SUBSTITUTED BENZIMIDAZOLES AS NON-NUCLEOSIDE INHIBITORS OF REVERSE TRANSCRIPTASE

Abstract: The present invention provides compositions and methods for the treatment of HIV infection. In particular, the present invention provides non-nucleoside inhibitors of reverse transcriptase (RT), as well as methods to treat HIV infection using these non-nucleoside inhibitors of RT. In preferred embodiments, the present invention provides a novel class of substituted benzimidazoles, effective in the inhibition of human immunodeficiency virus (HIV) RT.

Description: SUBSTITUTED BENZIMIDAZOLES AS NON-NUCLEOSIDE INHIBITORS OF REVERSE TRANSCRIPTASE The present application claims priority benefit of U.S. provisional application No. 60/038.509. filed February 25, 1997, pending, which is hereby incorporated herein by reference in its entirety. 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 HIV 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). HIV is classified as a retrovirus. 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." Bioche .. 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, and 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 HIV-infected patients. The second major class of RT inhibitors comprises the non-nucleoside RT inhibitors (NNRTI). such as tetrahydroimidazo(4,5,l-l-y χi,4)-berιzodiazepin-2-(lH)-one, and -thione (TIBO) derivatives, dipyridodiazepinones, pyridinones, bis(heteroaryl)piperazines (BΗAPs), 2' ,5 ' -bis-O-(tertbutyldimethylsilyl)-3 ' -spiro-5 ' ' -(4" -amino- 1 " ,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 (lΗ)-one (8-C1 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. Set, 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 KIN. 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 l-aryl-2-(2,6- difluorophenyl)benzimidazole compositions with general structure of Figure 12. In particularly preferred embodiments, X" is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl, bromine and chlorine. In other preferred embodiments, 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 other preferred embodiments, X" is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, 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 other preferred embodiments, X" is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl, bromine and chlorine: and R" is 2,6-difluorobenzyl. In yet other preferred embodiments, X" is selected from the group consisting of methoxyl and acetamide, and R" is 2,6-difluorobenzyl. In an alternative embodiment, the present invention provides l-(2,6- di luorophenyl)benzimidazole compositions with the general structure of Figure 13. In preferred embodiments, X' is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol. isopropenyl, bromine and chlorine. In other preferred embodiments, 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 diflourophenyl (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 other preferred embodiments, X' is selected from the group consisting of H and methyl, H, methyl, ethyl, cyano. methoxyl, nitro. amine. acetamide, methylamine, dimethylamine, propan-2-ol, 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 diflourophenyl (2,6- F 2 Ph), methylphenyl (2-CH 3 Ph), 2-fluoro-6-methyoxylphenyl, pyridyl (e.g., 4-Py, 3-Py), and naphthyl (e.g., 1-Nap. 2-Nap). In other preferred embodiments, X' is selected from the group consisting of H, methyl, ethyl, cyano. methoxyl, nitro, amine. acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl, bromine and chlorine; and R' is 2.6-difluorophenyl. In yet other preferred embodiments, X' is selected from the group consisting of methoxyl and acetamide, and R' is 2,6-difluorophenyl. In another alternative embodiment, the present invention provides 4-, 5-. 6-, or 7- substituted- l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole compositions of the general structure of Figure 23, wherein X"" is selected from the group consisting of H, methyl (CH 3 ), 4-methyl (4-CH 3 ), 5-methyl (5-CH 3 ), 6-methyl (6-CH 3 ), 7-methyl (7-CH 3 ), 4,5- dimethyl (4,5-CH 3 ), 4,6-dimethyl (4,6-CH 3 ), 4-chloro (4-C1), 5-chloro (5-C1). 6-chloro (6-C1). 4-bromo (4-Br), 5-bromo (5-Br), 4-nitro (4-NO 2 ), and 5-nitro (5-NO 2 ). In yet another embodiment, the present invention provides 4-substituted-l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole compositions of the general structure of Figure 24. wherein X'" is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl. nitro, amine, acetamide. methylamine, dimethylamine, propan-2-ol. isopropenyl, bromine and chlorine. 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, H, 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, ethyl, cyano, methoxyl, nitro. amine, acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl, phenyl, formyl. isopropyl. cyclopropyl, hydroxymethyl, 2,6-difluorobenzyloxymethyl, 2,6-diflourophenyl. 2-fluoro-6- methyoxylphenyl, pyridyl, naphthyl, 2,6-difluorobenzyl, benzyl, ethylbenzyl, 2.6- dichlorobenzyl, 2,3.4,5, 6-pentafluorobenzyl, pyridylmethyl, benzenesulfonyl, 2.6- difluorobenzoyl, and 3,3-dimethylallyl. 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., C-4, C-5, C-6, and C-7) 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 treatment of HIV infection/disease. In particularly preferred embodiments, the present invention provides compositions of substituted benzimidazoles with activity against HIV-1 RT. The present invention also provides methods for treatment of human immunodeficiency virus (HIV) infection, comprising the steps of: providing: i) a subject suspected of being infected with human immunodeficiency virus; and ii) a composition having anti-reverse transcriptase activity, wherein the composition comprises at least one substituted benzimidazole with at least one substitution at the C-2 site, and at least one substitution at the N-l site; exposing the subject to the composition; and observing for inhibition of anti-reverse transcriptase activity. In one preferred embodiment, the human immunodeficiency virus is HIV-1. In one embodiment, the method for treatment of HIV infection utilized substituted benzimidazoles with the general structure of Figure 12. In particularly preferred embodiments. X" is selected from the group consisting of H, methyl, ethyl, cyano. methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl. bromine and chlorine. In other preferred embodiments, 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 other preferred embodiments, X" is selected from the group consisting of H, methyl, ethyl, cyano. methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, 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 other preferred embodiments. X" is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol. isopropenyl. bromine and chlorine; and R" is 2.6- difluorobenzyl. In yet other preferred embodiments. X" is selected from the group consisting of methoxyl and acetamide, and R" is 2,6-difluorobenzyl. In an alternative embodiment, the method for treatment of HIV infection utilized substituted benzimidazoles with the general structure of Figure 13. In particularly preferred embodiments, X' is selected from the group consisting of H, methyl, ethyl, cyano. methoxyl. nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl, bromine and chlorine. In other preferred embodiments, 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 diflourophenyl (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 other preferred embodiments, X' is selected from the group consisting of H and methyl, H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, 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 diflourophenyl (2,6-F 2 Ph), methylphenyl (2- CH 3 Ph), 2-fluoro-6-methyoxylphenyl, pyridyl (e.g., 4-Py, 3-Py), and naphthyl (e.g., 1-Nap, 2- Nap). In other preferred embodiments, X' is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl, bromine and chlorine; and R' is 2,6-difluorophenyl. In yet other preferred embodiments, X' is selected from the group consisting of methoxyl and acetamide, and R' is 2,6-difluorophenyl. In another alternative embodiment, the method for treatment of HIV infection utilized substituted benzimidazoles with the general structure of Figure 23. In particularly preferred embodiments, X"" is selected from the group consisting of H, methyl (CH 3 ), 4-methyl (4- CH 3 ), 5-methyl (5-CH 3 ), 6-methyl (6-CH 3 ), 7-methyl (7-CH 3 ), 4,5-dimethyl (4,5-CH 3 ), 4,6- dimethyl (4,6-CH 3 ), 4-chloro (4-C1), 5-chloro (5-C1), 6-chloro (6-C1), 4-bromo (4-Br), 5- bromo (5-Br), 4-nitro (4-NO 2 ), and 5-nitro (5-NO 2 ). In yet another alternative embodiment, the method for treatment of HIV infection utilized substituted benzimidazoles with the general structure of Figure 24. In particularly preferred embodiments, X"' is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol. isopropenyl. bromine and chlorine. In addition, it is contemplated that the present invention encompasses analogs of the benzimidazole ring system which undergo 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. DESCRIPTION OF THE FIGURES Figure 1 shows the general structures of imidazole and benzimidazole. Figure 2 is a schematic of the retrosynthetic analysis of N-benzyl-2- alkylbenzimidazoles by alkylation of 2-substituted benzimidazoles. Figure 3 shows one embodiment for the synthesis of 2-aryl-benzimidazoles. Figure 4 shows one embodiment for the synthesis of hydroxymethyl substituted benzimidazole. Figure 5 shows the structure, as well as physical and biological data for l-(2,6- difluorobenzyl)-2-aryl-benzimidazoles. Figure 6 shows the structure, as well as physical and biological data for l-aryl-2-(2,6- difluorophenyl)-benzimidazoles. Figure 7 shows the structure, as well as physical and biological data for l-(2,6- difluorobenzyl)-2-substituted-benzimidazoles. Figure 8 shows the anti-RT activity of compounds 33 and 26. compared with TZB and TIBO. .Antiviral data are reported as the quantity of drug in μM required to reduce cell killing or virus production by 50% (EC 50 ). Figure 9 shows the "butterfly-like" shape of TZB and 39. Figure 10 shows the structure of four compounds that did not inhibit RT activity. Figure 11 shows the substitutions of the benzimidazole core ring that inhibited as well as substitutions that did not inhibit HIV RT. Figure 12 shows the structure of l-aryl-2-(2,6-difluorophenyl)benzimidazole. Figure 13 shows the structure of l-(2,6-difluorobenzyl)-2-benzimidazole. Figure 14 shows one embodiment for the synthesis of substituted l-(2.6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazoles. Figure 15 shows one embodiment for the reduction of the 4-nitro group of 3100 with tin chloride. Figure 16 shows the structure, physical, and enzyme inhibition data for 4-, 5-, 6- and 7-methyl-substituted l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-benzimidazoles. Figure 17 shows the structure, physical, and enzyme inhibition data for 4-. 5-, and 6- substituted l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazoles (Cl, Br, NO 2 ). Figure 18 shows the structure, physical, and enzyme inhibition data for 4- substituted l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazoles. Figure 19 shows the anti-RT activity of CH 3 , NH 2 , Cl, Br-substituted compounds, compared with TZB and TIBO. Antiviral data are reported as the quantity of drug in μM required to reduce cell killing or virus production by 50% (EC 50 ). Figure 20 is a summary graph showing the cytotoxicity and anti-viral effect of compound 33. Figure 21 is a summary graph showing the cytotoxicity and anti-viral effect of compound 34. Figure 22 is a summary graph showing the anti-viral results for inactive compound 2100. Figure 23 shows the structure of 5,6, or 7-substituted-l-(2,6-difluorobenzyl)-2-(2,6- difluoropheny l)benzimidazole . Figure 24 shows the structure of 4-substituted l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazole. Figure 25 shows the calculated and actual purities of various substituted l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazoles. Figure 26 shows one embodiment for the synthesis of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-4-cyanobenzimidazole. Figure 27 shows one embodiment for the synthesis of N-substituted-2-(2,6- difluorophenyl)-4-mefhoxylbenzimidazole. Figure 28 shows one embodiment for the syntheses of N-substituted-(2,6- difluorophenyl)-4-methylbenzimidazoles and N-substituted-(2,6-difluorophenyl)-4- ethylbenzimidazoles. Figure 29 shows one embodiment for the synthesis of substituted l-(2,6- difluorobenzyl)-2-arylbenzimidazoles. Figure 30 shows one embodiment for the synthesis of N-substituted-2-(cyclopropyl)-4- methoxylbenzimidazole. Figure 31 shows one embodiment of the synthesis of 4-substituted N-substituted-2- (2,6-difluorophenyl)benzimidazoles. Figure 32 shows the cross resistance profile of 4-Substituted l-(2,6-difluorobenzoyl)-2- (2,6-difluorophenyl)benzimidazoles in a cytopathic cell killing assay. Antiviral data are reported as the quantity of drug in μM required to reduce cell killing or virus production by 50% (EC 50 ). 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. Definitions To facilitate understanding of the invention, a number of terms are defined below. As used herein, the term "retrovirus" refers to the 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 "chemo therapeutic" 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 term "benzimidazole" is 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 atom or group in a molecule by another atom or group. As used herein, the term "TZB" refers to l-(2,6-difluorophenyl)-lH,3-thiazolo[3,4- α]benzimidazole. In preferred embodiments, the present invention encompasses 1 ,2- substituted benzimidazoles, including but not limited to l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-4-methylbenzimidazole. The term "cyclic compounds" refers to compounds having one (i.e., a monocyclic compounds) or more than one ( . 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 HIV RTs to function in the presence of compounds that are inhibitory to the RT of wild- type HIV. This resistance may result from any number of mutations, including but not limited to conformational changes in the RT structure, as well as 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 which are 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, and subcutaneous administration. 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). Imidizoles And Benzimidazoles In addition to compounds such as tetrahydroimidazo(4,5,l-l-y ' )(l,4)-benzodiazepin-2- (lH)-one. and -thione (TIBO) derivatives, dipyridodiazepinones, pyridinones. bis(heteroaryl)piperazines (BHAPs), 2',5'-bis-O-(tertbutyldimethylsilyl)-3'-spiro-5 * , -(4"- amino-l ".2"-oxathiole-2".2"-dioxide)pyrimidine (TSAO) derivatives, α- anilinophenylacetamide (α -APA), 4,5,6,7-tetrahydro-5-methylimidazo-[4,5,l- jk][l,4]benzodiazepine-2 (lH)-one (TIBO), and nevirapine, the potential therapeutic utility of imidazole compounds such as l-(2,6-difluorophenyl)-lH,3H-thiazolo[3,4- ]benzimidazole (TZB) 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-α]Benzimidazoles," II Farmaco 46:817-823 [1991]). As shown in Figure 1, imidazoles (i.e., glyoxaline, 1,2-diazole, iminazole, miazole, pyrro[6]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 (/. 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, N,N'-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 has 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-α] 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, TZB, has been shown to have HIV-1 RT inhibitory activity. However, there are some drawbacks to the use of TZB. (See, e.g., Chimirri et al, Anti-HIV Agents. I. Synthesis and In Vitro Anti-HIV Evaluation of Novel lH,3H-Thiazolo[3,4-α]Benzimidazoles," II Farmaco 46:817-823 [1991]; Chimirri et al, "Anti-HIV Agents. II. Synthesis and In Vitro Anti-HIV Evaluation of Novel 1H,3H- Thiazolo[3.4-l]Benzimidazoles," // 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 TZB 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 HIV-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 TZB 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 TZB. This indicated that opening the thiazolo ring of TZB 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 ΝΝRTIs 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 ΝΝRTIs, such as 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 HIV- 1 RT. Various approaches were taken in order to produce these compounds, including synthesizing benzimidazoles with substitutions at one or more positions. Synthesis Of Substituted Benzimidazoles Figure 3 provides one embodiment of a general outline of the approach for the synthesis of 2-aryl-benzimidazoles. As shown in Figure 3, a variety of 2-aryl-benzimidazoles were made available by use of the appropriate choice of acylating reagent. 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). In this Figure, "a" comprised aroyl chloride. pyridine/THF (tetrahydrofuran); "b" comprised Fe (17)/AcOH (iron acetic acid); "c" comprised 2,6-F 2 -BnBr (25) (2,6-difluorobenzylbromide)/ΝaH (sodium hydride)/THF; and "d" comprised BnBr (27) (benzyl bromide) or PhSO 2 Cl (44) (benzenesulfonyl chloride) or 2,6- F 2 BzCl (7) (2,6-difluorobenzoylchloride)/THF. 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 (25), the desired 2-aryl-l-(2,6-difluorobenzyl)-benzimidazoles (R 2 = 2.6- difluorophenyl [26 and 33]; 2-methylphenyl [36]; napthyl [37 and 38]; pyridyl [40 and 41]) 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 (25) to give compounds (35 and 39). Preparation of the hydroxymethyl substitute was achieved by acid- catalyzed condensation-cyclization of glycolic acid with either ø-phenylenediamine (1) or 2,3- diaminotoluene (3), using an approach similar to that described by Chimirri et al for the synthesis of TZB. (Chimirri et al, Anti-HIV Agents. I. Synthesis and In Vitro Anti-HIV Evaluation of Novel lH,3H-Thiazolo[3,4-α]Benzimidazoles," II Farmaco 46:817-823 [1991]; and 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]). One embodiment, showing this approach is presented schematically in Figure 4. In this Figure, "a" comprised glycolic or isobutyric acid/4 N HCl (hydrochloric acid)/reflux; "b" comprised 2,6- F 2 -BzCl (7) or 2,6-F 2 BnBr (25); "c" comprised t-butyldimethylsilylchloride (tBDMSCl)/ pyridine; "d" comprised Bu 4 NF (tetrabutylammonium fluoride)/THF; "e" comprised KMnO 4 (potassium permanganate); and "f ' comprised CrO 3 (chromium trioxide).. In the embodiment presented in Figure 4, the hydroxymethyl was then protected with t-butyldimethylsilyl (TBDMS) before N-alkylation 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 trioxide similarly yielded (50), along with the formyl product (51). The carboxylic acid form was not isolated. A final product prepared from the 2- hydroxymethylbenzimidazole (4) was the bis-2,6-difluorobenzyl derivative (32). A variety of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole compounds with general structure of Figure 12 were prepared by use of the appropriate choice of acylating reagent. Figure 26 shows the synthesis of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-4-cyanobenzimidazole (4007). In this Figure, "a" comprised difluorobenzoyl chloride/pyridine/THF; "b" comprised hydrazine/pyridine; "c" comprised iron powder; "d" comprised 2,6-difluoro-α-bromo-toluene; "e" comprised barium hydroxide/AcOH; and "f ' comprised 1.0 M solution of AlMe 2 ΝH 2 (dimethylaluminum amine)/xylene. Figure 27 shows the preparation of 2-(2.6-difluorophenyl)-4-methoxylbenzimidazoles with general structure of Figure 12. In this figure, "a" comprised K 2 CO 3 (potassium carbonate)/mefhyl iodide/acetone; "b" comprised difluorobenzoyl chloride/pyridine/THF; "c" comprised hydrazine/pyridine; "d" comprised iron powder; "e" comprised 2,6-difluoro-α-bromo-toluene; "f ' comprised benzyl bromide: "g" comprised (l-bromoethyl)benzene; and "h" comprised 3.3-dimethylallyl bromide. Figure 28 shows the preparation of 2-(2,6-difluorophenyl)-4-ethylbenzimidazole and 2-(2,6- difluorophenyl)-4-methylbenzimidazole with general structure of Figure 12. In this figure, "a" comprised difluorobenzoyl chloride; "b" comprised iron powder; "c" comprised 2.6-difluoro- α-bromo-toluene; "d" comprised 3.3-dimethylallyl bromide. Figure 31 shows the preparation of a variety of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole compounds with general structure of Figure 12. In this figure, "a" comprised 3,3-dimethylallyl bromide; "b" comprised iron powder; and "c" comprised concentrated H 2 SO 4 (sulfuric acid). A variety of l-(2,6-difluorobenzyl)benzimidazole compositions with general structure of Figure 13 was prepared. Figure 29 shows the preparation of l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-4-(N-substituted)benzimidazole with general structure of Figure 13. In this figure, "a" comprised SnCl 2 x2H 2 O (tin(II) chloride); "b" comprised methyl iodide/THF/ΝaH; and "c" comprised HCl. Figure 30 shows the preparation of l-(2,6-difluorobenzyl)-2- (cyclopropyl)-4-methoxylbenzimidazole (5016). In this figure, "a" comprised cyclopropanecarbonyl chloride; "b" comprised iron powder; "c" comprised 3,3-dimethylallyl bromide: and "d" comprised 2,6-difluoro-α-bromo-toluene. The final 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 TZB series. In this series, the optimal anti-HIV activity was achieved when the phenyl ring was substituted at the 2- and 6- position with fluorine. Treatment of benzimidazole (18 or 19) with benzyl bromide analogs (benzyl bromide itself, 2,6-dichloro-α-bromo-toluene, 2,3,4,5,6-pentafluoro-α-bromo-toluene), permitted the determination of whether compounds with hydrogen, chlorine, or multiple fluorines on Nl benzyl ring were better inhibitors of 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 compound (33). By reacting compound (18) or (19) with benzenesulfonyl chloride, compounds (45) and (46) were obtained in good yields. Similarly, treatment of compound 18 with 2.6-difluorobenzoyl chloride provided the l-(2,6-difluorobenzoyl)-2-(2,6-difluorophenyl)benzimidazole (47), allowing the testing of carbonyl as a linker. In addition, the introduction of nitrogen into the Nl -benzyl ring by synthesizing the 3 -pyridyl derivative (43) via alkylation with α-bromo-methylpyridine was investigated. Synthesis And Biological Activity of 4-, 5-, 6- And 7-Substituted Benzimidazoles In addition to the 1 ,2-substituted benzimidazoles described above, 4-, 5-, 6-. and 7- mono- and di-substitutions of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole. and its des-methyl analog (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 33 also exhibited desired activity. However, the 5- or 7-substituted analogues of 33 showed decreased RT inhibition. Variation of the benzimidazole ring portion of 33 was accomplished mostly through determining and then using the appropriate choice of starting material. The general approach utilized in the synthesis of the desired substituted l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazoles is outlined in Figure 14. As regiocontrolled benzylation of C- 2 substituted benzimidazoles was not expected for 5-, 6- or 7-substituted benzimidazoles. in order to control the regiochemistry, the N-acyl-nitroanilines were alkylated before reductive cyclization. In Figure 14, "a" comprises 2,6-difluorobenzoyl chloride/pyridine/THF (1 :1); "b" comprises ΝaOH (sodium hydroxide)/MeOH (methanol)/dioxane; "c" comprises Br 2 (bromine)/pyridine/THF; "d" comprises 2,6-F 2 BnBr/ΝaH/THF; and "e" comprises Fe/AcOH. As indicated in Figure 14, it was determined that acylation of a number of substituted nitroanilines with 2,6-difluorobenzoyl chloride (7) could yield the desired substituted N-(2,6- difluorobenzoyl)nitroanilines. In the case of the 4- or 5-chloro-nitroanilines, the predominate product was however found to be the bis-N-acylated products, 400 and 600. A variety of conditions involving time, temperature, the number of equivalents of reactants and the concentration were examined in order to identify suitable conditions for production of desired compounds. Unfortunately, appropriate conditions were not found that yielded the desired mono-acylated products, 500 and 700. However, it was fortunately determined that the mono- N-acyl-nitroaniline products could be obtained in high yields by selective de-acylation using ΝaOH in MeOH and dioxane. In most cases, alkylation of the N-acyl-nitro-aniline intermediates. 500 or 700 with 2.6-difluoro-α-bromo-toluene produced high yields of the desired N-(2,6-difluorobenzyl) products. The N-acyl-N-(2,6,-difluorobenzyl)nitroanilines were subsequently reductively cyclized under similar conditions employed in the development of the 1- and 2- substituted compounds. Synthesis of l-(2,6-difluorobenzoyl)-4-bromo-nitroanilide 1200 was accomplished by bromination of l-(2,6-difluorobenzoyl)nitroanilide (11). Benzylation and reductive cyclization as done with the 4-chloro derivative was found to provide 5-bromo-l-(2,6-difluorobenzyl)-2- (2,6-difluorophenyl)benzimidazole, 2100, in good yields. Synthesis of 5-nitrobenzimidazole. 2900, made use of 2-(2,6-difluorophenyl)benzimidazole, as described above. Mono-nitration of 2-(2.6-difluorophenyl)benzimidazole with nitric acid at room temperature yielded 5-nitro- benzimidazole 2900 as the only product. It was subsequently determined that alkylation with 2,6-difluoro-α-bromo-toluene occurred regiospecifically to yield the 5-nitro-l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)bermmidazole, 3200. Preparation of 4,5- dimethylbenzimidazole 2700 was accomplished starting from 2,3-dimethyl-6-nitroaniline. Benzylation with 2,6-difluoro-α-bromo-toluene was observed to occur regiospecifically due to the presence of 4-methyl group to yield 3000. Although an understanding of the mechanism is not necessary for the production and use of the present invention, mono acylation of 3-nitro-l,2-phenylenediamine with 2,6- difluorobenzoyl chloride (7), yielded a single product that was presumed to be the N-(2,6- difluorobenzoyl)-2-amino-3-nitroanilide, 800, on the assumption that acylation occurred at the less hindered C-l amino. Since cyclization of N-l or N-2 acylated product would lead to the desired 2-aryl-benzimidazole, detailed regiochemical analysis was not carried out. In contrast to all the previous reductive ring closures, cyclization of 800 was accomplished solely in the presence of refluxing acetic acid to yield 2-(2,6-difluorophenyl)-4-nitrobenzimidazole, 2800. Alkylation of 2800 with 2,6-difluoro-α-bromo-toluene provided a key intermediate in the preparation of a number of 4-substituted benzimidazole derivatives. As shown in Figure 15, reduction of the 4-nitro group of 3100 was accomplished with tin (II) chloride. In this Figure, "a" comprises 2,6-difluorobenzoyl chloride/pyridine/THF (1 :1); "b" comprises AcOH/reflux; "c" comprises 2,6-F 2 -BnBr/ΝaH/THF; "d" comprises SnCl 2 / AcOH HCl; "e" comprises Ac 2 O (acetic anhydride)/THF; "f ' comprises H 2 CO (formaldehyde)/ NaBH 4 (sodium borohydride)/H 2 SO 4 ; and "g" comprises NaNO 2 (sodium nitrite)/HBr (hydrogen bromide) or HCl. Compound 3300 was used to prepare the 4-bromo, 3400, and 4-chloro. 3500. benzimidazoles via Sandmeyer reactions (i.e., methods known in the art). The 4-iV-acetamido. 3600, was prepared by mono-acylation of 3300 with acetic anhydride. Treatment of 3300 with formaldehyde and sodium borohydride yielded the dimethylamino compound. 3700. RT Inhibition By 1 And 2- Substituted Benzimidazoles The testing of the 2-aryl-l-(2,6-difluorobenzyl)benzimidazoles for their HIV-1 RT inhibition activity indicated that a number of aromatic systems were tolerated at the C2 position. These results are shown in Figures 5 and 7. In this Figure, the IC 50 (μM) column indicates the quantity of drug required to reduce WT RT enzyme activity by 50% (IC 50 ). As shown in Figure 7, the ability to inhibit wild type RT (WTRT) by the hydrogen (49), methyl (35), hydroxymethyl (48), isopropyl (34), formyl (50), phenyl (39). and bis-2,6- difluorobenzyl (32) compounds was measured as the percent inhibition of nucleotide incorporation into an rC-dG template primer at 10 μmolar drug 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 yielded the best inhibitor, compound 33 (IC 50 =200 nM). Results included in Figure 8 for TIBO and TZB are in contrast with those reported by Pauwels et al. (Pauwels et al, "New Tetrahydroimidazo[4,5,l-jk][l,4]-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-retroviral Activity of a 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 from compounds 39 to 26 probably represented 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). This decrease in RT 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). These results indicated that some heteroaromatic systems can be introduced at C2 without penalty. However, compound 40 (i.e., the 3-pyridyl compound) 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 the NNRTI binding pocket can accommodate. These observations are shown in Figure 5. As shown in Figure 6, the benzenesulfonyl and 2,6-difluorobenzoyl derivatives (45, 46, and 47) did not show appreciable RT inhibition activity. Substitution on the phenyl ring by a pyridine ring (48) similarly led to lower inhibition (See, Figure 7). 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, Figure 6). Testing Of 4,5 And 5,6-Disubstituted And Mono-Substituted Benzimidazoles Against Reverse Transcriptase Testing of the 4,5, and 5,6- di-substituted, and mono-substituted benzimidazoles was determined by measuring the relative nucleotide incorporation using an rC-dG template primer at 1 μmol drug concentration (10-fold lower than used above), to the amount of incorporation with no inhibitor present utilizing WT HIV-1 RT. As seen in Figure 16, 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 % 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. 2400. can assume similar conformations as the 4-methyl derivative, 100, and the 6-methyl derivative, 2500, the decrease in % inhibition determined for the 5-methyl compound presumably must be due to differences in inductive effects. In the case of 3000, with 4.5-dimethyl groups, the significant inhibition found with 100 possessing a single methyl at C-4 was dramatically decreased by the presence of the C-5 methyl. It is was also observed that substitution at C-5 led to consistently less inhibition no matter what substitutent was examined, as shown in Figure 17. In comparing the 4-, 5-, and 6- chloro compounds, the 5-chloro shows approximately two-fold more activity than either the 4- or 6-chloro compounds, 3500 or 2300. A similar decrease is found when comparing the 4- bromo. 3400, with the 5-bromo, 2100. Even though the total inhibition was decreased by the presence of a strong withdrawing substitutent, this trend was also evident with the 4-nitro, 3100, and 5-nitro, 2900. These data led to further examination of the substitution at the C-4 position. As seen in Figure 18, most of the 4-substituted benzimidazoles synthesized 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 incorporation into a rC-dG template primer at 1 μmol drug concentration compared with the amount of incorporation with no inhibitor present; ii) the drug concentration required to inhibit 50% of nucleotide incorporation 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 is 100-fold more potent than the IC 50 for TZB and TIBO and is comparable to those determined for 8-C1 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). Cytopathic Cell Killing Assay In depth biological evaluation of the RT inhibitory properties of the most active 4-substituted 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 profile of the different compounds are found in Figures 8, 19 and 32. In these Figures, 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 purposes. As shown in Figure 8, 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. Figure 19 shows the cross-resistance profile with NNRTI-resistant HIV isolates from the cytopathic cell killing assay for a number of 4-substituted compounds (the methoxyl, N-methylacetamido, ethyl, chloro, amino, N-acetamido, and N-methylamino derivatives), 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. Figure 32 shows the effect of substitution of the N-l 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 VI 081 and Y181C variants. Figures 20, 21, and 22 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 compound 33, the 4-methyl derivative, the therapeutic index at 50% (TC 50 ) 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 it retains activity against HIV mutants that have lost sensitivity to these drugs (e.g., the V106A, Y181C, and Y188C isolates). Geometry Of TZB And l-(2,6-DifluorobenzyI)-2-Phenylbenzimidazole Semi-empirical quantum mechanical minimization at the AMI level was used to compare the geometry of TZB and l-(2,6-difluorobenzyl)-2-phenylbenzimidazole (39). As shown in Figure 9, considerable similarity was observed between the energy minimized "butterfly-like" shapes of TZB and 39. For TZB, 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 TZB, 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 TZB, at least two higher energy rotational isomers result in almost complete overlap. Although X-ray analysis is required to predict the correct "butterfly-like" orientation of this compound with RT and the NNRTI binding pocket, 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. Purity Of The Substituted Benzimidazoles The active benzimidazole compounds of the present invention were produced at a very high purity level. As shown in Figures 25, 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. 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); AlMe 2 NH 2 (dimethylaluminum amine); NaH (sodium hydride); NaNO 2 (sodium nitrite); NaOH (sodium hydroxide); KOH (potassium hydroxide); KMnO 4 (potassium permanganate); NaCI (sodium chloride); CuCl (copper chloride); SDS (sodium dodecyl sulfate): NaHSO 4 (sodium bisulfate); Na 2 S 2 O 3 (sodium thiosulfate); Na,SO 4 (sodium sulfate); TAE (Tris-Acetate-EDTA); MeOH/CH,Cl 2 (mefhanol/dichloromethane); FeSO 4 (ferrous sulfate): CuSO 4 (cuprous sulfate); MgSO 4 (magnesium sulfate); NaOAc (sodium acetate); DMF (dimethyl formamide); THF (tetrahydrofuran); NaHCO 3 (sodium bicarbonate); Na 2 CO 3 (sodium carbonate); HBr (hydrogen bromide); H 2 SO 4 (sulfuric acid); H 2 CO (formaldehyde); KBr (potassium bromide); DMSO (dimethyl sulfoxide); DMSO-i ή (fully deuterated dimethyl sulfoxide): CHC1 3 (chloroform); CDC1 3 (deuterated chloroform); CD 2 C1 2 (deuterated methylene chloride); CD 3 OD (deuterated methanol); NH 3 (ammonia); Ph (phenyl; C 6 H 5 ) Ac (ethanoate group): AcOH (acetic acid); Et 2 O (diethyl ether); EtOAc (ethyl acetate); CrO 3 (chromium trioxide): SnCl 2 x2H 2 O (tin (II) chloride); C (carbon); H (hydrogen); N (nitrogen); 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); TZB (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); t-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 (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. 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). 'H-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). 'H-NMR (200 MHz. DMSO-d 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 re-dissolved in CH 2 C1 2 , and washed with NaHCO 3 (sat. aq.), and NaCI (sat. aq.), dried Na^O . ,. filtered and concentrated. The 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), to a white powder. Η-NMR (300 MHz, CD 3 OD): δ 7.36 (br d. J= 11.1 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. 'H-NMR (200 MHz, DMSO- 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, CH 3 ), 1.34 (d, J=7.0 Hz, 6H, iPr). EXAMPLE 5 Preparation of N-(2,6-Diflurobenzoyl)-2-Nitroanilide In this Example, N-(2,6-diflurobenzoyl)-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 (7) (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 re-dissolved in ethylacetate, and washed with ΝaHSO 4 (5% solution), NaHCO 3 (sat. aq.), and NaCI (sat. aq.). The organic layer was dried under Na ^ 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%), with a melting point of 139°C. 'H-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). The product was 2.36 g (8.1 mmol, 55% yield) of slightly yellow crystals. 'H- 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 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 re-crystallized from diethylether/hexane (3:1) to produce 1.61 g (6.26 mmol, 53% yield) of white powder. 'H- 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%), and then recrystallized with ether/hexane (1 :1) to produce 2.2 g (8.6 mmol, 92% yield) of yellow crystals of N-(2-methylbenzoyl)-2-nitroanilide. 'H-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-( 1 -Νaphthoyl)-2-Methyl-6-Νitroanilide In this Example, N-(l-naphthoyl)-2-methyl-6-nitroanilide (14) 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 and recrystallized with ethyl acetate to produce 2.79 g (9.11 mmol. 91% yield) of white powder. 'H-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-naphthoyl)-2-methyl-6-nitroanilide (15) 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 and recrystallized with ethyl acetate to produce 2.29 g (7.48 mmol, 75% yield) of white powder. 'H-ΝMR (300 MHz, CD 2 C1 2 ): δ 9.15 (br s, IH, ΝH), 8.49 (s, IH, H r ). 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-Νicotinoyl-2-Methyl-6-Νitroanilide 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%). After stirring overnight and recrystallization from diethylether/hexane (3:1) 1.41 g (5.49 mmol, 55% yield) of white powder were produced. '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, J=1.7, 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) using Method B. 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 NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered and concentrated. The product was recrystallized from ethylacetate (6.24 g, 27.1 mmol, 85% yield of white powder). Η-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 56 ), 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) mixed as described for Method B. After recrystallization from diethylether/hexane (3/1) 1.1 g (4.48 mmol, 97%) of colorless crystals were produced, with a melting point of 148°C. Η-ΝMR (300 MHz, DMSO- rt ): δ 12.86 (s, IH, ΝH), 7.66 (m, IH. H 4 .), 7.33 (m, 2H, H 3 , 5 ,), 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. After recrystallization from diethylether/hexane (3/1) 1.2 g (5.76 mmol, 78%) of colorless crystals were produced, with a melting point of 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-Νapthyl)-4-Methylbenzimidazole In this Example, 2-(l-napthyl)-4-methylbenzimidazole (21) was produced using Method B. The 1 -naphthyl derivative shown as compound 14 (2.60 g, 11.7 mmol) and iron powder (17) (2.00 g), was purified by flash chromatography, eluting with 4% MeOH/CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1) 1.63 g (6.31 mmol, 54% yield) of white powder. 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-Napthyl)-4-Methylbenzimidazole In this Example, 2-(2-napthyl)-4-methylbenzimidazole (22), using Method B. The compound shown as compound (15) (2.25 g, 7.34 mmol) and iron powder (17) (1.60 g) gave after purification by flash chromatography eluting with 4% MeOH CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), resulted in the production of 1.00 g (3.88 mmol, 53% yield) white powder. Η-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, 3H, CH 3 ). 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 (16) (1.00 g, 3.89 mmol) and iron (17) (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 from ethylacetate resulted in the production of 0.72 g (3.44 mmol, 88% yield) of white powder; 'H-NMR (300 MHz, DMSO- ,): 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 (12) (1.02 g, 3.97 mmol) and iron powder (17) (1.10 g) were mixed as described for Method B. Recrystallization from ethylacetate resulted in the production of 0.70 g (3.34 mmol. 84% yield) of white powder: 'H-NMR (300 MHz, DMSO-i,): δ 8.75 (m, 2H, H 2 , 6 ,), 8.14 (m, 2H, H 2 , _ ), 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, 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (26) was prepared using Method C. The benzimidazole compound 18 (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. NaH (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. washed with NaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered and concentrated. The product was recrystallized from ethylacetate/hexane (1 :1) (2.62 g, 0.35 mmol, 85% yield of white powder), mp 145°C. 'H-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 ). Anal. (C 20 H 12 F 4 N 2 ) C,H,N. EXAMPLE 20 Preparation Of 1 -Benzyl-2-(2,6-Difluorophenyl)Benzimidazole In this Example, l-benzyl-2-(2,6-difluorophenyl)benzimidazole (28) was produced using Method C. The benzimidazole compound 18 (100 mg, 0.43 mmol) and benzylbromide (27) (66.4 ml, 0.56 mmol) were mixed as indicated for Method C. After recrystallization from diethylether/hexane (3:1) 77 mg (0.24 mmol, 56%) of colorless crystals were produced, with a melting point of 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, H 5 672 „ 4 ,. 6 „), 7.07-6.99 (m, 4H. H 3 , 5 . 3 ,, 5 «), 5.28 (s, 2H. CH 2 ). Anal. (C 20 H 14 F 2 N 2 xl/8H 2 O) C,H,N. EXAMPLE 21 Preparation Of 1 -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, using 2-(2,6-difluorophenyl)-4-methylbenzimidazole (19) (88mg, 0.33 mmol) and benzylbromide (27) (51 mL, 0.43 mmol) to produce, after recrystallization from diethylether/hexane (3:1), 67 mg (0.20 mmol, 61%) of colorless crystals, with a melting point of 112-117°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.46 (m, IH, H 4 ,), 7.26-7.22 (m, 3H, H 73 , . 5 „ ), 7.18-6.98 (m, 7H, H 5A3 , 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 (19) (0.50 g, 2.05 mmol) and 2,6-dichloro-α-bromo- toluene (0.74 g, 3.08 mmol, 150 M%) were treated using Method C for 2 hours, purified by flash chromatography, eluted with 4% MeOH/CH 2 Cl 2 and recrystallized from diethylether/hexane (3:1), to produce 0.70 g (1.74 mmol, 85% yield) of white powder; mp 202-203°C. 'H-NMR (300 MHz, CD 2 C1 2 ): δ 7.48 (m, IH, H 4 ), 7.26 (m, 2H, H 5 7 ), 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 ). Anal. (C 21 H 14 Cl 2 F 2 N 2 xl/4H 2 O)C,H,N. 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 (5) (3.25 g, 11.76 mmol) and 2,6- difluoro-α-bromo-toluene (25) (3.65 g, 150 M%) were treated according to Method C. for 4 h, and purified by flash chromatography with ethylacetate:hexane (1 :4) to produce 4.41 g (10.96 mmol, 93% yield) of white powder. 'H-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 5 ). 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 l-(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 (2) (92 mg, 0.62 mmol) and 2,6-difluoro-α-bromo-toluene (25) (334 mg, 1.61 mmol, 260 M%) were treated according to Method C. After recrystallization from diethylether/hexane (3:1), 66 mg (0.165 mmol, 27%) of colorless crystals were produced, with a melting point of 109°C. Η-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 564 , 4 „), 6.98-6.82 (m, 4H, H 3 , 5 , 3 ,, 5 „), 5.58 (s, 2H, NCH 2 PhF 2 ), 5.07 (s, 2H, OCH 2 ), 4.70 (s, 2H, OCH 2 PhF 2 ). Anal. (C 22 H 16 F 4 N 2 O x l/2H 2 O) C,H,N. 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. The compound 2-(2,6- difluorophenyl)-4-methylbenzimidazole (19) (400 mg, 1.63 mmol) and 2,6-difluoro-α-bromo- toluene (25) (1.87 mmol, 388 mg) were treated according to Method C. After stirring overnight and recrystallization with diethylether/hexane (3:1), 453 mg (1.22 mmol. 75% yield) of white powder were produced, with a melting point of 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 ). Anal (C 21 H, 4 F 4 N 2 )C,H,N. EXAMPLE 26 Preparation Of l-(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, using 2-isopropyl-4-methylbenzimidazole (6) (0.20 g 1.15 mmol) and 2,6-difluoro-α-bromo-toluene (25) (0.36 g, 1.74 mmol, 150 M%) stirred for 5 h, as described, purified by flash chromatography eluted with 4% MeOH CH 2 Cl 2 and recrystallized from diethylether/hexane (3:1) to yield 0.20 g (0.67 mmol, 58% yield) of white powder, with a melting point of 151-153°C. Η-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). Anal. (C, 8 H 18 F 2 N 2 )C,H,N. 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, using 2-methylbenzimidazole (204 mg, 1.54 mmol) and 2,6-difluoro- α-bromo-toluene (25) (351 mg, 1.70 mmol). Following recrystallization, from diethylether/hexane (3:1), 290 mg (1.12 mmol, 73%) of colorless crystals were produced, with a melting point of 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 ). Anal. (C 15 H 12 F 2 N 2 )C,H,N. 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, using 2-(2-methylphenyl)benzimidazole (20) (0.10 g, 0.48 mmol) and 2,6-difluoro-α-bromo-toluene (25) (0.15 g, 0.73 mmol, 150 M%). Purification by flash chromatography, eluted with 2% MeOH/CH 2 Cl 2 , and recrystallization with diethyl ether/hexane (3:1) produced 109 mg (0.33 mmol, 68%) of colorless crystals, with a melting point of 139°C. 'H-NMR (300 MHz, CDC1 3 ): δ 7.80 (m, IH, H 4 ), 7.43-7.23 (m, 7H, H 5673 , 4 . 56 , 7.21 (m, IH, H 4 „), 6.79 (m, 2H, H 3 ., 5 ..), 5.31 (s, 2H, CH 2 ), 2.23 (s, 3H, CH 3 ). Anal. (C 21 H 16 F 2 N 2 )C,H,N. EXAMPLE 29 Preparation Of 1 -(2,6-Difluorobenzyl)-2-( 1 -Napthyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(l-napthyl)-4-methylbenzimidazole (37) was produced according to Method C, using 2-(l-napthyl)-4-methylbenzimidazole (21) (0.30 g, 1.16 mmol) and 2,6-difluoro-α-bromo-toluene (25) (0.54 g, 2.60 mmol, 225 M%). After stirring overnight and purification by flash chromatography eluting with ethylacetate/hexane (1:4) and recrystallization from diethylether/hexane (3:1), 0.32 g (0.83 mmol, 72% yield) of white powder was produced, with a melting point of 121-123°C. 'H-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, IH), 7.11 (m, 2H), 6.67 (m, 2H), 5.28 (s, 2H, CH 2 PhF 2 ), 2.68 (s, 3H, CH 3 ). Anal. (C 25 H 18 F 2 N 2 ) C,H,N. EXAMPLE 30 Preparation Of 1 -(2,6-Difluorobenzyl)-2-(2-Napthyl)-4-Methylbenzimidazole In this Example, l-(2,6-difluorobenzyl)-2-(2-napthyl)-4-methylbenzimidazole (38) was produced according to Method C, using 2-(2-napthyl)-4-methylbenzimidazole (22) (0.30 g, 1.16 mmol) and 2,6-difluoro-α-bromo-toluene (25) (0.36 g, 1.74 mmol, 150 M%). and a second addition of 2,6-difluoro-α-bromo-toluene (0.18 g, 0.87 mmol. 75 M%) after 2 hours of stirring. This mixture was stirred overnight, purified by flash chromatography. eluted with ethylacetate/hexane (1 :4), and recrystallized from diethylether/hexane (3:1) to yield 0.35 g (0.91 mmol, 78% yield) of white powder, with a melting point of 175-176°C. 'H-NMR (300 MHz, CD 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 ). Anal. (C 25 H, 8 F 2 N 2 ) C,H,N. 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, using 2-phenylbenzimidazole (300 mg, 1.54 mmol) and 2,6-difluoro- α-bromo-toluene (25) (1.70 mmol, 110 M%). Recrystallization from diethyletheπhexane (3:1) yielded 300 mg (0.94 mmol, 63% yield) of colorless crystals, with a melting point of 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 5A4 „), 6.81 (m, 2H, H 3 ., 5 „), 5.55 (s, 2H, CH 2 ). Anal. (C 20 H 14 F 2 N 2 xl/4H 2 O)C,H,N. EXAMPLE 32 Preparation Of l-(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, using 2-(3-pyridyl)-4-methylbenzimidazole (23) (0:30 g, 1.43 mmol) and 2.6-difluoro-α-bromo-toluene (25) (0.49 g, 2.37 mmol, 165 M%). After stirring overnight, purification by flash chromatography eluting with 4% MeOH CH 2 Cl 2 , and recrystallization from diethylether/hexane (3:1) 0.34 g (1.02 mmol, 71% yield) of white powder was produced, with a melting point of 186-188°C. Η-NMR (300 MHz. CD 2 C1 2 ): δ 8.92 (dd. J=0.9, 2.3Hz, IH, H 2 „), 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 . 5 .), 5.51 (s. 2H, CH 2 PhF 2 ), 2.64 (s, 3H, CH 3 ). Anal. (C 20 H 15 F 2 N 3 )C,H,N. EXAMPLE 33 Preparation Of 1 -(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, using 2-(4-pyridyl)-4-methylbenzimidazole (24) (0.30 g, 1.43 mmol) and 2,6-difluoro- -bromo-toluene (25) (0.45 g, 2.17 mmol, 150 M%). After stirring overnight, purification by flash chromatography eluting with 4% MeOH CH 2 Cl 2 , and recrystallization from diethylether/hexane (3:1), 0.29 g (0.86 mmol, 60% yield) of white powder was produced with a melting point of 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 ). Anal. (C 20 H 15 F 2 N 3 )C,H,N. EXAMPLE 34 Preparation Of l-(2,3,4,5,6-Pentafluorobenzyl)- 2-(2,6-Difluorophenyl)-4-Methylbenzimidazole In this Example, 1 -(2,3,4,5, 6-pentafluorobenzyl)-2-(2,6-difluorophenyl)-4- methylbenzimidazole (42) was prepared according to Method C, using 2-(2,6-difluorophenyl)- 4-methylbenzimidazole (19) (0.31 g, 1.27 mmol) and 2,3,4,5, 6-pentafluoro-α-bromo-toluene (0.30 mL, 1.99 mmol, 155 M%). After stirring for 4 hours, purification by flash chromatography, elution with 4% MeOH CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), 0.33 g (0.77 mmol, 61% yield) of white powder was produced, with a melting point of 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 5 3 , 5 ,), 5.35 (s, 2H, CH 2 PhF 5 ), 2.64 (s, 3H, CH 3 ). Anal. (C 21 H π F 7 N 2 )C,H,N. 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, using 2-(2,6-difluorophenyl)-4- methylbenzimidazole (19) (0.21 g, 0.86 mmol) and α-bromo-methylpyridine (0.22 g, 1.28 mmol, 150 M%). After mixing for 1 hour, purification by flash chromatography eluting with ethylacetate/hexane (1:1) increasing to ethylacetate (100%), and recrystallization from diethyl ether/hexane (3:1), 0.24 g (0.73 mmol, 85% yield) of white powder was produced, with a melting point of 131-132°C. Η-NMR (300 MHz, CD 2 C1 2 ): δ 8.45 (d. J=3.4 Hz. IH, H 6 „), 8.32 (s. IH, H 2 „), 7.53 (m, IH, H 4 .), 7.25-7.03 (m, 7H, H 5 673 . 5 ,, 5 ,), 5.26 (s, 2H. CH 2 Py), 2.67 (s. 3H. CH 3 -Ar). Anal. (C 20 H 15 F 2 N 3 xl/2H 2 O)C,H,N. EXAMPLE 36 Preparation of l-(3,3-Dimethylallyl)-2-(Cyclopropyl)-4-Methoxylbenzimidazole In this Example, l-(3,3-dimethylallyl)-2-(cyclopropyl)-4-methoxylbenzimidazole was produced using Method C. 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, redissolved in ethylacetate, washed with water, NaHSO 4 (10% solution), NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered, and concentrated. Flash chromatography eluting with (1 :4) ethylacetate/hexane gave purified 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) (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 , washed with NaHSO 4 (10% solution), NaHCO 3 (sat. aq) and NaCI (sat. aq.), dried (Na 2 SO 4 ), 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): 'H-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 NaCI (sat. aq), dried (Na 2 SO 4 ), filtered and concentrated and 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: 'H-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). The compound 2-(cyclopropyl)-4-methoxylbenzimidazole (5014) (1.00 g, 5.32 mmol) and 3,3-dimethylallyl bromide (0.70 mL. 6.07 mmol, 115 M%) gave, after flash chromatography eluting with 2% MeOH/ CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), 1.08 g (4.21 mmol, 80% yield) of white crystals: mp 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, H 5 ), 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, 1 -benzenesulfonyl-2-(2,6-difluorophenyl)benzimidazole (45) was produced according to Method D. The benzimidazole compound 18 (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 (44) (0.25 mL, 0.35 g, 2.00 mmol, 150 M%) was added. After stirring for 2 h, the reaction was dissolved in ethylacetate, washed with NaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na 2 SO 4 ), 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 (0.41 g, (1.10 mmol. 83% yield) of white powder, with a melting point of 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 3 5 ), 7.07 (m, 2H. H 3 , 5 ,). Anal. (C 19 H, 2 F 2 N 2 SO 2 ) C. H, N. 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, using 2-(2,6-difluorophenyl)-4-methylbenzimidazole (19) (0.20 g, 0.82 mmol) and benzenesulfonyl chloride (44) (0.20 mL, 0.28 g. 1.58 mmol. 190 M%), purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallized from diethylether/hexane (3:1), to produce 0.24 g (0.02 mmol, 76% yield) of white powder, with a melting point of 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 5 ), 7.07 (m, 2H. H 3 . 5 .), 2.59 (s, 3H, CH 3 ), Anal. (C 20 H 14 F 2 N 2 SO 2 ) C,H,N. EXAMPLE 39 Preparation Of l-(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, using the benzimidazole compound 18 (30 mg. 0.13 mmol) dissolved in pyridine (0.5 mL) and chloroform (1.2 mL). To this mixture 2,6-difluorobenzoyl chloride (7) was added (20 μl, 0.16 mmol, 120 M%), and the mixture was stirred at room temperature for 5 h, diluted with chloroform, and washed with NaHSO 4 (2% solution). The organic layer was dried (Na 2 SO 4 ), filtered, and evaporated. The solid was recrystallized from diethylether/hexane to produce 19 mg of colorless crystals (40% yield), with a melting point of 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 , 4 „ ), 6.77 (m, 4H, H 3 . 5 , 5 .,). Anal. (C 20 H 10 F 4 N 2 O) C,H.N. 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, using l-(2,6-difluorobenzyl)-2-t- butyldimethylsilyloxymethyl-4-methylbenzimidazole (31) (1.82 g, 4.52 mmol) dissolved in THF (20mL). Tetrabutylammonium fluoride (1.45 g, 4.60 mmol, 100 M%) was then added. After 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 3 „ 5 „ 5 ), 5.68 (s, 2H, CH 2 PhF 2 ), 4.99 (s, 2H, CH 2 O), 2.57 (s, 3H, CH 3 ). Anal. (C 16 H 14 F 2 N 2 O) C,H,N. 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, using l-(2,6-difluorobenzyl)-2-hydroxymethyl-4-methylbenzimidazole (48) (1.82 g, 4.52 mmol) dissolved in 1.5 M H 2 SO 4 (40 mL). KMnO 4 (1.50 g, 9.49 mmol. 160 M%) was then added. 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. Η-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 ), Anal. (C 15 H 12 F 2 N 2 x l/4H 2 O) C,H,N. 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 (48) 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 NaCI, dried (Na 2 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 5 6J 4 ..), 6.90 (m, 2H. H 3 ., 5 „), 6.05 (s, 2H, Ch 2 PhF 2 ), 2.66 (s, 3H. CH 3 ). Anal. (C 16 H 12 F 2 N 2 Oxl/5H 2 O)C,H,N. EXAMPLE 43 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)- 4-cyanobenzimidazole (4007) Examples 43-48 provide l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole compositions with general structure of Figure 24. In this example, l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-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, DMSO- 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 , 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 , washed with ΝaHCO 3 (sat. aq.), and NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered, evaporated, and recrystallized from MeOH yielding 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 r,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) gave, after 1 h and recrystallization from MeOH. methyl 2- (2,6-difluorophenyl)benzimidazole-2-carboxylate (4004). (14.67 g. 50.9 mmol. 89% yield) of white solid: 'H-NMR (300 MHz. CD 2 C1 2 ) δ 10.92 (br, IH, NH), 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) and 2,6-difluoro-α-bromo-toluene (14.67 g, 70.86 mmol, 125 M%) gave after flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallization from diethylether, white crystals of methyl l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4005) (17.63 g, 42.55 mmol, 76 % yield, with mp 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 NaCI (sat. aq.), dried (Na^SO^, 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 l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (4006) ( 0.71 g, 1.77 mmol, 72 % yield) of white crystals with mp 179-180°C; Η-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 5 ), 6.85 (m, 2H. H 3 .. 5 -), 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, (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) (add slowly!), NaHCO 3 (sat. aq) and NaCI (sat. aq), dried (Na 2 SO 4 ), 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) with mp 153-155°C; 'H-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 .. .5 ~), 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 (4015) To methyl 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole-2-carboxylate (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 and the residue was redissolved in CH 2 C1 2 and washed with NaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na^SO , 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) gave 0.95 g (2.29 mmol, 95% yield) of white crystals: mp 149-150 °C; Η-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 .. s .), 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 (4016) 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 (4015) (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 NaCI (sat. aq.), dried (Na j SO,,), 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 with mp 156-158°C; Η-NMR (200 MHz. CD 2 C1 2 ) δ 7.53 (m, IH, H 4 .), 7.44- 16 (m, 4H, H 4 « 5>67 ), 7.07 (m, 2H, H 3 . ,5 ), 6.81 (m, 2H, H 3 - ), 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 (5006) 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, redissolved in ethylacetate, washed with water, NaHSO 4 (10% solution), NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered, and concentrated. Flash chromatography eluting with (1:4) ethylacetate/hexane gave purified white crystals of 2-methoxyl-6-nitroaniline (5002) (1.79 g, 10.65 mmol, 82% yield): Η-NMR (300 MHz, CD 2 C1 2 ) δ 7.69 (dd, J = 1.4, 8.9 Hz. IH, H s ), 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 (4) (22.0 mL, 174.4 mmol, 215 M%. After stirring overnight at room temperature, the reaction was concentrated to dryness and the residue was redissolved in CH 2 C1 2 , washed with NaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na^SO.,), 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, H 5 ), 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 . ,s .), 3.85 (s, 3H, OCH 3 ). iV,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 and the residue was redissolved in CH 2 C1 2 , washed with ΝaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered, evaporated, and recrystallized from methanol yielding white solids of N-(2,6- difluorobenzoyl)-2-methoxyl-6-nitroanilide (5004) (22.39 g, 72.6 mmol, 96% yield): Η- 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). Λ-(2,6-difluorobenzoyl)-2-methoxyl-6-nitroanilide (5004) (2.20 g, 7.15 mmol) and iron powder (2.20 g) gave, after 1 h and flash chromatography with 2% MeOH/CH 2 Cl 2 . white crystals of 2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5005) (1.68 g, 6.18 mmol, 86% yield): Η-NMR (300 MHz, CD 2 C1 2 ) δ 10.07 (br d, J= 36 Hz, IH, NH), 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) and 2,6- difluoro-α-bromo-toluene (1.30 g, 6.28 mmol, 130 M%) gave after flash chromatography eluting with 2% MeOH CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), white crystals of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5006) (1.68g, 4.35 mmol, 91% yield) with mp 154-155°C; 'H-NMR (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 . 5 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 ). .Anal. (C 21 H, 4 F 4 N 2 O) C, H, N. EXAMPLE 47 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)- 4-ethylbenzimidazole (4011) In this Example, 1 -(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) and 2,6-difluorobenzoyl chloride (3.50 mL, 27.83 mmol, 150 M%) gave, after stirring overnight at room temperature and flash chromatography with 2% MeOH/CH 2 Cl 2 and recrystallization from ethylacetate hexane (1 :4), 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 5 ), 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 . 5 ), 2.81 (q, J =7.6 Hz, 2H, CH 2 ), 1.29 (t, J =7.6 Hz, 3H, CH 3 ). iV-(2,6-Difluorobenzoyl)-2-ethyl-6-nitroanilide (4009) (2.00 g, 6.53 mmol) and iron powder (2.00 g) gave, after 0.5 h at room temperature, flash chromatography with 2% MeOH/CH 2 Cl 2 , and recrystallization from CH 2 C1 2 , 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 . 5 . 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) and 2,6- difluoro-α-bromo-toluene (0.72 g, 3.48 mmol, 130 M%) gave, after flash chromatography eluting with 2% MeOH CH 2 Cl 2 and recrystallization from diethylether/hexane (3:1), white crystals of l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-ethylbenzimidazole (4011) ( 0.79 g, 2.06 mmol. 76% yield) with mp 165-166°C; 'H-NMR (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 .. 5 ), 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 ). Anal. (C 22 H 16 F 4 N 2 ) C, H, N. EXAMPLE 48 Preparation of l-(2,6-Difluorobenzyl)-2-(2,6-Difluorophenyl)- 4-(N-methylamino)benzimidazole (4006) First, 1 -(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N- methylacetamido)benzimidazole (4005) was prepared. To l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)-4-(N-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 , washed with water, ΝaHSO 4 (10%) solution) and NaCI (sat. aq.), 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-difiuorobenzyl)-2- (2,6-difluorophenyl)-4-(N-methylacetamido)benzimidazole (0.89 g, 2.08 mmol, 63% yield, and 1.07 g recovered starting material): mp 155-156°C; Η-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, H 4 ..), 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 ), 5.38 (s, 2H, CH 2 PhF 2 ), 3.34 (s, 3H, ΝCH 3 ), 1.83 (s, 3H. NAc). Anal. (C 23 H 17 F 4 N 3 O) C, H, N. To l-(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, washed with ΝaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered, concentrated and purified by flash chromatography eluting with 2% methanol in CH 2 C1 2 gave l-(2.6-difluorobenzyl)-2-(2,6- difluorophenyl)-4-(N-methylamino)benzimidazole (4006) (0.35 g, 78 % yield): mp 194- 195°C; 'H-ΝMR (200 MHz, CD 2 C1 2 ) δ 7.52 (m, IH, H 4 ), 7.23 (m, IH, H 4 ), 7.13 (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. NCH 3 ). Anal. (C 21 H 15 F 4 N 3 ) C, H, N. EXAMPLE 49 Preparation of l-(2,6-Difluorobenzyl)-2-(Cyclopropyl)-4-Methoxylbenzimidazole (5016) Examples 49-50 provide l-(2,6-difluorobenzyl)-benzimidazole compositions with general structure of Figure 13. 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 , washed with NaHSO 4 (10% solution), NaHCO 3 (sat. aq) and NaCI (sat. aq.), dried (Na^O^, 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): 'H-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 NaCI (sat. aq), dried (Na 2 SO 4 ), filtered and concentrated and 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: 'H-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) and 2,6- difluoro-α-bromo-toluene (1.30 g, 6.28 mmol, 130 M%) gave after flash chromatography eluting with 2%> methanol/ CH 2 C1 2 and recrystallization from diethylether/hexane (3:1), white crystals of l-(2,6-difluorobenzyl)-2-(cyclopropyl)-4-methoxylbenzimidazole (5016) (1.54 g. 4.90 mmol. 92% yield) with mp 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-Difiuorobenzyl)-2-(2-Fluoro-6-Methoxylphenyl)-4-Nitrobenzimidazole (5008) To 2-(2-fluoro-6-methoxylphenyl)-4-nitrobenzimidazole (2.00 g, 8 mmol) and 2,6- difluoro-α-bromo-toluene (2.02 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 methanol and concentrated. The residue was dissolved in CH 2 C1 2 , washed with water and NaCI (sat. aq.), dried filtered, concentrated and purified by flash chromatography eluting with ethylacetate/hexane (1 : 1) (2.33 g, 5.64 mmol, 78%): mp 189-192°C; Η-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, H 6 ), 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 ). Anal. (C 21 H 14 F 3 N 3 θ 3 ) C, H, N. EXAMPLE 51 Preparation of 1 -(2,6-Difluorobenzyl)-2-(2-Fluoro-6-Methoxylphenyl)- 4-Aminobenzimidazole (5009) To 1 -(2,6-difluorobenzyl)-2-(2-fluoro-6-methoxylphenyl)-4-nitrobenzimidazole (5008) (2.00 g. 4.98 mmol) dissolved in acetic acid (20 mL) was added SnCl,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 NaCI (sat. aq.), dried (Na^O,,), filtered, evaporated, and recrystallized from methanol to give 3.26 g of white crystals, (8.78 mmol, 70% yield): mp 200-202°C; 'H-NMR (200 MHz, CD 2 C1 2 ) δ 7.45 (m, IH, H 4 ), 7.22 (m, IH, H 4 ), 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 ). Anal. (C 2I H 16 F 3 N 3 O) C, H. N. EXAMPLE 52 Preparation of l-Benzyl-2-(2,6-Difluorophenyl)-4-Methoxylbenzimidazole (5007) Examples 52-57 provide 2-(2,6-difluorobenzyl)benzimidazole compositions with general structure of Figure 12. 2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005) (2.02 g, 7.77 mmol) and benzyl bromide (1.20 mL, 10.1 mmol, 130 M%) gave after flash chromatography eluting with 2% MeOH/ CH 2 C1 2 and recrystallization from diethylether/hexane (3:1) 2.47 g (7.05 mmol, 90 % yield) of white crystals with mp 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 (5008) 2-(2,6-Difluorophenyl)-4-methoxylbenzimidazole (5005) (0.10 g, 0.38 mmol) and (1- bromoethyl)benzene (0.28 mL) gave after flash chromatography eluting with 2% MeOH/ CH 2 C1 2 and recrystallization from diethylether/hexane (3:1) 0.12 g (0.33 mmol. 86 %> yield) of white crystals: mp 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 (5009) To 2-(2,6-difluorophenyl)-4-methoxylbenzimidazole (5005) (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 NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallized from hexane (0.30 g, 0.91 mmol, 84% yield of white powder): mp 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, ), 1.64 (s, 3H, CH 3 ), 1.58 (s, 3H, CH 3 ). Anal. (C 19 H, 8 F 2 N 2 0) C,H,N. EXAMPLE 55 Preparation of 1 -(3,3-Dimethylallyl)-2-(2,6-difluorophenyl)-4-methylbenzimidazole (6003) To 2-(2,6-difluorophenyl)-4-methylbenzimidazole (6002) (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 NaCI (sat. aq.), dried (Na 2 SO 4 ), filtered and concentrated. The product was purified by flash chromatography eluting with 2% MeOH/CH 2 Cl 2 and recrystallized from hexane (0.40 g, 1.28 mmol, 63% yield of white powder): mp 78-79 °C; Η-NMR (200 MHz, CD 2 C1 2 ): 7.52 (m, IH, H 4 ), 7.26-7.02 (m, 5H, H 5 673 j ), 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 ). Anal. (C 19 H I8 F 2 N 2 ) C,H,N. EXAMPLE 56 Preparation of 1 -(3,3-Dimethylallyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (4013) To 2-(2,6-difluorophenyl)-4-nitrobenzimidazole (4012) (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 NaCI (sat. aq.), dried (Na^O , 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; 'H-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, H 4 -), 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 r ), 4.73(d, J= 7.0 Hz. 2H, H r ), 1.68 (s, 3H, CH 3 ), 1.62 (s, 3H, CH 3 ). Anal. (C„H 1S F 2 NA) C,H,N. EXAMPLE 57 Preparation of l-(3,3-Dimethylallyl)-2-(2,6-difluorophenyl)-4-aminobenzimidazole (4014) To l-(3,3-dimethylallyl)-2-(2,6-difluorophenyl)-4-nitrobenzimidazole (4013) (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 NaCI (sat. aq.), dried (Na 2 SO 4 ), 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): mp 107-108 °C. 'H-NMR (200 MHz, CD 2 C1 2 ): 7.54 (m, IH, H 4 .), 7.16- 7.05 (m, 3H, H 6 3 - 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 ). Anal. (C, 8 H 17 F 2 N 3 ) C,H,N. EXAMPLE 58 Preparation Of N,N-Bis-(2,6-Difluorobenzoyl)-4-Chloro-2-Nitroanilide Examples 58-89 describe the synthesis of 4-substituted benzimidazoles. 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 (7) (0.6 mL, 4.77 mmol, 78 M%>). 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 NaCI (sat. aq.). 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. 'H-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, H 3 5 ,3 5 ). 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, N,N-bis-(2,6-difluorobenzoyl)-4-chloro-2-nitroanilide (400) (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 , washed with NaHCO 3 (sat aq) and NaCI (sat aq), dried (Na 2 SO 4 ), 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 , washed with ΝaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na 2 SO 4 ), 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 (600) (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 , washed with NaHCO 3 (sat aq.) and NaCI (sat aq.), dried (Na 2 SO 4 ), 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. First, 3-nitro-l,2-phenylenediamine (13.3 g, 86.85 mmol) and 2.6-difluorobenzoyl chloride (7) (15.33 g, 10.95 mL, 86.85 mmol) were mixed, stirred overnight, and then recrystallized from ethylacetate/hexane to produce 12 g (41 mmol, 48% yield) of yellow crystals. Η-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 5 ), 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-NMR (300 MHz, CD 2 C1 2 ): δ 8.67 (s. IH, NH), 7.81(d, J= 8.4 Hz, IH. H 6 ), 7.48 (m, IH, H 4 ), 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 (7) (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. 'H-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 . 5 ), 2.42 (s, 3H, CH 3 ). EXAMPLE 66 Preparation Of N-(2,6-Difluorobenzoyl)-4-Bromo-2-Nitroanilide 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 (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 ΝaHCO 3 (sat. aq.). The solution was extracted with CH 2 C1 2 and the organic extract was washed with NaCI (sat. aq.), dried (Na j SO^, filtered and concentrated. The product was recrystallized from ethylacetate to produce 1.55 g, (4.34 mmol, 50 % yield) of yellow crystals. -NMR (200 MHz, CD 2 C1 2 ): δ 10.72 (br s, IH, NH), 8.85 (d J= 9.1 Hz. IH, H < ). 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-Νitroanilide 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 (1200) (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 , washed with ΝaHCO 3 (sat. aq.) and NaCI (sat. aq.), dried (Na 2 SO 4 ), 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-cQ (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 s 3 5 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-Νitroanilide 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 (500) (600 mg, 1.92 mmol) mixed with 2,6-difluoro-α-bromo-toluene (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, H 4 rotamer 2 & H 64 rotamer 1&2), 6.94-6.68 (m, 8H, H 3 5 3 5 , 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 (700) (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, another 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-ΝMR (200 MHz, DMSO-^) (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 343 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 (1100) (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. -ΝMR (300 MHz. DMSO- ,) (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 5 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= 7.7 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 (1000) (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 343 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 : . 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 (11) (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,C1 2 ): δ 7.82 (dd. J= 8.0, 1.5 Hz, IH, H 5 ), 7.52 (m, IH, H 4bz ), 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 1 -(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). Then, iron powder (17) (0.55 g) was added to the mixture. After 30 min, the reaction was concentrated to dryness, diluted with ethyl acetate, and adjusted to pH 7 with ΝaHCO, (sat. aq.). The organic solution was collected and washed with ΝaHCO. and ΝaCl, dried (Νa 2 SO 4 ), 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,,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 (1500) (620 mg, 1.41 mmol) and iron powder (17) (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, H 4 ), 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 5 ), 6.82 (m, 2H, H 3 5 ), 5.34 (s, 2H, CH 2 ). Anal. (C 20 H„C1F 4 Ν 2 ) C,H,N EXAMPLE 75 Preparation Of l-(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 (1600) (0.57 g, 1.30 mmol) and iron powder (17) (0.43 g) were mixed for 1 hour, and purified by flash chromatography eluted with 2% MeOH/CH 2 Cl, , and recrystallized from diethyl ether/ hexane (3:1), to produce 0.43 g (1.10 mmol, 85% yield) of white crystals. Η-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 n ClF 4 Ν 2 ) C,H,N. EXAMPLE 76 Preparation Of l-(2,6-Difluorobenzyl)- 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. Iron powder (17) (1.55 g, 3.71 mmol) and iron powder (17) (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. 'H-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 5 ), 6.81 (m, 2H, H 3 5 ), 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 (1800) (1.56 g, 3.73 mmol) and iron powder (17) (0.79 g) were mixed. After recrystallization from diethyl ether/hexane 0.89 g (2.41 mmol, 64% yield) of white crystals were produced. 'H-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 21 H 14 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 (1900) (300 mg, 0.72 mmol) and (20) (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, H 4 ), 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 -S ), 5.64 (s, 2H, CH 2 ), 2.74 (s, 3H. CH 3 ). Anal. (C 21 H 14 F 4 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 (900) (1.40 g, 4.57 mmol) and (20) (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 r 5 . 6 ), 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 (800) (12 g, 41 mmol) was dissolved in 130 mL of acetic acid, heated to reflux, and stirred 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 (Na^SO,,), filtered, and evaporated. The remaining crystals were recrystallized from ethylacetate/hexane to produce 7.7 g, (28 mmol, 68%) of crystals. Η- 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-Difiuorophenyl)-5-Nitrobenzimidazole In this Example, 2-(2,6-difluorophenyl)-5-nitrobenzimidazole (2900) was prepared according to Method F. 2-(2,6-difluorophenyl)-benzimidazole (11) (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 5 ). 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 (2700) (0.25 g, 0.97 mmol) and 2,6-difluoro- -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 6 ), 7.30 (cm, IH, H 4 ), 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 (2800) (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. Η-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,,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-nitrobenzιmidazole (3200) was prepared according to Method E. 2-(2,6-difluorophenyl)-5-nitrobenzimidazole (2900) (0.91 g, 3.31 mmol) and 2,6-difluoro-α-bromo-toluene (1.08 g, 5.22 mmol. 160 M%) were mixed, and a second addition of 2,6-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. Η-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 5 ), 6.84 (m, 2H, H 3 5 ), 5.44 (s, 2H, CH 2 PhF 2 ). Anal. (C 20 H,,F 4 N 3 O 2 ) C,H,N. EXAMPLE 85 Preparation Of 4-Amino-l-(2,6-Difluorobenzyl)- 2-(2,6-Difluorophenyl)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 (3100) (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 (Na^SO , 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 5 ), 6.52 (d, J= 7.7. 0.9 Hz. IH, H 5 ), 5.29 (s, 2H. CH 2 ), 4.42 (s, 2H, NH 2 ). Anal. (C 20 H 13 F 4 N 3 ) C,H,N. EXAMPLE 86 Preparation Of 4-Bromo-l-(2,6-Difluorobenzyl)- 2-(2,6-Difluorophenyl)Benzimidazole In this Example, 4-bromo-l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (3400) was produced according to Method E. 4-amino-l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazole (3300) (800 mg, 2.15 mmol) was suspended in HBr (48%>, 7 mL) at 0°C, then NaNO 2 (193 mg, 2.8 mmol) in water (1.5 mL) was slowly added. 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 adjusted to 5 with KOH 4N. The mixture was extracted with ethylacetate, dried (Na,SO 4 ), 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 4-Chloro- 1 -(2,6-Difluorobenzyl)- 2-(2,6-Difluorophenyl)Benzimidazole In this Example, 4-chloro-l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (3500) was prepared according to Method E. 4-amino-l-(2,6-difluorobenzyl)-2-(2,6- difluorophenyl)benzimidazole (3300) (800 mg, 2.15 mmol) was dissolved in concentrated HCl (7 mL) and water (5 mL) at 0°C, then NaNO 2 (193 mg, 2.8 mmol) in water (1.5 mL) was slowly added. 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 (Na 2 SO 4 ), 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 j ). 5.36 (s, 2H. CH 2 ). Anal. (C 20 H„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. 4-amino-l-(2,6- difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (3300) (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), washed with NaHCO 3 (25 mL) and NaCI (25 mL), dried (Na^O^, 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. Η-NMR (300 MHz, CD 2 C1 2 ): δ 8.49 (IH, br, NH), 8.20 (d. J= 7.8 Hz, IH, H 5 ). 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 ιS ), 6.82 (m, 2H, H 3 5 ), 5.34 (s, 2H, CH 2 PhF 2 ). 2.21 (s, 3H, Ac). Anal. (C 22 H I5 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 4- amino-l-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (3300) (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, washed with Νa 2 CO 3 and NaCI, dried (Na 2 SO 4 ), filtered. concentrated and recrystallized 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 5 ), 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 5 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 carrier. 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. Figure 7 shows the structures, formulae, weight, and the percentage of various compounds produced using the methods of the present invention, as well as remaining HIV RT activity as reported as a percent of the control in HIV RT inhibition assays. 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 evaluated 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 run in parallel as positive control drugs. 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 cell viability 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 20-22. Figure 20 shows the graph for compound 33. As indicated in this Figure, 33 exhibited very effective therapeutic dose. Figure 21 shows the graph for compound 34, another compound that also exhibited an effective therapeutic dose. Figure 22 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 11. 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. 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 nonnucleoside inhibitors of reverse transcriptase (RT). In particular, the present invention relates to stable analogues of l-(2,6-difluorophenyl)-lH,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 nonnucleoside 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 1. A l-aryl-2-(2,6-difluorophenyl)benzimidazole composition with general structure: wherein X" is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro. amine. acetamide, methylamine, dimethylamine, propan-2-ol, 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 l-aryl-2-(2,6-difluorophenyl)benzimidazole of Claim 1, wherein X" is selected from the group consisting of methoxyl and acetamide, and wherein R" is 2,6- difluorobenzyl. 3. The l-aryl-2-(2,6-difluorophenyl)benzimidazole of Claim 1. wherein R" is 2,6- difluorobenzyl. A l-(2.6-difluorophenyl)-2-benzimidazole composition with general structure: wherein X' is selected from the group consisting of H, methyl, ethyl, cyano. methoxyl, nitro. amine, acetamide, methylamine, dimethylamine, propan-2-ol, 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. 5. The l-(2,6-difluorophenyl)-2-benzimidazole of Claim 4. wherein X ' is selected from the group consisting of methoxyl and acetamide, and wherein R' is 2.6-difluorophenyl. 6. The l-(2,6-difluorophenyl)-2-benzimidazole of Claim 4. wherein R ' is 2,6- difluorophenyl. 7. A 4-. 5-. 6-. or 7-substituted- l-(2,6-difluorobenzyl)-2-(2.6- difluorophenyl)benzimidazole composition of general structure: wherein X"" is selected from the group consisting of 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. 8. A 4-substituted- 1 -(2,6-difluorobenzyl)-2-(2,6-difluoropheny l)benzimidazole composition of the general structure: wherein X' " is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol, isopropenyl. bromine and chlorine. 9. A method for treatment of 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, wherein said composition comprises at least one substituted benzimidazole. wherein said substituted benzimidazole contains at least one substitution at the C-2 site, and at least one substitution at the N-l site; 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. 1 1. The method of Claim 9, wherein said substituted benzimidazole is of the general structure: wherein X" is selected from the group consisting of H, methyl, ethyl, cyano. methoxyl, nitro. amine. acetamide, methylamine, dimethylamine, propan-2-ol, 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. 12. The method of Claim 1 1 , wherein X" is selected from the group consisting of consisting of methoxyl and acetamide, and wherein R" is 2,6-difluorobenzyl. 13. The method of Claim 1 1 , wherein R" is 2,6-difluorobenzyl. 14. The method of Claim 9, wherein said substituted benzimidazole is of the general structure: wherein X' is selected from the group consisting of H, methyl, ethyl, cyano, methoxyl, nitro. amine. acetamide, methylamine, dimethylamine. propan-2-ol, 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. 15. The method of Claim 14, wherein X' is selected from the group consisting of methoxyl and acetamide, and wherein R' is 2,6-difluorophenyl. 16. The method of Claim 14, wherein R' is 2,6-difluorophenyl. 17. The method of Claim 9. wherein said substituted benzimidazole is of the general structure: and wherein X"" is selected from the group consisting of methyl, 4-methyl, 5-methyl, 6- ethyl, 7-methyl, 4,5-dimethyl, 4,6-dimethyl, 4-chloro, 5-chloro, 6-chloro, 4-bromo. 5-bromo, 4-nitro, and 5-nitro. 18. The method of Claim 9, wherein substituted benzimidazole is of the general structure: and wherein X'" is selected from the group consisting of H, methyl, ethyl, cyano. methoxyl, nitro, amine, acetamide, methylamine, dimethylamine, propan-2-ol. isopropenyl, bromine and chlorine.

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, REPRESENTED BY THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES
Application year: 1998
Main classification: C07D235
IPC codes: A61K31, A61P31, A61P37, A61P43, C07D235, C07D401