SUBSTITUTED BENZIMIDAZOLES AS NON-NUCLEOSIDE INHIBITORS OF REVERSE TRANSCRIPTASE

Abstract: Benzimidazole derivatives substituted in position 2 by a 2,6 difluorophenyl and/or in position 1 by a 2,6-difluorobenzyl group are HIV-1 reverse transcriptase inhibitors useful in treatment of HIV infections.

Description: SUBSTITUTED BENZIMIDAZOLES AS NON-NUCLEOSIDE INHIBITORS OF REVERSE TRANSCRIPTASE The present application is a Continuation-in-Part of PCT publication WO 98/37072, published on August 27, 1998, which claims priority benefit of U.S. provisional application No. 60/038,509, filed February 25, 1997, abandoned. FIELD OF THE INVENTION The present invention is related to non-nucleoside inhibitors of reverse transcriptase (RT). In particular, the present invention relates to a novel class of substituted benzimidazoles effective in the inhibition of human immunodeficiency virus (HIV) RT. BACKGROUND OF THE INVENTION Since its recognition in 1981, the acquired immunodeficiency syndrome (AIDS) has become a major pandemic. The worldwide prevalence of HTV infection has been estimated at more than 18,500,000 cases, with an additional estimate of 1.5 million infected children (R. Famighetti, 1996 World Almanac and Book of Facts, World Almanac Books, Mahwah, New Jersey, [1995], p. 840). The etiologic agent associated with AIDS was identified as the human immunodeficiency virus (HIV). HTV is classified as a retro virus, as it contains reverse transcriptase (RT), a multi-functional enzyme that contains RNA-dependent DNA polymerase activity, as well as DNA-dependent DNA polymerase and ribonuclease H activities. These three activities are essential for the conversion of genomic retroviral RNA into double-stranded DNA that can then be integrated into an infected host cell genome. HIV is a D-type virus within the lentivirus family, with two major antigenic types (HIV-1 and HIV-2). HIV-1 and HIV-2 share approximately 40% genetic identity, although they can be readily distinguished based on differences in antibody reactivity to the envelope glycoprotein (M. Cloyd, "Human Retro viruses," in S. Baron (ed.), Medical Microbiology, University of Texas Medical Branch at Galveston, [1996], pp. 761-775). Both HIV-1 and HIV-2 have been associated with AIDS. The search for effective drugs against HIV has focused on targeting various critical components of the replication cycle of HIV-1. One important component in this cycle is the reverse transcriptase enzyme. Indeed, perhaps because of its pivotal role in the life cycle of HIV, it was the target of the first clinically approved anti- retroviral agents (see, Patel et al, "Insights into DNA Polymerization Mechanisms from Structure and Function Analysis of HIV-1 Reverse Transcriptase," Biochem., 34:5351-5363 [1995]), although other compounds such as protease inhibitors have recently been introduced. In addition to its critical role in HIV replication, targeting RT has a potential benefit in reducing the toxicity to the patient associated with many drugs, as human cells do not normally contain this RT activity. Therefore, the potential for targeted inhibition of only viral replication and not host cell multiplication is present. However, this potential has yet to be realized. There are two major classes of RT inhibitors. The first comprises nucleoside analogues, such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-didehydro-2',3'- dideoxythymidine (d4T), and 2',3'-dideoxycytidine (ddC). These compounds are analogs of normal deoxynucleoside triphosphates (dNTPs). However, these are not specific for HIV RT, and are incorporated into cellular DNA by host DNA polymerases; thus, these compounds can cause serious side effects. Moreover, administration of these analogs has resulted in the emergence of drug-resistant viral strains that contain mutations in their RT. Thus, these RT inhibitors have dangers that must be considered in developing treatment regimens for HTV-infected patients. The second major class of RT inhibitors comprises the non-nucleoside RT inhibitors (NNRTI), such as tetrahydroimidazo(4,5,l-lJA:)(l,4)-benzodiazepin-2-(lH)- one, and -thione (TIBO) derivatives, dipyridodiazepinones, pyridinones, bis(heteroaryl)piperazines (BΗAPs), 2',5'-bis-O-(tertbutyldimethylsilyl)-3'-spiro-5"- (4"-amino-l ",2"-oxathiole-2",2"-dioxide)pyrimidine (TSAO) derivatives, α - anilinophenylacetamide (α -APA), 8-chloro-4,5,6,7-tetrahydro-5-methylimidazo-[4,5,l- jk][l,4]benzodiazepine-2 (lH)-one (8-Cl TIBO), and nevirapine. (See, e.g., Pauwels et al, "Potent and Selective Inhibition of HIV-1 Replication in Vitro By a Novel Series of TIBO Derivatives," Nature 343:470-474 [1990]; Merluzzi et al, "Inhibition of HIV- 1 Replication by a Non-Nucleoside Reverse Transcriptase Inhibitor," Science 250:1411-1413 [1990]; Goldman and Stern, "Pyridinone Derivatives: Specific Human Immunodeficiency Virus Type 1 Reverse Transcriptase Inhibitors with Antiviral Activity," Proc. Natl. Acad. Sci. USA 88:6863-6867 [1991]; Romero and Tarpley, "Non-Nucleoside Reverse Transcriptase Inhibitors that Potently and Specifically Block Human Immunodeficiency Virus Type 1 Replication," Proc. Natl. Acad. Sci., USA 88:8806-8810 [1991]; Balzarini et al, "2',3'-Bis-O-(Tertbutyldimethylsilyl)-3'-Spiro- 5"-(4"-Amino-l",2"-Oxathiole-2",2"-Dioxide) Pyrimidine (TSAO) Nucleoside Analogs: Highly Selective Inhibitors of Human Immunodeficiency Virus Type 1 That are Targeted at the Viral Reverse Transcriptase," Proc. Natl. Acad. Sci. USA 89:4392- 4396 [1992]; Young, "Non-Nucleoside Inhibitors of HIV-1 Reverse Transcriptase," Perspect. Drug Discov. Des., 1:181-192; and Pauwels et al, "Potent and Highly Selective Human Immunodeficiency Virus Type 1 (HIV-1) Inhibition by a Series of α -Anilinophenylacetamide Derivatives Targeted at HIV-1 Reverse Transcriptase," Proc. Natl Acad. Sci., USA 90:1711-1715 [1993]). Unlike the nucleoside analogues, the NNRTIs do not act as chain terminators and do not bind at the dNTP-binding site. The majority of these compounds have been shown to share a common binding site unique to HIV-1 RT that is located in proximity to the RT polymerase active site. (See, Tantillo et al, "Locations of Anti- AIDS Drug Binding Sites and Resistance Mutations in Three-Dimensional Structure of HIV-1 Reverse Transcriptase. Implications for Mechanisms of Drug Inhibition and Resistance," J. Mol. Biol, 243:369-387 [1994]; Smith et al, "Molecular Modeling Studies of HIV-1 Reverse Transcriptase Nonnucleoside Inhibitors: Total Energy of Complexation as a Predictor of Drug Placement and Activity," Prot. Sci., 4:2203-2222 [1995]; Ding et al, "Structure of HIV-1 TR/TIBO R86183 Complex Reveals Remarkable Similarity in the Binding of Diverse Nonnucleoside Inhibitors," Nature Struct. Biol, 2:407-415 [1995]; and Nanni et al, "Review of HIV-1 Reverse Transcriptase Three Dimensional Structure: Implications for Drug Design," Perspect. Drug Discov. Des., 1:129-150 [1993]). NNRTIs are highly specific for HIV-1 RT, and do not inhibit either HIV-2 RT or normal cellular polymerases, resulting in lower cytotoxicity and fewer side effects than the nucleoside analogs. (See, e.g., Ding et al, "Structure of HIV-1 Reverse Transcriptase in a Complex with the Non-Nucleoside Inhibitor α-APA R 95845 at 2.8 A Resolution," Structure 3:365-379 [1995]). However, resistance to some of these compounds has been reported. (See, e.g., Nunberg et al, "Viral Resistance to Human Immunodeficiency Virus Type 1 -Specific Pyridinone Reverse Transcriptase Inhibitors," J. Virol, 65:4887-4892 [1991]; Tantillo et al, "Locations of Anti-AIDS Drug Binding Sites and Resistance Mutations in the Three-Dimensional Structure of HIV-1 Reverse Transcriptase: Implications for Mechanisms of Drug Inhibition and Resistance," J. Mol. Biol, 243:369-387; and Richman, "Resistance of Clinical Isolates of Human Immunodeficiency Virus to Antiretroviral Agents," Antimicrob. Agents Chemother., 37:1207-1213 [1993]). Despite recent developments in drug and compound design to combat HIV, there remains a need for a potent, non-toxic compound that is effective against wild type (WT) RTs, as well as RTs that have undergone mutations, and thereby become refractory to commonly used anti-HIV compounds. SUMMARY OF THE INVENTION The present invention is related to substituted benzimidazole compounds. In particular, the present invention provides non-nucleoside inhibitors of reverse transcriptase (RT) comprising a novel class of substituted benzimidazoles effective in the inhibition of human immunodeficiency virus (HIV) RT. In one embodiment, the present invention provides substituted benzimidazoles having the structure of Figure 7A. In one embodiment, X" is selected from the group consisting of hydrogen, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine. In another embodiment, R" is selected from the group consisting of 2,6-difluorobenzyl (2,6-F 2 Bn), benzyl (Bn), ethylbenzyl, 2,6-dichlorobenzyl (2,6-Cl 2 Bn), 2,3,4,5,6-pentafluorobenzyl (2,3,4,5,6-F 5 Bn), pyridylmethyl (CH 2 (3-Py), benzenesulfonyl (PhSO 2 ), 2,6- difluorobenzoyl (2,6-F 2 Bz), and 3,3-dimethylallyl. In yet another embodiment, X" is selected from the group consisting of hydrogen, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine; and R" is selected from the group consisting of 2,6-difluorobenzyl, benzyl, ethylbenzyl, 2,6-dichlorobenzyl, 2,3,4,5,6-pentafluorobenzyl, pyridylmethyl, benzenesulfonyl, 2,6-difluorobenzoyl, and 3,3-dimethylallyl. In a preferred embodiment, R" is 2,6-difluorobenzyl. In an alternative embodiment, the present invention provides substituted benzimidazoles with the general structure of Figure 7B. In one embodiment, X' is selected from the group consisting of hydrogen, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine. In another embodiment, R' is selected from the group consisting of phenyl (Ph), formyl (CHO), isopropyl (iPr), H, methyl (CH 3 ), cyclopropyl, hydroxymethyl (CH 2 OH), and 2,6-difluorobenzyloxymethyl (CH 2 O(2,6-F 2 Bn), 2,6 difluorophenyl (2,6- F 2 Ph), methylphenyl (2-CH 3 Ph), 2-fiuoro-6-methoxylphenyl, pyridyl (e.g., 4-Py, 3-Py), and naphthyl (e.g., 1-Nap, 2-Nap). In yet another embodiment, X' is selected from the group consisting of hydrogen and methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine; and R' is selected from the group consisting of phenyl, formyl, isopropyl, H, methyl, cyclopropyl, hydroxymethyl, 2,6-difluorobenzyloxymethyl, 2,6 difluorophenyl (2,6- F 2 Ph), methylphenyl (2-CH 3 Ph), 2-fluoro-6-methoxylphenyl, pyridyl (e.g., 4-Py, 3-Py), and naphthyl (e.g., 1-Nap, 2-Nap). In a preferred embodiment, R' is 2,6- difluorophenyl. In another alternative embodiment, the present invention provides substituted benzimidazoles with the general structure of Figure 13 A, wherein X"" is at least one substituent positioned at a benzimidazole carbon of a substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole and selected from C4, C5, C6, Cl, C4 and C5, and C4 and C6 of the substituted l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazole, and wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 4,5-dimethyl, 4,6- dimethyl, 4-ethyl, 4-cyano (CN), 4-methylenecyano (CH 2 CN), 4-methoxy, 4-nitro, 5- nitro, 4-amino, 4-N-acetamido (NHAc), 4-N-methylamino (NHCH 3 ), 4-N- dimethylamino [N(CH 3 ) 2 ], 4-isopropyl, 4-isoprenyl, 4-bromo, 5-bromo, 6-bromo, 4- chloro, 5-chloro, 6-chloro, fluoro, N-methylacetamido (NAcCH 3 ), methyl carboxylate (CO 2 Me), methyl acetamido ester (CH 2 OAc), hydroxy, CNH(NH 2 OH), amide (CONH 2 ), N-dimethylamide [CON(CH 3 ) 2 ], carboxylic acid, hydroxymethyl (CH 2 OH), formyl, chloromethyl, 4-methyleneazido (CH 2 N 3 ), aminomethyl (CH 2 NH 2 ), N- acetamidomethyl (CH 2 NHAc), CH 2 NCH 2 Ac, dimethyl ether (CH 2 OCH 3 ), 4- methylenethiocyanate (CH 2 NCS), and 4-methyleneacetylene (CH 2 CCH). In a preferred embodiment, X"" is selected from the group consisting of hydrogen, 4-methyl, 4- ethyl, 4-cyano, 4-methoxy, 4-nitro, 4-amino, 4-N-acetamido, 4-N-methylamino, 4-N- dimethylamino, 4-isopropyl, 4-isopropenyl, 4-bromo, 4-chloro, 4-methyleneazido, 4- methylenecyano, 4-methylenethiocyanate, and 4-methyleneacetylene. The present invention also provides pharmaceutical compositions of substituted benzimidazoles having the general structure of Figure 13 A, wherein X"" is selected from the group consisting of hydrogen, 4-methyl, 4-ethyl, 4-cyano, 4-methoxy, 4-nitro, 4-amino, 4-N- acetamido, 4-N-methylamino, 4-N-dimethylamino, 4-isopropyl, 4-isopropenyl, 4- bromo, 4-chloro, 4-methyleneazido, 4-methylenecyano, 4-methylenethiocyanate, and 4- methyleneacetylene. It is contemplated that the substituted benzimidazoles of the present invention comprise derivatives containing various groups. It is not intended that the present invention be limited to particular substituted benzimidazole derivatives. For example, it is intended that the present invention encompasses embodiments in which such groups as aromatic rings, hydrocarbons, and other structures are included. Such groups include, but are not limited to hydrogen, 4-methyl, 5-methyl, 6-methyl, 7- methyl, 4,5-dimethyl, 4,6-dimethyl, 4-chloro, 5-chloro, 6-chloro, 4-bromo, 5-bromo, 4- nitro, and 5-nitro, cyclopropyl, 2,6-difluorobenzyloxymethyl, 2,6-difluorophenyl, 2- fluoro-6-methoxyphenyl, pyridyl, naphthyl, 2,6-difluorobenzyl, benzyl, ethylbenzyl, 2,6-dichlorobenzyl, 2,3,4,5,6-pentafluorobenzyl, pyridylmethyl, benzenesulfonyl, 2,6- difluorobenzoyl, 3,3-dimethylallyl, fluoro, chloromethyl, methoxy, N-methylacetamide (NAcCH 3 ), ethyl, methyl carboxylate (CO 2 Me), methyl acetamido ester (CH 2 OAc), hydroxy, amine, N-acetamide (NHAc), N-methylamine (NHCH 3 ), N-diethylamine [N(CH 3 ) 2 ], cyano, CNH(NH 2 OH), amide (CONH 2 ), N-dimethylamide [CON(CH 3 ) 2 ], carboxylic acid, isopropyl, isoprenyl, hydroxymethyl (CH 2 OH), formyl, chloromethyl, aminomethyl (CH 2 NH 2 ), N-acetamidomethyl (CH 2 NHAc), CH 2 NCH 2 Ac, dimethyl ether (CH 2 OCH 3 ), 4-methyleneazido (CH 2 N 3 ), 4-methylenecyano, 4-methylenethiocyanate, and 4-methyleneacetylene. It is further intended that these groups be included in these compositions alone or in combination. It is also contemplated that the aromatic residues of various embodiments of the present invention may be replaced with hydrophobic residues, such as aliphatic groups. For example, the present invention encompasses alkylimidazoles, including, but not limited to 1 -(2,6-difluorobenzyl)-2-difluorophenyl-5,6-dialkylimidazole. It is further contemplated that the present invention includes embodiments in which the carbons (C) present on the benzyl ring (i.e., C4, C5, C6, and C7) are replaced with nitrogen (N), singly, or in combination (e.g., azapurines). It is contemplated that the substituted benzimidazoles of the present invention will find use in the treatment of HIV infection/disease. In particularly preferred embodiments, the present invention provides pharmaceutical compositions comprising substituted benzimidazoles with activity against HIV-1 RT. The present invention also provides methods for treating human immunodeficiency virus (HIV) infection, comprising the steps of: a) providing: i) a subject suspected of being infected with human immunodeficiency virus; and ii) a composition having anti-reverse transcriptase activity and comprising at least one substituted benzimidazole having a 2,6-difluorobenzyl substituent at the N-1 site of the benzimidazole ring; b) exposing the subject to the composition having anti-reverse transcriptase activity; and c) observing for inhibition of anti-reverse transcriptase activity. In one preferred embodiment, the human immunodeficiency virus is HIV-1. In one embodiment, the methods for treating HIV infection utilize substituted benzimidazoles further comprising a 2,6-difluorophenyl substituent at the C2 site of the benzimidazole ring. In particularly preferred embodiments, the methods for treating HIV infection utilize substituted benzimidazoles having the structure of Figure 13 A, wherein X"" is at least one substituent positioned at a benzimidazole carbon selected from C4, C5, C6, C7, C4 and C5, and C4 and C6 of a substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole, and wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 4,5- dimethyl, 4,6-dimethyl, 4-ethyl, 4-cyano (CN), 4-methylenecyano (CH 2 CN), 4- methoxy, 4-nitro, 5-nitro, 4-amino, 4-N-acetamido (NHAc), 4-N-methylamino (NHCH 3 ), 4-N-dimethylamino [N(CH 3 ) 2 ], 4-isopropyl, 4-isoprenyl, 4-bromo, 5-bromo, 6-bromo, 4-chloro, 5-chloro, 6-chloro, fluoro, N-methylacetamido (NAcCH 3 ), methyl carboxylate (CO 2 Me), methyl acetamido ester (CH 2 OAc), hydroxy, CNH(NH 2 OH), amide (CONH 2 ), N-dimethylamide [CON(CH 3 ) 2 ], carboxylic acid, hydroxymethyl (CH 2 OH), formyl, chloromethyl, 4-methyleneazido (CH 2 N 3 ), aminomethyl (CH 2 NH 2 ), N-acetamidomethyl (CH 2 NHAc), CH 2 NCH 2 Ac, dimethyl ether (CH 2 OCH 3 ), 4- methylenethiocyanate (CH 2 NCS), and 4-methyleneacetylene (CH 2 CCH). In preferred embodiments, X"" is selected from the group consisting of hydrogen, 4-methyl, 4- ethyl, 4-cyano, 4-methoxy, 4-nitro, 4-amino, 4-N-acetamido, 4-N-methylamino, 4-N- dimethylamino, 4-isopropyl, 4-isopropenyl, 4-bromo, 4-chloro, 4-methyleneazido, 4- methylenecyano, 4-methylenethiocyanate, and 4-methyleneacetylene. In another embodiment, the methods for treating human immunodeficiency virus infection utilize substituted benzimidazoles having the structure of Figure 7A, wherein X" is selected from the group consisting of hydrogen, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine; and R" is selected from the group consisting of 2,6-difluorobenzyl, benzyl, ethylbenzyl, 2,6-dichlorobenzyl, 2,3,4,5,6- pentafluorobenzyl, pyridylmethyl, benzenesulfonyl, 2,6-difluorobenzoyl, and 3,3- dimethylallyl. In a preferred embodiment, R" is 2,6-difluorobenzyl. In yet another embodiment, the methods for treating human immunodeficiency virus infection utilize substituted benzimidazoles having the structure of Figure 7B, wherein X' is selected from the group consisting of hydrogen and methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine; and R' is selected from the group consisting of phenyl, formyl, isopropyl, H, methyl, cyclopropyl, hydroxymethyl, 2,6-difluorobenzyloxymethyl, 2,6 difluorophenyl (2,6-F 2 Ph), methylphenyl (2-CH 3 Ph), 2-fluoro-6-methoxylphenyl, pyridyl (e.g., 4-Py, 3-Py), and naphthyl (e.g., 1-Nap, 2-Nap). In a preferred embodiment, R' is 2,6- difluorophenyl. Furthermore, the present invention provides methods for inhibiting HIV-1 reverse transcriptase, comprising the steps of: a) providing: i) a sample suspected of being infected with HIV-1 virus; and ii) a composition having anti-reverse transcriptase activity and comprising at least one substituted benzimidazole having a 2,6-difluorobenzyl substituent at the N-1 site of said benzimidazole; b) exposing the sample to the composition having anti-reverse transcriptase activity; and c) observing for inhibition of said anti-reverse transcriptase activity. In some embodiments, the methods for inhibiting HIV-1 reverse transcriptase utilize substituted benzimidazoles further comprising a 2,6-difluorophenyl substituent at the C2 site of the benzimidazole ring. In particularly preferred embodiments, the methods for inhibiting HIV-1 reverse transcriptase utilize substituted benzimidazoles having the structure of Figure 13 A, wherein X"" is at least one substituent positioned at a benzimidazole carbon selected from C4, C5, C6, C7, C4 and C5, and C4 and C6 of a substituted l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole, and wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 5- methyl, 6-methyl, 7-methyl, 4,5-dimethyl, 4,6-dimethyl, 4-ethyl, 4-cyano (CN), 4- methylenecyano (CH 2 CN), 4-methoxy, 4-nitro, 5-nitro, 4-amino, 4-N-acetamido (NHAc), 4-N-methylamino (NHCH 3 ), 4-N-dimethylamino [N(CH 3 ) 2 ], 4-isopropyl, 4- isoprenyl, 4-bromo, 5-bromo, 6-bromo, 4-chloro, 5-chloro, 6-chloro, fluoro, N- methylacetamido (NAcCH 3 ), methyl carboxylate (CO 2 Me), methyl acetamido ester (CH 2 OAc), hydroxy, CNH(NH 2 OH), amide (CONH 2 ), N-dimethylamide [CON(CH 3 ) 2 ], carboxylic acid, hydroxymethyl (CH 2 OH), formyl, chloromethyl, 4-methyleneazido (CH 2 N 3 ), aminomethyl (CH 2 NH 2 ), N-acetamidomethyl (CH 2 NHAc), CH 2 NCH 2 Ac, dimethyl ether (CH 2 OCH 3 ), 4-methylenethiocyanate (CH 2 NCS), and 4- methyleneacetylene (CH 2 CCH). In preferred embodiments, X"" is selected from the group consisting of hydrogen, 4-methyl, 4-ethyl, 4-cyano, 4-methoxy, 4-nitro, 4-amino, 4-N-acetamido, 4-N-methylamino, 4-N-dimethylamino, 4-isopropyl, 4-isopropenyl, 4- bromo, 4-chloro, 4-methyleneazido, 4-methylenecyano, 4-methylenethiocyanate, and 4- methyleneacetylene. In another embodiment, the methods for inhibiting HIV-1 reverse transcriptase utilize substituted benzimidazoles having the structure of Figure 7A, wherein X" is selected from the group consisting of hydrogen, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine; and R" is selected from the group consisting of 2,6-difluorobenzyl, benzyl, ethylbenzyl, 2,6-dichlorobenzyl, 2,3,4,5,6-pentafluorobenzyl, pyridylmethyl, benzenesulfonyl, 2,6-difluorobenzoyl, and 3,3-dimethylallyl. In a preferred embodiment, R" is 2,6-difluorobenzyl. In yet another embodiment, the methods for inhibiting HIV-1 reverse transcriptase utilize substituted benzimidazoles having the structure of Figure 7B, wherein X' is selected from the group consisting of hydrogen and methyl, H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine; and R' is selected from the group consisting of phenyl, formyl, isopropyl, H, methyl, cyclopropyl, hydroxymethyl, 2,6-difluorobenzyloxymethyl, 2,6 difluorophenyl (2,6-F 2 Ph), methylphenyl (2-CH 3 Ph), 2-fluoro-6-methoxylphenyl, pyridyl (e.g., 4-Py, 3-Py), and naphthyl (e.g., 1-Nap, 2-Nap). In a preferred embodiment, R' is 2,6-difluorophenyl. In addition, it is contemplated that the present invention encompasses analogs of the benzimidazole ring system which are capable of undergoing dissociation in the binding pocket of HIV RT, to give rise to electrophilic intermediates that react with nucleophilic sites in the pocket. Thus, it is contemplated that compounds that act as irreversible inhibitors of HIV RT also be encompassed as embodiments within the present invention. It is not intended that the compounds of the present invention be limited to any particular use. Indeed, it is intended that the compounds of the present invention will be utilized against organisms other than HIV. DEFINITIONS To facilitate understanding of the invention, a number of terms are defined below. As used herein, the term "retrovirus" refers to a group of viruses with RNA genomes. Retroviruses are characterized as having reverse transcriptase, the enzyme that allows the RNA genome to be transcribed into DNA. As used herein, the term "reverse transcriptase" refers to an enzyme with RNA- dependent DNA polymerase activity, with or without the usually associated DNA- dependent DNA polymerase and ribonuclease activity observed with wild-type reverse transcriptases. As used herein, the term "anti-viral" is used in reference to any compound, substance, or molecule capable of inhibiting or preventing viral replication and/or dissemination. It is intended that the term encompasses compounds capable of inhibiting viral replication by interfering with such activities as the reverse transcriptase activity of retroviruses. It is also intended to encompass "non-nucleoside reverse transcriptase inhibitors" (NNRTI). In preferred embodiments, the term is used in reference to substituted benzimidazole compounds. As used herein, the term "chemotherapeutic" refers to any compound, element, or substance useful against disease. In preferred embodiments, the term encompasses compounds such as the substituted benzimidazoles of the present invention. As used herein, the term "purified" refers to the removal of contaminants from a sample. Methods such as carbon, hydrogen and nitrogen analyses (CHN analysis, or "elemental analysis") may be used to determine the purity of compounds. In preferred embodiments, the CHN values of compounds of the present invention are very close to the predicted values. Correspondence of experimental with the predicted values to within 0.3% indicates high levels of purity. In particularly preferred embodiments, the compounds of the present invention have CHN values within 0.3% of the predicted values. In less preferred embodiments, the level of purity may be lower (i.e., greater than 0.3% difference between the predicted and actual CHN values). As used herein, the terms "benzimidazole" and "substituted benzimidazole" are used in reference to molecules with the core structure as indicated in Figure 1. It is intended that the term encompasses compounds in which substitutions, including additions, have been made to the chemical structure. The term encompasses, but is not limited to substitution reactions, wherein there is replacement of one or more atoms or group in a molecule by another atom or group. In a preferred embodiment, the present invention encompasses 1- and 2-substituted benzimidazoles (See e.g., Figure 7), including but not limited to l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- methylbenzimidazole (See e.g., Figure 13). As used herein, the term "substituent" is used in reference to functional and molecular groups present in the substituted benzimidazole. The terms "C2," "C4," "C5," "C6," "C7", etc. refer to a carbon in the benzimidazole ring and its position in the benzimidazole ring, following the numbering convention for the benzimidazole ring as indicated in Figure 1. For example, the term "C4 and C5" refers to the carbons at the 4 and 5 positions of the benzimidazole ring, while the term "C4 and C6" refers to carbons at the 4 and 6 positions of the benzimidazole ring. As used herein, the term "TBZ" refers to 1 -(2,6-difluorophenyl)- 1H,3- thiazolo[3,4-a]benzimidazole. The term "cyclic compounds" refers to compounds having one (i.e., a monocyclic compounds) or more than one (i.e., polycyclic compounds) ring of atoms. The term is not limited to compounds with rings containing a particular number of atoms. While most cyclic compounds contain rings with five or " six atoms, rings with other numbers of atoms (e.g., three or four atoms) are also contemplated by the present invention. The identity of the atoms in the rings is not limited, though the atoms are usually predominantly carbon atoms. Generally speaking, the rings of polycyclic compounds are adjacent to one another; however, the term "polycyclic" compound includes those compounds containing multiple rings that are not adjacent to each other. The term "heterocyclic compounds" refers broadly to cyclic compounds wherein one or more of the rings contains more than one type of atom. In general, carbon represents the predominant atom, while the other atoms include, for example, nitrogen, sulfur, and oxygen. Examples of heterocyclic compounds include benzimidazole, furan, pyrrole, thiophene, and pyridine. The terms "aromatic," "aromatic compounds," and the like refer broadly to compounds with rings of atoms having delocalized electrons. The monocyclic compound benzene (C 6 H 6 ) is a common aromatic compound. However, electron delocalization can occur over more than one adjacent ring (e.g., naphthalene [two rings] and anthracene [three rings]). Different classes of aromatic compounds include, but are not limited to, aromatic halides (aryl halides), aromatic heterocyclic compounds, aromatic hydrocarbons (arenes), and aromatic nitro compounds (aryl nitro compounds). As used herein, the terms "aliphatic" and "aliphatic compounds" refer to compounds which comprise carbon atoms in chains, rather than the ring structure of aromatic compounds. It is intended that these aliphatic moieties will be bound to additional elements in some embodiments. The terms "resistant" and "refractory" used in reference to "resistant mutants" of HIV and or HIV RT, refer to the ability of some HTV RTs to function in the presence of compounds that are inhibitory to the RT of wild-type HP/. This resistance may result from any number of mutations, including but not limited to conformational changes in the RT structure, as well as to the configuration of the RT bound to its substrate. The term "mixture" refers to a mingling together of two or more substances without the occurrence of a reaction by which they would lose their individual properties. The term "solution" refers to a liquid mixture. The term "aqueous solution" refers to a solution that contains some water. In many instances, water serves as the diluent for solid substances to create a solution containing those substances. In other instances, solid substances are merely carried in the aqueous solution (i.e., they are not dissolved therein). The term aqueous solution also refers to the combination of one or more other liquid substances with water to form a multi- component solution. The terms "sample" and "specimen" in the present specification and claims are used in their broadest sense. On the one hand, they are meant to include a specimen or culture. On the other hand, they are meant to include both biological and environmental samples. These terms encompass all types of samples obtained from humans and other animals, including but not limited to, body fluids such as urine, blood, fecal matter, cerebrospinal fluid (CSF), semen, and saliva, as well as solid tissue. These terms also refer to swabs and other sampling devices commonly used to obtain samples for culture of microorganisms. Biological samples may be animal, including human, fluid or tissue, food products and ingredients such as dairy items, vegetables, meat and meat by-products, and waste. Environmental samples include environmental material such as surface matter, soil, water, and industrial samples, as well as samples obtained from food and dairy processing instruments, apparatus, equipment, disposable, and non-disposable items. These examples are not to be construed as limiting the sample types applicable to the present invention. As used herein, the term "culture" refers to any sample or specimen which is suspected of containing one or more microorganisms. "Pure cultures" are cultures in which the organisms present are only of one strain of a particular genus and species. This is in contrast to "mixed cultures," which are cultures in which more than one genus, species, and/or strain of microorganism are present. As used herein, the term "organism" is used to refer to any species or type of microorganism, including but not limited to viruses. In particular, the term is used in reference to RNA viruses, such as the retroviruses. In preferred embodiments, the organism of interest is HIV. In particularly preferred embodiments, the organism of interest is HIV-1. The term "parenterally" refers to administration to a subject through some means other than through the gastrointestinal tract or the lungs. The most common mode of parenteral administration is intravenous. However, other modes of parenteral administration include, but are not limited to, intramuscular, intradermal, intrathecal, intranasal and subcutaneous administration. As used herein, the term "pharmaceutical composition" refers to compositions composed of one or more pharmaceutically acceptable diluents, excipients or carriers. As used herein, the phrase "pharmaceutical preparation suitable for parenteral administration" refers to a solution containing compound in a pharmaceutically acceptable form for parenteral administration. The characteristics of the form will depend on a number of factors, including the mode of administration. For example, a preparation for intravenous administration will often comprise compound dissolved in normal saline or sterile water for injection. Of course, the pharmaceutical preparations of the present invention are not limited to those diluents; indeed, other components or diluents known in the field of pharmaceuticals and pharmacy are within the scope of the present invention. The pharmaceutical preparation may contain diluents, adjuvants and excipients, among other components, provided that those additional components neither adversely effect the preparation (e.g., they do not cause degradation of the compound) nor the recipient (e.g., they do not cause a hypersensitivity reaction). DESCRIPTION OF THE FIGURES Figure 1 shows the general structures of imidazole and benzimidazole. Figure 2 is a schematic retrosynthetic analysis of N-benzyl-2- alkylbenzimidazoles by alkylation of 2-substituted benzimidazoles. Figure 3 is a schematic synthesis of substituted 2-(2,6- difluorophenyl)benzimidazoles. Figure 4 is a schematic synthesis of substituted l-(2,6- difluorophenyl)benzimidazoles. Figure 5 shows the "butterfly-like" shape of TBZ and 39. Figure 6 shows the substituted benzimidazoles that inhibited HIV RT, as well as substituted benzimidazoles that did not inhibit HIV RT. Figure 7 (Panels A-B) shows the structure of 1- and 2-(2,6- difluorophenyl)benzimidazoles of the present invention. Figure 8 is a schematic synthesis of substituted l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazoles. Figure 9 is a schematic synthesis of the reduction of the 4-nitro group of 3100 with tin chloride. Figure 10 is a summary graph showing the cytotoxicity and anti-viral effect of compound 33. Figure 11 is a summary graph showing the cytotoxicity and anti-viral effect of compound 34. Figure 12 is a summary graph showing the anti- viral results for inactive compound 2100. Figure 13 shows the structure of substituted benzimidazoles of the present invention. Panel A describes 4-, 5-, 6-, or 7-substituted-l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazoles, while Panel B shows 4-substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazoles of the present invention. Figure 14 is a schematic synthesis of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazoles of the present invention. Figure 15 is a schematic synthesis of N-substituted-2-(2,6-difluorophenyl)-4- methoxylbenzimidazoles. Figure 16 is a schematic syntheses of N-substituted-(2,6-difluorophenyl)-4- methylbenzimidazoles and N-substituted-(2,6-difluorophenyl)-4-ethylbenzimidazoles. Figure 17 is a schematic synthesis of substituted l-(2,6-difluorobenzyl)-2- arylbenzimidazoles. Figure 18 is a schematic synthesis of 4-substituted N-substituted-2-(2,6-- difluorophenyl)benzimidazoles. Figure 19 is a schematic synthesis of N-substituted-2-(cyclopropyl)-4- methoxylbenzimidazoles. Figure 20 shows the structure of IH, 3H-thiazolo[3,4-a]benzimidazoles. DESCRIPTION OF THE INVENTION The present invention provides substituted benzimidazole compounds, which act as non-nucleoside inhibitors of reverse transcriptase (RT). In particular, the present invention relates to a novel class of substituted benzimidazoles, effective in the inhibition of human immunodeficiency virus (HIV) RT. The Description of the Invention is subdived into I) Imidazoles and Benzimidazoles; II) Synthesis of Substituted Benzimidazoles; III) Biological Activity of Substituted Substituted Benzimidazoles; IV) Geometry of TBX and l-(2,6- Difluorobenyl)-2-Phenylbenzimidazole; and V) Purity of the Substituted Benzimidazoles. I. Imidazoles and Benzimidazoles In addition to compounds such as tefrahydroimidazo(4,5,l-l-y ' £)(l,4)- benzodiazepin-2-(lH)-one, and -thione (TIBO) derivatives, dipyridodiazepinones, pyridinones, bis(heteroaryl)piperazines (BΗAPs), 2',5'-bis-O-(tertbutyldimethylsilyl)- 3'-spiro-5"-(4"-amino-l ",2"-oxathiole-2",2' '-dioxide)pyrimidine (TSAO) derivatives, α-anilinophenylacetamide (α -APA), 8-chloro-4,5,6,7-tetrahydro-5- methylirnidazo-[4,5,l-jk][l,4]benzodiazepine-2 (lΗ)-one (8-Cl TIBO), and nevirapine, the potential therapeutic utility of imidazole compounds such as l-(2,6- difluorophenyl)-lH,3H-thiazolo[3,4-a]benzimidazole (TBZ) has been shown. (See, e.g., A. Chimirri et al, "Anti-HIV Agents: Synthesis and In Vitro Anti-HIV Evaluation of Novel lH,3H-Thiazolo[3,4-a]Benzimidazoles," 77 Farmaco 46:817-823 [1991]). As shown in Figure 1, imidazoles (i.e., glyoxaline, 1,2-diazole, iminazole, miazole, pyrro[ό]monazole, and l,3-diaza-2,4-cyclopentadiene), are five-membered heterocycles with the formula C 3 H 4 N 2 . The properties of these compounds permit the existence of cyclic aromatic structures (i.e., derivatives) with more than two nitrogens or other heteroatoms bonded together. Many derivatives of these heterocyclic structures are important biochemical intermediates. Figure 1 also shows the structure of benzimidazole (i.e., benziminazole, 1,3-benzodiazole, azindole, benzoglyoxaline, NN'-methenyl-o-phenylenediamine, with the formula C 7 H 6 Ν 2 ). The numbering conventions for the ring positions are indicated in these structures. Imidazoles (e.g., clotrimazole, miconazole, econazole, and isoconazole) have found clinical use as anti-fungals, as they inhibit fungal cell ergosterol synthesis, but do not readily interfere with cholesterol synthesis in host (e.g., mammalian) cells. However, these drugs have undesirable side effects when administered systemically, such as pruritis, anemia, hyponatremia, leukopenia, thrombocytopenia, and elevated liver enzymes. Thus, their use has mainly been limited to topical treatment of fungal infections. Ketoconazole (another imidazole) is water-soluble and is easily absorbed from the gastrointestinal tract for oral treatment of systemic fungal infections. Although good results are usually obtained with otherwise healthy patients, severe problems in immunocompromised patients have been reported. Benzimidazoles (e.g., thiabendazole, mebendazole, and albendazole) have found clinical use as anti-helmintics, as they are effective against both the larval and adult stages of nematodes that cause ascariasis, intestinal capillariasis, enterobiasis, trichuriasis, as well as single and mixed hookworm infection. However, as with the imidazoles, the toxicity of these compounds, and/or their limited bioavailability have limited their clinical utility. Benzimidazole derivatives have been investigated as anti-viral agents, and some have been recognized as being capable of inhibiting RNA viruses. (See, e.g., Gilbert et al, Antiviral Res., 9:355 [1988]). In addition, it has been recognized that thiazolobenzimidazole analogs may enhance the immune response. (See, e.g., Warren et al, Immunopharmacol, 1:269 ([1979]; Fenichel et al, Immunopharmacol, 2:491 [1981]; and U.S. Patent No. 4,214,089 to Fenichel et al, herein incorporated by reference). Other derivatives of thiazolobenzimidazole, such as 1 -phenyl substituted lH,3H-thiazole[3,4-a] benzimidazoles have also been reported as having anti-HIV-1 RT activity. (See, e.g., EP 0471991, to Monforte et al). As mentioned above, one thiazolobenzimidazole compound, TBZ, has been shown to have HIV-1 RT inhibitory activity. However, there are some drawbacks to the use of TBZ. (See, e.g., Chimirri et al, Anti-HIV Agents. I. Synthesis and In Vitro Anti-HIV Evaluation of Novel lH,3H-Thiazolo[3,4-a]Benzimidazoles," supra; Chimirri et al, "Anti-HIV Agents. II. Synthesis and In Vitro Anti-HIV Evaluation of Novel lH,3H-Thiazolo[3,4-l]Benzimidazoles," II Farmaco 46:925-933 [1991]; and Buckheit et al. , "Thiazolobenzimidazole: Biological and Biochemical Anti-Retroviral Activity of a New Non-Nucleoside Reverse Transcriptase Inhibitor," Antiviral Res., 21 :247-265 [1993]). One problem with TBZ is its susceptibility to metabolic oxidation of the thiazolo ring, resulting in the formation of less potent sulfoxide and sulfone metabolites (El Dareer et al, "Metabolism and Disposition of a Thiazolobenzimidazole Active Against Human Immunodeficiency Virus- 1," Drug Metabol Dispos., 21:231-235 [1993]). Another problem is the loss of antiviral activity against HIV strains with mutated RT. (See, Boyer et al, Analysis of Nonnucleoside Drug-Resistant Variants of Human Immunodeficiency Virus Type 1 Reverse Transcriptase," J. Virol, 67:2412- 2420; and Buckheit et al, "Comparative Anti-HIV Evaluation of Diverse HTV-1 Specific Reverse Transcriptase Inhibitor-Resistant Virus Isolates Demonstrates the Existence of Distinct Phenotypic Subgroups," Antiviral Res., 26:117-132 [1995]). During the development of the present invention, the drawbacks of TBZ were addressed in order to provide NNRTIs capable of efficiently and effectively inhibiting wild type, as well as mutated HIV-1 RT, with low toxicity levels, and a favorable therapeutic dose. During early stages in the development of the present invention, retrosynthetic analysis was applied to TBZ. This indicated that opening the thiazolo ring of TBZ could result in the production of compounds potentially useful for inhibition of HIV RT, and resulted in the development of the novel benzimidazoles disclosed herein. Figure 2 shows a schematic for one embodiment of the present invention, in which N- benzyl-2-alkylbenzimidazoles are synthesized by alkylation of 2-substituted benzimidazoles, as was attempted during the development of the present invention. These substituted N-benzyl-benzimidazoles were of interest as potentially providing enhanced inhibition of wild type RT, and the various clinically observed variant forms of HIV RT. This was one highly important aspect of the present invention, as most of the known NNRTIs are rendered ineffective by the emergence of mutant forms of HIV. (See, De Clercq, "HIV Resistance to Reverse Transcriptase Inhibitors," Biochem. Pharm., 47:155-169 [1994]). Especially in view of the development of resistance to compounds previously effective against HIV, it was of great interest to develop compounds effective against mutants of HIV RT. For example, development of a compound that was effective against Y181 C, a mutant that has a high degree of resistance to most NNRTIs (e.g., α -APA, nevirapine, and TIBO derivatives) was a major consideration in the development of the present invention. (See, e.g., "Structure of HIV-1 RT/TIBO R86183 Complex Reveals Similarity in the Binding of Diverse Nonnucleoside Inhibitors," Struct. Biol, 2:407-415 [1995]). Thus, during the development of the present invention, various compounds were developed and tested for their ability to inhibit both WT and mutated forms of HTV-1 RT. Various approaches were taken in order to produce these compounds, including synthesizing benzimidazoles with substitutions at one or more positions. II. Synthesis Of Substituted Benzimidazoles A. Synthesis of 1- and 2-Substituted Benzimidazoles A variety of 1- and 2-substituted benzimidazoles were prepared. Figure 3 provides a schematic approach for the synthesis of these compounds from nitroanilines and an appropriate choice of acylating reagent. In this Figure, "a" comprises aroyl chloride, pyridine/THF; "b" comprises Fe/AcOH; "c" comprises 2,6-F 2 -BnBr, NaH, THF; and "d" comprises BnBr or PhSO 2 Cl or 2,6-F 2 BzCl (7), THF. In most cases, it was found that high yields of the desired N-acyl-nitroaniline could be obtained from either 2-nitroaniline (8), or 2-methyl-6-nitroaniline (9). Only in the case of 1 -naphthyl derivative (14) was a mixture of mono and bis acylated product formed. Subsequent reductive cyclization of compounds 10-16 with iron yielded the desired 2-aryl- benzimidazoles 18-24. Following their coupling with 2,6-difluorophenyl-α- bromotoluene, the desired 2-aryl-l-(2,6-difluorobenzyl)-benzimidazoles were obtained. The first 2-substituted derivatives of N-2(2,6-difluorobenzyl)benzimidazole studied during the development of the present invention were the methyl, hydroxymethyl, isopropyl, carboxyl, formyl, and phenyl derivatives. With methyl and phenyl compounds, commercially available benzimidazoles were reacted with 2,6- difluorophenyl-α-bromotoluene to give l-(2,6-difluorobenzyl)-2-methylbenzimidazole (35) and l-(2,6-difluorobenzyl)-2-phenylbenzimidazole (39). Preparation of the hydroxymethyl substitute was achieved by acid-catalyzed condensation-cyclization of glycolic acid with either o-phenylenediamine or 2,3-diaminotoluene, using an approach similar to that described by Chimirri et al. for the synthesis of TBZ. (See, Figure 4. See also, Chimirri et al, Anti-HIV Agents. I. Synthesis and In Vitro Anti-HTV Evaluation of Novel lH,3H-Thiazolo[3,4-a]Benzimidazoles," supra; and Chimirri et al, "Anti-HIV Agents. II. Synthesis and In Vitro Anti-HIV Evaluation of Novel lH,3H-Thiazolo[3,4-l]Benzimidazoles," supra). Figure 4 provides a schematic of substituted N-2(2,6-difluorobenzyl)- benzimidazoles. In this Figure, "a" comprises glycolic or isobutyric acid, 4 Ν HC1, reflux; "b" comprises 2,6-F 2 -BzCl (7) or 2,6-F 2 BnBr (25); "c" comprises t- butyldimethylsilylchloride (tBDMSCl), pyridine; "d" comprises Bu 4 ΝF, THF; "e" comprises KMnO 4 ; and "f ' comprises CrO 3 . As shown in Figure 4, the hydroxymethyl intermediate was protected with t-butyldimethylsilyl (TBDMS), and subsequently N- alkylated with 2,6-difluorophenyl-α-bromotoluene (25). Removal of TBDMS from (31) resulted in the production of l-(2,6-difluorobenzyl)-2-hydroxymethyl-4- methylbenzimidazole (49). However, oxidation of the hydroxymethyl to the carboxylic acid was found to be problematic. When a strong oxidant (e.g., KMnO 4 ) was used, the isolated product (50) indicated that decarboxylation occurred under acidic reaction conditions. Oxidation under basic conditions with chromium oxide similarly yielded (50), along with the formyl product. The carboxylic acid form was not isolated. A final product prepared from the 2-hydroxymethylbenzimidazole (4) was the bis-2,6- difluorobenzyl derivative (32). B. Synthesis and Biological Activity of Substituted l-(2,6- difluorobenzyl)-2-(2,6-difiuorophenyl)Benzimidazoles In addition to the 1- and 2-substituted benzimidazoles described above, 4-, 5-, 6-, and 7- mono- and di-substitutions of l-(2,6-difluorobenzyl)-2-(2,6- difiuoropheny benzimidazole, and its des-methyl analog, l-(2,6-difluorobenzyl)-2-(2,6- difluorobenzyl)benzimidazole (26) were synthesized and their properties observed. On the basis of inhibition of HIV-1 cytopathic effect (i.e., protection from cell killing in the assay described in Example 91), it was determined that C-4 substituted analogs were consistently the most active compounds, as long as the substitution did not introduce strong electron withdrawing groups. Although it was less active, the 6- substituted analogs of l-(2,6-difluorobenzyl)-2-(2,6-difluorobenzyl)-4- methylbenzimidazole (33) also exhibited desired activity. However, the 5- or 7- substituted analogues of 33 showed decreased RT inhibition (See, Figure 6). A variety of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole compounds were prepared. The general approach utilized in the synthesis of the desired substituted l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazoles is outlined in Figure 8. In this Figure, "a" comprises 2,6-difluorobenzoyl chloride, pyridine:THF (1:1); "b" comprises NaOH, MeOH, dioxane; "c" comprises Br 2 , pyridine, THF; "d" comprises 2,6-F 2 BnBr, NaH, THF; and "e" comprises Fe, AcOH. Since a variety of substituted 6-nitroanilides are commercially available, this starting material was an ideal reagent to prepare a variety of differentially substituted benzimidazole derivatives. Depending on the type and regiochemistry of the different substitutents, the desired mono-acylated product could be obtained in good yields using 1.2 equivalents of 2,6-difluorobenzoyl chloride. In the case electron withdrawing substituents, benzoylation led to a mixture of mono and bis-acylated products. Variations in time, temperature, equivalents of reactants, and concentration were examined in unsuccessful efforts to produce only the desired mono-2,6-difluorobenzoyl products. The mono-2,6-difluorobenzoyl compounds were obtained in high yields by synthesizing the bis-2,6-difluorobenzoyl derivatives with excess 2,6-difluorobenzoyl chloride followed by selective base-catalyzed deacylation to the mono-benzoyl product. Depending on the desired regiochemistry of the final benzimidazoles, the mono-acylated 6-nitro-anilides were either reductively cyclized with iron (i.e., "Method B." See e.g., Example 12) and alkylated with 2,6-difluorobenzyl bromide (i.e., Method A. See e.g., Example 5) or alkylated with 2,6- difluorobenzyl bromide and then reductively cyclized. For instance, 2-Substituted 6-nitroanilides were reductively cyclized to 4-substituted benzimidazoles. Alkylation of the benzimidazole Nl position with 2,6-difluorobenzyl bromide proceeded with >92% regiochemical purity for a variety of 4-substituted compounds. In the case of 5-, 6- and 7- substituted benzimidazoles, regiochemical control was maintained by alkylation of the mono-acylated derivate (Method A) to Ν-(2,6-difluorobenzyl)-Ν-(2,6-difluorophenyl)- nitroanilides followed by reductive cyclization (Method B). Non-reductive acid catalyzed cyclization, in contrast, was used to synthesize l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole, a key intermediate for many C4 derivatives. Mono-acylation of 3-nitro-l,2-phenylenediamine with 2,6-difluorobenzoyl chloride yielded a single product that was subsequently cyclized with only acid and heat. Since cyclization of either N-1 or N-2 acylated product would lead to the desired 2-aryl-benzimidazole, detailed regiochemical analysis was not carried out on N-(2,6-difluorobenzoyl)-2-amino-3-nitroanilide. A side reaction found during the preparation of l-(2,6-difluorobenzyl)-2- (2,6-difluorophenyl)-4-nitrobenzimidazole (Example 83) and in other electron withdrawing benzimidazoles, was sodium methoxide displacement resulting from methanol used to quench the excess NaH following alkylation of l-(2,6- - difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole with 2,6-difluorobenzyl bromide. In order to prevent aromatic nucleophilic displacement, quenching of excess NaH was done subsequently with t-butanol. The 4-nitro group in l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitro- benzimidazole was reduced subsequently with tin (II) chloride in acetic acid to yield the 4-amino compound (Figure 9). Treatment of the 4-amino derivative with either HBr or HCl under Sandmeyer conditions yielded the 4-bromo and 4-chloro products, respectively. Alternatively, reaction of the 4-amino compound with formaldehyde and sodium borohydride provided the 4-dimethylamino derivative. Mono-acetylation of the 4-aminobenzimidazole derivative with acetic anhydride gave the 4-acetamido product. Subsequent alkylation of the 4-acetamido with methyl iodide yielded a mixture of N-methyl-N-acetamido and starting material. Deacylation of the N-methyl-N-acetamido under acidic conditions yielded the 4-methylamino compound. Other compounds prepared for this series were made via synthetic modification of other intermediates. Bromination of l-(2,6-difluorobenzoyl)-2- nitroanilide yielded l-(2,6-difluorobenzoyl)-4-bromo-2-nitroanilide. This derivative was then benzylated and reductively cyclized with standard conditions to yield l-(2,6-difluorobenzyl)-2- (2,6-difluorophenyl)-5-bromo-benzimidazole. Mono-nitration of 2-(2,6- difluorophenyl)benzimidazole with nitric acid at room temperature yielded the 5-nitro-benzimidazole derivative as the only product. Alkylation with 2,6-difluorobenzyl bromide occurred regiospecifically to yield the 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-5-nitro- benzimidazole. Figure 9 provides a schematic approach for the preparation of l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole substituted with chloro, bromo, nitro, amino, acetylamino, dimethylamino groups at the C-4 position of the benzimidazole ring. In this Figure, "a" comprises 2,6-difluorobenzoyl chloride, pyridine: THF (1:1); "b" comprises AcOH reflux; "c" comprises 2,6-F 2 -BnBr, NaH.THF; "d" comprises SnCl 2 , AcOH, HCl; "e" comprises Ac 2 O, THF; "f ' comprises H 2 CO, NaBH 4 , H 2 SO 4 ; and "g" comprises NaNO 2 , HBr or HCl. As shown in this Figure, reduction of the 4-nitro group of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)- 4-nitrobenzimidazole (Example 83) was accomplished with tin (II) chloride, which gives 4-amino- 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole 3300 (Example 85). Compound 3300 was used to prepare 4-bromo-l-(2,6-difluorobenzyl)- 2-(2,6-difluorophenyl)benzimidazole (Example 86) and 4-chloro- 1 -(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (Example 87) via the Sandmeyer reactions (i.e., methods known in the art). Monoacylation of compound 3300 with acetic anhydride gave l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- acetamidobenzimidazole (Example 88), while treatment of 3300 with formaldehyde and sodium borohydride yielded the dimethylamino compound l-(2,6-difluorobenzyl)- 2-(2,6-difluorophenyl)-4-N,N-dimethylaminobenzimidazole (Example 89). Furthermore, as depicted in Figure 14, the 4-methyl ester (4005) was a key intermediate for a number of 4-substituted benzimidazole derivatives. In this Figure, "a" comprises difluorobenzoyl chloride, pyridine/THF; "b" comprises hydrazine, pyridine; "c" comprises iron powder; "d" comprises 2,6-difluoro-a-bromo-toluene; "e" comprises barium hydroxide/ AcOH; and "f ' comprises 1.0 M solution of xylene.Treatment of the 4-methyl ester derivative with dimethylaluminium amine resulted in the 4-nitrile derivative . The 4-nitrile was used subsequently to prepare the 4-hydroxyamidino and 4-amido derivatives by hydrolysis with hydroxylamine and hydrogen peroxide, respectively. Bis methylation of the 4-amido derivative with sodium hydride and methyl iodide yielded the desired 4-(Ν,Ν-dimethyl)amido derivative. Alternatively, reaction of the 4-methyl ester derivative with barium hydroxide or methyl lithium yielded the 4-carboxylate and 4-isopropanol derivatives, respectively. Hydrolysis of the 4-isopropanol derivative with strong acid lead to the 4-isopropenyl in low yields. Reduction of the 4-methyl ester to yield the 4-hydroxymethy derivative, however, resulted in low yields under a number of reducing conditions (lithium aluminum hydride, NaBH 4 , borane). Consequently, the reduction step was carried out earlier in the synthesis with the precursor, methyl- N-(2,6-difluorobenzoyl)-6-nitro-2-anilide-carboxylate. Protection of the 2- hydroxymethyl-6-nitroanilide with acetic anhydride and subsequent modification as done with the 4-methyl ester led to the desire 4-hydroxy methyl benzimidazole derivative. This product was subsequently converted to the 4-formyl, 4-chloromethyl, 4-azidomethyl, 4-aminomethyl, 4-acetamidomethyl and 4-(N-methyl)acetamido derivatives. Figure 15 provides a schematic approach for the synthesis of l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxybenzimidazole and 2-(2,6- difluorophenyl)-4-methoxylbenzimidazoles. In this Figure, "a" comprises K 2 CO 3 , methyl iodide, acetone; "b" comprises difluorobenzoyl chloride, pyridine/THF; "c" comprises hydrazine, pyridine; "d" comprises iron powder; "e" comprises 2,6-difluoro- a-bromo-toluene; "f comprises benzyl bromide; "g" comprises (l-bromoethyl)benzene; and "h" comprises 3,3-dimethylallyl bromide. Figure 16 provides a schematic approach for the synthesis of 2-(2,6- difluorophenyl)-4-ethylbenzimidazoles and 2-(2,6-difluorophenyl)-4- methylbenzimidazoles. In this Figure, "a" comprises difluorobenzoyl chloride; "b" comprises iron powder; "c" comprises 2,6-difluoro-a-bromo-toluene; and "d" comprises 3,3-dimethylallyl bromide. Figure 17 provides a schematic approach for the synthesis of l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-substituted)benzimidazole (e.g., benzimidazoles substituted with ΝHAc, MeΝAc, and MeΝH). In this Figure, "a" comprises SnCl 2 x2H 2 O; "b" comprises methyl iodide, THF, ΝaH; and "c" comprises HCl. Figure 18 provides a schematic approach for the synthesis of other substituted benzimidazole compounds. In this Figure, "a" comprises 3,3-dimethylallyl bromide; "b" comprises iron powder; and "c" comprises concentrated H 2 SO 4 . In addition, other substituted benzimidazoles were prepared. For example, Figure 19 provides a schematic synthesis of l-(2,6-difluorobenzyl)-2-(cyclopropyl)-4- methoxylbenzimidazole (Example 49). In this Figure, "a" comprises cyclopropanecarbonyl chloride; "b" comprises iron powder; "c" comprises 3,3- dimethylallyl bromide; and "d" comprises 2,6-difluoro-a-bromo-toluene. The series of compounds synthesized as described above, were analyzed in order to determine whether the position and nature of the substituents on the benzyl ring at Ν-l, were analogous to those in the TBZ series. Treatment of 2-(2,6- difluorophenyl)benzimidazole (18) or 2-(2,6-difluorophenyl)-4-methylbenzimidazole (19) with benzyl bromide or its analogs (e.g., 2,6-dichloro-α-bromo-toluene, 2,3,4,5,6- pentafluoro-α-bromo-toluene), gave compounds with hydrogen, chlorine, or multiple fluorines on the Nl benzyl ring, which were compared for their ability to inhibit HIV- 1 RT. Since a number of NNRTI contain sulfonyl links (e.g., 2-nitrophenyl phenyl sulfone, and 5-chloro-3-(phenylsufonyl)-indole-2-carboxamide), it was also determined whether a sulfonyl group could replace the methylene linker in l-(2,6-difiuorobenzyl)- 2-(2,6-difluorobenzyl)-4-methylbenzimidazole (33). By reacting compounds 18 or 19 with benzenesulfonyl chloride, l-benzenesulfonyl-2-(2,6-difluorophenyl)benzimidazole (Example 37) and l-benzenesulfonyl-2-(2,6-difluorophenyl)4-methylbenzimidazole (Example 38) were obtained in good yields. Similarly, treatment of compound 18 with 2,6-difluorobenzoyl chloride provided the N-2,6-difluorobenzoate derivative 1- (2,6-difluorobenzoyl)-2-(2,6-difluorophenyl)benzimidazole (Example 39), allowing the testing of carbonyl as a linker. In addition, introduction of nitrogen into the Nl- benzyl ring was investigated. The 3-pyridyl derivative was synthesized via alkylation with α-bromo-methylpyridine, to yield l-(3-pyridylmethyl)-2-(2,6-difluorophenyl)-4- methylbenzimidazole (Example 35). In this series, the optimal anti-HIV activity was achieved when the phenyl ring was substituted at the 2 and 6 position with fluorine. It is not intended that the substituted benzimidazoles be limited to those compounds described above. It is contemplated that l-(2,6-difluorobenzyl)-2-(2,6- difluorobenzyl)benzimidazoles having 4-methylenethiocyanate (CH 2 NCS) and 4- methyleneacetylene (CH 2 CCH) will be used in the compositions and methods of the present invention. The chemical structures of some substituted benzimidazoles of the present invention are shown at Table 13. TABLE 13 C. Pharmaceutical Compositions The present invention contemplates using pharmaceutical compositions comprising the substituted benzimidazoles described above. The pharmaceutical compositions are composed of one or more pharmaceutically acceptable diluents, excipients or carriers, and are well-known to those skilled in the art (See e.g., U.S. Patent No. 5,356,917, supra). It is not intended that the present invention be limited by the particular nature of the therapeutic preparation. For example, such compositions can be provided together with physiologically tolerable liquid (e.g., saline), gel or solid carriers or vehicles, diluents, adjuvants and excipients, such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. These compositions typically contain l%-95% of active ingredient, preferably at least 2%-70%. In addition, the compositions may contain minor amounts of auxiliary substances such as wetting or emulsifying agents, stabilizing or pH buffering agents or preservatives if desired. The therapeutic compositions contemplated by the present invention are physiologically tolerable and compatible. These therapeutic preparations can be administered to humans in a manner similar to other therapeutic agents. In general, the dosage required for therapeutic efficacy will vary according to the type of use and mode of administration, as well as the particularized requirements of individual hosts (e.g., age, gender, weight, etc.). The preferred mode of administration of these preparations depends on several factors, including the stability of the preparation, the bioavailability of the compound following different routes of administration, and the frequency of dosing. III. Biological Activity of Substituted Benzimidazoles A. RT Inhibition By 1- And 2-Substituted Benzimidazoles The testing of the 2-aryl-l-(2,6-diflurobenzyl)-benzimidazoles for their HIV-1 RT inhibition activity indicated that a number of aromatic systems were tolerated at the C2 position. The structure, physical and biological data for 1 and 2-substituted benzimidazoles are shown in Tables 1-3. In these Tables, the IC 50 (μM) column indicates the quantity of drug required to reduce WT RT enzyme activity by 50% (IC 50 ). TABLE 1 TABLE 2 TABLE 3 As shown in Table 2, the ability to inhibit wild type RT (WTRT) by the hydrogen (50), methyl (35), hydroxymethyl (49), isopropyl (34), formyl (51), phenyl (39), and bis-2,6-difluorobenzyl (32) compounds was measured as the percent inhibition of nucleotide incoφoration into an rC-dG template primer at 10 μmolar drug 5 concentration. Except for compound 39 where the C2 was phenyl, all the substituents at the 2 position failed to appreciably inhibit HIV-1 RT. Substitution of the phenyl with fluorine at the 2 and 6 positions (i.e., compound 33) gave the best inhibition with IC 50 =200 nM. The results for TIBO and TBZ in this Table are in contrast with those reported by Pauwels et al. (Pauwels et al, "New Tetrahydroimidazo[4,5,l-jk][l,4]- [0 Benzodiazepin-2(lH)-One and Thione Derivatives are Potent Inhibitors of Human Immunodeficiency Virus type 1 Replication and are Synergistic with 2 ',3'- Dideoxynucleoside Analogs," Antimicrob. Agents Chemother., 38:2863-2870 [1994]), who reported an IC 50 for rC:dG of 0.06 μM for TIBO, and Buckheit et al. (Buckheit et al. , "Thiazolobenzimidazole: Biological and Biochemical Anti-rerroviral Activity of a [5 New Nonnucleoside Reverse Transcriptase Inhibitor," Antiviral Res., 21:247-265 [1993]), who reported an IC 50 for rC:dG of 0.5 μM for ribosomal RNA. Although knowledge of the precise mechanism is not necessary to successfully practice the invention, it is contemplated that because the fluorines do not dramatically alter the size of the 2-phenyl ring, the four- fold increase in inhibitory activity observed -0 for compound 26 in comparison with compound 39 (See, Table 1) probably represents some alteration in the aromatic interactions between the 2,6-difluorophenyl ring and the aromatic side chain residues surrounding the NNRTI binding pocket. Less conservative changes, such as the addition of an ortho-methyl to the 2-phenyl ring, led to a two-fold decrease in RT inhibition (See e.g., 36, Table 1). This decrease in RT 25 inhibition led to the examination of other planar aromatic systems. For example, changing the 2-phenyl to the 4-pyridyl resulted in almost no change in the IC 50 value. (See e.g., compounds 39 and 41, Table 1). These results indicate that some heteroaromatic systems can be introduced at C2 without penalty. However, the 3- pyridyl compound 40 (See, Table 1) showed considerably less activity. While it is again not necessary to understand precise mechanisms in order to use the various embodiments of present invention, it is possible that the lone pair of electrons on the 4-pyridyl system can be accommodated, in contrast to the use of the 3-pyridyl compound, in which unfavorable interactions result. Larger aromatic moieties at C2 (e g-, naphthyl), regardless of orientation, were found to result in complete loss of inhibitory activity, indicating that there was a limit to the size of the inhibitor NNRTI binding pocket can accommodate. These observations led to the development of compounds with IC 50 s in the micromolar range (e.g., as shown in Tables 1 and 2). Furthermore, benzenesulfonyl and benzoate derivatives (45, 46, and 47) did not show appreciable RT inhibition activity. Substitution on the phenyl ring by a pyridine ring (43) similarly led to lower inhibition. Removal of the fluorine at the 2 and 6 position (28 or 29), or its replacement with chlorine (30) also resulted in a decrease in inhibition. Likewise, addition of more fluorines on the benzyl ring (42) yielded a compound showing greatly decreased inhibition activity. (See, Table 2) B. Testing Of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyI)Benzimidazoles Against Reverse Transcriptase The structure, physical and enzyme inhibition data for l-(2,6-difluorobenzyl)-2- (2,6-difluorophenyl)-benzimidazoles are shown in Tables 5-7 and 11. Testing of the 4,5- and 4,6-di-substituted and mono-substituted benzimidazoles was determined by measuring the relative nucleotide incoφoration using an rC-dG template primer at 1 μmol drug concentration (10-fold lower than used above), to the amount of incoφoration with no inhibitor present utilizing WT HIV-1 RT. TABLE 5 %lnhlbrt No. X fbrrπuta p,"C anal. (1μM) « 2 H C^H^N* 138-140 C.H.N SO 41. CH, C^H^N, 147-149 C.H.N 22 42 e-CH, 172-173 C.H.N .42 43 7-CH, C^H^N, 177-178 CRN 1 45 4 > &«H 1 CaH 1β F 4 N a 176-177 C.H.N 26 8 4.611 1, CπH^Λ , 1SΪ-154 C.H.N 37 % inhibition is average of two experiments done in triplicates TABLE 6 48 4-NO, CjoHnFiNiO, 16&-170 C.H.N 51 49 S-NO, C^F^O, 168-169 C.H.N 30 % inhibition is average of two experiments done in triplicates TABLE 7 TABLE 11 ιc„ EC-. o X ftxπiula p, *C pnal. * (μM) (μM) 1 CH, 182-1 -6 CΛN 0.20 0.44 2 H C i oHoF.N, 138-140 C.H-N 0.11 1.70 4 OCH, C,,H,ΛN 2 0 154-155 CΛN 0.0073 0 06 7 NAeCH, C o H 1 ^H I 0 155-156 CH 0J2 0.02 7 CH.CH, C.ΛJP.N, 165-166 CΛN 17.5 0.82 0 CO^te CUHHFΛO, 184-186 CΛN ND NRVC SI CH,OAc CoHJF^A 126-127 CΛN ND 0.059 52 OH <VA#ftP 257-259 CΛN ND 0.65 S3 NH, C-gHuFtNj 168-170 CΛN 0-28 0.46 54 Br ςΛ,BffΛ 147-148 C 1.61 0.37 55 α C*H«|CIF_N, 163-164 CΛN 2.63 0.44 S6 NHA£ CnSuF^O 194-193 C 54.7 1.48 58 NHCH, 194 9S CΛN 4.94 1.70 59 NCCH,), tyvΛ 155-156 C N 40.0 2J7 (a CN CnHuF. j 156-157 CΛN ND 0.43 61 CNHfNϊVJH) CIWW 213-216 CΛN ND 0.19 62 CONH, C„H β F«N,0 . 260-261 CΛN ND 4.90 S3 CON(CH,y. CoHαFΛJ.O 213-214 CΛN ND NRVC 64 COjH 179-1 M CΛN ND NRVC CS opro 149-150 CΛN ND 6J4 £6 σpπoyl CaH^N, (56-158 C N ND 1.44 67 CHjOH C,,H,ΛN 1 0 157-158 CΛN ND 0.023 68 cao C I |H Q F < K J O 151-153 CΛN ND 0.12 69 CH^-1 C.Λ.CIFJ*, 143-1*4 CΛN ND 0.18 70 CH,N, C„H,JΛ 150-152 C N ND 0.045 71 CHjNH, CH.ΛN, 257-260 C N ND 0.037 72 CH^NHAc CΛΛNjO 178-179 C.H.N ND NRVC 73 CH,NCH,Λ-J C u H,^N 1 0 171-172 CΛ ND 0J8 74 CHjOCH, C B H M P,N 1 0 CΛN ND ND ocviitpiπe 0.035 NRVC, no reducύoα in viπl CPE CEMSS/NL4-3 As seen in Table 5, most of the methyl derivatives inhibited RT activity in this enzyme based assay. In these tests, the enzyme assay was conducted with WT RT. Although it is not necessary to understand precise mechanisms in order to use the present invention, a change in percent (%) inhibition was noted as the methyl group is moved from the 4 to 7 positions. In the case of the 5- and 7-methyl derivatives, the % inhibition is dramatically decreased from the 4- and 6-methyl derivatives. The observed decrease determined for the 7-methyl might be due to the adoption of a different conformation from the 4-methyl owing to steric interactions between the 7- methyl and the N-1 benzyl group. Since the 5-methyl derivative can assume similar conformations as the 4-methyl and 6-methyl derivatives, the decrease in % inhibition determined for the 5-methyl compound is presumed to be due to differences in inductive effects. In the case of 4,5-dimethyl groups, the significant inhibition of 33 possessing a single methyl at C-4 was dramatically decreased by the presence of the C- 5 methyl. It was also observed that substitution at C-5 led to consistently less inhibition no matter what substituent was examined. A comparison of the inhibitory activities of the 4-, 5-, and 6-chloro compounds in Table 6 shows that the 5-chloro compound has approximately two-fold less activity than either the 4-chloro or 6-chloro benzimidazoles. A similar decrease is found when comparing the 4-bromo with the 5- bromo benzimidazoles, as well as when comparing the 4-nitro with the 5-nitro benzimidazoles. These data led to further examination of the substitution at the C-4 position. As seen in Table 7, most l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)- benzimidazoles examined were able to inhibit RT in an assay utilizing WT RT enzyme. Three methods for the measurement of the inhibition of HIV-1 WT RT were used: i) the relative inhibition of nucleotide incoφoration into a rC-dG template primer at 1 μmol drug concentration compared with the amount of incoφoration with no inhibitor present; ii) the drug concentration required to inhibit 50% of nucleotide incoφoration into a rC-dG template primer by HIV-1 WT RT (IC 50 ); and iii) the drug concentration required to reduce cell killing or virus production of HIV-1 WT RT by 50% (EC 50 ). The most potent inhibitor of HIV-1 WT RT by all three measurements of RT inhibition was the 4-methoxyl (IC 50 = 0.0073 μM and EC 50 = 0.0046 μM). The IC 50 for the 4-methoxyl was found to be 100-fold more potent than the IC 50 for TZB and TIBO and is comparable to those determined for 8-Cl TIBO and nevirapine. Although the 4-methyl, 4-amino and 4-N-methylacetamido compounds all have similar IC 50 values (IC 50 = 0.20 μM, 0.28 μM, and 0.32 μM, respectively), the 4-Ν-methylacetamido compound is 20-fold more potent than the 4-methyl or 4-amino compounds as determined by the cytopathic cell killing assay (EC 50 = 0.02 μM). As illustrated in Tables 5 and 6, the level of inhibitory activity dramatically differs as the regiochemistry of substituents changes from the 4 to 7 position. Substitution at the 4 position enhanced the inhibitory activity relative to the other sites of substitution, regardless of the type of substituent [CH 3 (1 vs 41-43), Br (54 vs 38), Cl (55 vs 39-40), NO 2 (48 vs 49)]. A combination of a C4 substituent (CH 3 ) with an additional substituent at the 5 or 6 positions (1 vs 45 and 1 vs 46) led to lowered inhibitory activity suggesting a preference for C4 mono-substitution. Substitution at the 7 position with a CH 3 (43), however, was completely detrimental to potency. Molecular modeling of the 7-CH 3 (43) vs the 4-CH 3 (1) suggests an alternative and possibly non-productive conformation for the 7-CH 3 (43) NNRTI as a consequence of steric interactions between the C7 substituent and the N/ -2,6-difluorobenzyl group. In light of these results, analogs in Table 11 were synthesized and tested to determine whether the potency enhancement of a C4 group was general for any substituent or related to some chemical or structural property of the substituent. Evaluation of these compounds for the inhibition of HIV-1 was determined as the fifty percent cell culture inhibitory concentration (CIC J0 ) in CEMSS cell culture with WT virus (ΝL4-3). While a variety of C4 substituents [(NH 2 (53), Br (54), Cl (55), CN (60)] exhibited a modest potency-enhancing effect relative to the unsubstituted (2) or methyl (1) parent compounds, the methoxyl (44) substituent gave the best inhibition resulting in a dramatic 25-fold increase in the inhibitory activity against WT RT (IC 50 = 7.3 nM) over our lead compound (1). In contrast, the isosteric ethyl (47) and mono-methyl amino (58) were significantly poorer inhibitors. Analogs 50, 57-58 and 61-64 were synthesized and tested to determine whether an oxygen in any other type of substituent would exhibit potency-enhancing effects. Placing an N-methyl acetamide (57) at the C4 position significantly enhanced inhibitory potency while other carbonyl groups [CO 2 Me (50), CNHNHOH (61), CONH 2 (62), CON(CH 3 ) 2 (63), and CO 2 H (64)] were clearly detrimental to potency. Synthesis of compounds 65-73 and determination of each analog's CIC 50 value focused attention on whether hydrophobic or a methylene insert at the C4 position would show similar inhibitory effects as the des-methylene analogs (53-57). These results suggested In addition to obtaining CIC 50 values against WT virus, the most active compounds were evaluated against MT-4 cells infected with HIV-1 variants containing amino acid substitutions in RT (Table 4). Comparison of the 4-methyl (l) 1 with the methoxyl (44), ethyl (47), nitro (48), amino (53), bromo (54), chloro (55), acetamido (56), and dimethylamino (59) analogs revealed that the potent 4-methoxyl compound (44) retained the best activity against the different RT variants examined in the cytopathic cell killing assay. None of the different amino acid substitutions in RT dramatically decreased the inhibitory activity, except for the K100E and VI 081 variants. As is common with most NNRTI, the 4-methoxyl compound (44) failed to show any activity against the K103N mutation. As indicated above, maximum enzyme inhibition is obtained with compounds containing a C4 substituent. Although it is not necessary to understand the mechanism in order to practice the present invention, and it is not intended that the present invention be so limited, it is possible that the small change in IC 50 's reflects the ability of the NNRTI binding pocket to adjust in a way that maximizes the interaction with compounds having a C4 substituent. Furthermore, the l-(2,6 " -difluorobenzyl)-2-(2,6-difluorophenyl) substituted benzimidazoles of the present invention were compared against the clinically useful drugs (e.g., nevirapine) in Table 11. While nevirapine is active against many-HIV-1- - variant isolates, the 4-methoxyl compound (44) retains activity comparable with nevirapine while maintaining activity against the clinically important Y181C mutation. Although it is not necessary to understand the mechanism in order to practice the present invention, and it i not intended that the present invention be so limited, it is possible that the ability to inhibit the different HIV-1 virus isolates tested reflects the flexible nature of the l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole system to better compensate for the different structural changes arising as a consequence of amino acid changes in RT binding pocket. C. Cytopathic Cell Killing Assay In depth biological evaluation of the RT inhibitory properties of the most active 4-substituted 1 -(2,6-difluorobenzyl)-2-(2.6-difluorophenyl)benzimidazole compounds was determined with cultured MT-4 cells infected with WT and HIV-1 variants containing amino acid substitutions in RT, as described in Example 91 (See, Yang et al, "Characteristics of a Group of Nonnucleoside Reverse Transcriptase Inhibitors with Structural Diversity and Potent Anti-Human Immunodeficiency Virus Activity," Leukemia 9:S75-S85 [1995]). The cross-resistance profiles of the different compounds are presented in Tables 4 and 8-10. In these Tables, antiviral data are reported as the quantity of drug in μM required to reduce cell killing or virus production by 50% (EC 50 ). The various HIV isolates tested in the Figures are those corresponding to wild-type virus (NL4-3) and the other strains listed by their RT mutations. The three 4xAZT isolates included in the Figures represent AZT drug-resistant variants. For example, the 4xAZT L100I isolate has five mutations: four mutations confer increased resistance to AZT, and the other mutation is located within the NNRTI binding pocket. TZB and nevir. (nevirapine) are two well-known NNRTIs, included in this experiment for comparison puφoses. As shown in Table 4, the 4-methyl derivative 33 was consistently 3- to 4-fold better in the inhibition of the various viral isolates examined than the des-methyl analog 26. The increased inhibition observed for 33 suggested that substituents on the benzimidazole ring can significantly improve binding of this class of compounds to the NNRTI binding pocket residues. TABLE 4 Isolate 33 26 TZB TIBO NL4-3 (WT) 0.5 1.85 17 03 L74V 0.1 0.46 07 02 A98G 1.4 4.75 177 11 L1001 0.3 1.36 12.2 174 101E 16.7 >20 >20 174 103N 8.1 12.9 >20 174 VI 06 A 20 >20 >20 12.5 V108I 2.8 10.4 9.7 2.4 V179D 0.5 2.3 3.1 6.2 Y181C 6 15.2 16.3 4.2 Y188C 2.3 11.7 >20 >17.4 4xAZT 0.1 0.27 1.5 0.3 4xAZT/L1001 0.2 0.84 1.7 >17.4 4xAZT/Y181C 3.5 >20 14.5 2.0 C5 © o TABLE 10. Cross Resistance Profile of 1,2-substituted Benzimidazoles Based on Cytopathic Cell H Killing Assay (values in μM). U α. isolate CHj OCH, Cl Br NHAc N(CH3), NH, NH, NO, Et ΉBO CH 2 -N 3 NL4-3 0.5 0.165 0.5 0.5 1.97 2.8Θ 0.68 0.4 3.13 0.9 0.3 0.045 (WT) L100! 0.3 0.16 0.3 0.5 3.25 31. β 2.46 1.2 0.83 2.48 17.4 0.06 K101E 16.7 2.82 >20 >20 >50 >20 >50 >50 17.4 0.60 K103N 8.1 >50 10.2 >20 >100 >100 >50 3.1 >50 >50 17.4 1.48 V108I 2.B 2.82 3.2 4.2 >50 3.3 >50 >50 2.4 0.026 Y181C 6 0.26 Θ 4 10.7 >100 >100 3.99 9.2 >50 7.18 4.2 0.82 C5 184I 0.16 0.65 3.69 0.96 C5 Y18ΘH 0.26 >50 >50 13.2 O O Y1Θ8C 2.3 3.4 3.7 >17.4 0.22 Table 8 and 10 show the cross-resistance profile with NNRTI-resistant HIV isolates from the cytopathic cell killing assay for a number of 4-substituted compounds (the methyl, methoxyl, ethyl, chloro, bromo, amino, N-acetamido, N-methylacetamido, N-methylamino and N-dimethylamino derivatives, nitro and methylazido), as well as, TZB and nevirapine. The methoxyl, N-methyl acetamido, ethyl, chloro, amino, N-acetamido, and N-methyl amino derivatives were all found to inhibit HIV-1 better than TZB in the cytopathic cell killing assay. In the case of the methoxyl and Ν-methylacetamido derivative the cross-resistance profile was equal or better against the various variants than nevirapine, the only nonnucleoside inhibitor currently approved by the FDA for the treatment of AIDS. The only variant that showed no inhibition for the different compounds tested was the K103Ν isolate which also renders TZB and nevirapine ineffective. Table 9 shows the effect of substitution of the N-1 position on the ability to inhibit some NNRTI-resistant HIV isolates. Substitution of the 2,6-difluorobenzyl group by the prenyl side chain found in TIBO was seen to decrease the inhibitory activity for the V108I and Y181C variants. Figures 10-12 indicate the therapeutic index for three embodiments of the present invention. The therapeutic index is the difference between efficacy of the drug and cellular toxicity. In the case of 4-methyl derivative (33), the therapeutic index at 50% (TC JO ) was greater than one log in concentration. In summary, the methoxyl and N-methylacetamido compounds were found to possess the best overall biological profile of this series. These two embodiments were determined to inhibit many of the known clinically relevant non-nucleoside amino acid variants of HIV-1. It is contemplated that other substitutions or different attachment sites may result in further optimization of the compounds of the present invention. The present invention provides significant advantages over drugs such as TZB and nevirapine, as the compositions provided herein retain activity against HIV mutants that have lost sensitivity to these drugs (e.g., the V106A, Y181C, and Y188C isolates). IV. Geometry Of TBZ And l-(2,6-Difluorobenzyl)-2-PhenylbenzimidazoIe Semi-empirical quantum mechanical minimization at the AMI level was used to compare the geometry of TBZ and l-(2,6-difluorobenzyl)-2-phenylbenzimidazole (39). As shown in Figure 5, considerable similarity was observed between the energy minimized "butterfly-like" shapes of TBZ and 39. For TBZ, the "butterfly-like" shape was previously determined by x-ray and NMR methods. (See, A. Chimirri et al, "Thiazobenzimidazoles as Non-Nucleoside HIV-1 RT Inhibitors," Abst. II Congresso Congiunto Italiano-Spagnolo di Chimica farmaceutica," Ferrara, Italy, August 30- September 3, 1995, ML20). For 39 in contrast to TBZ, more than one "butterfly-like" conformation can be adopted by rotation of the molecule's benzyl side chain. Although the C2 phenyl of the AMI energy-minimized molecule 39 does not overlap the thiazolo ring of TBZ, at least two higher energy rotational isomers result in almost complete overlap. Although x-ray analysis is required to predict the correct "butterflylike" orientation of this compound with RT and the NNRTI binding pocket, since some of the predominant contributions to the binding of NNRTI to RT involve π stacking and hydrophobic interactions. The extra aromatic ring present in 39 might significantly influence these interactions. This ability of HIV-1 RT to accommodate extra phenyl rings resulted in investigation of additional aromatic moieties. V. Purity Of The Substituted Benzimidazoles The active benzimidazole compounds of the present invention were produced at a very high purity level. As shown in Table 12, the carbon, hydrogen and nitrogen analyses (CHN values) of these compounds were very close to the predicted values. CHN analysis (i.e., elemental analysis) as known to those in the art, determines the amount of the elements in accurately weighed samples of the compound, and matches them against the amounts predicted from the elemental formulae. Correspondence of experimental with the predicted values to within 0.3% indicates high levels of purity. Thus, it is clear that the substituted benzimidazoles of the present invention may be produced at very high purity levels. TABLE 12 Ro formula calculated found H N H N 26 C, 0 H U Γ < NJ 6742 339 786 6728 31-5 76 28 C M H H F,N j il/8H,0 7447 445 868 7443 445 863 29 C„H l4 F,N j xl/4H 2 0 74.43 4.91 827 7481 490 785 30 CUHKCIJF-NJ IΛJHJO 61.86 3.58 687 61.64 365 680 32 CJJH^N-O xl/2H 3 0 64.55 4.19 684 6463 ll 672 33 68.11 3.81 756 6817 390 7 4 34 CuH.^N- 71.98 6.04 933 72.06 605 925 3S C. j H.^N, 6976 468 1085 6956 477 1079 36 C„H F,N- 7544 482 838 7516 489 829 37 C U H„F 2 N, 78.11 4.72 729 78.00 475 719 38 78.11 4.72 729 7784 483 723 39 C»H,<Fϊ N xl«H,0 73.95 4.50 8.62 73.87 450 860 40 C N H l5 F j N 3 71.63 4.51 12.53 7174 455 1262 41 C„H I5 f 7 N 3 71.63 4.51 12.53 71.72 4.55 12.58 42 C„H I1 F,N, 59.44 2.61 6.60 59.35 2.6S 6.50 43 Cκ>H |j FϊN3*^H 2 0 69.76 4.68 12.20 69.59 4.38 12.29 4S CH.JFJ JSO, 61.62 3.27 756 61.68 3.34 760 46 CMHMFJNJSO, 62.49 3.67 7.29 62.50 3.71 724 47 C M H 10 F<N 7 0 64.87 2.72 7.56 64.88 277 746 48 C I6 H u F,N-0 66.66 4.89 972 66.74 4.94 971 49 C, 5 H,JFJNJ 4H 7 0 68.56 4.79 10.66 6852 460 107 SO C l6 H,,F,NιO xl/SH^O 66.29 4.31 966 6657 428 967 No formuli c-Joulucd found C H N C H N 3100 C 10 H π F,Nj 6469 3.53 1132 6463 35< II 20 3400 6392 3.66 1017 63.94 362 1010 3500 CιιH F < Nj 66.(6 4.29 1052 66.24 424 1047 3200 5463 2.64 6.37 5459 247 638 1800 C M >H l ,BrFJ>! 1 *3/4H 1 0 5353 2.81 624 53.23 249 610 3300 6147 2.84 717 6159 286 723 2000 C ϊ0 H u αF<Nι 61.47 2.84 717 61.37 290 7 IS 2100 61.47 2.84 717 61.31 292 704 2200 C„H,<F < Nι 68.11 3.81 7.56 68.22 390 760 2300 C 2I H U F < N, 6811 3.81 756 679-s 386 750 2400 Cι,H„F,N, 68 II 381 756 68.02 ) 89 749 2800 C n H,«F<N, 6875 4.20 7.29 68.68 < 15 728 2900 C M H,,F<N,Oj 59.86 2.76 10.47 59.96 278 1055 3000 C M H,,F<NJOJ 59.86 2.76 10.47 60.24 289 10.38 EXPERIMENTAL The following examples are provided in order to demonstrate and further illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof. Although embodiments have been described with some particularity, many modifications and variations of the preferred embodiment are possible without deviating from the invention. In the experimental disclosure which follows, the following abbreviations apply: PBS (phosphate buffered saline); MTT (3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyl-tetrazolium bromide); EDTA (ethylenedinitrotetraacetic acid disodium salt); HCl (hydrogen chloride); Tris (triphenylphosphine); NaCl (sodium chloride); SDS (sodium dodecyl sulfate); Na^O j (sodium thiosulfate); TAE (Tris-Acetate-EDTA); MeOH/CH 2 Cl 2 (methanol/dichloromethane); H 2 SO 4 (sulfuric acid); FeSO 4 (ferrous sulfate); CuSO 4 (cuprous sulfate); MgSO 4 (magnesium sulfate); NaOAc (sodium acetate); DMF (dimethyl formamide); THF (tetrahydrofuran); NaHCO 3 (sodium bicarbonate); HBr (hydrogen bromide); KBr (potassium bromide); DMSO (dimethyl sulfoxide); OMSO-d 6 (fully deuterated dimethyl sulfoxide); CHC1 3 (chloroform); CDC1 3 (deuterated chloroform); NH 3 (ammonia); Ph (phenyl; C 6 H 5 ) Ac (ethanoate group); Et 2 O (diethyl ether); EtOAc (ethyl acetate); CPE (cytopathic effect); ppm (parts per million); [α] (specific rotation); μL (microliters); μg (micrograms); mL (milliliters); L (liters); mg (milligrams); g (grams); hr or h (hours); mM (millimolar); M% (mole percent); μM (micromolar); nM (nanomolar); N (normal); nm (nanometers); min (minutes); mm (millimeter); kg (kilograms); δ (chemical shift); J or J (coupling constant); s (singlet); d (doublet); t (triplet); q (quartet); m (multiplet); vs (very strong); s (strong); m (medium); w (weak); vw (very weak); v (variable); mp (melting point); c (optical path length); NMR (Nuclear Magnetic Resonance); IR (Infrared Spectroscopy); MHz (megahertz); Hz (hertz); cm "1 (wavenumbers); eq (equivalents); M (Molar); μM (micromolar); N (Normal); mol (moles); mmol (millimoles); μmol (micromoles); nmol (nanomoles); g (grams); mg (milligrams); μg (micrograms); ng (nanograms); 1 or L (liters); ml (milliliters); μl (microliters); cm (centimeters); mm (millimeters); μm (micrometers); nm (nanometers); °C (degrees Centigrade); Ci (Curies); mCi (milliCuries); mp (melting point); TBZ (l-(2,6- difluorophenyl)-lH,3H-thiazolo[3,4-a]benzimidazole; RT (reverse transcriptase); WT (wild type); AZT (3'-azido-3'-deoxythymidine); NNRT (non-nucleoside reverse transcriptase); NNRTI (non-nucleoside reverse transcriptase inhibitors); BSA (bovine serum albumin); Et (ethyl); CHAPS (3-[(3-cholamidopropyl)dimethylammonio]-l- propane-sulfonate); ddC (2',3'-dideoxycytidine); TIBO (4,5,6,7-tetrahydro-5- methylimidazo[4,5,l-jk][l,4]benzodiazepin-2(lH)-one; THF (tetrahydrofuran); t- (tert);BDMSCl (t-butyldimethylsilylchloride); TBDMS (t-butyldimethylsilyl); IC 50 (inhibitory concentration, 50%); EC 50 (median effective concentration); Varian (Varian Analytical Instruments, San Fernando, CA); Sigma (Sigma Chemical Co., St. Louis, MO); and (Aldrich Chemical Company, Inc., Milwaukee, WI). Unless otherwise indicated, all chemicals and reagents were obtained from commercially available sources, such as Sigma and Aldrich. Where analyses are indicated by symbols of the elements, the observed results were within 0.4% of the theoretical values. Melting points were determined on an electrothermal apparatus using the supplied, stem-corrected thermometer and read, per methods known in the art. NMR spectra were recorded on a Varian 200 or 300 MHz spectrometer, with Me 4 Si as the internal standard. Merck silica gel (70-230 mesh and 230-400 mesh) were used for gravity and flash chromatography, respectively. Primes used in NMR assignments are defined by R' and R" in the structures shown in Figure 3. Examples 1-4 show the preparation of 2-hydroxymethyl benzimidazole derivatives with reagent and other substitutions as indicated. EXAMPLE 1 Preparation Of 2-Hydroxymethylbenzimidazole In this Example, 2-hydroxymethylbenzimidazole (2) was prepared by stirring o- phenylenediamine (1) (1.3 g, 12 mmol), and 85% glycolic acid (2.74 g, 36 mmol, 300 M%), in 4 N HCl (40 mL), under reflux for 4 hours. After cooling to room temperature, the pH was adjusted to 7, with NaOH. The resulting crystals were filtered, washed with water and dried in vacuo (0.71 g, 4.8 mmol, 40% yield). Η- NMR (300 MHz, DMSO- 6 ): δ 7.48 (m, 2H, H 4>7 ), 7.13 (m, 2H, H 5 6 ), 5.67 (t, J=5.5 Hz, IH, OH), 4.68 (d, J=5.5 Hz, 2H, CH 2 ). EXAMPLE 2 Preparation Of 2-Hydroxymethyl-4-Methylbenzimidazole In this Example, 2-hydroxymethyl-4-methylbenzimidazole (4) was prepared by stirring 2,3-diaminotoluene (3) (2.65 g 21.7 mmol), and 85% glycolic acid (8.20 g, 107.8 mmol, 500 M%) in 4 N HCl (80 mL), under reflux for 2 hours. After cooling to room temperature, the pH was adjusted to 7 with NaOH. The resulting brown precipitate was filtered, washed with water, and dried in vacuo (2.97 g, 18.3 mmol, 84% yield). Η-NMR (200 MHz, DMSO- / 6 ): δ 7.28 (br d, IH, H 7 ), 6.98 (dd, J=8.0, 7.3 Hz, IH, H 6 ), 6.90 (m, IH, H 5 ), 4.67 (s, 2H, CH 2 ), 2.49 (s, 3H, CH 3 ). EXAMPLE 3 Preparation Of 2-(t-Butyldimethylsilyloxymethyl)-4-Methylbenzimidazole In this Example, 2-(t-Butyldimethylsilyloxymethyl)-4-Methylbenzimidazole (5) was prepared by dissolving 2-hydroxymethyl-4-methylbenzimidazole (4) (1.50 g, 9.24 mmol) in pyridine (30 mL). To this mixture, t-BDMSCl (2.35 g, 15.6 mmol, 170 M%) was added. After 4 hours at room temperature, the reaction was concentrated to dryness. The residue was redissolved in CH 2 C1 2 , and washed with NaHCO 3 (sat. aq.), and NaCl (sat. aq.). The combined washings were dried with Na^O^ filtered and concentrated. The crude product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 , and then re-crystallized from hexane (2.15 g, 7.78 mmol, 84% yield), yielding white powders of 2-(t-Butyldimethylsilyloxymethyl)-4-methyl- benzimidazole. Η-NMR (300 MHz, CD 3 OD): δ 7.36 (br d, J=ll.l Hz, IH, H 7 ), 7.11 (dd, J=l l.l, 10.4 Hz, IH, H 6 ), 7.01 (br d, J=10.4 Hz, IH, H 5 ), 4.94 (s, 2H, CH 2 O), 2.55 (s, 3H, CH 3 ), 0.95 (s, 9H, Sit-Bu), 0.14 (s, 6H, Si(CH 3 ) 2 ). EXAMPLE 4 Preparation Of 2-Isopropyl-4-Methylbenzimidazole In this Example, 2-isopropyl-4-methylbenzimidazole (6) was prepared by dissolving 2,3-diaminotoluene (3) (1.00 g, 8.19 mmol), and isobutyric acid (4.0 mL, 43.1 mmol, 525 M%), in 4 N HCl (90 mL). After 2 hours at reflux, the reaction was cooled in an ice bath, and the pH adjusted to 7 with NaOH. The resulting precipitate was filtered and washed with water. Η-NMR (200 MHz, DMSO-rf 6 ): δ 12.02 (br, IH, NH), 7.26 (br, IH, H 7 ), 6.99 (dd, J=7.4, 7.7 Hz, IH, H 6 ), 6.87 (ddt, J=-0.8, 1.1, 7.4 Hz, IH, H 5 ), 3.14 (sep, J=7.0 Hz, IH, iPr), 2.48 (s, 3H, GH 3 ), 1.34 (d, J=7.0 Hz, 6H, iPr). EXAMPLE 5 Preparation of N-(2,6-Difluorobenzoyl)-2-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-2-nitroanilide (10) was prepared using "Method A." First, 2-nitroaniline (8) (1.1 g, 8.0 mmol) was dissolved in THF (10 mL) and pyridine (2 mL). Then, 2,6-difluorobenzoyl chloride (1.11 mL, 8.8 mmol, 110 M%) dissolved in THF (15 mL) was added to the first mixture. After stirring for 5 hours at room temperature, the reaction was concentrated to dryness. The residue was redissolved in ethylacetate, and washed with ΝaHSO 4 (5% solution), NaHCO 3 (sat. aq.), and NaCl (sat. aq.). The organic layer was dried under Na j SO^ filtered, and concentrated under reduced pressure. The residue was recrystallized from ethylacetate hexane, to produce crystals that were slightly yellow (1.7 g, 6.1 mmol, 76%). M.p. 139 °C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 10.77 (s, IH, NH), 8.89 (dd, J=1.2, 8.5 Hz, IH, H 3 ), 8.26 (dd, J=1.5, 8.5 Hz, IH, H 6 ), 7.75 (ddd, J=1.2, 7.9, 8.5 Hz, IH, H 5 ), 7.50 (m, IH, H 4 ), 7.29 (ddd, J=1.5, 7.9, 8.5 Hz, IH, H 4 ), 7.07 (m, 2H, H 3 , 5 ,). EXAMPLE 6 Preparation Of N-(2,6-Difluorobenzoyl)-2-Methyl-6-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-2-methyl-6-nitroanilide (11) was prepared using Method A. 2-methyl-6-nitroaniline (9) (2.25 g, 14.8 mmol) and 2,6- difluorobenzoyl chloride (7) (1.9 mL, 15 mmol, 100 M%) were mixed and stirred overnight. The solution was purified by gravity chromatography, and eluted with CH 2 Cl 2 /hexane/diethylether (380-120-10), yielding slightly yellow crystals of N-(2,6- difluorobenzoyl)-2-methyl-6-nitroanilide (2.36 g, 8.1 mmol, 55% yield). Η-ΝMR (300 MHz, CD 2 C1 2 ): δ 8.55 (s, IH, ΝH), 7.87 (dd, J=8.2, 0.92 Hz, IH, H 5 ), 7.61 (d, J=7.4 Hz, IH, H 3 ), 7.48 (m, IH, H 4 ), 7.38 (dd, J=7.4, 8.2 Hz, IH, H 4 ), 7.05 (m, 2H, H 3 , 5 ,), 2.43 (s, 3H, CH 3 ). EXAMPLE 7 Preparation Of N-Isonicotinoyl-2-Methyl-6-Nitroanilide In this Example, N-isonicotinoyl-2-methyl-6-nitroanilide (12) was prepared using Method A. 2-methyl-6-nitroaniline (9) (1.52 g, 10.0 mmol), and isonicotinoyl chloride hydrochloride (2.95 g, 19.7 mmol, 200 M%) were stirred together for 4 hours. A second addition of isonicotinoyl chloride hydrochloride (1.05 g, 5.90 mmol, 60 M%) was added, and the solution was stirred overnight. The preparation was recrystallized from diethylether hexane (3:1), to produce 1.61 g (6.26 mmol, 53% yield) of white powder. Η-ΝMR (300 MHz, CD 2 C1 2 ): δ 9.06 (br, IH, ΝH), 8.82 (m, 2H, H 2 . 6 .) 7.93 (br d, 7.9 Hz, IH, H 6 ), 7.77 (m, 2H, H 3 . 5 .), 7.63 (br d, J=8.0 Hz, IH, H 3 ), 7.40 (dd, J=7.9, 8.0 Hz, IH, H 4 ). EXAMPLE 8 Preparation Of N-(2-Methylbenzoyl)-2-Νitroanilide In This Example, N-(2-methylbenzoyl)-2-nitroanilide (13) was prepared by Method A, by mixing 2-nitroaniline (8) (1.28 g, 9.3 mmol) and o-toluoyl chloride (1.52 mL, 11.6 mmol, 125 M%). Recrystallization of the crude product from ether/hexane (1:1) produced yellow crystals of N-(2-methylbenzoyl)-2-nitroanilide (2.2 g, 8.6 mmol, 92% yield). Η-ΝMR (300 MHz, CD 2 C1 2 ): δ 10.75 (s, IH, ΝH), 8.98 (d, J=8.5 Hz, IH, H 3 ), 8.27 (d, J=8.5 Hz, IH, H 6 ), 7.72 (dd, J=8.5, 7.4 Hz, IH, H 5 ), 7.61 (d, J=8.4 Hz, IH, H 6 ), 7.41 (dd, J=8.5, 7.4 Hz, IH, H 4 ), 7.32 (t, J=7.4 Hz, IH, H 4 ), 7.31 (d, J=7.4 Hz, IH, H 3 ), 7.23 (dd, J=8.4, 7.4 Hz, IH, H 5 ), 2.56 (s, 3H, CH 3 ). EXAMPLE 9 Preparation Of N-(l-Naphthoyl)-2-Methyl-6-Nitroanilide In this Example, N-(l-naphthoyl)-2-methyl-6-nitroanilide was prepared by Method A, by mixing 2-methyl-6-nitroaniline (9) (1.52 g, 10.0 mmol) and 1-naphthoyl chloride (2.00 mL, 13.3 mmol, 130 M%). After one hour of stirring at room temp, a second volume of 1-naphthoyl chloride (1.0 mL, 6.65 mmol, 66 M%) was added. The mixture was stirred for 6 hours. The crude product was recrystallized from ethyl acetate, yielding white powders of Ν-(l-naphthoyl)-2-methyl-6-nitroanilide (2.79 g, 9.11 mmol, 91% yield). Η-NMR (200 MHz, CD 2 C1 2 ): δ 8.09-7.99 (m, 2H), 7.77 (m, IH), 7.66-7.41 (m, 5H), 7.23 (d, J=8.3 Hz, IH), 7.24 (dd, J=7.3 Hz, IH), 2.77 (s, 3H, CH 3 ). EXAMPLE 10 Preparation Of N-(2-Naphthoyl)-2-Methyl-6-Nitroanilide In this Example, N-(2-naρhthoyl)-2-methyl-6-nitroanilide was prepared according to Method A, by mixing 2-methyl-6-nitroaniline (9)(1.52 g, 10.0 mmol) and 2-naphthoyl chloride (2.00 mL, 13.3 mmol, 130 M%). After 1 hour of stirring, a second volume of 2-naphthoyl chloride (1.0 mL, 6.65 mmol, 66 M%) was added. The mixture was stirred for 6 hours. The crude product was recrystallized from methyl acetate to produce white powders of Ν-(2-Νaphthoyl)-2-Methyl-6-Νitroanilide (2.29 g, 7.48 mmol, 75% yield). Η-NMR (300 MHz, CD 2 C1 2 ): δ 9.15 (br s, IH, NH), 8.49 (s, IH, H,.), 8.06-7.86 (m, 5H, nap & H 5 ), 7.72-7.45 (m, 3H, nap & H 3 ), 7.37 (dd, J=7.73 Hz, IH, H 4 ), 2.43 (s, 3H, CH 3 ). EXAMPLE 11 Preparation Of N-Nicotinoyl-2-Methyl-6-Nitroanilide In this Example, N-Nicotinoyl-2-methyl-6-nitroanilide (16) was prepared by Method A, by mixing 2-methyl-6-nitroaniline (9) (1.52 g, 10.0 mmol) and nicotinoyl chloride hydrochloride (2.67 g, 15.0 mmol, 150 M%), and stirring the reaction overnight. Recrystallization of the crude product from diethylether/hexane (3:1) yielded N-nicotinyl-2-methyl-6-nitroanilide ( 1.41 g, 5.49 mmol, 55% yield). 'H-NMR (300 MHz, CD 2 C1 2 ): δ 9.16 (dd, J=0.8, 2.2 Hz, IH, H 2 ), 9.01 (br, IH, NH), 8.80 (dd, J=1.7, 4.8 Hz, IH, H 6 ), 8.23 (ddd, 5=1.1, 2.2, 8.0 Hz, IH, H 4 ), 7.92 (m, IH, H 5 ), 7.62 (br d, J=7.5 Hz, IH, H 3 ), 7.48 (ddd, J=0.8, 4.8, 8.0 Hz, IH, H 5 ), 7.39 (dd=7.5, 8.5 Hz, IH, H 4 ), 2.39 (s, 3H, CH 3 ). EXAMPLE 12 Preparation Of 2-(2,6-Difluorophenyl)benzimidazole In this Example, 2-(2,6-difluorophenyl)benzimidazole (18) was prepared using Method B. The basic method of "Method B" was used in subsequent Examples, as indicated below, with reagent and other substitutions made as indicated. First, 2-methyl-6-nitroaniline (9) (9.31 g, 31.9 mmol) was dissolved in glacial acetic acid (100 mL). Iron powder (17) (4.95 g) was then added. After 30 min at reflux, the reaction was concentrated to dryness, eluting with ethylacetate and washed with NaHCO 3 . The aqueous layer was back extracted with ethylacetate and the combined organic solution was washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried filtered and concentrated. The crude product was recrystallized from ethylacetate to yield white powders of 2-(2,6- Difluorophenyl)benzimidazole (6.24 g, 27.1 mmol, 85% yield). 'H-NMR (300 MHz, CD 2 C1 2 ): δ 9.92 (br, IH, NH), 7.69 (br, IH, H 47 ), 7.45 (m, IH, H..), 7.31 (ddd, J=3.2, 4.0, 6.0 Hz, H 5 6 ), 7.11 (m, 2H, H 3>>5 .). EXAMPLE 13 Preparation Of 2-(2,6-Difluorophenyl)-4-Methylbenzimidazole In this Example, 2-(2,6-difluorophenyl)-4-methylbenzimidazole (19) was produced using Method B. N-(2,6-difluorobenzoyl)-2-methyl-6-nitroanilide (11) (1.35 g, 4.62 mmol) and iron powder (17) (1.3 g) were mixed as described for Method B. Recrystallization of the crude product from diethylether/hexane (3/1) yielded colorless crystals of 2-(2,6-difluorophenyl)-4-methylbenzimidazole (1.1 g, 4.48 mmol, 97%). M.p. 148 °C. Η-ΝMR (300 MHz, OMSO-d 6 ): δ 12.86 (s, IH, ΝH), 7.66 (m, IH, H 4 .), 7.33 (m, 2H, H 3 . v ), 7.27-7.18 (m, IH, H 7 ), 7.15 (dd, J=8.0, 7.2 Hz, IH, H 6 ), 7.05 (d, J=7.2 Hz, IH, H 5 ), 2.55 (s, 3H, CH 3 ). EXAMPLE 14 Preparation Of 2-(2-Methylphenyl)Benzimidazole In this Example, 2-(2-methylphenyl)benzimidazole (20) was produced using Method B. N-(2-methylbenzoyl)-2-nitroanilide (13) (1.9 g, 7.4 mmol) and iron powder (17) (1.2 g) were mixed. Recrystallization of the crude product from diethylether/hexane (3/1) yielded colorless crystals of 2-(2-methylphenyl)benzimidazole 1.2 g (5.76 mmol, 78%). M.p. 215°C. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 7.63 (m, IH, H 6 .), 7.58 (dd, J=6.1, 3.2 Hz, 2H, H 4> 7 ), 7.39-7.21 (m, 3H, H 3 . 4 . 5 .), 7.25 (dd, J=6.1, 3.2 Hz, 2H, H 5> 6 ), 2.58 (s, 3H, CH 3 ). EXAMPLE 15 Preparation Of 2-(l-Νaphthyl)-4-Methylbenzimidazole In this Example, 2-(l-naphthyl)-4-methylbenzimidazole (21) was produced using Method B. The 1 -naphthyl derivative shown as compound 14 (Figure 3) (2.60 g, 11.7 mmol) and iron powder (17) (2.00 g) were reacted. Purification of the crude product by flash chromatography, eluting with 4% MeOH/CH 2 Cl 2 , and recrystallization from diethylether/hexane (3:1) yielded white powders of 2-(l-naphthyl)-4- methylbenzimidazole (1.63 g, 6.31 mmol, 54% yield). Η-NMR (200 MHz, CD 2 C1 2 ): δ 9.71 (br, IH, NH), 8.80 (m, IH), 8.01-7.89 (m, 2H), 7.81 (dd, J=1.3, 7.3 Hz, IH), 7.61-7.47 (m, 4H), 7.21 (dd, J=7.3, 7.6 Hz, IH), 7.11 (m, IH), 2.66 (s, 3H, CH 3 ). EXAMPLE 16 Preparation Of 2-(2-Naphthyl)-4-Methylbenzimidazole In this Example, 2-(2-naphthyl)-4-methylbenzimidazole (22), using Method B. The compound shown as compound 15 (Figure 3) (2.25 g, 7.34 mmol) and iron powder (17) (1.60 g) were reacted. The crude product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 , and recrystallization from diethylether/hexane (3:1), yielding white powders of 2-(2-naphthyl)-4- methylbenzimidazole (1.00 g, 3.88 mmol, 53% yield). 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.70 (br, IH, NH), 8.34 (dd, J=1.7, 8.6 Hz, IH), 7.99-7.87 (m, 3H), 7.57-7.51 (m, 2H), 7.50-7.43 (m, IH), 7.15 (dd, J=7.3, 7.5 Hz, IH, H 6 ), 7.04 (m, IH, H 5 ), 2.67 (s, EXAMPLE 17 Preparation Of 2-(3-Pyridyl)-4-Methylbenzimidazole In this Example, 2-(3-pyridyl)-4-methylbenzimidazole (23) was produced using Method B. N-Nicotinoyl-2-methyl-6-nitroanilide (Example 7) (1.00 g, 3.89 mmol) and iron (0.75 g) were mixed for 30 minutes. Additional iron powder (0.75 g) was then added, and the mixture prepared as described for Method B. Recrystallization of the crude product from ethylacetate yielded white powders of 2-(3-pyridyl)-4- methylbenzimidazole (0.72 g, 3.44 mmol, 88% yield). 'H-NMR (300 MHz, DMSO- d 6 ): δ 9.38 (dd, J=2.3, 0.9 Hz, IH, H 2 .), 8.67 (dd, J=1.7, 4.8 Hz, IH, H 6 .), 8.53 (ddd, J=1.7, 2.3, 8.0 Hz, IH, H 4 .), 7.58 (ddd, J=0.9, 4.8, 8.0 Hz, IH, H 5 .), 7.44 (dd, J=0.9, 8.1 Hz, H 7 ), 7.12 (dd, J=7.3, 8.1 Hz, IH, H 6 ), 7.02 (ddt, J=0.2, 0.9, 7.3 Hz, IH, H 5 ), 2.59 (s, 3H, CH 3 ). EXAMPLE 18 Preparation Of 2-(4-Pyridyl)-4-Methylbenzimidazole In this Example, 2-(4-pyridyl)-4-methylbenzimidazole (24) was produced using Method B. N-Isonicotinoyl-2-methyl-6-nitroanilide (Example 7) (1.02 g, 3.97 mmol) and iron powder (1.10 g) were mixed as described for Method B. Recrystallization of the crude product from ethylacetate yielded white powders of 2-(4-pyridyl)-4- methylbenzimidazole (0.70 g, 3.34 mmol, 84% yield). Η-ΝMR (300 MHz, DMSO- d 6 ): δ 8.75 (m, 2H, H 2 , 6 ,), 8.14 (m, 2H, H 2 . 5 ,), 7.46 (dd, J=0.9, 8.1 Hz, IH, H 7 ), 7.15 (dd, J=7.3, 8.1 Hz, IH, H 6 ), 7.05 (ddt, J=0.8, 0.9, 7.3 Hz, IH, H 5 ), 2.59 (s, 3H, CH 3 ). EXAMPLE 19 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)Benzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (26) was prepared using Method C. The basic method of "Method C" was used in subsequent Examples, as indicated below, with reagent and other substitutions made as indicated. 2-(2,6-difluorophenyl)benzimidazole (Example 12) (2.00 g, 8.70 mmol) and 2,6-difluoro-α-bromo-toluene (25) (2.85 g, 160 M%), were dissolved in THF (20 mL). To this mixture, ΝaH (0.75 g, 215 M%) was added. After mixing for 2 hours, the reaction was quenched with MeOH and concentrated. The residue was redissolved in ethylacetate, and washed with ΝaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na^O^, filtered and concentrated. The crude product was recrystallized from ethylacetate/hexane (1:1) yielding white powders of l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (2.62 g, 0.35 mmol, 85% yield. M.p. 145°C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 7.77 (m, IH, H 4 ), 7.54 (m, IH, H 4 .), 7.49m, IH, H 7 ), 7.29 (m, 2H, H 5>6 ), 7.24 (m, IH, H 4 .), 7.08 (m, 2H, H 3 . , 5 ,), 5.82 (m, 2H, H 3 . , 5 .), 5.30 (s, 2H, CH 2 PhF 2 ). EXAMPLE 20 Preparation Of l-Benzyl-2-(2,6-Difluorophenyl)Benzimidazole In this Example, l-benzyl-2-(2,6-difluorophenyl)benzimidazole (28) was produced using Method C. 2-(2,6-difluorophenyl)benzimidazole (Example 12) (100 mg, 0.43 mmol) and benzylbromide (27) (66.4 μl, 0.56 mmol) were mixed as indicated for Method C. Recrystallization of the crude product from diethylether/hexane (3:1) yielded colorless crystals of l-benzyl-2-(2,6- difluorophenyl)benzimidazole (77 mg, 0.24 mmol, 56%). M.p. 124°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.88 (d, J=7.7 Hz, IH, H 4 ), 7.47 (m, IH, H 4 ,), 7.34-7.22 (m, 6H, I . 4 -. 6 -), 7.07-6.99 (m, 4H, H 3 , 5 , 3 , ), 5.28 (s, 2H, CH 2 ). EXAMPLE 21 Preparation Of l-Benzyl-2-(2,6-Difluorophenyl)-4-Methylbenzimidazole In this Example, l-benzyl-2-(2,6-difluorophenyl)-4-methylbenzimidazole (29) was produced according to Method C. 2-(2,6-difluorophenyl)-4-methylbenzimidazole (Example 13) (88mg, 0.33 mmol) and benzylbromide (27) (51 μL, 0.43 mmol) were reacted. Recrystallization of the crude product from diethylether/hexane (3:1) yielded colorless crystals of l-benzyl-2-(2,6-difluorophenyl)-4-methylbenzimidazole (67 mg, 0.20 mmol, 61%). M.p. 112-117°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.46 (m, IH, H 4 .), 7.26-7.22 (m, 3H, H 73 . , ), 7.18-6.98 (m, 7H, H 5,63 . 5 . ,2 » >4 . >6 .), 5.25 (s, 2H, CH 2 ), 2.74 (s, 3H, CH 3 ). Anal. (C 21 H 16 F 2 N 2 xl/4H 2 O) calcd. C,H,N 74.43, 4.91, 8.27; found C,H,N 74.81, 4.90, 7.85. HRMS 334.1281 (calcd) 334.1266 (found) δ ppm 4.6. EXAMPLE 22 Preparation Of l-(2,6-Dichlorobenzyl)-2-(2,6-Difluorophenyl)-4-Methylbenzimidazole In this Example, l-(2,6-dichlorobenzyl)-2-(2,6-difluorophenyl)- 4-methylbenzimidazole (30) was produced using Method C. In this Example, 2-(2,6- difluorophenyl)-4-methylbenzimidazole (Example 13) (0.50 g, 2.05 mmol) and 2,6- dichloro-α-bromo-toluene (0.74 g, 3.08 mmol, 150 M%) were reacted for 2 hours. The crude product was purified by flash chromatography, eluted with 4% MeOH/CH 2 Cl 2 , and recrystallized from diethylether/hexane (3:1), yielding white powders of l-(2,6-dichlorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (0.70 g, 1.74 mmol, 85% yield). M.p. 202-203°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.48 (m, IH, H 4 ), 7.26 (m, 2H, H 57 ), 7.19 (dd, J=8.0, 8.2 Hz, IH, H 6 ), 7.14-6.98 (m, 5H, H 3 . ,5 - , 3 « ,4",5" ), 5.56 (s, 2H, CH 2 PhCl 2 ), 2.64 (s, 3H, CH 3 ). EXAMPLE 23 Preparation Of l-(2,6-Difluorobenzyl)-2-t-Butyldimethylsilyloxymethyl-4- Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-t-butyldimethylsilyloxymethyl-4- methylbenzimidazole (31) was produced using Method C. In this Example, 2-(t- Butyldimethylsilyloxymethyl)-4-Methylbenzimidazole (Example 3) (3.25 g, 11.76 mmol) and 2,6-difluoro-α-bromo-toluene (25) (3.65 g, 150 M%) were reacted for 4 h. The crude product was purified by flash chromatography eluting with ethylacetate:hexane (1:4), yielding white powders of l-(2,6-difluorobenzyl)-2-t- butyldimethylsilyloxymethyl-4-methylbenzimidazole (4.41 g, 10.96 mmol, 93% yield). Η-NMR (300 MHz, CD 2 C1 2 ): δ 7.32 (m, IH, H 4 „), 7.17 (br d, J=8.2 Hz, IH, H 7 ), 7.08 (dd, J=7.3, 8.2 Hz, IH, H 6 ), 7.00 (br d, J=7.3 Hz, IH, H ; ), 6.95 (m, 2H, H 3 » 5 .), 5.63 (s, 2H, CH 2 PhF 2 ), 5.13 (s, 2H, CH 2 O), 2.59 (s, 3H, CH 3 ), 0.94 (s, 9H, Si-tert- Bu), 0.14 (s, 6H, Si(CH 3 ) 2 ). EXAMPLE 24 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2,6-Difluorobenzyloxymethyl)Benzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorobenzyloxymethyl) benzimidazole (32) was produced using Method C. In this Example, 2- hydroxymethylbenzimidazole (Example 1) (92 mg, 0.62 mmol) and 2,6-difluoro-α- bromo-toluene (334 mg, 1.61 mmol, 260 M%) were reacted. Recrystallization of the crude product from diethylether/hexane (3:1) yielded colorless crystals of l-(2,6- difluorobenzyl)-2-(2,6-difluorobenzyloxymethyl)benzimidazole (66 mg, 0.165 mmol, 27%). M.p. 109°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.73 (m, IH, H 4 ), 7.38 (m, IH, H 7 ), 7.36-7.18 (m, 4H, H 5>6>4 , 4 .), 6.98-6.82 (m, 4H, H 3 . j5 . 3 . >5 .), 5.58 (s, 2H, NCH 2 PhF 2 ), 5.07 (s, 2H, OCH 2 ), 4.70 (s, 2H, OCH 2 PhF 2 ). EXAMPLE 25 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl) -4-methylbenzimidazole (33) was produced using Method C. 2-(2,6-difluorophenyl)-4- methylbenzimidazole (Example 13) (400 mg, 1.63 mmol) and 2,6-difluoro-α-bromo- toluene (1.87 mmol, 388 mg) were mixed and stirred overnight. Recrystallization of the crude product from diethylether hexane (3:1) yielded white powders of l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (453 mg, 1.22 mmol, 75% yield). M.p. 182-186°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.48 (m, IH, H 4 ), 7.32 (d, J=8.1 Hz, H 7 ), 7.20 (m, IH, H 4 „), 7.19 (dd, J=8.1, 7.2 Hz, IH, H 6 ), 7.09 (d, J=7.2 Hz, IH, H 5 ), 7.04 (m, 2H, H 3 . ,5 .), 6.79 (m, 2H, H 3 . 5 .), 5.33 (s, 2H, CH 2 ), 2.70 (s, 3H, CH 3 ). EXAMPLE 26 Preparation Of 1 -(2,6-Difluorobenzyl)-2-Isopropyl-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-isopropyl-4-methylbenzimidazole (34) was prepared according to Method C. 2-isopropyl-4-methylbenzimidazole (Example 4) (0.20 g 1.15 mmol) and 2,6-difluoro-α-bromo-toluene (0.36 g, 1.74 mmol, 150 M%) were stirred for 5 h. The crude product was purified by flash chromatography eluting with 4% MeOH CH 2 Cl 2 , and recrystallized from diethylether/hexane (3:1), yielding white powders of l-(2,6-difluorobenzyl)-2-isopropyl-4-methylbenzimidazole (0.20 g, 0.67 mmol, 58% yield). M.p. 151-153°C. 'H-NMR (200 MHz CD 2 C1 2 ): δ 7.30 (m, IH, H 4 .), 7.15 (br d, J=7.7 Hz, IH, H 7 ), 7.04 (dd, J=7.3, 7.7 Hz, IH, H 6 ), 6.96 (br d, J=7.3 Hz, IH, H 5 ), 6.82 (m, 2H, H 3 . ι5 .), 5.38 (s, 2H, CH 2 PhF 2 ), 3.40 (sep, J=6.8 Hz, IH, iPr), 2.57 (s, 3H, CH 3 ), 1.38 (d, J=6.8 Hz, 6H, iPr). EXAMPLE 27 Preparation Of l-(2,6-Difluorobenzyl)-2-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-methylbenzimidazole (35) was prepared according to Method C. 2-methylbenzimidazole (204 mg, 1.54 mmol) and 2,6-difluoro-α-bromo-toluene (351 mg, 1.70 mmol) were reacted. The crude product was purified by recrystallization from diethyletheπhexane (3:1), yielding colorless crystals of l-(2,6-difluorobenzyl)-2-methylbenzimidazole (290 mg, 1.12 mmol, 73%). M.p. 99°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.66 (m, J=8.0, 1.1, 0.6 Hz, IH, H 4 ), 7.37 (m, J=0.6, 1.1, 8.2 Hz, H 7 ), 7.30 (m, IH, H 4 .), 7.20 (m, J=8.0, 1.1, 7.3, H 5 ), 7.19 (m, J=8.2, 7.3, 1.1 Hz, IH, H 6 ), 6.92 (m, 2H, H 5 .) 5.35 (s, 2H, CH 2 ), 2.71 (s, 3H, ' CH 3 ). EXAMPLE 28 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2-Methylphenyl)Benzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2-methylphenyl)benzimidazole (36) was produced according to Method C. 2-(2-methylphenyl)benzimidazole (Example 14) (0.10 g, 0.48 mmol) was reacted with 2,6-difluoro-α-bromo-toluene (0.15 g, 0.73 mmol, 150 M%). The crude product was purified using flash chromatography eluting with 2% MeOH/CH 2 Cl 2 , and recrystallization with diethyl ether/hexane (3:1), yielding colorless crystals of l-(2,6-difluorobenzyl)-2-(2-methylphenyl)benzimidazole (109 mg, 0.33 mmol, 68%). M.p. 139°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.80 (m, IH, H 4 ), 7.43-7.23 (m, 7H, H 5Λ7>3 . ,4 . 5ι6 .), 7.21 (m, IH, H 4 „), 6.79 (m, 2H, H 3 . t5 „), 5.31 (s, 2H, CH 2 ), 2.23 (s, 3H, CH 3 ). EXAMPLE 29 Preparation Of 1 -(2,6-Difluorobenzyl)-2-( 1 -Naphthyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(l-naphthyl)-4-methylbenzimidazole (37) was produced according to Method C. 2-(l-naphthyl)-4-methylbenzimidazole (Example 15) (0.30 g, 1.16 mmol) and 2,6-difluoro-α-bromo-toluene (25) (0.54 g, 2.60 mmol, 225 M%) were reacted with stirring overnight. The crude product was purified by flash chromatography eluting with ethylacetate/hexane (1:4) and recrystallization from diethylether hexane (3:1), yielding white powders of l-(2,6- difluorobenzyl)-2-(l-naphthyl)-4-methylbenzimidazole (0.32 g, 0.83 mmol, 72% yield). M.p. 121-123°C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 8.00 (d, J=8.1 Hz, IH), 7.96 (d, J=8.1 Hz, IH), 7.66 (d, J=6.3 Hz, IH), 7.60 (t, J=7.5 Hz, IH), 7.53 (dt, J=1.3, 7.5 Hz, IH), 7.43 (dt, J=1.3, 7.6 Hz, IH), 7.28 (d, J=8.1 Hz, IH), 7.19 (t, J=7.5 Hz, 1H),.7.11 (m, 2H), 6.67 (m, 2H), 5.28 (s, 2H, CH 2 PhF 2 ), 2.68 (s 5 3H, CH 3 ). EXAMPLE 30 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2-Naphthyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2-naphthyl)-4-methylbenzimidazole (38) was produced according to Method C. 2-(2-naphthyl)-4-methylbenzimidazole (Example 16) (0.30 g, 1.16 mmol) was reacted with a first addition of 2,6-difluoro-α- bromo-toluene (0.36 g, 1.74 mmol, 150 M%), followed by a second addition of 2,6- difluoro-α-bromo-toluene (0.18 g, 0.87 mmol, 75 M%) after 2 hours of stirring. The reaction mixture was stirred overnight. The crude product was purified by flash chromatography eluting with ethylacetate/hexane (1:4), and recrystallized from diethylether/hexane (3:1), yielding white powders of l-(2,6-difluorobenzyl)-2-(2- naphthyl)-4-methylbenzimidazole (0.35 g, 0.91 mmol, 78% yield). M.p. 175-176°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.28(d, J=1.6 Hz, IH), 8.02 (d, J=8.5 Hz, IH), 7.96 (m, 2H), 7.83 (dd, J=1.7, 8.5 Hz, IH), 7.59 (m, 2H), 7.20(m, 2H), 7.12 (m, IH), 7:06 (m, IH), 6.80 (m, 2H), 5.60 (s, 2H, CH 2 PhF 2 ), 2.66 (s, 3H, CH 3 ). EXAMPLE 31 Preparation Of l-(2,6-Difluorobenzyl)-2-Phenylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-phenylbenzimidazole (39) was produced according to Method C. 2-phenylbenzimidazole (300 mg, 1.54 mmol) and 2,6-difluoro-α-bromo-toluene were reacted (1.70 mmol, 110 M%). The crude product was recrystallized from diethyletheπhexane (3:1), yielding colorless crystals of l-(2,6- difluorobenzyl)-2-phenylbenzimidazole (300 mg, 0.94 mmol, 63% yield). M.p. 163°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.82 (d, J=8.3 Hz, IH, H 4 ), 7.75 (m, 2H, 2H 3 . 5 .), 7.53 (m, 3H, H 2 , 4 . 6 .), 7.33 (d, J=8.3 Hz, IH, H 7 ), 7.25 (m, 3H, H JA4 .), 6.81 (m, 2H, H 3 ,, 5 , 5.55 (s, 2H, CH 2 ). EXAMPLE 32 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(3-Pyridyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(3-pyridyl)-4-methylbenzimidazole (40) was produced according to Method C. 2-(3-pyridyl)-4-methylbenzimidazole (Example 17) (0:30 g, 1.43 mmol) and 2,6-difluoro-α-bromo-toluene (0.49 g, 2.37 mmol, 165 M%) were reacted and stirred overnight. The crude product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 , and recrystallization from diethylether/hexane (3:1), yielding white powders of l-(2,6-difluorobenzyl)-2-(3- pyridyl)-4-methylbenzimidazole (0.34 g, 1.02 mmol, 71% yield). M.p. 186-188°C. Η- NMR (300 MHz, CD 2 C1 2 ): δ 8.92 (dd, J=0.9, 2.3Hz, IH, H ), 8.74 (dd, J=1.7, 4.9 Hz, IH, H 6 ), 8.05 (dt, J=2.0, 7.8 Hz, IH, H 4 .), 7.48 (ddd, J=0.9, 4.9, 7.8, IH, H 5 .), 7.24 (m, IH, H 4 „), 7.22 (br d, J=7.7 Hz IH, H 7 ), 7.15 (dd, J=7.7, 7.2, IH, H 6 ), 7.07 (dt, J=1.0, 7.2 Hz IH H 5 ), 6.83 (m, 2H, H 3 . ιS .), 5.51 (s, 2H, CH 2 PhF 2 ), 2.64 (s, 3H, CH 3 ). EXAMPLE 33 Preparation Of l-(2,6-Difluorobenzyl)-2-(4-Pyridyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(4-pyridyl)-4-methylbenzimidazole (41) was produced according to Method C. 2-(4-pyridyl)-4-methylbenzimidazole (Example 18) (0.30 g, 1.43 mmol) and 2,6-difluoro-α-bromo-toluene (0.45 g, 2.17 mmol, 150 M%) were reacted and stirred overnight. The crude product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 , and recrystallization from diethylether/hexane (3:1), yielding white powders of l-(2,6-difluorobenzyl)-2-(4- pyridyl)-4-methylbenzimidazole (0.29 g, 0.86 mmol, 60% yield). M.p. 171-172°C. 'H- NMR (300 MHz, CD 2 C1 2 ): δ 8.77 (dd, J=1.6, 4.4 Hz, 2H, H 2 . 6 .), 7.66 (dt, J=1.4, 4.4 Hz, 2H, H 3 . ,5 ,), 7.24 (m, IH, H 4 »), 7.22 (dd, J=0.8, 8.1 Hz, IH, H 7 ), 7:15 (dd, J=7.5, 8.1 Hz, IH, H 6 ), 7.07 (ddq, J=0.4, 0.8, 7.5 Hz, IH, H 5 ), 6.82 (m, 2H, H 3 . ;5 -), 5.54 (s, 2H, CH 2 PhF 2 ), 2.63 (s, 3H, CH 3 ). EXAMPLE 34 Preparation Of l-(2,3,4,5,6-Pentafluorobenzyl)-2-(2,6-Difluorophenyl)- 4-Methylbenzimidazole In this Example, l-(2,3,4,5,6-pentafluorobenzyl)-2-(2,6-difluorophenyl)-4- methylbenzimidazole (42) was prepared according to Method C. 2-(2,6- difluorophenyl)-4-methylbenzimidazole (Example 13) (0.31 g, 1.27 mmol) and 2,3,4,5,6-pentafluoro-α-bromo-toluene (0.30 mL, 1.99 mmol, 155 M%) were reacted and stirred for 4 h. The crude product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 , and recrystallization from diethylether/hexane (3:1), yielding white powders of l-(2,3,4,5,6-pentafluorobenzyl)-2-(2,6-difluorophenyl)- 4-methylbenzimidazole (0.33 g, 0.77 mmol, 61% yield). M.p. 155-156°C. 'H-NMR (200 MHz, CD 2 C1 2 ); δ 7.57 (m, IH, H 6 ), 7.29-7.23 (m, 2H, H 6>7 ), 7.19-7.05 (m, 3H, H„. ιS .), 5.35 (s, 2H, CH 2 PhF 5 ), 2.64 (s, 3H, CH 3 ). EXAMPLE 35 Preparation Of l-(3-Pyridylmethyl)-2-(2,6-Difluorophenyl)-4-Methylbenzimidazole In this Example, l-(3-pyridylmethyl)-2-(2,6-difluorophenyl)-4- methylbenzimidazole (43) was produced according to Method C. 2-(2,6- difluorophenyl)-4-methylbenzimidazole (Example 13) (0.21 g, 0.86 mmol) and α- bromo-methylpyridine (0.22 g, 1.28 mmol, 150 M%) were reacted and stirred for 1 h. The crude product was purified by flash chromatography eluting with ethylacetate/hexane (1:1) increasing to ethylacetate (100%), and recrystallization from diethyl etheπhexane (3:1), yielding white powders of l-(3-pyridylmethyl)-2-(2,6- difluorophenyl)-4-methylbenzimidazole (0.24 g (0.73 mmol, 85% yield). M.p. 131- 132°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.45 (d, J=3.4 Hz, IH, H 6 „), 8.32 (s, IH, H ), 7.53 (m, IH, H 4 .), 7.25-7.03 (m, 7H, H 5j67j3 . >5 . 4 . >5 .), 5.26 (s, 2H, CH 2 Py), 2.67 (s, 3H, CH 3 -Ar). EXAMPLE 36 Preparation of 1 -(3,3-Dimethylallyl)-2-(Cyclopropyl)-4-Methoxylbenzimidazole In this Example, l-(3,3-Dimethylallyl)-2-(cyclopropyl)-4- methoxylbenzimidazole was produced using Method C, by reacting 2-(Cyclopropyl)-4- methoxylbenzimidazole (5014, Example 49) (1.00 g, 5.32 mmol) and 3,3-dimethylallyl bromide (0.70 mL, 6.07 mmol, 115 M%). The crude product was purified by flash chromatography eluting with 2% MeOH CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of l-(3,3-dimethylallyl)-2- cyclopropyl-4-methoxylbenzimidazole (1.08 g, 4.21 mmol, 80% yield). M.p. 41-42°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.09 (dd, J= 8.1, 7.9 Hz, IH, H 6 ), 6.89 (dd, J= 8.1, 0.9 Hz, IH, Hj), 6.61 (dd, J = 7.9, 0.9 Hz, IH, H 7 ), 5.26 (m, IH), 4.81 (d, J=6.7 Hz, 2H), (3.94, s, 3H, OCH 3 ), 1.96 (m, IH), 1.86 (s, 3H, CH 3 ), 1.74 (d, J=1.2 Hz, 3H, CH 3 ), 1.21-0.98 (m, 4H). EXAMPLE 37 Preparation Of l-Benzenesulfonyl-2-(2,6-Difluorophenyl)benzimidazole In this Example, l-benzenesulfonyl-2-(2,6-difluorophenyl)benzimidazole (45) was produced according to Method D. The basic method of "Method D" was used in subsequent Examples, as indicated below, with reagent and other substitutions made as indicated. 2-(2,6-difluorophenyl)benzimidazole (Example 12) (0.31 g, 1.34 mmol) dissolved in THF (5 mL) was added to NaH (0.10 g, 190 M%). After 5 min, benzenesulfonyl chloride (0.25 mL, 0.35 g, 2.00 mmol, 150 M%) was added. After stirring for 2 h, the reaction was dissolved in ethylacetate, and washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na^O , filtered, and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and then recrystallized from diethylether/hexane (3:1), to yield white powders of l-benzenesulfonyl-2-(2,6-difluorophenyl)benzimidazole (0.41 g, (1.10 mmol, 83% yield). M.p. 104-106°C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 8.09 (m, IH, PhSO 2 ), 7.77 (m, IH, PhSO 2 ), 7.69 (m, 2H, PhSO 2 ), 7.66-7.53 (m, 2H, H 47 ), 7.51-7.39 (m, 4H, PhSO 2 , H„), 7.07 (m, 2H, H 3 . ,s .). EXAMPLE 38 Preparation Of 1 -Benzenesulfonyl-2-(2,6-Difluorophenyl)-4-Methylbenzimidazole In this Example, l-benzenesulfonyl-2-(2,6-difluorophenyl)-4- methylbenzimidazole (46) was produced according to Method D, by reacting 2-(2,6- difluorophenyl)-4-methylbenzimidazole (Example 13) (0.20 g, 0.82 mmol) and benzenesulfonyl chloride (0.20 mL, 0.28 g. 1.58 mmol, 190 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallized from diethylether/hexane (3:1), to produce white powders of 1- benzenesulfonyl-2-(2,6-difluorophenyl)-4-methylbenzimidazole (0.24 g, 0.02 mmol, 76% yield). M.p. 134-135°C. 'H-NMR (200 MHz, CD 2 C1 2 ): δ 7.89 (br d, J= 8.2 Hz, IH), 7.73-7.38 (m, 6H), 7.34 (dd, J= 7.4, 8.1 Hz, IH, H 6 ), 7.2 (br d, J= 7.4 Hz, IH, H s ), 7.07 (m, 2H, H 3 . 5 .), 2.59 (s, 3H, CH 3 ). EXAMPLE 39 Preparation Of 1 -(2,6-Difluorobenzoyl)-2-(2,6-Difluorophenyl)Benzimidazole In this Example, l-(2,6-difluorobenzoyl)-2-(2,6-difluorophenyl)benzimidazole (47) was produced according to Method D. To 2-(2,6-difluorophenyi)benzimidazole (Example 12) (30 mg, 0.13 mmol) dissolved in pyridine (0.5 mL) and chloroform (1.2 mL) was added 2,6-difluorobenzoyl chloride (20 μl, 0.16 mmol, 120 M%). The mixture was stiπed at room temperature for 5 h, diluted with chloroform, and washed with NaHSO 4 (2% solution). The organic layer was dried filtered, and evaporated. The solid was recrystallized from diethylether/hexane to produce 19 mg of colorless crystals (40% yield). M.p. 145°C. 'H-NMR (300 MHz, CDC1 3 ): δ 8.14 (m, IH, H 4 ), 7.89 (m, IH, H 7 ), 7.48 (m, 2H, H 5 6 ), 7.31-7.18 (m, 2H, H 4 r . ), 6.77 (m, 4H, H 3 , s , 3 . s .). EXAMPLE 40 Preparation Of l-(2,6-Difluorobenzyl)-2-Hydroxymethyl-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-hydroxymethyl-4- methylbenzimidazole (48) was prepared according to Method D. To l-(2,6- difluorobenzyl)-2-t-butyldimethylsilyloxymethyl-4-methylbenzimidazole (Example 23) (1.82 g, 4.52 mmol) dissolved in THF (20mL) was added tetrabutyl ammonium fluoride (1.45 g, 4.60 mmol, 100 M%). After stirring for 30 min at room temperature, the reaction was concentrated to dryness. The residue was suspended in water, filtered, and washed with water to produce 1.28 g, (4.44 mmol, 98% yield) of white powder. 'H-NMR (300 MHZ, CD 3 OD): δ 7.39(m, IH, H 4 -), 7.18 (br d, J= 8.3 Hz, IH, H 7 ), 7.09 (dd, J= 7.4, 8.3 Hz, IH, H 6 ), 7.05-6.97 (m, 3H, H >5 . 5 ), 5.68 (s, 2H, CH 2 PhF 2 ), 4.99 (s, 2H, CH 2 O), 2.57 (s, 3H, CH 3 ). EXAMPLE 41 Preparation Of l-(2,6-Difluorobenzyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-4-methylbenzimidazole (49) was prepared according to Method D. To l-(2,6-difluorobenzyl)-2-hydroxymethyl-4- methylbenzimidazole (Example 40) (1.82 g, 4.52 mmol) dissolved in 1.5 M H 2 SO 4 (40 mL) was added KMnO 4 (1.50 g, 9.49 mmol, 160 M%). After 1 h at room temperature, the reaction mixture was filtered and washed with water. The brown solid was collected, suspended in acetone/methanol and filtered. The filtrate was collected and purified by flash chromatography eluting with 10% MeOH/CH 2 Cl 2 increasing to 50% MeOH/CH 2 Cl 2 to produce 1.42 g (4.70 mmol, 80% yield) of white powder. 'H-NMR (200 MHz, CD 2 C1 2 ): δ 7.99 (br s, IH, H 2 ), 7.37 (br d , J= 7.9 Hz, IH, H 7 ), 7.32 (m, IH, H 4 .), 7.17 (dd, J= 7.3, 7.9 Hz, IH, H 6 ), 7.03 (d, J= 7.3 Hz, IH, H 5 ), 6.96 (m, 2H, H 3 . 5 „), 5.40 (s, 2H, CH 2 PhF 2 ), 2.59 (s, 3H, CH 3 ). EXAMPLE 42 Preparation Of l-(2,6-Difluorobenzyl)-2-Formyl-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-formyl-4-methylbenzimidazole (50) was prepared according to Method D. Pyridine (3.4 mL) dissolved in CH 2 C1 2 (50 mL) was added to CrO 3 (2.20 g). After 15 min., l-(2,6-difluorobenzyl)-2-hydroxymethyl-4- methylbenzimidazole (Example 40) dissolved in DMF was added to the mixture and stirred. After 20 m, the organic solution was decanted from a tarry black deposit. The organic solution was washed with 5% NaOH, 5% HCl, NaHCO 3 and NaCl, dried (Na,SO 4 ), filtered, and concentrated. Purification by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 gave 0.55 g (1.92 mmol. 44% yield) of l-(2,6-difluorobenzyl)- 2-formyl-4-methylbenzimidazole (50) and 0.17 g (0.66 mmol, 15% yield) of l-(2,6- difluorobenzyl)-4-methylbenzimidazole (49). Η-NMR (200 MHz, CD 3 OD): δ 10.13 (s, IH, CHO), 7.36-7.10 (cm, 4H, H 5Aτr ), 6.90 (m, 2H, H 3 ._ 5 .), 6.05 (s, 2H, Ch 2 PhF 2 ), 2.66 (s, 3H, CH 3 ). EXAMPLE 43 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-cyanobenzimidazole This Example, and subsequent Examples provide l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazole compositions with general structure of Figure 13B. In this example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyι)-4- cyanobenzimidazole (4007) was prepared in five steps from methyl NN-bis(2,6- difluorobenzoyl)-6-nitro-2-anilidecarboxylate (4002). To methyl 2-amino-6- nitrobenzoate (4001) (12.75 g, 65.0 mmol) dissolved in THF:pyridine (1:1) (300 mL) was added 2,6-difluorobenzoyl chloride (18.0 mL, 142.7 mmol, 220 M%). After a second addition at 7 h of 2,6-difluorobenzoyl chloride (8.0 mL, 64 mmol, 100 M%) and stirring overnight at room temperature, the reaction was concentrated. The residue was suspended in water and filtered. The filtrate was then suspended in boiling methanol and filtered, yielding methyl NN-bis(2,6-difluorobenzoyl)-6-nitro-2- anilidecarboxylate (4002) (28.26 g, 59.3 mmol, 91% yield): Η-ΝMR (200 MHz, OMSO-d 6 ) δ 8.41 (dd, J= 1.5, 8.2 Hz, IH, H 5 ), 8.29 (dd, J= 1.5, 8.0 Hz, IH, H 3 ), 7.86 (dd, J= 8.0, 8.2 Hz, IH, H 4 ), 7.55 (m, 2H, H 4 . 4 .), 7.13 (m, 4H, H 3 . 5 , 3 . 5 .), 3.86 (s, 3H, CO 2 Me). To methyl NN-bis(2,6-difluorobenzoyl)-6-nitro-2-anilidecarboxylate (4002) (28.20 g, 59.2 mmol) suspended in pyridine (300 mL) was added hydrazine (3.0 mL, 61.7 mmol, 105 M%). After 6 h at room temperature, the reaction was concentrated and the residue was redissolved in CH 2 C1 2 , and washed with ΝaHCO 3 (sat. aq.), and NaCl (sat. aq.). The combined washings were dried (NajSO,,), filtered, and evaporated. Recrystallization of the crude product from MeOH yielded methyl N-(2,6- difluorobenzoyl)-6-nitro-2-anilidecarboxylate (4003) (18.31 g, 54.5 mmol, 92% yield): 'H-ΝMR (200 MHz,CD 2 Cl 2 ) δ 10.81 (br, IH, ΝH), 8.22 (dd, J= 1.7, 8.1 Hz, IH, H 5 ), 8.15 (dd, J= 1.7, 8.1 Hz, IH, H 3 ), 7.50 (m, IH, H 4 .), 7.42 (dd, J= 8.1, 8.1 Hz, IH, H 4 ), 7.05 (m, 2H, H 3 . 5 .), 3.94 (s, 3H, CO 2 Me). Methyl N-(2,6-difluorobenzoyl)-6-nitro-2-anilidecarboxylate (4003) (19.33 g, 57.5 mmol) and iron powder (19.3 g) were reacted for 1 h. Recrystallization of the crude product from MeOH, yielded white solids of methyl 2-(2,6- difluorophenyl)benzimidazole-2-carboxylate (4004) (14.67 g, 50.9 mmol, 89% yield). 'H-ΝMR (300 MHz, CD 2 C1 2 ) δ 10.92 (br, IH, ΝH), 8.06 (d, J=8.1 Hz.lH, H 5 ), 7.97 (IH, dd, J= 1.0, 7.6 Hz, IH, H 7 ), 7.49 (m, IH, H 4 ), 7.37 (dd, J= 8.1, 7.6 Hz, IH, H 6 ), 7.14 (m, 2H, H 3 . 5 ), 4.01 (s, 3H, CH 3 ). Methyl 2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4004) (16.15 g, 56.0 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (14.67 g, 70.86 mmol, 125 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 , and recrystallization from diethylether, yielding white crystals of methyl l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4005) (17.63 g, 42.55 mmol, 76 % yield). M.p. 185-186°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.94 (dd, J= 1.1, 7.6 Hz, IH, H 5 ), 7.72 (dd, J= 1.1, 8.2 Hz, IH, H 7 ), 7.56 (m, IH, H 4 ), 7.37 (dd, J= 7.6, 8.2 Hz, IH, H 6 ), 7.26 (m, IH, H 4 -), 7.09 (m, 2H, H 3 5 ), 6.82 (m, 2H, H 3 .. 5 .), 5.39 (s, 2H, CH 2 PhF 2 ), 3.95 (s, 3H, CO 2 CH 3 ). To methyl 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2- carboxylate (4005) (1.02 g, 2.46 mmol) dissolved in methanol (20 mL) was added barium hydroxide (1.20 g). After 2 h, acetic acid was added and the reaction concentrated. The residue was redissolved in CH 2 C1 2 and washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (NajSO,,), filtered and concentrated. The product was purified by flash chromatography eluting with 8% MeOH/ CH 2 C1 2 and recrystallization from diethylether/ hexane (3:1) gave white crystals of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4006) ( 0.71 g, 1.77 mmol, 72 % yield). M.p. 179-180°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 8.06 (d, J= 7.8 Hz, IH, H 5 ), 7.76 (d, J= 8.1 Hz, IH, H 7 ), 7.62 (m, IH, H 4 .), 7.47 (dd, J= 7.8, 8.1 Hz, IH, H 6 ), 7.29 (m, IH, H 4 -), 7.14 (m, 2H, H 3 j5 ), 6.85 (m, 2H, H 3 . i5 ..), 5.45 (s, 2H, CH 2 PhF 2 ). To methyl 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2- carboxylate (4006) (2.00 g, 4.83 mmol) suspended in xylene (50 mL) was added a freshly prepared 1.0 M solution of AlMe 2 NH 2 (7 mL, 7.00 mmol, 145 M%). After 45 min at reflux, the reaction was concentrated and then redissolved in CH 2 C1 2 . The organic solution was washed with NaHSO 4 (10% solution, slow addition), NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (NajSO,,), filtered and concentrated. The product was purified by flash chromatography eluting with 1% methanol/ CH 2 C1 2 and recrystallization from diethylether, to produce white crystals of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-cyanobenzimidazole (4007) (1.50 g, 3.93 mmol, 81 % yield). M.p. 153-155°C. Η-NMR (200 MHz, CD 2 C1 2 ) δ 7.76 (dd, J= 1.1, 8.6 Hz, IH, H 5 ), 7.63 (dd, J= 1.0, 7.6 Hz, IH, H 7 ), 7.58 (m, IH, H 4 ), 7.37 (dd, J= 7.6, 8.6 Hz, IH, H 6 ), 7.28 (m, IH, H 4 . ), 7.1 l(m, 2H, H 3 >5 .), 6.83 (m, 2H, H 3 .. ιS ..), 5.40 (s, 2H, CH 2 PhF 2 ). EXAMPLE 44 Preparation of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)- 4-(propan-2-ol)benzimidazole To methyl 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2- carboxylate (4006, Example 43) (1.00 g, 2.41 mmol) dissolved in THF (20 mL) was added 3M methyl magnesium bromide (3.00 mL, 9.00 mmol). After 1 h, the reaction was concentrated. The residue was redissolved in CH 2 C1 2 , and washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na^O , filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals (0.95 g, 2.29 mmol, 95% yield). M.p. 149-150 °C; 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.55 (m, IH, H4'), 7.40 (d, J= 8.1 Hz, IH, H 5 ), 7.25 (m, 2H, H 4 „ 6 ), 7.16 (dd, J= 1.1, 7.6 Hz, IH, H 7 ), 7.10 (m, 2H, H 3 . 5 .), 6.82 (m, 2H, H 3 .. 5 „), 5.82 (s, IH, OH), 5.37 (s, 2H, CH 2 PhF 2 ), 1.67 (s, 6H, iPr). EXAMPLE 45 Preparation of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- (isopropenyl)benzimidazole To concentrated H 2 SO 4 (1.00 mL) at room temperature was added l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-(propan-2-ol)benzimidazole (Example 44) (0.45 g, 1.09 mmol). After 15 min, the reaction was diluted with ethylacetate. The organic solution was washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na^O,,), filtered and concentrated. The product was purified by flash chromatography eluting with 1% MeOH CH 2 Cl 2 and recrystallization from diethylether/ hexane (3:1) to produce 0.11 g (0.28 mmol, 30 % yield) of white crystals. M.p. 156-158°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.53 (m, IR V H 4 .), 7.44- 16 (m, 4H, H 4 . )5Λ7 ), 7.07 (m, 2H, H 3 5 .), 6.81 (m, 2H, H y . >$ ..), 6.03 (dq, J= 0.9, 2.4 Hz, IH, vinyl), 5.36 (dq, J= 1.5, 2.4 Hz, IH, vinyl), 5.35 (s, 2H, CH 2 PhF 2 ), 2.33 (dd, J= 0.8, 1.5 Hz, 3H, CH 3 ). EXAMPLE 46 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- methoxylbenzimidazole (5006) was prepared in four steps from 2-methoxyl-6- nitroaniline (5002). To 2-amino-3-nitrophenol (5001) (2.00g, 12.98 mmol) dissolved in acetone (20 mL) was added K 2 CO 3 (2.15 g), and methyl iodide (1.00 mL). After stirring overnight, the reaction was concentrated. The residue was redissolved in ethylacetate, and washed with water, NaHSO 4 (10% solution), NaCl (sat. aq.). The combined washings were dried (Na^O,,), filtered, and concentrated. The crude product was purified by flash chromatography eluting with (1:4) ethylacetate/hexane, yielding white crystals of 2-methoxyl-6-nitroaniline (5002) (1.79 g, 10.65 mmol, 82% yield). 'H-NMR (300 MHz, CD 2 C1 2 ) δ 7.69 (dd, J = 1.4, 8.9 Hz, IH, H 5 ), 6.92 (dd, J =1.4, 7.8 Hz, IH, H 3 ), 6.62 (dd, J =8.9, 7.8 Hz, IH, H 4 ), 6.42 (br, 2H, NH 2 ), 3.91 (s, 3H, OCH 3 ). To 2-methoxyl-6-nitroaniline (5002) (13.75 g, 81.8 mmol) dissolved in THF:pyridine (1:1) (300 mL) was added 2,6-difluorobenzoyl chloride (22.0 mL, 174.4 mmol, 215 M%. After stirring the reaction mixture overnight at room temperature, the reaction was concentrated to dryness. The residue was redissolved in CH 2 C1 2 , washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (NajSOJ, filtered and concentrated. The product was recrystallized from methanol to give white crystals of N,N-Bis-(2,6-difluorobenzoyl)-2-methoxyl-6-nitroanilide (5003) (33.7 g, 75.2 mmol, 92% yield). Η-ΝMR (300 MHz, CD 2 C1 2 ) δ 7.70 (dd, J= 1.4, 8.4 Hz, IH, Hj), 7.48 (dd, J= 8.4, 8.4 Hz, IH, H 4 ), 7.35 (2H, m, H 4 . 4 .), 7.15 (dd, J= 1.4, 8.4 Hz, IH, H 3 ), 6.87 (m, 4H, H 3 . 5 , 3 , 5 .), 3.85 (s, 3H, OCH 3 ). To N,N-bis-(2,6-difluorobenzoyl)-2-methoxyl-6-nitroanilide (5003) (33.7 g, 75.2 mmol) dissolved in pyridine (500 mL) was added hydrazine (4.50 mL, 92.6 mmol, 120 M%). After stirring overnight at room temperature, the reaction was concentrated. The residue was redissolved in CH 2 C1 2 , and washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na j SO , filtered, evaporated. The crude product was recrystallized from methanol, yielding white solids of N-(2,6- difluorobenzoyl)-2-methoxyl-6-nitroanilide (5004) (22.39 g, 72.6 mmol, 96% yield). 'H-ΝMR (200 MHz,CD 2 Cl 2 ): δ 8.82 (br, IH, ΝH), 7.51 (dd, J= 1.6, 8.1 Hz, IH, H 5 ), 7.45 (m, IH, H 4 ,), 7.35 (dd, J= 8.2, 8.3 Hz, IH, H 4 ), 7.12 (dd, J= 8.3, 1.6 Hz, IH, H 3 ), 7.01 (m, 2H, H 3 . ,5 .), 3.92 (s, 3H, OMe). N-(2,6-difluorobenzoyl)-2-methoxyl-6-nitroanilide (5004) (2.20 g, 7.15 mmol) and iron powder (2.20 g) were reacted for 1 h. The crude product was purified by flash chromatography with 2% MeOH CH 2 Cl 2 , yielding white crystals of 2-(2,6- difluorophenyl)-4-methoxylbenzimidazole (5005) (1.68 g, 6.18 mmol, 86% yield). Η- ΝMR (300 MHz, CD 2 C1 2 ): δ 10.07 (br d, J= 36 Hz, IH, ΝH), 7.40 (cm, IH), 7.29- 7.00 (cm, 4H), 6.75 (dd, J= 8.0, 13.8 Hz, IH), 4.00 (d, J= 4.2 Hz, 3H, OCH 3 ). 2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005) (1.25 g, 4.80 mmol) was reacted with 2,6-difluoro-a-bromo-toluene (1.30 g, 6.28 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5006) (1.68g, 4.35 mmol, 91% yield). M.p. 154-155°C. 'H-ΝMR (200 MHz, CD 2 C1 2 ): δ 7.52 (m, IH, H 4 ), 7.25 (m, IH, H 4 ~), 7.19 (dd, J = 7.8, 1.0 Hz, IH, H 5 ), 7.13-7.00 (m, 3H, H 3 ι5 . 6 ), 6.81 (m, 2H, H 3 . ,5 .), 6.72 (dd, J = 7.8, 1.0 Hz, H 7 ), 5.33 (s, 2H, CH 2 PhF 2 ), 4.00 (s, 3H, OCH 3 ). EXAMPLE 47 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-ethylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- ethylbenzimidazole (4011) was prepared in two steps from N-(2,6-difluorobenzoyl)-2- ethyl-6-nitroanilide (4009). 2-Ethyl-6-nitroaniline (4008) (3.10 g, 18.65 mmol) was reacted with 2,6-difluorobenzoyl chloride (3.50 mL, 27.83 mmol, 150 M%), and the reaction mixture was stirred overnight at room temperature. The crude product was purified by flash chromatography with 2% MeOH/CH 2 Cl 2 and recrystallization from ethylacetate/hexane (1 :4), yielding N-(2,6-difluorobenzoyl)-2-ethyl-6-nitroanilide (2.34 g, 7.64 mmol, 41% yield). 'H-ΝMR (200 MHz, CD 2 C1 2 ) δ 8.25 (br, IH, ΝH), 7.85 (dd, J = 1.7, 8.1 Hz, IH, H s ), 7.66 (dd, J = 1.7, 7.9 Hz, IH, H 3 ), 7.49 (m, IH, H 4 ), 7.45 (dd, J = 7.9, 8.1 Hz, IH, H 4 ), 7.06 (m, 2H, H 3 ι5 ), 2.81 (q, J =7.6 Hz, 2H, CH 2 ), 1.29 (t, J =7.6 Hz, 3H, CH 3 ). N-(2,6-Difluorobenzoyl)-2-ethyl-6-nitroanilide (4009) (2.00 g, 6.53 mmol) was reacted with iron powder (2.00 g) for 0.5 h at room temperature. The crude product was purified by flash chromatography eluting with 2% MeOH CH 2 Cl 2 , and recrystallization from CH 2 C1 2 , yielding white crystals of 2-(2,6-difluorophenyl)-4- ethylbenzimidazole (4010) (1.65 g, 6.39 mmol, 98% yield). 'H-ΝMR (200 MHz, CD 2 C1 2 ): δ 9.78 (br, IH, ΝH), 7.46 (br, IH, H 5 ), 7.45 (m, IH, H 4 ), 7.23 (dd, J = 7.4, 7.9 Hz, IH, H 6 ), 7.17-7.04 (m, 3H, H 3 j5 >7 ), 3.03 (br, 2H, CH 2 ), 1.39 (t, J = 7.7 Hz, 3H, CH 3 ). 2-(2,6-Difluorophenyl)-4-ethylbenzimidazole (4010) (0.70 g, 2.71 mmol) was reacted v/ith 2,6-difluoro-a-bromo-toluene (0.72 g, 3.48 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of l-(2,6- Difluorobenzyl)-2-(2,6-difluorophenyl)-4-ethylbenzimidazole (4011) ( 0.79 g, 2.06 mmol, 76% yield). M.p. 165-166°C. Η-ΝMR (200 MHz, CD 2 C1 2 ): δ 7.53 (m, IH, H 4 ), 7.32 (d, J = 8.2 Hz, IH, H 5 ), 7.29-7.16 (m, 2H, H 64 .), 7.14-7.01 (m, IH, H 7 ), 7.07 (m, 2H, H 3 >5 ), 6.81 (m, 2H, H 3 - s -), 5.33 (s, 2H, CH 2 ), 3.07 (q, J =7.6 Hz, 2H, CH 2 ), 1.35 (t, J = 7.6 Hz, 3H, CH 3 ). EXAMPLE 48 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4- (N-methylamino)benzimidazole First, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N- methylacetamido)benzimidazole (4005) was prepared (Example 88). To l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamido)benzimidazole (2.44 g, 5.90 mmol) and methyl iodide (0.60 mL, 9.69 mmol) dissolved in THF (30 mL) was added excess ΝaH. After stirring overnight, the solution was concentrated to dryness, diluted with CH 2 C1 2 , and washed with water, ΝaHSO 4 (10% solution) and NaCl (sat. aq.). The combined washings were dried (Na 2 SO 4 ), filtered, concentrated and purified by flash chromatography eluting with 2% methanol in CH 2 C1 2 to give l-(2,6-difluorobenzyl)-2- (2,6-difluorophenyl)-4-(N-methylacetamido)benzimidazole (0.89 g, 2.08 mmol, 63% yield). M.p. 155-156°C. 'H-ΝMR (200 MHz, CD 2 C1 2 ) δ 7.55 (m, IH, H 4 ), 7.48 (br d, J =7.4 Hz, IH, H 5 ), 7.31 (dd, J = 7.4, 7.7 Hz, IH, H 6 ), 7.27 (m, IH, IL,..), 7.14 (dd , J = 1.1, 7.7 Hz, IH, H 7 ), 7.09 (m, 2H, H 3 j5 ), 6.84 (m, 2H, H 3 .. >5 -.), 5.38 (s, 2H, CH 2 PhF 2 ), 3.34 (s, 3H, ΝCH 3 ), 1.83 (s, 3H, NAc). To 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N- methylacetamido)benzimidazole (4005) (0.50 g, 1.17 mmol) suspended in water (9.0 mL) was added HCl (1.0 mL). After 3 h at reflux, the solution was concentrated to dryness, diluted with ethylacetate, and washed with ΝaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na^O , filtered, concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH 2 C1 2 , yielding 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N- methylamino)benzimidazole (4006) (0.35 g, 78 % yield):. M.p. 194-195°C. 'H-ΝMR (200 MHz, CD 2 C1 2 ) δ 7.52 (m, IH, H 4 ), 7.23 (m, IH, H 4 . ), 7.1-3 (dd, J = 8.3, 8.0 Hz, IH, H 6 ), 7.07 (m, 2H, H 3 . ,5 ), 6.80 (m, 2H, H 3 - ,5 ..), 6.76 (d, J = 8.3 Hz, IH, H 5 ), 6.36 (d, J = 8.0 Hz, IH, H 7 ), 5.29 (s, 2H, CH 2 PhF 2 ), 2.96 (s, 3H, ΝCH 3 ). EXAMPLE 49 Preparation of 1 -(2,6-Difluorobenzyl)-2-(Cyclopropyl)-4-Methoxylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(cyclopropyl)-4- methoxylbenzimidazole (5016) was prepared in two steps from cyclopropanecarboxylic acid (2-methoxy-6-nitro-phenyl)-amide (5013). To 2-methoxyl-6-nitroaniline (5002) (4.15 g, 24.7 mmol) dissolved in THF:pyridine (1:1) (100 mL) was added cyclopropanecarbonyl chloride (2.7 mL, 29.8 mmol, 120 M%. After stirring at room temperature for 4 h, the reaction was concentrated to dryness and the residue was redissolved in CH 2 C1 2) and washed with NaHSO 4 (10% solution), NaHCO 3 (sat. aq) and NaCl (sat. aq.). The combined washings were dried (NajSO , filtered and concentrated. Cyclopropanecarboxylic acid (2-methoxyl-6-nitro-phenyl)-amide (5013) was recrystallized from methanol (4.90 g, 20.8 mmol, 84% yield of white crystals). Η-NMR (200 MHz, CD 2 C1 2 ): δ 7.82 (br, IH, NH), 7.44 (dd, J= 1.6, 8.1 Hz, iH, H 5 ), 7.25 (dd, J= 8.2, 8.1 Hz, IH, H 4 ), 7.16 (dd, J= 1.7, 8.2 Hz, IH, H 3 ), 3.95 (s, 3H, OCH 3 ), 1.65 (m, IH), 0.94 (m, 4H). Cyclopropanecarboxylic acid (2-methoxy-6-nitro-phenyl)-amide (5013) (7.80 g, 33.1 mmol) and iron powder (7.60 g) were suspended in acetic acid (200 mL) for 25 min at reflux. The reaction was concentrated and redissolved in ethyl acetate, and washed with NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (NajSO,,), filtered and concentrated. The crude product was purified by flash chromatography with 2% MeOH/CH 2 Cl 2 and recrystallization from diethyl ether/hexane (3:1), yielding white crystals of 2-(cyclopropyl)-4-methoxylbenzimidazole (5014) (4.90g, 26.1 mmol, 79% yield). Η-NMR (200 MHz, CD 2 C1 2 :) δ 7.07 (cm, 2H), 6.65 (cm, IH), 3.90 (s, 3H, OCH 3 ), 2.17-2.03 (m, IH), 1.22-0.96 (m, 4H). 2-(Cyclopropyl)-4-methoxylbenzimidazole (1.00 g, 5.32 mmol) (5014) was reacted with 2,6-difluoro-a-bromo-toluene (1.30 g, 6.28 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% methanol CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of l-(2,6- Difluorobenzyl)-2-(cyclopropyl)-4-methoxylbenzimidazole (5016) (1.54 g, 4.90 mmol, 92% yield). M.p. 136-139°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.31 (m, IH, H 4 .), 7.07 (dd, J= 8.0, 7.8 Hz, IH, H 6 ), 6.94 (m, 3H, H 3 . >5 5 ), 6.61 (dd, J = 7.8, 1.0 Hz, H 7 ), 5.46 (s, 2H, CH 2 PhF 2 ), 3.95 (s, 3H, OCH 3 ), 2.20-2.03 (m, IH), 1.18-0.97 (m, 4H). EXAMPLE 50 Preparation of l-(2,6-Difluorobenzyl)-2-(2-Fluoro-6-Methoxylphenyl)-4- Nitrobenzimidazole First, 2-(2,6-difluorophenyl)-4-nitrobenzimidazole was prepared. N-(2,6- difluorobenzoyl)-2-amino-3-nitroanilide (Example 5) was dissolved in acetic acid (150 mL) and heated to reflux. After heating overnight, the reaction mixture was cooled to room temperature, and concentrated. The residue was redissolved in methylene chloride, washed with NaHCO 3 (sat. soln.). The combined washings were dried with NajSO,,, filtered and evaporated. The crude product was purified by flash chromatography eluting with ethylacetate/hexane (1:1), and recrystallized from ethylacetate/hexane (1:4), yielding the 2-(2,6-difluorophenyl)-4-nitrobenzimidazole (7.90 g, 2.87 mmol, 72%). Η NMR (300 MHz, CD 2 C1 2 ): 11.00 (s, IH, NH), 8.23 (dd, J=8.2, 0.8 Hz, IH, H 5 ), 8.21 (dd, J=8.0, 0.8 Hz, IH, H 7 ), 7.54 (m, IH, H 4 ), 7.45 (dd, J=8.0, 8.2 Hz, IH, H 6 ), 7.13 (m, 2H, H 3 . 5 .). 2-(2,6-difluorophenyl)-4-nitrobenzimidazole (7.7 g, 28 mmol) was reacted with 2,6-difluorobenzylbromide (6.95 g, 33.6 mmol). The crude product was purified by recrystallization from diethylether.hexane (3:1), 9.8 g (24.4 mmol, 87%), yielding white crystals 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole. M.p. 168-170 °C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 8.13 (dd, J = 8.1, 0.9 Hz, IH, H 5 ), 7.86 (dd, J = 8.1, 0.9 Hz, IH, H 7 ), 7.59 (m, IH, H 4 .), 7.43 (dd, J = 8.1 Hz, H 6 ), 7.28 (m, IH, H 4 . ), 7.12 (m, 2H, H 3 j5 ), 6.84 (m, 2H, H 3 . 5 .), 5.44 (s, 2H, CH 2 ). To l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (2.00 g, 8 mmol)was added 2,6-difluorobenzylbromide (2.0.2 g, 9.76 mmol, 130 M%) dissolved in THF (20 mL) was added NaH (0.84 g, 21 mmol, 290 M%). After 8 h, the reaction was quenched with m ethanol and concentrated. The residue was dissolved in CH 2 C1 2 , and washed with water and NaCl (sat. aq.). The combined washings were dried (Na 2 SO 4 ), filtered, concentrated. The crude product was purified by flash chromatography eluting with ethylacetate:hexane (1:1) (2.33 g, 5.64 mmol, 78%). M.p. 189-192°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 8.11 (dd, J = 8.1, 1.0 Hz, IH, H 5 ), 7.84 (dd, J = 8.1, 1.0 Hz, IH, H 7 ), 7.52 (m, IH, H 4 .), 7.40 (dd, J = 8.1 Hz, IH, He), 7.26 (m, IH, H 4 ), 6.89-6.74 (m, 4H, H 3 . 5 . 3 .. 5 . ), 5.36 (d, J =3.4Hz, 2H, CH 2 PhF 2 (rotamers)), 3.73 (s, 3H, OCH 3 ). EXAMPLE 51 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2-Fluoro-4-Methoxylphenyl)- 4-Aminobenzimidazole To l-(2,6-difluorobenzyl)-2-(2-fluoro-4-methoxylphenyl)-4-nitrobenzimidazole (Example 50) (2.00 g, 4.98 mmol) dissolved in acetic acid (20 mL) was added SnCl 2 x2H 2 O (9.02 g) dissolved in concentrated HCl (8 mL). After stirring for 30 min at room temperature, the mixture was concentrated. The residue was diluted with CH 2 C1 2 and washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (NajSO 4 ), filtered, and evaporated. The crude product was recrystallized from methanol to give 3.26 g of white crystals, (8.78 mmol, 70% yield). M.p. 200-202°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.45 (m, IH, H 4 ), 7.22 (m, IH, IV), 7.05 (dd, J = 7.8, 7.6 Hz, IH, H 6 ), 6.85-6.72 (m, 5H, H 3 . ,5 . ), 6.50 (dd, J = 7.7, 1.0 Hz, IH, H 5 ), 5.21 (d, J =5.4 Hz, 2H, CH 2 PhF 2 (rotamers)), 4.34 (br, 2H, NH 2 ), 3.72 (s, 3H, OCH 3 ). EXAMPLE 52 Preparation of l-Benzyl-2-(2,6-Difluorophenyl)-4-Methoxylbenzimidazole 2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (2.02 g, 7.77 mmol) was reacted with benzyl bromide (1.20 mL, 10.1 mmol, 130 M%). The crude product was purified by flash chromatography eluting with 2% MeOH CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1- benzyl-2-(2.6-difluorophenyl)-4-methoxylbenzimidazole (2.47 g, 7.05 mmol, 90 % yield). M.p. 139-141°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.48 (m, IH, H 4 ), 7.25- 6.96 (m, 8H), 6.86 (dd, J = 0.8, 8.3 Hz, IH, H 5 ), 6.72 (dd, J= 8.0, 0.8 Hz, IH, H 7 ), 5.24 (s, 2H, CH 2 Ph), 4.01 (s, 3H, OCH 3 ). EXAMPLE 53 Preparation of l-(Ethylbenzyl)-2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole 2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (0.10 g, 0.38 mmol) was reacted with (l-bromoethyl)benzene (0.28 mL). The crude product was purified by flash chromatography eluting with 2% MeOH/ CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1- (ethylbenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (0.12 g, 0.33 mmol, 86 % yield). M.p. 139-141°C. 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.51 (m, IH, H 4 ), 7.25 (dd, J= 8.0, 8.1 Hz, IH, H 6 ), 7.17 (m, 3H, Ph), 7.06 (m, 2H, H 3 . 5 ), 7.04 (dd, J= 8.1, 0.8 Hz, IH, H 5 ), 6.91 (m, 2H, Ph), 6.74 (dd, J = 0.8, 8.0 Hz, H 7 ), 4.27 (t, J= 7.5 Hz, 2H), 4.03 (s, 3H, OCH 3 ), 3.00 (t, J= 7.5 Hz, CH 2 Ph). EXAMPLE 54 Preparation of 1 -(3,3-Dimethylallyl)-2-(2,6-Difluorophenyl)-4-Methoxylbenzimidazole To 2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5005, Example 46) (0.28 g, 1.08 mmol) and 3,3-dimethylallyl bromide (0.20 mL, 0.26 mmol, 160 M%) dissolved in THF (3 mL) was added NaH (60% dispersion in mineral oil) (0.15 g, 3.75 mmol, 350 M%). After 4 h, the reaction was quenched with MeOH and concentrated. The residue was redissolved in dichloromethane, washed with water and NaCl (sat. aq.), dried (Na^O,), filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallized from hexane to give white powders of l-(3,3-dimethylallyl)-2-(2,6-difluorophenyl)-4-methoxyl- benzimidazole (0.30 g, 0.91 mmol, 84% yield). M.p. 101-103 °C. 'H-NMR (200 MHz, CD 2 C1 2 ): 7.52 (m, IH, H 4 .), 7.24 (dd, J= 7.9, 8.2 Hz, IH, H 6 ), 7.08 (m, 2H, H 3 . 5 ..), 7.02 (dd, J= 0.9 , 8.2 Hz, IH, H 5 ), 6.73 (dd, J= 0.9, 7.9 Hz, IH, H 7 ), 5.19 (t, J= 7.0 Hz, IH, H 2 .), 4.02 (s, 3H, OCH 3 ), 4.62 (d, J= 7.0 Hz, 2H, H r ), 1.64 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ). EXAMPLE 55 Preparation of 1 -(3,3-Dimethylallyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole To 2-(2,6-difluorophenyl)-4-methylbenzimidazole (Example 13) (0.50 g, 2.05 mmol) and 3,3-dimethylallyl bromide (0.50 mL, 4.34 mmol, 210 M%) dissolved in THF (10 mL) was added NaH (60% dispersion in mineral oil) (0.17 g, 4.25 mmol, 200 M%). After 4 h, the reaction was quenched with MeOH and concentrated. The residue was redissolved in dichloromethane, washed with water and NaCl (sat. aq.), dried (NajSO , filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallized from hexane to yield white powders of l-(3,3-dimethylallyl)-2-(2,6-difluorophenyl)-4- methylbenzimidazole (0.40 g, 1.28 mmol, 63% yield). M.p. 78-79 °C. 'H-NMR (200 MHz, CD 2 C1 2 ): 7.52 (m, IH, H 4 .), 7.26-7.02 (m, 5H, H 5Λ7ι3 . )5 ..), 5.18 (t, J= 6.8 Hz, IH, H 2 ), 4.62 (d, J= 6.8 Hz, 2H, H, ), 2.64 (s, 3H, CH 3 ), 1.64 (s, 3H, CH 3 ), 1.57 (s, 3H, CH 3 ). EXAMPLE 56 Preparation of l-(3,3-Dimethylallyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole To 2-(2,6-difluorophenyl)-4-nitrobenzimidazole (Example 50) (2.50 g, 9.08 mmol) and 3,3-dimethylallyl bromide (2.00 mL, 17.35 mmol, 190 M%) dissolved in THF (25 mL) was added NaH (60% dispersion in mineral oil) (0.70 g, 17.5 mmol, 190 M%). After stirring overnight at room temperature, the reaction was quenched with MeOH and concentrated. The residue was redissolved in dichloromethane, washed with water and NaCl (sat. aq.), dried (Na 2 SO 4 ), filtered and concentrated. The product was purified by flash chromatography eluting with ethylacetate/hexane (1:1) and recrystallized from hexane (2.88 g, 8.39 mmol, 92% yield of white powder), mp 130-132 °C; Η-NMR (200 MHz, CD 2 C1 2 ): 8.15 (dd, J= 1.0, 8.1 Hz, IH, H 5 ), 7.77 (dd, J= 1.0, 8.2 Hz, IH, H 7 ), 7.59 (m, IH, IV), 7.44 (dd, J= 8.1, 8.2 Hz, IH, H 6 ), 7.14 (m, 2H, H 3 ,5 ), 5.19 (t, J= 6.8 Hz, IH, H 2 ), 4.73(d, J= 7.0 Hz, 2H, H, ), 1.68 (s, 3H, CH 3 ), 1.62 (s, 3H, CH 3 ). EXAMPLE 57 Preparation of l-(3,3-Dimethylallyl)-2-(2,6-difluorophenyl)-4-aminobenzimidazole To l-(3,3-dimethylallyl)-2-(2,6-difluoroρhenyl)-4-nitrobenzimidazole (Example 56) (2.00 g, 5.83 mmol) dissolved in glacial acetic acid (20 mL) was added iron powder (8.89 g). After 30 min at reflux, the reaction was concentrated to dryness, diluted with ethyl acetate and washed with NaHCO 3 . The aqueous layer was back extracted with ethyl acetate, and the combined organic solution was washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.), dried (NajSO,,), filtered and concentrated. The product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 and recrystallized from hexane (1.73 g, 5.52 mmol, 95% yield of white powder). M.p. 107-108 °C. Η-NMR (200 MHz, CD 2 C1 2 ): 7.54 (m, IH, H 4 -), 7.16-7.05 (m, 3H, H 63 . 5 ••), 6.80 (dd, J= 1.0, 8.2 Hz, IH, H 7 ), 6.55 (dd, J= 1.0, 7.6 Hz, IH, H 5 ), 5.20 (t, J= 6.8 Hz, IH, H 2 .), 4.60 (d, J= 6.8 Hz, 2H, H,.), 4.40 (br, 2H, NH 2 ), 1.66 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ). EXAMPLE 58 Preparation Of N,N-Bis-(2,6-Difluorobenzoyl)-4-Chloro-2-Nitroanilide In this Example, N,N-bis-(2,6-difluorobenzoyl)-4-chloro-2-nitroanilide (400) was prepared. First, 4-chloro-2-nitroaniline (1.05 g, 6.08 mmol) was dissolved in THF:pyridine (1:1) (20 mL), and 2,6-difluorobenzoyl chloride (7) was added (1.9 mL, 15.1 mmol, 250 M%). After 6 hours of mixing, a second aliquot of 2,6- difluorobenzoyl chloride (0.6 mL, 4.77 mmol, 78 M%) was added. After stirring overnight at room temperature, the reaction was concentrated to dryness. The residue was redissolved in CH 2 C1 2 , washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na 2 SO 4 ), filtered and concentrated. The product was recrystallized from ethylacetate (2.67 g, 5.90 mmol, 97% yield) to produce white crystals. Η-NMR (300 MHz, CD 2 C1 2 ): δ 8.15 (d, J= 2.4 Hz, IH, H 3 ), 7.67 (dd, J= 2.4, 8.5 Hz, IH, H 5 ), 7.51 (d, J= 8.5 Hz, IH, H 6 ), 7.36 (m, 2H, H 4 . 4 . ), 6.89 (m, 4H, EXAMPLE 59 Preparation Of N-(2,6-Difluorobenzoyl)-4-Chloro-2-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-4-chloro-2-nitroanilide (500) was prepared. First, NN-bis-(2,6-difluorobenzoyl)-4-chloro-2-nitroanilide (Example 58) (1.00 g, 4.42 mmol) was dissolved in methanol/dioxane (1:1) (40 mL), and sodium hydroxide (0.27 g, 6.75 mmol, 150 M%) was then added to the mixture. After stirring for 30 minutes at room temperature, the reaction was quenched with ΝaHSO 4 , diluted with CH 2 C1 2 , and washed with NaHCO 3 (sat aq) and NaCl (sat aq). The combined washings were dried (Na^O , filtered and concentrated. The product (1.28 g, 4.09 mmol, 93 % yield) was recrystallized from ethylene oxide/hexane (3:1). 'H-NMR (300 MHz, CD 2 C1 2 ): δ 10.72 (s, IH, NH), 8.91 (d, J= 9.1 Hz, IH, H 6 ), 8.27 (d, J= 2.5 Hz, IH, H 3 ), 7.71 (dd, J= 9.1, 2.5 Hz, IH, H 5 ), 7.52 (m, IH, H 4 ), 7.08 (m, 2H, H 3 >5 ). EXAMPLE 60 Preparation Of N,N-Bis-(2,6-Difluorobenzoyl)-5-Chloro-2-Nitroanilide In this Example, N,N-bis-(2,6-difluorobenzoyl)-5-chloro-2-nitroanilide (600) was prepared. First, 5-chloro-2-nitroaniline (1.02 g, 5.91 mmol) was dissolved in pyridine/THF (1 :1) (20 mL), and 2,6-difluorobenzoyl chloride (7) (1.50 mL, 11.9 mmol, 200 M%) was then added. After stirring overnight at room temperature, the reaction was concentrated to dryness. The residue was redissolved in CH 2 C1 2 , and washed with NaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na^O , filtered, and concentrated. The product was recrystallized from ethylacetate (2.50 g, 5.52 mmol, 93% yield of white crystals). 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.12 (dd, J = 8.5, 1.1 Hz, IH, H 3 ), 7.58 (AB, J= 2.4, 1.1 Hz, IH, H 6 ), 7.57 (AB, J= 2.4, 8.4 Hz, IH, H 4 ), 7.36 (m, 2H, H 4 . 4 ~), 6.89 (m, 4H, H 3 ,5 . 3 - 5 . ). EXAMPLE 61 Preparation Of N-(2,6-Difluorobenzoyl)-5-Chloro-2-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-5-chloro-2-nitroanilide (700) was prepared. First, N,N-bis-(2,6-difluorobenzoyl)-5-chloro-2-nitroanilide (Example 60) (1.00 g, 2.20 mmol) was dissolved in methanol/dioxane (1:1) (20 mL), and then sodium hydroxide (92 mg, 2.30 mmol, 105 M%) was added. After stirring for 30 minutes at room temperature, additional sodium hydroxide (92 mg, 2.30 mmol, 105 M%) was added. After an additional 15 minutes the reaction was quenched with ΝaHSO 4 , diluted with CH 2 C1 2 , and washed with NaHCO 3 (sat aq.) and NaCl (sat aq.). The combined washings were dried (Na^O , filtered and concentrated. The product was recrystallized from ethylene oxide/hexane (3:1) to produce 0.55 g, (1.85 mmol, 84% yield) of white crystals. 'H-NMR (200 MHz, CD 2 C1 2 ): δ 10.91 (s, IH, NH), 9.04 (d, J= 2.3 Hz, IH, H 6 ), 8.23 (d, J= 9.0 Hz, IH, H 4 ), 7.52 (cm, IH, H 4 ), 7.26 (dd, J= 2.3, 9.0 Hz, IH, H 4 ), 7.08 (m, IH, H 3 , 5 ). EXAMPLE 62 Preparation Of N-(2,6-Difluorobenzoyl)-2-Amino-3-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-2-amino-3-nitroanilide (800) was prepared according to Method A, described above, with the changes to the starting materials, notable variations, and/or additions to the method indicated as needed. Method A was also used to produce the compounds described in subsequent Examples, as indicated. 3-nitro-l,2-phenylenediamine (13.3 g, 86.85 mmol) and 2,6-difluorobenzoyl chloride (15.33 g, 10.95 mL, 86.85 mmol) were mixed and stiπed overnight. The crude product was recrystallized from ethylacetate/hexane to produce 12 g (41 mmol, 48% yield) of yellow crystals. 'H-ΝMR (300 MHz, OMSO-d 6 ): δ 10.23 (s, IH, ΝH), 7.99 (dd, J= 8.7, 1.4 Hz, IH, H 4 ), 7.71 (dd, J= 7.6 Hz, 1.4 Hz, IH, H 6 ), 7.62 (m, IH, H 4 ), 7.28 (m, 2H, H 3 ι5 ), 6.91 (s, 2H, ΝH 2 ), 6.76 (dd, J= 8.7, 7.6 Hz, IH, H 5 ). EXAMPLE 63 Preparation Of N-(2,6-Difluorobenzoyl)-2,3-Dimethyl-6-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-2,3-dimethyl-6-nitroanilide (900) was prepared according to Method A, using 2,3-dimethyl-6-nitroaniline (2.00 g, 12.04 mmol) and 2,6-difluorobenzoyl chloride (7) (1.50 mL, 13.93 mmol, 115 M%). After 3 hours of mixing, an additional (7) (0.50 mL, 4.64 mmol, 40 M%) was added to the mixture. After an additional 5 hours of mixing, the compound was recrystallized from ethylacetate/hexane (1:4) to produce 2.71 g (8.85 mmol, 74% yield) of yellow crystals. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 8.67 (s, IH, ΝH), 7.81(d, J= 8.4 Hz, IH, H 6 ), 7.48 (m, IH, IV), 7.28 (d, J= 8.4 Hz, IH, H 5 ), 7.05 (m, 2H, H 3 >5 ), 2.44 (s, 3H, CH 3 ), 2.31 (s, 3H, CH 3 ). EXAMPLE 64 Preparation Of N-(2,6-Difluorobenzoyl)-3-Methyl-6-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-3-methyl-6-nitroanilide (1000) was prepared according to Method A. First, 5-methyl-2-nitroaniline (4.95 g, 32.5 mmol) was mixed with 2,6-difluorobenzoyl chloride (4.50 mL, 41.8 mmol, 130 M%), as described. After recrystallization from ethylacetate, 8.71 g (29.8 mmol, 92 % yield) of yellow crystals were produced. Η-ΝMR (300 MHz, CD 2 C1 2 ): δ 10.85 (s, IH, ΝH), 8.75 (s, IH, H 2 ), 8.16 (d, J= 8.6, IH, H 5 ), 7.50 (m, IH, H 4 .), 7.48 (d, J= 8.6, IH, H 4 ), 7.06 (m, 2H, H 3 ), 2.50 (s, 3H, CH 3 ). EXAMPLE 65 Preparation Of N-(2,6-Difluorobenzoyl)-4-Methyl-2-Νitroanilide In this Example, N-(2,6-difluorobenzoyl)-4-methyl-2-nitroanilide (1100) was prepared according to Method A. First, 4-methyl-2-nitroaniline (4.95 g, 32.5 mmol) was mixed with 2,6-difluorobenzoyl chloride (7) (4.50 mL, 41.8 mmol, 130 M%), as described. After recrystallization from ethylacetate, 6.69 g (22.9 mmol, 70 % yield) of yellow crystals were produced. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 10.64 (s, IH, ΝH), 8.75 (d, J= 8.6, IH, H 6 ), 8.06 (s, IH, H 3 ), 7.52 (m, IH, H 4 -), 7.48 (d, J= 8.6, IH, H 5 ), 7.06 (m, 2H, H 3 ι5 ), 2.42 (s, 3H, CH 3 ). EXAMPLE 66 Preparation Of N-(2,6-Difluorobenzoyl)-4-Bromo-2-Νitroanilide In this Example, N-(2,6-difluorobenzoyl)-4-bromo-2-nitroanilide (1200) was prepared according to Method A. First, N-(2,6-difluorobenzoyl)-2-nitroanilide (Example 5) (1.20 g, 8.69 mmol) was suspended in 10 mL pyridine/THF (1:1). Bromine (0.5 mL) dissolved in acetic acid (0.5 mL) was then added to the mixture. After stirring for 1 hour at room temperature, the reaction was quenched with NaHCO 3 (sat. aq.). The solution was extracted with CH 2 C1 2 , and the organic extract was washed with NaCl (sat. aq.). The combined washings were dried (NajSO,,), filtered and concentrated. The product was recrystallized from ethylacetate to produce 1.55 g, (4.34 mmol, 50 % yield) of yellow crystals. 'H-NMR (200 MHz, CD 2 C1 2 ): δ 10.72 (br s, IH, NH), 8.85 (d J= 9.1 Hz, IH, H 5 ), 8.42 (d J= 2.4 Hz, IH, H 3 ), 7.84 (ddd, J= 0.5, 2.4, 9.1 Hz, IH, H 6 ), 7.52 (m, IH, H 4 ), 7.07 (m, 2H, H 3 >5 ). EXAMPLE 67 Preparation Of N-(2,6-Difluorobenzoyl)-N-(2,6-Difluorobenzyl)-4-Bromo-2-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-N-(2,6-difluorobenzyl)-4-bromo-2- nitroanilide (1400) was prepared according to Method E. Method E was also used to produce the compounds described in subsequent Examples, with the changes to the starting materials, notable variations, and/or additions to the method indicated as needed. N-(2,6-difluorobenzoyl)-4-bromo-2-nitroanilide (Example 66) (0.26 g, 0.73 mmol) and 2,6-difluoro-α-bromo-toluene (0.27 g, 1.30 mmol, 180 M%) were dissolved in THF (2 mL), to which ΝaH (0.15 g, 500 M%) was added. After 6 hours, the reaction was quenched with methanol and concentrated. The residue was redissolved in CH 2 C1 2 , and washed with ΝaHCO 3 (sat. aq.) and NaCl (sat. aq.). The combined washings were dried (Na^O,), filtered and concentrated. The product was purified by flash chromatography eluting with ethylacetate/hexane (1:4), and recrystallized from diethyl ether: hexane (3:1) to produce 0.26 g, (0.54 mmol, 74% yield) of white crystals. 'H-NMR (200 MHz, DMSO d 6 ) (rotamers): δ 8.30 (d, J= 2.3 Hz, IH, H 3 , rotamer 1), 8.25 (d, J= 2.3 Hz, IH, H 3 , rotamer 2), 8.02 (dd, J= 2.3, 8.5 Hz, IH, H 5 , rotamer 1), 7.85 (dd, J= 2.3, 8.5 Hz, IH, H 5 , rotamer 2), 7.68 (m, IH, H 4 -, rotamer 1), 7.54-7.27 (m, 5H, H 64 . rotamers 1 & H 64 4 -. rotamer 2), 7.16-6.94 (m, H 3 . ιS . ι3 .. ι5 .. rotamers 1&2), 5.63 (d, J=14.3 Hz, IH, CH 2 PhF 2 , rotamer 2), 4.99 (br, IH, CH 2 PhF 2 , rotamer 1), 4.87 (br, IH, CH 2 PhF 2 , rotamer 1), 4.86 (d, J=14.3 Hz, IH, CH 2 Ph, rotamer 2). EXAMPLE 68 Preparation Of N-(2,6-Difluorobenzoyl)-N-(2,6-Difluorobenzyl)-4-Chloro-2-Nitroanilide In this Example, N-(2,6-difluorobenzoyl)-N-(2,6-difluorobenzyl)-4-chloro-2- nitroanilide (1500) was prepared according to Method E, using N-(2,6- difluorobenzoyl)-4-chloro-2-nitroanilide (Example 59) (600 mg, 1.92 mmol) mixed with 2,6-difluoro-α-bromo-toluene (1300) (478 mg, 2.3 mmol). After recrystallization from diethyl ether/hexane (3:1), 620 mg (1.41 mmol, 74%) of white crystals was produced. Η-ΝMR (300 MHz, CD 2 C1 2 ) (rotamers): δ 8.02 (d, J= 2.4 Hz, IH, H 3 , rotamer 1), 7.95 (d, J= 2.4 Hz, IH, H 3 , rotamer 2), 7.57 (dd, J= 8.6, 2.4 Hz, IH, H 5 , rotamer 1), 7.50 (m, IH, H 4 -, rotamer 1), 7.30 (dd, J= 8.4, 2.4 Hz, IH, H 5 , rotamer 2), 7.35-7.03 (m, 5H, IV rotamer 2 & H 64 . rotamer 1&2), 6.94-6.68 (m, 8H, H 3 w fi ~, rotamer 1 & 2), 5.84 (d, J= 14.4, IH, CH 2 PhF 2 , rotamer 2), 4.94 (br s, 2H, CH 2 PhF 2 , rotamer 1), 4.82 (d, J= 14.4 Hz, IH, CH 2 PhF 2 , rotamer 2). EXAMPLE 69 Preparation Of N-(2,6-Difluorobenzoyl)-N-(2,6-Difluorobenzyl)-5-Chloro-2-Νitroanilide In this Example, N-(2,6-difluorobenzoyl)-N-(2,6-difluorobenzyl)-5-chloro-2- nitroanilide (1600) was prepared according to Method E. First, N-(2,6- difluorobenzoyl)-5-chloro-2-nitroanilide (Example 61) (1.95 g, 6.24 mmol) and 2,6- difluoro-α-bromo-toluene (1.40 g, 6.76 mmol, 110 M%) were mixed for 2 hours. Then, an additional volume of 2,6-difluoro-α-bromo-toluene (1.30 g, 100 M% ) was added. After 5 hours of mixing, an additional volume of 2,6-difluoro-α-bromo-toluene was added (0.75 g, 60 M%) was added. After mixing for 8 hours, purification by flash chromatography, elution with ethyl acetate/hexane (1:4 ) to produce 2.06 g (4.69 mmol, 75% yield) of white crystals. 'H-NMR (200 MHz, DMSO-</ 5 ) (rotamers): δ 8.08 (d, J= 9.4 Hz, IH, H 6 , rotamer 1), 8.03 (d, J= 8.8 Hz, IH, H 6 , rotamer 2), 7.79- 6.91 (m, 16H, H 3 43 4 5 . 3 . 4 .. 5 .. rotamer 1&2), 5.55 (d, J= 14.7, IH, CH 2 PhF 2 , rotamer 2), 5.12 (br, IH, CH 2 PhF 2 , rotamer 1), 4.99 (d, J= 14.7 Hz, IH, CH 2 PhF 2 , rotamer 2), 4.87 (br, IH, CH 2 PhF 2 , rotamer 1). EXAMPLE 70 Preparation Of N-(2,6-Difluorobenzoyl)-N-(2,6-Difluorobenzyl)-4-Methyl-2- Νitroanilide In this Example, N-(2,6-difluorobenzoyl)-N-(2,6-difluorobenzyl)-4-methyl-2- nitroanilide (1700) was prepared according to Method E. N-(2,6-difluorobenzoyl)-4- methyl-2-nitroanilide (Example 65) (2.00 g, 6.84 mmol) and 2,6-difluoro-α-bromo- toluene (2.12 g, 10.2 mmol, 150 M%) were mixed for 3 hours, and recrystallized from diethyl ether/hexane (3:1) to produce 2.80 g (6.69 mmol, 98% yield) of white crystals. 'H-ΝMR (300 MHz, OMSO-d 6 ) (rotamers): δ 7.89 (dd, J= 2.0, 0.9 Hz, IH, H 3 rotamer 1), 7.87 (dd, J= 2.0, 0.8 Hz, IH, H 3 rotamer 2), 7.66 (m, IH, H 4 . rotamer 1), 7.56 (ddd, J= 8.2, 2.0, 0.9 Hz, IH, H 5 rotamer 1), 7.43 (m, IH, H 4 - rotamer 2), 7.37- 7.27 (m, 5H, H 5 rotamer 2, H 3 ι5 . rotamer 1, H 4 - rotamer 1&2) 7.21 (d, J=8.2 Hz, IH, H 6 rotamer 1), 7.07 (m, 2H, H 3 5 . rotamer 2), 7.01-6.90 (m, 4H, H 3 - 5 .. rotamer 1&2), 6.83 (br d, J= 1.1 Hz, IH, H 6 rotamer 2), 5.71 (d, J= 14.4 Hz, IH, CHPhF 2 rotamer 2), 4.97 (d, J= 14.4 Hz, IH, CHPhF 2 rotamer 1), 4.83 (d, J= 14.4 Hz, IH, CHPhF 2 rotamer 1), 4.78 (d, J= 14.4 Hz, IH, CHPhF 2 rotamer 2), 2.41 (s, 3H, CH 3 rotamer 1), 2.27 (s, 3H, CH 3 rotamer 2). EXAMPLE 71 Preparation Of N-(2,6-Difluorobenzoyl)-N-(2,6-Difluorobenzyl)-5-Methyl- 2-Νitroanilide In this Example, N-(2,6-difluorobenzoyl)-N-(2,6-difluorobenzyl)-5-methyl-2- nitroanilide (1800) was prepared according to Method E. N-(2,6-difluorobenzoyl)-3- methyl-6-nitroanilide (Example 64) (2.00 g, 6.84 mmol) and 2,6-difluoro-α-bromo- toluene (2.12 g, 10.2 mmol, 150 M%) were mixed for 3 hours. After recrystallization from diethyl ether/hexane (3:1), 1.92 g (4.59 mmol, 67% yield) of white crystals were produced. Η-ΝMR (200 MHz, CD 3 OD) (rotamers): δ 7.92 (d, J= 8.5 Hz, IH, H 6 , rotamer 1), 7.89 (d, J= 8.5, IH, H 6 , rotamer 2), 7.60 (m, IH, H 4 ., rotamer 1), 7.44- 6.72 (m, 15H, H 3 43 5 . 3 - 4 - 5 -- rotamers 1 & H 343 - 4 - 5 3 - 4 - 5 ■ rotamer 2), 5.86 (d, J= 14.3 Hz, IH, CH 2 PhF 2 , rotamer 2), 4.98 (br, 2H, CH 2 PhF 2 , rotamer 1), 4.88 (d, J= 14.3 Hz, IH, CH 2 PhF 2 , rotamer 2), 2.35 (s, 3H, CH 3 , rotamer 1), 2.35 (s, 3H, CH 3 , rotamer 2). EXAMPLE 72 Preparation Of N-(2,6-Difluorobenzoyl)- N-(2,6-Difluorobenzyl)-2-Methyl-6-Νitroanilide In this Example, N-(2,6-difluorobenzoyl)-N-(2,6-difluorobenzyl)-2-methyl-6- nitroanilide (1900) was prepared according to Method E. First, 2,6-difluorobenzoyl-2- methyl-6-nitroanilide (Example 6) (450 mg, 1.54 mmol) and 2,6-difluoro-α-bromo- toluene (351 mg, 1.69 mmol) were mixed. After recrystallization from diethylether/methanol 490 mg (1.17 mmol, 76% yield) of colorless crystals was produced. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 7.82 (dd, J= 8.0, 1.5 Hz, IH, H 5 ), 7.52 (m, IH, H 4b2 ), 7.51 (dd, IH, J= 7.9, 1.6 Hz, IH, H 3 ), 7.42 (t, IH, J= 7.9 Hz, H 4 ), 7.25 (m, IH, H 4bn ), 7.12 (m, 2H, H 3bz,5bz ), 6.74 (m, 2H, H 3bn,5bn ), 4.80 (s, 2H, CH 2 ), 2.17 (s, 3H, CH 3 ). EXAMPLE 73 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-5-Bromobenzimidazole In this Example, l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-5- bromobenzimidazole (2100) was prepared according to Method F. Method F was also used to produce the compounds described in subsequent Examples, with the changes to the starting materials, notable variations, and or additions to the method indicated as needed. First, 2,6-difluoro-α-bromo-toluene (0.26 g, 0.54 mmol) was dissolved in glacial acetic acid (5 mL), followed by addition of iron powder (0.55 g) to the mixture. After 30 min, the reaction was concentrated to dryness, diluted with ethyl acetate, and adjusted to pH 7 with NaHCO 3 (sat. aq.). The organic solution was collected and washed with NaHCO 3 and NaCl, dried filtered, and concentrated. The product was purified by flash chromatography eluting with 2% MeOH CH 2 Cl 2 and then recrystallized from 3:1 diethyl ether hexane to produce 0.14 g (0.33 mmol, 62% yield) of white crystals. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.11 (dd, J= 0.6, 1.9 Hz, IH, H 4 ), 7.56 (cm, IH, H 4 -), 7.41 (AB, J= 1.9, 8.7 Hz, IH, H 5 ), 7.40 (AB, J= 0.6, 8.7 Hz, IH, H 6 ), 7.26 (cm, IH, H 4 .), 7.10 (cm, 2H, H 3 . ,5 ..), 6.83 (cm, 2H, H 3 5 ), 5.35 (s, 2H, CH 2 PhF 2 ). Anal. (C 20 H u BrF 4 N 2 x3/4H 2 O) C,H,N. EXAMPLE 74 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-5-Chlorobenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-5- chlorobenzimidazole (2200) was prepared according to Method F. N-(2,6- difluorobenzoyl)-N-(2,6-difluorobenzyl)-4-chloro-2-nitroanilide (Example 68) (620 mg, 1.41 mmol) and iron powder (200 mg ) were mixed for 3 hours. After recrystallization, 250 mg (0.64 mmol, 45%) of colorless crystals were produced, with a mp of 136°C. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 7.77 (d, J= 1.95 Hz, H 4 ), 7.55 (m, IH, IV), 7.42 (d, J= 8.7 Hz, IH, H 7 ), 7.27 (dd, J= 8.7, 1.95 Hz, IH, H 6 ), 7.26 (m, IH, H 4 .), 7.09 (m, 2H, H 3 ι5 ), 6.82 (m, 2H, H 3 . ,5 . ), 5.34 (s, 2H, CH 2 ). Anal. (C 20 H„C1F 4 N 2 ) C,H,N EXAMPLE 75 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-6-Chlorobenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-6- chlorobenzimidazole (2300) was prepared according to Method F. N-(2,6- difluorobenzoyl)-N-(2,6-difluorobenzyl)-5-chloro-2-nitroanilide (Example 69) (0.57 g, 1.30 mmol) and iron powder (17) (0.43 g) were mixed for 1 hour. The crude product was purified by flash chromatography eluted with 2% MeOH CH 2 Cl 2 , and recrystallized from diethyl ether/ hexane (3:1), to produce 0.43 g (1.10 mmol, 85% yield) of white crystals. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 7.73 (dd, J= 0.9, 8.6 Hz, IH, H 4 ), 7.56 (m, IH, H 4 - ), 7.51 (d, J= 1.9 Hz, IH, H 7 ), 7.29 (dd, J= 1.9, 8.6 Hz, IH, H 5 ), 7.27 (m, IH, H 4 .), 7.09 (m, 2H, H 3 . 5 ..), 6.84 (m, 2H, H 3 . 5 ), 5.33 (s, 2H, CH 2 PhF 2 ). Anal. (C 20 H U C1F 4 Ν 2 ) C,H,N. EXAMPLE 76 Preparation Of 1 -(2,6-Difiuorobenzyl)-2-(2,6-Difluorophenyl)-5-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-5- methylbenzimidazole (2400) was prepared according to Method F. N-(2,6- difluorobenzoyl)-N-(2,6-difluorobenzyl)-4-methyl-2-nitroanilide (Example 70) (1.55 g, 3.71 mmol) and iron powder (0.79 g) were mixed, and then recrystallized from diethyl ether/hexane (3:1), to produce 0.85 g (2.30 mmol, 62% yield) of white crystals. Η- NMR (300 MHz, CD 2 C1 2 ): δ 7.60-7.49 (cm, 2H, H 4 4 . ), 7.37 (d, J= 8.4 Hz, IH, H 7 ), 7.24 (m, 2H, H 4 ), 7.14 (m, IH, H 6 ), 7.09 (m, 2H, H 3 . j5 .), 6.81 (m, 2H, H 3 t5 ), 5.34 (s, 2H, CH 2 PhF 2 ), 2.47 (s, 3H, CH 3 ). Anal. (C 21 H 14 F 4 N 2 ) C,H,N. EXAMPLE 77 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-6-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-6- methylbenzimidazole (2500) was prepared according to Method F. N-(2,6- difluorobenzoyl)-N-(2,6-difluorobenzyl)-5-methyl-2-nitroanilide (Example 71) (1.56 g, 3.73 mmol) and iron powder (0.79 g) were mixed. After recrystallization from diethyl ether/hexane 0.89 g (2.41 mmol, 64% yield) of white crystals were produced. Η- ΝMR (300 MHz, CD 2 C1 2 ): δ 7.64 (cm, IH, H 4 ), 7.52 (m, IH, H 4 -), 7.30-7.19 (m, 2H, H 7 4 .), 7.14-7.03 (m, 3H, H 5 3 .. 5 . ), 6.81 (m, 2H, H 3 . 5 ), 5.33 (s, 2H, CH 2 PhF 2 ), 2.48 (s, 3H, CH 3 ). Anal. (C 2I H I4 F 4 Ν 2 ) C,H,N. EXAMPLE 78 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-7-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-7- methylbenzimidazole (2600) was prepared according to Method F. N-(2,6- difluorobenzoyl)-N-(2,6-difluorobenzyl)-2-methyl-6-nitroanilide (Example 72) (300 mg, 0.72 mmol) and iron powder (50 mg) were mixed. After recrystallization from ethyl acetate, 149 mg (0.15 mmol, 56% yield) of colorless crystals were produced, with a mp of 177°C. 'H-ΝMR (300 MHz, CD 2 C1 2 ): 7.62 (d, J= 8.2 Hz, IH, H 4 ), 7.45 (m, IH, IV), 7.18 (m, IH, H 4 ..), 7.17 (dd, J= 7.3, 8.2, IH, H 5 ), 7.08 (d, J= 7.3, H 6 ), 6.95 (m, 2H, H 3 ,5 ), 6.70 (m, 2H, H 3 . 5 . ), 5.64 (s, 2H, CH 2 ), 2.74 (s, 3H, CH 3 ). Anal. (C 21 H 14 F.Ν 2 ) C,H,N. EXAMPLE 79 Preparation of 2-(2,6-Difluorophenyl)-4,5-Dimethylbenzimidazole In this Example, 2-(2,6-difluorophenyl)-4,5-dimethylbenzimidazole (2700) was produced according to Method F. N-(2,6-difluorobenzoyl)-2,3-dimethyl-6-nitroanilide (Example 63) (1.40 g, 4.57 mmol) and iron powder (1.05 g) were mixed for 1 h, and recrystallized from ethylacetate to produce 1.07 g (4.14 mmol, 91% yield) of white crystals. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 7.49-7.37 (m, 2H, H 4 > 7 ), 7.16-7.07 (m, 3H, H 3 . s . ι6 ), 2.54 (br s, 3H, CH 3 ), 2.42 (s, 3H, CH 3 ). EXAMPLE 80 Preparation Of 2-(2,6-Difluorophenyl)-4-Νitrobenzimidazole In this Example, 2-(2,6-difluorophenyl)-4-nitrobenzimidazole (2800) was prepared according to Method F. N-(2,6-difluorobenzoyl)-2-amino-3-nitroanilide (Example 62) (12 g, 41 mmol) was dissolved in 130 mL of acetic acid, heated to reflux, and sthred for 12 hours. The reaction mixture was cooled to room temperature, neutralized with ΝaOH (4Ν), basified with NaHCO 3 (1%), and extracted with ethylacetate (3 x 300 mL). The combined organic layers were dried (NajSO , filtered, and evaporated. The remaining crystals were recrystallized from ethylacetate/hexane to produce 7.7 g, (28 mmol, 68%) of crystals. 'H-NMR (300 MHZ, CD 2 C1 2 ): δ 11.00 (s, IH, NH), 8.23 (dd, J= 8.2, 0.8 Hz, IH, H 5 ), 8.21 (dd, J= 8.0, 0.8 Hz, IH, H 7 ), 7.54 (m, IH, H 4 ), 7.45 (dd, J= 8.0, 8.2 Hz, IH, H 6 ), 7.13 (m, 2H, H 3 , 5 .). EXAMPLE 81 Preparation Of 2-(2,6-Difluorophenyl)-5-Nitrobenzimidazole In this Example, 2-(2,6-difluorophenyl)-5-nitrobenzimidazole (2900) was prepared according to Method F. 2-(2,6-difluorophenyl)-benzimidazole (Example 12) (2.00 g, 8.70 mmol) was dissolved in H 2 SO 4 (5.0 mL), and HNO 3 (5.0 mL) was added. After 2 hours at room temperature, the reaction was quenched with ice (50 mL), filtered and washed with water yielding a white solid (1.92 g, 80% yield). Η- NMR (300 MHz, CD 2 C1 2 ): δ 8.60 (d, J= 2.2 Hz, IH, H 4 ), 8.25 (dd, J= 2.2, 8.9 Hz, IH, H 7 ), 7.78 (d, J= 8.9 Hz, IH, H 6 ), 7.65 (m, IH, H 4 ), 7.24 (m, 2H, H 3 ι5 .). EXAMPLE 82 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4,5 - Dimethylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4,5- dimethylbenzimidazole (3000) was prepared according to Method E. 2-(2,6- difluorophenyl)-4,5-dimethylbenzimidazole (Example 79) (0.25 g, 0.97 mmol) and 2,6- difluoro-α-bromo-toluene (0.44 g, 2.12 mmol, 220 M%) were mixed. After flash chromatography, elution with 4% MeOH/CH 2 Cl 2 , and recrystallization from ethylacetate/hexane (1:1) 0.38 g (0.81 mmol, 83% yield) of white crystals was produced. 'H-NMR (300 MHz, CD 3 OD): δ 7.63 (cm, IH, H 4 ), 7.34 (cm, IH, H , 7.30 (cm, IH, IV), 7.16 (cm, IH, H 7 ), 7.13 (cm, 2H, H 3 . 5 ), 6.85 (cm, 2H, H 3 . ,5 ..), 5.40 (s, 2H, CH 2 PhF 2 ), 2.54 (s, 3H, CH 3 ), 2.40 (s, 3H, CH 3 ). Anal. (C 22 H 16 F 4 N 2 ) C,H,N. EXAMPLE 83 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-Nitrobenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- nitrobenzimidazole (3100) was prepared according to Method E. 2-(2,6- difluorophenyl)-4-nitrobenzimidazole (Example 80) (7.7 g, 28 mmol) and 2,6-difluoro- α-bromo-toluene (6.95 g, 33.6 mmol) were mixed as described. After recrystallization from diethyl ether/hexane (3:1), 9.8 g (24.4 mmol, 87%) of slightly brown crystals were produced, with a mp of 169°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.13 (dd, J= 8.1, 0.92 Hz, IH, H 5 ), 7.86 (dd, J= 8.1, 0.9 Hz, IH, H 7 ), 7.59 (m, IH, H 4 .), 7.43 (dd, J= 8.1 Hz, H 6 ), 7.28 (m, IH, H 4 . ), 7.12 (m, 2H, H 3 -5 ), 6.84 (m, 2H, H 3 .. 5 .), 5.44 (s, 2H, CH 2 ). Anal. (C 20 H π F 4 N 3 O 2 ) C,H,N. EXAMPLE 84 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-5-Nitrobenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-5- nitrobenzimidazole (3200) was prepared according to Method E. 2-(2,6- difluorophenyl)-5-nitrobenzimidazole (Example 81) (0.91 g, 3.31 mmol) and 2,6- difluoro-a-bromo-toluene (1.08 g, 5.22 mmol, 160 M%) were mixed, and a second addition of difluoro-α-bromo-toluene (0.47 g, 2.27 mmol, 70 M%) was added to the mixture after 1 hour of mixing. After flash chromatography, eluting with ethyl acetate/hexane (1:4), 1.09 g (2.71 mmol, 82% yield) of white crystals were produced. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.69 (dd, J= 0.5, 2.2 Hz, IH, H 4 ), 8.23 (dd, J= 2.2, 9.0 Hz, IH, H 6 ), 7.59 (dd, J= 0.5, 9.0 Hz, IH, H 7 ), 7.59 (m, IH, H 4 -), 7.28 (m, IH, H 4 . ), 7.12 (m, 2H, H 3 ι5 ), 6.84 (m, 2H, H 3 . j5 . ), 5.44 (s, 2H, CH 2 PhF 2 ). Anal. (C 20 H U F 4 N 3 O 2 ) C,H,N. EXAMPLE 85 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-Amino-benzimidazole In this Example, 4-amino- l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazole (3300) was produced according to Method E. l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (Example 83) (9.2 g, 23 mmol) was dissolved in acetic acid (130 mL), and SnCl 2 x2H 2 O (41.5 g) dissolved in concentrated HCl (35 mL) was added. After stirring for 3 hours at room temperature, the mixture was neutralized with NaOH (4N), basified with NaHCO 3 (5%), diluted with water to give a final volume of 3 L, and then extracted with ethylacetate (5 x 300 mL). The combined ethylacetate layers were dried filtered, and evaporated. The residue was purified by gravity chromatography, eluting with acetone/hexane (1 :1), and recrystallized from acetone/hexane/diethylether to produce 3.7 g of pink crystals (10 mmol, 44% yield), with a mp of 178°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.52 (m, IH, H 4 ), 7.23 (m, IH, H 4 .), 7.07 (m, 2H, H 3 - 5 ), 7.06 (dd, J= 8.1, 7.7 Hz, IH, H 6 ), 6.82 (d, J= 8.1 Hz, H 7 ), 6.81 (m, 2H, H 3 . j5 . ), 6.52 (d, J= 7.7, 0.9 Hz, IH, H 5 ), 5.29 (s, 2H, CH 2 ), 4.42 (s, 2H, NH 2 ). EXAMPLE 86 Preparation Of 4-Bromo-l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-Bromo- benzimidazole In this Example, 4-bromo- 1 -(2,6-difluorobenzy l)-2-(2,6- difluorophenyl)benzimidazole (3400) was produced according to Method E. To 1- (2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-amino-benzimidazole (Example 85) (800 mg, 2.15 mmol) suspended in HBr (48%, 7 mL) at 0°C was slowly added NaNO 2 (193 mg, 2.8 mmol) in water (1.5 mL). After stirring for 30 min at 0-5°C, the mixture was added to CuBr (373 mg, 2.6 mmol) dissolved in HBr (48%, 3 mL). After 30 min at room temperature, water (250 mL) was added, and the pH was adjusted to 5 with KOH 4N. The mixture was extracted with ethylacetate, dried (Na j SO , filtered, and evaporated. The crude brown crystals were purified by gravity chromatography eluting with hexane/acetone (2:1), and recrystallized with diethylether/hexane (3:1) to produce 610 mg, (1.4 mmol, 65% yield) of colorless crystals, with a mp of 147°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.56 (m, IH, H 4 ), 7.49 (dd, J= 7.7, 0.87 Hz, IH, H 5 ), 7.47 (d, J= 7.9 Hz, H 7 ), 7.26 (m, IH, H 4 .), 7.18 (dd, J= 8.2, 7.7 Hz, IH, H 6 ), 7.09 (m, 2H, H 3 5 .), 6.82 (m, 2H, H 3 . ,5 . ), 5.35 (s, 2H, CH 2 ). Anal. (C 20 H„BrF 4 N 2 xl/4H 2 O) C,H,N. EXAMPLE 87 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4-Chloro-benzimidazole In this Example, 4-chloro- 1 -(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazole (3500) was prepared according to Method E. To l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-aminobenzimidazole (Example 85) (800 mg, 2.15 mmol) dissolved in concentrated HCl (7 mL) and water (5 mL) at 0°C was slowly added NaNO 2 (193 mg, 2.8 mmol) in water (1.5 mL). After 30 min at 0-5°C, the mixture was added to CuCl (256 mg, 2.6 mmol) in concentrated HCl (2 mL) at 0°C. After rising to room temperature over 40 min, the pH was adjusted to pH 5, diluted with water (80 mL), extracted with ethylacetate, dried (NajSO,,), filtered, and evaporated. The residue was purified by gravity chromatography eluting with hexane/acetone (2:1), and recrystallized from acetone/hexane to produce 350 mg of yellow crystals (0.90 mmol, 42% yield), with a mp of 163°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.56 (m, IH, H 4 .), 7.43 (dd, J= 8.0, 1.1 Hz, IH, H 7 ), 7.31 (dd, J=7.8, 1.1 Hz, IH, H 5 ), 7.26 (m, IH, H 4 -.), 7.24 (dd, J= 8.0, 7.8 Hz IH, H 6 ), 7.09 (m, 2H, H 3 )5 ), 6.83 (m, 2H, H 3 - ι5 .), 5.36 (s, 2H, CH 2 ). Anal. (C 20 H U C1F 4 N 2 ) C,H,N. EXAMPLE 88 Preparation Of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)-4- Acetamidobenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- acetamidobenzimidazole (3600) was prepared according to Method E. l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)4-aminobenzimidazole (Example 85) ~ (0.30 g, 0.81 mmol) was dissolved in THF (3 mL), and acetic anhydride (100 mL, 1.06 mmol) was then added. After 3 hours, additional acetic anhydride (20 mL, 0.21 mmol) was added. After 5 hours, the reaction was concentrated to dryness, diluted with ethyl acetate (50 mL), and washed with NaHCO 3 (25 mL) and NaCl (25 mL). The combined washings were dried filtered, and concentrated. The product was recrystallized from diethyl ether/hexane (3:1) to produce 0.32 g (0.77 mmol, 95% yield) of white crystals. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 8.49 (IH, br, NH), 8.20 (d, J= 7.8 Hz, IH, H s ), 7.56 (m, IH, H 4 ), 7.26 (t, J= 7.9 Hz, IH, H 6 ), 7.26 (m, IH, H 4 . ), 7.19 (d, J= 7.9 Hz, IH, H 7 ), 7.10 (m, 2H, H 3 5 ), 6.82 (m, 2H, H 3 .._ 5 .), 5.34 (s, 2H, CH 2 PhF 2 ), 2.21 (s, 3H, Ac). Anal. (C 22 H 15 F 4 N 3 O) C,H,N. EXAMPLE 89 Preparation Of l-(2,6-Difluorobenzyl)- 2-(2,6-Difluorophenyl)-4-N,N-Dimethylaminobenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-N,N- dimethylaminobenzimidazole (3700) was prepared according to Method E. A slurry of 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-aminobenzimidazole (Example 85) (0.37 g, 1.0 mmol) and sodium borohydride (0.27 g) was added to a mixture of 3 M H 2 SO 4 (0.80 mL) and 37% H 2 CO (0.50 mL). After the addition was complete, the mixture was concentrated to dryness, diluted with ethyl acetate, and washed with Νa 2 CO 3 and NaCl. The combined washings were dried (NajSO , filtered, concentrated. The crude product was purified by recrystallization from diethyl ether/hexane (3:1) to produce 0.34 g (0.85 mmol, 85% yield) of white crystals. 'H- NMR (300 MHz, CD 2 C1 2 ): δ 7.51 (m, IH, H 4 ), 7.23 (m, IH, H 4 . ), 7.13 (t , J= 8.0 Hz, IH, H 6 ), 7.06 (m, 2H, H 3 ι5 ), 6.90 (d, J= 8.0 Hz, IH, H 5 ), 6.80 (m, 2H, H 3 - >5 ..), 6.48 (d, J= 8.0 Hz, IH, H 7 ), 5.30 (s, 2H, CH 2 PhF 2 ), 3.18 (s, 6H, N(CH 3 ) 2 ). Anal. (C 22 H 17 F 4 N 3 ) C,H,N. EXAMPLE 90 Reverse Transcriptase Assay In this Example, the effects of various compounds were tested for their ability to inhibit the RNA-dependent DNA polymerase (i.e., RT) activity of purified RT. Briefly, in the basic assay (e.g., controls), purified RT protein (0.015 mg/mL) was incubated in a 100 μL reaction mixture containing 25 mM Tris (pH 8.0), 75 mM KC1, 8 mM MgCl 2 , 2 mM dithiothreitol, 0.1 units poly (rC)-oligo(dG), 0.01 mM dGTP, lx BSA, 10 mM CHAPS, 0.025 mCi (α 35 S)dGTP (specific activity, 1000 Ci/mmol), for 1 hour at 37°C. In the test assays, various concentrations of anti-RT compounds were included in the reaction mixture. The assays were stopped by adding 1 mL of 10% trichloroacetic acid and 30 μL of denatured and sheared salmon sperm DNA (10 mg/mL) as a caπier. The labeled polymer was collected on Whatman glass GF/C filters by suction filtration, washed with 10% trichloroacetic acid and 95% ethanol, and the radioactivity was counted. Table 3 shows the structures, physical and biological data, as well as remaining HIV RT activity reported as a percent of the control in HIV RT inhibition assays, for various l-(2,6-difluorobenzyl)-2-substituted-benzimidazoles produced using the methods of the present invention. EXAMPLE 91 Cytopathic Cell Killing Anti- Viral Assay In this Example, the antiviral and cellular toxicity of NNRTIs was investigated, using the cytopathic cell killing assay described by Yang (Yang et al, "Characteristics of a Group of Non-nucleoside Reverse Transcriptase Inhibitors with Structural Diversity and Potent Anti-Human Immunodeficiency Virus Activity," Leukemia 9:S75- S85 [1995]). Briefly, in this method cells (e.g., the CEM-SS cell line, available from the NIAID AIDS Research and Reference Program [ARRRP]) were seeded at a density of 5 x 10 3 cells/well, into the wells of a 96-well microtiter plate. The cells were then infected with HIV virus (either mutant or WT), at a multiplicity of infection (MOI) previously determined to provide complete cell killing by 6 days of culture post- infection (e.g., MOI of 0.01-0.05). Each of the HIV isolates was pre-titered to induce equivalent levels of infection based on cell killing or virus production, prior to their use in these assays. A range of test compound concentrations was added to the wells in triplicate (e.g., serial half-log dilutions) to evaluate inhibition of HIV infection. Controls for each assay included drug controls (drug colorimetric control wells), drug cytotoxicity control wells (cells with drug), virus control wells (cells with virus), and cell viability controls (cells only). Positive control drugs (e.g., AZT and ddC) were also run in parallel. After six days of incubation at 37°C, cell viability was determined spectrophotometrically at 450 nm for each well, using the metabolic reduction of XTT to a soluble colored formazan. (See, Gartner and Popovic, "Virus Isolation and Production, in Aldovini and Walker (eds.), Techniques in HIV Research, Stockton Press, NY, pp. 69-63 [1991]; and Nara and Fischinger, "Quantitative Infectivity Assay for HIV-1 and HIV-2," Nature 332:469-470 [1988]). Antiviral and toxicity data were reported as the quantity of drug required to inhibit 50% of virus-induced cell killing or virus production (EC 50 ), and the quantity of drug required to reduce enzyme activity by 50% (IC 50 ). The in vitro therapeutic index (TI 50 ) was defined as the fold-difference between the EC 50 and IC 50 . The results for the various compounds are included in Figures 8 and 19. In addition, graphs showing the summary data for three compounds are shown in Figures 10-12. Figure 10 shows the graph for compound 33. As indicated in this Figure, 33 exhibited very effective therapeutic dose. Figure 11 shows the graph for compound 34, another compound that also exhibited an effective therapeutic dose. Figure 12 shows the graph for compound 2100, a compound that was found to be inactive. EXAMPLE 92 Comparisons Of Inactive Compounds With Active Compounds RT inhibition activity of previously described 5, 6, or 7-substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole compounds show that substituents with H, CH 3 , Cl, Br, and N(CH 3 ) 2 were found to inhibit HIV RT, while substitutions with NO 2 , and NHAc did not inhibit the enzyme. These results are illustrated in Figure 6. Although it is not necessary for an understanding of the present invention, it was determined that electron donating or halogen groups apparently increase RT inhibition activity, while electron withdrawing groups decrease inhibition activity. Furthermore, it is apparent that substitution in the 4,6 positions gave increased RT inhibition activity compared to substitutions at the 5 or 7 positions. In addition, it was observed that substitutions of the 4 position with electron donating or halogen groups led to greater HIV RT inhibition than substitution at the 6 position. These results are summarized in Figures 16 and 17. EXAMPLE 93 Preparation of N-(2,6-Difluorobenzoyl)-2,4-dimethyl-6-nitroanilide To 4,6-Dimethyl-2-nitroaniline (4.25 g, 25.6 mmol) and was added 2,6- difluorobenzoyl chloride (4.25 mL, 33.80 mmol, 130 M%), and the reaction mixture was stirred for 5 h. Recrystallization of the crude product from ethylacetate/hexane (1 :1) gave white crystals of N-(2,6-difluorobenzoyl)-2,4-dimethyl-6-nitroanilide (7.07 g, 90% yield). 'H NMR (200 MHz, CD 2 C1 2 ): δ 8.41 (br, IH, NH), 7.68 (br d, J=2.6 Hz, IH, H 5 ), 7.48 (m, IH, H 4 ), 7.42 (d, J=2.6 Hz, IH, H 3 ), 7.05 (m, 2H, H 3 . 5 ,), 2.42 (s, 3H, CH 3 ), 2.39 (s, 3H, CH 3 ). EXAMPLE 94 Preparation of 2-(2,6-Difluorophenyl)-4,6-dimethylbenzimidazole N-(2,6-Difluorobenzoyl)-2,4-dimethyl-6-nitroanilide (Example 93) (4.55 g, 14.9 mmol) was reacted with iron powder (3.45 g) for 0.5 h. Recrystallization of the crude product from diethylether/hexane (1:3) gave white crystals of 2-(2,6-difluorophenyl)- 4,6-dimethylbenzimidazole (3.35 g, 12.97 mmol, 87% yield). Η NMR (200 MHz, CD 2 C1 2 ): δ 9.69 (br, IH, NH), 7.43 (bm, 1H,H 4 ), 7.26 (br s, H 5 ), 7.09 (m, 2H 3 . > 5 .), 6.95 (br s IH, H 7 ), 2.59 (s, 3H, CH 3 ), 2.45 (s, 3H, CH 3 ). EXAMPLE 95 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4,6- dimethylbenzimidazole To 2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (Example 94) (0.50 g, 1.94 mmol) was added 2,6-difluoro-α-bromotoluene (0.52 g, 2.51 mmol, 130 M%). Flash chromatography of the crude product eluting with 2% methanol/CH 2 Cl 2 , and recrystallization from hexane gave white crystals of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-4,6-dimethylbenzimidazole (0.68 g, 1.77 mmol, 91% yield). 'H NMR (200 MHz, CD 2 C1 2 ): δ 7.51 (cm, IH, H 4 ), 7.23 (m, IH, H 4 „), 7.11 (m, IH, H 5 ), 7.05 (cm, 2H, H 3 . 5 .), 6.93 (m, IH, H 7 ), 6.80 (cm, 2H, H 3 .. 5 „), 5.29 (s, 2H, CH 2 PhF 2 ), 2.58 (s, 3H, CH 3 ), 2.44 (s, 3H, CH 3 ). EXAMPLE 96 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-(N-methylacetamido)-benzimidazole To 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88) (2.44 g, 5.90 mmol) and methyl iodide (0.60 mL, 9.69 mmol) dissolved in THF (30 mL) was added excess NaH. After stirring overnight, the solution was concentrated to dryness, diluted with CH 2 C1 2 , and washed with water, NaHSO 4 (10% soln) and NaCl (sat. aq). The combined washings were dried filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH 2 C1 2 , yielding l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-(N-methylacetamido)-benzimidazole (0.89 g, 2.08 mmol, 63 % yield). M.p. 155-156 °C. 'H NMR (200 MHz, CD 2 C1 2 ): δ 7.55 (m, IH, H 4 .), 7.48 (br d, J =7.4 Hz, IH, H 5 ), 7.31 (dd, J = 7.4, 7.7 Hz, IH, H 6 ), 7.27 (m, IH, IV), 7.14 (dd , J = 1.1, 7.7 Hz, IH, H 7 ), 7.09 (m, 2H, H 3 >5 ), 6.84 (m, 2H, H 3 • .), 5.38 (s, 2H; CH 2 PhF 2 ), 3.34 (s, 3H, NCH 3 ), 1.83 (s, 3H, NAc). EXAMPLE 97 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-(N-methylamino)benzimidazole To l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylacetamido)- benzimidazole (Example 96) (0.50 g, 1.17 mmol) suspended in water (9.0 mL) was added HCl (1.0 mL). After 3 h at reflux, the solution was concentrated to dryness, diluted with ethylacetate, and washed with NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na^O,,), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH 2 C1 2 , yielding 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylamino)- benzimidazole (0.35 g, 78 % yield). M.p. 194-195 °C. Η NMR (200 MHz, CD 2 C1 2 ): δ 7.52 (m, IH, H 4 ), 7.23 (m, IH, H 4 .), 7.13 (dd, J = 8.3, 8.0 Hz, IH, H 6 ), 7.07 (m, 2H, H 3 ι5 ), 6.80 (m, 2H, H 3 . ,5 . ), 6.76 (d, J = 8.3 Hz, IH, H 5 ), 6.36 (d, J = 8.0 Hz, IH, H 7 ), 5.29 (s, 2H, CH 2 PhF 2 ), 2.96 (s, 3H, NCH 3 ). EXAMPLE 98 Preparation of 2,6-Difluorobenzoic acid-(2-hydroxymethyl)-6-nitroanilide To methyl N-(2,6-difluorobenzoyl)-6-nitro-2-anilidecarboxylate (4003, Example 43) (4.50 g, 13.4 mmol) dissolved in THF (50 mL) at 0 °C was added lithium aluminum hydride (0.50 g, 13.2 mmol, 100 M%). After 30 min, the reaction was allowed to warm to room temperature followed by a second addition of lithium aluminum hydride (0.20 g, 5.26 mmol, 40 M%) at 2 h. After 4 h, the reaction was concentrated and the residue was redissolved in EtOAc, and washed with NaHSO 4 (10% so In), NaHCO 3 (sat. aq), and NaCl (sat. aq). The combined washings were dried (Na^O , filtered, and evaporated. The crude product was purified by flash chromatograph eluting with 4% MeOH/CH 2 Cl 2 , and recrystallized from CH 2 C1 2 yielding white solids of 2,6-Difluorobenzoic acid-(2-hydrθxymethyl)-6-nitroanilide (2.47 g, 8.01 mmol, 60% yield). Η NMR (200 MHz,CD 2 Cl 2 ): δ 7.92 (dd, J= 1.4, 8.2 Hz, IH, H j ), 7.79 (dd, J= 1.4, 7.8 Hz, IH, H 3 ), 7.54-7.43 (m, 2H, H 4 ,,H 4 ), 7.06 (m, 2H, H 3 . 5 .), 4.74 (s, 2H, CH 2 O). EXAMPLE 99 Preparation of 2,6-Difluorobenzoic acid-(2-acetoxymethyl)-6-nitroanilide To 2,6-difluorobenzoic acid-(2-hydroxymethyl)-6-nitroanilide (Example 98) (6.00 g, 19.5 mmol) dissolved in THF (85 mL) and triethylamine (4.00 mL) was added acetic anhydide (4.00 mL, 42.4 mmol, 220 M%). After stirring overnight at room temperature, the reaction was concentrated. The residue was then redissolved in EtOAc, and washed with NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (NajSO , filtered, and evaporated. The crude product was purified by flash chromatograph eluting with 4% MeOH/CH 2 Cl 2 and titrated from Et 2 O, yielding white solids of 2,6-difluorobenzoic acid-(2-acetoxymethyl)-6-nitroanilide (5.09 g, 14.5 mmol, 75% yield). 'HNMR (200 MHz,CD 2 Cl 2 ): δ 9.16 (br, IH, NH), 7.99 (dd, J= 1.5, 8.3 Hz, IH, H 5 ), 7.79 (dd, J= 1.5, 7.7 Hz, IH, H 3 ), 7.50 (m, IH, H 4 .), 7.49 (dd, J= 7.7, 8.3 Hz, IH, H 4 ), 7.06 (m, 2H, H 3 . 5 ,), 5.20 (s, 2H, CH 2 O), 2.09 (s, 3H, OAc). EXAMPLE 100 Preparation of Methyl 2-(2,6-difluorophenyl)benzimidazole-4-carboxylate Methyl N-(2,6-difluorobenzoyl)-6-nitro-2-anilidecarboxylate (4003, Example 43) (30.38 g, 90.35 mmol) and iron powder (30.80 g) were refluxed for 0.5 h. Recrystallization of the crude product from EtOAc gave white crystals of methyl 2-(2,6-difluorophenyl)-benzimidazole-4-carboxylate (18.47 g , 64.07 mmol, 71% yield). 'H-NMR (200 MHz, CD 2 C1 2 ): δ 10.92 (br, IH, NH), 8.06 (d, J= 8.1 Hz, IH, H 5 ), 7.97 (d, J= 1.1 Hz, IH, H 7 ), 7.49 (m, IH, H 4 .), 7.37 (dd, J = 7.7,8.1 Hz, H 6 ), 7.13 (m, 2H, H 3 ι5 ), 4.01 (s, 3H, CO 2 CH 3 ). EXAMPLE 101 Preparation of 2-(2,6-Difluorophenyl)-4-acetoxymethylbenzimidazole 2,6-Difluorobenzoic acid-2-(acetoxymethyl)-6-nitroanilide (Example 99) (2.82 g, 8.05 mmol) and iron powder (2.50 g) were refluxed for 0.5 h. The crude product was purified using flash chromatography with 2% methanol/CH 2 Cl 2 , and tritrated from 3:1 Et 2 O:hexane, to give white crystals of 2-(2,6-difluorophenyl)-4- acetoxymethylbenzimidazole (1.83 g , 6.05 mmol, 75% yield). 'H-NMR (200 MHz, CD 2 C1 2 ): δ 10.64 & 9.97 (rotamers) (br, IH, NH), 7.83 (m, IH), 7.45 (m, IH, H 4 .), 7.29 (m, 2H), 7.13 (m, 2H, H 3 , 5 -), 5.61& 5.46 (rolamCTS) (s, 2H, CH 2 O), 2.11 (s, 3H, Ac). EXAMPLE 102 Preparation of Methyl l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carboxylate Methyl 2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (Example 100) (16.15 g, 56.0 mmol) and 2,6-difluorobenzyl bromide (14.67 g, 70.86 mmol, 125 M%) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/ CH 2 C1 2 and recrystallization from diethylether, yielding white crystals of methyl l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylate (17.63 g, 42.55 mmol, 76 % yield). M.p. 184-186 °C. Η NMR (200 MHz, CD 2 C1 2 ): δ 7.94 (dd, J= 1.1, 7.6 Hz, IH, H 5 ), 7.72 (dd, J= 1.1, 8.2 Hz, IH, H 7 ), 7.56 (m, IH, H 4 ), 7.37 (dd, J= 7.6, 8.2 Hz, IH, H 6 ), 7.26 (m, IH, H 4 . ), 7.09 (m, 2H, H 3 >5 ), 6.82 (m, 2H, H 3 - ,5 . ), 5.39 (s, 2H, CH 2 PhF 2 ), 3.95 (s, 3H, CO 2 CH 3 ). EXAMPLE 103 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-acetoxymethylbenzimidazole 2-(2,6-Difluorophenyl)4-acetoxymethylbenzimidazole (Example 101) (3.55 g, 11.74 mmol) and 2,6-difluorobenzylbromide (3.40 g, 16.4 mmol, 140 M%) were reacted. The crude product was purified using flash chromatography eluting with 2% methanol/ CH 2 C1 2 and recrystallization from diethylether, yielding white crystals of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (5.94 g, 13.9 mmol, 76 % yield). M.p. 126-127 °C. 'HNMR (300 MHz, CD 2 C1 2 ): δ 7.54 (m, IH, H 4 .), 7.48 (m, IH, H 6 ), 7.33-7.27 (m, 2H, H 5 7 ), 7.25 (m, IH, H 4 . ), 7.08 (m, 2H, H 3 5 ), 6.82 (m, 2H, H 3 .. >s -), 5.54 (s, 2H, CH 2 PhF 2 ), 5.36 (s, 2H, CH 2 O), 2.08 (s, 3H, OAc). EXAMPLE 104 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylbenzimidazole To 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (Example 46) (0.30 g, 0.78 mmol) and hexadecyltrimethylammonium bromide (0.30 g) dissolved in acetic acid (9.0 mL) was added HBr (1.0 mL). After refluxing for 7 h, the reaction was concentrated. The residue was then diluted with EtOAc, and washed with NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washing were dried (NajSO,,), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/ CH 2 C1 2 and recrystallization from diethylether, yielding 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxyl- benzimidazole (0.25 g, 0.67 mmol, 86 % yield). M.p. 257- 259 °C. Η NMR (200 MHz, CD 2 C1 2 ): δ 7.57 (m, IH, H 4 ), 7.25 (m,_lH, H 4 . ), 7.17 (dd, J = 7.9, 8.3 Hz, IH, H 6 ), 7.12 (m, 2H, H 3 5 .), 6.99 (d, J=8.3 Hz, IH, H 7 ), 6.82 (m, 2H, H 3 .. 5 .), 6.73 <dd, J = 7.9, 1.0Hz, H 5 ), 5.35 (s, 2H, CH 2 PhF 2 ). EXAMPLE 105 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carbonitrile To methyl l-(2,6-difluorobenyl)-2-(2,6-difluorophenyl)benzimidazole-4- carboxylate (Example 102) (1.02 g, 2.46 mmol) suspended in xylene (60 mL) was added freshly prepared 1.0 M AlMe 2 NH 2 (20 mL). After 3 h at reflux, the reaction was concentrated. The residue was redissolved in CH 2 C1 2 and washed with NaHSO 4 (10% so In), NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (NajSO , filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/ CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals ofl-(2,6-Difluorobenzyl)-2- (2,6-difluorophenyl)- benzimidazole-4-carbonitrile (1.72 g, 4.51 mmol, 61 % yield). M.p. 156-157 °C; Η NMR (200 MHz, CD 2 C1 2 ): δ 7.76 (dd, J= 1.0, 8.6 Hz, IH, H 5 ), 7.63 (dd, J= 1.0, 7.6 Hz, IH, H 7 ), 7.58 (m, IH, H 4 ), 7.37 (dd, J= 7.6, 8.6 Hz, IH, H 6 ), 7.28 (m, IH, H 4 ~), 7.11 (m, 2H, H 3 . 5 .), 6.83 (m, 2H, H 3 . ,5 ..), 5.40 (s, 2H, CH 2 PhF 2 ). EXAMPLE 106 Preparation of N-Hydroxy l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carboxamidine To 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (0.60 g, 1.57 mmol) dissolved in ethanol (15 mL) and triethylamine (0.5 mL) was added hydroxylamine (0.14g , 130 M%). After 24 h at reflux, the reaction was concentrated. The residue was redissolved in CH 2 C1 2 and washed with NaHSO 4 (10% soln), NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (NajSO,,), filtered and concentrated. The crude product was purified by flash chromatography eluting with 4% methanol/ CH 2 C1 2 and recrystallization from methanol, yielding white crystals of N-hydroxy l-(2,6-difluorobenzyl)-2- - I l l - (2,6-difluorophenyl)benzimidazole-4-carboxamidine (0.57 g, 1.37 mmol, 87 % yield). M.p. 214-216 °C. Η NMR (200 MHz, CD 2 C1 2 ): δ 7.84 (dd, J= 1.1, 7.7 Hz, IH, H 5 ), 7.57 (m, IH, H 4 ), 7.54 (dd, J= 1.1, 8.2 Hz, IH, H 7 ), 7.30 (dd, J= 7.7, 8.2 Hz, IH, H 6 ), 7.28 (m, IH, H 4 ..), 7.11 (m, 2H, H 3 . 5 -), 6.83 (m, 2H, H 3 .._ 5 ..), 6.61 (br, 2H, NH 2 ), 5.39 (s, 2H, CH 2 PhF 2 ). EXAMPLE 107 Preparation of 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carboxylic acid amide To l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carbonitrile (Example 105) (1.10 g, 2.88 mmol) dissolved in ethanol (100 mL) and 3 M Na 2 CO 3 (10 mL) was added 30%) hydrogen peroxide (10 mL). After stirring overnight at room temperature, the reaction was concentrated. The residue was then redissolved in EtOAc, and washed with NaHSO 4 (10% soln), NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na^O,,), filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol/CH 2 Cl 2 and recrystallization from methanol, yielding white crystals of l-(2,6-difluorobenzyl)-2- (2,6-difluorophenyl)benzimidazole-4-carboxylic acid amide (0.83 g, 2.08 mmol, 72 % yield). M.p. 260-261 °C. 'H-NMR (200 MHz, CD 2 C1 2 ): δ 8.10 (dd, J= 1.1, 1.1 Hz, IH, H 5 ), 7.71 ( br d, J= 8.1 Hz, IH, H 7 ), 7.59 (m, IH, H 4 .), 7.43 (dd, J= 7.7, 8.1 Hz, IH, H 6 ), 7.28 (m, IH, H 4 .), 7.13 (m, 2H, H 3 ι5 ), 6.84 (m, 2H, H 3 - ι5 ..), 5.43 (s, 2H, CH 2 PhF 2 ), 1.92 (s, 2H, NH 2 ). EXAMPLE 108 Preparation of 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carboxylic acid dimethylamide To 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carboxylic acid amide (Example 107) (1.10 g, 2.88 mmol) and methyl iodide (0.12 mL) suspended in THF (5 mL) was added sodium hydride (0.15 g). After stirring overnight at room temperature, the reaction was diluted with EtOAc and washed with NaHSO 4 (10% soln), NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (Na^O^, filtered and concentrated. The crude product was purified by flash chromatography eluting with 5% methanol/CH 2 Cl 2 , yielding white crystals of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-4-carboxylic acid dimethylamide (0.20 g, 0.47 mmol, 90 % yield). M.p. 213-214 °C. Η NMR (300 MHz, CD 2 C1 2 ): δ 7.59-7.43 (m, 2H, H 4 , 5 ), 7.36- 7.20 (m, 3H, H 67 , 4 . ), 7.08 (m, 2H, H 3 ι5 .), 6.83 (m, 2H, H 3 - ,5 . ), 5.37 (s, 2H, CH 2 PhF 2 ), 3.12 (s, 3H, CH 3 ), 2.88 (s, 3H, CH 3 ). EXAMPLE 109 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carboxylate To methyl 1 -(2,6-difluorobenyl)-2-(2,6-difluorophenyl)benzimidazole-4- carboxylate (Example 102) (1.02 g, 2.46 mmol) dissolved in methanol (20 mL) was added barium hydroxide (1.20 g). After 2 h, acetic acid was added and the reaction concentrated. The residue was redissolved in CH 2 C1 2 and washed with NaHCO 3 (sat. aq) and NaCl(sat. aq). The combined washings were dried (NajSO , filtered and concentrated. The crude product was purified by flash chromatography eluting with 8% methanol/ CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole- 4-carboxylate (0.71 g, 1.77 mmol, 72 % yield). M.p. 178-180 °C. 'H-NMR (200 MHz, CD 2 C1 2 ): δ 8.06 (d, J= 7.8 Hz, III, H 5 ), 7.76 (d, J= 8.1 Hz, IH, H 7 ), 7.62 (m, IH, H 4 ), 7.47 (dd, J= 7.8, 8.1 Hz, IH, H 6 ), 7.29 (m, IH, H 4 .), 7.14 (m, 2H, H 3 ,5 ), 6.85 (m, 2H, H 3 - ιS ..), 5.45 (s, 2H, CH 2 PhF 2 ). EXAMPLE 110 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-benzimidazoyl-2-propanol To methyl 1 -(2,6-difluorobenyl)-2-(2,6-difluorophenyl)benzimidazole-4- carboxylate (Example 102) (1.02 g, 2.46 mmol) suspended in THF (5 mL) was added 1.4 M methyl lithium (0.95 mL). After 0.5 h, the reaction was diluted with EtOAc and washed with NaHSO 4 (10% soln) and NaCl(sat. aq). The combined washings were dried (NajSO,,), filtered and concentrated. The crude product was purified by flash chromatography eluting with 1 : 1 ethylacetate/hexane and recrystallization from hexane, yielding white crystals of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-benzimidazoyl-2-propanol (0.11 g, 0.27 mmol, 55 % yield). M.p. 149-150 °C. 'H-NMR (200 MHz, CD 2 C1 2 ): δ 7.55 (m, IH, H 4 ), 7.48 (d, J= 8.1 Hz, IH, H 5 ), 7.25 (m, 2H, H M . ), 7.16 (dd, J= 1.1, 7.6 Hz, IH, H 7 ), 7.10 (m, 2H, H 3 . 5 .), 6.82 (m, 2H, H 3 . 5 ..), 5.82 (s, IH, OH), 5.37 (s, 2H, CH 2 PhF 2 ), 1.67 (s, 6H, CH 3 ). Anal. (C 23 H 18 F 4 N 2 O) C,H,N. EXAMPLE 111 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-isopropenylbenzimidazole To l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-benzimidazoyl-2-propanol (Example 110) (0.45 g, 1.09 mmol) was added to H 2 SO 4 (1.00 mL). After 15 min. at room temperature, the reaction was diluted with EtOAc, and washed with NaHCO 3 (sat. aq) and NaCl (sat. aq). The combined washings were dried (NajSO,,), filtered and concentrated. The crude product was purified by flash chromatography eluting with 1% MeOH/CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), yielding white crystals of 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-isopropenylbenzimidazole (0.11 g, 0.28 mmol, 30 % yield). M.p. 156-158 °C. Η-NMR (200 MHz, CD 2 C1 2 ): δ 7.53 (m, IH, H 4 .), 7.44-7.16 (cm, 4H, H 4 .. 5Λ7 ), 7.07 (m, 2H, H 3 . 5 ), 6.81 (m, 2H, H 3 . ι5 ..), 6.03 (dq, J= 0.8, 2.4 Hz, IH, vinyl), 5.37 (s, 2H, CH 2 PhF 2 ), 5.36 (dq, J=1.5, 2.4 Hz, IH, vinyl), 2.33 (dd, J= 0.8, 1.5 Hz, 3H, CH 3 ). EXAMPLE 112 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-hydroxymethylbenzimidazole To l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetoxymethylbenzimidazole (Example 103) (1.45 g, 3.38 mmol) dissolved in methanol (19 mL) and water (1.0 mL) was added K 2 CO 3 (0.40 g). After 30 min, the reaction was concentrated, redissolved in EtOAc, and washed with NaHSO 4 (10% soln) and NaCl (sat. aq). The combined washings were dried (Na^O , filtered, and concentrated. Recrystallization of the crude product from diethylether :hexane (3:1) yielded white crystals of 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxymethylbenzimidazole (1.25 g, 3.24 mmol, 96 % yield). M.p. 157- 158 °C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 7.54 (m, IH, H 4 ), 7.43 (d, J= 7.9 Hz, IH, H 7 ), 7.30- 7.22 (m, 2H, H 64 ..), 7.18 (d, J= 7.5 Hz, IH, H 5 ), 7.09 (m, 2H, H 3 ι5 .), 6.82 (m, 2H, H 3 - ,5 . ), 5.37 (s, 2H, CH 2 PhF 2 ), 5.06 (d, J= 5.4 Hz, 2H, CH 2 O), 3.51 (t, J=5.4 Hz, IH, OH). EXAMPLE 113 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazole- 4-carbaldehyde To CrO 3 (1.26 g) dissolved in pyridine (1.0 mL) and CH 2 C1 2 (9.0 mL) was added l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylmethylbenzimidazole (Example 112) (0.49 g, 1.27 mmol) dissolved in pyridine :CH 2 C1 2 (1:1) (2 mL). After stiπing for 6 h, the reaction was filtered. The filtrate was diluted with CH 2 C1 2 , and washed with NaHCO 3 (sat. soln) and NaCl (sat. aq). The combined washings were dried (Na 2 SO 4 ), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 1% methanol/CH 2 Cl 2 . Recrystallization from diethyletheπhexane (3:1) yielded white crystals of l-(2,6-Difluorobenzyl)-2- (2,6-difluorophenyl)-benzimidazole-4-carbaldehyde (0.38 g, 0.99 mmol, 78 % yield). M.p. 151-153 °C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 10.82 (d, J= 0.6 Hz, IH, CHO), 7.83 (dd, J= 7.5, 1.1 Hz, IH, H7), 7.78 ( dd, J= 8.1, 1.1 Hz, H5), 7.58 (m, IH, H 4 ), 7.44 (ddd, J= 8.1, 7.5, 0.6 Hz, IH, H 6 ), 7.27 (m, IH, H 4 ..), 7.11 (m, 2H, H 3 . 5 -), 6.84 (m, 2H, H 3 . ι5 •), 5.42 (s, 2H, CH 2 PhF 2 ). EXAMPLE 114 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-chloromethylbenzimidazole To 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-hydroxylmethyl- benzimidazole (Example 112) (0.54 g, 1.40 mmol) dissolved in CHC1 3 (3.0 mL) was added SOCl 2 (0.15 mL, 2.06 mmol, 150 M%). After 3 h at room temperature, the reaction was diluted with CHC1 3 , and washed with NaHCO 3 (sat. soln) and NaCl (sat. aq). The combined washings were dried (Na^O , filtered and concentrated. The product was purified by flash chromatography eluting with 1% MeOH/CH 2 Cl 2 . Recrystallization from diethyletheπhexane (3:1) yielded white crystals of l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)-4-chloromethylbenzimidazole (0.52 g, 1.28 mmol, 92 % yield). M.p. 143- 144 °C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.55 (m, IH, IV), 7.48 (dd, J= 7.7, 1.1 Hz, IH, H 7 ), 7.36 (dd, J= 7.6 Hz, 1.1 Hz, IH, H 5 ), 7.30 (dd, J= 7.7, 7.6 Hz, IH, H 6 ), 7.25 (m, IH, H 4 ~), 7.09 (m, 2H, H 3 >5 .), 6.82 (m, 2H, H 3 - ,5 . ), 5.36 (s, 2H, CH 2 PhF 2 ), 5.07 (s, 2H, CH 2 C1). EXAMPLE 115 Preparation ofl-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazol- 4-yl-azidomethyl To l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-chloromethylbenzimidazole (Example 114) (1.31 g, 3.23 mmol) dissolved in DMF (10 mL) was added sodium azide (0.68 g, 10.5 mmol, 325 M%). After 1 h at room temperature, the reaction was diluted with CH 2 C1 2 , and washed with NaHCO 3 (sat. soln) and NaCl (sat. aq). The combined washings were dried filtered and concentrated. Recrystallization from diethyletheπhexane (3:1) yielded white crystals of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazol-4-yl-azidomethyl (1.23 g, 2.99 mmol, 93 % yield). M.p. 150-152 °C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.55 (m, IH, H 4 .), 7.50 (dd, J= 7.7, 1.6 Hz, IH, H 7 ), 7.32 (m, IH, H 6 ), 7.30 (m, 2H, H 5 , 4 ..), 7.09 (m, 2H, H r>5 .), 6.82 (m, 2H, H 3 . |5 ..), 5.37 (s, 2H, CH 2 PhF 2 ), 4.81 (s, 2H, CH 2 N 3 ). EXAMPLE 116 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazol- 4-yl-methylamine To l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazol-4-yl-azidomethyl (Example 115) (0.55 g, 1.34 mmol) dissolved in acetic acid (10 mL) was added zinc (0.55 g, 6.27 mmol, 630 M%). After 1 h at room temperature, the reaction was concentrated, redissolved with EtOAc, and washed with NaHCO 3 (sat. soln) and NaCl(sat. aq). The combined washings were dried(Na 2 SO 4 ), filtered and concentrated to give the crude product. The crude product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 increasing to 100% MeOH, yielding white crystals of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazol-4-yl-methylamine (0.16 g, 0.42 mmol, 31 % yield). M.p. 257-260 °C; Η- NMR (300 MHz, CD 2 C1 2 ): δ 7.59 (m, IH, H 4 ), 7.55 (m, IH, H 7 ), 7.35 (m, 2H, H 5 6 ), 7.27 (m, IH, H 4 ..), 7.12 (m, 2H, H 3 ι5 ), 6.83 (m, 2H, H 3 . 5 .), 5.40 (s, 2H, CH 2 PhF 2 ), 4.49 (s, 2H, CH 2 N). EXAMPLE 117 Preparation of N-l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- benzimidazol-4-methyl)-acetamide To 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazol-4-yl- methylamine (Example 116) (0.28 g, 0.73 mmol) dissolved in THF (10 mL) and triethylamine (0.2 mL) was added acetic anhydride (0.20 mL, 2.12 mmol, 300 M%). After 1.5 h at room temperature, the reaction was concentrated, redissolved with EtOAc, and washed with NaHCO 3 (sat. soln) and NaCl (sat. aq). The combined washings were dried filtered, and concentrated. The crude product was purified by flash chromatography eluting with 4% MeOH/CH 2 Cl 2 increasing to 8% MeOH/CH 2 Cl 2 , yielding white crystals of N-l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-benzimidazol-4-methyl)-acetamide (0.20 g (0.47 mmol, 65 % yield). M.p. 178-179 °C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.56 (m, IH, H 4 ), 7.42 (m, IH, H 7 ), 7.30-7.18 (m, 3H, H 5 -), 7.10 (m, 2H, H 3 j5 ), 6.90 (br, IH, NH), 6.82 (m, 2H, H 3 . ,5 ), 5.37 (s, 2H, CH 2 PhF 2 ), 4.79 (d, J= 5.9 Hz, 2H, CH 2 N), 1.92 (s, 3H, NAc). EXAMPLE 118 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)- 4-(N-acetyl-N-methyl)-aminomethylbenzimidazole To N- 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazol-4-methyl)- acetamide (Example 117) (0.25 g, 0.58 mmol) and methyl iodide (0.065 mL, 1.04 mmol, 180 M%) dissolved in THF (10 mL) was added sodium hydride (50 mg, 1.25 mmol, 215 M%). After stirring overnight at room temperature, the reaction was diluted with EtOAc, and washed with NaHSO 4 (10% soln) and NaCl (sat. aq). The combined washings were driedtNajSO , filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 increasing to 4% MeOH/CH 2 Cl 2 , yielding white crystals of l-(2,6-Difluorobenzyl)-2- (2,6-difluorophenyl)-4-(N-acetyl-N-methyl)-aminomethylbenzimidazole (0.24 g, 0.54 mmol, 94 % yield). M.p. 171-172 °C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.55 (m, IH, H 4 ), 7.44 & 7.40 (rotamers) (d, J= 8.3 Hz, IH, H 7 ), 7.32-7.20 (m, 2H), 7.15-7.04 (m, 3H), 6.82 (m, 2H, H 3 . ,5 . ), 5.37 & 5.35 (rotamers) (s, 2H, CH 2 PhF 2 ), 5.00 & 4.98 (rotamers) (s, 2H, CH 2 N), 3.04 & 2.96 (rotamers) (s, 3H, NCH 3 ), 2.15 & 2.11 (rotamers) (s, 3H, NAc). EXAMPLE 119 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazol- 4-yl-methoxymethyl To l-(2,6-difluorobenzyl)-2-(2.6-difluorophenyl)-4-hydroxymethyl- benzimidazole (Example 112) (0.20 g, 0.52 mmol) dissolved in THF (2 mL) was added methyl iodide (40 mL, 0.64 mmol, 120 M%) and sodium hydride (20 mg). After 2 h at room temperature, additional methyl iodide (20 mL, 0.32 mmol, 60 M%) was added. After 3 h, the reaction was diluted with EtOAc, and washed with NaHCO 3 (sat. soln) and NaCl (sat. aq). The combined washings were dried filtered and concentrated. The crude product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 , yielding white crystals of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazol-4-yl-methoxymethyl (0.10 g, 0.25 mmol, 48 % yield). 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.53 (m, IH, H 4 ), 7.43 (dd, J= 7.1, 2.2 Hz, IH, H 7 ), 7.34-7.28 (m, 2H, H 5>6 ), 7.24 (m, IH, H 4 ..), 7.08 (m, 2H, H 3 ι5 ), 6.81 (m, 2H, H 3 . ,5 . ), 5.35 (s, 2H, CH 2 PhF 2 ), 4.90 (s, 2H, CH 2 O), 3.45 (s, 3H, OCH 3 ). EXAMPLE 120 Preparation of 4-Azidomethyl-2-(2,6-difluόrobenzyl)- l-(2,6-difluorophenyl)benzimidazole To a solution of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4- chloromethylbenzimidazole (Example 114) (125 mg, 0.31 mmole) in 0.7mL of acetonitrile (not completely soluble) was added 5.9 mg (0.022 mmole) of 18-crown-6 ether, followed by 20 mg (0.31 mmole) of potassium cyanide. The reaction mixture was diluted with 0.4mL of dry methanol, and stirred for 24 hrs at room temperature. The reaction mixture was then diluted with methylene chloride (2 mL), filtered, washed with water, and the solution was dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was chromatographed on silica gel column eluted with 1:1 hexane/ethyl acetate, yielding 4-azidomethyl-2-(2,6-difluorobenzyl)- l-(2,6-difluorophenyl)benzimidazole (57 mg , 47% yield). From the above, it is clear that the present invention provide compositions and methods for the treatment of HIV infection. In particular, the present invention provides non-nucleoside inhibitors of reverse transcriptase (RT). In particular, the present invention relates to stable analogues of 1 -(2,6-difluorophenyl)- 1H,3H- thiazolo[3,4-a]benzimidazole, effective in the inhibition of human immunodeficiency virus (HIV) RT, with particular activity against HIV-1 RT. Furthermore, the present invention provides highly purified compositions with high activity against HIV-1 RT mutants that are refractory to inhibition with other non-nucleoside HIV-1 RT compounds. All publications and patents mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims.

Claims: CLAIMS A substituted benzimidazole having the structure wherein X" is selected from the group consisting of hydrogen, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine, and wherein R" is selected from the group consisting of 2,6-difluorobenzyl, benzyl, ethylbenzyl, 2,6-dichlorobenzyl, 2,3,4,5,6- pentafluorobenzyl, pyridylmethyl, benzenesulfonyl, 2,6-difluorobenzoyl, and 3,3- dimethylallyl. 2. The substituted benzimidazole of Claim 1, wherein R" is 2,6- difluorobenzyl. 3. A substituted benzimidazole having the structure wherein X' is selected from the group consisting of hydrogen, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, isopropyl, isopropenyl, bromine and chlorine; and wherein R' is selected from the group consisting of phenyl, formyl, isopropyl, H, methyl, cyclopropyl, hydroxymethyl, 2,6- difluorobenzyloxymethyl, 2,6- difluorophenyl, 2-fluoro-6-methoxylphenyl, methylphenyl, pyridyl, and naphthyl. 4. The substituted benzimidazole of Claim 3, wherein R' is 2,6- difluorophenyl. A substituted benzimidazole of general structure wherein X"" is at least one substituent positioned at a benzimidazole carbon selected from C4, C5, C6, C7, C4 and C5, and C4 and C6 of a substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole, and wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 4,5- dimethyl, 4,6-dimethyl, 4-ethyl, 4-cyano (CN), 4-methylenecyano (CH 2 CN), 4- methoxy, 4-nitro, 5-nitro, 4-amino, 4-N-acetamido (NHAc), 4-N-methylamino (NHCH 3 ), 4-N-dimethylamino [N(CH 3 ) 2 ], 4-isopropyl, 4-isoprenyl, 4-bromo, 5-bromo, 6-bromo, 4-chloro, 5-chloro, 6-chloro, fluoro, N-methylacetamido (NAcCH 3 ), methyl carboxylate (CO 2 Me), methyl acetamido ester (CH 2 OAc), hydroxy, CNH(NH 2 OH), amide (CONH 2 ), N-dimethylamide [CON(CH 3 ) 2 ], carboxylic acid, hydroxymethyl (CH 2 OH), formyl, chloromethyl, 4-methyleneazido (CH 2 N 3 ), aminomethyl (CH 2 NH 2 ), N-acetamidomethyl (CH 2 NHAc), CH 2 NCH 2 Ac, dimethyl ether (CH 2 OCH 3 ), 4- methylenethiocyanate (CH 2 NCS), and 4-methyleneacetylene (CH 2 CCH). 6. The substituted benzimidazole of Claim 5, wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 4-ethyl, 4-cyano, 4-methoxy, 4-nitro, 4-amino, 4-N-acetamido, 4-N-methylamino, 4-N-dimethylamino, 4-isopropyl, 4- isopropenyl, 4-bromo, 4-chloro, 4-methyleneazido, 4-methylenecyano, 4- methylenethiocyanate, and 4-methyleneacetylene. 7. The substituted benzimidazole of Claim 6, wherein said X"" is selected from the group consisting of 4-methoxy, 4-methyleneazido and 4-methylenecyano- 8. A pharmaceutical composition comprising the substituted benzimidazole of Claim 6. 9. A method for treating human immunodeficiency virus infection, comprising the steps of: a) providing: i) a subject suspected of being infected with human immunodeficiency virus; and ii) a composition having anti- reverse transcriptase activity and comprising at least one substituted benzimidazole having a 2,6-difluorobenzyl substituent at the N-1 site of said benzimidazole; b) exposing said subject to said composition; and c) observing for inhibition of said anti-reverse transcriptase activity. 10. The method of Claim 9, wherein said human immunodeficiency virus is HIV-1. 11. The method of Claim 9, wherein said substituted benzimidazole further comorises a 2,6-difluorophenyl substituent at the C2 site of said benzimidazole. 12. The method of Claim 9, wherein said substituted benzimidazole is of the general structure: wherein X"" is at least one substituent positioned at a benzimidazole carbon selected from C4, C5, C6, C7, C4 and C5, and C4 and C6 of a substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole, and wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 4,5- dimethyl, 4,6-dimethyl, 4-ethyl, 4-cyano (CN), 4-methylenecyano (CH 2 CN), 4- methoxy, 4-nitro, 5-nitro, 4-amino, 4-N-acetamido (NHAc), 4-N-methylamino (NHCH 3 ), 4-N-dimethylamino [N(CH 3 ) 2 ], 4-isopropyl, 4-isoprenyl, 4-bromo, 5-bromo, 6-bromo, 4-chloro, 5-chloro, 6-chloro, fluoro, N-methylacetamido (NAcCH 3 ), methyl carboxylate (CO 2 Me), methyl acetamido ester (CH 2 OAc), hydroxy, CNH(NH 2 OH), amide (CONH 2 ), N-dimethylamide [CON(CH 3 ) 2 ], carboxylic acid, hydroxymethyl (CH 2 OH), formyl, chloromethyl, 4-methyleneazido (CH 2 N 3 ), aminomethyl (CH 2 NH 2 ), N-acetamidomethyl (CH 2 NHAc), CH 2 NCH 2 Ac, dimethyl ether (CH 2 OCH 3 ), 4- methylenethiocyanate (CH 2 NCS), and 4-methyleneacetylene (CH 2 CCH). 13. The method of Claim 12, wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 4-ethyl, 4-cyano, 4-methoxy, 4-nitro, 4-amino, 4-N- acetamido, 4-N-methylamino, 4-N-dimethylamino, 4-isopropyl, 4-isopropenyl, 4- bromo, 4-chloro, 4-methyleneazido, 4-methylenecyano, 4-methylenethiocyanate, and 4- methyleneacetylene. 14. The method of Claim 13, wherein said X"" is selected from the group consisting of 4-methoxy, 4-methyleneazido, and 4-methylenecyano. 15. A method for inhibiting HIV-1 reverse transcriptase, comprising the steps of: a) providing: i) a sample suspected of being infected with HIV-1 virus; and ii) a composition having anti-reverse transcriptase activity and comprising at least one substituted benzimidazole, having a 2,6-difluorobenzyl substituent at the N-1 site of said benzimidazole; b) exposing said sample to said composition; and c) observing for inhibition of said anti-reverse transcriptase activity. 16. The method of Claim 15, wherein said substituted benzimidazole further comprises a 2,6-difluorophenyl substituent at the C2 substituent of said benzimidazole. 17. The method of Claim 15, wherein said substituted benzimidazole is of the general structure: wherein X"" is at least one substituent positioned at a benzimidazole carbon selected from C4, C5, C6, C7, C4 and C5, and C4 and C6 of a substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole, and wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 4,5- dimethyl, 4,6-dimethyl, 4-ethyl, 4-cyano (CN), 4-methylenecyano (CH 2 CN), 4- methoxy, 4-nitro, 5-nitro, 4-amino, 4-N-acetamido (NHAc), 4-N-methylamino (NHCH 3 ), 4-N-dimethylamino [N(CH 3 ) 2 ], 4-isopropyl, 4-isoprenyl, 4-bromo, 5-bromo, 6-bromo, 4-chloro, 5-chloro, 6-chloro, fluoro, N-methylacetamido (NAcCH 3 ), methyl carboxylate (CO 2 Me), methyl acetamido ester (CH 2 OAc), hydroxy, CNH(NH 2 OH), amide (CONH 2 ), N-dimethylamide [CON(CH 3 ) 2 ], carboxylic acid, hydroxymethyl (CH 2 OH), formyl, chloromethyl, 4-methyleneazido (CH 2 N 3 ), aminomethyl (CH 2 NH 2 ), N-acetamidomethyl (CH 2 NHAc), CH 2 NCH 2 Ac, dimethyl ether (CH 2 OCH 3 ), 4- methylenethiocyanate (CH 2 NCS), and 4-methyleneacetylene (CH 2 CCH). 18. The method of Claim 17, wherein said X"" is selected from the group consisting of hydrogen, 4-methyl, 4-ethyl, 4-cyano, 4-methoxy, 4-nitro, 4-amino, 4-N- acetamido, 4-N-methylamino, 4-N-dimethylamino, 4-isopropyl, 4-isopropenyl, 4- bromo, 4-chloro, 4-methyleneazido, 4-methylenecyano, 4-methylenethiocyanate, and 4- methyleneacetylene. 19. The method of Claim 18, wherein said X"" is selected from the group consisting of 4-methoxy, 4-methyleneazido, and 4-methylenecyano.

Inventors: MICHEJDA CHRISTOPHER J, MORNINGSTAR MARSHALL, ROTH THOMAS, MICHEJDA, CHRISTOPHER, J., MORNINGSTAR, MARSHALL, ROTH, THOMAS
Applicants: MICHEJDA CHRISTOPHER J, MORNINGSTAR MARSHALL, ROTH THOMAS, US HEALTH, MICHEJDA, CHRISTOPHER, J., MORNINGSTAR, MARSHALL, ROTH, THOMAS, THE GOVERNMENT OF THE UNITED STATES OF AMERICA, AS REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Application year: 2000
Main classification: C07D235
IPC codes: A61P31, C07D235, C07D401