WO2017019581A1

WO2017019581A1 - Process for making phosphorus-containing nucleoside prodrug compounds

Info

Publication number: WO2017019581A1
Application number: PCT/US2016/043806
Authority: WO
Inventors: Jamie M. MCCABE DUNN; Robert K. Orr; Andrew F. Nolting; Rebecca T. Ruck
Original assignee: Merck Sharp & Dohme Corp.
Priority date: 2015-07-29
Filing date: 2016-07-25
Publication date: 2017-02-02

Abstract

The present invention is directed to processes for making Compounds of Formula (IV): (IV) and salts thereof, wherein B, X, R1, R2, R3 and R4 are defined herein.

Description

PROCESS FOR MAKING PHOSPHORUS-CONTAINING NUCLEOSIDE PRODRUG COMPOUNDS FIELD OF THE INVENTION

The present invention is directed to a process for making Phosphorus-Containing Nucleoside Prodrug Compounds which may be useful for the treatment or prophylaxis of HCV infection. BACKGROUND OF THE INVENTION

Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals, and is estimated to affect approximately 2-15% of the world's population. Once infected, about 20% of people clear the virus, but the rest harbor HCV the rest of their lives. Ten to twenty percent of chronically infected individuals eventually develop liver-destroying cirrhosis or cancer. HCV is transmitted parenterally by contaminated blood and blood products, contaminated needles, sexually or vertically from infected mothers or carrier mothers to their off-spring.

Inhibition of HCV NS5B polymerase prevents formation of the double-stranded HCV RNA and therefore constitutes an attractive approach to the development of HCV-specific antiviral therapies.

Various substituted nucleoside compounds are known inhibitors of the HCV NS5B polymerase enzyme. Included in these nucleosides are nucleoside phosphoramidate compounds which may be useful in the treatment of infection by HCV and in the treatment, prophylaxis, or delay in the onset or progression of HCV infection. Representative nucleoside phosphoramidate compounds that may be useful for treating HCV infection are described, for example, in International Patent Publication Nos. WO 2013/177219 and WO 2014/058801.

The development of inhibitors of HCV NS5B polymerase with potential for the treatment of HCV infection has been reviewed in Poordad et al., J. Viral. Hepat. 19(7): 449-464 (2012); Asselah et al, Liver Int ., 29 Suppl 1:57-67(2009); and Chatel-Chaix et al. Current

Opinion in Virology, 2:588-598 (2012). Nucleoside analogs that inhibit HCV NS5B polymerase are disclosed, for example, in WO 2011/035231, WO 2005/003147, WO 2010/0081628, U.S. 7,879,815, WO 2010/075517, WO 2010/002877, and WO 2009/132123. Among these nucleoside analogs are prodrugs which have the 5' -OH group masked as a phosphoramidate moiety (also referred to as "McGuigan" prodrugs). See, for example, Bobeck et al., Antiviral Therapy, 15:935-950 (2010); and McGuigan et al, Bioorg Med Chem Lett, 20(16):4850-4854 (2010). US Patent No. 8,629,263 discloses reagents that can be used to add phosphoramidate groups onto nucleoside compounds to prepare McGuigan type prodrugs.

SUMMARY OF THE INVENTION

The present invention is directed to a process for making Phosphorus-Containing Nucleoside Prodrug Compounds of Formula (IV) which may be useful for the treatment and prophylaxis of HCV infection. More particularly, the present invention includes a process (alternatively referred to herein as "Process A") for preparing a compound of Formula (IV):

(IV)

or a pharmaceutically acceptable salt thereof, said process comprising the steps:

(A) contacting a compound of formula (I)

(I)

with a compound of formula (II):

(Π),

in the presence of a non-nucleophilic base, in an organic solvent A for a time and at a temperature sufficient to form a compound of formula (III):

(HI);

then:

(B) contacting the compound of formula (III) with a non-nucleophilic base, in an organic solvent B for a time and at a temperature sufficient to form a compound of formula (IV), wherein:

B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following

X is O, N, S or CH₂;

R¹ is H, C1-C3 alkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

R² is selected from H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, -CN, -N₃, - N(R¹ )₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and C3-C7 cycloalkyl; R³ is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R⁵ groups;

R⁴ is selected from C1-C6 alkyl, C2-C6 alkenyl, -(C1-C3 alkylene)_m-(C₃-Ci4 cycloalkyl) and -(C1-C3 alkylene)_m-(C6-Cio aryl);

each occurrence of R⁵ is independently selected from -C1-C6 alkyl, halo, -OR⁶, - C(0)R⁶, -CO2R⁶, -SR⁶, -Ci-C₆ hydroxyalkyl, -Ci-C₆ haloalkyl, -N(R⁶)₂, -S(0)R⁶, -S(0)₂R⁶, -CN and -N0₂;

each occurrence of R⁶ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene)_m-(C3-C₇ cycloalkyl), -(C1-C3 alkylene)_m-(C₆-Ci₀ aryl), -(C1-C3 alkylene)_m-(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene)_m-(5- or 6-membered monocyclic heteroaryl) or -(C1-C3 alkylene)_m-(9- or 10-membered bicyclic heteroaryl);

R⁷, R⁸ and R⁹ are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C₂-C₆ alkynyl, C3-C7 cycloalkyl, halo, -OR¹⁰, -SR¹⁰, -S(0)R¹⁰, -S(0)₂R¹⁰, -S(O)₂N(R¹⁰)_2i - NHC(0)OR¹⁰, -NHC(0)N(R¹⁴)₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, -0-(d-C₆ haloalkyl), - CN, -NO2, -N(R¹⁰)₂, -NH(Ci-C₆ alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C₆ alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R¹⁰, -C(0)OR¹⁰, -C(O)N(R¹⁰)₂ and - NHC(0)R¹⁰;

each occurrence of R¹⁰ is independently selected from H, C1-C10 alkyl, C1-C6 haloalkyl, Ci-C₆ hydroxyalkyl, -(C1-C3 alkylene)n-(C₃-C₇ cycloalkyl), -(C1-C3 alkylene)_n-(C₆-Cio aryl), -(C1-C₃ alkylene)_n-(4 to 7-membered heterocycloalkyl), -(C1-C₃ alkylene)_n-(5- or 6- membered monocyclic heteroaryl) and -(C1-C₃ alkylene)_n-(9- or 10-membered bicyclic heteroaryl);

R¹¹ is selected C6-C1₀ aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl, wherein said C6-C1₀ aryl group, said 5 or 6-membered

monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R⁵ groups;

R¹² is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C1₀ aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0₂, halo and C1-C6 haloalkyl;

R¹³ is selected from H and C1-C6 alkyl;

each occurrence of m is independently 0 or 1; and each occurrence of n is independently 0 or 1.

Other embodiments, aspects and features of the present invention are either further described in or will be apparent from the ensuing description, examples, and appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to a process for making Phosphorus-Containing Nucleoside Prodrug Compounds of Formula (I) which may be useful for inhibiting HCV NS5B polymerase, inhibiting the replication of HCV and for the treatment or prophylaxis of HCV infection.

Definitions and Abbreviations

The term "C_\-Ce alkyl" as used herein, refers to an aliphatic hydrocarbon group, having from 1 to 6 carbon atoms wherein one of its hydrogen atoms is replaced with a bond. A C1-C6 alkyl group may be straight or branched. Non-limiting examples of C1-C6 alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl and neohexyl. A C1-C6 alkyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, -NH(alkyl), - N(alkyl)₂, -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and - C(0)0-alkyl. In one embodiment, a C1-C6 alkyl group is linear. In another embodiment, a Ci- e alkyl group is branched. Unless otherwise indicated, a C1-C6 alkyl group is unsubstituted.

The term "alkenyl," as used herein, refers to an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and having one of its hydrogen atoms replaced with a bond. An alkenyl group may be straight or branched and contain from about 2 to about 15 carbon atoms. In one embodiment, an alkenyl group contains from about 2 to about 12 carbon atoms. In another embodiment, an alkenyl group contains from about 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 3- methylbut-2-enyl, n-pentenyl, octenyl and decenyl. An alkenyl group may be unsubstituted or substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy, -O-alkyl, -O-aryl, -alkylene-O-alkyl, alkylthio, -NH₂, -NH(alkyl), - N(alkyl)₂, -NH(cycloalkyl), -0-C(0)-alkyl, -0-C(0)-aryl, -0-C(0)-cycloalkyl, -C(0)OH and - C(0)0-alkyl. The term "C2-C6 alkenyl" refers to an alkenyl group having from 2 to 6 carbon atoms. Unless otherwise indicated, an alkenyl group is unsubstituted.

The term "alkylene," as used herein, refers to an alkyl group, as defined above, wherein one of the alkyl group's hydrogen atoms has been replaced with a bond. Non-limiting examples of alkylene groups include -CH₂-, -CH₂CH₂-, -CH₂CH₂CH₂-, -CH₂CH₂CH₂CH₂-, - CH(CH₃)CH₂CH₂-, -CH(CH₃)- and -CH₂CH(CH₃)CH₂-. In one embodiment, an alkylene group has from 1 to about 6 carbon atoms. In another embodiment, an alkylene group is branched. In another embodiment, an alkylene group is linear. In one embodiment, an alkylene group is - CH₂-. The term "C1-C6 alkylene" refers to an alkylene group having from 1 to 6 carbon atoms. The term "C1-C3 alkylene" refers to an alkylene group having from 1 to 3 carbon atoms.

The term "C6-C10 aryl" refers to phenyl and naphthyl. In one embodiment, an aryl group is phenyl.

The term "cycloalkyl" refers to a non-aromatic monocyclic or multicyclic ring system comprising from about 3 to about 14 ring carbon atoms. The term "3 to 7-membered cycloalkyl" refers to a monocyclic cycloalkyl group having from about 3 to about 7 ring carbon atoms. Examples of "3 to 7-membered cycloalkyl" groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. The term "7 to 14-membered cycloalkyl" refers to a multicyclic cycloalkyl group having from about 7 to about 14 ring carbon atoms. Examples of "7 to 14-membered cycloalkyl" groups include, but are not limited to adamantyl and octahydro indene. A cycloalkyl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein below. In one embodiment, a cycloalkyl group is unsubstituted. One or more ring carbon atoms of a cycloalkyl may be functionalized as a carbonyl group. An illustrative example of such a cycloalkyl (also referred to herein as a "cycloalkanoyl" group) includes, but is not limited to, cyclobutanoyl:

The term "halo" as used herein, refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

The term "5 or 6-membered monocyclic heteroaryl," as used herein, refers to an aromatic monocyclic ring system comprising about 5 to about 6 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. A 5 or 6-membered monocyclic heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. A 5 or 6-membered monocyclic heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. The term "5 or 6-membered monocyclic heteroaryl" also encompasses a 5 or 6-membered monocyclic heteroaryl group, as defined above, which is fused to a benzene ring. Non-limiting examples of 5 or 6-membered monocyclic heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, imidazolyl, benzimidazolyl, thienopyridyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, 1 ,2,4-triazinyl, benzothiazolyl and the like, and all isomeric forms thereof. Unless otherwise indicated, a 5 or 6-membered monocyclic heteroaryl group is unsubstituted.

The term "9 or 10-membered bicyclic heteroaryl," as used herein, refers to an aromatic bicyclic ring system comprising about 9 to about 10 ring atoms, wherein from 1 to 4 of the ring atoms is independently O, N or S and the remaining ring atoms are carbon atoms. A 9 or 10-membered bicyclic heteroaryl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. A 9 or 10-membered bicyclic heteroaryl group is joined via a ring carbon atom, and any nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of 9 or 10-membered bicyclic heteroaryls include imidazo[l ,2-a]pyridinyl, imidazo[2, l-b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, benzimidazolyl, quinazolinyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, benzothiazolyl, and the like, and all isomeric forms thereof. Unless otherwise indicated, a 9 or 10-membered bicyclic heteroaryl group is unsubstituted.

The term "heterocycloalkyl," as used herein, refers to a non-aromatic saturated monocyclic or multicyclic ring system comprising 3 to about 11 ring atoms, wherein from 1 to 4 of the ring atoms are independently O, S, N or Si, and the remainder of the ring atoms are carbon atoms. A heterocycloalkyl group can be joined via a ring carbon, ring silicon atom or ring nitrogen atom. In one embodiment, a heterocycloalkyl group is monocyclic and has from about 3 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is monocyclic has from about 4 to about 7 ring atoms. In another embodiment, a heterocycloalkyl group is bicyclic and has from about 7 to about 11 ring atoms. In still another embodiment, a heterocycloalkyl group is monocyclic and has 5 or 6 ring atoms. In one embodiment, a heterocycloalkyl group is monocyclic. In another embodiment, a heterocycloalkyl group is bicyclic. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Any -NH group in a heterocycloalkyl ring may exist protected such as, for example, as an -N(BOC), -N(Cbz), -N(Tos) group and the like; such protected heterocycloalkyl groups are considered part of this invention. The term "heterocycloalkyl" also encompasses a heterocycloalkyl group, as defined above, which is fused to an aryl (e.g. , benzene) or heteroaryl ring. A heterocycloalkyl group can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein below. The nitrogen or sulfur atom of the heterocycloalkyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclic heterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone and the like, and all isomers thereof.

A ring carbon atom of a heterocycloalkyl group may be functionalized as a carbonyl group. An illustrative example of such a heterocycloalkyl group is:

In one embodiment, a heterocycloalkyl group is a 5-membered monocyclic heterocycloalkyl. In another embodiment, a heterocycloalkyl group is a 6-membered monocyclic heterocycloalkyl. The term "3 to 6-membered monocyclic heterocycloalkyl" refers to a monocyclic heterocycloalkyl group having from 3 to 6 ring atoms. The term "4 to 7- membered monocyclic heterocycloalkyl" refers to a monocyclic heterocycloalkyl group having from 4 to 7 ring atoms. The term "7 to 1 1-membered bicyclic heterocycloalkyl" refers to a bicyclic heterocycloalkyl group having from 7 to 1 1 ring atoms. Unless otherwise indicated, a heterocycloalkyl group is unsubstituted. Unless expressly stated to the contrary in a particular context, any of the various cyclic rings and ring systems described herein may be attached to the rest of the compound of which they are a part at any ring atom (i.e., any carbon atom or any heteroatom) provided that a stable compound results.

Unless expressly stated to the contrary, all ranges cited above are inclusive; i.e., the range includes the values for the upper and lower limits of the range as well as all values in between.

When any variable occurs more than one time in a compound involved in the process of the invention (e.g., R5 or m), its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in a stable compound.

Unless expressly stated to the contrary, substitution by a named substituent is permitted on any atom in a ring (e.g., cycloalkyl, aryl, or heteroaryl) provided such ring substitution is chemically allowed and results in a stable compound.

In reference to the compounds used as reactants or reagents in the processes of the invention (e.g., compounds of formulas (I) and (II)), a "stable" compound is one whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow its use in the processes of the invention. In reference to Compound of Formula (II), a "stable" compound is a compound which can be prepared in accordance with the present invention and then isolated and whose structure and properties remain or can be caused to remain essentially unchanged for a period of time sufficient to allow use of the compound for its intended purpose; e.g., for use as a synthetic intermediate to make compounds capable of inhibiting HCV NS5B polymerase, and to make medicinally useful compounds, such as compounds useful for treating HCV infection in a subject.

When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in Organic Synthesis (1991), Wiley, New York.

The Phosphorus-Containing Nucleoside Prodrug Compounds can form salts which are also within the scope of this invention. The term "salt(s)", as used herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a Phosphorus-Containing Nucleoside Prodrug Compound contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. In one embodiment, the salt is a pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salt. In another embodiment, the salt is other than a pharmaceutically acceptable salt. Salts of the Compounds of Formula (II) may be formed, for example, by reacting a Phosphorus-Containing Nucleoside Prodrug Compound with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates) and the like.

Additionally, acids which are generally considered suitable for the formation of

pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of ^'Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, Inter national J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamine, t-butyl amine, choline, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen- containing groups may be quarternized with agents such as lower alkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g., decyl, lauryl, and stearyl chlorides, bromides and iodides), arylalkyl halides (e.g., benzyl and phenethyl bromides), and others.

All such acid salts and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention. In one embodiment, the acid salts and base salts of the invention are intended to be pharmaceutically acceptable salts within the scope of the invention. Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well-known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Sterochemically pure compounds may also be prepared by using chiral starting materials or by employing salt resolution techniques. Also, some of the Phosphorus-Containing Nucleoside Prodrug

Compounds may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be directly separated using chiral chromatographic techniques, such as chiral HPLC.

It is also possible that the Phosphorus-Containing Nucleoside Prodrug Compounds may exist in different tautomeric forms, and all such stable forms are embraced within the scope of the invention. For example, all stable keto-enol and imine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, hydrates and esters of the compounds), such as those which may exist due to the presence of asymmetric carbon or phosphorus atoms, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention. If a Phosphorus-Containing Nucleoside Prodrug Compound incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.

Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", and the like, is intended to apply equally to the salt, solvate and ester of enantiomers, diastereomers, rotamers, tautomers or racemates of the inventive compounds.

The following abbreviations are used below and have the following meanings: Ac is acetate, t-Bu is tertiary butyl, CPME is cyclopentylmethyl ether, DBN is 1,5- diazabicyclo[4.3.0]non-5-ene, DBU is l,8-diazabicyclo[5.4.0]undec-7-ene, DCM is dichloromethane, DMAP is dimethylaminopyridine, DME is dimethoxy ethane, DMF is dimethylformamide, DMSO is dimethylsulf oxide, Et₃N is triethylamine, EtOAc is ethyl acetate, HPLC is high performance liquid chromatography, IP Ac isopropyl acetate, KOtBu is potassium tert butoxide, LiHMDS is lithium hexamethyldisilazide, 2,6-lutidine is 2,6-dimethylpyridine, Me is methyl, MTBD is 7-methyl-l,5,7-triazabicyclo[4.4.0]dec-5-ene, MTBE is metyl tert-butyl ether, NaOMe is sodium methoxide, NaOtBu is sodium tert butoxide, NMP is N-methyl-2- pyrrolidinone, TFA is trifluoroacetic acid, THF is tetrahydrofuran, TLC is thin-layer chromatography, TMG is 1,1,3,3-tetramethylguanidine and TMP is 2,2,6,6- tetramethylpiperidine.

The Process of the Present Invention

The present invention is directed to a process for making Phosphorus-Containing

Nucleoside Prodrug Compounds of Formula (IV) which may be useful for inhibiting the replication of HCV and for the treatment or prophylaxis of HCV infection. One aspect of the present invention is the process for making Compounds of Formula (IV) as set forth above in the Summary of the Invention ("Process A"):

(IV)

a pharmaceutically acceptable salt thereof, said process comprising the steps:

(A) contacting a compound of formula (I)

(I) with a compound of formula (II):

(Π),

(HI);

then:

B is a natural or non-natural purine or pyrimidine base, or B is selected from one of the following groups:

X is O, N, S or CH₂;

R¹ is H, C1-C3 alkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

R² is selected from H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, -CN, -N₃, N(R¹ )₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and C3-C7 cycloalkyl; R³ is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R⁵ groups;

R¹³ is selected from H and C1-C6 alkyl;

In one embodiment, for Process A, Step A organic solvent A is selected from ethyl acetate, NMP, THF, 2-methyl THF, DMF, DCM, acetonitrile, IP AC, DME, DMSO and mixtures thereof.

In another embodiment, for Process A, Step A organic solvent A is THF.

In another embodiment, for Process A, Step A organic solvent A is a mixture of THF and DMF.

In another embodiment, for Process A, Step A organic solvent A is a mixture of ethyl acetate and NMP.

In yet another embodiment, Process A, Step A can be conducted in any organic solvent.

In one embodiment, the non-nucleophilic base used in Process A, Step A is an organic amine base.

In another embodiment, the non-nucleophilic base used in Process A, Step A is selected from DBU, TMG, DBN, MTBD and DMAP.

In another embodiment, the non-nucleophilic base used in Process A, Step A is

DBU.

In one embodiment, the non-nucleophilic base used in Process A, Step A is DBU and organic solvent A is THF.

In one embodiment, Process A, Step A is conducted at a temperature in a range of from about -20°C to about 70°C.

In another embodiment, Process A, Step A is conducted at a temperature in a range of from about -10°C to about 40°C.

In another embodiment, Process A, Step A is conducted at a temperature in a range of from about 0°C to about 30°C.

In still another embodiment, Process A, Step A is conducted at a temperature in a range of from about 0°C to about 15°C.

In another embodiment, Process A, Step A is conducted at a reaction about 0°C. In one embodiment, the non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.5 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.3 molar equivalents. In another embodiment, the non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.2 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process A, Step A is used in an amount of about 1 to about 1.1 molar equivalents.

In still another embodiment, the non-nucleophilic base used in Process A, Step A is used in an amount of about 1 molar equivalent.

In one embodiment, for Process A, Step A:

the organic solvent A is THF, DMF, EtOAc, NMP or a mixture thereof;

the base used is selected from DBU, TMG, DBN, MTBD and DMAP; and the process is conducted at a temperature in a range of from about -20°C to about

70°C.

In another embodiment, for Process A, Step A:

the organic solvent A is THF or a solvent mixture comprising THF; the base used is DBU;

the process is conducted at a temperature in a range of from about -10°C to about

40°C; and

the com ound of formula (I) used has the formula (la) or (lb):

(la) (lb) wherein:

R¹² is -O-phenyl, -O-pyridyl or -S-phenyl wherein said phenyl or pyridyl groups can each be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0₂, halo and Ci-C₆ haloalkyl;

R³ is -Ci-C₆ alkyl; and

R⁴ is -Ci-C₆ alkyl. In another embodiment, for Process A, Step A:

the organic solvent A is THF;

the base used is DBU;

the process is conducted at a temperature in a range of from about -10°C to about 40°C; and

the compound of formula (I) used has the formula (la^'), (la"), (lb') or (lb"):

wherein:

R is pentafluorophenoxy;

R³ is -Ci-C₆ alkyl; and

R⁴ is -Ci-C₆ alk l.

In another embodiment, for Process A, Step A:

the organic solvent A is THF;

the base used is DBU;

the process is conducted at a temperature in a range of from about 0°C to about

20°C; and

the compound of formula (I) used has the formula (la^'), (la"), (lb') or (lb"):

wherein:

R is pentafluorophenoxy;

R³ is methyl; and

R⁴ isopropyl.

In one embodiment, for Process A, Step B, organic solvent B is selected from DMF, 2-methyl-THF, CPME, acetonitrile, NMP, THF and mixtures thereof.

In another embodiment, for Process A, Step B, organic solvent B is acetonitrile.

In another embodiment, for Process A, Step B, organic solvent B is a mixture of DMF and 2-methyl-THF.

In yet another embodiment, Process A, Step B can be conducted in any organic solvent.

In one embodiment, the non-nucleophilic base used in Process A, Step B is an organic amine base.

In another embodiment, the non-nucleophilic base used in Process A, Step B is an alkali metal alkoxide base.

In another embodiment, the non-nucleophilic base used in Process A, Step B is a silyl-containing amide base.

In another embodiment, the non-nucleophilic base used in Process A, Step B is selected from DBU, DBN, TMG, TMP, Ν,Ν-dicyclohexylmethyl amine, NaOMe, NaOtBu, KOtBu and LiHMDS. In another embodiment, the non-nucleophilic base used in Process A, Step B is

DBU.

In one embodiment, the non-nucleophilic base used in Process A, Step B is DBU and organic solvent B is acetonitrile.

In one embodiment, the non-nucleophilic base used in Process A, Step B is DBU and organic solvent B is a mixture of DMF and 2-methyl-THF.

In one embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 1.5 to about 5 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 2 to about 4 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 2.5 to about 3.5 molar equivalents.

In still another embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 3 to about 3.5 molar equivalents.

In yet another embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 2 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 2.5 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 3 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process A, Step B is used in an amount of about 3.5 molar equivalents.

In one embodiment, Process A, Step B is conducted at a temperature in a range of from about -20°C to about 70°C.

In another embodiment, Process A, Step B is conducted at a temperature in a range of from about -10°C to about 40°C.

In another embodiment, Process A, Step B is conducted at a temperature in a range of from about 0°C to about 30°C.

In still another embodiment, Process A, Step B is conducted at a temperature in a range of from about 0°C to about 15°C.

In another embodiment, Process A, Step B is conducted at a reaction about 0°C.

In one embodiment, for Process A, Step B: the organic solvent B is selected from DMF, 2-methyl-THF, CPME, acetonitrile, NMP, THF and mixtures thereof ;

the base used is an organic amine; and

the process is conducted at a temperature in a range of from about -20°C to about 70°C.

In another embodiment, for Process A, Step B:

the organic solvent B is selected from DMF, 2-methyl-THF, CPME, acetonitrile, NMP, THF and mixtures thereof;

the base used is selected from DBU, DBN, TMG, TMP, N,N-dicyclohexylmethyl amine, NaOMe, NaOtBu, KOtBu and LiHMDS; and

-40°C. In another embodiment, for Process A, Step B:

the organic solvent A is a mixture of DMF and 2-methyl-THF;

the base used is DBU, DBN, TMG, TMP, Ν,Ν-dicyclohexylmethyl amine, NaOMe, NaOtBu, KOtBu and LiHMDS; and

the process is conducted at a temperature in a range of from about 0°C to about 20°C.

In another embodiment, for Process A, Step B:

the organic solvent A is a mixture of DMF and 2-methyl-THF;

the base used is DBU;

20°C; and

the base is present in an amount of from about 2.5 molar equivalents to about 3.5 molar equivalents. The following embodiments apply to Process A and Process C:

In one embodiment, X is O.

In one embodiment, B is a natural or non-natural pyrimidine base. In another embodiment, B is:

In one embodiment, R¹ is selected from C1-C6 alkyl and C2-C6 alkynyl.

In another embodiment, R¹ is C1-C3 alkyl.

In another embodiment, R¹ is methyl.

In another embodiment, R¹ is -C≡CH.

In one embodiment, R² is selected from C2-C6 alkenyl, -CI, -F, -CN, -N₃ and -

NH₂.

In one embodiment, R² is -C≡CH.

In another embodiment, R² is -CI.

In another embodiment, R² is -F.

In still another embodiment, R² is -CN.

In another embodiment, R² is -N₃.

In yet another embodiment, R² is -NH₂.

In one embodiment, R¹ is methyl and R² is selected from C2-C6 alkenyl, -CI, -F, - CN, -N₃ and -NH₂.

In another embodiment, R¹ is methyl and R² is -CI.

In another embodiment, R¹ is methyl and R² is -F.

In still another embodiment, R¹ is methyl and R² is -CN.

In another embodiment, R¹ is methyl and R² is -N₃.

In yet another embodiment, R¹ is methyl and R² is -NH₂.

In one embodiment, R³ is Ci-Ce alkyl.

In one embodiment, R⁴ is Ci-Ce alkyl.

In one embodiment, R³ and R⁴ are each independently Ci-Ce alkyl. In another embodiment, R³ is methyl.

In another embodiment, R⁴ isopropyl.

In still another embodiment, R³ is methyl and R⁴ isopropyl.

In one embodiment, R⁸ is H. In one embodiment, R¹¹ is C6-C1₀ aryl, which can be optionally substituted as set forth in formula (I) of Process A.

In another embodiment, R¹¹ is unsubstituted phenyl.

In one embodiment, R¹¹ is unsubstituted phenyl, R³ is methyl and R⁴ isopropyl.

In one embodiment, R¹² is -0-(C6-Cio aryl), which can be optionally substituted with up to 5 groups, each independently selected from -NO2 and halo.

In another embodiment, R¹² is -0-(5 or 6-membered monocyclic heteroaryl), which can be optionally substituted with up to 5 groups, each independently selected from halo.

In another embodiment, R¹² is -S-(C6-Cio aryl), which can be optionally substituted with up to 5 groups, each independently selected from halo.

In another embodiment, R¹² is -O-phenyl or -O-pyridyl, each of which can be optionally substituted with up to 5 groups, each independently selected from F, CI and -N0₂.

In one embodiment, R¹² is pentafluorophenoxy.

In another embodiment, R¹² is:

In one embodiment, R¹¹ is unsubstituted phenyl, R¹² is pentafluorophenyl; R³ is methyl and R⁴ isopropyl.

In one embodiment, R¹ is methyl; R² is selected from C2-C6 alkenyl, -CI, -F, -CN, -N₃ and -NH₂; X is O; and B is:

In another embodiment, R¹ is methyl; R² is selected from C2-C6 alkenyl, -CI, -F, - CN, -N3 and -NH2; R³ and R⁴ are each independently Ci-Ce alkyl; X is O; and B is:

In still another embodiment, R¹ is methyl; R² is selected from C2-C6 alkenyl, -CI,

F, -CN, -N3 and -NH₂; R³ and R⁴ are each independently C1-C6 alkyl; X is O; and B is:

In another embodiment, R¹ is methyl; R² is selected from C2-C6 alkenyl, -CI, -F,

CN, -N₃ and -NH₂; R³ and R⁴ are each independently C1-C6 alkyl; R_n is phenyl; X is O; and B is:

In yet another embodiment, R¹ is methyl; R² is selected from C2-C6 alkenyl, -CI, F, -CN, -N₃ and -NH₂; R³ and R⁴ are each independently Ci-C₆ alkyl; R¹¹ is phenyl; R¹² is pentafluorophenoxy; X is O; and B is:

In one embodiment, the compound of formula (I) used in Process A has the formula (la) or (lb):

(la) (lb) wherein:

R³ is -Ci-C₆ alkyl;

R⁴ is -Ci-C₆ alkyl; and

R¹² is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C1₀ aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0₂, halo and C1-C6 haloalkyl.

In another embodiment, the compound of formula (I) used in Process A has the formula (la'), (la"), (lb') or (lb"):

wherein:

R³ is -Ci-C₆ alkyl;

R⁴ is -Ci-C₆ alkyl; and R is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C10 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0₂, halo and C1-C6 haloalkyl. embodiment, the compound of formula (I) used in Process A is selected from:

In another embodiment, the compound of formula (I) used in Process A is:

In one embodiment, the compound of formula (II) used in Process A is a compound of formula (Ila):

(Ila) wherein R is selected from -CI, -F, -CN, C₂-C₆ alkynyl, -NH₂ and -N₃.

In one embodiment, the present invention provides a process ("Process B") for making a compound of formula (III):

or a pharmaceutically acceptable salt thereof, said process comprising contacting a compound of formula (I):

(I)

with a compound of formula (II):

(Π),

in the presence of a non-nucleophilic base, in an organic solvent A for a time and at a temperature sufficient to form a compound of formula (III),

wherein:

B is a natural or non-natural purine or pyrimidine base, or B is selected from of the following

X is O, N, S or CH₂;

R¹ is H, C1-C3 alkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

R² is selected from H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, -CN, -N₃, - N(R¹ )₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and C3-C7 cycloalkyl;

R³ is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R⁵ groups;

R⁴ is selected from C1-C6 alkyl, C₂-C6 alkenyl, -(C1-C3 alkylene)_m-(C₃-Ci4 cycloalkyl) and -(C1-C3 alkylene)_m-(C6-Cio aryl);

each occurrence of R⁵ is independently selected from -C1-C6 alkyl, halo, -OR⁶, - C(0)R⁶, -C0₂R⁶, -SR⁶, -Ci-C₆ hydroxyalkyl, -Ci-C₆ haloalkyl, -N(R⁶)₂, -S(0)R⁶, -S(0)₂R⁶, -CN and -N0₂;

each occurrence of R⁶ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C₃ alkylene)_m-(C₃-C7 cycloalkyl), -(C1-C₃ alkylene)_m-(C₆-Cio aryl), -(C1-C₃ alkylene)_m-(4 to 7-membered heterocycloalkyl), -(C1-C₃ alkylene)_m-(5- or 6-membered monocyclic heteroaryl) or -(C1-C₃ alkylene)_m-(9- or 10-membered bicyclic heteroaryl); R⁷, R⁸ and R⁹ are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C₂-C₆ alkynyl, C3-C7 cycloalkyl, halo, -OR¹⁰, -SR¹⁰, -S(0)R¹⁰, -S(0)₂R¹⁰, -S(O)₂N(R¹⁰)_2i - NHC(0)OR¹⁰, -NHC(0)N(R¹⁴)₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, -0-(Ci-C₆ haloalkyl), - CN, -NO2, -N(R¹⁰)₂, -NH(Ci-C₆ alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C₆ alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R¹⁰, -C(0)OR¹⁰, -C(O)N(R¹⁰)₂ and - NHC(0)R¹⁰;

each occurrence of R¹⁰ is independently selected from H, C1-C1₀ alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene)_n-(C₃-C7 cycloalkyl), -(C1-C3 alkylene)_n-(C₆-Cio aryl), -(C1-C3 alkylene)_n-(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene)_n-(5- or 6- membered monocyclic heteroaryl) and -(C1-C3 alkylene)_n-(9- or 10-membered bicyclic heteroaryl);

R¹¹ is selected C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl, wherein said C6-C1₀ aryl group, said 5 or 6-membered

R¹³ is selected from H and C1-C6 alkyl;

each occurrence of m is independently 0 or 1 ; and

each occurrence of n is independently 0 or 1.

In one embodiment, for Process B, organic solvent A is selected from ethyl acetate, NMP, THF, 2-methyl THF, DMF, DCM, acetonitrile, IP AC, DME, DMSO and mixtures thereof.

In another embodiment, for Process B, organic solvent A is THF.

In another embodiment, for Process B, organic solvent A is a mixture of THF and

DMF.

In another embodiment, for Process B, organic solvent A is a mixture of ethyl acetate and NMP.

In yet another embodiment, Process B can be conducted in any organic solvent. In one embodiment, the non-nucleophilic base used in Process B is an organic amine base.

In another embodiment, the non-nucleophilic base used in Process B is selected from DBU, TMG, DBN, MTBD and DMAP.

In another embodiment, the non-nucleophilic base used in Process B is DBU.

In one embodiment, the non-nucleophilic base used in Process B is DBU and organic solvent A is THF.

In one embodiment, Process B is conducted at a temperature in a range of from about -20°C to about 70°C.

In another embodiment, Process B is conducted at a temperature in a range of from about -10°C to about 40°C.

In another embodiment, Process B is conducted at a temperature in a range of from about 0°C to about 30°C.

In still another embodiment, Process B is conducted at a temperature in a range of from about 0°C to about 15°C.

In another embodiment, Process B is conducted at a temperature of about 0°C. In one embodiment, the non-nucleophilic base used in Process B is used in an amount of about 1 to about 1.5 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process B is used in an amount of about 1 to about 1.3 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process B is used in an amount of about 1 to about 1.2 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process B is used in an amount of about 1.1 molar equivalents.

In still another embodiment, the non-nucleophilic base used in Process B is used in an amount of about 1 molar equivalent.

In one embodiment, for Process B:

the organic solvent A is THF, DMF, EtOAc, NMP or a mixture thereof;

the base used is selected from DBU, TMG, DBN, MTBD and DMAP; and the process is conducted at a temperature in a range of from about -20°C to about In another embodiment, for Process B:

40°C; and

the com ound of formula (I) used has the formula (la) or (lb):

(la) (lb) wherein:

R is -O-phenyl, -O-pyridyl or -S-phenyl wherein said phenyl or pyridyl groups can each be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0₂, halo and C1-C6 haloalkyl;

R³ is -Ci-C₆ alkyl; and

R⁴ is -Ci-C₆ alkyl.

In another embodiment, for Process B:

the organic solvent A is THF;

the base used is DBU;

40°C; and

the compound of formula (I) used has the formula (la'), (la"), (lb') or (lb"):

wherein:

R¹² is pentafluorophenoxy;

R³ is -Ci-C₆ alkyl; and

R⁴ is -Ci-C₆ alkyl.

In another embodiment, for Process B:

the organic solvent A is THF;

the base used is DBU;

20°C; and

the compound of formula (I) used has the formula (la'), (la"), (lb') or (lb"):

R is pentafluorophenoxy;

R³ is methyl; and

R⁴ isopropyl.

In another embodiment, the present invention provides an altemate method ("Process C") for makin mpound of formula (IV):

(IV)

or a pharmaceutically acceptable salt thereof, said process comprising the step of contacting compound of formula (I):

(I) with a compound of formula (II):

(II),

in the presence of a non-nucleophilic base, in an organic solvent C, for a time and at a temperature sufficient to form a compound of formula (IV), wherein:

B is a natural or non-natural purine or pyrimidine base, or B is selected from of the following groups:

X is O, N, S or CH₂;

R¹ is H, C1-C3 alkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

R² is selected from H, d-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, -CN, -N₃, N(R¹ )₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and C3-C7 cycloalkyl;

R³ is selected from C1-C6 alkyl, C3-C7 cycloalkyl, phenyl or benzyl, wherein said

C3-C7 cycloalkyl group, said phenyl group and the phenyl moiety of said benzyl group can be optionally substituted with one or more R⁵ groups;

R⁷, R⁸ and R⁹ are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C₂-C₆ alkynyl, C3-C7 cycloalkyl, halo, -OR¹⁰, -SR¹⁰, -S(0)R¹⁰, -S(0)₂R¹⁰, -S(O)₂N(R¹⁰)_2i - NHC(0)OR¹⁰, -NHC(0)N(R¹⁴)₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, -0-(Ci-C₆ haloalkyl), - CN, -NO2, -N(R¹⁰)₂, -NH(Ci-C₆ alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C₆ alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R¹⁰, -C(0)OR¹⁰, -C(O)N(R¹⁰)₂ and - NHC(0)R¹⁰;

each occurrence of R¹⁰ is independently selected from H, C1-C10 alkyl, C1-C6 haloalkyl, Ci-C₆ hydroxyalkyl, -(C1-C3 alkylene)n-(C₃-C₇ cycloalkyl), -(C1-C3 alkylene)_n-(C₆-Cio aryl), -(C1-C3 alkylene)_n-(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene)_n-(5- or 6- membered monocyclic heteroaryl) and -(C1-C3 alkylene)_n-(9- or 10-membered bicyclic heteroaryl);

R¹¹ is selected C6-C10 aryl, 5 or 6-membered monocyclic heteroaryl and 9 or 10- membered bicyclic heteroaryl, wherein said C6-C10 aryl group, said 5 or 6-membered

R¹² is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C10 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0₂, halo and C1-C6 haloalkyl;

R¹³ is selected from H and C1-C6 alkyl;

each occurrence of m is independently 0 or 1 ; and

each occurrence of n is independently 0 or 1.

In one embodiment, for Process C, organic solvent C is selected from ethyl acetate, acetonitrile, NMP, THF, 2-methyl THF, DMF, DCM, acetonitrile, IP AC, DME, DMSO and mixtures thereof.

In another embodiment, for Process C, organic solvent C is selected from acetonitrile, NMP, THF, 2-methyl THF, DMF and mixtures thereof.

In another embodiment, for Process C, organic solvent C is a mixture of 2- methyl-THF and DMF.

In another embodiment, for Process C, organic solvent C is acetonitrile. In yet another embodiment, for Process C, can be conducted in any organic solvent.

In one embodiment, for Process C, the non-nucleophilic base used is an organic amine base.

In another embodiment, for Process C, the non-nucleophilic base used is selected from DBU, TMG, DBN, MTBD and DMAP.

In another embodiment, for Process C, the non-nucleophilic base used is DBU.

In one embodiment, for Process C, the non-nucleophilic base used is DBU and organic solvent C is THF.

In one embodiment, Process C is conducted at a temperature in a range of from about -30°C to about 50°C.

In another embodiment, Process C is conducted at a temperature in a range of from about -20°C to about 40°C.

In another embodiment, Process C is conducted at a temperature in a range of from about -15°C to about 20°C.

In another embodiment, Process C is conducted at a temperature in a range of from about -15°C to about 0°C.

In still another embodiment, Process C is conducted at a temperature in a range of from about -10°C to about 10°C.

In another embodiment, Process C is conducted at a reaction about -15°C.

In yet another embodiment, Process C is conducted at a reaction about 0°C.

In one embodiment, the non-nucleophilic base used in Process C is used in an amount of about 1.5 to about 5 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 2 to about 4 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 2.5 to about 3.5 molar equivalents.

In still another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 3 to about 3.5 molar equivalents.

In yet another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 2 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 2.5 molar equivalents. In another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 3 molar equivalents.

In another embodiment, the non-nucleophilic base used in Process C is used in an amount of about 3.5 molar equivalents.

In one embodiment, for Process C:

the organic solvent C is selected from acetonitrile, NMP, THF, 2-methyl THF, DMF and mixtures thereof;

the base used is an organic amine; and

the process is conducted at a temperature in a range of from about -30°C to about

50°C.

In another embodiment, for Process C:

the organic solvent C is acetonitrile;

the base used is selected from DBU, TMG, DBN, MTBD and DMAP;

the process is conducted at a temperature in a range of from about -20°C to about

50°C; and

In another embodiment, for Process C:

the organic solvent C is acetonitrile;

the base used is DBU;

the process is conducted at a temperature in a range of from about -15°C to about

0°C; and

the compound of formula (I) used has the formula (la'), (la"), (lb') or (lb"):

wherein:

R¹² is pentafluorophenoxy;

R³ is -Ci-C₆ alkyl; and

R⁴ is -Ci-C₆ alkyl.

In one embodiment, the compound of formula (IV) that is made by Process A or Process C is selected from:

In one embodiment, the compound of formula (II) that is made by Process A or Process B is selected from:

EXAMPLES

General Methods

Solvents, reagents, and intermediates that are commercially available were used as received. Reagents and intermediates that are not commercially available were prepared in the manner as described below. ^XH NMR spectra were obtained on a Bruker Ultrashield 500 (500 MHz) and are reported as ppm downfield from Me4Si with multiplicities, coupling constants in Hertz and number of protons indicated parenthetically. Where LC/MS data are presented, analyses was performed using an Waters Acquity UPLC MS system with LC column: -BEH C18 column, 1.0 x 50 mm, 1.7 urn, UV: 215 nm, 2-min gradient, 10-95% B, 0.5 ul injection LC, Scan: 170-900 amu, ESI positive, min integration delay. The observed parent ion is given. Flash column chromatography was performed using pre-packed normal phase silica from Teledyne ISCO. Unless otherwise indicated, column chromatography was performed using a gradient elution of DCM/MeOH, from 0% MeOH to 5% MeOH.

EXAMPLE 1

Preparation of Compound 1

To a solution of (R)-isopropyl 2-(((i?) -(perfluorophenoxy)(phenoxy)phosphoryl) amino) propanoate (la, 0.43 g, 0.94 mmol, made using the methods described in International Publication No. WO 2014/062596) and l-((2i i^£5i?)-3-ethynyl-4-hydroxy-5- (hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (lb, 0.25 g, 0.94 mmol, made using the methods described in International Publication No. WO 2012/142085) in THF (9 mL) at 0 °C was added DBU (0.15 mL, 0.99 mmol). The reaction was cooled to 0 °C and allowed to stir at this temperature for 3 hours, then quenched with 0.5 M citric acid. The bi- phasic mixture was then diluted with EtOAc and the organic layer was separated and the aqueous layer was back extracted once with EtOAc. The combined organic layers were washed with 10% brine, dried over MgS0₄, filtered and concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel to provide 0.37 g (74%) of compound 1: ^XH NMR (500 MHz, A₆-DMSO): 5 1.18 (dd, J = 6.2, 3.9 Hz, 6 H), 1.22 (s, 3 H), 1.27 (d, J = 7.1 Hz, 3 H), 3.46 (s, 1 H), 3.69-3.65 (m, 1 H), 3.90-3.81 (m, 2 H), 4.03 (d, J = 8.5 Hz, 1 H), 4.60 (t, J = 8.8 Hz, 1 H), 4.90-4.85 (m, 1 H), 5.36 (t, J = 4.5 Hz, 1 H), 5.69 (d, J = 8.1 Hz, 1 H), 6.21-6.14 (m, 2 H), 7.25-7.18 (m, 3 H), 7.39 (t, J = 7.8 Hz, 2 H), 8.10 (d, J = 8.1 Hz, 1 H), 11.49 (s, 1 H). ¹ C NMR (126 MHz, A₆-DMSO): δ 172.3 (d, J = 6.4 Hz), 162.8, 150.6 (d, J = 6.7 Hz), 150.5, 140.0, 129.6 (2C), 124.7, 120.2 (d, J = 4.8 Hz, 2C), 101.7, 89.4, 82.9, 81.9 (d, J = 4.9 Hz), 76.6, 76.2 (d, J = 5.1 Hz), 68.0, 57.9, 49.9, 46.6 (d, J = 4.0 Hz), 21.5, 21.4, 19.8 (d, J = 5.9 Hz), 19.0. MS = 536.33 (M+l). EXAMPLE 2

Preparation of Compound 2

Using the method described in Example 1 above, and substituting 1- ((2R, 3R, 4R, 5i?)-3-chloro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione (2a, 0.25 g, 0.90 mmol) for compound lb provided 0.44 g (89%) of compound 2: ^XH NMR (500 MHz, d₆-DMSO) 5 1.18 (dd, J = 6.3, 2.3 Hz, 6 H), 1.27 (d, J = 7.1 Hz, 3 H), 1.57 (s, 3 H), 3.66-3.62 (m, 1 H), 3.88-3.83 (m, 2 H), 4.08 (d, J = 9.0 Hz, 1 H), 4.78 (br s, 1 H), 4.91-4.86 (m, 1 H), 5.48 (s, 1 H), 5.72 (d, J = 8.2 Hz, 1 H), 6.35-6.29 (m, 2 H), 7.26-7.19 (m, 3 H), 7.40 (t, J = 7.8 Hz, 2 H), 8.18 (d, J = 8.3 Hz, 1 H), 11.55 (s, 1 H). ¹ C NMR (126 MHz, de-DMSO) δ 172.3 (d, J = 5.9 Hz), 162.8, 150.6, 150.5 (d, J = 6.6 Hz), 139.3, 129.7 (2C), 124.8, 120.2 (d, J = 4.9 Hz, 2C), 102.2, 91.1, 81.1, 75.8, 74.7 (br s), 68.0, 57.6, 50.0, 22.4, 21.5, 21.4, 19.7 (d, J = 6.3 Hz). MS = 546.30 (M+l).

EXAMPLE 3

Preparation of Compound 3

Using the method described in Example 1 above, and substituting (i?)-isopropyl

2-(((i?)-(perfluorophenoxy)(phenoxy)phosphoryl)amino) propanoate (0.42 g, 0.94 mmol) and (2i?, 3i?, ^,5i?)-2-(2,4-dioxo-3,4-dihydropyrirnidin-l(2H)-yl)-4-hydroxy-5-(hydroxymethyl)-3- methyltetrahydrofuran-3-carbonitrile (3a, 0.25 g, 0.94 mmol) with DBU (0.15 mL, 0.98 mmol) for compound lb, provided gave 0.29 g (58%) of compound 3: ^XH NMR (500 MHz, CDCl₃): δ 1.29 (dd, J = 12.0, 6.2 Hz, 6 H), 1.44 (s, 3H), 1.46 (d, J = 8.0 Hz, 3 H), 3.51 (dd, J = 13.5, 2.1

Hz, 1 H), 3.83 (d, J = 13.5, 1 H), 3.95 (d, J = 8.2 Hz, 1 H), 4.13-4.05 (m, 1 H), 4.40 (dd, J = 12.9, 9.8 Hz, 1 H), 4.73 (t, J = 8.6 Hz, 1 H), 5.09-5.04 (m, 1 H), 5.77 (d, J = 8.2 Hz, 1 H), 6.38 (s, 1 H), 7.27-7.24 (m, 3 H), 7.40 (t, J = 7.8 Hz, 2 H), 7.97 (d, J = 8.2 Hz, 1 H), 9.37 (s, 1 H). ¹ C NMR (126 MHz, CDCl₃): δ 172.9 (d, J = 8.1 Hz), 162.9, 150.3, 150.0 (d, J = 7.6 Hz), 139.5, 130.1 (2C), 126.1, 120.9 (d, J = 4.4 Hz, 2C), 118.0, 103.1, 87.1, 82.7 (d, J = 2.3 Hz), 76.0 (d, J = 4.3 Hz), 70.1, 58.5, 50.5, 48.1 (d, J = 6.1 Hz), 21.8, 21.8, 21.1 (d, J = 4.3 Hz), 17.0. MS = 537.32 (M+l).

EXAMPLE 4

Preparation of Compound 4

Using the method described in Example 1 above, and substituting (i?)-isopropyl 2-(((i?)-(perfluorophenoxy)(phenoxy)phosphoryl)arnino)propanoate (0.44 g, 0.96 mmol) and 1- ((2R, 3R, 4R, 5i?)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione (4a, 0.25 g, 0.96 mmol) for compound lb, provided 0.47 g (92%) of compound 4 : ^lH NMR (500 MHz, CDCl₃): δ 1.25 (dd, J = 6.3, 2.7 Hz, 6 H), 1.44-1.40 (m, 6 H), 3.52 (d, J = 13.4 Hz, 1 H), 3.85 (d, J = 13.4 Hz, 1 H), 4.06-3.97 (m, 2 H), 4.48 (dd, J =

12.5, 9.8 Hz, 1 H), 4.71-4.63 (m, 1 H), 5.05-5.00 (m, 1 H), 5.74 (d, J = 8.2 Hz, 1 H), 6.17 (d, J = 18.0 Hz, 1 H), 7.22 (dd, J = 13.1, 7.5 Hz, 3 H), 7.35 (t, J = 7.8 Hz, 2 H), 7.97 (d, J = 8.2 Hz, 1 H), 9.99 (s, 1 H). ¹ C NMR (126 MHz, CDCl₃): δ 172.9 (d, J = 8.3 Hz), 163.5, 150.7, 150.1 (d, J = 7.5 Hz), 139.7, 129.9 (2C), 125.8 (d, J = 1.4 Hz), 120.7 (d, J = 4.5 Hz, 2C), 103.1, 99.7 (dd, J = 186.9, 5.6 Hz), 88.7 (br d, J = 38.2 Hz), 80.7 (d, J = 3.1 Hz), 73.9 (dd, J = 15.1, 4.3 Hz), 69.8,

58.6, 50.5, 21.8, 21.7, 21.1 (d, J = 4.2 Hz), 16.6 (d, J = 25.3 Hz). MS = 530.33 (M+l).

EXAMPLE 5

Preparation of Compound 5

Using the method described in Example 1 above, and substituting (i?)-isopropyl

2-(((i?)-(perfluorophenoxy)(phenoxy)phosphoryl)arnino)propanoate (0.40 g, 0.88 mmol) and 1- ((2R, 3R, 4S, 5i?)-3-azido-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2- yl)pyrimidine-2,4(lH,3H)-dione (5a, 0.25 g, 0.88 mmol) for compound lb, provided 0.30 g (62%) of compound 5: ^lH NMR (500 MHz, CDCl₃): δ 1.27-1.25 (m, 6 H), 1.44-1.42 (m, 6 H), 3.46 (d, J = 13.5 Hz, 1 H), 3.80 (d, J = 13.5 Hz, 1 H), 3.90 (d, J = 9.1 Hz, 1 H), 4.06-4.01 (m, 1 H), 4.45 (dd, J = 12.8, 9.9 Hz, 1 H), 4.69 (t, J = 9.2 Hz, 1 H), 5.06-5.01 (m, 1 H), 5.76-5.74 (m, 1 H), 5.89-5.88 (m, 1 H), 7.25-7.21 (m, 3 H), 7.37 (q, J = 7.9 Hz, 2 H), 8.03 (d, J = 8.2 Hz, 1 H), 9.79 (s, 1 H). ¹ C NMR (126 MHz, CDCl₃): δ 172.8 (d, J = 8.3 Hz), 163.4, 150.7, 150.0 (d, J = 7.4 Hz), 139.7, 130.0 (2C), 126.0, 120.7 (d, J = 4.3 Hz, 2C), 103.0, 89.1, 81.4 (d, J = 2.1 Hz), 76.5 (d, J = 4.6 Hz), 69.9, 69.9 (d, J = 6.3 Hz), 58.7, 50.6, 21.8, 21.7, 21.3 (d, J = 4.0 Hz), 15.9. MS = 553.35 (M+l).

EXAMPLE 6

Preparation of Compound 6

Using the method described in Example 1 above, and substituting (i?)-isopropyl 2-(((i?)-(perfluorophenoxy)(phenoxy)phosphoryl)amino)propanoate (0.41 g, 0.91 mmol) and 1- ((2R, 3R, 4R, 5i?)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)-3- methylpyrimidine-2,4(lH,3H)-dione (6a, 0.25 g, 0.91 mmol) for compound lb, provided 0.46 g (93%) of compound 6: ^XH NMR (500 MHz, CDCl₃): δ 1.21 (dd, J = 6.2, 2.0 Hz, 6 H), 1.39-1.35 (m, 6 H), 3.29 (s, 3 H), 3.87-3.52 (m, 3 H), 3.98-3.91 (m, 2 H), 4.38 (dd, J = 12.5, 9.8 Hz, 1 H), 4.68-4.60 (m, 1 H), 5.00-4.95 (m, 1 H), 5.75 (d, J = 8.2 Hz, 1 H), 6.17 (d, J = 18.2 Hz, 1 H), 7.19-7.16 (m, 3 H), 7.32 (t, J = 7.8 Hz, 2 H), 7.87 (d, J = 8.2 Hz, 1 H). ¹ C NMR (126 MHz, CDCk): δ 172.7 (d, J = 8.3 Hz), 162.6, 151.2, 150.1 (d, J = 7.3 Hz), 137.3, 129.8 (d, J = 1.1 Hz, 2C), 125.7 (d, J = 1.4 Hz), 120.6 (d, J = 4.5 Hz, 2C), 102.3, 99.6 (dd, J = 186.9, 5.7 Hz), 89.3 (br d, J = 38.8 Hz), 80.5 (d, J = 2.7 Hz), 73.8 (dd, J = 16.6, 4.7 Hz), 69.6, 58.6, 50.4 (d, J = 1.0 Hz), 27.7, 21.7, 21.6, 20.9 (d, J = 4.3 Hz), 16.3 (d, J = 25.4 Hz). MS = 544.36 (M+l).

EXAMPLE 7

Preparation of Compound 7

Using the method described in Example 1 above, and substituting (2R, 3S, 4R, 5R)- 5-(2-amino-6-methoxy-9H-purin-9-yl)-4-azido-2-(hydroxymethyl)-4-methyltetrahydrofuran-3-ol (7a, 0.25 g, 0.74 mmol) for compound lb, provided 0.38 g (84%) of compound 7: ^XH NMR (500 MHz, CDCk): δ 1.23 (d, J = 6.4 Hz, 6 H), 1.26 (s, 3 H), 1.41 (d, J = 7.0 Hz, 3 H), 3.76 (dd, J = 13.1, 2.0 Hz, 1 H), 4.04-4.02 (m, 1H), 4.07 (s, 3 H), 4.17-4.11 (m, 2 H), 5.02-4.96 (m, 1 H), 5.47 (t, J = 9.3 Hz, 1 H), 5.74 (s, 1 H), 7.24-7.15 (m, 2 H), 7.37-7.27 (m, 4 H), 7.89 (s, 1 H). ¹ C NMR (126 MHz, CDCk): δ 172.7 (d, J = 8.2 Hz), 162.0, 159.4, 152.4, 150.5 (d, J = 7.0 Hz), 138.0, 129.9 (2C), 125.5, 120.4 (d, J = 4.8 Hz, 2C), 116.1, 91.0, 81.7 (d, J = 3.8 Hz), 77.2 (d, J = 4.2 Hz), 70.3 (d, J = 4.9 Hz), 69.6, 59.6, 54.2, 50.7 (d, J = 1.6 Hz), 21.7, 21.7, 21.3 (d, J = 4.1 Hz), 16.4. MS = 606.41 (M+l).

EXAMPLE 8

Preparation of Compound 8

To a solution of DBU (0.52 mL, 3.4 mmol) in DMF (1.4 mL) and 2-Methyl-THF (1.0 mL) at 0 °C was added a solution of compound 1 (0.71 g, 0.95 mmol) in DMF (0.6 mL) and 2-Methyl-THF (0.5 mL). The internal temperature was kept below 5 °C during addition and then the reaction was allowed to warm to room temperature and allowed to stir overnight. The reaction was quenched by addition of 0.5 M citric acid and diluted with EtOAc. The organic layer was removed and the aqueous layer was back extracted twice with EtOAc. The combined organic layers were washed with 10% aqueous LiCl twice and then concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel to provide 0.35 g (83%) of compound 8: ^XH NMR (500 MHz, d₆-DMSO): δ 1.15 (s, 3 H), 1.20 (dd, J = 8.0, 6.3 Hz, 6 H), 1.33 (d, J = 7.1 Hz, 3 H), 3.61 (s, 1 H), 3.81-3.76 (m, 1 H), 4.19-4.14 (m, 1 H), 4.32 (d, J = 9.8 Hz, 1 H), 4.61 (dd, J = 15.8, 7.3 Hz, 2 H), 4.91-4.86 (m, 1 H), 5.78 (d, J = 8.1 Hz, 1 H), 5.95 (t, J = 11.8 Hz, 1 H), 6.26 (s, 1 H), 7.50 (d, J = 8.2 Hz, 1 H), 11.65 (s, 1 H). ¹ C NMR (126 MHz, d₆-DMSO): δ 172.9 (d, J = 3.8 Hz), 162.6, 150.3, 139.2, 102.4, 91.8, 82.1, 80.5 (d, J = 5.1 Hz), 77.4, 71.4 (d, J = 6.8 Hz), 68.2, 68.1 (d, J = 8.4 Hz), 49.3, 44.3 (d, J = 7.4 Hz), 21.5, 21.4, 20.1 (d, J = 7.6 Hz), 18.92. MS = 442.25 (M+l).

EXAMPLE 9

Preparation of Compound 9

A solution of DBU (1.0 mL, 6.5 mmol) in a mixture of DMF (2.8 mL) and 2-

Methyl-THF (2.0 mL) was cooled to 0 °C, then to the cooled mixture was added a solution of compound 2 (1.0 g, 1.8 mmol) in a mixture of DMF (1.2 mL) and 2-Methyl-THF (0.9 mL). The internal reaction temperature was kept below 5 °C during addition and then the reaction was allowed to warm to room temperature and allowed to stir overnight. The reaction was then quenched by addition of 0.5 M citric acid and diluted with EtOAc. The organic layer was removed and the aqueous layer was back extracted twice with EtOAc. The combined organic layers were washed with 10% aqueous LiCl twice and then concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel to provide 0.68 g (84%) of compound 9: ^XH NMR (500 MHz, d₆-DMSO): δ 1.20 (dd, J = 7.8, 6.2 Hz, 6 H), 1.34 (d, J = 7.2 Hz, 3 H), 1.49 (s, 3 H), 3.86-3.78 (m, 1 H), 4.29-4.24 (m, 1 H), 4.53 (d, J = 9.8 Hz, 1 H), 4.66- 4.62 (m, 2 H), 4.92-4.87 (m, 1 H), 5.81 (d, J = 8.1 Hz, 1 H), 6.03 (dd, J = 13.5, 10.3 Hz, 1 H), 6.42 (s, 1 H), 7.52 (d, J = 8.2 Hz, 1 H), 11.70 (s, 1 H). ¹ C NMR (126 MHz, d₆-DMSO): δ 172.9 (d, J = 3.9 Hz), 162.5, 150.4, 138.7, 102.8, 93.7, 79.8 (d, J = 4.5 Hz), 72.2 (d, J = 8.0 Hz), 70.7 (d, J = 7.2 Hz), 68.3, 68.0 (d, J = 8.5 Hz), 49.3, 22.5, 21.5, 21.4, 20.1 (d, J = 7.7 Hz). MS 452.20 (M+l).

EXAMPLE 10

Alternate Preparation of Compound 8

To a solution of compound la (0.43 g, 0.94 mmol) and compound lb (0.25 g, 0.94 mmol) in acetonitrile (9.4 mL) at -15 °C was added DBU (0.50 mL, 3.29 mmol). The reaction was kept at -15 °C for 2 hours and then placed at 0 °C and allowed to stir overnight. The next morning the reaction was quenched with 0.5 M citric acid and diluted with EtOAc, organic layer was washed with 10% LiCl aqueous solution and then combined aqueous layers were extracted twice with EtOAc. The combined organics were concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel to provide 0.20 g (48%) of isopropyl ((2R, 4aR, 6R, 7R, 7a5)-6-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)-7-ethynyl-7- methyl-2-oxidotetrahydro-4H-furo[3,2-d][l,3,2]dioxaphosphinin-2-yl)-D-alaninate.

EXAMPLE 11

Preparation of Compound 11

To a solution of compound la (0.40 g, 0.88 mmol) and compound 5a (0.25 g,

0.88 mmol) in acetonitrile (8.8 mL) at -15 °C was added DBU (0.47 mL, 3.10 mmol). The reaction was kept at -15 °C for 2 hours and then placed at 0 °C and allowed to stir overnight. The next morning the reaction was quenched with 0.5 M citric acid and diluted with EtOAc, organic layer was washed with 10% LiCl aqueous solution and then combined aqueous layers were extracted twice with EtOAc. The combined organics were concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel to provide 0.14 g (34%) of compound 11: ^XH NMR (500 MHz, d₆-DMSO): δ 1.21-1.16 (m, 6 H), 1.33 (d, J = 8.1 Hz, 3 H), 1.34 (s, 3H), 3.81 (br d, J = 10.4 Hz, 1 H), 4.19 (t, J = 8.7 Hz, 1 H), 4.48 (d, J = 9.9 Hz, 1 H), 4.63-4.54 (m, 2 H), 4.93-4.88 (m, 1 H), 5.81 (d, J = 8.1 Hz, 1 H), 6.01-5.94 (m, 2 H), 7.52 (d, J = 8.2 Hz, 1 H), 11.68 (s, 1 H). ¹ C NMR (126 MHz, d₆-DMSO): δ 172.9 (d, J = 4.1 Hz), 162.7, 150.4, 139.0, 102.8, 91.2, 80.6 (d, J = 4.9 Hz), 70.3 (d, J = 7.3 Hz), 68.3, 68.3 (d, J = 8.0 Hz), 67.5 (d, J = 7.1 Hz), 49.4, 21.5, 21.5, 20.0 (d, J = 7.7 Hz), 15.7. MS = 459.28 (M+l).

EXAMPLE 12

Preparation of Compound 12

To a solution of compound la (0.42 g, 0.94 mmol) and compound 3a (0.25 g, 0.94 mmol) in acetonitrile (9.4 mL) at -15 °C was added DBU (0.49 mL, 3.3 mmol). The reaction was kept at -15 °C for 2 hours and then placed at 0 °C and allowed to stir overnight. The next morning the reaction was quenched with 0.5 M citric acid and diluted with EtOAc, organic layer was washed with 10% LiCl aqueous solution and then combined aqueous layers were extracted twice with EtOAc. The combined organics were concentrated in vacuo and the resulting residue was purified using flash column chromatography on silica gel to provide 0.15 g (35%) of compound 12: ^lH NMR (500 MHz, d₆-DMSO): δ 1.19 (dd, J = 10.3, 6.2 Hz, 6 H), 1.30 (s, 3 H), 1.32 (d, J = 7.21 Hz, 3 H), 3.81-3.73 (m, 1 H), 4.21 (td, J = 9.9, 5.5 Hz, 1 H), 4.68-4.51 (m, 3 H), 4.92-4.87 (m, 1 H), 5.80 (d, J = 8.2 Hz, 1 H), 6.04 (dd, J = 13.4, 10.1 Hz, 1 H), 6.46 (s, 1 H), 7.57 (d, J = 8.2 Hz, 1 H), 11.72 (s, 1H). ¹ C NMR (126 MHz, d₆-DMSO): δ 172.8 (d, J = 4.0 Hz), 162.6, 150.2, 139.0, 118.3, 102.8, 88.7, 80.1 (d, J = 4.5 Hz), 71.4 (d, J = 7.3 Hz), 68.3, 67.8 (d, J = 8.6 Hz), 49.3, 44.9 (d, J = 7.2 Hz), 21.5, 21.5, 19.9 (d, J = 7.8 Hz), 17.1. MS = 401.24 (M(- iPr) +l). EXAMPLE 13

Alternate Preparation of Compound 9

To a solution of compound la (0.41 g, 0.90 mmol) and compound 2a (0.25 g, 0.90 mmol) in acetonitrile (9.0 mL) at -15 °C was added DBU (0.48 mL, 3.16 mmol). The reaction was kept at -15 °C for 2 hours and then placed at 0 °C and allowed to stir overnight. The next morning the reaction was quenched with 0.5 M citric acid and diluted with EtOAc, organic layer was washed with 10% LiCl aqueous solution and then combined aqueous layers were extracted twice with EtOAc. The combined organics were concentrated in vacuo. The resulting residue was purified using flash column chromatography on silica gel to provide 0.23 g (56%) of compound 9.

While the foregoing specification teaches the principles of the present invention, with examples provided for the purpose of illustration, the practice of the invention encompasses all of the usual variations, adaptations and/or modifications that come within the scope of the following claims. All publications, patents and patent applications cited herein are incorporated by reference in their entirety into the disclosure.

Claims

WHAT IS CLAIMED IS:

1. A p

(A) contacting a compound of formula (I):

(I)

with a compound of formula (II):

(Π),

(HI);

then:

X is O, N, S or CH₂;

R¹ is H, C1-C3 alkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

R² is selected from H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, -CN, -N₃, - N(R¹ )₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and C3-C7

cycloalkyl;

each occurrence of R⁵ is independently selected from -C1-C6 alkyl, halo, -OR⁶, - C(0)R⁶, -C0₂R⁶, -SR⁶, -Ci-C₆ hydroxyalkyl, -Ci-C₆ haloalkyl, -N(R⁶)₂, -S(0)R⁶, -S(0)₂R⁶, -CN and -N0₂; each occurrence of R is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene)_m-(C₃-C7 cycloalkyl), -(C1-C3 alkylene)_m-(C₆-Cio aryl), -(C1-C3 alkylene)_m-(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene)_m-(5- or 6-membered monocyclic heteroaryl) or -(C1-C3 alkylene)_m-(9- or 10-membered bicyclic heteroaryl);

R⁷, R⁸ and R⁹ are each independently selected from H, C1-C6 alkyl, C2-C6 alkenyl,

C₂-C₆ alkynyl, C3-C7 cycloalkyl, halo, -OR¹⁰, -SR¹⁰, -S(0)R¹⁰, -S(0)₂R¹⁰, -S(O)₂N(R¹⁰)_2i - NHC(0)OR¹⁰, -NHC(0)N(R¹⁴)₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, -0-(d-C₆ haloalkyl), - CN, -NO2, -N(R¹⁰)₂, -NH(Ci-C₆ alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C₆ alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R¹⁰, -C(0)OR¹⁰, -C(O)N(R¹⁰)₂ and - NHC(0)R¹⁰;

each occurrence of R¹⁰ is independently selected from H, C1-C1₀ alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene)_n-(C3-C7 cycloalkyl), -(C1-C3 alkylene)_n-(C6-Cio aryl), -(C1-C3 alkylene)_n-(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene)_n-(5- or 6- membered monocyclic heteroaryl) and -(C1-C3 alkylene)_n-(9- or 10-membered bicyclic heteroaryl);

R¹³ is selected from H and C1-C6 alkyl;

each occurrence of m is independently 0 or 1 ; and

each occurrence of n is independently 0 or 1.

2. A process for making a compound of formula (IV):

(IV)

or a pharmaceutically acceptable salt thereof, said process comprising the step of contacting a compound of formula (I):

(I)

with a compound of formula (II):

(Π),

X is O, N, S or CH₂;

R¹ is H, C1-C3 alkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

R⁴ is selected from C1-C6 alkyl, C₂-C6 alkenyl, -(C1-C3 alkylene)_m-(C₃-Ci4 cycloalkyl) and -(C1-C3 alkylene)_m-(C₆-Cio aryl);

each occurrence of R⁶ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene)_m-(C3-C₇ cycloalkyl), -(C1-C3 alkylene)_m-(C₆-Ci₀ aryl), -(C1-C3 alkylene)_m-(4 to 7-membered heterocycloalkyl), -(C1-C₃ alkylene)_m-(5- or 6-membered monocyclic heteroaryl) or -(C1-C₃ alkylene)_m-(9- or 10-membered bicyclic heteroaryl);

R⁷, R⁸ and R⁹ are each independently selected from H, C1-C6 alkyl, C₂-C6 alkenyl, C₂-C₆ alkynyl, C3-C7 cycloalkyl, halo, -OR¹⁰, -SR¹⁰, -S(0)R¹⁰, -S(0)₂R¹⁰, -S(O)₂N(R¹⁰)₂, - NHC(0)OR¹⁰, -NHC(0)N(R¹⁴)₂, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, -0-(Ci-C₆ haloalkyl), - CN, -NO2, -N(R¹⁰)₂, -NH(Ci-C₆ alkylene)-(5- or 6-membered monocyclic heteroaryl), -NH(C C₆ alkylene)-(9- or 10-membered bicyclic heteroaryl), -C(0)R¹⁰, -C(0)OR¹⁰, -C(O)N(R¹⁰)₂ and - NHC(0)R¹⁰;

each occurrence of R¹⁰ is independently selected from H, C1-C1₀ alkyl, C1-C6 haloalkyl, Ci-C₆ hydroxyalkyl, -(C1-C3 alkylene)_n-(C₃-C7 cycloalkyl), -(C1-C3 alkylene)_n-(C₆-Cio aryl), -(C1-C3 alkylene)_n-(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene)_n-(5- or 6- membered monocyclic heteroaryl) and -(C1-C₃ alkylene)_n-(9- or 10-membered bicyclic heteroaryl);

monocyclic heteroaryl group and said 9 or 10-membered bicyclic heteroaryl group can be optionally substituted with one or more R⁵ groups; R is selected from -0-(C6-Cio aryl), -0-(5 or 6-membered monocyclic heteroaryl) and -S-(C6-Cio aryl), wherein said 5 or 6-membered monocyclic heteroaryl group or any of said C6-C10 aryl groups can be optionally substituted with up to 5 groups, each independently selected from C1-C6 alkyl, -N0₂, halo and C1-C6 haloalkyl;

R¹³ is selected from H and Ci-Ce alkyl;

each occurrence of m is independently 0 or 1 ; and

each occurrence of n is independently 0 or 1.

3. The process of claim 1, wherein the non-nucleophilic base used in steps A and B is selected from DBU, TMG, DBN, MTBD and DMAP.

4. The process of claim 1, wherein organic solvent A is selected from organic solvent A is a mixture of THF and DMF or a mixture of ethyl acetate and NMP.

5. The process of claim 1, wherein organic solvent B is a mixture of DMF and 2-methyl-THF.

6. The process of claim 4 or 5, wherein the non-nucleophilic base used in steps A and B is DBU.

7. A process for makin a compound of formula (III):

(III) or a pharmaceutically acceptable salt thereof, said process comprising contacting a compound of formula (I):

with a compound of formula (II):

(Π),

wherein:

X is O, N, S or CH₂;

R¹ is H, C1-C3 alkyl, C₂-C₃ alkenyl or C₂-C₃ alkynyl;

R² is selected from H, Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo, -CN, -N₃, N(R")2, Ci-C₆ haloalkyl, Ci-C₆ hydroxyalkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl and C3-C7 cycloalkyl;

R⁴ is selected from Ci-C₆ alkyl, C₂-C₆ alkenyl, -(C1-C3 alkylene)_m-(C3-Ci₄ cycloalkyl) and -(C1-C3 alkylene)_m-(C6-Cio aryl); each occurrence of R is independently selected from -C1-C6 alkyl, halo, -OR , - C(0)R⁶, -CO2R⁶, -SR⁶, -Ci-C₆ hydroxyalkyl, -Ci-C₆ haloalkyl, -N(R⁶)₂, -S(0)R⁶, -S(0)₂R⁶, -CN and -N0₂;

each occurrence of R⁶ is independently H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C3 alkylene)_m-(C3-C7 cycloalkyl), -(C1-C3 alkylene)_m-(C6-Cio aryl), -(C1-C3 alkylene)_m-(4 to 7-membered heterocycloalkyl), -(C1-C3 alkylene)_m-(5- or 6-membered monocyclic heteroaryl) or -(C1-C3 alkylene)_m-(9- or 10-membered bicyclic heteroaryl);

each occurrence of R¹⁰ is independently selected from H, C1-C1₀ alkyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl, -(C1-C₃ alkylene)_n-(C₃-C7 cycloalkyl), -(C1-C₃ alkylene)_n-(C₆-Cio aryl), -(C1-C₃ alkylene)_n-(4 to 7-membered heterocycloalkyl), -(C1-C₃ alkylene)_n-(5- or 6- membered monocyclic heteroaryl) and -(C1-C₃ alkylene)_n-(9- or 10-membered bicyclic heteroaryl);

R¹³ is selected from H and C1-C6 alkyl;

each occurrence of m is independently 0 or 1 ; and

each occurrence of n is independently 0 or 1.

8. The process of claim 7, wherein the non-nucleophilic base is selected from DBU, TMG, DBN, MTBD and DMAP.

9. The process of claim 7 or 8, wherein organic solvent C is selected from a mixture of THF and DMF or a mixture of ethyl acetate and NMP.

10. The process of any of claims 7-9, wherein the non-nucleophilic base is

DBU.

11. The process of any of claims 1-10, wherein the compound of formula (I) has the formula (la'), (la"), (lb') or (lb"):

wherein:

R¹² is pentafluorophenoxy;

R³ is -Ci-C₆ alkyl; and

R⁴ is -Ci-C₆ alkyl.

12. The process of claim 11, wherein the compound of formula (I) is:

13. The process of any of claims 1-12, wherein the compound of formula (II) has the formula (Ila):

(Ila) wherein R² is selected from -CI, -F, -CN, C2-C6 alkynyl, -NH₂ and

15. The process of claim 2, wherein the compound of formula (IV) that is

16. The process of claim 7, wherein the compound of formula (III) that is made by said process is selected from:

-59-