BR112017020168B1 - POLYMERASE INHIBITOR COMPOUNDS FOR HEPATITIS C VIRUS, USES THEREOF, AS WELL AS COMBINATION - Google Patents

Abstract

HEPATITIS C VIRUS POLYMERASE INHIBITORS. The present invention provides, among other things, compounds represented by general Formula I and pharmaceutically acceptable salts thereof, wherein L and A (and additional substituents) are as defined in the classes and subclasses in herein, and compositions (e.g., pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection .

Description

[0001] The invention provides compounds, compositions, and methods for inhibiting the hepatitis C virus.

BACKGROUND OF THE INVENTION

[0002] Hepatitis C virus (HCV) is an enveloped positive-sense single-stranded RNA virus of the genus Hepacivirus, which belongs to the Flaviviridae family. HCV infection is a leading cause of liver disease and cirrhosis in humans. Transmission occurs primarily through percutaneous exposure to infected blood, which typically involves injected drug use or injury from blood-contaminated objects, but is also associated with sexual contact with infected partners. Due to viral testing, the risk of transmission through blood transfusion or transplantation is extremely low. The infection is often asymptomatic, or symptoms are mild, and about 15 to 20% of infected people are able to clear the virus without treatment. However, the infection in the remaining 80 to 85% of infected people develops into a persistent infection, which can occur throughout life, causing liver disease, which can result in cirrhosis and hepatocellular carcinoma. HCV infection is the most common chronic hematogenous disease in the United States, affecting approximately 4 million people and causing approximately 12,000 deaths each year. "Evaluation of Acute Hepatitis C Infection Surveillance — United States, 2008", MMWR, November 5, 2010, 59(43). Approximately 170 million people around the world have chronic hepatitis C infection. Chen et al., Int J Med Sci, 2006, 3(2):47 to 52. Personal consequences of HCV infection include decreased life expectancy, debilitating chronic liver disease and possible liver cancer, and the risk of parasite infection. - sexual partners and health service professionals. Economic consequences of chronic HCV infection in the United States are extremely large. Direct medical costs were estimated at $10.7 billion per year for the 10-year period 2010 to 2019, with societal costs projected at $54.2 billion and the cost of morbidity from disability projected at $21.3 billion . ID

[0003] The hepatitis C virus has been intensively studied and much is known about its genetics and biology. For an overview of this subject, see Tan, Ed., Hepatitis C Viruses: Genomes and Molecular Biology, Horizon Bioscience, Norfolk, UK (2006). HCV has a simple genome that resides in a single open reading frame of about 9.6 kb. The genome is translated in the infected cell to yield a single polyprotein consisting of about 3000 amino acids, which is then proteolytically processed by host and viral enzymes to produce at least 10 structural and non-structural (NS) proteins. The virus is diversified in infected humans into 16 different antigenic and/or genetically identifiable subtypes or genotypes, some of which are further subdivided into subtypes.

[0004] HCV mutates rapidly as it replicates, and is believed to exist as a viral quasi-species, meaning that it mutates rapidly as it replicates to generate several genetic varieties that compete with the virus that has been comparable evolutionary physique. This intrinsic generation of several strains in a single infected person makes it quite difficult to isolate a single strain for vaccine development, and is believed to be associated with difficulty in developing a vaccine, the development of virus resistance in specific pharmaceuticals, and the persistence of the virus in the host. It is possible that the virus has the capacity to develop into an immunologically distinct quasi-species under the pressure of the host's immune response, which thereby allows it to survive and persist.

[0005] Another factor that makes it difficult to develop treatments for HCV infection is the narrow host range and a remarkably difficult problem of propagating the virus in cell culture. Most research has been carried out using pseudoparticle systems. Pseudoparticles consist mainly of nucleocapsids surrounded by a lipid envelope and contain HCV glycoprotein complexes. These pseudoparticles were used to elucidate the early stages of the viral replication cycle and receptor binding, and to study neutralizing antibodies. Nevertheless, pseudoparticles have a significant limitation in that they cannot recapitulate the complete replication cycle. Other systems described for HCV investigation include culture of subgenomic RNAs in Huh-7 cells, and culture in primary human hepatocytes, and surrogate models, such as bovine viral diarrhea virus (BVDV).

[0006] Significant research has also been done on synthetic RNA replicons, which self-amplify in human hepatoma cells and recapitulate much, but not all, of the HCV replication cycle. To date, such replicons have been subgenomic and also lacked the capacity to yield infectious viral particles. Furthermore, such a replicon system seems to work only with the use of HCV genotype 1b (HCV1b). More recently, HCV cell culture has become possible through the isolation of the JFH-1 clone (HCV 2a). While its uniqueness remains incompletely understood, JFH-1 replicates to high levels in Huh-7 (hepatocellular carcinoma) cells and other cell types in culture, and produces infectious particles. The serial passage of JFH-1 caused it to become genetically conditioned to cell culture conditions and it may no longer be representative of clinical isolates of the virus, however, the viral particles are apparently functional virions, as far as where they are infectious in culture and in inoculated animals that bear human liver xenografts. Apparently, the replication efficiency of JFH-1 significantly depends on the clone's NS5B gene. Replacement by NS5B genes from other genotypes is difficult. Woerz et al., 2009, J Viral Hepat, 16(1):1 to 9. Other replicon systems have been developed with various replication markers and for different HCV genotypes, which include HCV 1a and HCV 2a. See, Huang et al., "Hepatitis C Virus-related Assays", Chapter 2 in Hepatitis C: Antiviral Drug Discovery and Development, S-L Tan and Y He, editions, Caister Academic Press (2011), pages 56 to 57.

[0007] Approved pharmaceutical treatments include injection of interferon, typically pegylated versions that include peginterferon alfa-2a (Pegasys®) or peginterferon alfa-2b (PegIntron®). Clinical use of pegylated interferon was approved by the FDA in 2001. Ribavirin (eg, Ribasphere®, Virazole®, Copegus®, Rebetol®), a guanosine analog that has broad-spectrum activity against viruses, is used to treat HCV, however, does not appear to be effective against HCV when used as a monotherapy. Current standard of care therapy includes administering peginterferon in combination with ribavirin. This regimen is limited because of side effects (eg, flu-like symptoms, leukopenia, thrombocytopenia, depression, and anemia) and only moderate efficacy; success is dependent, in part, on the genotype that predominates in the patient. See, Ghany et al., Hepatology, 2011, 54(4):1433 to 1444.

[0008] In addition to the pegylated interferon/ribavirin regimen, three different direct-acting antiviral agents have been approved for use in humans who have HCV infection. These include sofosbuvir (Sovaldi®; Gilead Sciences), an NS5B polymerase inhibitor; simeprevir (Olysio®; Janssen Pharmaceuticals), an NS3 protease inhibitor, and ledipasvir (Gilead Sciences), an NS5A inhibitor. Several alternative pharmaceutical approaches for the treatment of HCV infection are still under research and development. For example, recombinant and modified interferon molecules have also been the subject of development programs, which include, for example, recombinant interferon alpha (BLX-883; Locteron®; Biolex/Octoplus) and albinterferon alfa 2b (Zalbin®; Human Genome Sciences).

[0009] The HCV protein NS3-4A, a serine protease, which is an essential enzyme for virus replication, has been the subject of intensive pharmaceutical research. Several companies seek to develop inhibitors of this enzyme. Some of the foregoing molecules are telaprevir (Incivek®, VX-950; Vertex) and boceprevir (Victrelis®, SCH503034; Merck and Co.), each of which has been approved as a direct-acting antiviral agent. These various molecules may be useful as stand-alone therapeutics, however, some are also being investigated in combination with interferon/ribavirin therapies and/or compounds that may be effective against HCV through other mechanisms. However, viral resistance to individual protease inhibitors is believed to occur easily. Morrison and Haas, In Vivo, May 2009, 42 to 47.

[0010] HCV NS5B polymerase is also undergoing study. This protein is an RNA-dependent RNA polymerase (RdRp), which is essential for the synthesis of viral RNA, and consequently, for the completion of the virus life cycle. An overview of the NS5B protein is available in Chapter 10 of Tan, supra.

[0011] Several groups are currently working on the development of NS5B polymerase inhibitors. Wang et al. (J Biol Chem 2003, 278(11), 9489 to 9495) reports that certain non-nucleoside molecules bind to an allosteric site on the polymerase, which interferes with a conformational change required for activity. Biswal et al. (J Biol Chem, 2005, 280(18), 18202 to 18210) reports crystal structures that indicate that the NS5B polymerase exhibits two conformations, with a crude structure similar to the classical finger, palm, and thumb domains of other polymerases. This paper also shows cocrystal structures for two polymerase-bound inhibitors, and offers hypotheses about the mechanism of polymerase inhibition. Li et al. (J Med Chem, 2007, 50(17):3969 to 3972 ) reports on some dihydropyrone compounds that would be orally available allosteric inhibitors. Also see, Li et al., J Med Chem, 2009, 52:1255 to 1258.

[0012] NS5B inhibitors can be broadly classified into three groups: nucleoside analogues (NI), non-nucleoside analogues (NNI), and pyrophosphate compounds (PPi). See, Powdrill et al., Viruses, 2010, 2:2169-2195 and Appleby et al., "Viral RNA Polymerase Inhibitors", chapter 23 in Viral Genome Replication, Cameron et al., editions, Springer Science+Business Media 2009.

[0013] Nucleoside analogue (NI) compounds, which bind to the enzyme's active site and compete with natural nucleoside triphosphates, interfere with viral RNA synthesis. Several of these compounds have entered clinical trials. Nucleoside inhibitors include, for example, IDX184 (Idenix), RG7128 (RO5024048; Pharmasset/Roche), and especially the recently approved sofosbuvir (SOVALDI®, PSI-7977; Gilead/Pharmasset).

[0014] Non-nucleoside inhibitors, in contrast, appear to bind at allosteric sites in NS5B - of which about 4 are well characterized. Id. NNI compounds include, for example, filibuvir (Pfizer), tegobuvir (GS 9190; Gilead), VX-222 (Vertex), A-837093 (Abbott), ABT-072 (Abbott), ABT-333 ( Abbott) and PF-868554 (Pfizer).

[0015] Also among the non-nucleoside inhibitors of NS5B are a number of thiophene-2-carboxylic acids and derivatives thereof. See, for example, Chan et al., Bioorg Med Chem Lett, 2004, 14, 793-796; International patent publications at WO 02/100846 A1, WO 02/100851 A2, WO 2004/052879 A2, WO 2004/052885 A1, WO 2006/072347 A2, WO 2006/119646 A1, WO 2008/017688 A1, WO 2008/ 043791 A2, WO 2008/058393 A1, WO 2008/059042 A1, WO 2008/125599 A1, and WO 2009/000818 A1. Also see U.S. Patent No. 6,881,741 B2, 7,402,608 B2 and 7,569,600 B2. Also see, Yang et al., Bioorg Med Chem Lett 2010, 20, 4614-4619 regarding some bioisoesters of such compounds. Other similar compounds are described, for example, in U.S. Patent No. 6,887,877 B2 and 6,936,629 B2.

[0016] Pyrophosphate (PPi) compounds mimic natural pyrtophosphates released during nucleotidyl transfer reactions.

[0017] Several NI and NNI compounds have shown safety or efficacy in clinical trials, however, few have yet achieved approval for use in the treatment of humans. PPi compounds, on the other hand, are generally in the research stage.

[0018] There remains a deep need for more effective pharmaceutical therapies, which include drugs that are useful as single agents or in combination with other active agents, for the treatment of hepatitis C infection in humans.

SUMMARY OF THE INVENTION

[0019] The present invention provides compounds represented by the general Formula I: and salts (e.g. pharmaceutically acceptable salts) thereof, L, A, D and E being as defined in the classes and subclasses herein and compositions (e.g. pharmaceutical compositions) comprising such compounds, which compounds are useful as inhibitors of hepatitis C virus polymerase, and thus are useful, for example, as medicaments for the treatment of HCV infection and diseases associated with or consequential thereon.

[0020] In certain other embodiments, the invention provides pharmaceutical compositions comprising a compound of the invention, the compound being present in an amount effective to inhibit HCV polymerase activity. In certain other embodiments, the invention provides pharmaceutical compositions comprising a compound of Formula I and optionally further comprising an additional active agent to obtain the therapeutic effect. In still other embodiments, the additional active agent is an agent that has anti-HCV activity or function.

[0021] In yet another aspect, the present invention provides methods for inhibiting HCV polymerase activity in a subject (or optionally in a biological sample ex vivo or in vitro), comprising administering to the subject (or bringing into contact with the biological sample) with an effective inhibitory amount of a compound of Formula I.

[0022] In yet another aspect, the present invention provides methods for treating any disorder constitutively associated with HCV infection or replication or that involves HCV polymerase activity, comprising administering to a subject in need thereof, an amount therapeutically effective use of a compound of Formula I.

DETAILED DESCRIPTION

[0023] In one aspect, the invention provides compounds having the given structure as Formula I: or a pharmaceutically acceptable salt thereof, wherein: L is (a): -(CH2)x-[O(CH2)w]yO-(CRd2)z- each Rd is selected from hydrogen, methyl and phenyl 1a, or both Rd, together with the carbon to which they are attached, form C3-5 cycloalkyl; w is 2 to 4; x is 2 to 6; eyez are each independently 0 to 5, with the proviso that when y is 0, then (x+z) is 4 to 11; or (b): -(CH2)m-G1-C(O)-G2-C(Rb)2-G3-C(O)-G4-(CRc2)n-, wherein m is 1 or 2; n is 0 to 5; each of G1, G2, G3, and G4 is independently zero, 0, or NRa; Ra is independently hydrogen or C1-4alkyl, each Rb is selected from hydrogen and methyl, or both Rb, together with the carbon to which they are attached, form C3-5 cycloalkyl, each Rc is independently hydrogen or methyl; and A is selected from C1-3 alkyl, -C(O)CH3, -CO2H, -CONHOH, -CO2-C1-4 alkyl, -C(O)NH2, -NH2, hydroxyl, chloropyridinyl, - OC1-2alkylene-CO2H, -OC1-2alkylene-CO2C1-4alkyl, –SC(O)CH3, It is where D is -C(O)CH3, -(C0-3alkylene)-CO2H, -(C0-3alkylene)-CO2C1-5alkyl, -(C0-3alkylene)-CONHOH, -C(O)CH=C(OH) )CO2H, -C(O)CH=C(OH)CO2C1-4alkyl, -CO2CH2C(O)NH2, -CO2CH2SC1-4alkyl, -CO2Bn, or -CO2CH2CO2C1-4alkyl, and E is null, halo, C1-4 alkyl , -OC1-4 alkyl, -NH-C1-4 alkyl, -C0-3alkylene-NH2, or NO2.

[0024] In some embodiments, the invention provides compounds of Formula I: or a pharmaceutically acceptable salt thereof, wherein: L is -(CH2)x(OCH2CH2)yO-(CH2)z-, wherein x = 2 to 6, y = 0 to 5 and z = 0 to 5; provided that when y is 0, then (x+z) is 4 to 11; and A is selected from -CO2H, -CO2-C1-4 alkyl, chloropyridinyl, or , where D is -CO2H or -CO2-C1-4 alkyl, and E is null, halo, C1-4 alkyl, -NH-C1-4 alkyl, -Co—3alkylene-NH2, or NO2.

[0025] In some embodiments, the invention provides compounds of Formula I, where E is null, fluorine, methyl, NH2 or NO2.

[0026] In some embodiments, the invention provides compounds of Formula I, where x = 2, w = 2, y = 1 and z = 1.

[0027] In some embodiments, the invention provides compounds of Formula I, where x = 3, y = 1 and z = 1.

[0028] In some embodiments, the invention provides compounds of Formula I, where y is 1 to 4.

[0029] In some embodiments, the invention provides compounds of Formula I, wherein L is -(CH2)x-(OCH2CH2)y-O-(CH2)z-.

[0030] In some embodiments, the invention provides compounds of Formula I, wherein L is —(CH2)m-G1-C(O)-G2-C(Rb)2-G3-C(O)-G4-( CH2)n-. In some embodiments, the invention provides compounds of Formula I, wherein (i) G1 is null and G2 is NH and/or (ii) G3 is null and G4 is NH.

[0031] In some embodiments, the invention provides compounds of Formula I, wherein A is -CO2H, -CONHOH, -CO2-C1-4 alkyl, -C(O)NH2, -OC1-2alkylene-CO2H, or alkyl - OC1-2alkylene-CO2C1-4.

[0032] In some embodiments, the invention provides compounds of Formula I, wherein A is , D is -(C0-3alkylene)-CO2H, alkyl -(C0-3alkylene)-CO2C1-5 or -(C0-3alkylene)-CONHOH and E is null. In some embodiments, the invention provides compounds of Formula I, wherein A is , D is -CO2H, -CO2CH3, -CÜ2Et, -CÜ2iPr, or -CO2-nBu, and E is null.

[0033] In some embodiments, the invention provides compounds of Formula I, wherein D is in the para or meta position on the phenyl group.

[0034] In various embodiments, the invention provides compounds of Formula I, wherein each Rd is independently selected from hydrogen, methyl and phenyl, or both Rd together with the carbon to which they are attached form cyclopropyl, cyclobutyl, or cyclopentyl; w is 2, 3 or 4; x is 2, 3, 4, 5 or 6; y is 0, 1, 2, 3, 4 or 5; and z is 0, 1, 2, 3, 4 or 5. In some embodiments, when y is 0, (x+z) is 4, 5, 6, 7, 8, 9, 10 or 11. In various embodiments, a invention provides compounds of Formula I, wherein m is 1 or 2; n is 0, 1, 2, 3, 4 or 5; each Ra is independently hydrogen, methyl, ethyl, propyl, or butyl; each Rb being independently selected from hydrogen and methyl, or both Rb together with the carbon to which they are attached form cyclopropyl, cyclobutyl or cyclopentyl; and each Rc being independently hydrogen or methyl. In various embodiments, the invention provides compounds of Formula I, wherein L is -(CH2)x-[O(CH2)w]yO-(CRd2)z—; the is ; D is -CO2H, alkyl -CO2C1-5 or -CONHOH; E is null; x is 4 to 6 (eg 5); y is 0 to 1 and w is 2 (for example, y is 0); z is 0 to 2 (eg 1); and/or both Rd are hydrogen. In various embodiments, the invention provides compounds of Formula I, where x is 5, y is 0, z is 1, both Rd are hydrogen, A is , D is -CO2H (for example, -CO2H in the para position on the phenyl group) and E is null.

[0035] In another aspect, the invention provides a compound selected from:

[0036] 6-(N-(2-(2-(3-acetyl-benzyloxy)-ethoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (2-8A);

[0037] 6-[(2-{2-[2-(3-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro) methylamide -phenyl)-benzofuran-3-carboxylic acid (2-8B);

[0038] 6-{[2-(2-{2-[2-(3-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-methanesulfonyl-amino}-5-cyclopropyl- 2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8C);

[0039] 6-({2-[2-(2-{2-[2-(3-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino acid methylamide )-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8D);

[0040] 6-[(2-{2-[2-(2-{2-[2-(3-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}- acid methylamide ethyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8E);

[0041] 6-({2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-acid methylamide 3-carboxylic (2-8F);

[0042] 6-[(2-{2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro) methylamide -phenyl)-benzofuran-3-carboxylic acid (2-9G);

[0043] 6-{[2-(2-{2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-methanesulfonyl-amino}-5-cyclopropyl- 2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8H);

[0044] 6-({2-[2-(2-{2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino acid methylamide )-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8I);

[0045] 6-[(2-{2-[2-(2-{2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}- acid methylamide ethyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8J);

[0046] 4-{3-2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy acid ethyl ester )-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-9A);

[0047] 4-(3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) ethyl ester amino}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-9B);

[0048] 4-[3-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] acid ethyl ester) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic (2-9C);

[0049] 4-{3-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6) ethyl ester -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-9D);

[0050] 4-(3-{2-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl- benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-9E );

[0051] 4-{4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic (2-9F);

[0052] 4-(4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) ethyl ester amino}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-9G);

[0053] 4-[4-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] acid ethyl ester) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic (2-9H);

[0054] 4-{4-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6) ethyl ester -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-9I);

[0055] 4-(4-{2-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl- benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic (2-9J );

[0056] 4-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-10A);

[0057] 4-(3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-10B);

[0058] 4-[3-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) acid amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic (2-10C);

[0059] 4-{3-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] acid) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-10D);

[0060] 4-(3-{2-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6 acid) -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-10E);

[0061] 4-{4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-10F);

[0062] 4-(4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-10G);

[0063] 4-[4-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) acid amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic (2-10H);

[0064] 4-{4-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] acid) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-10I);

[0065] 4-(4-{2-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6 acid) -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-10J);

[0066] 6-(N-(3-(2-((3-acetylbenzyl)-oxy)-ethoxy)-propyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3 - carboxamide (3-6A);

[0067] 4-{3-[2-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester propoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (3-7A);

[0068] 4-{3-[2-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-propoxy)- acid ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (3-8A);

[0069] 6-({2-[3-(3-Acetyl-benzyloxy)-propoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-acid methylamide 3-carboxylic acid (3-6B);

[0070] 4-{3-[3-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid propoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (3-8B);

[0071] 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-(2-(2-hydroxyethoxy)-ethoxy)-ethoxy)-ethyl)methylsulfonamido)-N-methylbenzofuran- 3-carboxamide (4-5);

[0072] 6-(N-(2-(2-(2-(2-aminoethoxy)-ethoxy)-ethoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran -3-carboxamide (4-10);

[0073] 6-(N-(2,5,8,11-tetraoxatridecan-13-yl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (5-4A) );

[0074] 6-({2-[2-(2-Butoxy-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-acid methylamide 3-carboxylic acid (5-4B);

[0075] 2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-benzoyl (6-6A);

[0076] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-benzoyl (6-6B);

[0077] 3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-benzoyl (6-6C);

[0078] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethoxymethyl}-benzoic acid (6-6D);

[0079] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethoxymethyl}-benzoic acid (6-6E);

[0080] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethoxymethyl}-benzoic acid (6-6F);

[0081] 2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid benzoyl (6-7A);

[0082] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid benzoyl (6-7B);

[0083] 3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid benzoyl (6-7C);

[0084] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxymethyl}-benzoic acid (6-7D);

[0085] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxymethyl}-benzoic acid (6-7E);

[0086] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxymethyl}-benzoic acid (6-7F);

[0087] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- ethyl ester ethoxymethyl]-benzoyl (6-8B1);

[0088] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- propyl ester ethoxymethyl]-benzoyl (6-8B2);

[0089] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- butyl ester ethoxymethyl]-benzoyl (6-8B3);

[0090] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- pentyl ester ethoxymethyl]-benzoyl (6-8B4);

[0091] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid carbamoyl methyl ester ethoxymethyl]-benzoyl (6-8B5);

[0092] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- methylsulfanylmethyl ester ethoxymethyl]-benzoyl (6-8B6);

[0093] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- benzyl ester ethoxymethyl]-benzoyl (6-8B7);

[0094] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- ethoxycarbonylmethyl ester ethoxymethyl]-benzoyl (6-8B8);

[0095] 4-{[(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethylcarbamoyl)-methyl]-carbamoyl acid }-butyric (7-7);

[0096] 4-(3-{[(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethylcarbamoyl) ethyl ester )-methyl]-carbamoyl}-phenyl)-butyric (7-9);

[0097] 4-(3-{[(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethylcarbamoyl)-methyl acid ]-carbamoyl}-phenyl)-butyric (7-10);

[0098] 4-[(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxycarbonylmethyl)-carbamoyl]-butyric acid ( 8-6);

[0099] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino} acid ethyl ester) - acetylamino)-acetylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-13A);

[00100] 4-[3-({2-[(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino) ethyl ester }-acetyl)-methyl-amino]-acetylamino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (913B);

[00101] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino} acid ethyl ester) - acetylamino)-2-methyl-propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-13C);

[00102] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino) ethyl ester }-acetylamino)-cyclopropanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-13D);

[00103] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino) ethyl ester }-acetylamino)-cyclopentanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-13E);

[00104] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino} acid ethyl ester) - acetylamino)-propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-13F);

[00105] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino) acid - acetylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-14A);

[00106] 4-[3-({2-[(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetyl acid) )-methylamino]-acetylamino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-14B);

[00107] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino) acid -2-methyl-propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-14C);

[00108] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino acid) )-cyclopropanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-14D);

[00109] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino} acid) -acetylamino)-cyclopentanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-14E);

[00110] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino) acid - propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic (9-14F);

[00111] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)- acid methyl ester acetylamino]-pentanoic (10-3A);

[00112] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)- acid methyl ester acetylamino]-2-methyl-pentanoic (10-3B);

[00113] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)-acetylamino]- acid pentanoic (10-4A);

[00114] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)-acetylamino]- acid 2-methyl-pentanoic (10-4B);

[00115] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethyl}-benzoic acid (11-5A);

[00116] 3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethyl}-benzoic acid (11-5B);

[00117] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethyl}-benzoic acid (11-5C);

[00118] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethyl}-benzoic acid (11-6A);

[00119] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzo-furan-6-yl]-methanesulfonyl-amino}-ethoxy acid )-ethoxy]-ethyl}-benzoic acid (11-6B);

[00120] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzo-furan-6-yl]-methanesulfonyl-amino}-ethoxy acid )-ethoxy]-ethyl}-benzoic acid (11-6C);

[00121] 2-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-propyl}-benzoic acid (12-6A);

[00122] 2-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzo-furan-6-yl]-methanesulfonyl-amino}-ethoxy acid )-ethoxy]-propyl}-benzoic acid (12-7A);

[00123] 3-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-propyl}-benzoic acid (12-7B);

[00124] 4-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-propyl}-benzoic acid (12-7C);

[00125] 4-[2-(4-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-butoxy)- acid methyl ester ethyl]-benzoyl (13-7C);

[00126] 4-[4-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester butyl]-benzoyl (13-7A);

[00127] 4-[3-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-propoxy)- acid methyl ester propyl]-benzoyl (13-7B);

[00128] 4-(7-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-heptyl)-benzoic acid methyl ester (13 -7D);

[00129] 4-(2-(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamido)butoxy)-ethyl)benzoic acid (13-8C);

[00130] 4-[4-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-butyl]- acid benzoyl (13-8A);

[00131] 4-[3-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-propoxy)-propyl]- acid benzoyl (13-8B);

[00132] 4-(7-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-heptyl)-benzoic acid (13-8D) ;

[00133] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-benzoic acid (14-6A);

[00134] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-benzoic acid (14-6B);

[00135] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-benzoic acid (14-6C);

[00136] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-benzoic acid (14-7A);

[00137] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-benzoic acid (14-7B);

[00138] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-benzoic acid (14-7C);

[00139] 4-(6-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-hexyloxy)-benzoic acid ethyl ester (15-7);

[00140] 4-(6-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-hexyloxy)-benzoic acid (15-8) ;

[00141] 4-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxymethyl)-benzoic acid methyl ester (16 -6);

[00142] 4-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxymethyl)-benzoic acid [16-7] ;

[00143] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- ethyl ester ethoxymethyl]-2-fluoro-benzoic acid (17A-7);

[00144] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 2-fluoro-benzoic (17A-8A);

[00145] 5-Cyclopropyl-6-({2-[2-(4-fluoro-3-hydroxycarbamoyl-benzyloxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-2-(4-fluoro-phenyl) methylamide )-benzofuran-3-carboxylic (17A-8B);

[00146] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 2-methoxy-benzoic acid (17B-8);

[00147] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-3-methyl-benzoyl (18-9B);

[00148] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-2-methyl-benzoyl (18-9A);

[00149] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 3-methyl-benzoyl (18-10B);

[00150] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 2-methyl-benzoyl (18-10A);

[00151] 2-(2-((6-chloropyridin-3-yl)-methoxy)-ethoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (19-8B);

[00152] 6-({2-[2-(2-Chloro-pyridin-4-ylmethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl) methylamide )-benzofuran-3-carboxylic (19-8A);

[00153] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- ethyl ester ethoxymethyl]-naphthalene-1-carboxylic acid (20-7);

[00154] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid naphthalene-1-carboxylic acid (20-8);

[00155] S-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- ester of thioacetic acid ethyl](21-5);

[00156] 6-(N-(2-(3-(3-acetylphenyl)-propoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (22 -10);

[00157] 4-{3-[3-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-propyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic (22-11);

[00158] 4-(3-(3-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl) methylsulfonamido)-ethoxy)-propyl) acid -phenyl)-2-hydroxy-4-oxobut-2-enoic (22-12);

[00159] {2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- tert-butyl ester) ethoxy)-ethoxy]-ethoxy}-acetic [23-5A];

[00160] 2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-propionic (23-5B);

[00161] {2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy) acid ethyl ester -ethoxy]-ethoxy}-acetic (23-5C);

[00162] {2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy] acid - ethoxy}-acetic (23-6A);

[00163] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-propionic (23-6B);

[00164] 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-({2-[2-(2-hydroxycarbamoylmethoxy-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-benzofuran- 3-carboxylic (23-6C);

[00165] 6-({2-[2-(2-Carbamoylmethoxy-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran- acid methylamide 3-carboxylic (23-7A);

[00166] 3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-propionic (24-3);

[00167] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-propionic (24-4);

[00168] {2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy) acid ethyl ester -ethoxy]-ethoxy}-phenyl-acetic acid (25-4);

[00169] {2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy] acid - ethoxy}-phenyl-acetic acid (25-5);

[00170] 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-[(2-{2-[2-(hydroxycarbamoyl-phenyl-methoxy)-ethoxy]-ethoxy}-ethyl)-methanesulfonyl acid methylamide - amino]-benzofuran-3-carboxylic acid (25-6);

[00171] 1-[2-(2-{2-[(5-Cyclopropyl-3-methylcarbamoyl-2-p-tolyl-benzofuran-6-yl)-methanesulfonyl-amino]-ethoxy} tert-butyl ester -ethoxy)-ethoxy]-cyclopentanecarboxylic acid (26-6A);

[00172] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino tert-butyl ester) }-ethoxy)-ethoxy]-ethoxy}-2-methyl-propionic (26-6B);

[00173] 1-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzo-furan-6-yl]-methanesulfonyl-amino}-ethoxy acid )-ethoxy]-ethoxy}-cyclopentanecarboxylic (26-7A);

[00174] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-2-methyl-propionic (26-7B);

[00175] 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-[(2-{2-[2-(1-hydroxycarbamoyl-1-methyl-ethoxy)-ethoxy]-ethoxy}- acid methylamide ethyl)-methanesulfonyl-amino]-benzofuran-3-carboxylic (26-8B);

[00176] [5-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- tert-butyl ester pentyloxy]-acetic acid (27-8A);

[00177] [5-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-pentyloxy]-acetic acid ( 27-9A);

[00178] 2-[5-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-pentyloxy]- acid propionic (27-9B);

[00179] 5-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxy)-pentanoic acid tert-butyl ester (28-7A);

[00180] 5-((5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamido)-pentyl)-oxy)-pentanoic acid (28-8A);

[00181] 5-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxy)-2-methyl-pentanoic acid ( 28-8B);

[00182] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-2-nitro-benzoyl (29-7);

[00183] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 2-nitro-benzoyl (29-8);

[00184] 2-Amino-4-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino} methyl ester - ethoxy)-ethoxymethyl]-benzoic acid (29-9);

[00185] 2-Amino-4-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy) acid - ethoxymethyl]-benzoyl (29-10);

[00186] 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-[methanesulfonyl-(2-{2-[2-(2-oxo-propoxy)-ethoxy]-ethoxy}-ethyl) methylamide -amino]-benzofuran-3-carboxylic acid (30-1);

[00187] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-propionic (30-2);

[00188] 3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-propionic (30-3);

[00189] 3-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-benzoic acid (30-4);

[00190] 6-({2-[3-(3-Acetyl-phenyl)-propoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)- acid methylamide benzofuran-3-carboxylic acid (30-5);

[00191] 6-[({[(3-Acetyl-benzylcarbamoyl)-methyl]-carbamoyl}-methyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran- 3-carboxylic (30-6);

[00192] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzo-furan-6-yl]-methanesulfonyl-amino}-ethoxy acid )-ethoxy]-ethoxymethyl}-benzoic acid (30-7);

[00193] 4-(3-{3-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethoxy)-ethoxy]-propyl}-phenyl)-2,4-dioxo-butyric (30-8);

[00194] 4-{3-[4-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid butoxy]-phenyl}-2,4-dioxo-butyric acid (30-9);

[00195] 4-[3-(3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) acid amino}-ethoxy)-ethoxy]-ethoxy}-propyl)-phenyl]-2,4-dioxo-butyric (30-10);

[00196] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-2-methoxy-benzoic acid (30-11);

[00197] 4-(3-{4-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethoxy)-ethoxy]-butyl}-phenyl)-2,4-dioxo-butyric (30-12);

[00198] 4-{2-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] acid) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-benzoic acid (30-13);

[00199] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- ethyl ester ethoxymethyl]-2-fluoro-benzoic acid (30-14);

[00200] 4-[3-(5-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) acid amino}-ethoxy)-ethoxy]-ethoxy}-pentyl)-phenyl]-2,4-dioxo-butyric (30-15); It is

[00201] 4-[3-(4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) acid amino}-ethoxy)-ethoxy]-ethoxy}-butyl)-phenyl]-2,4-dioxo-butyric (30-16);

[00202] and pharmaceutically acceptable salts thereof.

[00203] In another aspect, the invention provides compounds that have the given structure as Formula I: or a pharmaceutically acceptable salt thereof, wherein: L is C7-20 alkylene (e.g., C7-10 alkylene); and A is selected from C1-3alkyl, -C(O)CH3, -CO2H, -CONHOH, -Cθ2-Ci—4alkyl, -C(O)NH2, -NH2, hydroxyl, chloropyridinyl, -OCi- 2alkylene-CO2H, -OCi-2alkylene-CO2Ci—4alkyl, -SC(O)CH3, It is , where D is -C(O)CH3, -(C0-3alkylene)-CO2H, -(C0-3alkylene)-CO2C1-5alkyl, -(C0-3alkylene)-CONHOH, -C(O)CH=C( OH)CO2H, -C(O)CH=C(OH)CO2C1-4alkyl, -CO2CH2C(O)NH2, -CO2CH2SC1-4alkyl, -CO2Bn, or -CO2CH2CO2C1-4alkyl, and E is null, halo, C1-4alkyl , -OC1-4alkyl, -NH-C1-4alkyl, -C0-3alkylene-NH2, or NO2.

[00204] In another aspect, the invention provides a composition comprising any of the aforementioned compounds and at least one pharmaceutically acceptable excipient.

[00205] In another aspect, the invention provides a method of treating or preventing infection or reactivation of the hepatitis C virus in a host, comprising administering to the host a therapeutic amount of a compound or composition, as disclosed herein.

[00206] In another aspect, the invention provides a method of reducing a hepatitis C virus polymerase activity in a host, comprising administering to the host a therapeutic amount of a compound or composition, as disclosed herein.

[00207] In another aspect, the invention provides a method for reducing replication of the hepatitis C virus in a host, comprising administering to the host a therapeutic amount of a compound or composition, as disclosed herein.

[00208] In the aforementioned methods, the invention provides embodiments in which the method further comprises administering to the host at least one other active agent. Such active agents may be active agents that have antiviral activity or function, for example anti-HCV. For example, such active agents may be selected from the group consisting of interferons, ribavirin, HCV NS5B nucleoside polymerase inhibitors, HCV NS5B non-nucleoside polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A, HCV Entry Inhibitors, HCV NS3 Inhibitors, HCV NS3 Helicase Inhibitors, HCV NS4B Inhibitors, and Human Cyclofin Inhibitors.

[00209] In another aspect, the invention provides a combination comprising a compound as disclosed herein together with at least one other active agent. Such active agents may be active agents that have antiviral activity or function, for example anti-HCV. For example, such active agents may be selected from the group consisting of interferons, ribavirin, HCV NS5B nucleoside polymerase inhibitors, HCV NS5B non-nucleoside polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A, HCV Entry Inhibitors, HCV NS3 Inhibitors, HCV NS3 Helicase Inhibitors, HCV NS4B Inhibitors, and Human Cyclofin Inhibitors.

[00210] In another aspect, the invention provides a combination comprising a composition comprising a compound as disclosed herein and a pharmaceutically acceptable excipient, together with a composition comprising at least one other active agent and an excipient pharmaceutically acceptable. Such active agents may be active agents that have antiviral activity or function, eg anti-HCV. For example, such active agents may be selected from the group consisting of interferons, ribavirin, nucleoside HCV NS5B polymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors and human cyclophin inhibitors. For example, such combinations can comprise a composition comprising a compound of Formula I and a pharmaceutically acceptable excipient, together with two or more other compositions comprising other such active agents and pharmaceutically acceptable excipients.

[00211] The invention further provides compounds that may be useful as prodrugs. For example, compounds containing a carboxyl group can be modified to a variety of prochemical moieties using conventional techniques. For example, a chemical carboxyl moiety in a compound of Formula I may be substituted for or modified to corresponding amides, carbamates, carbonates or esters, provided that biotransformation processes can yield the appropriate carboxyl form of the parent compound. Ideally, the prodrug form will, upon biotransformation, yield the parent compound at a high recovery ratio and will be non-toxic or have no significant safety concerns.

[00212] Accordingly, in one aspect, compounds of Formula I are provided wherein D is a carboxyl group that is esterified, for example, the -C(O)OH group is replaced by the -C(O)O-RP group, wherein RP is -C1-4alkyl, -C1-4alkyl-OC(O)O-C1-4alkyl, 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl, or -C1-4alkyl -NR'R", where R' and R" are independently hydrogen or -C1-4 alkyl.

[00213] In some embodiments, prodrug forms of a compound of Formula I may have reduced potency for inhibiting HCV polymerase activity. Alternatively, such prodrug forms may have an IC50 against HCV polymerase that is at least 50-fold, at least 100-fold, at least 150-fold, at least 200-fold, or at least 500-fold greater than the IC50 of the carboxyl form corresponding unmodified compound.

[00214] In one aspect of the invention, in the compounds of Formula I, the group L comprises a main chain of carbon (alkylene) or carbon and oxygen (ether). In such cases, the backbone may comprise 7 to 10 carbon atoms or carbon and oxygen. In some embodiments, L is -(CH2)x(OCH2CH2)y-O- (CH2)z-, where x = 2 to 6, y = 0 to 5, and z = 0 to 5; since when y is 0, then (x+z) is 4 to 11.

[00215] In some modalities, x = 2, y = 0 to 2 and z = 2 to 4.

[00216] In some embodiments, x = 2, y = 0 and z = 4.

[00217] In some modalities, x = 2, y = 1 and z = 1 to 3.

[00218] In some embodiments, x = 2, y = 1 and z = 1.

[00219] In some embodiments, x = 2, y = 1 and z = 2.

[00220] In some embodiments, x = 2, y = 1 and z = 3.

[00221] In some modalities, x = 2, y = 2 and z = 0 to 1.

[00222] In some embodiments, x = 2, y = 2 and z = 0.

[00223] In some embodiments, x = 2, y = 2 and z = 1.

[00224] In some modalities, x = 3, y = 0 and z = 3.

[00225] In some embodiments, x = 4, y = 0 and z = 2.

[00226] In some embodiments, x = 5, y = 0 and z = 0 to 4.

[00227] In some embodiments, x = 5, y = 0 and z = 1.

[00228] In some modalities, x = 5, y = 0 and z = 4.

[00229] In some embodiments, x = 6, y = 0 and z = 0.

[00230] In some embodiments, L is C7 alkylene.

[00231] Throughout the description of this invention, any scope of any variable, which includes m, n, w, x, y and z, may, unless otherwise specified, be used independently with the scope of any other example of a variable.

GENERAL PREPARATION OF COMPOUNDS

[00232] The compounds of the invention may be prepared by any suitable synthetic route, using chemical techniques and apparatus known to the skilled organic chemist. Details of syntheses of exemplary compounds are provided in the Examples below. General definitions of such synthetic processes are provided to aid understanding of the invention.

[00233] It will be appreciated that the compounds of Formula I may contain one or more asymmetric carbon atoms and may exist in racemic, diastereomeric and optically active forms. All such racemic compounds, enantiomers and diastereomers are contemplated to be within the scope of the present invention. Methods are known in the art for separating isomers, such as enantiomers and diastereomers, which include chemical and physical methods. It will be further appreciated that certain compounds of the present invention can exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.

[00234] Certain compounds of the present invention may occur as atropisomers, which are stereoisomers that exhibit rotation locked about a single bond, in which the steric interconversion barrier to such rotation is high enough to allow isolation of individual conformers. Atropisomers can be thermally equilibrated and the interconversion barrier can be measured kinetically.

[00235] The present invention also includes isotopically labeled compounds of Formula I. The isotopically labeled compounds are identical to the compounds of this invention, however, to be produced to replace one or more atoms by another isotope of the same element. For example, a selected atom can be changed from an isotope that is abundant in nature to a rare isotope. Exemplary isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, chlorine, such as 2H, 3H, 11C, 13C, 14C 13N, 15O, 17O, 35S, 18F, 36Cl. Certain isotope-labelled compounds (eg, 3 H and 14 C) are useful in compound or substrate tissue distribution studies. Certain heavier isotopes (eg 2H) may provide therapeutic advantages resulting from the greatest possible metabolic stability.

[00236] Also included in the present invention are salts, (e.g., pharmaceutically acceptable salts) of the compounds of Formula I. Any salt that is consistent with the overall stability and utility of the compounds of Formula I can be provided using methods conventional. Suitable salts include, without limitation, salts of acidic or basic groups which may be present in the compounds provided herein. Under certain acidic conditions, the compound can form a wide variety of salts with various inorganic and organic acids. Acids that can be used to prepare pharmaceutically acceptable salts of such basic compounds are those that form salts that comprise pharmacologically acceptable anions which include, but are not limited to, acetate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, cansylate, carbonate, chloride, bromide, iodide, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, hydrabamine, hydroxynaphthoate, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate (methylenesulfonate), methylsulfate, muscate, napsylate, nitrate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, succinate, sulfate, tannate, tartrate, theoclate, triethiodide and pamoate. Under certain basic conditions, the compound can form base salts with various pharmacologically acceptable cations. Examples without limitation of such salts include alkali metal or alkaline earth metal salts, and particularly calcium, magnesium, sodium, lithium, zinc, potassium and iron salts, as well as tetraalkylammonium salts. General information regarding pharmaceutically acceptable salts can be found in Stahl PH, and Wermuth CG, editions, Handbook of Pharmaceutical Salts: Properties, Selection and Use, 2002, Wiley-VCH/VHCA Weinheim/Zurich.

[00237] The present invention also relates to providing hydrates and other solvates of compounds of Formula I. Thus, hydrates and other solvates of compounds of Formula I and hydrates and other solvates of salts of compounds of Formula I are included in the scope of this invention.

[00238] Esters, which include pharmaceutically acceptable esters of the compounds of Formula I, are included within the scope of the present invention. Esters include stable carboxylic acid esters - COOR, for example, wherein R is selected from optionally substituted alkyl, alkoxyalkyl, aralkyl, aryloxyalkyl, branched or straight chain aryl; or, for example, -CH2OC(O)R' or -CH2OCO2R' where R' is alkyl (for example, R' is tert-butyl). Unless otherwise specified, any alkyl chemical moiety present in such esters suitably contains 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.

[00239] If there must be, in this descriptive report, a discrepancy between a represented structure and a name given to that structure, the represented structure must be assigned more weight. Additionally, if the stereochemistry of a structure or a portion of a structure is not indicated with conventionally accepted notation, for example, bold or dashed lines, the structure or portion thereof should be interpreted as encompassing all stereoisomers of that structure. .

[00240] A compound of Formula I and its salts (e.g., pharmaceutically acceptable salts) may exist in crystalline forms, which may appear as different polymorphs or pseudopolymorphs. As used herein, the term crystalline "polymorphism" means the ability of a crystalline compound to exist in different crystal structures. Polymorphism can generally occur as a response to changes in temperature, pressure, or both. Polymorphism can also result from variations in the crystallization process. Polymorphs can be distinguished by various physical characteristics known in the art, such as X-ray diffraction patterns, solubilities and melting points. Polymorphism can result from differences in crystal packing (packaging polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, the term crystalline "pseudopolymorphism" means the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the present invention may exist due to differences in crystal packing (packaging pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The present invention encompasses all polymorphs and pseudopolymorphs of the compounds of Formula I and their pharmaceutically acceptable salts.

[00241] A compound of Formula I and its salts or solvates may also exist as amorphous solids. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of atoms in the solid. This definition also applies when the crystal size is two nanometers or less. Additives, which include solvents, can be used to create the amorphous forms of the present invention. The present invention encompasses all amorphous forms of the compounds of Formula I and their salts (for example, pharmaceutically acceptable salts) and solvates.

[00242] In one aspect, the invention provides a composition comprising a compound according to Formula I or a salt (e.g. a pharmaceutically acceptable salt) or solvate thereof. Such compositions may additionally comprise at least one additional component, such as a pharmaceutically acceptable excipient.

METHODS OF USE

[00243] In another aspect, the invention provides a method of treating a hepatitis C virus infection in a host, comprising administering to the host a therapeutic amount of at least one compound according to Formula I or a pharmaceutically acceptable salt. acceptable of the same. Similarly, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt of such a compound, for use in treating an HCV infection in a host. In some embodiments, the method further comprises administering to the host at least one other therapeutically active agent selected from the group consisting of interferons, ribavirin, taribavirin, nucleoside HCV polymerase inhibitors, non-nucleoside HCV polymerase inhibitors , HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors and HCV NS4B inhibitors. In some embodiments, the compound can be used to prevent HCV infection in a host. In some embodiments, the compound can be used to limit infection in a host. In some embodiments, the host is a human subject.

[00244] In another aspect, the invention provides a method of treating a hepatitis C virus reactivation in a host, which comprises administering to the host a therapeutic amount of at least one compound according to Formula I or a pharmaceutically acceptable salt. acceptable of the same. Similarly, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt of such a compound, for use in treating an HCV infection in a host. In some embodiments, the method further comprises administering to the host at least one other therapeutically active agent selected from the group consisting of interferons, ribavirin, taribavirin, nucleoside HCV polymerase inhibitors, non-nucleoside HCV polymerase inhibitors , HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors and HCV NS4B inhibitors. In some embodiments, the compound can be used to prevent HCV infection in a host. In some embodiments, the compound can be used to limit infection in a host. In some embodiments, the host is a human subject.

[00245] In another aspect, the invention provides a method of inhibiting or reducing hepatitis C virus polymerase activity in a host, comprising administering to the host a therapeutic amount of at least one compound according to Formula I or a pharmaceutically acceptable salt thereof. Similarly, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt of such a compound, for use in inhibiting or reducing HCV polymerase activity in a host. In some embodiments, the method further comprises administering to the host at least one other therapeutically active agent selected from the group consisting of interferons, ribavirin, taribavirin, HCV nucleoside polymerase inhibitors, Non-nucleoside HCV, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors and HCV NS4B inhibitors. In some embodiments, the host is a human subject.

[00246] In a further aspect, the invention provides a method of inhibiting or reducing replication of hepatitis C virus polymerase in a host, comprising administering to the host a therapeutic amount of at least one compound according to Formula I or a pharmaceutically acceptable salt thereof. Similarly, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt of such a compound, for use in inhibiting or reducing HCV polymerase replication in a host. In some embodiments, the method further comprises administering to the host at least one other therapeutically active agent selected from the group consisting of interferons, ribavirin, taribavirin, HCV nucleoside polymerase inhibitors, HCV nucleoside polymerase inhibitors, non-nucleoside inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, and HCV NS4B inhibitors. In some embodiments, the host is a human subject.

[00247] In another aspect, the invention provides a method of treating HCV-associated liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia and/or liver fibrosis in a host, comprising administering to the host a therapeutic amount of at least one compound according to Formula I or a pharmaceutically acceptable salt thereof. Similarly, there is provided a compound according to Formula I, or a pharmaceutically acceptable salt of such a compound, for use in HCV-associated liver cirrhosis, chronic liver disease, hepatocellular carcinoma, cryoglobulinemia and/or liver fibrosis in a host. In some embodiments, the method further comprises administering to the host at least one other therapeutically active agent selected from the group consisting of interferons, ribavirin, taribavirin, HCV nucleoside polymerase inhibitors, Non-nucleoside HCV, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors and HCV NS4B inhibitors.

[00248] In another aspect, the invention provides a use of a compound according to Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a hepatitis C virus infection in a host. In some embodiments, the host is a human subject.

[00249] In another aspect, the invention provides a use of a compound according to Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting or reducing hepatitis C virus polymerase activity in a host. In some embodiments, the host is a human subject.

[00250] In another aspect, the invention provides a use of a compound according to Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for inhibiting or reducing replication of hepatitis C virus polymerase in a host. In some embodiments, the host is a human subject.

[00251] The invention provides, in a further aspect, a combination comprising at least one compound of Formula I or a pharmaceutically acceptable salt thereof together with at least one other active agent, especially interferon, ribavirin and/or an anti-inflammatory agent. Additional HCV.

[00252] In a further aspect of the present invention there is provided a compound chosen from compounds of Formula I or a pharmaceutically acceptable salt thereof for use in human or veterinary medical therapy, particularly in the treatment or prevention of viral infection, particularly infection by flaviviruses, for example, HCV infection.

[00253] In another aspect, the invention provides the use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment and/or prophylaxis of viral infection, particularly HCV infection.

[00254] In another aspect, the invention provides a compound of Formula I or a pharmaceutically acceptable salt thereof for use in treating HCV disease in a human.

[00255] In another aspect, the invention provides a compound prepared to be administered in combination with at least one active agent selected from the group consisting of interferons, ribavirin, HCV NS5B nucleoside polymerase inhibitors, HCV nucleoside polymerase inhibitors non-nucleoside HCV NS5B inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors, and human cyclophin inhibitors.

[00256] In another aspect, the invention provides a combination comprising: a) a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof and b) a therapeutically effective amount of at least one active agent selected from the group consisting of interferons, ribavirin, nucleoside HCV NS5B polymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors , HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors and human cyclophin inhibitors.

[00257] In another aspect, the invention provides a use of a compound of Formula I or a pharmaceutically acceptable salt thereof in combination with at least one active agent selected from the group consisting of interferons, ribavirin, polymerase inhibitors HCV NS5B Nucleoside Polymerase Inhibitors, HCV NS5B Non-Nucleoside Polymerase Inhibitors, HCV NS3-4A Protease Inhibitors, HCV NS5A Inhibitors, HCV Entry Inhibitors, HCV NS3 Inhibitors, HCV NS3 Helicase Inhibitors, HCV NS4B and human cyclophin inhibitors, for manufacturing a drug for treating HCV disease in a human.

[00258] In another aspect, the invention provides a use of a compound of Formula I or a pharmaceutically acceptable salt thereof in the production of a dosage form for treating HCV disease in a human being, the dosage form comprising 1 to 1000 mg of a compound of Formula I or a pharmaceutically acceptable salt thereof, and an effective amount of at least one active agent selected from the group consisting of interferons, ribavirin, HCV NS5B nucleoside polymerase inhibitors deo, non-nucleoside HCV NS5B polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors, and human cyclophin inhibitors, the dosage form being suitable for administration to a human.

[00259] In yet another aspect, the invention provides methods for inhibiting HCV polymerase activity in a biological sample, comprising contacting the biological sample with an effective inhibitory amount of a compound of Formula I or a pharmaceutically acceptable salt of the same. In some embodiments, the biological sample is a blood, tissue, or other fluid sample. In some embodiments, the biological sample is a culture of host cells, for example, hepatocytes, or hepatocellular carcinoma cells, infected with HCV. For a survey of biological assay systems in which compounds of the invention can be demonstrated, see, Huang et al., "Hepatitis C Virus-related Assays", chapter 2 in Hepatitis C: Antiviral Drug Discovery and Development, S-L Tan and Y He, edits, Caister Academic Press (2011).

[00260] Such methods may be useful in research or in the clinic, for example, in identifying HCV genotypes amenable to inhibition with the compounds of the invention or in identifying individuals who can be beneficially treated with the use of compounds or compositions of the invention. In some embodiments, the HCV genotype is 1 or the HCV genotype is 1a or the HCV genotype is 1b.

[00261] In various embodiments of the methods, presented above, for using the compounds of Formula I for the treatment or prevention of HCV infection or the sequelae of such infection, the HCV may be genotypically unidentified. In other embodiments, the HCV is HCV genotype 1, optionally HCV genotype 1a or 1b. In other embodiments, the HCV can be selected from other HCV genotypes, which include HCV genotypes 2 and/or 3.

[00262] Without wishing to be bound by theory, it is believed that compounds of Formula I that exhibit inhibition of HCV replication or infectivity derive their activity through interaction with or binding to an allosteric site that controls protein conformation of HCV NS5B and which thereby inhibits viral RNA synthesis in the host cell. Compounds of Formula I which exhibit inhibition of HCV replication or infectivity are believed to interact with or bind to NNI IV. As demonstrated in the Examples below, compounds of Formula I exhibit potent inhibition of NS5B RdRp activity in an in vitro biochemical assay, as well as inhibition of HCV replication as measured in an HCV replicon cell assay.

DEFINITIONS

[00263] It is understood that the compounds of the invention, as described herein, may be substituted for a variety of substituents or functional chemical moieties. In general, the term "substituted", whether or not preceded by the term "optionally", and substituents contained in the formulas of this invention, refer to the replacement of hydrogen radicals in a given structure by the radical of a specified substituent. When more than one position in any given structure can be substituted by more than one substituent selected from a specified group, the substituents shall, unless otherwise indicated, be understood to be independent, i.e., they may be the same. same or different in each position. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic, carbon and heteroatom substituents of organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. Additionally, this invention is not intended to be limited in any way by the permissible substituents of organic compounds. Combinations of substituents and variables envisioned by this invention are preferably those that result in the formation of stable compounds useful, as described herein, for example, in the treatment and prevention of disorders associated with HCV infection.

[00264] The term "aliphatic", as used herein, includes both saturated and unsaturated straight chain (ie, unbranched) or branched aliphatic hydrocarbons, which are optionally substituted by one or more functional groups. As will be appreciated by one of ordinary skill in the art, "aliphatic" is herein intended to include, but is not limited to, alkyl, alkenyl, alkynyl chemical moieties. Thus, as used herein, the term "alkyl" includes straight and branched alkyl groups. An analogous convention applies to other generic terms such as "alkenyl", "alkynyl" and the like. Additionally, as used herein, the terms "alkyl", "alkenyl", "alkynyl" and the like, encompass both substituted and unsubstituted groups.

[00265] In certain embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1 to 20 aliphatic carbon atoms (C1-20). In certain other embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain from about 1 to 10 aliphatic (C1-10) carbon atoms. In still other embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1 to 8 aliphatic (C1-8) carbon atoms. In still other embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1 to 6 aliphatic (C1-6) carbon atoms. In still other embodiments, the alkyl, alkenyl and alkynyl groups employed in the invention contain about 1 to 4 carbon atoms (C1-4). Aliphatic groups include, for example, methyl, ethyl, n-propyl, isopropyl (iPr), allyl, n-butyl (nBu), sec-butyl, isobutyl, tert-butyl, n-pentyl, sec-pentyl, isopentyl, tert -pentyl, n-hexyl, sec-hexyl and the like, which may bear one or more substituents. Alkenyl groups include, for example, ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl and the like. Alkynyl groups include, for example, ethynyl, 2-propynyl (propargyl), 1-propynyl and the like.

[00266] The term "alkyl", as used herein, refers to a saturated straight chain or branched hydrocarbon. Alkyl groups can occur as monovalent or divalent radicals in compounds disclosed herein. In some embodiments, alkyl groups have 1 to 10 (C1-10), 1 to 6 (C1-6), 1 to 4 (C1-4), or 1 to 3 (C1-3) carbon atoms. Representative saturated straight chain alkyl substituents include methyl, ethyl, n-propyl, n-butyl, n-pentyl and n-hexyl; while branched saturated alkyl substituents include isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl and the like.

[00267] The term "Bn", as used herein, refers to a benzyl group.

[00268] The terms "amine" and "amino", as used herein, refer to a group having the formula -NR'R", where R' and R" are both hydrogen. The term "alkylamine", as used herein, refers to a group having the formula -NR'R", where R' is hydrogen or alkyl, and R" is alkyl. Thus, the term alkylamine includes monoalkylamine and dialkylamine. The term "aminoalkyl", as used herein, refers to a group having the formula -alkyl-NR'R", where R' and R" are independently hydrogen or alkyl.

[00269] The term "ether", as used herein, refers to a group that has the formula R'-O-R", where R' and R" are independently alkyl or other substituent attached to oxygen through an carbon atom, for example -CH2-O-CH2 or -CH2-O-aryl-(CH2)3. The term "thioether", as used herein, refers to a similar group having the formula R'-S-R". The term "(thio)ether", as used herein, refers to a group comprising an ether or thioether functionality, or which have hybrid ether and thioether functionality, for example -CH 2 -O-CH 2 -S-CH 2 -.

[00270] The term "excipient", as used herein, refers to a natural or synthetic substance formulated together with the active ingredient of a composition. Excipients may be included in a composition for various functions or to impart various properties to the composition. For example, excipients may be included for the purpose of augmenting formulations that contain potent active ingredients (thus often referred to as "bulking agents", "fillers" or "diluents"). Alternatively, excipients can be included in a formulation to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as facilitating drug absorption or solubility. Selection of appropriate excipients also depends on the route of administration and dosage form, as well as the active ingredient and other factors. For example, for oral administration consideration may be given to colorants, flavors, glidants, lubricants and the like. Excipients can also be useful in the production process, to aid in the handling of the active substance involved, such as facilitating powder flow or non-stick properties. Excipients may be employed to aid formulation stability, such as preventing denaturation over expected shelf life, or to prevent or arrest microbial (eg, bacterial, fungal) growth (preservatives).

[00271] The term "IC50", as used herein, refers to an amount, concentration, or dosage of a particular test compound that achieves 50% inhibition of a maximal response in an in vitro assay — such as a biochemical or enzymatic assay — which measures such a response.

[00272] The term "halo" or "halogen", as used herein, refers to F, Cl, Br or I.

[00273] The term "HCV polymerase" as used herein refers to the HCV NS5B polymerase.

[00274] The term "pharmaceutically acceptable", as used herein in relation to an ingredient (such as an active ingredient, a salt or solvate thereof, or an excipient) that can be included in a pharmaceutical formulation for administration to a patient, refers to that ingredient which is acceptable in the sense of being compatible with any other ingredients present in the pharmaceutical formulation and which are not harmful to the patient. Indeed, pharmaceutical norms and standards require that all excipients in drugs administered to humans and other animals, as well as the chemical decomposition or metabolism products of such excipients, be identified and shown to be safe. The acronym GRAS is often applied to such materials, meaning they are "Generally Recognized As Safe".

[00275] The term "prevent" as used herein means that the compounds of the present invention are useful when administered to a patient who has not been diagnosed as possibly having the disease at the time of administration, but who would normally be expected to develop the disease or be at higher risk for the disease. Generally speaking, the term "prevent" refers to administering a compound of the invention before the onset of symptoms, particularly to patients at risk of contracting HCV infection. The compounds of the invention will delay the development of disease symptoms, delay the onset of the disease or prevent the individual from developing the disease.

[00276] The term "prodrug", as used in this document, refers to a chemical compound that has little or no pharmacological activity per se or that has properties that are preferable for administration, however, that has the ability to to undergo biotransformation to a therapeutically active metabolite of interest. For example, a prodrug form of a compound of Formula I may, by itself, have little or no inhibitory activity against HCV polymerase, however, it would undergo biotransformation in the patient's body to the active form of the compound. As another example, a prodrug form of a compound of Formula I may have one or more physicochemical properties, for example, solubility, which impart a different pharmacokinetic or pharmacodynamic profile to the compound. Biotransformation can include hydrolysis, oxidation, photolysis, or via physiological or metabolic processes, for example, by enzymatic modification. A prodrug can be thought of as including the therapeutic compound covalently linked to a prochemical moiety, and the biotransformation process removing or modifying the prochemical moiety to yield the therapeutic compound. Common functional groups on compounds that may be substituted for or modified to contain a prochemical moiety include, for example, amino, carbonyl, carboxyl, hydroxyl, phosphonyl, and thiolyl groups. See, for example, Rautio et al., Nat Rev Drug Discov, 2008, 7:255-270. If a parent drug contains one of these chemical moieties, the compound can be modified using bioreversible chemistry to contain a moiety. pro-chemistry. Alternatively, the prodrug can be prepared with the prochemical moiety incorporated in an early synthetic stage, as may be desired.

[00277] The term "solvate", as used herein, refers to a complex of varying stoichiometry formed by a solute (in this invention, a compound of Formula I or a salt thereof) and a solvent. Such solvents for the purpose of the invention cannot interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. However, solvates which have non-pharmaceutically acceptable solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of Formula I and their pharmaceutically acceptable salts. Most preferably, the solvent used is water and the resulting solvate can also be called a hydrate. As used herein, and unless otherwise indicated, the term "hydrate" means a compound provided herein or a salt thereof additionally includes a stoichiometric or non-stoichiometric amount of water bound by non-covalent intermolecular forces .

[00278] The term "stable", as used in this document, refers to compounds that have sufficient stability to allow their production, and that maintain the integrity of the compound for a period of time sufficient to be detected and, preferably, for a period of time sufficient to be useful for the purposes detailed in this document. For example, a compound of the invention should be sufficiently stable to allow purification or isolation or identification; or should be sufficiently stable to permit formulation into a pharmaceutically acceptable dosage form.

[00279] The term "subject" as used herein is an animal, typically a mammal, more typically a human, such as a patient. The term "host", as used herein, is a cell, such as a hepatocyte, or a human patient or other individual suspected of having, or determined to have been, infected with HCV, as determined using genetic techniques. or conventional serology.

[00280] The term "substituted", as used herein, refers to a chemical moiety in which at least one hydrogen atom is replaced by a substituent other than hydrogen. For example, if a phenyl group is said to be optionally substituted, at least one of the hydrogens on the phenyl ring is replaced by a non-hydrogen substituent. Typically such substituents are small chemical moieties such as halo, hydroxyl, C1-4 alkyl, C1-4 alkoxy or cyano. Such substitutions, in general, contribute to a desirable property for the molecule or at least do not substantially detract from the desirable properties of the molecule, and in any case, must be sufficiently stable for use according to the purposes presented in the present document.

[00281] The term "therapeutic amount", as used herein, refers to an amount of a compound that would reasonably be expected by the medical professional to have a particular therapeutic effect on the patient, when taking into account such factors as sex, age , genetic history, body mass, body surface area, mode of administration, and the like, regardless of the idiosyncrasies of the patient's physiology. The therapeutic effect may be contemplated in the treatment, prevention, and/or management of an HCV infection or a condition or symptom associated with such infection, or the delay or minimization of one or more symptoms associated therewith. The term "therapeutic amount" can therefore encompass an amount that improves overall therapy, reduces or prevents symptoms or causes of HCV infection, or enhances the therapeutic efficacy of another therapeutic agent. It is possible that a therapeutic amount of a compound may achieve different results when administered to different patients. In some cases, an amount of a compound that produces therapeutic benefit for one patient may yield little or no benefit for another patient, but it is still considered a therapeutic amount. In some embodiments, a therapeutic amount of an active compound is an amount determined by the United States Food and Drug Administration (or a related organization in another country or region) to be safe and effective in treating HCV infection or other disease or specified disorder in a human patient.

[00282] It will be appreciated that the reference in this document to "therapy" and/or "treatment" includes, however, without limitation the prevention, delay, prophylaxis, improvement and/or cure of HCV infection or medical symptoms, ailments or other consequential or associated sequelae (collectively, "HCV disease"). Thus, it will be appreciated that references in this document to treatment or prevention of HCV infection include treatment or prevention of chronic HCV infection, acute HCV infection, or any of the diseases and disorders associated with HCV, such as liver fibrosis, fatty liver , cirrhosis, cryoglobulinemia and hepatocellular carcinoma. Accordingly, the terms "treat", "treatment" and "under treatment", as used herein, refer to alleviating or reducing the severity of a symptom associated with HCV infection or a condition consequent upon such infection. In certain embodiments, compounds of the invention will delay or delay the progression of HCV infection, or a condition consequent upon such infection, thereby making it possible for the individual to enjoy a longer lifespan or a better quality of life.

[00283] The term "subtherapeutic amount", as used herein, refers to an amount of a compound that, if administered alone, is expected to exhibit no therapeutic effect or any significant therapeutic effect in the patient, when taking into account consideration the above factors. Subtherapeutic amounts of a compound of Formula I may be useful in combination therapy, in which, for example, two or more active compounds are administered to achieve a therapeutic effect.

[00284] Therapeutic or treatment effect can be measured in any manner known in the art. Therapeutic effect may be observed in asymptomatic HCV patients by delaying, reducing or preventing the onset or development of one or more symptoms characteristic of HCV disease. For example, the therapeutic effect can be observed by delaying, reducing or preventing a liver pathology. As another example, the therapeutic effect can be observed through viral load reduction (such as by qPCR assessment of the number of HCV RNA copies in the patient's blood). See, for example, Highleyman L. and Franciscus A., "HCV Diagnostic Tools: HCV Viral Load Tests," HCSP Fact Sheet, v.3, May 2011 [http://www.hcvadvocate.org/hepatitis/factsheets_pdf/ viralload.pdf].

[00285] The term "effective amount" as used herein refers to an amount of a compound that, when supplied to a host cell or system in vitro or ex vivo, would be expected to exhibit an obvious or measurable effect on the system. For example, in an acellular or cellular assay system suitable for measuring HCV polymerase activity, compounds of Formula I can inhibit or reduce such HCV polymerase activity when provided in an effective amount. As another example, in a cellular assay system suitable for measuring HCV replication or infectivity, compounds of Formula I can inhibit or reduce such HCV activity when provided in an effective amount.

PHARMACEUTICAL COMPOSITIONS AND DOSAGE FORMS

[00286] The invention provides compositions, and in particular, pharmaceutical compositions, comprising any one of the compounds of Formula I (for example, a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt or solvate thereof) in combination with at least one pharmaceutically acceptable excipient. See, for example, RC Rowe, Handbook of Pharmaceutical Excipients, 6th edition, 2009, Pharmaceutical Press.

[00287] While various embodiments of compositions in accordance with the invention are presented in detail below, it will be understood by the person skilled in the art that compounds of Formula I are not limited to use in compositions specifically adapted for administration as medicaments, however, that many other compositions comprising any of the compounds of Formula I can be produced using conventional materials and methods. Accordingly, the invention provides compositions comprising any one of the compounds of Formula I (e.g., a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a salt or solvate thereof) in combination with at least one vehicle, carrier, diluent, excipient, or a mixture of one or more of the foregoing ingredients. For example, it is expected that any of the compounds of Formula I may appear in solution with a solvent that is considered unacceptable for administration to humans or other individuals. Additionally, any of the compounds of Formula I can be prepared as a salt of a compound which is deemed unacceptable for administration to humans or other individuals. The person skilled in the art will understand how to prepare and interconvert such salt forms of the compounds, and such compositions comprising such compounds, by conventional techniques.

[00288] The amounts of various compounds of Formula I to be administered can be determined by standard procedures that take into account factors such as potency (IC50), efficacy (EC50) and biological half-life of compound, age, patient size and weight, and the patient's associated disease or disorder. The importance of these and other factors to consider are known to those of ordinary skill in the art.

[00289] Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds of Formula I with poor oral bioavailability, relatively larger doses will have to be administered. Oral administration is a convenient method of administering the compounds of Formula I.

[00290] Suitably the pharmaceutical composition is in unit dosage form. For oral administration, for example, a tablet or capsule can be administered; for nasal application a metered aerosol dose can be administered; for transdermal application, a topical or patch formulation can be administered; and for transmucosal delivery, a buccal patch can be administered.

[00291] Each dosage unit for oral administration may contain from 0.01 to 500 mg/Kg, for example from 0.1 to 50 mg/Kg, of a compound of Formula I or a pharmaceutically acceptable salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal, or transdermal routes can contain from 0.01 mg to 100 mg/kg of a compound of Formula I. A topical formulation can contain 0.01 to 5.0% of a compound of Formula I. The active ingredient may be administered from 1 to 4 times a day, for example once, twice or three times a day, sufficient to obtain the desired pharmaceutical activity.

[00292] The pharmaceutical compositions may be formulated into various dosage forms, which include, but are not limited to, dosage forms for oral, parenteral or topical administration. Pharmaceutical compositions may also be formulated as modified release dosage forms, which include, but are not limited to, delayed, extended, sustained, sustained, pulsatile, controlled, accelerated, rapid, targeted and timed release dosage forms, and gastric retention. Such dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 21st edition, 2005, Lippincott Williams &Wilkins; Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems, 9th edition, 2010, Lippincott Williams & Wilkins.

[00293] In one aspect of the invention, pharmaceutical compositions are provided in a dosage form for oral administration, comprising a compound provided herein, including a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof , or a pharmaceutically acceptable salt, solvate; and at least one pharmaceutically acceptable excipient.

[00294] In another aspect of the invention, pharmaceutical compositions are provided in a dosage form for parenteral administration, comprising a compound provided herein, which include a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt or solvate thereof; and at least one pharmaceutically acceptable excipient.

[00295] In yet another aspect of the invention, the pharmaceutical compositions are provided in a dosage form for topical administration, comprising a compound provided herein, which includes a single enantiomer, a mixture of enantiomers, or a mixture of diastereomers thereof, or a pharmaceutically acceptable salt, solvate; and at least one pharmaceutically acceptable excipient.

[00296] The pharmaceutical compositions provided herein may be provided in single or multiple dosage form. A unit dosage form as used herein refers to a physically discrete unit suitable for administration to an individual, and individually packaged as known in the art. Each unit dose contains a predetermined quantity of the active ingredient (or active ingredients) sufficient to produce the desired therapeutic effect, in association with the required at least one pharmaceutically acceptable excipient. Examples of a unit dosage form include an ampoule, syringe, and individually packaged tablet and capsule. A unit dosage form can be administered in fractions or multiples thereof. A multiple-dosage form is a plurality of identical unit-dosage forms packaged in a single container to be administered in a segregated unit-dosage form. Examples of multiple dosage forms include, without limitation, vials, bottles, blister packs, and cartons of tablets or capsules.

[00297] The pharmaceutical compositions provided herein can be administered at once, or multiple times at time intervals. It is understood that the dosage and duration of treatment suitable for a particular patient may vary with the age, weight and condition of the patient being treated, and may be determined empirically using known test protocols or by extrapolation from in vivo testing. or in vitro or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted from time to time according to individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions provided herein.

ORAL ADMINISTRATION

[00298] The pharmaceutical compositions provided herein may be provided in solid, semi-solid or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, capsules, pills, lozenges, dragees, lozenges, wafers, pellets, medicated chewing gum, granules, bulk powders, effervescent or non-effervescent powders or granules, solutions, emulsions, suspensions, wafers, granules, elixirs and syrups.

[00299] In addition to the active ingredient (or active ingredients), pharmaceutical compositions for oral administration may contain one or more pharmaceutically acceptable excipients, which include, but are not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants , glidants, coloring agents, ink migration inhibitors, sweetening agents and flavoring agents. Suitable pharmaceutically acceptable excipients are known and described in the art. See, for example, RC Rowe, Handbook of Pharmaceutical Excipients, 6th edition, 2009, Pharmaceutical Press.

[00300] Binders or granulators impart cohesion to a tablet to ensure that the tablet remains intact after compression. Suitable binders or fillers include, but are not limited to, starches, such as corn starch, potato starch, and pregelatinized starch (e.g., STARCH 1500); gelatin; sugars, such as sucrose, glucose, dextrose, molasses and lactose; Natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss extract, panwar gum, ghatti gum, isabgol (psyllium) mucilage husks, polyvinylpyrrolidone (PVP), Veegum, larch arabinogalactan, tragacanth in powder and guar gum; celluloses, such as ethylcellulose (EC), cellulose acetate, carboxymethylcellulose (CMC), methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch and mixtures thereof. In certain embodiments, the binder or filler is present from about 50 to about 99% by weight in the pharmaceutical compositions provided herein.

[00301] Suitable diluents include, but are not limited to, calcium diphosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered sugar. Certain diluents, such as mannitol, lactose, sorbitol, sucrose and inositol, when present in sufficient quantity, can impart properties to some compressed tablets that allow disintegration in the mouth through mastication. Such compressed tablets can be used as chewable tablets.

[00302] Suitable disintegrants include, but are not limited to, agar; bentonite; celluloses, such as methylcellulose and CMC; wood products; natural sponge; cation exchange resins; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; crosslinked celluloses, such as croscarmellose; cross-linked polymers such as crospovidone; crosslinked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycollate; polacrylin potassium; starches, such as corn starch, potato starch, tapioca starch and pregelatinized starch; clays; alignments; and mixtures thereof. The amount of a disintegrant in the pharmaceutical compositions provided herein varies under the type of formulation, and is readily discernible to those of ordinary skill in the art. In certain embodiments, pharmaceutical compositions provided herein contain from about 0.5 to about 15% or from about 1 to about 5% by weight of a disintegrant.

[00303] Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; sodium stearyl fumarate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerol polyethylene glycol (PEG) behenate; stearic acid; stearic fumaric acid; sodium lauryl sulfate; baby powder; hydrogenated vegetable oil, which includes peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; lycopodium; silica or silica gels, such as AEROSIL® 200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL® (Cabot Co., Boston, MA); and mixtures thereof. In certain embodiments, pharmaceutical compositions provided herein contain from about 0.1 to about 5% by weight of a lubricant.

[00304] Suitable glidants include, but are not limited to, colloidal silicon dioxide, CAB-O-SIL® and asbestos-free talc.

[00305] Suitable coloring agents include, but are not limited to, any of the approved and certified water soluble FD&C dyes, water soluble FD&C dyes suspended in alumina hydrate and color lakes, and mixtures thereof. A color lake is the adsorption combination of a water-soluble dye with a hydrated oxide of a heavy metal, which results in an insoluble form of the dye.

[00306] Suitable flavoring agents include, but are not limited to, natural flavorings extracted from plants, such as fruit, and synthetic blends of compounds that produce a pleasant taste sensation, such as mint and methylsalicylate.

[00307] Suitable sweetening agents include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerin, and artificial sweeteners such as saccharin and aspartame.

[00308] Suitable emulsifying agents include, but are not limited to, gelatin, acacia, tragacanth, bentonite and surfactants such as polyoxyethylene sorbitan monooleate (TWEEN® 20), polyoxyethylene sorbitan monooleate 80 (TWEEN® 80) and triethanolamine.

[00309] Suitable dispersing and suspending agents include, but are not limited to, CMC Sodium, Pectin, Tracanth, Veegum, Acacia, HPMC and PVP.

[00310] Suitable preservatives include, but are not limited to, glycerin, p-hydroxybenzoic acid esters (eg, methyl and propyl paraben), benzoic acid, sodium benzoate and alcohol.

[00311] Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate and polyoxyethylene lauryl ether.

[00312] Suitable solvents include, but are not limited to, glycerin, sorbitol, ethyl alcohol and syrup.

[00313] Suitable non-aqueous liquids used in emulsions include, but are not limited to, mineral oil and cottonseed oil.

[00314] Suitable organic acids include, but are not limited to, citric and tartaric acid.

[00315] Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

[00316] It should be understood that a particular excipient may serve more than one function, even with the same formulation.

[00317] The pharmaceutical compositions provided herein may be provided as compressed tablets, crushed tablets, chewable dragees, rapidly dissolving tablets, multi-compressed tablets, enteric-coated tablets, sugar-coated tablets or film-coated tablets. Enteric coated tablets are tablets coated with substances that resist the action of stomach acid, but dissolve or disintegrate in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenylsalicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalates. Sugar-coated tablets are compressed tablets surrounded by a sugar coating, which can be beneficial in hiding unwanted taste or odor and protecting the tablets from oxidation. Film-coated tablets are compressed tablets that are coated with a thin layer or film of a water-soluble material. Film coatings include, but are not limited to, hydroxyethylcellulose, sodium CMC, polyethylene glycol 4000, and cellulose acetate phthalate. Film coating imparts the same general characteristics as sugar coating. Multi-compressed tablets are compressed tablets produced from more than one compression cycle, which include layered, press-coated and dry-coated tablets.

[00318] Tablet dosage forms can be prepared from the active ingredient in powder, crystalline or granular forms, alone or in combination with at least one pharmaceutically acceptable excipient; which includes, for example, a binder, disintegrant, controlled release polymer, lubricant, diluent and/or colorant. Sweetening and flavoring agents are especially useful in the formation of chewable tablets and dragees.

[00319] The pharmaceutical compositions provided herein can be provided as soft or hard capsules, which can be produced from, for example, gelatin, methylcellulose, pullulan, starch or calcium alginate. The hard gelatine capsule, also known as a dry filled capsule (DFC), consists of two sections, one of which slides over the other, thus completely enveloping the active ingredient. The elastic soft capsule (SEC) is a soft globular shell, such as a gelatin shell, which is plasticized by the addition of glycerin, sorbitol or a similar polyol. Soft gelatin shells may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those as described herein, which include, but are not limited to, methyl and propyl parabens and sorbic acid. The liquid, semi-solid and solid dosage forms provided herein can be encapsulated in a capsule using conventional methods. Suitable liquid and semi-solid dosage forms include, but are not limited to, solutions and suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules may also be coated as known to those skilled in the art in order to modify or maintain dissolution of the active ingredient.

[00320] The pharmaceutical compositions provided herein may be provided in liquid and semi-solid dosage forms, which include, but are not limited to, emulsions, solutions, suspensions, elixirs and syrups. An emulsion is a two-phase system in which a liquid is dispersed in the form of small globules throughout another liquid, which may be oil in water or water in oil. Emulsions can include a non-aqueous pharmaceutically acceptable liquid or solvent, emulsifying agent and preservative. Suspensions can include a pharmaceutically acceptable suspending agent and preservative. Aqueous alcoholic solutions may include a pharmaceutically acceptable acetal, such as a di(lower alkyl) acetal of a lower alkyl aldehyde, for example, acetaldehyde diethyl acetal; and a water-miscible solvent having one or more hydroxyl groups, such as propylene glycol and ethanol. Elixirs are clear, sweetened, hydroalcoholic solutions. Syrups are concentrated aqueous solutions of a sugar, for example sucrose, and may also contain a preservative. For a liquid dosage form, for example, a solution in a polyethylene glycol may be diluted with a sufficient amount of a pharmaceutically acceptable liquid carrier, for example, water, to be conveniently measured for administration.

[00321] Other useful liquid and semi-solid dosage forms include, but are not limited to, those containing an active ingredient, for example, a compound of Formula I and a dialkylated mono- or polyalkylene glycol, which includes, 1,2-dimethoxymethane, ethylene glycol dimethyl ether, ethylene glycol dimethyl triether, ethylene glycol dimethyl tetraether, polyethylene glycol-350-dimethyl ether, polyethylene glycol-550-dimethyl ether, polyethylene glycol-750-dimethyl ether, wherein 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These formulations may additionally comprise one or more antioxidants, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid , sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters, and dithiocarbamates.

[00322] The pharmaceutical compositions provided herein for oral administration may also be provided in the form of liposomes, micelles, microspheres or nanosystems. Micelle dosage forms can be prepared as described in U.S. Patent No. 6,350,458.

[00323] The pharmaceutical compositions provided herein may be provided as effervescent or non-effervescent granules or powders, to be reconstituted into a liquid dosage form. Pharmaceutically acceptable excipients used in non-effervescent granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable excipients used in the effervescent granules or powders can include organic acids and a source of carbon dioxide.

[00324] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, which include delayed, sustained, pulsed, controlled, targeted and programmed release forms.

[00325] The pharmaceutical compositions provided herein may be co-formulated with other active ingredients that do not convey the desired therapeutic action, or with substances that supplement the desired action.

PARENTERAL ADMINISTRATION

[00326] The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion or implantation, for local or systemic administration. Parenteral administration, as used herein, includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, and subcutaneous administration.

[00327] The pharmaceutical compositions provided herein can be formulated in any dosage forms that are suitable for parenteral administration, which include solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science. See, for example, Remington: The Science and Practice of Pharmacy, supra; Handbook of Pharmaceutical Excipients; above.

[00328] Pharmaceutical compositions intended for parenteral administration may include one or more pharmaceutically acceptable excipients, which include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents, or preservatives against the growth of microorganisms, stabilizers, solubility enhancers, isotonic agents, buffering agents, antioxidants, local anesthetics, dispersing and suspending agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants, lyoprotectants, thickening agents, temperature adjusting agents pH and inert gases. Suitable pharmaceutically acceptable excipients are known and described in the art. See, for example, Handbook of Pharmaceutical Excipients, supra.

[00329] Suitable aqueous vehicles include, but are not limited to, water, saline, physiological saline or phosphate buffered saline (PBS), sodium chloride injection, Ringer's injection, isotonic dextrose injection, water injection sterile and injection of dextrose and lactated Ringer's. Non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, coconut oil medium chain triglycerides and palm kernel oil. Water-miscible carriers include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide, and dimethyl sulfoxide.

[00330] Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, cresols, mercurials, benzyl alcohol, chlorobutanol, thimerosal, benzalkonium chloride (for example, benzethonium chloride), methyl and propyl parabens and sorbic acid . Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin and dextrose. Suitable buffering agents include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, which include sodium bisulfite and metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable dispersing and suspending agents are those as described herein, which include sodium CMC, HPMC and PVP. Suitable emulsifying agents include those described herein, which include polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80 and triethanolamine oleate. Suitable sequestering or chelating agents include, but are not limited to, EDTA. Suitable pH adjusting agents include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, which include α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutylether-β-cyclodextrin, and sulfobutylether-7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

[00331] The pharmaceutical compositions provided herein may be formulated for single or multiple dosage administration. Single-dose formulations may be packaged, for example, in an ampoule, a vial or a syringe. In certain embodiments, the multi-dose parenteral formulations contain an antimicrobial agent at bacteriostatic or fungistatic concentrations. In certain embodiments, the parenteral formulations provided herein are sterile, as known and practiced in the art.

[00332] In one embodiment, the pharmaceutical compositions are provided as sterile, ready-to-use solutions. In another embodiment, the pharmaceutical compositions are provided as sterile dry soluble products, which include lyophilized powders and hypodermic tablets, to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as sterile, ready-to-use suspensions. In yet another embodiment, the pharmaceutical compositions are provided as sterile dry insoluble products to be reconstituted with a vehicle before use. In yet another embodiment, the pharmaceutical compositions are provided as sterile, ready-to-use emulsions.

[00333] The pharmaceutical compositions provided herein can be formulated as immediate or modified release dosage forms, which include delayed, sustained, pulsed, controlled, targeted and programmed release forms.

[00334] The pharmaceutical compositions can be formulated as a suspension, solid, semi-solid or thixotropic liquid, for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid internal matrix, which is surrounded by an outer polymeric membrane that is insoluble in body fluids, yet allows the active ingredient in the pharmaceutical compositions to disperse therethrough.

[00335] Suitable internal matrices include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxanes, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of acrylic and methacrylic acid esters, collagen, crosslinked polyvinyl alcohol and crosslinked partially hydrolyzed polyvinyl acetate.

[00336] Suitable external polymeric membranes include polyethylene, polypropylene, ethylene/vinyl acetate copolymers, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, silicone rubbers, polydimethylsiloxanes, neoprene rubber, po- chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidene chloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber epichlorohydrin rubbers, ethylene/vinyl alcohol copolymer, terpolymer of ethylene/vinyl acetate/vinyl alcohol and ethylene/vinyloxyethanol copolymer.

TOPICAL ADMINISTRATION

[00337] The pharmaceutical compositions provided herein can be administered topically to the skin, orifices or mucosa. Topical administration as used herein includes (intra)dermal, conjunctival, intracorneal, intraocular, ophthalmic, auricular, transdermal, nasal, vaginal, urethral, respiratory and rectal administration.

[00338] The pharmaceutical compositions provided in this document can be formulated in any dosage forms that are suitable for topical administration for local or systemic effect, which includes emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, powders, sauces, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, irrigations, sprays, suppositories, bandages and dermal patches. The topical formulation of pharmaceutical compositions provided herein may also comprise liposomes, micelles, microspheres, nanosystems and mixtures thereof.

[00339] Pharmaceutically acceptable excipients suitable for use in the topical formulations provided in this document include, but are not limited to, aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, enhancers solubility agents, isotonic agents, buffering agents, antioxidants, local anesthetics, dispersing and suspending agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, penetration enhancers, cryoprotectants, lyoprotectants, thickening agents and gases inert. Suitable pharmaceutically acceptable excipients are known and described in the art. See, for example, Handbook of Pharmaceutical Excipients, supra.

[00340] The pharmaceutical compositions can also be administered topically via electroporation, iontophoresis, phonophoresis, sonophoresis, or microneedle or needle-free injection, such as POWDERJECT™ (Chiron Corp., Emeryville, CA) and BIOJECT™ (Bio- ject Medical Technologies Inc., Tualatin, OR).

[00341] The pharmaceutical compositions provided herein may be provided in the form of ointments, creams or gels. Suitable ointment vehicles include hydrocarbon or oleaginous vehicles, which include lard, benzoin lard, olive oil, cottonseed oil, and other oils; white petrolatum; emulsifiable or absorbable vehicles, such as hydrophilic petrolatum, hydroxystearin sulfate, and anhydrous lanolin; water-removable vehicles such as hydrophilic ointment; water-soluble ointment vehicles, which include glycols of varying molecular weight; and emulsion vehicles, whether water-in-oil (W/O) emulsions or oil-in-water (O/W) emulsions, which include cetyl alcohol, glyceryl monostearate, lanolin, and stearic acid. These vehicles are emollients, however, generally require the addition of antioxidants and preservatives.

[00342] Suitable cream foundations can be oil-in-water or water-in-oil. Cream vehicles may be water washable, and contain an oil phase, an emulsifier, and an aqueous phase. The oil phase is also called the "internal" phase, which generally comprises petrolatum and a fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, though not necessarily, exceeds the oil phase by volume, and usually contains a humectant. The emulsifier in a cream formulation can be a non-ionic, anionic, cationic or amphoteric surfactant.

[00343] Gels are suspension type semi-solid systems. Single-phase gels contain organic macromolecules distributed substantially uniformly throughout a liquid carrier. Suitable gelling agents include cross-linked acrylic acid polymers such as carbomers, carboxypolyalkylenes, CARBOPOL®; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; cellulosic polymers such as HPC, HEC, HPMC, hydroxypropylmethylcellulose phthalate and methylcellulose; gums, such as tragacanth and xanthan gum; sodium alginate; and gelatin. To prepare a uniform gel, dispersing agents such as alcohol or glycerin can be added, or the gelling agent can be distributed by grinding, mechanical mixing and/or agitation.

[00344] The pharmaceutical compositions provided in this document can be administered rectally, urethrally, vaginally or perivaginally in the form of suppositories, pessaries, probes, plasters or poultices, pastes, powders, sauces, creams, malagma, contraceptives, ointments, solutions , emulsions, suspensions, tampons, gels, foams, sprays or enemas. Such dosage forms can be produced using conventional processes, such as are described in Remington: The Science and Practice of Pharmacy, supra.

[00345] Rectal, urethral and vaginal suppositories are solid bodies for insertion into body orifices, which are solid at ordinary temperatures, but melt or soften at body temperature to release the active ingredient (or active ingredients) into the orifices. Pharmaceutically acceptable excipients used in rectal and vaginal suppositories include bases or vehicles, such as stiffening agents, which impart a melting point in the vicinity of body temperature to the formulation. Suitable carriers include, but are not limited to, cocoa butter (theobroma oil), glycerin gelatin, carbowax (polyoxyethylene glycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono, di, and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethyl methacrylate, polyacrylic acid; and glycerin gelatin. Combinations of the various vehicles can be used. Rectal and vaginal suppositories may further comprise antioxidants, as described herein, which include sodium bisulfite and metabisulfite. Rectal and vaginal suppositories can be prepared by the compressed or molded method. The typical mass of a rectal and vaginal suppository is about 2 to about 3 g.

[00346] The pharmaceutical compositions provided herein can be administered intranasally or by inhalation into the respiratory tract. Pharmaceutical compositions may be provided in the form of an aerosol or solution for delivery using a pressurized container, pump, spray, atomizer, such as an atomizer that uses electrohydrodynamics to produce a fine mist, or nebulizer, alone or in conjunction with combination with a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane. Pharmaceutical compositions can also be provided as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose or phospholipids; or nasal drops. For intranasal use, the powder may comprise a bioadhesive agent, which includes chitosan or cyclodextrin.

[00347] Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulizer may be formulated to contain ethanol, aqueous ethanol or a suitable alternative agent, solvent or solvent system to distribute, solubilize or extend the release of the active ingredient provided herein; and/or a propellant as a solvent; and/or a surfactant such as sorbitan trioleate, oleic acid or an oligolactic acid.

[00348] The pharmaceutical compositions provided herein can be micronized to a size suitable for delivery via inhalation, such as about 50 micrometers or less, or about 10 micrometers or less. Particles of such sizes can be prepared using a comminuted method known to those skilled in the art, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization or spray drying.

[00349] Capsules, blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder blend of the pharmaceutical compositions provided herein; a suitable powder base, such as lactose or starch; and a performance modifier such as leucine, mannitol or magnesium stearate. Lactose can be anhydrous or in the form of monohydrates. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. Pharmaceutical compositions provided herein for inhaled/intranasal administration may additionally comprise a suitable flavoring agent, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

[00350] The pharmaceutical compositions provided herein for topical administration can be formulated to be immediate release or modified release, which includes delayed, sustained, pulsed, controlled, targeted and programmed release.

COADMINISTRATION AND COMBINATIONS

[00351] The terms "coadministration" and "in combination with" include the administration of two or more pharmaceutically active agents (e.g., a compound of Formula I and another antiviral agent or second agent) either simultaneously, together or sequentially without limitation of specific time. In one embodiment, both agents are present in the patient's cell or body at the same time or exert their biological or therapeutic effect at the same time. In one embodiment, the two or more active agents are in the same composition or unit dosage form. In another embodiment, the two or more active agents are provided in separate compositions or unit dosage forms.

[00352] The above combinations may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with at least one pharmaceutically acceptable excipient thereof represent an additional aspect - end of the invention. Thus, in some embodiments, the invention provides compositions comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, and further comprising one or two additional compounds that have anti-HCV activity. Alternatively, in some embodiments, the invention provides the combined use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient, and which further comprises the use of one or two additional compounds having anti-HCV, each in a composition with at least one pharmaceutically acceptable excipient or together in a composition with at least one pharmaceutically acceptable excipient.

[00353] In some embodiments, the invention provides the combined use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, to prepare a composition comprising the compound of Formula I, one or two additional compounds that have anti-inflammatory activity. HCV, and a pharmaceutically acceptable excipient.

[00354] The components of the combinations can be administered sequentially or simultaneously, or in subcombinations, in separate or combined pharmaceutical formulations. Appropriate combinations can be identified by those skilled in the art.

[00355] The compounds of Formula I and other individual components of such combinations may be provided in therapeutic or subtherapeutic amounts. Regardless of whether each component in the combination is properly provided in an amount that would otherwise be considered therapeutic or subtherapeutic, and regardless of whether the components are directed to the same or different specific therapeutic effects, a combination according to the invention is administered in an amount that a practitioner skilled in the art would consider adequate for the treatment of HCV as described herein. In such cases, the combination is said to be administered in a therapeutic amount. Accordingly, an amount of a compound of the invention may be considered subtherapeutic if administered alone, however, would be considered a therapeutic amount if the combination or co-administration regimen is found to be therapeutically effective. For example, an amount of a compound of Formula I can be administered in an amount that achieves a therapeutic effect, for example, a reduction in hepatitis C viral load, in combination with one or more other active agents.

[00356] In some embodiments, a compound of Formula I can be administered in combination with one or more other antiviral agents. In some embodiments, a compound of Formula I can be administered in combination with two other antiviral agents. In some embodiments, a compound of Formula I can be administered in combination with three other antiviral agents. In some embodiments, a compound of Formula I can be administered in combination with four other antiviral agents. Such combinations are sometimes referred to as "cocktails". Some combinations of antiviral agents are used in the clinic to improve the ability of mutated HCV to overcome the inhibitory activity of a single agent. The use of a compound of Formula I in such combinations can therefore convey useful therapeutic advantages.

[00357] Combinations or co-administration of the compounds of the invention with other active agents may desirably exhibit synergistic effects (i.e., the effect that is obtained when the active ingredients are administered together is greater than the sum of the effects of each agent administered separately ) and/or a higher barrier to drug resistance. For example, if two agents are co-administered, their combined effect may be synergistic if a therapeutic effect is obtained, notwithstanding that the two agents would not be expected to yield an equivalent therapeutic effect if administered separately or together. On the contrary, the antagonism of two agents can be said to exist if their combined effect is less than the sum of the effects of each agent administered separately. Synergy, drug resistance and antagonism can be measured using any method that is generally accepted in the art, such as using concentration response curves for a parameter of interest. Synergy, drug resistance, or antagonism for a given combination can be determined for inhibition of HCV infection, HCV polymerase activity, a pharmacokinetic or pharmacodynamic effect, or the like.

[00358] Doses and dosage regimens of the compounds of Formula I together with second active agents and combinations thereof should depend on the specific indication being treated, the age and condition of the patient and the severity of adverse effects, and can be adjusted accordingly by those who are versed in the art. Examples of doses and dosage regimens for other active chemical moieties can be found, for example, in the Physician's Desk Reference, and will require adaptation for use in the methods of the invention.

[00359] Accordingly, in some embodiments, a therapeutic amount of a combination comprising a compound of Formula I and at least one other active agent is administered to the patient to a patient in need thereof. In some embodiments, the administered amount of at least one other active agent is subtherapeutic. In some embodiments, the administered amount of the at least one other active agent is therapeutic. In some embodiments, the administered amount of the compound of Formula I is subtherapeutic. In other embodiments, the administered amount of the compound of Formula I is therapeutic.

[00360] Active agents suitable for use in combination with a compound of Formula I can be agents that have activity against HCV directly or indirectly, for example, compounds that inhibit or reduce HCV replication or infectivity. HCV agents include, but are not limited to, interferons, antiviral agents (e.g., ribavirin, taribavirin (viramidine), amantadine), nucleoside HCV NS5B polymerase inhibitors, non-nucleoside HCV NS5B polymerase inhibitors, HCV protease inhibitors, HCV NS5A inhibitors, HCV NS4B inhibitors, HCV NS3 helicase inhibitors, host cell entry inhibitors and human cyclophin inhibitors.

[00361] In some embodiments, a compound of the invention can be administered in combination with one or more interferon molecules. Exemplary interferons include, without limitation, natural, recombinant, and modified (e.g., PEG-linked, albumin-linked) interferon molecules. Interferons include, but are not limited to, interferon alfa-2a (Roferon®), interferon alfa-2b (Intron®), interferon alfacon-1 (Infergen®), peginterferon alfa-2a (Pegasys®) or peginterferon alfa-2b (PegIntron®), recombinant interferon alpha (BLX-883; Locteron®), and albinterferon alpha 2b (Zalbin®).

[00362] In some embodiments, a compound of Formula I can be administered in combination with an interferon and ribavirin. In such cases, the compound of the invention can be said to be used to supplement the current standard of care. In some other embodiments, a compound of the invention is administered in combination with ribavirin.

[00363] In some embodiments, a compound of Formula I can be administered in combination with one or more compounds that inhibit HCV serine protease activity (NS3-4A). Such protease inhibitors include, without limitation, telaprevir (Incivek™; VX-950; Vertex), boceprevir (Victrelis™; SCH503034; Merck), simeprevir (TMC435; Janssen/Tibotec/Medevir), damageprevir (ITMN-191/RG7227; Hoffmann-La Roche/Genentech), faldaprevir (BI 201335; Boehringer Ingelheim), BI 12202 (Boehringer Ingelheim), vaniprevir (MK-7009; Merck), MK-5172 (Merck), paritaprevir (ABT-450; Abbvie); VX500 (Vertex), PHX1766 (Phenomix), BILN2061 (Boehringer Ingelheim), GS-9256 (Gilead), GS-9451 (Gilead), asunaprevir (BMS-650032; Bristol-Myers Squibb), VX-985 (Vertex), sovaprevir (ACH-1625; Achillion), ACH-2684 (Achillion) and narlaprevir (SCH900518; Merck).

[00364] In some embodiments, a compound of Formula I can be administered in combination with one or more HCV nucleoside polymerase inhibitors (NS5B). Suitable NI compounds include, but are not limited to, IDX184 (Idenix), mericitabine (RG7128, R-7128, RO5024048; Hoffmann-La Roche/Genentech), PSI-7851 (Pharmasset), PSI-938 (Pharmasset), sofosbuvir ( SOVALDI®, PSI-7977; Gilead/Pharmasset), TMC647055 (Janssen); and VX-135 (Vertex), as well as phosphoramidate nucleotide analogs such as INX-189 (Inhibitex), TMC649128 (Tibotec/Medevir). Combinations of Formula I compounds with other NS5B inhibitors can be used, for example combinations with ALS-2200 or ALS-2158 (Vertex and Alios Biopharma)

[00365] In some embodiments, a compound of Formula I can be administered in combination with one or more non-nucleoside inhibitors of HCV polymerase (NS5B). Suitable NNI compounds include, without limitation, compounds that bind to or inhibit activity through one of the identified NNI sites on the NS5B protein. See, Powdrill et al., Viruses, 2010, 2:2169-95 and Appleby et al., "Viral RNA Polymerase Inhibitors", chapter 23 in Viral Genome Replication, Cameron et al., editions, Springer Science+Business Media 2009. These NNI compounds can be classified on the basis of where they interact.

[00366] Accordingly, in some embodiments, a compound of Formula I can be co-administered, or provided in combination, with an NNI I inhibitor compound, an NNI II inhibitor compound, an NNI III inhibitor compound, or an NNI inhibitor compound IV, or a combination of such compounds. Accordingly, in some embodiments, a compound of Formula I can be administered in combination with one or more compounds selected from:

[00367] NNI I compounds which include, but are not limited to, JTK-109 (Japan Tobacco), BILB-1941 (Boehringer Ingelheim), MK-3281 (Merck), BI 207127 (Boehringer Ingelheim);

[00368] NNI II compounds which include but are not limited to filibuvir (PF-868554; Pfizer), VX-759 (VCH-759; Vertex), VCH-916 (Vertex), VX-222 (VCH-222; Vertex) , GS-9669 (Gilead);

[00369] NNI III compounds which include, but are not limited to, GSK625433 (Glaxo SmithKline), ANA-598 (Anadys/Roche), dasabuvir (ABT-333; Abbvie), ABT-072 (Abbott), setrobuvir (ANA-598l; Hoffmann-La Roche/Genentech); or

[00370] NNI IV compounds which include but are not limited to HCV-796 (ViroPharma/Wyeth), tegobuvir (GS-9190; Gilead), IDX375 (Idenix).

[00371] In other embodiments, a compound of Formula I can be administered in combination with one or more other NS5B polymerase inhibitors which include, but are not limited to, BMS 791325 (Bristol-Myers Squibb), R1626 (Roche), A-848837 (Abbott) and A-837093 (Abbott), as well as compounds disclosed in International Patent Publications No. WO 02/100846 A1, WO 02/100851 A2, WO 2004/052879 A2, WO 2004/052885 A1, WO 2006/072347 A2, WO 2006/119646 A1, WO 2008/017688 A1, WO 2008/043791 A2, WO 2008/058393 A1, WO 2008/059042 A1, WO 2008/125599 A1, and WO 2009/000818 A1; U.S. Patent No. 6,881,741 B2, 6,887,877 B2 and 6,936,629 B2, 7,402,608 B2 and 7,569,600 B2; and Yang et al., Bioorg Med Chem Lett, 2010, 20:4614-19.

[00372] In some embodiments, a compound of Formula I can be administered in combination with an active compound that inhibits another activity or function of a target selected from HCV metalloprotease, HCV serine protease, HCV polymerase, HCV helicase HCV, HCV NS4B protein, HCV entry, HCV assembly, HCV egress, HCV NS5A protein, and inosine-5'-monophosphate dehydrogenase (IMPDH). For example, a compound of the invention can be administered in combination with one or more compounds selected from:

[00373] NS5A (regulatory protein) inhibitors, e.g. daclatasvir (BMS-790052; Bristol-Myers Squibb), BMS-824383 (Bristol-Myers Squibb), AZD7295 (AstraZeneca), PPI-461 (Presidio), PPI- 688 (Presidio), GS-5885 (Gilead), ACH-2928 (Achillion), IDX-719 (Idenix), ombitasvir (ABT-267; Abbvie); ledipasvir (GS-5885; Gilead), ACH-3102 (Achillion), GS-5816 (Gilead), JNJ-56914845 (GSK 2336805; Janssen), MK-8742 (Merck);

[00374] NS3 (peptidase/helicase) inhibitors, eg BMS-650032 (Bristol-Myers Squibb);

[00375] NS4B (regulatory protein) inhibitors, eg clemizol (Eiger Biopharmaceuticals); host cell entry inhibitors, for example ITX5061 (iTherX); It is

[00376] Cyclophilin inhibitors, such as cyclophilin-A inhibitors, for example, Debio 025 (alisporivir), SCY-635, NIM811, and other cyclosporine derivatives (cyclosporine).

[00377] In some embodiments, a compound of Formula I can be administered in combination with two or more compounds that inhibit HCV activities or functions. For example, a compound of Formula I can be administered in combination with combinations of HCV NS5B (polymerase) inhibitors and NS5A (regulatory protein) inhibitors, such as sofosbuvir+ledipasvir (HARVONI®; Gilead) and sofosbuvir with GS-5816. As another example, a compound of Formula I can be administered in combination with combinations of HCV NS5B (polymerase) inhibitors, such as TMC435 and NS5A (regulatory protein) inhibitors, such as JNJ-56914845.

[00378] In some embodiments, a compound of Formula I can be administered in combination with one or more compounds that inhibit activities or functions of HCV and one or more compounds that have other activities. For example, a compound of Formula I can be administered in combination with combinations of an NS3-4A protease inhibitor, i.e. enhanced with ritonavir (NORVIR®; Abbvie), which inhibits CYP3A4, a host enzyme that can metabolize protease inhibitors. These include, for example, ritonavir-boosted ABT-450 and ritonavir-boosted damageprevir.

[00379] In some embodiments, a compound of Formula I can be employed in combination with multiple active agents. As an example of such combinations, a compound of Formula I can be employed in combination with a protease inhibitor (eg, paritaprevir) boosted with ritonavir, and an NS5A inhibitor (eg, ombitasvir), optionally with ribavirin.

[00380] In some embodiments, a compound of Formula I can be administered in combination with a compound selected from interleukin 2, interleukin 6, interleukin 12, a compound that enhances the development of a type 1 helper T cell response, RNA interference, antisense RNA, imiquimod, ribavirin, an IMPDH inhibitor, amantadine, and rimantadine.

[00381] The compounds of Formula I can also be used in combination with other therapeutic agents, for example therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (eg, theophylline), mucolytic agents, antimuscarinics, antileukotrienes, cell adhesion inhibitors (eg, ICAM antagonists), antioxidants (eg, N-acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants, and /or antimicrobial agents. The compounds of Formula I can also be used in combination with gene replacement therapy.

[00382] Although the active chemical moieties mentioned herein as second active agents can be identified as free active chemical moieties, salt forms (which include with hydrogen or coordination bonds), solvates or as non-covalent derivatives (e.g. chelates , complexes and clathrates) of such active chemical moieties, it is to be understood that the given representative commercial drug products are not limiting, and free active chemical moieties, or salts or other derivative forms of the active chemical moieties may alternatively be maids. Accordingly, reference to an active chemical moiety should be understood to encompass not only the free active chemical moiety, but any salt, solvate or other form of pharmacologically acceptable derivative that is consistent with the specified parameters of use.

EXAMPLES

[00383] The chemical examples, synthetic schemes and intermediates provided herein are intended to illustrate suitable synthetic routes for preparing the compounds of the invention (and their intermediates), to assist in the understanding of the present invention. With proper handling and protection of any chemical functionality, the synthesis of compounds of Formula I is achieved through methods analogous to those described herein. Suitable protecting groups can be found, for example, in P.G.M. Wuts and T.W. Greene, Greene's Protective Groups in Organic Synthesis, 4th Edition, 2006, Wiley Interscience.

[00384] Methods for testing the activity of the compounds of the invention are described in the examples. Those skilled in the art will know of other methods for identifying compounds that have activity against the NS5B polymerase. For example, McKercher et al., Nucl Acids Res, 2004, 32(2):422 to 431 describe a method to identify NS5B inhibitory compounds; Burton JR, Everson, GT, Clin Liver Dis. 2009, 13, 453 to 465; Soriano et al., Expert Opin Pharmacother, 2013, 14, 1161 to 1170.

[00385] Synthetic intermediates were analyzed by LC-MS. Final products were analyzed and confirmed by LC-MS and 1H NMR. LC-MS method: instrument was Agilent 1100 HPLC and Agilent 3200 mass spectrometer with ESI(+) detector. The analytical column used was a Synergi Hydro-RP column (00B-4375-E0; Phenomenex), and compounds were eluted for 3 minutes (10% to 95% acetonitrile (ACN) in water, which contains 0.1 % trifluoroacetic acid). EXAMPLE 1 ETHYL 3-(4-FLUOROPHENYL)-3-OXOPROPANOATE (1-2).

[00386] To a stirred solution of potassium t-butoxide (323 g, 2.89 mol) in toluene (1 L) was added diethyl carbonate (533 g, 4.51 mol) at RT, and the mixture was heated to 80°C for one hour. 1-(4-fluorophenyl)-ethanone (250 g, 1.80 mol) in toluene (2 L) was added to the reaction mixture slowly and stirred at 70 °C for two hours, then cooled to RT and stirring was continued for 16 hours. The reaction mixture was quenched with dilute HCl, then diluted with water and extracted with ethyl acetate (EtOAc; 3 X 800 mL). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude compound was purified by fractional distillation to obtain 1-2 (210 g, 55% yield, 1 mol) as a pale yellow liquid. MS = 211.2 [M+1]+. ETHYL 2-(4-FLUOROPHENYL)-5-HYDROXYBENZOFURAN-3-CARBOXYLATE (1-3).

[00387] To a stirred solution of ethyl 3-(4-fluorophenyl)-3-oxopropanoate (5 g, 23 mmol) in toluene (75 ml) was added ZnCl2 (1 M in diethyl ether) (34 ml, 34, 5 mmol) slowly at 110°C. p-Benzoquinone (3.4 g, 30.9 mmol) in tetrahydrofuran (THF) was added dropwise and stirring was continued for 6 hours at 110°C. The reaction mixture was cooled to RT, water (100 ml) was added and the mixture was extracted with EtOAc (100 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude compound was purified by column chromatography (100 to 200 µl silica) to afford 1-3 (2.6 g, 36% yield) as a brown solid. MS = 301.0 [M+1]+. ETHYL 2-(4-FLUOROPHENYL)-5-ISOPROPOXYBENZOFURAN-3-CARBOXYLATE (1-4).

[00388] Cesium carbonate (Cs2CO3; 58.3 g, 33 mmol) was added to a solution of 1-3 (50 g, 166.6 mmol) in dimethylformamide (DMF) (250 ml) followed by the addition of 2- bromopropane (80 mL, 83 mmol) dropwise. Then, the reaction mixture was heated to 60°C and stirred for two hours. After consumption of starting material (by TLC), the reaction mixture was diluted with cold water (100 ml) and extracted with EtOAc (100 ml). The organic layer was washed with brine (50 ml), dried over Na 2 SO 4 and concentrated. The crude compound was purified by washings with diethyl ether and pentane to afford 1-4 (45 g, 79% yield) as an off-white solid. MS = 343.1 [M+1]+. ETHYL 2-(4-FLUOROPHENYL)-5-ISOPROPOXY-6-BENZOFURAN-3-CARBOXYLATE (1-5).

[00389] To a stirred solution of 1-4 (45 g, 131.5 mmol) in chloroform (500 ml) was added dropwise 70% HNO3 (80 ml) in CHCl3 (200 ml) at 0 °C and stirred at TA for two hours. Upon completion of the reaction as indicated by TLC, the mixture was poured into cold water (100 ml), extracted with EtOAc (100 ml). The organic layer was washed with brine (50 ml), dried over Na 2 SO 4 and concentrated. The crude compound was purified by washing with diethyl ether and pentane to afford 1-5 (44 g, 86% yield) as a yellow solid. ETHYL 2-(4-FLUOROPHENYL)-5-HYDROXY-6-BENZOFURAN-3-CARBOXYLATE (1-6).

[00390] Boron trichloride (BCl3; 500 ml, 85.7 mmol) was added to a stirred solution of 1-5 (44 g, 113.3 mmol) in dichloromethane (DCM; 900 ml) at 0 °C and at The reaction was continued under stirring at the same temperature for two hours. Upon completion of the reaction as indicated by TLC, the mixture was poured into cold water (200 ml), extracted with DCM (2 x 300 ml). The combined organic layer was washed with brine (100 mL), dried over Na 2 SO 4 , and concentrated. The crude compound was purified by pentane washes to afford 1-6 (38 g, 110.14 mmol, 97%) as a yellow solid. MS = 344.1 [M+1]+. ETHYL 2-(4-FLUOROPHENYL)-6-NITRO-5-(TRIFLUOROMETHYLSULFONYLOXY)-BENZOFURAN-3-CARBOXYLATE (1-7).

[00391] N-Phenylbis(trifluoromethanesulfonamide) (phenyltriflimide; 24.8 g, 69.5 mmol) was added to a stirred solution of 1-6 (20 g, 57.9 mmol) in ACN/DMF (500 mL, 10 :1) at 0°C and the reaction was continued under stirring at 0°C for two hours. Upon completion of the reaction (by TLC), the reaction mixture was poured into cold water (100 ml), extracted with EtOAc (3 X 100 ml). The combined organic layer was washed with water (50 ml), brine (50 ml), dried over Na 2 SO 4 and concentrated. The crude compound washed with pentane (100 ml) and dried to afford 1-7 (27.6 g, quantitative yield) as an off-white solid. ETHYL 5-CYCLOPROPYL-2-(4-FLUOROPHENYL)-6-NITROBENZOFURAN-3-CARBOXYLATE (1-8).

[00392] To a stirred degassed solution of 1-7 (27.6 g, 57.9 mmol) in toluene (250 ml) was added cyclopropyl boronic acid (7.46 g, 86.79 mmol), bromide sodium hydroxide (6.14 g, 59.6 mmol), potassium fluoride (11.4 g, 191.52 mmol). After degassing for 20 minutes, Pd(PPh3)4 (2 g, 1.73 mmol) was added and the reaction was continued under stirring at 110°C for 16 hours. After completion of the reaction was indicated by TLC, the mixture was poured into cold water (500 ml), extracted with EtOAc (3 X 250 ml). The combined organic layer was washed with brine (100 mL), dried over Na 2 SO 4 , and concentrated. The crude compound was purified by column chromatography (230 to 400 silica) using 13% DCM in hexane to afford 1-8 (8 g, 21.68 mmol, 38% yield) as a yellow solid. MS = 370 [M+1]+. ETHYL 6-AMINO-5-CYCLOPROPYL-2-(4-FLUOROPHENYL)BENZOFURAN-3-CARBOXYLATE (1-9).

[00393] To a stirred solution of 1-8 (5.7 g, 15.43 mmol) in a mixture of methanol (MeOH), THF and water (3:3:1) was added zinc dust (4.03 g, 61.73 mmol) and NH4Cl at RT and the mixture was heated at 80°C for 6 hours. Upon completion of the reaction as indicated by TLC, the mixture was filtered through a celite pad, washed with EtOAc. Filtered concentrated under reduced pressure, crude residue was diluted with EtOAc (100 ml) and washed with water (100 ml), brine (50 ml), dried with Na 2 SO 4 and concentrated. The crude compound was washed with pentane (30 ml) to afford 1-9 (5.2 g, quantitative) as an orange solid. MS = 340 [M+1]+. ETHYL 5-CYCLOPROPYL-2-(4-FLUOROPHENYL)-6-(N-(METHYLSULFONYL)-METHYLSULFONAMIDO)-BENZOFURAN-3-CARBOXYLATE (1-10).

[00394] To a stirred solution of 1-9 (5.2 g, 15.33 mmol) in DCM (70 ml) was added mesylchloride (2.72 ml, 35.2 mmol), triethylamine (11.62 ml, 76.66 mmol) at 0°C and the reaction was continued under stirring at RT for two hours. Upon completion of starting material as indicated by TLC, the mixture was poured into cold water (50 ml), extracted with DCM (100 ml). The organic layer was washed with brine (50 ml), dried over Na 2 SO 4 and concentrated to afford 1-10 (6 g, 79% yield) as an orange solid. MS = 496.4 [M+1]+. 5-CYCLOPROPYL-2-(4-FLUOROPHENYL)-6-(METHYLSULFONAMIDO)BENZOFURAN-3-CARBOXYLIC ACID (1-11).

[00395] To a stirred solution of 1-10 (6 g, 12.12 mmol) in a mixture of MeOH, THF and H2O (3:3:1, 75 ml) was added NaOH (1.93 g, 48, 48 mmol) at RT and stirred for 6 hours at 80°C. After completion of the reaction as indicated by TLC, the reaction mixture was concentrated to remove organic volatiles, the crude compound was diluted with water (20 mL), and neutralized using 1 N HCl (pH ~3 to 4 ), extracted with EtOAc (100 ml). The organic layer was washed with brine (50 ml), dried over Na 2 SO 4 and concentrated. The crude compound was washed with pentane to afford 1-11 (4.9 g, quantitative) as an off-white solid. MS = 390.1 [M+1]+. 5-CYCLOPROPYL-2-(4-FLUOROPHENYL)-N-METHYL-6-(METHYLSULFONAMIDO)BENZOFURAN-3-CARBOXAMIDE (1-12).

[00396] To a solution of 1-11 (14 g, 35.9 mmol) in DCM (150 ml) was added HATU (27.3 g, 71.9 mmol), DIPEA (18.8 ml, 107.9 mmol) mmols) at 0 °C and the reaction was continued under stirring at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the mixture was poured into cold water (100 ml), extracted with EtOAc (100 ml). The organic layer was washed with water (50 ml), brine (50 ml), dried over Na 2 SO 4 and concentrated. The crude compound was purified by column chromatography (100 to 200 silica) and washes with DCM and pentane to afford 1-12 (11 g, 75.8% yield) as an off-white solid. MS = 403.5 [M+H]+. EXAMPLE 2 1-(3-BROMOMETHYL-PHENYL)-ETHANONE (2-2A).

[00397] To a stirred solution of 1-m-tolylethanone 2-1A (25 g, 186.43 mmol) in ACN (ACN; 200 mL) was added NBS (36.4 g, 205.07 mmol) and azoisobutyronitrile ( AIBN; 3.06 g, 18.64 mmol) at room temperature (room; RT). The reaction mixture was heated at 90°C for 6 hours (hour) under N2 atmosphere. The reaction mixture solvent was evaporated under reduced pressure and the crude residue washed with toluene (500 ml) and the precipitate filtered (NBS). The filtrate evaporated under reduced pressure and the crude residue was purified by flash column chromatography (100 to 200 silica) using 3% EtOAc (EtOAc) in petroleum ether (pet. ether) to afford 2-2A (27.6 g, 129.57 mmol, 70% yield) as an off-white solid. MS (ESI): m/z 213.0 (M+1)+. Step-A above was adapted using 1-p-tolyl-ethanone 2-1b to prepare 2-2b. 2-(2-(TETRAHYDRO-2H-PYRAN-2-YLOXY)-ETHOXY)-ETHANOL (2-4A).

[00398] To a stirred solution of 2,2'-oxydiethanol 2-3A (30 g, 282.70 mmol) in DCM (900 ml) was added dihydropyran (DHP; 20.6 ml, 226.16 mmol) and pyridinium p-toluenesulfonate (PTSA; 5.3 g, 28.27 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water (600 mL), extracted with CH 2 Cl 2 (3 X 800 mL), the combined organic layers were washed with brine (2 X 100 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH (MeOH) in DCM to afford 2-4A (16 g, 84.21 mmol, 30% yield) as a thick yellow liquid . Step-B was adapted by replacing 2-3b through 2-3e with 2-3a to prepare the following tetrahydro-2h-pyran (thp) compounds:

[00399] 2-3B (30 g, 0.2 mmol) was used to prepare 2-4B (10 g, 21% yield).

[00400] 2-3C (30 g, 0.15 mmol) was used to prepare 2-4C (7 g, 16% yield).

[00401] 2-3D (10 g, 42.0 mmol) was used to prepare 2-4D (3.01 g, 22.2% yield).

[00402] 2-3E (10 g, 35.0 mmol) was used to prepare 2-4E (4.02 g, 30.8% yield). 1-(3-(2-(2-TETRA-2H-PYRAN-2-YLOXY)-ETHOXY)-ETOXY)-METHYL)-PHENYL)-ETHANONE (2-5A).

[00403] To a stirred solution of 1-(3-(bromomethyl)-phenyl)-ethanone 2-2A (8 g, 42.1 mmol) in THF (50 mL) was added NaH (1.6 g, 42, 1 mmol) at 0°C, and reaction was continued at RT for 30 minutes, 2-4A (9.3 g, 44.2 mmol) in THF (30 ml) was added to the reaction mixture at 0°C for 5 minutes and reaction was continued at RT for 16 hours. The reaction mixture was quenched with cold water (100 ml) and extracted with EtO-Ac (3 X 200 ml). The combined organic layers were washed with water (2 X 200 ml), brine (150 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/hexanes to afford 2-5A (3.8 g, 11.80 mmol, 28% yield) as a thick yellow liquid. MS (ESI): m/z 344.9 (M+23)+. The C-step was adapted by replacing 2-4b through 2-4e with 2-4a, respectively, to prepare the following compounds:

[00404] 2-4B (1.3 g, 5.0 mmol) was used to prepare 2-5B (3.8 g, 28% yield).

[00405] 2-4C (2.5 g, 9.027 mmol) was used to prepare 2-5C (1.7 g, 46% yield). MS (ESI): m/z 428.2 (M+18)+.

[00406] 2-4D (3.0 g, 9.32 mmol) was used to prepare 2-5D (1.51 g, 35.7% yield). MS (ESI): m/z 477.2 (M+23)+.

[00407] 2-4E (3.0 g, 8.19 mmol) was used to prepare 2-5E (1.71g, 41.2% yield).

[00408] The C-step was also adapted by replacing 2-2b with 2-2a, along with 2-4a through 2-4e, respectively, to prepare the following compounds:

[00409] 2-4A (1.6 g, 8.4 mmol) was used to prepare 2-5F (910 mg, 32% yield). MS (ESI): m/z 340.2 (M+18)+.

[00410] 2-4B (1.4 g, 5.0 mmol) was used to prepare 2-5G (790 mg, 38% yield).

[00411] 2-4C (1.3 g, 4.67 mmol) was used to prepare 2-5H (750 mg, 38% yield).

[00412] 2-4D (1.5 g, 4.658 mmol) was used to prepare 2-5I (950 mg, 45% yield). MS (ESI): m/z 472.3 (M+18)+.

[00413] 2-4E (1.8 g, 4.92 mmol) was used to prepare 2-5J (1.02 g, 41% yield). MS (ESI): m/z 516.3 (M+18)+. 1-(3-(2-(2-HYDROXYETHOXY)-ETHOXY)-METHYL)-PHENYL)-ETHANONE (2-6A).

[00414] To a stirred solution of 2-5A (3.8 g, 11.8 mmol) in MeOH (40 ml) was added pyridinium p-toluenesulfonate (PPTS; 0.59 g, 2.30 mmol) at 0 °C and stirred at RT for 16 hours. Solvents were distilled off under reduced pressure. The obtained residue was extracted with EtOAc (3 X 150 ml). The combined organic layer was washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 5% acetone: in DCM to afford 2-6A (1.4 g, 5.88 mmol, 50% yield) as a gummy liquid. MS (ESI): m/z 239.0 (M+1)+.

[00415] The above procedure was adapted to prepare the following compounds:

[00416] 2-5B (720 mg, 5.0 mmol) was used to prepare 2-6B (589 mg, 84% yield). MS not collected.

[00417] 2-5C (1.7 g, 4.146 mmol) was used to prepare 2-6C (1.2 g, 89%). MS (ESI): m/z 327.1 (M+1)+.

[00418] 2-5D (1.5 g, 3.3 mmol) was used to prepare 2-6D (850 mg, 70%). MS (ESI): m/z 371.1 (M+1)+.

[00419] 2-5E (1.7 g, 3.4 mmol) was used to prepare 2-6E (1.1 g, 78%). MS (ESI): m/z 415.2 (M+1)+.

[00420] 2-5F (900 mg, 2.8 mmol) was used to prepare 2-6F (650 mg, 97%). MS (ESI): m/z 239.1 (M+1)+.

[00421] 2-5G (790 mg, 2.1 mmol) was used to prepare 2-6G (600 mg, 92%). MS (ESI): m/z 283.1 (M+1)+.

[00422] 2-5H (1.3 g, 4.67 mmol) was used to prepare 2-6H (750 mg, 38%). MS (ESI): m/z 412 (M+1)+.

[00423] 2-5I (950 mg, 2.092 mmol) was used to prepare 2-6I (560 mg, 72%). MS (ESI): m/z 369.3 (M+1)+.

[00424] 2-5J (1.02 g, 2 mmol) was used to prepare 2-6J (800 mg, 94%). MS (ESI): m/z 415.2 (M+1)+. ETHYL 2-(2-(3-ACETYLBENZYLOXY)-ETHOXY)-METHANESULFONATE (2-7A).

[00425] Methanesulfonyl chloride (0.7 ml, 8.80 mmol) was added to a solution of 2-6A (1.4 g, 5.88 mmol) in DCM (50 ml) and triethylamine (2.5 ml , 17.6 mmol) at 0 °C and stirred at RT for one hour. The reaction mixture was diluted with water (50 ml), extracted with DCM (3 X 100 ml). The combined organic layer was washed with brine (100 mL), dried over Na 2 SO 4 , and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 2-7A (1.8 g, 5.69 mmol, 97% yield) as a gummy liquid. MS (ESI): m/z 316.8 (M+1)+.

[00426] The above procedure was adapted to prepare the following compounds:

[00427] 2-6B (700 mg, 2.4 mmol) was used to prepare 2-7B (650 mg, 68%). MS (ESI): m/z 361.1 (M+1)+.

[00428] 2-6C (400 mg, 1.226 mmol) was used to prepare 2-7C (420 mg, 85%). MS not collected.

[00429] 2-6D (850 mg, 2.29 mmol) was used to prepare 2-7D (800 mg, 78%). MS (ESI): m/z 466.2 (M+18)+.

[00430] 2-6E (500 mg, 2.29 mmol) was used to prepare 2-7E (460 mg, 70%). MS not collected.

[00431] 2-6F (650 mg, 2.7 mmol) was used to prepare 2-7F (660 mg, 76%). MS (ESI): m/z 317 (M+1)+.

[00432] 2-6G (600 mg, 2.1 mmol) was used to prepare 2-7G (540 mg, 72%). MS (ESI): m/z 361.0 (M+1)+.

[00433] 2-6H (600 mg, 1.46 mmol) was used to prepare 2-7H (460 mg, 78%). MS not collected.

[00434] 2-6I (560 mg, 1.513 mmol) was used to prepare 2-7I (600 mg, 88%). MS (ESI): m/z 466.3 (M+18)+.

[00435] 2-6J (800 mg, 1.92 mmol) was used to prepare 2-7J (610 mg, 64%). MS (ESI): m/z 493.1 (M+1)+. 6-(N-(2-(2-(3-ACETYL-BENZYLOXY)-ETHOXY)-ETHYL)-METHYLSULFONAMIDO)-5-CYCLOPROPYL-2-(4-FLUOROPHENYL)-N-METHYLBENZOFURAN-3-CARBOXAMIDE (2- 8A).

[00436] To a stirred solution of [1-12] (1.6 g, 4.00 mmol) in DMF (40 ml) was added potassium carbonate (1.6 g, 11.90 mmol) followed by 2- 7A (1.8 g, 5.60 mmol), catalytic amount of tetrabutylammonium iodide at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (75 mL), washed with water (2 X 40 mL), brine (25 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH-DCM to afford 2-8A (1.3 g, 2.09 mmol, 42% yield) as an off-white solid . MS (ESI): m/z 622.9 (M+1)+.

[00437] The above procedure was adapted to prepare the following compounds:

[00438] 6-[(2-{2-[2-(3-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro) methylamide -phenyl)-benzofuran-3-carboxylic acid (2-8B). 2-7B (535 mg, 1.4 mmol) was used to prepare 2-8B (518 mg, 63%). MS (ESI): m/z 667.2 (M+1)+.

[00439] 6-{[2-(2-{2-[2-(3-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-methanesulfonyl-amino}-5-cyclopropyl- 2-(4-Fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8C). 2-7C (380 mg, 0.940 mmol) was used to prepare 2-8C (320 mg, 57%). MS (ESI): m/z 711.1 (M+1)+.

[00440] 6-({2-[2-(2-{2-[2-(3-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino acid methylamide )-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8D). 2-7D (536 mg, 1.19 mmol) was used to prepare 2-8D (550 mg, 73%). MS (ESI): m/z 755.2 (M+1)+.

[00441] 6-[(2-{2-[2-(2-{2-[2-(3-acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}- acid methylamide ethyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8E). 2-7E (411 mg, 0.83 mmol) was used to prepare 2-8E (402 mg, 64%). MS (ESI): m/z 799.2 (M+1)+.

[00442] 6-({2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran- acid methylamide 3-carboxylic acid (2-8F). 2-7F (377 mg, 1.19 mmol) was used to prepare 2-8F (460 mg, 75%). MS (ESI): m/z 623.2 (M+1)+.

[00443] 6-[(2-{2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethyl)-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro) methylamide -phenyl)-benzofuran-3-carboxylic acid (2-9G): 2-7G (429 mg, 1.1 mmol) was used to prepare 2-8G (420 mg, 65%). MS (ESI): m/z 665.6 (M+1)+.

[00444] 6-{[2-(2-{2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethyl]-methanesulfonyl-amino}-5-cyclopropyl- 2-(4-Fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8H): 2-7H (1.18 g, 3.61 mmol) was used to prepare 2-8H (1.4 g, quantitative) . MS (ESI): m/z 711.3 (M+1)+.

[00445] 6-({2-[2-(2-{2-[2-(4-Acetyl-benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino acid methylamide )-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8I). 2-7I (434 mg, 0.970 mmol) was used to prepare 2-8I (300 mg, 53%). MS (ESI): m/z 755.3 (M+1)+.

[00446] 6-[(2-{2-[2-(2-{2-[2-(4-acetyl benzyloxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethyl acid methylamide )-methanesulfonyl-amino]-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid (2-8J). 2-7J (440 mg, 0.89 mmol) was used to prepare 2-8J (350 mg, 58%). MS (ESI): m/z 799.3 (M+1)+.

[00447] 4-{3-2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy acid ethyl ester )-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-9A).

[00448] To a stirred solution of 2-8A (0.35 g, 0.56 mmol) in THF (5 ml) was added potassium hexamethyldisilazane at -78 °C and the reaction mixture was warmed to -55 °C for an hour. Diethyl oxalate was added to the reaction mixture at -78°C and the reaction mixture was heated at -55°C for two hours under a nitrogen atmosphere. The reaction was quenched with ammonium chloride solution, and extracted with EtOAc (3 X 40 mL). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography using neutral silica (100 to 200 silica) in 2% MeOH-DCM to afford (0.7 g, crude compound) 2-9A as a brown gummy solid. MS (ESI): m/z 721.1 (M-1)+.

[00449] The above procedure was adapted to prepare the following compounds:

[00450] 4-(3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) ethyl ester amino}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-9B): 2-8B (100 mg, 0.15 mmol) was used to prepare 2-9B (60 mg, crude). MS (ESI): m/z 767.2 (M+1)+.

[00451] 4-[3-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] ethyl ester) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic (2-9C): 2-8C (160 mg, 0.225 mmol) was used to prepare 29C (110 mg, crude). MS (ESI): m/z 811.2 (M+1)+.

[00452] 4-{3-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6) ethyl ester -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic (2-9D): 2-8D ( 100 mg, 0.13 mmol) was used to prepare 2-9D (50 mg, 44%). MS (ESI): m/z 855.3 (M+1)+.

[00453] 4-(3-{2-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl- benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-9E ): 2-8E (100 mg, 0.12 mmol) was used to prepare 2-9E (75 mg, 66%). MS (ESI): m/z 899.3 (M+1)+.

[00454] 4-{4-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-9F): 2-8F (100 mg, 0.16 mmol) was used to prepare 2-9F (150 mg ). MS (ESI): m/z 723.1 (M+1)+.

[00455] 4-(4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) ethyl ester amino}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-9G): 2-8G (100 mg, 0.15 mmol) was used to prepare 2-9G (115 mg, crude). MS (ESI): m/z 767.0 (M+1)+.

[00456] 4-[4-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] ethyl ester) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic (2-9H): 2-8H (100 mg, 0.14 mmol) was used to prepare 29H (80 mg, crude). MS (ESI): m/z 811.6 (M+1)+.

[00457] 4-{4-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6) ethyl ester -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic (2-9I): 2-8I ( 100 mg, 0.132 mmol) was used to prepare 2-9I (90 mg, crude). MS (ESI): m/z 855.3 (M+1)+.

[00458] 4-(4-{2-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-) ethyl ester benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic (2-9J ): 2-8J (150 mg, 0.19 mmol) was used to prepare 2-9J (120 mg, 71%). MS (ESI): m/z 899.4 (M+1)+.

[00459] 4-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-10A).

[00460] To a stirred solution of crude mixture of 2-8A (0.7 g, 0.97 mmol) in THF and water (8 ml; 4:1) was added LiOH (0.14 g, 5.82 mmol ) at 0°C and the reaction was continued at RT for two hours. After completion of the reaction (TLC), solvents were evaporated using a rotary evaporator (Hiedolph rotavapour), residue extracted with pet ether. (50ml). Then, the aqueous layer was neutralized with 1N HCl (10 ml) followed by extraction with EtOAc (3 X 100 ml). The combined organic layers were washed with brine (2 X 50 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC to afford 2-10A (50 mg) as an off-white solid. MS (ESI): m/z 693.7 (M-1)+.

[00461] The above procedure was adapted to prepare the following compounds:

[00462] 4-(3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-10B): 2-9B (60 mg, crude) was used to prepare 2-10B (5, 0 mg). MS (ESI): m/z 739.3 (M+1)+.

[00463] 4-[3-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) acid amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (2-10C): 2-9C (120 mg, 0.148 mmol) was used to prepare 2-10C (4 mg, 4%). MS (ESI): m/z 781.6 (M-1)+.

[00464] 4-{3-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] acid) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-10D): 2-9D (50 mg, 0.06 mmol) was used to prepare 2-10D (5 mg, 10%). MS (ESI): m/z 827.2 (M+1)+.

[00465] 4-(3-{2-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6 acid) -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic (2-10E): 2 -9E (40 mg, 0.05 mmol) was used to prepare 2-10E (5 mg, 11%). MS (ESI): m/z 870.6 (M+1)+.

[00466] 4-{4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (2-10F): 2-9F (90 mg, crude) was used to prepare 2-10F (8.6 mg). MS (ESI): m/z 692.9 (M1)-.

[00467] 4-(4-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (2-10G): 2-9G (50 mg, crude) was used to prepare 2-10G (3, 6 mg). MS (ESI): m/z 739.3 (M+1)+.

[00468] 4-[4-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-) acid amino}-ethoxy)-ethoxy]-ethoxy}-ethoxymethyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (2 10H): 2-9H (60 mg, 0.074 mmol) was used to prepare 2-10H (11.5 mg, 19%). MS (ESI): m/z 783.3 (M+1)+.

[00469] 4-{4-[2-(2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl] acid) -methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic (2-10I): 2-9I (60 mg, 0.0705 mmol) was used to prepare 2-10I (6 mg, 10%). MS not collected.

[00470] 4-(4-{2-[2-(2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6 acid) -yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxymethyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic (2-10J): 2 -9J (70 mg, 0.08 mmol) was used to prepare 2-10J (10 mg, 14%). MS (ESI): m/z 871.8 (M+1)+.

EXAMPLE 3

[00471] 1-(3-((2-hydroxyethoxy)-methyl)-phenyl)-ethanone (3-2A).

[00472] To a stirred solution of 2-2A (5 g, 23.5 mmol) in THF (50 mL) was added ethane-1,2-diol (1.31 g, 21.22 mmol) and Ag2O (8 .15 g, 35.3 mmol) at RT, then refluxed for 12 hours. The reaction mixture was filtered and the filtrate was concentrated, then diluted with EtOAc (300 mL). The combined organic layers were washed with water (2 X 200 ml), brine (150 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc/hexanes to afford 3-2A (2.01 g, 10.3 mmol, 44.6% yield) as - mo a thick colorless liquid. MS (ESI): m/z 195.06 (M+1)+.

[00473] By adapting the above procedure (step-A), propane-1,2-diol (1 g, 4.73 mmol) was replaced by ethane-1,2-diol to prepare 3-2B (670 mg, 68 %). MS (ESI): m/z 209.0 (M+1)+.

[00474] 2-((3-Acetylbenzyl)-oxy)-ethyl-4-methylbenzenesulfonate (3-3A).

[00475] Sulfonyl-p-toluene chloride (740 mg, 3.91 mmol) was added to a solution of 3-2A (630 mg, 3.01 mmol) in DCM (15 ml) and triethylamine (1.45 ml , 9.6 mmol) at 0°C and DMAP (cat. amount), stirred at RT for one hour. The reaction mixture was diluted with water (100 ml) and extracted with DCM (3 X 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 3-3A (710 mg, 2.06 mmol, 64.2% yield) as brown gummy liquid. MS (ESI): m/z 348.9 (M+1)+.

[00476] 1-(3-((2-(3-hydroxypropoxy)-ethoxy)-methyl)-phenyl)-ethanone (3-4A):.

[00477] To a stirred solution of 1,3-propanediol (0.73 ml, 10.1 mmol) in THF (10 ml) was added NaH (37 mg, 2.2 mmol) at 0 °C and the reaction was continued at RT for 30 minutes, 3-3A (710 mg, 2.01 mmol) in THF (5 ml) was added to the reaction mixture at 0°C over 5 minutes and the reaction was refluxed for 4 hours. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3 X 100 mL), the combined organic layers were washed with water (2 X 100 mL), brine (150 mL), dried over Na 2 SO 4 and concentrated . The residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc/hexanes to afford 3-4A (260 mg, 1.08 mmol, 50% yield) as a thick colorless liquid. MS (ESI): m/z 253.1 (M+1)+. 3-(2-((3-Acetylbenzyl)-oxy)-ethoxy)-propyl methanesulfonate (3-5A).

[00478] Methanesulfonyl chloride (0.11 ml, 1.4 mmol) was added to a solution of 3-4A (300 mg, 1.10 mmol) in DCM (10 ml) and triethylamine (0.51 ml, 3 .5 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water (50 ml) and extracted with DCM (3 X 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 25% EtOAc in hexanes to afford 3-5A (355 mg, 0.81 mmol, 90% yield) as a brown liquid. MS (ESI): m/z 331.1 (M+1)+. 6-(N-(3-(2-((3-acetylbenzyl)-oxy)-ethoxy)-propyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide ( 3-6A).

[00479] To a stirred solution of 1-12 (350 mg, 0.80 mmol) in DMF (10 ml) was added potassium carbonate (360 mg, 2.60 mmol) followed by 3-5A (345 mg, 1 .01 mmol), catalytic amount of TBAI at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (100 mL), then washed with water (2 X 50 mL), brine (50 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 45% EtOAc/pet ether. to afford 3-6A (380 mg, 0.59 mmol, 69% yield) as an off-white solid. MS (ESI): m/z 636.9 (M+1)+. 4-{3-[2-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-propoxy)- acid ethyl ester ethoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (3-7A).

[00480] To a stirred solution of 3-6A (100 mg, 0.12 mmol) in THF (5 ml) was added potassium bis(trimethylsilyl)amide (KHMDS; 0.39 ml, 0.31 mmol) to - 78°C and the reaction mixture was warmed to -55°C for one hour. Then, diethyl oxalate (0.03 ml, 0.21 mmol) was added to the reaction mixture at -78°C and the reaction mixture was warmed to -55°C for two hours under a nitrogen atmosphere. The reaction mixture was quenched with ammonium chloride solution, extracted into EtOAc (3 X 40 ml). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography using neutral silica (100 to 200 silica) 5% acetone DCM to afford (90 mg, crude) 3-7A as a brown gummy liquid. MS (ESI): m/z 737.2 (M+1)+. 4-{3-[2-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-propoxy)-ethoxymethyl]- acid phenyl}-2-hydroxy-4-oxo-but-2-enoic (3-8A).

[00481] To a stirred solution of 3-7A (90 mg, 0.10 mmol) in THF and water (5 mL, (1:1)) was added LiOH (20 mg, 0.70 mmol) at 0 °C and the reaction was continued at RT for 5 h. Upon completion of the reaction (by TLC), solvents were evaporated with a rotary evaporator and the residue extracted with ether (50 ml). The aqueous layer was neutralized with 1N HCl (5 ml) followed by extraction with EtOAc (3 X 50 ml). The combined organic layers were washed with brine (2 X 50 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC to afford 3-8A (3.5 mg, 3% yield) as a pale brown solid. MS (ESI): m/z 709.2 (M+1)+.

[00482] 4-{3-[3-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid propoxymethyl]-phenyl}-2-hydroxy-4-oxo-but-2-enoic acid (3-8B): The procedure given above was adapted by substituting 3-2B for 3-2A in step-B, followed by appropriate modification of subsequent steps C to F to prepare 3-8B. MS (ESI): m/z 709.6 (M+1)+. 6-({2-[3-(3-Acetyl-benzyloxy)-propoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-acid methylamide -carboxylic acid (3-6B) was prepared during step-E of this procedure. EXAMPLE 4 2,2,3,3-tetramethyl-4,7,10,13-tetraoxa-3-silapentadecan-15-ol (4-2).

[00483] To a stirred solution of 2,2'-(2,2'-oxybis(ethane-2,1-diyl)bis(oxy))diethanol 4-1 (5 g, 25.7 mmol) in DCM ( 100 ml) was added imidazole (2.1 g, 30.9 mmol) and tert-butyldimethylsilyl chloride (TBDMSCl; 3.48 g, 23.1 mmol) at 0°C and stirred at RT for 6 hours. The reaction mixture was diluted with DCM (100 ml) and washed with water (2 X 100 ml) and brine (50 ml). The organic layer was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc/pet ether. to give 4-2 (1.8 g, 5.8 mmol, 22% yield) as an off-white solid. 2,2,3,3-Tetramethyl-4,7,10,13-tetraoxa-3-silapentadecan-15-yl methanesulfonate (4-3).

[00484] To a stirred solution of 4-2 (0.2 g, 0.65 mmol) in DCM (10 ml) was added methanesulfonyl chloride (0.1 ml, 0.78 mmol) and triethylamine (0.13 ml, 0.9741 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water (20 ml), extracted with DCM (3 X 20 ml), the combined organic layers were washed with brine (2 X 10 ml), dried with Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/pet ether. to afford 4-3 (0.1 g, 0.26 mmol, 40% yield) as a yellow liquid. 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2,2,3,3-tetramethyl-4,7,10,13-tetraoxa-3-silapentadecan-15-yl) - methylsulfonamido)benzofuran-3-carboxamide (4-4).

[00485] To a stirred solution of 1-12 (0.05 g, 0.12 mmol) in DMF (10 mL) was added K2CO3 (0.052 g, 0.37 mmol) followed by 43 (0.072 g, 0.18 mmol), catalytic amount of TBAI at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (15 ml) washed with water (2 X 10 ml), brine (15 ml) and dried with Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH-DCM to afford 4-4 (0.02 g, 0.03 mmol, 23% yield) as a solid. whitish. MS (ESI): m/z 710.2 (M+18)+. 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-(2-(2-hydroxyethoxy)-ethoxy)-ethoxy)-ethyl)methylsulfonamido)-N-methylbenzofuran-3-carboxamide (4-5).

[00486] To a stirred solution of 4-4 (0.1 g, 0.14 mmol) in THF (5 ml) was added tetrabutylammonium fluoride (0.2 ml, 0.16 mmol) at 0 °C and stirred at RT for 4 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride solution. The cooled solution was extracted with EtOAc (3 X 10 ml). The combined organic layer was washed with brine (20 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 5% MeOH-DCM to afford 4-5 (0.05 g, 0.08 mmol, 60% yield) as an off-white solid. MS (ESI): m/z 601.1 (M+23)+. 15-azido-2,2,3,3-tetramethyl-4,7,10,13-tetraoxa-3-silapentadecane (4-6).

[00487] To a stirred solution of 4-3 (1.5 g, 3.88 mmol) in DMF (30 ml) was added sodium azide (303 mg, 4.6 mmol) at RT and stirred at 60 °C for 20 hours. After consumption of the starting material (by TLC), the reaction was diluted with water (90 ml) and extracted with EtOAc (3 X 40 ml). The combined organic layer was washed with brine (80 mL), dried over Na 2 SO 4 , and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexanes to provide 4-6 (750 mg, 2.25 mmol, 58% yield) as a yellow liquid. 2-(2-(2-(2-azidoethoxy)-ethoxy)-ethoxy)-ethanol (4-7).

[00488] To a stirred solution of 4-6 (750 mg, 2.25 mmol) in THF (20 ml) was added tetra-n-butylammonium fluoride (TBAF; 2.7 ml, 2.7 mmol) at 0 °C, and heated the reaction mixture to RT and stirring was continued for two hours. The reaction mixture was diluted with water and extracted with EtOAc (2 X 30 ml) washed with water (30 ml), brine (30 ml) and dried with Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 40% EtOAc in pet ether. to afford 4-7 (400 mg, 1.82 mmol, 81% yield) as a yellow liquid. 2-(2-(2-(2-Azidoethoxy)-ethoxy)-ethoxy)-ethyl methanesulfonate (4-8).

[00489] To a stirred solution of 4-7 (400 mg, 1.82 mmol) in DCM (10 ml) was added methanesulfonyl chloride (0.17 ml, 2.19 mmol) and triethylamine (0.6 ml, 4.38 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water (10 ml), extracted with DCM (3 X 15 ml). The combined organic layers were washed with brine (2 X 10 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc/pet ether. to afford 4-8 (390 g, 1.31 mmol, 72% yield) as a yellow liquid. 6-(N-(2-(2-(2-(2-azidoethoxy)-ethoxy)-ethoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (49).

[00490] To a stirred solution of 1-12 (439 mg, 1.09 mmol) in DMF (10 ml) was added potassium carbonate (451 g, 3.27 mmol) followed by 4-8 (390 mg, 1 .31 mmol) and catalytic amount of tetrabutylammonium iodide at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (30 ml), washed with water (2 X 15 ml), brine (25 ml), dried with Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexane to provide 4-9 (320 g, 0.53 mmol, 48% yield) as an off-white solid. MS (ESI): m/z 648.3 (M+45)+. 6-(N-(2-(2-(2-(2-aminoethoxy)-ethoxy)-ethoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3- carboxamide (410).

[00491] To a stirred solution of 4-9 (320 g, 0.530 mmol) in THF:H2O (1:1, 10 ml) was added trimethyl phosphine at 0 °C and the reaction mixture was heated to 50 °C and stirred for 16 hours. Upon completion of the reaction (by TLC), the mixture was diluted with water, extracted with EtOAc (3 X 10 ml). The combined organic layers were washed with brine (2 X 10 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography using neutral silica (100 to 200 silica) with 5% MeOH-DCM to afford 4-10 (0.15 g, 0.26 mmol, 49% yield) as a brown gummy solid. MS (ESI): m/z 578 (M+1)+. EXAMPLE 5 2-(2,5,8,11-tetraoxatridecan-13-yloxy)tetrahydro-2H-pyran (5-1A).

[00492] To a stirred suspension of NaH in THF was added a solution of 2-4C (500 mg, 1.8 mmol) in THF (5 ml) at 0 °C and the mixture was stirred at RT for 30 minutes. The mixture was cooled to 0°C, MeI was added and the mixture was allowed to stir at RT for two hours under a nitrogen atmosphere. The reaction mixture was quenched with cold water, extracted with EtOAc (3 X 80 ml). The organic layer washed with water (50 ml), brine (50 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 5-1A (280 mg, 0.95 mmol, 52% yield) as a yellow liquid.

[00493] By replacing butyl iodide with methyl iodide in step-A, 2-4B (1 g, 4.27 mmol) was used to prepare 5-1B (718 mg, 58% yield). 2,5,8,11-tetraoxatridecan-13-ol (5-2A).

[00494] To a solution of 2-(2,5,8,11-tetraoxatridecan-13-yloxy)tetrahydro-2H-pyran 5-1A (280 mg, 0.96 mmol) in MeOH (5 ml) was PPTS (24 mg, 0.096 mmol) is added and stirred at 0°C to RT for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain crude compound. The crude compound obtained was purified using silica gel column chromatography with 5% MeOH in DCM to afford 5-2A (180 mg, 0.87 mmol, 90% yield) as a pale yellow liquid. .

[00495] Adapting the above procedure, 5-1B (710 mg, 2.44 mmol) was used to prepare 5-2B (406 mg, 78%). 2,5,8,11-Tetraoxatridecan-13-yl methanesulfonate (5-3A).

[00496] To a stirred solution of 5-2A (180 mg, 0.87 mmol) in DCM (5 ml) was added triethylamine (0.18 ml, 1.3 mmol) and methanesulfonyl chloride (0.1 ml, 1.13 mmol) at 0°C and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (40 ml) and washed with water (2 X 10 ml), brine (10 ml) and dried with Na 2 SO 4 , the organic phase was concentrated under reduced pressure to obtain the crude compound. This was purified using silica gel 100 to 200 column chromatography using 2% MeOH in DCM to afford 5-3A (200 mg, 0.699 mmol, 80% yield) as a yellow liquid.

[00497] Adapting the above procedure, 5-2B (406 mg, 1.91 mmol) was used to prepare 5-3B (440 mg, 78%). 6-(N-(2,5,8,11-tetraoxatridecan-13-yl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (5-4A).

[00498] To a solution of 1-12 (110 mg, 0.29 mmol) in DMF (3 ml) was added potassium carbonate (120 mg, 0.9 mmol) followed by 5-3A (102 mg, 0. 35 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (30 ml), washed with water (20 ml), brine (15 ml) and dried with Na 2 SO 4 , the organic phase was concentrated under reduced pressure to obtain the crude compound. The crude compound obtained was purified using silica gel 230 to 400 column chromatography using 15% acetone in DCM to afford 5-4A (67 mg, 0.11 mmol, 45% yield) as a solid white. MS (ESI): m/z 592.8 (M+1)+.

[00499] 6-({2-[2-(2-Butoxy-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran- acid methylamide 3-carboxylic acid (5-4B): Adapting the above procedure, 5-3B (150 mg, 0.52 mmol) was used to prepare 5-4B (13 mg, 4.2%). MS = 590.85 [M+1]+. EXAMPLE 6 Methyl 2-(bromomethyl)-benzoate (6-2A).

[00500] To a stirred solution of methyl 2-methylbenzoate 6-1A (5 g, 33.3 mmol) in ACN (200 ml) was added NBS (5.3 g, 30 mmol) and AIBN (547 mg, 3 .33 mmol) at RT. The reaction mixture was heated at 90°C for 6 hours under a nitrogen atmosphere. The reaction mixture solvent was evaporated under reduced pressure and the crude residue washed with toluene (500 ml) and the precipitate filtered (NBS). The filtrate evaporated under reduced pressure and the crude residue was purified by flash column chromatography (100 to 200 silica) using 2% EtOAc/pet ether. to afford 6-2A (5 g, 22.1 mmol, 65.7% yield) as a thick yellow liquid.

[00501] Adapting the above procedure, methyl 4-methylbenzoate 6-1B (5 g, 33.3 mmol) was used to prepare 6-2B (4.5 g, 60%). MS (ESI): m/z 231.0 (M+1)+. Methyl-2-((2-2(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-methyl)benzoate (6-3A).

[00502] To a solution of NaH (116 mg, 2.6 mmol) in THF (20 ml) was added 2-4A (552 mg, 2.9 mmol) at 0 °C and stirred at RT for one hour. The reaction mixture was again cooled to 0 °C, 6-2A (600 mg, 2.6 mmol) was added and stirred at RT for 16 h. The reaction mixture was quenched with cold water and diluted with EtOAc (50 ml), washed with water (50 ml), brine (25 ml) and dried over Na 2 SO 4 , the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (15% EtOAc in hexane) to provide 6-3A (350 mg, 1.03 mmol, 40.4% yield). MS (ESI): m/z 339 (M+1)+.

[00503] The above procedure was adapted to prepare the following compounds:

[00504] 6-2B (7.28 g, 31.8 mmol) was used to prepare 6-3B (4 g, 41%). MS (ESI): m/z 255.0 (M-THP+1)+.

[00505] Methyl 3-methylbenzoate 6-2C (1.2 g, 5.113 mmol; TCI) was used to prepare 6-3C (0.3 g, 25%). MS (ESI): m/z 369.0 (M+1)+.

[00506] The above procedure was adapted, replacing 2-4A with 2-4B, to prepare the following compounds:

[00507] 6-2A (1 g, 4.04 mmol) was used to prepare 6-3D (450 mg, 21%). MS (ESI): m/z 383.0 (M+1)+.

[00508] 6-2B (820 mg, 3.5 mmol) was used to prepare 6-3E (450 mg, 41%). MS (ESI): m/z 299 [M-THP+1]+.

[00509] 6-2C (0.753 g, 3.29 mmol) was used to prepare 6-3F (550 mg, 50%). MS (ESI): m/z 299 [M-THP+1]+. Methyl 2-((2-(2-hydroxyethoxy)-ethoxy)-methyl)benzoate (6-4A).

[00510] To a solution of 6-3A (310 mg, 0.916 mmol) in MeOH (5 ml) was added PPTS (46 mg, 0.18 mmol) and stirred at 0 °C to RT for 16 h. The reaction mixture was distilled and diluted with excess EtOAc (100 ml), washed with water (100 ml), brine (50 ml) and dried over Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using combiflash column chromatography (30% EtOAc in hexane) to afford 6-4A (150 mg, 0.59 mmol, 65% yield). MS (ESI): m/z 315 (M+1)+.

[00511] By adapting the above procedure, the following compounds were made:

[00512] 6-3B (4 g, 12.12 mmol) was used to prepare 6-4B (2.7 g, 90%). MS (ESI): m/z 240 (M-CH3+1)+.

[00513] 6-3C (0.3 g, 0.88 mmol) was used to prepare 6-4C (300 mg, 100%). MS (ESI): m/z 255 (M+1)+.

[00514] 6-3D (260 mg, 0.65 mmol) was used to prepare 6-4D (140 mg, 70%). MS (ESI): m/z 299.0 (M+1)+.

[00515] 6-3E (450 mg, 1.178 mmol) was used to prepare 6-4E (210 mg, 60%). MS (ESI): m/z 299.3 (M+1)+.

[00516] 6-3F (550 mg, 1.43 mmol) was used to prepare 6-4F (280 mg, 65%). MS (ESI): m/z 299.3 (M+1)+. 2-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxymethyl]-benzoic acid methyl ester (6-5A).

[00517] Methanesulfonyl chloride (0.05 ml, 0.7 mmol) at 0°C was added to a solution of 6-4A (150 mg, 0.5 mmol) in DCM (5 ml) and triethylamine (0. 13 ml, 0.7 mmol) and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml), brine (20 ml) and dried over Na 2 SO 4 , the organic phase was concentrated under reduced pressure to obtain 6-5A (170 mg, 0.51 mmol, 87% yield) as a yellow colored liquid.

[00518] The above procedure was adapted to prepare the following compounds:

[00519] 6-4B (2.7 g, 8.49 mmol) was used to prepare 6-5B (2.7 g, 77%). MS (ESI): m/z 333.5 (M+1)+.

[00520] 6-4C (0.3 g, 1.181 mmol) was used to prepare 6-5C (280 mg, 46%). MS (ESI): m/z 350.1 (M+18)+.

[00521] 6-4D (300 mg, 1 mmol) was used to prepare 6-5D (370 mg, 97%). MS (ESI): m/z 377.0 (M+1)+.

[00522] 6-4E (200 mg, 0.671 mmol) was used to prepare 6-5E (220 mg, 87%). MS (ESI): m/z 377.3 (M+1)+.

[00523] 6-4F (280 mg, 0.939 mmol) was used to prepare 6-5F (340 mg, 95%). MS (ESI): m/z 377.3 (M+1)+. 2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid methyl ester benzoyl (6-6A).

[00524] To a solution of 1-12 (141 mg, 0.350 mmol) in DMF (5 ml) was added potassium carbonate (144 mg, 1.04 mmol) followed by 6-5A (140 mg, 0.4 mmol ), and the catalytic amount of TBAI then stirred at 70°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (25 ml) and dried with Na 2 SO 4 , the organic phase was concentrated under reduced pressure. The crude compound was purified using combiflash column chromatography (20% EtOAc in hexane) to provide 6-6A (120 mg, 0.188 mmol, 46.9% yield). MS (ESI): m/z 639.4 (M+1)+.

[00525] The above procedure was adapted to prepare the following compounds:

[00526] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-benzoyl (6-6B): 6-5B (2.7 g, 8.13 mmol) was used to prepare 6-6B (2.5 g, 48%). MS (ESI): m/z 638.8 (M+1)+.

[00527] 3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-benzoyl (6-6C): 6-5C (0.15g, 0.45 mmol) was used to prepare 6-6C (0.08 g, 39.4%). MS (ESI): m/z 639.0 (M+1)+.

[00528] 2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethoxymethyl}-benzoic acid (6-6D): 6-5D (170 mg, 0.45 mmol) was used to prepare 6-6D (115 mg, 51.8%). MS (ESI): m/z 683.6 (M+1)+.

[00529] 4-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethoxymethyl}-benzoic acid (6-6E): 6-5E (210 mg, 0.55 mmol) was used to prepare 6-6E (180 mg, 53%). MS (ESI): m/z 683.5 (M+1)+.

[00530] 3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethoxymethyl}-benzoic acid (6-6F): 6-5F ((340 mg, 0.90 mmol) was used to prepare 6-6F (240 mg, 47%). MS (ESI): m /z 682.7 (M+1)+. 2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]-benzoic acid (6 -7A).

[00531] To a solution of 6-6A (50 mg, 0.07 mmol) in THF, MeOH and water (4:1:1) was added LiOH (11 mg, 0.47 mmol) and stirred at RT for 16 H. Upon completion of the reaction as indicated by TLC, the reaction mixture was neutralized with 1N HCl and then extracted with EtOAc (2 X 50 mL). The combined organic layer was washed with brine (25 mL), dried over Na 2 SO 4 , and concentrated. The crude compound was purified by pentane washes to obtain 6-7A (25.5 mg, 0.04 mmol, 51.8% yield) as an off-white solid. MS (ESI): m/z 623.3 (M+1)+.

[00532] The above procedure was adapted to prepare the following compounds:

[00533] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid benzoyl (6-7B): 6-6B (2.4 g, 3.761 mmol) was used to prepare 6-7B (1.2 g, 52%). MS (ESI): m/z 625.5 (M+ 1)+.

[00534] 3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid benzoyl (6-7C): 6-6C (0.05 g, 0.073 mmol) was used to prepare 6-7C (0.03 g, 66%). MS (ESI): m/z 625.0.(M+1)+.

[00535] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxymethyl}-benzoic acid (6-7D): 6-6D (80 mg, 0.11 mmol) was used to prepare 6-7D (35 mg, 44%). MS (ESI): m/z 669.3 (M+1)+.

[00536] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxymethyl}-benzoic acid (6-7E): 6-6E (100 mg, 0.14 mmol) was used to prepare 6-7E (45 mg, 46%). MS (ESI): m/z 667.0 (M-1)+.

[00537] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxymethyl}-benzoyl (6-7F):6-6F (100 mg, 0.14 mmol) was used to prepare 6-7F (50 mg, 51%). MS (ESI): m/z 691.5 (M+23)+. 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid ethyl ester benzoyl (6-8B1).

[00538] To a solution of 6-7B (50 mg, 0.08 mmol) in DMF (5 ml), was added potassium carbonate (13 mg, 0.09 mmol) followed by ethyl bromide (1-bromo ethane ; 0.9 ml, 0.08 mmol), catalytic amount of TBAI, then stirred at RT for 16 h. The reaction was diluted with EtOAc (50 ml) washed with water (50 ml), brine (10 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using pentane washes to afford 6-8B1 (10.21 mg, 0.15 mmol, 20% yield). MS (ESI): m/z 653.2 (M+1)+.

[00539] The above procedure was adapted to prepare the following compounds:

[00540] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- propyl ester Ethoxymethyl]-benzoyl (6-8B2):1-bromopropane (13 mg, 0.09 mmol) was used to prepare 6-8B2 (32 mg, 66%). MS (ESI): m/z 695.6 (M+1)+.

[00541] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- butyl ester ethoxymethyl]-benzoyl (6-8B3): 1-bromobutane (6 mg, 0.04 mmol) was used to prepare 6-8B3 (15 mg, 55%). MS (ESI): m/z 681.6 (M+1)+.

[00542] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- pentyl ester ethoxymethyl]-benzoyl (6-8B4): 1-bromopentane (18.1 g, 0.12 mmol) was used to prepare 6-8B4 (22 mg, 40%). MS (ESI): m/z 716.7 (M+23)+.

[00543] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid carbamoyl methyl ester ethoxymethyl]-benzoyl (6-8B5): 2-chloroacetamide (50 mg, 0.08 mmol) was used to prepare 6-8B5 (3.7 mg, 6.2%). MS (ESI): m/z 682.0 (M+1)+.

[00544] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- methylsulfanylmethyl ester ethoxymethyl]-benzoyl (6-8B6): Chloromethylsulfanylmethane (50 mg, 0.08 mmol) was used to prepare 6-8B6 (40 mg, 72%). MS (ESI): m/z 685.0 (M+1)+.

[00545] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- benzyl ester ethoxymethyl]-benzoyl (6-8B7): Bromobenzene (50 mg, 0.08 mmol) was used to prepare 6-8B7 (30 mg, 52%). MS (ESI): m/z 715.0 (M+1)+.

[00546] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxycarbonylmethyl ester ethoxymethyl]-benzoyl (6-8B8): Ethyl 2-bromoacetate (11.7 mg, 0.071 mmol) was used to prepare 6-8B8 (32 mg, 71%). MS (ESI): m/z 711.6 (M+1)+. EXAMPLE 7 2-(tert-Butoxycarbonylamino)ethyl methanesulfonate (7-2).

[00547] Methanesulfonyl chloride (2.4 ml, 31.25 mmol) was added to a solution of tert-butyl 2-hydroxyethylcarbamate 7-1 (5 g, 31.25 mmol) in DCM (40 ml) and triethylamine ( 6.5 ml, 46.87 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water (100 ml) and extracted with DCM (3 X 150 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 10% EtO-Ac in hexanes to afford 7-2 (3.5 g, 14.64 mmol, 47% yield ) as a gummy liquid. tert-Butyl 2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-ethylcarbamate (7-3).

[00548] To a stirred solution of 1-12 (0.06 g, 0.15 mmol) in DMF (5 ml) was added potassium carbonate (0.062 g, 0.44 mmol) followed by 7-2 (0.053 g , 0.22 mmol) and a catalytic amount of TBAI at 80 °C for 10 h. The reaction mixture was cooled to RT and diluted with EtOAc (25 ml), washed with water (2 X 15 ml), brine (15 ml), dried with Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 7-3 (0.02 g, 2.09 mmol, 24% yield) as a solid whitish. 6-(N-(2-aminoethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methyl benzofuran-3-carboxamide (7-4).

[00549] To a stirred solution of 7-3 (0.1 g, 0.18 mmol) in DCM (5 ml) was added TFA (0.06 ml) at 0 °C and stirred at RT for two hours. Solvents were evaporated under reduced pressure and the crude residue was purified by pentane washes to afford 74 (0.04 g, 0.09 mmol, 50% yield) as a gummy liquid. tert-Butyl 2-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-ethylamino)-2-oxoethylcarbamate (7-5) .

[00550] To a stirred solution of 7-4 (15 mg, 0.03 mmol) in DCM (5 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 0.08 g, 0.042 mmol ), hydroxybenzotriazole (HOBT; 0.06 g, 0.04 mmol), and triethylamine (0.01 mL, 0.01 mmol), followed by the addition of 2-(tert-butoxycarbonylamino)acetic acid (0.05 g, 0.04 mmol) at 0 °C and continuous stirring at RT for 10 h. The reaction mixture was diluted with cold water (20 ml) and extracted with EtOAc (3 X 10 ml). The combined organic layers were washed with water (2 X 25 ml), brine (30 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by preparative TLC to afford 7-5 (0.01 g, 0.01 mmol, 50% yield) as a thick yellow liquid. MS (ESI): m/z 503.3 (M-Boc)+. 6-(N-(2-(2-aminoacetamido)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (7-6).

[00551] To a stirred solution of 7-5 (0.05 g, 0.07 mmol) in DCM (5 ml) was added TFA (0.3 ml) at 0 °C. The reaction mixture was stirred at RT for one hour. Solvents were evaporated under reduced pressure and the crude residue was purified by pentane washes to afford 7-6 (0.01 g, 0.02 mmol, 25% yield) as gummy liquid. MS (ESI): m/z: 503.2 (M+1)+.

[00552] 4-{[(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethylcarbamoyl)-methyl]-carbamoyl acid }-butyric (7-7).

[00553] To a stirred solution of 7-6 (0.02 g, 0.04 mmol) in DMF (5 ml) was added triethylamine (0.02 g, 0.19 mmol) followed by dihydro-pyran- 2,6-dione (0.01 g, 0.09 mmol), and catalytic amount of TBAI at RT for 16 h. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 X 20 mL) washed with water (2 X 50 mL), brine (50 mL), dried with Na 2 SO 4 and concentrated. The residue was purified by preparative TLC to afford 7-7 (5 mg, 0.008 mmol, 21% yield) as an off-white solid. MS (ESI): m/z 617.2 (M+1)+.

[00554] 4-(3-{[(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethylcarbamoyl) ethyl ester )-methyl]-carbamoyl}-phenyl)-butyric acid (7-9).

[00555] To a stirred solution of 7-6 (50 mg, 0.09 mmol) in DCM (5 ml) was added HATU (75 mg, 0.19 mmol), DIPEA (0.05 ml, 0.29 mmol ) and 7-8 at 0°C and the reaction was continued for 12 h at RT. The reaction mixture was diluted with water (50 ml), extracted with EtOAc (3 X 50 ml). The combined organic layers were washed with brine (50 ml), dried over Na 2 SO 4 and concentrated to afford 7-9 (60 mg, crude) as a thick brown mass. MS (ESI): m/z 721.3 (M+1)+.

[00556] 4-(3-{[(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethylcarbamoyl)-methyl acid ]-carbamoyl}-phenyl)-butyric (7-10).

[00557] To a stirred solution of 7-9 (40 mg, 0.05 mmol) in THF and water (3 ml; 1:1) was added LiOH (5 mg, 0.16 mmol) at 0 °C and reaction was continued at RT for 5 hours. Upon completion of the reaction, the solvents were evaporated under reduced pressure. The residue was extracted with ether (20ml). The aqueous layer was neutralized with 1N HCl (5 ml) followed by extraction with EtOAc (3 X 20 ml). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by preparative HPLC to afford 7-10 (3.5 mg, 7.3%) as a light thick mass. EXAMPLE 8 2-Bromoethyl 2-aminoacetate (8-2).

[00558] To a stirred solution of 2-aminoacetic acid 8-1 (1 g, 13.33 mmol) in DCM (25 ml) was added thionyl chloride (1.47 ml, 19.99 mmol) and 2-bromoethanol (1.65 g, 13.33 mmol) at 0°C and stirred at RT for 10 hours. The reaction mixture was diluted with water (50 ml) and extracted with DCM (3 X 75 ml). The combined organic layers were concentrated and dried under reduced pressure. The crude residue was purified by pentane/ether washes to afford 8-2 (0.5 g, 2.77 mmol, 20% yield) as an off-white solid. 2-Bromoethyl 2-(tert-butoxycarbonylamino)acetate (8-3).

[00559] To a stirred solution of 8-2 (0.5 g, 2.77 mmol) in dioxane (5 ml) and water (5 ml) was added Boc anhydride (0.69 ml, 3.02 mmol) and sodium bicarbonate (0.23 g, 2.77 mmol) at 0 °C and stirring was continued at RT for 16 h. The reaction mixture was quenched with water (20 ml) and extracted with EtOAc (3 X 25 ml). The combined organic layers were washed with water (2 X 20 ml), brine (30 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washings with pentane and ether to afford 8-3 (0.3 g, 1.06 mmol, 52% yield) as a thick yellow liquid. 2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamido)-ethyl 2-(tert-butoxycarbonylamino)acetate (8-3).

[00560] To a stirred solution of 1-12 (0.25 g, 0.62 mmol) in DMF (10 ml) was added potassium carbonate (0.25 g, 1.86 mmol) followed by 8-3 ( 0.23 g, 0.82 mmol) and catalytic amount of TBAI at 80 °C for 10 h. The reaction mixture was cooled to RT and diluted with EtOAc (40 mL) washed with water (2 X 25 mL), brine (30 mL) and dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 8-4 (0.26 g, 0.43 mmol, 50% yield) as a solid brown. 2-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamido)-ethyl 2-aminoacetate (8-5).

[00561] To a stirred solution of 8-4 (0.05 g, 0.08 mmol) in DCM (5 ml) was added trifluoroacetic acid (1 ml) at 0 °C and stirred at RT for one hour. Solvents were evaporated under reduced pressure and the crude residue was purified by washings with pentane and ether to afford 8-5 (0.02 g, 0.05 mmol, 47% yield) as a gummy liquid. MS (ESI): m/z 503.8 (M+1)+. 4-[(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxycarbonylmethyl)-carbamoyl]-butyric acid (8-6 ).

[00562] To a stirred solution of 8-5 (0.025 g, 0.05 mmol) in DMF (5 ml) was added triethylamine (0.03 ml, 0.25 mmol) followed by dihydro-pyran-2,6- dione (0.014 g, 0.12 mmol) and catalytic amount of TBAI at RT for 10 hours. The reaction mixture was diluted with water (15 mL) and extracted with EtOAc (3 X 20 mL), washed with water (2 X 50 mL), brine (50 mL), dried over Na 2 SO 4 and concentrated. The crude residue was purified by preparative TLC to afford 8-6 (5 mg, 0.008 mmol, 16% yield) as an off-white solid. MS (ESI): m/z 615.8 (M-1)-. EXAMPLE 9 1-(3-(azidomethyl)phenyl)ethanone (9-2).

[00563] To a stirred solution of 1-(3-(bromomethyl)phenyl)ethanone 91 (3 g, 14.08 mmol) in ACN (42 ml) was added sodium azide (1.38 g, 21.32 mmol ) at 0°C. The reaction mixture was heated to reflux for 10 hours under a nitrogen atmosphere. Solvents were evaporated under reduced pressure and the crude residue was diluted with water (50 ml) and extracted with EtOAc (3 X 50 ml). The combined organic layers were washed with brine (2 X 30 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 10% EtOAc/pet ether. to afford 9-2 (2.23 g, 13.09 mmol, 93% yield) as a colorless liquid. 1-(3-(aminomethyl)-phenyl)-ethanone (9-3).

[00564] To a stirred solution of 9-2 (2 g, 11.42 mmol) in THF:H2O (20 ml) was added trimethylphosphine (57 ml, 57.15 mmol) at 0 °C and the reaction mixture was stirred at RT for 10 hours. The reaction mixture was diluted with water (60 ml), extracted with EtOAc (3 X 60 ml). The combined organic layers were washed with brine (2 X 30 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washings with ether and pentane to afford 9-3 (1.36 g, 9.14 mmol, 77% yield) as a thick yellow liquid. tert-butyl 3-acetylbenzylcarbamate (9-4).

[00565] To a stirred solution of 9-3 (0.3 g, 2.013 mmol) in DCM (10 ml) was added Boc anhydride (0.5 ml, 2.19 mmol) and triethylamine (0.7 ml, 5.03 mmol) at 0°C and stirring was continued at RT for 20 hours. The reaction mixture was quenched with water (30 ml) and extracted with DCM (3 X 50 ml). The combined organic layers were washed with water (2 X 40 ml), brine (30 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 12% EtO-Ac/hexanes to afford 9-4 (0.26 g, 1.06 mmol, 53% yield ) as a thick yellow liquid. MS (ESI): m/z 267.1 (M+18)+. 1(Z)-ethyl 4-(3-((tert-butoxycarbonylamino)-methyl)-phenyl)-2-hydroxy-4-oxobut-2-enoate (9-5).

[00566] To a stirred solution of 9-4 (0.6 g, 2.41 mmol) in THF (20 mL) was added KHMDS at -78 °C, and the reaction mixture was stirred at -78 °C for one hour. Then, diethyl oxalate (0.49 mL, 3.61 mmol) was added to the reaction mixture at -78 °C and the reaction mixture was warmed to -60 °C for 30 min. The reaction mixture was quenched with ammonium chloride solution, extracted into EtOAc (3 X 40 ml). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography using neutral silica (100 to 200 silica) with 15% EtOAc/hexanes to provide 95 (0.55 g, 1.57 mmol, 65% yield) as a brown gummy solid. MS (ESI): m/z 348.1 (M-1)-. 4-(3-Aminomethyl-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid ethyl ester (9-6).

[00567] To a stirred solution of 9-5 (0.55 g, 1.57 mmol) in dioxane (20 ml) was added dioxane HCl (10 ml) at 0 °C and stirring was continued at RT for 6 H. Solvents were evaporated under reduced pressure and the crude residue was purified by pentane washes to afford 9-6 (0.3 g, 1.05 mmol, 66% yield) as a brown solid. MS (ESI): m/z 250.3 (M+1) +. Ethyl 2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamido)acetate (9-7).

[00568] To a stirred solution of 1-12 (1 g, 2.48 mmol) in DMF (20 ml) was added potassium carbonate (1.03 g, 7.46 mmol) followed by ethyl bromoacetate (500 mg , 2.99 mmol), catalytic amount of tetrabutylammonium iodide at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (75 ml), washed with water (2 X 50 ml), brine (25 ml), dried with Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH-DCM to afford 9-7 (980 mg, 2 mmol, 80% yield) as an off-white solid. MS (ESI): m/z 489.1 [M+H]+. 2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamide)acetic acid (9-8).

[00569] To a stirred solution of 9-7 (980 mg, 2 mmol) in THF and water (10 ml; 4:1) was added LiOH (289 mg, 12 mmol) at 0 °C and the reaction was continued at AT for 6 hours. Upon completion of the reaction (by TLC), the solvents were evaporated on a rotary evaporator, the residue was extracted with ether (15 ml). Then, the aqueous layer was neutralized with 1N HCl (10 ml) followed by extraction with EtOAc (3 X 25 ml). The combined organic layers were washed with brine (2 X 15 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by washing with pentane to afford 9-8 (900 mg, 1.96 mmol, 97% yield) as a brown solid. MS (ESI): m/z 459.0 [MH]+. Methyl 2-aminoacetate (9-10A).

[00570] To a stirred solution of 2-aminoacetic acid 8-1 (2 g, 26.64 mmol) in MeOH (20 ml) was added thionyl chloride (5.8 ml, 79.92 mmol) at 0°C and stirred at RT for 16 hours. Solvents were evaporated under reduced pressure and the crude residue was purified by pentane/ether washes to afford 9-10A (2.7 g, 21.6 mmol, 81% yield) as a brown solid.

[00571] The above procedure (Step H) was adapted to prepare the following compounds:

[00572] Methylaminoacetic acid (1 g, 11.2 mmol) was used to prepare 9-10B (3 g, quantitative).

[00573] 2-Amino-2-methyl-propionic acid (2 g, 29.12 mmol) was used to prepare 9-10C (4 g, quantitative).

[00574] 1-Amino-cyclopropanecarboxylic acid (1 g, 9.89 mmol) was used to prepare 9-10D (1.4 g, 94%).

[00575] 1-Amino-cyclopentanecarboxylic acid (1 g, 7.75 mmol) was used to prepare 9-10E (1.4 g, 94%). Methyl 2-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)acetamido)acetate (9-11A).

[00576] To a stirred solution of 9-8 (0.2 g, 0.43 mmol) in DMF (10 mL) was added EDCI (0.17 g, 0.91 mmol), HOBT (0.06 g, 0.48 mmol), DIPEA (0.37 ml 2.17 mmol), followed by addition of 9-10A (0.08 g, 0.65 mmol) at 0 °C. The reaction was stirred at RT for 10 hours. The reaction mixture was diluted with cold water (20 ml) and extracted with EtOAc (3 X 30 ml). The combined organic layers were washed with water (2 X 25 ml), brine (30 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc/hexanes to afford 9-11A (0.17 g, 0.32 mmol, 74% yield) as a liquid thick yellow. MS (ESI): m/z 532.1 (M+1)+.

[00577] The above procedure (Step I) was adapted to prepare the following compounds:

[00578] 9-10B (63 mg, 0.54 mmol) was used to prepare 9-11B (250 mg, 83%).

[00579] 9-10C (0.2 g, 0.43 mmol) was used to prepare 9-11C (0.14 g, 80%). MS (ESI): m/z 560.1 (M+1)+.

[00580] 9-10D (150 mg, 0.33 mmol) was used to prepare 9-11D (160 mg, 88%). MS (ESI): m/z 602.1 [M-1]+.

[00581] 9-10E (150 mg, 0.33 mmol) was used to prepare 9-11E (162 mg, 88%).

[00582] 2-Amino-propionic acid methyl ester hydrochloride 9-10F (200 mg, 0.43 mmol; Sigma Aldrich) was used to prepare 9-11F (230 mg, 98%). 2-(2-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methyldo)acetamido)acetic acid (9-12A).

[00583] To a stirred solution of 9-11A (0.24 g, 0.45 mmol) in THF and water (10 ml; 4:1) was added LiOH (0.04 g, 1.80 mmol) at 0 °C and the reaction was continued at RT for two hours. After completion of the reaction (TLC), the solvents were evaporated on a rotary evaporator, the residue was extracted with ether (50 ml). Then, the aqueous layer was neutralized with 1N HCl (10 ml) followed by extraction with EtOAc (3 X 50 ml). The combined organic layers were washed with brine (2 X 30 mL), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washing with pentane to afford 9-12A (0.107 g, 0.20 mmol, 65% yield) as a gummy liquid. MS (ESI): m/z 516.0 (M-1)-.

[00584] The above procedure was adapted to prepare the following compounds:

[00585] 9-11B (95 mg, 0.16 mmol) was used to prepare 9-12B (60 mg, 66%). MS (ESI): m/z 530.0 (M-1)-.

[00586] 9-11C (0.17 g, 0.32 mmol) was used to prepare 9-12C (0.12 g, 88%). MS (ESI): m/z 544.1 (M-1)-.

[00587] 9-11D (150 mg, 0.2 mmol) was used to prepare 9-12D (110 mg, 78%). MS (ESI): m/z 542.0 [M-1]-.

[00588] 9-11E (160 mg, 0.27 mmol) was used to prepare 9-12E (113 mg, 72%).

[00589] 9-11F (190 mg, 0.39 mmol) was used to prepare 9-12F (134 mg, 73%). MS (ESI): m/z 529.9 [M-1]-. 4-(3-{[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)- acid ethyl ester acetylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-13A).

[00590] To a stirred solution of 9-6 (0.15 g, 0.43 mmol) in DMF (8 ml) was added EDCI (0.16 g, 0.61 mmol), HOBT (0.043 g, 0. 32 mmol) and DIPEA (0.25 ml, 1.45 mmol), followed by addition of 9-12A (0.12 g, 0.43 mmol) at 0 °C, and the reaction was continued at RT for 12 h . The reaction mixture was diluted with cold water (20 ml) and extracted with EtOAc (3 X 30 ml). The combined organic layers were washed with water (2 X 25 ml), brine (30 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 60% EtOAc/hexanes to afford 9-13A (0.23 g, crude) as an off-white solid. MS (ESI): m/z 749.6 (M+1)+.

[00591] The above procedure was adapted to prepare the following compounds:

[00592] 4-[3-({2-[(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino) ethyl ester }-acetyl)-methyl-amino]-acetylamino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-13B): 9-12B (130 mg, 0.24 mmol) was used to prepare 9-13B (150 mg, crude). MS (ESI): m/z 761.0 (M-1)-.

[00593] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino} acid ethyl ester) -acetylamino)-2-methyl-propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-13C): 9-12C (0.13 g, 0.238 mmol) was used to prepare 9-13C (0.12 g, crude). MS (ESI): m/z 775.2 (M+1)+.

[00594] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino) ethyl ester }-acetylamino)-cyclopropanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-13D): 9-12D (90 mg, 0.16 mmol) was used to prepare 9-13D (152 mg, 83%). MS (ESI): m/z 775.4 [M+1]+.

[00595] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino) ethyl ester }-acetylamino)-cyclopentanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-13E): 9-12E (80 mg, 0.14 mmol) was used to prepare 9-13E (150 mg, 84%). MS (ESI): m/z 801.3 [M-1]-.

[00596] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino} acid ethyl ester) -acetylamino)-propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-13F): 9-12F (120 mg, 0.23 mmol) was used to prepare 9-13F (164 mg, 94%). MS (ESI): m/z 761.3 [M-1]-.

[00597] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino) acid -acetylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-14A).

[00598] To a stirred solution of 9-13A (0.1 g, 0.13 mmol) in THF and water (10 mL; 4:1) was added LiOH (0.01 g, 0.53 mmol) at 0 °C and the reaction was continued at RT for two hours. After completion of the reaction (TLC), the solvents were evaporated on a rotary evaporator, the residue was extracted with ether (15 ml). Then, the aqueous layer was neutralized with 1N HCl (10 ml) followed by extraction with EtOAc (3 X 25 ml). The combined organic layers were washed with brine (2 X 15 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washing with pentane and preparative HPLC to afford 9-14A (0.017 g, 0.02 mmol, 17% yield) as a brown solid. MS (ESI): m/z 718.8 (M-1)-.

[00599] The above procedure was adapted to prepare the following compounds:

[00600] 4-[3-({2-[(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetyl acid) )-methyl-amino]-acetylamino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-14B): 9-13B (150 mg, 0.19 mmol) was used to prepare 9-14B (5 mg, 2.8%). MS (ESI): m/z 732.9 (M-1)-.

[00601] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino) acid -2-methyl-propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic (9-14C): 9-13C (0.13 g, 0.16 mmol) was used to prepare 9-14C (0.035 g, 36%). MS (ESI): m/z 749.2 (M+1)+.

[00602] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino acid) )-cyclopropanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-14D): 9-13D (150 mg, 0.19 mmol) was used to prepare 9 -14D (35 mg, 20%). MS (ESI): m/z 745.9 [M-1]-.

[00603] 4-[3-({[1-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino acid) )-cyclopentanecarbonyl]-amino}-methyl)-phenyl]-2-hydroxy-4-oxo-but-2-enoic acid (9-14E): 9-13E (150 mg, 0.19 mmol) was used to prepare 9 -14E (30 mg, 22%). MS (ESI): m/z 774.8 [M+1]+.

[00604] 4-(3-{[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino) acid -propionylamino]-methyl}-phenyl)-2-hydroxy-4-oxo-but-2-enoic acid (9-14F): 9-13F (80 mg, 0.1 mmol) was used to prepare 9-14F (3 mg, 3.8%). MS (ESI): m/z 732.8 [M-1]-. EXAMPLE 10 Methyl 5-aminopentanoate hydrochloride (10-2A).

[00605] To a stirred solution of piperidin-2-one 10-1A (500 mg, 5.05 mmol) in MeOH (10 ml) HCl gas was passed. The reaction mixture was stirred at RT for 4 h under N 2 atmosphere. Then, the reaction mixture was heated to 55°C and stirring was continued for 16 hours. The reaction solvents were evaporated under reduced pressure and the crude residue was washed with diethyl ether to afford 10-2A (608 mg, 129.57 mmol, 72% yield) as an off-white solid.

[00606] Step A above was adapted using 3-methylpiperidin-2-one 10-1B (250 mg, 2.2 mmol) to prepare 10-2B (300 mg, 80%).

[00607] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)- acid methyl ester acetylamino]-pentanoic acid (10-3A).

[00608] To a solution of 9-12A (125 mg, 0.24 mmol) in DMF (4 ml) was added HOBT (48 mg, 0.36 mmol), DIPEA (0.15 ml, 0.84 mmol) and EDC.HCl (100 mg, 0.53 mmol) at 0°C. After 15 minutes, 10-2A (51 mg, 0.26 mmol) was added at 0 °C and the reaction was continued under stirring at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the mixture was poured into cold water (10 ml), extracted with EtOAc (25 ml). The organic layer was washed with water (20 ml), brine (10 ml), dried over Na 2 SO 4 and concentrated. The crude compound was purified by column chromatography (100 to 200) on silica to afford 10-3A (110 mg, 72% yield) as an off-white solid. MS (ESI): m/z 632.0 [M+1]+.

[00609] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)- acid methyl ester acetylamino]-2-methyl-pentanoic (10-3B). Step B above was adapted using 10-2B (27 mg, 0.17 mmol) to prepare 10-3B (70 mg, 95.4%). MS (ESI): m/z 644.9 [M+1]+. 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)-acetylamino]-pentanoic acid (10 -4A).

[00610] To a stirred solution of 10-3A (100 mg, 1.59 mmol) in THF (4 ml) and water (1 ml) was added LiOH (229 mg, 9.54 mmol) at 0 °C and reaction was continued at RT for 16 hours. After completion of the reaction (TLC), the solvents were concentrated under reduced pressure, the residue was extracted with ether (10 ml). The aqueous layer was neutralized with 1N HCl (1 ml) followed by extraction with EtOAc (3 X 10 ml). The combined organic layers were washed with brine (2 X 10 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by pentane washes to afford 10-4A (22 mg, 0.035 mmol, 22.6% yield) as an off-white solid. MS (ESI): m/z 616.8 [M+1]+.

[00611] 5-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-acetylamino)-acetylamino]- acid 2-methyl-pentanoic (10-4B). Step C above was adapted using 10-3B (60 mg, 0.09 mmol) to prepare 10-4B (45 mg, 78% yield). MS (ESI): m/z 629.5 [M+1]+. EXAMPLE 11 (E)-Methyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)vinyl)benzoate (11-2A).

[00612] To a stirred solution of 2-(2-vinyloxy)ethoxy)ethanol (2.03 g, 15.33 mmol; Sigma-Aldrich) in DMF, silver acetate was added at RT. After 5 min, 11-1A (800 mg, 3.06 mmol) and triphenylphosphine (80 mg, 0.30 mmol) were added to the reaction mixture which was then degassed with N2 for 15 minutes. Palladium acetate (38.62 mg, 0.0575) was added and the mixture heated to 70°C for 16 hours. Upon completion of the reaction, the mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried (Na2SO4) and concentrated. The crude compound was purified by column chromatography to afford 11-3A (0.365 g, 1.37 mmol, 45% yield) as a thick brown liquid. MS (ESI): m/z 267.17 [M+1]+.

[00613] The above procedure was adapted to prepare the following compounds:

[00614] 3-iodo-benzoic acid ethyl ester 11-1B (800 mg, 2.89 mmol) was used to prepare 11-2B (700 mg, 86%). MS (ESI): m/z 281.28 [M+1]+.

[00615] 4-iodo-benzoic acid methyl ester 11-1C (800 mg, 3.06 mmol) was used to prepare 11-2C (350 mg, 43%). MS (ESI): m/z 267.14 [M+1]+.

[00616] Methyl 2-(2-(2-(2-hydroxyethoxy)-ethoxy)-ethyl)benzoate (11-3A).

[00617] To a stirred solution of 11-2A (0.36 g, 1.37 mmol) in ethanol was added Pd on carbon (0.036 mg, 10% w/w) at RT for 4 h under a hydrogen atmosphere (balloon ). Upon completion of the reaction, the mixture was filtered through a celite pad and washed with EtO-Ac. The combined organic layer was dried with Na2SO4 and concentrated. The crude residue was purified by column chromatography to obtain 11-3A (0.32 g, 1.19 mmol, 86% yield) as a dark brown thick liquid. MS (ESI): m/z 269.22 [M+1]+.

[00618] The above procedure was adapted to prepare the following compounds:

[00619] 11-2B (700 mg, 2.5 mmol) was used to prepare 11-3B (563 mg, 80%). MS (ESI): m/z 283.19 [M+1]+.

[00620] 11-2B (200 mg, 0.75 mmol) was used to prepare 11-3B (190 mg, 84%). MS (ESI): m/z 269.18 [M+1]+.

[00621] 2-{2-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxy]-ethyl}-benzoic acid methyl ester (11-4A).

[00622] To a stirred solution of 11-3A (308 mg, 1.15 mmol) in DCM was added triethylamine (0.32 ml, 2.3 mmol) at 0 °C. After 5 min, mesyl chloride (0.13 ml, 1.73 mmol) was added to the reaction mixture at the same temperature. The mixture was allowed to stir at RT for two hours. Then, the mixture was diluted with water, extracted with DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated to obtain the crude compound. This was purified by column chromatography to provide 11-4A (338 mg, 0.98 mmol, 85% yield) as a colorless liquid. MS (ESI): m/z 347.26 [M+1]+.

[00623] The above procedure was adapted to prepare the following compounds:

[00624] 11-3B (415 mg, 1.47 mmol) was used to prepare 11-4B (420 mg, 84%).

[00625] 11-3C (190 mg, 0.71 mmol) was used to prepare 11-4C (230 mg, 93.8%). MS (ESI): m/z 347.1 [M+1]+.

[00626] 2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonylamino}-ethoxy) acid methyl ester -ethoxy]-ethyl}-benzoic acid (11-5A).

[00627] To a stirred solution of [1-12] (160 mg, 0.39 mmol) in DMF, potassium carbonate (109 mg, 0.76 mmol) was added at RT. After 5 min, 11-4A (165 mg, 0.47 mmol), catalytic amount of TBAI was added to the reaction and heated to 70 °C. The reaction was maintained at 70 to 75°C for 16 hours. Upon completion of the reaction indicated by TLC, the mixture was diluted with cold water, extracted with EtOAc. The organic layer was washed with water, brine, dried over Na 2 SO 4 and concentrated. The crude compound was purified by column chromatography to obtain 11-5A (132 mg, 0.2 mmol, 50.9% yield) as an off-white semi-solid. MS (ESI): m/z 653.41 [M+1]+.

[00628] The above procedure was adapted to prepare the following compounds:

[00629] 3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethyl}-benzoic acid (11-5B): 11-4B (253 mg, 0.744 mmol) was used to prepare 11-5B (168 mg, 39%). MS (ESI): m/z 667.34 [M+1]+.

[00630] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid methyl ester ethoxy)-ethoxy]-ethyl}-benzoic acid (11-5C): 11-4C (225 mg, 0.56 mmol) was used to prepare 11-5C (145 mg, 40%). MS (ESI): m/z 653.37 [M+1]+.

[00631] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethyl}-benzoic acid (11-6A).

[00632] To a stirred solution of 11-5A (100 mg, 0.15 mmol) in THF and water (4 mL, 4:1) was added LiOH (21 mg, 0.9 mmol) at 0 °C and reaction was continued at RT for 16 h. After completion of the reaction (TLC), the solvents were evaporated in a rotary evaporator. The crude residue was extracted with ether (2 X 20 ml). The aqueous layer was neutralized with 1N HCl (10 mL), then extracted with EtOAc (3 X 30 mL). The combined organic layers were washed with brine (20 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washings with diethyl ether and pentane to afford 11-6A (32 mg, 0.05 mmol, 33% yield) as a white solid. MS (ESI): m/z 639.39 [M+1]+.

[00633] The above procedure was adapted to prepare the following compounds:

[00634] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethyl}-benzoic acid (11-6B):11-5B (60 mg, 0.09 mmol) was used to prepare 11-6B (17 mg, 29%). MS (ESI): m/z 639.3 [M+1]+.

[00635] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethyl}-benzoic acid (11-6C): 11-5C (100 mg, 0.15 mmol) was used to prepare 11-6C (25 mg, 25%). MS (ESI): m/z 639.3 [M+1]+.

EXAMPLE 12

[00636] 2-(2-(2-(allyloxy)-ethoxy)-ethoxy)tetrahydro-2H-pyran (12-1).

[00637] To a stirred suspension of NaH in THF (80 ml) was added a solution of 2-4A (8 g, 42 mmol) in THF (20 ml) at 0 °C and the mixture was stirred at RT for 30 min . Then, the mixture was cooled to 0 °C, allyl bromide (5.6 g, 44 mmol) was added and allowed to stir at RT for 16 h under a nitrogen atmosphere. The reaction mixture was quenched with cold water and extracted with EtOAc (3 X 100 ml). The organic layer was washed with water (80 ml), brine (80 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 12-1 (9 g, 39 mmol, 92% yield) as a pale yellow liquid.

[00638] (E)-methyl 2-(3-(2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethoxy)-prop-1-enyl)benzoate (12- 2A).

[00639] To a stirred solution of methyl 2-iodobenzoate 11-1A (1 g, 3.8 mmol) in DMF (8 ml) was added 12-1 (2.2 g, 11.4 mmol), triphenylphosphine and silver acetate (639 mg, 3.8 mmol) at RT. The reaction mixture was degassed for 15 min with argon, palladium acetate (128 mg, 0.19 mmol) was added and the mixture heated to 80 °C for 18 h. The reaction mixture was filtered through a celite pad, washed thoroughly with EtOAc. The filtrate is washed with water and brine, dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/pet ether. to afford 12-4A (300 mg, 0.82 mmol, 23% yield) as a yellow liquid. MS (ESI): m/z 364.0 (M+1)+.

[00640] Methyl 2-(3-(2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-propyl)benzoate (12-3A).

[00641] To a solution of 12-2A (300 mg, 0.82 mmol) in EtOH (5 ml) was added 10% Pd/C (90 mg) and stirred at RT for 3 h under H2 atmosphere. The reaction mixture was filtered through a bed of Celite and washed with 10% MeOH-EtOAc. The filtrate was distilled under reduced pressure to obtain 12-3A (300 mg, 0.81 mmol, quantitative yield).

[00642] Methyl 2-(3-(2-(2-hydroxyethoxy)-ethoxy)-propyl)benzoate (12-4A).

[00643] To a solution of 12-3A (300 mg, 0.81 mmol) in MeOH (5 mL) was added PPTS (41 mg, 0.16 mmol) and stirred at 0°C to RT for 16 hours. The reaction mixture was distilled and over-diluted (100 ml), washed with water (100 ml), brine (50 ml) and dried over Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using CombiFlash® column chromatography (Teledyne Isco) (40% EtOAc in hexane) to afford 12-4A (160 mg, 0.56 mmol, 69% yield). MS (ESI) : m/z 305.2 (M+23)+.

[00644] 2-{3-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxy]-propyl}-benzoic acid methyl ester(12-5A).

[00645] Methanesulfonyl chloride (0.07 ml, 0.85 mmol) at 0 °C was added to a solution of 12-4A (160 mg, 410.56 mmol) in DCM (5 ml) and triethylamine (0. 13 ml, 0.9 mmol) and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml) and brine (20 ml) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure to obtain 12-5A (130 mg, 0.34 mmol, 61% yield) as a yellow liquid. MS (ESI): m/z 375.0 (M+1)+.

[00646] 2-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy methyl ester )-ethoxy]-propyl}-benzoic acid (12-6A).

[00647] To a solution of 1-12 (116 mg, 0.28 mmol) in DMF (5 ml) was added potassium carbonate (120 mg, 0.86 mmol) followed by 12-7A (130 mg, 0. 34 mmol), catalytic amount of TBAI, then stirred at 70 °C for 16 h. The reaction was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (25 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound obtained was purified using combiflash column chromatography (30% EtOAc in hexane) to afford 12-6A (129 mg, 0.19 mmol, 69% yield) as an off-white solid. MS (ESI): m/z 666.7 (M+1)+.

[00648] 2-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-propyl}-benzoic acid (12-7A).

[00649] To a solution of 12-6A (80 mg, 0.12 mmol) in THF, MeOH and water (4:1:1) was added LiOH (15 mg, 0.6 mmol) and stirred at RT for 16 hours. Upon completion as indicated by TLC, the reaction mixture was neutralized with 1N HCl and then extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude compound was purified using pentane washes to afford 12-7A (25 mg, 0.038 mmol, 32% yield) as an off-white solid. MS (ESI): m/z 653.4 (M+1)+.

[00650] The above procedure was adapted to prepare the following compounds:

[00651] 3-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid Ethoxy]-propyl}-benzoic acid (12-7B): Ethyl 3-iodobenzoate 11-1B was substituted for methyl 2-iodobenzoate 11-1A in Step A, with appropriate modification of subsequent steps, to prepare 12-7B . MS (ESI): m/z 653.4 (M+1)+.

[00652] 4-{3-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-propyl}-benzoic acid (12-7C): Methyl 4-iodobenzoate 11-1C was substituted for methyl 2-iodobenzoate 11-1A in Step A, with appropriate modification of subsequent steps, to prepare 12-7C . MS (ESI): m/z 653.4 (M+1)+. EXAMPLE 13 (2-bromoethoxy)tetrahydro-2H-pyran (13-2).

[00653] To a solution of 2-bromoethanol 13-1 (5 g, 40 mmol) in DCM (250 ml) was added p-toluenesulfonic acid (760 mg, 4 mmol) followed by dihydropyran (4.3 ml, 48 mmol ) at 0°C and stirred at RT for 5 hours. The reaction mixture was diluted with EtOAc (100 ml), washed with water (100 ml), brine (10 ml) and dried over Na 2 SO 4 and concentrated under reduced pressure at 25°C. The crude compound was purified using silica gel chromatography (5% EtO-Ac in hexanes) to afford 13-2 (5 g, 24 mmol, 60% yield) as a pale yellow liquid. 2-(2-(but-3-enyloxy)-ethoxy)tetrahydro-2H-pyran (13-3AT).

[00654] To a solution of NaH (885 mg, 24 mmol) in THF (50 ml) was added 13-2 (5 g, 24 mmol) at 0 °C and stirred at RT for one hour. The reaction mixture was again cooled to 0 °C, homoallyl alcohol (1.9 ml, 22.8 mmol) was added and stirred at RT for 16 hours. The reaction mixture was quenched with cold water and diluted with EtOAc (50 ml) washed with water (50 ml), brine (10 ml) dried with Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (5% EtOAc in hexanes) to provide 13-3AT (1.5 g, 7.5 mmol, 31% yield) as a red colored liquid. pale yellow. (E)-methyl (13-5C) 4-(2-(4-hydroxybutoxy)vinyl)benzoate.

[00655] To a solution of 4-iodo-benzoic acid methyl ester 11-1C (1.2 g, 4.5 mmol) in DMF (5 ml) was added 4-vinyloxybutan-1-ol 13-3C (2.65 g, 22.9 mmol; TCI), Ag(OAc) 2 (751 mg, 4.5 mmol) and TPP (117 mg, 0.45 mmol) sequentially and degassed for 15 min, followed by addition of Pd(OAc) 2 (100 mg, 0.14 mmol) and again degassed for 5 min and stirred at 70 °C for 16 h. The reaction was cooled to RT and diluted with EtOAc (200 ml), washed with water (200 ml), brine (50 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by silica gel chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 13-4C (520 mg, 2.08 mmol, 43% yield) as a thick liquid brown. MS (ESI): m/z 251.2 [M+1]+.

[00656] The above procedure was adapted to prepare the following compounds:

[00657] 13-3A (783 mg, 3 mmol) was used to prepare 13-4A (600 mg, 46%). MS (ESI): m/z 357.3 (M+1)+.

[00658] 3-allyloxy-propan-1-ol 13-3B (1.7 g, 14.65 mmol) was used to prepare 13-4B (300 mg, 39%). MS (ESI): m/z 251.2 [M+1]+.

[00659] Hept-6-en-1-ol 13-3D (1 g, 8.77 mmol) was used to prepare 13-4D (800 mg, 80%). MS (ESI): m/z = 249.2 [M+H]+. Methyl 4-(2-(4-hydroxybutoxy)-ethyl)benzoate (13-5C).

[00660] To a solution 13-4C (520 mg, 2.08 mmol) in ethanol (5 ml) was added 20% Pd(OH)2/C (30 mg) and stirred at RT for 3 hours under an atmosphere of H2. The reaction mixture was filtered through a bed of celite and washed with 10% MeOH-EtOAc. The filtrate was distilled under reduced pressure, the crude compound was purified by column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to provide 13-5C (400 mg, 1.58 mmol, 76% yield) .MS (ESI): m/z 253.0 (M+1)+.

[00661] The above procedure was adapted to prepare the following compounds:

[00662] 13-4A (600 mg, 1.79 mmol) was used to prepare 13-5A (530 mg, 87%).

[00663] 13-4B (300 mg, 1.2 mmol) was used to prepare 13-5B (160 mg, 52%). MS (ESI): m/z 253.2 (M+1)+.

[00664] 13-4D (800 mg, 3.22 mmol) was used to prepare 13-5D Methyl 4-(3-(2-hydroxyethoxy)butyl)benzoate (13-5A).

[00665] To a solution of 13-5AT (530 mg, 1.5 mmol) in MeOH (5 ml) was added PPTS (79 mg, 0.3 mmol) and stirred at 0°C to RT for 16 hours. The reaction mixture was distilled and diluted with excess EtOAc (100 ml), washed with water (100 ml), brine (50 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified using combiflash column chromatography (18% EtOAc in hexanes) to afford 13-5A (250 mg, 0.99 mmol, 66% yield). MS (ESI): m/z 253.2 (M+1)+. Methyl 4-(2-(4-(methylsulfonyloxy)butoxy)ethyl)benzoate (13-6C).

[00666] Methanesulfonyl chloride (0.15 ml, 1.90 mmol) at 0°C was added to a solution of 13-5C (400 mg, 1.58 mmol) in DCM (5 ml) and triethylamine (0. 53 ml, 3.79 mmsol) and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml), brine (20 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to provide 13-6C (400 mg, 1.21 mmol, 75% yield) as a colorless liquid. MS (ESI): m/z 331.3 (M+1)+.

[00667] The above procedure was adapted to prepare the following compounds:

[00668] 13-5A (250 mg, 0.99 mmol) was used to prepare 13-6A (300 mg, 93%). MS (ESI): m/z 331.2 (M+1)+.

[00669] 13-5B (160 mg, 0.63 mmol) was used to prepare 13-6B (165 mg, 78%). MS (ESI): m/z 331.2 (M+1)+. 13-5D (600 mg, 2.4 mmol) was used to prepare 13-6D (700 mg, 93.3%). Confirmed by 1H NMR. 4-[2-(4-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-butoxy)-ethyl]- acid methyl ester benzoyl (13-7C).

[00670] To a stirred solution of 1-12 (304 mg, 0.75 mmol) in DMF (5 ml) was added potassium carbonate (313 mg, 2.27 mmol) followed by 13-6C (300 mg, 0 .91 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (25 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified using column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to provide 13-7C (280 mg, 0.44 mmol, 59% yield) as an off-white solid. MS (ESI): m/z 637.4 (M+1)+.

[00671] The above procedure was adapted to prepare the following compounds:

[00672] 4-[4-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester butyl]-benzoyl (13-7A): 13-6A (197 mg, 0.59 mmol) was used to prepare 13-7A (130 mg, 34%). MS (ESI): m/z 637.3 (M+1)+.

[00673] 4-[3-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-propoxy)- acid methyl ester propyl]-benzoyl (13-7B): 13-6B (160 mg, 0.48 mmol) was used to prepare 13-7B (130 mg, 42%). MS (ESI): m/z 637.0 (M+1)+.

[00674] 4-(7-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-heptyl)-benzoic acid methyl ester (13 -7D): 13-6D (195 mg, 0.62 mmol) was used to prepare 13-7D (110 mg, 28%). MS (ESI): m/z 635.6 (M+1)+.

[00675] 4-(2-(4-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamido)butoxy)ethyl)benzoic acid (13 -8C).

[00676] To a stirred solution of 13-7C (100 mg, 0.157 mmol) in THF, MeOH and water (4:1:1; 6 ml) was added LiOH (19 mg, 0.785 mmol) and stirred at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the reaction mixture was neutralized with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), and concentrated. The crude compound was purified by DCM and pentane washes to afford 13-8C (40 mg, 0.064 mmol, 41% yield) as an off-white solid. MS (ESI): m/z 621.5 (M-1)+.

[00677] The above procedure was adapted to prepare the following compounds:

[00678] 4-[4-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-butyl]- acid benzoyl (13-8A): 13-7A (50 mg, 0.07 mmol) was used to prepare 13-8A (16 mg, 35%). MS (ESI): m/z 623.3 (M+1)+.

[00679] 4-[3-(3-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-propoxy)-propyl]- acid benzoyl (13-8B): 13-7B (90 mg, 0.14 mmol) was used to prepare 13-8B (40 mg, 45%). MS (ESI): m/z 623.1 (M+1)+.

[00680] 4-(7-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-heptyl)-benzoic acid (13-8D) : 13-7D (60 mg, 0.09 mmol) was used to prepare 13-8D (27 mg, 46%). MS (ESI): m/z 621.3 (M+1)+. EXAMPLE 14 2-(2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethylmethanesulfonate (14-1).

[00681] Methanesulfonyl chloride (1.1 ml, 13.88 mmol) at 0 °C was added to a solution of 2-4B (2.5 g, 10.68 mmol) in THF (22 ml) and triethylamine ( 3 ml, 21.36 mmol) and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (150 ml) and washed with water (100 ml), brine (100 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel 100 to 200 column chromatography (3% MeOH in DCM) to afford 14-1 (3 g, 9.61 mmol, 91% yield) as an oily liquid. pale yellowish. Ethyl 2-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethoxy)-ethoxy)benzoate (14-3A).

[00682] To a solution of 14-1 (800 mg, 2.56 mmol) in DMF (10 ml) was added potassium carbonate (353 mg, 2.56 mmol) followed by ethyl 2-hydroxybenzoate 14-2A ( 553 mg, 3.33 mmol) and stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (100 ml), washed with water (100 ml), and brine (50 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The obtained crude compound was purified using silica gel chromatography (40% EtOAc in hexanes) to provide 14-4A (700 mg, 1.83 mmol, 71% yield). MS (ESI): m/z 382.73 (M+1)+.

[00683] The above procedure was adapted to prepare the following compounds:

[00684] Ethyl 3-hydroxybenzoate 14-2B (553 mg, 3.33 mmol) was used to prepare 14-3B (700 mg, 73%). MS (ESI): m/z 399.8 (M+18)+.

[00685] Ethyl 4-hydroxybenzoate 14-2C (553 mg, 3.33 mmol) was used to prepare 14-3C (800 mg, 81%). MS (ESI): m/z 405.4 (M+23)+. Ethyl 2-(2-(2-(2-hydroxyethoxy)-ethoxy)-ethoxy)benzoate (14-4A).

[00686] To a stirred solution of 14-3A (700 mg, 1.83 mmol) in DCM (10 ml) was added pyridinium p-toluenesulfonate (353 mg, 2.56 mmol) at 0 °C and stirred at RT for 4 hours. The reaction mixture was diluted with water (100 ml), extracted with DCM (3 X 50 ml), the combined organic layers were washed with brine (2 X 50 ml), dried with Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using (40% EtOAc in hexanes) to afford 14-4A (400 mg, 1.34 mmol, 74% yield) as a colorless oily liquid. MS (ESI): m/z 252.9 (M+1)+.

[00687] The above procedure was adapted to prepare the following compounds:

[00688] 14-3B (720 mg, 1.83 mmol) was used to prepare 14-4B (450 mg, 80%). MS (ESI): m/z 252.9 (M+1)+.

[00689] 14-3C (800 mg, 2.09 mmol) was used to prepare 14-4C (520 mg, 83%). MS (ESI): m/z 252.9 (M+1)+. 2-{2-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxy]-ethoxy}-benzoic acid ethyl ester (14-5A).

[00690] Methanesulfonyl chloride (229 mg, 2.01 mmol) at 0°C was added to a solution of 14-4A (400 mg, 1.34 mmol) in DCM (6 ml) and triethylamine (339 mg, 3 .35 mmol) and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml), then brine (20 ml), dried over Na 2 SO 4 , and the organic phase concentrated under reduced pressure to give the crude compound. The obtained compound was purified using silica gel 100 to 200 column chromatography (50% EtOAc in hexanes) to afford 14-5A (440 mg, 1.17 mmol, 87% yield) as a gummy liquid pale brown. MS (ESI): m/z 377.3 (M+1)+.

[00691] The above procedure was adapted to prepare the following compounds:

[00692] 14-4B (300 mg, 1 mmol) was used to prepare 14-5B (280 mg, 74%). MS (ESI): m/z 376.7 (M+1)+.

[00693] 14-4C (300 mg, 1 mmol) was used to prepare 14-5C (305 mg, 80%). MS (ESI): m/z 376.7 (M+1)+. 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethyl ester ethoxy]-ethoxy}-benzoic acid (14-6A).

[00694] To a solution of 1-12 (250 mg, 0.62 mmol) in DMF (3 ml) was added potassium carbonate (257 mg, 1.86 mmol) followed by 14-5A (280 mg, 0. 74 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (25 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure to obtain the crude compound. The obtained crude compound was purified using silica gel chromatography (50% EtOAc in hexanes) to provide 14-6A (200 mg, 0.29 mmol, 47% yield). MS (ESI): m/z 681.5 (M-1)-.

[00695] The above procedure was adapted to prepare the following compounds:

[00696] 3-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-benzoic acid (14-6C): 14-5B (280 mg, 0.74 mmol) was used to prepare 14-6B (150 mg, 29%). MS (ESI): m/z 682.7 (M+1)+.

[00697] 4-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-benzoic acid (14-6C): 14-5C (280 mg, 0.74 mmol) was used to prepare 14-6C (180 mg, 35%). MS (ESI): m/z 683.3 (M+1)+. 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]- acid ethoxy}benzoic(14-7A).

[00698] To a solution of 14-6A (50 mg, 0.073 mmol) in THF and water (4:1; 4 ml) was added LiOH (8 mg, 0.36 mmol) and stirred at RT for 16 hours. Upon completion as indicated by TLC, the reaction mixture was neutralized with 1N HCl and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated to obtain the crude compound. The crude compound obtained was purified by preparative TLC to obtain 14-7A (20 mg, 0.030 mmol, 41% yield) as an off-white solid. MS (ESI): m/z 655.5 (M+1)+.

[00699] The above procedure was adapted to prepare the following compounds:

[00700] 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-benzoic acid (14-7B): 14-6B (75 mg, 0.11 mmol) was used to prepare 14-7B (20 mg, 27%). MS (ESI): m/z 654.8 (M+1)+.

[00701] 4-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-benzoic acid (14-7C): 14-6C (100 mg, 0.14 mmol) was used to prepare 14-7C (30 mg, 31%). MS (ESI): m/z 655.3 (M+1)+. EXAMPLE 15 6-(tetrahydro-2H-pyran-2-yloxy)hexan-1-ol (15-2).

[00702] To a stirred solution of 15-1 (4 g, 33.8 mmol) in DCM (200 ml) was added dihydropyran (2.78 ml, 30.5 mmol) and PPTS (1.2 g, 6, 8 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water (300 ml), extracted with DCM (3 X 250 ml). The combined organic layers were washed with brine (2 X 100 ml) and dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH/DCM to afford 15-2 (2 g, 9.9 mmol, 30% yield) as a thick colorless liquid. 6-(Tetrahydro-2H-pyran-2-yloxy)hexyl methanesulfonate (15-3).

[00703] Methanesulfonyl chloride (0.8 g, 3.96 mmol)) was added to a solution of 15-2 (0.33 ml, 4.4 mmol) in DCM (10 ml) and triethylamine (1.15 ml, 8.6 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water (25 ml) extracted with DCM (3 X 50 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 15-3 (850 mg, 3.04 mmol, 78% yield) as a thick colorless liquid. . Ethyl 4-(7-(tetrahydro-2H-pyran-2-yloxy)heptyl)benzoate (15-4).

[00704] To a stirred solution of 14-2C (400 mg, 2.4 mmol) in DMF (10 ml) was added potassium carbonate (332.5 mg, 2.65 mmol), 15-3 (742 mg, 2.65 mmol) at RT and the reaction was continued under stirring at 70°C for 16 hours. The reaction mixture was quenched with cold water (20 ml) and extracted with EtOAc (3 X 50 ml). The combined organic layers were washed with water (2 X 20 ml), brine (15 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/hexanes to afford 15-4 (600 mg, 1.72 mmol, 71% yield) as a light pink solid. MS (ESI): m/z 373.47 [M+23]+. Ethyl 4-(6-hydroxyhexyloxy)benzoate (15-5).

[00705] To a stirred solution of 15-4 (570 g, 1.63 mmol) in MeOH (5 ml) was added pyridinium p-toluenesulfonate (91 mg, 0.33 mmol) at 0 °C and stirred at RT for 16 hours. Solvents were distilled off under reduced pressure. The obtained residue was extracted with EtOAc (3 X 50 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 5% acetone:DCM to afford 15-5 (348 mg, 1.31 mmol, 80% yield) as a gummy liquid. MS (ESI): m/z 266.97 [M+1]+. Ethyl 4-(6-(methylsulfonyloxy)hexyloxy)benzoate (15-6).

[00706] Methanesulfonyl chloride (0.12 ml, 1.56 mmol)) was added to a solution of 15-5 (345 mg, 1.29 mmol) in DCM (10 ml) and triethylamine (0.4 ml, 3.1 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water (25 ml), extracted with DCM (3 X 20 ml). The combined organic layers were washed with brine (25 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexanes to provide 15-6 (385 mg, 1.12 mmol, 86.8% yield) as a thick colorless liquid . MS (ESI): m/z 344.7 [M+1]+. 4-(6-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-hexyloxy)-benzoic acid ethyl ester (15-7) .

[00707] To a stirred solution of 1-12 (250 mg, 0.62 mmol) in DMF (10 ml) was added potassium carbonate (257 mg, 1.86 mmol) followed by [15-6] (256 mg , 0.74 mmol), catalytic amount of tetrabutylammonium iodide at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (50 mL), washed with water (2 X 50 mL), brine (25 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH: DCM to afford 15-7 (252 mg, 0.39 mmol, 60% yield) as an off-white solid. MS (ESI): m/z 651.4 [M+1]+. 4-(6-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-hexyloxy)-benzoic acid (15-8).

[00708] To a stirred solution of 15-7 (80 mg, 0.12 mmol) in THF and water (4 ml, 4:1) was added LiOH (17.7 mg, 0.73 mmol) at 0°C and the reaction was continued at RT for 16 hours. After completion of the reaction (TLC), solvents were evaporated on a rotary evaporator, the residue was extracted with ether (25 ml). Then the aqueous layer was neutralized with 1N HCl (2 ml) followed by extraction with EtOAc (3 X 20 ml). The combined organic layers were washed with brine (2 X 15 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by preparative HPLC to obtain 15-8 (18 mg, 0.03 mmol, 24% yield) as an off-white solid. MS (ESI): m/z 622.74 [M+H]+. EXAMPLE 16 5-(tetrahydro-2H-pyran-2-yloxy)-pentan-1-ol (16-2).

[00709] To a stirred solution of 16-1 (20 g, 192 mmol) in DCM (400 ml) was added dihydropyran (14 g, 163.4 mmol) and pyridinium p-toluenesulfonate (3.6 g, 19, 2 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water (500 ml), extracted with DCM (3 X 350 ml). The combined organic layers were washed with brine (2 X 100 ml) and dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH/DCM to afford 16-2 (5.6 g, 30 mmol, 15% yield) as a thick colorless liquid. Methyl 4-((5-(tetrahydro-2H-pyran-2-yloxy)-pentyloxy)-methyl)benzoate (16-3).

[00710] To a solution of NaH (536 mg, 22.3 mmol) in THF (40 ml) was added 16-2 (2.8 g, 14.89 mmol) at 0 °C and stirred at RT for one hour . The reaction mixture was again cooled to 0 °C, methyl 4-(bromomethyl)benzoate 6-2B (3.58 g, 15.63 mmol) was added, and stirred at RT for 6 hours. The reaction mixture was quenched with cold water and diluted with EtOAc (100 mL), washed with water (50 mL), brine (25 mL), dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (15% EtOAc in hexane) to afford 16-3 (1 g, 2.97 mmol, 20% yield). MS (ESI): m/z 359.3 [M+23]+. Methyl 4-((5-hydroxypentyloxy)methyl)benzoate (16-4).

[00711] To a stirred solution of 16-3 (1 g, 2.97 mmol) in MeOH (5 mL) was added pyridinium p-toluenesulfonate (75 mg, 0.29 mmol) at 0 °C and stirred at RT for 16 hours. Solvents were distilled off under reduced pressure. The obtained residue was extracted with EtOAc (3 X 50 ml). The combined organic layer was washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 5% acetone-DCM to afford methyl 16-4 (720 mg, 2.85 mmol, 96% yield) as a gummy liquid. MS (ESI): m/z 253.2 [M+1]+. Methyl 4-((5-(methylsulfonyloxy)-pentyloxy)-methyl)benzoate (16-5).

[00712] Methanesulfonyl chloride (0.28 ml, 3.4 mmol) was added to a solution of 16-4 (850 mg, 3.37 mmol) in DCM (10 ml) and triethylamine (0.4 ml, 3 .1 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water (25 ml), extracted with DCM (3 X 20 ml). The combined organic layers were washed with brine (25 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexanes to provide 16-5 (600 mg, 1.8 mmol, 63% yield) as a thick colorless liquid. .MS (ESI): m/z 331.2 [M+1]+. 4-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxymethyl)-benzoic acid methyl ester (16-6) .

[00713] To a stirred solution of 1-12 (600 mg, 1.52 mmol) in DMF (10 ml) was added potassium carbonate (627 mg, 4.54 mmol) followed by 16-5 (600 mg, 1 .82 mmol), catalytic amount of tetrabutylammonium iodide at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (50 mL), washed with water (2 X 50 mL), brine (25 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH-DCM to afford 16-6 (850 mg, 1.33 mmol, 89% yield) as an off-white solid. MS (ESI): m/z 637.33 [M+H]+. 4-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxymethyl)-benzoic acid (16-7).

[00714] To a stirred solution of 16-6 (850 mg, 1.34 mmol) in THF and water (10 ml; 4:1) was added LiOH (192 mg, 8.02 mmol) at 0 °C and reaction was continued at RT for 16 hours. Upon completion of reaction (TLC), solvents were evaporated via rotary evaporator, and the residue was extracted with ether (25 ml). The aqueous layer was neutralized with 1N HCl (2 ml) and extracted with EtOAc (3 X 20 ml). The combined organic layers were washed with brine (2 X 15 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by preparative HPLC to obtain 16-7 (72 mg, 0.12 mmol, 8.6% yield) as an off-white solid. MS (ESI): m/z 623.3 [M+1]+. EXAMPLE 17A Ethyl 2-fluoro-5-methylbenzoate (17A-2).

[00715] To a stirred solution of 2-fluoro-5-methylbenzoic acid 17A-1 (2 g, 12.9 mmol) in EtOH (20 ml) was added H2SO4 (0.1 ml, catalytic) at 0 °C and the reaction was refluxed for two hours. The reaction mixture was concentrated and the residue was added cold water (100 ml) and extracted with EtOAc (3 X 200 ml). The combined organic layers were washed with water (2 X 200 ml), brine (150 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 15% EtOAc/hexanes to afford 17A-2 (2.2 g, 12.08 mmol, 95% yield) as a thick colorless liquid. MS = 183.1 [M+H]+. Ethyl 5-(bromomethyl)-2-fluorobenzoate (17-3A).

[00716] To a stirred solution of 17-2A (2.2 g, 12.09 mmol) in ACN (20 ml) was added NBS (2.32 g, 13.1 mmol) and AIBN (198 mg, 1, 21 mmol) at RT. The reaction mixture was heated to 90°C for 6 hours under a nitrogen atmosphere. The reaction mixture solvent was evaporated under reduced pressure and the crude residue was washed with toluene (100 ml) and the filtrate was precipitated (NBS). The filtrate was evaporated under reduced pressure and the crude residue was purified by flash column chromatography (100 to 200 silica) using 5% EtOAc/pet ether. to afford 17-3A (2.51 g, 19.61 mmol, 81% yield) as a colorless liquid. Ethyl 2-fluoro-5-((2-(2-((tetrahydro-2H-pyran-2-yl)-oxy)-ethoxy)-ethoxy)-methyl)benzoate (17A-4).

[00717] To a stirred solution of 2-4A (656 mg, 3.40 mmol) in THF (5 ml) was added NaH (165 mg, 3.40 mmol) at 0 °C, and the reaction was continued at RT for 30 min. 17A-3 (1.0g, 3.8 mmol) in THF (10 ml) was added to the reaction mixture at 0°C over 5 min and the reaction was continued at RT for 16 hours. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3 X 100 mL), the combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over Na 2 SO 4 and concentrated . The residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/hexanes to afford 17A-4 (270 mg, 0.729 mmol, 8.9% yield) as a thick yellow liquid. MS = 283.1 [M-THP]+. Ethyl 2-fluoro-5-((2-(2-hydroxyethoxy)-ethoxy)-methyl)benzoate (17A-5).

[00718] To a stirred solution of 17A-4 (270 mg, 0.72 mmol) in MeOH (5 mL) was added PPTS (37 mg, 0.014 mmol) at 0 °C and stirred at RT for 12 hours. Solvents were distilled off under reduced pressure. The obtained residue was extracted with EtOAc (3 X 50 ml), the combined organic layers were washed with brine (50 ml), dried with Na 2 SO 4 and concentrated to provide 17A-5 (190 mg, 0.61 mmol, 91% yield ) as a brown gummy liquid. MS = 283.09 [M-1]-. 2-Fluoro-5-[2-(2-methanesulfonyloxy-ethoxy)-ethoxymethyl]-benzoic acid ethyl ester (17A-6).

[00719] Methanesulfonyl chloride (0.06 ml, 0.79 mmol) was added to a solution of 17A-5 (190 mg, 0.61 mmol) in DCM (5 ml) and triethylamine (0.28 ml , 1.91 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water (50 ml) extracted with DCM (3 X 50 ml), the combined organic layers were washed with brine (50 ml), dried with Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 25% EtOAc in hexane to afford 17A-6 (108 mg, 0.32 mmol, 44.8% yield) as a colorless gummy liquid. MS = 382.09 [M+18]+. 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]-2 acid ethyl ester -fluoro-benzoic(17A-7).

[00720] To a stirred solution of 1-12 (100 mg, 0.24 mmol) in DMF (5 ml) was added potassium carbonate (103 mg, 0.74 mmol) followed by 17A-6 (108 mg, 0 .29 mmol), a catalytic amount of TBAI at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (50 ml), washed with water (2 X 40 ml), brine (25 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 25% EtOAc:pet ether. to afford 17A-7 (59 mg, 0.088 mmol, 35.2% yield) as an off-white solid. MS = 670.9 [M+1]+. 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]-2-fluoro acid - benzoyl (17A-8A).

[00721] To a stirred solution of 17A-7 (50 mg, 0.07 mmol) in THF and water (3 mL; 1:1) was added LiOH (18 mg, 0.74 mmol) at 0 °C and reaction was continued at RT for 5 h. After completion of the reaction (TLC), the solvents were evaporated under reduced pressure, the residue was extracted with ether (50 ml). Then the aqueous layer was neutralized with 1N HCl (5 ml) followed by extraction with EtOAc (3 X 20 ml). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The residue was washed with ether pentene to afford 17A-8A (14.2 mg, 30.1% yield) as an off-white solid. MS = 641.29 [M-1]-. 5-Cyclopropyl-6-({2-[2-(4-fluoro-3-hydroxycarbamoyl-benzyloxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-2-(4-fluoro-phenyl)-benzofuran-3 acid - carboxylic acid (17A-8B).

[00722] To a stirred solution of hydroxylamine hydrochloride (1 g, 14.34 mmol) in MeOH (1.5 ml) was added KOH (1.2 g, 21.51 mmol) in MeOH at 0 °C. One ml of this solution was added to a solution of 17A-7 (50 mg, 0.07 mmol) in MeOH at 0 °C, and the reaction was continued at RT for one hour. Upon completion of the reaction (TLC), the solvents were evaporated under reduced pressure, then water was added and the solution was neutralized with 1N HCl (5 mL), followed by extraction with EtOAc (3 X 20 mL). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The residue was purified with preparative HPLC to afford 17A-8B (5 mg, 10% yield) as a brown solid. MS = 658.2 [M+1]+. EXAMPLE 17B Methyl 2-methoxy-5-methylbenzoate (17B-2).

[00723] To a stirred solution of 2-hydroxy-5-methylbenzoic acid 17B-1 (3 g, 19.73 mmol) in DMF (50 ml) was added K2CO3 (8.2 g, 59.21 mmol) and iodide of methyl (2.7 mL, 43.41 mmol) at 0 °C and the reaction was stirred at RT for 6 hours. To the reaction mixture was added cold water (100 ml) and extracted with EtOAc (3 X 100 ml), the combined organic layers were washed with water (2 X 200 ml), brine (150 ml), dried with Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 15% EtOAc/hexanes to afford 17B-2 (3.4 g, 18.88 mmol, 85% yield) as a thick colorless liquid. MS (ESI): m/z 181.1 (M+1)+.

[00724] 5-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 2-methoxybenzoic (17B-8): From 17B-2, substituted for 17A-2 in Step B, the procedure given in Example 17A was adapted to prepare 17B-8. MS (ESI): m/z 654.8 (M+1)+. EXAMPLE 18 Methyl 4-iodo-2-methylbenzoate (18-2A).

[00725] To a solution of 4-iodo-2-methyl-benzoic acid 18-1A (2 g, 7.62 mmol) in MeOH (20 ml) was added thionyl chloride (1.5 ml, 10.87 mmol ) at 0°C and stirred at reflux for 6 hours. The reaction mixture was distilled and diluted with EtOAc (50 ml), washed with water (100 ml), NaHCO 3 solution (50 ml), dried with Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (10% EtOAc in hexanes) to afford 18-2A (1.8 g, 6.55 mmol, 85.7% yield) as a liquid. oily brown. Methyl 4-formyl-3-methylbenzoate (18-3B).

[00726] A stirred solution of 18-2B (3.2 g, 11.5 mmol; TCI) in THF was treated with isopropyl magnesium chloride (i-PrMgCl) in THF (22.8 mL of 2.0 M in THF, 46 mmol) at -15°C. After two hours of stirring at the same temperature, dry DMF (4.3 ml, 57.5 mmol) was added and the reaction was allowed to warm to 23°C over one hour. After consumption of starting material (by TLC), the reaction was quenched with 1M aqueous HCl (60 mL), followed by extraction with EtOAc, dried with Na2SO4 and concentrated. The crude compound was purified by flash column chromatography (100 to 200 silica) using 5% EtOAc in hexanes to afford 18-3B (1.4 g, 7.8 mmol, 70% yield) as a solid whitish. MS (ESI): m/z 179.2 (M+1)+.

[00727] Step B above was adapted using methyl 4-iodo-2-methylbenzoate (18-2A) (1.8 g, 6.52 mmol) to prepare 18-3A (906 mg, 78 %). Methyl 4-(hydroxymethyl)-3-methylbenzoate (18-4B).

[00728] To a stirred solution of 18-3B (1.4 g, 7.8 mmol) in MeOH, was added NaBH4 (0.29 g, 7.8 mmol) at 0 °C and stirred at RT for 30 min . After consumption of starting material (TLC), the reaction mixture was quenched with saturated ammonium chloride solution, then MeOH was distilled off and the aqueous layer was extracted with EtOAc, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude product was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexane to provide 18-4B (1.2 g, 6.6 mmol, 84% yield) as a colorless liquid. MS (ESI): m/z 181.0 (M+1)+.

[00729] Step C above was adapted using 18-3A (900 mg, 5.0 mmol) to prepare 18-4A (801 mg, 88%). MS (ESI): m/z 81.17 [M+1]+. Methyl 4-(bromomethyl)-3-methylbenzoate (18-5B).

[00730] To a stirred solution of 18-4B (1.2 g, 6.6 mmol) in DCM, was added phosphorus tribromide (0.64 ml, 6.6 mmol) at 0 °C and stirred at RT for 30 min. After consumption of the starting material (by TLC), the reaction was quenched with saturated NaHCO 3 solution and extracted with DCM. The organic layer was dried with Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100 to 200 silica) using 5% EtOAc in hexane to provide 18-5B (0.95 g, 3.9 mmol, 59% yield) as a colorless semi-solid.

[00731] Step D above was adapted using 18-4A (1.42 g, 7.88 mmol) to prepare 18-5A (920 mg, 48%). Methyl 3-methyl-4-((2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethoxy)-methyl)benzoate (18-6B).

[00732] To a stirred solution of 2-4A (0.745 g, 3.9 mmol) in THF (20 ml) was added NaH (102 mg, 4.29 mmol) in portions at 0 °C and stirred at RT for one hour, then a solution of 18-5B (950 mg, 3.9 mmol) in THF (10 mL) is added at the same temperature and stirred at RT for 4 h. The reaction mixture was quenched with saturated ammonium chloride solution and diluted with EtOAc (100 ml), washed with water (100 ml), brine (50 ml) and dried with Na2SO4 and the organic phase was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexane to afford 18-6B (500 mg, 1.42 mmol, 36% yield) as a pale yellow liquid. MS (ESI): m/z 269.0 (M-THP+1)+.

[00733] Step E above was adapted using [18-5A (650 mg, 3.81 mmol) to prepare [18-6A (602 mg, 44%). MS (ESI): m/z 370.39 [M+18]+. Methyl 4-((2-(2-hydroxyethoxy)-ethoxy)-methyl)-3-methylbenzoate (18-7B).

[00734] To a solution of 18-6B (500 mg, 1.42 mmol) in MeOH (10 ml) was added PPTS (35.6 mg, 0.14 mmol) and stirred at 0°C to RT for 16 hours . The reaction mixture was distilled and diluted with excess EtOAc (50 ml), washed with water (50 ml), brine (20 ml), dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexane to afford 187B (270 mg, 1.0 mmol, 71% yield) as a yellow liquid. MS (ESI): m/z 269.0 (M+1)+.

[00735] Step F above was adapted using 18-6A (600 mg, 1.7 mmol) to prepare 18-7A (252 mg, 57%). MS (ESI): m/z 269.2 [M+1]+. 4-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxymethyl]-3-methyl-benzoic acid methyl ester (18-8B).

[00736] To a stirred solution of 18-7B (0.270 g, 1.01 mmol) in DCM (6 ml) was added triethylamine (0.33 ml, 2.41 mmol) and methanesulfonyl chloride (0.097 ml, 1, 2 mmol) at 0°C and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml), brine (20 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100 to 200 silica) using 25% EtOAc in hexane to provide 18-8B (250 mg, 0.72 mmol, 71% yield) as a colorless liquid. MS (ESI): m/z 347.0 (M+1)+.

[00737] Step G was adapted using 18-7A (260 mg, 0.9 mmol) to prepare 18-8A (270 mg, 80.4%). MS (ESI): m/z 347.1 [M+1]+. 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]-3 acid methyl ester -methyl-benzoyl (18-9B).

[00738] To a solution of 1-12 (252 mg, 0.62 mmol) in DMF (5 ml) was added potassium carbonate (260 mg, 1.88 mmol) followed by 18-8B (250 mg, 0. 72 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (15 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexane to afford 18-9B (210 mg, 0.32 mmol, 51% yield) as an off-white solid. MS (ESI): m/z 653.3 (M+1)+.

[00739] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid methyl ester ethoxymethyl]-2-methyl-benzoyl (18-9A): Step H was adapted using 18-8A (225 mg, 1.55 mmol) to prepare 18-9A (184 mg, 50%). MS (ESI): m/z 653.2 [M+1]+.

[00740] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 3-methyl-benzoyl (18-10B).

[00741] To a solution of 18-9B (100 mg, 0.15 mmol) in THF and water (4:1; 6 mL) was added LiOH.H2O (22 mg, 0.91 mmol) and stirred at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the reaction mixture was neutralized with 1N HCl and then extracted with EtOAc (3 X 20 mL). The combined organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude compound was purified by column chromatography (100 to 200 silica) using 2% MeOH in DCM, followed by DCM and pentane wash to afford 18-10B (45 mg, 0.07 mmol, 46% yield) as an off-white solid. MS (ESI): m/z 639.0 (M+1)+.

[00742] 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid 2-methyl-benzoyl (18-10A): This procedure was adapted using 18-9A (100 mg, 0.1 mmol) to prepare 18-10A (37 mg, 38%). MS (ESI): m/z 639.3 [M+1]+. EXAMPLE 19 Methyl 2-chloroisonicotinate (19-2A).

[00743] To a solution of 2-chloroisonicotinic acid 19-1A (5 g, 31.8 mmol) in MeOH (50 ml) was added SOCl2 (2.7 ml, 38.2 mmol) in portions at 0°C, and the mixture was stirred at RT for 16 hours. The solvent was evaporated under reduced pressure. The reaction was quenched with saturated sodium carbonate and diluted with EtOAc (50 mL), washed with water (50 mL), brine (20 mL) and dried over Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound obtained was purified using silica gel chromatography (15% EtOAc in hexanes) to provide 19-2A (4.4 g, 25.7 mmol, 81% yield) as an off-white solid. MS (ESI): m/z 172.1 (M+1)+.

[00744] Step A was adapted using 6-chloronicotinic acid to prepare 19-2B. (6-chloropyridin-3-yl)-methanol (19-3B).

[00745] To a solution of 19-2B (500 mg, 2.693 mmol) in MeOH (5 ml) was added sodium borohydride (153 mg, 4.04 mmol) in portions at 0°C and stirred at RT for 16 hours . The reaction was quenched with saturated ammonium chloride and diluted with EtOAc (50 ml) washed with water (50 ml), brine (20 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure to obtain the crude compound. The crude composition was purified using silica gel chromatography (30% EtOAc in hexanes) to provide 19-3B (230 mg, 1.60 mmol, 59% yield) as a pale yellow solid. MS (ESI): m/z 144.0 (M+1)+.

[00746] Step B was adapted using 19-2A (1 g, 5.8 mmol) to prepare 19-3A (800 mg, 95%). MS (ESI): m/z 144.0 (M+1)+. 5-(bromomethyl)-2-chloropyridine (19-4B).

[00747] To a solution of 19-3B (115 mg, 0.804 mmol) in DCM (3 ml) was added carbon tetrabromide (320 mg, 0.965 mmol), triphenylphosphine (210 mg, 0.965 mmol) and stirred at 0 °C to RT for 16 hours. The reaction mixture was diluted with excess DCM (20 ml), washed with water (20 ml), brine (10 ml) and dried over Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound obtained was purified using silica gel chromatography (8% EtOAc in hexanes) to provide 19-4B (100 mg, 0.48 mmol, 60% yield). MS (ESI): m/z 206.0 (M-1)+.

[00748] Step C was adapted using 19-3A (800 mg, 5.5 mmol) to prepare 19-4A (600 mg, 52%). MS (ESI): m/z 206.1 (M-1)+. 2-(chloro-5-((2-(2-((tetrahydro-2H-pyran-2-yl)oxy)-ethoxy)-ethoxy)-methyl)-pyridine) (19-5B).

[00749] To a solution of 2-4A (77 mg, 0.40 mmol) in THF (2 ml) was added NaH (12 mg, 0.48 mmol) in portions at 0 °C and stirred at RT for 1 h and then a solution of 19-4B in THF (100 mg, 0.40 mmol; 1 ml) is added at the same temperature and stirred at RT for 3 hours. The reaction was quenched with saturated ammonium chloride and diluted with EtOAc (50 ml) washed with water (50 ml), brine (20 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure to obtain the crude compound. The crude compound was purified using silica gel chromatography (35% EtOAc in hexanes) to afford 19-5B (70 mg, 0.22 mmol, 55% yield) as a brown gummy liquid. MS (ESI): m/z 316.3 (M+1)+.

[00750] Step D was adapted using 19-4A (600 mg, 2.9 mmol) to prepare 19-5A (300 mg, 30%). MS (ESI): m/z 316.3 (M+1)+. 2-(2-((6-chloropyridin-3-yl)-methoxy)-ethoxy)-ethanol (19-6B).

[00751] To a solution of 19-5B (70 mg, 0.22 mmol) in MeOH (1 ml) was added PPTS (11 mg, 0.04 mmol) and stirred at 0°C to RT for 16 hours. The reaction mixture was distilled and diluted with excess EtO-Ac (20 ml), washed with water (20 ml), brine (10 ml) and dried over Na2SO4 and the organic phase was concentrated under reduced pressure to obtain a crude compound . The crude compound was purified using silica gel chromatography (50% EtOAc in hexanes) to provide 19-6B (40 mg, 0.173 mmol, 78% yield) as a brown gummy liquid. Confirmed by 1H NMR.

[00752] Step E was adapted using 19-5A (300 mg, 0.95 mmol) which was used to prepare 19-6A (100 mg, 45%). MS (ESI): m/z 232.1 (M+1)+. 2-(2-((6-Chloropyridin-3-yl)-methoxy)-ethoxy)-ethyl methanesulfonate (19-7B).

[00753] Methanesulfonyl chloride (29 mg, 0.26 mmol) was added to a solution of 19-6B (40 mg, 0.17 mmol) in DCM (1 ml) and triethylamine (43 mg, 0.4329 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with excess DCM (10 ml) and washed with water (10 ml), brine (10 ml) and dried over Na 2 SO 4 , and the organic phase concentrated under reduced pressure to obtain the crude compound. The obtained compound was purified using silica gel 100 to 200 column chromatography (40% EtOAc in hexanes) to afford 19-7B (36 mg, 0.116 mmol, 67% yield) as a brown oily liquid. MS (ESI): m/z 310.18 (M+1)+.

[00754] Step F was adapted using 19-6A (100 mg, 0.43 mmol) was used to prepare 19-7A (100 mg, 76%). MS (ESI): m/z 310.1 (M+1)+. 2-(2-((6-chloropyridin-3-yl)-methoxy)-ethoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (19- 8B).

[00755] To a solution of 1-12 (39 mg, 0.097 mmol) in DMF (1 ml) was added potassium carbonate (40 mg, 0.291 mmol) followed by 19-7B (36 mg, 0.11 mmol), catalytic amount of TBAI then stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (20 ml), washed with water (20 ml), brine (15 ml) and dried with Na2SO4 and the organic phase was concentrated under reduced pressure. The obtained crude product was purified using preparative TLC method to provide 19-8B (25 mg, 0.04 mmol, 34% yield). MS (ESI): m/z 616.4 (M+1)+.

[00756] 6-({2-[2-(2-Chloro-pyridin-4-ylmethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl) methylamide )-benzofuran-3-carboxylic acid (19-8A). Step G was adapted using 19-7A (100 mg, 0.32 mmol) to prepare 19-8A (39 mg, 17%). MS (ESI): m/z 616.2 (M+1)+. EXAMPLE 20 Ethyl 4-methyl-1-naphthoate (20-2).

[00757] To a solution of 20-1 (5 g, 26.9 mmol) in ethanol (50 ml) was added thionyl chloride (4.8 g, 40.32 mmol) at 0°C and stirred at reflux for 6 hours. The reaction mixture was distilled and diluted with EtOAc (100 ml), washed with water (100 ml), NaHCO 3 solution (50 ml) and dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (10% EtOAc in hexanes) to afford 20-2 (5 g, 23.63 mmol, 87% yield) as a brown oily liquid. MS (ESI): m/z 215.1 (M+1)+. Methyl 4-(bromomethyl)-1-naphthoate (20-3).

[00758] To a solution of 20-2 (1 g, 4.67 mmol) in ACN (40 ml) was added N-bromosuccinimide (744 mg, 4.20 mmol), azoisobutyronitrile (76 mg, 0.46 mmol) and stirred at reflux for 6 hours. The reaction mixture was diluted with EtOAc (100 ml), washed with water (100 ml), brine (50 ml) and dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (3% EtOAc in hexanes) to provide 20-3 (600 mg, 2.05 mmol, 44% yield). MS (ESI): m/z 293.1 (M+1)+. Ethyl 4-((2-(2-((tetrahydro-2H-pyran-2-yl)-oxy)-ethoxy)-ethoxy)-methyl)-1-naphthoate (20-4).

[00759] To a solution of 2-4A (800 mg, 4.21 mmol) in THF (20 ml) was added NaH (121 mg, 5.05 mmol) in portions at 0 °C and stirred at RT for one hour and added a solution of 20-3 (1.47 g, 5.05 mmol) in THF (10 ml) at the same temperature and stirred at RT for 3 hours. The reaction mixture was quenched with saturated ammonium chloride and diluted with EtOAc (100 ml), washed with water (100 ml), brine (50 ml), dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (30% EtOAc in hexanes) to afford 20-4 (600 mg, 1.49 mmol, 35% yield) as a pale green gummy liquid. MS (ESI): m/z 420.4 (M+18)+. Ethyl 4-((2-(2-hydroxyethoxy)-ethoxy)-methyl)-1-naphthoate (20-5).

[00760] To a solution of 20-4 (600 mg, 1.49 mmol) in MeOH (10 ml) was added PPTS (37.7 mg, 0.15 mmol) and stirred at 0°C to RT for 16 hours . The reaction mixture was distilled and diluted with excess EtO-Ac (50 ml), washed with water (50 ml), brine (20 ml) and dried over Na 2 SO 4 and concentrated under reduced pressure to obtain the crude compound. The crude compound obtained was purified using silica gel chromatography (50% EtOAc in hexanes) to afford 20-5 (365 mg, 1.15 mmol, 77% yield) as a pale green gummy liquid . MS (ESI): m/z 319.3 (M+1)+. 4-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxymethyl]-naphthalene-1-carboxylic acid ethyl ester (20-6).

[00761] Methanesulfonyl chloride (193 mg, 1.69 mmol) at 0 °C was added to a solution of 20-5 (360 mg, 1.13 mmol) in DCM (5 ml) and triethylamine (286 mg, 2 .83 mmol) and stirred at RT for two hours. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml), brine (20 ml), dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified using silica gel 100 to 200 column chromatography (40% EtOAc in hexanes) to afford 20-6 (355 mg, 0.89 mmol, 79% yield) as an oily liquid. pale green. MS (ESI): m/z 397.2 (M+1)+. 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]-naphthalene acid ethyl ester -1-carboxylic acid (20-7).

[00762] To a solution of 1-12 (250 mg, 0.62 mmol) in DMF (4 ml) was added potassium carbonate (257 mg, 1.86 mmol) followed by 20-6 (295 mg, 0. 74 mmol), the catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (15 ml), dried over Na 2 SO 4 , and concentrated under reduced pressure. The crude compound was purified using silica gel 100 to 200 column chromatography (40% EtOAc in hexanes) to provide 20-7 (180 mg, 0.25 mmol, 39% yield) as a solid solid. -whitened. MS (ESI): m/z 703.3 (M+1)+. 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]-naphthalene-1 acid - carboxylic (20-8).

[00763] To a solution of 20-7 (100 mg, 0.14 mmol) in MeOH, THF and water (1:4:1; 6 mL) was added LiOH.H2O (28 mg, 0.71 mmol) and stirred at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the reaction mixture was neutralized with 1N HCl and then extracted with EtOAc (3 X 25 mL). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude compound was purified by preparative TLC to afford 20-8 (30 mg, 0.04 mmol, 31% yield) as an off-white solid. MS (ESI): m/z 673.5 (M+1)+. EXAMPLE 21 2-(2-(Tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethyl methanesulfonate (21-1).

[00764] To a stirred solution of 2-4A (300 mg, 1.57 mmol) in DCM, was added triethylamine (0.3 ml, 1.88 mmol) at 0°C. After 5 min, mesyl chloride (0.15 mL, 1.88 mmol) was added to the reaction mixture at the same temperature, then the reaction was heated to stir at RT for two hours. The reaction mixture was diluted with water and extracted with DCM (3 X 30 ml). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated. The crude compound was purified by column chromatography to afford 21-1 (390 mg, 1.45 mmol, 92% yield) as an off-white solid. 5-cyclopropyl-2-(4-fluorophenyl)-N-methyl-6-(N-(2-(2-(tetrahydro-2H-pyranyloxy)ethoxy)ethyl)-methylsulfonamido)benzofuran-3-carboxamide (21-2).

[00765] To a stirred solution of 1-12 (300 mg, 0.75 mmol) in DMF (10 ml) was added potassium carbonate (309 mg, 2.24 mmol) followed by 21-1 (237 mg, 0 .89 mmol), catalytic amount of tetrabutylammonium iodide at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (50 mL), washed with water (2 X 40 mL), brine (25 mL) and dried over Na 2 SO 4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH-DCM to afford 21-2 (312 mg, 0.54 mmol, 73% yield) as an off-white solid. MS (ESI): m/z 572.8 (M-1)-. 5-cyclopropyl-2-(4-fluorophenyl)-6-(N-(2-(2-hydroxyethoxy)-ethyl)-methylsulfonamido)-N-methylbenzofuran-3-carboxamide (21-3).

[00766] To a stirred solution of 21-2 (312 mg, 0.54 mmol) in MeOH (6 ml) was added pyridinium p-toluenesulfonate (30 mg, 0.11 mmol) at 0 °C and stirred at RT for 16 hours. Solvents were distilled off under reduced pressure. The obtained residue was extracted with EtOAc (3 X 20 ml). The combined organic layer was washed with brine (10 ml), dried over Na 2 SO 4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (100 to 200 silica) using 5% acetone-DCM to afford 21-3 (200 mg, 0.4 mmol, 76%) as a gummy liquid. MS (ESI): m/z 491.4 (M+1)+. Methanesulfonic acid 2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethyl ester (21-4) .

[00767] To a stirred solution of 21-3 (40 mg, 0.08 mmol) in DCM, was added triethylamine (0.02 ml, 0.19 mmol) at 0°C. After 5 min, mesyl chloride (0.007 ml, 0.09 mmol) was added to the reaction mixture at the same temperature. The reaction mixture was allowed to stir at RT for two hours. Thereafter, the reaction mixture was diluted with water and extracted with DCM (2 X 20 ml). The combined organic layer was washed with brine, dried over Na 2 SO 4 and concentrated under reduced pressure. The crude compound was purified by column chromatography to obtain 21-4 (41 mg, 0.07 mmol, 90% yield) as an off-white solid. MS (ESI): m/z = 569.4 (M+1)+. Thioacetic acid S-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethyl] ester ( 21-5).

[00768] To a stirred solution of 21-4 (41 mg, 0.7 mmol) in DMF (2 ml), potassium thioacetate (KSAc; 8.15 mg, 0.072 mmol) was added slowly at 0 °C and stirred at RT for 16 hours. The reaction mixture was diluted with water (15 ml), extracted with EtOAc (3 X 25 ml). The combined organic layers were washed with brine (2 X 15 ml) and dried over Na 2 SO 4 and concentrated under reduced pressure. The crude residue was purified by flash column chromatography (100 to 200 silica) using 10% EtOAc/hexane to provide 21-5 (16 mg, 0.029 mmol, 41% yield) as a colorless solid. MS (ESI): m/z 548.6 [M+1]+. EXAMPLE 22 1-(3-(3-hydroxyprop-1-en-1-yl)-phenyl)-ethanone (22-2). To a stirred solution of 1-(3-iodophenyl)ethanone 22-1 (200 mg, 0.81 mmol) in DMF (3 mL) was added allyl alcohol (252 mg, 4.06 mmol), AgOAc (137 mg, 0.81 mmol), TPP (21 mg, 0.081 mmol). The mixture was purged with argon for 15 min and Pd(OAc) 2 (27 mg, 0.04 mmol) was added at RT. The reaction mixture was heated at 70 °C for 16 h under a nitrogen atmosphere. The reaction mixture was diluted with water (10 mL) extracted with EtOAc (3 X 50 mL), the combined organic layers were washed with brine (2 X 40 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (100 to 200 silica) using 20 to 25% EtO-Ac/pet ether. to afford 22-2 (100 mg, 0.56, 69.9% yield) as a colorless liquid. MS=177.1 [M+1]+. 1-(3-(3-hydroxypropyl)-phenyl)-ethanone (22-3).

[00769] To a stirred solution of 22-2 (200 mg, 1.13 mmol) in EtOH (10 ml) was added NaHCO3 (95 mg, 1.13 mmol), Pd/C (10% w/w) 15 mg, at RT. The reaction mixture was stirred for 3 h under H2 atmosphere (1 atm). The reaction mixture was filtered through a bed of celite, washed with EtOAc (50 mL), the combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure to afford 22-3 (190 mg, 0.94, 95% yield) as a colorless liquid. 3-(3-Acetylphenyl)-propyl methanesulfonate (22-4).

[00770] Methanesulfonyl chloride (0.137 ml, 1.68 mmol) was added to a solution of 22-3 (250 mg, 1.40 mmol) in DCM (10 ml) and triethylamine (0.591 ml, 4.21 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water (50 ml), extracted with DCM (3 X 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 15% EtOAc in hexanes to provide 22-4 (180 mg, 0.703 mmol, 50.1% yield) as a colorless liquid. MS = 257.1 [M+1]+. 2-((tetrahydro-2H-pyran-2-yl)-oxy)-ethanol (22-6).

[00771] To a stirred solution of ethane-1,2-diol 22-5 (5 g, 80.6 mmol) in DCM (50 ml) was added DHP (6.4 g, 76.61 mmol) and PTSA ( 1.53 g, 8.06 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water (150 ml), extracted with DCM (3 X 200 ml), the combined organic layers were washed with brine (2 X 100 ml), dried with Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc-pet ether. to afford 22-6 (1.2 g, 8.21, 10.2% yield) as pale yellow liquid. 1-(3-(3-(2-((tetrahydro-2H-pyran-2-yl)-oxy)-ethoxy)-propyl)-phenyl)-ethanone (227).

[00772] To a stirred solution of 22-6 (926 mg, 6.3 mmol) in DMSO (6 ml) was added NaOH (284 mg, 5.07 mmol) at 0 °C and the reaction was continued at RT for 30 min. 22-4 (650 mg, 2.53 mmol) in DMSO (4 mL) was added to the reaction mixture at 0 °C for 5 min. and the reaction was continued at RT for one hour. The reaction mixture was quenched with cold water (100 ml) and extracted with EtOAc (3 X 100 ml). The combined organic layers were washed with water (2 X 200 ml), brine (150 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 15% EtOAc/hexanes to afford 22-7 (420 mg, 1.37 mmol, 54.5% yield) as a thick colorless liquid. MS = 324.1 [M+1]+. 1-(3-(3-(2-hydroxyethoxy)-propyl)-phenyl)ethanone (22-8).

[00773] To a stirred solution of 22-7 (400 mg, 1.3 mmol) in MeOH (10 ml) was added PPTS (70 mg, 0.26 mmol) at 0°C and stirred at RT for 16 hours. Solvents were distilled off under reduced pressure. The obtained residue was extracted with EtOAc (3 X 100 ml). The combined organic layers were washed with brine (100 mL), dried over Na 2 SO 4 and concentrated to afford 22-8 (210 mg, 0.945 mmol, 72.4% yield) as a colorless gummy liquid. 2-(3-(3-Acetylphenyl)-propoxy)-ethyl methanesulfonate (22-9).

[00774] Methanesulfonyl chloride (0.1 ml, 1.29 mmol) was added to a solution of 22-8 (210 mg, 0.95 mmol) in DCM (50 ml) and triethylamine (0.4 ml, 2 .8 mmol) at 0°C and stirred at RT for one hour. The reaction mixture was diluted with water (50 ml), extracted with DCM (3 X 100 ml). The combined organic layers were washed with brine (100 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 30% EtOAc in hexanes to afford 22-9 (220 mg, 0.733 mmol, 77.7% yield) as a gummy liquid. 6-(N-(2-(3-(3-acetylphenyl)-propoxy)-ethyl)-methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (22-10) .

[00775] To a stirred solution of 1-12 (100 mg, 0.24 mmol) in DMF (5 ml) was added potassium carbonate (103 mg, 0.74 mmol) followed by 22-9 (110 mg, 0 .37 mmol), catalytic amount of TBAI at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (75 mL), washed with water (2 X 40 mL), brine (25 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 30% EtO-Ac:pet ether. to afford 22-10 (110 mg, 0.181 mmol, 73.3% yield) as an off-white solid. MS = 607.11 [M+1]+. 4-{3-[3-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-propyl acid ethyl ester ]-phenyl}-2-hydroxy-4-oxo-but-2-enoic (22-11).

[00776] To a stirred solution of 22-10 (50 mg, 0.082 mmol) in THF (3 ml) was added KHMDS (0.247 ml, 0.24 mmol) at -78 °C, and the reaction mixture was warmed to -55°C for one hour. Then, diethyl oxalate (0.048 mL, 0.31 mmol) was added to the reaction mixture at -78 °C and the reaction mixture was warmed to -55 °C for 2 h under a nitrogen atmosphere. The reaction mixture was quenched with ammonium chloride solution, extracted into EtOAc (3 X 40 ml). The combined organic layers were washed with brine (2 X 20 mL), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography using neutral silica (100 to 200 silica) in 2% MeOH-DCM to afford (40 mg, crude compound) 2211 as a brown gummy mass. MS = 707.24 [M+1]+. 4-(3-(3-(2-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)-ethoxy)-propyl)-phenyl acid )-2-hydroxy-4-oxobut-2-enoic (22-12).

[00777] To a stirred solution of 22-11 (40 mg, 0.056 mmol) in THF and water (1 ml; (1:1)) was added LiOH (8 mg, 0.33 mmol) at 0°C and reaction was continued at RT for 5 h. After completion of the reaction (TLC), the solvents were evaporated under reduced pressure, the residue was extracted with ether (50 ml). Then, aqueous layer was neutralized with 1N HCl (5 ml) followed by extraction with EtOAc (3 X 20 ml). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by preparative HPLC to obtain 22-12 (4 mg) as light thick mass. MS = 679.1 [M+1]+. EXAMPLE 23 t-Butyl 2-(2-(2-(2-hydroxyethoxy)-ethoxy)-ethoxy)acetate (23-3A).

[00778] To a stirred solution of 2,2'-(ethane-1,2-diylbis(oxy))diethanol 23-1 (5 g, 33.33 mmol) in DMSO (50 ml) was added tert- Potassium butoxide (2.2 g, 20 mmol) at 0 °C, and tert-butyl 2-bromoacetate 23-2A (2.5 mL, 15.43 mmol) were added to the reaction mixture at 0 °C. Then, the reaction mixture was heated to 60°C and stirred for 16 hours. The reaction mixture was quenched with cold water (100 ml) and extracted with EtOAc (3 X 200 ml). The combined organic layers were washed with water (2 X 200 ml), brine (150 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 40% EtOAc/hexanes to afford 23-3A (1.2 g, 4.87 mmol, 13.6% yield) as a thick liquid yellow. Confirmed by 1H NMR. 2,2,3,3-tetramethyl-4,7,10-trioxa-3-siladodecan-12-ol (23-2B1):

[00779] To a stirred solution of 23-1 (20 g, 133.33 mmol) in dichloromethane (100 mL) was added imidazole (5.4 g, 79.99 mmol) and TBDMSCl (10.0 g, 66. 66 mmol) at 0°C and stirred at RT for 10 hours. The reaction mixture was diluted with DCM (200 ml) and washed with water (2 X 100 ml) and brine (50 ml). The organic layer was concentrated under reduced pressure and the crude residue was purified by flash column chromatography (100 to 200 silica) using 20% ethyl acetate/pet ether. gave 23-2B1 (10 g, 37.87 mmol, 28% yield) as a colorless liquid. 2,2,3,3-Tetramethyl-4,7,10-trioxa-3-siladodecan-12-yl methanesulfonate (23-2B2).

[00780] Methanesulfonyl chloride (1.5 ml, 18.93 mmol) and triethylamine (3.2 ml, 22.72 mmol) were added to a solution of 23-2B1 (5 g, 18.93 mmol) in DCM (100 ml) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water (25 ml), extracted with DCM (3 X 25 ml). The combined organic layers were washed with saturated NaHCO 3 solution (10 ml), brine (25 ml), dried over Na 2 SO 4 and concentrated. This crude compound was purified by flash column chromatography (100 to 200 silica) using 15% EtOAc/hexanes to provide 23-2B2 (1.1 g, 3.21 mmol, 85% yield) as a colorless liquid. Ethyl 2,2,3,3,14-pentamethyl-4,7,10,13-tetraoxa-3-silapentadecan-15-oate (23-2B3).

[00781] To a stirred solution of 23-2X (0.35 g, 2.96 mmol) in THF (5 ml) was added NaH (0.23 g, 5.92 mmol) in THF (10 ml) at 0 °C, and the reaction was continued at RT for 30 min. 23-2B2 (1.1 g, 3.21 mmol) in THF (5 mL) was added to the reaction mixture at 0 °C over 5 min, and the reaction was warmed to RT and stirred for 16 hours. The reaction mixture quenched with cold water (50 ml) and extracted with EtOAc (3 X 30 ml). The combined organic layers were washed with water (2 X 20 ml), brine (15 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/hexanes to provide 23-2B3 (0.14 g, 0.38 mmol, 11% yield) as a colorless liquid. Ethyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)propanoate (23-3B). To a stirred solution of 23-2B3 (1.7 g, 4.67 mmol) in THF (20 ml) was added 1M TBAF in THF solution (8.0 ml, 8.0 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with water and extracted with EtOAc (3 X 50 mL), the combined organic layers were washed with brine (25 mL), dried over Na 2 SO 4 and concentrated to afford 23-3B (1 g, 4 mmol, 86 %) as a thick yellow liquid. {2-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxy]-ethoxy}-acetic acid tert-butyl ester (23-4A).

[00782] Methanesulfonyl chloride (0.13 ml, 1.59 mmol) was added to a solution of 23-3A (0.42 g, 1.59 mmol) in DCM (15 ml) and triethylamine (0.33 ml , 2.38 mmol) at 0 °C and stirred at RT for one hour. The reaction mixture was diluted with water (50 ml), extracted with DCM (3 X 20 ml). The combined organic layers were washed with brine (25 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexanes to afford 23-4A (0.3 g, 0.87 mmol, 55% yield) as a gummy liquid. 2-{2-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxy]-ethoxy}-propionic acid ethyl ester (23-4B). Step B above was adapted using 23-3B (1 g, 4.0 mmol) to prepare 23-4B (1.3 g, 99%). {2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- tert-butyl ester ethoxy]-ethoxy}-acetic (23-5A).

[00783] To a stirred solution of 1-12 (0.1 g, 0.24 mmol) in DMF (15 ml) was added potassium carbonate (0.10 g, 0.74 mmol) followed by 23-4A ( 0.12 g, 0.37 mmol), catalytic amount of TBAI at 80°C for 10 hours. The reaction mixture was cooled to RT and diluted with EtOAc (25 mL) washed with water (2 X 20 mL), brine (25 mL) and dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 30% EtO-Ac/pet ether. to afford 23-5A (0.06 g, 0.09 mmol, 62% yield) as an off-white solid. MS (ESI): m/z 693.3 (M+1)+.

[00784] 2-{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}- acid ethyl ester ethoxy)-ethoxy]-ethoxy}-propionic (23-5B): Step C above was adapted using 23-4B (0.15 g, 0.37 mmol) to prepare 23-5B (0.14 g , 59%). MS (ESI): m/z 635.1 (M+1)+.

[00785] {2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy) acid ethyl ester -ethoxy]-ethoxy}-acetic (23-5C): Step C above was also adapted using 23-4C (382 mg, 1.22 mmol) to prepare 23-5C (355 mg 70%). MS (ESI): m/z 621.1 (M+1)+.

METHOD A:

[00786] {2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy] acid -ethoxy}-acetic acid (23-6A).

[00787] To a stirred solution of 23-5A (0.06 g, 0.09 mmol) in DCM (3 ml) was added TFA (1 ml) at 0 °C and the reaction was continued to stir at RT for one hour. Upon completion of the reaction (TLC), the solvents were removed by rotary evaporation. The crude residue was purified by flash column chromatography (100 to 200 silica) using 2% MeOH/DCM to afford 23-6A (0.005 g, 0.008 mmol, 8.9% yield) as an off-white solid. MS (ESI): m/z 615.3 (M+23)+. METHOD B: 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-propionic (23-6B).

[00788] To a stirred solution of 23-5B (0.14 g, 0.220 mmol) in THF and water (8 ml; 4:1) was added LiOH (0.02 g, 0.66 mmol) at 0°C and the reaction was continued at RT for 3 hours. After completion of the reaction (TLC), the solvents were evaporated on a rotary evaporator, the residue was extracted with ether (20 ml). Then, the aqueous layer was neutralized with 1N HCl (5 ml) followed by extraction with EtOAc (3 X 30 ml). The combined organic layers were washed with brine (2 X 25 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washing with pentane and ether to afford 23-6B (0.08 g, 0.13 mmol, 60% yield) as an off-white solid. MS (ESI): m/z 607.0 (M+1)+. 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-({2-[2-(2-hydroxycarbamoylmethoxy-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-benzofuran-3-carboxylic acid methylamide (23-6C).

[00789] To a stirred solution of NH 2 OH·HCl (1 g, 14.34 mmol) in MeOH (1.5 mL) was added KOH (1.2 g, 21.51 mmol) in MeOH at 0 °C. The freshly prepared solution of hydroxylamine (2 ml) in MeOH was added to the solution of 23-5C (50 mg, 0.08 mmol) in MeOH at 0°C and the reaction was continued at RT for one hour. Upon completion of the reaction (TLC), solvents were evaporated under reduced pressure, then water was added and neutralized with 1N HCl (5 mL) followed by extraction with EtOAc (3 X 20 mL). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified with preparative TLC to afford 23-6C (15 mg, 0.02 mmol, 30% yield) as an off-white solid. MS (ESI): m/z 608.7 (M+1)+. 6-({2-[2-(2-Carbamoylmethoxy-ethoxy)-ethoxy]-ethyl}-methanesulfonyl-amino)-5-cyclopropyl-2-(4-fluoro-phenyl)-benzofuran-3-carboxylic acid methylamide (23-7A).

[00790] To a stirred solution of 23-6A (0.03 g, 0.50 mmol) in DCM (20 ml) was added HATU (0.57 g, 1.52 mmol), DIPEA (0.4 ml, 2.53 mmol) and ammonium chloride (0.054 g, 1.01 mmol) at 0°C and stirred at RT for 4 hours. The reaction mixture was diluted with water and extracted with DCM (3 X 25 ml). The combined organic layer was washed with brine (25 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 5% MeOH-DCM to afford 23-7A (0.15 g, 0.25 mmol, 51% yield) as a gummy liquid. MS (ESI): m/z 592.2 (M+1)+. EXAMPLE 24 Ethyl 3-(2-(2-(2-hydroxyethoxy)-ethoxy)-ethoxy)-propanoate (24-1).

[00791] To a stirred solution of 2,2'-(ethane-1,2-diylbis(oxy))diethanol 23-1 (2 g, 13.3 mmol) in THF (30 ml) was added NaH (0. 48 g, 0.012 mmol) at 0 °C and the reaction was continued at RT for two hours. Ethyl 3-bromopropanoate (2.16 g, 0.012 mmol) in THF (10 ml) was added to the reaction mixture at 0 °C over 5 min and the reaction was continued at RT for 16 hours. The reaction mixture was quenched with cold water (100 ml) and extracted with EtOAc (3 X 200 ml). The combined organic layers were washed with water (2 X 50 ml), brine (50 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (230-400 silica) using 50% EtOAc/hexanes to afford 24-1 (150 mg, 0.6 mmol, 5% yield) as a colorless liquid. 2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxyethanol (24-2).

[00792] To a stirred solution of 24-1 (500 mg, 2 mmol) in DCM (5 ml) was added triethylamine (0.36 ml, 2.6 mmol) and methanesulfonyl chloride (0.2 ml, 2.4 mmol) at 0°C and stirred at RT for two hours. The reaction mixture was diluted with excess DCM (40 ml) and washed with water (2 X 20 ml), brine (20 ml) and dried over Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound was purified using 230-400 silica gel column chromatography using 80% EtOAc/hexanes to provide 24-2 (390 mg, 1.18 mmol, 60% yield) as a colorless liquid . 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethyl ester ethoxy]-ethoxy}-propionic (24-3).

[00793] To a solution of 1-12 (370 mg, 0.92 mmol) in DMF (5 ml) was added potassium carbonate (470 mg, 1.15 mmol) followed by 24-2 (380 mg, 1, 15 mmol), catalytic amount of TBAI and stirred at 70°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (30 ml), washed with water (2 X 20 ml), brine (15 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using column chromatography on silica gel 230 to 400 using 5% acetone in DCM to afford the title compound 24-3 (420 mg, 0.66 mmol, 71% yield) as an off-white solid. MS (ESI): m/z 634.80 (M+1)+. 3-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]- acid ethoxy}-propionic (24-4).

[00794] To a stirred solution of 24-3 (250 mg, 0.4 mmol) in THF and water (4 ml, 4:1) was added LiOH (56 mg, 2.0 mmol) at 0 °C and reaction was continued at RT for 16 hours. After completion of the reaction (TLC), the solvents were evaporated on a rotary evaporator. The crude residue was extracted with ether (2 X 30 ml). The aqueous layer was neutralized with 1N HCl (10 ml) followed by extraction with EtOAc (3 X 50 ml). The combined organic layers were washed with brine (20 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washings with diethyl ether and pentane to afford 24-4 (50 mg, 0.08 mmol, 20% yield) as a white solid. MS (ESI): m/z 606.85 (M+1)+. EXAMPLE 25 Ethyl 2-phenyl-2-(2-(2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethoxy)-ethoxy)acetate (25-1).

[00795] To a stirred solution of ethyl mandalate (0.6 g, 3.33 mmol) in THF (30 ml) was added NaH (0.16 g, 42.1 mmol) at 0 °C, and the reaction was continued at RT for 30 min. 2-(2-(2-(Tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethoxy)-ethyl methanesulfonate 14-1 (1.14 g, 3.66 mmol) in THF (10 ml ) was added to the reaction mixture at 0°C over 5 min, and the reaction was warmed to RT and stirred for 16 hours. The reaction mixture was quenched with cold water (50 ml) and extracted with EtOAc (3 X 30 ml). The combined organic layers were washed with water (2 X 20mL), brine (15 mL), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtO-Ac/hexanes to afford 25-1 (0.14 g, 0.36 mmol, 11% yield) as a thick yellow liquid. MS (ESI): m/z 414.3 (M+18)+. Ethyl 2-(2-(2-(2-hydroxyethoxy)-ethoxy)-ethoxy)-2-phenylacetate (25-2).

[00796] To a stirred solution of 25-1 (1.6 g, 4.04 mmol) in MeOH (20 mL) was added pyridinium p-toluenesulfonate (0.1 g, 0.40 mmol) at 0 °C , and stirred at RT for one hour. Solvents were distilled off under reduced pressure. The crude residue was extracted with EtOAc (3 X 20 ml), the combined organic layers were washed with brine (25 ml), dried over Na 2 SO 4 and concentrated. The residue was purified by flash column chromatography (100 to 200 silica) using 5% MeOH/DCM to afford 25-2 (0.74 g, 2.37 mmol, 58% yield) as a thick yellow liquid. MS (ESI): m/z 330.2 (M+18) +. {2-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxy]-ethoxy}-phenyl-acetic acid ethyl ester (25-3).

[00797] Methanesulfonyl chloride (0.1 ml, 1.28 mmol) was added to a solution of 25-2 (0.4 g, 1.28 mmol) in DCM (10 ml) and triethylamine (0. 27 ml, 1.92 mmol) at 0 °C and stirred at RT for one hour. The reaction mixture was diluted with water (25 ml), extracted with DCM (3 X 25 ml). The combined organic layers were washed with brine (25 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc in hexanes to afford 25-3 (0.4 g, 1.025 mmol, 80% yield) as a gummy liquid. MS (ESI): m/z 408.2 (M+18)+. {2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy] acid ethyl ester -ethoxy}-phenyl-acetic acid (25-4).

[00798] To a stirred solution of 1-12 (0.29 g, 0.721 mmol) in DMF (15 ml) was added K2CO3 (0.2 g, 2.163 mmol) followed by 25-3 (0.33 g, 0 .86 mmol), catalytic amount of TBAI at 80°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (25 mL) washed with water (2 X 20 mL), brine (25 mL) and dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 5% MeOH-DCM to afford 25-4 (0.2 g, 0.28 mmol, 40% yield) as a solid. whitish. MS (ESI): m/z 718.9 (M+23)+. Acid{2-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]-ethoxy} -phenyl-acetic acid (25-5).

[00799] To a stirred solution of 25-4 (0.08 g, 0.114 mmol) in THF and water (6 ml; 4:1) was added LiOH (0.02 g, 0.46 mmol) at 0°C and the reaction was continued at RT for two hours. Upon completion of the reaction (by TLC), solvents were evaporated on a rotary evaporator, the residue was extracted with ether (25 ml). The aqueous layer was neutralized with 1N HCl (5 ml) followed by extraction with EtOAc (3 X 15 ml). The combined organic layers were washed with brine (2 X 15mL), dried over Na 2 SO 4 and concentrated. The crude residue was purified by washing with pentane and ether to afford 25-5 (40 mg, 0.06 mmol, 52% yield) as an off-white solid. MS (ESI): m/z 669.1 (M+1)+. 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-[(2-{2-[2-(hydroxycarbamoyl-phenyl-methoxy)-ethoxy]-ethoxy}-ethyl)-methanesulfonyl-amino] acid methylamide -benzofuran-3-carboxylic acid (25-6).

[00800] To a stirred solution of hydroxylamine hydrochloride (1 g, 14.34 mmol) in MeOH (1.5 ml) was added KOH (1.2 g, 21.51 mmol) in MeOH at 0 °C. The freshly prepared solution of hydroxylamine (1 ml) in MeOH was added to the solution of 25-4 (150 mg, 0.22 mmol) in MeOH at 0 °C and the reaction was continued at RT for one hour. Upon completion of the reaction (TLC), solvents were evaporated under reduced pressure, then water was added and neutralized with 1N HCl (5 mL) followed by extraction with EtOAc (3 X 20 mL). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The crude residue was purified with preparative TLC to afford 25-6 (70 mg, 0.12 mmol, 50% yield) as an off-white solid. MS (ESI): m/z 683.9 (M+1)+. EXAMPLE 26 2-(2-(2-(trityloxy)-ethoxy)-ethoxy)-ethanol (26-1).

[00801] To a stirred solution of 23-1 (1 g, 6.66 mmol) in DCM (25 ml) was added trityl chloride (1.67 g, 5.99 mmol) and triethylamine (1.7 ml, 13.32 mmol) at 0°C and stirring was continued at RT for 4 hours under a nitrogen atmosphere. The reaction mixture was diluted with water (2 x 50 ml) and extracted with DCM (3 x 50 ml). The combined organic layers were evaporated under reduced pressure and the crude residue was purified by flash column chromatography (100 to 200 silica) using 25% EtOAc/pet ether. to afford 26-1 (900 mg, 2.29 mmol, 34% yield) as an off-white solid. tert-Butyl 1-(2-(2-(2-(trityloxy)-ethoxy)-ethoxy)-ethoxy)cyclopentanecarboxylate (26-2).

[00802] To a solution of 26-1 (8 g, 20.4 mmol) in THF (100 ml) was added NaH (880 mg, 18.37 mmol) in portions at 0 °C, then stirred for one hour and then added to a solution of t-butylbromoacetate (8 g, 40.82 mmol) in THF (50 ml) at 0°C and stirred at RT for 24 hours. The reaction mixture was quenched with saturated ammonium chloride solution (300 ml) and diluted with EtOAc (400 ml), washed with water (100 ml), and dried over Na2SO4, and the organic phase was concentrated under reduced pressure to obtain the raw compound. The crude compound was purified using silica gel chromatography (10% EtOAc in hexanes) to afford 26-2 (4.5 g, 8.9 mmol, 43% yield) as a colorless gummy liquid. MS (ESI): m/z 524.2 (M+1)+. tert-Butyl 1-(2-(2-(2-(trityloxy)-ethoxy)-ethoxy)-ethoxy)cyclopentanecarboxylate (26-3A).

[00803] To a solution of 26-2 (500 mg, 0.98 mmol) and 1,4-diiodobutane (459 mg, 1.48 mmol) in THF (10 ml) was added lithium diisopropylamide (LDA; 2 M in THF) (1.97 mL, 1.97 mmol) at -40 °C and the reaction was stirred at RT for one hour. The reaction was quenched with saturated NH 4 Cl solution (50 ml) and diluted with EtOAc (50 ml), washed with water (20 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (10% EtOAc in hexanes) to provide 26-3A (170 mg, 0.30 mmol, 40% yield) as a colorless oily liquid. Confirmed by 1H NMR. tert-Butyl 12,12-dimethyl-1,1,1-triphenyl-2,5,8,11-tetraoxatridecan-13-oate (26-3B).

[00804] To a solution of 26-2 (700 mg, 1.78 mmol) in THF (10 ml) at -78 °C was added LiHMDS (1 M in THF) (4.1 ml, 4.1 mmol) followed by methyl iodide (0.4 ml, 5.35 mmol) in THF (8 ml) was added and stirred at the same temperature for two hours. The reaction mixture was quenched with saturated ammonium chloride solution (50 ml) and diluted with EtOAc (50 ml), washed with water (20 ml) and dried over Na 2 SO 4 . The organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (5% EtOAc in hexanes) to provide 26-3B (500 mg, 0.93 mmol, 67% yield) as a colorless oily liquid. MS (ESI): m/z 566.3[M+1]+. tert-Butyl 5-((5-hydroxypentyl)oxy)-2-methylpentanoate (26-4A).

[00805] To a solution of 26-3A (1.5 g, 2.67 mmol) in DCM (15 ml) were added 3.8 ml of triisopropylsilane and 0.8 ml of TFA at 0°C and stirred for 5 min. The reaction mixture was diluted with EtOAc (100 ml), washed with water (100 ml), brine (50 ml) and dried with Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (60% EtOAc in hexanes) to provide 26-4A (800 mg, 2.51 mmol, 94% yield) as a colorless oily liquid.

[00806] (26-3B) (500 mg, 0.94 mmol) was substituted for [26-3A in the above procedure to prepare [26-4B (210 mg, 77%). Ethyl 4-((2-(2-hydroxyethoxy)-ethoxy)-methyl)-1-naphthoate 1-{2-[2-(2-methanesulfonyloxy-ethoxy)-ethoxy]-ethoxy}-cyclopentanecarboxylic acid tert-butyl ester (26-5A).

[00807] Methanesulfonyl chloride (430 mg, 3.77 mmol) at 0°C was added to a solution of 26-4A (800 mg, 2.51 mmol) in DCM (10 ml) and triethylamine (635 mg, 6 .28 mmol) and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (100 ml) and washed with water (100 ml), brine (50 ml) and dried over Na 2 SO 4 and the organic phase concentrated under reduced pressure. The crude compound was purified using silica gel 100 to 200 filter column chromatography to afford 26-5A (600 mg, 1.515 mmol, 60% yield) as a pale brown oily liquid.

[00808] Step E above was adapted using 26-4B (210 mg, 0.72 mmol) substituted for 26-4A to prepare 26-5B (200 mg, 75%). 1-[2-(2-{2-[(5-Cyclopropyl-3-methylcarbamoyl-2-p-tolyl-benzofuran-6-yl)-methanesulfonyl-amino]-ethoxy}-ethoxy) tert-butyl ester -ethoxy]-cyclopentanecarboxylic acid (26-6A).

[00809] To a solution of 1-12 (507 mg, 1.26 mmol) in DMF (6 ml) was added potassium carbonate (528 mg, 3.78 mmol) followed by 26-5A (600 mg, 1, 51 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction mixture was cooled to RT and diluted with EtOAc (100 ml), washed with water (100 ml), brine (50 ml) and dried with Na2SO4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel 100 to 200 column chromatography (50% EtOAc in hexanes) to provide 26-6A (156 mg, 0.22 mmol, 17% yield) as a gummy liquid colorless. MS (ESI): m/z 720.3 (M+18)+.

[00810] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino tert-butyl ester) }-ethoxy)-ethoxy]-ethoxy}-2-methyl-propionic (26-6B): 26-5B (100 mg, 0.26 mmol) was substituted for 26-5A in the above procedure to prepare 26-6B (102 mg, 84%). MS (ESI): m/z 694.3 (M+23)+. 1-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxy]- acid ethoxy}-cyclopentanecarboxylic acid (26-7A).

[00811] To a solution of 26-6A (80 mg, 0.12 mmol) in DCM (2 mL) was added TFA at 0 °C and stirred at RT for two hours. Upon completion of the reaction as indicated by TLC, water was added to the reaction mixture and then extracted with excess DCM. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude compound was purified by preparative TLC to afford 26-7A (50 mg, 0.07 mmol, 68% yield) as a white solid. MS (ESI): m/z 646.9 (M+1)+.

[00812] 2-{2-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)- acid ethoxy]-ethoxy}-2-methyl-propion (26-7B): Starting from Step D in the procedure described above, 26-3B was substituted for 26-3A, and Steps D through G were adapted to prepare 26- 7B. MS (ESI): m/z 620.95 [M+1]+. 5-Cyclopropyl-2-(4-fluoro-phenyl)-6-[(2-{2-[2-(1-hydroxycarbamoyl-1-methyl-ethoxy)-ethoxy]-ethoxy}-ethyl)- acid methylamide methanesulfonyl-amino]-benzofuran-3-carboxylic acid (26-8B).

[00813] To a stirred solution of 26-7B (30 mg, 0.048 mmol) in DCM (2 ml) was added NH2OH·HCl (5 mg, 0.07 mmol), HATU (36.8 mg, 0.09 mmol ) and DIPEA (187 mg, 1.45 mmol) at 0 °C and the reaction was continued at RT for 16 hours. Upon completion of the reaction (TLC), solvents were evaporated under reduced pressure, then water was added and neutralized with 1N HCl (5 mL) followed by extraction with EtOAc (3 X 20 mL). The combined organic layers were washed with brine (2 X 20 ml), dried over Na 2 SO 4 and concentrated. The residue was purified with preparative HPLC to afford 26-8B (5 mg, 0.07 mmol, 16% yield) as a brown solid. MS (ESI): m/z 636.26 [M+1]+. EXAMPLE 27 ((2-bromoethoxy)-methanetrityl)tribenzene (27-2). To a stirred solution of 2-bromoethanol 27-1 (10 g, 80.0 mmol) in DCM (250 mL) was added trityl chloride (20 g, 72 mmol) and triethylamine (22.4 mL, 160 mmol ) at 0°C. The reaction mixture was stirred at RT for 10 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and extracted with DCM (3 X 500 ml). The combined organic layers were evaporated under reduced pressure and the crude residue was purified by flash column chromatography (100 to 200 silica) using 5% EtOAc/pet ether. to afford 27-2 (16 g, 43.71 mmol, 54% yield) as an off-white solid. 5-(2-(trityloxy)-ethoxy)-pentan-1-ol (27-3).

[00814] To a stirred solution of 27-2 (3 g, 15.95 mmol) in DMF (50 mL) was added NaH (0.96 g, 23.96 mmol) at 0 °C and the reaction was warmed to AT for 30 minutes. Pentane-1,5-diol (6 g, 17.55 mmol) in DMF (10 ml) was added to the reaction mixture at 0 °C over 5 min and the reaction was continued at RT for 16 h. The reaction was quenched with cold water (100 ml) and extracted with EtOAc (3 X 150 ml). The combined organic layers were washed with water (2 X 100mL), brine (150mL), dried over Na 2 SO 4 and concentrated. The crude residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/hexanes to provide 27-3 (1 g, 2.56 mmol, 17% yield) as a thick yellow liquid. tert-Butyl 2-(5-(2-(trityloxy)-ethoxy)-pentyloxy)acetate (27-5A).

[00815] To a solution of 27-3 (1.95 g, 10.25 mmol) and 23-2A (1.95 g, 10.25 mmol) in toluene (20 ml) and 5N NaOH (aq.) (20 mL) tetra n-butyl hydrogen ammonium sulfate (800 mg, 2.05 mmol) was added and stirred at RT for 48 hours. The reaction mixture was diluted with EtOAc (100 ml), washed with water (100 ml), brine (50 ml) and dried with Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (6% EtOAc in hexanes) to provide 27-5A (1 g, 1.984 mmol, 77% yield) as a colorless oily liquid. tert-butyl 2-(5-(2-hydroxyethoxy)pentyloxy)acetate (27-6A)

[00816] To a solution of 27-5A (1 g, 1.98 mmol) in DCM (10 ml) was added 0.5 ml of triisopropylsilane (TIS) and 0.5 ml of TFA at 0°C and stirred for 5 min. The reaction was diluted with EtOAc (100 ml) washed with water (100 ml), brine (50 ml) and dried over Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude residue was purified using silica gel chromatography (40% EtOAc in hexanes) to provide 27-6A (300 mg, 1.14 mmol, 58% yield) as a colorless oily liquid. . [5-(2-Methanesulfonyloxy-ethoxy)-pentyloxy]-acetic acid tert-butyl ester (27-7A).

[00817] Methanesulfonyl chloride (195 mg, 1.71 mmol) at 0°C was added to a solution of 27-6A (300 mg, 1.14 mmol) in DCM (5 ml) and triethylamine (231 mg, 2 .29 mmol) and stirred at RT for two hours. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml), brine (20 ml) and dried over Na 2 SO 4 . The organic layer was concentrated under reduced pressure. The crude residue was purified using silica gel 100 to 200 column chromatography (30% EtOAc in hexanes) to afford 27-7A (320 mg, 0.94 mmol, 82% yield) as an oily liquid colorless. [5-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-pentyloxy]- acid tert-butyl ester acetic acid (27-8A).

[00818] To a solution of 1-12 (315 mg, 0.78 mmol) in DMF (3 ml) was added potassium carbonate (325 mg, 2.35 mmol) followed by 27-7A (320 mg, 0. 94 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (20 ml) and dried with Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude residue was purified using silica gel 100 to 200 column chromatography (40% EtOAc in hexanes) to provide 27-8A (250 mg, 0.38 mmol, 49% yield) as a gray solid . MS (ESI): m/z 647.1 (M+1)+. [5-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-pentyloxy]-acetic acid (27-9A ).

[00819] To a solution of 27-8A (50 mg, 0.07 mmol) in DCM (2 ml) was added 0.5 ml of TFA at 0 °C and stirred at RT for two hours. Upon completion as indicated by TLC, water is added to the reaction mixture (20 ml) and then extracted with excess DCM (20 ml). The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude residue was purified by preparative TLC to afford 27-9A (12 mg, 0.02 mmol, 25% yield) as a white solid. MS (ESI): m/z 589.6 (M+1)+.

[00820] 2-[5-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-pentyloxy]- acid propionic acid (27-9B): Starting from Step C in the procedure described above, 2-bromo-propionic acid tert-butyl ester 27-4B was substituted for 27-4A and Steps C through G were adapted to prepare 27-9B. MS (ESI): m/z 603.5 (M+1)+. EXAMPLE 28 tert-Butyl 5-bromopentanoate (28-2A).

[00821] To a solution of 28-1A (5 g, 27.62 mmol) in DCM, was added oxalyl chloride (5.2 g, 41.436 mmol) and the catalytic amount of DMF at 0°C and stirred at RT for 30 min, then t-BuOH (8.2 g, 110.49 mmol) was added at 0 °C and stirred at RT for 15 min. The reaction mixture was completely distilled, then water (100 ml) was added and extracted with EtOAc (100 ml). The organic layer was washed with water (50 ml), NaHCO3 solution (50 ml) and dried over Na2SO4, and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (3% EtOAc in hexanes) to provide 28-2A (5 g, 21.18 mmol, 77% yield) as a colorless oily liquid. tert-Butyl 5-bromo-2-methylpentanoate (28-2B).

[00822] To a solution of propionic acid tert-butyl ester 281B (300 mg, 2.30 mmol) in THF (5 ml) was added 1,3-dibromopropane (0.35 ml, 3.46 mmol) and LDA in THF (2.3 mL, 4.61 mmol) at -40 °C and stirred for two hours. The reaction was quenched with saturated ammonium chloride solution and extracted with EtOAc (100 ml) washed with water (100 ml), brine (50 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (40% EtOAc in hexanes) to afford 28-2B (290 mg, 1.16 mmol, 51% yield) as a pale yellow oily liquid. tert-Butyl 5-(5-(trityloxy)pentyloxy)pentanoate (28-4A).

[00823] To a solution of 5-trityloxy-pentan-1-ol 28-3 (551 mg, 1.588 mmol) and 28-2A (1.5 g, 6.35 mmol) in toluene (6 ml) and 5N of NaOH aq. (20 mL) was added tetra n-butyl hydrogen ammonium sulfate (495 mg, 1.27 mmol) and stirred at 50°C for 48 hours. The reaction mixture was diluted with EtOAc (100 ml), washed with water (100 ml), brine (50 ml) and dried with Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (3% EtOAc in hexanes) to afford 28-4A (220 mg, 0.43 mmol, 27% yield) as a colorless oily liquid. tert-Butyl 5-((5-hydroxypentyl)-oxy)-pentanoate (28-5A).

[00824] To a solution of 28-4A (220 mg, 0.44 mmol) in DCM (5 ml) was added triisopropylsilane (TIS; 5 ml) and TFA (0.1 ml) at 0 °C and stirred for 5 minutes. The reaction was diluted with EtOAc (50 ml), washed with water (50 ml), brine (25 ml) and dried over Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel chromatography (50% EtOAc in hexanes) to provide 28-5A (40 mg, 0.15 mmol, 33% yield) as a colorless oily liquid. tert-Butyl 5-((5-((methylsulfonyl)-oxy)-pentyl)-oxy)-pentanoate (28-6A)

[00825] Methanesulfonyl chloride (26 mg, 0.23 mmol) at 0 °C was added to a solution of 28-5A (40 mg, 0.15 mmol) in DCM (2 ml) and triethylamine (39 mg, 0 .38 mmol) and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (20 ml) and washed with water (20 ml), brine (10 ml) and dried over Na 2 SO 4 , and the organic phase concentrated under reduced pressure. The crude compound was purified using silica gel 100 to 200 column chromatography (40% EtOAc in hexanes) to provide 28-6A (45 mg, 0.133 mmol, 86% yield) as a brown oily liquid. 5-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxy)-pentanoic acid tert-butyl ester (28- 7A).

[00826] To a solution of 1-12 (281 mg, 0.69 mmol) in DMF (1 ml) was added potassium carbonate (290 mg, 2.09 mmol) followed by 28-6A (260 mg, 0. 76 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (50 ml), washed with water (50 ml), brine (20 ml) and dried with Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound was purified using silica gel 100 to 200 column chromatography (40% EtOAc in hexanes) to afford 28-7A (180 mg, 0.279 mmol, 36% yield) as a gray solid. MS (ESI): m/z 645.0 (M+1)+. 5-((5-(N-(5-Cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)-methylsulfonamido)-pentyl)-oxy)-pentanoic acid (28-8A ).

[00827] To a solution of 28-7A (18 mg, 0.03 mmol) in DCM (1 ml) was added TFA at 0°C and stirred at RT for 16 hours. Upon completion of the reaction (by TLC), water (10 ml) was added, and the mixture was extracted with EtOAc (10 ml). The organic layer was washed with brine, dried over Na2SO4 and concentrated. The crude compound was purified by preparative TLC to afford 28-8A (8 mg, 0.014 mmol, 50% yield) as a gray solid. MS (ESI): m/z 586.9 (M+1)+. 5-(5-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-pentyloxy)-2-methyl-pentanoic acid (28-8B ). Starting from Step B in the procedure described above, 28-2B was substituted for 28-2A, and Steps B through F were adapted to prepare 28-8B. MS (ESI): m/z 603.5 (M+1)+. EXAMPLE 29 Methyl 4-(hydroxymethyl)-2-nitrobenzoate (29-2).

[00828] To a stirred solution of 4-(methoxycarbonyl)-3-nitrobenzoic acid 29-1 (5 g, 22.2 mmol) in THF (100 mL) was added and oxalyl chloride (2.27 mL, 26, 6 mmol) and DMF (0.3 ml) were added at 0°C. The reaction mixture was stirred at the same temperature for one hour. The organic solvent was removed under reduced pressure and the residue was dissolved in DME (30ml). This solution was added to a suspension of sodium borohydride (3.3g, 88.8mmol) in DME (20ml) at 0°C and the mixture was stirred for 4 hours. Upon completion of the reaction (by TLC), 1N hydrochloric acid (50 ml) was poured into the reaction mixture and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude compound was purified by column chromatography (100 to 200 silica) using 25% EtOAc/pet ether. to afford 29-2 (3.7 g, 20.6 mmol, 80% yield) as an off-white solid. MS (ESI): m/z 180.0 (M+1)+. Methyl 4-(bromomethyl)-2-nitrobenzoate (29-3).

[00829] To a solution of 29-2 (3 g, 14.2 mmol) in DCM (80 ml) was added carbon tetrabromide (5.17 g, 15.6 mmol), triphenylphosphine (4.08 g , 15.6 mmol) and stirred at 0 °C to RT for 4 h. The reaction mixture was diluted with DCM (50 ml), washed with water (100 ml), brine (100 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified by column chromatography (100 to 200 silica using 10% EtOAc in hexane) to provide 29-3 (2.5 g, 9.19 mmol, 65% yield). MS (ESI): m/z 244.0 (M-NO2+18)+. Methyl 2-nitro-4-((2-(2-(tetrahydro-2H-pyran-2-yloxy)-ethoxy)-ethoxy)-methyl)benzoate (29-4).

[00830] To a stirred solution of 2-4A (1.5 g, 7.8 mmol) in THF (5 mL) was added NaH (187 mg, 7.8 mmol) at 0 °C, and the reaction was continued at RT for 30 min. Then, 29-3 (2.34 g, 8.58 mmol) in THF (10 mL) was added to the reaction mixture at 0°C over 5 min. and the reaction was continued at RT for 16 hours. The reaction mixture was quenched with cold water (100 mL) and extracted with EtOAc (3 X 100 mL), the combined organic layers were washed with water (2 X 100 mL), brine (100 mL), dried over Na 2 SO 4 and concentrated . The residue was purified by flash column chromatography (100 to 200 silica) using 20% EtOAc/hexanes to afford 29-4 (1.1 g, 2.87 mmol, 31% yield) as a thick yellow liquid. MS (ESI): m/z 300.0 (M-THP+1)+. Methyl 4-((2-(2-hydroxyethoxy)-ethoxy)-methyl)-2-nitrobenzoate (29-5).

[00831] To a stirred solution of 29-4 (1.1 g, 2.87 mmol in MeOH (10 ml) was added PPTS (72 mg, 0.28 mmol) at 0°C and stirred at RT for 12 hours The reaction mixture was distilled and diluted with excess EtOAc (20 ml), washed with water (20 ml), brine (10 ml) and dried with Na 2 SO 4 and the organic phase was concentrated under reduced pressure to obtain a crude compound. The crude compound was purified by flash column chromatography (100 to 200 silica) using 40% EtOAc/hexanes to afford 29-5 (600 mg, 2.01 mmol, 69% yield) as pale yellow liquid. ESI): m/z 300.0 (M+1) + 4-[2-(2-Methanesulfonyloxy-ethoxy)-ethoxymethyl]-2-nitro-benzoic acid methyl ester (29-6).

[00832] To a stirred solution of 29-5 (600 mg, 2.01 mmol) in DCM (10 ml) were added triethylamine (0.67 ml, 4.81 mmol) and methanesulfonyl chloride (0.19 ml, 2.41 mmol) at 0°C and stirred at RT for one hour. The reaction mixture was diluted with excess DCM (50 ml) and washed with water (50 ml), brine (30 ml) and dried with Na 2 SO 4 , and the organic phase concentrated under reduced pressure. The crude compound was purified by column chromatography (100 to 200 silica) using 30% EtOAc/hexane to afford 29-6 (610 mg, 1.62 mmol, 80% yield). MS (ESI): m/z 378.0 (M+1)+. 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]- acid methyl ester 2-nitro-benzoic acid.

[00833] To a stirred solution of 1-12 (544 mg, 1.35 mmol) in DMF (10 ml) was added potassium carbonate (560 mg, 4.06 mmol) followed by 29-6 (610 mg, 1 .62 mmol), catalytic amount of TBAI, then stirred at 70°C for 16 hours. The reaction was cooled to RT and diluted with EtOAc (40 ml) washed with water (20 ml), brine (20 ml) and dried with Na 2 SO 4 , and the organic phase was concentrated under reduced pressure. The crude compound was purified by column chromatography (100 to 200 silica) using 30% EtOAc/hexane to provide 29-7 (530 mg, 0.775 mmol, 57% yield) as a pale yellow solid. MS (ESI): m/z 683.0 (M+1)+. 4-[2-(2-{[5-Cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl]-2-nitro acid - benzoic.

[00834] To a solution of 29-7 (200 mg, 0.292 mmol) in MeOH, THF and water (1:4:1) (8 ml) was added LiOH.H2O (42 mg, 1.75 mmol) and stirred at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the reaction mixture was neutralized with 1N HCl and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated. The crude compound was purified by column chromatography (100 to 200 silica) using 2% MeOH/DCM to afford 29-8 (80 mg, 0.12 mmol, 40% yield) as an off-white solid. MS (ESI): m/z 670.0 (M+1)+. 2-Amino-4-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy) methyl ester -ethoxymethyl]-benzoyl (29-9).

[00835] To a stirred solution of 29-7 (200 mg, 0.292 mmol) in THF/water (1:1, 8 mL) was added zinc (114 mg, 1.756 mmol) and NH4Cl (93 mg, 1.756 mmol) to the RT and stirred at 70°C for 4 hours. Upon completion of the reaction as indicated by TLC, the reaction mixture was filtered. The reaction mixture was distilled and diluted with excess EtOAc (20 ml), washed with water (20 ml), brine (10 ml) and dried over Na 2 SO 4 and the organic phase was concentrated under reduced pressure. The crude compound was purified by flash column chromatography (100 to 200 silica) using 40% EtOAc in hexane to afford 29-9 (140 mg, 0.21 mmol, 73% yield) as a yellow solid. MS (ESI): m/z 654.0 (M+1)+. 2-Amino-4-[2-(2-{[5-cyclopropyl-2-(4-fluoro-phenyl)-3-methylcarbamoyl-benzofuran-6-yl]-methanesulfonyl-amino}-ethoxy)-ethoxymethyl] acid -benzoyl (29-10).

[00836] To a solution of 29-9 (90 mg, 0.137 mmol) in MeOH, THF and water (1:4:1, 4 ml) was added LiOH.H2O (20 mg, 0.826 mmol) and stirred at RT for 16 hours. Upon completion of the reaction as indicated by TLC, the reaction mixture was neutralized with 1N HCl and then extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated to obtain the crude compound. This crude composition was purified by column chromatography (100 to 200 silica) using 2% MeOH/DCM, followed by washing with DCM and pentane to provide 29-10 (40 mg, 0.119 mmol, 45% yield) as a whitish solid. MS (ESI): m/z 640.0 (M+1)+.

EXAMPLE 30

[00837] The following compounds were made by methods generally in accordance with those described above, with the use of suitable reagents and conventional adaptation of reaction conditions. Esters and other carboxylic acid derivatives were prepared from or converted to the corresponding carboxylic acid compounds using conventional methods.

EXAMPLE 31

[00838] RNA-dependent HCV NS5B RNA assay (polymerase) and IC50 determination. Reaction mixtures consisted of 50 mM Hepes-KOH, pH 7.5, 5 mM MgCl2, 5 mM DTT, 2% glycerol, 0.01% Triton® X-100, 0.5 uM substrate polyA:U16, purified HCV RNA-dependent HCV RNA polymerase, 10 µM d-UTP, and 32P-UTP (Perkin Elmer). Reaction mixtures were incubated at 30°C for 60 minutes and then filtered through a Zeta probe membrane (BioRad). The filter was washed with 5X SSC (75 mM sodium citrate, pH 7 and 750 mM NaCl), and radiolabeled RNA products were quantified by microbeta (Perkin Elmer). For IC50 determination, different concentrations of inhibitors were added to the polymerase reaction mixtures, and incubated at 37°C for 60 minutes. IC50 values were determined using GraFit (Erithaus software).

[00839] Table 1 presents IC50 data obtained using the biochemical assay to test representative compounds. Data are presented as follows: "+++" means < 0.1 µM; "++" means > 0.1 μM but < 1.0 μM; "+" means > 1.0 µM. TABLE 1

EXAMPLE 32

[00840] HCV replicon assay and EC50 determination.The HCV replicon assay is based on the luciferase reporter cell line (Huh-luc/neo-ET). This reporter cell line is a human liver carcinoma cell line (Huh-7) stably transfected with an autonomously replicating bicistronic HCV subgenomic RNA replicon (Lohmann et al., 1999, Science, 285, 110-113). Inhibition of HCV RNA replication was monitored by analyzing reporter luciferase activity. Briefly, HCV replicon cells were incubated with inhibitors for 72 hours at 37°C. After incubation, duplicate plates were treated and incubated in parallel for assessment of cellular toxicity by XTT staining and anti-HCV activity by measurement of reporter luciferase activity. Human interferon alpha 2B or ribavirin was used as a reference compound. EC50 values were determined using GraFit (Erithaus software) or Excel.

[00841] Table 2 presents the EC50 data obtained using this HCV replicon assay to test representative compounds. Data are presented as follows: "+++" means < 0.1 µM; "++" means > 0.1 μM and < 1.0 μM; "+" means > 1.0 µM. TABLE 2

[00842] All publications, including but not limited to patents and patent applications, cited in this descriptive report are incorporated by reference into this document in their entirety, as if each individual publication were specifically and individually presented in its entirety.

[00843] While various aspects and embodiments of this invention have been described, the basic examples and general formulas and schemes may be altered to provide other embodiments that utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than the specific embodiments which have been represented by way of example.

Claims (21)

1. Compound, characterized by the fact that it has the structure: or a pharmaceutically acceptable salt thereof, wherein: L is -(CH2)x(OCH2CH2)yO-(CH2)z-x is 2 to 6; y is 0 to 5; and z is 1 to 5, with the proviso that when y is 0, then (x+z) will be 4 to 11; and A is selected from -CO2H, -CONHOH, -CO2-C1-4alkyl, -C(O)NH2, -OCi-2alkylene-CO2H, -OCi—2alkylene-CO2Ci—4alkyl, It is , where D is -C(O)CH3, -(C0-3alkylene)-CO2H, -(C0-3alkylene)-CO2C1-5alkyl, -(C0-3alkylene)-CONHOH, -C(O)CH=C( OH)CO2H, -C(O)CH=C(OH)CO2C1-4alkyl, -CO2CH2C(O)NH2, -CO2CH2SC1-4alkyl, -CO2Bn, or -CO2CH2CO2C1-4alkyl, and E is null, halo, C1-4alkyl , -OC1-4alkyl, -NH-C1-4alkyl, -C0-3alkylene-NH2 or NO2. 2. Compound, according to claim 1, characterized by the fact that E is null, fluorine, methyl, NH2 or NO2. 3. Compound, according to claim 1 or 2, characterized by the fact that x = 3, y = 1 and z = 1. 4. Compound, according to claim 1 or 2, characterized by the fact that y is 1 to 4. 5. Compound, according to any one of claims 1 to 4, characterized in that A is , D is -(Co-3alkylene)-CO2H, -(Co—3alkylene)-CO2Ci—5alkyl or -(Co—3alkylene)-CONHOH and E is null. 6. Compound according to claim 5, characterized in that D is in the para or meta position in the phenyl group. 7. Compound, according to claim 1, characterized by the fact that A is 8. Compound according to claim 7, characterized in that D is -CO2H. 9. Compound, according to claim 7 or 8, characterized by the fact that E is null. 10. Compound according to any one of claims 7 to 9, characterized in that x is 4 to 6, preferably 5. 11. Compound according to any one of claims 7 to 10, characterized in that z is 1 or 2, preferably 1. 12. Compound, according to any one of claims 7 to 11, characterized in that y is 0. 13. Compound, according to claim 1, characterized by the fact that it is listed below: 14. Compound, according to claim 13, characterized by the fact that it has the structure: 15. Compound according to any one of claims 1 to 14, characterized in that it is for use in a method to treat or prevent infection or reactivation of the hepatitis C virus in a host, or to reduce the activity of hepatitis C virus polymerase in a host, or to reduce hepatitis C virus replication in a host. 16. Compound, according to claim 15, characterized in that it further comprises at least one active agent selected from the group consisting of interferons, ribavirin, HCV NS5B nucleoside polymerase inhibitors, HCV polymerase inhibitors HCV NS5B non-nucleoside inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors and inhibitors of human cyclophilin. 17. Combination, characterized in that it comprises a compound, as defined in any one of claims 1 to 14, together with at least one active agent selected from interferons, ribavirin, HCV NS5B nucleoside polymerase inhibitors, HCV polymerase inhibitors non-nucleoside HCV NS5B, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors and inhibitors human cyclophilin pains. 18. Use of a compound, as defined in any one of claims 1 to 14, characterized in that it is in the manufacture of a drug to treat or prevent infection or reactivation of the hepatitis C virus in an individual. 19. Use of a compound, as defined in any one of claims 1 to 14, characterized in that it is in the manufacture of a drug to reduce a polymerase activity of the hepatitis C virus in an individual. 20. Use of a compound, as defined in any one of claims 1 to 14, characterized in that it is in the manufacture of a drug to reduce the replication of the hepatitis C virus in an individual. 21. Use according to any one of claims 18 to 20, characterized in that the drug is for combined use with at least one active agent selected from the group consisting of interferons, ribavirin, NS5B nucleoside polymerase inhibitors of HCV, HCV NS5B non-nucleoside polymerase inhibitors, HCV NS3-4A protease inhibitors, HCV NS5A inhibitors, HCV entry inhibitors, HCV NS3 inhibitors, HCV NS3 helicase inhibitors, HCV NS4B inhibitors and human cyclophilin inhibitors.