SE1451080A1

SE1451080A1 - Methods for the preparation of diasteromerically pure phosphoramidate prodrugs

Info

Publication number: SE1451080A1
Application number: SE1451080A
Authority: SE
Inventors: Pedro Pinho; Staffan Torssell
Original assignee: Medivir Ab
Priority date: 2014-09-16
Filing date: 2014-09-16
Publication date: 2016-03-17

Abstract

Methods for the preparation of diastereomerically pure phosphoramidate prodrugs of nucleosides, and intermediates useful for the preparation are provided. The nucleosides are useful for the treatment of hepatitis C and cancer.

Description

M337 prio-lb METHODS FOR THE PREPARATION OF DIASTEROMERICALLY PURE PHOSPHORAMIDATE PRODRUGS FIELD OF THE INVENTION The invention relates generally to methods for preparing prodrugs of nucleoside triphosphate inhibitors of cancer, or of viral infection, such as inhibitors of hepatitis C virus RNA- dependent RNA polymerase.

BACKGROUND OF THE INVENTION Nucleoside inhibitors of viral polymerases and cancers are typically active as the nucleoside triphosphate (NTP). Conventional nucleoside drugs are phosphorylated by host cellular kinases to the triphopshate active form. 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; GardeIli, 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.

The first generations of phosphoramidate prodrugs, such as AZT phosphoramidates (McGuigan 1993, J Med Chem 36 1048-1052) or BMS/Inhibitex INX-189 (W02010/081082) were prepared as diasteroemeric mixtures at the phosphorous atom. Merck, ldenix and Achillion are believed to have clinical trials ongoing in relation to diverse phosphoramidate prodrugs of HCV-inhibitory nucleosides. 1 M337 prio-lb Gemcitabine is an example of an anticancer nucleoside, which has been put into clinical trials by Nucana as a phosphoramidate prodrug (W02005/01237). Nucana also works with phosphoramidate prodrugs of other anticancer nucleosides including clofarabine, fludarabin, cladribine (W02006/100439) and FUDR (W02012117246). Nucana's phosphoramidate prodrugs are typically a diastereomeric mixture at the phosphorous.

Subsequent generations of phosphoramidate prodrugs of an inhibitor of hepatitis C virus RNA-dependent RNA polymerase, such as Sofosbuvir (W02008/121634) are diasteromerically pure at the phosphorous. Notably, the antiviral activity of phosphate prodrugs can markedly depend upon the chirality of the phosphorous in the prodrug (GardeIli, J. Med. Chem. 2009, 52, 53945407; Meppen, Abstracts of Papers, 236th ACS National Meeting, Philadelphia, PA, United States, August 17-21, 2008 (2008), MEDI-404.).

Pharmasset, later bought by Gilead, have described chiral phosphoramidate reagents in W02010/135569, W02011/123645 and W02012/012465 useful in the preparation of sofosbuvir.

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

W02012/012465 discloses methods and intermediates for preparing diasteromerically pure phosphoramidate prodrugs of nucleosides that are useful for the treatment of hepatitis C infection. The phosphorylating reagent disclosed therein is a phosphoramidate having an aryloxy or heteroaryloxy group, 0-Ar, attached to the phosphorus atom as leaving group, i.e. a compound of formula Aa or Ab: wherein Ar is a (C8-C)aryl or heteroaryl which is substituted with one or more halogen, NO2, or (C1-C8)haloalkyl, and Ar is different from R4.

SUMMARY OF THE INVENTION Provided are methods for preparing prodrugs of nucleoside triphosphate inhibitors of cancer, or of viral infection, such as inhibitors of hepatitis C virus RNA-dependent RNA polymerase.

Formula Aa R6 -. o R400 IR6P\ 1lv O—Ar o R6 o -' R° Formula Ab 2 M337 prio-lb 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, a method for preparing a compound of Formula la or lb is provided: 0 R40,,,,, ii 'F'........., RLN4 ° Rd R6 o R6-0 R22 R2 Formula laFormula lb or a pharmaceutically acceptable salt or acid thereof; wherein: each R1, R2, R7, R22, R23 or R24 is independently H, OR11, NR11R12, C(0)NR11R12, -0C(0)NR11R12, C(0)0R11, OC(0)0R11, S(0)nRa, S(0)2NR11R12, N3, ON, 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, R23 or 1-‹.-,24 on adjacent carbon atoms when taken together are - 0(00)0- or -0(CR11R12)0_ 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 Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl; each Rc or Rd is independently H, (01-C8)alkyl, (C2-08)alkenyl, (C2-C8)alkynyl, (03- Cs)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(Ci-Cs)alkyl, heterocyclyl(Ci-Cs)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl provided that Rc and Rd are not the same; 3 M337 prio-lb each R is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(Ci-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(Ci-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C)aryl, heterocyclyl, heteroaryl, -C(=0)(C1-C8)alkyl, -S(0)n(C1-C8)alkyl or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, - S(0)n- or -NRa-; and wherein each (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(Ci-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R4, R, R6, R7, R1 1 or R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2, NH(Ra), NH2, NO2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, C(0)R8, OC(0)Ra, S(0)nRa S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra: said method comprising : providing a compound of Formula ll HO Formula ll and treating the compound of Formula ll with a compound of Formula Illa and a base 0I I0 R6 ,i,N14 , 0-P - S-Ar Rd Rc O\ Formula Illa thereby forming a compound of Formula la or treating the compound of Formula ll with a compound of Formula Illb and a base R4 4 M337 prio-lb 0R 1 IR6 / ,,,‘, kl i 'S—Ar Rd RC 0\ Formula IIlb thereby forming a compound of Formula lb; wherein: each Ar is (C6-C20)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is substituted with one or more halogen, NO2, or (C1-C8)haloalkyl and optionally substituted with one or more ON, N3, N(Ra)2, C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa, S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4.

In another aspect, the invention provides novel intermediates disclosed herein which are useful for preparing compunds of Formula la or Formula lb.

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 la from a compound of Formula ll and a compound of Formula IIla, or preparing a compound of Formula lb from compound of Formula ll and a compound of Formula IIlb 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 i-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 -20 °C to about 90 °C, more preferably about -10 °C to about 60 °C.

The solution of Formula ll 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 i-butylmagnesium chloride. A further preferred base is t-butylmagnesium chloride. Typical, but non-limiting, examples of non-nucleophilic bases are sodium hydride, potassium hydride, lithium R4 M337 prio-lb 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 will depend on the Base attached to the furanose ring. The ratio is about 1:1 to about 3:1, preferably about 1.1:1 to about 2.1:1. 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 IIla or Formula IIIIb for about 30 minutes to about 24 hours, preferably about one to about four hours. The molar ratio of the compound of Formula II to the compound of Formula IIla or Formula IIlb 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 la or lb or a pharmaceutically salt or ester thereof, Formula la is Formula IVa, Formula lb is Formula IVb and Formula ll is Formula V: R6o Base R24". R23 R22R2 0 R404,, II 4 0Base C1/4/R24%11-"qdR7 R23 R1 R--0 Rd R22 Formula IVaFormula IVb HOBase R24".111R7 R23R1 R22R2 Formula V In one embodiment of the method for preparing a compound of Formula IVa or IVb from a compound of Formula V, R1 is H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is optionally substituted (Cr C8)alkyl. In another aspect of this embodiment, R1 is methyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R1 is F. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is OR11. In another aspect of this embodiment, R2 is Cl. In another aspect 6 M337 prio-lb of this embodiment, R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is CN. In another aspect of this embodiment, R is H. In another aspect of this embodiment, one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (Ci-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl or optionally substituted (C3-C8)carbocyclyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R23 is H. In another aspect of this embodiment, R22 is OR11. In another aspect of this embodiment, R22 is OH. In another aspect of this embodiment, R24 is N3. In another aspect of this embodiment, R24 is H. In another aspect of this embodiment, Base is selected from the group consisting of: R8 X2NX2' N-.N1 R9 _ N'R9 and wherein: each X1 is independently N or CR19; each X2 is independently NR11, 0, or S(0)n; each R8 is independently halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NNHR11, -CH=N(OR11), -CH(0R11)2, -C(=0)NR11R12, -C(=S)NR11R12, - C(0)0R11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=0)(C1-C8)alkyl, -S(0)n(C1-C8)alkyl, aryl(C1-C8)alkyl, OR11 or SR11; each n is independently 0, 1, or 2; each R9 or R16 is independently H, halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NHNR11, -CH=N(0R11), -CH(0R11)2, - c(=0)NR11R12, -C(=S)NR11R12, -c(=0)0R11, 1-‹ -11, OR11 or SR11; each R11 or R12 is 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, heterocyclyl, heteroaryl, -C(=0)(C1C8)alkyl, -S(0)n(C1-C8)alkyl or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S(0)n- or -NRa-; 7 M337 prio-lb wherein each (Ci-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, heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R4, R, R6, R7, R9, R9, R19, R" or R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2,NH(Ra), NH2, NO2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0),Ra, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra.

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

HNH2 N \ NH2 NHNH2 . N--------- "--- N S 'N,....-N, N NH7 H N.

N N 1 NH2 N" NH2 N 'N' '0 0 0 H30, N CONH2 VNIV HNNH LO N H2 HN N LLO 41/1r, and 0 (NH N In another aspect of this embodiment, Base is selected from the group consisting of: 0 NH( "-C.3 CON H2 H andNno, 8 M337 prio-lb In another embodiment of the method for preparing a compound of Formula IVa or IVb from a compound of Formula V, R1 is H, halogen, optionally substituted (Ci-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; R2 is OR11 or halogen; R22 is OR" and each R, R23 and R24 is H. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R1 is methyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R1 is F. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (Cr C8)alkyl. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is CN. In another aspect of this embodiment, one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (Ci-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is (C3-C8)carbocyclyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Base is selected from the group consisting of: R.° R8 x2 ‘1*'' and wherein: each X1 is independently N or CR18; each X2 is independently NR", 0, or S(0).; each R8 is independently halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, - CH(=NR11), -CH=NNHR11, -CH=N(0R11), -CH(0R11)2, -C(=0)NR11R12, -C(=S)NR11R12, - C(0)0R11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=0)(C1-C8)alkyl, -S(0)(C1-C8)alkyl, aryl(C1-C8)alkyl, OR" or SR11; each n is independently 0, 1, or 2; 9 M337 prio-lb each R9 or R1° is independently H, halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NHNR11, -CH=N(0R11), -CH(0R11)2, - c(.0)NR11R12, -C(=S)NR11R12,-11, OR11 or SR; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=0)(C1C8)alkyl, -S(0)n(Ci-C8)alkyl or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S(0)n- or wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4- C8)carbocyclylalkyl, aryl(Ci-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R4, R, R6, R7, R8, R9, R, R11 or R12 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(Ra)2,NH(Ra), NH2, NO2, C(0)N(R12, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra.

In another aspect of this embodiment, Base is selected from the consisting of: NH2 2 NH2 N N i \\.

N1-120 Jt N.

N '< NH2NH2 <NN NH2 S/ I NH2NH2 NH2NH2 HN \ j--N and ---- In another aspect of this embodiment, Base is selected from the group NH2 00 F.,, _,J*1,H1„-IL- -,-'NH-C - ""-- '' NH [[1L 1 F N CONH2 N M337 prio-lb HNNH 0 NH2 HN)\-N LLO and In another aspect of this embodiment, Base is selected from the group 0 'NH N F• N, -CONF-i2HNH NH2 H and In another embodiment of the method for preparing a compound of Formula IVa or IVb from a compound of Formula V, R1 is H, halogen or CH3; R2 is OR11 or halogen; R6 is optionally substituted (C1-C8)alkyl or (C3-C8)carbocycly1; one of Rc and Rd is H and the other one is optionally substituted (C1-C8)alkyl; R22 is OR11, and each R, R23 and R24 is H. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R1 is CH3. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is CN. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, R4 is optionally substituted napthyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Base is selected from the group consisting of: R'R8R8 3 z/X1-i•----"•:‘,N 'N---,'-- X2. ...--' • ;--'----' s,•,} X'••...,X'.,„,_,.2N \i .X1X1\' _-•„--.1.\\ .1,L ..,,,,..,\, NI'- ----- - 9,=---- ',.--- R9N' .R9 "N"W' and wherein: each X1 is independently N or CR; each X2 is independently NR11, 0, or S(0)n; 11 M337 prio-lb each R8 is independently halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR"), -CH=NNHR11, -CH=N(0R11), -CH(0R11)2, -C(=0)NR11R12, -C(=S)NR11R12, - C(0)0R11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=0)(C1-C8)alkyl, -S(0)n(C1-C8)alkyl, aryl(C1-C8)alkyl, OR11 or SR11; each n is independently 0, 1, or 2; each R9 or R1° is independently H, halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NHNR11, -CH=N(OR11), -CH(0R11)2, -C(=S)NR11R12,-11, OR11 or SR; each Ril or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(=0)(C1C8)alkyl, -S(0)n(C1-C8)alkyl or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S(0)n- or wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4- C8)carbocyclylalkyl, aryl(Ci-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R4, R, R6, R7, R8, R9, R, R11 or R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2,NH(Ra), NH2, NO2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, ORa or Ra.

In another aspect of this embodiment, Base is selected from the group consisting of: N T NH \ N-- NH2 7 NH NH2 </ !t NH2 1\JJ,H2.HNH, N NH2NH2 I / o-,..

‘.---I ,.- -.- iN NH3 N HN NH2 N /N 1 and In another aspect of this embodiment, Base is selected from the group 12 M337 prio-lb NH2 0 pC H3 NLH „-CONH2 O HN-1'NH LO NH20 HN N NH LL 0 41.01.,0`and In another aspect of this embodiment, Base is selected from the group .H,-.,C,...--1.

NH ' '1-". NH . ..t{..........:_o "C) I F00NH2 Fl O 4 NH and In another embodiment of the method for preparing a compound of Formula IVa or IVb from a compound of Formula V, R1 is H, Cl or CH3; R2 is OR11 or halogen; R6 is optionally substituted (C1-C8)alkyl; one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl; R22 is OR11, each R, R23 and R24 is H and Base is selected from the group consisting of: R" R8 • R"R8 Ki N N' wherein: each X1 is independently N or CR19; each X2 is independently NR11, 0, or S(0)n; each R8 is independently halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, - CH(=NR11), -CH=NNHR11, -CH=N(0R11), -CH(0R11)2, -C(=0)NR11R12, -C(=S)NR11R12, - C(0)0R11, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (a4-C8)carbocyclylalkyl, (C6-C28)aryl, heterocyclyl, heteroaryl, -C(=0)(C1-C8)alkyl, -S(0)n(C1-C8)alkyl, aryl(C1-C8)alkyl, OR11 or SR11; each n is independently 0, 1, or 2; each R9 or R19 is independently H, halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NHNR11, -CH=N(0R11), -CH(0R11)2, - C(0)NR11R12, -C(=S)NR11R12, -C(=0)0R11, R11, OR11 or SR; each R11 or R12 is independently 13 M337 prio-lb H, (Ci-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl, heteroaryl, -C(.0)(Ci08)alkyl, -S(0)n(C1-C8)alkyl or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S(0)n- or wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C8-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R1, R2, R22, R23, R24, R4, R6, R6, R7, R8, R9, R, R11 or R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2,NH(Ra), NH2, NO2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, ORa or Ra.

In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is CH3. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R1 is F and R2 is Cl. In another aspect of this embodiment, R1 is CH3 and R2 is Cl. In another aspect of this embodiment, R1 R2 are both Cl. In another aspect of this embodiment, R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, R4 is optionally substituted napthyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1 to 5 halogen atoms. In another aspect of this embodiment, Ar is halo pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another aspect of this embodiment, Base is adenine.

In another aspect of this embodiment, Base is guanine.

In another aspect of this embodiment, Base is 2,6 diaminopurine.

In another aspect of this embodiment, Base is 7-deazaadenine.

NH2 In another aspect of this embodiment, Base is 14 NH2 2j1 In another aspect of this embodiment, Base is — In another aspect of this embodiment, Base is In another aspect of this embodiment, Base is In another aspect of this embodiment, Base is In another aspect of this embodiment, Base is NH2 HNN In another aspect of this embodiment, Base is In another aspect of this embodiment, Base is cytosine.

In another aspect of this embodiment, Base is 5-fluorouracil.

In another aspect of this embodiment, Base is thymine.

F N CONH2 0 In another aspect of this embodiment, Base is In another aspect of this embodiment, Base is — M337 prio-lb In another aspect of this embodiment, Base is In another aspect of this embodiment, Base is I HN NH o ~A/ 1H 2 HN N 0 ..n.n.n./ In another embodiment of the method for preparing a compound of Formula la or lb or a pharmaceutically acceptable salt or ester thereof, Formula la is Formula Vla, Formula lb is Formula Vlb and Formula II is Formula VII: Formula Via Formula Vlb 0 R6o R8 0 R40k,„ II P j 0 R2---N 0 H%w, , ‘"/#1R° H R6-0Rd IR8 .-.

R22R2 R8 HO Formula VII wherein each R1 is independently H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; each R2 is independently halogen or OR11 ; each R is H; each R22 is OR11 and the remaining variables are defined as for Formulae la or lb or 11 or Illa or 111b.

In one embodiment of the method for preparing a compound of Formula Via or Formula Vlb from a compound of Formula VII, X1 is CR. In another aspect of this embodiment, R1° is H. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is F. In 16 M337 prio-lb another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R1 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R1 is methyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted ethenyl. In another aspect of this embodiment, R1 is optionally substituted(C2-C8)alkynyl. In another aspect of this embodiment, R1 is optionally substituted ethynyl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H. In another aspect of this embodiment, one of Rcor Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is (03-C8)carbocyclyl. In another aspect of this embodiment, R4 is optionally substituted (060)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl.

In another embodiment of the method for preparing a compound of Formula Vla or Formula Vlb from a compound of Formula VII, X1 is CH, R1 is H, Cl or CH3 and one of RC or Rd is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (Cr C8)alkyl. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (01-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (01-C8)alkyl.. In another aspect of this embodiment, R6 is optionally substituted (03-08)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR11—I-K12. In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH.

In another embodiment of the method for preparing a compound of Formula Vla or Formula Vlb from a compound of Formula VII, X1 is CH, R1 is H, Cl or CH3 one of Rc or Rd is H and R7 is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment, R1 is Cl and R2 is F. In another aspect of this embodiment, R1 is CH3 and R2 is Cl. In another aspect of 17 M337 prio-lb this embodiment, R1 and R2 are both CI. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, one of IR and Rd is H and the other of Rc and Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc and Rd is H and the other of Rc and Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (CcC8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another aspect of this embodiment, R8 is NR11-1-(12. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is OH.

In another embodiment of the method for preparing a compound of Formula la or lb or a pharmaceutically acceptable salt or ester thereof, Formula la is Formula VI, Formula lb is Formula Vlb and Formula ll is Formula VII: H‘""'"IR7 H.5... R1 IR-.'2"'-i2 Formula Vla R a N\ R- 0 IR6c) R8 0 ''"iRc R'-0Rd 0 R404,„ II , 'P Rj 0—CH2 --...N N H‘%""."1"/R7 HR1 1--_ R22-1.2 $ Formula Vlb 18 M337 prio-lb R8 Formula VII wherein each R1 is independently H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; each R2 is independently halogen or OR11 ; each R is H; each R22 is OR11 and the remaining variables are defined as for Formulae la or lb or II or IIla or 111b.

In one embodiment of the method for preparing a compound of Formula Via or Formula Vlb from a compound of Formula VII, X1 is CR. In another aspect of this embodiment, R1° is H. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is F. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R1 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R1 is methyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted ethenyl. In another aspect of this embodiment, R1 is optionally substituted(C2-C8)alkynyl. In another aspect of this embodiment, R1 is optionally substituted ethynyl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is CN. In another aspect of this embodiment, one of Rc or Rd is H. In another aspect of this embodiment, one of Rcor Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted optionally substituted (C3-C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C8-C28)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl.

In another embodiment of the method for preparing a compound of Formula Via or Formula Vlb from a compound of Formula VII, X1 is CH, R1 is H, CI or CH3 and one of Rc or Rd is H. In 19 M337 prio-lb another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (Cr C8)alkyl. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl.. In another aspect of this embodiment, R6 is optionally substituted (C3-C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR111-< In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH. In another aspect of this embodiment, R9 is H. In -•12. another aspect of this embodiment, R9 is NR111-< In another aspect of this embodiment, R9 is OR11. In another aspect of this embodiment, R8 is NR11IN and R9 is H. In another aspect of this -•12 embodiment, R8 is NR111-< and R9 is NR11 In another embodiment of the method for preparing a compound of Formula Vla or Formula Vlb from a compound of Formula VII, X1 is CH, R1 is H, Cl or CH3 one of Rc or Rd is H and R7 is CN. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, one of Rc and Rd is H and the other of Rc and Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc and Rd is H and the other of Rc and Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (03-08)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (06-020)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR11.--02.

In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R9 is OH. In another aspect of this embodiment, R9 is H. In another aspect of this embodiment, R9 is NeR12. In another aspect of this embodiment, R9 is OR11. In another aspect of this embodiment, R8 is NRiiRi2 and 1-< is H. In another aspect of this embodiment, R8 is NH2 and R9 is H. In another aspect of this embodiment, R8 is NR11R12 and R9 is NR11-1-<12. In another aspect of this embodiment, R8 is NH2 and R9 is NH2. In another aspect of this embodiment, R8 is OH and R9 is NH2.

R12.

M337 prio-lb In another embodiment of the invention, a method is provided for the preparation of a compound of Formula IIla or Formula IIlb 0 / 0 S-Ar Rd Rc 0 0 R6/ 0- Rd IR' 0\ R4R4 Formula IllaFormula Illb Or wherein: each Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl; each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C)aryl, (C2-C)heterocycly1 or heteroaryl provided that Rc and Rd are not the same; each R is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-08)carbocyclyl, (a4C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-08)alkenyl, (C2-08)alkynyl, (C3-08)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, 0C(0)NH(Ra), OC(0)NH2, C(0)0Ra, 0C(0)0Ra, S(0)nRa, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, ORa or Ra; and each Ar is (08-0)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-08)haloalkyl, ON, N3, N(Ra)2, C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4; said method comprising: (d) providing a diastereomeric compound of Formula VIII 0R R6 0 / Re 0 S-Ar R4 Formula VIII and 21 M337 prio-lb (e) dissolving the compound of Formula VIII in a suitable solvent and inducing crystallization by cooling the solution; thereby forming a pure diasteromer of Formula Ila or Formula 111b.

In one embodiment of the method of preparing a compound of Formula IIla or Formula 111b, R6 is H and one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted C3-C8cycoalkyl. In another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1 to 5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R.

In another embodiment of the method of preparing a compound of Formula Illa or Formula 111b, R6 is H, one of Rc or Rd is H, R6 is optionally substituted (01-08)alkyl, and R4 is optionally substituted (06-028)aryl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (01-08)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2-propyl. In another aspect of this embodiment, Rd is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogens. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R.

In another embodiment of the method of preparing a compound of Formula Illa or Formula 111b, R6 is H, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (01-08)alkyl, R6 is optionally substituted (01-08)alkyl, and R4 is optionally substituted phenyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2-propyl. In another aspect of this embodiment, R4 is phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another 22 M337 prio-lb aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R.

In another embodiment of the method of preparing a compound of Formula IIla or Formula 111b, R is H, one of Rc or Rd is H and the other of IR or Rd is CH3, R6 is optionally substituted (Cr C8)alkyl, and R4 is optionally substituted phenyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)secondary or tertiary alkyl. In another aspect of this embodiment, R6 isoptionally substituted 2-propyl. In another aspect of this embodiment, R6 is 2-propyl. In another aspect of this embodiment, R4 is phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R.

The diastereomeric mixture of the compound of Formula VIII is typically 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 i-butyl ether, methyl i-butyl ether, Cr C8halogenated alkanes, 0-C8hydrocarbons, tetrahydrofuran, toluene, xylene, dioxane and the like. In another embodiment, the compound of Formula VIII is dissolved in a suitable solvent and crystallization is induced by addition of a C-C8hydrocarbon or 0-08 cyclic hydrocarbon. In one embodiment, the compound of Formula VIII is dissolved in an ether solvent and crystallization is induced by addition of a C-C8 hydrocarbon. In a typical embodiment, the compound of Formula VIII is dissolved in diethyl ether and crystallization is induced by the addition of hexane.

In a further embodiment, the compound of Formula VIII is dissolved in a C-C8hydrocarbon and crystallization is induced by cooling the solution. In a preferred embodiment, the compound of Formula VIII is dissolved in hexane or heptane and crystallization is induced by cooling the solution.

The diastereomeric mixture of the compound of Formula VIII is typically resolved by crystallization of the compound of Formula VIII from a suitable solvent at a temperature of about 80 °C to about -20 °C. Preferably, the temperature is about 30 °C to about -20 °C, more preferably about ambient to -10 °C. 23 M337 prio-lb The diastereomeric mixture of the compound of Formula VIII is typically 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 `)/0 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, a compound of formula VIII 7(-1 A Rc 0 S—Ar R4 R60 lb R6, R4OH Rd base base 0 CI —P —CI OR R NR6, R4 0,11* C I HSa-sA0 base lc R pf I N C S—Ar R4 VIII la Formula VIII is prepared as illustrated in the scheme 1: Scheme 1 Condensation of phosphoryl trichloride with a desired alcohol R4OH in the presence of a base such as Et3N or DIEA or similar in an inert solvent like dichloromethane, diethyl ether, tetrahydrofuran or the like, followed by reaction with an amino acid derivative (lb) in the presence of a base like Et3N or DIEA or similar provides the chlorophosphoramidate (1c). The obtained chlorophosphoramidate is then converted to the phosphorylating agent (VIII) by 24 M337 prio-lb reaction with the desired thiophenol Ar-SH in the presence of a base like triethylamine or similar.

Alternatively, the synthesis of a compound of formula VIII can start from a phosphorus trihalide, and oxidation to the desired phosphate performed as the last step. This method is illustrated in Scheme 2.

R4OHP ....P.,xIX XbaseR4 2a R5 Ar 1I ArSH baseR6,0N„S P --,I Rc 0,R4 R I R6,NH lb Rd Rc a. base 0 R 0 )- R6,I1 —ID* 0./ \S–Ar -- 0 Rd -Rc \ R4 Rd oxidation R i P Rd -Rc O , 'R' 2b Scheme 22cXis a halogenVIII Reaction of phosphorus trihalide with the desired alcohol R4-0H in an inert solvent such as dichloromethane, or an ether like diethyl ether or tetrahydrofuran or the like, in the presence of a base such as triethylamine or similar followed by reaction with an amino acid derivative (1b) in the presence of a base like Et3N or DIEA or similar provides the phosphinamine 2b. Displacement of the remaining halo atom with a thioaryl or thioheteroaryl derivative ArSH, carried out in a solvent like DCM or similar in the presence of a base such as Et3N or similar, provides the thio detivative (2d). Oxidation finally, effected for instance by treatment with mCPBA, tert-butylhydroperoxide or any other convenient oxidation agent, provides the phosphoramidate reagent (VIII).

In another embodiment, a compound of Formula Illa or Formula Illb is provided 0 17 R 0 60R60 N,&N1,,,, "r Rc u S—ArRdRc0 S—Ar \\ A R4R" Formula IllaOrFormula Illb or a salt or ester thereof; wherein: each Ra, R4 or R6 is 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-C28)aryl, heterocyclyl or heteroaryl; M337 prio-lb each Rc or Rd is independently H, (Ci-Cs)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(Ci-Cs)alkyl, heterocyclyl(Ci-Cs)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; each R is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(Ci-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl; wherein each (Ci-Cs)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(Ci-Cs)alkyl, heterocyclyl(Ci-Cs)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(R12, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, S(0)nRa, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra; and each Ar is a (06-020)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-08)haloalkyl, CN, N3, N(R12; C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa, S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4.

In another embodiment of the compound of Formula IIla or Formula 111b, R is H and one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-08)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08)alkyl. In another aspect of this embodiment, R6 is optionally substituted (03- C8)cycloalkyl.ln another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R4 is optionally substituted (06-020)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5- dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R. In another aspect of this embodiment, the moiety of Formula IIla or Formula IIlb comprises a nitrogen-linked ester of a naturally occurring a-amino acid. 0 R6c) Rd 26 M337 prio-lb In another embodiment of the compound of Formula IIla or Formula 111b, R is H, one of R' or Rd is H, R6 is optionally substituted (C1-C8)alkyl and R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, one of R' or Rd is H and the other of R' or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of R' or Rd is H and the other is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2- propyl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is henyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5- dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R' and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to R' and Rd is R. In another aspect of this embodiment, the moiety 1R6c) of Formula IIla or Formula 1111b comprises a nitrogen-linked ester of a naturally occurring a-amino acid.

In another embodiment of the compound of Formula IIla or Formula 111b, R is H, one of R' or Rd is H and the other of R' or Rd is optionally substituted (C1-C8)alkyl, R6 is optionally substituted (01-08)alkyl and R4 is optionally substituted phenyl. In another aspect of this embodiment, one of R' or Rd is H and the other is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2-propyl. In another aspect of this embodiment, R4 is phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5- dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to R' and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to R' and Rd is R. In another aspect of this embodiment, the moiety of Formula IIla or Formula IIlb comprises a nitrogen-linked ester of a naturally occurring a-amino acid. 0 1R6c) R 27 M337 prio-lb In another embodiment of the compound of Formula IIla or Formula IIlb R is H, one of Rc or Rd is H and the other of Rc or Rd is CH3, R6 is optionally substituted (C1-C8)alkyl, and R4 is optionally substituted phenyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2-propyl. In another aspect of this embodiment, R6 is 2-propyl. In another aspect of this embodiment, R4 is phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R. In another aspect of this embodiment, the moiety 0RI R6 IC)NY Rd -Rc of Formula IIla or Formula IIlb comprises a nitrogen-linked ester of a naturally occurring a-amino acid.

In one embodiment, a compound of Formula IIla is provided 07 N , R6 0P j \ R 0- S—Ar \ R4 Formula IIla In another embodiment, a compound of Formula IIlb is provided 0 75 0 //l,. i \ -Rc 0 S—Ar \ R4 R6o Formula Illb In one embodiment of the compound of formula VIII or diastereomer of formula Illa orIllb, R is H and one of Rc and Rd is H.

In one embodiment of the compound of formula VIII or diastereomer of formula Illa orIllb, R6 is optionally substituted (01-08)alkyl or (03-08)cycloalkyl. In one aspect of this embodiment, R6 is methyl, ethyl, 1-methylbutyl, 2-ethylbutyl, cyclopentyl or preferably isopropyl. 28 M337 prio-lb In one embodiment of the compound of formula VIII or diastereomer of formula IIla or 111b, R4 is phenyl.

In one embodiment of the compound of formula VIII or diastereomer of formula IIla or 111b, one of Rc and Rd is H and the other one is CH3. In one aspect of this embodiment, the stereochemistry at the chiral center to which IR' and Rd are attached, is S, i.e. that of an L-amino acid.

In one embodiment of the compound of formula VIII or diastereomer of formula IIla or 111b, Ar is 3,5-dichlorophenyl or pentafluorophenyl.

In another embodiment, compounds of Formula IIla or Formula IIlb are provided which compounds are selected from the group consisting of: =0 EII "Cl-■/''NeF-)s H 0 Oil CI CI =0 _ :II /C)\/*N'1:).

NI H 0 0 S 01 0 CI CI =0 EII /*(:)NNo'F-)s H 0 Oil CI CI =0 _ :II /"()\/;N N'P I H 0 0 S 01 411 CI Cl =0 EII .....,..0"ep.......

N- H( 0 S 01 1100 CI CI =0 EII 0•P,....

N'' IS IIHO 0 1CI CI .....„,- .■-■....0...../...:.,N.,.p......ss =0 EII H 0 111101 CI CI ........- /./C)-■/:', =0 _ :II N'Ij N HO 0 I S Oil CI 1 CI 29 M337 prio-lb ....,...........„...„0 =0 ii P of -`■ z _ 0- 0 F S 0F 4111 F F /...../o ../..... F 0 = 0 II P H 0 F I* Pll F e F F F 0 cr- --,-------Ne H 0(5- F S 1F 41 F F F 0 a 0 E II ,P...... N‘ A H 0 F S si F Si F F F ii ,..0P z _ E =00- F S F F POI F F , , ...........„..........,0 - E 0 I, ,P.,.....

H 0 F . F OP F F F =0 ii P He -`■ Nz ni0(- 0 F S F F POI F F 0 0 = - 0 II N‘ A H ,P 0 F S 0 F 4 1° F F F and or salts or esters thereof.

In another embodiment, a method is provided for the preparation of a compound of Formula VIII 07 0 N, 0lp.' - /\ .-IRc 0 S—Ar \ R4 Formula VIII or a salt or ester thereof, wherein each Ra, R4 or R6 is 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-C)aryl, heterocyclyl or heteroaryl; R6 31 M337 prio-lb each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C28)aryl, heterocyclyl or heteroaryl provided that Rc and Rd are not the same; each R is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbooyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C28)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, 0(0)NH(Ra), C(0)NH2, O0(0)N(R12, 00(0)NH(Ra), O0(0)NH2, 0(0)0Ra, O0(0)0Ra, S(0)nRa S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2N1-12, OR or Ra; and each Ar is (06-020)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-08)haloalkyl, CN, N3, N(Ra)2) 0(0)N(Ra)2, O0(0)N(Ra)2, C(0)0Ra, O0(0)0Ra, 0(0)Ra, OC(0)Ra, S(0)nRa, S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4; said method comprising: providing a chirally pure amino acid ester of Formula IX or a salt thereof 0 R 1 NH Rd Rc Formula IX treating the compound of Formula IX with a compound of Formula X in the presence of a base ? X3-P-X3 1 0,R4 Formula X wherein each X3 is halogen; and treating the resulting mixture with ArSH; 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. dichloromethane, dichloroethane and ethers, e.g. dioxane, tetrahydrofuran, 32 M337 prio-lb diethyl ether 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 generally conducted in the presence of a nonnucleophilic base. Non-limiting examples of non-nucleophilic bases are tertiary amines, e.g. 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 molar 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 molar 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 thiophenolic compound ArSH where Ar is defined as herein. The mole ratio of the compound of Formula X to ArSH is typically about 1.1:1 to about 1:1.1, preferably about 1:1. After the addition of ArSH, 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, R is H and one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (Ci08) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is (03-08) cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5-dichlorophenyl. In another 33 M337 prio-lb aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring a-amino acid.

In another embodiment of the method of preparing a compound of Formula VIII, R is H, one of Rc or Rd is H, R6 is optionally substituted (C1-C8)alkyl, and R4 is optionally substituted (06C)aryl. In another aspect of this embodiment, one of Rc or Rd is H and the other is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other is CH3. In another aspect of this embodiment, R6 is optionally substituted (C1-C8) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2- propyl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5- dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring a-amino acid.

In another embodiment of the method of preparing a compound of Formula VIII, R is H, one of Rc or Rd is H and the other one is optionally substituted (C1-C8)alkyl, R6 is optionally substituted (C1-C8)alkyl, and R4 is optionally substituted phenyl. In another aspect of this embodiment, one of Rc or Rd is H and the other one is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2-propyl. In another aspect of this embodiment, R4 is phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5- dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring alpha-amino acid.

In another embodiment of the method of preparing a compound of Formula VIII, R is H, one of Rc or Rd is H and the other of Rc or Rd is CH3, R6 is optionally substituted (C1-C8)alkyl, and R4 is optionally substituted phenyl. In another aspect of this embodiment, R6 is optionally substituted (01-08) secondary or tertiary alkyl. In another aspect of this embodiment, R6 is optionally substituted 2-propyl. In another aspect of this embodiment, R6 is 2-propyl. In another aspect of this embodiment, R6 is (C3-08)carbocycly1 In another aspect of this embodiment, R4 is phenyl. In 34 M337 prio-lb another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, Ar is phenyl which is substituted with 1-5 halogen atoms. In another aspect of this embodiment, Ar is pentafluorophenyl. In another aspect of this embodiment, Ar is 3,5- dichlorophenyl. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is S. In another aspect of this embodiment, the chirality at the carbon directly attached to Rc and Rd is R. In another aspect of this embodiment, the compound of Formula IX or salt thereof, is an ester of a naturally occurring a-amino acid.

In another embodiment of the method for preparing a compound of Formula la or lb or a pharmaceutically acceptable salt or ester thereof, Formula la is Formula Xla, Formula lb is Formula Xlb and Formula 11 is Formula XII: R8 NR9 RN1 "11R7 HR1 Rd R22-R2 Formula XlaFormula Xlb R8 R R6N 1p ,,, # -..o""P 4 0 Rd RC OR4 HOR9 HI""IR7 R22 Formula XII wherein: each R1 is independently H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; each R2 is independently halogen or OR11; each R is H; each R22 is OR11, and the remaining variables are defined as for Formulae la or lb or 11 or Illa or 111b.

In one embodiment of the method for preparing a compound of Formula Xla or Formula Xlb from a compound of Formula XII, X1 is CR. In another aspect of this embodiment, R1° is H. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is F. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R1 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R1 is methyl. In M337 prio-lb another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted ethenyl. In another aspect of this embodiment, R1 is optionally substituted (C2-08)alkynyl. In another aspect of this embodiment, R1 is optionally substituted ethynyl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-08)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C3-C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (06-020)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl.

In another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb from a compound of Formula XII, X1 is CH, R1 is H, Cl or CH3 and one of Rc or Rd is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is CI and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (01-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C3- C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (06-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8is NR11-1-<12. In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R9 is OH. In another aspect of this embodiment, R9 is H. In another aspect of this embodiment, R9 is NR11-1-‹02.

In another aspect of this embodiment, R9 is OR11. In another aspect of this and R9 is NR11R12. is NwiRi2 36 M337 prio-lb In another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb from a compound of Formula XII, X1 is CH, R1 is H, Cl or CH3, one of Rc or Rd is H and R7 is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R 22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl and R22 is OH. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (0308) cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR11-1-‹12. In another aspect of this embodiment, R8 is OR11 . In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH. In another aspect of this embodiment, R9 is H. In another aspect of this embodiment, R9 is NRii.-I-K 12. In another aspect of this embodiment, R9 is OR11. In another aspect of this embodiment, R8 is NR11R12 and R9 is H. In another aspect of this embodiment, R8 is NH2 and R9 is H. In another aspect of this —— embodiment, R8 is NR111-<12is NR11I-K12. and R9In another aspect of this embodiment, R8 is NH2 and R9 is NH2. In another aspect of this embodiment, R8 is OR11 and R9 is NH2. In another aspect of this embodiment, R8 is OH and R9 is NH2.

In one embodiment of the method for preparing a compound of Formula Xla or Formula Xlb from a compound of Formula XII, X1 is N. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is F. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R1 is optionally substituted (01-08)alkyl. In another aspect of this embodiment, R1 is methyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted ethenyl. In another aspect of this embodiment, R1 is optionally substituted (02-08)alkynyl. In another aspect of this embodiment, R1 is optionally substituted ethynyl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl and R22 is OH. In another aspect of this embodiment, each R1 is Cl and each R2 is F. In another aspect of this embodiment, each R1 is CH3 and each R2 is Cl. In another aspect of this embodiment, each R1 and R2 is Cl. In another 37 M337 prio-lb aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is optionally substituted (02- C8)alkynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C3-C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-020)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl.

In another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb from a compound of Formula XII, X1 is N, R1 is H, Cl or CH3 and one of War Rd is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl and R22 is OH. In another aspect of this embodiment, each R1 is Cl and each R2 is F. In another aspect of this embodiment, each R1 is CH3 and each R2 is Cl. In another aspect of this embodiment, each R1 and R2 is Cl. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is optionally substituted (02- C8)alkynyl. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is CN. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R4 is optionally substituted (06-020)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR11R12 In another aspect of this embodiment, R9 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH. In another aspect of this embodiment, R9 is H. In another aspect of this embodiment, R9 is NR11-12. In another aspect of this embodiment, R9 is OR11. In another aspect of this embodiment, R8 is NR11N-1-<12 and R9 is H. In another aspect of this embodiment, R8 is NR11R12 and R9 is NR11R12.

In another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb from a compound of Formula XII, X1 is N, R1 is H, Cl or CH3, one of Rc or Rd is H and R7 is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is CI.In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment, R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl 38 M337 prio-lb and R22 is OH. In another aspect of this embodiment, each R1 is CI and each R2 is F. In another aspect of this embodiment, each R1 is CH3 and each R2 is Cl. In another aspect of this embodiment, each R1 and R2 is Cl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C3-C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another .-12 aspect of this embodiment, R8 is NRii I-KIn another aspect of this embodiment, R8 is OR11 In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH. In another aspect of this embodiment, R9 is H. In another aspect of this embodiment, R9 is 1-< In another aspect of this embodiment, R9 is OR11. In another aspect of this - embodiment, R8 is NR11 1-<12 and R9 is H. In another aspect of this embodiment, R8 is NH2 and R9 is H. In another aspect of this embodiment, R8 is NR11R12 and R9 is NRii.-1-<12.

In another aspect of this embodiment, R8 is NH2 and R9 is NH2. In another aspect of this embodiment, R8 is OR11 and R9 is NH2. In another aspect of this embodiment, R8 is OH and R9 is NH2.

In another embodiment of the method for preparing a compound of Formula la or lb or a pharmaceutically acceptable salt or ester thereof, Formula la is Formula X111a, Formula lb is Formula XIllb and Formula 11 is Formula XIV: 0 R40/o, II R 0 Rc R6-0Rd Formula XIllb H R6o Formula XIlla HO Formula XIV 39 M337 prio-lb wherein: each R1 is independently H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; each R2 is independently halogen or OR11; each R is H; each R22 is OR11 and the remaining variables are defined as for Formulae la or lb or 11 or IIla or 111b.

In one embodiment of the method for preparing a compound of Formula XIlla or Formula XIllb from a compound of Formula XIV, X1 is CR. In another aspect of this embodiment, R1° is H. In another aspect of this embodiment, R1° is CH3. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is F. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R1 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R1 is methyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted ethenyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R1 is optionally substituted ethynyl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl and R22 is OH. In another aspect of this embodiment, each R1 is Cl and each R2 is F. In another aspect of this embodiment, each R1 is CH3 and each R2 is Cl. In another aspect of this embodiment, each R1 and R2 is CI.In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is optionally substituted (C2- C8)alkynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of IR' or Rd is H. In another aspect of this embodiment, one of IR' or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C3-C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl.

In another embodiment of the method for preparing a compound of Formula XIlla or Formula XIllb from a compound of Formula XIV, X1 is CH, R1 is H, Cl or CH3 and one of RC or Rd is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl M337 prio-lb and R22 is OH. In another aspect of this embodiment, each R1 is Cl and each R2 is F. In another aspect of this embodiment, each R1 is CH3 and each R2 is Cl. In another aspect of this embodiment, each R1 and R2 is Cl. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is optionally substituted (02- C8)alkynyl. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is CN. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR11-I-K12. In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH.

In another embodiment of the method for preparing a compound of Formula XIlla or Formula XIllb from a compound of Formula XIV, X1 is CH, R1 is H, Cl or CH3, one of Rc or Rd is H and R7 is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl and R22 is OH. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-08)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08)alkyl. In another aspect of this embodiment, R4 is optionally substituted (06C)aryl. In another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR11-1-<12. In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH.

In one embodiment of the method for preparing a compound of Formula XIlla or Formula XIllb from a compound of Formula XIV, X1 is CF. In another aspect of this embodiment, R1 is H. In another aspect of this embodiment, R1 is F. In another aspect of this embodiment, R1 is Cl. In another aspect of this embodiment, R1 is optionally substituted (01-08)alkyl. In another aspect of this embodiment, R1 is methyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkenyl. In another aspect of this embodiment, R1 is optionally substituted ethenyl. In another aspect of this embodiment, R1 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R1 is optionally substituted ethynyl. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, 41 M337 prio-lb each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is Cl and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (C1-C8 )alkyl. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (01-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (03- C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (C6-C20)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl.

In another embodiment of the method for preparing a compound of Formula Xla or Formula Xlb from a compound of Formula XII, X1 is CF, R1 is H, CI or CH3 and one of Rc or Rd is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is CI and R22 is OH. In another aspect of this embodiment, R7 is H. In another aspect of this embodiment, R7 is optionally substituted (01-08)alkyl. In another aspect of this embodiment, R7 is CH3. In another aspect of this embodiment, R7 is optionally substituted (C2-C8)alkynyl. In another aspect of this embodiment, R7 is ethynyl. In another aspect of this embodiment, R7 is ON. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (01-C8)alkyl. In another aspect of this embodiment, R6 is optionally substituted (01-08)alkyl. In another aspect of this embodiment, R4 is optionally substituted (06C)aryl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NR11-1-<02. In another aspect of this embodiment, R8 is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is OH.

In another embodiment of the method for preparing a compound of Formula XIlla or Formula XIllb from a compound of Formula XIV, X1 is CF, R1 is H, CI or CH3, one of Rc or Rd is H and R7 is H. In another aspect of this embodiment, R2 is F. In another aspect of this embodiment, R2 is Cl. In another aspect of this embodiment, R2 is OH. In another aspect of this embodiment R22 is OH. In another aspect of this embodiment, each R2 and R22 is OH. In another aspect of this embodiment, each R2 is F and R22 is OH. In another aspect of this embodiment, each R2 is CI and R22 is OH. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl. In another aspect of this embodiment, one of Rc or Rd is H and the other of Rc or Rd is CH3. In another aspect of this embodiment, R6 is optionally substituted (01-08)alkyl. In another aspect of this embodiment, R6 is optionally substituted (03- C8)cycloalkyl. In another aspect of this embodiment, R4 is optionally substituted (06-C20)aryl. In 42 M337 prio-lb another aspect of this embodiment, R4 is optionally substituted phenyl. In another aspect of this embodiment, Ar is optionally substituted phenyl. In another aspect of this embodiment, R8 is NRii R12. In another aspect of this embodiment, R8is OR11. In another aspect of this embodiment, R8 is NH2. In another aspect of this embodiment, R8 is 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 1" means a compound of Formula 1 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-C2oalkyl), 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-l-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2- methy1-2-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-methyl2-butyl (-OH(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-methy1-2- pentyl (-CH(CH3)CH(CH3)0H20H3), 4-methyl-2-pentyl (-OH(CH3)CH2CH(CH3)2), 3-methy1-3- pentyl (-C(0H3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethy1-2-butyl (- C(CH3)2CH(CH3)2), 3,3-dimethy1-2-butyl (-CH(0H3)C(0H3)3, and octyl (-(0H2)70H3).

"Alkoxy" means a group having the formula -0-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. 01-C2oalkoxy), 1 to 12 carbon atoms(i.e. CI-Cu alkoxy), or 1 to 6 carbon atoms (i.e. C1-C6alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-0-CH3 or -0Me), ethoxy (-0CH2CH3 or -0Et), t-butoxy (-0-C(CH3)3 or -0tBu) 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-C2ohaloalkyl), 1 to 12 carbon atoms (i.e. C1-C12haloalkyl), or 1 to 6 43 M337 prio-lb 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, sp2 double bond. For example, an alkenyl group can have 2 to 20 carbon atoms (i.e. 02-020 alkenyl), 2 to 8 carbon atoms (i.e. 02-08 alkenyl), or 2 to 6 carbon atoms (i.e. C2-C6alkeny1). Examples of suitable alkenyl groups include, but are not limited to, ethylene or vinyl (-CH=CH2), ally! (-CH2CH=CH2), cyclopentenyl (-05H7), and 5-hexenyl (-CH2CH2CH2CH2CH=0H2).

"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. 02-0 alkynyl), 2 to 8 carbon atoms (i.e. 02-C8 alkynyl), or 2 to 6 carbon atoms (i.e. 02-06 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenic (-CECH), propargyl (-CH2CECH), 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(0H3)-), 1,2-ethyl (-0H20H2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(0H3)-), 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, an 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 (-CEO-), propargyl (-CH2CEC-), and 4-pentynyl (-CH2CH2CH2CEC-).

"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 sp3. Nonlimiting types of amino include -N H2, - N(alkyl)2, -NH(alkyl), -N(carbocycly1)2, - NH(carbocycly1), -N(heterocycly1)2, -NH(heterocycly1), - 44 M337 prio-lb N(aryl)2, -NH(ary1), - N(alkyl)(ary1), -N(alkyl)(heterocycly1), -N(carbocyclyI)(heterocycly1), - N(ary1)(heteroary1), -N(alkyl)(heteroary1), 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(benzy1)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(0)-0H), - NH(alkylene-C(0)-0-alkyl), -N(alkylene-C(0)-0H)2, -N(alkylene-C(0)-0-alky1)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 sp3 carbon 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-y1 and the like. The arylalkyl group can comprise 7 to 20 carbon atoms, e.g., the alkyl moiety is 1 to 6 carbon atoms and the aryl moiety is 6 to 14 carbon atoms.

"Arylalkenyl" refers to an acyclic alkenyl radical in which one of the hydrogen atoms bonded to a carbon atom, typically a terminal or sp3 carbon atom, but also an sp2 carbon atom, is replaced with an aryl radical. The aryl portion of the arylalkenyl can include, for example, any 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 sp3 carbon atom, but also an sp2 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 carbocycly1" means, M337 prio-lb 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, -Rb, -0-, =0, -ORb, -SRb, -S-, -NRb2, -N+Rb3, =NRb, -CX3, -CN, -OCN, -SCN, -N=C=O, -NCS, -NO, -NO2, =N2, -N3, - NHC(=0)Rb, -0C(=0)Rb, -NHC(=0)NRb2, -S(=0)2-, -S(=0)20H, -S(=0)2Rb, -0S(.0)20Rb, - S(=0)2NRb2, -S(=0)Rb, -0P(=0)(0Rb)2, -P(=0)(0Rb)2, -P(=0)(0R-)2, -P(=0)(OH)2, - P(0)(0Rb)(0), -C(=0)Rb, -C(=0)X, -C(S)Rb, -C(0)0Rb, -C(0)0-, -C(S)ORb, -C(0)SRb, - C(S)SRb, -C(0)NRb2, -C(S)NRb2, -C(=NRb)NRb2, where each X is independently a halogen: F, Cl, Br, or I; and each Rb is independently H, alkyl, aryl, arylalkyl, a heterocycle, or a protecting group or prodrug moiety. Alkylene, alkenylene, and alkynylene groups may also be similarly substituted. Unless otherwise 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, 0, 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., 0, 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., 0, N, or S) the resulting heteroalkyl groups are, respectively, an alkyl ether (e.g., -CH2CH2-0-CF13, etc.), an alkyl amine (e.g., -CH2NHCH3, -CH2N(CH3)2, etc.), or a thioalkyl ether (e.g.,-CH2-SCH3). If a terminal carbon atom of the alkyl group is replaced with a heteroatom (e.g., 0, N, or S), the resulting heteroalkyl groups are, respectively, a hydroxyalkyl group (e.g.,-CH2CH2-0H), an aminoalkyl group (e.g., -CH2NH2), or an alkyl thiol group (e.g. -CH2CH2-SH). A heteroalkyl group can have, for example, Ito 20 carbon atoms, Ito 10 carbon atoms, or 1 to 6 carbon atoms. A C1-C6 heteroalkyl group means a heteroalkyl group having 1 to 6 carbon atoms. 46 M337 prio-lb "Heterocycle" or "heterocycly1" 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. 0, N, or S). The terms "heterocycle" or "heterocycly1" 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: ,N N \ yH 0 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, 6H1,2,5-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, 13- 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: 0 . 1 -"0--.

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, 47 M337 prio-lb 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, 6pyridazinyl, 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 13-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 sp3 carbon atom, is replaced with a heterocyclyl radical (i.e. a heterocyclyl-alkylene- moiety). Typical heterocyclylalkyl 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 Modem Heterocyclic Chemistry. One skilled in the art will also understand that the heterocyclyl group can be attached to the alkyl portion of the heterocyclyl alkyl by means of a carbon-carbon bond or a carbon-heteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclyl alkyl group comprises 3 to 20 carbon atoms, e.g., the alkyl portion of the arylalkyl group is 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-l-yl, imidazolylmethyl, oxazolylmethyl, thiadiazolylmethyl, etc., 6-membered sulfur, oxygen, and/or nitrogen containing heterocycles such as piperidinylm ethyl, 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 sp3 carbon atom, but also a sp2 carbon atom, is replaced with a heterocyclyl radical (i.e. a heterocyclyl-alkenylene-moiety). The heterocyclyl portion of the heterocyclylalkenyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkenyl portion of the heterocyclylalkenyl 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 heterocyclylalkenyl by means of a carbon-carbon bond or a carbonheteroatom bond, with the proviso that the resulting group is chemically stable. The 48 M337 prio-lb heterocyclylalkenyl group comprises 4 to 20 carbon atoms, e.g., the alkenyl portion of the heterocyclylalkenyl 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 sp3 carbon atom, but also an sp2 carbon atom, is replaced with a heterocyclyl radical (i.e. a heterocyclylalkynylene- moiety). The heterocyclyl portion of the heterocyclylalkynyl group includes any of the heterocyclyl groups described herein, including those described in Principles of Modern Heterocyclic Chemistry, and the alkynyl portion of the heterocyclylalkynyl 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 heterocyclylalkynyl by means of a carbon-carbon bond or a carbonheteroatom bond, with the proviso that the resulting group is chemically stable. The heterocyclylalkynyl 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(0)(alkyl, aryl, alkylaryl, or arylalkyl), N6-benzylpurine, N6- halopurine, N6-vinylpurine, N6-acetylenic purine, N6-acyl purine, N6-hydroxyalkyl purine, N6- allylaminopurine, N6-thioallylpurine, N2-alkylpurines, N-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, C-alkylpyrimidines, C- benzylpyrimidines, C-halopyrimidines, C-vinylpyrimidine, C- acetylenic pyrimidine, C-acyl pyrimidine, C-hydroxyalkyl purine, C-amidopyrimidine, C-cyanopyrimidine, C-5- iodopyrimidine, C6-iodo-pyrimidine, C- Br-vinyl pyrimidine, C6-Br- vinyl pyrimidine, C- nitropyrimidine, C-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 [12,4]triazolo[4,3- f][1,2,4]triazines, all of which are optionally substituted. The purine and pyrimidine bases of Formula ll are linked to the ribose sugar, or analog thereof, through a nitrogen atom or carbon 49 M337 prio-lb 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 tbutyldiphenylsilyl, trityl, alkyl groups, and acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl.

"Carbocycle" or "carbocycly1" 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 bicyclocarbocycles includes naphthyl, tetrahydronapthalene, and decaline.

"Carbocyclylalkyl" refers to 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- 0-aryl, -alkylene-O-alkylene-aryl, -alkylene-NH-aryl, -alkylene-NH-alkylenearyl, -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-earbazolyl, -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)- M337 prio-lb carbazoly1,-CH(CH3)-imidazolyl, -OH(CH3)-thiazolyl, -CH(0H3)-isoxazoly1,-OH(0H3)-pyrazolyl, - CH(0H3)-isothiazolyl, -CH(CH3)-quinoly1,-CH(0H3)-isoquinolyl, -CH(0H3)-pyridazyl, -CH(0H3)- pyrimidyl, -OH(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 substituents 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 lXIV (e.g., the carbon atoms of said (C1-C8)alkyl may be optionally replaced by -0-, -S-, or -NRa-) means that one or more of the methylene groups of the (C1-08)alkyl may be replaced by 0, 1, 2, or more of the groups specified (e.g., -0-, -S-, or -NRa-).

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

"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, JeffamineTm); 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 0R R6N Rd Rc which may comprise a radical of a nitrogen-linked ester of a naturally occurring alpha 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 51 M337 prio-lb described for the substitutent R6, particularly those in which R6 is 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 substituents needed to provide a valence of four should be assumed to be hydrogen. For example, R N. .0 \ R40 0 H"' " has the same meaning as R R5„.J,tr4 .

„. ./ R\ .\\ ; --H ..0 7 "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 cr 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 52 M337 prio-lb 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 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.

It is to be noted that all enantiomers, diastereomers, and racemic mixtures, tautomers, polymorphs, pseudopolymorphs of compounds within the scope of Formula l- 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 53 M337 prio-lb 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, Nat, Lit, Kt, Cal-2 and Mg+2, ammonium and NRa4+ (wherein Ra is 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 Nat and NRa4+. 54 M337 prio-lb 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 Rc and Rd of 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 5 M337 prio-lb under high resolution analytical procedures such as electrophoresis, crystallization and/or chromatography. Diastereomers may have different physical attributes such as, but not limited to, solubility, chemical stabilities and crystallinity and may also have different biological properties sue 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 Elie!, 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 I, D and L, or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with S, (-), or I 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., "Ra" 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, tArtnrkfurxr , 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: 56 M337 prio-lb OH N'NH Re ‘.* 'OH 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 N. All such isotopic variations of these molelcules are provided by the instant invention.

Detailed Description of the Embodiments Various embodiments of the invention will now be illustrated by the following examples. The Examples are just intended to further illustrate the invention and are by no means limiting the scope of the invention. The compound names were generated by Chem Draw Ultra software, Cambridgesoft, version 12.0.2.

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.

Acacetyl Bzbenzoyl DCMdichloromethane DIBAIDiisobutylaluminium hydride DMAP4-dimethylaminopyridine DME1,2-dimethoxyethane DMSOdimethylsulfoxide 57 DMFdimethylform amide drdiastereomeric ratio Et0Acethyl acetate ESelectrospray ionization ES+electrospray ionization positive mode ES-electrospray ion izationnegative mode HMDShexamethyldisilazane HPLCHigh performance liquid chromatography LDAlithium diisopropylamide mCPBAmeta-chloroperbenzoic acid MeCNacetonitrile Me0Hmethanol m/z or m/emass to charge ratio [MH]+mass plus 1 [MHTmass minus 1 Ms0Hmethanesulfonic acid Msmethanesulfonyl MS or msmass spectrum NBSN-bromosuccinimide NCSN-chlorosuccinimide NFSIN-fluorobenzenesulfonimide NMRnuclear magnetic resonance rtroom temperature TBAFtetrabutylammonium fluoride TMSCIchlorotrimethylsilane TMSBrbromotrimethylsilane TMSIiodotrimethylsilane TEA or Et3Ntriethylamine TBAtributylamine TBAPtributyl ammonium pyrophosphate TBSCIt-butyldimethylsilyl chloride TEABtriethylammonium bicarbonate TFAtrifluoroacetic acid TIPStriisopropylsilyl TIPS-CItriisopropylsilyl chloride TLCthin layer chromatography Trtriphenylmethyl 58 M337 prio-lb Tol4-methylbenzoyl 6parts per million down field from tetramethylsilane Example R1 o II _ 1=) ONH2 CI" I CI OPh ,.. p-F-Ph-SH ,.. 0Et3NEt3N - 0 0 R1 (2S)-Isopropyl 2-((((4-fluorophenyl)thio)(phenoxy)phosphoryl)amino)propanoate (R1) Phenyl dichlorophosphate (1.30 g, 6.14 mmol) was added under nitrogen to a solution at -10 °C of (S)-isopropyl 2-aminopropanoate hydrochloride (1.03 g, 6.14 mmol) in DCM (10 mL) followed by dropwise addition of triethylamine (2 eq.) over 20 min. The mixture was stirred between -10 °C and 0°C for 1h, then cooled to -100°C and a solution of 4-fluorothiophenol in DCM (2 mL) was added followed by dropwise addition of triethylamine (1.1 eq.) over 10-15min. The reaction was stirred for 30 min, then solids were filtered off and the solids were washed with DCM (mL) and discarded. The solution was concentrated, the residue taken into ethyl acetate (15 mL) and remaining solids were removed by filtration and the solids were washed with ethyl acetate (5 mL). The solution was concentrated and the residue dried under vacuum which gave the title compound as a colourless oil (2.33 g, 95%). 31P-NMR showed a 1:1 mixture of P-diastereomers. The racemic reagent was used in coupling to the nucleoside.

Example R2 0,1NH2 0 0 Cl''Cl C 1 CI OPh ,.. F-Ph-SH ,..

Et3NEt3N R2 (2S)-Isopropyl 2-((((perfluorophenyl)thio)(phenoxy)phosphoryl)amino)propanoate (R2) Phenyl dichlorophosphate (2.60 g, 11.9 mmol) was added under N2 to a solution at -10 °C of (S)-isopropyl 2-aminopropanoate hydrochloride (2.00 g, 11.9 mmol) in dry DCM (20 mL) followed by dropwise addition of Et3N (2.1 Eq.) over 20 min. The thick white slurry was stirred at -10 °C for 45 min, then pentafluorophenol (2.46 g, 11.9 mmol) in dry DCM (4 mL) was added via syringe followed by dropwise addition of Et3N (1.1 eq.) over 10 min. The reaction mixture was stirred at -10 °C for 30 min, then the precipitate was filtered off and the filtrated was diluted with methyl tert-butyl ether (40 mL). The organic layer was washed with HCI (0.1 M aq.), twice with KHCO3 (sat. aq.), dried (MgSO4) and concentrated under reduced pressure. The residue was 59 M337 prio-lb purified by flash chromatography (hexane:Et0Ac 5:1) which gave a diastereomeric mixture on the P-atom of the title compound; one pure fraction (900 mg, 16%, diastereomeric ratio 44:56) and one impure fraction (1.05 g, 19%, diastereomeric ratio: 85:15). MS (ES-'-) 470.00 [M-'-H].

Crystallization: The impure fraction was dissolved in hexanes and concentrated twice, then dissolved in hexanes (5 mL). Crystallization was induced by scratching and cooling in an ice-bath, then the slurry was left at room temperature for 72h. The crystals were filtered off and washed with cold hexanes which gave a single diastereomer at the P-atom of the title compound as colourless needles (166 mg, 9%, dr >95:5 according to 19F- and 31P-NMR).

The mother liquor was concentrated and the crystallization was repeated using hexanes (5 mL) which gave further single diastereomer of the title compound (150 mg, 8%, dr >95:5 according to 19F- and 31P-NMR).

The purified 44:56-diastereomeric mixture from above (700 mg) was dissolved in hexanes (5 mL), cooled to 0 °C and seeded with crystals of single diastereomer (5 mg). The mixture was stored at 4 °C over night, then formed crystals were filtered off and washed with cold hexanes which gave further single diastereomer of the title compound as large colourless needles (120 mg, 6%, dr >95:5 according to 19F- and 31P-NMR).

Example R3 Cl o ig,= ci- 1 a9 .C)NH2OPh3,5-d i-CI-Ph-SHCl CI 0Et3N Et3N0 HO R3 ((2S)-Isopropyl 2-((((3,5-dichlorophenyl)thio)(phenoxy)phosphoryl)amino)propanoate (R3) Phenyl dichlorophosphate (3.78 g, 17.9 mmol) was added under nitrogen to a solution at -10 °C of (S)-isopropyl 2-aminopropanoate hydrochloride (1.03 g, 6.14 mmol) in DCM (36 mL) followed by dropwise addition of triethylamine (2.1 eq.) over 20 min. The mixture was stirred between -10 °C and 0 °C for 45 min. The temperature was lowered to -10 °C and a solution of 3,5- dichlorothiophenol in DCM (8 mL) was added followed by dropwise addition of triethylamine (1.1 eq.) over 10-15 min. The reaction was stirred for 30 min, then concentrated. The residue was dissolved in isopropyl acetate (60 mL) and solids were filtered off, washed with isopropyl acetate (2x10 mL) and discarded. The organic layer was washed with an aqueous solution of KHCO3 (5%, 2x20 mL), dried (Na2SO4), filtered and concentrated. The afforded crude product was purified by column chromatography on silica eluted with 25% Et0Ac in hexanes, which gave the title compound as a mixture of diastereomers at the P-atom (4.82 g, 60%). 60 M337 prio-lb Example R4 0 II:' CI' 1 CI C)NH2 OPh ip. p-CI-Ph-SH 0Et3NEt3N )0- CI R4 (2S)-Isopropyl 2-((((4-chlorophenyl)thio)(phenoxy)phosphoryl)amino)propanoate (R4) Phenyl dichlorophosphate (2.56 g, 12.1 mmol) was added under nitrogen to a solution at -10 °C of (S)-isopropyl 2-aminopropanoate hydrochloride (2.03 g, 12.1 mmol) in DCM (36 mL) followed by dropwise addition of triethylamine (2.1 eq.) over 20 min. The mixture was stirred between -10 °C and 0 °C for 45 min. The temperature was lowered to -10 °C and a solution of 4- dichlorothiophenol in DCM (4 mL) was added followed by dropwise addition of triethylamine (1.1 eq.) over 10-15 min. The reaction was stirred for 30 min, then concentrated. The residue was dissolved in tert-butyl methyl ether (40 mL) and solids were filtered off, washed with tert-butyl methyl ether (2x10 mL) and discarded. The organic combined layers were washed twice with saturated KHCO3, dried (Na2SO4), filtered and concentrated. The afforded crude product was purified by column chromatography on silica eluted with 30% Et0Ac in hexanes, which gave the title compound as a mixture of diastereomers at the P-atom (4.00 g, 80%). MS (ES-) 412.02 [MH].

Example Cl RO To1O—Nc Step c Cl Cl Cl Step a 0- \-0OHO OH CIStep d z To C1 c Step b ( Cla, R = H Clb, R = Tol Step e 0 N NHBz TolOA ClStep f Tolo Cl Cle _ ToIo Cl Cid To R3 t-BuMgCI Step h 0 II 0-P-OPh Cl OPh 9 N .- ,....„.r0..............--....17..0 I-1 0 0 0 r.-,i- N NH (C10 Ho Cl Cl H N 0 N.

RO—,N.- CI RO CI / Cif, R = Tol Step g k Clg, R = H Step a) (4R,5R)-3,3-Dichloro-4-hydroxy-5-(hydroxymethyl)dihydrofuran-2(3H)-one lactone formation (C1a) 61 M337 prio-lb A solution of (R)-isopropyl 2,2-dichloro-4-((S)-2,2-dimethy1-1,3-dioxolan-4-y1)-3- hydroxybutanoate (16.4 g, 54.3 mmol) prepared as described in J. Chem. Perkin Trans I, 1982, 2063-2066, in acetonitrile (150 mL), water (4.2 mL) and TFA was refluxed for 3 hours, then p-toluene sulfonic acid monohydrate (516 mg, 2.71 mmol) and toluene (60 mL) were added. The solvent was distilled off and new portions of toluene (3x60 mL) were added during the distillation, which lasted about three hours. The reaction solution was concentrated in vacuo and used crude in the next step.

Step b) (2R,3R)-4,4-Dichloro-2-(((4-methylbenzoyl)oxy)methyl)-5-oxotetrahydrofuran-3-y14- methylbenzoate (Cl b) Et3N (16.5 g, 163 mmol) was added at 0 °C to a solution of the crude compound Cl a in dry THF followed by drop wise addition of p-toluoyl chloride (21.9 g, 136 mmol). The mixture was stirred at rt over night, then cooled to 0 °C and DMAP (332 mg, 2.71 mmol), Et3N (1.65 g, 16.3 mmol) and p-toluoyl chloride were added. The mixture was stirred for 2 h at rt then the reaction was quenched with Me0H. Most of the THF was removed in vacuo and about of Et0Ac (500 mL) was added. The organic phase was washed twice with 0.5M HCI, once with a saturated solution of sodium hydrogen carbonate and once with brine. The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The product was crystallized from isohexane (50 mL) and toluene (25 mL). The crystals were filtered of, washed with isohexane (50 mL) then toluene:isohexane 2/1, and dried in vacuo. The mother liquid was concentrated and purified by chromatography on a short silica column eluted with isohexane and 20% Et0Ac. The product was crystallized from isohexane and dried in vacuo. Total yield: 20.7 g, 87%.

Step c) (2R,3R)-4,4-dichloro-5-hydroxy-2-(((4-methylbenzoyl)oxy)methyl)tetrahydrofuran-3-y14- methylbenzoate (Cl c) A 1M solution of lithium tri-tert-butoxyaluminohydride (52.1 mL, 52.1 mmol) was added drop wise at -25 °C to a solution of Olb (19.0 g, 43.4 mmol) was dissolved in dry THF (180 mL) the reaction was stirred for 15 min at -20°C. The cooling bath was removed and the reaction was allowed to come to 10°C. The reaction was quenched with saturated ammonium chloride solution (400 ml) and crashed ice. Et0Ac (400 ml) was added and the mixture was stirred for 1 h . The organic phase was separated and the water phase was extracted four times with of Et0Ac (4 x 100m1). The combined organic phases were washed with 0.5M HCI (150 mL), brine (2 x 100 mL), dried (Na2SO4), filtered and concentrated. The afforded crude product was used in the next step without further purification Step d) (2R,3R)-4,4-Dichloro-5-((diphenoxyphosphoryl)oxy)-2-(((4-nnethylbenzoyl)oxy)methyl)- tetrahydrofuran-3-y14-methylbenzoate (Old) 62 M337 prio-lb A solution of phosphoric acid diphenyl ester chloride in toluene (40 mL) was added drop wise at 10°C to a solution of the crude product from previous step in a mixture of toluene (140 mL) and Et3N (5.25 g, 51.9 mmol). The mixture was stirred at rt for 64h, then cooled to 0 °C, and a mixture of 1M HCI (50 mL) diluted with Et0Ac (200 mL) was added. The phases were separated and the organic phase was washed with water, saturated sodium hydrogen carbonate solution and brine. The organic phase was dried (Na2SO4), filtered and concentrated. The product was crystallized from isopropanol / Et0Ac and dried under vacuum which gave 11.8 g of the title compound. The mother liquid was concentrated and the residue crystallized from isopropanol dried under vacuum which gave further 7.5 g of the title compound. The mother liquid was concentrated and purified by silica gel chromatography eluted with isohexane and 5 to 10% Et0Ac which gave further 8.5 g of the title compound. Total yield: 96%. MS (ES+) 688.1 [M+NH4].

Step e) (2R,3R,5R)-5-(4-benzamido-2-oxopyrimidin-1(2H)-y1)-4,4-dichloro-2-(((4- methylbenzoyl)oxy)methyptetrahydrofuran-3-y14-methylbenzoate (Cl e) A suspension of N-benzoyl cytosine (1.92 g, 8.94 mmol) and ammonium sulfate (4.72 mg, 0.036 mmol) in HDMS (13.6 mL, 65.4 mmol) was boiled under argon for two hours, then cooled to rt and concentrated in vacuo. The residue was dissolved in chlorobenzene (100 mL) and a solution of C1d (3.00 g, 4.49 mmol) in chlorobenzene (70 mL) was added under argon. Tin (IV) tetrachloride was added drop wise at rt and the mixture was refluxed for 90 min. The reaction was cooled and poured into a saturated solution of ammonium chloride. The product was extracted four times with Et0Ac and the combined organic phases were washed with brine, dried (Na2SO4), filtered and concentrated. The product was purified by silica gel chromatography with DCM and 2 to 4% methanol and then crystallized from ethanol. Yield 1.11 g, 35% Step f) (2R,3R,5R)-4,4-Dichloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yI)-2-(((4- methylbenzoyl)oxy)methyl)tetrahydrofuran-3-y14-methylbenzoate (Cif) A suspension of Cl e (1.06 g, 1.33 mmol) in 70% acetic acid was refluxed for 20h, then concentrated onto silica and purified by silica gel column chromatography eluted with DCM and 0 to 20% ethyl acetate, which gave the title compound (537 mg, 76%). MS (ES+) 533.0 [M+H].

Step g) 1-((2R,4R,5R)-3,3-Dichloro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)pyrimidine2,4(1H,3H)-dione (C1g) A suspension of Cif (2.78 g, 5.21 mmol) in 7M ammonia in methanol (110 mL) was stirred overnight at rt. TLC not ready. The reaction was allowed to stay over weekend at rt. The 63 M337 prio-lb mixture was evaporated on silica gel and purified by column chromatography with DCM and 3 to 10% methanol and diethyl ether and 4% methanol. The product was dried in vacuo. Yield 558 mg, 36%. MS (ES-'-) 297.0 [M4-H]. 1H NMR (500 MHz, DMSO-d6) 6 11.57 (s, 1H, 14), 8.06 (d, J = 8.2 Hz, 1H, 12), 6.76 (d, J = 6.3 Hz, 1H, 6), 6.41 (s, 1H, 7), 5.72 (dd, J = 8.1, 1.4 Hz, 1H, 17), 5.47 (t, J = 4.6, 4.6 Hz, 1H, 13), 4.35 — 4.27 (m, 1H, 2), 3.87 — 3.76 (m, 2H), 3.68 — 3.62 (m, 2H). 130 NMR (126 MHz, DMSO-d6) 6 162.60, 150.29, 138.96, 101.93, 93.47, 90.12, 81.38, 75.36, 66.23, 58.01, -0.00.

Step h) (25)-Isopropyl 2-(((((2R,3R,5R)-4,4-dichloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yI)- 3-hydroxytetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate (Cl) A flame dried two-necked flask was loaded with sugar Cif (100 mg, 0.337 mmol) and the system placed under nitrogen. THF (2 mL) was added and the suspension was gently heated to obtain a clear solution. The solution was cooled to -10 °0 and a solution of tert-butylmagnesium chloride in THF was added dropwise. DMPU (0.9 mL) was added and the mixture was stirred at room temperature for 10 min. A solution of reagent R3 (181 mg, 0.404 mmol) in THF (1 mL) was added and the resulting mixture was stirred at room temperature overnigh. The reaction was quenched with 0.5M hydrochloric acid (1.5 mL) and diluted with ethyl acetate (10 mL). The organic layer was dried (Na2SO4), filtered and concentrated. The product was isolated using C18 preparative HPLC without separating the two phosphorus diastereomers which gave the title compound as a 3:1 mixture of P-diastereomers (42 mg, 22%). 64 M337 prio-lb

Claims

CLAIMS 1. A method for preparing a compound of Formula la or lb: 0 R404„, = / 0 Base tR7 R23Ri RdR22 Formula lb R6,o Formula la or a pharmaceutically acceptable salt or acid thereof; wherein: each R1, R2, R7, R22, R23 or R24 is independently H, OR11, NR11R12, C(0)NR11R12, -0C(0)NR11R12, C(0)0R11, OC(0)0R11, S(0)nRa S(0)2NR11R12, N3, CN, halogen, (C1-C8)alkyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, (C2-C8)alkenyl, (02- C8)alkynyl or aryl(C C8)alkyl; or any two R1 , R2 , R7, R22 , R23 or R24 on adjacent carbon atoms when taken together are - 0(C0)0- or -0(CR11R12)0- 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 Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, (C2-C20)heterocycly1 or heteroaryl; each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each R is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl; each R11 or R12 is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- C2o)aryl, heterocyclyl, heteroaryl, -C(=0)(C1-C8)alkyl, -S(0)n(C1-C8)alkyl, or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered 6 M337 prio-lb heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S(0),- or -NRa-; and wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each IR', Rd, R1, R2, R22, R23, R24, R4, R, R6, R7, R11 or R12 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(R12, N H(Ra), NH2, NO2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, 00(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0R8 , OC(0)0Ra, C(0)1Ra, OC(0)Ra, S(0)nRa S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra; said method comprising :

1. providing a compound of Formula II HO Base R24R7 R23R1 R22R2 Formula II and 2. treating the compound of Formula II with a compound of Formula Illa and a base R6 0 7 0 N,& Rc cf ‘s-Ar \ R4 0 Formula Illa thereby forming a compound of Formula la, or (c) treating the compound of Formula II with a compound of Formula Illb and a base Formula Illb thereby forming a compound of Formula lb; wherein: each Ar is (06-020 aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-C8)haloalkyl, ON, N3, N(Ra)2, 0 R60 66 M337 prio-lb C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)Ra, S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4.

2. The method of claim 1 wherein Formula la is Formula IV a, Formula lb is Formula IVb and Formula II is Formula V: 0 R 0 N/b, II 0 OR4 0 R40//„ // ° 0‘ R--0 Rd R6o Base R24".""IIR7 R23 R22 R2 Formula IVaFormula IVO R22R2 Formula V

3. The method of claim 1 or 2 wherein Base is selected from the group consisting of: ..X1-......---,,, Xl, \\_-N, ../}-,.. R8Rs x= NN R8 X2 N and ----- wherein: each X1 is independently N or CR18; each X2 is independently NR11, 0, or S(0)n; each R8 is independently halogen, NR11R12, N(R11)0R11, NR11NR11R12, N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NNHR11, -CH=N(0R11), -CH(0R11)2, -C(=0)NR11R12, -C(=S)NR11R12 -C(0)0R11, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C4-C8)carbocyclylalkyl, (C6- C2o)aryl, heterocyclyl, heteroaryl, -C(=0)(C1-C8)alkyl, -S(0)n(C1-C8)alkyl, aryl(C1-C8)alkyl, OR11 or SR'; each n is independently 0, 1, or 2; 67 M337 prio-lb NRiiNR11-12, each R9 or R19 is independently H, halogen, NRK N3, NO, NO2, CHO, CN, -CH(=NR11), -CH=NHNR11, -CH=N(0R11), -CH(0R11)2, -C(=0)NR11R12, - C(=S)NR11R12, -C(=0)0R11, R11, OR11 or SR; each R11 or R12 is independently H, (C1- C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C)aryl, heterocyclyl, heteroaryl, -C(=0)(C1- C8)alkyl, -S(0)n(Ci-C8)alkyl or R11 and R12 taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with -0-, -S(0),- or wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (Cr C8)carbocyclylalkyl, aryl(Ci-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl of each R, Rd, R1, R2, R22, R23, R24, R4, R, R6, R7, Rs, R9, R, R11 or R12 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(Ra)2,NH(Ra), NH2, NO2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa , S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra.

4. The method of any one of claims 1-3 wherein Base is selected from the group consisting of: ,NH2 I N- 0NH, /1,\I--------- 'NHN-,„--- .,... .i ././1 ,:` N 1. _.-------1...\, I- 21, N'..‘..-..*N -1N. -----('..‘NH- NH2 h NH2 H NH2 0„ N r- 3H2NH ./...-'''=i-- '....N S:.,ti<,1I \::---=-- . ..-.,----•\- N ,. 'N.N NH7 H N and -- NH2 N F N CONH2 68 M337 prio-lb NH20 HN -/L N)*1 NH ILI \N/%0 andI HNLNH LL 0

5. The method of any one of claims 1-3 wherein Formula la is Formula Vla, Formula lb is Formula Vlb and Formula II is Formula VII: R8R8 0 R40/6„, II 'P R4° 0 / R6-0 Rd N/".0 Ho"""1/R7 HR1 R222 Formula Vla Formula Vlb R8 HO Ho" R22 R8 NR9 R1 r-R2 R6-----0 Rd Ho'''.'""i1R7 H..-....„. R1 z...": R221.2 Formula VII

6. The method of any one of claims 1 -3 wherein Formula la is Formula Xla, Formula lb is Formula Xlb and Formula II is Formula XII: R8 R6o Formula XlaFormula Xlb R 110 N,,,, j 0 Ho""1R7 R1 R22 "R2 69 M337 prio-lb R8 N HON%\ R9 Hm". R1 R22 -R2 Formula XII wherein: each R1 is independently H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; each R2 is independently halogen or OR11; each R is H; and each R22 is OR11.

7. The method of any one of claims 1-3 wherein Formula la is Formula X111a, Formula lb is Formula XIllb and Formula II is Formula XIV: R8 0 IR6o Rd H‘" H. Formula XIllb 0 I0 ((N R 4 0N—< OR4 H"''\""iR7 0 H.— (..R1 . R1 IR-2R2 Formula XIlla wherein: each R1 is independently H, halogen, optionally substituted (C1-C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl; each R2 is independently halogen or OR11; each R is H; and each R22 is OR11.

8. The method of any one of claims 1-7 wherein R1 is H, halogen, optionally substituted (Cr C8)alkyl, optionally substituted (C2-C8)alkenyl or optionally substituted (C2-C8)alkynyl.

9. The method of any one of claims 1-8 wherein R1 is H, CH3, F or Cl. 70 M337 prio-lb

10. The method of any one of claims 1-8 wherein R1 is CH3, or Cl, and R2 is F or Cl.

11. The method of any one of claims 1-10 wherein each R, R23 and R24 is H.

12. The method of any one of claims 1-11 wherein one of Rc or Rd is H and the other of Rc or Rd is optionally substituted (C1-C8)alkyl.

13. The method of any one of claims 1-12 wherein R6 is optionally substituted (C1-C8)alkyl or optionally substituted (C3-C8)cycloalkyl.

14. The method of any one of claims 1-13 wherein R8 is NR11R12 or OR11.

15. The method of any one of claims 1-14 wherein R9 is H or NR' R12.

16. The method of any one of claims 1-15 wherein when R8 or R9 is OR11 or NR11R12 then each Ril and R12 of said OR11 or NR11 iiR 2 is H.

17.

The method of any one of claims 1-16 wherein R8 is NH2 and R9 is H. 18 The method of any one of claims 1-16 wherein R8 is OH and R9 is H.

19. The method of any one of claims 1-18 wherein R4 is optionally substituted (C6-C20)aryl.

20. The method of any one of claims 1-19 further comprising a method of preparing a compound of Formula Illa or Formula 111lb 070 0 R6N■6„, j 0R 0"P i \ Rc cf ‘s—ArRd*Rc 0 S—Ar \\ R4 R4 Formula Illb wherein: each Ra, R4 or R is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06- C)aryl, heterocyclyl or heteroaryl; Formula IllaOr 71 M337 prio-lb each IR' or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, (C2C)heterocyclylor heteroaryl; each R is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(Ci-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(R12; NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, S(0)nRa, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra; and each Ar is (06-02) aryl or a 5 to 20 membered or heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-08)haloalkyl ON, N3, N(R12, C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4; said method comprising: 4. providing a diastereomeric compound of Formula VIII 07 R6 - A *IRc 0 S-Ar R4 Formula VIII and 5. dissolving the compound of Formula VIII in a suitable solvent and inducing crystallization by cooling the solution; thereby forming a pure diastereomer of Formula Ila or Formula 111b.

21. The method of claim 20 further comprising a method of preparing a compound of Formula VIII 72 M337 prio-lb 07 R60 N, * A Rc 0 S-Ar \ R4 Formula VIII wherein: each Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each Rc or Rd is independently H, (C1-C8)alkyl, (02- C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl; each R is 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, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (02-C8)alkenyl, (02-C8)alkynyl, (C3-08)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(R12 NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), 0(0)NH2, O0(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, S(0)nRa S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra; and each Ar is (06-0) aryl or 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-08)haloalkyl ON, N3, N(R12, C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa, S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4; said method comprising: 6. providing a chirally pure amino acid ester of Formula IX or a salt thereof o RI R6,0NH Rd Rc Formula IX , 7. treating the compound of Formula IX with a compound of Formula X in the presence of a base 73 M337 prio-lb X3-P-X3 0,R4 Formula X wherein each X3 is halogen; and (h) treating the resulting mixture with ArSH; thereby forming a compound of Formula VIII.

22. A method of preparing a compound of Formula IIla or Formula IIlb 0 r0 R 10 RNI 610Fe I., 1 \ 'IR' 01 Ns-Armc 0 S-Ar \\ R-A R4 Formula Illb or a salt or ester thereof, wherein: each Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each R is 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, heterocyclyl or heteroaryl; wherein each (C1-C6)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(R12; NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, S(0)nRa , S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra; and each Ar is (C6-C20)aryl or 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (C1-C8)haloalkyl ON, N3, N(Ra)2, C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa , S(0)2N(R12, OR or Ra with the proviso that Ar is different from R4; Formula IllaOr 74 M337 prio-lb said method comprising: 4. providing a diastereomeric compound of Formula VIII 07 R60 N, A IR' 0 S-Ar \ R4 Formula VIII and 5. dissolving the compound of Formula VIII in a suitable solvent and inducing crystallization by cooling the solution; thereby forming a pure diastereomer of Formula IIla or Formula 111b.

23. The method of claim 22 further comprising a method of preparing a compound of Formula VIII 0 75 0 R6oN * A IR' 0 S-Ar \ R4 Formula VIII or a salt or ester thereof, wherein each Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each R is 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-C)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or 7 M337 prio-lb more halo, hydroxy, ON, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, S(0)Ra S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra; and each Ar is (C6-C) aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-08)haloalkyl ON, N3, N(Ra)2) C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa , S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4; said method comprising: (f) providing a chirally pure amino acid ester of Formula IX or a salt thereof R6,o Formula IX 7. treating the compound of Formula IX with a compound of Formula X in the presence of a base iii X3-1D-X3 1 0,R4 Formula X wherein each X3 is halogen; and 8. treating the resulting mixture with ArSH; thereby forming a compound of Formula VIII.

24. The method of any one of claims 20-23 wherein the compound Formula Illa or Formula Illb is 7 I\1R6 ID\''0 *Rc cf \s-Ar \ ,, R" o R6o 0 7 N,,,, )) .r , i \ 'Rc 0 S-Ar \ R4 Formula IllaorFormula Illb or a salt or ester thereof; wherein: each Ra, R4 or R6 is independently (01-08)alkyl, (02-08)alkenyl, (02-08)alkynyl, (03- C8)carbocyclyl, (a4-08)carbocyclylalkyl, aryl(01-C8)alkyl, heterocycly1(01-C8)alkyl, (06- 76 M337 prio-lb C20)aryl, heterocyclyl or heteroaryl; each Rc or Rd is independently H, (C1-08)alkyl, (02-C8)alkenyl, (02-C8)alkynyl, (03- C8)carbocyclyl, (C4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6- C2o)aryl, heterocyclyl or heteroaryl; each R is 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-C)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C20)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, ON, N3, N(Ra)2, NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NE12, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, S(0)nRa S(0)2NH(Ra), S(0)2NH2, OR or Ra; and each Ar is (06-020) aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (01-08)haloalkyl ON, N3, N(Ra)2, C(0)N(Ra)2, OC(0)N(Ra)2, 0(0)0Ra, 00(0)0Ra, C(0)Ra, O0(0)Ra, S(0)nRa , S(0)2N(R12, OR or Ra with the proviso that Ar is different from R4.

25. The method of any one of claims 20-24 wherein R is H and one of Rc or Rd is H.

26. The method of any one of claims 20-25 wherein R6 is optionally substituted (C1-C8)alkyl or optionally substituted (03-08)cycloalkyl, and R4 is optionally substituted (06-020)aryl.

27. The method of any one of claims 20-26 wherein R4 is optionally substituted phenyl.

28. The method of any one of claims 20-27 wherein one of Rc or Rd is H and the other of Rc or Rd is CH3.

29. The method of any one of claims 20-28 wherein Ar is optionally substituted phenyl.

30. The method of any one of claims 20-29 wherein the chirality at the carbon directly attached to Rcand Rd is S.

31. The method of any one of claims 20-30 wherein the chirality at the carbon directly attached to Rcand Rd is R. 77 M337 prio-lb

32. The method of any one of claims 20-31 wherein the compound of formula IIla or IIlb is selected from the group consisting of CI CI CI CI CI CI CI CI CI =0 1 1 -..„..............0.„.........„/".„„N,s HO 0 CI CI CI Cl =0 1 1 -..,..............0.„,„/"..„ N1 P.,...s HO 0 CI CI CI = = 0. ./ 0 CI CI =0 I I 0 , ...... 0. .„, P..... Cr-- ''''-'NI ‘ I S HO CI o CI CI CI CI CI 78 0 U_ / 0 = O. -■ 0 Z1 0 b U_ U_ 0 0 \ U_ U_ U_ U_ U_ U_ \ 0 0 (7) r_.) U_U_ 0 0 U_U_ U_ 0 \ 0 U_ U_ U_U_ 0 0 (7) (.7.) M337 prio-lb /\/c) - 0 = 0 I I z _ (F S 011F 4111 F F F ....,. = - 0 0 = E 0 II 1\1‘‘ A-S H 0 F F Pell F F F ...........i.„.0 0 = E H 0 I I (- F 0 F 41 F F F 0 = = 0 II IV ‘A H 0 F S 0 F 0 F F F ; or salts or hydrates thereof.

33. A compound of the formula VIII wherein: each Ra, R4 or R6 is independently (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each Rc or Rd is independently H, (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (03- C8)carbocyclyl, (a4-C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (06C)aryl, heterocyclyl or heteroaryl; each R is 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-C)aryl, heterocyclyl or heteroaryl; wherein each (C1-C8)alkyl, (C2-C8)alkenyl, (C2-C8)alkynyl, (C3-C8)carbocyclyl, (04- C8)carbocyclylalkyl, aryl(C1-C8)alkyl, heterocyclyl(C1-C8)alkyl, (C6-C)aryl, heterocyclyl or heteroaryl of each Rc, Rd, R4, R or R6 is, independently, optionally substituted with one or more halo, hydroxy, CN, N3, N(R12; NH(Ra), NH2, C(0)N(Ra)2, C(0)NH(Ra), C(0)NH2, OC(0)N(Ra)2, OC(0)NH(Ra), OC(0)NH2, C(0)0Ra, OC(0)0Ra, S(0)nRa, S(0)2N(Ra)2, S(0)2NH(Ra), S(0)2NH2, OR or Ra; and 0 / * A Rc 0 S-Ar R4 Formula VIII 80 M337 prio-lb each Ar is (C6-C)aryl or a 5 to 20 membered heteroaryl wherein said aryl or heteroaryl is optionally substituted with one or more halogen, NO2, (C1-C8)haloalkyl ON, N3, N(Ra)2, C(0)N(Ra)2, OC(0)N(Ra)2, C(0)0Ra, OC(0)0Ra, C(0)Ra, OC(0)Ra, S(0)nRa S(0)2N(Ra)2, OR or Ra with the proviso that Ar is different from R4: or a salt, hydrate or N-oxide thereof.

34. A diastereomer of the compound of claim 33 with the stereochemistry depicted in Formula IIla: 0 0 70 I\1 \ -Rc 6 S—Ar \ R4 Formula IIla

35. A diastereomer of the compound of claim 33 with the stereochemistry depicted in Formula IIlb: 07 R60 N,„ 1 \ Rc 0 S—Ar \ IR- A Formula Illb

36. The diastereomer or compound of any one of claims 33-35, wherein R6 is H and one of Rc or Rd is H.

37. The diastereomer or compound of any one of claims 33-36, wherein R6 is optionally substituted (C1-C8)alkyl or optionally substituted (C3-C8)cycloalkyl.

38. The diastereomer or compound of claim 37, wherein R6 is methyl, ethyl, 1-methylbutyl, 2- ethylbutyl, cyclopentyl or preferably isopropyl. 38. The diastereomer or compound of any one of claims 33-37, wherein R4 is phenyl.

39. The diastereomer or compound of any one of claims 33-38, wherein one of Rc and Rd is H and the other one is CH3. 81 M337 prio-lb stereochemistry at the chiral 39, wherein Ar is 3,5-