Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

Description

FIELD OF THE INVENTION

The invention relates generally to methods for preparing compounds with antiviral activity, most particularly to prodrugs of inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

BACKGROUND OF THE INVENTION

The hepatitis C virus (HCV) is a leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 32:98-112, 2000) and may lead to hepatic fibrosis, cirrhosis and hepatocellular carcinoma (Cale, P., Gastroenterolgy Clin. Biol. 2009, 33, 958). A significant focus of current antiviral research is directed toward the development of improved methods of treatment of chronic HCV infections in humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American, October: 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).

Currently, there are primarily two antiviral compounds, ribavirin, a nucleoside analog, and interferon-alpha (α) (IFN), which 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 anemia. The combination of IFN and ribavirin has been reported to be effective in the management of chronic hepatitis C (Scott, L. J., et al. Drugs 2002, 62, 507-556) but less than half the patients given this treatment show a persistent benefit. 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, WO2008/089105 and WO2008/141079 but additional treatments for HCV infections have not yet become available for patients. Therefore, drugs having improved antiviral and pharmacokinetic properties with enhanced activity against development of HCV resistance, improved oral bioavailability, greater efficacy, 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.

RNA-dependent RNA polymerase (RdRp) is one of the best studied targets for the development of novel HCV therapeutic agents. The NS5B polymerase is a target for inhibitors in early human clinical trials (Sommadossi, J., WO 01/90121 A2, US 2004/0006002 A1). These enzymes have been extensively characterized at the biochemical and structural level, with screening assays for identifying selective 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 therapies since HCV does not replicate in the laboratory and there are difficulties in developing cell-based assays and preclinical animal systems.

Inhibition of viral replication by nucleosides has been extensively studied (De Clercq, E. (2001) J. Clin. Virol. 22:73-89) including nucleosides that inhibit RdRp. Generally, the antiviral activity of these nucleosides are attributed to the conversion of the nucleosides to their nucleoside triphosphates (NTPs) which act as inhibitors of DNA and RNA polymerases or as chain terminators following incorporation into the lengthening viral DNA or RNA strand. However, many NTPs lack adequate specificity for viral polymerases compared to host polymerases and, as a result, cause substantial toxicity. This has led to efforts to modify the core structures of nucleosides to achieve higher selectivity but many of the structural modifications have simultaneously compromised NTP production in the cells (Yamanaka, Antimicrob. Agents Chemother. 1999: 190-193).

The poor conversion of the nucleoside to NTP can often be attributed to the inability of nucleoside kinases to convert the nucleoside to the nucleoside 5′-monophosphate (NMP). NMP prodrugs have been used to bypass poor nucleoside kinase activity (Schultz, Bioorg. Med. Chem. 2003, 11, 885). Among these prodrugs, NMP phosphoramidates have been reported to increase intracellular concentrations of NTP compared to the nucleoside alone (McGuigan, J. Med. Chem. 1993, 36, 1048-1052). However, these NMP prodrugs are substrates for esterases and phosphodiesterases in the blood and other body tissues which can cleave the prodrug to a charged molelcule or to the nucleoside, respectively. The charged molecule is then impermeable to the target organ or cell and the nucleoside is poorly phosphorylated intracellularly.

The development of a highly effective, non-toxic NMP prodrug is largely an unpredictable trial and error exercise requiring the balancing of the stability of the NMP prodrug in blood with the ability of the prodrug to reach a target organ or cell, be absorbed or actively taken up by the target cell, being efficiently cleaved to the NMP intracellularly and subsequently converted to a NTP that is selective for inhibiting the viral polymerase (Perrone, J. Med. Chem. 2007, 50, 1840-49; Gardelli, J. Med. Chem. 2009, 52, 5394-5407). For the case of an orally effective RdRp inhibitor for treating HCV infection, the NMP prodrug would need to be chemically stable to the conditions of the upper intestinal tract, be efficiently absorbed from the intestinal tract, survive the many esterases of the intestinal cells and blood, be efficiently extracted by the hepatocytes, and be cleaved to the NMP and subsequently converted to a NTP in hepatocytes that is specific for inhibiting the HCV NS5B polymerase. Notably, the anti-HCV activity of phosphate prodrugs can markedly depend upon the chirality of the phosphorous in the prodrug (Gardelli, J. Med. Chem. 2009, 52, 5394-5407; Meppen, Abstracts of Papers, 236th ACS National Meeting, Philadelphia, Pa., United States, Aug. 17-21, 2008 (2008), MEDI-404.).

Babu, Y. S., WO2008/089105 and WO2008/141079, discloses ribosides of pyrrolo[1,2-f][1,2,4]triazine nucleobases with antiviral, anti-HCV, and anti-RdRp activity.

Butler, et al., WO2009132135, disclose 1′ substituted ribosides and prodrugs comprising pyrrolo[1,2-f][1,2,4]triazine nucleobases which have anti-HCV and anti-RdRp activity but does not disclose species of the 3′-O-acylated derivatives of those ribosides or the expected properties of such derivatives. Cho, et al., U.S. 61/353,351, discloses 3′-O-acylated 1′ substituted ribosides phosphate prodrugs comprising pyrrolo[1,2-f][1,2,4]triazine nucleobases that have anti-HCV activity that are efficiently delivered to the liver after oral administration. The efficient delivery of the prodrugs to the liver is dependent on the chirality of the phosphorous prodrug.

In view of the importance of anti-HCV therapeutics that are NMP prodrugs with chiral phosphorous atoms such as those described by Cho, et al., Gardelli, et al., Perrone et al., and Meppen, et al., new efficient methods of producing chiral phosphates of these prodrugs are needed.

SUMMARY OF THE INVENTION

Provided are methods for preparing compounds that inhibit hepatitis C virus. The compounds are prodrugs of nucleoside monophosphates that, when administered to animals, are intracellularly converted to nucleoside triphosphates. The chirality of the phosphorous atom determines the efficiency of the conversion to the nucleoside triphosphate in the animal. The method disclosed, provides a convergent synthesis of these single diastereomeric prodrugs which is an improvement over the previously disclosed chromatographic methods of separating a single diastereomer from a mixture of diastereomers.

In one embodiment, provided is a method for preparing a compound of Formula Ia or Ib:

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or a pharmaceutically acceptable salt or acid thereof;

wherein:

each R¹, R², R⁷, R²², R²³or R²⁴is independently H, OR¹¹, NR¹¹R¹², C(O)NR¹¹R¹², —OC(O)NR¹¹R¹², C(O)OR¹¹, OC(O)OR¹¹, S(O)_nR^a, S(O)₂NR¹¹R¹², N₃, CN, halogen, (C₁-C₈)alkyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl or aryl(C₁-C₈)alkyl;

or any two R¹, R², R⁷, R²², R²³or R²⁴on adjacent carbon atoms when taken together are —O(CO)O— or —O(CR¹¹R¹²)O— or when taken together with the ring carbon atoms to which they are attached form a double bond;

each Base is independently a naturally occurring or modified purine or pyrimidine base linked to the furanose ring through a carbon or nitrogen atom;

each n is independently 0, 1, or 2;

each R^a, R⁴or R⁶is independently (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl;

each R^cor R^dis independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl provided that R^cand R^dare not the same;

each R⁵is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl;

each R¹¹or R¹²is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_n(C₁-C₈)alkyl or R¹¹and R¹²taken 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(O)_n— or —NR^a—; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^c, R^d, R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷, R¹¹or R¹²is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, NO₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, C(O)R^a, OC(O)R^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a;

said method comprising:

(a) providing a compound of Formula II

and

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(b) treating the compound of Formula II with a compound of Formula IIIa and a base

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thereby forming a compound of Formula Ia or

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thereby forming a compound of Formula Ib;

wherein:

each Ar is a (C₆-C₂₀) aryl or heteroaryl wherein said (C₆-C₂₀) aryl or heteroaryl is substituted with one or more halogen, NO₂, or (C₁-C₈)haloalkyl and optionally substituted with one or more CN, N₃, N(R^a)₂, C(O)N(R^a)₂, OC(O)N(R^a)₂, C(O)OR^a, OC(O)OR^a, C(O)R^a, OC(O)R^a, S(O)_nR^a, S(O)₂N(R^a)₂, OR^aor R^awith the proviso that Ar is different from R⁴. In another aspect, Base is not uracil. In another aspect, Base is not cytosine.

In another aspect, the invention also provides novel intermediates disclosed herein which are useful for preparing Formula Ia or Formula Ib.

In other aspects, methods for the synthesis, analysis, separation, isolation, purification, and characterization of the novel intermediates 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 limit the invention to those embodiments. On the contrary, the invention is intended to cover all alternatives, modifications, and equivalents, which may be included within the scope of the present invention.

Typically, the method of for preparing a compound of Formula Ia from Formula II and Formula IIIa or Formula Ib from Formula II and Formula IIIb is performed in a suitable solvent. The suitable solvent is preferably an anhydrous, non-acid, non-hydroxylic solvent. Non-limiting examples of suitable solvents are ethers, for example, diethyl ether, diisopropyl ether, di t-butyl ether, tetrahydrofuran, dioxane and various glyme solvents; dimethylformamide or dimethylacetamide. A preferred solvent is tetrahydrofuran. The concentration of Formula II in the solvent is typically about 0.01 to about 1 mole per liter of solvent. The method is performed at a temperature of about 0° C. to about 80° C., more preferably about 20° C. to about 60° C.

The solution of Formula II is typically treated with a hindered base or a non-nucleophilic base. Typical, but non-limiting, examples of hindered bases are t-butyllithium, sec-isobutyllithium, lithium or sodium diisopropylamide and t-butylmagnesium halides. A preferred hindered base is t-butylmagnesium chloride. Typical, but non-limiting, examples of non-nucleophic bases are sodium hydride, potassium hydride, lithium hydride and calcium hydride. The hindered bases or non-nucleophic bases may be used as solutions in or as undiluted bases. Preferably, the bases are used as solutions in anhydrous, non-hydroxylic solvents wherein the concentration of the base in the solvent is about 0.5 to about 3 moles per liter. The molar ratio of base to the compound of Formula II is about 1:1 to about 3:1, preferably about 1.1:1 to about 1.5:1. The solution of the compound of Formula II is typically treated with the base for about 5 minutes to about two hours, preferably less than 30 minutes.

The mixture of the solution of the compound of Formula II and the base is treated with a compound of Formula IIIa or Formula IIIb for about 30 minutes to about 24 hours, preferably about one to about four hours. The molar ratio of the compound Formula II to the compound of Formula IIIa or Formula IIIb is typically about 1:1 to about 1:4. Preferably, the molar ratio is about 1:1.1 to about 1:2.

In another embodiment of the method for preparing a compound of Formula Ia or Ib or a pharmaceutically salt or ester thereof, Formula Ia is Formula IVa, Formula Ib is Formula IVb and Formula II is Formula V:

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In one embodiment of the method for preparing a compound of Formula IVa or IVb from a compound of Formula V, R¹is H, halogen, optionally substituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R¹is methyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkenyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is F. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OR¹¹. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, R⁵is H. In another aspect of this embodiment, one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R²³is H. In another aspect of this embodiment, R²²is OR¹¹. In another aspect of this embodiment, R²²is OH. In another aspect of this embodiment, R²⁴is N₃. In another aspect of this embodiment, R²⁴is H. In another aspect of this embodiment, Base is selected from the group consisting of:

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wherein:

each X¹is independently N or CR¹⁰;

each X²is independently NR¹¹, O, or S(O)_n;

each R⁸is independently halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NNHR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₄-C₈)carbocyclylalkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_n(C₁-C₈)alkyl, aryl(C₁-C₈)alkyl, OR¹¹or SR¹¹;

each n is independently 0, 1, or 2;

each R⁹or R¹⁰is independently H, halogen, NR¹¹R¹², N(R¹¹)OR¹¹, NR¹¹NR¹¹R¹², N₃, NO, NO₂, CHO, CN, —CH(═NR¹¹), —CH═NHNR¹¹, —CH═N(OR¹¹), —CH(OR¹¹)₂, —C(═O)NR¹¹R¹², —C(═S)NR¹¹R¹², —C(═O)OR¹¹, R¹¹, OR¹¹or SR¹¹;

each R¹¹or R¹²is independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl, heteroaryl, —C(═O)(C₁-C₈)alkyl, —S(O)_nC₁-C₈)alkyl or R¹¹and R¹²taken 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(O)_n— or —NR^a—; and

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^c, R^d, R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹or R¹²is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, NO₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, C(O)R^a, OC(O)R^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a. In another aspect, Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, Base is selected from the group consisting of:

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In another aspect of this embodiment, Base is selected from the group consisting of

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In another aspect of this embodiment, Base is selected from the group consisting of

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In another embodiment of the method for preparing a compound of Formula IVa or IVb from a compound of Formula V, R¹is H, halogen, optionally substituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionally substituted (C₂-C₈)alkynyl; R²is OR¹¹or halogen; R²²is OR¹¹and each R⁵, R²³and R²⁴is H. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R¹is methyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkenyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is F. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment, R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Base is selected from the group consisting of:

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wherein:

each X¹is independently N or CR¹⁰;

each X²is independently NR¹¹, O, or S(O)_n;

each n is independently 0, 1, or 2;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^c, R^d, R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹or R¹²is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, NO₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, C(O)R^a, OC(O)R^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a. In another aspect, Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, Base is selected from the group consisting of:

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In another aspect of this embodiment, Base is selected from the group consisting of

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In another aspect of this embodiment, Base is selected from the group consisting of

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In another embodiment of the method for preparing a compound of Formula IVa or IVb from a compound of Formula V, R¹is H or CH₃; R²is OR¹¹or halogen; R⁶is optionally substituted (C₁-C₈)alkyl; one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl; R²²is OR¹¹, and each R⁵, R²³and R²⁴is H. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is CH₃. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment, R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is CH₃. In another aspect of this embodiment, R⁷is ethynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, R⁴is optionally substituted napthyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Base is selected from the group consisting of:

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wherein:

each X¹is independently N or CR¹⁰;

each X²is independently NR¹¹, O, or S(O)_n;

each n is independently 0, 1, or 2;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^c, R^d, R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹or R¹²is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, NO₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, C(O)R^a, OC(O)R^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a. In another aspect, Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, Base is selected from the group consisting of:

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In another aspect of this embodiment, Base is selected from the group consisting of

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In another aspect of this embodiment, Base is selected from the group consisting of

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wherein:

each X¹is independently N or CR¹⁰;

each X²is independently NR¹¹, O, or S(O)_n;

each n is independently 0, 1, or 2;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^c, R^d, R¹, R², R²², R²³, R²⁴, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹or R¹²is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, NO₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, C(O)R^a, OC(O)R^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a. In another aspect Base is not uracil. In another aspect, the Base is not cytosine.

In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is CH₃. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment, R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is CH₃. In another aspect of this embodiment, R⁷is ethynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, R⁴is optionally substituted napthyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Base is

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In another aspect of this embodiment, Base is

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In another embodiment of the method for preparing a compound of Formula Ia or Ib or a pharmaceutically acceptable salt or ester thereof, Formula Ia is Formula VIa, Formula Ib is Formula VIb and Formula II is Formula VII:

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wherein:

each R¹is independently H, halogen, optionally substituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionally substituted (C₂-C₈)alkynyl;

each R²is independently halogen or OR¹¹;

each R⁵is H;

each R²²is OR¹¹and

the remaining variables are defined as for Formulas Ia or Ib or II or IIIa or IIIb.

In one embodiment of the method for preparing a compound of Formula VIa or Formula VIb from a compound of Formula VII, X¹is CR¹⁰. In another aspect of this embodiment, R¹⁰is H. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is F. In another aspect of this embodiment, R¹is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R¹is methyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkenyl. In another aspect of this embodiment, R¹is optionally substituted ethenyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is optionally substituted ethynyl. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl.

In another embodiment of the method for preparing a compound of Formula VIa or Formula VIb from a compound of Formula VII, X¹is CH, R¹is H or CH₃and one of R^cor R^dis H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is CH₃. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is ethynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁹is OR¹¹. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is H. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is NR¹¹R¹².

In another embodiment of the method for preparing a compound of Formula VIa or Formula VIb from a compound of Formula VII, X¹is CH, R¹is H or CH₃, one of R^cor R^dis H and R⁷is CN. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)allyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally is NR¹¹R¹². In substituted nitrophenyl. In another aspect of this embodiment, R⁸another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁹is OR¹¹. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is H. In another aspect of this embodiment, R⁸is NH₂and R⁹is H. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁸is NH₂and R⁹is NH₂. In another aspect of this embodiment, R⁸is OH and R⁹is NH₂.

In another embodiment, provided is a method of preparing a compound of Formula IIIa or Formula IIIb

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wherein:

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^c, R^d, R⁴, R⁵or R⁶is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a; and

said method comprising:

(d) providing a diastereomeric compound of Formula VIII

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and

(e) crystallizing the compound of Formula VIII from a suitable solvent;

thereby forming a pure diasteromer of Formula IIIa or Formula IIIb.

In one embodiment of the method of preparing a compound of Formula IIIa or Formula IIIb, R⁵is H and one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl.

In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R.

In another embodiment of the method of preparing a compound of Formula Ina or Formula IIIb, R⁵is H, one of R^cor R^dis H, R⁶is optionally substituted (C₁-C₈)alkyl, and R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R.

In another embodiment of the method of preparing a compound of Formula IIIa or Formula IIIb, R⁵is H, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl, R⁶is optionally substituted (C₁-C₈)alkyl, and R⁴is optionally substituted phenyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁴is phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R.

In another embodiment of the method of preparing a compound of Formula IIIa or Formula IIIb, R⁵is H, one of R^cor R^dis H and the other of R^cor R^dis CH₃, R⁶is optionally substituted (C₁-C₈)alkyl, and R⁴is optionally substituted phenyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁶is 2-propyl. In another aspect of this embodiment, R⁴is phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R.

The diastereomeric mixture of the compound of Formula VIII is resolved by crystallization of the compound of Formula VIII from a suitable solvent. Non-limiting examples of suitable solvents are diethyl ether, dipropyl ether, di t-butyl ether, methyl t-butyl ether, C₁-C₆halogenated alkanes, C₅-C₈hydrocarbon, tetrahydrofuran, toluene, xylene, dioxane and the like. In another embodiment, the compound of Formula IV is dissolved in a suitable solvent and crystallization is induced by addition of a C₅-C₈hydrocarbon or C₅-C₈cyclic hydrocarbon. In a preferred embodiment, the compound of Formula VIII is dissolved in an ether solvent and crystallization is induced by addition of a C₅-C₈hydrocarbon. In a particularly preferred embodiment, the compound of Formula VIII is dissolved in diethyl ether and crystallization is induced by the addition of hexane.

The diastereomeric mixture of the compound of Formula VIII is resolved by crystallization of the compound of Formula VIII from a suitable solvent at a temperature of about 80° C. to about −20° C. Preferrably, the temperature is about 30° C. to about −20° C., more preferably about ambient to −10° C.

The diastereomeric mixture of the compound of Formula VIII is resolved by crystallization of the compound of Formula VIII from a suitable solvent wherein the concentration of the compound of Formula VIII in solution is about 25 g to about 1000 g per liter of solvent. More typically, the concentration of the compound of Formula VIII is about 50 to 500 g per liter of solvent.

The resolution of the diastereomeric mixture of the compound of Formula VIII by crystallization may be promoted by the addition of seed crystals of the pure diastereomer. Seed crystals of pure diastereomers may be obtained through purification of the diastereomeric mixture of the compound of Formula VIII by liquid chromatography, chiral liquid chromatography, high pressure liquid chromatography, or chiral high pressure liquid chromatography such as by the non-limiting methods described herein.

Typically, the crystallization of the diastereomeric mixture of the compound of Formula VIII produces a mixture of diastereomers containing at least 60% of a single diastereomer. More typically, the mixture produced contains at least 70% of a single diastereomer, most typically, at least 80% of a single diastereomer, preferably at least 90% of a single diastereomer, and more preferably at least 95% of a single diastereomer. Higher diastereomeric purity, for example at least 99% diastereomeric purity, may be obtained by one or more subsequent crystallizations. The yield of crystalline material from a single crystallization is typically about 10 to 45%, more typically about 20-35%.

In another embodiment, provided is a compound of Formula IIIa or Formula IIIb

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or a salt or ester thereof;

wherein:

each R^cor R^dis independently H, (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₃)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl provided that R^cand R^dare not the same;

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl or heteroaryl of each R^c, R^d, R⁴, R⁵or R⁶is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a; and

In another embodiment of the compound of Formula IIIa or Formula IIIb, R⁵is H and one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the moiety

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of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of a naturally occurring α-amino acid.

In another embodiment of the compound of Formula IIIa or Formula IIIb, R⁵is H, one of R^cor R^dis H, R⁶is optionally substituted (C₁-C₈)alkyl and R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the moiety

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of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of a naturally occurring α-amino acid.

In another embodiment of the compound of Formula IIIa or Formula IIIb, R⁵is H, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl, R⁶is optionally substituted (C₁-C₈)alkyl and R⁴is optionally substituted phenyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁴is phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the moiety

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of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of a naturally occurring α-amino acid.

In another embodiment of the compound of Formula IIIa or Formula IIIb, R⁵is H, one of R^cor R^dis H and the other of R^cor R^dis CH₃, R⁶is optionally substituted (C₁-C₈)alkyl, and R⁴is optionally substituted phenyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁶is 2-propyl. In another aspect of this embodiment, R⁴is phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the moiety

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of Formula IIIa or Formula IIIb comprises a nitrogen-linked ester of a naturally occurring α-amino acid.

In another embodiment, provided are compounds of Formula IIIa or Formula IIIb selected from the group consisting of:

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or salts or esters thereof.

In another embodiment, provided is a method of preparing a compound of Formula VIII

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wherein

wherein each (C₁-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)carbocyclyl, (C₄-C₈)carbocyclylalkyl, aryl(C₁-C₈)alkyl, heterocyclyl(C₁-C₈)alkyl, (C₆-C₂₀)aryl, (C₂-C₂₀)heterocyclyl, heteroaryl of each R^c, R^d, R⁴, R⁵or R⁶is, independently, optionally substituted with one or more halo, hydroxy, CN, N₃, N(R^a)₂, NH(R^a), NH₂, C(O)N(R^a)₂, C(O)NH(R^a), C(O)NH₂, OC(O)N(R^a)₂, OC(O)NH(R^a), OC(O)NH₂, C(O)OR^a, OC(O)OR^a, S(O)_nR^a, S(O)₂N(R^a)₂, S(O)₂NH(R^a), S(O)₂NH₂, OR^aor R^a; and

said method comprising:

(f) providing a chirally pure amino acid ester of Formula IX or a salt thereof

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(g) treating the compound of Formula IX with a compound of Formula X in the presence of a base

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wherein each X³is halogen; and

(h) treating the resulting mixture with ArOH;

thereby forming a compound of Formula VIII.

Typically, the chirally pure amino acid of Formula IX or a salt thereof is dissolved or suspended in a suitable non-nucleophilic solvent. Non-limiting non-nucleophilic solvents include haloalkanes, e.g., methylene chloride, dichloroethane and ethers, e.g. dioxane, tetrahydrofuran and glymes. Typically, the suspension or solution contains about 0.1 to about 5 moles of the compound of Formula IX per liter of solvent.

The suspension or solution of the chirally pure amino acid of Formula IX is treated with a compound of Formula X. Typically, the reaction is conducted at about −20 to about 60° C. The mole ratio of the compound of Formula IX to the compound of Formula X is about 1:2 to about 2:1, preferably about 1:1. The reaction is conducted in the presence of a non-nucleophilic base. Non-limiting examples of non-nucleophilic bases are tertiary amines, e.g. triethylamine, diisopropylethylamine and triethylamine; metal hydrides, e.g. LiH, NaH and CaH₂; and nitrogen containing heterocycles, e.g. pyridine and dimethylaminopyridine. In a preferred embodiment, the base is a tertiary amine such as triethylamine. When the compound of Formula IX is a salt of a mono-protic acid, the mole ratio of base to the compound of Formula IX is typically about 2:1. If the compound of Formula IX is a free base, the mole ratio of base to the compound of Formula IX is about 1:1.

The reaction of the compound of Formula IX with the compound of Formula X may be followed by many conventional means known to those skilled in the art. Such means include thin-layer chromatography and hplc. When the reaction between the compound Formula IX and the compound of Formula X is complete, the reaction is treated with a phenolic compound ArOH where Ar is defined as herein. The mole ratio of the compound of Formula X to ArOH is about 1.1:1 to about 1:1.1, preferably about 1:1. After the addition of ArOH, additional base is required, typically enough base to neutralize the acid generated in the reaction. Typically, the additional base is a non-nucleophilic base such as described above.

The compound of Formula VIII is isolated by conventional means known to those skilled in the art. For example, the salt formed in the reaction may be precipitated from the reaction mixture and the compound of Formula VIII isolated by evaporation of the solvent followed by crystallization or chromatography.

In one embodiment of the method of preparing a compound of Formula VIII, R⁵is H and one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring α-amino acid.

In another embodiment of the method of preparing a compound of Formula VIII, R⁵is H, one of R^cor R^dis H, R⁶is optionally substituted (C₁-C₈)alkyl, and R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring α-amino acid.

In another embodiment of the method of preparing a compound of Formula VIII, R⁵is H, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl, R⁶is optionally substituted (C₁-C₈)alkyl, and R⁴is optionally substituted phenyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁴is phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring α-amino acid.

In another embodiment of the method of preparing a compound of Formula VIII, R⁵is H, one of R^cor R^dis H and the other of R^cor R^dis CH₃, R⁶is optionally substituted (C₁-C₈)alkyl, and R⁴is optionally substituted phenyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈) secondary or tertiary alkyl. In another aspect of this embodiment, R⁶is optionally substituted 2-propyl. In another aspect of this embodiment, R⁶is 2-propyl. In another aspect of this embodiment, R⁴is phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, Ar is optionally substituted para-nitrophenyl. In another aspect of this embodiment, Ar is para-nitrophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis S. In another aspect of this embodiment, the chirality at the carbon directly attached to R^cand R^dis R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring α-amino acid.

In another embodiment of the method for preparing a compound of Formula Ia or Ib or a pharmaceutically acceptable salt or ester thereof, Formula Ia is Formula XIa, Formula Ib is Formula XIb and Formula II is Formula XII:

embedded image

wherein:

each R¹is independently H, halogen, optionally substituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionally substituted (C₂-C₈)alkynyl;

each R²is independently halogen or OR¹¹;

each R⁵is H;

each R²²is OR¹¹and the remaining variables are defined as for Formulas Ia or Ib or II or IIIa or IIIb.

In one embodiment of the method for preparing a compound of Formula XIa or Formula XIb from a compound of Formula XII, X¹is CR¹⁰. In another aspect of this embodiment, R¹⁰is H. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is F. In another aspect of this embodiment, R¹is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R¹is methyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkenyl. In another aspect of this embodiment, R¹is optionally substituted ethenyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is optionally substituted ethynyl. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl.

In another embodiment of the method for preparing a compound of Formula XIa or Formula XIb from a compound of Formula XII, X¹is CH, R¹is H or CH₃and one of R^cor R^dis H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is CH₃. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is ethynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁹is OR¹¹. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is H. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is NR¹¹R¹².

In another embodiment of the method for preparing a compound of Formula XIa or Formula XIb from a compound of Formula XII, X¹is CH, R¹is H or CH₃, one of R^cor R^dis H and R⁷is H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁹is OR¹¹. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is H. In another aspect of this embodiment, R⁸is NH₂and R⁹is H. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁸is NH₂and R⁹is NH₂. In another aspect of this embodiment, R⁸is OR¹¹and R⁹is NH₂. In another aspect of this embodiment, R⁸is OH and R⁹is NH₂.

In one embodiment of the method for preparing a compound of Formula XIa or Formula XIb from a compound of Formula XII, X¹is N. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is F. In another aspect of this embodiment, R¹is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R¹is methyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkenyl. In another aspect of this embodiment, R¹is optionally substituted ethenyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is optionally substituted ethynyl. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl.

In another embodiment of the method for preparing a compound of Formula XIa or Formula XIb from a compound of Formula XII, X¹is N, R¹is H or CH₃and one of R^cor R^dis H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is CH₃. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is ethynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹is NR¹¹R¹².

In another aspect of this embodiment, R⁹is OR¹¹. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is H. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is NR¹¹R¹².

In another embodiment of the method for preparing a compound of Formula XIa or Formula XIb from a compound of Formula XII, X¹is N, R¹is H or CH₃, one of R^cor R^dis H and R⁷is H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH. In another aspect of this embodiment, R⁹is H. In another aspect of this embodiment, R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁹is OR¹¹. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is H. In another aspect of this embodiment, R⁸is NH₂and R⁹is H. In another aspect of this embodiment, R⁸is NR¹¹R¹²and R⁹is NR¹¹R¹². In another aspect of this embodiment, R⁸is NH₂and R⁹is NH₂. In another aspect of this embodiment, R⁸is OR¹¹and R⁹is NH₂. In another aspect of this embodiment, R⁸is OH and R⁹is NH₂.

In another embodiment of the method for preparing a compound of Formula Ia or Ib or a pharmaceutically acceptable salt or ester thereof, Formula Ia is Formula XIIIa, Formula Ib is Formula XIIIb and Formula II is Formula XIV:

embedded image

wherein:

each R¹is independently H, halogen, optionally substituted (C₁-C₈)alkyl, optionally substituted (C₂-C₈)alkenyl or optionally substituted (C₂-C₈)alkynyl;

each R²is independently halogen or OR¹¹;

each R⁵is H;

each R²²is OR¹¹and

the remaining variables are defined as for Formulas Ia or Ib or II or IIIa or IIIb.

In one embodiment of the method for preparing a compound of Formula XIIIa or Formula XIIIb from a compound of Formula XIV, X¹is CR¹⁰. In another aspect of this embodiment, R¹⁰is H. In another aspect of this embodiment, R¹⁰is CH₃. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is F. In another aspect of this embodiment, R¹is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R¹is methyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkenyl. In another aspect of this embodiment, R¹is optionally substituted ethenyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is optionally substituted ethynyl. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl.

In another embodiment of the method for preparing a compound of Formula XIIIa or Formula XIIIb from a compound of Formula XIV, X¹is CH, R¹is H or CH₃and one of R^cor R^dis H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is CH₃. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is ethynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH.

In another embodiment of the method for preparing a compound of Formula XIIIa or Formula XIIIb from a compound of Formula XIV, X¹is CH, R¹is H or CH₃, one of R^cor R^dis H and R⁷is H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH.

In one embodiment of the method for preparing a compound of Formula XIIIa or Formula XIIIb from a compound of Formula XIV, X¹is CF. In another aspect of this embodiment, R¹is H. In another aspect of this embodiment, R¹is F. In another aspect of this embodiment, R¹is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R¹is methyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkenyl. In another aspect of this embodiment, R¹is optionally substituted ethenyl. In another aspect of this embodiment, R¹is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R¹is optionally substituted ethynyl. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl.

In another embodiment of the method for preparing a compound of Formula XIa or Formula XIb from a compound of Formula XII, X¹is CF, R¹is H or CH₃and one of R^cor R^dis H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, R⁷is H. In another aspect of this embodiment, R⁷is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁷is CH₃. In another aspect of this embodiment, R⁷is optionally substituted (C₂-C₈)alkynyl. In another aspect of this embodiment, R⁷is ethynyl. In another aspect of this embodiment, R⁷is CN. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH.

In another embodiment of the method for preparing a compound of Formula XIIIa or Formula XIIIb from a compound of Formula XIV, X¹is CF, R¹is H or CH₃, one of R^cor R^dis H and R⁷is H. In another aspect of this embodiment, R²is F. In another aspect of this embodiment, R²is OH. In another aspect of this embodiment R²²is OH. In another aspect of this embodiment, each R²and R²²is OH. In another aspect of this embodiment, each R²is F and R²²is OH. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, one of R^cor R^dis H and the other of R^cor R^dis CH₃. In another aspect of this embodiment, R⁶is optionally substituted (C₁-C₈)alkyl. In another aspect of this embodiment, R⁴is optionally substituted (C₆-C₂₀)aryl. In another aspect of this embodiment, R⁴is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted nitrophenyl. In another aspect of this embodiment, R⁸is NR¹¹R¹². In another aspect of this embodiment, R⁸is OR¹¹. In another aspect of this embodiment, R⁸is NH₂. In another aspect of this embodiment, R⁸is OH.

Definitions

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

When trade names are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename 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 salt, 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 have 1 to 20 carbon atoms (i.e, C₁-C₂₀alkyl), 1 to 8 carbon atoms (i.e., C₁-C₈alkyl), or 1 to 6 carbon atoms (i.e., C₁-C₆alkyl). Examples of suitable 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, i-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), 2-pentyl (—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-1-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-2-pentyl (—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-2-butyl (—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 molecule via an oxygen atom. The alkyl portion of an alkoxy group can have 1 to 20 carbon atoms (i.e., C₁-C₂₀alkoxy), 1 to 12 carbon atoms (i.e., C₁-C₁₂alkoxy), or 1 to 6 carbon atoms (i.e., C₁-C₆alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (—O—CH₃or —OMe), ethoxy (—OCH₂CH₃or —OEt), t-butoxy (—O—C(CH₃)₃or —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 have 1 to 20 carbon atoms (i.e., C₁-C₂₀haloalkyl), 1 to 12 carbon atoms (i.e., C₁-C₁₂haloalkyl), or 1 to 6 carbon atoms (i.e., C₁-C₆alkyl). Examples of suitable haloalkyl groups include, but are not limited to, —CF₃, —CHF₂, —CFH₂, —CH₂CF₃, and the like.

“Alkenyl” is a hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp²double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e., C₂-C₂₀alkenyl), 2 to 8 carbon atoms (i.e., C₂-C₈alkenyl), or 2 to 6 carbon atoms (i.e., C₂-C₆alkenyl). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), cyclopentenyl (—C₅H₇), 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 have 2 to 20 carbon atoms (i.e., C₂-C₂₀alkynyl), 2 to 8 carbon atoms (i.e., C₂-C₈alkyne,), 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 (—CH₂C≡CH), 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 atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 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 have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkenylene radicals include, but are not limited to, 1,2-ethylene (—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 have 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 derivative of ammonia, having the formula —N(X)₂, where each “X” is independently H, substituted or unsubstituted alkyl, substituted or unsubstituted carbocyclyl, substituted or unsubstituted heterocyclyl, etc. The hybridization of the nitrogen is approximately sp^a. 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, is 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 sp³carbon atom, is replaced with an aryl radical. Typical arylalkyl groups include, but are not limited to, benzyl, 2-phenylethan-1-yl, naphthylmethyl, 2-naphthylethan-1-yl, naphthobenzyl, 2-naphthophenylethan-1-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 sp³carbon atom, but also an sp²carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any of the 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 is 6 to 14 carbon atoms.

“Arylalkynyl” refers to an acyclic alkynyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon 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” means, unless otherwise stated, 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⁻, ═O, —OR^b, —SR^b, —S⁻, —NR^b₂, N⁺R^b₃, 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(═O)₂OR^b, —S(═O)₂NR^b₂, —S(═O)R^b, —OP(═O)(OR^b)₂, —P(═O)(OR^b)₂, —P(═O)(O⁻)₂, —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^b₂, where each X is independently a halogen: F, Cl, Br, or I; and each R^bis 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 indicated, when the term “substituted” is used in conjunction with groups such as arylalkyl, which have 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 ingredient, as a result of spontaneous chemical reaction(s), enzyme catalyzed chemical reaction(s), photolysis, and/or metabolic chemical reaction(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-XIV should be selected in order to provide a compound which is sufficiently stable to provide a pharmaceutically useful compound which can be formulated into an acceptably stable pharmaceutical composition. Compounds of Formula I-XIV which have such stability are contemplated as falling within the scope of the present invention.

“Heteroalkyl” refers to an alkyl group where one or more carbon atoms have 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 molecule is 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 molecule 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)₂, etc.), or a thioalkyl ether (e.g., —CH₂—S—CH₃). If a terminal carbon atom of the 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 have, for example, 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. A C₁-C₆heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms.

“Heterocycle” or “heterocyclyl” as used herein includes by way of example and not limitation those heterocycles described in Paquette, Leo A.; Principles of Modern Heterocyclic Chemistry (W.A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; The Chemistry of Heterocyclic Compounds, A Series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566. In one specific embodiment of the invention “heterocycle” includes a “carbocycle” as defined herein, wherein one or more (e.g. 1, 2, 3, or 4) carbon atoms have 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 is:

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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, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazoly, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, β-carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl, isatinoyl, and bis-tetrahydrofuranyl:

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By 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 pyridazine, 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 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl, 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, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline. Still more typically, nitrogen bonded heterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl, and 1-piperidinyl.

“Heterocyclylalkyl” refers to an acyclic alkyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkylene-moiety). Typical heterocyclyl alkyl groups include, but are not limited to heterocyclyl-CH₂—, 2-(heterocyclyl)ethan-1-yl, and the like, wherein the “heterocyclyl” portion includes any of the heterocyclyl groups described above, including those described in Principles of Modern 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 1 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 containing heterocycles such as thiazolylmethyl, 2-thiazolylethan-1-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylmethyl, piperazinylmethyl, 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 sp³carbon atom, but also a sp²carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkenylene-moiety). The heterocyclyl portion of the heterocyclyl alkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern 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 of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp³carbon atom, but also an sp carbon atom, is replaced with a heterocyclyl radical (i.e., a heterocyclyl-alkynylene-moiety). The heterocyclyl portion of the heterocyclyl alkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern 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-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkynyl group comprises 4 to 20 carbon atoms, e.g., the alkynyl portion of the heterocyclyl alkynyl group is 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 in the aromatic ring include oxygen, sulfur, and nitrogen. Non-limiting examples of heteroaryl rings include all of those aromatic rings listed in the definition of “heterocyclyl”, including pyridinyl, pyrrolyl, oxazolyl, indolyl, isoindolyl, purinyl, furanyl, thienyl, benzofuranyl, benzothiophenyl, carbazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, quinolyl, isoquinolyl, pyridazyl, pyrimidyl, pyrazyl, etc.

The term “purine” or “pyrimidine” base comprises, but is not limited to, adenine, N⁶-alkylpurines, N⁶-acylpurines (wherein acyl is C(O)(alkyl, aryl, alkylaryl, or arylalkyl), N⁶-benzylpurine, N⁶-halopurine, N⁶-vinylpurine, N⁶-acetylenic purine, N⁶-acyl purine, N⁶-hydroxyalkyl purine, N⁶-allylaminopurine, N⁶-thioallyl purine, N²-alkylpurines, N²-alkyl-6-thiopurines, thymine, cytosine, 5-fluorocytosine, 5-methylcytosine, 6-azapyrimidine, including 6-azacytosine, 2- and/or 4-mercaptopyrmidine, uracil, 5-halouracil, including 5-fluorouracil, C⁵-alkylpyrimidines, C⁵-benzylpyrimidines, C⁵-halopyrimidines, C⁵-vinylpyrimidine, C⁵-acetylenic pyrimidine, C⁵-acyl pyrimidine, C⁵-hydroxyalkyl purine, C⁵-amidopyrimidine, C⁵-cyanopyrimidine, C⁵-5-iodopyrimidine, C⁶-iodo-pyrimidine, C⁵—Br-vinyl pyrimidine, C⁶—Br-vinyl pyrimidine, C⁵-nitropyrimidine, C⁵-amino-pyrimidine, N²-alkylpurines, N²-alkyl-6-thiopurines, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, and pyrazolopyrimidinyl. Purine bases include, but are not limited to, guanine, adenine, hypoxanthine, 2,6-diaminopurine, and 6-chloropurine. Additional non-classical purine bases include pyrrolo[1,2-f][1,2,4]triazines, imidazo[1,5-f][1,2,4]triazines, imidazo[1,2-f][1,2,4]triazines, and [1,2,4]triazolo[4,3-f][1,2,4]triazines, all of which are optionally substituted. The purine and pyrimidine bases of Formula II are linked to the ribose sugar, or analog thereof, through a nitrogen atom or carbon atom of the base. Functional oxygen and nitrogen groups on the base can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art, and include, but are not limited to, trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, and t-butyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

“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 have 3 to 7 ring atoms, still more typically 5 or 6 ring atoms. Bicyclic carbocycles have 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-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-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 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 have the general formulae -alkylene-O-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylene-aryl, -alkylene-S-aryl, -alkylene-S-alkylene-aryl, etc. In addition, any of the alkylene 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. Non-limiting examples of heteroaryl alkyl include —CH₂-pyridinyl, —CH₂-pyrrolyl, —CH₂-oxazolyl, —CH₂-indolyl, —CH₂-isoindolyl, —CH₂-purinyl, —CH₂-furanyl, —CH₂-thienyl, —CH₂-benzofuranyl, —CH₂-benzothiophenyl, —CH₂-carbazolyl, —CH₂-imidazolyl, —CH₂-thiazolyl, —CH₂-isoxazolyl, —CH₂-pyrazolyl, —CH₂-isothiazolyl, —CH₂-quinolyl, —CH₂-isoquinolyl, —CH₂-pyridazyl, —CH₂-pyrimidyl, —CH₂-pyrazyl, —CH(CH₃)-pyridinyl, —CH(CH₃)-pyrrolyl, —CH(CH₃)-oxazolyl, —CH(CH₃)-indolyl, —CH(CH₃)-isoindolyl, —CH(CH₃)-purinyl, —CH(CH₃)-furanyl, —CH(CH₃)-thienyl, —CH(CH₃)-benzofuranyl, —CH(CH₃)-benzothiophenyl, —CH(CH₃)-carbazolyl, —CH(CH₃)-imidazolyl, —CH(CH₃)-thiazolyl, —CH(CH₃)-isoxazolyl, —CH(CH₃)-pyrazolyl, —CH(CH₃)-isothiazolyl, —CH(CH₃)-quinolyl, —CH(CH₃)-isoquinolyl, —CH(CH₃)-pyridazyl, —CH(CH₃)-pyrimidyl, —CH(CH₃)-pyrazyl, etc.

The term “optionally substituted” in reference to a particular moiety of the compound of Formula I-XIV (e.g., an optionally substituted aryl group) refers to a moiety wherein all substiutents are hydrogen or wherein one or more of the hydrogens of the moiety may be replaced by substituents such as those listed under the definition of “substituted”.

The term “optionally replaced” in reference to a particular moiety of the compound of Formula I-XIV (e.g., the carbon atoms of said (C₁-C₈)alkyl may be optionally replaced by —O—, —S—, or —NR^a—) means that one or more of the methylene groups of the (C₁-C₈)alkyl may be replaced by 0, 1, 2, or more of the groups specified (e.g., —O—, —S—, or —NR^a—).

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*)H₂CH₃or alkylene moiety —CH₂(C*)H₂(C*)H₂CH₂— the C* atoms would be considered to be the non-terminal carbon atoms.

“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, Jeffamine™); and diacid ester and amides including succinate, succinamide, diglycolate, malonate, and caproamide.

The terms such as “oxygen-linked”, “nitrogen-linked”, “carbon-linked”, “sulfur-linked”, or “phosphorous-linked” 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.

Some embodiments of the compounds of Formula I-XIV comprise the moiety

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which may comprise a radical of a nitrogen-linked ester of a naturally occurring α-amino acid. Examples of naturally occurring amino acids include isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine, alanine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine, glycine, proline, selenocysteine, serine, tyrosine, arginine, histidine, ornithine and taurine. The esters of these amino acids comprise any of those described for the substitutent R⁶, particularly those in which R⁶is optionally substituted (C₁-C₈)alkyl.

Unless otherwise specified, the carbon atoms of the compounds of Formula I-XIV are intended to have a valence of four. In some chemical structure representations where carbon atoms do not have a sufficient number of variables attached to produce a valence of four, the remaining carbon substitutents needed to provide a valence of four should be assumed to be hydrogen. For example,

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has the same meaning as

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“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 in the synthesis of the parental drug substance. Chemical protecting groups and strategies for protection/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 in an ordered and planned fashion. 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 resistance to enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be referred to as prodrugs. Another function of a protecting group is to convert the parental drug into a prodrug, 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 in general it is more desirable if the products are pharmacologically innocuous.

“Prodrug moiety” means a labile functional group which separates 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 Academic Publishers, pp. 113-191). 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 metabolite or drug itself

The phosphate group may be a phosphate prodrug moiety. The prodrug moiety may be sensitive to hydrolysis. Alternatively, the prodrug moiety may be sensitive to enzymatic cleavage, such as a lactate ester or a phosphonamidate-ester group.

It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula I-IV and pharmaceutically acceptable salts thereof are embraced by the present invention. All mixtures of such enantiomers and diastereomers are within the scope of the present invention.

A compound of Formula I-XIV 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 result from differences in crystal packing (packing polymorphism) or differences in packing between different conformers of the same molecule (conformational polymorphism). As used herein, crystalline pseudopolymorphism means the ability of a hydrate or solvate of a compound to exist in different crystal structures. The pseudopolymorphs of the instant invention may exist due to differences in crystal packing (packing pseudopolymorphism) or due to differences in packing between different conformers of the same molecule (conformational pseudopolymorphism). The instant invention comprises all polymorphs and pseudopolymorphs of the compounds of Formula I-IV and their pharmaceutically acceptable salts.

A compound of Formula I-XIV 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 definition 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 all amorphous forms of the compounds of Formula I-IV and their pharmaceutically acceptable salts.

Selected substituents comprising the compounds of Formula I-XIV are present to a recursive degree. In this context, “recursive substituent” means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number of compounds may be present in any given embodiment. One of ordinary skill in the art of medicinal 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. Recursive substituents are an intended aspect of the invention. One of ordinary skill in the art of medicinal chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in an embodiment of the invention, they may recite another instance of themselves, 0, 1, 2, 3, or 4 times.

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 associated with measurement of the particular quantity).

Any reference to the compounds of the invention described herein also includes a reference to a physiologically acceptable salt thereof. Examples of physiologically acceptable salts of the compounds of the invention include salts derived from an appropriate base, such as an alkali metal or an alkaline earth (for example, Na⁺, Li⁺, K⁺, Ca⁺²and Mg⁺²), ammonium and NR^a₄⁺ (wherein R^ais defined 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, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic 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, bromine, and iodine. Physiologically acceptable salts of a compound of a hydroxy group include the anion of said compound in combination with a suitable cation such as Na⁺ and NR^a₄⁺.

For therapeutic use, salts of active ingredients 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 find use, for example, in the preparation or purification of a physiologically acceptable compound. All salts, whether or not derived form a physiologically acceptable acid or base, are within the scope of the present invention.

Finally, it is to be understood that the compositions herein comprise compounds of the invention in 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-XIV have chiral centers, e.g. chiral carbon or phosphorus atoms. For example, the phosphorous atoms of Formula I-XIV may be chiral because they have four different substituents. The compounds of the invention thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the invention include enriched or resolved optical isomers at any or all asymmetric, chiral atoms. In other words, the chiral centers apparent from the depictions 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 all 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 separation 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 stereospecific reactions, beginning with the appropriate stereoisomer of the desired starting material.

The term “chiral” refers to molecules which have the property of non-superimposability of the mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner.

The term “stereoisomers” refers to compounds which have 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 chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, reactivities and biological properties. For example, the compounds of Formula I-XIV may have a chiral phosphorus atom when phosphorus has four different substitutents, e.g., Formula XIV, where the chirality is R or S. When R^cand R^dof the amino acid of the phosphoramidate of Formula IV are different, there are two centers of chirality in the molecule leading to potential diastereomeric mixtures of compounds, e.g. R,S; S,R; S,S and R,R isomers. Mixtures of diastereomers may be separate under high resolution analytical procedures such as electrophoresis, crystallization and/or chromatography. Diastereomeres may have different physical attributes such as, but not limited to, solubility, chemical stabilities and crystallinity and may also have different biological properties such as, but not limited to, enzymatic stability, absorption and metabolic stability.

“Enantiomers” refer to two stereoisomers of a compound which are non-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally follow S. P. Parker, Ed., McGraw-Hill Dictionary 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 have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and l, D and L, or (+) and (−) are employed to designate the sign of rotation of plane-polarized light by the compound, with S, (−), or l meaning that the compound is levorotatory while a compound prefixed with R, (+), or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of one another. A specific 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^a” 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, custom character , 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 resonance structure may be depicted, all such 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 all their possible tautomeric forms are within the scope of the invention.

One skilled in the art will recognize that nucleoside bases such as the pyrrolo[1,2-f][1,2,4]triazine nucleosides can exist in tautomeric forms. For example, but not by way of limitation, structures (a) and (b) can have equivalent tautomeric forms as shown below:

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All possible tautomeric forms of the heterocycles and nucleobases in all of the embodiments disclosed herein are within the scope of the invention.

The compounds of Formula I-XIV also include molecules that incorporate isotopes of the atoms specified in the particular molecules. Non-limiting examples of these isotopes include D, T, ¹⁴C, ¹³C and ¹⁵N. All such isotopic variations of these molelcules are provided by the instant invention.

EXAMPLES

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-methylpropionitrile)

Bn
benzyl

BnBr
benzylbromide

BSA
bis(trimethylsilyl)acetamide

BzCl
benzoyl chloride

CDI
carbonyl diimidazole

DABCO
1,4-diazabicyclo[2.2.2]octane

DBN
1,5-diazabicyclo[4.3.0]nonene-5

DDQ
2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DBU
1,5-diazabicyclo[5.4.0]undecene-5

DCA
dichloroacetamide

DCC
dicyclohexylcarbodiimide

DCM
dichloromethane

DMAP
4-dimethylaminopyridine

DME
1,2-dimethoxyethane

DMTCl
dimethoxytrityl chloride

DMSO
dimethylsulfoxide

DMTr
4,4′-dimethoxytrityl

DMF
dimethylformamide

EtOAc
ethyl acetate

ESI
electrospray ionization

HMDS
hexamethyldisilazane

HPLC
High pressure liquid chromatography

LDA
lithium diisopropylamide

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

rt or r.t.
room temperature

TBAF
tetrabutylammonium fluoride

TMSCl
chlorotrimethylsilane

TMSBr
bromotrimethylsilane

TMSI
iodotrimethylsilane

TEA
triethylamine

TBA
tributylamine

TBAP
tributylammonium pyrophosphate

TBSCl
t-butyldimethylsilyl chloride

TEAB
triethylammonium bicarbonate

TFA
trifluoroacetic acid

TLC or tlc
thin layer chromatography

Tr
triphenylmethyl

Tol
4-methylbenzoyl

δ
parts per million down field from tetramethylsilane

Preparation of Compounds

Compound 1a-1f

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To a solution of 1a (22.0 g, 54.9 mmol, prepared according to the procedures described in J.O.C., 2004, 6257) in methanol (300 mL) was dropwise added acetyl chloride (22 mL) at 0° C. using a dropping funnel over a period of 30 min. and then stirred at room temperature for 16 h. The mixture was concentrated, re-dissolved in ethyl acetate (400 mL), washed with ice-cold 2 N NaOH, and concentrated to dryness, affording the crude methyl ether 1b as an oil. MS=437.2 (M+Na⁺).

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To a solution of 1b (obtained from the previous step) in methanol (300 mL) was added 0.5 M sodium methoxide solution in methanol (20 mL, 10 mmol), and stirred for 16 h at room temperature. The reaction was quenched with 4.0 N HCl solution in dioxane (2.5 mL, 10 mmol). The mixture was then concentrated, affording the crude 1c. MS=201.0 (M+Na⁺).

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A mixture of 1c (obtained from the previous step), Tritron X-405 (70% in water, 6.0 g), 50% KOH (in water, 85 g) in toluene (500 mL) was heated to reflux with a Dean-Stark trap attached. After 1 h collecting ˜25 mL of water, benzyl chloride (33 g, 260 mmol) was added and continued to reflux with stirring for 16 h. The mixture was then cooled and partitioned between ethyl acetate (400 mL) and water (300 mL). The organic layer was washed with water (300 mL), and concentrated. The residue was purified by silica gel column chromatography (˜20% EtOAc/hexanes), affording the methyl ether 1d as an oil (22.0 g, 89% in three steps). ¹H NMR (300 MHz, CDCl₃): δ 7.3 (m, 15H), 4.5-4.9 (m, 7H), 4.37 (m, 1H), 3.87 (d, 1H), 3.56 (m, 2H), 3.52 (s, 3H), 1.40 (s, 3H).

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To a solution of 1d (22.0 g, 49.0 mmol) in acetic acid (110 mL) was added ˜3 M sulfuric acid (prepared by mixing 4.8 g of concentrated sulfuric acid with 24 mL of water) and stirred at 70° C. for 8 h. The mixture was concentrated to a volume of ˜20 mL, and partitioned between ethyl acetate and ice-cold 2N NaOH. The ethyl acetate layer was concentrated, and purified by silica gel column chromatography (˜35% EtOAc/hexanes), affording 1e as an oil (17.0 g, 80%). MS=457.2 (M+Na⁺).

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To a solution of 1e (45 g, 104 mmol) in DMSO (135 mL) was dropwise added acetic anhydride (90 mL, 815 mmol) at room temperature under argon. The mixture was stirred for 16 h at room temperature, and then poured into ice-water (1 L) while stirring. After ice was completely melted (˜30 min), ethyl acetate (˜500 mL) was added. The organic layer was separated. This extraction process was repeated three times (3×500 mL). The organic extracts were combined and concentrated. The residue was purified by silica gel column chromatography (˜20% EtOAc/hexanes), affording 1f as an oil (39 g, 88%). ¹H NMR (300 MHz, DMSO-d₆): δ 7.3 (m, 15H), 4.4-4.8 (m, 7H), 4.08 (d, J=7.5 Hz, 1H), 3.75 (dd, J=2, 4, 11.4 Hz, 1H), 3.64 (dd, J=5.4, 11.4 Hz, 1H), 1.51 (s, 3H).

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To a dry, argon purged round bottom flask (100 mL) were added 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (234 mg, 1.10 mmol) (prepared according to WO2007056170) and anhydrous THF (1.5 mL). TMSCl (276 μL, 2.2 mmol) was then added and the reaction mixture stirred for 2 h. The flask was placed into a dry ice/acetone bath (˜−78° C.) and BuLi (2.5 mL, 4.0 mmol, 1.6M in hexanes) was added dropwise. After 1 h, a solution of 1f (432.5 mg, 1.0 mmol) in THF was cooled to 0° C. and then added to the reaction flask dropwise. After 1 h of stirring at −78° C., the flask was warmed to 0° C. and sat. NH₄Cl (5 mL) was added to quench the reaction. The organics were extracted using EtOAc (3×10 mL) and the combined organic layers were dried using MgSO₄. The solvent was removed under reduced pressure and the crude material was purified using flash chromatography (hexanes/EtOAc). 560 mg (90%) of 2a was isolated as a mixture of two anomers. LC/MS=567.2 (M+H⁺). ¹H NMR (300 MHz, CDCl₃): δ 7.85 (m, 1H), 7.27 (m, 15H), 7.01 (m, 1H), 6.51 (m, 1H), 4.66 (m, 8H), 4.40 (m, 2H), 3.79 (m, 3H), 1.62 (s, 2′-CH₃from the one anomer), 1.18 (s, 2′-CH₃from the other anomer).

Alternative Procedures for 2a

To a dry, argon purged round bottom flask were added 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (9.6 g, 45 mmol) and anhydrous THF (60 mL). TMSCl (12.4 mL, 99 mmol) was then added and the reaction mixture stirred for 2 h. The flask was placed into a dry ice/acetone bath (˜−78° C.) and BuLi (98 mL, 158 mmol, 1.6M in hexanes) was added dropwise. After 1 h, this reaction mixture was added to a solution of 1f (13.0 g, 30 mmol) in THF at −78° C. via cannula. After 2 h of stirring at −78° C., the flask was warmed to 0° C. Saturated NH₄Cl (150 mL) was added to quench the reaction. The organics were extracted using EtOAc (3×100 mL) and the combined organic layers were dried using MgSO₄. The solvent was removed under reduced pressure and the crude material was purified using flash silica gel chromatography (hexanes/EtOAc). 7.5 g (44%) of the desired material 2a was isolated. LC/MS=567.2 (M+H⁺).

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To a solution of compound 2a (1 g, 1.77 mmol) in CH₂Cl₂(20 mL) at 0° C. was added TMSCN (1.4 mL, 10.5 mmol) and BF₃-Et₂O (1 mL, 8.1 mmol). The reaction mixture was stirred at 0° C. for 0.5 h, then at room temperature for additional 0.5 h. The reaction was quenched with NaHCO₃at 0° C., and diluted with CH₃CO₂Et. The organic phase was separated, washed with brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by chromatography on silica gel, eluted with CH₃CO₂Et-hexanes (1:1 to 2:1), to give the desired compound 5a (620 mg, 61%) as an isomeric mixture. MS=576.1 (M+H⁺).

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To a solution of compound 5a (150 mg, 0.26 mmol) in CH₂Cl₂(4 mL) at −78° C. was added BCl₃(2 mL, 1M in CH₂Cl₂). The reaction mixture was stirred at −78° C. for 1 h. The reaction was quenched at −78° C. by dropwise addition of TEA (2 mL) and MeOH (5 mL). The mixture was allowed to warm up to room temperature, evaporated, and co-evaporated with MeOH several times. The residue was treated with NaHCO₃(1 g in 10 mL H₂O), concentrated and purified by HPLC to give the desired product Compound 5 (48 mg, 60%). ¹H NMR (300 MHz, D₂O): δ 7.74 (s 1H), 6.76 (d, J=5 Hz, 1H), 6.73 (d, J=5 Hz, 1H), 4.1 (m, 1H), 3.9 (m, 1H), 3.8 (m, 2H), 0.84 (s, 3H). MS=305.9 (M+H⁺). The other alpha-anomer was also obtained (9 mg, 11%): ¹H NMR (300 MHz, D₂O): δ 7.70 (s 1H), 6.8 (d, J=5 Hz, 1H), 6.7 (d, J=5 Hz, 1H), 4.25 (d, J=9 Hz, 1H), 4.07 (m, 1H), 3.85 (m, 1H), 3.7 (m, 1H), 1.6 (s, 3H). MS=306.1 (M+H⁺).

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Compound A (commercially available, 4.99 g, 23.8 mmol) was dissolved in dichloromethane (100 mL) and alanine isopropyl ester hydrochloride (3.98 g, 23.8 mmol) was added. The resulting clear solution was cooled −78° C. for 30 min. Triethylamine (6.63 mL, 47.5 mmol) was added dropwise over 15 min. The mixture was then allowed to warm to room temperature. After 16 h, the solvent was removed by argon stream. The residue was re-dissolved in MTBE (25 mL) and the insoluble was removed by filtration under argon. The filtrate was then condensed by argon stream and the crude product B was used for the next reaction without further purification. ¹H NMR (300 MHz, CDCl₃): 7.1-7.4 (m, 5H), 5.1 (m, 1H), 4.35 (m, 1H), 4.15 (m, 1H), 1.5 (d, 3H), 1.2 (m, 6H). ³¹P NMR (121.4 MHz, CDCl₃): δ 7.8 and 8.4 (2 s).

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Alanine isopropyl ester hydrochloride (7.95 g, 47.4 mmol) was suspended in dichloromethane (100 mL). Compound A (10 g, 47.4 mmol) was added. Triethylamine (13.2 mL, 95 mmol) was then dropwise added over a period of 15 min. (internal reaction temperature; −10° C.˜−3° C.). When the reaction was almost complete (by phosphorous NMR), p-nitrophenol (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 temperature. When the reaction was complete, MTBE (100 mL) was added. The white precipitate was removed by filtration. The filter cake was washed with MTBE (3×50 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 C as a 1:1 ratio of diasteromeric mixture (14.1 g, 77%). ¹H NMR (300 MHz, CDCl₃): δ 8.22 (2d, 2H), 7.2-7.4 (m, 7H), 5.0 (m, 1H), 4.09 (m, 1H), 3.96 (m, 1H), 1.39 (2d, 3H), 1.22 (m, 6H). MS=409.0 (M+H⁺), 407.2 (M−H⁺).

Separation of Two Diatereomers of Compound C

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

Column: Chiralpak IC, 2×25 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% hepane and 30% IPA (S)-compound C: retention time 43 min. ³¹P NMR (161.9 MHz, CDCl₃): δ −2.99 (s). (R)-compound C: retention time 62 min. ³¹P NMR (161.9 MHz, CDCl₃): δ −3.02 (s).

Alternatively, the two diasteromers were separated by crystallization under the following procedures;

Compound C 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 C) 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 of the crystalline material 35%-35% The crystalline material contains ˜95% of (S)-compound C and ˜5% of (R)-compound C. Re-crystallization afforded 99% diastereomerically pure (S)-isomer.

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To a dry, argon purged round-bottom flask were added compound 5 (1.0 g, 3.28 mmol) and anhydrous THF (15 mL). The slurry was stirred for 10 min. and the flask was place in a water bath at room temperature. t-Butylmagnesium chloride in THF (1.0 M, 4.91 mL) was dropwise added, and the mixture was stirred for an additional 10 min. A solution of (S)-C (2.68 g, 6.55 mmol) in THF (10 mL) was then added. The flask was place in a heating oil bath pre-set at 50° C. and the mixture was stirred until compound 1 was almost consumed. After ˜2.5 h, the reaction mixture was cooled to room temperature, and methanol (5 mL) was added. Solvents were removed under reduced pressure and the residue was purified by silica gel column chromatography (70% ethyl acetare/hexanes to remove less polar impurities, 10% methanol/dichloromethane to elute the product), affording (S)-6 as an off-white solid (1.45 g, 77%). ¹H NMR (400 MHz, DMSO-d₆): δ 7.89 (s, 1H), 7.84 (brs, 2H), 7.36 (t, 2H), 7.23 (d, 2H), 7.17 (t, 1H), 6.87 (d, J=4.4 Hz, 1H), 6.74 (d, J=4.4 Hz, 1H), 6.02 (dd, 1H), 5.96 (s, 1H), 5.41 (d, 1H), 4.82 (m, 1H), 4.38 (dd, 1H), 4.22 (q, 1H), 4.16 (m, 1H), 3.81 (m, 1H), 3.67 (dd, 1H), 1.22 (d, 3H), 1.11 (dd, 6H), 0.89 (s, 3H). ³¹P NMR (161.9 MHz, DMSO-d₆): δ 3.99 (s). MS=575.0 (M+H⁺), 572.7 (M−H⁺).

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To a dry, argon purged round-bottom flask were added compound 7 (prepared according to J. Med. Chem., 2005, 48, 5504-5508, 100 mg, 0.38 mmol), anhydrous THF (3 mL) and anhydrous NMP (1 mL). The slurry was stirred for 10 min. and the flask was place in a water bath at room temperature. t-Butylmagnesium chloride in THF (1.0 M, 0.76 mL) was dropwise added, and the mixture was stirred for an additional 10 min. A solution of (S)-C (313 mg, 0.76 mmol) in THF (2 mL) was then added. The flask was place in a heating oil bath pre-set at 55° C. and the mixture was stirred until compound 7 was almost consumed. After ˜2.5 h, the reaction mixture was cooled to room temperature, and methanol (1 mL) was added. Solvents were removed under reduced pressure and the residue was purified by RP-HPLC followed by silica gel column chromatography, affording (S)-8 (130 mg, 65%). ¹H NMR (400 MHz, CDCl₃): δ 8.51 (brs, 1H), 7.46 (d, 1H), 7.2-7.4 (m, 5H), 6.28 (d, 1H), 5.70 (dd, 1H), 5.01 (m, 1H), 4.49 (m, 2H), 3.8-4.1 (m, 4H), 1.41 (d, 3H), 1.35 (d, 3H), 1.24 (d, 6H). ³¹P NMR (162.1 MHz, CDCl₃): δ 3.70 (s). MS=530.0 (M+H⁺), 528.0 (M−H⁺). Chiral HPLC retention time (Chiralpak AS-H, 250×4.6 mm 5 micron, 100% CH₃CN, 1 mL/min flow rate); 6.5 min vs. 5.2 min for the R-isomer).

Using the general procedures described for the preparation of Compound (S)-C or Compound (R)-C, Compounds 10-24 may be prepared.

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Using the general procedures described for the preparation of Compound (S)-6, Compounds 25-38 may be prepared using either Compound (S)-C or Compound (R)-C.

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Claims

1. A method for preparing a compound of Formula Ia or Ib:
2. The method of claim 1 wherein Formula Ia is Formula IVa, Formula Ib is Formula IVb and Formula II is Formula V:
3. The method of claim 1 wherein Base is selected from the group consisting of:
4. The method of claim 3 wherein Base is selected from the group consisting of:
5. The method of claim 1 wherein Formula Ia is Formula VIa, Formula Ib is Formula VIb and Formula II is Formula VII:
6. The method of claim 1 wherein Formula Ia is Formula XIa, Formula Ib is Formula XIb and Formula II is Formula XII:
7. The method of claim 1 wherein Formula Ia is Formula XIIIa, Formula Ib is Formula XIIIb and Formula II is Formula XIV:
8. The method of claim 1 wherein R1 is H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl.
9. The method of claim 8 wherein R1 is H, CH3 or F.
10. The method of claim 1 wherein each R5, R23 and R24 is H.
11. The method of claim 1 wherein one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl.
12. The method of claim 1 wherein R6 is optionally substituted (C1-C8)alkyl.
13. The method of claim 1 wherein R8 is NR11R12 or OR11.
14. The method of claim 13 wherein R9 is H or NR11R12.
15. The method of claim 1 wherein when R8 or R9 is OR11 or NR11R12 then each R11 and R12 of said OR11 or NR11R12 is H.
16. The method of claim 14 wherein R8 is NH2 and R9 is H.
17. The method of claim 1 wherein R4 is optionally substituted (C6-C20)aryl.
18. The method of claim 1 wherein the compound of Formula VIII is dissolved in an ether solvent and the crystallization is induced by addition of a C5-C8 hydrocarbon.
19. The method of claim 1 wherein the compound of Formula VIII is dissolved in diethyl ether or methyl-t-butyl ether and crystallization is induced by the addition of hexane.
20. The method of claim 19 wherein the compound of Formula VIII is dissolved in diethyl ether and crystallization is induced by the addition of hexane.
21. The method of claim 1 further comprising a method of preparing a compound of Formula VIII
22. A method of preparing a compound of Formula IIIa or Formula IIIb
23. The method of claim 22 wherein the compound of Formula VIII is dissolved in an ether solvent and the crystallization is induced by addition of a C5-C8 hydrocarbon.
24. The method of claim 23 wherein the compound of Formula VIII is dissolved in diethyl ether or methyl-t-butyl ether and crystallization is induced by the addition of hexane.
25. The method of claim 24 wherein the compound of Formula VIII is dissolved in diethyl ether and crystallization is induced by the addition of hexane.
26. The method of claim 22 further comprising a method of preparing a compound of Formula VIII
27. The method of claim 22 wherein R5 is H and one of Rc or Rd is H.
28. The method of claim 22 wherein R6 is optionally substituted (C1-C8)alkyl and R4 is optionally substituted (C6-C20)aryl.
29. The method of claim 22 wherein R4 is optionally substituted phenyl.
30. The method of claim 22 wherein one of Rc or Rd is H and the other of Rc or Rd is CH3.
31. The method of claim 22 wherein Ar is optionally substituted para-nitrophenyl.
32. The method of claim 22 wherein the chirality at the carbon directly attached to Rc and Rd is S.
33. The method of claim 22 wherein the chirality at the carbon directly attached to Rc and Rd is R.
34. The method of claim 22 wherein the compound is selected from the group consisting of

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application of International Application No. PCT/US2011/044581, filed Jul. 19, 2011, which claims the benefit of U.S. Provisional Application No. 61/365,621, filed Jul. 19, 2010. The contents of the aforementioned applications are incorporated herein by reference in their entirety.

PCT Information

Filing Document	Filing Date	Country	Kind	371c Date
PCT/US2011/044581	7/19/2011	WO	00	6/25/2013

Publishing Document	Publishing Date	Country	Kind
WO2012/012465	1/26/2012	WO	A

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Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

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