OA16370A

OA16370A - Mass transfert column.

Info

Publication number: OA16370A
Application number: OA1201300138
Authority: OA
Inventors: Luciano Scibola; Stefano Favilli
Original assignee: Sime Srl
Priority date: 2010-10-11
Filing date: 2011-10-11
Publication date: 2015-10-07

Abstract

A mass exchange column (60) for exchanging mass between a first gaseous or liquid stream (24) and a second liquid stream (25), comprising a vertical elongated container (11) divided in at least two longitudinal exchange chambers (75,76) by a preferably vertical dividing wall (85), and a longitudinal passageway (86), arranged in a proximity (15) of the dividing wall (85), preferably at least partially arranged within the dividing wall (85), for conveying the first stream (24) between an outlet port (12) of the first chamber (75) and the inlet port (13) of the second chamber (76), wherein (86) a phase separation means is provided (40) along the passageway, which is adapted to receive the first stream (24) and to separate it into a main liquid or gaseous portion (27) as the first stream (24) and a secondary portion (27') that contains a liquid phase formed by condensation of one part of said stream (24) within said passageway (86), or due to an entrainment by said first stream (24) during the contact with said second stream (25) liquid. In a particular exemplary embodiment, the dividing wall (85) comprises two parallel walls (21,22) and a hollow space (86') defined by the two parallel walls (21,22), and the passageway (86) comprises a portion of this hollow space (86') that is limited by the two parallel walls (21,22). This way, it is not necessary to provide ducts to allow the passage of a stream (24) that has to be consecutively treated in the two chambers (75,76), which reduces installation time and costs of the column (60), and limits possible leakage points. Furthermore, it is possible to feed the liquid portion and/or the gas portion of the first stream (24) separately into the second chamber (76), into convenient sections of the second chamber (76), in order to limit the extension of such contact means as trays or packings that are required for the separation which takes place within the second chamber (76).

Description

2’-FLUORO SUBSTITUTED CARBA-NUCLEOSIDE ANALOGS FOR

ANTIVIRAL TREATMENT

FIELD OF THE INVENTION

The invention relates generally to compounds with antiviral activity, more particularly nucleosides active against Flaviviridae infections and most particularly to inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

BACKGROUND OF THE INVENTION

Viruses comprising the Flaviviridae family comprise at least three distinguishable généra including pestiviruses, flaviviruses, and hepaciviruses (Calisher, et al., J. Gen. ViroL, 1993, 70, 37-43). Whilepestiviruses cause many economically important animal diseases such as bovine viral diarrhea virus (BVDV), classical swine fever virus (CSFV, hog choiera) and border disease of sheep (BDV), their importance in human disease is less well characterized (Moennig, V., et al., Adv. Vir. Res. 1992, 48, 53-98). Flaviviruses are responsable for important human diseases such as dengue fever and yellow fever while hepaciviruses cause hepatitis C virus infections in humans. Other important viral infections caused by the Flaviviridae family include West Nîle virus (WNV) Japanese encephalitis virus (JEV), tick-bome encephalitis virus, Junjin virus, Murray Valley encephalitis, St Louis encephalitis, Omsk hémorrhagie fever virus and Zika virus. Combined, infections from the Flaviviridae virus family cause significant mortality, morbidity and économie losses throughout the world. Therefore, there is a need to develop effective treatments for Flaviviridae virus infections.

The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 32:98-112, 2000) so a significant focus of current antiviral research is directed toward the development of improved methods of treatment of chronic HCV infections in hum ans (Di Besceglie, A.M. and Bacon, B. R., Scientific American, Oct.: 80-85, (1999); Gordon, C. P., et al., J. Med, Chem. 2005, 48, 1-20; Maradpour, D.; et al., Nat. Rev, Micro. 2007,5(6), 453-463). A number of HCV treatments are reviewed by Bymock et al. in Antiviral Chemistry & Chemotherapy, 11:2; 79-95 (2000).

RNA-dependent RNA polymerase (RdRp) is one of the best studied targets for the development of novel HCV therapeutic agents. The NS 5 B polymerase is a target for inhibitors in early human clinical trials (Sommadossi, J., WO 01/90121 A2, US 2004/0006002 Al ). These enzymes hâve been extensively characterized at the biochemical and structural level, with screening assays for identifying sélective inhibitors (De Clercq, E. (2001) J. Pharmacol. Exp.Ther. 297:1-10; De Clercq, E. (2001) J. Clin. Virol. 22:73-89). Biochemical targets such as NS5B are important in developing HCV thérapies since HCV does not replicate in the laboratory and there are difficulties in developing cell-based assays and preclinical animal Systems.

Currently, there are primarily two antiviral compounds, ribavirin, a nucleoside analog, and interferon-alpha (a) (IFN), that are used for the treatment of chronic HCV infections in humans. Ribavirin alone is not effective in reducing viral RNA levels, has significant toxicity, and is known to induce anémia. The combination of IFN and ribavirin has been reported to be effective în the management of chronic hepatitis C (Scott, L. J., et al. Drugs 2002, 62, 507-556) but less than half the patients infected with some génotypes show a persistent benefit when gîven this treatment. Other patent applications disclosing the use of nucleoside analogs to treat hepatitis C virus include WO 01/32153, WO 01/60315, WO 02/057425, WO 02/057287, WO 02/032920, WO 02/18404, WO 04/046331, W02008/089105 and W02008/14Î079 but additional treatments for HCV infections hâve not yet become avaîlable for patients.

ο

Virologie cures of patients with chronic HCV infection are difficult to achieve because of the prodigious amount of daily virus production in chronically infected patients and the high spontaneous mutability of HCV virus (Neumann, et al., Science 1998, 282, 103-7; Fukimoto, et al., Hepatology, 1996, 24, 1351-4; Domingo, et al., Gene, 1985, 40, 1-8; Martell, et al., J. Virol. 1992, 66, 3225-9. Experimental antiviral nucleoside analogs have been shown to induce viable mutations in the HCV virus both in vivo and in vitro (Migliaccro, et al., J. Biol. Chem. 2003, 926; Carroll, et al., Antîmicrobial Agents Chemotherapy 2009, 926; Brown, A. B., Expert Opin. Investig. Drugs 2009,18, 709-725). Therefore, drugs having improved antiviral properties, particularly enhanced activity against résistant strains of virus; improved oral bioavailability; fewer undesirable side effects and extended effective half-life in vivo (De Francesco, R. et al. (2003) Antiviral Research 58:1-16) are urgently needed.

Certain ribosides ofthe nucleobases pyrrolo[l,2-f][l,2,4]triazine, imidazo[l,5f][l,2,4]triazine, imidazo[l,2-f][l,2,4]triazine, and [l,2,4]triazolo[4,3-f][l,2,4]triazine have been disclosed in Carbohydrate Research 2001, 331(1), 77-82; Nucleosides & Nucléotides (1996), 15(1-3), 793-807; Tetrahedron Letters (1994), 35(30), 5339-42; Heterocycles (1992), 34(3), 569-74; J. Chem. Soc. Perkin Trans. 1 1985, 3, 621-30; J. Chem. Soc. Perkin Trans. 1 1984, 2, 229-38; WO 2000056734; Organic Letters (2001), 3(6), 839-842; J. Chem. Soc. Perkin Trans. 1 1999, 20, 2929-2936; and J. Med. Chem. 1986,29(11),2231-5. However, these compounds have not been disclosed as useful for the treatment of HCV.

Ribosides of pyrrolo[l,2-f][l,2,4]triazinyl, imidazo[l,5-f][l,2,4]triazinyl, imidazo[l,2-f][l,2,4]triazinyl, and [l,2,4]triazolo[4,3-f][l,2,4]triazinyl nucleobases with antiviral, anti-HCV, and anti-RdRp activity have been disclosed b y Babu, Y. S., W02008/089105 and W02008/141079; Cho, et al., W02009/132123 and Francom, et al. W02010/002877. Butler, et al., WO2009/132135, has disclosed anti-viral pyrrolo[ 1,2-f][ 1,2,4]triazinyl, imidazo[ 1,5-f][ 1,2,4]triazinyl, imidazo[l ,2f][l,2,4]triazinyl, and [l,2,4]triazolo[4,3-f][l,2,4]triazinyl nucleosides wherein the 1 ’ position of the nucleoside sugar is substituted.

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SUMMARY OF THE INVENTION

Provided are compounds that inhibit vîruses of the Flaviviridae family. The invention also comprises compounds of Formula I or Formula IV-VI that inhibit viral nucleic acid polymerases, particularly HCV RNA-dependent RNA polymerase (RdRp), rather than cellular nucleic acid polymerases. The compounds of Formula I or Formula IV-VI hâve been dîscovered to be efficacious against both wild type and S282T mutant strains of HCV virus. Therefore, a compound of Formula I or Formula IV-VI are useful for treating Flaviviridae infections in humans and other animais.

In one embodiment, provided are compounds of Formula I:

Formula I or a pharmaceutically acceptable sait, thereof;

wherein;

R¹ is (Ci-Cg)alkyl, (C4-C8)carbocyclylalkyl, (C]-Cg)substituted alkyl, (C₂-C₈)alkenyl, (CS-Cgjsubstituted alkenyl, (C2-Cg)alkynyl, (Cx-Cgjsubstituted alkynyl, or aryl(Ci-Cg)alkyl;

R² is halogen;

each R³, R⁴, or R⁵ is independently H, OR^a, N(R^a)2î N3î CN, NO2, S(O)nR^a, halogen, (Ci-Cg)alkyl, (C4-Cg)carbocyclyl alkyl, (Ci-Cg)substituted alkyl, (C2~Cg)alkenyl, (C2-Cg)substituted alkenyl, (C₂“Cg)alkynyl, (C^-Cgjsubstituted alkynyl, or aryl(Ci-C₈)alkyl;

X or any two of R³, R⁴ or R⁵ on adjacent carbon atoms when taken together are O(CO)O- or when taken together with the ring carbon atoms to which they are attached form a double bond;

R⁶ is H, OR^a, N(R^a)2, N3) CN, NO2, S(O)nR^a, -C(=O)R^H, -C(=O)OR¹¹, C(=O)NRR¹², -C(=O)SR^lI> -S(O)Rⁿ, -S(O)2R^H, -S(O)(ORⁿ), -S(O)2(OR^1]), -SO2NR^HR¹², halogen, (Cj-Cg)alkyl, (C4-C₈)carbocyclylalkyl, (Cj-C₈) substituted alkyl, (C2-C₈)alkenyl, (C₂-C₈) substituted alkenyl,' (C₂-C₈)alkynyl, (C₂-C₈)substituted alkynyl, or aryI(Ci-C₈)alkyl;

each n îs independently 0, 1, or 2;

each R^a is independently H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C]-C8)alkyl, (C4-Cg)carbocyclylalkyl, -C(=O)R^1], -C(=O)OR¹¹, -C(=O)NRⁿR¹², -C(=O)SR^1!, -S(O)R^h, -S(O)2Rⁿ, -S(O)(OR¹¹), -S(O)2(ORⁿ), or -SO2NRⁿR¹²;

R⁷ is H, -C(=O)Rⁿ, -C(=O)OR^h, -C(=O)NR¹¹R¹², -Cf-OjSR¹¹, -S(O)R¹¹, S(O)2R^h, -S(O)(ORⁿ), -S(O)2(ORⁿ), -SO2NRⁿR¹², or

W· each Y or Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ^(OjfOR), or N-NR₂;

W¹ and W², when taken together, are -Y³(C(R^y)₂)3Y³-; or one of W¹ or W²together with either R³ or R⁴ is -Y³- and the other of W¹ or W² is Formula la; or W¹and W² are each, independently, a group of the Formula la:

ο

Formula la wherein:

each Y² is independently a bond, O, CR2, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), N-NR2, S, S-S, S(O), or S(O)₂;

each Y is independently O, S, or NR;

M2 is 0, 1 or 2;

each R^x is independently R^y or the formula:

wherein:

each Mla, Mlc, and Mld is independently 0 or 1;

M12cis 0, 1,2,3,4, 5,6, 7, 8,9, 10, 11 or 12;

each R^y is independently H, F, Cl, Br, I, OH, R, -C(=Y^I)R, -C(=Y')OR, C(=Y^l)N(R)2, -N(R)2, -⁺N(R)3, -SR, -S(O)R, -S(O)₂R, -S(O)(OR), -S(O)₂(OR), OC(=Y’)R, -OC(=Y')OR, -OC(=Y')(N(R)₂), -SC(=Y^l)R, -SC(=Y')OR, SC(=Y*)(N(R)2), -NtRjC^Y^R, -N(R)C(=Y^l)OR, -N(R)C(=Y')N(R)2, -SO₂NR₂, -CN, —N₃, -NO_2} -OR, or W³; or when taken together, two R^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

each R îs independently H, (Ci-Cg) alkyl, (CpCg) substituted alkyl, (C₂Cg)alkenyl, (C₂-Cg) substituted alkenyl, (C₂-C_g) alkynyl, (C₂-C_g) substituted alkynyl, C&-C₂o aryl, C6~C₂o substituted aryl, C₂-C₂o heterocyclyl, C₂-C₂o substituted heterocyclyl, arylalkyl or substituted arylalkyl;

W³ is W⁴ or W⁵; W⁴ is R, -CtY^R⁷, -C(Y^])W⁵, -SO2R^y, or -SO2W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ is independently substituted with 0 to 3 R^y groups;

each X¹ or X² is independently C-R¹⁰ or N;

ο each R⁸ is halogen, NRⁿR¹², N(R^ll)ORⁿ, NR^liNR¹¹R¹², N3, NO, NO2, CHO, CN, -CH(=NRⁿ), -CH=NNHR¹¹, -CH=N(ORⁿ), -CH(OR^ll)2, -C(=O)NR^UR¹², -C(=S)NR^1IR¹², -C(=O)0Rⁿ, (C_rC_g)aIkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C4-C₈)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(Ci-C₈)alkyl, -SiOUCrC^alkyl, aryl(C₁-C₈)alkyl, OR¹¹ or SR^1!;

each R⁹ or R¹⁰ is independently H, halogen, NRⁿR¹², N(Rⁿ)ORⁿ, NR¹¹NR¹¹R’², N₃, NO, NO₂, CHO, CN, -CH(=NR¹¹), -CH=NHNR^li, -CH=N(ORⁿ), -CHtOR¹¹);, -C(=O)NR^UR¹², -C(=S)NR¹¹R¹², -C(=O)ORⁿ, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (Ci-Cg)alkyl, (C₂-C₈)alkenyl, (C₂C₈)alkynyl, (C^Csjcarbocyclyl alkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(Cj-C8)alkyl, -S(O)_n(Ci-C_s)alkyl or aryl(C_t-C₈)aIkyl; or R and R taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NR^a-;

wherein each (Ci-Cg)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl or aryI(Ci-C₈)alkyl of each R¹, R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(R^a)2or OR^a; and wherein one or more of the nonterminal carbon atoms of each said (Ci-Cg)alkyl may be optionally replaced with -O-, -S-or-NR^a-.

In another embodiment, provided are compounds of Formula I or Formula IVVI and pharmaceutically acceptable salts thereof and all racemates, enantiomers, diastereomers, tautomers, polymorphs, pseudopolymorphs and amorphous forms thereof.

In another embodiment, provided are novel compounds of Formula I or Formula IV-VI with activity against infectious Flaviviridae viruses. Without wishing to be bound by theory, the compounds of the invention may inhibit viral RNAdependent RNA polymerase and thus inhibit the réplication of the virus. They are useful for treating human patients infected with a human virus such as hepatitis C.

In another embodiment, provided are pharmaceutical compositions comprising an effective amount of a Formula I or a Formula IV-VI compound, or a pharmaceutically acceptable sait thereof, in combination with a pharmaceutically acceptable diluent or carrier.

In another embodiment, the présent application provides for combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of Formula I or Formula IV-VI; or a pharmaceutically acceptable sait, solvaté, or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alphaglucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucléotide inhibitors of HCV NS5B polymerase, nonnucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixtures thereof.

In another embodiment, the présent application provides for a method of inhibitîng HCV polymerase, comprising contacting a cell infected with HCV with an effective amount of a compound of Formula I or Formula IV-VI; or a pharmaceutically acceptable salts, solvaté, and/or ester thereof.

In another embodiment, the présent application provides for a method of inhibitîng HCV polymerase, comprising contacting a cell infected with HCV with an effective amount of a compound of Formula I or Formula IV-VI; or a pharmaceutically acceptable salts, solvaté, and/or ester thereof; and at least one additional therapeutic agent.

In another embodiment, the présent application provides for a method of treating and/or preventing a disease caused by a viral infection wherein the viral infection is caused by a virus selected from the group consisting of dengue virus, yellow fever virus, West Nile virus, Japanese encephalitis virus, tick-bome encephalitis virus, Junjin virus, Murray Valley encephalitis virus, St Louis encephalitis virus, Omsk hémorrhagie fever virus, bovine viral diarrhea virus, Zika virus and Hepatitis C virus; by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula I or Formula IV-VI, or a phannaceutically acceptable sait thereof.

In another embodiment, the présent application provides for a method of treating HCV in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I or Formula IV-VI; or a pharmaceutically acceptable sait, solvaté, and/or ester thereof.

In another embodiment, the présent application provides for a method of treating HCV in a patient, comprising administering to said patient a therapeutically effective amount of a compound of Formula I or Formula IV-VI; or a phannaceutically acceptable sait, solvaté, and/or ester thereof; and at least one additional therapeutic agent.

Another aspect of the invention provides a method for the treatment or prévention of the symptoms or effects of an HCV infection in an infected animal which comprises administering to, Le. treating, said animal with a pharmaceutical combination composition or formulation comprising an effective amount of a Formula I compound or Formula IV-VI, and a second compound having anti-HCV properties.

In another aspect, the invention also provides a method of inhibiting HCV, comprising administering to a mammal infected with HCV an amount of a Formula I or Formula IV-VI compound, effective to inhibit the réplication of HCV in infected cells in said mammal.

In another aspect, provided is the use of a compound of Formula I or Formula IV-VI for the manufacture of a médicament for the treatment of Flaviviridae viral infections. In another aspect, provided is a compound of Formula I or Formula IV-VI for use in treating a Flaviviridae viral infection. In one embodiment, the Flaviviridae viral infection is acute or chronic HCV infection. In one embodiment of each aspect of use and compound, the treatment results in the réduction of one or more of the viral loads or clearance of RNA in the patient.

In another aspect, the invention also provides processes and novel intermediates disclosed herein which are usefiil for preparîng Formula I or Formula IV-VI compounds of the invention.

In other aspects, novel methods for synthesîs, analysis, séparation, isolation, purification, characterization, and testing of the compounds of this invention are provided.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying description, structures and formulas. While the invention will be described in conjunction with the enumerated embodiments, it will be understood that they are not intended to lirait the invention to those embodiments. On the contrary, the invention is intended to cover ail alternatives, modifications, and équivalents, which may be included within the scope of the présent invention.

In another aspect, compounds of Formula I are represented by Formula II:

R⁴ F

Formula II or a pharmaceutically acceptable sait, thereof;

wherein:

R¹ is (C]-Cg)alkyl, (C4-C_s)carbocyclylalkyl, (C]-Cg) substituted alkyl, (C₂-C_g)alkenyl, (C2~C₈)substituted alkenyl, (C₂-C_g)alkynyl, (C₂-Cg)substituted alkynyl, or aryl(Cj-Cg)alkyl;

each R³, R⁴, or R⁵ is independently H, OR^a, N(R^a)2, N3, CN, NO2, S(O)nR^a, ' halogen, (Cj-Cg)alkyl, (C4-Cg)carbocyclylalkyl, (Ci-Cg)substituted alkyl, (C2-Cg)alkenyl, (C₂-Cg)substituted alkenyl, (C₂-C_g)alkynyl, (C₂-C_g)substituted alkynyl, or aryl(Ci-Cg)alkyl;

or any two of R³, R⁴ or R⁵ on adjacent carbon atoms when taken together are O(CO)O- or when taken together with the ring carbon atoms to which they are attached form a double bond;

R⁶ is H, OR^a, N(R^a)2, N3, CN, NO2, S(O)nR^a, -C(=O)R¹¹, -C(=O)OR¹¹, C(=O)NR^UR’², -C(=O)SRⁿ, -S(O)Rⁿ, -S(O)2R^h, -S(O)(OR^1!), -S(O)2(OR^h), -SO2NR^llR¹², halogen, (Ci-Cg)alkyl, (C4-Cg)carbocyclylalkyl, (C]-Cg)substituted alkyl, (C₂-Cg)alkenyl, (C₂-Cg)substituted alkenyl, (C₂-Cg)alkynyl, (C₂-Cg)substituted alkynyl, or aryl(Ci-Cg)alkyl;

each n is independently 0, 1, or 2;

each R^a is independently H, (Ci-Cg)alkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, aryl(Ci-C8)alkyl, (C4-Cg)carbocyclylalkyl, -C(=O)R^U, -C(=O)ORⁿ, -C(=O)NRⁿR¹², -C(=O)SR^]-S(O)R’*, -S(O)2R^] -S(O)(OR**), -S(O)2(OR^u), or -SO2NR*^!R¹²;

R⁷ is H, -C(=O)Rⁿ, -C(=O)OR^1!, ~C(=O)NRⁿR¹², -C(=O)SRⁿ, -S(O)Rⁿ, S(O)2Rⁿ, -SfOXOR¹¹), -S(O)2(OR¹¹), -SO2NR^hR¹², or

W· each Y or Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or

N-NR₂;

W¹ and W², when taken together, are -Y³(C(R^y)2)3Y³-; or one of W¹ or W²together with either R³ or R⁴ is -Y³- and the other of W¹ or W² is Formula la; or W¹2 t and W are each, independently, a group ofthe Formula la:

wherein:

each Y² is independently a bond, O, CR2f NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), N-NR2, S, S-S, S(O), or S(O)₂;

each Y is independently O, S, or NR;

M2 is 0, 1 or 2;

each R* is independently R^y or the formula:

wherein:

each Mla, Mlc, and Mld is independently 0 or 1;

M12cis 0, 1,2, 3,4, 5,6, 7, 8,9, 10, 11 or 12;

each R^y îs independently H, F, Cl, Br, I, OH, R, -C(=Y^l)R, -C(=Y^l)OR, C(=Y¹)N(R)2, -N(R)2, -⁺N(R)3, -SR, -S(O)R, -S(O)₂R, -S(O)(0R), -S(O)₂(OR), OC(=Y')R, -OC(=Y¹)OR, -OC(=Y¹)(N(R)2), -SC(=Y‘)R, -SC^Y^OR, SC(=Y')(N(R)2), -N(R)C(=Y')R, -N(R)C(=Y^!)OR, -N(R)C(=Y¹)N(R)2j -so₂nr₂,

-CN, -N₃₎ -NO_2; -OR, or W³; or when taken together, two R^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

each R is independently H, (Cj-Cg) alkyl, (Ci-C₈) substituted alkyl, (C₂C₈)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl, (C₂-C₈) substituted alkynyl, Cé~C₂o aryl, C&-C₂o substituted aryl, C₂-C₂₀ heterocyclyl, C₂-C₂o substituted heterocyclyl, arylalkyl or substituted arylalkyl;

W³ is W⁴ or W⁵; W⁴ is R, -C(Y^])R^y, -C(Y^l)W⁵, -SO2R^y, or -SO2W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ is independently substituted with 0 to 3 R^ygroups;

each X¹ or X² is independently C-R¹⁰ or N;

each R⁸ is halogen, NRⁿR¹², NfR^OR¹¹, NR¹¹NR¹¹R¹², N3, NO, NO2, CHO, CN, -CH(=NR¹¹), -CH=NNHR¹¹, -CH=N(OR), -CH(OR^u)2, -C(=O)NR^hR¹², -C(=S)NR^liR¹², -C(=O)OR^h, (Ci-Cg)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C4-C₈)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(Ci-C_g)alkyl, -S(O)_n(C_rC₈)alkyl, aryl(Ci-C₈)alkyl, OR¹¹ or SR¹¹;

each R⁹ or R¹⁰ îs independently H, halogen, NR^1]R¹², N(Rⁿ)OR¹¹, NR^llNRⁿR¹², N3, NO, NO2, CHO, CN, -CH(=NR¹¹), -CH=NHNR¹¹, -CH=N(ORⁿ), -CH(OR^h)2) -C(=O)NRⁿR¹², -C(=S)NR^hR¹², -C(=O)OR^h, R¹¹, OR¹¹ or SR¹¹;

each R¹¹ or R¹² is independently H, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂C₈)alkynyl, (C₄-C₈)carbocyclyl alkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(C]-C₈)alkyl, -S(O)_n(Cj-C₈)alkyl or aryl(Ci-C₈)alkyl; or R¹¹ and R¹² taken together with a nitrogen to which they are both attached fonn a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or-NR^a-;

wherein each (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl or aryl(Ci~C₈)alkyl of each R¹, R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(R^a)2 or OR^a; and wherein one or more of the nonterminal carbon atoms of each said (Cj-C₈)alkyl may be optionally replaced with -O-, -S-or-NR^a-.

In one embodiment of the invention of Formula II, R¹ is (Cj-C^alkyl, (C2-C8) alkenyl or (C2-Cs)alkynyl. In another aspect of this embodiment, R¹ is (Ci-Cgjalkyl. In another aspect of this embodiment, R¹ is methyl, CH2F, or ethynyl. In another aspect of this embodiment, R¹ is methyl. In another aspect of this embodiment, R¹ is (Ci-Cg)alkyl and R⁶is H. In another aspect of this embodiment, R¹ is (Ci-Cg)alkyl and at least one of X or X is N. In another aspect of this embodiment, R is (Ci-Cg)alkyl and R⁶ is CN, OH, or CH3.

In one embodiment of Formula II, R³ is H, OR^a, N(R^a)2, N3, CN, SR^a, halogen, (Ci-Cs)alkyl, (C2-Cs)alkenyl or (C₂-C8)alkynyl. In one aspect of this embodiment, R is H. In another aspect of this embodiment, R is H and R is (Ci-Csjalkyl, (C₂-C_s) alkenyl or (C₂-C8)alkynyl. In another aspect of this embodiment, R is H and R¹ is (Cj-Cgjalkyl. In another aspect of this embodiment, R³ is H and R¹ methyl, CH2F, or ethynyl. In another aspect of this embodiment, R is H and R is methyl. In another aspect of this embodiment, R³ is H, R¹ is (Ci-Cg)alkyl and at least one of X¹or X² is N. In another aspect of this embodiment, R³ is H, R¹ is methyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R³ is H, R¹ is (C]-Cs)alkyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R³ is H, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R³is H, R¹ îs methyl and R⁶ is H.

In one embodiment of Formula II, R⁴ is H, OR^a, N(R^a)2, N3j CN, SR^a, halogen, (Ci-C8)alkyl, (C2-Cg)alkenyl or (C2-Cs)alkynyl. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R^! is (Ci-Cg)alkyl, (C2-Cg) alkenyl or (C2~Cg)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-C8)alkyl, (C₂-C_g) alkenyl or (C₂-Cg)alkynyL In another aspect of this embodiment, R⁴ is OR^a and R¹ îs (Cj-Cg)alkyl. In another aspect of this embodiment, R⁴ îs OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this

0L embodiment. R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and R⁶ is CN, OH, or CH3 In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-Cg)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-Cg)alkyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

In one embodiment of Formula II, R⁵ is H, OR^a, N(R^a)2, N3, CN, SR^a, halogen, (Ci-Cgjalkyl, (C2-Cg)alkenyl or (C^-Cgjalkynyl. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl, (C2-Cg) alkenyl or (C2~Cg)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci“Cs) alkyl, (C2-Cg) alkenyl or (C2-Cg)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and at least one of X or X is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cs)alkyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (Cj-Cg)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X²îs N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-Cg)alkyl and R⁶ is CN, OH, orCH3 In another aspect of this embodiment, R is OH, R is methyl and R is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and ό 5

R is H. In another aspect of this embodiment, R is N3.

In another embodiment of Formula II, R⁵ is H. In another aspect of this embodiment, R⁴ is H or 0R^a. In another aspect of this embodiment, R⁴ is 0R^a. In another aspect of this embodiment, R⁴ îs 0R^a and R¹ is (Ci-C8)alkyl, (C2-Cg) alkenyl 10 or (C₂-C_s)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl, (C2-Cg) alkenyl or (C2-Cg)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, 15 R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X³ is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and R⁶ is CN, OH, or CH3 In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ îs OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-Cg)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-Cg)alkyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and

R⁶ is H.

In another embodiment of Formula II, R⁶ is H, CN, OR^a or CH₃. In another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶is OH. In another aspect of this embodiment R⁶ is CH3. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl, (Cî-Cg) alkenyl or (C₂-Cg)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl, (C2-Cg) alkenyl or (C2-Cg)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl. In another aspect of this embodiment, R⁴ is 0R^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is 0R^a, R¹ is (C]-Cg)alkyl and at least one of X¹ or X² îs N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ îs 0R^a, R¹ is (C|-Cg)alkyl and R⁶ is CN, OH, or CH₃ In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ îs 0R^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ îs OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-C8)alkyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-C8)alkyl and R⁶ is CN, OH, or CH3 In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

In another embodiment of Formula II, R⁶ is CN, 0R^a or CH₃. In another aspect of this embodiment R ⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶ is OH. In another aspect of this embodiment R⁶ is CH3. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹îs (Ci~Cs)alkyl, (C₂-C₈) alkenyl or (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Cj-Cg)alkyl, (C₂-C₈) alkenyl or (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Cj-Cg) alkyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or

X² îs N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Cj-C8)alkyl and R⁶ is CN, OH, or CH3 In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (Cj— C8)alkyl and at least one of

X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X^! or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Cj-Cg) alkyl and R⁶ is CN, OH, or CH3 In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH3.

In one embodiment of Formula II, R⁷ is H, -C(=O)Rⁿ, -C(=O)OR¹¹, C(=O)SR^uor

T . In a aspect of this embodiment, R is H. In another aspect of this

711 711 embodiment, R is -C(=O)R . In another aspect of this embodiment, R is -C(=O)R wherein R¹¹ is (Ci-Cgjalkyl. In another aspect of this embodiment, R⁷ îs

W² . Jn another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶ is OH. In another aspect of this embodiment R⁶is CH3. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹is (Ci-Cg)alkyl, (C2-Cg) alkenyl or (C₂-Cg)alkynyL In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cs)alkyl. In another aspect ofthis embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X^! or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cg)alkyl and R⁶ is CN, OH, or CH3 In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (Cj-Cgjalkyl and ai least one ofX¹ or X²is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Cj-Cg)alkyl and R⁶ is CN, OH, or CH3 In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ îs H.

In one embodiment of Formula II, X¹ is N or C-R¹⁰. In another aspect of this embodiment, X*¹ îs N. In another aspect of this embodiment, X¹ is C-R¹⁰. In another aspect of this embodiment, X is C-H. In another aspect of this embodiment, X isN and X² is C-H. In another aspect of this embodiment, X¹ is C-R¹⁰ and X² is CH. In another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is

CN. In another aspect of this embodiment R⁵ is 0R^a. In another aspect of this embodiment R⁵ is OH. In another aspect of this embodiment R⁶ is CH3. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴is OR^a. In another aspect of this embodiment, R⁴ is 0R^a and R¹ is (Ci-C8)alkyl, (C₂-Cg) alkenyl or (C₂-Cg)alkynyl. In another aspect of this embodiment, R⁴ is 0R^a and R¹ is (Cj-Cs)alkyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cs)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Cj-Cg)alkyl and R⁶ is CN, OH, or CH₃ In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-Cs)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Cj-Cg)alkyl and R⁶ is CN, OH, or CH3.

In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

*

In another embodiment of Formula II, each R is independently halogen,

NR^1]R¹², N(Rⁿ)ORⁿ, NR^1INR¹¹R¹², OR¹¹ or SR^U. In another aspect ofthis embodiment, R¹ is methyl, CH₂F or ethynyl. In another aspect of this embodiment,

R¹ is methyl. In another aspect of this embodiment, R⁹ is H, halogen, or NRⁿR¹². In another aspect of this embodiment, R⁹ is H, halogen, or NR^UR¹² and R¹ is methyl, CH2F, or ethynyl. In another aspect of this embodiment, R⁹ is H, halogen, or NR¹ ’R¹²and R¹ is methyl. In another aspect of this embodiment, R⁸ is NH2 and R⁹ is H or halogen. In another aspect of this embodiment, R⁸ is NH₂ and R⁹ is H or halogen and

R¹ is methyl, CH2F, or ethynyl. In another aspect of this embodiment, R⁸ is NH2 and

R⁹ is H or halogen and R·¹ is methyl. In another aspect of this embodiment, R⁸ and R⁹

Q 1 are each NH₂. In another aspect of this embodiment, R and R are each NH₂ and R is methyl. In another aspect of this embodiment, R⁸ and R⁹ are each NH2 and R¹ is methyl, CH2F or ethynyl. In another aspect of this embodiment, R is OH and R is

NH₂. In another aspect of this embodiment, R⁸ is OH, R⁹ is NH2 and R¹ is methyl. In another aspect of this embodiment, R is OH, R is NH2 and R is methyl, CH₂F, or ethynyl. In another aspect of this embodiment R⁶ is H. Ln another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶ is OH. In another aspect of this embodiment R⁶ is CH₃.

In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-C_s)alkyl, (C₂-Cg) alkenyl or (C₂-Cg)alkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-Cg)alkyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ îs OR^a, R¹ is (Ci-Cg)alkyl and at least one of X¹ or X² is N. ln another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² îs N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (C]-Cg)alkyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ îs OH, R¹ is (Ci-Cgjalkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (C]-Cg)alkyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

In another embodiment of Formula II, each R¹⁰ is, independently, H, halogen, CN or optionally substituted heteroaryl. In another aspect of this embodiment, R¹ is methyl. In another aspect of this embodiment, R¹ is methyl, CH^F or ethynyl. In another aspect of this embodiment, R⁹ is H, halogen, or NR^{1 l}R¹². In another aspect of tliis embodiment, R⁹ is H, halogen, or NR¹ *R¹² and R¹ is methyl. In another aspect of this embodiment, R⁹ is H, halogen, or NR¹ *R¹² and R¹ is methyl, CH2F, or ethynyl. In another aspect of this embodiment, R is NH2 and R is H or halogen. In another aspect of this embodiment, R⁸ is NH2 and R⁹ is H or halogen and R¹ is methyl. In another aspect of this embodiment, R⁸ is NH2 and R⁹ îs H or halogen and R¹ is methyl, CH2F, or ethynyl. In another aspect of this embodiment, R and R are each NH2. In

Q Q 1 another aspect of this embodiment, R and R' are each NH2 and R is methyl. In another aspect of this embodiment, R and R are each NH2 and R is methyl, CH2F or ethynyl. In another aspect of this embodiment, R⁸ is OH and R⁹ is NH2. In another aspect of this embodiment, R⁸ is OH, R⁹ is NH2 and R¹ is methyl. In another aspect of this embodiment, R is OH, R is NH2 and R is methyl, CH2F, or ethynyl. In another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶îs OH. In another aspect of this embodiment R⁶ is CH3. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-C^jalkyl, (C2-Cg) alkenyl or (CN-Cslalkynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is (Ci-C₈)alkyl. In another aspect of this embodiment, R⁴ îs OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Cj-Cs)alkyl and at least one of

X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is (Ci-Cgjalkyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ îs methyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is FI. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is (C]-C8)alkyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is (Ci-Cg)alkyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

In another embodiment, compounds of Formula I or Formula II are represented by Formula III:

Formula III or a pharmaceutically acceptable sait, thereof;

wherein:

R¹ is CH₃, CH₂F, or ethynyl and ail remaining variables are defined as for Formula I.

In one embodiment of Formula III, R⁴ is H, OR^a, N(R^a)2, N3, CN, SR^a, halogen, (C]-C8)alkyl, (C₂-C₈)alkenyl or (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ îs OR^a and R¹ is CH3, CH2F, or ethynyl. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ îs H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁵ is H.

In another embodiment of Formula III, R⁶ is H, CN, OR^a or CH3. In another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶is OH. In another aspect of this embodiment R⁶ is CHj. Ln another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹ îs methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X* or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ îs H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ îs OH, R¹ îs methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ îs OH, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

In another embodiment of Formula III, R⁶ is CN, OR^a or CH3. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶ is OH. In another aspect of this embodiment R⁶ is CH3. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴ is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X²is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ îs methyl and R⁶is CN, OH, or CH₃.

In one embodiment of Formula III, R⁷ is H, -C(=O)R^H, -C(=O)OR¹¹, C(=O)SR^Hor

. In a aspect of this embodiment, R⁷ is H. In another aspect of this

W¹ embodiment, R⁷ is -C(=O)R¹¹. In another aspect of this embodiment, R⁷ is -C(=O)R^!1 ] t a *7 a wherein R is (Ci-Cs)alkyl. In another aspect of this embodiment, R is

W· . In another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶ is OH. In another aspect of this embodiment R⁶îs CH3. In another aspect of this embodiment, R⁴ is H or OR^a. Ih another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ îs OR^a, R¹ îs methyl and at least one of X¹ or X³ is N. In another aspect of this embodiment, R⁴ îs OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ îs H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X³ is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

In one embodiment of Formula III, X¹ is N or C-R¹⁰. In another aspect of this embodiment, X^] is N. In another aspect of this embodiment, X¹ is C-R¹⁰. In another aspect of this embodiment, X is C-H. In another aspect of this embodiment, X is N and X² is C-H. In another aspect of this embodiment, X¹ is C-R¹⁰ and X² is CH. In another aspect of this embodiment R⁵ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶ is OH. In another aspect of this embodiment R⁶ is CH₃. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴is OR^a. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ îs methyl and at least one of X¹ or is N.

In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ îs OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at Ieast one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

g

In another embodiment of Formula III, each R is independently halogen,

NR^1,R¹²,N(R¹¹)OR¹¹,NR¹¹NR¹¹R¹²,OR¹¹orSR¹¹. In another aspect of this embodiment, R¹ is methyl, CH2F or ethynyl. In another aspect of this embodiment, R¹ is methyl. In another aspect of this embodiment, R⁹ is H, halogen, orNRⁿR¹². In another aspect of this embodiment, R⁹ is H, halogen, or NR^UR¹² and R¹ is methyl,

CH2F, or ethynyl. In another aspect of this embodiment, R⁹ is H, halogen, or NR^UR¹²and R is methyl. In another aspect of this embodiment, R isNH2andR is H or gQ halogen. In another aspect of this embodiment, R is NH2 and R is H or halogen and R is methyl, CH2F, or ethynyl. In another aspect of this embodiment, R is NH2 and R⁹ is H or halogen and R¹ is methyl. In another aspect of this embodiment, R⁸ and R⁹

A Qt are each NH2. In another aspect of this embodiment, R and R are each NH2 and R is methyl, CH2F or ethynyl. In another aspect of this embodiment, R and R are each 1 89

NH₂ and R is methyl. In another aspect of this embodiment, R is OH and R is NH2. In another aspect of this embodiment, R is OH, R is NH2 and R is methyl, CH2F, or ethynyl. In another aspect of this embodiment, R is OH, R is NH2 and R is methyl.

In another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶ is OR^a. In another aspect of this embodiment R⁶ îs OH. In another aspect of this embodiment R⁶ is CH3. In another aspect of this embodiment, R⁴ is H or OR^a. In another aspect of this embodiment, R⁴is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at Ieast one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ îs methyl and R⁶ is CN, OH, or CH3. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ is OH and R¹ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at Ieast one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁵ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹is methyl and R⁶ is H.

In another embodiment of Formula III, each R¹⁰ is, independently, H, halogen, CN or optionally substituted heteroaryl. In another aspect of this embodiment, R¹ is methyl. In another aspect of this embodiment, R⁹ is H, halogen, or NR¹ 'R¹². In another aspect of this embodiment, R⁹ is H, halogen, or NR¹ ’R¹² and R¹ is methyl. In another aspect of this embodiment, R isNH₂andR is H or halogen. In another aspect of this embodiment, R⁸ is NH2 and R⁹ is H or halogen and R¹ is methyl. In another aspect of this embodiment, R and R are each NH2. In another aspect of this embodiment, R⁸ and R⁹ are each NH₂ and R¹ is methyl. In another aspect of this embodiment, R is OH and R is NH₂. In another aspect of this embodiment, R is OH, R⁹ îs NH2 and R¹ is methyl. In another aspect of this embodiment R⁶ is H. In another aspect of this embodiment R⁶ is CN. In another aspect of this embodiment R⁶is 0R^a. In another aspect of this embodiment R⁶ is OH. In another aspect of this embodiment R⁶ is CH3. In another aspect of this embodiment, R⁴ is H or 0R^a. In another aspect of this embodiment, R⁴ is OR^a and R¹ is methyl. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OR^a, R¹ îs methyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OR^a, R¹ is methyl and R⁶ is H. In another aspect of this embodiment, R⁴ îs OH and R’ is methyl. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and at least one of X¹ or X² is N. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is CN, OH, or CH₃. In another aspect of this embodiment, R⁴ is OH, R¹ is methyl and R⁶ is H.

In another embodiment, provided are compounds of Formula IV:

Formula IV or a pharmaceutically acceptable sait, thereof;

wherein:

R^l is (Ci-Cs)alkyl, (C^Cgjcarbocyclylalkyl, (Ci-Cg)substituted alkyl, (C2-Cg)alkenyl, (C₂-C₈)substituted alkenyl, (C₂-Cs)alkynyl, (C₂-Cg)substituted alkynyl, or aryl(Ci-Cg)alkyl;

R is halogen;

R³, R⁴, and R⁵ are each independently H, halogen, OR^a, N(R^a)2, N3, CN, NO2) S(O)nR^a, (Ci-Cs)alkyl, (CA-CgJcarbocyclylalkyl, (Ci-C8)substituted alkyl, (C2-Cg)alkenyl, (CD-C.gjsubstituted alkenyl, (C₂-Cg)alkynyl, (C₂-Cg)substituted alkynyl, or aryKCj-Cgjalkyl;

each n is independently 0, 1, or 2;

each R^a is independently H, (Ci-Cg)alkyl, (C2-Cs)alkenyl, (C2-C8)alkynyl, aryl(Ci-Cs)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)Rⁿ, -C(=O)OR¹¹, -C^OjNR^R¹², -C(=O)SR, -S(O)R, -S(O)2Rⁿ, -S(O)(OR^1J), -S^OR¹¹), or -SO2NR^1]R^!2;

R⁷ is H, -C(=O)Rⁿ, -C(=O)OR^U, -C(=O)NRⁿR¹², -C(=O)SRⁿ, -S(O)R, S(O)2Rⁿ, -S(O)(OR^h), -S(O)2(OR¹¹), ^SO₂NRR¹², or

Y

W²

Y is O, S, NR, ^(OjiR), N(OR), ^(O)(OR), or N-NR₂;

W¹ and W², when taken together, are -Y³(C(R^y)₂)sY³-; or one of W¹ or W² together with either R³ or R⁴ is -Y³- and the other of W¹ or

W is Formula la; or

W¹ and W² are each, independently, a group of Formula IVa:

Formula IVa wherein:

each Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ^(OXOR), or N-NR₂;

each Y² is independently a bond, O, CE2, NR, ⁺N(O)(E), N(OR), 'Ύΐ(θχθΕ), N-NR2, S, S-S, S(O), or S(O)₂;

each Y³ is independently O, S, or NR;

M2 is 0, 1 or 2;

each R* is a group of Formula IVb:

Formula IVb

wherein:

each Ml a, Mlc, and Mld is independently 0 or l;

Ml2c is 0, 1,2,3,4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R^y is independently H, F, Cl, Br, I, OH, -C(=Y¹)R, -C(=Y¹)R¹³, C(=Y*)OR, -C(=Y')N(R)2j -N(R)2> -⁺N(R)j, -SR, -S(O)R, -S(O)2R, -S(O)₂R¹³, S(O)(OR), -S(O)2(OR), -OC(=Y*)R, -OC(=Y’)OR, -OC(=Y¹)(N(R)2), -SC(=Y*)R, SC(=Y*)OR, -SC(=Y*)(N(R)₂), -N(R)C(=Y^I)R, -N(R)C(=Y^!)OR, -N(R)C(=Y’)N(R)₂, -SO₂NR_2î -CN, -N₃, -NO_2j -OR, (Ci-Cj) alkyl, (C₂-Cg)alkenyl, (C₂-Cs) alkynyl, Ce-C₂q aryl, C₃-C₂o carbocyclyl, C₂-C₂o heterocyclyl, arylalkyl, heteroarylalkyl;

wherein each (Cj-Cg) alkyl, (C₂-C_g)alkenyl, (C₂-C_g) alkynyl, C₆-C₂o aryl, C₃-C₂o carbocyclyl, C₂-C₂o heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R groups;

or when taken together, two R^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

each R is independently H, (Ci-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C_g) alkynyl, C₆~C₂₀ aryl, C₃-C₂q carbocyclyl, C₂-C₂o heterocyclyl, or arylalkyl;

each R⁸ is halogen, NR^{1 !}R¹², N(R^l')OR'¹, NR¹ W'R¹², N3î NO, NO2, OR^{] 1}orS(O)nRⁿ;

each R⁹ is independently H, halogen, NR^R¹², N(R^li)OR¹¹, NR^1INR^I1R¹², N3, NO, NO2, CHO, CN, -CH(=NRⁿ), -CH=NHNR^]1, -CH=N(OR^h), -CH(OR^I!)2î -C(=O)NR¹¹R¹², -C(-S)NR^!1R¹², -C(=O)ORⁿ, R¹’, OR¹¹ or S(O)_nR^H;

each Rⁿ or R¹² is independently H, (Ci-C_g)alkyl, (C₂-C_g)alkenyl, (C₂C_s)aîkynyl, (C₄-C_g) carbocyclylalkyl, optionally substituted aryl, optionally

C substituted heteroaryl, -C(=O)(Ci-C₈)alkyl, -S(O)_n(Ci~Cs)alkyl or aryl(C[-C₈)alkyl; or II 12

R and R taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NR^b-;

each R is independently a carbocycle or heterocycle optionally substituted 10 with 1-3 R²⁰ groups;

each R²⁰ is independently, halogen, CN, N3, N(R)2, OR, -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -C^Y’jR, -C(=Y¹)OR, or C(=Y¹)N(R)2;

wherein each (Ci-Cs)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl oraryl(Ci-C₈)alkyl of each R¹, R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^b)₂ or OR^b; and wherein one or more of the nonterminal carbon atoms of each said (Ci-Cg)alkyl may be optionally replaced with -O-, -S- or-NR^b;

each R^b îs independently H, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, aryl(C_rC_s)alkyl, (C₄-C₈)carbocyclylalkyl, -C(=O)R²¹, -C(=O)OR²’, -C(=O)NR²¹R²²,

-C(=O)SR²¹, -S(O)R^2!, -S(O)2R²’, -S(O)(OR²¹), -S(O)2(OR²¹), or -SO₂NR²¹R²²;

each R²¹ or R²² is independently H, (Cj-Cs)alkyl, (C₂-C₈)alkenyl, (C₂C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, -C(=O)(C₁-C₈)aIkyl, -S(O)_n(Ci-C₈)alkyl or aryl(C]-C₈)alkyl;

with the optional proviso that compounds 1, ld, le, 2, TP-1, A-l, 8, and 21 are 25 excluded.

In another aspect of this embodiment Y and Y¹ is O. In another aspect of this embodiment R⁸ is halogen, NR^HR¹², N(Rⁿ)OR¹¹, NR^llNRⁿR¹², OR¹¹ or S(O)_nR¹¹. In another aspect of this embodiment R⁹ îs H, halogen, S/OJnR¹¹ or NR^I]R¹². In another aspect of this embodiment R⁴ is OR^a. In another aspect of this embodiment

R¹ is CH₃. In another aspect of this embodiment R² is F. In another aspect of this embodiment R⁷ îs

wherein Y is -O-; W¹ is Formula la and W² together with R⁴ is -O-.In another embodiment, compounds of Formula IV are represented by Formula V:

Formula V wherein R¹ is methyl or ethynyl, and R⁴ is OR^a. In another aspect of this embodiment R⁷ is H or

In another aspect ofthis embodiment, compound of Formula V are represented the following structures:

In another embodiment, provided are compounds of Formula VI:

Formula VI or a pharmaceutically acceptable sait, thereof;

wherein:

R⁴ is OR^a;

each n is independently 0, 1, or 2;

each R^a is independently H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(C]-C8)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)Rⁿ, -C(=O)OR^H, -C(=O)NR^llR¹², -C(=O)SR, -S(O)R, -S/ORR¹¹, -S(O)(OR^h),-S(O)2(ORⁿ), or -SO₂NR^!1R¹²;

R⁷ is H, -C(=O)Rⁿ, -C(=O)OR¹¹, -C(=O)NRⁿR¹², -C(=O)SR^U, -S(O)R^l), S(O)2R¹¹, -S(O)(OR^1!), -S(O)2(OR^!1), -SO^'R¹², or

Y

w²

Y is O, S, NR, ⁺N(O)(R), N(OR), +N(O)(OR), or N-NR₂;

W¹ and W², when taken together, are -Y³(C(R^y)₂)3Y³-; or one of W¹ or W² together with R⁴ îs - Y³- and the other of W¹ or W² is Formula la; or

W¹ and W² are each, independently, a group of Formula Via:

Formula Via wherein:

each Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or

N-NR₂;

each Y² is independently a bond, O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR),

N-NR₂, S, S-S, S(O), or S(O)₂;

each Y is independently O, S, or NR;

M2 is 0, 1 or 2;

each R* is a group of Formula VIb:

_Ry wherein:

each Μ1 a, Μ1 c, and Midis independently 0 or 1 ;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R^y is independently H, F, Cl, Br, I, OH, “C(=Y')R, -C^Y'jR¹³, C(=Y')OR, -C(=Y’)N(R)2î -N(R)2, -⁺N(R)3, -SR, -S(O)R, -S(O)₂R, -S(O)₂R^]3, S(O)(OR), -S(0)2(OR), -OC(=Y‘)R, -OC(=Y')OR, -OC(=Y¹)(N(R)2), -SC^Y^R, SC(=Y*)OR, -SC(=Y¹)(N(R)2), -N(R)C(=Yⁱ)R, -N(R)C(=Y’)OR, -N(R)C(=Y¹)N(R)2,

Λ

-SO₂NR₂, -CN,-N_3î -NO₂, -OR, (CrC₈) alkyl, (C₂-C_s)alkenyl, (C₂-C₈) alkynyl, C6-C₂o aryl, C3-C20 carbocyclyl, C₂-C₂o heterocyclyl, arylalkyl, heteroarylalkyl;

wherein each (Cj-Cg) alkyl, (C₂-Cg)alkenyl, (C₂-Cg) alkynyl, C₆-C₂o aryl, C₃-C₂o carbocyclyl, C₂-C₂o heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1 -3 R groups;

each R is independently H, (Ci-Cg) alkyl, (C₂-Cg)alkenyl, (C₂-Cg) alkynyl, Cô-C₂₀ aryl, C3-C20 carbocyclyl, C₂-C₂o heterocyclyl, or arylalkyl;

each R¹¹ or R¹² is independently H, (Ci-Cg)alkyl, (C₂-Cg)alkenyl, (C₂C_s)alkynyl, (C^Csjcarbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(Cj-C_s)aIkyl, -S(O)_n(Ci-Cg)alkyl or aryl(Ci-Cg)alkyl;

each R¹³ is independently a carbocycle or heterocycle optionally substituted with 1 -3 R²⁰ groups;

each R²⁰ is independently, halogen, CN, N3, N(R)2, OR, -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), -C(=Y*)R, -C(=Y')OR, or C(=Y¹)N(R)2;

wherein each (Cj-Cg)alkyl, (C₂-Cg)alkenyl, (C₂-C₈)alkynyl or aryl(C|-C_s)alkyl of each R⁴, R¹¹ or R¹² is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(R^b)2 or OR^b; and wherein one or more of the non-terminal carbon atoms of each said (Cj-Cg)alkyl may be optionally replaced with -O-, -S- or -NR^b;

each R^b is independently H, (CrCs)alkyl, (C2-Cg)alkenyl, (C2-C8)alkynyl, aryl(C]-C8)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)R²¹, -C(=O)OR²¹, -C(=O)NR²¹R²², -C(=O)SR²¹, -S(O)R²¹, -S(O)2R²’, -S(O)(OR²¹), -S(O)2(OR²¹), or-SO2NR²¹R²²;

each R²¹ or R²² is independently H, (Ci-Cg)alkyl, (C₂-Cg)alkenyl, (C₂Cg)alkynyl, (C^Cgjcarbocyclylalkyl, -C(=O)(C]-Cg)alkyl_} -S(O)_n(C]-Cg)alkyl or aryl(Ci-Cg)alkyl; and with the optional proviso that compounds 1, le, ld, le, 2, TP-1, A-l, 8, and 21 are excluded.

In another aspect of this embodiment R^a is H, (Ci-Cg)alkyl, or -C(=O)(C]Cy alkyl; R⁷ or R⁷ together with R⁴ is

wherein a is the point of attachment to R ; b is the point of attachment to R⁴;

Ar is phenyl or naphthyl, wherein the phenyl and naphthyl are optionally substituted with 1-3 R²⁰ groups;

each R^y is independently (Ci-Cg) alkyl or C₅-C₆ carbocyclyl, wherein the alkyl and carbocyclyl are optionally substituted with 1-3 R groups;

each R is independently H, (Ci-Cs) alkyl, or arylalkyl; and each R²⁰ is independently halogen, CN, N(R)₂, OR, -SR, -S(O)R, -S(O)₂R, S(O)(OR), -S(O)₂(OR), -C(=O)R, -C(=O)OR, or C(=O)N(R)₂.

In another embodiment, compounds of Formula IV-VI are represented by compounds having a structure:

or a pharmaceutically acceptable sait, thereof.

i 1₂

In one embodiment of Formulas I-III and Formulas IV-VI, R or R is independently H, (Cj-Cg)alkyl, (Cj-Csjalkenyl, (C₂-C₈)alkynyl, (C4-Cs)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl,

-C(=O)(C]-Cg) alkyl, -S(O)_n(C]-C8)alkyI or aryl(C]-C8)alkyl. In another embodiment, R¹¹ and R¹² taken together with a nitrogen to which they are both attached, form a 3 to membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NR^a*. Therefore, by way of example and not limitation, the moiety -NR^R¹² can be represented by the heterocycles:

and the like.

In another embodiment of Formulas I-III and Formulas IV-VI, each R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is, independently, (Ci-Cs)alkyl, (C2-C_s)alkenyl, (C2-Cs)alkynyl or aryi(Ci-Cg)alkyl, wherein said (Ci-Ce)alkyl, (C2-Cg)alkenyl, (C2-C_g)alkynyl or aryl(Ci-C_g)alkyl are, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(R^a)2 or OR^a. Therefore, by way of example and not limitation, R³, R⁴, R⁵, R⁵, R¹¹ or R¹² could represent moieties such as -CH(NH₂)CH3, -

Φ

CH(OH)CH₂CH₃, -CH(NH₂)CH(CH₃)₂, -CH₂CF₃, -(CH₂)₂CH(N₃)CH_3j -(CH₂)₆NH₂and the like.

In another embodiment of Formula I-III and Formula IV-VI, R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is (Ci-Cg)alkyl wherein one or more of the non-terminal carbon atoms of each said (Ci-Cs)alkyl may be optionally replaced with -O-, -S- or -NR^a-. Therefore, 10 by way of example and not limitation, R³, R⁴, R⁵, R⁶, R¹¹ or R¹² could represent moieties such as -CH₂OCH₃, -CH₂OCH₂CH₃, -CH₂OCH(CH₃)_2î -CH₂SCH₃, (CH₂)₆OCH₃, -(CH₂)₆N(CH₃)₂ and the like.

In another embodiment, Formulas I-III is a compound selected from the group consisting of

ίο

H 0' V HO' F

I

H

and HÔ F ;

or a pharmaceutically acceptable sait or ester thereof.

In another embodiment, provided is a compound useful for the synthesis of the compounds of Formula I selected from the group consisting of

thereof.

or salts or esters

DEFINITIONS

Unless stated otherwise, the following terms and phrases as used herein are intended to hâve the following meanings:

When trade names are used herein, applicants intend to independently include the trade name product and the active pharmaceutical ingredient(s) of the trade name product.

As used herein, a compound of the invention or a compound of Formula I means a compound of Formula I or a pharmaceutically acceptable sait, thereof. Similarly, with respect to isolatable intermediates, the phrase a compound of Formula (number) means a compound of that formula and pharmaceutically acceptable salts, thereof.

“Alkyl” is hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. For example, an alkyl group can hâve 1 to 20 carbon atoms (i.e., C]-C₂o alkyl), 1 to 8 carbon atoms (i.e., Ci-C_g alkyl), or 1 to 6 carbon atoms (i.e., Cj-Cs alkyl). Examples of suîtable alkyl groups include, but are not limited to, methyl (Me, CH₃), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH₃), 2-propyl (i-Pr,

ΐ-propyl, -CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, -CH₂CH₂CH₂CH₃), 2-methyl- 1-propyl (i-Bu, i-butyl, -CH₂CH(CH3)₂), 2-butyl (s-Bu, s-butyl, -CH(CH₃)CH₂CH₃), 2-methyl-

2- propyl (t-Bu, t-butyl, -C(CH₃)₃), 1-pentyl (n-pentyl, -CH₂CH₂CH₂CH₂CH3), 2pentyl (-CH(CH3)CH₂CH₂CH3), 3-pentyl (-CH(CH₂CH₃)₂), 2-methyl-2-butyl (-C(CH₃)₂CH₂CH₃), 3-methyl-2-butyl (-CH(CH3)CH(CH₃)₂), 3-methyl-1-butyl (-CH₂CH₂CH(CH₃)₂), 2-methyl-l-butyl (-CH₂CH(CH₃)CH₂CH3), 1-hexyl (-CH₂CH2CH₂CH₂CH₂CH₃), 2-hexyl (-CH(CH₃)CH₂CH2CH₂CH₃), 3-hexyl (CH(CH₂CH₃)(CH₂CH₂CH₃)), 2-methyl-2-pentyl (-C(CH3)₂CH₂CH₂CH₃), 3-methyl-2pentyl (-CH(CH₃)CH(CH₃)CH₂CH₃), 4-methyl-2-pentyl (-CH(CH₃)CH₂CH(CH₃)₂),

3- methyl-3-pentyl (-C(CH₃)(CH₂CH₃)₂), 2-methyl-3-pentyl (-

CH(CH₂CH₃)CH(CH₃)₂), 2,3-dimethyl-2-butyl (-C(CH₃)₂CH(CH₃)₂), 3,3-dimethyl-2butyl (-CH(CH₃)C(CH₃)₃, and octyl (-(CH₂)7CH₃).

“Alkoxy” means a group having the formula -O-alkyl, in which an alkyl group, as defined above, is attached to the parent molécule via an oxygen atom. The alkyl portion of an alkoxy group can hâve 1 to 20 carbon atoms (Le., Ci-C₂o alkoxy), 20 1 to 12 carbon atoms(z.e., Ci-Ci₂ alkoxy), or 1 to 6 carbon atoms(z.e., Cj-Cé alkoxy).

Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH₃or -OMe), ethoxy (-OCH₂CH₃ or -OEt), t-butoxy (-O-C(CH₃)₃ or -OtBu) and the like.

“Haloalkyl” is an alkyl group, as defined above, in which one or more hydrogen atoms of the alkyl group is replaced with a halogen atom. The alkyl portion of a haloalkyl group can hâve 1 to 20 carbon atoms (Le., Ci-C₂o haloalkyl), 1 to 12 carbon atoms(i.e., C1-C12 haloalkyl), or 1 to 6 carbon atoms(z.e., Ci-Cé alkyl). Examples of suitable haloalkyl groups include, but are not limited to, -CF_3s -CHF₂, -CFH₂, -CH₂CF₃, and the like.

“Alkenyl” îs a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp double bond. For example, an alkenyl group can hâve 2 to 20 carbon atoms (Le., C₂-C₂q alkenyl), 2 to 8 carbon atoms (i.e., C₂-Cg alkenyl), or 2 to 6 carbon atoms (Le., C₂-C& alkenyl). Ex amples of suitable alkenyl groups include, but are not limited to, ethyl ene or vinyl (-CH-CH₂), allyl (-CH₂CH=CH₂), cyclopentenyl (-CslT?), and 5-hexenyl (-CH₂CH₂CH₂CH₂CH=CH₂).

“Alkynyl” is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp triple bond. For example, an alkynyl group can hâve 2 to 20 carbon atoms (i.e., C₂-C₂o ÎO alkynyl), 2 to 8 carbon atoms (i.e., C₂-C₈ alkyne,), or 2 to 6 carbon atoms (i.e., C₂-C₆alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-C=CH), propargyl (-CH₂CsCH), and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen 15 atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can hâve 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH₂-),

1,1-ethyl (-CH(CH₃)-), 1,2-ethyl (-CH₂CH₂-), 1,1-propyl (-CH(CH₂CH₃)-), 1,2-propyl (-CH₂CH(CH₃)-), 1,3-propyl (-CH₂CH₂CH₂-), 1,4-butyl (-CH₂CH₂CH₂CH₂-), and the like.

“Alkenylene” refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. For example, and alkenylene group can hâve 1 to 20 carbon atoms, 1 to 10 carbon atoms, 25 or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2ethylene (-CH=CH-).

“Alkynylene” refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkyne.

For example, an alkynylene group can hâve 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkynylene radicals include, but are not limited to, acetylene (-C=C-), propargyl (-CH₂C=C-), and 4-pentynyl (-CH₂CH₂CH₂C=C-).

“Amino” refers generally to a nitrogen radical which can be considered a dérivative of ammonia, having the formula -N(X)₂, where each “X” îs independently H, substituted or unsubstîtuted alkyl, substituted or unsubstîtuted carbocyclyl, substituted or unsubstîtuted heterocyclyl, etc. The hybridization of the nitrogen is approximately sp³. Nonlimiting types of amino include-NH₂, -N(alkyl)₂, -NH(alkyl), -N(carbocyclyl)₂, NH(carbocyclyl), -N(heterocyclyl)₂, -NH(heterocyclyl), -N(aryl)2, -NH(aryl), N(alkyl)(aryl), -N(alkyl)(heterocyclyl), -N(carbocyclyl)(heterocyclyl), N(aryl)(heteroaryl), -N(alkyl)(heteroaryl), etc. The term “alkylamino” refers to an amino group substituted with at least one alkyl group. Nonlimiting examples of amino groups include-NH₂, -NH(CH₃), -N(CH₃)₂, -NH(CH₂CH₃), - N(CH₂CH₃)₂, NH(phenyl), -N(phenyl)₂, -NH(benzyl), -N(benzyl)₂, etc. Substituted alkylamino refers generally to alkylamino groups, as defined above, in which at least one substituted alkyl, as defined herein, îs attached to the amino nitrogen atom. Non-limiting examples of substituted alkylamino includes -NH(alkylene-C(O)-OH), -NH(alkylene-C(O)-O-alkyl), -N(alkylene-C(O)-OH)₂, -N(alkylene-C(O)-O-alkyl)₂, etc.

“Aryl” means an aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. For example, an aryl group can have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 10 carbon atoms. Typical aryl groups include, but are not limited to, radicals derived from benzene (e.g., phenyl), substituted benzene, naphthalene, anthracene, biphenyl, and the like.

“Arylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-l-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-l-yl and the like. The arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

“Arylalkenyl” refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, but also an sp² carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any ofthe aryl groups disclosed herein, and the ©

alkenyl portion of the arylalkenyl can include, for example, any of the alkenyl groups disclosed herein. The arylalkenyl group can comprise 8 to 20 carbon atoms, e.g., the alkenyl moiety is 2 to 6 carbon atoms and the aryl moiety îs 6 to 14 carbon atoms.

“Arylalkynyl” refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typicalîy a terminal or sp carbon atom, but also an sp carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkynyl can include, for example, any of the aryl groups disclosed herein, and the alkynyl portion of the arylalkynyl can include, for example, any of the alkynyl groups disclosed herein. The arylalkynyl group can comprise 8 to 20 carbon atoms, e.g., the alkynyl moiety is 2 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

The term “substituted” in reference to alkyl, alkylene, aryl, arylalkyl, alkoxy, heterocyclyl, heteroaryl, carbocyclyl, etc., for example, “substituted alkyl”, “substituted alkylene”, “substituted aryl”, “substituted arylalkyl”, “substituted heterocyclyl”, and “substituted carbocyclyl”, unless otherwise indicated, means alkyl, alkylene, aryl, arylalkyl, heterocyclyl, carbocyclyl respectively, in which one or more hydrogen atoms are each independently replaced with a non-hydrogen substituent.

Typical substituents include, but are not limited to, -X, -R^b, -O', =0, -OR^b, -SR^b, -S‘, -NR^b2, -N⁺R^bî, =NR^b, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO₂, =N₂, -N₃, -NHC(=O)R^b, -OC(=O)R^b, -NHC(=O)NR^b2, -S(=O)2-, -S(=O)2OH, -S(=O)2R^b, -OS(=0)2OR^b, -S(=O)2NR^b2, -S(=O)R^b, -OP(=O)(OR^b)2,-P(=O)(0R^b)2, -Ρ(=Ο)(0’)₂, 25 -P(=O)(OH)₂, -P(O)(OR^b)(O'), -C(=O)R^b, -C(=O)X, -C(S)R^b, -C(O)OR^b, -C(O)O’,

-C(S)OR^b, -C(O)SR^b, -C(S)SR^b, -C(O)NR^b2, -C(S)NR^b2, -C(=NR^b)NR^b ₂, where each X is independently a halogen: F, Cl, Br, or I; and each R^b is independently H, alkyl, aryl, arylalkyl, a heterocycle, or a protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise 30 indicated, when the term substituted is used in conjunction with groups such as arylalkyl, which hâve two or more moieties capable of substitution, the substituents can be attached to the aryl moiety, the alkyl moiety, or both.

The term “prodrug” as used herein refers to any compound that when administered to a biological system generates the drug substance, i.e., active ingrédient, ©

as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reactîon(s). A prodrug is thus a covalently modified analog or latent form of a therapeutically active compound.

One skilled in the art will recognize that substituents and other moieties of the compounds of Formula I-III and Formula IV-VI should be selected in order to provide a 10 compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. The définitions and substituents for various genus and subgenus of the présent compounds are described and illustrated herein. It should be understood by one skilled in the art that any combination ofthe définitions and substituents described above should not 15 resuit in an inopérable species or compound. “Inopérable species or compounds” means compound structures that violâtes relevant scientific principles (such as, for example, a carbon atom connecting to more than four covalent bonds) or compounds too unstable to permit isolation and formulation into pharmaceutically acceptable dosage forms.

“Heteroalkyl” refers to an alkyl group where one or more carbon atoms hâve been replaced with a heteroatom, such as, O, N, or S. For example, if the carbon atom of the alkyl group which is attached to the parent molécule îs replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkoxy group (e.g., -OCH3, etc.), an amine (e.g., -NHCH₃, -N(CH₃)₂, etc.), or a thioalkyl group (e.g.,

-SCH₃). If a non-terminal carbon atom of the alkyl group which is not attached to the parent molécule is replaced with a heteroatom (e.g., O, N, or S) the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH₂CH₂-O-CH₃, etc.), an alkyl amine (e.g., -CH₂NHCH₃, -CH₂N(CH₃)_2j etc.), or a thioalkyl ether (e.g.,-CH₂-S-CH₃). If a terminal carbon atom ofthe alkyl group is replaced with a heteroatom (e.g., O, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g., -CH₂CH₂-OH), an aminoalkyl group (e.g., -CH₂NH₂), or an alkyl thiol group (e.g., -CH₂CH₂“SH). A heteroalkyl group can hâve, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or I to 6 carbon atoms. A C_rC₆ heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.

' “Heterocycle” or “heterocyclyl” as used herein includes b y way of example and not limitation those heterocycles described in Paquette, Léo A.; Princîples of Modem Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Sériés of Monographs” (John Wiley & Sons, New York, 1950 to présent), in particular Volumes 13, 14, 16, 19, and 28; and Z Am. Chem. Soc. (1960) 82:5566. In one spécifie embodiment of the invention “heterocycle” includes a “carbocycle” as defîned herein, wherein one or more (e.g. 1,2, 3, or 4) carbon atoms hâve been replaced with a heteroatom (e.g. O, N, or S). The terms “heterocycle” or “heterocyclyl” includes saturated rings, partially unsaturated rings, and aromatic rings (i.e., heteroaromatic rings). Substituted heterocyclyls include, for example, heterocyclic rings substituted with any of the substituents disclosed herein including carbonyl groups. A non-limiting example of a carbonyl substituted heterocyclyl îs:

tk ,NH

O

Examples of heterocycles include by way of example and not limitation pyridyl, dihydroypyridyl, tetrahydropyridyl (piperidyl), thiazolyl, tetrahydrothiophenyl, sulfur oxidized tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthalenyl, indolyl, indolenyl, quinolinyl, îsoquinolinyl, benzimidazolyl, piperidinyl, 4pîperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-l,2,5-thiadiazinyl, 2H,6H-1,5,2dithîazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizînyl, isoindolyl, 3H-indolyl, lH-indazoly, purinyl, 4H-quinolizînyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aHcarbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazînyl, isochromanyl, ©

chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

B y way of example and not limitation, carbon bonded heterocycles are bonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or 6 of a pyridazîne, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2,4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1,3,4, 5, 6, 7, or 8 of an isoquinoline. Still more typically, carbon bonded heterocycles include 2pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimîdinyl, 5-pyrimidinyl, 6pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles are bonded at position 1 of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3pyrroline, imidazole, imidazolidine, 2-nnidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1Hindazole, position 2 of a isoîndole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or B-carboline. Still more typically, nitrogen bonded heterocycles include 1-azîridyl, 1-azetedyl, l-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

“Heterocyclylalkyl” refers to an acyclic alkyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene- moiety). Typical heterocyclyl alkyl groups include, but are not Iimited to heterocyclyl-CH2-, 216370 (heterocyclyl)ethan-I-yl, and the like, wherein the “heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modem Heterocyclic Chemistry. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkyl group comprises 3 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is l to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms. Examples of heterocyclylalkyls include by way of example and not limitation 5-membered sulfur, oxygen, and/or nitrogen contaîning heterocycles such as thiazolylmethyl, 2-thîazolylethan-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen contaîning heterocycles such as piperidinylmethyl, piperazinylniethyl, morpholinylmethyl, pyridinylmethyl, pyridizylmethyl, pyrimidylmethyl, pyrazinylmethyl, etc.

“Heterocyclylalkenyl” refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³ carbon atom, but also a sp² carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclylalkenylene- moiety). The heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described în Principles of Modem Heterocyclic Chemistry, and the alkenyl portion of the heterocyclyl alkenyl group includes any of the alkenyl groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkenyl portion of the heterocyclyl alkenyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkenyl group comprises 4 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclyl alkenyl group is 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.

“Heterocyclylalkynyl” refers to an acyclic alkynyl radical in which one ofthe hydrogen atoms bonded to a carbon atom, typically a terminal or sp carbon atom, but also an sp carbon atom, is replaced with aheterocyclyl radical (Le., aheterocyclyl16370

Q alkynylene- moiety). The heterocyclyl portion of the heterocyclyl alkynyl group includes any ofthe heterocyclyl groups described herein, including those described in Principles of Modem Heterocyclic Chemistry, and the alkynyl portion of the heterocyclyl alkynyl group includes any of the alkynyl groups disclosed herein. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkynyl portion of the heterocyclyl alkynyl by means of a carbon-carbon bond or a carbon-hetero atom bond, with the proviso that the resulting group is chemîcally stable. The heterocyclyl alkynyl group comprises 4 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group îs 2 to 6 carbon atoms and the heterocyclyl moiety is 2 to 14 carbon atoms.

“Heteroaryl” refers to an aromatic heterocyclyl having at least one heteroatom in the ring. Non-limiting examples of suitable heteroatoms which can be included în the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include ail of those aromatic rings listed in the définition of “heterocyclyl”, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofùranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquînolyl, pyridazyl, pyrimidyl, pyrazyl, etc.

“Carbocycle” or “carbocyclyl” refers to a saturated (i.e., cycloalkyl), partially unsaturated (e.g., cycloakenyl, cycloalkadienyl, etc.) or aromatic ring having 3 to 7 carbon atoms as a monocycle, 7 to 12 carbon atoms as a bicycle, and up to about 20 carbon atoms as a polycycle. Monocyclic carbocycles hâve 3 to 7 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles hâve 7 to 12 ring atoms, e.g., arranged as a bicyclo [4,5], [5,5], [5,6] or [6,6] system, or 9 or 10 ring atoms arranged as a bicyclo [5,6] or [6,6] system, or spiro-fused rings. Non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-lenyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-l-enyl, 1cyclohex-2-enyl, l-cyclohex-3-enyl, and phenyl. Non-limiting examples of bicyclo carbocycles includes naphthyl, tetrahydronapthalene, and decaline.

“Carbocyclylalkyl” refers to an acyclic alkyl radical in which one of the

C hydrogen atoms bonded to a carbon atom is replaced with a carbocyclyl radical as described herein. Typical, but non-limiting, examples of carbocyclylalkyl groups include cyclopropylmethyl, cyclopropylethyl, cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl.

“Arylheteroalkyl” refers to a heteroalkyl as defined herein, in which a hydrogen atom (which may be attached either to a carbon atom or a heteroatom) has been replaced with an aryl group as defined herein. The aryl groups may be bonded to a carbon atom of the heteroalkyl group, or to a heteroatom of the heteroalkyl group, provided that the resulting arylheteroalkyl group provides a chemically stable moiety. For example, an arylheteroalkyl group can hâve the general formulae -alkyl eneO-aryl, -alkylene-O-alkyl ene-aryl, -alkyl en e-NH-aryl, -alkylene-NH-alkyl ene-aryl, -alkyl ene-S-aryl, -alkylene-S-alkylene-aryl, etc. In addition, any of the alkyl ene moieties in the general formulae above can be further substituted with any of the substituents defined or exemplified herein.

“Heteroarylalkyl” refers to an alkyl group, as defined herein, in which a hydrogen atom has been replaced with a heteroaryl group as defined herein. Nonlîmiting examples of heteroaryl alkyl include -CH₂-pyridinyl, -CH₂-pyrrolyl, -CH₂-oxazolyl, -CH₂-indolyl, -CH₂-isoindolyl, -CH₂-purinyl, -CH₂-furanyl, -CH₂-thîenyl, -CH₂-benzo furanyl, -CH₂-benzothiophenyl, -CH₂-carbazolyI, ~CH₂-îinidazolyl, -CH₂-thiazolyl, -CH₂-isoxazolyl, -CH₂-pyrazolyl, -CH₂-isothîazoIyl, -CH₂-quinoIyl, -CH₂-isoquinolyl, -CH₂-pyridazyl, -CH₂-pyrimidyl, -CH₂-pyrazyl, -CH(CH₃)-pyridinyI, -CH(CH₃)-pyrrolyl, -CH(CH₃)-oxazolyl, -CH(CH₃)-indolyl, -CH(CH₃)-isoindolyl, -CH(CH₃)-purinyI, -CH(CH₃)-furanyl, -CH(CH₃)-thienyl, -CH(CH₃)-benzofuranyl, -CH(CH₃)-benzothiophenyl, -CH(CH₃)-carbazoIyl, -CH(CH₃)-imidazolyl, -CH(CH₃)-thiazolyl, -CH(CH₃)-isoxazolyl, -CH(CH₃)~pyrazolyl, -CH(CH₃)-isothiazolyl, -CH(CH₃)-quînolyl, -CH(CH₃)-isoquinolyl, -CH(CH₃)-pyridazyl, -CH(CH₃)-pyrimidyl, -CH(CH₃)-pyrazyI, etc.

The term “optionally substituted” in reference to a particular moiety of the compound of Formula I-III and Formula IV-VI (e.g., an optionally substituted aryl group) refers to a moiety wherein ail substituents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced b y substituents such as those listed under the définition of “substituted” or as otherwise indicated.

The tenu “optionally replaced” in reference to a particular moiety of the compound of Formula I-III and Formula IV-VI (e.g., the carbon atoms of said (CiC_g)alkyl may be optionally replaced by -O-, -S-, or -NR^a-) means that one or more of the methylene groups of the (C_t-Cg)alkyl may be replaced by 0, 1,2, or more of the groups specified (e.g., -O-, -S-, or-NR³-).

The term “non-terminal carbon atom(s)” in reference to an alkyl, alkenyl, alkynyl, alkylene, alkenylene, or alkynylene moiety refers to the carbon atoms in the moiety that intervene between the first carbon atom of the moiety and the last carbon atom in the moiety. Therefore, by way of example and not limitation, in the alkyl moiety -CH₂(C*)H₂(C*)H₂CH₃ or alkylene moiety -CH₂(C*)H₂(C*)H₂CH₂- the C* atoms would be considered to be the non-terminal carbon atoms.

Certain Y and Y¹ alternatives are nitrogen oxides such as ⁺N(O)(R) or ⁺N(O)(OR). These nitrogen oxides, as shown here attached to a carbon atom, can also be represented by charge separated groups such as

respectively, and are intended to be équivalent to the aforementioned représentations for the purposes of describîng this invention.

Linker or “link” means a chemical moiety comprising a covalent bond or a chain of atoms. Linkers include repeating units of alkyloxy (e.g. polyethyleneoxy,

PEG, polymethyleneoxy) and alkylamino (e.g. polyethyleneamino, Jeffamîne™); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.

The tenus such as “oxygen-linked”, “nitrogen-linked”, “carbon-linked”, “sulfur-linked”, or “phosphorous-lînked” mean that if a bond between two moieties can be formed by using more than one type of atom in a moiety, then the bond formed between the moieties is through the atom specified. For example, a nitrogen-linked

amino acid would be bonded through a nitrogen atom of the amino acid rather than through an oxygen or carbon atom of the amino acid.

Unless otherwise specified, the carbon atoms of the compounds of Formula IIII and Formula IV-VI are intended to hâve a valence of four. In some chemical structure représentations where carbon atoms do not hâve a sufficient number of variables attached to produce a valence of four, the remaining carbon substituents needed to provide a valence of four should be assumed to be hydrogen. For example,

“Protecting group” refers to a moiety of a compound that masks or alters the properties of a functional group or the properties of the compound as a whole. The chemical substructure of a protecting group varies widely. One function of a protecting group is to serve as an intermediate în the synthesis of the parental drug substance. Chemical protecting groups and strategies for protectîon/deprotection are well known in the art. See: Protective Groups in Organic Chemistry, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991. Protecting groups are often utilized to mask the reactivity of certain functional groups, to assist in the efficiency

of desired chemical reactions, e.g. making and breaking chemical bonds în an ordered and planned fashîon. Protection of functional groups of a compound alters other physical properties besides the reactivity of the protected functional group, such as the polarity, lipophilicity (hydrophobicity), and other properties which can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

Protected compounds may also exhibit altered, and in some cases, optimized properties in vitro and in vivo, such as passage through cellular membranes and résistance to enzymatic dégradation or séquestration. In this rôle, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another 15 function of a protecting group is to couvert the parental drug into a prodru g, whereby the parental drug is released upon conversion of the prodrug in vivo. Because active prodrugs may be absorbed more effectively than the parental drug, prodrugs may possess greater potency in vivo than the parental drug. Protecting groups are removed either in vitro, in the instance of chemical intermediates, or in vivo, in the case of prodrugs. With chemical intermediates, it is not particularly important that the resulting products after deprotection, e.g. alcohols, be physiologically acceptable, although în general it is more désirable if the products are pharmacologically innocuous.

“Prodrug moiety” means a labile functional group which séparâtes from the active inhibitory compound during metabolism, systemically, inside a cell, by hydrolysis, enzymatic cleavage, or by some other process (Bundgaard, Hans, “Design and Application of Prodrugs” in Textbook of Drug Design and Development (1991), P. Krogsgaard-Larsen and H. Bundgaard, Eds. Harwood Academie Publishers, pp. 113191). Enzymes which are capable of an enzymatic activation mechanism with the phosphonate prodrug compounds of the invention include, but are not limited to, amidases, esterases, microbial enzymes, phospholipases, cholinesterases, and phosphases. Prodrug moieties can serve to enhance solubility, absorption and lipophilicity to optimize drug delivery, bioavailability and efficacy.

A prodrug moiety may include an active métabolite or drug itself.

Exemplary prodrug moieties include the hydrolytically sensitive or labile acyloxymethyl esters -CH2OC(=O)R³⁰ and acyloxymethyl carbonates -CH2OC(=O)OR³⁰ where R³⁰ is Cj-Ce alkyl, Ci~C₆ substituted alkyl, C₆-C2o aryl or C6-C20 substituted aryl. The acyloxyalkyl ester was used as a prodrug strategy for carboxylic acids and then applied to phosphates and phosphonates by Farquhar et al (1983) J. Pharm. Sel. 72: 324; also US Patent Nos. 4816570, 4968788, 5663159 and 5792756. In certain compounds of the invention, a prodrug moiety is part of a phosphate group. The acyloxyalkyl ester may be used to deliver phosphoric acids across cell membranes and to enhance oral bioavailability. A close variant of the acyloxyalkyl ester, the alkoxycarbonyloxyalkyl ester (carbonate), may also enhance oral bioavailability as a prodrug moiety in the compounds of the combinations of the invention. An exemplary acyloxymethyl ester is pivaloyloxymethoxy, (POM) -CH20C(=O)C(CH3)3- An exemplary acyloxymethyl carbonate prodrug moiety is pivaloyloxymethylcarbonate (P OC) -CH2OC(=O)OC(CH3)₃.

The phosphate group may be a phosphate prodrug moiety. The prodrug moiety may be sensitive to hydrolysis, such as, but not limited to those comprising a pivaloyloxymethyl carbonate (POC) or POM group. Altematively, the prodrug moiety may be sensitive to enzymatic potentiated cleavage, such as a lactate ester or a phosphonamidate-ester group.

Aryl esters of phosphorus groups, especially phenyl esters, are reported to enhance oral bioavailability (DeLambert et al (1994) J. Med. Chem. 37: 498). Phenyl esters containing a carboxylic ester ortho to the phosphate have also been described (Khamnei and Torrence, (1996) J. Med. Chem. 39:4109-4115). Benzyl esters are reported to generate the parent phosphonic acid. In some cases, substituents at the ortho-or para-position may accelerate the hydrolysis. Benzyl analogs with an acylated phénol or an alkylated phénol may generate the phenolic compound through the action of enzymes, e.g. esterases, oxidases, etc., which in tum undergoes cleavage at the benzylic C-0 bond to generate the phosphoric acid and the quinone methide intermediate. Examples of this class of prodrugs are described by Mitchell et al (1992) J. Chem. Soc. Perkin Trans. 12345; Brook et al WO 91/19721. Still other benzyhc prodrugs hâve been described containing a carboxylic ester-containing group attached to the benzylic methylene (Glazier et al WO 91/19721). Thio-containîng prodrugs are reported to be useful for the intracellular delivery of phosphonate drugs. These proesters contain an ethylthio group in which the thiol group is either esterified with an acyl group or combined with another thiol group to form a disulfide. Deesteri fi cation or réduction of the disulfide generates the free thio intermediate which subsequently breaks down to the phosphoric acid and episulfide (Puech et al (1993) Antiviral Res., 22: 155-174; Benzaria et al (1996) J. Med. Chem. 39: 4958). Cyclic phosphonate esters hâve also been described as prodrugs of phosphoruscontaining compounds (Erion et al, US Patent No. 6312662).

It is to be noted that ail enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula I, Formula II, Formula III, Formula IV, Formula V, or Formula VI and pharmaceutically acceptable salts thereof are embraced by the présent invention. Ail mixtures of such enantiomers and diastereomers are within the scope of the présent invention.

A compound of Formula I-III and Formula IV-VI and its pharmaceutically acceptable salts may exist as different polymorphs or pseudopolymorphs. As used herein, crystalline polymorphism means the ability of a crystalline compound to exist in different crystal structures. The crystalline polymorphism may resuit from différences in crystal packing (packing polymorphism) or différences in packing between different conformera of the same molécule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvaté of a compound to exist in different crystal structures. The pseudopolymorphs of the instant invention may exist due to différences in crystal packing (packing pseudopolymorphism) or due to différences in packing between different conformera of the same molécule (conformational pseudopolymorphism). The instant invention comprises ali polymorphs and pseudopolymorphs of the compounds of Formula I-III and Formula IV-VI and their pharmaceutically acceptable salts.

A compound of Formula I-III and Formula IV-VI and its pharmaceutically acceptable salts may also exist as an amorphous solid. As used herein, an amorphous solid is a solid in which there is no long-range order of the positions of the atoms in the solid. This définition applies as well when the crystal size is two nanometers or less. Additives, including solvents, may be used to create the amorphous forms of the instant invention. The instant invention comprises ail amorphous forms of the compounds of Formula I-III and Formula IV-VI and their pharmaceutically acceptable salts.

Selected substituents comprising the compounds of Formula I-ΠΙ and Formula IV-VI are présent to a recursive degree. In this context, “recursîve substituent” means that a substituent may recite another instance of itself. Because of the recursîve nature of such substituents, theoretically, a large number of compounds may be présent in any given embodiment. For example, R^x comprises a R^y substituent. R^ycan be R. R can be W³. W³ can be W⁴ and W⁴ can be R or comprise substituents comprising R^y. One of ordinary skill in the art of médicinal chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by way of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.

B y way of ex ample and not limitation, W³ and R^y are recursive substituents în certain embodiments. Typically, each recursive substituent can independently occur 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5,4, 3, 2, 1, or 0, times in a given embodiment. More typically, each recursive substituent can independently occur 12 or fewer times in a given embodiment. Even more typically, each recursive substituent can independently occur 3 or fewer times in a given embodiment. For example, W³ will occur 0 to 8 times, R^y will occur 0 to 6 tîmes in a given embodiment. Even more typically, W³ will occur 0 to 6 times and R^y will occur 0 to 4 times in a gîven embodiment.

Recursîve substituents are an intended aspect of the invention. One of ordinary skîll in the art of médicinal chemistry understands the versatility of such substituents. To the degree that recursive substituents are présent in an embodiment ofthe invention, the total number will be determined as set forth above.

The modifier about used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (e.g., includes the degree of error assocîated with measurement of the particular quantity).

The compounds of the Formula I-III and Formula IV-VI may comprise a phosphate group as R⁷, which may be a prodrug moiety

Y

wherein each Y or Y¹ is, independently, O, S, NR, ^(OJÎR), N(OR), ^(OROR), or N-NR₃;

W¹ and W², when taken together, are -Y³(C(R^y)₃)3Y³-; or one of W¹ or W² together with either R³or R⁴ is -Y³- and the other of W¹ or W² is Formula la; or W¹ and W² are each, independently, a group of Formula la:

wherein:

each Y is independently O, S, or NR;

M2 is 0, 1 or 2;

each R^y is independently H, F, Cl, Br, I, OH, R, -C(=Y^l)R, -C(=Y')OR, C^Y'jNtRR, -N(R)2, -NiRh -SR, -S(O)R, -S(O)2R, -S(O)(OR), -S(O)2(OR), OC(=Y')R, -OC(=Y*)OR, -OC(=Y^l)(N(R)2), -SC(=Y¹)R, -SC(=Yⁱ)OR, -

SC(=Y')(N(R)₂), -N(R)C(==Y')R, -N(R)C(=Y')OR, or -N(R)C(=Y')N(R)_2> -SO₂NR₂, -CN, —N₃, -NO₂, -OR, a protecting group or W³; or when taken together, two R^y on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms;

each R^x îs independently R^y, a protecting group, or the formula:

M1a

M12c M1c

M1d wherein:

Mla, Mlc, and Ml d are independently 0 or I;

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R îs H, halogen, (Cj-C₈) alkyl, (C]-C₈) substituted alkyl, (C₂-C₈) alkenyl, (C₂-Cg) substituted alkenyl, (C₂-C₈) alkynyl, (C₂-C₈) substituted alkynyl, 0₆-0₂ο aryl, C6-C₂o substituted aryl, C₂-C₂o heterocycle, C₂-C₂o substituted heterocyclyl, arylalkyl, substituted arylalkyl or a protecting group;

W³ is W⁴ or W⁵; W⁴ is R, -C(Y¹)R^y, -C(Y*)W⁵, -SO2R^y, or -SO2W⁵; and W⁵ is a carbocycle or a heterocycle wherein W⁵ is independently substituted with 0 to 3 R^ygroups.

W⁵ carbocycles and W⁵ heterocycles may be independently substituted with 0 to 3 R^y groups. W⁵ may be a saturated, unsaturated or aromatic ring comprising a mono- or bicyclic carbocycle or heterocycle. W⁵ may hâve 3 to 10 ring atoms, e.g., 3 to 7 ring atoms. The W⁵ rings are saturated when containing 3 ring atoms, saturated or mono-unsaturated when containing 4 ring atoms, saturated, or mono- or dîunsaturated when containing 5 ring atoms, and saturated, mono- or di-unsaturated, or aromatic when containing 6 ring atoms.

A W⁵ heterocycle may be a monocycle having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, and S) or a bicycle having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O,

P, and S). W⁵ heterocyclic monocycles may hâve 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S); or 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). W⁵ heterocyclic bicycles hâve 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, and S) arranged as a bicyclo [4,5], [5,5], [5,6], or [6,6] system; or 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 hetero atoms selected from N and S) arranged as a bicyclo [5,6] or [6,6] system. The W⁵ heterocycle may be bonded to Y²through a carbon, nitrogen, sulfur or other atom by a stable covalent bond.

W⁵ heterocycles include for example, pyridyl, dihydropyridyl isomers, piperidine, pyridazînyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furanyl, thiofuranyl, thienyl, and pyrrolyl. W⁵ also includes, but is not limited to, examples such as:

W⁵ carbocycles and heterocycles may be independently substituted with 0 to 3

R groups, as defined above. For example, substituted W⁵ carbocycles include:

Examples of substituted phenyl carbocycles include:

Embodiments of R⁷ or R⁷ together with R⁴ include the structures

wherein a is the point of attachment to R⁷; b is the point of attachment to R⁴;

Ar is phenyl or naphthyl, wherein the phenyl and naphthyl are optionally on substituted with 1-3 R groups;

each R^y is independently (Cj-Cg) alkyl or Cs-Cg carbocyclyl, wherein the alkyl and carbocyclyl are optionally substituted with 1-3 R²⁰ groups;

each R is independently H, (C\-Ce) alkyl, or arylalkyl; and each R²⁰ is independently halogen, CN, N(R)2, OR, -SR, -S(O)R, -S(O)₂R, S(O)(OR), -S(O)₂(OR), -C(=O)R, -C(=0)OR, or C(=O)N(R)₂.

Y

II

Embodiments of W² of Formula I-III and Formula IV-VI compounds include substructures such as:

O _DX

Il /R \ y2b '^R^x wherein each Y^2b is, independently, O or N(R). In another aspect of this embodiment, each Y^2b is O and each R^x is independently:

Y² wherein M12c is 1, 2 or 3 and each Y² is independently a bond, O, CR₂, or S. In another aspect of this embodiment, one Y^2b-R* is NH(R) and the other Y^2b-R^x is O-

wherein Ml2c is 2. In another aspect of this embodiment, each Y^2b is O and each R^x is independently:

-il , wherein Ml2c is 2. In another aspect of this embodiment, each Y is O and each R^x îs independently;

Other embodiments of

W¹ of Formulas Ι-ΙΠ and Formulas IV-VI compounds include substructures such as:

wherein each Y³ is, independently, O or N(R). In another aspect of this embodiment, each Y³ is O. In another aspect of this embodiment, the substructure îs:

wherein R^y is W⁵ as defined herein.

W¹

Another embodiment of of Formula I-III and Formula IV-VI includes the substructures:

wherein each Y^2c is, independently, O, N(R^y) or S.

Another embodiment of

of Formula I-III and Formula IV-VI »

compounds includes the sub structures wherein one of W or W together with either

R³ or R⁴ is -Y³- and the other of W¹ or W² is Formula la. Such an embodiment is represented by a compound of Formula Ib selected from:

In another aspect of the embodiment of Formula Ib, each Y and Y³ is O. In another aspect of the embodiment of Formula Ib, W¹ or W² is Y^2b-R^x; each Y, Y³ and 10 Y^2b is O and R^x is:

wherein Ml 2c is 1, 2 or 3 and each Y² is independently a bond, O, CR₂, or S. In another aspect of the embodiment of Formula Ib, W¹ or W² is Y^2b-R^x; each Y, Y³and Y^2b is O and R^x is:

wherein Ml2c is 2. In another aspect of the embodiment of Formula Ib, W¹ or W² is Y^2b-R^x; each Y, Y³ and Y^2b is O and R^x is:

Another embodiment of

Y

II

of Formula I-III and Formula IV-VI compounds includes a substructure:

wherein W⁵ is a carbocycle such as phenyl or substituted phenyl. In another aspect of this embodiment, the substructure is:

9¼ wherein Y is O or N(R) and the phenyl carbocycle is substituted with 0 to 3

R groups. In another aspect of this embodiment of the substructure, R^x is:

wherein M12c is I, 2 or 3 and each Y² is independently a bond, O, CR₂₎ or S.

Another embodiment of

of Formula I-ΠΙ and Formula IV-VI includes substructure:

The chiral carbon of the amino acid and lactate moieties may be either the R or

S configuration or the racemic mixture.

Another embodiment of of Formula I-III and Formula IV-VI is substructure wherein each Y² is, independently, -O- or -NH-. In another aspect of this embodiment, R^y is (C[-C8) alkyl, (Ci-Cg) substituted alkyl, (C2-C8) alkenyl, (C2-C8) substituted alkenyl, (C2-C8) alkynyl or (C2-C8) substituted alkynyl. In another aspect of this embodiment, R^y is (Ci-C8) alkyl, (Cj-C₈) substituted alkyl, (C₂-Cg) alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl or (C₂-C₈) substituted alkynyl; and R is CH₃. In another aspect of this embodiment, R^y is (C[-C₈) alkyl, (Cj-Cg) substituted alkyl, (C₂-C₈) alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C₈) alkynyl or (C₂-C₈) substituted alkynyl; R is CH₃; and each Y² is -NH-. In a aspect of this embodiment, W^l and W² are, independently, nitrogen-linked, naturally occurring amino acids or naturally occurring amino acid esters. In another aspect of this embodiment, W¹ and W² are, independently, naturally-occurring 2-hydroxy carboxylic acids or naturallyoccurring 2-hydroxy carboxylic acid esters wherein the acid or ester is linked to P through the 2-hydroxy group.

Another embodîment of of Formula I, Formula Π, Formula

III, Formula IV, Formula V, or Formula VI is substructure;

Ο

cl ^R^x

In one aspect of this embodiment, each R* is, independently, (Ci-Cg) alkyl. In another aspect of this embodiment, each R* is, independently, C6-C₂q aryl or C₆-C₂q substituted aryl.

In a preferred embodiment,

of Formulas Ι-ΙΠ and Formula IVAnother embodiment of

VI is substructure

wherein W and W are independently selected from one of the formulas in

Tables 20.1-20.37 and Table 30.1 below. The variables used in Tables 20.1-20.37 (e.g., W²³, R²¹, etc.) pertain only to Tables 20.1-20.37, unless otherwîse indicated.

The variables used in Tables 20.1 to 20.37 have the following définitions: each R²¹ is independently H or (C[-Cg)alkyl;

-k Tl T 'Tjî ία each R is independently H, R , R or R wherein each R is independently substituted with 0 to 3 R²³;

each R²³ is independently R^23a, R^23b, R²³⁰ or R^23d, provided that when R²³ is bound to a heteroatom, then R²³ is R^23c or R^2îd;

each R^23a is independently F, Cl, Br, I, -CN, N₃ or -NO₂;

each R^23b is independently Y²¹;

each R^23c is independently-R^2x, -N(R^2x)(R^2x), -SR^2x, -S(O)R^2x, -S(O)2R^2x, S(O)(0R^2x), -S(O)2(OR^2x), -OC(=Y²¹)R^2x, -OC(=Y²¹)OR^2x, -OC(=Y^2!)(N(R^2x)(R²*)), -SC(=Y²¹)R^2x, -SC(=Y²¹)OR^2x, -SC(=Y²¹)(N(R^2x)(R^2x)), -N(R^2x)C(=Y²¹)R^2x, N(R^2x)C(=Y²¹)OR^2x, or -N(R^2x)C(=Y²¹)(N(R^2x)(R^2x)) ;

each R^23d is independently -C(=Y²¹)R^2x, -C(=Y^2,)OR^2x or C(=Y²¹)(N(R^2x)(R^2x));

each R^2x is independently H, (Ci-Cg)alkyl, (C2-Cg)alkenyl, (C₂-Cg)alkynyl, aryl, heteroaryl; or two R^2x taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NR²¹-; and wherein one or more of the non-terminal carbon atoms of each said (Ci-Cg)alkyl may be optionally replaced with -O-, -S- or-NR²¹-;

each R²⁴ is independently (Cj-Cg)alkyl, (C2-Cg)alkenyl, or (C₂-C8)alkynyl;

each R²⁵ is independently R²⁴ wherein each R²⁴ is substituted with 0 to 3 R²³groups;

each R^25a is independently (C]-Cg)alkylene, (C₂-C_g)alkenylene, or (C₂Cg)alkynylene any one of which said (Ci-Cg)alkylene, (Cs-Cgjalkenylene, or (C₂Cg)alkynylene is substituted with 0-3 R²³ groups;

each W²³ is independently W²⁴ or W²⁵;

each W²⁴ is independently R²⁵, -C(=Y²¹)R²⁵, -C(=Y²¹)W²⁵, -SO2R²⁵, or SO2W²⁵;

each W²⁵ is independently carbocycle or heterocycle wherein W²⁵ is independently substituted with 0 to 3 R groups; and

Ί 1 each Y is independently O or S.

Table 20.1

O O

Table 20.2

Table 20.3

Table 20.4

Table 20.5

Table 20.6

Table 20,7 yy²³

yy23 yy²³

W²³

R²⁵

Table 20.9

Table 20. ΙΟ

Table 20. Il

HO HO HO

62 63

Table 20.12

Table 20.13

Table 20.14

Table 20.15

W²³

Table 20.17

Table 20.18

Table 20.19

Table 20.20

Table 20.21

121

122

123

124

125

126

127

128

Table 20.23

W²³

R²⁵ R25 _R25 _R25

.21

Table 20.25 ^W²³ ^R²⁵

148 149

150 151 152

153

< ,w²³ 0	^R²⁵ 0	^R²⁴ 0
10 ¹⁵⁴	155	156
Table 20.26
<< ,W²³ N	,R²⁵ N	^R²⁴ N i
I H	I H	i H
160	161	162
< W²³ N	^R²⁵ N	R²⁴ N I
I R²³	R²³	R²³
166	167	168

^Z - o-^R!’ SZ W

157	158 159
^R²¹ N 1	Ή N 1	^R²³ N I
I H	1 H	I H
163	164	165
^R²¹ N	N	^R²³ N \|
\| R²³	R²³	R²³
169	170	171

Table 20.27

172	173
0	O
	St^cAr”
174	175
0	O
0 O H	%^Ach,
176	177
0 0 CH
178	179

Table 20.28

Table 20,30

Table 20.31

209

212

213

220

Table 20.36

Table 30.1

Embodiments of R^x include esters, carbamates, carbonates, thioesters, amides, thioamides, and urea groups:

Any reference to the compounds of the invention described herein also includes a reference to a physiologically acceptable sait thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali métal or an alkaline earth (for example, Na⁺, Li⁺, K⁺> Ca⁺- and Mg⁺2)₅ ammonium and NRZ (wherein R is defîned herein). Physiologically acceptable salts of a nitrogen atom or an amino group include (a) acid addition salts formed with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acids, phosphoric acid, nitric acid and the like; (b) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartane acid, succinic acid, maleic acid, fumarîc acid, gluconic acid, citri c acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobîonic acid, tannîc acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts formed from elemental anions for example, chlorine, bromîne, and iodine. Physiologically acceptable salts of a compound of a hydroxy group include the anîon of said compound in combination with a suitable cation such as Na⁺ and NR/^-.

For therapeutic use, salts of active ingrédients of the compounds of the invention will be physiologically acceptable, i.e. they will be salts derived from a

physiologically acceptable acid or base. However, salts of acids or bases which are not physiologically acceptable may also fînd use, for example, in the préparation or purification of a physiologically acceptable compound. Ail salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the présent invention.

Finally, it is to be understood that the compositions herein comprise compounds of the invention în their un-ionized, as well as zwitterionic form, and combinations with stoichiometric amounts of water as in hydrates.

The compounds of the invention, exemplified by Formula I- III and Formula IV-VI may hâve chiral centers, e.g. chiral carbon or phosphorus atoms. The compounds of the invention thus include racemic mixtures of ail stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or ail asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictîons are provided as the chiral isomers or racemic mixtures. Both racemic and diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized, substantially free of their enantiomeric or diastereomeric partners, are ail within the scope of the invention. The racemic mixtures are separated into their individual, substantially optically pure isomers through well-known techniques such as, for example, the séparation of diastereomeric salts formed with optically active adjuncts, e.g., acids or bases followed by conversion back to the optically active substances. In most instances, the desired optical isomer is synthesized by means of stéréo spécifie reactions, beginning with the appropriate stereoisomer of the desired starting material.

The term chiral refers to molécules which hâve the property of nonsuperimposability of the mirror image partner, while the term achiral refers to molécules which are superimposable on their mirror image partner.

The term stereoisomers refers to compounds which hâve identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space.

Diastereomer refers to a stereoisomer with two or more centers of chîrality and whose molécules are not mirror images of one another. Diastereomers hâve

100 different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities. Mixtures of diastereomers may separate under high résolution analytica] procedures such as electrophoresis and chromatography.

Enantiomers refer to two stereoîsomers of a compound which are nonsuperimposable mirror images of one another.

Stéréochemical définitions and conventions used herein generally follow S. P.

Parker, Ed., McGraw-Hill Dictionarv of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds (1994) John Wiley & Sons, Inc., New York. Many organic compounds exist in optically active forms, i.e., they hâve the ability to rotate the plane of plane15 polarized light. ln describing an optically active compound, the préfixés D and L or R and S are used to dénoté the absolute configuration of the molécule about its chiral center(s). The préfixés d and 1, D and L, or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with S, (-), or 1 meaning that the compound is levorotatory while a compound prefixed with R, (+), or d is dextrorotatory. For a given chemical structure, these stereoîsomers are identical except that they are mirror images of one another. A spécifie stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms racemic mixture and racemate refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

Whenever a compound described herein is substituted with more than one of the same designated group, e.g., R or R¹, then it will be understood that the groups may be the same or different, i.e., each group is independently selected. Wavy lines, , indicate the site of covalent bond attachments to the adjoining substructures, groups, moieties, or atoms.

The compounds of the invention can also exist as tautomeric isomers in certain cases. Although only one delocalized résonance structure may be depicted, all such

101 forms are contemplated within the scope of the invention. For example, ene-amine tautomers can exist for purine, pyrimidine, imidazole, guanidine, amidine, and tetrazole Systems and ail their possible tautomeric forms are within the scope of the invention.

One skilled in the art will recognize that the pyrrolo[l,2-f][l,2,4]triazine, imidazofLS-fJfl^^Jtriazine, imidazo[l,2-f][l,2,4]triazine, and [l,2,4]triazolo[4,3f][l ,2,4]triazine nucleosides can exist in tautomeric forms. For example, but not by way of limitation, structures (a) and (b) can hâve équivalent tautomeric forms as shown below:

Ail possible tautomeric forms of the heterocycles in ail of the embodiments disclosed herein are within the scope of the invention.

Methods of Inhibition of HCV polymerase

Another aspect of the invention relates to methods of inhibitîng the activity of

HCV polymerase comprising the step of treating a sample suspected of containing

102

HCV with a composition of the invention.

Compositions of the invention may act as inhibitors of HCV polymerase , as intermediates for such inhibitors or hâve other utilities as described below. The inhibitors will bind to locations on the surface or in a cavity of HCV polymerase having a geometry unique to HCV polymerase . Compositions binding HCV 10 polymerase may bind with varying degrees of reversibility. Those compounds binding substantially irreversibly are idéal candidates for use în this method of the invention. Once labeled, the substantially irreversibly binding compositions are useful as probes for the détection of HCV polymerase . Accordingly, the invention relates to methods of detecting HCV polymerase in a sample suspected of containing 15 HCV polymerase comprising the steps of: treating a sample suspected of containing HCV polymerase with a composition comprising a compound of the invention bound to a label; and observing the effect of the sample on the actîvity of the label. Suîtable labels are well known in the diagnostics field and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromogens.

The compounds herein are labeled in conventional fashion using functional groups such as hydroxyl, carboxyl, sulfhydryl or amino.

Within the context of the invention, samples suspected of containing HCV polymerase include naturel or man-made materials such as living organisms; tissue or cell cultures; biological samples such as biological material samples (blood, sérum, 25 urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like);

laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like. Typically the sample will be suspected of containing an organism which produces HCV polymerase , ffequently a-pathogenic organism such as HCV.

Samples can be contained in any medium including water and organic solvent\water mixtures. Samples include living organisms such as hum ans, and man made materials such as cell cultures.

The treating step of the invention comprises adding the composition of the invention to the sample or it comprises adding a precursor of the composition to the

103 sample, The addition step comprises any method of administration as described above.

If desired, the activity of HCV polymerase after application of the composition can be observed by any method including direct and indirect methods of detectîng HCV polymerase activity. Quantitative, qualitative, and semiquantitative methods of determining HCV polymerase activity are ail contemplated. Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable.

Organisms that contain HCV polymerase include the HCV virus. The compounds of this invention are useful in the treatment or prophylaxis of HCV 15 infections in animais or in man.

However, in screening compounds capable of inhibiting human immunodeficiency viruses, it should be kept in rnind that the results of enzyme assays inay not correlate with cell culture assays. Thus, a cell based assay should be the primary screening tool.

Screens for HCV polymerase Inhibitors.

Compositions of the invention are screened for înhibitory activity against HCV polymerase by any of the conventional techniques for evaluating enzyme activity. Within the context of the invention, typically compositions are first screened for inhibition of HCV polymerase in vitro and compositions showing înhibitory activity are then screened for activity in vivo. Compositions having in vitro Ki (înhibitory constants) of less then about 5 X 10'6 M, typically less than about 1 X 10’ 7 M and preferably less than about 5 X 10'8 M are preferred for in vivo use.

Useful in vitro screens hâve been described in detail and will not be elaborated here. However, the examples describe suitable in vitro assays.

Pharmaceutical Formulations

The compounds of this invention are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are

104 prepared in stérile form, and when intended for delivery by other than oral administration generally will be isotonie. AU formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients (1986). Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextran, hydroxyalkyl cellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10.

While it is possible for the active ingrédients to be administered aione it may be préférable to présent them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingrédient, as above defined, together with one or more acceptable carriers therefore and optionally other therapeutic ingrédients. The carrier(s) must be acceptable in the sense of being compatible with the other ingrédients of the formulation and physiologically innocuous to the récipient thereof.

The formulations include those suitable for the foregoîng administration rouies. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Techniques and formulations generally are found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). Such methods include the step of bringing into association the active ingrédient with the carrier which constitûtes one or more accessory ingrédients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingrédient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the présent invention suitable for oral administration may be presented as discrète units such as capsules, cachets or tablets each containing a predetermined amount of the active ingrédient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid émulsion or a water-in-oil liquid émulsion. The active ingrédient may also be administered as a bolus, electuary or paste.

A tabiet is made by compression or molding, optionally with one or more

105 accessory ingrédients. Compressed tablets may be prepared by compressing in a suitable machine the active ingrédient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingrédient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingrédient therefrom.

For infections of the eye or other extemal tissues e.g. mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active 15 ingredîent(s) in a range between 0.1 % and 20% in incréments of 0.1 % w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingrédients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingrédients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polycthylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or pénétration of the active ingrédient through the skin or other affected areas. Examples of such dermal pénétration enhancers include dimethyl sulphoxide and related analogs.

The oily phase of the émulsions of this invention may be constituted from known ingrédients in a known manner. While the phase may comprise merely an 30 emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilie emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsîfier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and

106 the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and émulsion stabilîzers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate.

The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, nonstaîning and washable product with suitable consi stency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stéarate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stéarate, 2-ethylhexyI palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination dependîng on the properties required. Alternative!y, high melting point lipids such as white soft paraffin and/or liquid paraffin or other minerai oils are used.

Pharmaceutical formulations according to the présent invention comprise a combination according to the invention together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingrédient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dîspersible powders or granules, émulsions, hard or soft capsules, syrups or élixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable préparation. Tablets containing the active ingrédient în admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for ex ample, inert diluents, such as calcium or sodium carbonate, lactose, calcium or sodium phosphate; granulating and disintegrating

107 agents, such as maize starch, or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnésium stéarate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl di stéarate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingrédient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingrédient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl m ethylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally-occurring phosphatide (e.g., lecithîn), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stéarate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. >

Oil suspensions may be formulated by suspending the active ingrédient in a vegetable oil, such as arachis oil, olive oil, sesame oîl or coconut oîl, or in a minerai oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral préparation.

108

These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for préparation of an aqueous suspension by the addition of water provide the active ingrédient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be présent.

The pharmaceutical compositions ofthe invention may also be in the form of oil-in-water émulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a minerai oil, such as liquid paraffm, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally-occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexîtol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The émulsion may also contain sweetening and flavoring agents. Syrups and élixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservatîve, a flavoring or a coloring agent.

The pharmaceutical compositions of the invention may be in the form of a stérile injectable préparation, such as a stérile injectable aqueous or oleagînous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The stérile injectable préparation may also be a stérile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehîcles and solvents that may be employed are water, Ringer’s solution and isotonie sodium chloride solution. In addition, stérile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In

109 addition, fatty acids such as oleic acid may likewise be used in the préparation of injectables.

The amount of active ingrédient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately l to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% ofthe total compositions (weight:weight). The pharmaceutical composition can be prepared to provide easîly measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 pg ofthe active ingrédient per milliliter of solution in order tliat infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for topical administration to the eye also include eye drops wherein the active ingrédient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingrédient. The active ingrédient is preferably présent in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10%, and particularly about l .5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingrédient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingrédient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingrédient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository wîth a, suitable base comprising for example cocoa butter or a salicylate.

Formulations suitable for intrapulmonary or nasal administration hâve a particle size for example in the range of 0.1 to 500 microns, such as 0.5, l, 30, 35 etc., which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingrédient. Formulations suitable for aérosol or

110 dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of HCV infections as described below.

Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingrédient such carriers as are known in the art to be appropriate.

Formulations suitable for parentéral administration include aqueous and nonaqueous stérile injection solutions which may contain antî-oxidants, buffers, bacteriostats and solutés which render the formulation isotonie with the blood of the intended récipient; and aqueous and non-aqueous stérile suspensions which may include suspending agents and thickening agents.

The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a ffeeze-dried (lyophilized) condition requiring only the addition of the stérile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from stérile powders, granules and tablets ofthe kind previously described. Preferred unît dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingrédient.

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

The invention further provides veterinary compositions comprising at least one active ingrédient as above defined together with a veterinary carrier therefore.

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingrédient. These veterinary compositions may be administered orally, parenterally or by any

111 other desired route.

Compounds of the invention are used to provide controlled release pharmaceutical formulations containing as active ingrédient one or more compounds of the invention (controlled release formulations) in which the release of the active ingrédient are controlled and regulated to allow less frequency dosing or to improve the pharmacokinetic or toxicity profile of a given active ingrédient.

Effective dose of active ingrédient dépends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses) or against an active viral infection, the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about

0.0001 to about 100 mg/kg body weight per day; typically, from about 0.01 to about mg/kg body weight per day; more typically, from about .01 to about 5 mg/kg body weight per day; most typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.

Routes of Administration

One or more compounds of the invention (herein referred to as the active ingrédients) are administered by any route appropriate to the condition to be treated.

Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parentéral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and épidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the récipient. An advantage of the compounds of this invention îs that they are orally bioavailable and can be dosed orally.

Combination Therapy

Combinations ofthe compounds of Formula I-III and Formula IV-VI are typically selected based on the condition to be treated, cross-reactivitîes of ingrédients

112 and pharmaco-properties of the combination. For example, when treating an infection (e.g., HCV), the compositions of the invention are combined with other active therapeutic agents (such as those described herein).

Compositions of the invention are also used in combination with one or more other active ingrédients. Preferably, the other active therapeutic ingrédients or agents are interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other antifibrotic agents, endothelin antagonists, nucleoside or nucléotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV 1RES inhibitors, pharmacokinetic enhancers or other drugs for treating HCV; or mixtures thereof.

More specifically, one or more compounds of the présent invention may be combined with one or more compounds selected from the group consisting of

1) interferons, e.g., pegylated rIFN-alpha 2b (PEG-Intron), pegylated rIFNalpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalîn), interferon alfacon-1 (Infergen), interferon alpha-nl (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (oméga DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021, glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), and belerofon,

2) ribavirin and its analogs, e.g., ribavirin (Rebetol, Copegus), and taribavirin (Viramidine),

3) HCV NS3 protease inhibitors, e.g., bocepreyir (SCH-503034 , SCH-7), telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BI1230, MK-7009, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451, BMS790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH553O, YH5531, and ITMN-191 (R-7227),

113

4) alpha-glucosidase l inhibitors, e.g., celgosivir (MX-3253), Miglitol, and UT-231B,

5) hepatoprotectants, e.g., emericasan (IDN-6556), ME-3738, GS-9450 (LB84451), silibilin, and MitoQ,

6) nucleoside or nucléotide inhibitors of HCV NS5B polymerase, e.g., RI626, R7128 (R4048), IDX184, IDX-102, PSI-7851, BCX-4678, valopicitabine (NM-283), and MK-0608,

7) non-nucleoside inhibitors of HCV NS5B polymerase, e.g., filibuvir (PF868554), ABT-333, ABT-072, BI-207127, VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190,

8) HCV NS5A inhibitors, e.g., AZD-2836 (A-831), AZD-7295 (A-689), and BMS-790052,

9) TLR-7 agonists, e.g., imiquimod, 852A, GS-9524, ANA-773, ANA-975, AZD-8848 (DSP-3025), PF-04878691, and SM-360320,

10) cyclophillin inhibitors, e.g., DEBIO-025, SCY-635, and NIM811,

11) HCV IRES inhibitors, e.g., MCI-067,

12) pharmacokinetic enhancers, e.g., BAS-100, SPI-452, PF-4194477, TMC41629, GS-9350, GS-9585, and roxythromycin,

13) other drugs for treating HCV, e.g., thymosin alpha 1 (Zadaxin), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), GS-9525, KRN-7000, civacir, Gl-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033Î, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI4065, BMS-650032, BMS-791325, Bavituximab, MDX-1106 (ONO4538), Oglufanide, FK-788, and VX-497 (merimepodib)

14) mevalonate decarboxylase antagonists, e.g., statins, HMGCoA synthase inhibitors (e.g., hymeglusin), squalene synthesis inhibitors (e.g., zaragozic acid);

15) angiotensin II receptor antagonists, e.g., losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan;

114

16) angiotensin-converting enzyme inhibitors, e.g., captopril, zofenopnl, enalapril, ramipril, quinapril, perindopril, lisinopril, benazepril, fosinopril;

17) other anti-fibrotic agents, e.g., amiloride and

18) endothelin antagonists, e.g. bosentan and ambrisentan.

In yet another embodiment, the présent application discloses pharmaceutical compositions comprising a compound of the présent invention, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof, in combination with at least one additional therapeutic agent, and a pharmaceutically acceptable carrier or excipient.

According to the présent invention, the therapeutic agent used in combination with the compound or composition of the présent invention can be any agent having a therapeutic effect when used in combination with the compound of the présent invention. For example, the therapeutic agent used in combination with the compound or composition of the présent invention can be interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucléotide inhibitors of HCV NS5B polymerase, non-nu cl eosi de inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers or other drugs for treating HCV; or mixtures thereof.

More specifically, compositions of one or more compounds of the présent invention may be combined with one or more compounds selected from the group consisting of

1) interferons, e.g., pegylated rIFN-alpha 2b (PEG-Intron), pegylated rïFNalpha 2a (Pegasys), rIFN-alpha 2b (Intron A), rIFN-alpha 2a (Roferon-A), interferon alpha (MOR-22, OPC-18, Alfaferone, Alfanative, Multiferon, subalin), interferon alfacon-1 (Infergen), interferon alpha-nl (Wellferon), interferon alpha-n3 (Alferon), interferon-beta (Avonex, DL-8234), interferon-omega (oméga DUROS, Biomed 510), albinterferon alpha-2b (Albuferon), IFN alpha XL, BLX-883 (Locteron), DA-3021,

115 glycosylated interferon alpha-2b (AVI-005), PEG-Infergen, PEGylated interferon lambda (PEGylated IL-29), and belerofon,

3) HCV NS3 protease inhibitors, e.g., boceprevir (SCH-503034 , SCH-7), telaprevir (VX-950), VX-813, TMC-435 (TMC435350), ABT-450, BI-201335, BE 1230, MK-7009, SCH-900518, VBY-376, VX-500, GS-9256, GS-9451, BMS790052, BMS-605339, PHX-1766, AS-101, YH-5258, YH5530, YH5531, and ITMN-191 (R-7227),

4) alpha-glucosidase 1 inhibitors, e.g., celgosivir (MX-3253), Miglitol, and UT-231B,

5) hepatoprotectants, e.g., emericasan (IDN-6556), ME-3738, GS-9450 (LB84451), silibiün, and MitoQ,

6) nucleoside or nucléotide inhibitors of HCV NS5B polymerase, e.g., R1626, R7128 (R4048), IDX184, IDX-102, PSE7851, BCX-4678, valopicitabine (NM-283), and MK-0608,

7) non-nucleoside inhibitors of HCV NS5B polymerase, e.g., filibuvir (PF868554), ABT-333, ABT-072, BE207127, VCH-759, VCH-916, JTK-652, MK-3281, VBY-708, VCH-222, A848837, ANA-598, GL60667, GL59728, A-63890, A-48773, A-48547, BC-2329, VCH-796 (nesbuvir), GSK625433, BILN-1941, XTL-2125, and GS-9190,

10) cyclophillin inhibitors, e.g., DEB10-025, SCY-635, and NIM811,

11) HCV IRES inhibitors, e.g., MCI-067,

116

13) other drugs for treating HCV, e.g., thymosin alpha 1 (Zadaxm), nitazoxanide (Alinea, NTZ), BIVN-401 (virostat), PYN-17 (altirex), KPE02003002, actilon (CPG-10101), GS-9525, KRN-7000, civacir, GI-5005, XTL-6865, BIT225, PTX-111, ITX2865, TT-033i, ANA 971, NOV-205, tarvacin, EHC-18, VGX-410C, EMZ-702, AVI 4065, BMS-650032, BMS-791325, Bavituxiinab, MDX-1106 (ONO4538), Oglufanide, FK-788, and VX-497 (merimepodib)

14) mevalonatedecarboxylase antagonîsts, e.g., statins, HMGCoA synthase inhibitors (e.g., hymeglusin), squalene synthesis inhibitors (e.g., zaragozic acid);

15) angiotensin II receptor antagonîsts, e.g., losartan, irbesartan, olmesartan, candesartan, valsartan, telmisartan, eprosartan;

16) angiotensîn-converting enzyme inhibitors, e.g., captopril, zofenopril, enalapril, ranripril, quinapril, perindopril, lisinopril, benazepril, fosinopril;

17) other anti-fibrotic agents, e.g., amiloride and

18) endothelin antagonîsts, e.g. bosentan and ambrisentan.

In yet another embodiment, the présent application provides a combination pharmaceutical agent comprising:

a) a first pharmaceutical composition comprising a compound of the présent invention, or a pharmaceutically acceptable sait, solvaté, or ester thereof; and

b) a second pharmaceutical composition comprising at least one additional therapeutic agent selected from the group consisting of HIV protease inhibîting compounds, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV, and combinations thereof.

Combinations of the compounds of Formula I-III and Formula IV-VI and additional active therapeutic agents may be selected to treat patients infected with HCV and other conditions such as HIV infections. Accordingly, the compounds of

117

Formula I-III and Formula IV-VI may be combined with one or more compounds useful in treating HIV, for ex ample HIV protease inhibiting compounds, HIV nonnucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucléotide inhibitors of reverse transcriptase, HIV integrase inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, interferons, ribavirin analogs, NS3 protease inhibitors, NS5a inhibitors, alphaglucosidase 1 inhibitors, cyclophilin inhibitors, hepatoprotectants, non-nucleoside inhibitors of HCV, and other drugs for treating HCV.

More specifically, one or more compounds of the présent invention may be combined with one or more compounds selected from the group consîsting of 1) HIV 15 protease inhibitors, e.g., amprenavir, atazanavir, fosamprenavir, indinavir, lopinavir, ritonavir, lopinavir + ritonavir, nelfinavir, saquinavir, tipranavir, brecanavir, darunavir, TMC-126, TMC-114, mozenavir (DMP-450), JE-2147 (AG 1776), AG1859, DG35, L-756423, RO0334649, KNI-272, DPC-681, DPC-684, and GW640385X, DG 17, PPL-100, 2) a HIV non-nucleoside inhibitor of reverse transcriptase, e.g., capravirine, emivîrine, delaviridine, efavirenz, nevirapine, (+) calanolîde A, etravirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, and TMC-120, TMC-278 (rilpivirine), efavirenz, BILR 355 BS, VRX 840773, UK453,061, RDEA806, 3) a HIV nucleoside inhibitor of reverse transcriptase, e.g., zidovudine, emtricitabine, didanosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, elvucitabine, alovudine, MIV-210, racivir (±-FTC), D-d4FC, emtricitabine, phosphazide, fozivudine tidoxil, fosalvudine tidoxil, apricitibine (AVX754), amdoxovir, KP-1461, abacavir + lamivudine, abacavir + lamivudine + zidovudine, zidovudine + lamivudine, 4) a HIV nucléotide inhibitor of reverse transcriptase, e.g., tenofovir, tenofovir disoproxil fumarate + emtricitabine, tenofovir disoproxil fumarate + emtricitabine + efavirenz, and adefovir, 5) a HIV integrase inhibitor, e.g., curcumin, dérivatives of curcumin, chicoric acid, dérivatives of chicoric acid, 3,5-dicaffeoylquinic acid, dérivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, dérivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, dérivatives of caffeic acid phenethyl ester, tyrphostîn, dérivatives of tyrphostîn,

118 quercetin, dérivatives of quercetin, S-1360, zintevir (AR-177), L-870812, and L870810, MK-0518 (raltegravir), BMS-707035, MK-2048, BA-011, BMS-538158, GSK364735C, 6) a gp41 inhibitor, e.g., enfuvîrtide, sifuvirtide, FB006M, TRI-1144, SPC3, DES6, Locus gp41, CovX, and REP 9, 7) a CXCR4 inhibitor, e.g., AMD-Q10, 8) an entry inhibitor, e.g., SP01A, TNX-355, 9) a gpl20 inhibitor, e.g., BMS-488043 and BlockAide/CR, 10) a G6PD and NADH-oxidase inhibitor, e.g., immunitin, 10) a CCR5 inhibitor, e.g., aplaviroc, vicriviroc, INCB9471, PRO-140, INCB15050, PF232798, CCR5mAb004, and maraviroc, 11) an interferon, e.g., pegylated rIFN-alpha 2b, pegylated rIFN-alpha 2a, rIFN-alpha 2b, IFN alpha-2b XL, rIFN-alpha 2a, consensus IFN alpha, infergen, rebif, locteron, AVI-005, PEG-infergen, pegylated

IFN-beta, oral interferon alpha, feron, reaferon, intermax alpha, r-IFN-beta, infergen + actimmune, IFN-omega with DUROS, and albuferon, 12) ribavirin analogs, e.g., rebetol, copegus, VX-497, and viramidine (taribavîrin) 13) NS5a inhibitors, e.g., A831, A-689 and BMS-790052, 14) NS5b polymerase inhibitors, e.g., NM-283, valopicitabine, R1626, PSI-6130 (R1656), IDX184, PSI-7851, HCV-796, BILB 1941,

MK-0608, NM-107, R7128, VCH-759, PF-868554, GSK625433, and XTL-2125, 15)

NS3 protease inhibitors, e.g., SCH-503034 (SCH-7), VX-950 (Telaprevir), ITMN191, and BILN-2065,16) alpha-glucosidase 1 inhibitors, e.g., MX-3253 (celgosivir) and UT-231B, 17) hepatoprotectants, e.g., IDN-6556, ME 3738, MitoQ, and LB84451, 18) non-nucleoside inhibitors of HCV, e.g., benzimidazole dérivatives, benzo25 1,2,4-thiadiazine dérivatives, and phenylalanine dérivatives, 19) other drugs for treating HCV, e.g., zadaxin, nitazoxanide (alinea), BIVN-401 (virostat), DEBIO-025, VGX-410C, EMZ-702, AV1 4065, bavîtuximab, oglufanide, PYN-17, KPE02003002, actilon (CPG-10101), KRN-7000, civacir, GI-5005, ANA-975, XTL-6865, ANA 971, NOV-205, tarvacin, EHC-18, and.NIM811, 19) pharmacokinetic enhancers, e.g.,

BAS-100 and SP1452, 20)RNAse H inhibitors, e.g., ODN-93 and ODN-112, 21) other anti-HIV agents, e.g., VGV-1, PA-457 (bevirimat), ampligen, HRG214, cytolin, polymun, VGX-410, KD247, AMZ 0026, CYT 99007, A-221 HIV, BAY 50-4798, MDX010 (iplimumab), PBS119, ALG889, and PA-1050040.

119

It is also possible to combine any compound of the invention with one or more other active therapeutic agents in a unitary dosage form for simultaneous or sequential administration to a patient. The combination therapy may be administered as a simultaneous or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration of a compound of the invention with one or more other active therapeutic agents generally refers to simultaneous or sequential administration of a compound of the invention and one or more other active therapeutic agents, such that therapeutically effective amounts of the compound of the invention and one or more other active therapeutic agents are both présent in the body of the patient.

Co-administration includes administration of unit dosages of the compounds of the invention before or after administration of unit dosages of one or more other active therapeutic agents, for example, administration of the compounds of the invention within seconds, minutes, or hours of the administration of one or more other active therapeutic agents. For example, a unit dose of a compound of the invention can be administered first, followed within seconds or minutes by administration of a unit dose of one or more other active therapeutic agents. Altematively, a unit dose of one or more other therapeutic agents can be administered first, followed by administration of a unit dose of a compound of the invention within seconds or minutes. In some cases, it may be désirable to administer a unit dose of a compound of the invention first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more other active therapeutic agents. In other cases, it may be désirable to administer a unit dose of one or more other active therapeutic agents first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound of the invention.

The combination therapy may provide “synergy” and “synergistic”, i.e. the effect achieved when the active ingrédients used together is greater than the sum of the effects that results ffoin using the compounds separately. A synergistic effect may be attained when the active ingrédients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in

120 parallel as separate formulations; or (3) by some other regimen, When delivered in alternation therapy, a synergistic effect inay be attained when the compounds are administered or delivered sequentially, e.g. in separate tablets, pills or capsules, or by different injections în separate syringes. In general, during alternation therapy, an effective dosage of each active ingrédient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingrédients are administered together. A synergistic anti-viral effect dénotés an antiviral effect which is greater than the predicted purely additive effects of the individual compounds of the combination.

In still yet another embodiment, the présent application provides for methods of inhibiting HCV polymerase in a cell, comprising: contactîng a cell infected with HCV with an effective amount of a compound of Formula I-III and Formula IV-VI, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof, whereby HCV polymerase is inhibited.

In still yet another embodiment, the présent application provides for methods of inhibiting HCV polymerase in a cell, comprising: contactîng a cell infected with HCV with an effective amount of a compound of Formula 1-111 and Formula IV-VI, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof, and at least one additional active therapeutic agent, whereby HCV polymerase is inhibited.

In still yet another embodiment, the présent application provides for methods of inhibiting HCV polymerase in a cell, comprising: contactîng a cell infected with HCV with an effective amount of a compound of Formula I-III and Formula IV-VI, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof, and at least one additional active therapeutic agent selected from the group consisting of one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensîn system, other anti-fibrotic agents, endothelin antagonists, nucleoside or nucléotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7

121 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixtures thereof.

In still yet another embodiment, the présent application provides for methods of treating HCV in a patient, comprising; administering to the patient a therapeutically effective amount of a cornpound of Formula I-III and Formula IV-VÏ, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof.

In still yet another embodiment, the présent application provides for methods of treating HCV în a patient, comprising: administering to the patient a therapeutically effective amount of a cornpound of Formula I-III and Formula IV-VI, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof, and at least one additional active therapeutic agent, whereby HCV polymerase is inhibited.

In still yet another embodiment, the présent application provides for methods of treating HCV in a patient, comprising: administering to the patient a therapeutically effective amount of a cornpound of Formula I-III and Formula IV-VI, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof, and at least one additional active therapeutic agent selected from the group consisting of one or more interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the renin-angiotensin system, other anti-fibrotic agents, endothelin antagonists, nucleosîde or nucléotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixtures thereof.

In still yet another embodiment, the présent application provides for the use of a cornpound of the présent invention, or a pharmaceutically acceptable sait, solvaté, and/or ester thereof, for the préparation of a médicament for treating an HCV infection in a patient.

Métabolites of the Compounds of the Invention

Also falling within the scope of this invention are the in vivo metabolic products ofthe compounds described herein, to the extent such products are novel and

122 unobvious over the prior art. Such products may resuit for example from the oxidation, réduction, hydrolysis, amidation, estérification and the like of the administered compound, primarily due to enzymatic processes. Accordingly, the invention includes novel and unobvious compounds produced by a process comprising contacting a compound of this invention with a mammal for a period of time sufficient to yield a metabolic product thereof. Such products typically are identified by preparing a radiolabelled (e.g. '-⁴C or ^H) compound of the invention, administering it parenterally in a détectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, or to man, allowing sufficient time for metabolism to occur (typically about 30 seconds to 30 hours) and isolating its conversion products from the urine, blood or other biological samples. These products are easily isolated since they are labeled (others are isolated by the use of antibodies capable of binding epitopes surviving in the métabolite). The métabolite structures are determined in conventional fashion, e.g. by MS or NMR analysis. In general, analysis of métabolites is done in the same way as conventional drug metabolism studies well-known to those skilled in the art. The conversion products, so long as they are not otherwise found in vivo, are useful in diagnostic assays for therapeutic dosing of the compounds of the invention even if they possess no HCV polymerase inhibitory activity of their own.

Recipes and methods for determining stability of compounds in surrogate gastrointestinal sécrétions are known. Compounds are defined herein as stable in the gastrointestinal tract where less than about 50 mole percent of the protected groups are deprotected in surrogate intestinal or gastric juice upon incubation for 1 hour at 37°C. Simply because the compounds are stable to the gastrointestinal tract does not mean that they cannot be hydrolyzed in vivo. The prodrugs of the invention typically will be stable in the digestive System but may be substantially hydrolyzed to the parental drug in the digestive lumen, liver or other metabolic organ, or within cells in general.

Examples

Ο

123

Certain abbreviations and acronyms are used in describing the experimental details. Although most of these would be understood by one skilled in the art, Table 1 contains a list of many of these abbreviations and acronyms.

Table 1. List of abbreviations and acronyms.

Abbreviation	Meaning
Ac₂O	acetic anhydride
AIBN	2,2’-azobis(2-methylpropionitriIe)
Bn	benzyl
BnBr	benzylbromide
BSA	bis(trimethylsilyl)acetainide
BzCl	benzoyl chloride
CDI	carbonyl diimidazole
DABCO	1,4-dîazabicyclo[2.2.2]octane
DBN	l,5-diazabicyclo[4.3.0]non-5-ene
DDQ	2,3-dichloro-5,6-dicyano-1,4-benzoquinone
DBU	l,5-diazabicyclo[5.4.0]undec-5-ene
DCA	dichloroacetamide
DCC	dicyclohexylcarbodiimide
DCM	dichloromethane
DMAP	4-dimethylaminopyridine
DME	1,2-dimethoxyethane
DMTC1	dimethoxytrityl chloride
DMSO	dimethylsulfoxide
DMTr	4,4’-dimethoxytrityl
DMF	dimethylformamide
EtOAc	ethyl acetate
ESI	electrospray ionization
HMDS	hexamethyldisilazane

124

HPLC	High pressure liquid chromatography
LDA	lithium diisopropyiamide
LRMS	low resolution mass spectrum
MCPBA	meta-chloroperbenzoic acid
MeCN	acetonitrile
MeOH	methanol
MMTC	mono methoxytrityl chloride
m/z or m/e	mass to charge ratio
MH⁺	mass plus 1
MH'	mass minus 1
MsOH	methanesulfonic acid
MS or ms	mass spectrum
NBS	N-bromosuccinimide
Ph	phenyl
rt or r.t.	room température
TBAF	tetrabutylammonium fluoride
TMSC1	chlorotrimcthylsilane
TMSBr	bromotrimethylsilane
TMSI	iodotrimethylsilane
TMSOTf	(trimethylsilyl)trifluoromethylsulfonate
TEA	tri ethy lamine
TBA	tributylamine
TBAP	tributylammonium pyrophosphate
TBSC1 t	t-butyldimethylsilyl chloride
TEAB	triethylammonium bicarbonate
TFA	trifluoroacetic acid
TLC or tic	thin layer chromatography
Tr	triphenylmethyl
Toi	4-methylbenzoyI

125

Turbo Grignard	1:1 mixture of isopropylmagnesium chloride and lithium chloride
δ	parts per million down field from tetramethylsilane

Préparation of Compounds

Compound 1

BuLi, BF₃-Et₂O

THF

1b

To a suspension of7-bromo-2,4-bis-methylsulfanyl-imidazo[2,lf][l,2,4]triazine (prepared according to W02008116064, 500 mg, 1.72 mmol) în anhydrous THF (5 mL) was dropwise added BuLi (1.6 M in hexanes, 1.61 mL, 2.41 mmol) at -78°C. The suspension became red brown solution after 5 min, and then a mixture of la (prepared according to WO 200631725, 675 mg, 1.81 mmol) and boron trifluoride etherate (2.40 mL, 1.89 mmol) in THF (5 mL) was added dropwise to the mixture. After stirring for 2 h at -78°C, saturated NH4CI was added to quench the réaction. The mixture was diluted with ethyl acetate; the organic layer was washed with brine and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc / hexanes), affording lb as a rich yellow foam (650 mg, 67%). ’H NMR (400 MHz, CDCI3): δ 8.13 (d, 2H), 8.03 (d, 2H), 7.81 (d, IH), 7.59 (t, IH), 7.45 (m, 3H), 7.36 (t, 2H), 6.40 (brs, IH), 6.01 (dd, IH), 4.78 (m, 2H), 4.60 t

(dd, IH), 2.68 (s, 3H), 2.45 (s, 3H), 1.62 (d, 3H). ^!9F NMR (376 MHz, CDC1₃): Ô 167.5. MS- 585.1 (M + H⁺).

126

Et₃SiH

BF₃-Et₂O

CH₂CI₂

1b

1c

To a solution of lb (820 mg, 1.40 mmol) in dichloromethane (20 mL) were added boron trifluoride etherate (2 mL) and triethylsilane (2 mL), and stirred at room température for 16 h. Additional boron trifluoride etherate (1 mL) and triethylsilane (1 mL) were added, and stirred for 7 d. The mixture was diluted with dichloromethane and saturated sodium bicarbonate. The organic layer was washed sequentïally with water, saturated ammonium chloride and brine, dried over magnésium sulfate, and concentrated. The residue was purified by silica gel column chromatography (EtOAc / hexanes), affording le (605 mg, 76%). 'H NMR (400 MHz, CDC1₃): δ 8.10 (d,7= 7.2Hz, 2H), 8.00 (d,7 = 7.2 Hz, 2H), 7.66 (s, IH), 7.61 (t,7=7.2 Hz, IH), 7.53 (t, 7= 7.2 Hz, IH), 7.46 (t, 7 =7.2 Hz, 2H), 7.38 (t,7=7.2 Hz, 2H), 5.78 (m, 2H), 4.80 (dd, IH), 4.68 (m, IH), 4.60 (dd, IH), 2.68 (s, 3H), 2.65 (s, 3H), 1.32 (d, 3H). ⁱ⁹F NMR (376 MHz, CDC1₃): δ-149.9. MS.-569.1 (M + H⁺).

1c

1)NH₃

2)NaOEt/THF

1d

Compound le (635 mg, 1.12 mmol) was placed in a steel bomb reactor. Liquid ammonia (~30 mL) was charged and the bomb reactor was tightly sealed. The mixture was stirred at 50°C for 16 h. After coolîng to room température, ammonia was evaporated and the solid residue was dissolved in THF (10 mL) and MeOH (10 mL). Sodium ethoxide (25% wt. 0.63 mL) was added and stirred at 60°C for 40 min.

127

The mixture was neutralized with AcOH and concentrated. The residue was purified by RP HPLC, affording the product ld (175 mg, 48%). ^lH NMR (400 MHz, DMSOd₆): δ 8.21 (brs, 2H), 7.60 (s, IH), 5.45 (brs, IH), 5.43 (d, IH), 4.91 (t, IH), 3.92 (m, IH), 3.76 (m,2H), 3.57 (m, 1 H), 2.44 (s, 3H), 1.09 (d, 3H). ¹⁹F NMR (376 MHz, DMSO-dô): δ-153.5. MS = 330.1 (M + H⁺).

MCPBA

CH₂CI₂

1d

1e

To a solution of ld (175 mg, 0.53 mmol) in dichloromethane (11 mL) was added MCPBA (370 mg, ~ 1.5 mmol) and stirred at room température for 16 h. The mixture was concentrated, affording crude le which was used for the next reaction without purification. MS = 362.0 (M + H⁺).

NH₃

1e

Compound le (obtained from the prevîous reaction) was placed in a steel bomb reactor. Liquid ammonia (-30 mL) was charged, and the bomb reactor was tîghtly sealed. The mixture was stirred at 115°C for 3 d. After cooling to room température, ammonia was evaporated. The solid residue was purified by RP HPLC, affording compound 1 (105 mg, 66% in two steps). 'H NMR (400 MHz, D₂O): δ 7.31 (s, IH), 5.43 (d,J= 25.2 Hz, IH), 4.07 (dd,J=9.6, 23.2, 1 H), 3.89 (m, 1 H), 3.83 (dd,

128

J= 2.4, 12.8 Hz, IH), 3.67 (dd, J= 4.8, 12.8 Hz, IH), 1.05 (d, J= 22.8 Hz, 3H). ^l9F

NMR (376 MHz, D₂O): δ -153.5. MS = 299.2 (M + H⁺).

Compound 2

To a solution of compound 1 (82 mg, 0.28 mmol) in water (340 mL) was added adenosine deaminase (A5168 bovine spleen type IX from Sigma-Aldrich, 0.125 Unit per mL of water) and stirred at 37°C for 4 h. The mixture was concentrated and purifîed by RP HPLC, affording compound 2 (56 mg, 68%). *H NMR (400 MHz, D₂O): δ 7.35 (s, IH), 5.46 (d, J =25.2 Hz, IH), 4.08 (dd, J= 9.6, 22.6, IH), 3.93 (m, IH), 3.87 (dd, J=2.4, 12.8 Hz, 1H),3.71 (dd, J=4.8, 12.8 Hz, IH), 1.12 (d, J=23.2 Hz, 3H). ¹⁹F NMR (376 MHz, D₂O): δ -153.4. MS = 300.2 (M + H⁺).

Compound 3

THF

3b

To a suspension of 7-bromo-pynOlo[2,l-f][l,2,4]triazni-4-ylamine (prepared according to W02007056170, 2.13 g, 10 mmol) in THF (20 mL) was added TMSC1 (2.66 mL, 21 mmol) and stirred at room température for 16 h under argon. After cooling to -78°C, a solution of BuLi (1.6 M, 21 mL, 33 mmol) in hexanes was added

129 dropwise. The mixture was stirred for 1 h at the same température. A solution of la (prepared according to WO 200631725,4.46 g, 12 mmol) in THF (10 mL) was then added. After stirring for 2 h at -78°C, saturated ammonium chioride was added to quench the reaction. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate/hexanes), affording3b as ayellow solid (1.6 g, 32%). MS = 507.1 (M + H⁺).

Alternative procedure for Compound 3b using 1,2-bis[(chlorodimethyl)silanyljethane instead of chlorotrimethylsilane

To a suspension of 7-bromo-pyrrolo[2,l-f][l,2,4]triazin-4-ylamine (500 mg, 2.35 mmol) in THF (6.5 mL) was added BuLi (1.6 M in hexanes, 1.6 mL) at -78°C. After 30 min., a solution of l,2-bis-[(chlorodimethyl)silanyl]ethane (538 mg, 2.4 mmol) in THF (1.2 mL) was added. After 45 min., BuLi (1.6 mL) was added. After an additional 30 min., BuLi (1.5 mL) was added. After 30 min., a solution of la (610 mg, 1.64 mmol) în THF (2 mL) was then added dropwise. The resulting mixture was stirred at -78°C for 2 h under argon. Acetic acid (0.7 mL) was added dropwise to quench the reaction, followed by addition of saturated ammonium chioride. The mixture was extracted with ethyl acetate. The organic extract was concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexanes), affording 3b (320 mg, 40%). The starting la was also recovered (350 mg) from the chromatography.

3c

130

To a solution of compound 3b (50 mg, 0.1 mmol) and TMSCN (67 uL, 0.5 mmol) in acetonitrile (2.0 mL) at 0°C was added TMSOTf (91 uL, 0.5 mmol). The reaction mixture was stirred at room température for 1 h, then at 65°C for 3 d. The reaction was quenched with saturated NaHCO₃ at room température, and diluted with CHjCCbEt. The organic phase was separated, washed with brine, dried over Na₂SC>4, filtered and concentrated. The residue was purified by RP-HPLC (acetonitrile / water), to give the desired compound 3c (28 mg, 54%). MS =516.1 (M + H⁺).

28% NH3 in water

3c

MeOH

To a solution of 3c (56 mg, 0.11 mmol) in méthanol (1.2 mL) was added ammonium hydroxide (28% in water, 0.8 mL) and stirred at room température for 16 h. The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile), affording compound 3 (20 mg, 60%). ’H NMR (500 MHz, D₂O): δ 7.88 (s, IH), 7.07 (d, IH), 6.92 (d, IH), 4.17 (m, 2H), 4.04 (dd, IH), 3.87 (dd, IH), 1.15 (d, 3H). MS = 308.1 (M + H⁺).

Compound 4

131

To a solution of compound 3b (60 mg, 0.12 mmol) in methanol (0.5 mL) was added ammonium hydroxide (28% in water, 0.5 mL) and stirred at room température for 16 h. The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile), affording compound 4 (25 mg, 70%). MS = 299.1 (M + H ).

Compound 5

Compound 3b was converted to compound 5a by a procedure similar to conversion of lb to le. Compound 5a was then converted to compound 5 by a procedure similar to conversion of 3c to 3. ^lH NMR (300 MHz, D2O): δ 7.68 (s, IH), 6.75 (d, J =4.5 Hz, IH), 6.65 (d, J =4.5 Hz, 1 H), 5.65 (d, J =25.2 Hz, IH), 3.95 (m, 3H), 3.74 (dd, IH), 0.98 (d, J= 22.8 Hz, 3H). ¹⁹F NMR (282 MHz, D2O): Ô 154.2. MS = 283.2 (M + H⁺).

General procedure for préparation of a nucleoside triphosphate:

132

To a pear-shaped flask (5-15 mL) îs charged with a nucleoside (~20 mg). Trimethyl phosphate (0.5-1.0 mL) is added. The solution is cooled with ice-water bath. POC1₃ (40-45 mg) is added and stirred at 0°C until the reaction is complété (1 to 4 h; the reaction progress is monitored by ion-exchange HPLC; analytical samples are prepared by taking ~3 pL of the reaction mixture and dilutîng it with 1.0 M Et₃NH₂CO₃ (30-50 pL)). A solution of pyrophosphate-Bu₃N (250 mg) and Bu₃N (90105 mg) in acetonitrile or DMF (1-1.5 mL) is then added. The mixture is stirred at 0°C for 0.3 to 2.5 h, and then the reaction is quenched with 1.0 M Et₃NH₂CO₃ (-5 mL). The resulting mixture is stirred for additional 0.5-1 h while warming up to room température. The mixture is concentrated to dryness, re-dissolved in water (4 mL), and purified by ion exchange HPLC. The fractions containing the desired product is concentrated to dryness, dissolved in water (-5 mL), concentrated to dryness, and again dissolved in water (~5 mL). NaHCO₃ (30-50 mg) is added and concentrated to dryness. The residue is dissolved in water and concentrated to dryness again. This process is repeated 2-5 fîmes. The residue is then subjected to C-18 HPLC purification, affording the desired product as a sodium or sait. Altematively, the crude reaction mixture is subjected to C-18 HPLC first and then ion exchange HPLC purification to afford the desired product as a triethylammonium sait.

Compound TP-1

TP-1

Compound TP-1 was prepared by the general method using Compound 2 as starting material. ‘H NMR (300 MHz, D₂O): Ô 7.44 (s, IH), 5.45 (d, 7=25.5 Hz,

IH), 4.0-4.4 (m, 4H), 3.05 (m, NCH₂CH₃), 1.10 (m, NCH₂CH₃ and 2^J-C-CH₃). ³¹P

133

NMR (121.4 MHz, D₂O): δ -9.5 (d, 7=22.1 Hz), -11.0 (d, J= 19.9 Hz), -23.2 (t, J = 23.0 Hz). ¹⁹F NMR (282 MHz, D₂O): δ -153.9.

Cornpound TP-2

0 0 n n u HO-P-O-P-O-P-O

OH OH OH

Cornpound TP-2 was prepared by the general method using Cornpound 3 as starting material. ^lH NMR (300 MHz, D2O): δ 7.82 (s, 1H), 7.03 (d, 1H), 6.90 (d, 1H), 4.1-4.4 (m, 4H), 3.05 (m, NCH2CH3), 1.10 (m, NCH2CH3 and 2’-C-CH3). ³¹P NMR (121.4 MHz, D2O): δ -10.7 (d, J= 19.5 Hz),-11.3 (d,7 = 19.8 Hz), -23.1 (t,7 = 19.8 Hz).

Cornpound TP-3

Cornpound TP-3 was prepared by the general method using Cornpound 5 as starting material. 'H NMR (300 MHz, D₂O): Ô 7.73 (s, 1H), 6.87 (d, 1H), 6.82 (d, 1H), 5.71 (d, J= 24.6 Hz, 1H), 4.0-4.4 (m, 4H), 3.05 (m, NCH₂CH₃), 1.14 (m, NCH₂CH₃), 1.00 (d, J= 22.8 Hz, 3H, 2’-C-CH₃). ^3ÎP NMR (121.4 MHz, D2O): δ -8.1 (d, 7=22.1 Hz),-11.1 (d,7= 19.9 Hz),-22.7 (t, 7= 23.0 Hz). ^l9F NMR (282 MHz, D2O): δ -155.6. MS = 520.9 (M - H⁺).

134

Compound TP-8a

Compound TP-8a was prepared by the general method using Compound 8 as starting material. ‘H NMR (300 MHz, D₂O): δ 7.95 (s, IH), 7.68 (s, IH), 5.63 (d, J -25.5 Hz, IH), 4.0-4.4 (m,4H),3.05 (m,NCH₂CH₃), 1.10 (m, NCH₂CH₃ and 2’-C10 CH₃). ³¹P NMR (121.4 MHz, D2O): δ -9.20 (d, J= 22.1 Hz), -11.07 (d, J= 19.9 Hz), 23.82 (t, J =23.0 Hz). ¹⁹F NMR (282 MHz, D2O): δ-155.9. MS = 521.6 (M - H⁺).

General procedure for préparation of a nucleoside prodrug (Method A):

To a solution of a nucleoside (0.1 mmol) in trimethylphosphite (1.0 mL) are added 7/f-tetrazole (42 mg, 0.6 mmol) followed by addition of 2,2-dimethylthiopropionic acid S-(2-{diisopropylamino-[2-(2,2-dimethyl-propionylsulfanyl)-

135 ethoxyj-phosphanyloxy)-ethyl) ester (prepared according to J. Med. Chem., 1985, 38, 3941, 90 mg, 0.2 mmol) at 0°C. After stirring for 2 h, 30% hydrogen peroxide in H₂O (140 pL) was added to the mixture. The mixture was then allowed to warm up to room température. After 30 min stirring, 1 M Na₂S₂O₃ in H₂O (5 mL) was added to quench the reaction. The organic layer was washed with saturated aqueous Na₂CO₃(10 mL x 2), brine, concentrated in vacuo. The residue was purified by RP-HPLC (MeCN-H₂O gradient) to afford a prodrug A.

Compound A-l

HÔ F

A-1

Compound A-l was prepared by Method A using compound 1 as starting material. ‘H NMR (400 MHz, CDC1₃): δ 7.42 (s, IH), 5.47 (d, J= 26.4 Hz, IH), 4.95 (brs, 2H), 4.59 (m, 2H), 4.35 (m, IH, 4’-H), 4.18 (m, 2H, 5’-H), 4.10 (m, 4H), 3.13 (m, 4H), 1.24 (d, 3H), 1.22 (s, 9H), 1.19 (d, 9H). ^3IPNMR (161.9 MHz, CDC1₃); δ 1.26. MS = 667.1 (M + H⁺).

General procedure for préparation of a nucleoside prodrug (Method B):

Non-limiting examples of mono-phosphoramidate prodrugs comprising the instant invention may be prepared according to general Scheme 1.

Scheme 1

136

			0
			II
0		R^y O	ArO—P—Cl \|
\| [ ArO—P—Cl 1 Cl		H₂N_V/ //	r NH
	HCl V-R
			R^x 11
			O
19a		19b	19c

The general procedure comprises the reaction of an amino acid ester sait 19b, e.g., HCl sait, with an aryl dichlorophosphate 19a in the presence of about two to ten équivalents of a suitable base to give the phosphoramîdate 19c. Suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and DMAP, tertiary amines such as triethylamine and DAB CO, and substituted amidines such as DBN and DBU. Tertiary amines are particularly preferred. Preferably, the product of each step is used directly in the subséquent steps without recrystallization or chromatography. Spécifie, but non-limiting, examples of 19a, 19b, and 19c can be found in WO 2006/121820 that is hereby incorporated by reference in its entirety. A nucleoside base 19d reacts with the phosphoramîdate 19c in the presence of a suitable base. Suitable bases include, but are not limited to, imidazoles, pyridines such as lutidine and DMAP, tertiary amines such as triethylamine and DAB CO, and substituted amidines such as DBN and DBU. The product B may be isolated by recrystallization and/or chromatography.

Compound B-l pc

137

Phenyl ethoxyalaninyl phosphorochloridate (124 mg, 0.42 mmol; prepared according to McGuigan et al, J. Med. Chem. 1993, 36, 1048-1052) was added to a mixture of Compound 3 (20 mg, 0.065 mmol) and N-methylimidazole (42 pL, 0.52 mmol) in anhydrous trimethyl phosphate (0.8 mL). The reaction mixture is stirred for 3 h at room température, and then methanol was added to quench the reaction. The methanol solvent îs removed under reduced pressure. The residue was purified by reverse-phase HPLC and then by silica gel column chromatography (100% ethyl acetate), affording compound B-l (10 mg, 27%). ^3IP NMR (121.4 MHz, CDCI3): δ 3.42, 3.77. MS = 563.0 (M + H⁺), 561.0 (M - H⁺).

Compound B-2

About 3.1 mmol of 4-chlorophenyl 2-propyloxyalaninyl phosphorochloridate (prepared according to McGuigan et al, J. Med. Chem. 1993, 36, 1048-1052) îs added to a mixture of about 0.5 mmol of Compound 3 and about 3.8 mmol of Nmethylimidazole in about 3 mL anhydrous trimethyl phosphate. The reaction mixture is stirred for about one hour to 24 hours at room température and methanol is added to

138 quench the reaction. The methanol solvent is removed under reduced pressure. The residue îs purified b y rev erse-phase HPLC to give compound B-2.

Compound B-3

Compound B-3 was obtained by a similar procedure used for compound B-l. ³¹P NMR (121.4 MHz, CDC1₃): δ -3.50, 3.76. MS = 577.2 (M + H⁺).

Compound B-4

Compound B-4 was obtained by a similar procedure used for compound B-l.

³¹P NMR (162 MHz, CD₃OD): δ 2.2. MS = 633.4 (M + H⁺).

Compound B-5

139

B-5

Compound B-5 was obtained by a similar procedure used for compound B-l. ^3IP NMR (162 MHz, CDC1₃): δ 4.15, 4.27. MS = 549.3 (M + H⁺).

Compound B-6

B-6

Compound B-6 was obtained by a similar procedure used for compound B-l. ³¹P NMR (162 MHz, CDC1₃): δ 3.50, 4.07. MS = 613.1 (M + H⁺).

Compound B-7

Compound B-7 was obtained by a similar procedure used for compound B-l, using compound 5 as parent nucleoside. ^3lP NMR (162 MHz, CDC1₃): δ 3.37, 3.97. MS = 538.1 (M + H⁺).

Compound B-8

Compound B-8 was obtained by a similar procedure used for compound B-l, using compound 5 as parent nucleoside. ³¹P NMR (162 MHz, CDC1₃): δ 3.69,4.39. MS = 588.1 (M + H⁺).

Alternative procedure for préparation of a nucleoside prodrug (Method C):

Into a flask containing ethyl L-valine hydrochloride (2.5 g, 13.8 mmoL, 1 equiv.) was added CH2CI2 (46 mL, 0.3 M) and phenyl dichlorophosphate (2.1 mL, 13.8 mmoL, 1 equiv.) before being cooled to-10°C. After 10 minutes, TEA (3.8 mL, 13.8 mmoL, 1 equiv) was added slowly to the reaction mixture over five minutes. The reaction was allowed to proceed for an hour beforep-nitrophenol (1.9 g, 13.8 mmoL,

141 equiv.) was added to the reaction mixture followed by addition of more TEA (3.8 mL, 13.8 mmoL, 1 equiv.) over five minutes. The reaction was allowed to warm up and proceed for another two hours. The reaction was concentrated in vacuo and taken up in diethyl ether (200 mL). The insoluble salts were filtered off and the filtrate concentrated in vacuo. Flash column chromatography was carried out using 4/1 Hex / EtOAc to fumish a clear oil as C-la.

^!H NMR (400 MHz, CDClj): d 8.21 (s, 2 H), 7.41 - 7.20 (m, 7 H), 4.22 -4.05 (m, 3 H), 2.46 (s, 2 H), 1.99 (dd, J=23.0, 20.1 Hz, 2 H), 1.68 (s, 1 H), 1.20-1.05 (m, 8 H). ^3,P NMR (162 MHz, CDC1₃): d -2.79 (dd, J= 28.0, 4.2 Hz).

LC MS m/z 422.99 [M + H⁺].

Compound C-l

Into a flask containing compound 3 (70 mg, 0.23 mmoL, 1 equiv.) was added THF (1 mL, 0.2 M) and NMP (1 mL, 0.2 M) before cooling to 0°C. t-BuMgCl (560 pL, 2.5 equiv., IM THF) was added slowly and allowed to stîr for 5 minutes before the above phenolate C-la (207 mg, 0.46 minoL, 2 equiv. dissolved in 500 pL of THF) was added. The reaction mixture was warmed to 50°C. The reaction was monitored by LCMS. Once the reaction was complété, the mixture was then concentrated in vacuo, and the residue was purified by HPLC, affording Compound C-l.

^lH NMR (400 MHz, CDC1₃) d 7.87 (s, 1 H), 7.24 - 7.10 (m, 4 H), 7.03 (t, J = 7.2 Hz, 1 H), 6.81 (d, J=4.6Hz, 1 H), 6.52 (d, J =4.7 Hz, 1 H), 5.61 (s,2H),4.46 (dd,J = 24.0, 11.4 Hz, 2 H), 4.33 - 4.14 (m, 2 H), 4.06 (dt, J= 7.2, 4.2 Hz, 2 H), 3.82 - 3.70 (m, 1 H), 3.63 (t,J= 10.6 Hz, 2 H), 1.98 (s, 1 H), 1.17 (dd,J= 14.8, 7.6 Hz, 3 H), 0.82 (dd, 22.8, 6.8 Hz, 6 H).

142 ³¹P NMR (162 MHz, CDC1₃): d 5.11.

¹⁹F NMR (376 MHz, CDCI₃): d -152.28.

LC MS m/z 591.21 [M + H⁺].

Compound C-2a was obtained in a procedure similar to that exemplifïed for Compound C-la but using the méthionine ester.

^lH NMR (400 MHz, CDC1₃) d 8.19 (s, 2 H), 7.44-7.03 (m, 7 H), 4.11 (s, 2 H), 3.81 (d,7= 44.5 Hz, IH), 2.04 (s, 3 H), 1.61 (s, 2 H), 1.21 (d,7= 6.1 Hz, 2 H), 1.01-0.65 (m,4H).

³¹P NMR (162 MHz, CDCI3) d -2.00 (d,7= 12.9 Hz).

LC MS m/z 455.03 [M + H⁺],

Compound C-2

Compound C-2 was obtained in a procedure similar to that exemplified for Compound C-l using Compound 3 and C-2a.

143 ’HNMR (400 MHz, CDC1₃) d 7.96 (d,7= 15.8 Hz, IH), 7.40-7.06 (m, 13H), 6.93 (d,7=6.7 Hz, IH), 6.70 (s, 1 H), 5.98 (s, 1H),4.54 (dd, 7=21.6,11.7 Hz, 2H), 4.32 (d, 7 = 12.0 Hz, 2H), 4.14 (dt, 7= 13.0, 6.4 Hz, 4H), 2.44 (d,7= 7.5 Hz, 2H), 2.00 (d, 7= 16.2 Hz, 5H), 1.89 (s, 2H), 1.35-1.13 (m, 7H).

³¹P NMR (162 MHz, CDC1₃) d 4.12, 3.58.

^,9F NMR (376 MHz, CDCI3) d -152.28 (s).

LC MS m/z 623.27 [M + H⁺],

Compound C-3a was obtained in a procedure similar to that exemplified for Compound C-la but using a tryptophan ester.

’H NMR (400 MHz, CDC1₃) d 8.18 - 8.03 (m, 3 H), 7.29 - 7.08 (m, 8 H), 7.36 - 6.98 (m, 3 H), 4.41 -4.11 (m, 1 H), 4.15-3.95 (m 2 H), 3.68 - 3.80 (m, 1 H), 3.33-3.04 (m, 2 H), 1.06-1.17 (m, 3 H).

³¹P NMR (162 MHz, CDCI3) d -2.87, -2.99.

LC MS m/z 510.03 [M + H⁺],

Compound C-3

144

Compound C-3 was obtained in a procedure similar to that exemplified for Compound C-l using Compound 3 and C-3a.

^!H NMR (400 MHz, CDC1₃) d 8.27 (s, IH), 7.84 (s, IH), 7.47 (s, IH), 7.36 - 6.77 (m, 11 H), 6.57 (s, 1 H), 4.40-3.96 (m, 6 H), 3.20 (s, 4 H), 2.60 (s, IH), 1.30- 1.04 (m, 6 H).

^3IP NMR (162 MHz, CDC1₃) d 4.02, 3.75 ^î9F NMR (376 MHz, CDC1₃) d-152.13.

LC MS m/z 678.32 [M + H⁺].

Compound C-4a was obtained in a procedure similar to that exemplified for Compound C-l a by substituting the phenylalanine ester.

'H NMR (400 MHz, CDC1₃) d 8.15 (t, J= 8.7 Hz, 2H), 7.43 - 7.11 (m, 10 H), 7.04 (ddd, J= 11.4, 6.7, 2.9 Hz, 2 H), 4.32 (ddd, J = 15.3, 11.3,6.1 Hz, 4 H), 4.15 - 3.99 (m, 7 H), 3.74 (td, J= 11.0, 5.0 Hz, 8 H), 3.01 (d, J= 5.7 Hz, 2 H), 1.17 (td, J= 7.1, 5.2 Hz, 2 H).

X

145 ³¹P NMR (162 MHz, CDC1₃) d -2.97, -2.99.

LC MS m/z 471.03 [M + H⁺],

Compound C-4

Compound C-4 was obtained în a procedure similar to that exemphfied for

Compound C-l using Compound 3 and C-4a.

‘H NMR (400 MHz, CDC1₃) d 7.92 (d, J= 13.2 Hz, IH), 7.46 - 6.97 (m, 17H), 6.91 (s, IH), 6.75 (s, 1H), 4.10 (dd, 29.6, 19.2 Hz, 8H), 2.97 (s, 3H), 1.32 - 1.05 (m, 7H).

³¹P NMR (162 MHz, CDC1₃) d 5.11.

¹⁹F NMR (376 MHz, CDCI3) d -152.34 (s).

LC MS m/z 639.24 [M + H⁺J.

Compound C-5a was obtained in a procedure similar to that exemplified for Compound C-la but using tire proline ester.

©

146

Ή NMR (400 MHz, CDC1₃) d 8.20 (d, J= 7.8 Hz, 2 H), 7.45 - 7.08 (m, 7 H), 4.37 (td, J= 8.0, 3.8 Hz, 2 H), 4.17 - 3.98 (m, 2 H), 3.61 - 3.34 (m, 2 H), 2.21 - 1.77 (m, 3 H), 1.19 (td, 7.1, 3.8 Hz, 3 H).

³¹P NMR (162 MHz, CDC1₃) d -3.92, -3.96.

LC MS m/z 420.98 [M + H⁺].

Compound C-5

Compound C-5 was obtained in a procedure similar to that exemplified for Compound C-l using Compound 3 and C-5a.

^!H NMR (400 MHz, CDC13) d 7.95 (d, J= 4.5 Hz, 1 H), 7.39 - 7.10 (m, 4 H), 6.92 (dd, J= 16.0,4.6 Hz, 1 H), 6.69 (s, 1H),6,O3 (bs, 2 H), 4.46-4.36 (m, 1 H), 4.363.96 (m, 4 H), 3.37 (d, J = 58.9 Hz, 2 H), 2.26 - 1.66 (m,4H), 1.39- 1.12 (m, 8 H). ³¹P NMR (162 MHz, CDC13) d 3.47, 2.75.

¹⁹F NMR (376 MHz, CDC1₃) d -152.36.

LC MS m/z 589.14 [M + H⁺].

147

Compound C-6

Compound C-6 was obtained in a procedure similar to that exemplified for Compound C-l using Compound 3 and the sulphone analog of C-la.

^!H NMR (400 MHz, CDCl₃) d 7.93 (s, 1 H), 7.89 (s, I H), 7.35 - 7.01 (m, 5 H), 6.93 (d, J=2.8Hz„ 1 H), 6.58 (d, J =2.8 Hz, 1 H), 5.79 (bs, 2 H), 4.30 (s, 6 H), 4.11 (d, J = 7.0 Hz, 6H), 3.10-2.84 (m, 3 H), 2.75 (s, 3 H), 2.54 (s, 6 H), 1.31 -1.15 (m, 6 H). ³¹P NMR (162 MHz, CDC1₃) d 3.39, 3.33.

¹⁹F NMR (376 MHz, CDC1₃) d -152.40

LC MS m/z 655.24 [M + H⁺].

Compound PD-A-8b

148

PD-A-8b

To a solution of Compound 8 (200 mg, 0.71 mmol) in THF (1 mL) and NMP (1 mL) under an atmosphère of argon at 0°C was added tert-butyl magnésium chloride (1.0 M în THF, 1.06mL, 1.06 mmol). After 15 minutes, compound 30d-l (280 mg, 0.71 mmol) was added as a solution in THF. After 5 minutes, the reaction mixture was allowed to warm to room température and was stirred for 2 hours. The reaction mixture was cooled to 0°C, quenched with MeOH, and concentrated. The reaction was purified by silica gel chromatography and then RP HPLC, affording PD-A-8b (225 mg, 59%). ’H NMR (400 MHz, CDCfi): d 8.09 (two s, 1H), 7.54 (two s, 1H), 7.31-7.12 (m, 5H), 5.66 (dd, 1H), 4.52-4.45 (m, 2H), 4.19-4.03 (m, 4H), 3.87-3.69 (m, 1H), 1.35-1.15 (m, 9H). ³¹P NMR (161 MHz, CDC1₃): d4.14 (s), 3.55 (s). LC/MS = 539 (M + H⁺).

Rétention time: 1.94 min

LC: Thermo Electron Surveyor HPLC MS: Fînnigan LCQ Advantage MAX Mass Spectrometer Column: Phenomenex Polar RP 30 mm X 4.6 mm Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5%-100% ACN, 1.95 min-3.5 mîn 100% ACN, 3.5 min-3.55 min 100%-5% ACN, 3.55 min-4 min 5% ACN.

149

Préparation of30d-l

Compound 30d-l was prepared from 30a in a matter similar to that of 30d-2 substituting alanine ethyl ester hydrochloride for alanine isopropyl ester hydrochloride.

Compound (S)-PD-A-8c

(S)-PD-A-8c

150

Compound (S)-PD-A-8c was prepared in a matter similar to that of PD-A-8b substituting (S)-30d-2 for 30d-l. ’H NMR (400 MHz, CDCh): d 8.14 (s, IH), 7.60 (s, IH), 7.1-7.3 (m, 5H), 5.66 (dd, IH), 5.02 (m, IH), 4.50 (m, IH), 4.40 (m, IH), 4.14.3 (m, 2H), 3.98 (m, IH), 3.78 (m, IH), 3.18 (brs, IH), 1.15-1.4 (m, 12H). ³¹PNMR (161 MHz, CDC1₃): d 3.70 (s).

LC/MS = 553 (M + H⁺).

Préparation of (S)-30d-2

O ci-p-ci !

y^NH₂ ^HCI

p-Nitrophenol

TEA/CH₂CI₂

Alanine isopropyl ester hydrochloride (7.95 g, 47.4 mmol) was suspended in dichloromethane (100 mL). Compound 31a (10 g, 47.4 mmol) was added. Triethylamine (13.2 mL, 95 mmol) was then dropwise added over a period of 15 min. (internai reaction température; -10°C - -3 °C). When the reaction was almost complété (by phosphorous NMR),p-nîtrophenol (6.29 g, 45.0 mmol) was added as a solid in one portion. To the resulting slurry was added triethylamine (6.28 mL, 45 mmol) over a period of 15 min. The mixture was then warmed up to room température. When the reaction was complété, MTBE (100 mL) was added. The white precipitate was removed by filtration. The filter cake was washed with MTBE (3 x 50 mL). The filtrate and washings were combined and concentrated. The residue was purified by silica gel column chromatography (0 to 50% ethyl acetate / hexanes), affording compound 30d-2 as a 1:1 ratio of diastereomeric mixture (14.1 g, 77%). ’H NMR (300 MHz, CDC1₃): δ 8.22 (2d, 2H), 7.2-7.4 (m, 7H), 5.0 (m, IH), 4.09 (m,

IH), 3.96 (m, IH), 1.39 (2d, 3H), 1.22 (m, 6H). MS = 409.0 (Μ + H ), 407.2 (M H⁺).

151

Séparation of two diatereomers of compound 30d-2

diastereomeric mixture at phosphorous

The two diastereomers were separated by chiral column chromatography under the following conditions;

Column: Chiralpak IC, 2 x 25 cm

Solvent system: 70% heptane and 30% isopropanol (IPA)

Flow rate: 6 mL/min.

Loading volume per run: 1.0 mL

Concentration of loading sample: 150 mg / mL in 70% heptane and 30% IPA (S)-compound 30d-2: rétention time 43 inin. ³¹P NMR (162.1 MHz, CDCI3): δ -2.99 (s)· (R)-compound 30d-2: rétention time 62 min. ³¹P NMR (162.1 MHz, CDCI3): δ -3.02 (s).

Altematively, the two diastereomers were separated by crystallizatîon under the following procedure;

152

Compound 30d-2 was dissolved in diethyl ether (-10 mL/ gram). While stirring, hexanes was then added until the solution became turbid. Seed crystals (-10 mg / gram of compound 30d-2) were added to promote crystallization. The resulting suspension was gently stirred for 16 h, cooled to - 0 °C, stirred for an additional 2 h, and filtered to collect the crystalline material (recovery yield ofthe crystalline material 35%-35%). The crystalline material contains -95% of (S)-compound 30d-2 and -5% of (R)-compound 30d-2. Re-crystallization afforded 99% diastereomerically pure (S)-isomer.

The following PD-A compounds as examples are made by the general procedures:

Compound PD-A-8d

Compound PD-A-8e

Compound PD-A-8Î

Compound PD-A-8g

Compound PD-A-8H

General procedure for préparation of a nucleoside prodrug (Method D):

Non-limiting examples of 3’-0-acyalted mono-phosphoramidate prodrugs comprising the instant invention may be prepared according to general Scheme 2.

Scheme 2

The general procedure comprises the réaction of PD-A (R⁴ = OH) with a carboxylic acid or an actîvated carboxylate such as an acyl chloride or an acid anhydride, which is generally known to those skilled in the art (Journal of Médicinal Chemistry, 2006,49, 6614 and Organic Letters, 2003, 6, 807). When R⁸ = NH₂, protection of the amino group may be necessary. Briefly, to a solution of compound PD-A in acetonitrile (2 mL) is added VW-dimethyformamide dimethyl acetal (-1.1 eq.) and stirred at room température for 1 h. After the protection of 6-amîno group is complété, the mixture is then concentrated to dryness. To the residue are added a dehydrating agent such as DCC (~ 4 eq.), acetonitrile and a carboxylic acid (- 2 eq.). The mixture is stirred at room température for 24 -48 h. Water (0.2 mL) and trifluoroacetic acid (0.1 mL) are added at 0°C and stirred at room température for 64 h. Sodium bicarbonate was added at 0°C. The mixture is stirred at room température for 0.5 h and filtered. The filtrate is concentrated and the residue was purified by silica gel column chromatography to afford compound PD-B. If an acyl chloride or an acid anhydride is used, a suitable base, such as triethylamine, îs added instead of a dehydrating agent.

Compound PD-B-8Î

155 nh₂

To a solution of PD-A-8b (100 mg, 0.19 mmol) in DCM (1.0 mL) under an atmosphère of argon at room température was added V.jV-dimethylfonnamidediinethylacetal (25 pL, 0.19 mmol). After 30 minutes, the reaction mixture was concentrated. The reaction was taken up in DCM and concentrated. This process was repeated twice. The resulting residue was taken up în THF (1.0 mL) and cooled to 0°C under an atmosphère of argon. To the solution was added triethylamine (79 pL, 0.57 mmol) and DMAP (5mg, 0.04 mmol). After 5 minutes, isobutyryl chloride (60 pL, 0.57 mmol) was added. After 10 minutes, the reaction was allowed to warm to room température and was stirred for 3 hours. The mixture was cooled to 0°C, quenched with a 5% TFA solution in water, and then allowed to stir at room température for 4 hours. The resulting mixture was extracted with ethyl acetate (3x). The combined organic layers were dried with sodium sulfate, filtered and concentrated. The residue was purified by RP HPLC (acetonitrile / water), affording PD-B-81 (71 mg, 61%). *H NMR (400 MHz, CDC1₃): d 8.17 (two s, IH), 7.66 (two s, IH), 7.34-7.14 (m, 5H), 5.69 (dd, IH), 5.56-5.43 (m, IH), 4.55-4.01 (m, 5H), 3.793.69 (m, IH), 2.70-2.64 (m, IH), 1.37-1.17 (m, 15H). ^3,P NMR (161 MHz, CDC1₃): d 2.99 (s), 2.88 (s).

LC/MS = 609 (M + H⁺). Rétention time: 2.21 min LC: Thermo Electron Surveyor HPLC MS: Finnigan LCQ Advantage MAX Mass Spectrometer Column: Phenoinenex Polar RP 30 mm X 4.6 mm Solvents: Acetonitrile with 0.1 % formîc acid, Water with 0.1 % formic acid

156

Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5%-100% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100%-5% ACN, 3.55 min-4 min 5% ACN.

The following PD-B compounds as examples are made by the general procedures:

Compound PD-B-8j

Compound PD-B-8I
		NH;
	”V°y	x
d	w- Ô F X

Compound PD-B-8n

Compound PD-B-80

General procedure for préparation of a nucleoside prodrug (Method E):

158

Non-limiting examples of 3’,5’-cyclic mono-phosphoramidate prodrugs comprising the instant invention may be prepared according to general Scheme 3.

Scheme 3

Scheme 3 illustrâtes chemical processes that may be useful for préparation of cornpound PD-C. Accordingly, PD-Al is converted to PD-C in the presence of a base when Ar is substituted with an électron withdrawing group such as /j-nitro orp15 chloro group (European Journal of Médicinal Chemistry, 2009, 44, 3769).

Altematively, cornpound 40 is converted to Cornpound 41 according to Bioorganic , and Médicinal Chemistry Letters, 2007, 17, 2452, which is then coupled with a amino acid ester sait to form PD-C.

Cornpound PD-C-8q

159

A solution of PD-A-8p in DMSO is treated at room température with potassium Abutoxide (-1 eq.) and the resulting mixture is stirred for about 10 min. to about 2 h. The mixture îs then cooled to 0°C and neutralized with IN HCl to ~ pH 6.

The mixture is purified by HPLC to afford compound PD-C-8q.

Additionally, the following PD-C compounds as examples are made by the general procedures:

Compound PD-C-8r

Compound PD-C-8s

160

Compound PD-C-8t

NH₂

Compound PD-D-8u

Compound 8

Compound 8 is dissolved in PO(OMe)₃ (0.1 - 0.5 M solution) and cooied to 0°C under argon. To this stirring solution is added POCi₃ (1.0 - 5.0 eq.) dropwise, and the reaction mixture is allowed to warrn to room température for about 2 -16 h. The resulting solution is added dropwise to a rapidly stirring solution of acetonitrile and 0.05 - 0.5 M aqueous KOH. When addition is complété, the solvents are removed under reduced pressure. The resulting residue is dissolved in water and purified by HPLC to give Compound 41-1.

2) ÎPA

1) DCM, PO(OMe)₃, DMF oxaiyl-CI

Compound 41-1

Compound PD-D-8u

161

A solution of Compound 41-1 in DCM and PO(OMe)₃ is prepared and cooled to 0°C. To this solution is added oxalyl chloride (1.0 - 5.0 eq.) followed by a catalytic amount of DMF. The mixture is allowed to stir for about 10 min. to about lh. When activation is complété, a large volume of 2-propanol is added to the reaction mixture and allowed to stir and warm to room température. The solvents are removed under reduced pressure, and the resulting crude material is purifîed by préparative HPLC to give Compound PD-D-8u.

Compound PD-E-8v

2) DCM, TEA

1) DCM, PO(OMe)₃, DMF oxalyl-CI

Compound 41-1

Compound PD-E-8v

Compound PD-E-8v is prepared from Compound 41-1 in a matter similar to that of Compound PD-D-8u substituting 2-aminopropane for 2-propanol.

Compound PD-F-8w

162

Compound PD-F-8w is prepared in a matter similar to that of Compound 20 substituting Compound 8 for Compound 18.

Compound PD-G-8x

About 90 mM Compound 8 în THF is cooled to about -78°C and about 2.2 to about 5 équivalents of Nbutylmagnesium chloride (about 1 M in THF) is added. The mixture is warmed to about 0°C for about 30 min and is again cooled to about -78°C. A solution of (25)-2-{(chloro(l-phenoxy)phosphoryl) amino) ethyl isobutyrate (W02008085508) (1 M in THF, about 2 équivalents) is added dropwise. The cooling is removed and the reaction is stirred for about one to about 24 hours. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The extracts are dried and evaporated and the residue purified by chromatography to give Compound PD-G-Sx.

Compound 6

ch₃oh

AcOH

Compound 4 (about 0.04 mmol) and anhydrous MeOH (about 5 mL) is treated with acetic acid (about 5 mL) and the reaction is stirred overnight at room température. Saturated NaHCO₃ îs added to neutralîze the reaction mixture and the crude material is purified using a HPLC system (acetonitriIe-H₂O) to give 6.

163

Compound 7

3b

2. NH₃

1. AI(CH₃)₃

To a dry, argon purgcd round bottom flask (50 mL) is added compound 3 b (about 0.39 mmol) and anhydrous dichloromethane (about 10 mL). The flask is placed into a dry ice/acetone bath (~ -78°C) and the solution is stirred for about 10 min. BF3-Et₂O (about 0.10 mL) is added dropwise and the réaction îs stirred for about 10 min. AlMe₃ (about 1.16 mmol, 2.0 M in toluene) is then added. After a few minutes, the dry ice/acetone bath is removed and the reaction mixture is stirred at room température to about 45°C over about 4 h to about 4 d. A solution of pyridine (about 2 mL) in MeOH (about 10 mL) is added and the solvent is removed under reduced pressure. The crude material is purified by chromatography and is treated with ammonium hydroxide in methanol for about 16 h at about room température. The mixture îs concentrated and the residue is purified by HPLC to give 7.

Compound 8

BuLi THF

8b

To a suspension of 7-bromoimidazo[l,2-f|[l,2,4]triazîn-4-amine (obtained according to ACS Médicinal Chemistry Letters, 2010, I, 286; 375 mg, 1.75 mmol) in

164

THF (4.0 mL) under an atmosphère of argon was added 1,2-bîs[(chlorodîmethyl)silanyljethane (452 mg, 2.10 mmol). After 60 min, the reaction was cooled to ~78°C and BuLi (1.6 M in THF, 3.8 mL, 6.10 mmol) was added. After 10 min at -78°C, a solution of la (obtained according to WO 200631725, 782 mg, 2.10 mmol) in THF ( 1.0 mL) was added dropwise. The resulting mixture was stirred at 78°C for 1 hour. Saturated aqueous ammonium chloride was added and allowed to warm to 0°C. Water was added until ail solids became soluble. The mixture was extracted with ethyl acetate. The organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate / hexanes), affording 8b (606 mg, 59%) as a yellow solid.

LC/MS = 508 (M+H⁺)

Rétention time: 2.17-2.26 min

LC: Thermo Electron Surveyor HPLC

MS: Fînnigan LCQ Advantage MAX Mass Spectrometer

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5%-100% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100%-5% ACN, 3.55 min-4 min 5% ACN.

nh₂ O /°^\ o r m Bz^z Y V br \_Λοη	Et₃SiH	nh₂ o
2—s. _ZÔ F	BF₃-Et₂O	O F
Bz		Bz
8b		8c

To a solution of compound 8b (510 mg, 1.39 mmol) in dichloroethane (10.0 mL) at 0°C under an atmosphère of argon, was added triethyl silane (1.77 mL, 11.09 mmol) and then BF₃*Et₂O (1.41 mL, 11.09 mmol). The reaction mixture was stirred at 55°C for 16h. The reaction was cooled to 0°C and quenched with saturated NaHCO₃ (aq). The reaction was extracted with DCM and then EtOAc. The

165 combined organic phase was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes), affording 8c (453 mg, 64%). ^!H NMR (400 MHz, CDC1₃): d 8.10-7.94 (m, 5H), 7.67.33 (m, 7H), 5.91 (dd, IH), 5.78 (d, 7=24.6 Hz, IH), 4.87 (dd, IH), 4.70 (m, IH), 4.58 (dd, IH), 1.31 (d,7=22.4 Hz, 3H).

LC/MS = 491 (M⁺).

Rétention time: 2.36 min.

LC: Thermo Electron Surveyor HPLC

MS: Finnigan LCQ Advantage MAX Mass Spectrometer

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid Gradient: 0 mîn-0.1 min 5% ACN, 0.1 min-1.95 min 5%-100% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100%-5% ACN, 3.55 min-4 min 5% ACN.

8c Compound 8

To a solution of 8c (500 mg, 01.02 mmol) in THF (5.0 mL) was added lithium hydroxide (122 mg, 5.09 mmol) as a solution in H₂O (5.0 mL) and was stirred at room température for lh. The reaction was cooled to 0°C and was neutralized with IN HCl in water (5.1 mL). The mixture was concentrated and the residue was purified by RP HPLC (water / acetonitrile), affording Compound 8 (185 mg, 64%). ’H NMR (400 MHz, CD3OD): d 7.97 (s, 1H),7.63 (s, 1H),5.54 (d, 7=24.8 Hz, 1 H), 4.03 (dd, IH), 3.88 (m, 1 H), 3.71 (dd, IH), 1.80 (d, 7=22.1 Hz, 3H).

LC/MS = 284 (M+H⁺).

Rétention time: 1.06 min.

LC: Thermo Electron Surveyor HPLC

MS: Finnigan LCQ Advantage MAX Mass Spectrometer

166

Column: Phenomenex Polar RP 30 mm X 4.6 mm

Solvents: Acetonitrile with 0.1% formic acid, Water with 0.1% formic acid

Gradient: 0 min-0.1 min 5% ACN, 0.1 min-1.95 min 5%-l00% ACN, 1.95 min-3.5 min 100% ACN, 3.5 min-3.55 min 100%-5% ACN, 3.55 min-4 min 5% ACN.

Alternative procedure for Compound 8

NaBH₄

Compound 8

Compound le (crude obtained from the previous reaction step) was dissolved in EtOH. Excess sodium borohydride was added in portions until the reaction was nearly complété. The mixture was neutralized with acetic acid. The mixture was concentrated and the solid residue was purified by silica gel column chromatography (0-10% MeOH / dichloromethane), affording compound 27 (210 mg, 50% in two steps).

Additional alternative procedure for Compound 8

1d 8

Raney Ni (about 500 mg) was neutralized by washing with H₂O, and added to a solution of ld (about 100 mg) in éthanol (about 10 mL). The mixture was then heated to 80°C until the réaction is complété. The catalyst was removed by filtration

and the solution was concentrated in vacuo. The mixture was concentrated and the residue was purified by HPLC to give 8.

167

Compound 9

Into a flask containing Compound 3 (120 mg, 0.39 mmoL, 1 equiv.) was added PO(OMe)₃ (1.5 mL, 0.25 M) and cooled to 0°C before adding POC1₃ (125 pL, 1.37 nimoL, 3.5 equiv,). The reaction mixture was allowed to stir for 5 hr before the reaction was quenched with water. It was directly purified by HPLC to fumish the monophosphate Compound 9.

LC MS m/z 387.95 [M + H⁺],

Compound 10

Into a flask containing Compound 9 (30 mg, 0.078 mmoL, 1 equiv.) was added NMP (0.8 mL, 0,1 M) followed by addition of TEA (43 pL, 0.31 mmoL, 4 equiv.), tetrabutylammonium bromide (25 mg, 0.078 mmoL, 1 equiv.) before adding chloromethylisopropyl carbonate (60 μL, 0.38 mmoL, 5 equiv.). The reaction mixture was heated to 50°C and allowed to stir overnight. It was purified directly by HPLC, affording Compound 10.

168 ^!H NMR (400 MHz, CDCl₃)d 7.98 (s, 1 H), 7.01 (d, J-4.7 Hz, 1 H), 6.72 (d, J =4.7

Hz, 1 H), 6.04 (bs, 2 H), 5.74-5.61 (m, 4 H), 4.91 (ddt, J= 12.6,9.4,6.3 Hz, 2 H),

4.64-4.28 (m,4H), 1.37-1.19 (m, 15 H).

³¹P NMR (162 MHz, CDC1₃) d -4.06.

¹⁹F NMR (376 MHz, CDC1₃) d -76.58, -151.95 TFA sait.

LC MS m/z 620.03[M + H*].

Compound II

A solution of Compound B-2 in DMSO is treated with about 3 mole équivalents of potassium Fbutoxide for about 15 min to 24 hours. The reaction is quenched with IN HCl and Compound 11 is isolated by reverse-phase HPLC.

Compound 12

169

1b

12a

Raney Ni v

2. NH₃

1. TMSCN

TMSOTf

12b

Compound lb (about I mmol) îs placed în a steel bomb reactor. The reactor is charged with liquid ammonia (about 30 mL) and the mixture is stirred at about 0°C to 50°C for about 16 h. The ammonia is evaporated and the residue is purified to give

12a. A solution of 12a (about 100 mg) in éthanol (about 10 mL) is treated with

Raney Ni (about 500 m g) that is neutralized by washing with H₂O. The mixture is then heated to about 35 to about 80°C until the reaction is complété. The catalyst is removed by filtration and the solution is concentrated in vacuo. The mixture is concentrated and the residue is purified by HPLC to give 12b. To a solution of compound 12b (about 50 mg) and TMSCN (about 0.5 mmol) in acetonitrile (about 2.0 mL) at about 0°C is added TMSOTf (about 0.5 mmol). The reaction mixture is stirred at room température for about 1 h, then at 65°C for about 3 d. The reaction is quenched with saturated NaHCO₃ at room température, and diluted with CH₃CO₂Et. The organic phase was separated, washed with brine, dried over Na₂SO4, filtered and concentrated. The residue is purified by RP-HPLC then dissolved în méthanol (about 1 mL). Ammonium hydroxide (28% in water, about 0.8 mL) is added and the

mixture îs stirred at about room température for 16 h. The mixture is concentrated and the residue is purified by RP HPLC to give 12.

Compound 13

170

Compound 13 is prepared in the same manner as Compound 9 using

Compound 12 as a starting material.

Compound 14

O

Compound 14 is prepared by treating Compound 13 with about one to about five équivalents of DCC in pyridine and heating the réaction to reflux for about one to about 24 hours. Compound 14 is isolated by conventional ion ex ch ange and rev ersephase HPLC.

Compound 15

171

A solution of about 0.4 mmol of Compound 14 in about 10 mL of DMF is treated with about 0.8 mmol of DIPEA and about 0.8 mmol of chloromethyl isopropyl carbonate (W02007/027248). The reaction is heated to about 25 to about 80°C for about 15 min to about 24 hours. The solvent is removed under vacuum and the residue is purified by HPLC to give Compound 15.

Compound 16

Compound 3 (about 0.22 mmoL) is dissolved in anhydrous pyridine (about 2 mL) and chlorotrimethylsilane (about 0.17 mL) is added. The mixture is stirred at about 0 °C to about 25°C for about one to about 24 hours. Additional chlorotrimethylsilane (about 0.1 mL) is added and the reaction is stirred for about one to about 24 hours. 4.4’-Dimethoxytrityl chloride (about 0.66 mmol) and DMAP (about 0.11 to about 0.22 mmol) is sequentially added. The mixture is stirred for about one to about 24 hours. A solution of TBAF (1.0 M, about 0.22 mL) in THF is added and the reaction is stirred for about one to about 24 hours. The mixture is partitioned between ethyl acetate and water. The ethyl acetate layer is dried and concentrated. The residue is purified chromatography to afford Compound 16.

172

A mixture of about L25 mmol of Compound 16 and about 1.9 mmol of triethylammonium 2-(2,2-dimethyl-3-(trityloxy)propanoylthio)ethyl phosphinate (W02008082601) is dissolved in anhydrous pyridine (about 19 mL). Pivaloyl chloride (about 2,5 mmol) is added dropwise at about -30 to about 0°C and the solution is stirred at for about 30 min to about 24 hours. The reaction is diluted with methylene chloride and is neutralized with aqueous ammonium chloride (about 0.5M). The methylene chloride phase îs evaporated and the residue is dried and îs purified by chromatography to give Compound 17.

To a solution of about 0.49 mmol of Compound 17 in anhydrous carbon tetrachloride (about 5 mL) is added dropwise benzylamine (about 2.45 mmol). The reaction mixture is stirred for about one to about 24 hours. The solvent is evaporated and the residue is purified by chromatography to give Compound 18.

Compound 20

173

A solution of about 2 mmol of Compound 18 in methylene chloride (about 10 mL) is treated with an aqueous solution of trifluoroacetic acid (90%, about 10 mL). The reaction mixture is stirred at about 25 to about 60 °C for about one to about 24 hours. The reaction mixture is diluted with éthanol, the volatiles are evaporated and the residue is purified b y chromatography to give Compound 20.

Compound 21

About 90 mM Compound 2 in THF is cooled to about -78 °C and about 2.2 to about 5 équivalents of i-butylmagnesium chloride (about 1 M in THF) is added. The mixture is warmed to about 0 °C for about 30 min and is again cooled to about -78 °C.

A solution of (2S)-2-{[chloro(l-phenoxy)phosphoryl]amino}propyl pivaloate (W02008085508) (1 M in THF, about 2 équivalents) is added dropwise. The cooling is removed and the reaction is stirred for about one to about 24 hours. The reaction is quenched with water and the mixture is extracted with ethyl acetate. The extracts are dried and evaporated and the residue purified by chromatography to give Compound

21.

Compound 22

174

22a

Compound 22a was obtained in a procedure similar to that for préparation of C-l a.

’H NMR (400 MHz, CDClj) d 8.11 (d, 7= 9.0 Hz, 2 H), 8.02 (s, 1 H), 7.48 (t, J= 7.5 Hz, 2 H), 7.42-7.25 (m, 4 H), 7.21 (dt, J = 14.9, 5.5 Hz, 2 H), 7.08 (t, J= 7.3 Hz, 2 H), 5.17 - 5.03 (m, 2 H), 4.99 (dd, 7 = 16.5, 9.7 Hz, 2 H), 3.44 (s, IH), 3.35 - 3.21 (m, 2 H), 3.19 (d, J= 9.2 Hz, IH), 3.00 - 2.80 (m, 2 H).

³ⁱP NMR (162 MHz, CDC1₃) d4.27.

LC MS m/z 452.09 [M + H⁺],

H

22b

Compound 22b was obtained in a procedure similar to that for préparation of C-l using Compound 3 and 22a.

'H NMR (400 MHz, CD₃OD) d7.76 (d, 7=6.3 Hz, IH), 7.38 (t,7=8.2 Hz, 1 H), 7.27-7.12 (m, 4 H), 7.06 - 6.81 (m, 3 H), 6.74 (dd,7= 4.6, 3.5 Hz, 1 H), 4.95 - 4.79 (m, 1 H), 4.35 - 3.90 (m, 4 H), 3.23 (dt, 7= 3.2, 1.6 Hz, 3H), 3.18 - 3.05 (m, 2 H), 2.82 (dt, 7 = 14.7, 7.3 Hz, 2 H), 1.15 (d, 7= 22.4 Hz, 3 H).

³¹PNMR(162 MHz, CD₃OD) d 10.76, 10.71.

LC MS m/z 620.05 [M + H⁺],

175

Compound 22

Into a flask containing the 22b (50 mg, 0.08 inmoL, 1 equiv.) was added éthanol (4 mL) followed by Pd(OH)₂ ( 56 mg, 0.08 mmoL, 1 equiv.) and ammonium formate (42 mg, 0.64 mmoL, 8 equiv.). The reaction was heated to 80°C for about an hour. The solid was filtered off and the material purifîed by HPLC.

'H NMR (400 MHz, DMSO-d₆) d 10.72 (s, IH), 7.91 (s, 1 H), 7.95 - 7.89 (bs, 2 H), 7.41 (d, J=7.7Hz, 1 H), 7.26 (d, J=8.1 Hz, 1 H), 7.19-6.66 (m, 3 H), 4.20-3.75 (m, 3 H), 2.99 (dd, J= 16.5, 9.6 Hz, 2 H), 2.89 - 2.70 (m, 2 H), 2.48 - 2.58 (m, 8 H), 1.10 (d, J =22.3 Hz, 3 H).

^3,P NMR (162 MHz, DMSO-d₀) d 7.49.

ⁱ⁹F NMR (376 MHz, DMSO-d_ô) d -154.89.

LC MS m/z 530.21 [M + H⁺].

Compound 23

Compound 3 Compound 23

Compound 3 (250mg, 0.82mmol) was dissolved in PO(OMe)₃ (5 mL, 0.16M) and cooled to 0°C under argon. To this stirring solution was added POC1₃ (0.32 mL, 4,1 mmol) slowly dropwise, and the reaction mixture allowed to warm to room température for 16 h. The resulting solution was added dropwise to a rapidly stirring solution of acetonitrile (400 mL) and 0.08M aqueous KO H (300 mL), When addition was complété, the reaction progrès s was checked by LCMS. When the reaction was

176 complété, solvents were removed under reduced pressure. The resulting solid residue was dissolved in water and purified by HPLC to give 140mg of Compound 23 (yield; 47%).

'H-NMR (400MHz; CDjOD) : d 8.15 (s, IH), 7.40 (d, IH; J = 4.8Hz), 7.09 (d, IH; J = 4.8Hz), 4.64 (dd, 1 H; J = 24Hz, 7.2Hz ), 4.50-4.36 (m, 3H), 1.32 (d, 3H; J=22Hz). ¹⁹F-NMR (376MHz; CD₃OD) : d -153.11.

^3,P-NMR (162MHz; CD₃OD) : d -2.20.

MS [M + H⁺] - 370.2.

Compound 24

A solution of Compound 23 (7mg, 0.02 mmol) in DCM (2 mL) and PO(OMe)î (1 mL) was prepared and cooled to 0°C. To this solution was added oxalyl-Cl (10 pL) followed by DMF (2 pL). The mixture was allowed to stir for 1 min before an aliquot was taken out and quenched in MeOH and then checked by LCMS for activation. Successive amounts of oxalyl-Cl (10 pL) and DMF (2 pL) were added until activation was complété. At this point, a large volume of 2-propanol (5 mL) was added to the reaction mixture and allowed to stir and warm to room température. Once the reaction was complété, the solvents were removed under reduced pressure, and the resulting crude material was purified by préparative HPLC to give 5.5 mg of Compound 24 (yield 70%).

’H-NMR (400MHz; DMSO-d₆) : d 8.26 (br, IH), 8.15 (br, IH), 7.97 (s, IH), 7.00 (d, IH; J =4.4Hz), 6.88 (d, IH; J = 4.4Hz), 4.59-4.51 (m, 2H), 4.37-4.25 (m, 2H), 1.23 (d, 3H; J=22.8Hz).

177 ^I9F-NMR (376MHz; CD₃OD) : d -151.72.

^3,P-NMR (162MHz; CD₃OD) : d -5.69. MS [M + H⁺] = 412,0.

Coinpound 25

Cornpound 25 was prepared from Cornpound 23 in a matter similar to that of Cornpound 24 substituting the heptyl ester of alanine for 2-propanol (yield 5.3%). ’H-NMR (400MHz; CD₃OD) : d 7.91 (s, 1H), 6.98 (d, 1H; J = 4.8Hz), 6.92 (d, 1H; J = 4.8Hz), 5.29 (dd, 1H; J = 24.4Hz, 8.8Hz), 4.66-4.60 (m, 2H), 4.48-4.40 (m, 1H), 4.15-4.11(m,3H),3.92(dd, 1H; J = 9.6Hz, 7.2Hz), 1.67-1.64 (m, 3H), 1.40-1.27 (m, 15H),0.91-0.87(m, 6H).

¹⁹F-NMR (376MHz; CD₃OD) : d -151.46.

³¹P-NMR (162MHz; CD₃OD) : d 7.36.

MS [M + H⁺] = 539.4.

Cornpound 26

178

Compound 26

Compound 26 is prepared from compound 22 in a matter similar to that for préparation of compound 10,

Antiviral Activity

Another aspect of the invention relates to methods of inhibitîng viral infections, comprising the step of treating a sample or subject suspected of needîng such inhibition with a composition of the invention,

Within the context of the invention samples suspected of containing a virus include natural or man-made materials such as living organisms; tissue or cell cultures; biologieal samples such as biologieal material samples (blood, sérum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, and the like); laboratory samples; food, water, or air samples; bioproduct samples such as extracts of cells, particularly recombinant cells synthesizing a desired glycoprotein; and the like, Typically the sample will be suspected of containing an organism which induces a viral infection, ffequently a pathogenic organism such as a tumor virus, Samples can be contained in any medium including water and organic solvent\water mixtures, Samples include living organisms such as humans, and man made materials such as cell cultures.

If desired, the anti-virus activity of a compound of the invention after application of the composition can be observed by any method including direct and indirect methods of detecting such activity. Quantitative, qualitative, and semiquantitative methods of determining such activity are ail contemplated, Typically one of the screening methods described above are applied, however, any other method such as observation of the physiological properties of a living organism are also applicable,

The antiviral activity of a compound of the invention can be measured using standard screening protocol s that are known. For example, the anti viral activity of a

179 compound can be measured using the following general protocols.

Cell-based Flavivirus Immunodetection assay

BHK21 or A549 cells are trypsinized, counted and diluted to 2xl0⁵ cells/mL in Hams F-12 media (A549 cells) or RPMI-1640 media (BHK21 cells) supplemented with 2% fêtai bovine sérum (FBS) and 1% penicillin/streptomycin. 2xl0⁴ cells are dispensed in a clear 96-well tissue culture plates per well and placed at 37°C, 5% CO₂overnight. On the next day, the cells are infected with viruses at multiplicity of infection (MOI) of 0.3 in the presence of varied concentrations of test compounds for 1 hour at 37°C and 5% CO₂ for another 48 hours. The cells are washed once with PBS and fixed with cold methanol for 10 min. After washing twice with PBS, the fixed cells are blocked with PBS containing 1% FBS and 0.05% Tween-20 for 1 hour at room température. The primary antibody solution (4G2) is then added at a concentration of 1:20 to 1:100 in PBS containing 1% FBS and 0.05% Tween-20 for 3 hours. The cells are then washed three times with PBS followed by one hour incubation with horseradish peroxidase(HRP)-conjugated anti-mouse IgG (Sigma, 1:2000 dilution). After washing three times with PBS, 50 microliters of 3,3’,5,5’tetramethylbenzidine (TMB) substrate solution (Sigma) is added to each well for two minutes. The reaction is stopped by addition of 0.5 M sulfuric acid. The plates are read at 450 nm absorbance for viral load quantification. After measurement, the cells are washed three times with PBS followed by incubation with propîdium iodide for 5 min. The plate is read in a Tecan Safire™ reader (excitation 537 nm, émission 617 nm) for cell number quantification. Dose response curves are plotted from the mean absorbance versus the log of the concentration of test compounds. The ECgo is calculated by non-linear régression analysis. A positive control such as N-nonyldeoxynojirimycin may be used.

Cell-based Flavivirus cytopathic effect assay

For testing against West Nile virus or Japanese encephalitis virus, BHK21 cells are trypsinized and diluted to a concentration of 4 x 10⁵ cells/mL in RPMI-1640

I80 media supplemented with 2% FBS and 1% penicillin/streptomycin. For testing against dengue virus, Huh7 cells are trypsînizcd and diluted to a concentration of 4 x 10⁵ cells/mL in DMEM media supplemented with 5% FBS and 1% penicillin/streptomycîn. A 50 microliter of cell suspension (2 x 10⁴ cells) is dispensed per well in a 96-well optical bottom PIT polymer-based plates (Nunc). Cells are grown overnight în culture medium at 37°C, 5% CO₂, and then infected with West Nile virus (e.g. B956 strain) or Japanese encephalitis virus (e.g. Nakayama strain) at MOI = 0.3, or with dengue virus (e.g. DEN-2 NGC strain) at MOI = 1, in the presence of different concentrations of test compounds. The plates containing the virus and the compounds are further incubated at 37°C, 5% CO₂ for 72 hours. At the end of incubation, 100 microliters of CellTiter-Glo™ reagent is added into each well. Contents are mixed for 2 minutes on an orbital shaker to induce cell lysis. The plates are incubated at room température for 10 minutes to stabilîze luminescent signal. Luminescence reading is recorded using a plate reader. A positive control such as Nnonyl-deoxynojirimycin may be used.

Antiviral Activity in a Mouse Model of Dengue Infection.

Compounds are tested in vivo in a mouse model of dengue virus infection (Schul et al. J. Infectious Dis. 2007; 195:665-74). Six to ten week old AG129 mice (B&K Universal Ltd, ΗΠ, UK) are housed in individually ventilated cages. Mice are injected intraperitoneally with 0.4 mL TSV01 dengue virus 2 suspension. Blood samples are taken by rétro orbital puncture under isoflurane anesthésia. Blood samples are collected in tubes containing sodium citrate to a final concentration of 0.4%, and immediately centrifuged for 3 minutes at 6000g to obtain plasma. Plasma (20 microliters) is diluted in 780 microliters RPMI-1640 medium and snap ffozen in liquid nitrogen for plaque assay analysis. The remaîning plasma is reserved for cytokine and NSI protein level détermination. Mice develop dengue vîremia rising over several days, peaking on day 3 post-infection.

For testing of antiviral activity, a compound of the invention is dissolved in

181 vehicle fluid, e.g. 10% éthanol, 30% PEG 300 and 60% D5W (5% dextrose in water; or 6N HCl (1.5 eq):lN NaOH (pH adjusted to 3.5): 100 mM citrate buffer pH 3.5 (0.9% v/v:2.5% v/v: 96.6% v/v). Thirty six 6-10 week old AG129 mice are divided into six groups of six mice each. Ail mice are infected with dengue virus as described above (day 0). Group 1 is dosed by oral gavage of 200 mL/mouse with 0.2 mg/kg of a compound of the invention twice a day (once early in the moming and once late in the aftemoon) for three consecutive days starting on day 0 (first dose just before dengue infection). Groups 2, 3 and 4 are dosed the same way with 1 mg/kg, 5 mg/kg and 25 mg/kg of the compound, respectively. A positive control may be used, such as (2R,3R,4R,5R)-2-(2-amino-6-hydroxy-purin-9-yl)-5-hydroxymethyl-3-methyl15 tetrahydro-furan-3,4-diol, dosed by oral gavage of 200 inicroliters/mouse the same way as the previous groups. A further group is treated with only vehicle fluid.

On day 3 post-infection approximately 100 microliter blood samples (antîcoagulated with sodium citrate) are taken from the mice by retro-orbîtal puncture under isoflurane anesthésia. Plasma is obtained from each blood sample by centrifugation and snap frozen in liquid nitrogen for plague assay analysis. The collected plasma samples are analyzed by plague assay as described in Schul et al. Cytokines are also analyzed as described by Schul. NS 1 protein levels are analyzed using a Platelia™ kit (BioRad Laboratories). An anti-viral effect is indicated by a réduction in cytokine levels and/or NSI protein levels.

Typically, réductions in viremia of about 5-100 fold, more typically 10-60 fold, most typically 20-30 fold, are obtained with 5-50 mg/kg bid dosages of the compounds of the invention.

HCV IC_So Détermination

Assay Protocol: Either wild type or S282T (Migliaccio, et al, J. Biol. Chem.

2003,49164-49170; Klumpp, et al., J. Biol. Chem. 2006, 3793-3799) mutant polymerase enzyme was used in this assay. NS 5b polymerase assay (40 pL) was

C

182 assembled by adding 28 pL polymerase mixture (final concentration: 50 mM TrisHCl at pH 7.5, 10 mM KCL, 5 mM MgCl₂, l mM DTT, 10 mM EDTA, 4 ng/pL of RNA template, and 75 nM HCV Δ21 NS5b polymerase) to assay plates followed by 4 pL of compound dilution. The polymerase and compound were pre-incubated at 35°C for 10 minute before the addition of 8 pL of nucléotide substrate mixture (33P10 α-labeled competing nucléotide at Km and 0.5 mM of the remaining three nucléotides). The assay plates were covered and incubated at 35°C for 90 min. Reactions were then filtered through 96-well DEAE-81 filter plates via vacuum. The filter plates were then washed under vacuum with multiple volumes of 0.125 M NaHPCU, water, and éthanol to remove unincorporated label. Plates were then counted on TopCount to assess the level of product synthesis over background controls. The IC50 value is determined using Prism fitting program.

Preferably, compounds described herein inhibited NS5b polymerase with an ICso’s below 1000 μΜ, more preferably below 100 pM, and most preferably below 10 pM. For example, compound TP-1 has an IC₅o of 0.15 pM against both wild type

HCV polymerase and the S282T mutant enzyme. Table II below shows the activity of TP-1 and TP-2 against both wild type and the S282T mutant enzyme compared to the activities obtained with the triphosphate of 2’-methyl guanidine and the triphosphate of (2R,3R,4R,5R)-2-(4-aminopyrrolo[l,2-f][l,2,4]triazîn-7-yl)-3,4dihydroxy-5-(hydroxymethyl)-3-methyl-tetrahydrofuran-2-carbonitrile. This demonstrates that replacing the 2’ OH of the pyrrolo[ 1,2-f][ 1,2,4]triazin-7-yl nucleosides with a 2’ F unexpectedly confers activity against résistant S282T HCV mutant strains of virus.

Table II

	WT	S282T
Triphosphate	IC50(uM)	IC50(uM)	Note

C

183

HÔ OH from J. Bio. Chem.,

2003,278, 49164 (200 fold shift)

HÔ F

TP-3

0.15

0.525

0.24

0.034

0.15

111

1.60 (1 fold shift)

WO/2009/132135 (242 fold shift) (7 fold shift)

0.30

1.6 (5.3 fold shift)

TP-8a

184

HCV EC₅o Détermination o

Replicon cells were seeded in 96-well plates at a density of 8 x 10 cells per well in 100 pL of culture medium, excluding Geneticin. Compound was serially diluted in 100% DMSO and then added to the cells at a 1:200 dilution, achieving a final concentration of 0.5% DMSO and a total volume of 200 pL. Plates were incubated at 37°C for 3 days, after which culture medium was removed and cells were lysed in lysis buffer provided by Promega’s luciferase assay system. Following the manufacturer’s instruction, 100 pL of luciferase substrate was added to the lysed cells and luciferase activity was measured in a TopCount luminometer. Preferably, compounds described herein hâve ECSO's below 1000 pM, more preferably below 100 pM, and most preferably below 10 pM. The activities of représentative compounds of Formula I are shown in the Table III below.

Table III

Compound No.	EC50, pM
A-l	23
B-l	1.4-4.3
B-3	16-28
B-4	8.4-19
B-5	1.93-25.5
B-6	3.75-11.1
B-7	63-73
B-8	35-60
C-l	67-70
C-2	3.9-12
C-3	43-84
C-4	9.8-31
C-5	24-28

185

C-6	11
10	6.5-8
22	31-45
23	39.4-40.3
24	40.3-70.5
25	9.7-10
PD-A-8b	0.68

The cytotoxicity of a compound of the invention can be determined using the following general protocol.

Metabolism Studies:

Applicants hâve observed that monophosphate prodrugs of nucleoside analogs with a nitrogen at the X¹ position can hâve enhanced activity over their counterparts with a carbon at the X¹ position. This différence in activity correlates to the amount of the active triphosphate analogs of the compounds în cells. This can be quantified by a metabolism study which quantifies the intracellular concentration of the triphosphate analogs. The higher intracellular concentration of the triphosphate métabolite correlates to the prodrug with enhanced activity.

For example, comparison of the prodrug compound B-7 with prodrug compound PD-A-8b shows increased activity when the X¹ position is nitorgen. This can be observed in Table III, where the HCV EC50 for the compound where the X¹ position is nitrogen (compound PD-A-8b) is 0.68 μΜ compared to 63-73 μΜ for compound B-7. The activation of prodrug analog PD-A-8b (to its triphosphate analog TP-8a) was found to be more than two orders of magnitude more efficient than that observed for its prodrug counterpart where the X¹ position is carbon, B-7 (to its triphosphate analog TP-3), as seen in Table IV.

Experimental:

186

Huh-luc/neo replicon cells containing HCV génotype lb subgenomic replicons were maintained in Dulbecco’s modified eagle medium containing glutamax supplemented with 10% heat inactivated fêtai bovine sérum, penicillin-streptomycin, and G418 disulphate sait solution. Cells were transferred to twelve well tissue culture plates by trypsonizatîon and grown to confluency (0.88 X 10⁶ cells/well). Cells were treated for 24 hours with 10 μΜ nucleoside, or 10 μΜ prodrug. After 24 hours, cells were washed 2 times with 2.0 mL ice cold 0.9% sodium chloride saline. Cells were then scraped into 0.5 mL 70% methanol (MeOH) and ffozen overnight to facilitate the extraction of nucléotide métabolites. Extracted cell material in 70% MeOH was transferred into tubes and dried. After drying, samples were resuspended in ImM Ammonium phosphate pH 8.5 containing internai standard (100 nM C1ATP). Intracellular leveis of the nucleoside triphosphates were quantified based on authentic standard curves by liquid chromatography coupled to tandem mass spectrometry.

Results

Table IV: Intracellular triphosphate analog concentrations formed in Huh-luc/neo replicon cells following 24 hour incubations with 10 μΜ PD-A-8b and B-7.

Prodrug	Triphosphate	Intracellular Triphosphate Analog Concentration (pmol/million)
B-7	TP-3	< 0.1l^a
PI)-A-8b	TP-8a	20.5^b
^a Intracellular concentrations were below the lower limit of quantification of the assay. ^b Value is the average of results from 2 separate wells.

Cytotoxicitv Cell Culture Assay (Détermination of CC50):

The assay is based on the évaluation of cytotoxic effect of tested compounds using a metabolic substrate.

ztssiiy protocol for détermination of CC50:

1. Maintain MT-2 cells in RPMI-1640 medium supplemented with 5% fêtai bovine sérum and antibiotics.

187

2. Distribute the cells into a 96-well plate (20,000 cell in 100 pL media per well) and add various concentrations of the tested compound in triplicate (100 pL/well). Include untreated control.

3. Incubate the cells for 5 days at 37°C.

4. Préparé XTT solution (6 ml per assay plate) în dark at a concentration of 2mg/ml in a phosphate-buffered saline pH 7.4. Heat the solution in a water-bath at 55°C for 5 min. Add 50 pL of N-methylphenazonium methasulfate (5 pg/mL) per 6 mL ofXTT solution.

5. Remove 100 pL media from each well on the assay plate and add 100 pL of the XTT substrate solution per well. Incubate at 37°C for 45 to 60 min in a CCh incubator.

6. Add 20 pL of2% Triton X-l 00 per well to stop the metabolic conversion ofXTT.

7. Read the absorbance at 450 nm with subtractîng off the background at 650 nm.

8. Plot the percentage absorbance relative to untreated control and estimate the CC50 value as drug concentration resulting in a 50% inhibition of the cell growth. Consider the absorbance being directly proportional to the cell growth.

AU publications, patents, and patent documents cited herein above are incorporated by reference herein, as though individually incorporated by reference. The invention has been described with reference to various spécifie and preferred embodiments and techniques. However, one skilled in the art will understand that many variations and modifications may be made while remaining within the spirit and scope of the invention.

Claims

What is claimed is

1. A compound of Formula IV:

Fonnula IV or a pharmaceutically acceptable sait, thereof;

wherein:

R¹ is (Ci-Cg)alkyl, (C₄-C₈)carbocyclylalkyl, (Cj-Cg) substituted alkyl, (C₂-Cs)alkenyl, (C₂-C₈) substituted alkenyl, (C₂-C_s)alkynyl, (C₂-C₈) substituted alkynyl, or aryl(Ci-C₈)alkyl;

R² is halogen;

R³, R⁴, and R⁵ are each independently H, halogen, OR^a, N(R^a)2, N3, CN, NO2, S(O)nR^a, (Ci-C8)alkyl, (C4-C₈)carbocyclylalkyl, (C]-C₈)substituted alkyl, (C₂-C₈) alkenyl, (C₂-C₈)substituted alkenyl, (C₂-Cg)alkynyl, (C₂-C₈)substituted alkynyl, or aryl(C]-C₈)alkyI;

or any two of R³, R⁴ or R⁵ on adjacent carbon atoms when taken together are O(CO)O- or when taken together with the ring carbon atoms to which they are attached form a double bond;

each n is independently 0, 1, or 2;

each R^a is independently H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(Ci-C8)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)R^H} -C(=O)ORⁿ, -C(=O)NRⁿR¹², -C(=O)SR^1!, -S(O)R^h, -S(O)2R^h, -S(O)(OR^h), -S(O)2(OR^h), or ~SO₂NR^hR¹²;

189

R⁷ is H, -C(=O)R¹¹, -C(=O)OR¹¹, -C(=O)NR^1,R¹², -C(=O)SR¹¹, -S(O)R^h, S(O)2R^1!, -S(O)(OR^h), -SfOHOR¹¹), -SO2NR¹¹R¹², or

Y

W²

Y is O, S, NR, NiOXR), N(OR), ⁺N(O)(OR), or N-NR₂;

W¹ and W², when taken together, are -Y³(C(R^y)₂)jY³-; or one of W¹ or W² together with either R³ or R⁴ is -Y³- and the other of W^! or

W² is Formula la; or

W^! and W² are each, independently, a group of Formula IVa:

Formula IVa wherein:

each Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(0R), or N-NR₂;

each Y² is independently a bond, O, CR2, NR, ⁺N(O)(R), N(0R), ^(OXOR), N-NR2, S, S-S, S(O), or S(O)₂;

each Y³ is independently O, S, or NR;

M2 is 0, 1 or 2;

each R^x is a group of Formula IVb:

Formula IVb wherein:

each Mla, Ml c, and Mld is independently 0 or 1;

M12c is 0, 1, 2,3,4, 5, 6, 7, 8, 9, 10, 11 or 12;

each R^y is independently H, F, Cl, Br, I, OH, -C(=Y^l)R, -C(=Y')R¹³, C(=Y’)OR, -C(=Y¹)N(R)2, -N(R)2, -Wh -SR, -S(O)R, -S(O)2R, -S(O)2R¹³, S(O)(0R), -S(O)2(OR), -OC(=Y^l)R, -OC(=Y¹)OR, -OC(=Y^l)(N(R)2), -SC(=Y^l)R, SC(=Y*)OR, -SC(=Y‘)(N(R)2), -N(R)C(=Y^])R, -N(R)C(=Y^])OR, -N(R)C(=Y¹)N(R)₂, -SO₂NR₂, -CN, -N₃, -NO₂, -OR, (C1-C_S) alkyl, (C₂-C₈)alkenyl, (C₂-Cg) alkynyl, C₆-C₂₀ aryl, C₃-C₂o carbocyclyl, C₂-C₂o heterocyclyl, arylalkyl, heteroarylalkyl;

wherein each (Ci-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl, C(,-C₂o aryl, C3-C20 carbocyclyl, C₂-C₂o heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R groups;

or when taken together, two R^y on the same carbon atom form a carbocyclîc ring of 3 to 7 carbon atoms;

each R is independently H, (Cj-Cg) alkyl, (C₂-C₈)alkenyl, (C₂-Cg) alkynyl, Q-C^o aryl, C3-C20 carbocyclyl, C₂-C₂o heterocyclyl, or arylalkyl;

each R⁸ is halogen, NR^1!R¹², N(R^!1)ORⁿ, NR^]1NR^]1R¹², N3, NO, NO2, OR¹¹orS(O)nRⁿ;

each R⁹ is independently H, halogen, NR^R¹², N(Rⁿ)ORⁿ, NR⁾¹NR¹¹R¹², N3, NO, NO2, CHO, CN, -CH(=NR¹¹), -CH=NHNR”, -CH=N(ORⁿ), -CH(OR^H)2, -C(=O)NRⁿR¹², -C(=S)NR¹¹R¹², -C(=O)OR¹¹, R¹¹, OR¹¹ or S(O)_nRⁿ;

each R¹¹ or R¹² is independently H, (Ci-Cg)alkyl, (C₂-C₈)alkenyl, (C₂Cg)alkynyl, (C4-Cg)carbocyclylalkyl, optionally substituted aryl, optionally

191 substituted heteroaryl, -C(=O)(C_rC8) alkyl, -S(O)_n(Cj-Cg)alkyl or aryl(Cj-Cg)alkyl; or R and R taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -O-, -S- or -NR^b-;

each R¹³ îs independently a carbocycle or heterocycle optionally substituted with 1-3 R²⁰ groups;

each R²⁰ is independently, halogen, CN, N3, N(R)2, OR, -SR, -S(O)R, -S(O)2R, -S(0)(OR), -S(O)2(OR), -C(=Y')R, -C(=Y¹)OR, or C(=Y*)N(R)2;

wherein each (Ci-Cg)alkyl, (C₂-Cg)alkenyl, (C₂-Cg)alkynyl or aryI(C|-Cg)alkyl of each R¹, R³, R⁴, R⁵, R⁶, R¹¹ or R¹² is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(R^b)2 or OR^b; and wherein one or more of the nonterminal carbon atoms of each said (Ci-Cg)alkyl may be optionally replaced with -O-, -S- or-NR^b;

each R^b îs independently H, (Cj-Csjalkyl, (C2-Cg)alkenyl, (C2-Cg)alkynyl, aryl(Ci-C8)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)R²¹, -C(=0)OR²¹, -C(=O)NR²¹R²², -C(=O)SR²¹, -S(O)R²¹, -S(O)2R²¹, -S(O)(0R²¹), -S(O)2(OR²¹), or -SO2NR²¹R²²; and each R²’ or R²² is independently H, (Ci-Cg)alkyl, (C₂-Cg)alkenyl, (C₂Cg)alkynyl, (C4-Cg)carbocyclylalkyl, -C(=O)(Ci-Cg)alkyl, -S(O)_n(Ci-Cg)alkyl or aryl(C]-C_g)alkyl.
2.

The compound according to claim 1 wherein each Y and Y¹ is O.

8 * 1112
3. The compound according to claim 2 wherein R is halogen, NR R ,

N(Rⁿ)ORⁿ, NR¹¹NR¹'R¹², OR¹¹ or SfO^R¹¹.
4. The compound according to claim 3 wherein R⁹ is H, halogen,

S(O)_nR^u orNR^1!R¹².
5, The compound according to claim 4 wherein R⁴ is OR^a.

192
6. The compound according to claim 5 wherein R¹ is CH₃.
7. The compound according to claim 6 wherein R is F.
8. The compound according to claim 7 wherein R⁷ is

Y

II w² wherein Y is -O-; W¹ is Formula la and W² together with R⁴ is -O-.
9.

The compound according to claim 1 represented by Formula V:

R⁴ F

Formula V

20 wherein R¹ is methyl or ethynyl, and R⁴ is OR^a.

7 »
10. The compound according to claim 9 wherein R is H or

193

II
11. The compound according to claim 1 with the following structures:

194
12. A compound of Formula VI:

R⁴ F

Formula VI or a pharmaceutically acceptable sait, thereof;

wherein:

R⁴ is OR^a;

each n is independently 0, 1, or 2;

each R^a is independently H, (Ci-Cg)alkyl, (C2-Cg)alkenyl, (C2-Cs)alkynyl, aryl(Ci-C8)alkyl, (C4-C8)carbocyclyl alkyl, -C(=O)R^ll> -C(=O)OR^H, -C(=O)NRⁿR¹², -C(=O)SR¹¹, -SlOJR¹¹, -S(O)2R¹¹, -S(O)(ORⁿ), -S(O)2(OR^H), or -SO2NR¹¹R¹²;

R⁷ is H, -C(=O)Rⁿ, -C(=O)OR¹¹, -C(=O)NR^llR¹², -C(=O)SR¹¹, -S(O)R^U, S(O)2R^h, -S(O)(OR^h), -S(O)2(OR^h), -SO₂NR^HR¹², or

195

Y îs O, S, NR, N(0)(R), N(OR), ^(OjiOR), or N-NR₂;

W¹ and W², when taken together, are -Y³(C(R^y)₂)3Y³~; or one of W¹ or W² together with R⁴ is -Y³- and the other of W¹ or W² is Formula la; or

W¹ and W² are each, independently, a group of Formula Via:

Formula Via wherein:

each Y¹ is, independently, O, S, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR), or

N-NR₂;

each Y² is independently a bond, O, CR₂, NR, ⁺N(O)(R), N(OR), ⁺N(O)(OR),

N-NR₂, S, S-S, S(O), or S(O)₂;

each Y is independently O, S, or NR;

M2 is 0, 1 or 2;

each R^x is a group of Formula VIb:

196

Formula Vlb wherein: each Mla, Mlc, and Mld îs independently 0 or 1;

M12c is 0, 1,2,3,4, 5, 6, 7, 8, 9, 10, 11 or 12;

10 each R^y is independently H, F, Cl, Br, I, OH, -C(=Y^!)R, -C(=Y')R¹³, C(=Y')OR, -C(=Y’)N(R)2, -N(R)2, -*N(R)3, -SR, -S(O)R, -S(O)2R, -S(O)2R¹³, S(O)(OR), -S(O)2(OR), -OC(=Y')R, -OC(=Y‘)OR, -OC(=Y¹)(N(R)2), -SC^Y'jR, SC(=Y^l)OR, -SC(=Y^I)(N(R)2), -N(R)C(=Y')R, -N(R)C(=Yⁱ)OR, -N(R)C(=Y’)N(R)₂, -SO₂NR₂, -CN, -N₃, -NO₂, -OR, (Cj-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl,

15 C₆~C₂₀ aryl, C₃-C₂o carbocyclyl, C₂-C₂₀ heterocyclyl, arylalkyl, heteroarylalkyl;

wherein each (C]-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl, C6-C₂₀ aryl,

C₃-C₂o carbocyclyl, C₂-C₂o heterocyclyl, arylalkyl, or heteroarylalkyl is optionally substituted with 1-3 R groups;

each R is independently H, (C_t-C₈) alkyl, (C₂-C₈)alkenyl, (C₂-C₈) alkynyl,

20 Cû-C₂o aryl, C3-C2Q carbocyclyl, C₂-C₂o heterocyclyl, or arylalkyl;

each R^!1 or R¹² is independently H, (C)-C₈)alkyl, (C₂-C₈)alkenyl, (C₂C₈)alkynyl, (C4-C₈)carbocyclylalkyl, optionally substituted aryl, optionally substituted heteroaryl, -C(=O)(Ci-C₈)alkyl, -S(O)_n(Ci-C₈)alkyl or aryl(Cj-C_s)alkyl;

each R¹³ is independently a carbocycle or heterocycle optionally substituted

25 with 1 -3 R²⁰ groups;

each R²⁰ is independently, halogen, CN, N₃, N(R)₂, OR, -SR, -S(O)R, -S(O)₂R, -S(O)(OR), -S(O)₂(OR), -C(=Y’)R, -C(=Y')OR, or C(=Y*)N(R)₂;

wherein each (Ci-Cs)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl or aryl(Ci-C₈)alkyl of each R⁴, R¹¹ or R¹² is, independently, optionally substituted with one or more halo, 30 hydroxy, CN, N3, N(R^b)2 or OR^b; and wherein one or more of the non-terminal carbon atoms of each said (Ci-Cg)alkyl may be optionally replaced with -O-, -S- or -NR^b;

each R^b is independently H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, aryl(Ci-C8)alkyl, (C4-C8)carbocyclylalkyl, -C(=O)R²¹, -C(=O)OR²¹, -C(=O)NR^2lR²², -C(=O)SR²ⁱ, -S(O)R²¹, -S(O)2R²¹, -S(O)(OR²¹), -S(O)2(OR²¹), or-SO2NR²¹R²²; and

197 each R² or R²² is independently H, (Cj-Cg)alkyl, (C2-Cg)alkenyl, (C₂Cg)alkynyl, (C^Cgjcarbocyclylalkyl, -C(=O)(C|-C₈)alkyl, -S(O)_n(Ci-Cs)alkyl or aryl(Ci-Cg)alkyl.
13. The compound according to claim 12 wherein:

R^a is H, (Ci-Cg)alkyl, or -C(=O)(C,-C₆)alkyl;

R⁷ or R⁷ together with R⁴ is wherein y

a is the point of attachement to R ;

b is the point of attachement to R⁴;

Ar is phenyl or naphthyl, wherein the phenyl and naphthyl are optionally substituted with 1-3 R²⁰ groups;

each R^y is independently (Ci-Cg) alkyl or C5-C₆ carbocyclyl, wherein the alkyl and carbocyclyl are optionally substituted with 1-3 R groups;

each R is independently H, (Ci-Câ) alkyl, or arylalkyl; and

Ο

198

5 each R²⁰ is independently halogen, CN, N(R)₂, OR, -SR, -S(O)R, -S(O)₂R, S(O)(OR), -S(0)₂(OR), -C(=O)R, -C(=0)OR, or C(=O)N(R)₂.
14. A compound having a structure:

nh₂ ob or a pharmaceutically acceptable sait, thereof.
15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

C?

201
16. The pharmaceutical composition of claim 15 further comprising at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, NS5a inhibitors, alpha-glucosidase l inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the reninangiotensin system, endothelin antagonists, other anti-fibrotic agents, nucleosîde or nucléotide inhibitors of HCV NS5B polymerase, non-nucleosîde inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV 1RES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixtures thereof.
17. Use of a cornpound of claim 1 în the manufacture of a pharmaceutical composition for treating a Flaviviridae virus infection în a mammal in need thereof, wherein said composition is for administration of a therapeutically effective amount of said cornpound of claim 1.
18. The use of claim 17 wherein the viral infection is a Hepatîtis C virus infection.
19. The use of claim 18 wherein the viral infection is caused by a S282T mutant of Hepatîtis C virus.
20. The use of claim 17 further comprising administration of at least one additional therapeutic agent selected from the group consisting of interferons, ribavirin or its analogs, HCV NS3 protease inhibitors, N S 5a inhibitors, alpha-glucosidase 1 inhibitors, hepatoprotectants, mevalonate decarboxylase antagonists, antagonists of the reninangîotensin System, endothelin antagonists, other anti-fibrotic agents, nucleosîde or nucléotide inhibitors of HCV NS5B polymerase, non-nucleoside inhibitors of HCV NS5B polymerase, HCV NS5A inhibitors, TLR-7 agonists, cyclophillin inhibitors, HCV IRES inhibitors, pharmacokinetic enhancers and other drugs for treating HCV; or mixtures thereof.