, hydrochloride, hydroiodide, sulfate, nitrate, perchlorate, phosphate p-toluenesulfonic, benzenesulfonic or methanesulfonic salt.

It will be appreciated by those skilled in the art that organoboronic acids and/or their organoboronate esters may form "ate" complex addition salts, such as organoborate complex addition salts, in the presence of suitable nucleophilic complexing reagents. Suitable nucleophilic complexing reagents include, but are not limited to alkali metal hydroxides, for example lithium hydroxide, sodium hydroxide or potassium hydroxide, or fluoride. Examples of organoborate complex addition salts and methods for their preparation will be readily apparent. For example, one such suitable organoborate complex addition salt is an alkali metal trihydroxyorganoborate salt, such as a sodium trihydroxyorganoborate salt. By way of illustration, sodium trihydroxyarylborate and sodium trihydroxyalkylborate complex addition salts and methods for their preparation are described in Cammidge, A.N. et al, Org. Lett, 2006, 8, 4071-4074. Pharmaceutically acceptable "ate" complex addition salts as described herein are also considered to be within the scope of this invention.

The present invention features suitable pharmaceutically acceptable salts of the compounds of Formulas (I), (II), (MB), (III), (NIB), or (NIC), including acid salts, for example sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium and tris (tromethamine - tris(hydroxymethyl)aminomethane) salts and the like, or mono- or dibasic salts with the appropriate acid for example organic carboxylic acids such as acetic, lactic, tartaric, malic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, sulfuric, phosphoric and sulfamic acids and the like.

The present invention features pharmaceutically acceptable base addition salts of a compound of Formulas (I), (II), (MB), (III), (NIB), or (NIC), which are salts of a strong base, for example, sodium, lysine, ammonium, N-methyl-D-glucamine, potassium, choline, arginine (for example L-arginine) or magnesium. In a further aspect the salt is sodium, lysine, ammonium, N-methyl-D-glucamine, potassium, choline or arginine (for example L- arginine).

The invention includes within its scope all possible stoichiometric and non- stoichiometric forms of the salts of the compounds of Formulas (I), (II), (MB), (III), (1MB), or (NIC),. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates". For example, a complex with water is known as a "hydrate". Solvates of the compounds of Formulas (I), (II), (MB), (III), (1MB), or (NIC), and solvates of the salts of the compounds of Formulas (I), (II), (MB), (III), (1MB), or (NIC), are included within the scope of the present invention.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds Formulas (I), (II), (MB), (III), (1MB), or (NIC), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form compounds defined in the first aspect which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All protected derivatives and prodrugs of compounds defined in the first aspect are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within the compounds of Formulas (I), (II), (MB), (III), (NIB), or (NIC). Suitable prodrugs for compounds of the invention include: esters, carbonate esters, hemi-esters, phosphate esters, nitro esters, sulfate esters, sulfoxides, amides, carbamates, azo-com pounds, phosphamides, glycosides, ethers, acetals ketals, boronic esters and boronic acid anhydrides.

The compounds of Formulas (I), (II), (MB), (III), (NIB), or (NIC), have been found to exhibit antiviral activity, specifically HCV inhibitory activity, and may therefore useful in treating or preventing viral infections, such as HCV infections, or diseases associated with such infections, particularly when administered in combination with one or more alternative therapeutic agents. In vitro studies have been performed which demonstrate the usefulness of compounds described herein as antiviral agents when administered in combination with a second therapeutic agent.

The present invention provides a method for treating and/or preventing viral infections, such as HCV infections, or diseases associated with such infections which method comprises administering to a subject, for example a human, in need thereof, a therapeutically effective amount of a first compound of Formulas (II) or (MB), or a pharmaceutically acceptable salt thereof, in combination with a second compound having a structure of Formulas (I), (III), (1MB), or (NIC), or a pharmaceutically acceptable salt thereof.

One embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II). In another embodiment of the present invention, there is provided a method of treatment of Hepatitis C in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (II) in combination with a compound of Formula (III), and an interferon.

Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), an interferon, and a nucleoside analogue. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), and a metabolic pathway inhibitor. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), a metabolic pathway inhibitor, an interferon, and a nucleoside analogue. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), and an HCV NS3/4A protease inhibitor. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering to the human a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), and an HCV NS5A inhibitor. Another embodiment of the present invention provides a method of treatment of Hepatitis C Virus in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I), an HCV NS3/4A protease inhibitor, and an HCV NS5A replication factor inhibitor. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), an HCV NS3/4A protease inhibitor, an interferon, and a nucleoside analogue. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), a metabolic pathway inhibitor, an HCV NS3/4A protease inhibitor, an interferon, and a nucleoside analogue. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), an HCV NS5A replication factor inhibitor, an interferon, and a nucleoside analogue. Another embodiment of the present invention provides a method of treatment of Hepatitis C in a human in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I) in combination with a compound of Formula (II), an HCV NS3/4A protease inhibitor, an HCV NS5A replication factor inhibitor, an interferon, and a nucleoside analogue.

In a specific embodiment of the present invention, the interferon is selected from the group consisting of interferon alfa-2a, peginterferon alfa-2a, interferon alfa-2b, peginterferon alfa-2b, an interferon alfa-2b analogue, interferon alpha-2b XL, interferon alfacon-1 , interferon alfa-n1 , interferon omega, HDV-interferon, peginterferon beta, peginterferon lambda, and interferon-alpha5. In another specific embodiment of the present invention, the interferon is selected from the group consisting of interferon alfa-2a, peginterferon alfa-2a, interferon alfa-2b, peginterferon alfa-2b, an interferon alfa-2b analogue, interferon alfacon-1 , and interferon alfa n1.

In another specific embodiment of the present invention, the metabolic pathway inhibitor is ritonavir. In another specific embodiment of the present invention, the metabolic pathway inhibitor is ritonavir, which is administered at a daily dose of 100 mg. In another specific embodiment of the present invention, the metabolic pathway inhibitor is ritonavir, which is administered at a daily dose of 200 mg.

In another specific embodiment of the present invention, the nucleoside analogue is ribavirin. In another specific embodiment of the present invention, the nucleoside analogue is ribavirin, which is administered at a daily dose of 800 mg. In another specific embodiment of the present invention, the nucleoside analogue is ribavirin, which is administered at a daily dose of 1000 mg. In another specific embodiment of the present invention, the nucleoside analogue is ribavirin, which is administered at a daily dose of 1200 mg.

In another specific embodiment of the present invention, HCV NS3/4A protease inhibitor is selected from the group consisting of boceprevir, telaprevir, simeprevir, danoprevir, narlaprevir, vaniprevir, and asunaprevir. In another specific embodiment of the present invention, HCV NS3/4A protease inhibitor is selected from the group consisting of boceprevir and telaprevir.

In another specific embodiment of the present invention, the compound of Formula

(I) is

In another specific embodiment of the present invention, the compound of Formula

(II) is

In another specific embodiment of the present invention, the compound of Formula

It will be appreciated that reference herein to therapy or treatment may include, but is not limited to prevention, retardation, prophylaxis, and cure of the disease. The present invention provides compounds and pharmaceutical compositions for the treatment and prevention of viral infections, such as HCV infections, as well as diseases associated with viral infections in living hosts. It will further be appreciated that references herein to treatment or prophylaxis of HCV infection include treatment or prophylaxis of HCV- associated disease such as liver fibrosis, cirrhosis and hepatocellular carcinoma.

Within the context of the present invention, the terms describing the indications used herein are classified in the Merck Manual of Diagnosis and Therapy, 17 ^th Edition and/or the International Classification of Diseases 10 ^th Edition (ICD-10). The various subtypes of the disorders mentioned herein are contemplated as part of the present invention.

Pharmaceutical compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions.

For instance, for oral administration in the form of a tablet or capsule, the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.

Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. A powder mixture is prepared by mixing the compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. Optional ingredients include other binders such as starch, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, polyethylene glycol, waxes and the like. The powder mixture can be wet-granulated with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials, and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet-forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The compounds of the present invention can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the compound in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, compositions for oral administration can be

microencapsulated. The composition can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like.

The agents for use according to the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

Pharmaceutical compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986). Pharmaceutical compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols or oils.

Pharmaceutical compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the compositions may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

For purposes of the present invention, the following structures represent the structures associated with Compounds A, B, C and D described below. Also, for purposes of the Compound A, B, C and D descriptions below, Compound A can independently only be either one or the other of the two structures indicated under Compound A below, but it can never both at the same time.

Compound B:

Compound C:

Ribavirin

Compound D:

Pegylated Interferon

In other embodiments of the present invention, Compound A refers to only the following structure:

Compounds A and B may be employed in combination in accordance with the invention by administration simultaneously in a unitary pharmaceutical composition including both compounds. Alternatively, the combination may be administered separately in separate pharmaceutical compositions, each including one of the compounds A and B in a sequential manner wherein, for example, Compound A or Compound B is

administered first and the other second. Such sequential administration may be close in time (e.g. simultaneously) or remote in time. Furthermore, it does not matter if the compounds are administered in the same dosage form, e.g. one compound may be administered parenterally and the other compound may be administered orally. Suitably, both compounds are administered orally. Optionally, Compound C may be administered in combination with either or both of Compounds A and B or may be administered separately in separate pharmaceutical composition. Compound C may be administered simultaneously with either or both of Compounds A and B or may be administered in a sequential manner relative to either or both of Compounds A and B. Optionally,

Compound D may be administered in combination with any or all of Compounds A, B, and C or may be administered separately in separate pharmaceutical composition. Compound D may be administered simultaneously with any or all of Compounds A, B, and C or may be administered in a sequential manner relative to any or all of Compounds A, B, and C.

Thus, in one embodiment, one or more doses of Compound A are administered simultaneously or separately with one or more doses of Compound B. Unless otherwise defined, in all dosing protocols described herein, the regimen of compounds administered does not have to commence with the start of treatment and terminate with the end of treatment, it is only required that the number of consecutive days in which both compounds are administered and the optional number of consecutive days in which only one of the component compounds is administered, or the indicated dosing protocol - including the amount of compound administered, occur at some point during the course of treatment.

In one embodiment, multiple doses of Compound A are administered

simultaneously or separately with multiple doses of Compound B.

In another embodiment, multiple doses of Compound A are administered simultaneously or separately with one dose of Compound B.

In another embodiment, one dose of Compound A is administered simultaneously or separately with multiple doses of Compound B.

In another embodiment one dose of Compound A is administered simultaneously or separately with one dose of Compound B.

In all the above embodiments Compound A may be administered first or

Compound B may be administered first.

The combinations may be presented as a combination kit. By the term

"combination kit" or "kit of parts" as used herein is meant the pharmaceutical composition or compositions that are used to administer Compound A and Compound B according to the invention. Optionally, the kit may further comprise pharmaceutical composition or compositions that are used to administer Compound C and optionally Compound D. When Compound A and Compound B are administered simultaneously, the combination kit can contain Compound A and Compound B in a single pharmaceutical composition, such as a tablet, or in separate pharmaceutical compositions. Optionally, the kit may contain Compounds A, B, and C in a single pharmaceutical composition, such as a tablet, or any two of Compounds A, B, and C in a single pharmaceutical composition, or each of Compounds A, B, and C in a separate pharmaceutical composition. Optionally, the kit may contain Compounds A, B, C, and D in a single pharmaceutical composition, such as a tablet, or any three of Compounds A, B, C, and D in a single pharmaceutical composition, or any two of Compounds A, B, C, and D in a single pharmaceutical composition, or each of Compounds A, B, C, and D in a separate pharmaceutical composition. When Compounds A and B are not administered simultaneously, the combination kit will contain Compound A and Compound B in separate pharmaceutical compositions either in a single package or Compound A and Compound B in separate pharmaceutical compositions in separate packages. Optionally, the kit may contain Compounds A, B, and C in separate pharmaceutical compositions either in a single package or in separate packages. Optionally, the kit may contain Compounds A, B, C, and D in separate pharmaceutical compositions either in a single package or in separate packages.

In one embodiment of the invention there is provided a kit of parts comprising components:

Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier.

In another embodiment of the invention there is provided a kit of parts comprising components:

Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier, wherein the components are provided in a form which is suitable for sequential, separate, and/or simultaneous administration.

In another embodiment of the invention there is provided a kit of parts comprising components:

a first container comprising Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

a second container comprising Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier, and a container means for containing said first and second containers. In another embodiment of the invention there is provided a kit of parts comprising components:

Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

Compound C in association with a pharmaceutically acceptable excipient, diluents, or carrier. In another embodiment of the invention there is provided a kit of parts comprising components:

Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

Compound C in association with a pharmaceutically acceptable excipient, diluents, or carrier, wherein the components are provided in a form which is suitable for sequential, separate, and/or simultaneous administration. In another embodiment of the invention there is provided a kit of parts comprising components:

a first container comprising Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier;

a second container comprising Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

a third container comprising Compound C in association with a pharmaceutically acceptable excipient, diluents, or carrier, and a container means for containing said first, second, and third containers. In another embodiment of the invention there is provided a kit of parts comprising components:

Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier; Compound C in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

Compound D in association with a pharmaceutically acceptable excipient, diluents, or carrier. In another embodiment of the invention there is provided a kit of parts comprising components:

Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier;

Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier;

Compound C in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

Compound D in association with a pharmaceutically acceptable excipient, diluents, or carrier, wherein the components are provided in a form which is suitable for sequential, separate, and/or simultaneous administration.

In another embodiment of the invention there is provided a kit of parts comprising components:

a first container comprising Compound A in association with a pharmaceutically acceptable excipient, diluents, or carrier;

a second container comprising Compound B in association with a pharmaceutically acceptable excipient, diluents, or carrier;

a third container comprising Compound C in association with a pharmaceutically acceptable excipient, diluents, or carrier; and

a fourth container comprising Compound D in association with a pharmaceutically acceptable excipient, diluents, or carrier, and a container means for containing said first, second, third, and fourth containers.

Suitably the combinations of this invention are administered within a "specified period". By the term "specified period" as used herein is meant the interval of time between the administration of, for example, one of Compound A and Compound B and the other of Compound A and Compound B. Unless otherwise defined, the specified period can include simultaneous administration. When Compound A and Compound B are administered once a day, the specified period refers to administration of Compound A and Compound B during a single day. When one or both compounds are administered more than once a day, the specified period is calculated based on the first administration of each compound on a specific day. All administrations of a compound of the invention that are subsequent to the first during a specific day are not considered when calculating the specific period.

Suitably, if the compounds are administered within a "specified period" and not administered simultaneously, they are administered within about 24 hours of each other - in this case, the specified period will be about 24 hours; suitably they will be administered within about 12 hours of each other - in this case, the specified period will be about 12 hours; suitably they will be administered within about 1 1 hours of each other - in this case, the specified period will be about 1 1 hours; suitably they will be administered within about 10 hours of each other - in this case, the specified period will be about 10 hours; suitably they will be administered within about 9 hours of each other - in this case, the specified period will be about 9 hours; suitably they will be administered within about 8 hours of each other - in this case, the specified period will be about 8 hours; suitably they will be administered within about 7 hours of each other - in this case, the specified period will be about 7 hours; suitably they will be administered within about 6 hours of each other - in this case, the specified period will be about 6 hours; suitably they will be administered within about 5 hours of each other - in this case, the specified period will be about 5 hours; suitably they will be administered within about 4 hours of each other - in this case, the specified period will be about 4 hours; suitably they will be administered within about 3 hours of each other - in this case, the specified period will be about 3 hours; suitably they will be administered within about 2 hours of each other - in this case, the specified period will be about 2 hours; suitably they will be administered within about 1 hour of each other - in this case, the specified period will be about 1 hour. As used herein, the administration of Compound A and Compound B in less than about 45 minutes apart is considered simultaneous administration.

Suitably, when the combination of the invention is administered for a "specified period", the compounds will be co-administered for a "duration of time". By the term "duration of time" as used herein is meant that each of the compounds of the invention are administered for an indicated number of consecutive days.

Regarding "specified period" administration: Suitably, each of the compounds will be administered within a specified period for at least one day - in this case, the duration of time will be at least one day; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 3 consecutive days - in this case, the duration of time will be at least 3 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 5 consecutive days - in this case, the duration of time will be at least 5 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 7 consecutive days - in this case, the duration of time will be at least 7 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 14 consecutive days - in this case, the duration of time will be at least 14 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 30 consecutive days - in this case, the duration of time will be at least 30 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 60 consecutive days - in this case, the duration of time will be at least 60 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 90 consecutive days - in this case, the duration of time will be at least 90 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 180 consecutive days - in this case, the duration of time will be at least 180 days; suitably, during the course of treatment, each of the compounds will be administered within a specified period for at least 365 consecutive days - in this case, the duration of time will be at least 365 days.

Further regarding "specified period" administration: Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for from 1 to 4 days over a 7 day period, and during the other days of the 7 day period Compound A will be administered alone or optionally with Compound C and optionally Compound D. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for 12 cycles or 84 days; suitably for continuous administration.

Suitably, during the course of treatment, Compound A and Compound B will be administered within a specified period for 1 day during a 7 day period, and during the other days of the 7 day period Compound A will be administered alone or optionally with Compound C and optionally Compound D. Suitably, this 7 day protocol is repeated for 2 cycles or for 14 days; suitably for 4 cycles or 28 days; suitably for 12 cycles or 84 days; suitably for continuous administration.

Suitably, if the compounds are not administered during a "specified period", they are administered sequentially. By the term "sequential administration", and derivates thereof, as used herein is meant that one of Compound A and Compound B is

administered for two or more consecutive days and the other of Compound A and Compound B is subsequently administered for two or more consecutive days. Also, contemplated herein is a drug holiday utilized between the sequential administration of one of Compound A and Compound B and the other of Compound A and Compound B. As used herein, a drug holiday is a period of days after the sequential administration of one of Compound A and Compound B and before the administration of the other of Compound A and Compound B where neither Compound A nor Compound B is administered. Suitably the drug holiday will be a period of days selected from: 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 1 1 days, 12 days, 13 days, and 14 days.

Regarding sequential administration: Suitably, one of Compound A and Compound B is administered for from 2 to 30 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A and Compound B for from 2 to 30 consecutive days. Suitably, one of Compound A and Compound B is administered for from 2 to 21 consecutive days, followed by an optional drug holiday, followed by administration of the other of Compound A and Compound B for from 2 to 21 consecutive days. Suitably, one of Compound A and Compound B is administered for from 2 to 14 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of the other of Compound A and Compound B for from 2 to 14 consecutive days. Suitably, one of Compound A and Compound B is administered for from 3 to 7 consecutive days, followed by a drug holiday of from 3 to 10 days, followed by administration of the other of Compound A and Compound B for from 3 to 7 consecutive days.

Suitably, Compound B will be administered first in the sequence, followed by an optional drug holiday, followed by administration of Compound A. Suitably, Compound B is administered for from 2 to 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound A for from 2 to 21 consecutive days. Suitably, Compound B is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of Compound A for from 3 to 21 consecutive days. Suitably, Compound B is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound A for from 3 to 21 consecutive days.

Suitably, Compound A will be administered first in the sequence, followed by an optional drug holiday, followed by administration of Compound B. Suitably, Compound A is administered for from 2 to 21 consecutive days, followed by an optional drug holiday, followed by administration of Compound B for from 2 to 21 consecutive days. Suitably, Compound A is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 1 to 14 days, followed by administration of Compound B for from 3 to 21 consecutive days. Suitably, Compound A is administered for from 3 to 21 consecutive days, followed by a drug holiday of from 3 to 14 days, followed by administration of Compound B for from 3 to 21 consecutive days.

It is understood that a "specified period" administration and a "sequential" administration can be followed by repeat dosing or can be followed by an alternate dosing protocol, and a drug holiday may precede the repeat dosing or alternate dosing protocol.

Suitably, the amount of Compound A (based on weight of unsalted/unsolvated amount) administered as part of the combination according to the present invention will be in the range of 0.01 to 100 mg per kilogram body weight of the recipient (e.g. a human) per day; suitably, the amount will be selected in the range of 0.1 to 30 mg per kilogram body weight per day; suitably, the amount will be selected in the range of 0.1 to 10 mg per kilogram body weight per day; suitably, the amount will be selected in the range of 0.5 to 10 mg per kilogram body weight per day. The desired dose may be presented as one, two, three, four, five, six or more sub-doses administered at appropriate intervals throughout the day. In some cases the desired dose may be given on alternative days or other appropriate schedule, for example, weekly, or monthly. These sub-doses may be administered in unit dosage forms, for example, containing 0.5 to 100 mg, 5 to 1000 mg or 50 to 500 mg, or 20 to 500 mg, of active ingredient per unit dosage form.

The following non-limiting examples illustrate the present invention. EXAMPLES

It will be appreciated by those skilled in the art that when solvents are used in reactions it is desirable to use anhydrous solvents. It is further desirable to conduct reactions under an inert atmosphere, for example under nitrogen or argon, where appropriate.

Abbreviations

μΙ_ = microliters

μΜ = micromolar

NMR = nuclear magnetic resonance

br = broad

d = doublet

δ = chemical shift

°C = degrees celcius

dd = doublet of doublets DMEM Dulbeco's Modified Eagle's Medium

DMF N,N-dimethylformamide

DMSO dimethylsulfoxide

9 gram

hr hours

HCV hepatitus C virus

HPLC high performance liquid chromatography

Hz hertz

J coupling constant (given in Hz unless otherwise

indicated)

m multiplet

M molar

M+H ⁺ parent mass spectrum peak plus H ⁺

mg milligram

ml_ milliliter

mM millimolar

mmol millimole

MS mass spectrum

nM nanomolar

ppm parts per million

s singlet

t triplet

The compounds of the present invention may be prepared by one of skill in the art according to the synthetic examples and teachings found within the following applications: U.S. Published Patent Application No. US 201 10152237; PCT Patent Application No. PCT/US2012/049681 ; PCT Patent Application No. PCT/US2012/050268. and PCT Patent Application No. PCT/US201 1/024822, all four of which are incorporated herein in their entireties. The compounds of the present invention may also be prepared by one of skill in the art by following the synthetic examples below.

Preparation of Example I:

Intermediate 1 : (2S.2'S.3aS.3a'S.6aS.6a'S )-0'2.02-(biphenylene-2.6-diylbis(2-oxoethane-2.1-diyl)) 1 -di-tert-butyl bis(hexahydrocvclopenta[blpyiTole-1.2(2H)-dicarboxylate)

l,l'-(2,6-Diphenylenediyl)bis(2-bromoet ianone) (1.5g, 1.90 mmol) was dissolved in Acetonitrile (10 mL). (2S,3aS,6aS)-l-(tert-butoxycarbonyl)octahydrocyclopenta[b]py rrole-2- carboxylic acid (1.215 g, 4.76 mmol) and DIEA (ImL, 5.71 mmol) was added and the solution was stirred at 65°C for 4h. The solid material was filtered and solvent was evaporated to provide the crude compound which was purified by isco column using 40g of silica cartridge with hexane/ethyl acetate (increasing gradient from 0% to 100% EA).

Yield : 92%; ES LC-MS m/z = 743 (M+H) ⁺ ;

1H NMR (400 MHz, DMSO-d 6) δ ppm 7.70 (m, 2 H), 7.40 (m, 2 H), 7.06 (m, 2 H), 5.49 (s, 4 H),4.39 (m, 2 H), 4.10 (m, 2 H), 2.67 (m, 3 H), 2.45 (m, 1 H), 2.33 (m, 1 H), 1.83 - 2.02 (m, 3 H), 1.73- 1.82 (m, 3 H), 1.68 (m, 4 H), 1.37 (m, 21 H). Intermediate 2: r2S.2 ^l S.3aS.3a'S.6aS.6a ^l SVdi-tert-butyl 2.2'-r5.5'-rbiphenylene-2.6-divnbisriH- imidazole-5.2-diyl))bis(hexahvdrocvclopenta[blpyrrole-l(2H)- carboxylate)

To a stirred solution of (2S,2'S,3aS,3a'S,6aS,6a'S)-0'2,02-(biphenylene-2,6- diylbis(2-oxoethane-2, 1 -diyl)) 1 -di-tert-butyl bis(hexahydrocyclopenta[b]pyrrole- 1 ,2(2H)- dicarboxylate) (1.3 g, 1.750 mmol, 92 %> yield) in 1,4-Dioxane (10 mL) in a sealed tube was added ammonium acetate (0.147 g, 1.904 mmol). The reaction mixture was refluxed at 100°C for lOh. After cooling down, the solid at the bottom was filtered off and washed with ethyl acetate. The filtrate was evaporated and the residue was purified by flash column using 40g of silica cartridge with hexane/ethyl acetate (increasing gradient from 0% to 100% EA) to give the product as a brown solid.

Yield : 45%; ES LC-MS m/z = 703 (M+H) ⁺ ;

1H NMR (400 MHz, DMSO-d6) δ ppm 11.43 - 12.03 (m, 2 H), 7.40 (m, 2 H), 7.19 - 7.26 (m, 2H), 7.09 - 7.17 (m, 2 H), 6.69 - 6.87 (m, 2 H), 4.81 (m, 2 H), 4.15 (m, 2 H), 2.68 (m, 2 H), 2.30 -2.44 (m, 2 H), 1.87 - 2.02 (m, 3 H), 1.83 (m, 3 H), 1.63 (m, 4 H), 1.45 (m, 9 H), 1.28 - 1.38 (m, 4H), 1.24 (m, 9 H).

Intermediate 3: 2.6-bis(2-((2S.3aS.6aS ^N )-octahvdrocvclopenta[blpyrrol-2-yl ^N )-lH-imidazol-5- yDbiphenylene tetrahydrochloride

To the (2S,2'S,3aS,3a ^, S,6aS,6a'S)-di-tert-butyl 2,2'-(5,5'-(biphenylene-2,6- diyl)bis(lH-imidazole-5,2-diyl))bis(hexahydrocyclopenta[b]py rrole-l(2H)-carboxylate) (500 mg, 0.711 mmol) in Tetrahydrofuran (THF) (2ml) was slowly added HC1 (3.56 ml, 14.23 mmol) in dioxane. The solution was stirred for 12h at rt and solvent was evaporated, ether (50mL) was added and the dark brown solid was filtered and dried in house vacuum (2h) which provided tetra-HCl salt of the amine which was used in the next step without further purification.

Yield : 84%; ES LC-MS m/z = 503 (M+H) ⁺ ;

1H NMR (400 MHz, DMSO-d 6) <5ppm 10.39 (m, 2 H), 9.51 (m, 2 H), 7.98 (s, 2 H), 7.43 (d, J=7.3 Hz, 2H), 7.31 (s, 2 H), 6.96 (d, J=7.3 Hz, 2 H), 4.84 (m, 2 H), 4.17 (m, 4 H), 2.99 (m, 2 H), 2.58 - 2.76 (m,2 H), 2.06 (m, 3 H), 1.87 - 2.00 (m, 1 H), 1.75 (m, 2 H), 1.65 (m, 6 H).

Example 1 : dimethyl rr2S.2 ^l S.3R.3 ^l RVrr2S.2 ^l S.3aS.3a ^l S.6aS.6a ^l SV2.2 ^l -(5.5 ^l -rbiphenylene-2.6- diyl)bis(lH-imidazole-5.2-diyl))bis(hexahvdrocvclopenta[blpy rrole-2.1(2H)-diyl))bis(3-hvdroxy- 1 -oxobutane-2.1 -diyl))dicarbamate

To the crude 2,6-bis(2-((2S,3aS,6aS)-octahydrocyclopenta[b]pyrrol-2-yl)-l H- imidazol-5-yl)biphenylene (80 mg, 0.16 mmol) in Ν,Ν-Dimethylformamide (2ml) was added

(2S,3R)-3-hydroxy-2-((methoxycarbonyl)amino)butanoic acid (71mg, 0.4mmol), HATU (60.5 mg, 0.16 mmol) and DIEA (0.06 ml, 0.32 mmol), the solution was stirred at rt for 4h. The reaction was partitioned between ethyl acetate (5mL) and sat. aq. NaHCC (2mL). The organic phase was separated and dried over sodium sulphate and evaporated in vacuo to give the crude product which was purified on Gilson-HPLC, eluting with 5 to 80 % acetonitrile/ water (0.2 % NH _3: H ₂ 0), to give the pure product.

Yield : 17%; ES LC-MS m/z = 821.3 (M+H) ⁺ ;

1H NMR (400 MHz, DMSO-d6) δ ppm 12.05 (m, 1 H), 11.65 (m, 1 H), 7.40 (s, 1 H), 7.26 (m, 2H), 7.20 (m, 2 H), 7.14 (s, 1 H), 7.09 (s, 1 H), 6.73 (m, 2 H), 5.54 (m, 1 H), 5.10 (m, 2 H), 4.80 (m, 2 H), 4.71 (m, 2 H), 4.32 (m, 1 H), 4.19 (m, 2 H), 3.74 (m, 2 H), 3.56 (s, 6 H), 2.77 (m, 2 H), 2.28 - 2.45 (m, 2 H), 2.05 (m, 4 H), 1.77 (m, 4 H),1.53 (m, 4 H), 0.99 - 1.13 (m, 7 H).

Preparation of Example 2:

Example 2: dimethyl ii2S.2 ^, S.3R.3 ^, Ryii2S.2 ^, S.3aS.3a ^, S.6aS.6a ^, SV2.2 ^, -i5.5 ^, -ito^

diyl bis(lH-imidazole-5.2-diyl bis(hexahvdrocvclopenta[blpyrrole-2.U2H ^N )-diyl ^N ) ^N )bis(3-methoxy-

1 -oxobutane-2.1 -divDMicarbamate

This example was made similar to the one explained for example 1 using (2S,3R)-3- methoxy-2-((methoxycarbonyl)amino)butanoic acid.

Yield : 12%; ES LC-MS m/z = 849.4 (M+H) ⁺ ;

1H NMR (400 MHz, DMSO-d6) <5ppm 11.60 - 12.11 (m, 2 H), 7.54 (m, 2 H), 7.39 (s, 2 H), 7.17 (m, 2 H), 7.05 - 7.13 (m, 2 H), 6.94 - 7.04 (m, 1 H), 6.72 (m, 2 H), 5.07 (m, 2 H),4.78 (m, 2 H), 4.39 (m, 1 H), 4.25 (m, 2 H), 3.49 - 3.58 (m, 7 H), 3.44 (m, 2 H), 3.17- 3.22 (m, 6 H), 2.75 (m, 2 H), 2.29 - 2.43 (m, 2 H), 2.09 (m, 3 H), 1.92 - 2.03 (m, 1 H), 1.80 - 1.89 (m, 2H), 1.68 - 1.79 (m,

2 H), 1.51 (m, 3 H), 0.95 - 1.14 (m, 6 H).

Example 3: 6-(N-(7-chloro-1-hvdroxy-1 ,3-dihvdrobenzo[cl[1 ,21oxaborol-5- yl)methylsulfonamido)-5-cvclopropyl-2-(4-fluorophenyl)-N-met hylbenzofuran-3- carboxamide

Step 1 : methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)be nzofuran-6- yl)methylsulfonamido)-2-nitrobenzoate

A solution of 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(methylsulfonami do)benzofuran- 3-carboxamide (1.0 g, 2.49 mmol), methyl 5-fluoro-2-nitrobenzoate (0.99 g, 4.97 mmol), and potassium carbonate (1.03 g, 7.45 mmol) in HMPA (6.2 mL) was stirred at 60 °C for 3 days. The solution was diluted with EtOAc and water and the organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered, evaporated and purified by silica gel chromatography (0-80% EtOAc/hexanes) to afford the title compound (1.33 g, 92%) as a yellow solid. ¹ H NMR (400 MHz, CHLOROFORM-c/) δ ppm 7.99 (d, J=9.09 Hz, 1 H), 7.85 - 7.92 (m, 2 H), 7.56 (s, 1 H), 7.53 (s, 1 H), 7.50 (dd, J=9.09, 2.64 Hz, 1 H), 7.43 (d, J=2.64 Hz, 1 H), 7.19 - 7.26 (m, 2 H), 5.80 (d, J=4.59 Hz, 1 H), 3.90 (s, 3 H), 3.34 (s, 3 H), 3.02 (d, J=4.98 Hz, 3 H), 1.91 (tt, J=8.37, 5.31 Hz, 1 H), 1.01 (br. s., 1 H), 0.89 (br. s., 1 H), 0.73 - 0.85 (m, 1 H), 0.58 (br. s., 1 H).

Step 2: methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

A solution of methyl 5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-

(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-2-nit robenzoate (1.33 g, 2.29 mmol) and 10% Pd/C (cat.) in MeOH (20 mL) was stirred under a hydrogen atmosphere (15 psi) for 1.5 h. The solution was filtered through celite and evaporated to afford the title compound (1.26 g, quant.) as a light yellow solid that was used without further purification. Step 3: methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate

A solution of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.60 g, 2.91 mmol) and NCS (0.39 g, 2.91 mmol) in 80 mL CH ₃ CN was stirred at 40 °C for 30 mins. Additional NCS (0.39 g, 2.91 mmol) was added, the reaction mixture was heated at 40 °C for another 30 mins, evaporated onto silica gel, and purified by silica gel chromatography (0-70% EtOAc/hexanes) to afford the title compound (1.29 g, 76%) as a light pink solid. ¹ H NMR (400 MHz, CHLOROFORM-c ) δ ppm 8.00 (d, J=2.54 Hz, 1 H), 7.85 - 7.92 (m, 2 H), 7.71 (s, 1 H), 7.65 (d, J=2.63 Hz, 1 H), 7.43 (s, 1 H), 7.15 - 7.22 (m, 2 H), 6.36 (br. s., 2 H), 5.85 (d, J=4.78 Hz, 1 H), 3.87 (s, 3 H), 3.19 (s, 3 H), 2.98 (d, J=4.88 Hz, 3 H), 2.15 - 2.30 (m, 1 H), 0.31 - 1.1 1 (m, 4 H).

Step 4: methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate Sodium nitrite (0.17 g, 2.42 mmol) was added to a 0 °C solution of methyl 2-amino-3- chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarba moyl)benzofuran-6- yl)methylsulfonamido)benzoate (1.29 g, 2.20 mmol) in acetonitrile (7.3 ml) and 48% aqueous HBr (7.3 ml) at 0 °C and the reaction mixture was stirred at 0 °C for 30 mins, Copper(l) bromide (0.38 g, 2.64 mmol) was added and the solution was heated at 50 °C for 30 mins. The reaction mixture was cooled to RT, diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to afford the title compound (1.24 g, 86%) as a white foam. ¹ H NMR (400 MHz, CHLOROFORM-c/) δ ppm 7.86 - 7.93 (m, 2 H), 7.50 - 7.63 (m, 4 H), 7.17 - 7.25 (m, 2 H), 5.79 (br. s., 1 H), 3.92 (s, 3 H), 3.28 (s, 3 H), 3.01 (d, J=4.88 Hz, 3 H), 1.94 - 2.04 (m, 1 H), 0.76 - 1.09 (m, 3 H), 0.55 (br. s., 1 H).

Step 5: 6-(N-(4-bromo-3-chloro-5-((methoxymethoxy)methyl)phenyl)meth ylsulfonamido)-5- cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxam ide

LiBH ₄ (2.85 ml, 5.71 mmol) solution (2M in THF) was added dropwise to a 0 °C solution of methyl 2-bromo-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3- (methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate (1.24 g, 1.90 mmol) in Tetrahydrofuran (THF) (13.5 ml) and Methanol (1.3 ml). The reaction mixture was stirred at 0 °C for 1 h and quenched with 1 M NaOH. The reaction mixture was diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered and evaporated. The crude alcohol was taken up in THF (14 ml_). DIEA (1.0 ml, 5.71 mmol) and MOM-CI (0.36 ml, 4.76 mmol) were added and the reaction mixture was stirred at 50 °C overnight. Sat'd NaHC0 ₃ was added and the mixture was extracted with EtOAc. The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered, evaporated and purified by silica gel chromatography (0-50% EtOAc/hexanes) to obtain the title compound (1.08 g, 85%) as a white foam. ¹ H NMR (400 MHz, CHLOROFORM-c ) δ ppm 7.86 - 7.93 (m, 2 H), 7.61 (s, 1 H), 7.50 (d, 1 H), 7.49 (s, 1 H), 7.42 (d, J=2.83 Hz, 1 H), 7.18 - 7.25 (m, 2 H), 5.80 (br. s., 1 H), 4.73 (s, 2 H), 4.62 (s, 2 H), 3.38 (s, 3 H), 3.27 (s, 3 H), 3.01 (d, J=4.98 Hz, 3 H), 2.05 - 2.14 (m, 1 H), 0.75 - 1.11 (m, 3 H), 0.58 (br. s., 1 H).

Step 6: 6-(N-(7-chloro-1-hydroxy-1 ,3-dihydrobenzo[c][1 ,2]oxaborol-5- yl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-met hylbenzofuran-3- carboxamide

A solution of 6-(N-(4-bromo-3-chloro-5-

((methoxymethoxy)methyl)phenyl)methylsulfonamido)-5-cyclo propyl-2-(4-fluorophenyl)-N- methylbenzofuran-3-carboxamide (0.25 g, 0.38 mmol), potassium acetate (0.15 g, 1.50 mmol), PdCI ₂ (dppf)-CH ₂ CI ₂ adduct (0.031 g, 0.038 mmol), bis(pinacolato)diboron (0.29 g, 1.13 mmol) in 1 ,4-Dioxane (3.75 ml) was degassed, purged with nitrogen and heated at 90°C for 15 h. The reaction mixture was diluted with EtOAc and water, filtered through celite, and evaporated. The brown residue was dissolved in THF (5 ml_), and 1 M HCI (5 ml_) and the solution was heated at 70 °C for 4 h. MeOH (2 ml_) was added and the solution was heated at 70 °C for another 15 h and diluted with EtOAc and water. The organic layer was washed with brine, dried (Na ₂ S0 ₄ ), filtered, evaporated and purified by silica gel chromatography (100% EtOAc to 10% MeOH/CH ₂ CI ₂ ) to obtain the title compound as a clear oil. MeOH was added and the precipitate was collected by vacuum filtration, washed with MeOH and dried to afford the title compound (0.0831 g, 39%) as a light tan solid. The filtrate was purified by reverse phase chromatography (5-100% CH ₃ CN/H ₂ 0 (0.1 % formic acid)) to afford an additional batch of the title compound (0.0146 g, 7%) as a white solid. ¹ H NMR (400 MHz, DMSO-c 6) δ ppm 9.17 (s, 1 H), 8.50 (d, J=4.68 Hz, 1 H), 8.09 (s, 1 H), 7.94 - 8.02 (m, 2 H), 7.37 - 7.46 (m, 3 H), 7.28 (d, J=1 .56 Hz, 1 H), 7.22 (s, 1 H), 4.96 (s, 2 H), 3.47 (s, 3 H), 2.84 (d, J=4.59 Hz, 3 H), 2.02 - 2.14 (m, 1 H), 0.98 (br. s., 1 H), 0.82 (br. s., 2 H), 0.49 (br. s., 1 H). LCMS {m/z, ES ⁺ ) = 569.2 (M+H+).

Intermediate IB: methyl {(l _t y)-l-[((2 _t y)-2-{4-[4'-(aminoacetyl)-4-biphenylyll-li7-imidazol- 2-yll-l-pyrrolidinyl carbonyll-2-methylpropyllcarbamate Intermediate IB can be prepared as illustrated by the reaction scheme below.

A solution of 1 ^elJiylethyl[2-(4 ^, -{2-[(2S -l-((2S -3-methyl-2- { [(methyloxy)carbonyl] amino } butanoyl)-2 -pyrrolidinyl] - l//-imidazol-4-y 1 } -4- biphenylyl)-2-oxoethyl]carbamate (Intermediate 11) (3.8g, 6.3mmol) in DCM (40mL) was treated with HCl (lOmL, 4M in dioxane) to give methyl {(15)-1-[((25)-2-{4-[4'- (aminoacetyl)-4-biphenylyl] - 1 //-imidazol-2-yl } - 1 -pyrrolidinyl) carbonyl] -2 - methylpropyl} carbamate (Intermediate IB) as light yellow solid (3.5g, quant.).

Intermediate 2B: (3SJS,9S)-7,9-dimethyl-2-{N-[(methyloxy)carbonyll-L-valyl}-6 a0- dioxa-2-azaspiro [4.5] decane-3 -carboxylic acid

Intermediate 2B can be prepared as illustrated in the reaction scheme below.

14 2

To a stirred solution of methyl (3S,7S,9S)-7,9-dimethyl-2-{7V- [(methyloxy)carbonyl]-L-valyl}-6,10-dioxa-2-azaspiro[4.5]dec ane-3-carboxylate

(Intermediate 14) (360mg, 0.932mmol) in a mixed solvents of THF (4mL), i-butanol (ImL) and water (ImL) was added LiOH (44mg, 1.86mmol). The resulting mixture was stirred for 2 hrs at rt before acidified with IN HCl to pH ~3 and further diluted with ethyl acetate (lOOmL). The solution was washed with brine. The organic layer was dried over Na ₂ S0 ₄ , filtered and evaporated to give (3S,7.S',9 ₁ S)-7,9-dimethyl-2-{A^-[(methyloxy)carbonyl]-L- valyl}-6,10-dioxa-2-azaspiro[4.5]decane-3-carboxylic acid (Intermediate 2B) (315mg, yield: 91%) as solid. ES LC-MS m/z =373 (M+H) ⁺ .

Example 4: methyl r(1 )-l-(i(2 _t y)-2-r4-(4 ^l -{2-r(3SJS.9,y)-7.9-dimethyl-2-((2 _t $)-3-methyl- 2-{[(methyloxy)carbonyllamino|butanoyl)-6.10-dioxa-2-azaspir o[4.51dec-3-yll-l//- imidazol-4-v -4-biphenylyl)- l//-imidazol-2-yl ^" |- 1 -pyrrolidinyll carbonyl)-2- methylpropyl] carbamate

Example 4

To a stirred solution of ((35,7S,9.S)-7,9-dimethyl-2-{Af-[(methyloxy)carbonyl]-L- valyl}-6,10-dioxa-2-azaspiro[4.5]decane-3-carboxylic acid (Intermediate 2B) (96mg, 0.258mmol) in DMF (2mL) were added TEA (78mg, 0.773mmol) and HATU (108mg, 0.284mmol). After ~3min stirring, methyl {(l S)-l -[((2S)-2-{4-[4'-(aminoacetyl)-4- bipheny lyl] - 1 H-imidazol-2-yl } - 1 -pyrrolidinyl)carbonyl] -2-methylpropyl } carbamate dihydro chloride (Intermediate IB) (149mg, 0.258mmol) was introduced. After the reaction was stirred for additional 2 hrs at rt, the mixture was directly loaded to RP HPLC, eluting with 5 to 80 % acetonitrile/ water (0.2 % NH ₃ H ₂ 0 (cone.)) to give methyl [(1S)-1-({(2S)- 2-[4-(4'-{2-[(3S' S',9S -7,9-dime1-iyl-2-((2S -3-metliyl-2-

{[(methyloxy)carbonyl]amino}butanoyl)-6,10-dioxa-2-azaspi ro[4.5]dec-3-yl]-li7- imidazol-4-yl} -4-biphenylyl)- l/f-imidazol-2-yl]- 1 -pyrrolidinyl} carbonyl)-2- methylpropyl] carbamate (Intermediate 3B) as solid (135mg, yield: 61 %). 'HNMR (400 MHz, CHLOROFORM -J) δ ppm 10.40 - 11.01 (m, 1 H) 7.32 - 8.30 (m, 10 H) 5.28 (br. s., 2 H) 4.53 - 4.96 (m, 4 H) 4.17 - 4.53 (m, 1 H) 3.40 - 4.17 (m, 11 H) 2.83 - 3.22 (m, 1 H) 2.26 - 2.74 (m, 3 H) 1.54 - 2.26 (m, 8 H) 0.47 - 1.43 (m, 18 H). ES LC-MS m/z = 858.6 (M+H) ⁺ .

To a stirred solution of methyl [(15 -({(2S -2-[4-(4 ^, -{2-[(3S' S',9S -7,9-dimethyl- 2-((2.S)-3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-6,10-dioxa-2- azaspiro [4.5 ] dec-3 -yl] - 1 //-imidazol-4-yl } -4-biphenylyl)- 1 //-imidazol-2 -yl] - 1 - pyrrolidinyl }carbonyl)-2-methylpropyl] carbamate (Intermediate 3) (135mg, 0.157mmol) in dioxane (3mL) was added ammonium acetate (121mg, 1.57mmol). The reaction mixture was heated to 110 °C in a sealed tube overnight. Cooled down to rt, filtered off excess of ammonium acetate. The filtrate was evaporated and the residue was purified by column chromatography (silica gel, 0 -15% methanol in ethyl acetate) to give methyl [(lS)-l-({(2S)-2-[4-(4'-{2-[(3S,7S,9S)-7,9-dimethyl-2-((2S)- 3-methyl-2- {[(methyloxy)carbonyl]amino}butanoyl)-6,10-dioxa-2-azaspiro[ 4.5]dec-3-yl]-lH- imidazol-4-yl} -4-biphenylyl)-l H-imidazol-2-yl]- 1 -pyrrolidinyl} carbonyl)-2- methylpropyl] carbamate (Example 4) as solid (81mg, yield: 58%). 'HNMR (400 MHz, CHLOROFORM -J) δ ppm 10.23 - 11.01 (m, 1 H) 7.31 - 8.08 (m, 8 H) 7.23 (d, J=8.03 Hz, 2 H) 5.13 - 5.89 (m, 4 H) 3.34 - 4.69 (m, 13 H) 2.84 - 3.31 (m, 2 H) 2.63 - 2.84 (m, 1 H) 2.29 - 2.53 (m, 1 H) 1.85 - 2.29 (m, 4 H) 1.56 - 1.85 (m, 4 H) 1.16 - 1.47 (m, 6 H) 0.63 - 1.16 (m, 12 H). HRMS: (M+H) ⁺ calcd: 835.4456; found: 835.4458.

Example 5: methyl rri _t $ ^, )-2-methyl-l-rir2 _t y)-2-r4-r4 ^l - i2-rr8 _t $ ^, )-7-rr2 _t y)-3-methyl-2- {r(methyloxy)carbonyllaminolbutanoyl)-l,4-dioxa-7-azaspiro[4 .41non-8-yll-l//-imidazol-

Methyl [(l ₁ S -2-methyl-l-({(2S -2-[4-(4 ^, -{2-[(8S -7-((2S -3-methyl-2- {[(methyloxy)carbonyl] amino}butanoyl)-l,4-dioxa-7-azaspiro[4.4]non-8-yl]-l//-imida zol- 4-yl} -4-biphenylyl)-l//-imidazol-2-yl]- 1 -pyrrolidinyl} carbonyl)propyl] carbamate was obtained from (85)-7-{N-[(methyloxy)carbonyl]-L-valyl}-l,4-dioxa-7- azaspiro[4.4]nonane-8-carboxylic acid (Intermediate 17) and methyl {(l S)-l-[((2S)-2-{4-

[4'-(aminoacetyl)-4-biphenylyl]-lH-imidazol-2-yl}-l-pyrro lidinyl)carbonyl]-2- methylpropyl} carbamate dihydro chloride (Intermediate IB), following the similar two-step synthetic procedures outlined in Example 4. ^! H NMR (400 MHz, CHLOROFORM-i ) δ ppm 10.00 - 11.36 (m, 2 H) 7.56 (br. s., 10 H) 7.02 - 7.34 (m, 2 H) 5.05 - 5.89 (m, 4 H) 3.76 - 4.65 (m, 6 H) 3.53 - 3.83 (m, 6 H) 2.77 - 3.54 (m, 2 H) 2.26 - 2.70 (m, 2 H) 1.45 -

2.26 (m, 6 H) 0.61 - 1.25 (m, 12 H). HRMS: (M+H) ⁺ calcd: 797.3986; found: 797.3981.

Example 6: Pharmaceutical Composition Quantity

Component

(mg/tablet)

Compound of Example 3 - (Sprav

Dried Dispersion): 420

Compound of Example 2:

400

Microcrystalline Cellulose (-100 μιη) 165

Microcrystalline Cellulose (-20 μιη) 129.3

Croscarmellose Sodium 22.56

Colloidal Silicone Dioxide 7.5

Magnesium Stearate 5.64

Total Tablet Weight (mg/tablet) 1 150

A tablet, further comprising ribavirin, may be prepared according to the procedu of Example 2 using the quantities from the table above.

Example 7: Pharmaceutical Composition

A tablet, further comprising ritonavir, may be prepared according to the procedu ple 6 using the quantities from the table above.