OA17044A

OA17044A - Substituted nucleosides, nucleotides and analogs thereof.

Info

Publication number: OA17044A
Application number: OA1201400269
Authority: OA
Inventors: Leonid Beigelman; Guangyi Wang; David Bernard Smith; Jerome Deval; Marija Prhavc
Original assignee: Alios Biopharma, Inc.
Priority date: 2011-12-22
Filing date: 2012-12-20
Publication date: 2016-03-04

Abstract

Disclosed herein are nucleosides, nucleotides and analogs thereof, pharmaceutical compositions that include one or more of nucleosides, nucleotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a disease and/or a condition, including an infection from a paramyxovirus and/or an orthomyxovirus, with a nucleoside, a nucleotide and an analog thereof.

Description

SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF

BACKGROUND

Field [0001] The présent application relates to the fields of chemistry, biochemistry and medicine. More particulariy, disclosed herein are nucleoside, nucléotides and analogs thereof, pharmaceutical compositions that include one or more nucleosides, nucléotides and analogs thereof, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus and/or an orthomyxovirus viral infection with one 10 or more nucleosides, nucléotides and analogs thereof.

Description [0002] Respiratory viral infections, including upper and lower respiratory tract viral infections, infects and is the leading cause of death of millions of people each year. Upper 15 respiratory tract viral infections involve the nose, sinuses, pharynx and/or larynx. Lower respiratory tract viral infections involve the respiratory System below the vocal cords, including the trachea, primary bronchi and lungs.

[0003] Nucleoside analogs are a class of compounds that hâve been shown to exert antiviral activity both in vitro and in vivo, and thus, hâve been the subject of widespread research 20 for the treatment of viral infections. Nucleoside analogs are usually therapeutically inactive compounds that are converted by host or viral enzymes to their respective active antimetabolites, which, in tum, may inhibit polymerases involved in viral or cell prolifération. The activation occurs by a variety of mechanisms, such as the addition of one or more phosphate groups and, or in combination with, other metabolic processes.

SUMMARY [0004] Some embodiments disclosed herein relate to a compound of Formula (I), Formula (Π) and/or Formula (III), or a pharmaceutically acceptable sait of the foregoing.

[0005] Some embodiments disclosed herein relate to methods of ameliorating and/or 30 treating a paramyxovirus viral infection that can include administering to a subject suffering from the paramyxovirus viral infection an effective amount of one or more compounds of Formula (I), Formula (Π) and/or Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formula (I)» Formula (Π) and/or Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing.

Other embodiments described herein relate to using one or more compounds of Formula (I), Formula (Π) and/or Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, in the manufacture of a médicament for ameliorating and/or treating a paramyxovirus viral infection. Still other embodiments described herein relate to compounds of Formula (I), Formula (Π) and/or Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, that can be used for ameliorating and/or treating a paramyxovirus viral infection. Yet still other embodiments disclosed herein relate to methods of ameliorating and/or treating a paramyxovirus viral infection that can include contacting a cell infected with the paramyxovirus with an effective amount of one or more compounds of Formula (I), Formula (Π) and/or Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formula (I), Formula (Π) and/or Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing. Some embodiments disclosed herein relate to methods of inhibiting the réplication of a paramyxovirus that can include contacting a cell infection with the paramyxovirus with an effective amount of one or more compounds of Formula (I), Formula (Π) and/or Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formula (I). Formula (Π) and/or Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing. For example, the paramyxovirus vira! infection can be caused by a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus (including a respiratory syncytial viral infection), a metapneumovirus, hendravirus, nipahvirus, measles, sendai virus, mumps, a human parainfluenza virus (HPIV-1, HPIV-2, HPIV-3 and HPIV-4) and/or a metapneumovirus.

[0006] Some embodiments disclosed herein relate to methods of ameliorating and/or treating an orthomyxovirus viral infection that can include administering to a subject suffering from the orthomyxovirus viral infection an effective amount of one or more compounds of Formula (I), Formula (Π) and/or Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, or a pharmaceutical composition that includes one or more compounds of Formula (I), Formula (Π) and/or Formula (Ht), or a pharmaceutically acceptable sait of the foregoing. Other embodiments described herein relate to using one or more compounds of Formula (D. Formula (Π) and/or Formula (III). or a pharmaceutically acceptable sait of the foregoing, in the manufacture of a médicament for ameliorating and/or treating an orthomyxovirus viral infection. Still other embodiments described herein relate to compounds of Formula (I), Formula (Π) and/or Formula (ΙΓΓ), or a pharmaceutically acceptable sait of the foregoing, that can be used for ameliorating and/or treating an orthomyxovirus viral infection. Yet still other embodiments disclosed herein relate to methods of ameliorating and/or treating an orthomyxovirus viral infection that can include contacting a cell infected with the orthomyxovirus with an effective amount of one or more compounds of Formula (I), Formula (Π) and/or Formula (ΠΓ), or a pharmaceuticai!y acceptable sait of the foregoing, or a pharmaceuticai composition that includes one or more compounds of Formula (I), Formula (Π) and/or Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing. Some embodiments disclosed herein relate to methods of inhibiting the réplication of an orthomyxovirus that can include contacting a cell infection with the orthomyxovirus with an effective amount of one or more compounds of Formula (I), Formula (Π) and/or Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, or a pharmaceuticai composition that includes one or more compounds of Formula (I), Formula (Π) and/or Formula (ΙΠ). or a pharmaceutically acceptable sait of the foregoing. For example, the orthomyxovirus viral infection can be an influenza viral infection (such as influenza A, B and/or C).

[0007] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a paramyxovirus viral infection and/or an orthomyxovirus viral infection that can include administering to a subject suffering from the viral infection an effective amount of a compound described herein or a pharmaceutically acceptable sait thereof (for example, one or more compounds of Formulae (I), (Π) and/or (ΓΠ), or a pharmaceutically acceptable sait of the foregoing), or a pharmaceuticai composition that includes one or more compounds described herein, in combination with one or more agents described herein. Some embodiments disclosed herein relate to methods of ameliorating and/or treating a paramyxovirus viral infection and/or an orthomyxovirus viral infection that can include contacting a cell infected with the virus with an effective amount of a compound described herein or a pharmaceutically acceptable sait thereof (for example, one or more compounds of Formulae (I), (Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing), or a pharmaceuticai composition that includes one or more compounds described herein, in combination with one or more agents described herein.

BRIEF DESCRIPTION OFTHE DRAWINGS [0008] Figure 1 shows example RSV agents.

DETAILED DESCRIPTION [0009] Paramyxoviridae famîly is a famîly of single stranded RNA viruses. Several généra of the paramyxoviridae family include henipavirus, morbillivirus, respirovirus,

rubulavirus, pneumovirus and metapneumovirus. These viruses can be transmitted person to person via direct or close contact with contaminated respiratory droplets or fomites. Species of henipavirus include hendravirus and nîpahvirus. A species of morbillivirus is measles. Species of respirovirus include sendai virus and human parainfluenza viruses 1 and 3; and species of 5 rubulavirus include mumps virus and human parainfluenza viruses 2 and 4. A species of metapneumovirus is human metapneumovirus.

[0010] Human Respiratory Syncytial Virus (RSV), a species of pneumovirus, can cause respiratory infections, and can be associated with bronchiolitis and pneumonia. Symptoms of an RSV infection include coughing, sneezing, runny nose, fever, decrease in appetite, and 10 wheezing. RSV is the most common cause of bronchiolitis and pneumonia in children under one year of âge in the world, and can be the cause of tracheobronchitis in older children and adults. In the United States, between 75,000 and 125,000 infants are hospitalized each year with RSV. Among adults older than 65 years of âge, an estimated 14,000 deaths and 177,000 hospitalizations hâve been attributed to RSV.

[0011] Treatment options for people infected with RSV are currently limited.

Antibiotics, usualiy prescribed to treat bacterial infections, and over-the-counter médication are not effective in treating RSV and may help only to relieve some of the symptoms. In severe cases, a nebulized bronchodilator, such as albuterol, may be prescribed to relieve some of the symptoms, such as wheezing. RespiGram® (RSV-IGIV, Medlmmune, approved for high risk 20 children younger than 24 months of âge), Synagis® (palivizumab, Medlmmune, approved for high risk children younger than 24 months of âge), and Virzole® (ribavirin by aérosol, ICN pharmaceuticals) hâve been approved for treatment of RSV.

[0012] Symptoms of the measles include fever, cough, runny nose, red eyes and a generalized rash. Some individuals with measles can develop pneumonia, ear infections and 25 bronchitis. Mumps leads to swelling of the salivary glands. Symptoms of mumps include fever, loss of appetite and fatigue. Individuals are often immunized against measles and mumps via a three-part MMR vaccine (measles, mumps, and rubella). Human parainfluenza virus includes four serotypes types, and can cause upper and Iower respiratory tract infections. Human parainfluenza virus 1 (HPIV-1) can be associated with croup; human parainfluenza virus 3 30 (HPIV-3) can be associated with bronchiolitis and pneumonia. According to the Centers of Disease Control and Prévention (CDC), there are no vaccines against human parainfluenza virus.

[0013] Influenza is a single stranded RNA virus and a member of the Orthomyxoviridae family. There are currently three species of influenza; influenza A, influenza B and influenza C. Influenza A has been further classified based on the viral surface proteins into hemagglutinin (H or HA) and neuramididase (N). There are approximateiy 16 H antigens (H1 to H16) and 9 N antigens (NI to N9). Influenza A indudes several subtype, induding H INI, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, H10N7. As with RSV, influenza viruses can be transmitted from person to person via direct contact with infected sécrétions and/or contaminated surfaces or objections. Complications from an influenza viral infection include pneumonia, bronchitis, déhydration, and sinus and ear infections. Médications currently approved by the FDA against an influenza infection include amantadine, rimantadine, Relenza® (zanamivir, GlaxoSmïthKline) and Tamiflu® (oseltamivir, Genentech).

Définitions [0014] Unless defîned otherwise, ail technical and scientific terms used herein hâve the same meaning as is commonly understood by one of ordinary skill in the art. Ail patents, applications, published applications and other publications referenced herein are incorporated by référencé in their entirety unless stated otherwise. In the event that there are a plurality of définitions for a term herein, those in this section prevail unless stated otherwise.

[0015] As used herein, any R group(s) such as, without limitation, R^1A, R^2A, R^3A, R^4A, R^5a, R^6A, R^ta, R^8a, R^9a, R^ioa, R^11a, R^I2A, R^13a, R^14a, R^13A. R^16a, R^17a, R^18A, R^l9A, R^20a,

R^2,a

A r24A

R^3c, R^4c, R^5c, R⁶⁰. R^7C, R^8C, R⁹⁰, R^10C, R^11c, R^I2C, R¹³⁰, r'^4C, r'^3C. R^I6C, R^l7C, R^18c, R^i9C, R^20C, R^2ic, R^22C and R^23C represent substituents that can be attached to the indicated atom. An R group may be substituted or unsubstituted. If two R groups are described as being taken together'* the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heterocycle. For example, without limitation, if R* and R^b of an NR^a R^b group are indicated to be taken together, it means that they are covalently bonded to one another to form a ring:

In addition, if two “R” groups are described as being “taken together” with the atom(s) to which they are attached to form a ring as an alternative, the R groups are not limited to the variables or substituents defîned previously.

[0016] Whenever a group is described as being “optionally substituted that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted if substituted, the substituent(s) may be selected from one or more the indicated substituents. If no substituents are indicated, it is meant that the indicated “optionally substituted” or “substituted group may be substituted with one or more group(s) îndividually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, mercapto, alkylthio, arylthio, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-caiboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group, and protected dérivatives thereof.

[0017] As used herein, C_a to Cb in which “a” and “b are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the cycloalkynyl, ring of the aryl, ring of the heteroaryl or ring of the heteroalicyclyl can contain from “a to “b, inclusive, carbon atoms. Thus, for example, a Ci to C4 alkyl” group refers to ail alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CHjhCH-, CH3CH2CH2CH2-, CH3CH₂CH(CH3)- and (CHjhC-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, cycloalkynyl, aryl, heteroaryl or heteroalicyclyl group, the broadest range described in these définitions is to be assumed.

[0018] As used herein, “alkyl refers to a straîght or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may hâve 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., I to 20 carbon atoms” means that the alkyl group may consist of I carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the présent définition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having I to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 6 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl or similar désignations. By way of example only, C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, nbutyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.

[0019] As used herein, ‘’alkenyl’’ refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted.

[0020] As used herein, “alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted.

[0021] As used herein, “cycloalkyl” refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring System. When composed of two or more rings, the rings may be joined together in a fused fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typicaï cycloalkyl groups include, but are in no way limited to, cyclopropyl. cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0022] As used herein, “cycloalkenyl” refers to a mono- or multi- cyclic hydrocarbon ring System that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron System throughout ail the rings (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connected together in a fused fashion. A cycloalkenyl group may be unsubstituted or substituted.

[0023] As used herein, “cycloalkynyl” refers to a mono- or multi- cyclic hydrocarbon ring System that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron System throughout ail the rings. When composed of two or more rings, the rings may be joined together in a fused fashion. A cycloalkynyl group may be unsubstituted or substituted.

[0024] As used herein, “aryl” refers to a carbocyclic (ail carbon) monocyclic or multicyclic aromatic ring System (including fused ring Systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron System throughout ail the rings. The number of carbon atoms in an aryl group can vary. For example, the aryl group can be a CeC|< aryl group. a C6-C10 aryl group, or a Ce aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0025] As used herein. “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring System with fully delocalized pi-electron System) that contaîn(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The number of atoms in the ring(s) of a heteroaryl group can vary. For example, the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s). Furthermore, the term “heteroaryl” includes fused ring Systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3oxadiazole, 1.2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline, and triazine. A heteroaryl group may be substituted or unsubstituted.

[0026] As used herein, “heterocyclyl” or “heteroalicyclyl refers to three-, four-, five, six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic, and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout ail the rings. The heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur, and nitrogen. A heterocycle may further contain one or more carbonyl or thiocarbonyl functionalitîes, so as to make the définition include oxo-systems and thio-systems such as lactams, lactones, cyclic imîdes, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heteroalicyclic may be quatemized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples of such “heterocyclyl” or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathîin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin. dihydrouracil, trioxane, hexahydro-l,3,5-triazine, imidazolîne, imidazolidine, isoxazoline, tsoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidîne TV-Oxide, piperidine, pîperazine, pyrrolîdine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone, and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline, and 3,4-methylenedioxyphenyl).

[0027] As used herein, “aralkyl” and ‘’aryl(alkyl)’’ refer to an aryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3phenylalkyl, and naphthylalkyl.

[0028] As used herein, “heteroaralkyl” and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group. The lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, imidazolylalkyl, and their benzo-fused analogs.

[0029] A “(heteroalicyclyl)alkyr and ’*(heterocyclyl)alkyl” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl)methyl, (piperidin-4-yl)ethyl, (piperidin-4-yl)propyl, (tetrahydro-2H-thîopyran-4-yl)methyl, and (l,3-thiazinan-4-yl)methyl.

[0030] “Lower alkylene groups are straight-chaîned -CH₂- tethering groups, forming bonds to connect molecular fragments via their termina! carbon atoms. Examples include but are not limited to methylene (-CH₂-), ethylene (-CH₂CH₂-), propylene (CH₂CH₂CH₂-), and butylène (-CH₂CH₂CH₂CH₂-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent(s) listed under the 20 définition of “substituted.” [0031] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, a cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, 25 sec-butoxy, tert-butoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0032] As used herein, ”acyl” refers to a hydrogen, alkyl, alkenyl, alkynyl, or aryl connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0033] As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, and 2,2dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0034] As used herein, “haloalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g,, mono-haloalkyl, di-haloalkyl and tri17044 ίο haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, tnfluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.

[0035] As used herein, “haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and trihaloalkoxy). Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0036] As used herein, “arylthio” refers to RS-, in which R is an aryl, such as, but not limited to, phenyl. An arylthio may be substituted or unsubstituted.

[0037] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. A sulfenyl may be substituted or unsubstituted.

[0038] A “sulfinyl group refers to an *‘-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0039] A “sulfonyl group refers to an SOjR group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.

[0040] An “O-carboxy” group refers to a RC(=O)O-” group în which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl, as defined herein. An Ocarboxy may be substituted or unsubstituted.

[0041] The terms “ester and “C-carboxy refer to a -C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.

[0042] A “thiocarbonyl group refers to a “-C(=S)R group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.

[0043] A “trihalomethanesulfonyl group refers to an “X3CSO2- group wherein each X is a halogen.

[0044] A “trihalomethanesulfonamido group refers to an “X₃CS(O)2N(Ra)- group wherein each X is a halogen, and Ra hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl.

[0045] The term “amino” as used herein refers to a -NHi group.

[0046] As used herein, the term hydroxy refers to a-OH group.

[0047]

A “cyano*’ group refers to a “-CN group.

[0048] The term “azido” as used herein refers to a -Nj group.

[0049] An “isocyanato group refers to a *’-NCO” group.

[0050] A “thiocyanato” group refers to a “-CNS” group.

[0051] An “isothîocyanato” group refers to an “ -NCS” group.

[0052] A “mercapto” group refers to an “-SH” group.

[0053] A “carbonyl” group refers to a C=O group.

[0054] An “S-sulfonamido” group refers to a “-SOîNÎRaRb)’’ group in which Ra and Rb can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl. heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl) alkyl. An S-sulfonamido may be substituted or unsubstituted.

[0055] An “N-sulfonamido” group refers to a “RSOîNîRa)-” group in which R and R_a can be independently hydrogen, alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. An N-sulfonamido may be substituted or unsubstituted.

[0056] An ‘Ό-carbamyl group refers to a “-OC(=O)N(RaRb)’’ group in which R a and R_b can be independently hydrogen, alkyl. alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl. aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. An O-carbamyl may be substituted or unsubstituted.

[0057] An “N-carbamyl” group refers to an “ROC(=O)N(Ra)-” group in which R and Ra can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl. cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. An N-carbamyl may be substituted or unsubstituted.

[0058] An “O-thiocarbamyr group refers to a “-OC(=S)-N(R_aRb)” group in which Ra and Rb can be independently hydrogen, alkyl, alkenyl. alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. An O-thiocarbamyl may be substituted or unsubstituted.

[0059] An “N-thiocarbamyl” group refers to an “ROC(=S)N(Ra)-’* group in which R and Ra can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. An N-thiocarbamyl may be substituted or unsubstituted.

[0060] A “C-amido*’ group refers to a “-C(=O)N(R_aRb)” group in which Ra and Rb can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl.

aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. A C-amido may be substituted or unsubstituted.

[0061] An “N-amido” group refers to a *'RC(=O)N(Ra)-” group in which R and Ra can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, (heteroaryl)alkyl or (heteroalicyclyl)alkyl. An N-amido may be substituted or unsubstituted.

[0062] The term “halogen atom” or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Eléments, such as, fluorine, chlorine, bromine and îodine.

[0063] Where the numbers of substituents is not specified (e.g. haloalkyl), there may be one or more substituents présent. For example “haloalkyl” may include one or more of the same or different halogens. As another example, “Ci-Cj alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0064] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless îndicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).

[0065] The term “nucleoside is used herein in its ordinary sense as understood by those skilled in the art, and refers to a compound composed of an optionally substituted pentose moiety or modified pentose moiety attached to a heterocyclic base or tautomer thereof via a Nglycosidic bond, such as attached via the 9-position of a purine-base or the 1-position of a pyrimidine-base. Examples include, but are not limited to, a ribonucleoside comprising a rîbose moiety and a deoxyribonucleoside comprising a deoxyribose moiety. A modified pentose moiety is a pentose moiety in which an oxygen atom has been replaced with a carbon and/or a ca±on has been replaced with a sulfur or an oxygen atom. A “nucleoside” is a monomer that can hâve a substituted base and/or sugar moiety. Additionally, a nucleoside can be incorporated into larger DNA and/or RNA polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog dru g.

[0066] The term “nucléotide” is used herein in its ordinary sense as understood by those skilled in the art, and refers to a nucleoside having a phosphate ester bound to the pentose moiety, for example, at the 5’-position.

[0067] As used herein, the term “heterocyclic base refers to an optionally substituted nitrogen-containing heterocyclyl that can be attached to an optionally substituted pentose moiety or modified pentose moiety. In some embodiments, the heterocyclic base can be selected from an optionally substituted purine-base, an optionally substituted pyrimidine-base and an optionally substituted triazole-base (for example, a 1,2,4-triazole). The term “purine-base” is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. Similarly, the term “pyrimidine-base is used herein in its ordinary sense as understood by those skilled in the art, and includes its tautomers. A non-limiting list of optionally substituted purine-bases includes purine, adenine, guanine, hypoxanthine, xanthine, alloxanthine, 7-alkylguanine (e.g. 7-methylguaninc), theobromine, caffeine, uric acid and isoguanine. Examples of pyrimidine-bases include, but are not limited to, cytosinc, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 5-methylcytosine). An example of an optionally substituted triazole-base îs 1.2,4-triazole-3-carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, e-oxo-N^-alkyladenine (e.g., 8-oxo-N⁶methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N⁴,N⁴-ethanocytosin, Ν⁶,Ν^όethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5-bromouracil), pseudoisocytosinc, isocytosine, isoguanine, and other heterocyclic bases described in U.S. Patent Nos. 5,432,272 and 7,125,855, which are incorporated herein by référencé for the limited purpose of disclosing additional heterocyclic bases. In some embodiments. a heterocyclic base can be optionally substituted with an amine or an enol protecting group(s).

[0068] The term *‘-N-linked amino acid refers to an amino acid that is attached to the indicated moiety via a maîn-chain amino or mono-substituted amino group. When the amino acid is attached in an -N-linked amino acid, one of the hydrogens that is part of the main-chain amino or mono-substituted amino group is not présent and the amino acid is attached via the nitrogen. N-linked amino acids can be substituted or unsubstituted.

[0069] The term “-N-linked amino acid ester dérivative refers to an amino acid in which a main-chain carboxylic acid group has been converted to an ester group. In some embodiments, the ester group has a formula selected from alkyl-O-C(=O)-, cycloalkyl-O-C(=O), aryl-O-C(=O)- and aryl(a!kyl)-O-C(=O)-. A non-limiting list of ester groups include substituted and unsubstituted versions of the following: methyl-O-C(=O)-, ethyl-O-C(=O)-, npropyl-O-C(=O)-, îsopropyl-O-C(=O)-, n-butyl-O-C(=O)-, isobutyl-O-C(=O)-, tcrt-butyl-OC(=O)-, neopentyl-O-C(=O)-, cyclopropyl-O-C(=O)-, cyclobutyl-O-C(=O)-, cyclopentyl-OC(=O)-_t cyc!ohexyl-O-C(=O)-, phenyl-O-C(=O)-, benzyl-O-C(=O)-, and naphthyl-O-C(=O)-. N-linked amino acid ester dérivatives can be substituted or unsubstituted.

[0070] The term “-O-linked amino acid” refers to an amino acid that is attached to the indicated moiety via the hydroxy from its main-chain carboxylic acid group. When the amino acid is attached in an -O-linked amino acid, the hydrogen that is part of the hydroxy from its maîn-chain carboxylic acid group is not présent and the amino acid is attached via the oxygen. O-linked amino acids can be substituted or unsubstituted.

[0071] As used herein, the terni “amino acid” refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amîno acids, β-amino acids, γamino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoïeucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, omithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citnilüne, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.

[0072] The terms phosphorothîoate” and “phosphothioate” refer to a compound of the general formula î 5 ^:p—o—|

O' · its protonated forms (for example.

O and

OH

) and its tautomers (such as

[0073] As used herein, the terni “phosphate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example, <j>H (j)H

O=P—O—1 O=P—O—<

I ¹ I * o and OH ). As used herein, the terms “monophosphate, “diphosphate,” and “triphosphate” are used in their ordinary sense as understood by those skilled in the art, and include protonated forms.

[0074] The terms “protecting group” and “protecting groups” as used herein refer to any atom or group of atoms that is added to a molécule in order to prevent existing groups in the molécule from undergoing unwanted chemical réactions. Examples of protecting group moieties are described in T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3. Ed. John Wiley & Sons, 1999, and in J.F.W. McOmie, Protective Groups in Organic Chemistry Plénum Press, 1973, both of which are hereby incorporated by référencé for the limited purpose of disclosing suitable protecting groups. The protecting group moiety may be chosen in such a way, that they are stable to certain reaction conditions and readily removed at a convenient stage using methodology known from the art. A non-limiting list of protecting groups include benzyl; substituted benzyl; alkylcarbonyls and alkoxycarbonyls (e.g., t-butoxycaibonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyi ether, a substituted benzyl ether; tetrahydropyranyl ether, silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, tbutyldimethylsilyl, tri-ûo-propylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or tbutyldiphenylsilyl); esters (e.g. benzoate ester); carbonates (e.g. methoxymethylcarbonate); sulfonates (e.g. tosylate or mesylate); acyclic ketal (e.g. dimethyl acetal); cyclic ketals (e.g., 1,3dioxane, 1,3-dioxolanes, and those described herein); acyclic acetal; cyclic acetal (e.g., those described herein); acyclic hemiacetal; cyclic hemiacetal; cyclic dithioketals (e.g., 1,3-dithiane or 1,3-dithiolane); orthoesters (e.g., those described herein) and triarylmethyl groups (e.g., trityl; monomethoxytrity! (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4-trimethoxytrityl (TMTr); and those described herein).

[0075] The term “pharmaceutically acceptable sait” refers to a sait of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the sait is an acid addition sait of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a sait such as an ammonium sait, an alkalï métal sait, such as a sodium or a potassium sait, an alkaline earth métal sait, such as a calcium or a magnésium sait, a sait of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0076] Terms and phrases used in this application, and variations thereof, especially in the appended daims, unless otherwise expressly stated, should be construed as open ended as opposed to limitîng. As examples of the foregoîng, the term ’including’ should be read to mean ‘including, without limitation,’ ’including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,* ‘containing,’ or ‘characterized by/ and is inclusive or open-ended and does not exciude additional, unrecited éléments or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof; and use of terms like 'preferably, ‘preferred,’ ‘desired,’ or 'désirable,' and words of similar meaning should not be understood as implying that certain features are critical, essential, or even important to the structure or function of the invention, but instead as merely intended to highlight alternative or additional features that may or may not be utilized in a particular embodiment. In addition, the term “comprising is to be interpreted synonymously with the phrases having at least or including at least. When used in the context of a process, the term comprising means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition or device, the term comprising means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components. Likewise, a group of items linked with the conjunction ‘and’ should not be read as requiring that each and every one of those items be présent in the grouping, but rather should be read as ‘and/or’ unless expressly stated otherwise. Similarly, a group of items linked with the conjunction *or’ should not be read as requiring mutual exclusivity among that group, but rather should be read as ‘and/or’ unless expressly stated otherwise.

[0077] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article a or “an” does not exclude a plurality. A single processor or other unit may fulfill the functions of several items recited in the daims. The mere fact that certain measures are recited in mutually different dépendent daims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the daims should not be construed as limiting the scope.

[0078] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-con figuration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stéréoisomeric mixture. In addition it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof.

[0079] Likewise, it is understood that, in any compound described, ail tautomeric forms are also intended to be included. For example ail tautomers of a phosphate and a phosphorothîoate groups are intended to be inctuded. Examples of tautomers of a phosphorothioate include the following:

Furthermore, ail tautomers of heterocyclic bases known in the art are intended to be included, including tautomers of natural and non-natural purine-bases and pyrimidine bases.

[0080] It is to be understood that where compounds disclosed herein hâve unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen-1 (protium) and hydrogen-2 (deuterium).

[0081] It is understood that the compounds described herein can be labeled isotopicalty. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolîc stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be présent in the compound. At any position of the compound that a hydrogen atom may be présent, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen-1 (protium) and hydrogen-2 (deuterium). Thus, référencé herein to a compound encompasses ail potential isotopic forms unless the context clearly dictâtes otherwise.

[0082] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvatés, and hydrates. In some embodiments, the compounds described herein exist in soivated forms with pharmaceutically acceptable solvents such as water, éthanol, or the like. In other embodiments, the compounds described herein exist in unsolvated form. Solvatés contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, éthanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. In addition, the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered équivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.

[0083] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

Compounds

Some embodiments disclosed herein relate to a compound selected from or a pharmaceutically acceptable sait of the [0084]

Formula (I), Formula (Π) and Formula (ΙΠ), foregoing:

73A

R^1oa-P— wherein: B^1A, B¹⁸ and B^,c can be independently an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^,A can be selected from hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino acid, 2^1A 72 a 73 a _R ^6A _o—p—R^8AO—γ—R^10A-P—

OR^7A, R^9A and R^11A ; when the dashed line (----) of Formula (I) is a single bond, R^2A can be CH₂, and R^ÎA can be O (oxygen); when the dashed line (-----) of

Formula (I) is absent, R^2A can be selected from an optionally substituted Cm alkyl, an optionally substituted C₂6 alkenyl, an optionally substituted Cm alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted -Ο-Cm alkyl, an optionally substituted O-C₃^ alkenyl, an optionally substituted Ο-Cm alkenyl and cyano, and R^3A can be selected from OH, -OC(=O)R^aand an optionally substituted O-linked amino acid; R^IB can be selected from O', OH,

optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R^1C and R^2C can be independently selected from O*, OH, an optionally substituted Ci -6 alkoxy.

, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; or R^IC can be

R^2C can be O' or OH; R^2B and R^3C can be independently selected from an optionally substituted

C].6 alkyl, an optionally substituted C₂^ alkenyl, an optionally substituted C?6 alkynyl, an optionally substituted -O-C|.₆ alkyl, an optionally substituted -O-C3.6 alkenyl, an optionally 10 substituted-O-Cî^ alkynyl, an optionally substituted C3.6 cycloalkyl and cyano; R^4C can be selected from OH, -OC(=O)R ^c and an optionally substituted O-linked amino acid; R^4A, R^3B and R^!C can be independently a halogen; R^SA, R^4B and R⁶⁰ can be independently hydrogen or halogen; R^6A, R^7A and R^8A can be independently selected from absent, hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(C].

alkyl), an optionally substituted *-{CR^l!AR^16A)_p-O-Ci.24 alkyl, an optionally substituted *-

(CR'^R^-O-C^ alkenyl,

^m and R^7a can be absent or hydrogen; or R^6A and R *

taken together to form a moiety selected from an optionally substituted

and an

optionally substituted , wherein the oxygens connected to R^6a and R^7A, the phosphorus and the moiety form a six-membered to ten-membered ring System; R^9A can be independently selected from an optionally substituted C1.24 alkyl, an optionally substituted C₂.24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, NR^3OAR^3IA, an optionally substituted N-Iinked amino acid and an optionally substituted N-linked amino acid ester dérivative; R^IOA and R^IIA can be independently an optionally substituted N-linked amino acid or an optionally substituted Nlinked amino acid ester dérivative; R^l2A, R^I3A and R^14A can be independently absent or hydrogen; each R'^sa, each R^I6A, each R^,7A and each R^18A can be independently hydrogen, an optionally substituted C_t.24 alkyl or alkoxy; R^I9A, R^20A, R^22A, R^23A, R^SB, R^6B, R^8B, R^9B, R⁹⁰, R^,oc, R^12C and R^t3C can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; R^2IA, R^24A, R^7B, R^IOB, R^IIC and R^l4C can be independently selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-Ct.24 alkyl and an optionally substituted -O-aryl; R^25A, R^29A, R^1,B and R^,5C can be independently selected from hydrogen, an optionally substituted C|.24 alkyl and an optionally substituted aryl; R^I6C, R^17C and R^18C can be independently absent or hydrogen; R^26A and R^27A can be independently -ON or an optionally substituted substituent selected from C₂.s organylcarbonyl, C₂.s alkoxycarbonyl and C2-8 organylaminocarbonyl; R^28A can be selected from hydrogen, an optionally substituted Ci.24-alkyl, an optionally substituted C₂.24 alkenyl, an optionally substituted C₂.24 alkynyl, an optionally substituted cycloalkyl and an optionally substituted C3.6 cycloalkenyl; R^30A and R^3lA can be independently selected from hydrogen, an optionally substituted Ci.24-alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C₂.₂4 alkynyl, an optionally substituted C3.6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl; for Formula (ΙΠ),------can be a single bond or a double bond; when-----is a single bond, each R^7C and each R^8C can be independently hydrogen or halogen; and when------ is a double bond, each R^7C is absent and each R^8C can be independently hydrogen or halogen; R^A and R ^c can be independently an optionally substituted C].24-alkyl, m and n can be independently 0 or 1; p and q can be independently selected from 1,2 and 3; r can be 1 or 2; Z^lA, Z^2A, Z^3A, Z^4A, Z^1B, Z^2B and Z^IC can be independently O or S; and provided that when the dashed >2A

R^O—P—| line (------) of Formula (D is absent; R^{1 A} is R^9A wherein R^8A is an unsubstituted Cm alkyl or phenyl optionally para-substituted with a halogen or methyl and R^9A is methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from glycine, alanine, valine, leucine, phenylalanine, tryptophan, méthionine and proline; R^3A is OH; R^4A is fluoro; R^5A is fluoro or hydrogen; and B^1A is an unsubstituted uracil; then R^2A cannot be -OCH3; provided that when the dashed line (-----) of Formula (I) is absent; R^1A is H; R^3A is

OH; R^4A is fluoro; R^SA is fluoro; and B^IA is an unsubstituted cytosine; then R^2A cannot be allenyl; provided that when the dashed line (--) of Formula (I) is absent; R^IA is H; R^3A is OH;

R^4A is fluoro; R^3A is hydrogen; and B^IA is an unsubstituted thymine; then R^2A cannot be C] alkyl substituted with an optionally substituted N-amido (for example, -NC(=O)CFî); and provided that when the dashed line (---) of Formula (I) is absent; R^IA is H; R^3A is OH; R^4A is fluoro;

R^îa is fluoro; and B^1A is an unsubstituted cytosine; then R^2A cannot be ethynyl.

[0085] In some embodiments, the compound can be a compound of Formula (I), or a pharmaceutically acceptable sait thereof, wherein: B^1A can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;

SA G r^6Ao—P—|

R^,a can be selected from hydrogen, OR^7A

P—| R^10A-P—|

R^9a and R^11A ; when the dashed line (--) of Formula (I) is a single bond, R^7a is CH₂, and R^3A is O (oxygen); when the dashed line (----) of Formula (I) is absent, R^2A can be selected from an optionally substituted

Cm alkyl, an optionally substituted C₂-e alkenyl, an optionally substituted C₂^ alkynyl, an optionally substituted -Ο-Cm alkyl, an optionally substituted -O-Cî^ alkenyl, an optionally substituted -O-C3-6 alkynyl and cyano, and R^3A is OH; R^4A can be a halogen; R^5A can be hydrogen or halogen; R^6A, R^7A and R^8A can be independently selected from absent, hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted ary!(Ci^ alkyl), an optionally substituted *-(CR^lîAR^16A)p-O-Ci.24 alkyl, an

o r^12Ao—

JL ⁰ î or^14A

-J^m and R^7a can be absent or hydrogen; or R^6A and R^7A can be

taken together to form a moiety selected from an optionally substituted

and an optionally substituted

, wherein the oxygens connected to R^6A and R^7A, the phosphores and the moiety form a six-membered to ten-membered ring System;. R^9A can be independently selected from an optionally substituted C1.24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C₂-24 alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, NR^30AR^31A, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R^IOA and R^1IA can be independently an optionally substituted N-linked amino acid or an optionally substituted N17044 linked amino acid ester dérivative; R^I2A, R^,ÎA and R^,4A can be independently absent or hydrogen;

each R ⁵ , each R¹⁶ , each R^,7A and each R^,8A can be independently hydrogen, an optionally substituted Ci.24 alkyl or alkoxy; R^19A, R^20A, R^22A and R^23A can be independently selected from hydrogen, an optionally substituted Cj.24 alkyl and an optionally substituted aryl; R^2IA and R^24Acan be independently selected from hydrogen, an optionally substituted Ci.24 alkyl, an optionally substituted aryl, an optionally substituted -O-Ci.24 alkyl and an optionally substituted -O-aryl; R²⁵* and R²⁹* can be independently selected from hydrogen, an optionally substituted Ci.24 alkyl and an optionally substituted aryl; R^26A and R^27A can be independently -ON or an optionally substituted substituent selected from C2_8 organylcarbonyl, C2.g alkoxycarbonyl and C2.g organylaminocarbonyl; R^28A can be selected from hydrogen, an optionally substituted Cj.24-alkyl, an optionally substituted C₂.₂₄ alkenyl, an optionally substituted C₂.₂₄ alkynyl, an optionally substituted C3-6 cycloalkyl and an optionally substituted C3-6 cycloalkenyl; R^30A and R^3IA can be independently selected from hydrogen, an optionally substituted C].₂₄-alkyl, an optionally substituted C₂.₂₄ alkenyl, an optionally substituted C₂.₂₄ alkynyl, an optionally substituted cycloalkyl and an optionally substituted C37; cycloalkenyl; m can be 0 or 1 ; p and q can be independently selected from 1, 2 and 3; r can be 1 or 2; Z^IA, Z^2A, Z^3A and Z⁴* can be independently O or S. In some embodiments, a compound of Formula (I) can hâve a structure shown herein, provided that when the dashed line (-----) of Formula (I) is absent; R^tA is

R^9A wherein R^8A is an unsubstituted Cm alkyl or phenyl optionally para-substituted with a halogen or methyl and R^9A is methyl ester, ethyl ester, isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from glycine, alanine, valine, leucine, phenylalanine, tryptophan, méthionine and proline; R^3A is OH; R^4A is fluoro; R^5A is fluoro or hydrogen; and B^1A is an unsubstituted uracîl; then R^2A cannot be -OCH3; provided that when the dashed line (----) of Formula (I) is absent; R^1A is H; R^3A is OH; R^4A is fluoro; R^ÎA is fluoro; and

B^lA is an unsubstituted cytosine; then R¹* cannot be allenyl; provided that when the dashed line (----) _of Formula (D is absent; R^tA is H; R^3A is OH; R^4A is fluoro; R^ÎA is hydrogen; and B^IA is an unsubstituted thymine; then R^2A cannot be Ci alkyl substituted with an N-amido; and provided that when the dashed line (----) of Formula (I) is absent; R^lA is H; R^3A is OH; R^4A is fluoro; R^îa is fluoro; and B^lA is an unsubstituted cytosine; then R^2A cannot be ethynyl.

[0086] In some embodiments, R^,a can be

ΊΑ

R^6AO—p—|

7A OR . In some embodiments.

R^6A and R^7A can be both hydrogen. In other embodiments, R^6A and R^7A can be both absent. In still other embodiments, at least one R^6A and R^7A can be absent. In yet still other embodiments, at least one R^6A and R^7A can be hydrogen. Those ski lied in the art understand that when R^6A5 and/or R^7A are absent, the associated oxygen(s) will hâve a négative charge. For example, when

R^6a is absent, the oxygen associated with R^6A will hâve a négative charge. In some embodiments, Z^IA can be O (oxygen). In other embodiments, Z^IA can be S (sulfur). In some embodiments, R^1A can be a monophosphate. In other embodiments, R^1A can be a monothiophosphate.

ΊΑ [0087] In some embodiments, when R^IA is

OR^7A, one of R^6A and R^7A can be hydrogen, and the other of R^6A and R^7A is selected from an optionally substituted C1.24 alkyl, an optionally substituted C2.24 aikenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(Ci_6 alkyl). In some 15 embodiments, one of R^6A and R^7A can be hydrogen, and the other of R^6A and R^7A can be an optionally substituted Ci.24 alkyl. In other embodiments, both R^6A and R^7A can be independently selected from an optionally substituted Ct.24 alkyl, an optionally substituted C2-24 aikenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C3.6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl 20 and an optionally substituted aryl(Ci^ alkyl). In some embodiments, both R^6A and R^7A can be an optionally substituted C1.24 alkyl. In other embodiments, both R^6A and R^7A can be an optionally substituted C2.₂4 aikenyl. In some embodiments, R^6A and R^7A can be independently an optionally substituted version of the following: myristoleyl, myristyl, palmitoleyl, palmityl, sapîenyl, oleyl, elaidyl, vaccenyl, linoleyl, α-hnolenyl, arachidonyl, eicosapentaenyl, erucyl, docosahexaenyl, 25 caprylyl, capryl, lauryl, stearyl, arachidyl, behenyl, lignoceryl, and cerotyl.

[0088] In some embodiments, at least one of R^6A and R^7A can be *-(CR^ISAR^l6A)p-OCj.24 alkyl. In other embodiments, R^6A and R^7A can be both *-(CR^tSAR^,6A)p-O-Ci.24 alkyl. In some embodiments, each R^,SA and each R^,6A are hydrogen. In other embodiments, at least one of R^,sa and R^16a is an optionally substituted C1.24 alkyl. In other embodiments, at least one of

R^,ÎA and R^,6A is an alkoxy (for example, benzoxy). In some embodiments, p can be 1. In other embodiments, p can be 2. In still other embodiments, p can be 3.

[0089] In some embodiments, at least one of R^6A and R^7A can be *-(CR^,7AR’^8A)q-OC2.24 alkenyl. In other embodiments, R^6A and R^7A can be both *-(CR^,7AR^,8A)q-O-C2.₂4 alkenyl. In some embodiments, each R^t7A and each R^t8A are hydrogen. In other embodiments, at least one of R^,7A and R^t8A is an optionally substituted C].24 alkyl. In some embodiments, q can be 1. In other embodiments, q can be 2. In still other embodiments, q can be 3. When at least one of R^6a and R^7A is *-(^’^5ΑΗ^,6Α)ρ-Ο-0ι.24 alkyl or *-(CR^,7AR^,8A)q-O-C₂.₂₄ alkenyl, the C₁₂₄ alkyl can be selected from caprylyl, capryl, lauryl, myristyl, palmityl, stearyl, arachidyl, behenyl, lignoceryl, and cerotyl, and the C₂.₂₄ alkenyl can be selected from myristoleyl, palmitoleyl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, Ct-linolenyl, arachidonyl, eicosapentaenyl, erucyl and docosahexaenyl.

Z^1Ar^6Ao—P—| [0090] In some embodiments, when R^tA is OR^7A, at least one of R^6A and

hydrogen, an optionally substituted Cj.₂4 alkyl, an optionally substituted C₂.₂₄ alkenyl, an optionally substituted C₂.₂₄ alkynyl, an optionally substituted Cj^ cycloalkyl, an optionally substituted C3.6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(C|^ alkyl).

In some embodiments, at least one of R^6A and R^7A can be

[0091]

In some embodiments, both R^6A and R^7A can be

When one or both of R^6A and R^7a are

and R^20a can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl;

A and R can be selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl and an optionally substituted -O-aryt.

In some embodiments, R^l9A and R^20A can be hydrogen. In other embodiments, at least one of R^l9A and R^20A can be an optionally substituted C1.24 alkyl or an optionally substituted aryl. In some embodiments, R^2lA can be an optionally substituted C1.24 alkyl. In other embodiments, R can be an optionally substituted aryl. In still other embodiments, R can be an optionally substituted -O-C1.24 alkyl or an optionally substituted -O-aryl.

[0092]

In some embodiments, both R^6A and R^7A can be

When one or both of R^6A and R^7A are

and R^23A can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; R^24A can be independently selected from hydrogen, an optionally substituted Ci.

alkyl, an optionally substituted aryl, an optionally substituted -O-C].2< alkyl and an optionally (5 substituted -O-aryl; and Z*^A can be independently O (oxygen) or S (sulfur). In some embodiments, R^22a and R^23A can be hydrogen. In other embodiments, at least one of R^22A and R^2JA can be an optionally substituted C1.24 alkyl or an optionally substituted aryl. In some embodiments, R^24A can be an optionally substituted C1.24 alkyl. In other embodiments, R^24Acan be an optionally substituted aryl. In still other embodiments, R^24A can be an optionally 20 substituted -O-C1.24 alkyl or an optionally substituted -O-aryl. In some embodiments, Z^4A can be O (oxygen). In other embodiments, Z^4A can be or S (sulfur). In some embodiments, one or both of R^6a and R^7A can be isopropylcarbonyloxymethyl. In some embodiments, one or both of R^6A and R^7A can be pivaloyloxymethyl.

independently -CeN or an optionally substituted substituent selected from C₂.e organylcarbonyl, C₂-a alkoxycarbonyl and C₂.a organylaminocarbonyl; R^28A can be selected from hydrogen, an optionally substituted Ci.₂4-alkyl, an optionally substituted C₂.₂4 alkenyl, an optionally substituted C₂.₂4 alkynyl, an optionally substituted Cj.6 cycloalkyl and an optionally substituted

C3.6 cycloalkenyl; and r can be 1 or 2. In some embodiments, R^26A can be -ON and R^27A can be an optionally substituted C₂.s alkoxycarbonyl, such as -C(=O)OCH₃. In other embodiments, R^26A can be -ON and R^27A can be an optionally substituted C₂.e organylaminocarbonyl, for 10 example, -C(=O)NHCH₂CH₃ and -C(=O)NHCH₂CH₂phenyI. In some embodiments, both R^26A and R^27A can be an optionally substituted C₂.g organylcarbonyl, such as -C(=O)CH₃. In some embodiments, both R^26A and R^27A can be an optionally substituted C|.e alkoxycarbonyl, for example, -C(=O)OCH₂CH₃ and -C(=O)OCH₃. In some embodiments, including those a

described in this paragraph, R can be an optionally substituted Cu-alkyl. In some embodiment, R^28a can be methyl or tert-butyl. In some embodiments, r can be 1. In other embodiments, r can be 2.

[0094]

include, but are not limited to the following:

O

1 cr oh₃	Oa

t
h
	S \—OCHjCHj
/	0 and

[0095] In some embodiments, R^6A and R^7A can be both an optionally substituted aryl.

In some embodiments, at least one of R^6A and R^7A can be an optionally substituted aryl. For example, both R^6A and R^7A can be an optionally substituted phenyl or an optionally substituted naphthyl. When substituted, the substituted aryl can be substituted with 1, 2, 3 or more than 3 substituents. When more the two substituents are présent, the substituents can be the same or different. In some embodiments, when at least one of R^6A and R^7A is a substituted phenyl, the substituted phenyl can be a para-, ortho- or meta-substituted phenyl.

/ 1 Λ * [0096] In some embodiments, R and R can be both an optionally substituted aryl(C|_6 alkyl). In some embodiments, at least one of R^6A and R^7A can be an optionally substituted aryl(C[^ alkyl). For example, both R^6A and R^7A can be an optionally substituted benzyl. When substituted, the substituted benzyl group can be substituted with 1, 2, 3 or more than 3 substituents. When more the two substituents are présent, the substituents can be the same or different. In some embodiments, the aryl group of the aryl(C|^ alkyl) can be a para-, ortho- or meta-substituted phenyl.

[0097] In some embodiments, R^6A and R^7A can be both some embodiments, at least one of R^6A and R^7A can be

S R^25A. In some embodiments, R^WA can be hydrogen. In other embodiments, R^25A can be an optionally substituted C].₂4 alkyl. In still other embodiments, R^UA can be an optionally substituted aryl. In some embodiments, R^UA can be a Cm alkyl, for example, methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and 5 straight-chained).

[0098]

In some embodiments, R^6A and R^7A can be both

embodiments, at least one of R^6A and R^7A can be R²⁹*. In some embodiments, R^29A can be hydrogen. In other embodiments, R^29A can be an optionally substituted Ci.₂4 alkyl. In some embodiments, R^29A can be a Cm alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, 10 iso-butyl and t-butyl. In still other embodiments, R^29A can be an optionally substituted aryl, such as an optionally substituted phenyl or an optionally substituted naphthyl.

[0099] In some embodiments, , R^,A can be ÔR^7A; R^6A can be

can be absent or hydrogen; R^I2A, R^I3A and R^I4A can be independently absent or hydrogen; and m can be 0 or 1. In some embodiments, m can be 0, and 15 R^7A, R^i2a and R^13A can be independently absent or hydrogen. In other embodiments, m can be 1, and R^7A, R^l2A, R^i3a and R^I4A can be independently absent or hydrogen. Those skilled in the art understand that when m is 0, R^6A can be diphosphate, when Z^IA is oxygen, or an alphathiodiphosphate, when Z^IA is sulfur. Likewise, those skilled in the art understand that when m is 1, R^6A can be triphosphate, when Z^IA is oxygen, or an alpha-thiotriphosphate, when Z^1A is sulfur.

[0100]

In some embodiments, R^6A and R^7A can be taken together to form an

* optionally substituted

For example, R^1A can be an optionally substituted

When substituted, the ring can be substituted 1, 2, 3 or 3 or more times. When substituted with multiple substituents, the substituents can be the same or different. In some embodiments, when

R^lA is , the ring can be substituted with an optionally substituted aryl group and/or an optionally substituted heteroaryl. An example of a suitable heteroaryl is pyridinyl. In some *

« embodiments, R^6A and R^7A can be taken together to form an optionally substituted

, wherein R^32A can be an optionally substituted aryl, an optionally such as substituted heteroaryl or an optionally substituted heterocydyl.

[0101] In some embodiments, R and R can be taken together to form an optionally substituted

, wherein the oxygens connected to R^6A and R^7A, the phosphorus and the moiety form a six-membered to ten*membered ring system. Example of an

[0102] In some embodiments, R^6A and R^7A can be the same. In some embodiments.

R^6a and R^7a can be the different.

[0103]

In some embodiments, Z^1A can be oxygen. In other embodiments, Z^IA can be sulfur.

G r^0AO—P—| [0104] In some embodiments, R^IA can be R^9A . In some embodiments, R^8A can be selected from absent, hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted C₂.₂4 alkenyl, an optionally substituted C₂.24 alkynyl, an optionally substituted C₃^ cycloalkyl and an optionally substituted C₃^ cycloalkenyl; and R^9A can be independently selected from an optionally substituted Cj.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C₂.₂4 alkynyl, an optionally substituted C₃_6 cycloalkyl and an optionally substituted C₃-c cycloalkenyl.

[0105] In some embodiments, R^8A can be hydrogen, and R^9A can be an optionally substituted C[_6 alkyl. Examples of suitable alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In other embodiments, R^8A can be hydrogen, and R^9A can be NR^3OAR^3IA, wherein R³⁰ and R³¹ can be independently selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C₃^ cycloalkyl and an optionally substituted C₃^ cycloalkenyl.

[0106] In some embodiments, R^8A can be absent or hydrogen; and R^9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative. In other embodiments, R^8A can be an optionally substituted aryl; and R^9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative. In still other embodiments, R^8A can be an optionally substituted heteroaryl; and R^9Acan be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative. In some embodiments, R^9A can be selected from alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan, valine and ester dérivatives thereof. Examples of an optionally substituted N-linked amino acid ester dérivatives include optionally substituted versions of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some embodiments, R^9A can hâve the structure

wherein R^33A can be selected from hydrogen, an optionally substituted Ci^-alkyl, an optionally substituted C₃^ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C)^ alkyl) and an optionally substituted haloalkyl; R^34A can be selected from hydrogen, an optionally substituted alkyl, an optionally substituted Ci-6 haloalkyl, an optionally substituted C3^ cycloalkyl, an optionally substituted Ce aryl, an optionally substituted C]o aryl and an optionally substituted aryl(Ci^alkyl); and R^35A can be hydrogen or an optionally substituted Ci^-alkyl; or R³⁴* and R^35A can be taken together to form an optionally substituted C3-e cycloalkyl.

[0107] When R^34A is substituted, R^34A can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R^34A can be an unsubstituted Ci^-alkyl, such as those described herein. In some embodiments, R^34A can be hydrogen. In other embodiments, R^34A can be methyl. In some embodiments, R^33A can be an optionally substituted Ci-6 alkyl. Examples of optionally substituted Ci-6-alkyls include optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straightchained). In some embodiments, R^33A can be methyl or isopropyl. In some embodiments, R^33Acan be ethyl or neopentyl. In other embodiments, R^33A can be an optionally substituted C3^ cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R^33A can be an optionally substituted cyclohexyl. In still other embodiments, R^33Acan be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R^33A can be an optionally substituted aryl(Ci-6 alkyl). In some embodiments, R^33Acan be an optionally substituted benzyl. In some embodiments, R^33A can be an optionally substituted Cj-e haloalkyl, for example, CFj. In some embodiments, R^33A can be hydrogen. In other embodiments, R^33A can be an optionally substituted Ci4-alkyl, such as methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^33A can be methyl. In some embodiments, R^34A and R^33A can be taken together to form an optionally substituted C3-e cycloalkyl. Examples of optionally substituted C₃_6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R^34A and R^33A, the carbon to which R³⁴* and R^33A are attached may be a chiral center. In some embodiment, the carbon to which R^34A and R^33A are attached may be a (R)-chiral center. In other embodiments, the carbon to which R^MA and R^35A are attached may be a (S)-chiral center.

[0108]

In some embodiments, when R^1A is other embodiments, when R^IA is

can be S (sulfur).

•j3A

R10A-P— [0109] In some embodiments, R^1A can be R^11A . In some embodiments, R^10Aand R^11A can be both an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative. In some embodiments, R^IOA and R^11A can be independently selected from alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine.

phenylalanine, threonine, tryptophan, valine and ester dérivatives thereof. In some embodiments, R^10A and R^llA can be an optionally substituted version of the following: alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some embodiments, R^IOA and R^,tA can independently hâve the structure

wherein R^36A can be selected from hydrogen, an optionally substituted C|^-alkyl, an optionally substituted C₃.6 cycloalkyi, an optionally substituted aryl, an optionally substituted aryl(C[^ alkyl) and an optionally substituted haloalkyl; R^37A can be selected from hydrogen, an optionally substituted C14 alkyl, an optionally substituted Ci^ haloalkyl, an optionally substituted C34 cycloalkyi, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted arylfCt^ alkyl); and R^38A can be hydrogen or an optionally substituted Ci^-alkyl; or R^37A and R^38A can be taken together to form an optionally substituted C₃.6 cycloalkyi.

[0Π0] When R^37A is substituted, R^37A can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R^37A can be an unsubstituted C|^-alkyl, such as those described herein. In some embodiments, R^37A can be hydrogen. In other embodiments, R^37A can be methyl. In some embodiments, R^36A can be an optionally substituted Q-e alkyl. Examples of optionally substituted Ci^-alkyls include optionally substituted variants of the foliowing: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straightchained). In some embodiments, R^36A can be methyl or isopropyl. In some embodiments, R^36Acan be ethyl or neopentyl. In other embodiments, R^36A can be an optionally substituted C3.6 5 cycloalkyl. Exemples of optionally substituted C₃^ cycloalkyl include optionally substituted variants of the foliowing: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R^36A can be an optionally substituted cyclohexyl. In still other embodiments, R^36Acan be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R^36A can be an optionally substituted aryl(Ci_6 alkyl). In some embodiments, R^36A10 can be an optionally substituted benzyl. In some embodiments, R^36A can be an optionally substituted Cj_6 haloalkyl, for example, CF3. In some embodiments, R^38A can be hydrogen. In other embodiments, R^38A can be an optionally substituted Ci-4-alkyl, such as methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^38A can be methyl. In some embodiments, R^37A and R^38A can be taken together to form an optionally substituted C3-6 15 cycloalkyl. Examples of optionally substituted C3-6 cycloalkyl include optionally substituted variants of the foliowing: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R^37A and R^38A, the carbon to which R^37A and R^38A are attached may be a chiral center. In some embodiment, the carbon to which R^37A and R^38A are attached may be a (R)-chiral center. In other embodiments, the carbon to which R^37A and R^38A are attached may be a (S)-chiral center.

[0111]

Examples of suitable

include the foliowing:

W

»

♦ t

[0112] In some embodiments, R^10A and R^I1A can be the same. In some embodiments.

R^ioa and R^lIA can be the different.

[0113] In some embodiments, Z^3A can be O (oxygen). In other embodiments, Z^3Acan be S (sulfur).

[0114] In some embodiments, R^,A can be hydrogen. In some embodiments, R^IA can be an optionally substituted acyl. In other embodiments, R^lA can be -C(=O)R^39A, wherein R^39Acan be selected from an optionally substituted C1-12 alkyl, an optionally substituted C₂.j₂ alkenyl, an optionally substituted C₂.j₂ alkynyl, an optionally substituted C₃.g cycloalkyl, an optionally substituted C₅.₈ cycloalkenyl, an optionally substituted C6.10 aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(Cm alkyl), an optionally substituted heteroaryl(Cm alkyl) and an optionally substituted heterocyclyl(Cm alkyl). In some embodiments, R^39A can be a substituted Cm2 alkyl. In other embodiments, R^39Acan be an unsubstituted Cj.i2 alkyl.

[0115] In still other embodiments, R^1A can be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, omithine, hypusine, 2aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alphaethyl-glycine, alpha-propyl-glycine and norleucine. In some embodiments, the O-linked amino

acid can hâve the structure > ^nh2 , wherein R^40A can be selected from hydrogen, an optionally substituted Ci^ alkyl, an optionally substituted Cj^ haloalkyl, an optionally substituted Cj^ cycloalkyl, an optionally substituted Cû aryl, an optionally substituted Cio aryl and an optionally substituted aryl(C|^ alkyl); and R^4,A can be hydrogen or an optionally substituted C_M-alkyl; or R⁴⁰¹* and R^4,A can be taken together to form an optionally substituted C3.6 cycloalkyl. Those skilled in the art understand that when R^IA is an optionally substituted Olinked amino acid, the oxygen of R^IAO- of Formula (I) is part of the optionally substituted O15 linked amino acid. For example, when R^IA is

is the oxygen of R^IAO- of Formula (I).

[0116] When R⁴⁰* is substituted, R^40A can be substituted with one or more substîtuents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R⁴⁰* can be 20 an unsubstituted Cj^-alkyl, such as those described herein. In some embodiments, R⁴⁰⁷* can be hydrogen. In other embodiments, R⁴⁰'* can be methyl. In some embodiments, R^4IA can be hydrogen. In other embodiments, R^4,A can be an optionally substituted Ct4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^4IA can be methyl. Depending on the groups that are selected for R^40A and R^41A, the carbon to which 25 R^4oa and R^4IA are attached may be a chiral center. In some embodiment, the carbon to which

R⁴⁰* and R^4,A are attached may be a (R)-chiral center. In other embodiments, the carbon to which R^40a and R^4,A are attached may be a (S)-chiral center.

[0117] Examples of suitable θ NH₂ include the following:

[0118] In some embodiments, the dashed line (-----) can be a single bond, R^2A can be CH₂, and R^3A can be O (oxygen). When the dashed line (---) is a single bond, R^2A is CH₂, and R^3A is O (oxygen), a 4-membered ring is formed that inciudes the 4’-carbon and 3’-carbon of the pentose ring. In other embodiments, the dashed line (---) can be absent, R^2A can be selected from an optionally substituted Ci^ alkyl, an optionally substituted C₂^ alkenyl, an optionally substituted C₂^ alkynyl, an optionally substituted -O-Ci^ alkyl, an optionally 10 substituted -O-C₃^ alkenyl, an optionally substituted alkynyl and cyano, and R^3A can be selected from OH, -OC(=O)R ^A and an optionally substituted O-Iinked amino acid.

[0119] Various groups can be attached to the 4’-position of the pentose ring. In some embodiments, R^2A can be an optionally substituted C|^ alkyl. Examples of suitable alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and 15 straight-chained), and hexyl (branched and straight-chained). In some embodiments, R^2A can be an unsubstituted alkyl. In other embodiments, R^2A can be a substituted C|^ alkyl. For example, R^2A can be a halogen substituted Ci^ alkyl, a hydroxy substituted Ci^ alkyl, an alkoxy substituted Cie alkyl or a sulfenyl substituted alkyl (for example, alkyl-S-C]^ alkyl). In other embodiments, R^2A can be a C|^ haloalkyl. In other embodiments, R^2A can be an 20 optionally substituted C2_6 alkenyl. In some embodiments, R^2A can be a substituted C2^ alkenyl.

In other embodiments, R^2A can be an unsubstituted C2^ alkenyl. For example, R^2A can be ethenyl, propenyl or allenyl. In still other embodiments, R^2A can be an optionally substituted C2. e alkynyl. In some embodiments, R^2A can be a substituted C2^ alkynyl. In other embodiments, R^2a can be an unsubstituted C2^ alkynyl. Suitable C₂.6 alkynyls include ethynyl and propynyl.

In yet still other embodiments, R^2A can be an optionally substituted C3j6 cycloalkyl. In some embodiments, R^2A can be a substituted C3^ cycloalkyl. In other embodiments, R^2A can be an unsubstituted C₃^ cycloalkyl. A non-lïmitîng list of C₃^ cycloalkyls include cyclopropyl.

cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R^2A can be an optionally substituted -O-Cj^ alkyl. In some embodiments, R^2A can be a substituted -O-C]^ alkyl. In other embodiments, R^2A can be an unsubstituted -O-Ci^ alkyl. Examples of suitable O-Ci^ alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched and straight-chained), and hexoxy (branched and straight-chained). In other embodiments, R^2A can be an optionally substituted -O-Cj^ alkenyl. In some embodiments, R^2Acan be a substituted -O-C3^ alkenyl. In other embodiments, R^2A can be an unsubstituted -O-C3. 6 alkenyl. In still other embodiments, R^2A can be an optionally substituted -O-C3.6 alkynyl. In some embodiments, R^2A can be a substituted -O-C₃^ alkynyl. In other embodiments, R^2A can be an unsubstituted -O-C345 alkynyl. In yet still other embodiments, R^2A can be cyano.

[0120] The groups attached to the 3’-position of the pentose ring can vary. In some embodiments, including those of paragraph [0119], R^3A can be OH. In other embodiments, including those of paragraph [0119], R^3A can be an optionally substituted O-linked amino acid. Examples of suitable O-linked amino acids include alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, omithine, hypusine, 2-aminoisobutyric acid, dehydroalaniner gamma-aminobutyric acid, citrullîne, beta-alanine, alpha-ethyl-glycine, alphapropyl-glycine and norleucine. In some embodiments, the O-linked amino acid can hâve the

structure ^{0 NH}2 , wherein R^42A can be selected from hydrogen, an optionally substituted Ci4 alkyl, an optionally substituted C|^ haloalkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted C* aryl, an optionally substituted Cio aryl and an optionally substituted aryl(C|^ alkyl); and R^43A can be hydrogen or an optionally substituted Cu-alkyl; or R^42A and R^43a can be taken together to form an optionally substituted C3.6 cycloalkyl.

[0121] When R^42A is substituted, R^42A can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R^42A can be an unsubstituted C|^-alkyl, such as those described herein. In some embodiments, R^42A can be hydrogen. In other embodiments, R^43A can be methyl. In some embodiments, R^43A can be hydrogen. In other embodiments, R^43A can be an optionally substituted CM-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^43A can be methyl. Depending on the groups that are selected for R^42A and R^43A, the carbon to which

R^42A and R^43a are attached may be a chiral center. In some embodiment, the carbon to which

R^42a and R^43a are attached may be a (R)-chiral center. In other embodiments, the carbon to which R^42a and R^43A are attached may be a (S)-chïral center.

[0122] Examples of suitable θ NH₂ include the following:

[0123] In still other embodiments, including those of paragraph [0119], R^3A can be OC(=O)R^a, wherein r^a can be an optionally substituted C|.24 alkyl. In some embodiments, R can be a substituted Ci-β alkyl. In other embodiments, R can be an unsubstituted Ci.g alkyl. In still other embodiments, including those of paragraph [0119], R^3A can be an optionally substituted -O-acyl. In yet still other embodiments, including those of paragraph [0119], R^3A can be -OC(=O)R^44A, wherein R⁴⁴' can be selected from an optionally substituted Cm2 alkyl, an optionally substituted C₂.i₂ alkenyl, an optionally substituted C₂.i₂ alkynyl, an optionally substituted Cj.s cycloalkyl, an optionally substituted Cj.g cycloalkenyl, an optionally substituted Cô-io aryl, an optionally substituted heteroaryl, an optionally substituted heterocydyl, an optionally substituted aryl(C|^ alkyl), an optionally substituted heteroaryl(C|^ alkyl) and an optionally substituted heterocyc!yl(Ci^ alkyl). In some embodiments, R⁴⁴* can be a substituted Ci.|2 alkyl. In other embodiments, R^44A can be an unsubstituted C|,t2 alkyl.

[0124] Various substituents can be présent at the 2’-position of the pentose ring. In some embodiments, R^ÎA can be hydrogen. In other embodiments, R^ÎA can be halogen, for example, fluoro. In some embodiments, R^4A can be halogen, such as fluoro. In some embodiments, R^ÏA can be hydrogen and R^4A can be halogen. In other embodiments, R^4A and R^ÎAcan both be halogen.

[0125] In some embodiments, -— can be a single bond, R^4A can be fluoro, R^5A can be hydrogen and R^2A can be a C]_6 haloalkyl. In some embodiments, -— can be a single bond, R^4Acan be fluoro, R^ÏA can be hydrogen, R^2A can be a C₍_6 haloalkyl and B^,A can be cytosine.

[0126] In some embodiments, R^2A cannot be methoxy. In some embodiments, R^2A cannot be methoxy when B^IA is substituted or unsubstituted uracil. In some embodiments, B^lAis substituted or unsubstituted cytosine. In other embodiments, B^,A is substituted or unsubstituted thymine. In still other embodiments, B^,A cannot be an unsubstituted uracil. In some embodiments, R^2A cannot be methoxy when Z^lA is

R^9A , wherein R^8A is an unsubstituted C|^ alkyl or a para-substituted phenyl; and R^9A is an optionally substituted Nlinked amino acid or an optionally substituted N-linked amino acid ester dérivative. In some embodiments, R^2A cannot be methoxy when Z^,A is

R^9A . In some embodiments, R^2A

-2A cannot be an alkoxy (for example, when Z^,A is

R^9A ). In some embodiments, B^,A cannot be cytosine when R^2A is an unsubstituted alkenyl or an unsubstiuted alkynyl. In some embodiments, B^IA cannot be thymine when R^2A is an optionally substituted alkyl. In some embodiments, R^2A cannot be an unsubstituted alkoxy (such as methoxy), an optionally substituted alkenyl (such as allenyl), an unsubstituted alkynyl (such as ethynyl) or a Ci alkyl substituted with a non-halogen substituent. In some embodiments, R^2A cannot be an unsubstituted alkoxy (such as methoxy), an optionally substituted alkenyl (such as allenyl), an optionallys substituted substituted alkynyl (such as ethynyl) or a C₍4 alkyl substituted with a non-halogen substituent. In some embodiments R^,a cannot be H. In some embodiments R^1acannot be H when B^,a is an optionally substituted cytosine or an optionally substituted thymine.

[0127] Various optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more of the amine and/or amino groups may be protected with a suitable protecting group. For example, an amino group may be protected by transforming the amine and/or amino group to an amide or a carbamate. In some embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can hâve one of the following structures:

wherein: R*² can be selected from hydrogen, halogen and NHR^J2, wherein R¹² can be selected from hydrogen, -C(=O)R^K2 and -C(=O)OR¹²·, R^B2 can be halogen or NHR^W2, wherein R^W2 can 5 be selected from hydrogen, an optionally substituted C|^ alkyl, an optionally substituted C2^ alkenyl, an optionally substituted C3-e cycloalkyl, -C(=O)R^M2 and -C(=O)OR^N2; R⁰² can be hydrogen or NHR⁰², wherein R⁰² can be selected from hydrogen, -C^OJR¹*² and -C(=O)OR^Q2; R⁰² can be selected from hydrogen, halogen, an optionally substituted Ci^ alkyl, an optionally substituted C2^ alkenyl and an optionally substituted C₂^ alkynyl; R^E2 can be selected from 10 hydrogen, hydroxy, an optionally substituted alkyl, an optionally substituted C₃.8 cycloalkyl,

-C(=O)R^R2 and -C(=O)OR^S2; Rⁿ can be selected from hydrogen, halogen, an optionally substituted Ci^ alkyl, an optionally substituted C2^ alkenyl and an optionally substituted C2^ alkynyl; Y² and Y³ can be independently N (nitrogen) or CR¹², wherein Rⁿ can be selected from hydrogen, halogen, an optionally substituted C|^-alkyl, an optionally substituted C2^-alkenyl 15 and an optionally substituted C₂^-alkynyl; R^C2 can be an optionally substituted alkyl; R¹¹²can be hydrogen or NHRⁿ, wherein Rⁿ can be independently selected from hydrogen, C(=O)R^U2 and -C(=O)OR^V2; and R^K2, R^u, R^M2, R^N2, R¹*², R^Q2, R^R2, R^S2, R^U2 and R⁷² can be independently selected from alkyl, C₂₆ alkenyl, C₂^ alkynyl, C₃^ cycloalkyl, C_wcycloalkenyl, C₆.₁₀ aryl, heteroaryl, heteroalicyclyl, aryl(C|^ alkyl), heteroaryl(C|^ alkyl) and 20 heteroalicyclyl(Ci_6 alkyl). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the définition of “substituted.

embodiments, B

In still other [0128] In some embodiments, B^,A can

«aaap can be hydrogen. In other embodiments, B R^B2 can be NH₂. In other embodiments, R^B2 embodiments, B^IA can be

NH	I T
, such as	1 ΛΛ	. In
NHR^K		NHa
k		A
		0%

, for example, yet still other embodiments, B^,A can . In some embodiments, R⁰² . In some embodiments, can be NHR^W2, wherein R^W2 can be -C(=O)R^M2 or

OrG²

[0129] In some embodiments, a compound of Formula (I) can hâve a structure selected from one of the following:

the foregoing. In some embodiments of this paragraph, B^lA can be an optionally substituted purine base. In other embodiments of this paragraph, B ^A can be an optionally substituted pyrimidine base. In some embodiments of this paragraph, B^,A can be guanine. In other embodiments of this paragraph, B^lA can be thymine. In still other embodiments of this paragraph, B^1A can be cytosine. In yet still other embodiments of this paragraph, B^lA can be uracit. In some embodiments of this paragraph, B^lA can be adenine. In some embodiments of this paragraph, R^JA can be hydrogen. In other embodiments of this paragraph, R^lA can be an optionally substituted acyl. In still other embodiments of this paragraph, R^IA can be mono-, dior tri-phosphate. In yet other embodiments of this paragraph, R^IA can be phosphoroamidate. In some embodiments of this paragraph, R^IA can be an acyloxyalkyl ester phosphate prodrug.

[0130] In some embodiments, the compound can be a compound of Formula (Π). or a pharmaceutically acceptable sait thereof, wherein: B^,b can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group:

R\	B⁶⁸
	' r^7B	o9B θ
	X . ^R\z	X H
R^ib can be selected from O, OH,	0 ,	JL· ^r10B

, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R can be selected from an optionally substituted Ci-6 alkyl, an optionally substituted C₂^ alkenyl, an optionally substituted C₂_6 alkynyl, an optionally substituted -O-C^ alkyl, an optionally substituted -O-Ci^ alkenyl, an optionally substituted alkynyl and cyano; R³⁸ can be a halogen; R^4B can be hydrogen or halogen; R^5B, R^6B, R^8B and R⁹⁸ can be independently selected from hydrogen, an optionally substituted Cj.₂4 alkyl and an optionally substituted aryl; R^7B and R^J0B can be independently selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl and an optionally substituted -O-aryl; R^IIB can be selected from hydrogen, an optionally substituted C|.₂4 alkyl and an optionally substituted aryl; Z^IB and Z^2B can be independently O or S.

[0131] In some embodiments, R¹⁸ can be O'. In other embodiments, R^,B can be OH.

wherein R^ÎB and R⁶⁸ [0132] In some embodiments, R can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; and R⁷⁸ can be selected from hydrogen, an optionally substituted Cj.

alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl and an optionally substituted -O-aryl. In some embodiments, R^ÎB and R^6B can be hydrogen. In other embodiments, at least one of R^5B and R^6B can be an optionally substituted C1.24 alkyl or an optionally substituted aryl. In some embodiments, R⁷⁸ can be an optionally substituted Ci-24 alkyl. In other embodiments, R^7B can be an optionally substituted aryl. In still other embodiments, R⁷⁸ can be an optionally substituted -O-C|.₂4 alkyl or an optionally substituted 10 O-aryl.

[0133]

In some embodiments, R¹⁸ can be

wherein R⁸⁸ and R⁹⁸ can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; R^,0B can be independently selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl and an optionally substituted -O-aryl; and Z can be independently O (oxygen) or S (sulfur). In some embodiments, R^8B and R⁹⁸ can be hydrogen. In other embodiments, at least one of R⁸⁸ and R⁹⁸ can be an optionally substituted C1.24 alkyl or an optionally substituted aryl. In some embodiments, R¹⁰⁸ can be an optionally substituted C1.24 alkyl. In other embodiments, R¹⁰⁸ can be an optionally substituted aryl. In still other embodiments, R¹⁰⁸ can be an optionally substituted -O-C1.24 alkyl or an optionally substituted -O-aryl. In some embodiments, Z^2B can be O (oxygen). In other embodiments, Z²⁸ can be or S (sulfur). In some embodiments, R¹⁸ can be isopropylcarbonyloxymethyloxy. In some embodiments, R¹⁸ can be pivaloyloxymethyloxy.

[0134]

In some embodiments, R¹⁸ can be

O

embodiments, R¹¹⁸ can be hydrogen. In other embodiments, R¹¹⁸ can be an optionally substituted C1.24 alkyl. In still other embodiments, R¹¹⁸ can be an optionally substituted aryl. In some embodiments, R¹¹⁸ can be a alkyl, for example, methyl, ethyi, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained).

[0135] In some embodiments, R^,B can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative. For example, R ^B can be optionally substituted version of the following: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan, valine and ester dérivatives thereof. In some embodiments, R^IB can be selected from alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some

embodiments, R^1B can hâve the structure , wherein R^12B can be selected from hydrogen, an optionally substituted CM-alkyl, an optionally substituted Cm cycloalkyl, an optionally substituted aryl, an optionally substituted aryl (Cm alkyl) and an optionally substituted haloalkyl; R^l3B can be selected from hydrogen, an optionally substituted Cm alkyl, an optionally substituted Cm haloalkyl, an optionally substituted C_3Î cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cjo aryl and an optionally substituted aryI(CM alkyl); and R^l4B can be hydrogen or an optionally substituted Cu-alkyl; or R^,3B and R^14B can be taken together to form an optionally substituted Cm cycloalkyl.

[0136] When R^13B is substituted, R^13B can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R^13B can be an unsubstituted CM-alkyl, such as those described herein. In some embodiments, R^,3B can be hydrogen. In other embodiments, R^,3B can be methyl. In some embodiments, R^t2B can be an optionally substituted Cm alkyl. Examples of optionally substituted CM-alkyls include optionally substituted variants of the following: methyl, ethyl, π-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straightchained). In some embodiments, R^12B can be methyl or isopropyl. In some embodiments, R^t2Bcan be ethyl or neopentyl. In other embodiments, R^,2B can be an optionally substituted C3^ cycloalkyl. Examples of optionally substituted Cm cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R^12B can be an optionally substituted cyclohexyl. In still other embodiments, R^I2Bcan be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R^I2B can be an optionally substituted aryl(CM alkyl). In some embodiments, R^,2bcan be an optionally substituted benzyl. In some embodiments, R^12B can be an optionally substituted Cm haloalkyl, for example, CF3. In some embodiments, R^,4B can be hydrogen. In other embodiments, R^14B can be an optionally substituted Cn-alkyl, such as methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^I4B can be methyl. In some embodiments, R^,3B and R^,4B can be taken together to form an optionally substituted C₃^ cycloalkyl. Examples of optionally substituted C₃_6 cycloalkyl include optionally substituted 5 variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R^I3B and R^14b, the carbon to which R^13B and R^,4B are attached may be a chiral center. In some embodiment, the carbon to which R^I3B and R^,4B are attached may be a (R)-chiral center. In other embodiments, the carbon to which R^I3B and R^I4B are attached may be a (S)-chiral center.

[0138] A variety of substituents can be présent at the 4’-position of the pentose ring. In some embodiments, R²⁰ can be an optionally substituted Ci^ alkyl. Examples of suitable Ci^ alkyls include methyl, ethyi, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R²⁰can be an unsubstituted C(^ alkyl. In other embodiments, R²⁰ can be a substituted Ci^ alkyl. For example, R²⁰ can be a halogen substituted Ci^ alkyl, a hydroxy substituted Ci^ alkyl, an alkoxy substituted Ci^ alkyl or a sulfenyl substituted alkyl (for example, -C^ alkyl-S-C|^ alkyl). In other embodiments, R²⁰ can be a Ci^ haloalkyl. . In other embodiments, R²⁰ can be an optionally substituted C2.6 alkenyl. In some embodiments, R²⁰ can be a substituted alkenyl. In other embodiments, R²⁰ can be an unsubstituted C2^ alkenyl. For example. R²⁰ can be ethenyl, propenyl or allenyl. In still other embodiments, R²⁰ can be an optionally substituted C24 alkynyl. In some embodiments, R²⁰ can be a substituted C2^ alkynyl. In other embodiments, R²⁰ can be an unsubstituted C2^ alkynyl. Suitable €2^ alkynyls include ethynyl and propynyl. In yet still other embodiments, R²⁰ can be an optionally substituted €3^ cycloalkyl. In some embodiments, R²⁰ can be a substituted C34 cycloalkyl. In other embodiments, R²⁰ can be an unsubstituted C34 cycloalkyl. A non-limiting list of C34 cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R²⁰ can be an optionally substituted -O-C|^ alkyl. In some embodiments, R²⁰ can be a substituted -O-C14 alkyl. In other embodiments, R²⁰ can be an unsubstituted -O-C|^ alkyl. Examples of suitable O-C|^ alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, nbutoxy, isobutoxy, tert-butoxy, pentoxy (branched and straight-chained), and hexoxy (branched and straight-chained). In other embodiments, R²⁰ can be an optionally substituted -O-C3.6 alkenyl. In some embodiments, R²⁰ can be a substituted - O-C3.6 alkenyl. In other embodiments, R²⁰ can be an unsubstituted -O-C3.6 alkenyl. In still other embodiments, R²⁰ can be an optionally substituted -O-C3.6 alkynyl. In some embodiments, R²⁰ can be a substituted 17044

O-Cj-6 alkynyl. In other embodiments, R^2B can be an unsubstituted -O-Cj^ alkynyl. In yet still other embodiments, R^2B can be cyano.

[0139] Variety of substituents can be présent at the 2*-position of the pentose ring. In some embodiments, R^4B can be hydrogen. In other embodiments, R^4B can be halogen, such as 5 fluoro. In some embodiments, R^3B can be halogen, such as fluoro. In some embodiments, R^4Bcan be hydrogen and R^3B can be halogen. In other embodiments, R^3B and R^4B can be both halogen. For example, R^3B and R^4B can be both fluoro.

[0140] In some embodiments, Z^1B can be O (oxygen). In other embodiments, Z^,B can be S (sulfur).

[0141] Various optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more of the amine and/or amino groups may be protected with a suitable protecting group. For example, an amino group may be protected by transforming the amine and/or amino group to an amide or a carbamate. In some embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can hâve one of the foliowing structures:

wherein: R^AB2 can be selected from hydrogen, halogen and NHR^JB2, wherein R^JB2 can be selected from hydrogen, -C(=O)R^KB2 and -C(=O)OR^LB2; R^BB2 can be halogen or NHR^v,3'^!, 20 wherein R^W2 can be selected from hydrogen, an optionally substituted Cialkyl, an optionally substituted C2-6 alkenyl, an optionally substituted Cj.g cycloalkyl, -C(=O)R^MB2 and C(=O)OR^nbî; R^cb2 can be hydrogen or NHR^OB2, wherein R^OB2 can be selected from hydrogen, C(=O)R^PB2 and -C(=O)OR^QBÎ; R^DB2 can be selected from hydrogen, halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2.6 alkenyl and an optionally substituted C₂-6 25 alkynyl; R^EB2 can be selected from hydrogen, hydroxy, an optionally substituted C|^ alkyl, an optionally substituted C3.8 cycloalkyl, -C(=O)R^RB2 and -C(=O)OR^S82; R^raî can be selected from hydrogen, halogen, an optionally substituted Cm alkyl, an optionally substituted C₂^ alkenyl and an optionally substituted C2.6 alkynyl; Y^2B and Y³⁸ can be independently N (nitrogen) or CR®², wherein R®² can be selected from hydrogen, halogen, an optionally substituted CM-alkyl, an optionally substituted C2-6-alkenyl and an optionally substituted C2^-alkynyl; R^CB2 can be an 5 optionally substituted Cm alkyl; R^HB2 can be hydrogen or NHR¹⁸², wherein R⁷⁸² can be independently selected from hydrogen, -C(=O)R^UB2 and -C(=0)0R^VB2; and R*³², R¹*², R^MB2, R^NB2, R^pb2, R^qb2, R^rbz, R^SB2, R⁰⁸² and R^VB2can be independently selected from Cm alkyl, C2-6 alkenyl, C2.6 alkynyl, C34 cycloalkyl, C34 cycloalkenyl, Ce-ίο aryl, heteroaryl, heteroalicyclyl, aryl(C].e alkyl), heteroaryl(CM alkyl) and heteroalicyclyl(Ci4 alkyl). In some embodiments, the 10 structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the définition of substituted.”

O

[0142] In some embodiments, B

		0
	<A>
embodiments, B¹⁸ can be «aIaa
XL	A-
	1
	aÀv , such as	1 ΛΛΛ? ,

ln still other embodiments, B¹⁸ can be

In yet still other embodiments. B¹⁸ can

. In some embodiments, R⁰⁸²

can be hydrogen. In other embodiments, B R⁸⁸² can be NH2. In other embodiments, R¹ . In some embodiments, ⁸⁸² can be NHR*⁸², wherein R*⁸² can be _RGB2

(

N C(=0)R^mb2 or ~<Ζ(=Ο)ΟΚ^Ν82. In still other embodiments, B^1b can be wlv

R^HB2 . In some embodiments, B

[0143] In some embodiments, a compound of Formula (Π) can hâve the following

embodiments of this paragraph, B^1b can be an optionally substituted purine base. In other embodiments of this paragraph, B^,b can be an optionally substituted pyrimidine base. In some embodiments of this paragraph, B¹⁸ can be guanine. In other embodiments of this paragraph, B¹⁸ can be thymine. In still other embodiments of this paragraph, B^ib can be cytosine. In yet still other embodiments of this paragraph, B^,b can be uracil. In some embodiments of this paragraph, B^ib can be adenine. In some embodiments of this paragraph, Z¹⁸ can be oxygen. In some embodiments of this paragraph, Z¹⁸ can be sulfur. In still other embodiments of this paragraph, R¹⁸ can be alkylcarbonyloxyalkoxy.

[0144] In some embodiments, the compound can be a compound of Formula (IH), or a pharmaceutically acceptable sait thereof, wherein: B^1C can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^,c and R^2C can be independentlyselected from O, OH, an optionally substituted Ci^ alkoxy,

optionally substituted N-linked amino acid and an optionally substituted Ν-ünked amino acid ester dérivative; R^îc can be selected from an optionally substituted Ci-6 alkyl, an optionally substituted C₂^ alkenyl, an optionally substituted C₂^ alkynyl, an optionally substituted -O-Cj^ 5 alkyl, an optionally substituted -O-C₃^ alkenyl, an optionally substituted -O-C₃_6 alkynyl, an optionally substituted C₃^ cycloalkyi and cyano; R^4C can be selected from OH, -0C(=0)R ^c and an optionally substituted O-linked amino acid; R^ÎC can be a halogen; R⁶⁰ can be hydrogen or halogen; R⁹⁰, R^10C, R^,2C and R^l3C can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; R^lIC and R^I4C can be independently 10 selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl and an optionally substituted -O-aryl; R^,ÎC can be selected from hydrogen, an optionally substituted Cj.24 alkyl and an optionally substituted aryl;----can be a single bond or a double bond; when------is a single bond, each R^7C and each R^8C can be independently hydrogen or halogen; and when-----ts a double bond, each R^7C is absent and each R can be independently hydrogen or halogen; Z can be O (oxygen) or S (sulfur); and

R ^c can be an optionally substituted Ci.₂4-alkyt.

[0145] ln some embodiments,----can be a single bond such that Formula (ΙΠ) has

hydrogen or halogen. In some embodiments, the R and the R groups can ail be hydrogen. In 20 other embodiments, one R^7C can be halogen, one R^7C can be hydrogen and both R^8C groups can ait be hydrogen. [n still other embodiments, one R^7C can be halogen, one R^7C can be hydrogen, one R^8C can be halogen and one R^8C can be hydrogen. In some embodiments, the carbon adjacent to the phosphores and the 5’-carbon can each be independently a (S)-chiral center. In some embodiments, the carbon adjacent to the phosphores and the S’-carbon can each be 25 independently a (R)-chiral center.

[0146] In some embodiments, the structure

can be a double bond such that Formula (ΙΠ) has wherein each R^7C is absent and each R^8C can be independently hydrogen or halogen. In some embodiments, both R^8C groups can be hydrogen. In other embodiments, one R^8C can be halogen and the other R^8C can be hydrogen. In some embodiments, both R^8C groups can be halogen. In some embodiments, the double bond has a (Z)-configuration. In some embodiments, the double bond has a (E)-configuration.

[0147] In some embodiments, R^lc and/or R^2C can be O'. In other embodiments, R^,cand/or R^2C can be OH. In some embodiments, R^tc and R^2C can be both OH.

o9C d10C a°>Ç^r· [0148] In some embodiments, R^,c and/or R^2C can be O wherein

R and R can be independently selected from hydrogen, an optionally substituted C1.24 alkyl and an optionally substituted aryl; and R^,,c can be selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-Cj.24 alkyl and an optionally substituted -O-aryt. In some embodiments, R⁹⁰ and R^l0Ccan be hydrogen. In other embodiments, at least one of R⁹⁰ and R^10Ccan be an optionally substituted C1.24 alkyl or an optionally substituted aryl. In some embodiments, R^,,c can be an optionally substituted C1.24 alkyl. In other embodiments, R^,,c can be an optionally substituted aryl. In still other embodiments, R^,,ccan be an optionally substituted -O-C1.24 alkyl or an optionally substituted r9C d10C

Αχγ·”¹

O-aryl. In some embodiments, R^,c and R^2C can be both O .

[0149]

In some embodiments, R^lc and/or R^2C can be

wherein R^,2C and R^lîc can be independently selected from hydrogen, an optionally substituted Cj.24 alkyl and an optionally substituted aryl; R^uc can be independently selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -OC]>24 alkyl and an optionally substituted -O-aryl; and Z^,c can be independently O (oxygen) or S (sulfur). In some embodiments, R^12c and R^l3C can be hydrogen. In other embodiments, at least one of R^12c and R^l3C can be an optionally substituted Ci.24 alkyl or an optionally substituted aryl. In some embodiments, R^,4ccan be an optionally substituted Ci.24 alkyl. In other embodiments, R^l4Ccan be an optionally substituted aryl. In still other embodiments, R^l4ccan be an optionally substituted -O-C|.₂4 alkyl or an optionally substituted -O-aryl. In some embodiments, Z^lc can be O (oxygen). In other embodiments, Z^lc can be or S (sulfur). In some embodiments, R^ICand/or R^2C can be isopropylcarbonyloxymethoxy. In some embodiments, R^IC and/or R^2C can be

pivaloyloxymethoxy. _R12C d13C O	In	some	embodiments, R^,c	and R^2C	can	be	both
Λ,Χ,Α	'_R14C	In	some	embodiments,	R^,c and R^2C	can	be	both
isopropylcarbonyloxymethoxy.	In	other	embodiments.	R^,c and R^2C	can	be	both

pivaloyloxymethoxy.

[0150]

In some embodiments, R^lc and/or R^2C can be

In some embodiments, R^ISC can be hydrogen. In other embodiments, R^1SC can be an optionally substituted C|.₂4 alkyl. In still other embodiments, R^,sc can be an optionally substituted aryl. In some embodiments, R^lsc can be a Ci^ alkyl, for example, methyl, ethyl, n-propyl, isopropyl, nbutyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R^IC and R^2C can be both

O

[0151] In some embodiments, R^lc and/or R^2C can be an optionally substituted Nlinked amino acid or an optionally substituted N-linked amino acid ester dérivative. For example, R^IC and/or R^:c can be optionally substituted version of the following: alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, îsoleucine, leucine, lysine, méthionine, phenyialanine, threonine, tryptophan, valine and ester dérivatives thereof. In some embodiments, R^,c and/or R^2C can be selected from alanine isopropyl ester, alanine cyclohexyl ester, alanine neopentyl ester, valine isopropyl ester and leucine isopropyl ester. In some embodiments, R^lc and/or R^2C can hâve the structure

can be selected from hydrogen, an optionally substituted

alkyl, an optionally substituted Cj^ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci^ alkyl) and an optionally substituted haloalkyl; R^20C can be selected from hydrogen, an optionally substituted C|^ alkyl, an optionally substituted haloalkyl, an optionally substituted C3^ cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci^ alkyl); and R^2IC can be hydrogen or an optionally substituted Ci-4-alkyl; or R^20C and R^21C can be taken together to form an optionally substituted C3.6 cycloalkyl.

[0152] When R^20C is substituted, R^20C can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R^20C can be an unsubstituted Ci^-alkyl, such as those described herein. In some embodiments, R^20C can be hydrogen. In other embodiments, R^20C can be methyl. In some embodiments, R^19C can be an optionally substituted C|^ alkyl. Examples of optionally substituted Ci^-alkyls inciude optionally substituted variants of the following: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straightchained). In some embodiments, R^I9C can be methyl or isopropyl. In some embodiments, R^19Ccan be ethyl or neopentyl. In other embodiments, R^i9C can be an optionally substituted C₃^ cycloalkyl. Examples of optionally substituted C3.6 cycloalkyl inciude optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R^l9C can be an optionally substituted cyclohexyl. In still other embodiments, R¹⁹⁰can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R^l9Ccan be an optionally substituted aryl(C|^ alkyl). In some embodiments, R^I9Ccan be an optionally substituted benzyl. In some embodiments, R^l9C can be an optionally substituted Ci^ haloalkyl, for example, CF₃. In some embodiments, R^2IC can be hydrogen. In other embodiments, R^21C can be an optionally substituted Ct^-alkyl, such as methyl, ethyl, npropyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^2IC can be methyl. In some embodiments, R^20C and R^2ic can be taken together to form an optionally substituted cycloalkyl. Examples of optionally substituted C3.6 cycloalkyl inciude optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Depending on the groups that are selected for R^20C and R^2,c, the carbon to which R^20C and R^2IC are attached may be a chiral center. In some embodiment, the carbon to which R^20C and R^2IC are attached may be a (R)-chiral center.

In other embodiments, the carbon to which R^20C and R^2IC are attached may be a (S)-chiral center.

groups include the following: h₃cq h₃ç h

»

H₃CO h₃c, H

M.

[0153] Examples of suitable _R19CqR20C ^21C

t

[0154] In some embodiments, R^IC and R^2C can be the same. In other embodiments, R^IC and R^2C can be different.

[0155]

In some embodiments, R^,c can be

can be 0' or OH, wherein R^I6C, R^l7C and R^ISC can be absent or hydrogen; and n can be 0 or 1. Those skilled in the art understand that when R^I6C, R^nc and/or R^lsc are absent, the associated oxygen will be negatively charge. In some embodiments, when n is 0, the compound of Formula (ΙΠ) will be a diphosphate. In other embodiments, when n is 1, the compound of Formula (ΙΠ) will be a triphosphate.

[0156] A variety of substîtuents can be présent at the 4’-position of the pentose ring. In some embodiments, R^3C can be an optionally substituted C|^ alkyl. Examples of suitable Ci^ alkyls include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained), and hexyl (branched and straight-chained). In some embodiments, R^îccan be an unsubstituted alkyl. In other embodiments. R^3C can be a substituted C]^ alkyl. For example, R^3C can be a halogen substituted C]_6 alkyl. In other embodiments, R^3C can be an optionally substituted C2-6 alkenyl. In some embodiments, R^3C can be a substituted C2-6 alkenyl. In other embodiments, R^3C can be an unsubstituted C2-$ alkenyl. For example, R^3C can be ethenyl, propenyl or allenyl. In still other embodiments, R^3C can be an optionally substituted C2. 6 alkynyl. In some embodiments, R^3C can be a substituted C2-6 alkynyl. In other embodiments, R^3C can be an unsubstituted C2-6 alkynyl. Suitable C2-6 alkynyls include ethynyl and propynyl. In yet still other embodiments, R^3C can be an optionally substituted C36 cycloalkyl. In some embodiments, R^3C can be a substituted C3-6 cycloalkyl. In other embodiments, R^3C can be an unsubstituted C3^ cycloalkyl. A non-limiting list of C3^ cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. In some embodiments, R^3C can be an optionally substituted -O-Ci ô alkyl. In some embodiments, R^3C can be a substituted -O-Cj^ alkyl. In other embodiments, R can be an unsubstituted -O-Cj_6 alkyl. Examples of suitable O-Ci ô alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, tert-butoxy, pentoxy (branched and straight-chained), and hexoxy (branched and straight-chained). In other embodiments, R^3C can be an optionally substituted -O-C3.6 alkenyl. In some embodiments, R^3Ccan be a substituted -O-C3.6 alkenyl. In other embodiments, R^3C can be an unsubstituted -O-C3. 6 alkenyl. In still other embodiments, R can be an optionally substituted -O-C3 6 alkynyl. In some embodiments, R^3C can be a substituted -O-C36 alkynyl. In other embodiments, R^3C can be an unsubstituted -O-C3-6 alkynyl. In yet still other embodiments, R^3C can be cyano.

[0157] The substituents that can be présent on the 3’-position of the pentose ring can vary. In some embodiments, R^4C can be OH. In other embodiments, R^4C can be an optionally substituted Ο-linked amino acid. Examples of suitable O-linked amino acids include alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, 5 histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan and valine. Additional examples of suitable amino acids include, but are not limited to, omithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, betaalanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine. In some embodiments, the O23C

linked amino acid can hâve the structure ⁰hydrogen, an optionally substituted Cm alkyl, an ^NHa , wherein R^22C can be selected from optionally substituted Cm haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cto aryl and an optionally substituted aryl(CM alkyl); and R^23C can be hydrogen or an optionally substituted Cu-alkyl; or R^22C and R^23C can be taken together to form an optionally substituted

Cj-é cycloalkyl.

[0158] When R^22C is substituted, R^22C can be substituted with one or more substituents selected from N-amido, mercapto, alkylthio, an optionally substituted aryl, hydroxy, an optionally substituted heteroaryl, O-carboxy, and amino. In some embodiments, R²²⁰ can be an unsubstituted CM-alkyl, such as those described herein. In some embodiments, R^22C can be hydrogen. In other embodiments, R^22C can be methyl. In some embodiments, R^23C can be 20 hydrogen. In other embodiments, R^23C can be an optionally substituted Ci4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^23C can be methyl. Depending on the groups that are selected for R^22c and R^23C, the carbon to which R²²⁰ and R^23C are attached may be a chiral center. In some embodiment, the carbon to which R^22C and R^23C are attached may be a (R)-chiral center. In other embodiments, the carbon to 25 which R^22C and R^23C are attached may be a (S)-chîral center.

include the following:

[0159] Examples of suitable

[0160] In still other embodiments, R^4C can be -OC(=O)R^c, wherein R”^c can be an optionally substituted C|.24 alkyl. In some embodiments, R”^c can be a substituted C|.j2 alkyl. In other embodiments, R ^c can be an unsubstituted Ci.i2 alkyl. In still other embodiments, R ^c can be a substituted Ci.g alkyl. In yet still other embodiments, R ^c can be an unsubstituted Ci-g alkyl. In some embodiments, R^4C can be an optionally substituted acyl. In other embodiments, R^4C can be -OC(=O)R , wherein R can be selected from an optionally substituted Ci.|2 alkyl, an optionally substituted C₂.i₂ alkenyl, an optionally substituted C₂.i₂ alkynyl, an optionally substituted C3.8 cycloalkyl, an optionally substituted C5.8 cycloalkenyl, an optionally substituted C6-10 aryl, an optionally substituted heteroaryl, an optionally substituted heterocydyl, an optionally substituted aryl(Cj^ alkyl), an optionally substituted heteroaryKCi^ alkyl) and an optionally substituted heterocyclyl(Ci45 alkyl). In some embodiments, R ^c can be a substituted Cj-12 alkyl. In other embodiments, R ^c can be an unsubstituted Cm₂ alkyl.

[0161] A variety of substituents can also be présent at the 2’-position of the pentose ring. In some embodiments, R⁶⁰ can be hydrogen. In other embodiments, R⁶⁰ can be halogen, such as fluoro. In some embodiments, R^ÎC can be halogen, such as fluoro. In some embodiments, R^6C can be hydrogen and R^sc can be halogen. In other embodiments, R^sc and R⁶⁰can be both halogen. For example, R^!c and R⁶⁰ can be both fluoro.

[0162] Various optionally substituted heterocyclic bases can be attached to the pentose ring. In some embodiments, one or more of the amine and/or amino groups may be protected with a suitable protecting group. For example, an amino group may be protected by transforming the amine and/or amino group to an amide or a carbamate. In some embodiments, an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with one or more protected amino groups can hâve one of the following structures:

wherein: R^AC2 can be selected from hydrogen, halogen and NHR^JC2, wherein R^JC2 can be selected from hydrogen, -C(=O)R^KC2 and -C(=0)0R^LC2; R^BC2 can be halogen or NHR^WC2, 5 wherein R^WC2 can be selected from hydrogen, an optionally substituted Ci-β alkyl, an optionally substituted C2-6 alkenyl, an optionally substituted C3-8 cycloalkyl, -C(=0)R^MC2 and C(=0)0R^NC2; R^CC2 can be hydrogen or NHR⁰⁰², wherein R⁰⁰² can be selected from hydrogen, C(=0)R^pc2 and -C(=0)0R°^C2; R⁰⁰² can be selected from hydrogen, halogen, an optionally substituted Ci-e alkyl, an optionally substituted C2.6 alkenyl and an optionally substituted C2-6 alkynyl; R^EC2 can be selected from hydrogen, hydroxy, an optionally substituted Ci-e alkyl, an optionally substituted C3.8 cycloalkyl, -C(=0)R^RC2 and -C(=0)0R^SC2; R^ra can be selected from hydrogen, halogen, an optionally substituted Ci^alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl; Y^2C and Y^3C can be independently N (nitrogen) or CR^IC2, wherein R^IC2 can be selected from hydrogen, halogen, an optionally substituted Ci^-alkyl, an 15 optionally substituted C2^-alkenyl and an optionally substituted C2^-alkynyl; R⁰⁰² can be an optionally substituted Ci-e alkyl; R^HC2 can be hydrogen or NHR^TC2, wherein R^TC2 can be independently selected from hydrogen, -C(=0)R^UC2 and -C(=0)0R^VC2; and R^KC2, R¹⁰², R^MC2, R^NC2, R”³, R⁰⁰², R^RC2, R^SC2, R^UC2 and R^VC2can be independently selected from alkyl, C2.6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3.6 cydoalkenyl, Cô-io aryl, heteroaryl, heteroalicyclyl, 20 aryl(Ci-e alkyl), heteroaryl(Ci_6 alkyl) and heteroalicyclyl(Ci^ alkyl). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with substituents selected from the list of substituents provided for the définition of “substituted.

embodiments. B _RBC2 still other [0163] In some embodiments, B

be . In some embodiments, R⁰⁰² embodiments, B^lc can be . In some embodiments, , wherein R^WC2 can be <ZWV* , for example,

NHR^EC2

can be hydrogen. In other embodiments, B R^BC2 can be NH2. In other embodiments, R

In yet still other embodiments, B^IC can

	OR⁰⁰²
Ζ'Ίί
ï In still other embodiments, B^1C can be	A_n^\_rHC2 . In

C(=O)R^MC2 or -C(=O)OR^NC2.

[0164] In some embodiments, the compound of Formula (ΙΠ) can hâve one of the

some embodiments of this paragraph, B^,c can be an optionally substituted purine base. In other embodiments of this paragraph. B^1C can be an optionally substituted pyrimidîne base. In some embodiments of this paragraph, B^IC can be guanine. In other embodiments of this paragraph, B^IC can be thymine. In still other embodiments of this paragraph, B^IC can be cytosine. In yet 10 still other embodiments of this paragraph, B^IC can be uracil. In some embodiments of this paragraph, B^IC can be adenine. In some embodiments of this paragraph, R^IC and R^2C can each be an optionally substituted Cm alkyl. In other embodiments of this paragraph. R^IA can be an optionally substituted acyl. In still other embodiments of this paragraph, R^,c and R^2C can form a mono-, di- or tri-phosphate. In yet other embodiments of this paragraph, R^IC and R^2C can each 15 be an alkylcarbonyloxyalkoxy. In some embodiments of this paragraph, R⁴⁰ can be OH. In some embodiments of this paragraph, R^ÎC can be F and R⁶⁰ can be hydrogen.

[0165]

Examples of suitable compounds of Formula (I) include, but are not limited to the foliowing:

foregoing.

[0166]

, or a pharmaceutically acceptable sait of the foregoing.

[0167] Further examples of a compound of Formula (I) include, but are not limited to the foliowing:

H₃C^/V^Z%

ο

sait of the foregoing.

[0168] Examples of a compound of Formula (Π) include, but are not limited to, the following:

pharmaceutically acceptable sait of the foregoing.

[0169] Examples of a compound of Formula (Π1) include, but are not limited to, the following:

pharmaceutically acceptable sait of the foregoing.

[0170] Further examples of a compound of Formula (ΙΠ) include, but are not limited to, the following:

pharmaceutically acceptable sait of the foregoing.

Synthesis [0171] Compounds of Formula (I) Formula (Π) and Formula (K), and those described herein may be prepared in various ways. Some compounds of Formulae (I), (Π) and (ΠΙ) can be obtained commercially and/or prepared utilizing known synthetic procedures. General synthetic routes to the compounds of Formulae (D, (Π) and (ΙΠ), and some examples of starting materials used to synthesize the compounds of Formulae (I). (Π) and (III) are shown and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the daims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed synthèses and to devise altemate routes based on the disclosures herein; all such modifications and altemate routes are within the scope of the daims.

Scheme 1

(Q

[0172] As shown in Scheme 1, compounds of Formula (I) can be prepared from a nucleoside, for example, a nucleoside of Formula (A). In Scheme 1, R^3a, R^4a, R^5a, and B^,a can be the same as R^3A, R^4A, R^SA, and B^,A as described herein for Formula (I), and PG¹ is a suitable protecting group. A hydroxyalkyl group can be formed at the 4’-position of the pentose ring using suitable conditions known to those skilled in the art. Examples of suitable conditions for forming a hydroxyalkyl include the use of 2-iodoxybenzoic acid (IBX) aqueous formaldéhyde and sodium borohydride. A compound of Formula (B) can be oxidized to an aldéhyde using a suitable oxidizing agent(s) to form a compound of Formula (C). An example of suitable oxidizing agent is Dess-Martin periodinane. An optionally substituted C₂₆ alkenyl or an optionally substituted C₂.6 alkynyl can be formed at the 4’-position using methods known to those skilled in the art, for example, Wittig reagent and n-BuLi, Wîttig-type reactions, Peterson olefination reaction, and Corey Fuchs reaction. An optionally substituted Ci^ alkyl can be obtained by hydrogenating the unsaturated group attached to the 4’-position, for example, using hydrogen over palladium on carbon.

[0173] Altematively, a compound of Formula (B) can be transformed to a haloalkyl using a suitable agent(s), for example, to an iodide using imidazole, triphenylphosphine and iodine; to a fluoro using dîethylaminosulfur trifluoride (DAST); or to a chloro using triphenylphosphine and carbontetrachloride in dichloroethylene (DCE). An iodoalkyl can be transformed to an unsubstituted alkyl group using methods known to those skilled in the art, for example, hydrogen over palladium on carbon. A compound of Formula (C) can be reacted with hydroxylamine to form an oxime. The oxime can be transformed to a cyano group using methods known to those skilled in the art, for example, using methanesulfonyl chloride.

Scheme 2

[0174] As shown in Scheme 2, compounds of Formula (I), where R^2A is an optionally 5 substituted -O-Cj^ alkyl, an optionally substituted -O-C3.6 alkenyl or an optionally substituted -O—C₃^ alkynyl, can be prepared from a nucleoside, for example, a nucleoside of Formula (A). In Scheme 2, R²⁴, R^3a, R^4a, R^5a and B^,a can be the same as R^2A, R^3A, R^4A, R^5A and B^,A as described herein for Formula (I), and PG² can be a suitable protecting group. The nucleoside can undergo élimination and form an olefin having the general formula of Formula (D). A 10 compound of Formula (D) can be treated with an iodinating reagent in the presence of lead carbonate and an alkoxy source to form a compound of Formula (E). A compound of Formula (E) can then be transformed to a compound of Formula (I) through displacement of the iodide with an oxygen nucleophile.

Scheme 3

Scheme 4

(G) [0175] Compounds of Formula (1) having a phosphores containing group attached to the 5’-position of the pentose ring can be prepared using various methods known to those skilled in the art. Examples of methods are shown in Schemes 3 and 4. A phosphores containing precursor can be coupled to the nucleosîde, for example, a compound of Formula (F) or a compound of Formula (G). As shown in Scheme 3, following the coupling of the phosphores containing precursor, any leavîng groups can be cleaved under suitable conditions, such as hydrolysis. Further phosphores containing groups can be added using methods known to those skilled in the art, for example using a pyrophosphate.

[0176] In some embodiments, an alkoxide can be generated from a compound of Formula (G) using an organometallic reagent, such as a Grignard reagent. The alkoxide can be coupled to the phosphores containing precursor. Suitable Grignard reagents are known to those skilled in the art and include, but are not limited to, alkylmagnesium chlorides and alkylmagnésium bromîdes. In some embodiments, an appropriate base can be used. Examples of suitable bases include, but are not limited to, an amine base, such as an alkylamine (including mono-, di- and tri-alkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted îmidazoles (e.g., N-methylimidazole)). Altematively, a phosphores containing precursor can be added to the nucleosîde and form a phosphite. The phosphite can be oxidized to a phosphate using conditions known to those skilled in the art.

Suitable conditions include, but are not limited to, meta-chloroperoxybenzoic acid (MCPBA) or and todine as the oxidiztng agent and water as the oxygen donor.

[0177] When compounds of Formula (I) hâve Z^1A, Z^2A or Z^3A being sulfur, the sulfur can be added in various manners known to those skilled in the art. In some embodiments, the S r6AqJ__C| _{or 0H}taI sulfur can be part of the phosphores containing precursor, for example, R .. t r^0Ao—P—Cl

R^9A . Altematively, the sulfur can be added using a sulfurization reagent. Suitable sulfurization agents are known to those skilled in the art, and include, but are not limited to, elemental sulfur, Lawesson’s reagent, cyclooctasulfur, 3H-l,2-Benzodithiole-3-one-l,l-dîoxide (Beaucage’s reagent), 3-((N,N-dimethylaminomethyIidene)amino)-3H-l,2,4-dithiazole-5-thione (DDTT) and bis(3-triethoxysilyl)propyl-tetrasulfïde (TEST).

[0178] Suitable phosphores containing precursors can be commercially obtained or prepared by synthetic methods known to those skilled in the art. Examples of general structures of phosphores containing precursors are shown in Schemes 3 and 4.

Scheme 5:

oxidatîon reagenl (Z sulfurization reagent (Z [0179] A method for forming a compound of Formula (Π) is shown in Scheme 5. In Scheme 5, R^lb, R^2b, R^3b, R^4b and B^,b can be the same as R¹⁰, R²⁰, R³⁰, R⁴⁰ and B¹⁰ as described herein for Formula (Π), each L^l can be a halogen, a sulfonate ester or an amine (mono- or disubstituted), and X can be oxygen or sulfur. As shown in Scheme 5, a compound having a hydroxy group attached to the 3’-carbon and a hydroxy group attached to the 5'-carbon can be reacted with a compound having the formula, (R^,b)P(L*)2, in the presence of a base, to produce a phosphite compound. Suitable bases are known to those skilled in the art and described herein. The phosphores can then be oxîdized to phosphores(V) using a suitable oxidîzing agent, to produce a compound where X is O (oxygen). Altematively, the phosphite compound can be reacted with a sulfurization reagent to produce a compound where X is S (sulfur). Suitable 5 oxidîzing and sulfurization agents are known to those skilled in the art. For example, the oxidation can be carried out using iodine as the oxidîzing agent and water as the oxygen donor. Suitable sulfurization agents are described herein.

Scheme 6

R^1C—P I _Rx

R^1C—P [0180]

A method for forming a compound of Formula (ΙΠ) is shown in Scheme 6. In Scheme 6, R^k, R^2c, R^3c, R⁴*, R^Sc, R⁶⁰ and B^,c can be the same as R^1C, R^2C, R^3C, R^4C, R^sc, R⁶⁰and B as described herein for Formula (ΙΠ), and R and R are not shown. The oxygen attached to the 5’-carbon of the compound of Formula (H) can be oxîdized to a ketone using methods and reagents known to those skilled in the art. For example, an oxidizing agent, such as Dess-Martin periodinane, can be utilized. A phosphorus-containing reagent can then be added to a compound of Formula (J) in the presence of a strong base (e.g., sodium hydride). The double bond can be hydrogenated, for example using hydrogen gas or Pd/C, to a single bond. Additional phosphates can be added via phosphorylation to form a di- or tri-phosphate using 20 suitable reagents, such as a pyrophosphate (e.g., tetrabutylammonium pyrophosphate).

[0181] An acyl group can be added to the 5'-position and/or the 3’-position of a compound of Formula (I) or (ΙΠ) using methods known to those skilled in the art. One suitable method is using an anhydride in pyridine.

[0182] During the synthesis of any of the compounds described herein, if desired, any hydroxy groups attached to the pentose ring, and any -NH and/or NH₂ groups présent on the B^u, B^lb and B^,c can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. For example, when R^3a and/or R^ is a hydroxy group, R^3a and/or R^ can be protected with a triarylmethyl group or a silyl group. Likewise, any -NH and/or NH2 groups présent on the B^Ia, B^lb and B^,c can be protected, such as with a triarylmethyl and a silyl 10 group(s). Examples of triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrity! (DMTr), 414^,,4-trimethoxytrityl (TMTr),. 4,4',4-tris- (benzoyloxy) trityl (TBTr), 4,4',4'*-tris (4,5-dichIorophtha!imido) trityl (CPTr), 4,4',4-tris (Ievulinyloxy) trityl (TLTr), p-anisyl-1- naphthylphenylmethyl, di-o-anisyl-Inaphthylmethyl, p-tolyldipheylmethyl, 3-(imidazo!ylmethyl)-4,4’-dimethoxytrityl, 915 phenylxanthen-9-yI (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyIoxytrityl, 4hexadecyloxytrityl, 4,4'-dioctadecyltrityl, 9-(4- octadecyloxyphenyl) xanthen-9-yl, l,l’-bis-(4methoxyphenyl)-r-pyrenylmethyl, 4,4',4-tris- (tert-butylphenyl) methyl (TTTr) and 4,4’-di-3, 5hexadienoxytrityl. Examples of silyl groups include, but are not limited to, trimethylsilyl (TMS), rm-butyldimethylsîlyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsîly!

(TBDPS), tri-ho-propylsilyloxymethyl and [2-(trimethyIsiIyl)ethoxy]methyl. Altematively, R^3aand R^4a and/or R⁴* and R^Sc can be protected by a single achiral or chiral protecting group, for example, by forming an orthoester, a cyclic acetal or a cyclic ketal. Suitable orthoesters include methoxymethylene acetal, ethoxymethylene acetal, 2-oxacyclopentyIidene orthoester, dimethoxymethylene orthoester, 1-methoxyethylidene orthoester, I-ethoxyethylidene orthoester, 25 methylidene orthoester, phthalide orthoester 1,2-dimethoxyethylidene orthoester, and alphamethoxybenzylidene orthoester; suitable cyclic acetals include methylene acetal, ethylidene acetal, t-butylmethylidene acetal, 3-(benzyloxy)propyI acetal, benzylidene acetal, 3,4dimethoxybenzylidene acetal and p-acetoxybenzylidene acetal; and suitable cyclic ketals include l-t-butylethylidene ketal, l-phenylethylidene ketal, isopropylidene ketal, cyclopentylidene ketal, 30 cyclohexylidene ketal, cycloheptylidene ketal and l-(4-methoxyphenyI)ethyIidene ketal. Those skilled in the art will appreciate that groups attached to the pentose ring and any -NH and/or NH₂ groups présent on the B^la, B^Ib and B^lc can be protected with various protecting groups, and any protecting groups présent can be exchanged for other protecting groups. The sélection and exchange of the protecting groups is within the skill of those of ordinary skill in the art. Any protecting group(s) can be removed by methods known in the art, for example, with an acid (e.g., a minerai or an organic acid), a base or a fluoride source.

Pharmaceutical Compositions [0183] Some embodiments described herein relates to a pharmaceutical composition, that can include an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0184] The term “pharmaceutical composition” refers to a mixture of one or more compounds disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitâtes administration of the compound to an organism. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid. Pharmaceutical compositions will generally be tailored to the spécifie intended route of administration.

[0185] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the bioiogicai activity and properties of the compound.

[0186] As used herein, a “carrier refers to a compound that facilitâtes the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitâtes the uptake of many organic compounds into cells or tissues of a subject.

[0187] As used herein, a diluent” refers to an ingrédient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or désirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.

[0188] As used herein, an excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, fabrication, disintegrating ability etc., to the composition. A diluent” is a type of excipient.

[0189] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingrédients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dépendent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0190] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsuiating, entrapping or tableting processes. Additionally, the active ingrédients are contained in an amount effective to achieve its intcnded purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0191] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aérosol, injection and parentéral delivery, including intramuscular, subcutaneous, întravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0192] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound dïrectly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up seleétively by the organ.

[0193] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingrédient. The pack may for example comprise métal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a govemmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions that can include a compound described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Methods of Use:

[0194] Some embodiments described herein relate to a method of ameliorating, treating and/or preventing a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection, which can include .administering to a subject an effective amount of one or more compounds described herein, or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing). In some embodiments, the subject is identified as suffering from the viral infection (for example, a paramyxovirus viral infection or an orthomyxovirus viral infection).

[0195] Other embodiments described herein relate to a method of inhibiting viral réplication of a virus selected from a paramyxovirus and an orthomyxovirus, which can include contacting a cell infected with the virus with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, an effective amount of a compound of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (III), or a pharmaceutically acceptable sait of the foregoing).

[0196] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate a respiratory syncytial viral (RSV) infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent a respiratory syncytial viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the réplication of a respiratory syncytial virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the RSV polymerase complex.

[0197] In other embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate an influenza viral infection. In other embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent an influenza viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the réplication of an influenza virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the influenza polymerase complex.

[0198] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or amelîorate a hendraviral infection and/or nipahviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II). or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (II) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent a hendraviral infection and/or nipahviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the réplication of a hendravirus and/or nipahvirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of

Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to Înhibit the hendravirus polymerase complex and/or nipahvirus polymerase complex.

[0199] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate measles. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (II) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent measles. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (0, a compound of Formula (Π) and/or a compound of Formula (III), or a pharmaceutically acceptable sait of the foregoing) can be used to inhîbit the réplication of a measles virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the measles polymerase complex.

[0200] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that inciudes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate mumps. In some embodiments, an effective amount of one or more compounds of Formula (I), or a 5 pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that inciudes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable 10 sait of the foregoing) can be used to prevent mumps. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that inciudes one or more compounds described 15 herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the réplication of a mumps virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of 20 one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that inciudes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the mumps polymerase complex.

[0201] In some embodiments, an effective amount of one or more compounds of

Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that inciudes one or more compounds described herein (e.g., a 30 compound of Formula (I). a compound of Formula (II) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate a sendai viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π). or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceuticai composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent a sendai viral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceuticai composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (M), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibït the réplication of a sendai virus. In some embodiments, an effective amount of one or more compounds of Formula (I). or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceuticai composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the sendai virus polymerase complex.

[0202] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceuticai composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate a HPIV1 infection and/or HPIV-3 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceuticai composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent a HPIV-1 infection and/or HPIV-3 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of

Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the réplication of HPIV- and/or HPIV-3. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the HPIV-1 polymerase complex and/or HPIV-3 polymerase complex.

[0203] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate a HPIV- infection and/or HPIV-4 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent a HPIV-2 infection and/or HPIV-4 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (W), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the réplication of HPIV17044 and/or ΗΡΓν-4. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the HPIV-2 polymerase complex and/or HPIV-4 polymerase complex.

[0204] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to treat and/or ameliorate a human metapneumovïral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (II) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent a human metapneumovïral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the réplication of a human metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Fbrmula (ΙΠ), or a pharmaceutically acceptable sait thereof. and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to inhibit the human metapneumovirus polymerase complex.

[0205] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that inciudes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate an upper respiratory viral infection caused by a virus selected from a henipavirus, a morbillivïrus, a respirovirus, a rubulavirus, a pneumovirus, a metapneumovirus and influenza virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sali thereof, an effective amount of one or more compounds of Formula (III), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition lhat inciudes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate a lower respiratory viral infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, a metapneumovirus and influenza virus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that inciudes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (Π) and/or a compound of Formula (Œ), or a pharmaceutically acceptable sali of the foregoing) can be used treat and/or ameliorate one or more symptoms of an infection caused by a virus selected from a henipavirus, a morbillivirus, a respirovirus, a rubulavirus, a pneumovirus, a metapneumovirus and influenza virus (such as those described herein).

[0206] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate an upper respiratory viral infection caused by RSV infection, measles, mumps, parainfluenza infection, metapneumovîrus and/or influenza infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate a lower respiratory viral infection caused by RSV infection, measles, mumps, parainfluenza infection, metapneumovîrus and/or influenza infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I) a compound of Formula (II) and/or a compound of Formula (III), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate one or more symptoms of an infection caused by RSV infection, measles, mumps, parainfluenza infection, metapneumovîrus and/or influenza infection (such as those described herein).

[0207] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitîs due to a RSV infection, influenza infection and/or human parainfluenza virus 3 (HPIV-3) infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΓΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate pneumonia due to a RSV infection, influenza infection and/or human parainfluenza virus 3 (HPIV-3) infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate croup due to a RSV infection, influenza infection and/or human parainfluenza virus 1 (HPIV-1) infection.

[0208] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I). a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate a fever, cough, runny nose, red eyes, a generalized ras h, pneumonia, an ear infection and/or bronchitis due to measles. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (III), or a pharmaceutically acceptable sait of the foregoing) can be used treat and/or ameliorate swelling of the salivary glands, fever, loss of appetite and/or fatigue due to mumps.

[0209] In some embodiments, an effective amount of one or more compounds of Formula (I). or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent an influenza viral infection. In some embodiments, the influenza viral infection can be an influenza A viral infection. In other embodiments, the influenza viral infection can be an influenza B viral infection. In still other embodiments, the influenza viral infection can be an influenza C viral infection. In some embodiments, one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, and/or one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, can be used to treat and/or ameliorate one or more subtypes of influenza. For example, one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, and/or one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, can be used to treat Η1ΝΙ and/or H3N2.

[0210] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, an effective amount of one or more compounds of Formula (ΠΙ), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing) can be used to prevent a human parainfluenza viral infection. In some embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 1 (HPIV-1). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 2 (HPIV-2). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 3 (HPIV-3). In other embodiments, the human parainfluenza viral infection can be a human parainfluenza virus 4 (HPIV-4). In some embodiments, one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, and/or one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, can be used to treat and/or ameliorate one or more subtypes of human parainfluenza virus. For example, one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (Π), or a pharmaceutically acceptable sait thereof, and/or one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, can be used to treat HPIV-1 and/or HPIV-3.

[0211] The one or more compounds of Formula (I) or a pharmaceutically acceptable sait thereof, one or more compounds of Formula (II), or a pharmaceutically acceptable sait thereof, and/or one or more compounds of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, that can be used to treat, ameliorate and/or prevent a paramyxovirus and/or or an orthomyxovirus viral infection can be a compound of Formula (0, or pharmaceutically acceptable sait thereof, and/or a compound of Formula (Π), or a pharmaceutically acceptable sait thereof, and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait thereof, 5 provided in any of the embodiments described in paragraphs [0084]-[0170].

[0212] As used herein, the terms “prevent” and “preventing,” mean a subject does not develop an infection because the subject has an immunity against the infection, or if a subject becomes infected, the severity of the disease is less compared to the severity of the disease if the subject has not been administered/receîved the compound. Examples of forms of prévention 10 include prophylactic administration to a subject who has been or may be exposed to an infectious agent, such as a paramyxovirus (e.g., RSV) and/or an orthomyxovirus (e.g., infiuenza).

[0213] As used herein, the terms “treat, “treating, “treatment, “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be 15 considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0214] The terms “therapeutically effective amount and effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the bioiogicai or médicinal response indicated. For example, a therapeutically effective amount of compound 20 can be the amount needed to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Détermination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The therapeutically effective amount of the compounds 25 disclosed herein required as a dose will dépend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the spécifie animal under considération. The dose can be tailored to achieve a desired effect, but will dépend on such factors as weight, diet, concurrent médication and other factors which those skilled in the medical arts will recognize.

[0215] Various indicators for determining the effectiveness of a method for treating a viral infection, such as a paramyxovirus and/or an orthomyxovirus infection, are known to those skilled in the art. Example of suitable indicators include, but are not limited to, a réduction in viral load, a réduction in viral réplication, a réduction in time to séroconversion (virus undetectable in patient sérum), a réduction of morbidity or mortality in clinical outcomes, and/or other indicator of disease response.

[0216] In some embodiments, an effective amount of a compound of Formulae (I), (Π) and/or (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, is an amount that is effective to reduce viral titers to undetectable levels, for example, to about 1000 to about 5000, to about 500 to about 1000, or to about 100 to about 500 genome copies/mL sérum. In some embodiments, an effective amount of a compound of Formulae (I), (Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, is an amount that is effective to reduce viral load compared to the viral load before administration of the compound of Formulae (I) ,(Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing. For example, wherein the viral load is measure before administration of the compound of Formulae (I), (Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, and again after completion of the treatment régime with the compound of Formulae (I), (Π) and/or (ΠΙ), or a pharmaceutically acceptable sait of the foregoing (for example, 1 week after completion). In some embodiments, an effective amount of a compound of Formulae (I), (Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can be an amount that is effective to reduce viral load to lower than about 100 genome copies/mL sérum. In some embodiments, an effective amount of a compound of Formulae (I), (Π) and/or (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, is an amount that is effective to achieve a réduction in viral titer in the sérum of the subject in the range of about 1.5-log to about a 2.5-log réduction, about a 3-log to about a 4-log réduction, or a greater than about 5-log réduction compared to the viral load before administration of the compound of Formulae (I), (Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing. For example, wherein the viral load is measure before administration of the compound of Formulae (I), (II) and/or (III), or a pharmaceutically acceptable sait of the foregoing, and again after completion of the treatment régime with the compound of Formulae (I), (Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing (for example, 1 week after completion).

[0217] In some embodiments, a compound of Formulae (I), (Π) and/or (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, can resuit in at least a 1, 2, 3,4, 5, 10, 15, 20, 25, 50, 75, 100-fold or more réduction in the réplication of a paramyxovirus and/or an orthomyxovirus relative to pre-treatment levels in a subject, as determined after completion of the treatment régime (for example, 1 week after completion). In some embodiments, a compound of Formulae (I), (Π) and/or (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can resuit in a réduction of the réplication of a paramyxovirus and/or an

100 orthomyxovirus relative to pre-treatment levels in the range of about 2 to about 5 fold, about 10 to about 20 fold, about 15 to about 40 fold, or about 50 to about 100 fold. In some embodiments, a compound of Formulae (I). (Π) and/or (LU), or a pharmaceutically acceptable sait of the foregoing, can resuit in a réduction of paramyxovirus réplication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more réduction of paramyxovirus réplication compared to the réduction of paramyxovirus réduction achieved by ribavirin (Virazole®), or may achieve the same réduction as that of ribavirin (Virazole®) therapy in a shorter period of time, for example, in one week, two weeks, one month, two months, or three months, as compared to the réduction achieved after six months of ribavirin (Virazole®) therapy. In some embodiments, a compound of Formulae (D, (Π) and/or (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, can resuit in a réduction of orthomyxovirus réplication in the range of 1 to 1.5 log, 1.5 log to 2 log, 2 log to 2.5 log, 2.5 to 3 log, 3 log to 3.5 log or 3.5 to 4 log more réduction of orthomyxovirus réplication compared to the réduction of orthomyxovirus réduction achieved by oseltamivir (Tamiflu®), or may achieve the same réduction as that of oseltamivir (Tamiflu®) therapy in a shorter period of time, for example, in one week, two weeks, one month, two months, or three months, as compared to the réduction achieved after six months of oseltamivir (Tamiflu®) therapy.

[0218] In some embodiments, an effective amount of a compound of Formula (I). a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, is an amount that is effective to achieve a sustained viral response, for example, non-detectable or substantially non-detectable paramyxovirus and/or orthomyxovirus RNA (e.g., less than about 500, less than about 400, less than about 200, or less than about 100 genome copies per milliliter sérum) is found in the subject’s sérum for a period of at least about one week, two weeks, one month, at least about two months, at least about three months, at least about four months, at least about five months, or at least about six months following cessation of therapy.

[0219] After a period of time, infectious agents can develop résistance to one or more therapeutic agents. The term “résistance as used herein refers to a viral strain displaying a delayed, lessened and/or null response to a therapeutic agent(s). For example, after treatment with an antiviral agent, the viral load of a subject infected with a résistant virus may be reduced to a lesser degree compared to the amount în viral load réduction exhibited by a subject infected with a non-resistant strain. In some embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΓ), or a pharmaceutically acceptable sait of the foregoing, can be administered to a subject infected with RSV that is résistant to one or more

101 different anti-RSV agents (for example, ribavirin). In some embodiments, development of résistant RSV strains can be delayed when subjects are treated with a compound of Formula (I). a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, compared to the development of RSV strains résistant to other RSV drugs. In some embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can be administered to a subject infected with an influenza virus that is résistant to one or more different anti-influenza agents (for example, amantadine and rimantadine). In some embodiments, development of résistant influenza strains can be delayed when subjects are treated with a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, compared to the development of influenza strains résistant to other influenza drugs.

[0220] In some embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can decrease the percentage of subjects that expérience complications from a RSV viral infection compared to the percentage of subjects that expérience complication being treated with ribavirin. In some embodiments, a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can decrease the percentage of subjects that expérience complications from an influenza viral infection compared to the percentage of subjects that expérience complication being treated with oseltamivir. For example, the percentage of subjects being treated with a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, that expérience complications can be 10% , 25%, 40%, 50%, 60%, 70%, 80% and 90% less compared to subjects being treated with ribavirin or oseltamivir.

[0221] In some embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, or a pharmaceutical composition that includes a compound described herein, can be used in combination with one or more additional agent(s). In some embodiments, a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can be used in combination with one or more agents currently used for treating RSV. For example, the additional agent can be ribavirin, palivizumab and RSV-IGIV. For the treatment of RSV, additional agents include but are not limited to ALN-RSV01 (Alnylam Pharmaceuticals), BMS-433771 (l-cyclopropyl-3-I[l-(4hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one), RFI-641 ((4,4-bis-{4,617044

102 bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(l,3,5)triazin-2-ylamino)-biphenyl-2,2disulfomc-acid)), RSV604 ((S)-I’(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-lHbenzo[e][ 1,4]di-azepin-3-yl)-urea), MDT-637 ((4Z)-2-methylsulfanyl-4-[(E)-3-thiophen-2ylprop-2-enylidene]-I,3-thiazol-5-one), BTA9881, TMC-353121 (Tibotec), MBX-300, YM53403 (N-cyclopropyl-6-[4-[(2-phenylbenzoyl)amino]benzoyl]-4,5-dihydrothieno[3,2d][I]benzazepine-2-carboxamide), motavizumab (Medi-524, Medlmmune), Medî-559, Medi534, Medi-557, RV568 and a RSV-F Particle Vaccine (Novavax). In some embodiments, a compound of Formula (I). a compound of Formula (II) and/or a compound of Formula (ΙΠ). or a pharmaceutically acceptable sait of the foregoing, can be used in combination with one or more agents currently used for treating influenza. For example, the additional agent can be amantadine, rimantadine, zanamivir and oseltamivir. For the treatment of influenza, additional agents include but are not limited to peramivir ((lS,2S,3S,4R)-3-[(lS)-l-acetamido-2ethylbutyl]-4-(diaminomethylideneamino)-2-hydroxycyclopentane-l-carboxylic acid), laninamivir ((4S,5R,6R)-5-acetamido-4-carbamimidamido-6-[(lR,2R)-3-hydroxy-2methoxypropyl]-5,6-dihydro-4H-pyran-2-carboxylic acid), favipiravir (T-705, 6-fluoro-3hydroxy-2-pyrazinecarboxamide), fludase (DAS181, NexBio), ADS-8902 (Adamas Pharmaceuticals), IFN-b (Synairgen), beraprost (4-[2-hydroxy-l-[(E)-3-hydroxy-4-methyloct-len-6-ynyl]-2,3,3a,8b-tetrahydro-lH-cyclopenta[b][ l}benzofuran-5-yl]butanoic acid), Neugene® and VGX-3400X (Inovio).

[0222] In some embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (HT), or a pharmaceutically acceptable sait of the foregoing, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can be administered in one pharmaceutical composition, and at least one of the additional agents can be administered in a second pharmaceutical composition. If there are at least two additional agents, one or more of the additional agents can be in a fîrst pharmaceutical composition that includes a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (ΠΓ), or a pharmaceutically acceptable sait of the foregoing, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.

103 [0223] The order of administration of a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, with one or more additional agent(s) can vary. In some embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a 5 pharmaceutically acceptable sait of the foregoing, can be administered prior to ail additional agents. In other embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a 10 pharmaceutically acceptable sait of the foregoing, can be administered concomîtantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait of the foregoing, can be administered subséquent to the administration of at least one additional agent. In some embodiments, a compound of Formula (I), a compound of Formula 15 (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, can be administered subséquent to the administration of ail additional agents.

[0224] A potential advantage of utilizïng a compound of Formula (I), a compound of Formula (II) and/or a compound of Formula (III), or a pharmaceutically acceptable sait of the foregoing, in combination with one or more additional agent(s) described in paragraph [0221], 20 Including pharmaceutically acceptable salts and prodrugs thereof, may be a réduction in the required amount(s) of one or more compounds of paragraph [0221] (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example, RSV and/or influenza), as compared to the amount required to achieve same therapeutîc resuit when one or more compounds described in paragraph [0221], including 25 pharmaceutically acceptable salts and prodrugs thereof, are administered without a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΠΙ), or a pharmaceutically acceptable sait the foregoing. For example, the amount of a compound described in paragraph [0221], including a pharmaceutically acceptable sait and prodrug thereof, can be less compared to the amount of the compound described in paragraph [0221], including a 30 pharmaceutically acceptable sait and prodrug thereof, needed to achieve the same viral load réduction when administered as a monotherapy. Another potential advantage of utilizing a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait of the foregoing, in combination with one or more additional agent(s) described in paragraph [0221], including pharmaceutically acceptable salts and prodrugs

104 thereof, is that the use of two or more compounds having different mechanism of actions can create a higher barrier to the development of résistant viral strains compared to the barrîer when a compound is administered as monotherapy.

[0225] Additional advantages of utilizing a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait the foregoing, in combination with one or more additional agent(s) described in paragraph [0221], including pharmaceutically acceptable salts and prodrugs thereof, may include little to no cross résistance between a compound of Formula (I). a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait the foregoing, and one or more additional agent(s) described in paragraph [0221] (including pharmaceutically acceptable salts and prodrugs thereof); different routes for élimination of a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait the foregoing, and one or more additional agent(s) described in paragraph [0221] (including pharmaceutically acceptable salts and prodrugs thereof); little to no overlapping toxicities between a compound of Formula (I), a compound of Formula (Π) and/or a compound of Formula (ΙΠ), or a pharmaceutically acceptable sait the foregoing, and one or more additional agent(s) described in paragraph [0221] (including pharmaceutically acceptable salts and prodrugs thereof); little to no significant effects on cytochrome P450; and/or little to no pharmacokinetic interactions between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) described in paragraph [0221] (including pharmaceutically acceptable salts and prodrugs thereof).

[0226] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vaiy depending upon the âge, weight, the severity of the affliction, and mammalian species treated, the particular compounds employed, and the spécifie use for which these compounds are employed. The détermination of effective dosage levels, that is the dosage levels necessary to achieve the desired resuit, can be accomplished by one skilled in the art using routine methods, for example, human clinical trials and in vitro studies.

[0227] The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Altematively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art. Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.01 mg and 3000 mg of each active ingrédient, preferably between 1 mg and

105

700 mg, e.g. 5 to 200 mg. The dosage may be a single one or a sériés of two or more given in the course of one or more days, as is needed by the subject. In some embodiments, the compounds will be administered for a period of contînuous therapy, for example for a week or more, or for months or years.

[0228] In instances where human dosages for compounds hâve been established for at least some condition, those same dosages may be used, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from EDjo or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxîcîty studies and efficacy studies in animais.

[0229] In cases of administration of a pharmaceutically acceptable sait, dosages may be calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to admînister the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly aggressive diseases or infections.

[0230] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will dépend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to détermine plasma concentrations. Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or sélective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0231] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxîcîty or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adéquate (precluding toxîcîty). The magnitude of an administrated dose în the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic évaluation methods. Further, the dose and perhaps

106 dose frequency, will also vary according to the âge, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinaiy medicine.

[0232] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often prédictive of toxicity in animais, such as mammals, or more specifically, humans. Altematively, the toxicity of particular compounds in an animal mode!, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to détermine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or régime.

EXAMPLES [0233] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the daims.

EXAMPLE 1 Préparation of Compound (la)

MMTrO

NHMMTr

MMTrÔ F

MMTrO HO-'”' MMTrd

P1-4

MMTrO

P1-3

[0234] Préparation of (Pl-2): To an ice cooled solution of Pl-1 (10.0 g, 40.8 mmol) in dry pyridine (100 mL) was added TBSC1 in pyridine (IM, 53 mL) dropwise at room température (R.T.). The reaction mixture was stirred at R.T. for 16 hours. The reaction mixture was then quenched with water, concentrated to give a residue. The residue was separated by

107 ethyl acetate (EA) and saturated NaHCO₃ aq. solution. The organic phase was dried and concentrated. The residue was purified on a silica gel column (5% MeOH in DCM) to give a crude 5’-O-TBS protected intermediate as a white solid (13.4 g, 91%). The intermediate was dissolved in anhydrous DCM (100 mL) and sym-collidine (17.9 g, 149.2 mmol), AgNO₃ (25 g,

149.2 mmol) and MMTrCl (45 g, 149.2 mmol) were added. The mixture was stirred at R.T. for 16 hours. The mixture was quenched with water, and the organic layer was separated and concentrated. The residue purified on a silica gel column (30% PE in EA) to give the crude product. The crude product was dissolved in IM TBAF (50 mL) in THF. The mixture was stirred at R.T. for 2 hours. The solvent was removed, and the residue was purified on a silica gel column (50% PE in EA) to give Pl-2 as a white solid (21.4 g, 66% for three steps).

[0235] Préparation of (Pl-3): To a solution of pyridine (521 mg, 6.59 mmol) in anhydrous DMSO (5 mL) was added TFA (636 mg, 5.58 mmol) dropwise at 10°C under nitrogen. The reaction mixture was stirred until the solution became clear. The solution was then added into a mixture of Pl-2 (4.0 g, 5.07 mmol) and DCC (3.86 g, 18.76 mmol) in anhydrous DMSO (18 mL) at R.T. under nitrogen. The reaction mixture was stirred at 30°C ovemight. Water (80 mL) was added into the mixture, diluted with EtOAc (100 mL) and filtered. The filtrate was extracted with DCM (100 mL x 6). The organic layer was washed with saturated aq. NaHCO₃, dried over NajSOj and concentrated in vacuo. The residue was purified on a silica gel column eluted with 1% MeOH in DCM to give the intermediate (3.5 g, 87.7%) as a yellow solid. The intermediate (3.5 g, 4.45 mmol) was dissolved in dioxane (25 mL) and aq. HCHO (668 mg, 22.25 mmol) was added at R.T. 2N NaOH (4.5 mL, 8.9 mmol) was then added. The reaction mixture was stirred at 30°C ovemight. NaBH4 (593 mg, 15.6 mmol) was added in by portions at 5°C, and the mixture was stirred at R.T. for 15 min. The reaction was quenched with water, and the mixture was extracted with EtOAc (100 mL x 3). The organic layer was dried over Na₂SÜ4 and concentrated in vacuo. The residue was purified on a silica gel column eluted with 1% MeOH in DCM to give Pl-3 as a yellow solid (2.5 g, 67%). ^lH NMR (CDCI₃, 400 MHz) δ6.82-7.50 (m, 29H), 5.40 (d, J = 23.2 Hz, 1H), 4.99 (d, J - 7.6 Hz, 1H),

4.46 (dd, J_t = 6.0 Hz, J₂ = 54.4 Hz, 1H), 3.94 (dd, J_{ - 4.4 Hz, J₂ = 12.4 Hz, 1H), 3.78 (s, 6H), 3.42-3.69 (m, 2H), 2.71-3.05 (m, 2H), 2.45 (m, 1H).

[0236] Préparation of (PI-4): To an ice cooled solution of Pl-3 (4.0 g, 4.9 mmol) in dry pyridine (20 mL) was added dropwise TBSC1 in pyridine (IM, 5.88 mL). The reaction mixture was stirred at R.T. for 16 hours. The reaction mixture was then quenched with water, concentrated to give a residue. The residue was separated in EA and saturated aq. NaHCO₃. The organic layer was separated and dried, and then concentrated. The residue was purified on a

108 silica gel column (1% MeOH in DCM) to give the întermediate as a yellow solid (3.2 g, 70%). ’H NMR (CDCI3, 400 MHz) <J7.53-6.83 (m, 29H), 5.51 (d, J = 21.2 Hz, JH), 4.98 (d, J = 7.6 Hz, 1H), 4.67 (dd, J, = 5.6 Hz, J₂ = 22.4 Hz, 1H), 4.22 (dd, J_t » 5.6 Hz, J₂ = 53.2 Hz, 1H), 4.07 (m, 1H), 3.89 (m, 1H), 3.80 (s, 6H), 3.70-3.67 (m, IH), 3.03-2.98 (m, 1H), 2.26 (m, JH), 0.93 (s, 9H), 0.l0(s, 6H).

[0237] The obtained întermediate was dissolved in anhydrous DCM (20 mL) and collidine (360 mg, 3 mmol), and AgNO₃ (500 mg, 3 mmol) and MMTrCI (606 mg, 2 mmol) were added. The mixture was stirred at R.T. for 16 hours. The reaction mixture was quenched with water, and the organic layer was separated and concentrated. The residue was purified on a silica get column (0.5% MeOH in DCM) to give the futly protected întermediate as a yellow solid (3.3 g, 80%). The întermediate was dissolved in IM TBAF in THF (5 mL) and was stirred at R.T. for 2 hours. The solution was concentrated, and the residue was purified on a silica gel column (1% MeOH in DCM) to give a mixture of Pl-3 and Pl-4, which was separated by HPLC séparation (MeCN and 0.1 % HCOOH in water) to give Pl-4 as a white solid (1.5 g, 25%).

[0238] Préparation of (Pl-5): Pl-4 f 1.5 g, 1.22 mmol) was suspended in anhydrous DCM (50 mL), and Dess Martin periodinane (1.2 g, 2.73 mmol) was added at 0°C. The reaction mixture was stirred at R.T. for 3 hours. The reaction mixture was then quenched with saturated aq. NajSîOj and Na^COj. The organic layer was separated and dried, and then concentrated to give the aldéhyde întermediate as a white solid.

[0239] A solution of CICHîPPhjBr (2.19 g, 5.6 mmol) in anhydrous THF (40 mL) was cooled to -78°C. n-BuLi (2.5 M, 2.3 mL) was added in dropwise. After the addition, the mixture was stirred at 0°C for 2 hours. A solution of the aldéhyde in anhydrous THF (10 mL) was then added. The mixture was stirred at R.T. for 16 hours. The reaction was quenched with saturated NH4CI aq. and extracted by EA. The organic layer was separated, dried and concentrated. The residue was purified on a silica gel column (1% MeOH in DCM) to give the întermediate as a yellow solid (1.1 g, 73%). To a solution of the întermediate (1.1 g, 0.98 mmol) tn anhydrous THF (40 mL) was added n-BuLi (2.5M, 6 mL) -78°C dropwise. The mixture was stirred at -78°C for 5 hours and then quenched with a saturated NH4CI aq. solution. The mixture was extracted with EA. The organic layer was separated, dried and concentrated. The residue was purified on a silica gel column (2% MeOH in DCM) to give Pl-5 as a yellow solid (910 mg, 86%).

[0240] Préparation of (la): Pl-5 (910 mg, 0.84 mmol) was suspended in 80% CHjCOOH (50 mL), and the reaction mixture was stirred at 40°C for 15 hours. The solvents were evaporated, and the residue was co-evaporated with toluene to remove traces of acid and

109 water. The residue was purified by HPLC séparation (MeCN and 0.1% HCOOH in water) to give pure compound la as a white solid (101 mg, 45%). H NMR (MeOD, 400 MHz) S7.9Q (d, J = 7.2 Hz, IH), 6.04 (d, J = 19.6 Hz, IH), 5.87 (d, J = 7.6 Hz, IH), 5.00 (dd, J_t = 5.2 Hz, J₂ =

53.6 Hz, IH), 4.47 (dd, J/ = 5.2 Hz, J₂ = 22.8 Hz, IH), 3.86 (d, J = 12.4 Hz, IH), 3.73 (d, J =

12.4 Hz, IH), 3.08 (s, IH); ESI-TOF-MS: m/z 270.09 [M + H]*, 539.17 [2M + H]⁺.

EXAMPLE 2

Préparation of Compound (2a)

1a 2a [0241] To a stirred solution of compound la (50 mg, 0.186 mmol) in anhydrous THF (3 mL) was added dropwise a solution of r-BuMgCl (0.37 mL, IM in THF) at -78°C. The mixture was then stirred at 0°C for 30 min and re-cooled to -78°C. A solution of phenyl (isopropoxy-L-alaninyl) phosphorochloridate (104 mg, 0.4 mmol) in THF (0.5 mL) was added dropwise. After addition, the mixture was stirred at 25°C for 16 hours. The reaction was quenched with HCOOH (80% aq.) at 0°C. The solvent was removed, and the residue was purified on silica gel (DCM:MeOH = 50:1 to 10:1) to give compound 2a as a white solid (a mixture of two P isomers, 8.0 mg, 7.9 %). 'H NMR (MeOD, 400 MHz) £7.71,7.68 (2d, J = 7.6 Hz, IH), 7.17-7.37 (m, 5H), 6.02, 6.00 (2d, J = 20.4 Hz, IH), 5.90, 5.86 (2d, J = 7.6 Hz, IH), 5.03-5.18 (m, IH), 4.91-4.99 (m, IH), 4.45-4.55 (m, IH), 4.34-4.43 (m, IH), 4.26-4.33 (m, IH), 3.87-3.95 (m, IH), 3.25, 3.22 (2s, IH), 1.29-1.34 (m, 3H), 1.20-1.22 (m, 6H). ^3,P NMR (MeOD, 162 MHz) £3.44,3.27. ESl-LCMS: m/z 539.0 [M + H]⁺.

110

EXAMPLE3

Préparation of Compound (3a)

HÔ 'F

P3-1

HO—

TBSÔ' 'F

TBSÔ 'F

P3-2

P3-3

TBDPSO->Y^Oy^N~%

TBDPSO-XzOx/^N~^_o

Ρ3-6

TBSÔ 'F

P3-4

TBSÔ F

P3-7

TBDPSO-X^Oy

TBSÔ 'F

P3-5

P3-8

3a [0242] Préparation of (P3-2): To a solution of P3-1 (100.0 g, 406.5 mmol) in pyridine (750 mL) was added DMTrCI (164.9 g, 487.8 mmol). The solution was stirred at R.T. for 15 hours. MeOH (300 mL) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over NaiSOj and concentrated. The residue was dissolved in DCM (500 mL). Imidazole (44.3 g, 650.4 mmol) and TBSC1 (91.9 g, 609.8 mmol) was added. The reaction mixture was stirred at R.T. for 14 hours. The reaction solution was washed with NaHCÜ3 and brine. The organic layer was dried over Na^SOj, and concentrated to give the crude as a light yeliow solid. The crude (236.4 g, 356.6 mmol) was dissolved in 80% HOAc aq. solution (500mL). The mixture was stirred at R.T. for 15 hours. The mixture was diluted with EtOAc and washed with a NaHCÛ3 solution and brine. The organic layer was dried over Na^SOj and purified by silica gel column chromatography (1-2% MeOH in DCM) to give P3-2 (131.2 g, 89.6%) as a light yeliow solid.¹ H NMR (DMSO-J6. 400 MHz) J11.39 (s, 1H), 7.88 (d, J = 7.2 Hz, 1 H), 5.89 (dd, - 18.0 Hz, J₂ = 2.0 Hz, 1 H), 5.64 (d, J = 8.0 Hz, 1 H), 5.21 (dd, J,=J₂- 7.2 Hz.iH), 5.18-5.03 (m, 1H), 4.37-4.29 (m, 1H), 3.86 (dd, J/ = J₂ = 3.2 Hz, 3H), 3.78-3.73 (m, 1 H), 3.51-3.56 (m, 1H), 3.31 (s, lH),0.89(s, 9H),0.11 (s, 6H); ESI-MS: m/z 802 [M + Hf.

[0243] Préparation of (P3-3): To a solution of P3-2 (131.2 g, 364.0 mmol) in anhydrous CH3CN (1200 mL) was added IBX (121.2 g, 432.8 mmol) at R.T. The reaction

111 mixture was refluxed for 3 hours and then cooled to 0°C. The precipitate was filtered-off, and the filtrate was concentrated to give the crude aldéhyde (121.3 g) as a yellow solid. The aldéhyde was dissolved in 1,4-dioxane (1000 mL). 37% CHjO (81.1 mL, 1.3536 mol) and 2M NaOH aq. solution (253.8 mL, 507.6 mmol) were added. The mixture was stirred at R.T. for 2 hours and then neutralized with AcOH to pH » 7. To the solution were added EtOH (400 mL) and NaBHj (51.2 g, 1.354 mol). The mixture was stirred at R.T. for 30 minutes. The mixture was quenched with saturated aq. NH4CI and extracted with EA. The organic layer was dried over NaîSCL and concentrated. The residue was purified by silica gel column chromatography (1-3% MeOH in DCM) to give P3-3 (51.4 g, 38.9 %) as a white solid.

[0244] Préparation of (P3-4): To a solution of P3-3 (51.4 g, 131.6 mmol) in anhydrous DCM (400 mL) were added pyridine (80 mL) and DMTrCl (49.1 g, 144.7 mmol) at 0°C. The réaction was stirred at R.T. for 14 hours, and then treated with MeOH (30 mL). The solvent was removed, and the residue was purified by silica gel column chromatography (1-3% MeOH in DCM) to give a mono-DMTr protected intermediate as a yellow foam (57.4 g, 62.9%). To the intermediate (57.4 g, 82.8 mmol) in CH2CI2 (400 mL) was added imidazole (8.4 g, 124.2 mmol) and TBDPSC1 (34.1 g, 124.2 mmol). The mixture was stirred at R.T. for 14 hours. The precipitate was filtered off, and the filtrate was washed with brine and dried over Na2SÜ4. The solvent was removed to give the residue (72.45 g) as a white solid. The solid was dissolved in 80% HOAc aq. solution (400 mL). The mixture was stirred at R.T. for 15 hours. The mixture was diluted with EtOAc and washed with NaHCOj solution and brine. The organic layer was dried over Na2SO4 and purified by silica gel column chromatography (1-2% MeOH în DCM) to give P3-4 (37.6 g, 84.2%) as a white solid. *H NMR (CD3OD, 400 MHz) δ7.76 (d, J = 4.0 Hz, IH), 7.70 (dd, J_t = 1.6 Hz, J₂ = 8.0 Hz, 2H), 7.66-7.64 (m, 2H), 7.48-7.37 (m, 6H), 6.12 (dd, J_t= 2.8 Hz, J₂= 16.8 Hz, IH), 5.22 (d, J = 8.0 Hz, 1H).5.2O~5.O5 (m, IH), 4.74 (dd, J/= 5.6 Hz, J₂= 17.6 Hz, IH), 4.16 (d, J = 12.0 Hz, IH), 3.87-3.80 (m, 2H), 3.56 (d, J = 12.0 Hz, IH), 1.16 (s, 9H), 0.92 (s, 9H), 0.14 (s, 6H).

[0245] Préparation of (P3-5): To a solution of P3-4 (11.8 g, 18.8 mmol) in anhydrous DCM (100 mL) was added Dess-Martin periodinane (16.3 g, 37.6 mmol) at 0°C under nitrogen. The reaction was stirred R.T. for 2.5 hours. Water (100 mL) was added, and the mixture was then filtered. The filtrate was washed with saturated aq. NaHCOj and concentrated. The crude residue was purified by silica gel column chromatography (20% EtOAc in hexane) to give P3-5 as a white solid (10.1 g, 86.0%).

[0246] Préparation of (P3-6): To a mixture of methyltriphenylphosphonium bromide (15.7 g, 48.5 mmol) in anhydrous THF (100 mL) was added n-BuLi (19.4 mL, 48.48

112 mmol) at -78°C under nitrogen. The reaction was stîrred at 0°C for 30 minutes. A solution of

P3-5 (10.1 g, 16.2 mmol) in anhydrous THF (70 mL) was added dropwise at 0 C under nitrogen. The reaction was stirred at R.T. for 1.5 hours. The reaction was quenched by NH4CI and extracted with EtOAc. The crude product was purified by silica gel column chromatography (20% EtOAc in hexane) to give P3-6 as a white solid (8.3 g, 82.2%)?H NMR (CDCI3, 400 MHz) £8.16 (s, IH), 8.81 (d, J =8.0 Hz, 1 H), 7.58-7.67 (m,4H), 7.37-7.46 (m, 6H), 6.17 (d, J = 16.0 Hz, IH), 5.91 (dd, J, = 10.8 Hz, J₂ = 17.6 Hz, IH), 5.42 (d, J = 17.6 Hz, IH), 5.22-5.30 (m, 2H), 4.60-4.84 (m, 2H), 3.69 (dd, J_t = 11.6 Hz, J₂ = 21.2 Hz, 2H), 1.10 (s, 9H), 0.91 (s, IH), 0.12 (d, J =8.0 Hz, 6H).

[0247] Préparation of (P3-7): To a solution of P3-6 (6.3 g, 10.09 mmol) in anhydrous CH3CN (50 mL) were added TPSC1 (6.1 g, 20.2 mmol), DMAP (2.5 g, 20.2 mmol) and NEts (3 mL) at R.T. The reaction was stirred at R.T. for 2 hours. NH4OH (25 mL) was added, and the reaction was stirred for 1 hour. The mixture was diluted with DCM (150 mL) and washed with water, 0.1 M HCl and saturated aq. NaHCOa. The solvent was removed, and the crude product was purified by silica gel column chromatography (2% MeOH in DCM) to give P3-7 as a yellow solid (5.9 g, 93.6%).

[0248] Préparation of (P3-8); To a solution of P3-7 (5.9 g, 9.5 mmol) in MeOH (10 mL) was added Pd/C (1.5 g) at R.T. The reaction was stirred at R.T. for 2 hours under H₂(balloon). The mixture was filtered, and the filtrate was concentrated in vacuo to give P3-8 as a white solid (5.4 g, 91.3%).

[0249] Préparation of (3a): To a solution of P3-8 (5.4 g, 8.6 mmol) in MeOH (60 mL) was added NH4F (10.0 g), and the reaction mixture was refiuxed ovemight. After cooling to R.T., the mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (10% MeOH in DCM) to give compound 3a as a white solid (1.6 g, 67.8%). 'H NMR (CD3OD, 400 M Hz) £8.08 (d, J = 7.6 Hz, IH), 6.07 (dd, J_t= 3.2 Hz, J₂ = 15.6 Hz, IH), 5.88 (d, J = 7.2 Hz, IH), 5.04 (ddd, J_t = 3.2 Hz, J₂ = 5.2 Hz, J₃ = 54.0 Hz, IH), 4.45 (dd, J_t - 5.2 Hz, J₂ =17.2 Hz, IH), 3.76 (d, J = 12.0 Hz, IH), 3.57 (d, J = 12.0 Hz, IH), 1.78-1.85 (m, IH), 1.58-1.67 (m, IH), 0.95 (t, J= 7.6 Hz, 3H); ESI-MS: m/z 274 [M + H]⁺, 547 [2M + H]⁺.

113

EXAMPLE 4

Préparation of Compound (4a)

TBDPSO

TBSC5'

P3-7

[0250] To a solution of P3-7 (280 mg, 0.45 mmol) in MeOH (10 mL) was added NH4F (1.0 g) at R.T. The reaction mixture was refluxed for 5 hours. After coolîng to R.T., the mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (10% MeOH in DCM) to give compound 4a as a white solid (82 mg, 67.2%L6 g, 67.8%). ^lH NMR (CDjOD, 400 M Hz) <78.11 (d, J= 7.6 Hz, IH), 5.99-6.08 (m, 2H), 5.88 (d, J= 7.6 Hz, IH), 5.47 (dd, Λ « 1.2 Hz, J₂ = 17.2 Hz, IH), 5.26 (dd, Λ - 1.6 Hz, Λ =11.2 Hz, IH), 4.97 (d, J = 5.2 Hz, 0.5H),4.82 (d, J = 7.6 Hz, 0.5H), 4.52 (dd, J_t - 5.2 Hz, J₂= 23.2 Hz, IH), 3.65 (d, J- 12.4 Hz, 1H),3.54 (d, J = 12.4 Hz, IH); ESI-MS: m/z 272 [M + H]⁺, 543 [2M + H]⁺.

EXAMPLE 5

Préparation of Compound (5a)

TBDPSO

[0251] Préparation of (P5-1): To a solution of P3-6 (600 mg, 0.96 mmol) in MeOH (30 mL) was added 10% Pd/C (320 mg) at R.T. The mixture was stirred under H₂ balloon at R.T. for 3 hours. The reaction mixture was filtered, and the filtrate was concentrated to give P51 (540 mg, 89.8 %) as a colorless solid. The crude product was used directly for the next step without purification.

[0252] Préparation of (5a): To a solution of P5-1 (540 mg, 0.86 mmol) in MeOH (8 mL) was added NH4F (1.2 g, 32.4 mmol) R.T. The mixture was refluxed for 30 hours. The solid was removed by filtration, and the filtrate was concentrated. The residue was purification by silica gel column chromatography (2.5%-9%MeOH in DCM) to give compound 5a (190 mg, 80.6%) as a colorless solid. ‘H NMR (CDjOD, 400 MHz) δ 8.05 (d, J = 8.0 Hz, IH), 6.09 (dd,

114 =4.0 Hz, J₂ =14.8 Hz, 1H), 5.04-5.20 (m ,1H), 4.42 (dd, J, = 5.2 Hz, J₂ = 13.6 Hz, 1H), 3.71 (d,

J = 11.6 Hz, 1H), 3.57(d, J = 12.0 Hz, 1H), 1.61-1.82 (m,2H), 0.94 (t,J=7.2Hz, 3H).

	EXAMPLE 6 Préparation of Compound (6a)
^Η0'\°υ^νΛ HO— \_J TBSÔ 'F P3-3	rC» TBSO-\z°V^N_^ —- tbso—'y_/ ⁰---- TBSÔ' *F P6-1	NH. H/ HÔ “F 6a

[0253] Préparation of (P6-1): To a solution of P3-3 (800 mg, 2.05 mmol) in anhydrous DCM (15 mL) were added imidazole (558 mg, 8.2 mmol), TBSC1 (1.2 g, 8.2 mmol) and AgNOj (700 mg, 4.1 mmol) at R.T. The reaction mixture was stirred at R.T. ovemight. The mixture was filtered, and the filtrate was washed with brine and concentrated in vacuo. The residue was purified by column chromatography on silica gel to give P6-1 as a white solid (950 mg, 79.2%).

[0254] Préparation of (6a): To a solution of P6-1 (600 mg, 0.97 mmol) in anhydrous CHjCN (18 mL) was added DMAP (239 mg, 2.91 mmol), NEtj (294 mg, 2.91 mmol) and TPSC1 (879 mg, 2.91 mmol) at R.T. The reaction was stirred at R.T. for 1 hour. NH4OH (9 mL) was added, and the réaction was stirred for 3 hours. The mixture was diluted with EtOAc (200 mL) and washed with water, 0.1 M HCl and saturated aq. NaHCOj. The organic layer was separated, dried and concentrated to give a crude residue. The crude residue was purified by column chromatography on silica gel to give the product as a white solid (500 mg, 83.3%). The solid was treated with NH4F (1.0 g) in MeOH (20 mL) at refluxed température for 5 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (15% MeOH in DCM) to give compound 6a as a white solid (132 mg, 59.3%).’H NMR (DMSO-</6, 400 MHz) J7.89 (d, J = 7.6 Hz, 1H), 7.22 (d, J -

18.8 Hz, 2H), 6.09 (dd, J, = 4.4 Hz, J₂ = 14.8 Hz, 1H), 5.73 (d, J = 5.2 Hz, 1H), 5.52 (d, J = 5.6 Hz, 1H), 5.12 (t, J =4.8 Hz, 1 H), 4.90-5.06 (m, 1H), 4.50 (t, J =6.0 Hz, 1 H), 4.27-4.33 (m, 1H), 3.66 (dd, J_t = 5.2 Hz, J₂ = 12.0 Hz, 1H), 3.47-3.58 (m, 3H); ESI-MS: m/z 276 [M + H]⁺, 551 [2M + H]⁺.

115

EXAMPLE 7

Préparation of Compound (7a)

P34

TBDPSO

nh₄f [0255] Préparation of (P7-1): A mixture of P3-4 (1.60 g, 2.5 mmol), PPhj (1.3 g, 5 5.0 mmol) and CC1₄ (0.76g, 5.0 mmol) in DCE (20 mL) was heated to 130°C under microwave irradiation under N₂ for 40 mins. After cooled to R.T., the solvent was removed, and the residue was purified on a silica gel column (PE/EA = 50/1 to 10/1) to give P7-1 (1.1 g, 68.8%) as a white solid.

[0256] Préparation of (P7-2): P7-1 (0.80 g, 1.3 mmol), DMAP (0.3 g, 2.6 mmol), 10 TPSC1 (0.8 g, 2.6 mmol) and EtjN (0.3 g, 2.6 mmol) were dissolved in MeCN (30 mL). The mixture was stirred at R.T. for 14 hours. NHj in THF (saturated at 0°C, 100 mL) was added to the mixture, and the mixture was stirred at R.T. for 2 hours. The solvent was removed, and the residue was purified by column (DCM/MeOH = 100:1 to 50:1) to give P7-2 (0.63 g, 78.8%) as a white solid.

[0257] Préparation of (7a): To a solution of P7-2 (0.63 g, 0.98 mmol) in MeOH (10 mL) was added NH₄F (0.3 g), and the reaction was refluxed for 12 hours. The reaction was cooled to R.T., and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (10% MeOH in DCM) to give compound 7a as a white solid (153 mg, 53.5%). ^lH NMR (CDjOD, 400 M Hz) J 8.05 (d, J= 7.2 20 Hz, IH), 6.14 (dd, J_t = 3.6 Hz, J₂ =15.2 Hz, IH), 5.92 (d, J= 7.2 Hz, IH), 5.15 (ddd, J_t = 4.0

Hz, J₂ = 5.2 Hz, Jj = 53.6 Hz, IH), 4.57 (dd, J_t = 4.8 Hz, J₂ = 15.2 Hz, IH), 3.93 (d, J = 11.6 Hz, IH), 3.75-3.84 (m, 3H); ESI-MS: m/z 294 [M + Hf, 587 [2M + H]⁺.

116

EXAMPLE 8 Préparation of Compound (8a)

TBDPSO

[0258] To a solution of P7-1 (630 mg, 0.5 mmol) in MeOH (10 mL) was added NH4F (0.1 g), and the reaction was refluxed for 12 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (10% MeOH in DCM) to give compound 8a as a white solid (153 mg, 53.5%). 'H NMR (CDjOD, 400 M Hz) £7.99 (d, J = 8.0 Hz, IH), 6.17 (dd, J_t = 4.4 Hz, J₂ =14.4 Hz, IH), 5.70 (d, J = 8.0 Hz, IH), 5.22 (ddd, Ji = J₂ = 4.8 Hz, J₃ = 53.2 Hz, IH), 4.55 (dd, J_t = 5.2 Hz, J₂ - 12.4 Hz, IH), 3.88 (d, 7« 12.0 Hz, IH), 3.76-3.79 (m, 3H); Negative-ESI-MS: m/z 293 [M - H]\ .

EXAMPLE 9 Préparation of Compound (9a)

TBDPS

TBDPSO

Λ’

TBDPSO HO—'

TBDPSO [0259] Préparation of (P9-1): A mixture of P3-4 (3.2 g, 5.0 mmol), PhaP (5.2 g, 20 mmol), iodine (2.60 g, 10.2 mmol) and imidazole (1.4 g, 20mmol) in anhydrous THF (40 mL) was stirred at 80°C for 14 hours. The reaction was cooled to R.T. and quenched with saturated aq. NaiSiOj. The solution was extracted with EA. The organic layer was dried over NajSO.» and concentrated. The residue was purified by silica gel column chromatography (20-50% EA in PE) to give P9-1 (1.6 g, 68.2%) as a white solid.

117 [0260] Préparation of (P9-2): A mixture of P9-1 (1.4 g, 0.2 mmol), EtjN (40 mg,

0.4mmol) and Pd/C in EtOH (20 mL) was stirred at R.T. under H₂ (balloon) ovemight. The precipitate was filtered off, and the filtrate was concentrated. The residue was purifîed on a silica gel column (20%-50% EtOAc in PE) to give P9-2 as a white solid (1.1 g, 78%). ’H NMR (CDCb, 400 MHz) <78.11 (brs, IH), 7.76 (d, J = 8.0 Hz, IH), 7.39-7.67 (m, 10H), 6.18 (dd, Λ =

3.2 Hz, = 14.4 Hz, IH), 5.26-5.30 (m, IH), 4.86 (m, IH), 4.42 (dd, J, = 5.2 Hz, J₂ = 15.2 Hz, IH), 3.81 (d,J = 11.2 Hz, 1H),3.58 (d, J= 11.2 Hz, IH), 1.16 (s, 3H), 1.11 (s,9H),0.91 (s,9H), 0.13 (s, 3H), 0.08 (s,3H).

[0261] Préparation of (P9-3): P9-2 (650 mg, 1.1 mmol), DMAP (270 mg, 2.2 mmol), TPSC1 (664 mg, 2.2 mol) and EtjN (222 mg, 2.2 mmol) were dissolved in MeCN (20 mL). The mixture was stirred at R.T. for 14 hours. The reaction was added NHj in THF (saturated at 0°C), and the mixture was stirred at R.T. for 2 hours. The solvent was removed, and the residue was purifîed on a silica gel column (1-10% MeOH in DCM) to give P9-3 (430 mg, crude) as a light yellow syrup.

[0262] Préparation of (9a): A mixture of P9-3 (430 mg, 0.7 mmol) and NH4F (97 mg, 2.1mmol) in MeOH (10 mL) was refluxed for 14 hours. The solvent was removed, and the residue was purifîed on a silica gel column (5%-10% MeOH in DCM) to give compound 9a as a white solid (64.8 mg, 35.4%). ^lH NMR (CDjOD, 400 MHz) <78.10 (d, J= 7.6 Hz, IH), 6.03 (dd, J_t =2.0 Hz, J2 = 16.8 Hz, IH), 5.87 (d, J = 7.6 Hz, IH), 4.98 (m, IH),4.37 (dd, J/ = 5.2 Hz, J₂ =

21.6 Hz, IH), 3.59 (dd, J, = 12.0 Hz, J₂ = 28.4 Hz, 2H), 1.23 (d, J = 0.8 Hz,3H).

EXAMPLE 10

Préparation of Compound (10a)

[0263] To a stirred solution of P9-2 (400 mg, 0.65 mmol) in MeOH (20 mL) was added NH4F (52 mg, 1.5 mmol). The mixture was refluxed ovemight. The solvent was removed, and the residue was purifîed on a silica gel column (5-10% MeOH in DCM) to give compound 10a (140 mg, 82.4%) as a white solid. *H NMR (CDjOD, 400 MHz) <78.05 (d, J =

8.4 Hz, IH), 6.06 (dd, Λ = 2.8 Hz, J₂ = 16.4 Hz, IH), 5.67 (d , J= 8.0 Hz, IH), 5.08 (m, IH),

118

4.37 (d, Λ = 5.2 Hz, J₂ = 18.8 Hz, IH), 3.59 (dd, J, =12.0 Hz, J₂ = 26.4 Hz, 2H), 1.23 (s, 3H). ESI-TOF-MS: m/z 283 [M + Na]\

EXAMPLE H Préparation of Compound (lia)

TBDPSO

Hd F

11a

TBDPSO

H₂C=C—

TBSÔ

P11-3

To a solution of P3-5 (2.1 g, 3.5 mmol) in mmol) at -78°C. The [0264] Préparation of (PI 1-1):

anhydrous THF (25 mL) was added ethynylmagnesium bromide (5.1 reaction was stirred at 0°C for 3 hours. The réaction was quenched with saturated aq. NH4CI (10 mL). The mixture was diluted with EtOAc (200 mL) and washed with water and brine. The organic layer was dried and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluting with DCM: MeOH = 60:1) to give Pll-1 as a white solid (870 mg, 83.3%).

[0265] Préparation of (PI 1-2): Pll-1 (870 mg, 1.34 mmol) was dissolved in anhydrous DCM (12 mL), and methyl chloroformate (2.3 mL) and pyridine (2.5 mL) were added at R.T. The reaction mixture was stirred at R.T. for 1 hour. The mixture was diluted with DCM and washed with saturated aq. NaHCOj. The organic layer was separated, dried and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluting with PE: EtOAc = 8: 1) to give a crude product as a white solid (830 mg, 88.4%). To a mixture of Pd₂(dba)j (55 mg, 0.06 mmol) in anhydrous DMF (12 mL) was added P(nBu)j (35 mg, 0.17 mmol) and HCOONH4 (108 mg, 1.7 mmol) at R.T. under nitrogen. The reaction mixture was stirred at R.T. for 30 min. A solution of the crude product (830 mg, 1.16 mmol) in anhydrous DMF (16 mL) was added, and the reaction mixture was stirred at 70°C for 3 hours. The reaction was diluted with EtOAc and washed with brine. The organic layer was separated, dried and concentrated to give a residue. The residue was purified by column chromatography

119 on silica gel (eluting with PE: EtOAc - 9: 1) to give Pll-2 as a white solid (510 mg, 67.6%).’H

NMR (CD₃0D, 400 M Hz) J7.61-7.75 (m, 5H), 7.36-7.47 (m, 6H), 6.04 (d, J = 18.8 Hz, IH),

5.34 (t, J = 6.8 Hz, IH), 5.21 (dd, Ji = 1.2 Hz, J₂ = 12 Hz, IH), 5.10 (q, Λ = 5.2 Hz, J₂ - 53.6 Hz, IH), 4.80-4.92 (m, IH), 4.59-4.79 (m, 2H), 3.86 (d, J= 12.0 Hz, IH), 3.75 (d, J= 12.0 Hz, 1 H), 1.09 (s, 9H), 0.92 (d, J = 4.4 Hz, 9H), 0.15 (t, J = 4.0 Hz, 6H).

[0266] Préparation of (Pll-3): To a solution of Pll-2 (490 mg, 0.77 mmol) in anhydrous MeCN (15 mL) was added TPSC1 (700 mg, 2.31 mmol), DMAP (282 mg, 2.31 mmol) and TEA (234 mg, 2.31 mmol) at R.T. The reaction mixture was stirred at room température for 1 hour. Then NH4OH (8 mL) was added and the reaction mixture was stirred for another 4 hours. The mixture was diluted with EtOAc and washed with water, 1.0 M aq. HCl and saturated aq. NaHCO₃ The organic layer was separated and dried, concentrated to give the residue which was purified by HPLC séparation (MeCN and 0.1% HCOOH in water) to give Pll-3 as a white solid (190 mg, 38.8%).'H NMR (CD₃OD, 400 MHz) J7.88 (d, J = 7.2 Hz, IH), 7.63-7.70 (m, 4H), 7.37-7.48 (m, 6H), 6.12 (d, J = 18.4 Hz, IH), 5.49 (d, J - 7.6 Hz, IH),

5.34 (t, J = 6.8 Hz, IH), 4.84-5.01 (m, 2H), 4.66-4.78 (m, 2H), 3.89 (d, J = 11.6 Hz, IH), 3.75 (d, J = 11.6 Hz, IH), 1.10 (s, 9H), 0.91 (d, J =3.2 Hz, 9H), 0.13 (t, J= 52 Hz, 6H).

[0267] Préparation of (lia): To a solution of Pll-3 (130 mg, 0.21 mmol) in MeOH (8 mL) was added NH4F (1 g), and the reaction mixture was refluxed for 6 hours. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with DCM:MeOH = 13:1) to give compound lia as a white solid (47 mg, 79.1 %).*H NMR (CD₃OD, 400MHz) J8.07 (d, J-7.6 Hz, IH), 6.05 (dd, J_t= 1.2 Hz, J₂ = 16.8 Hz, IH), 5.86 (d, J = 7.6 Hz, IH), 5.40 (dd, J_t^J₂ = 6.8 Hz, IH), 4.87-4.99 (m, 3H), 4.46-4.80 (m, IH), 3.75 (d, J= 12.4 Hz, IH), 3.68 (d, J= 12.4 Hz, 1 H); ESI-MS: m/z 284.02 [M + H]⁺, 567.08 [2M + H]⁺.

120

EXAMPLE 12 Préparation of Compound (12a)

TBDPSO

[0268] Préparation of (P12«l): To a solution of P3-4 (500 mg, 0.8 mmol) in anhydrous toluene (12 mL) was added DAST (0.3 mL, 2 mmol) at -65°C under nitrogen. The reaction mixture was stirred at R.T. for 2 hours. The reaction was quenched with saturated aq. NaHCOj and extracted with EtOAc. The organic layer was separated, dried and concentrated to give the residue. The residue was purified by column chromatography on silica gel (eluting with PE: EtOAc - 9: 1) to give P12-1 as a yellow solid (170 mg, 42.5%). ’H NMR (CD3OD, 400 MHz) £7.66 (dd, J_t = 1.6 Hz, J₂ = 18.0 Hz, 4H), 7.54 (d, J = 7.6 Hz, IH), 7.35-7.47 (m, 6H), 6.59 (dd, J, = 5.6 Hz, J₂ = 14.0 Hz, IH), 5.78 (d, J= 7.6 Hz, IH), 5.05-5.24 (m, 2H), 4.93 (d, J =

7.6 Hz, IH). 4.57 (d, J = 7.6 Hz. IH).3.93-4.00 (m, 2H), 1.07 (d, J= 2.4 Hz,9H).

[0269] Préparation of (P12-2): To a solution of P12-1 (100 mg, 0.2 mmol) in anhydrous MeCN (5 mL) was added TPSC1 (182 mg, 0.6 mmol), DMAP (68 mg, 0.6 mmol) and TE A (61 mg, 0.6 mmol) at R.T. under nitrogen. The reaction mixture was stirred at R.T. for 1 hour. NH4OH (3mL) was added, and the reaction was stirred for 2 hours. The mixture was diluted with EtOAc and washed with water, 1.0 M HCl and saturated aq. NaHCO3. The organic layer was separated, dried and concentrated to give a residue. The residue was purified by column chromatography on silica gel (DCM:MeOH = 50:1) to give P12-2 as a yellow solid (96 mg, 96%).

[0270] Préparation of (12a): To a solution of P12-2 (96 mg, 0.2 mmol) in MeOH (5 mL) was added NH4F (500 mg) at R.T. The reaction was refluxed for 3 hours. The mixture was filtered, and the residue was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give compound 12a as a white solid (25 mg, 48.7%). ’H NMR (CD3OD, 400 MHz) £7.85 (d, J = 7.6 Hz, IH), 6.59 (dd, J, = 5.2 Hz, J₂ - 12.8 Hz, IH), 6.04 (d, J - 7.6 Hz, IH), 5.10-5.26 (m, 2H),

121

4.79-4.90 (m, IH), 4.57 (d, J= 7.6 Hz, IH), 3.82 (d, J= 12.4 Hz, IH), 3.76 (dd, J_t = 1.6 Hz, J₂ -

12.4 Hz, IH); ESI-MS: m/z 257.9 [M + H]⁺, 514.8 [2M + H]⁺.

EX AMPLE 13 Préparation of Compound (13a)

MMTrO

[0271] Préparation of (P13-1): To a solution of compound 3a (700 mg, 2.56 mmol) in anhydrous pyridine (5 mL) were added TBDPSCI (2.8 g, 10.24 mmol), imidazole (522 mg, 7.68 mmol) and AgNOj (870 mg, 5.12 mmol) at R.T. under N₂. The reaction mixture was 10 stirred at R.T. for 3 hours. The mixture was diluted with MeOH and filtered. The mixture was concentrated, and the residue was purified by column chromatography on silica gel (eluting with DCM: MeOH = 80:1 — 40:1) to give the crude intermediate as a yellow solid (1.05 g, 80.8%).*H NMR (DMSO-J6, 400 MHz) 6Ί.Ί5 (d, J = 7.6 Hz, IH), 7.61-7.65 (m, 4H), 7.41-7.50 (m, 7H), 6.02 (dd, J_t = 2.8 Hz, J₂ = 17.2 Hz, IH), 5.69 (d, J = 6.0 Hz, IH), 5.56 (d, J = 7.6 Hz, IH), 4.9615 5.11 (m, 1 H), 4.37-4.46 (m, IH), 3.82 (d, J = 10.8 Hz, IH), 3.62 (d, J= 10.8 Hz, IH), 1.70-1.78 (m, IH), 1.53-1.59 (m, IH), 1.02 (s, 9H),0.79 (t, J = 7.6 Hz, 3H). To a solution of the crude intermediate (1.0 g, 1.96 mmol) in anhydrous DCM (15 mL) were added xym-collidine (1.4 g, 11.76 mmol), AgNO₃ (1.0 g, 5.88 mmol) and MMTrCI (4.8 g, 15.6 mmol) at R.T. under N₂. The reaction mixture was stirred at R.T. ovemight. The mixture was filtered and concentrated.

The residue was purified by column chromatography on silica gel (eluting with PE:EtOAc=2: 1) to give crude fui! protected intermediates as a white solid( 1.1 g, 53.1%). To a solution of the crude intermediate (600 mg, 0.57 mmol) in THF (5 mL) was added TB AF (446 mg, 1.71 mmol)) at R.T. The reaction was stirred at 40~50ⁿC ovemight. The crude product was purified by column chromatography on silica gel eluted with PE:EtOAc ss 3:2 to give crude P13-1 (350 mg,

75.1%) as a yellow solid.

[0272] Préparation of (13a): To a solution of P13-1 (300 mg, 0.37 mmol) in CH3CN (2.5 mL) were added NMI (2.5 mL) and a solution of phenyl(îsopropoxy-L-alaninyl) phosphorochloridate (2.55 g, 7.4 mmol) in CHjCN (2.5 mL) at R.T. under N2. The reaction mixture was stirred at R.T. for 3 hours. The mixture was concentrated in vacuo. The residue 30 was purified by column chromatography on silica gel (PE:EtOAc = 1:1) to give crude product as

122 a yellow on (500 mg, 81%). The crude product was further treated with 80% HCOOH (70 mL) at R.T. overnight. The mixture was concentrated in vacuo, and the crude product was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give compound 13a as a white solid (a mixture of two P isomers, 86 mg, 40.3% two steps). ^lH NMR (CD₃OD, 400 MHz) £7.75, 7.71 (2d, J = 7.6 Hz, IH), 7.33-7.38 (m, 2H), 7.19-7.26 (m, 3H), 6.02-6.10 (m. IH), 5.87,5.82 (2d, J = 7.6 Hz, IH), 4.99-5.02 (m, 0.5H), 4.72-4.82 (m, 1.5H), 4.14-4.43 (m, 3H), 3.89-3.94 (m, 1H),1.68-1.81 (m, 6H), 1.51-1.56 (m, IH), 1.30-1.43 (m, 8H), 0.96-1.01 (m, 3H) ; ESI-MS: m/z

582.93 [M + H]⁺.

EXAMPLE 14

Préparation of Compound (14a)

NHMMTr

MMTrÔ F

P13-1

MMTrÔ F

P14-1

NHMMTr

HÔ 'F

14a [0273] Préparation of (P14-1): To a stirred solution of P13-1 (451 mg, 0.55 mmol) and NMI (lmL) in anhydrous acetonitrile (2 mL) was added dropwise a solution of 2-chloro-8methyl-4H-benzo[d][l,3,2]dioxaphosphinine (855 mg, 4.2 mmol) in acetonitrile (0.2 mL) at 0°C under N₂. The mixture was stirred at R.T. for 2 hours. Solution of I₂ (3.2 g, 12.6 mmol), pyridine (9 mL), H₂O(3 mL) and DCM(3 mL) was added. The reaction mixture was stirred for 30 mîns. The reaction was quenched with NaS₂O₃ solution and extracled with EA. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by column on silica gel (PE: EA » 1:1 to 1:2) to give P14-1 (205 mg, 37%) as a white solid.

[0274] Préparation of (14a): PI4-1 (205 mg, 0.21 mmol) was dissoived in 80% HCOOH aq. solution, and the mixture was stirred at R.T. for 16 hours. The solvent was removed, and the residue was purified by RP HPLC (HCOOH system) to give compound 14a as a mixture of 2 P-isomers (24 mg, 18%). 'H NMR (CD3OD, 400 MHz) <5 7.60,7.53 (2d, J = 8.0 Hz, IH), 7.21-7.25 (m, IH), 7.02-7.12 (m, 2H), 5.95. 5.87 (2dd, J_t = 2.4 Hz, J₂ = 18.0 Hz, IH),

123

5.71,5.69 (2d, J = 8.0 Hz, 1H), 5.38-5.53 (m, 2H), 5.06,5.04 (2ddd, J_t = 2.4 Hz, J₂ = 5.6 Hz, Λ = 54.0 Hz, 1H), 4.32-4.49 (m, 2H), 2.26 (d, J= 3.6 Hz, 3H), 1.83-1.92 (m, 1H), 1.64-1.72 (m, 1H), 0.96, 0.93 (2t, J = 7.6 Hz, 3H). ³¹P NMR (CD₃OD, 162 MHz) £-8.22, -8.50; ESI-LCMS: m/z 456 [M + H]*.

EXAMPIÆ 15

Préparation of Compound (15a)

P3-8

[0275] Stepl. Préparation of (P15-1): To a mixture of P3-8 (2.2 g, 2.5 mmol), 10 AgNO₃ (844 mg, 5.0 mmol) and collidine (907 mg, 7.5 mmol) in anhydrous DCM (10 mL) was added MMTrCl (1.54 g, 5.0 mmol) under N2. The reaction mixture was stîrred at R.T. ovemight, The reaction mixture was filtered through a Buchner Funnel. The filtrate was washed with saturated NaHCCh solution and brine. The organic layer was separated, dried over anhydrous NajSOj and filtered. The filtrate was concentrated to dryness. The residue was 15 purified by column on silica gel (PE:EA - 10:1 to 1:2) to give the intermediate (2.3 g, 84%), which was dissolved in a solution of TBAF in THF (IM, 2.6 mL) under N2. The reaction mixture was stîrred at R.T. ovemight. The residue was dissolved in EA (200 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous Na^SO-i and filtered. The filtrate was concentrated to dryness, and the residue was purified by column on 20 silica gel (DCM/MeOH = 100:1 to 30:1) to give P15-1 as a white foam (1.3 g, 94%).

[0276] Préparation of (15a): To a stîrred solution of P15-1 (300 mg, 0.55 mmol) and proton sponge (235 mg, 1.1 mmol) in anhydrous MeCN (9 mL) was added with a solution of POCI3 (169 mg, 1.1 mmol) in MeCN (I mL) via syringe at 0°C. The mixture was stîrred at R.T. for 40 mins. A mixture of (S)-cyclohexyl 2-aminopropanoate hydrochloride (525 mg, 2.55 25 mmol) and TEA (0.1 mL) was added at 0°C. The mixture was warmed to R.T. and stîrred for 3 hours. The reaction mixture was quenched with saturated NaHCO₃, and extracted with EA (100 mL x 2). The combined organic layers was dried over NaiSCL, concentrated and purified by silica gel column (1-4% MeOH in DCM) to give the crude product (400 mg, 78.15%) as a yellow solid. The crude product was treated with 80% HCOOH (50mL) at R.T. for 16 hours. 30 The solvent was removed, and the residue was purified by RP HPLC to give compound 15a as a

124 white solid (40 mg, 14%). 'H NMR (MeOD, 400 MHz) δ 7.82 (d, J = 7.6 Hz, IH), 6.09 (dd, Ji = 2.8 Hz, J₂ - 14.0 Hz,!H), 5.98 (d, J - 7.6 Hz, 1H), 5.CM (ddd, J_t = 3.2 Hz, J₂ = 5.6 Hz, J₃ =

53.6 Hz, 1H), 4.71-4.77 (m, 2H), 4.45 (dd, J_t = 5.6 Hz, J₂ = 12.4 Hz, 1H), 4.14-4.18 (m, !H), 3.97-4.01 (m, 1H), 3.84-3.92 (m, 2H), 1.31-1.87 (m, 28H), 0.99 (t, J = 7.2 Hz, 3H). ^3IP NMR 5 (CD₃OD, 162 MHz) δ 13.94; ESI-LCMS: m/z 660 [M + H]⁺.

EXAMPLE 16 Préparation of Compound (16a)

4a 16a [0277] To a stirred solution of compound 4a ( 150 mg, 0.56 mmol) in anhydrous THF (3 mL) was added dropwise a solution of t-BuMgCI (1.2 mL, IM in THF) at -78°C. The mixture was stirred at 0°C for 30 min and re-cooled to -78°C. A solution of phenyl(isopropoxy-Lalaninyl) phosphorochloridate (312 mg, 1.2 mmol) in THF (1.0 mL) was added dropwise. After addition, the mixture was stirred at 25°C for 16 hours. The reaction was quenched with HCOOH (80% aq.) at 0°C. The solvent was removed, and the residue was purified on silica gel (DCM'.MeOH = 50:1 to 10:1) to give compound 16a as a white solid (24.0 mg, 15 %).’H NMR (MeOD, 400 MHz) £7.76 (d, J = 7.2 Hz, 1H), 7.17-7.38 (m, 5H), 6.01-6.08 (m, 2H), 5.81 (d, J =

7.6 Hz, !H), 5.54-5.58 (m, !H), 5.35-5.38 (m, 1H), 4.92-4.97 (m, 2H), 4.45-4.52 (m, 1H), 4.084.19 (m, 2H), 3.88-3.92 (m, 1H), 1.28-1.33 (m, 3H), 1.20-1.22 (m, 6H); ^3,PNMR (CD3OD, 162

MHz) δ 736; ESI-LCMS: m/z 541.0[M + H]⁺.

125

EXAMPLE 17 Préparation of Compound (17a)

P3-7 P17-1

17a [0278] Préparation of (P17-1): To a solution of P3-7 (1.4 g, 2.3 mmol) in MeOH (50 mL) was added NH4F (8.0 g) at R.T. The reaction mixture was refluxed ovemight. After cooling to R.T., the mixture was filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (10% MeOH in DCM) to give P17-1 as a white solid (410 mg, 77.8%).

[0279] Préparation of (P17): To a stirred solution of P17-1 (60 mg, 0.19 mmol) in anhydrous THF (3 mL) was added dropwise a solution of i-BuMgCl (0.38 mL, IM in THF) at 78°C. The mixture was stirred at 0°C for 30 min and re-cooled to -78°C. A solution of phenyl(isopropoxy-L-alaninyl) phosphorochloridate (104 mg, 0.4 mmol) in THF (0.5 mL) was added dropwise. After addition, the mixture was stirred at 25°C for 16 hours. The reaction was quenched with HCOOH (80% aq.) at 0°C. The solvent was removed, and the residue was purified on silica gel (DCM:MeOH = 50:1 to 10:1) to give compound 17a as a white solid ( a mixture of two P isomers, 11.0 mg, 11 %). *H NMR (MeOD, 400 MHz) δΊ.ΊΧ (2d, J = 8.0 Hz, 1H), 7.17-7.37 (m, 5H), 5.98-6.07 (m, 2H), 5.61,5.68 (2d, 8.0 Hz, 1H), 5.53-5.58 (m, 1H),

5.35-5.40 (m, 1 H), 5.08-5.10 (m, (H), 4.93-4.99 (m, 1 H), 4.52-4.53 (m, 1H), 4.16-4.21 (m, 1H), 4.06-4.11 (m, (H), 3.86-3.94 (m, 1H), 1.28-1.34 (m, 3H), 1.20-1.22 (m, 6H). ^3lP NMR (MeOD, 162 MHz) <Î3.72,3.45. ESI-LCMS: m/z 542.0 [M + H]*.

126

EXAMPLE 18

Préparation of Compound (18a)

P3-5 slH

TBDPSCTVOyN-<_o ____JODPSO^Vy^N^_o

TBSd 'F TBSO 'F

P18-1 P18-2

P18-3 18a [0280] Préparation of (P18-1): To a solution of (chloromethyl)triphenylphosphonium chloride (2.1 g, 6.0 mmol) in anhydrous THF (10 mL) was added dropwise n-BuLi (4.6 mL, 6.0 mmol) at -70°C under nitrogen. The reaction was stirred at -70°C for 50 mins. A solution of compound P3-9 (950 mg, 1.5 mmol) in anhydrous THF (5 mL) was added at -70°C, and the reaction was stirred at 0°C for 3 hours. The reaction was quenched by saturated aq. NHjCl and extracted with EtOAc. The organic layer was separated, dried and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluting with PE:EtOAc = 6:1) to give P18-1 as a yellow gum (900 mg, 91.2%).

[0281] Préparation of (P18-2): To a solution of compound P18-1 (600 mg, 0.91 mmol) in anhydrous THF (18 mL) was added dropwise n-BuLi (4.7 mL, 10.9 mmol) at -70°C under nitrogen. The réaction was stirred at -70°C for 3 hours. The reaction was quenched by saturated aq. NHjCl and extracted with EtOAc. The organic layer was separated, dried and concentrated to give a residue. The residue was purified by column chromatography on silica gel (eluting with PE:EtOAc = 8:1—511) to give P18-2 as a white solid (300 mg, 53.0%).

[0282] Préparation of (PI8-3): To a solution of P18-2 (300 mg, 0.44 mmol) in MeOH (10 mL) was added NH4F (1.0 g) at R.T. The reaction was refluxed for 3 hours. After cooling R.T., the mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluting with DCM:MeOH = 50:1-30:1 ) to give P18-3 as a white solid (135 mg, 78.1%).*H NMR (CD3OD, 400 MHz) £7.84 (d, J = 8.0 Hz, 1H), 6.06 (dd, Λ = 1.6 Hz, J₂ =19.6 Hz, 1H), 5.67 (d, J = 8.4 Hz, 1H), 5.18-5.03 (m, 1H), 4.50 (dd, J/ = 5.2 Hz,Λ =21.6 Hz, 1H), 3.85 (d, J= 12.4 Hz, 1H), 3.72 (d, J- 12.4 Hz, 1H), 3.09 (s, 1H).

127 [0283] Préparation of (18a): To a solution of P18-3 (130 mg, 0.5 mmol) in anhydrous THF (4 mL) was added dropwise t-BuMgCI (1.0 mL, 1.0 mmol) at -70°C under nitrogen. The reaction was stirred at R.T. for 30 mins. A solution of phenyl(isopropoxy-Lalaninyl) phosphorochloridate in anhydrous THF(1M, 0.8 mL, 0.78 mmol) was added at -70°C, and the reaction mixture was stirred at R.T. for 5 hours. The reaction was quenched by HCOOH, and the mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (DCM:MeOH - 60:1) to give compound 18a as a white solid (a mixture of two P isomers, 25 mg, 7.7%). *H NMR (CD3OD, 400 MHz) £7.64, 7.60 (2d, J = 7.6 Hz, IH), 7.32-7.36 (m, 2H), 7.16-7.25 (m, 3H), 5.95-6.01 (m, IH), 5.67, 5.62 (2d, J = 8.0 Hz, IH), 5.10-5.25 (m, IH), 4.93-4.97 (m, IH), 4.49-4.59 (m, IH), 4.33-4.42 (m, IH), 4.24-4.29 (m, IH), 3.86-3.94 (m, IH), 3.25, 3.22 (2s, IH), 1.28-1.34 (m, 3H), 1.20-1.23 (m, 6H); ESI-MS: m/z

540.2 [M + H]⁺.

EXAMPLE 19

Préparation of Compound (19a)

ΝΗΜΜΠ7

O=p-tf -_F O NC^-°

P19-1

P19-2

P19-3 [0284] Préparation of (P19-1): P15-2(1.2 g, 2.2 mmol) was dissoived in dry acetonitrile (20 mL), and 0.45 M tetrazole (24.0 mL, 11.0 mmol) and 3(bis(diisopropylamino)phosphinooxy)propanenitrile (1.13 g, 3.74 mmol) was added. The reaction mixture was stirred for 1 hour under N₂ at R.T. TBDPH (2.7 mL, 15 mmol) was added, and the mixture was stirred for 1 hour. The reaction was quenched by Na₂S₂0j solution and extracted with EA. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified by column on silica gel (DCM:MeOH = 100:1 to 40:1) to give P19-1 as a white solid (759 mg, 52%).

128 [0285] Préparation of (P19-2): P19-1 (750 mg, 1,14 mmol) was dissolved in saturated NH3 in MeOH solution. The mixture was stirred for 2 hours at R.T. The solution was concentrated to dryness to give crude PI 9-2 as a yellow solid (662 mg, 100%). *H NMR (DMSO-J<5,400 MHz) £8.60 (s,lH), 8.28 (s, IH), 7.48 (d, J= 7.6 Hz, IH), 7.12-7.29 (m, 12H),

6.83 (d, J= 8.8 Hz, 2H), 6.29 (d, J= 7.6 Hz, IH), 5.88 (d,7 = 8.8 Hz, IH), 5.10 (d, J = 4.8 Hz, IH), 4.42-4.45 (m, IH), 3.72 (s, 3H), 1.64-1.91 (m, 2H), 1.10-1.13 ( m, 2H), 0.83-0.86 (m, 3H). ^3,P NMR (CD3OD, 400 MHz) £-4.48; Negative-ESI-LCMS: m/z 606 [M - H]'.

[0286] Préparation of (P19-3): PI9-2 (292 mg, 0.47 mmol) was co-evaporated with pyridine twice and dissolved in anhydrous DMF (0.5 mL). DIPEA (1.2 mL) was added and followed by 2,2-dimethyl-propionic acid iodomethyl ester (680 mg, 2.8 mmol). The reaction mixture was stirred at R.T. under N2 for 16 hours. The reaction was quenched by Na2S2Û₃solution and extracted with EA. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified by column on silica gel (DCMrMeOH = 100:1 to 30:1) to give P19-3 as a white solid (95 mg, 30%).

[0287] Préparation of (19a): P19-3 (95 mg, 0.13 mmol) was dissolved in a 80% HCOOH aq. solution, and the mixture was stirred at R.T. for 16 hours. The solvent was removed, and the residue was purified by RP HPLC (MeCN and 0.1% HCOOH in water) to give compound 19a as a white solid (10 mg, 17%). 'H NMR (CDjOD, 400 MHz) £7.69 (d, J = 7.2 Hz, IH), 5.91 (d, 7 = 7.6 Hz, IH), 5.84 (d, 7= 22.0 Hz, IH), 5.73 (d, 7= 14.0 Hz, 2H), 5.52 (d,7 = 5.2 Hz, IH), 5.13-5.22 (m, IH), 4.53-4.61 (m, IH), 4.31 (d, 7 = 9.6 Hz, IH), 1.92-2.08 (m, 2H), 1.23 (s, 9H), 1.03-1.07 (m, 3H); ^3IP NMR (CD3OD, 162 MHz) £-7.93; ESl-LCMS: m/z 450 [M + H]⁺.

129

EXAMPLE 20

Préparation of Compound (20a)

P20-3

P20-4

P20-5

P20-8 [0288] Préparation of (P20-1): To a stirred suspension of P3-1 (20.0 g, 8i.3mmol), imidazole (15.9 g, 234.0 mmol), PPh₃ (53.5 g, 203.3 mmol) and pyridine (90 mL) in anhydrous

THF (360 mL) was added dropwise a solution of h (41.3 g, 162.6mmol) in THF (350 mL) at

0°C. After addition, the mixture was warmed to R.T. and stirred for 14 hours. The solution was quenched with aq. Na₂S2O3 (150 mL) and extracted with EA. The organic layer was dried over

Na₂SO4 and concentrated. The residue was purified on a silica gel column (DCM:MeOH =

100:1 to 10:1) to afford P20-1 as a white solid (22.1 g, 76.4%). ‘H NMR (CD₃OD, 400 MHz) δ

7.70 (d, J =8.0 Hz, IH), 5.88 (dd, Λ = 1.6 Hz. J₂= 20.8 Hz, IH), 5.71 (d, J =8.4 Hz, IH), 5.24 (dd, Ji = 2.0 Hz, J2 = 5.2 Hz, IH), 5.10 (dd, J_t = 2.0 Hz, J₂ = 5.2 Hz IH), 3.78-3.83 (m, IH), 3.61-3.65 (m, IH),3.44 (dd, Jt-J₂- 6.0 Hz, 1 H).

[0289] Préparation of (P20-2): To a stirred solution of P20-1 (22.1 g, 62.1 mmol) 15 in anhydrous THF (200 mL) was added dropwise DBU (14.2 g, 93.1 mmol) in THF (50 mL) at

0°C over 10 mins. The mixture was stirred at 60°C for 6 hours. The reaction was quenched with aq. NaHCOj (200 mL) and extracted with EA. The organic layer was washed with brine and

130 dned over Na₂SÛ4. The solvent was removed, and the residue was purified on a silica gel column (MeOH:DCM = 1/100 to 1/30) to afford P20-2 as a white solid (8.7 g, 61.5%). *H NMR (CDjOD, 400 MHz) δ 7.51 (d, J = 8.0 Hz, IH), 6.05 (dd, J_t =1.2 Hz, J₂ = 17.2 Hz, IH), 5.73 (d, J = 8.0 Hz, IH), 5.26 (dd, J_t = 1.2 Hz, J₂ = 4.8 Hz, IH), 5.13 (dd, J_t = 1.2 Hz, J₂ = 4.8 Hz, IH), 4.63 (dd, J_t =2.0 Hz, J₂ = 3.2 Hz, IH), 4.41 (dd, J_t = J₂ = 2.0 Hz, IH).

[0290] Préparation of (P20-3): To a stirred solution of P20-2 (3.2 g, 14.0 mmol) in anhydrous pyridine(10 mL) and DCM (100 mL) was added dropwise a solution of TBSC1 (4.2 g, 28,0 mmol)at 0°C. Stirring was continued at R.T. for 18 hours. The mixture was diluted with DCM. The organic layer was washed with brine and dried over Na₂SO4. The solvent was removed, and the residue was purified on a silica gel column (10% MeOH in DCM) to afford P20-3 as a white solid (3.4 g, 70.8%).

[0291] Préparation of (P20-4): To a stirred solution of NaHCO₃ in H₂O (250 mL) and acetone (200 mL) was added oxone (30.0 x 4 g) at 0°C. The mixture was warmed to R.T., and the dîstîllate was collected at -78°C (120 mL) under slightly reduced pressure to give a solution of DMDO in acetone. To a stirred solution of P20-3 (250.0 mg, 0.7 mmol) in DCM (20 mL) were added a DMDO (120 mL) solution at -40°C and MgSÛ4. The mixture was warmed to R.T. and then stirred for 2 hours. The solution was filtrated, and the filtrate was used for the next-step directly.

[0292] Préparation of (P20-5): To a stirred solution of P20-4 (500.0 mg, 1.4 mmol) in anhydrous DCM (50 mL) was added allyl-trimethyl-silane (760.0mg, 6.7mmol) and SnCL (1.2 g, 4.5 mmol) at -40°C. The mixture was warmed and stirred at 0°C for 1 hour. The reaction was quenched with saturated NaHCO₃ and extracted with DCM. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified on a silica gel column (20-50% EA in PE) to give P20-5 as a white foam (120 mg, 41%). ‘H NMR (CD₃OD, 400 MHz) δ 8.01 (d, J =

8.4 Hz, IH), 6.12 (dd, J_t = 3.6 Hz, J₂ = 15.2 Hz, IH), 5.87-5.96 (m,lH), 5.71 (d, J = 8.4 Hz, 1 H), 5.06-5.22 (m, 3H), 4.60 (dd, J_t = 5.6 Hz, J₂ = 14.4 Hz, l H), 3.72 (d, J = 11.6 Hz, 1 H), 3.48 (d, J = 11.6 Hz, 1 H), 2.62-2.67 (m, t H), 2.23-2.29 (m, l H); ESI-LCMS: m/z = 422 [M + Na]⁺.

[0293] Préparation of (P20-6): To a stirred solution of P20-5 (270.0 mg, 0.7 mmol) in dry DCM were added imidazole (400.0mg, 5.9mmol) and TBSC1 (390.0 mg, 2.6 mmol) at R.T. The mixture was stirred at R.T. for 18 hours. The solution was diluted with EA. The solvent was washed with brine and dried over Na₂SO4. The solvent was removed, and the residue was purified on a silica gel column (20-40% EA in PE) to afford compound P20-6 as a white foam (280 mg, 80.7%). ESI-LCMS: m/z 537 [M + Na]*.

131 [0294] Préparation of (P20-7): To a stirred solution of P20-6 (280.0 mg, 0.5 mmol) in dry MeCN were added TPSC1 (350.0 mg, 1.2 mmol), NEtj (400.0 mg, 4.0 mmol) and DMAP (270.0 mg, 2.2 mmol) at R.T. The mixture was stirred at R.T. for 18 hours. The solution was quenched with ammonium. The organic layer was washed with brine and dried over Na2SÛ4. The solvent was removed, and the residue was purified by TLC (using EA) to afford compound P20-7 as a white foam (240.0 mg, 85.7%). ESI-LCMS: m/z 514 [M + H]⁺.

[0295] Préparation of (P20-8): To a stirred solution of P20-7 (270.0 mg, 0.5 mmol) in dry DCM were added AgNOj (1.5 g, 8.8mmol), MMTrCl (450.0 mg, 1.5 mmol) and collidine (500.0 mg, 4.1 mmol) at R.T. The mixture was stirred at R.T. for 18 hours. The solution was diluted with DCM. The organic layer was washed with brine and dried over Na^SCL. The solvent was removed, and the residue was purified on a silica gel column (20-40% EA in PE) to afford compound P20-8 as a white foam (300 mg, 81.6%). ESI-LCMS: m/z 786 [M + H]⁺.

[0296] Préparation of (20a): To a stirred solution of P20-8 (170.0 mg, 0.3 mmol) in dry MeOH was added NH4F (300.0 mg, 8.1 mmol), and the mixture was refluxed for 24 hours. The solvent was removed under reduced pressure, and the residue was purified on a silica gel column (2-5% MeOH in DCM) to give the crude product. The crude product was further purified by RP HPLC (water and 0.1% HCOOH in MeCN) to afford compound 20a as a white solid (47.0 mg, 49.8%). *H NMR (CD3OD, 400 MHz) Ô 8.13 (d, J = 8.4 Hz, IH), 6.12 (dd, J, =

3.2 Hz, J₂ = 12.0 Hz, IH), 5.87-5.97 (m, 2H),4.98-5.14 (m, 3H), 4.45 (dd, Λ = 5.2 Hz, J₂ = 17.6 Hz, IH), 3.71 (d,J= 11.6 Hz, IH), 3.54 (d, J = 11.6 Hz, 1 H), 2.54-2.59 (m, IH), 2.33-2.39 (m, I H); ESI-LCMS: m/z 286 [M + H]⁺.

EXAMPLE 21

Préparation of Compound (21a)

NHMMTr

TBSO

O

TBSO

O

TBSO F

P20-8

TBSO' 'F

P21-1

NHMMTr

NHj

HO' 'F

P21-2

H (5 'F

21a

132 [0297] Préparation of (P21-1): To a stirred solution of P20-8 (250.0 mg, 0.3 mmol) in MeOH was added Pd/C (500.0 mg), and the mixture was stirred under H₂ (balloon) for 18 hours at R.T. The reaction was filtered, and the solvent removed under reduced pressure. The residue was purified by prcp. TLC (30% EtOAc in PE) to afford P21-1 as a white foam (210.0 mg, 84.0%).

[0298] Préparation of (P21-2): To a stirred solution of P21-1 (210.0 mg, 0.3 mmol) in dry THF was added TBAF (1 mL, Immol), and the mixture was stirred at R.T. for 18 hours. The solvent was removed under reduced pressure, and the residue was purified by prep. TLC (30% EtOAc in PE) to give compound 21a as a white foam (111.2 mg, 74.6%). *H NMR (DMSO-J6,400 MHz) £8.49 (s, 1H). 7.75 (d, J = 6.8 Hz, IH), 6.83-7.32 (m, I4H), 6.25 (d, J =

7.6 Hz, IH), 5.95 (dd, J_t « 4.8 Hz, J₂ = 14.8 Hz, IH), 5.48 (d, J = 5.6 Hz, IH), 4.86-5.15 (m, 2H), 4.15-4.21 (m, IH), 3.72 (s, 3H), 3.38-3.49 (m, 2H), 1.24-1.58 (m, 4H), 0.84 (t, J = 7.2 Hz, 3H); ESI-MS: m/z 560 [M + H]⁺.

[0299] Préparation of (P21): Compound P21-2 (81 mg) was dissolved in a mixture (5 mL) of formic acid (80%) and water (20%). The resulting solution was stirred at R.T. for 3 hours and then concentrated. The residue was co-evaporated with methanol/toluene three times. Chromatography on silica gel with 5-12% methanol in DCM gave a mixture of two compounds, which was dissolved in methanol with a drop of concentrated aqueous ammonia and concentrated. The residue was purified on silica gel with 5-12% methanol in DCM to give compound 21a (27 mg) as a white solid; ’H NMR (CD3OD, 400 MHz) £8.05 (d, J = 7.6 Hz, IH), 6.06 (dd, J, = 2.8 Hz, J₂= 16 Hz, IH), 5.87 (d, J = 7.6 Hz, IH), 5.10 (dd, J = 3.2, 5.2 Hz, 0.5H), 4.96 (dd, 3.2, 5.2 Hz, 0.5H), 4.42 (dd, J = 5.6, 17.2 Hz, IH), 3.67 (dd, J = 11.6, 76 Hz, 2H), 1.70-1.79 (m, IH), 1.31-1.61 (m, m, 3H), 0.94 (t, J- 6.8 Hz, 3H). MS: m/z 417 [M + 2methylheptylamine]*.

133

EXAMPLE 22

Préparation of Compound (22a)

P20-2 P22-1P22-2

O NHBzNH

JH /^N/Si

BzO-\A/H BzO-\A?H H0-y,0 «S ,οΛ_/ ⁰---- ⁰--- ^KJ

BzO' 'F Bz<5 'FHÛ 'F

P22-3 P22-422a [0300] Préparation of (P22-1): To a solution of P20-2 (5.23 g, 23.1 mmol) in anhydrous MeOH (50 mL) was added PbCO₃(12.7 g, 46.3 mmol) at R.T. A solution of I₂ (11.7 g, 46.3 mmol) in MeOH (10 mL) was then added dropwise at 0°C. The reaction mixture was stirred at R.T. for ovemight. The reaction was quenched with Na₂S₂O₃ and dissolved in EA. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by column (DCM/MeOH = 100/1 to 20/1) to give P22-1 as a white solid (5.6 g, 71.8%). ‘H NMR (CD₃OD, 400 MHz) £7.67 (d, J = 8.0 Hz, IH), 5.88 (dd, J, = J₂ = 7.6 Hz, IH), 5.73 (d, J = 8.0 Hz, IH),

5.24 (dd, J, = 4.4 Hz, J₂ = 6.4 Hz, IH), 5.11 (dd, J_f = 6.4 Hz, J₂ = 6.0 Hz, IH); 4.65 (dd, J_t = 20.0 Hz, J₂ = 20.4 Hz, IH), 3.67 (d, J= 11.6 Hz, IH), 3.54 (d, J= 11.6 Hz, IH), 3.43 (s, 3H).

[0301] Préparation of (P22-2): To a stirred solution of P22-1 (5.6 g, 14.5 mmol) in anhydrous pyridine (20 mL) was added dropwise BzCl (2.9 g, 20.9 mmol) at 0°C. The mixture was stirred at R.T. for 10 hours. The reaction was quenched with H₂O, and the solution was concentrated. The residue was dissolved in EA and washed with saturated NaHCO₃. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on a silica gel column (20-40% EA in PE) to give P22-2 as a white foam (4.9 g, 74.2%).

[0302] Préparation of (P22-3): P22-2 (4.9 g, 10.0 mmol), BzONa (14.4 g, 100 mmol) and 15-crown-5 (22.0 g, 100 mmol) were suspended in DMF (200 mL). The mixture was stirred at 60-70°C for 3 days. The precipitate was removed by filtration, and the filtrate was diluted with EA. The solvent was washed with brine and dried over Na₂SO₄. The solvent was removed, and the residue was purified on a silica gel column (20-60% EA in PE) to afford P223 as a white foam (2.3 g, 47.9%).

134 [0303] Préparation of(P22-4): P22-3 (2.3 g, 4.8 mmol), DMAP ( 1.2 g, 9.6 mmol), TPSC1 (2.9 g, 9.6 mmol) and Et₃N (0.97 g, 9.6 mmol) were suspended in MeCN (10 mL). The mixture was stirred at R.T. for 14 hours. NH₃ in THF (saturated at 0°C, 100 mL) was added to the mixture, and the mixture stirred at R.T. for 2 hours. The solvent was removed, and the 5 residue was purifîed by column (DCM/MeOH = 100:1 to 50:1 ) to give the crude product ( 1.2 g).

The crude product was dissolved in pyridine, and BzCl (0.42 g, 3.0 mmol) was added. The mixture was stirred at R.T. for 16 hours and quenched with water. The solvent was removed, and the residue was purifîed on a silica gel column (PE:EA = 2:1 to 1:1) to give P22-4 as a white foam (460 mg, 31%).

[0304] Préparation of (22a): P22-4 (0.46 g, 0.8 mmol) was dissolved in saturated methanolic ammonia (100 mL), and the mixture was stirred at R.T. for 14 hours. The solvent was removed, and the residue was dissolved in H₂O and washed with DCM. The aqueous phase was lyophilized and further purifîed by prep. HPLC (0.1% formic acid in water/acetonitrile) to give compound 22a as a white solid (145 mg, 78.9 %). ’H NMR (CDjOD, 400 MHz) <77.88 (d,

J = 7.6 Hz, IH), 6.03 (d, J = 18.4 Hz, IH), 5.87 (d, J = 7.6 Hz, IH), 4.86-5.00 (m, IH), 4.49 (dd, J, = 23.2 Hz, J₂ = 22.8 Hz, IH), 3.90 (d, J- 12.0 Hz, IH), 3.66 (d, J = 12.0 Hz, IH), 3.41 (s, 3H); ESI-MS: m/z 276 [M + H]⁺.

135

EXAMPLE 23

Préparation of Compound (23a) ,0 ,0

NPMB

TBDPSCT DMTiOBnd

NPMB

Hô

23a

HÛ 'F [0305] Préparation of (P23-2): To a solution ofP23-1 (3.1 g, 4.5 mmol) in DMF (30 mL) was added anhydrous K₂CO₃ (1.24 g, 9.03 mmol) and PMBC1 (1.40 g, 9.03 mmol). The mixture was stirred at ambient température ovemight. The reaction was quenched with water and extracted with EA. The organic layer was concentrated, and the residue was purified on a silica gel column (PE:EA =10:1 to4:l) to give the intermediate as a white solid (2.36 g, 74.8%). ’H NMR (CDClj, 400 MHz) £7.29-7.88 (m, 23H), 6.83-6.98 (m, 6H), 6.35-6.45 (m, 1H), 4.51-

5.50 (m, 6H), 3.89-3.95 (m, 9H), 3.66-3.71 (m, 2H),3.O3 (d, J = 1 !.2Hz, IH), 1.21 (s, 9H), 0.89 (m, 9H), 0.01-0.11 (m, 6H). The intermediate was used in the next step.

[0306] To a stirred solution of the intermediate (11.0 g, 10.47 mmol) in anhydrous THF (100 mL) was added TBAF (8.20 g, 31.42 mmol) at R.T., and the mixture was stirred at R.T. for 5 hours. The solution was removed, and the residue was purified on a silica gel column (PE: EA=5:1 to 1:1) to give a second intermediate as a white solid (5.99 g, 82%).

[0307] To a stirred solution of the second intermediate (500 mg, 0.716 mmol) in anhydrous DMF(10 mL) was added NaH (51.5 mg, 2.14 mmol) and BnBr (365 mg, 2.14 mmol) dropwise at 0°C. The mixture was stirred at R.T. for ovemight. The solution was quenched with water and extracted with EA. The concentrated organic phase was purified on a silica gel column (PE:EA = 10:1 to 4:1 ) to give a third intermediate as a white solid (496 mg, 79%).

136 [0308] The third intermediate (2.5 g, 2.84 mmol) was dissolved in 80% HOAc (25 mL) at R.T., and the mixture was stirred at R.T. for ovemight. The reaction was quenched with MeOH, and the solvent was removed. The crude was purified on a silica gel column (PE:EA = 5:1 to l:l)togiveP23-2asawhitesolid(1.2g, 73%).

[0309] Préparation of (P23-3): To a stirred solution of DAST (1.39 g, 8.68 mmol) in anhydrous toluene (15 mL) was added dropwise a solution of P23-2 (1.0 g, 1.73 mmol) at 78°C. The mixture was stirred at -78°C for 30 mins. The solution was heated to 60°C gradually and then stirred ovemight. The mixture was poured into saturated Na₂COj solution. The concentrated organic phase was purified on a silica gel column (PE:EA = 10:1 to 4:1) to give P23-3 as a white solid (449 mg, 45%). ^JH NMR (CDjOD, 400 MHz) £7.87 (d, J = 8.4 Hz, 1H), 7.27-7.37 (m, 12H), 6.82-6.84 (m, 2H), 6.14 (dd, J = 16.8,2.0Hz, 1H), 5.18-5.50 (m, 4H), 4.96 (s, 2H), 4.45-4.88 (m, 7H), 3.67-3.89 (m, 5H).

[0310] Préparation of (P23-4): A mixture of P23-3 (1.20 g, 2.07 mmol) and CAN (3.41 g, 6.23 mmol) in a solution of MeCN:Water (3:1, 10 mL) was stirred at R.T. ovemight. Brine (10 mL) was added, and the mixture was extracted with EA. The combined organic extracts were dried and evaporated under reduced pressure. The residue was purification by chromatography on silica gel (PE:EA = 10:1 to 2:1) to give P23-4 as a yellow solid (475 mg, 49.8%).

[0311] Préparation of (P23-5): To a stirred solution of P23-4 (550 mg,210 mmol) in anhydrous MeCN (10 mL) were added TPSC1 (725 mg, 2.40 mmol), DMAP (293 mg, 2.40 mmol) and TEA (242 mg, 2.40 mmol) at R.T., and the mixture was stirred at R.T. ovemight. NH4OH (25 mL) was added, and the mixture was stirred for 2 hours. The solvent was removed, and the residue was purified on a silica gel column (PE:EA = 8:1 to 2:1) to give P23-5 as a white solid (700 mg crude).¹ H NMR (CDjOD, 400 MHz) £7.86 (d, J = 8.4 Hz, 1H), 7.27-7.36 (m, 10H), 6.13 (dd, J_t = 17.2 Hz, J₂ - 2.0 Hz, 1H), 5.48-5.53 (m, 1H), 5.11-5.26 (m, 1H), 4.44-4.74 (m, 7H), 3.89 (dd, J_t = 10.4 Hz, J₂ = 2.0 Hz, 1H), 3.69 (dd, J_t = 10.8 Hz, J₂ =1.6 Hz, 1H).

[0312] Préparation of (P23-6): To a stirred solution of P23-5 ( 1.0 g, 2.18 mmol) in anhydrous DCM (15 mL) was added MMTrCl (2.02 g, 6.56 mmol) and AgNOj (l.il g, 6.56 mmol) at R.T., and the mixture was stirred at R.T. ovemight. The solid was filtered off and washed with DCM. The filtrate was washed with brine and dried over Na₂SO4. The organic phase was concentrated, and the residue was purified on a silica gel column (PE:EA= 8:1 to 2:1) to give P23-6 as a white solid (520 mg, 41%).

[0313] Préparation of (P23-7): To a stirred solution of P23-6 (520 mg, 0.713 mmol) in acetone were added ammonium formate (2.0 g, 31.7 mmol, in portions) and 10%

137 palladium on carbon (1.0 g). The mixture was refluxed for 12 hours. The catalyst was filtered off and washed with solvent. The filtrate was added EA and washed with brine. The concentrated organic phase was purified by column chromatography (DCM:MeOH = 100:1 to 15:I)and prep. TLC to give P23-7 as a white solid (270 mg, 69.0%).*H NMR (CDjOD, 400

MHz) S8.54 (s, 1H), 7.73 (d, J = 7.6 Hz, 1H), 7.13-7.32 (m, 12H), 6.83 (d, J= 8.4 Hz, 2H), 6.29 (d, J = 7.6 Hz, IH), 5.99-6.04 (m, IH), 5.82 (d, J =5.6 Hz, 1 H), 5.39 (t, J = 5.2 Hz, 1H), 5.09 (t,

J = 5.2 Hz, IH),4.32-4.58 (m, 3H), 3.54-3.72 (m, 5H). ES1-MS: m/z 549.6 [M + H]⁺.

[0314] Préparation of (23a): P23-7 (130 mg, 0.236 mmol) was dissolved in 80%

HCOOH (20 mL) at R.T., and the mixture was stirred at 50°C for 12 hours. The solvent was 10 removed, and the residue was co-evaporated with toluene twice. The residue was re-dissolved in

MeOH (20 mL) at 60°C and stirring was continued for 48 hours. The solvent was removed, and the residue was purified by column chromatography (DCM:MeOH = 100:1 to 10:1) to give compound 23a as a white solid (45 mg, 69.0%).*H NMR (CD3OD, 400 MHz) J8.00 (d, J = 7.6

Hz, IH), 6.13 (dd, Ji = 16.0 Hz, J₂ = 4.0 Hz, IH), 5.89 (d, J = 7.6 Hz, IH), 5.18-5.21 (m, IH),

5.05-5.07 (m, IH), 4.60 (s, IH), 4.51-4.57 (m, 2H), 3.84 (dd, J_t =12.0 Hz, J₂ = 2.0 Hz, IH), 3.75 (dd, Ji = 12.0 Hz, J₂ = 2.0 Hz, IH). ES1-MS: m/z 277.8 [M + H]⁺, 554.8 [2M + Hf.

138

EXAMPLE 24

Préparation of Compound (24a)

NHBz

HCl

P24-2

P24-3

P24-4

P24-6

Ρ24TBDPS

TBSÔ

P24-11

TBDPSO^Vz°x/^l'‘ V

--λΧ °TBSC5' F

P24-10

P24-1

TBDPSO HOTBSÔ

P24-7

TBDPSO

HÔ* F

24a [0315] Préparation of (P24-2): To a solution of P24-1 (30.0 g, 100.0 mmol) in 5 pyridine (300 mL) was added BzCl (56.0 g, 400 mmol) at 25°C. The mixture was stirred at 25°C for 15 hours. The mixture was concentrated and purified by column chromatography (PE:EA = 20:1 to 2:1) to give crude P24-2 (55.0 g, 81%).

[0316] Préparation of (P24-3): P24-2(55.O g, 92 mmol) was dissolved in 80% HOAc aq. solution, and the mixture was refluxed for 14 hours. The solvent was removed under 10 reduced pressure, and the residue was co-evaporated with toluene. The residue was purified on a silica gel column (PE/EA = 4:1 to 2:1) to give P24-3 as a white solid (39.2 g, 83%).

139 [0317] Préparation of (P24-4): P24-3 (39.2 g, 83 mmol) was dissolved in saturated methanohc ammonia, and the resulting solution was stîrred at R.T. for 15 hours. The solvent was removed, and the residue was purified on a silica gel column (DCM/MeOH = 50:1 to 20:1) to give P24-4 (21.0 g, 95.8%).

[0318] Préparation of (P24-5): To a solution of P24-4 (21.0 g, 79.5 mmol) in pyridine (250 mL) was added DMTrCl (28.2 g, 83.5 mmol) at 0°C. The solution was stîrred at R.T. for 15 hours. The reaction was quenched with MeOH and concentrated to dryness under reduced pressure. The residue was dissolved în EtOAc and washed with water. The organic layer was dried over Na₂SO4 and concentrated. The residue was dissolved in DCM (300 mL). Imidazole (13.6 g, 200 mmol) and TBSC1 (30.0 g, 200 mmol) were added. The reaction mixture was stîrred at R.T. for 12 hours. The reaction mixture was washed with NaHCO₃ and brine. The organic layer was dried over Na₂SO4 and concentrated. The residue (48.5 g, 79.5 mmol) was dissolved in 80% HOAc aq. solution (400 mL). The mixture was stîrred at R.T. for 20 hours. The mixture was diluted with EtOAc and washed with NaHCO₃ solution and brine. The organic layer was dried over NaîSOj and purified by silica gel column chromatography (1-2% MeOH in DCM) to give P24-5 as a white solid (21.0 g, 70%). ^lH NMR (400 MHz, MeOD) £7.83 (d, J = 8.0 Hz. 1H), 6.14 (dd, Λ = 6.0 Hz, J₂ = 10.0 Hz, 1H), 5.73 (d, J = 8.4 Hz, 1H), 4.38-4.46 (m, 1H), 3.89-3.91 (m, IH), 3.88 (dd, J, = 2.8 Hz, J₂ = 5.2 Hz, 1H), 3.72 (dd, J_t - 2.8 Hz, J₂ = 5.2 Hz, 1H), 0.93 (s, 9H), 0.15 (m, 6H). ESI-MS: m/z 379.1 [M + H]*.

[0319] Préparation of (P24-6): To a solution of P24-5 (21.0 g, 55.6 mmol) in anhydrous CH₃CN (200 mL) was added IBX (17.1 g, 61.1 mmol) at R.T. The reaction mixture was refluxed for 1 hour and then cooled to 0°C. The precipitate was filtered off, and the filtrate was concentrated to give the aldéhyde as a yellow solid (21.0 g, 55.6 mmol). To a solution of the aldéhyde (21.0 g, 55.6 mmol) in dioxane (200 mL) were added 37% CH2O (22.2 mL, 222.4 mmol) and 2N NaOH aq. solution (55.6 mL, 111.2 mmol). The mixture was stîrred at R.T. for 2 hours and then neutralized with AcOH to pH = 7. To the reaction were added EtOH (50 mL) and NaBH* (12.7 g, 333.6 mmol). The mixture was stîrred at R.T. for 30 mins. The reaction was quenched with saturated aq. NH4CI. extracted with EA. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified by silica gel column chromatography (1-3% MeOH in DCM) to give P24-6 as a white solid (13.5 g, 59.5%).

[0320] Préparation of (P24-7): To a solution of P24-6 (13.5 g, 33.1 mmol) in DCM (100 mL) were added pyridine (20 mL) and DMTrCl (11.2 g, 33.1 mmol) at 0°C. The solution was stîrred at 25°C for 3 hours, and then treated with MeOH (30 mL). The solvent was removed, and the residue was purified by silica gel column chromatography (DCM:MeOH =

140

300:1 to 100:1) to give a residue. The residue was dissolved in anhydrous pyridine (150 mL) and TBDPSC1 (16.5 g, 60 mmol) and AgNOj (10.2 g, 60 mmol) were added. The mixture was stirred at 25°C for 15 hours, and then filtered and concentrated. The mixture was dissolved in EtOAc and washed with brine. The organic layer was dried over Na₂SO₄. Purified by silica gel column chromatography (DCM:MeOH = 300:1 to 100:1) gave the product as a yellow solid (16.2 g, 85.3%). The solid was dissolved in 80% HOAc aq. solution (400 mL). The mixture was stirred at R.T. for 15 hours. The mixture was diluted with EtOAc and washed with NaHCOj solution and brine. The organic layer was dried over Na₂SÛ4 and purified by silica gel column chromatography (DCM:MeOH = 200:1 to 50:1) to give P24-7 as a white solid (9.5 g, 86.5%).'H NMR (CDjOD. 400 MHz) J7.39-7.70 (m, HH), 6.34-6.38 (m, IH), 5.12 (d, J = 8.0 Hz, IH), 4.79 (dd, J, = 10.0 Hz, J₂ = 16.0 Hz, IH), 4.14 (dd, J, = 1.6 Hz, J₂ = 11.6 Hz, IH), 3.48-3.84 (m, 2H), 3.49 (dd, J_t - 1.6 Hz, J₂ = 11.6 Hz, 1H),1.12 (s, 9H), 0.92 (s, 9H), 0.16 (s, 6H).

[0321] Préparation of (P24-8): To a solution of P24-7 (6.0 g, 9.3 mmol) in anhydrous DCM (80 mL) was added Dess-Martin periodinane (7.9 g, 18.6 mmol) at 0°C under nitrogen. The reaction was stirred at R.T. for 1 hour. The solvent was removed in vacuo, and the residue was triturated with diethyl ether (50 mL). The mixture was filtered through a pad of MgSO₄, and the organic solvent was stirred with an equal volume of Na₂S₂O3.5H₂O in saturated NaHCOj (50 mL) until the organic layer became clear (approx. 10 min). The organic layer was separated, washed with brine, and dried over MgSO₄. After concentration in vacuo, P24-8 was obtained as a red solid (5.8 g.98%).

[0322] Préparation of (P24-9): To a mixture of methyltriphenyiphosphonium bromide (9.6 g, 27.0 mmol) in anhydrous THF (60 mL) was added n-BuLi (10.8 mL, 27.0 mmol) at -70°C under nitrogen. The reaction was stirred at 0°C for 30 mins. A solution of P24-8 (5.8 g, 9.0 mmol) in anhydrous THF (20 mL) was added dropwise at 0°C under nitrogen. The reaction was stirred at R.T. for 12 hours. The reaction was quenched with NH4CI and extracted with EtOAc. The organic layer was separated, dried and concentrated, and the residue was purified by silica gel column chromatography (DCM:MeOH » 300:1 to 100:1) to give P24-9 as a white solid (3.0 g, 51%).

[0323] Préparation of (P24-10): To a solution of P24-9 (2.9 g, 4.5 mmol) in anhydrous MeOH (20 mL) was added Pd/C (1.4 g) at 25°C under hydrogen atmosphère. The mixture was stirred at 25°C for 1 hour. The solution was filtered, evaporated to dryness and purified on a silica gel column (DCM:MeOH =3 00:1 to 100:1) to give P24-10 as a white solid (2.3 g, 79.3 %).

141 [0324] Préparation of (P24-11): To a solution of P24-10 (1.0 g, 1.55 mmol) in anhydrous CH3CN (20 mL) were added TPSC1 (940 mg, 3.1 mmol), DMAP (380 mg, 3.1 mmol) and NEt₃ (470 mg, 4.6 mmol) at R.T. The reaction was stirred at R.T. for 5 hours. NH4OH (8 mL) was added, and the réaction was stirred for 1 hour. The mixture was diluted with DCM (150 mL) and washed with water, 0.1 M HCI and saturated aq. NaHCO3. The solvent was removed, and the residue was purified by silica gel column chromatography (PE:EA = 10:1 to 1:1) to give the crude product as a yellow solid (900 mg, 90 %). To a solution of the crude product in DCM (10 mL) were added MMTrCI (930 mg, 3.0 mmol), AgNOj (510 mg, 3.0 mmol) and colliding (720 mg, 6.0 mmol) at R.T. The reaction was stirred for 12 hours at R.T. The reaction was fiitered, concentrated and purified by silica gel column chromatography (DCM:MeOH=200:l to 50:1) to give P24-11 as a yellow solid (1.1 g, 77.6%).

[0325] Préparation of (P24-12): To a solution of P24-11 (1.1 g, 1.2 mmol) in MeOH (40 mL) was added NH4F (1.0 g, 30 mmol) at 25°C and stirred at 70°C for 15 hours. The solution was fiitered and evaporated to dryness, and the residue was purified by silica gel column (DCM:MeOH = 200:1 to 20:1) to give P24-12 as a white solid (450 mg, 66.6%). *H NMR (400 MHz, MeOD) £8.58 (s, IH), 7.62 (d, J = 7.6 Hz, IH), 7.13-7.30 (m, 12H), 6.83-6.85 (m, 2H),

6.29 (d, J = 7.6 Hz, 1 H), 6.18 (d, J = 6.0 Hz, 1 H), 5.94 (t, J = 8.0 Hz, 1 H), 5.22 (t, J = 5.2 Hz, IH), 4.28-4.37 (m, IH), 3.72 (s, 3H), 3.57-3.62 (m, IH), 1.39-1.60 (m, 2H), 0.79-0.84 (m, 3H). ESI-LCMS: m/z 563.6 [M + H]⁺.

[0326] Préparation of (24a): P24-12 (250 mg, 0.44 mmol) was dissoived in 80% HCOOH in H₂O (6.0 g) at 25°C. The mixture was stirred at 35°C for 15 hours. The solution was evaporated to dryness, dissoived in MeOH (30 mL) and stirred at 60°C for 12 hours. The solution was evaporated to dryness and purified by silica gel column chromatography (DCM:MeOH = 100:1 to 100:1) to give compound 24a as a white solid (125.6 mg, 97%). ’H NMR (400 MHz, MeOD) £7.91 (d, J - 7.6 Hz, IH), 6.19 (t, J = 7.6 Hz, IH), 5.90 (d, J = 7.2 Hz, IH), 4.47 (t, J=13.6 Hz, 1 H), 3.67 (d,J= 12.0 Hz, IH), 3.52 (d, J= 12.0 Hz, IH), 1.73-1.82 (m, IH), 1.53-1.63 (m, lH),095 (t,J=7.6 Hz, 3H). ESI-LCMS: m/z 291.9 [M+H]⁺.

142

EXAMPLE 25

Préparation of Compound (25a)

TBSO

P25-3

P25-4

NHMMTr

«sN « ' λ	zP
TBDPSOVz^C<_>N
	NH
TBSÔ ''F	NHMMTr
P25-5
_n r	A/
TBDPSO^\z°x>N.
—Λ /	-
------ )_____f
TBSÔ F	NHMMTr
P25-7

NHMMTr

P25-6

P25-8

25a [0327] Préparation of (P25-2): To a solution of P25-1 (20.0 g, 70.16 mmol) in anhydrous pyridine (200 mL) was added imidazole (19.08 g, 280.7 mmol) and TBSCi (42.10 g,

280.7 mmol) at 25°C. The solution was stirred at 25°C for 15 hours, and then concentrated to dryness under reduced pressure. The residue was washed with EtOAc to give the crude product as a white solid (36.4 g). The crude product was dissolved in THF (150 mL) and H₂O (100 mL), and then HOAc (300 mL) was added. The solution was stirred at 80°C for 13 hours. The 10 reaction was cooled to R.T., and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved washed with EtOAc and dried to give P25-2 as a white solid (31.2 g, 60.9%).

[0328] Préparation of (P25-3): To a stirred solution of P25-2 (31.2 g, 78.2 mmol) in anhydrous pyridine (300 mL) was added Ac₂O (11.96 g, 117.3 mmol). The mixture was

143 stirred at 25°C for 18 hours. MMTrCl (72.3 g, 234.6 mmol) and AgNOj (39.9 g, 234.6 mmol) were then added. The solution was stirred at 25 C for 15 hours. And H₂O was added to quench the reaction. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na₂SO4 and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purifîed by silica gel (DCM:MeOH = 200.T to 50:1) to give the product. The product was dissolved in NHj/MeOH (300 mL), and the mixture was stirred at 25°C for 20 hours. The solvent was removed, and the residue was purifîed on a silica gel column (DCM:MeOH = 100:1 to 50:1) to give P25-3 as a yellow solid (28.6 g, 86.5 %). *H NMR (400 MHz, MeOD) <78.01 (s, IH), 7.237.35(m, 12H), 6.85-6.87 (m, 2H), 5.60 (dd, J_t - 11.2 Hz, J₂ = 5.6 Hz, IH), 4.78-4.94 (m, ]H),

4.44 (dd, J_t = 8.0 Hz, J₂ = 4.8 Hz, IH), 3.78 (s, 3H), 3.60-3.63 (m, IH), 3.50 (dd, J_t = 32.0 Hz, J₂ = 12.0 Hz, 2H), 3.32 (s, 3H), 0.94 (s, 9H), 0.12-0.14 (m, 6H).

[0329] Préparation of (P25-4): To a solution of P25-3 (7.24 g, 10.79 mmol) in anhydrous CHjCN (100 mL) was added IBX (3.93 g, 14.03 mmol) at 20°C. The réaction mixture was refluxed at 90°C for I hour. The reaction was filtered, and the filtrate was concentrated to give the aldéhyde as a yellow solid (7.1 g). To a solution of the aldéhyde (7.1 g,

10.6 mmol) in dioxane (80 mL) was added 37% CH₂O (4.2 mL, 42.4 mmol) and 2N NaOH aq. solution (8.0 mL, 15.9 mmol). The mixture was stirred at 25°C for 2 hours and then neutralized with AcOH to pH = 7. To reaction was added EtOH (30 mL) and NaBH» (2.4 g, 63.6 mmol), the reaction was then stirred for 30 mins. The mixture was quenched with saturated aq. NH4CI. The mixture was extracted with EA, and the organic layer was dried over Na₂SO₄. The solvent was removed, and the residue was purified by silica gel column chromatography (DCM:MeOH « 200:1 to 50:1) to give P25-4 as a yellow solid (4.86 g, 65.4%).

[0330] Préparation of (P25-5): To a solution of P25-4 (3.8 g, 5.4 mmol) in DCM (40 mL) were added pyridine (10 mL) and DMTrCl (1.8 g, 5.4 mmol) at 0®C. The solution was stirred at 25°C for 1 hour. The reaction mixture was treated with MeOH (15 mL) and concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 200:1 to 50:1) to give the mono-DMTr protected intermediate as a yellow solid (3.6 g, 66.4 %). To a solution of the intermediate in anhydrous pyridine (30 mL) were added TBDPSC1 (2.96 g,

10.8 mmol) and AgNOj (1.84 g, 10.8 mmol). The mixture was stirred at 25°C for 15 hours. The mixture was filtered and concentrated, and then dissolved in EtOAc and washed with brine. The organic layer was dried over Na₂SO4, and then concentrated. The residue was purified by silica gel column chromatography (DCM:MeOH = 200:1 to 50:1) to give the pure intermediate as a white solid (3.8 g, 85.1%). To a solution of the intermediate (3.6 g, 2.9 mmol) in anhydrous

144

DCM (50 mL) was added ChCHCOOH (1.8 mL) în anhydrous DCM (18 mL) at -78°C. The mixture was stirred at -10°C for 30 mins. The mixture was quenched with saturated aq. NaHCOj and extracted with DCM. The organic layer was dried over Na:SO₄, and then purified by silica gel column chromatography (DCM:MeOH = 200:1 to 50:1) to give P25-5 as a white solid (2.2 g, 80.7%).

[0331] Préparation of (P25-6): P25-5 (2.2 g, 2.3 mol) was added to a suspension of Dess-Martin periodinane (2.5 g, 5.8 mol) in anhydrous CH2CI2 (30 mL) at 25°C. The mixture was stirred at 25°C for 4 hours. The solvent was removed in vacuo, and the residue triturated with diethyl ether (30 mL). The mixture was filtered through a pad of MgSO₄. The organic solvent was stirred with an equal volume of NaiSîOj.SHîO in saturated NaHCOj (30 mL) until the organic layer became clear (approx. 10 min). The organic layer was separated, washed with brine, and dried over MgSO₄. The solvent was removed in vacuo to give P25-6 as a yellow solid (2.1 g, 95%).

[0332] Préparation of (P25-7): To a stirred solution of methyl-triphenylphosphonium bromide (2.3 g , 6.6 mmol) in anhydrous THF (30 mL) was added dropwise nBuLi (2.6 mL, 6.6 mmol, 2.5 M în THF) at -78°C over 1 minute. Stirring was continued at 0°C for 1 hour, P25-6 (2.1 g, 2.2 mmol) was added to the mixture, and then stirred at 25°C for 15 hours. The reaction was quenched with saturated NH₄C1 (50 mL). The mixture was extracted with EtOAc. The combined organic phase was dried with Na2SO₄, filtered and evaporated to dryness to give a light yellow oil. The oil was purified by column chromatography (DCM:MeOH = 200:1 to 50:1) to give P25-7 as a white solid (1.6 g, 76%).

[0333] Préparation of (P25-8): To a solution of P25-7 (1.6 g, 1.7 mmol) in MeOH (50 mL) was added NH4F (1.5 g, 40 mmol), and the mixture was stirred at 70°C for 15 hours. The solution was filtered and evaporated to dryness. The residue was purified by silica gel column (DCM:MeOH = 200:1 to 20:1) to give P25-8 as a white solid (450 mg, 49%). *H NMR (400 MHz, MeOD) £7.95 (s, IH), 7.21-7.33 (m, 12H), 6.82-6.84 (m, 2H), 5.92 (dd, J_t = 11.2 Hz, J₂~ 17.6 Hz, IH), 5.55-5.59 (m, IH), 5.18-5.31 (m, 2H), 4.54-4.68 (m, IH), 4.26-4.33 (m, I H), 3.76 (s, 3H), 3.43 (dd, J_t = 12.4 Hz, J₂ = 36.4 Hz, 2H). ES1-LCMS: m/z 584.1 [M + H]⁺.

[0334] Préparation of (25a): P25-8 (130 mg, 0.22 mmol) was dissolved in 80% HCOOH and the mixture was stirred at 25°C for 1 hour. Then the solution was evaporated to dryness. The residue was dissolved in MeOH (30 mL) and stirred at 60°C for 12 hours. Then the solution was evaporated to dryness, and the residue was washed by EtOAc to give P25 as a white solid (52.3 mg, 76%).^lH NMR (400 MHz, MeOD)£8.03 (s, IH), 6.17 (dd, J_t = 3.2 Hz, J₂= 16.8 Hz, IH), 6.03 (dd, J, = 11.2 Hz, J₂ = 17.2 Hz, IH), 5.50 (dd, J, =1.6 Hz, J₂ = 17.2 Hz,

145

IH), 5.23-5.38 (m, 2H),4.76 (dd, J_t = 4.8 Hz, J₂ - 18.0 Hz, IH), 3.60 (dd, Λ = 12.0 Hz, J₂ =

44.8 Hz, 2H). ESI-MS: m/z 334.1 [M + Naf.

EXAMPLE 26

Préparation of Compound (26a)

TBDPSO .N

P26-2

NHMMTr

[0335] Préparation of (P26-1): To a stirred solution of P25-6 (2.1 g, 2.2 mmol) in pyridine was added HONHj.HCl (0.61 g, 8.8 mmol) at 25°C. The mixture was stirred at 25°C for 2 hours. The mixture was concentrated, and the residue was purified by column chromatography (DCM:MeOH = 200: t to 50: t) to give P26-1 as a white solid (1.8 g, 83%).

[0336] Préparation of (P26-2): To a stirred solution of P26-1 (1.4 g, 1.47 mmol) in DCM were added TEA (0.44 g, 4.4 mmol) and methanesulfonyl chloride (0.34 g, 2.9 mmol) at 0°C. The mixture was stirred at 25°C for 1 hour. The mixture was quenched with saturated aq. NaHCOj and extracted with DCM. The organic phase was dried with Na₂SO4, filtered and evaporated. The residue was purified by column chromatography (DCM:MeOH = 200:1 to 50:1) to give P26-2 as a white solid (1.1 g,79%).

[0337] Préparation of (P26-3): To a solution of P26-2 (1.1 g, 1.18 mmol) in MeOH (50 mL) was added NH4F (1.5 g, 40 mmol), and the mixture was stirred at 70ⁿC for 15 hours. The solution was filtered and evaporated to dryness. The residue was purified by silica gel column (DCM:MeOH = 200:1 to 20:1) to give P26-3 as a white solid (400 mg, 71%). ’H NMR (400 MHz, MeOD) J7.80 (s, IH), 7.20-7.32 (m, I2H), 6.86-6.88 (m, 2H), 5.82 (dd, Jt = 2.0 Hz,

146

Λ = 20.0 Hz, IH), 4.51-4.66 (m, IH), 3.94 (dd, J_t = 5.2 Hz, J₂ = 20.8 Hz, IH), 3.78 (s, 3H), 3.56 (dd, J_t = 12.4 Hz, Λ = 42.0 Hz, 2H). ESI-LCMS: m/z 583.1 [M + H]⁺.

[0338] Préparation of (26a): P26-3 (200 mg, 0.34 mmol) was dissolved in 80% HCOOH aq. solution. The mixture was stirred at 25°C for 1 hour. The solution was evaporated to dryness, dissolved in MeOH (30 mL) and stirred at 60°C for 12 hours. The solvent was removed, and the residue was washed by EtOAc to give compound 26a as a white solid (100.4 mg, 95%). *H NMR (400 MHz, MeOD) £7.90 (s, IH), 6.34 (dd, J_t = 2.0 Hz, J₂ = 19.6 Hz, IH),

5.49 (ddd, J₂ = 1.6 Hz, J₂ = 4.4 Hz, Jj - 52.4 Hz, IH), 5.01 (dd, J, = 4.8 Hz, J₂ = 20.8 Hz, IH),

3.93 (dd, Jt = 12.4 Hz, J₂ = 44.8 Hz, 2H). ESI-MS: m/z 311.1 [M + H]⁺.

EXAMPLE 27 Préparation of Compound (27a)

P25-6

[0339] Préparation of (P27-1): To a stirred solution of chloromethyl-triphenylphosphonium chloride (1.9 g , 5.4 mmol) in anhydrous THF (30 mL) was added dropwise nBuLÎ (2.16 mL, 5.4 mmol, 2.5 M in THF) at -78°C over 10 mîns. Stirring was continued at 78°C for 2 hours. P25-6 (1.7 g, 1.8 mmol) was added, and the mixture and stirred at 25°C for 15 hours. The reaction was quenched with saturated NH4CI (50 mL). The mixture was extracted with EtOAc. The combined organic phase was dried with Na^SOj, filtered and evaporated to dryness to give a light yellow oil. The oil was purified by column chromatography (DCM:MeOH = 200:1 to 50:1 ) to give P27-1 as a white solid ( 1.2 g, 70%).

147 [0340] Préparation of (P27-2): To a stirred solution of P27-1 (1.2 g, 1.3 mmol) in anhydrous THF (20 mL) was added dropwise n-BuLi (8.0 mL, 20 mmol, 2.5 M in THF) at -78°C over 10 minutes. Stirring was continued at -78°C for 4 hours. The reaction was quenched with saturated NH4CI (50 mL). The mixture was extracted with EtOAc (50 x 2 mL). The combined organic phase was dried over NaîSO-i, filtered and evaporated to dryness. The residue was purified by column chromatography (DCM:MeOH = 200:1 to 50:1) to give P27-2 as a white solid (1.0 g, 83%).

[0341] Préparation of (P27-3): To a solution of P27-2 (1.0 g, 1.1 mmol) in MeOH (40 mL) was added NH4F (1.5 g, 40 mmol), and the mixture was stirred at 70°C for 25 hours.

The solution was filtered, and the filtrate was evaporated to dryness. The residue was purified on a silica gel column (DCM:MeOH = 200:1 to 20:1) to give P27-3 as a white solid (240 mg, 38%). ’H NMR (400 MHz, MeOD) £7.85 (s, IH), 7.21-7.31 (m, 12H), 6.84-6.87 (m, 2H), 5.67 (dd, Λ =1.6 Hz, J₂ = 19.2 Hz, IH), 4.47-4.62 (m, IH), 3.94 (dd, J_t = 5.2 Hz, J₂ = 22.4Hz, IH), 3.77 (s, 3H), 3.56 (dd, J, = 12.4 Hz, J₂ - 47.2 Hz, 2H), 3.04 (s, 1 H). ESI-LCMS: m/z 582.1 [M +

H]⁺.

[0342] Préparation of (27a): P27-3 (130 mg, 0.22 mmol) was dissolved in 80% HCOOH aq. solution. The mixture was stirred at 25°C for 1 hour. The solution was evaporated to dryness. The residue was dissolved in MeOH (30 mL) and stirred at 60°C for 12 hours. The solvent was removed, and the residue was washed with EtOAc to give compound 27a as a white 20 solid (43.0 mg, 63%). ’H NMR (400 MHz, MeOD) £7.95 (s, IH), 6.22 (dd, J_t = 2.4 Hz, J₂ = 18.4Hz, IH), 5.49 (ddd, J_t = 2.0 Hz, J₂ = 4.8 Hz, J₃ = 53.2 Hz, IH), 4.77 (dd, J_t = 5.2 Hz, J₂ = 20.0 Hz, IH), 3.79 (dd, J_t = 12.4 Hz, J₂ = 46.8 Hz, 2H), 3.12 (s, 3H). ESI-MS: m/z 310.1 [M + H]⁺.

148

EXAMPLE 28

Préparation of Compound (28a)

P25-1 P28-1 P28-2

[0343] Préparation of (P28-1); To a stirred solution of P25-1 (5.7 g. 20 mmol) in 5 anhydrous pyridine (20 mL) was added dropwise AC2O (5.8 mL, 60 mmol) at 0°C. The mixture was stirred at R.T. for 10 hours. AgNO3 (8.5 g, 50 mmol) and MMTrCl (15.5 g, 50 mmol) were added. The mixture was stirred at R.T. for 10 hours. The solution was quenched with saturated NaHCCh and extracted with EA. The organic layer was dried over Na^SO-i and concentrated. The residue was purified on a silica gel column (DCM/MeOH = 100:1 to 50:1) to afford the 10 intermediate as a light yellow solid (12.1 g, 93.4%). The solid was treated with saturated NH3 in

MeOH at R.T. for 14 hours. The solvent was removed, and the residue was purified by silica gel column chromatography (DCM/MeOH = 80:1 to 30:1) to afford P28-1 as a white solid (9.2 g, 87.5%).

[0344] Préparation of (P28-2): To a stirred solution ofP28-1 (9.2 g, 16.5mmol) in 15 dry THF (300 mL) were added imidazole (9.0 g, 132 mmol) and PPI13 (34.8 g, 132 mmol). A solution of I2 (26.0 g, 103 mmol) in THF (100 mL) was added dropwise under N2 at 0°C. The mixture was stirred at R.T. for 18 hours. The reaction was quenched with N32S2Û3 solution, and the mixture was extracted with EtOAc. The organic layer was dried over Na^SO-i and

149 concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH =

80:1 to 30:1) to give P28-2 as a light yellow solid (10.3 g, 93.4%).

[0345] Préparation of (P28-3): To a stirred solution of P28-2 (10.2 g, 15.3 mmol) in dry THF (300 mL) was added DBU (4.7 g, 30.1 mmol). The mixture was stirred at 60°C for 8 hours. The solution was diluted with NaHCOj solution and extracted with EtOAc. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified by silica gel column chromatography (ΡΕ/EtOAc = 3:1 to 1:3) to afford P28-3 as a light yellow foam (6.2 g, 75.6 %). ‘H NMR (CD₃OD, 400 MHz) 81.11(s, 1H), 7.23-7.76 (m, 14H), 6.74 (d, J = 0.8 Hz, 2H), 5.835.88 (dd, J_t = 2.8 Hz, J₂ = 16.0 Hz, 2H), 4.57-4.89 (m, 2H), 4.30-4.35(m, 1H), 4.79 (s, 3H). ESIMS: m/z 540 [M + H]⁺.

[0346] Préparation of (P28-4): To a stirred solution of P28-4 (5.42 g, 10 mmol) in anhydrous CH₃OH (100 mL) were added PbCO₃ (13.7 g, 53.Immol) followed by a solution of I₂(12.3 g, 48.9 mmol) in CH₃OH (300 mL) at 0°C. The mixture was stirred at R.T. for 10 hours. The solution was quenched with a Na₂S₂O₃ solution and extracted with DCM. The organic layer was washed with NaHCO₃ solution, dried over Na₂SO4 and concentrated. The residue was purified by pre-HPLC (MeCN and 0.1% HCOOH in water) to give the pure product as a white foam (2.4 g, 34 %). The product was dissolved in dry pyridine (20 mL) and BzC! (723 mg, 5.2 mmol) was added dropwise at 0°C. The mixture was stirred at 0°C for 1 hour. The solution was quenched with NaHCO₃ solution, and extracted with EtOAc. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified by silica gel column chromatography (ΡΕ/EtOAc = 5:1 to :1) to afford P28-4 as a white solid (2.1 g, 77.1%).

[0347] Préparation of (P28-5): P28-4 (2.0 g, 2.5 mmol), BzONa (3.6 g, 25 mmol) and 15-crown-5 (5.5 g, 25 mmol) were suspended in DMF (50 mL). The mixture was stirred at 110-125°C for 5 days. The precipitate was removed by filtration, and the filtrate was diluted with EA. The solution was washed with brine and dried over Na₂SO4. The solvent was removed, and the residue was purified on a silica gel column (PE/EA = 10/1 to 2/1) to afford crude P28-5 as a light yellow foam ( 1.6 g, 80%).

[0348] Préparation of (P28-6): P28-5 (1.6 g, 2.0mmol) was dissolved in methanolic ammonia (100 mL, saturated), and the mixture was stirred at R.T. for 20 hours. The solvent was removed, and the residue was purified on a silica gel column (DCM/MeOH = 100:1 to 20:1) to give P28-6 as a white solid (410 mg, 34.9%). *H NMR (400 MHz, MeOD) £7.84 (s, 1H), 7.207.33 (m, 12H), 6.83-6.86 (m, 2H), 5.64 (dd, J, - 1.6 Hz, J₂ = 18.4 Hz, 1H), 4.46-4.62 (m, 1H), 4.08 (dd, J, = 6.0 Hz, J₂ = 22.0 Hz, 1H), 3.76 (s. 3H), 3.58 (dd, J, = 12.4 Hz, J₂ = 30.4 Hz. 2H),

3.31 (s, 3H). ESI-LCMS: m/z 588.1 [M + H]⁺.

150 [0349] Préparation of (28a): P28-8 (200 mg, 0.34 mmol) was dissoived in 80% HCOOH and the mixture was stirred at 25°C for 1 hour. The solution was evaporated to dryness, and the residue was dissoived in MeOH (30 mL) and stirred at 60°C for 12 hours. The solvent was removed, and the residue washed with EtOAc to give compound 28a as a white solid (46.1 mg, 43%). ’H NMR (400 MHz, MeOD) £7.92 (s, IH), 6.22 (dd, J/ = 1.6 Hz, J₂ =

18.8 Hz, IH), 5.25 (ddd, J_t = 1.6 Hz, J₂ = 6.0 Hz, Jj = 54.0 Hz. IH), 4.89-4.91 (m, IH), 3.87 (d,

11.6 Hz, IH), 3.67 (d, J = 12.0 Hz. 1H),3.44 (s, 3H). ESI-MS: m/z 316.1 [M + H]⁺.

EXAMPLE 29 Préparation of Compound (29a)

O [0350] DEAD (40% in toluene, 0.15 mL, 0.33 mmol) was added to a stirred solution of triphenylphosphine (78 mg, 0.3 mmol) in anhydrous 1,4-dîoxane (0.5 mL) at 0°C under argon. The mixture was warmed up to R.T. and compound 10a (26 mg, 0.1 mmol) and bis(pivaloyloxymethyl)phosphate (98 mg, 0.3 mmol) were added. The resulting mixture was stirred at 65°C for 3 days. Diisopropylethylamine (50 gL) was added, and the mixture was stirred at 70°C for 3 days. Another reaction of the same scale was conducted separately. The two reaction mixtures were combined and concentrated. Chromatography on silica gel with 510% methanol in DCM gave the desired product (20 mg) with a minor impurity. A second chromatography on silica gel, followed by RP HPLC with acetonitrile/water, gave the compound (2.8 mg ) as a colorless residue; ^lH NMR (CD3OD, 400 MHz) £7.65 (d, J = 8.0 Hz, IH), 5.94 (dd, J, = 2.4 Hz, J₂ = 18.8 Hz. IH), 5.70 (d, J = 8.0 Hz, IH), 5.69 (d, J = 0.8 Hz, IH), 5..68 (s, 1 H), 5.654 (d, J = 1.2 Hz, 1 H), 5.650 (s, I H), 5.21 (dd, J = 2.0,5.2 Hz, 0.5H), 5.07 (dd, 2.0, 5.2 Hz, 0.5H), 4.42 (dd, J = 5.6, 20.8 Hz, IH), 4.14 (m, 2H), 1.223 (s, 9H), 1.220 (m, 9H); ^3lP NMR (CD3OD) 4.92 (s); MS: m/z 698 [M + 2-methyIheptyIamine]⁺.

151

EXAMPLE 30

Préparation of Compound (30a)

80% aq. HCOOH _

35-37°C; 3 h

[0351] Préparation of (1-2): To a solution of 1-1 (313 mg; 0.55 mmol) in THF (8 mL) under Ar was added a solution of triethylammonium bis(POM)phosphate in THF (prepared from bis(POM)phosphate (215 mg ; 1.2 equiv), THF (2 mL) and Et₃N (0.1 mL; 1.3 equiv)). The resulting mixture cooled in an ice-bath. Diisopropylethyl amine (0.38 mL; 4 equiv) was added. BOP-C1 (280 mg; 2 equiv) and 3-nitro-l,2,4-triazole (125 mg; 2 equiv) was then added. The reaction mixture was stirred at 0°C for 90 mins. The mixture was diluted with CH2CI2 (60 10 mL) and washed with saturated aq. NaHCOj (2 x 10 mL) and brine. The combined aqueous layers were back extracted with CH2CI2 (—20 mL). The combined organic extract was dried (Na₂SO4) and evaporated. The residue purified on silica (25 g column) with CH2CI2 /i-PrOH solvent system (2-10% gradient). Yield: 140 mg (27%).

[0352] Préparation of (30a): A solution of 1-2 (110 mg; 0.13 mmol) in 80% aq.

formic acid was heated at 35-37°C for 3 hours. The mixture was evaporated to give an oily residue. The residue was co-evaporated 2 times with toluene. Purification on a silica gel column (10 g) with CH2CI2 /MeOH solvent system (4-10% gradient) to afford compound 30a (46 mg, 59% yield). ^3IP-NMR (DMSO-dé): δ -4.45. MS: m/z 646 (M+46-1).

152

EXAMPLE 31

Préparation of Compound (31a)

NHDMT

2-1

ΒΟΡ-CI, DIPEA, NT

THF; 0°C; 90 rrin

NHDMT

80% aq. HCOOH 35-37°C;3h

[0353] Préparation of (2-2): To a solution of 2-1 (370 mg; 0.64 mmol) in THF (10 mL) under Ar was added triethylammonium bis(POM)phosphate (330 mg; 1.2 equiv). The mixture cooled in ice-bath, and diisopropylethyl amine (0.42 mL; 4 equiv) was added. BOP-Cl (305 mg; 2 equiv) and 3-nitro-l,2,4-triazole (137 mg; 2 equiv) was then added. The reaction mixture was stirred at 0°C for 90 mins. The mixture was diluted with CH2CI2 (50 mL) and washed with saturated aq. NaHCOj (2 x 10 mL) and brine. The combined aqueous layers were 10 back extracted with CH₂C1₂ (-20 mL). The combined organic extract was dried (NajSO^, evaporated, and the residue purified on silica (25 g column) with CH2CI2 /i-PrOH solvent System (2-10% gradient). Yield: 154 mg (27%).

[0354] Préparation of (31a): A solution of 2-2 (68 mg; 0.08 mmol) in 80% aq. formic acid was stirred at R.T. for 3 hours. The mixture was evaporated to an oily residue. The 15 residue was co-evaporated 2 times with toluene. Purification on a silica gel column (10 g) with CH2CI2 /MeOH solvent System (4-10% gradient; target compound eluted with 8% MeOH) afforded 31a (35 mg, 78% yield). ^JIP-NMR (DMSO-dô): δ -4.19. MS: m/z 580 (M-l), 646 (M+46-1), 55O(M-3O-1).

153

EXAMPLE 32

Préparation of Compound (32a)

O

hc5 ¥

3-1

ΒΟΡ-CI, DIPEA, NT

THF; 0°C; 90 min

[0355] To a solution of 3-1 (71 mg; 0.26 mmol) in THF (4 mL) under Ar was added triethylammonium bis(POM)phosphate (144 mg; 1.2 equiv), and the resulting mixture was cooled in an ice-bath, and diisopropylethyl amine (0.18 mL; 4 equiv) was added. BOP-C1 (132 mg; 2 equiv) and 3-nitro-l,2,4-triazole (59 mg; 2 equiv) was then added. The reaction mixture was stirred at 0°C for 1 hour. The mixture was diluted with CH2CI2 (50 mL) and washed with saturated aq. NaHCO₃ (2x10 mL) and brine. The combined aqueous layers were back extracted 10 with CH2CI2 (-20 mL). The combined organic extract was dried (Na,S Ou), evaporated, and the residue was purified on silica (10 g column) with C^Ch/MeOH solvent system (4-10% gradient), Compound 32a was repurified by RP-HPLC (35-90%B; A: water, B: MeOH). Yield 75 mg (50%). ³¹P-NMR (DMSO-dô): δ-4.14. MS: m/z 627 (M+46-1), 551 (M-30-l).

154

EXAMPLE 33 Préparation of Compound (33a)

[0356] Préparation of (4-2): To a solution of 4-1 (0.29 g; 0.5 mmol) in MeCN (8 mL) was added 5-ethylthio-lH-tetrazole in MeCN (0.25 M; 2.4 mL; 1.2 equiv). BisSATEphosphoramidate (0.24 g; 1.05 equiv.) in MeCN (1.5 mL) was added over 90 mins. The reaction mixture was stirred for 4 hours at R.T., and then cooled to -40°C. MCPBA (0.23 g; 2 equiv.) in CHjCh (3 mL) was added. The mixture was allowed to warm to R.T. and diluted with

EtOAc(50 mL). The mixture was washed with 10% aq. NaHSOj (2 x 10 mL), saturated aq. 10 NaHCOj (2 x 10 mL) and brine. The mixture was then dried (NajSOa). The evaporated residue was purified on silica (10 g column) with CH2CI2 /MeOH solvent System (4-10% gradient) to afford 4-2 (0,26 g, 55% yield).

[0357] Préparation of (33a): A solution of 4-2 (0.21 g; 0.22 mmol) in 80% aq. AcOH (15 mL) was stirred 4 hours at R.T. The mixture was evaporated and purified on silica 15 (10 g column) with CfyCl, /MeOH solvent System (4-10% gradient). Yield: 0.13 g (90%). ^3IPNMR (DMSO-dô): δ -2.00. MS: m/z 686 (M+46-1).

155

EXAMPLE 34

Préparation of Compounds (34a)-(34e)

î ? ..

OH OH OH ?

I

[0358] i,2,4*Triazol (42 mg, 0.6 mmol) was suspended of dry CHjCN (1 mL).

Triethylamine was added (0.088 mL, 0.63 mmol), and the mixture was vortexed to obtain a clear solution. After addition of POCI3 (0.01 mL, 0.1 mmol), the mixture was vortexed and left for 20 min. The mixture was then centrifugated. The supematant was added to the protected nucleoside (0.05 mmol), and the mixture was kept at ambient température for 1 hour. Tris(tetrabutylammonium) hydrogen pyrophosphate (180 mg, 0.2 mmol) was added, and the 10 mixture was kept for 2 hours at R.T. The reaction was quenched with water, evaporated, dissolved in 80% formic acid and left for 2 hours at R.T. Formic acid was evaporated, and the residue dissolved in water (5 mL) and extracted with EA (2 x 2 mL). The aqueous fraction was loaded onto column HiLoad 16/10 with Q Sepharose High Performance (linear gradient of NaCl from 0 to IN in 50mM TRIS-buffer (pH = 7.5)). Fractions containing the triphosphate were 15 combined, concentrated and desalted by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex) using a linear gradient of methanol from 0 to 20% in 50mM triethylammonium acetate buffer (pH 7.5) for elution. The following compounds shown in Table 1 were synthesized according this procedure:

Table 1 - Triphosphates obtained from Example 34

Compound

^3lPNMR Pot

³¹pnmr Ρβ

^J1PNMR _

MS (M')

156

^{0 0 0} -- N _n ho-H-o-P-o-Lo^o^Qy⁰ Ah Ah Ah //^—C ^Ν*γ^ΝΗ HO F '_Nh₂ 34a	-11.31 d	-20.82 t	-5.48 d	550.2
^{0 0 0} rssN _n H0-P-0-P-0-Î-0'*\z0_>anM^ oh oh Ah ^Ν=γ^ΝΗ HO Φ M 34b	-9.13 d	-18.18 t	-2.85 d	548.2
0 0 0 «sN n HO-P-O-P-O-P-O^VxO^nMM oh oh Ah /ⁿ⁼Y^NHHO F NH₂ 34c	-10.95 d	-20.62 bs	-5.37 bs	552.2
ô ô ô ~ “ ΗΟ-Η-Ο-Ρ-Ο-Ρ-οΆ^Ο^αΝ MM OH OH OH /° >-/ Nas/^NH HÔ* F \h₂ 34d	-11.24 d	-20.82 t	-5.48 d	554.2
ΗΟ-ί-Ο-^-Ο-Ρ-Ο-χχΟ^Ν^Α?⁰ OH OH OH Nss/^NH ^N HÔ* 'F 34e	-12.06 d	-20.97 t	-5.69 d	549.2

157

EXAMPLE 35 Préparation of Compound (35a)

O

NHa

HO F [0359] 1,2,4-Triazol (42 mg, 0.6 mmol) was suspended in dry CH3CN (1 mL). 5 Triethylamine was added (0.088 mL, 0.63 mmol), and the mixture was vortexed to obtain a cîear solution. After addition of POCI3 (0.01 mL, 0. î mmol), the mixture was vortexed and left for 20 mins. The mixture was centrifugated, and the supematant was added to the protected nucleoside (0.05 mmol). The mixture was kept at ambient température for 1 hour. Tris(tetrabutylammonium) hydrogen pyrophosphate (180 mg, 0.2 mmol) was added, and the 10 mixture was kept for 2 hours at R.T. The reaction was quenched with water, evaporated, dissoived in ammonium hydroxide and left for 2 hours at R.T. The solvent was evaporated, and the residue dissoived in water (10 mL). The mixture was loaded onto a column HiLoad 16/10 with Q Sepharose High Performance. Séparation was done in linear gradient of NaCl from 0 to IN in 50mM TRIS-buffer (pH7.5). The fractions containing the product were combined, 15 concentrated and desalted by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex).

A linear gradient of methanol from 0 to 20% in 50mM triethylammonium acetate buffer (pH 7.5) was used forelution, MS (M-l): 532.1. ^3IP-NMR (Sppm): -5.12 (d), -11.31 (d) and -20.43 (t).

158

EXAMPLE 36

Préparation of Compounds (36a)-(36d)

NH₂

O *

HO F

N—

POCLj/PO(OMe)₃pyrophosphate

R R

2’-Deoxy-2^,-fluoro-4’-alkyl-cytidine (0.09 [0360]

to mmol) was dîssolved in the mixture of DMF (5 mL) and Ν,Ν’-dimethylacetate in DMF (0.110 mL, 0.9 mmol). The reaction mixture left at R.T. ovemight. The solvent was evaporated, and the residue purified by flash chromatography in gradient of methanol in DCM from 3% to 20%. The N-Protected nucleoside was concentrated in vacuum, dried and dîssolved in dry trimethylphosphate (0.7 mL). The solution was cooled to 4°C and POClj (0.017 mL, 0.18 mmol) was added. In 1 hour, tributylamine (0.102 mL, 0.3 mmol) was added at R.T. Tributylammonium pyrophosphate (156 mg. 0.34 mmol) was then added. Dry DMF (about 0.100 mL) was added to solubîlize pyrophosphate. After 2 hours, the reaction was quenched with TEAB-buffer. The product was isolated by ion-cxchange chromatography on AKTA Explorer as described in Example 35. The fractions containing the product were concentrated and treated with NH4OH for 2 hours at R.T. The product was desalted by RP HPLC as described in Example 35.

Table 2 - Triphosphates obtained from Example 36

	^JIPNMR Pa	^J1PNMR Ρβ	^JIPNMR py	MS (M”)
^,ΝΗί ? 1? ïï ho-p-o-p-o-p-o^o^ Ah oh oh /U 0 HO F 36a	-11.38 bs	-22.88 bs	-7.62 bs	512.1
^>H₂000 ZAf Il II II ί N HO-P-O-P-O-P-O^ry^^NOH OH OH ο ^HO F	-11.49 bs	-20.41 bs	-5.34 bs	510.0

159

36b
î î î r* HO-P-O-P-O-P-O-. O N^ OH OH OH Λ? \_J O 'nO 36c	-11.96 bs	-22.07 t	-5.66 d	508.3
JW₂ î î ? ΗΟ-Ρ-ο-Ρ-Ο-Ρ-Ο-ν,Ο Ν-^ OH OH OH P' / O 'h<s 36d	-11.90 d	-23.23 t	-10.66 d	514.0
NH_Z OH OH OH H0-^-0-£-0-£-0—χ 0 ^{11 11 11} . Zjf’ r D O 0 0 f^r\T ^Γ πσ f 36e	-11.77 d	-23.05 t	-9.70 s	529.9
nh₂ OH OH OH HO-P-O-P-O-P-O—χ n ii n « '•Λ 0 0 0 y--° ho’ î 36f	-11.74 d	-23.37 t	-10.85 d	539.2
NHj oh oh oh Η0-Ρ-0-Ρ-0-Ρ-0—Χ 0 /¹¼ 0 & o —J HÔ f 36g	-11.87 d	-23.32 t	-10.83 d	523.9
NHj oh oh oh HO-P-O-P-O-P-O—x o s s s JXY ° 'ho* f 36h	-11.48 d	-23.26 t	-10.63 d	526.1
NHj OH OH OH H0-P-0-P-0-P-0—X n .N-Z n n il 'r n 0 0 0 y--\_/ ^U ---1 HÔ 'f 361	-11.67 d	-23.22 t	-10.77 d	554.1
NHj OH OH OH HO-P-O-P-O-P-O—X 0 δ δ o2\j ° 36J	-11.97 d	-23.34 t	-10.92 d	523.9

160

EXAMPLE 37 Préparation of Compounds (37a)

[0361] Compound 37a was synthesized by reaction of phosphor(tris-triazolide) with 4’-ethyl-2’-deoxy-2’-fluoro-uridine as described Examples 34 and 35. MS (M-l): 513.1. ^3IPNMR (δ ppm): -9.43 (bs), -11.68 (d) and -23.09 (bs).

EXAMPLE 38 Préparation of Compounds (38a)

[0362] The starting nucleostde (15 mg, 0.05 mmol) was dissolved in dry trimethylphosphate (3 mL). The solution was cooled to 4°C. POClj (0.013 mL, 0.125 mmol) was added, followed by pyridine (0.01 mL, 0.125 mmol). In 1 hour, tributylamine (O.O35mL, 0.125 mmol) was added at R.T. followed by tributylammonium pyrophosphate (156 mg, 0.34 mmol). Dry DMF (about 0.100 mL) was added to solubilize pyrophosphate. In 2 hours, the reaction was quenched with TEAB-buffer. The product was isolated by ion-exchange chromatography on AKTA Explorer as described in Example 35. The fractions containing the product were concentrated and treated with NH*OH for 2 hours at R.T. The product was desalted by RP HPLC as described in Example 35. MS (M-l): 529.9. ³¹P-NMR (δppm): 9.42(d), -11.59(d) and -23.03(t).

161

EXAMPLE 39

Préparation of Compound (40a) ho^a,M_o

HO' 'F

40-1 f NPMB

Bnd 'F

40-2

J f NPMB ho-^o_v ⁿ-< _

J (^z NPMB ΒηΟ-χ/Κ/^ BzO^'YJ ⁰-BnO' 'F

40-4 <^z NPMB BnO-V/k/H ΗΟ^·\_/ O —

BnÔ 'F

40-5

NHMMTr fXl ΒηΟ-νΛ/·-^ -BnO' 'F

40-9 *IPMB

ΒηΟ-χ,Ο_ν ^Ν“< __ >Λ_/

BnO' 'F

40-7 rCn BnO-\.O^.^N_ ></ °

BnO' 'F

40-8

NHMMTr

Hd 'F

40-10

NH, fSl

H<J >.

40a [0363] Préparation of (40-2): To a solution of 40-1 (50.0 g, 205 mmol) in pyridine (250 mL) was added DMTrCl (75.0 g, 225.0 mmol). The solution was stirred at R.T. for 15 hours. MeOH (120 mL) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EA and washed with water. The organic layer was dried over Na^SO.» and concentrated to give the crude 5’-O-DMTr intermediate (80.52g) as a light yellow solid. The intermediate was dissolved in anhydrous DMF (300 mL), and K2CO3 (80.52g,

583.2 mmol) was added followed by PMBC1 (31.7 g, 109.2 mmol). The mixture was stirred at

R.T. ovemight. The reaction was diluted with EA and washed with brine. The organic phase was dried over NajSCh and concentrated to give crude 5’-O-DMTr-N3-PMB FdU (98.8 g) as a light yellow solid. The solid was dissolved in DMF (300 mL), and NaH (10.42 g, 260.5 mmol) was added followed by BnBr (73.8 g, 434.2 mmol). The reaction was stirred at R.T. ovemight and then was quenched with water. The solution was diluted with EA and washed with brine. The organic phase was dried over Na₂SO4 and concentrated to give the crude fully blocked FdU intermediate, which was purified on a silica gel column (PE:EA = 10:1 to 3:1) to the pure fully blocked FdU (101.1 g). The intermediate was treated with 80% HOAc (900 mL) at R.T.

162 ovemight, and the solvent was removed. The residue was purified on a silica gel column to give 40-2 as a white foam (42.1 g, 30.2% for 4 steps).

[0364] Préparation of (40-3): To a solution of 40-2 (42.1 g, 92.6 mmol) in anhydrous CH₃CN (300 mL) was added IBX (28.5 g, 121.7 mmol) at R.T. The reaction mixture 5 was refluxed for 1 hour and then cooled to 0°C. The precîpitate was filtered-off, and the filtrate was concentrated to give the crude aldéhyde (39.22 g) as a yellow solid. To a solution of the aldéhyde (39.22 g) in 1,4-dioxane (250 mL) was added 37% CH₂O (28.1 mL, 345.6 mmol) and 2N NaOH aqueous solution (86.4 mL, 172.8 mmol). The mixture was stirred at R.T. for 2 hours and then neutralized with AcOH to pH = 7. EtOH (200 mL) and NaBH₄ (19.7 g, 518.6 mmol) 10 were added, stirred at R.T. for 30 mîns. The mixture was quenched with saturated aqueous

NH4CI, and extracted with EA. The organic layer was dried over Na2SO₄ and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 4:1 to 2:1) to give 40-3 (25.5 g, 55.7%) as a white solid.

[0365] Préparation of (40-4): To a stirred solution of 40-3 (25.5 g, 52.5 mmol) in 15 anhydrous pyridine (150 mL) and anhydrous CH₃CN (150 mL) was added BzCI (6.6 g, 52.47 mmol) dropwise at 0°C. The mixture was stirred at R.T. for 14 hours. The reaction was quenched with H₂O, and the solution was concentrated. The residue was dissolved in EA and washed with saturated NaHCO₃. The organic layer was dried over Na2SO₄ and concentrated. The residue was purified on a silica gel column (PE/EA = 5:4) to give the mono-Bz protected 20 întermediate (18.1 g, 60.0%) as a white foam. To a stirred solution of this întermediate (18.1 g, 30.68 mmol) in DMF (100 mL) were added Cs2CO₃ (30.0 g, 92.03 mmol) and BnBr (10.4 g, 61.36 mmol). The mixture was stirred at R.T. ovemight. The reaction was quenched with saturated NH₄C1 aq., extracted with EA and washed with brine. The solvent was removed to give crude 40-4 (19.3g, 95.1%) as a light yellow solid.

[0366] Préparation of (40-5): To a stirred solution of 40-4 (19.3 g, 28.4 mmol) in anhydrous MeOH (230 mL) was added NaOMe (24.9 g, 460 mmol) at R.T. The mixture was stirred for 1 hour. The reaction was quenched with AcOH (10 mL) and concentrated. The residue was purified on a silica gel column (PE/EA = 1/2) to afford 40-5 (11.2 g, 54.0%) as a white solid.

[0367] Préparation of (40-6): To a stirred solution of compound 40-5 (200 mg,

0.347 mmol) in anhydrous DCM (5 mL) was added DMP (168 mg, 0.674 mmol) at R.T. The mixture was stirred at R.T. for 2 hours. The solvent was removed, and the residue was purified on a silica ge! column (PE:EA = 5:1 to 1:1) to give the aldéhyde crude as a light yellow solid (200 mg). T o a stirred solution of the aldéhyde (200 mg) in anhydrous THF (5 mL) was added

163

MeMgBr (1.0 mL, 1.01 mmol) at -78 C. The mixture was stirred at -78°C for 1 hour. The reaction was quenched with saturated NH4CI aq .and extracted with EA. The concentrated organic phase was purified by column chromatography (PE: EA = 5:1 to 1:1) to give 40-6 (a mixture of stereomers, 135 mg, 65%) as a white solid.

[0368] Préparation of (40-7): To a stirred solution of DAST (1.64 g, 10.17 mmol) in anhydrous toluene (40 mL) was added dropwise a solution of compound 40-6 (1.2 g, 2.03 mmol) at -78°C. The mixture was stirred at -78°C for 30 mins. The solution was warmed to 60°C slowly and stirring was continued ovemight. The mixture was poured into a saturated NaiCOj solution. The concentrated organic phase was concentrated and purified on a silica gel column (PE:EA = 10:1 to 3:1) to afford 40-7 as a white solid (1.08 g, 83.88%). *H NMR (CD3OD, 400 MHz) £7.87 (d, J= 8.4Hz, IH), 7.27-7.37 (m, 12H), 6.82-6.84 (m, 2H), 6.14 (d, J =16.8,2.0Hz, IH), 5.18-5.50 (m, 4H), 4.96 (s, 2H), 4.45-4.88 (m, 7H), 3.67-3.89 (m, 5H).

[0369] Préparation of (40-8): A mixture of compound 40-7 (0.91g, 1.54 mmol) and CAN (2.53 g, 4.61 mmol) in a 3:1 solution of MeCN:water (10 m L) was stirred at R.T. ovemight. Brine (10 mL) was added, and the mixture was extracted with EA. The combined organic extracts were dried and evaporated under reduced pressure. Purification by chromatography on silica gel column with PE: EA=10:l to 2:1 afforded 40-8 as a yellow solid (305 mg, 41.96%).

[0370] Préparation of (40-9): To a stirred solution of 40-8 (350 mg, 0.74 mmol) in anhydrous MeCN (8 mL) were added TPSC1 (449 mg, 1.48 mmol), DMAP (180 mg, 1.48 mmol) and TEA (374 mg, 3.70 mmol) at R.T. The mixture was stirred at R.T. ovemight. NH4OH (15 mL) was added, and the mixture was stirred for 2 hours. The solvent was removed, and the residue was purified on a silica gel column with PE: EA=8:1 to 1:1 to afford the crude (380 mg crude), which was dissolved in anhydrous DCM (10 mL). A mixture of MMTrCl (695mg, 2.25mmol) and AgNO₃ (380mg, 2.25 mmol) was added at R.T., and the mixture was stirred at R.T. ovemight. The solid was filtered off and washed with DCM. The filtrate was washed with brine and dried over Na^SOj The concentrated organic phase was purified on a silica gel column (PE:EA = 8:1 to 2:1 ) to afford 40-9 as a yellow solid (460 mg, 81.33%).

[0371] Préparation of (40-10): To a stirred solution of compound 40-9 (450 mg, 0.61 mmol) in acetone were added ammonium formate (1.29 g, 20.6mmol, in portions) and 10% palladium on carbon (1.0 g). The mixture was refluxed for 12 h. The catalyst was filtered off and washed with acetone. The filtrate was diluted with EA and washed with brine. The concentrated organic phase was purified by column chromatography (DCM:MeOH = 100:1 to 15:1) to afford 40-10 as a white solid (250 mg, 72.8%). ^lH NMR (DMSO-d6,400 M Hz) £8.56

164 (s, IH), 7.73 (d, J = 7.6 Hz, IH), 7.14-7.28 (m, 12H), 6.84 (d, J = 8.8 Hz, 2H), 6.30 (d, J = 7.6 Hz, IH), 6.03-6.08 (m, IH), 5.84 (d, J = 5.2 Hz. IH), 5.33-5.35 (m, IH), 4.97-5.18 (m, IH), 4.86-4.90 (m, IH), 4.34 (d, J = 4.4 Hz, IH), 3.72 (s, 3H), 3.54-3.57 (m, 2H), 1.28 (dd, J_{ = 6.4 Hz, J₂ = 25.6 Hz, 3H). ESI-MS: m/z 563.50 [M + H]⁺.

[0372] Préparation of (40a): 40-10 (101 mg, 0.179 mmol) was dissolved in 80% HOAc (20 mL) at R.T, The mixture was stirred at 50°C for 5 hours. The solvent was removed, and the residue was co-evaporated with toluene twice. The residue was purified by column chromatography (DCM:MeOH « 100:1 to 10:1) to afford 40a as a white solid (36.6 mg, 70.26%). 'H NMR (CDjOD, 400 MHz) £7.98 (d, J = 7.6 Hz, IH), 6.20-6.24 (m, IH), 5.92 (d, J = 7.2 Hz, IH), 5.17-5.30 (m, IH), 4.99-5.14 (m, IH), 4.51-4.86 (m, IH), 3.78 (d, J = 1.6 Hz, 2H), 1.35-1.43 (m, 3H). ESI-MS: m/z 291.84 [Μ + H]⁺, 582.81 [2M + H]⁺.

EXAMPLE 40 Préparation of Compound (41a)

TBDPSO

TBSO

414

TBSO

TBDPSO

/Λη

TBDPSO-^VO^-4_____ vÆJ ⁰ ”

TBSÛ 'F

41-3

NH₂

Yn vzw

HO' 'F

41a [0373] Préparation of (41-2): To a solution of 41-1 (3 g, 4.8 mmol) in anhydrous DCM (50 mL) were added BzCl (1.3 g, 9.6 mmol), DMAP (1.1 g, 9.6 mmol) and NEtj (4 mL) at R.T. The reaction was stirred at R.T. for 2 hours. Water was added, and the reaction was stirred for another 1 hour. The mixture was diluted with DCM (150 mL) and washed with water, 0.1 M HCl and saturated aqueous NaHCOj. The solvent was removed, and the crude product was purified by silica gel column chromatography (25% EtOAc in PE) to give 41-2 as a yellow solid (2.8 g, 80.0%).

[0374] Préparation of (41-3): A mixture of 41-2 (2.6 g, 3.6 mmol) and Pd(OAc)₂(100 mg) in DCM (50 mL) was suspended in a solution of CH2N2 in Et₂O (generated by standard procedure, 350 mL) at -78°C. The réaction was stirred to R.T. ovemight. The mixture was quenched with HOAc, and the reaction was stirred for another 1 hour. The mixture was diluted with EtOAc (150 mL) and washed with water and saturated aqueous NaHCOj. The solvent was

165 removed, and the crude was dissolved in NHj.MeOH (sat., 100 mL). The reaction was stirred to R.T. ovemight. The crude product was purified by silica gel column chromatography (25% EtOAc in PE) to give 41-3 as a yellow solid (800 mg, 35.2%).

[0375] Préparation of (41-4): To a solution of 41-3 (800 mg, 1.3 mmol) in 5 anhydrous CHjCN (50 mL) were added TPSC1 (755 mg, 2.5 mmol), DMAP (305 mg, 2.5 mmol) and NEtj (400 mg, 4 mmol) at R.T. The reaction was stirred at R.T. for 2 hours. NH4OH (25 mL) was added, and the reaction was stirred for another I hour. The mixture was diluted with DCM (150 mL) and washed with water, 0.1 M HCI and saturated aqueous NaHCOj. The solvent was removed, and the crude product was purified by silica gel column chromatography 10 (25% EtOAc in PE) to give 41-4 as a yellow solid (340 mg, 42.5%).

[0376] Préparation of (41a): To a solution of 41-4 (200.0 mg) in MeOH (10 mL) was added NH4F (600 mg). The reaction was refluxed for 24 hours. The solvent was removed, and the residue was purified by column chromatography on silica gel (DCM: MeOH = 15: 1) to give 41a (50.0 mg, 55.9%) as a white solid. *H NMR (CDjOD, 400 M Hz) J 8.13 (d, J = 7.6 15 Hz, IH), 6.01 (dd, J_t = 2.4 Hz, J₂ = 15.6 Hz, IH),5.85 (d, J = 7.6 Hz, IH), 5.04-4.89 (m,lH), 4.52 (dd. Ji = 5.2 Hz, J₂ = 19.6 Hz, IH). 3.66 (s, 2H), 1.00-0.94 (m, IH), 0.54-0.30 (m, 4H); ESI-MS: m/z 285.82 [M + H]⁺, 570.84 [2M + H]⁺.

166

EXAMPLE 41

Préparation of Compound (42a)

MMTrO'

MMTrO F

42-2

MMTrO F

42-5

Τί0-\ζ0^*^Νη

Tfo—'\J —-MMTrO' 'F

42-4

NHDMTr

οΊ-ΑΎ °·

MMTrd

c W

MMTrO î

42-8

NHDMTr

MMTrO' 'F

42-6

MMTrO

NHDMTr [0377] Préparation of (42-2): To a solution of 42-1 (50 g, 203 mmol) in anhydrous 5 pyridine (200 mL) was added TBDPSC1 (83.7 g, 304 mmol, 1.5 eq). The reaction was stirred ovemight at R.T. The solution was concentrated under reduced pressure to give a syrup, which was partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnésium sulfate and concentrated to give the 5-OTBDPS ether as a white foam (94 g). The crude ether was dissolved in anhydrous DCM (300 mL), and silver nitrate 10 (66.03 g, 388.4 mmol, 2.0 eq) and collidine (235 mL, 1.94 mol, 10 eq) were added. The mixture was stirred at R.T., and MMTrCl (239.3 g, 776.8 mmol, 4 eq) was added. After being stirred ovemight at R.T., the mixture was filtered through Celite and filtrate was diluted with MTBE. The solution was washed successively with IM cîtric acid, diluted brine and 5% sodium bicarbonate. The organic solution was dried over sodium sulfate and concentrated under 15 vacuum to give the fully protected intermediate as a yellow foam. The crude intermediate was dissolved in anhydrous THF (250 mL) and treated with TBAF (60 g, 233 mmol, 1.2 eq). The mixture was stirred for 2 hours at R.T., and the solvent was removed under reduced pressure. The residue was taken into ethyl acetate and washed brine. After drying over magnésium

167 sulfate, the solvent was removed m vacuo. The residue was purified by column chromatography (PE:EA = 5:1 to 1:1 ) to give 42-2 as a white foam (91 g, 86.4%).

[0378] Préparation of (42-3): To a solution of 42-2 (13.5 g, 26 mmol) in DCM (100 mL) was added pyridine (6.17 mL, 78 mmol, 3 eq). The solution was cooled to 0°C and DessMartin periodinane (33.8 g, 78 mmol, 3 eq) was added. The mixture was stirred for 4 hours at R.T. and quenched by the addition of a 4% Na2S₂0j/4% sodium bicarbonate aqueous solution (to pH 6, “150 mL). The mixture was stirred for another 15 mins. The organic layer was separated, washed with diluted b ri ne and concentrated under reduced pressure. The residue was dissolved in dioxane (100 mL), and the solution was treated with 37% aqueous formaldéhyde (21.2 g, 10 eq) and 2N aqueous sodium hydroxide (10 eq). The reaction mixture was stirred at R.T. ovemight. The reaction was quenched with saturated NH4CI (—150 mL), and the mixture was concentrated under reduced pressure. The residue was partitioned between ethyi acetate and 5% sodium bicarbonate. The organic phase was separated, washed with brine, dried over magnésium sulfate and concentrated. The residue was purified by column chromatography (MeOH:DCM = 100:1 ~50:1 ) to give 42-3 as a white foam (9.2 g, 83.6%).

[0379] Préparation of (42-4): 42-3 (23 g, 42.0 mmol) was co-evaporated with toluene twice. The residue was dissolved in anhydrous DCM (250 mL) and pyridine (20 mL). The solution was cooled to -35°C. Triflic anhydride (24.9 g, 88.1 mmol, 2.1 eq) was added dropwise over 10 mins. At this température, the reaction was stirred for 40 mins and then was quenched with water (50 mL) at 0°C. The mixture was stirred 30 mins, and extracted with EA (150 mL x 2). The organic phase was dried over Na^SOi, and filtered through a silica gel pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE:EA = 100:1-1:1) to give 42-4 as a brown foam (30.0 g, 88.3%).

[0380] Préparation of (42-5): 42-4 (30 g, 36.9 mmol) was co-evaporated twice with toluene and dissolved in anhydrous DMF (150 mL). The solution was cooled to 0°C, and treated with sodium hydride (60% in minerai oil; 1.5 g, 40.6 mmol). The reaction was stirred at R.T. for 1 h. Lithium chloride (4.6 g, 110.7 mmol, 3 eq) was added. Stlrring was continued for 2 hours when LCMS indicated complété conversion of the anhydro triflate intermediate to anhydrochloro compound. The mixture was taken into 100 mL of half saturated ammonium chloride and ethyi acetate. The organic phase was separated, washed with diluted brine and concentrated under reduced pressure. The residue was dissolved in THF (150 mL), and the solution was treated with 1N aqueous sodium hydroxide (—41 mL, 40.1 mmol, 1.1 eq). The mixture was stirred at R.T. for lh. The reaction was diluted with half saturated sodium bicarbonate (—60 mL) and extracted with EA. The organic phase was dried (magnésium sulfate) and concentrated

168 under reduced pressure. The residue was purified by column chromatography (DCM:MeOH = 300:1-60:1) to give 42-5 as a yeliow foam (18.3 g, 87.6%).

[0381] Préparation of (42-6): To a solution of 42-5 (18.3 g, 32.33 mmol) in anhydrous DCM (150 mL) was added TBSC1 (17.7 g, 64.6 mmol) and imidazole (6.6 g, 97 mmol). The reaction was stirred ovemight at R.T. The reaction was diluted with water and extracted with DCM. The organic layer was separated, washed with brine, dried over NajSQ» and concentrated. The residue was purified by column chromatography (DCM:MeOH = 300:1-80:1) to give 42-6 as a white foam (18.4 g, 83.7%).

[0382] Préparation of (42-7): A solution of 42-6 (18.4 g, 27.1 mmol), DMAP (6.6 g, 54.0 mmol) and TEA (5.4 g ,54.0 mmol) in MeCN (450 mL) was treated with 2,4,6triispropylbenzenesulfonyl chioride (16.3 g, 54.0 mmol). The mixture was stirred at R.T. for 3 hours. NH4OH (70 mL) was added, and the mixture was stirred for 2 hours. The solution was evaporated under reduced pressure, and the residue was purified on a silica gel column (DCM/MeOH = 100:1 to 15:1) to give the crude (18.0 g). The crude was dissolved in anhydrous DCM (150 mL). CoHidine (8.1 g, 66.3 mmol, 2.5 eq), silver nitrate (4.5 g, 26.5 mmol, 1.0 eq) and DMTrCI (13.4 g. 39.7 mmol, 1.5 eq) were added. The reaction was stirred ovemight at R.T. The mixture was filtered through Celite. The filtrate was washed with brine and extracted with DCM. The organic layer was separated, dried over Na₂SO4 and concentrated. The residue was purified by column chromatography (PE:EA = 60:1-3:1) as a yeliow foam. The foam was dissolved in THF (150 mL) and TB AF (10.4 g, 39.7 mmol, 1.5 eq) was added. The reaction was stirred at R.T. After being concentrated, the mixture was washed with brine and extracted with EA. The organic layer was separated, dried over NaiSCh and concentrated. The residue was purified by column chromatography (PE:EA =60:l-EA) to give 42-7 as a yeliow foam (21.3 g, 92.4%).

[0383] Préparation of (42-8): To a solution of 42-7 (2.0 g, 2.3 mmol) in anhydrous DCM (20 mL) was added Dess-Martin periodinane (1.95 g, 4.6 mmol) at 0°C under nitrogen. The réaction was stirred at R.T. for 5 hours. The mixture was diluted with EtOAc ( 100 mL), and washed with a mixture of saturated aqueous Na₂S₂Oj and saturated aqueous NaHCOj. The crude product was purified by column chromatography on silica gel (PE: EtOAc = 2: 1) to give 42-8 (1.8 g, 90%) as a yeliow solid.

[0384] Préparation of (42-9): To a solution of tetramethyl methylenediphosphonate (390 mg, 1.68 mmol) in anhydrous THF (10 mL) was added NaH (84 mg, 2.1 mmol) at 0°C under nitrogen. The reaction was stirred at 0°C for 30 min. A solution of 42-8 (1.2 g, 1.4 mmol) in anhydrous THF (10 mL) was added dropwise at 0°C. The mixture was stirred at R.T. for 1 h.

169

The reaction was quenched with saturated aqueous NH4CI, and the crude product was purified by column chromatography on silica gel (DCM: MeOH = 150: 1) to give 42-9 (1.2 g, 88.2%) as a yellow solid. ^lH NMR (DMSO-d6,400 M Hz) £ 8.51 (s. IH), 7.46-7.09 (m, 22H), 6.88-6.82 (m, 6H), 6.62 (q, J_t = 17.2 Hz, J₂ = 22.4 Hz, IH), 6.12 (d, J = 7.2 Hz, IH), 5.86-5.75 (m. 2H), 5.43 (d, J = 25.2 Hz, IH), 4.63 (dd, J_t = 4.8 Hz, J₂ = 21.2 Hz, IH), 4.45 (d, J = 12.0 Hz, IH),

3.94 (d, J = 12.0 Hz, IH), 3.72 (s, 9H), 3.53 (q, Λ = 11.2 Hz, J₂ = 16.0 Hz, 6H); ESI-MS: m/z

971.59 [M + H]\ [0385] Préparation of (42a): A solution of 42-9 (300 mg) in 80% HOAc (26 mL) was stirred at 80-90°C for 2 h. The solvent was removed, and the crude product was purified by column chromatography on silica gel (DCM: MeOH 20: 1) to give 42a (70 mg, 57%) as a white solid. 'H NMR (DMSO-d6, 400 M Hz) £ 7.61 (d, J = 7.6 Hz, IH), 7.35 (d, J = 15.2 Hz, 2H), 6.72 (q, J, = 17.6 Hz, J₂ = 24.4 Hz, IH), 6.23 (d, J= 6.0 Hz, IH), 5.99-5.85 (m, 2H), 5.74 (q, J =

7.2 Hz, IH), 5.37-5.21 (m, IH), 4.69-4.61 (m, IH), 3.96 (d, J= 12.4 Hz, IH), 3.82 (d, J= 12.0 Hz. IH), 6.72 (q, J_t = 5.2 Hz, J₂ = 10.8 Hz, 6H); ESI-MS: m/z 397.81 [M + H]⁺.

EXAMPLE 42 Préparation of Compound (43a)

A <( NPMB BnO—% q NHO O BnÔ 'F

43-1 ,0

NPMB

43-3

ΝΗΜΜΤΓ

BnÔ 'F

43-4

NHMMTr

43-5

[0386] Préparation of (43-2): To a stined solution of 43-1(3.8 g, 6.6 mmol) in anhydrous DMF ( lOOmL) was added NaH (2.2 g) followed by CHjI (9.3 g, 66 mmol) at 0°C. Stirring was continued at R.T. ovemight. The reaction was quenched with saturated NH4CI aq. The mixture was diluted with EA and washed with brine. The organic layer was dried over NaiSQ» and concentrated. The residue was purified by silica gel column chromatography (PE:EA = 2:1) to give 43-2 (3.0 g, 70%) as a white solid.

170 [0387] Préparation of (43-3): A mixture of 43-2 (3.0 g, 5.1 mmol) and CAN (5.56 g, 10.2 mmol) in a 3:1 solution of MeCN:Water (16 mL) was stirred at R.T. ovemight. The solution was diluted with brine (10 mL ) and was extracted with EA. The combined organic extracts were dried and evaporated under reduced pressure. Purification by chromatography on silica (PE:EA =1:1) gave 43-3 as a yellow solid ( 1.71 g, 72%).

[0388] Préparation of (43-4): To a stirred solution of 43-3 (1.7 g, 3.6 mmol) in anhydrous MeCN (50 mL) were added TPSC1 (2.2 g, 7.2 mmol), DMAP (880 mg, 7.2 mmol) and TEA (1.1 g ,10.8 mmol) at R.T. The mixture was stirred at R.T. ovemight. NH4OH (25 mL) was added, and the mixture was stirred for 2 hours. The solvent was removed, and the residue was purified on a silica gel column (PE:EA = 8:1 to 2:1) to give the intermediate (1.4 g). The intermediate was dissoived in anhydrous DCM (30 mL), and MMTrCI (1.6 g, 5.2 mmol), AgNOj (1.4 g, 7.8 mmol) and collidine (1.57 g, 13 mmol) were added. The mixture was stirred at R.T. ovemight. The solid was filtered off and washed with DCM. The filtrate was washed with brine and dried over Na₂SO4 The concentrated organic phase was purified on a silica gel column (PE:EA = 3:2) to give 43-4 (1.1g, 57.9%) as a white solid.

[0389] Préparation of (43-5): To a stirred solution of 43-4 (550 mg, 0.74 mmol) in acetone were added ammonium formate (1.0 g, 15.8 mmol, in portions) and 10% palladium on carbon (1.0 g). The mixture was refluxed for 48 hours. The catalyst was filtered off and washed with the acetone. The filtrate was diluted with EA, washed with brine and dried. The concentrated organic phase was purified by column chromatography (DCM:MeOH = 50:1) to give 43-5 (330 mg, 72%).

[0390] Préparation of (43a): 43-5 (200 mg, 0.36 mmol) was dissoived in 80% CH3COOH (20 mL) at R.T. The mixture was stirred at 60°C for 12 hours. The solvent was removed. The residue was purified by column chromatography (DCM:MeOH = 10:1), and the resulting solid was washed with DCM to give pure 43a as a white solid (44mg, 42%). ’H NMR (CD3OD, 400 MHz) £8.02 (d, J = 7.2 Hz, 1 H), 6.14 (dd, J, = 3.6 Hz, J₂ = 15.2 Hz, 1 H), 5.88 (d, J = 7.2 Hz, IH), 5.10 (ddd, Λ = 4.0 Hz, Λ = 5.2 Hz, Jj = 53.6 Hz, IH), 4.47 (dd, J, = 5.2 Hz, J₂= 14.8 Hz, IH), 3.84 (d, J= 12.0 Hz, IH), 3.70 (d, /= 12.0 Hz, IH), 3.58-3.64 (m, 2H), 3.36 (s, 3H). ES1-MS: m/z 290 [M + H]⁺.

171

EXAMPLE 43 Préparation of Compound (44a)

44-1

H O ©

1) POMO-P-O EtjNH

POMO

ΒΟΡ-CI, DIPEA NT

THF; r.t: 90 min

2) 60% aq HCOOH 35°C; 30 mins

[0391] To a solution of triethylammonium bis(POM)phosphate (0. 3 mmol, prepared from 100 mg of bis(POM)phosphate and 50 pL of EtjN) in THF (3 mL) was added nucleoside

44-1 (150 mg: 0.26 mmol). The mixture was cooled in ice-bath. DÎisopropylethyl amine (0.18 mL; 4 equiv) was added then, followed by BOP-C1 (132 mg; 2 equiv) and 3-nitro-l,2,4-triazole (59 mg; 2 equiv). The reaction mixture was stirred at 0°C for 90 mins., and then diluted with CH2O2 (30 mL) and washed with saturated aq. NaHCOj and brine. The combined aqueous 10 layers were back extracted with CH2CI2. The combined organic extract was dried (Na2SO₄), evaporated, and the residue purified on silica (10 g column) with CH2CI2 /i-PrOH solvent System (3-10% gradient). The obtained mixture of products were treated for 30 mins at 35°C with 80% aq. HCOOH, and then evaporated and coevaporated with toluene. The evaporated residue was purified on silica (10 g column) with CH2CI2 /MeOH solvent System (5-10% gradient) to obtain 15 44a (8 mg, 5%). ^3IP-NMR (DMSO-de): δ -5.07. MS: m/z = 668 (M+46-1).

172

EXAMPLE 44

Préparation of Compound (45a)

DMTÔ 'F

45-1

80% aq HCOOH

r.t; 30 min

ΒΟΡ-CI, D1PEA NT

THF: 0°C: 90 min

To a solution of triethylammonium [0392] Préparation of (45-2):

bis(POM)phosphate (0. 7 mmol, prepared from 233 mg of bis(POM)phosphate and 0.1 mL of EtjN) in THF (8 mL) was added nucleoside 45-1 (253 mg; 0.42 mmol), followed by diisopropylethyl amine (0.36 mL; 5 equiv), BOP-C1 (268 mg; 2,5 equiv) and 3-nitro-1,2,4triazole (120 mg; 2.5 equiv). The reaction mixture was stirred at R.T. for 2 hours. The mixture was diluted with CH₂C1₂ (40 mL) and washed with saturated aq. NaHCOj and brine. The combined aqueous layers were back extracted with CH₂C1₂. The combined organic extract was dried (Na₂SO4), evaporated, and the residue was purified on silica (10 g column) with hexanes/EtOAc solvent system (40-100% gradient) to yield 45a (180 mg, 47%).

[0393] Préparation of (45a): A solution of compound 45-2 (0.12 g; 0.13 mmol) in 80% aq. HCOOH (8 mL) was stirred 30 mins. at R.T. The mixture was evaporated, 15 coevaporated with toluene and purified on silica (10 g column) with CH₂Cl₂/MeOH solvent system (4-10% gradient) to yield 45a (55 mg, 70%). ^3,P-NMR (DMSO-<U): δ -4.36. MS: m/z =

647 (M+46-1).

173

EXAMPLE 45 Préparation of Compound (46a)

[Me₂CHC(O)]₂O Py

NHMMT

[0394] Préparation of (46-2): A mixture of 46-1 (170 mg; 0.3 mmol) in pyridine (3 mL) and isobutyric anhydride (0.1 mL; 2 equiv) was stirred o/n at R.T. The mixture was concentrated, and the residue was partitioned between EtOAc (30 mL) and saturated aq. NaHCOj. The organic layer was washed with water, brine and dried (NaiSOj). The residue was purified on silica (10 g column) with a hexanes/EtOAc solvent System (30 to 100% gradient) to afford 46-2 (180 mg, 85%).

[0395] Préparation of (46a): A solution of 46-2 (0.18 g; 0.25 mmol) in 80% aq.

HCOOH (5 mL) was heated for 3 hours at 36°C. The mixture was then evaporated, coevaporated with toluene and purified on silica (10 g column) with a CHiCli/MeOH solvent System (4-10% gradient) to afford 46a (75 mg, 70%). MS: m/z = 434 (M+l).

15	EXAMPLE 46
	Préparation of Compound (47a)
NHDMT 1	NHDMT	NHj
t X _c ^H°7^y ⁰	o (X [MeCH₂C(O)bO / ^ΟΛ,^ογ^Ν ° 80% aq HCOOH Py Cl-' \_/ rt;3h	Ôiy'¹'
ho' >	d >	0' 'F
48-1	^=O 47-2	J^o ⁴⁷⁴

174

10396] Préparation of (47-21: 47-2 was prepared from 46-1 (274 mg, 0.46 mmol) and propyonic anhydride (0.12 mL, 2 equiv.) in pyridine (5 mL) in the same manner as described for 46-2 (260 mg, 80%).

[0397] Préparation of (47a): 47-2 (120 mg, 0.2 mmol) was treated with 80% aq. 5 HCOOH at R.T. for 3 hours. The mixture was evaporated, coevaporated with toluene and purified on silica (10 g column) with a CH₂Cl₂/MeOH solvent system (4-10% gradient) to yield 47a (62 mg, 75%). MS: m/z = 404 (M-l).

EXAMPLE 47

Préparation of Compound (48a)

NHDMT I	NHDMT I	nh₂
ex HO-^^o?,^{N 0} [MeCH₂C(O)bO CI-' VJ Py ' _	il ^N 0 \|[ / ⁰ 80% aq HCOOH / CI-'\_/ rt;3h .	il ^N IL JL .p-AV
h<3' >	(J* >	? ^v
46-1	Ao 48-2	Ao⁴⁸⁸

[0398]

Préparation of (48-2): 48-2 was prepared from 46-1 (150 mg, 0.27 mmol) and valeric anhydride (0.11 mL, 2 equiv.) in pyridine (3 mL) in the same manner as described for 46-2(150 mg, 73%).

[0399] Préparation of (48a): 48-2 (140 mg. 0.18 mmol) was treated with 80% aq.

HCOOH at R.T. for 3 hours. The mixture was evaporated and purified on silica (10 g column) with a CH₂CI₂/MeOH solvent system (4-10% gradient) to yield 48a (70 mg, 84%). MS: m/z = 462 (M+l).

175

EXAMPLE 48

Préparation of Compounds (49a), (50a) and (51a)

80% aq HCOOH rt;3h

[0400] Préparation of (49-2), (50-2) and (51-2); To a solution of 46-1 (1.26 g, 2.12 5 mmol) în pyridine (15 mL) were added n-octanoic acid (0.34 mL, 1.0 equiv.), DCC (60% in xylene; 0.81 mL, 1 equiv.) and DMAP (52 mg; 0.2 equiv.). The resuiting mixture was stirred for 6 hours at R.T. The mixture was evaporated, and the residue partitioned between CH₂C1₂ (100 mL) and saturated aq. NaHCOj (25 mL). The organic layer was washed with water, brine and dried (Na₂SO₄). The residue was treated with toluene. The solid material was filtered off, and 10 the filtrate was purified on silica (25 g column) with a heaxanes/EtOAc solvent System (30100% gradient) to yield 49-2 (0.57 g, 32%), 50-2 (0.18 g, 12%), and 51-2 (0.2 g, 13%).

[0401] Préparation of (49a): A mixture of 49-2 (114 mg, 0.13 mmol) and 80% aq, formic acid was stirred for 3 hours at R.T. The mixture was evaporated and coevaporated with toluene and purified on silica (10 g column) with a CH₂Cl₂/MeOH solvent System (2-8% 15 gradient) to yield 49a (53 mg, 75%). MS: m/z = 544 (M-l).

[0402] Préparation of (50a): 50a (44 mg, 75% yield) was prepared from 50-2 (104 mg, 0.14 mmol) in the same manner as described for 49a by using a 4-10% gradient of MeOH in CH₂C1₂ for purification. MS: m/z = 418 (M-l).

176 [0403] Préparation of (Sla): Sla (60 mg, 71% yield) was prepared from 50-2 (140 mg, 0.2 mmol) in the same manner as described for 49a by using a 4-10% gradient of MeOH in CH2O2 for purification. MS: m/z = 418 (M-l).

EXAMPLE 49

Préparation of Compound (52a)

HO

CDi, DMAP, TEA, THF 80°C; 1 h

EtOAc

HCVdloxane

2xHCt [0404] Préparation of (52-2): A solution of y-(terr-butoxycarbonyl)-L-valine (0.41 g, 1.9 mmol) and carbonyldiimidazole (0.31 g, 1.9 mmol) in THF (9 mL) was stirred at R.T. for

1.5 hours. The mixture was then stirred at 40°C for 20 mîns. The mixture was added to a solution of 7a (0.42 g, 1.43 mmol) and DMAP (25 mg, 0.2 mmol) in DMF (8 mL) and TEA (4 mL) at 80°C. The reaction mixture was stirred at 80°C for I h, then cooled and concentrated. The residue was partitioned between fert-butyl methyl ether (100 mL) and water. The organic layer was washed with water, brine and dried (NaiSOu). The residue was purified on silica (25 g column) with a CHjCli/MeOH solvent system (2*10% gradient) to yield 52-2 (0.32 g, 90% in the mixture with 5'-isomer), which was repurified by RP-HPLC (10-100% B; A: water, B: MeOH). Yield: 0.25 g (35%).

[0405] Préparation of (52a): A solution of 52-2 (0.12 g; 0.24 mmol) in EtOAc (0.6 mL) was treated with HCl/dioxane (4 M; 0.6 mL) for 20 mins. with vigorous shaking. The white precipitate was filtered, washed with dîethyl ether and dried to yield 52a as the dihydrochloride sait (95 mg; 85%). MS: m/z = 391 (M-l).

EXAMPLE 50

Préparation of Compound (53a)

HO

Cl—'’' \ DMTCÏ*

53-1

53-2

177 [0406] Préparation of (53-2): To a solution of N-Boc-Val-OH (0.16 g, 0.74 mmol) and Et₃N (0.14 mL, 1.0 mmol) in THF was added 53-1. The resulting mixture was evaporated, coevaporated with pyridine and toluene and dissolved in THF (4 mL). DIPEA (0.38 mL, 2.2 mmol) was added, followed by BOP-C1 (0.28 g, 1.1 mmol) and 3-nitro-l,2,4-triazole (0.13 g, 1.1 mmol). The reaction mixture was stireed at R.T. for 1 h. The mixture was diluted with CH2CI2 (40 mL) and washed with saturated aq. NaHCO₃ and brine. The combined aqueous layers were back extracted with CH2CI2. The combined organic extract was dried (Na₂SO₄), evaporated, and the residue was purified on silica (10 g column) with a hexanes/0.5 % Et₃N/EtOAc solvent System (20-100% gradient) to yield 53-2 (0.39 g, 81%).

[0407] Préparation of (53a): A mixture of 14-2 (0.37 g, 0.33 mmol) and 80% aq. HCOOH (10 mL) was stirred at R.T. for 3 hours. The mixture was evaporated, and the residue was partitioned between water and CH2CI2. The aqueous layer was washed with CH2CI2 and evaporated. The solid residue was suspended in EtOAc (1.5 mL) and treated with 4N HCl in dioxane (1.5 mL) with vigorous shaking. The solid was filtered, washed with diethyl ether and purified by RP-HPLC (A: 0.5N HCOOH in water, B: 0.5 N HCOOH in acetonitrile). The resulting formic acid sait of 5'-O-valyn ester was converted into 53a dîhydrochloride sait (63 mg. 40%) by suspending in EtOAc (2 mL) and treatment with 4N HCl/dioxane (2 mL). MS: m/z = 391 (M-l).

EXAMPLE 51 Préparation of Compound (39a)

[0408] Préparation of (39-2): A solution of 39-1 (1.3 g, 1.4 mmol) in anhydrous MeOH (20 mL) was charged with Pd/C (1.3 g) and stirred at 25°C under hydrogen (1 atm) atmosphère for 1 hour. The solution was filtered, evaporated to dryness, and purified on a silica gel column (DCM:MeOH = 100:1 to 50:1 ) to give 39-2 ( 1.2 g, 92.3 %) as a white solid.

[0409] Préparation of (39-3): To a solution of 39-2 (1.2 g, 1.3 mmol) in MeOH (40 mL) was added NHjF (370 mg, 10 mmol) at 25°C and stirred at 60°C for 6 hours. The solution

178 was filtered, evaporated to dryness, and purified on a silica gel column (DCM:MeOH = 200:1 to 20:1) to give 39-3 as a white solid (249 mg, 30.7%). *H NMR (MeOD, 400 MHz) J7.92 (s, IH), 7.19-7.33 (m, 12H), 6.83-6.85 (m, 2H), 5.50 (dd, Λ= 4.0 Hz, J₂ = 14.8 Hz, IH), 4.19-4.88 (m, IH), 4.22 (dd, Λ = 5.2 Hz, J₂ = 16.0 Hz, IH), 3.76 (s, 3H), 3.41 (dd, Λ = 12.0 Hz, J₂ - 36.8 5 Hz, 2H), 1.52-1.74 (m, 2H), 0.87 (t, J~7.6 Hz, 3H); ESI-LCMS: m/z 586.1 [M + Hf.

[0410] Préparation of (39a): A solution of 39-3 of 80% formic acid/20% water (3 mL) stood at RT for 2 hours, and then was concentrated to dryness. The residue was coevaporated with MeOH/toluene (3 times) and then ethyl acetate added. The suspension in ethyl acetate was heated at 70°C for 5 mins. The solvent was removed using a pipet. This washing 10 was repeated 3 times. The resulting product (44mg) was further purified on reverse-phase HPLC using acetonitrile/water as mobile phase to give 39a (20 mg) as an off-white solid. *H NMR (DMSO, 400 MHz) J7.92 (s, IH), 10.82 br, IH), 7.96 (s, IH), 6.56 (s, 2H), 5.99 (dd, J = 6.0,

12.8 Hz, IH), 5.65 (d, J = 4.8 Hz, IH), 5.58, 5.45 (2t, J = 5.2 Hz, 0.5H, 0.5H), 5.25 (br, IH), 4.19-4.88 (m, IH), 4.22 (dd, Λ = 5.2 Hz, J₂ = 16.0 Hz, IH), 3.76 (s, 3H), 3.41 (dd, Λ = 12.0 Hz, 15 J₂ = 36.8 Hz, 2H), 1.52-1.74 (m, 2H), 0.87 (t, J = 7.6 Hz, 3H); ESI-LCMS: m/z 443.6 [M + 6methyl-2-heptylamine)]⁺.

EXAMPLE 52

Préparation of Compounds (55a) and (56a)

55a 56a

^och3 [0411] 1,2,4-Triazol (21 mg, 0.3 mmol) was dissolved in the mixture of CHjCN (0.7 mL) and EtjN (44 pL, 0.31 mmol). POCIj (9ul, 0.1 mmol) was added, and the mixture was kept at R.T. for 20 mins. The white precipîtate was filtered, and the filtrate added to the dry nucleoside (28 mg, 0.05 mmol). The reaction was controlled by TLC and monitored by the 25 disappearance of the starting nucleoside. After completion of the reaction, tetrabutylammonium sait of pyrophosphate (150 mg) was added, followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 hours at ambient température, the reaction was diluted with water (4 mL) and

179 extracted with DCM (2x5 mL). The combined organic extracts were evaporated, dtssolved in 5 mL of 80% HCOOH and left for 2 hours at R.T. The reaction mixture was concentrated and distributed between water (5 mL) and DCM (5 mL). The aqueous fraction was loaded on the column HiLoad 16/10 with Q Sepharose High Performance. Séparation was done in a linear gradient of NaCl from 0 to IN in 50mM TRIS-buffer (pH7.5). Two fractions were obtained. The first fraction, containing the monophosphate (55a) was eluted at 70-75%B. and triphosphate (56a) was eluted at 75-80%B. Both fractions were desalted by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer.

EXAMPIÆ 53

Préparation of Compounds (56b-e)

[0412] 1,2,4-Triazol (21 mg, 0.3 mmol) was dissolved in the mixture of CH₃CN (0.7 mL) and Et₃N (44 gL, 0.31 mmol). POCI₃ (9u1,0.1 mmol) was added, and the mixture was kept at R.T. for 20 mins. The white precipitate was filtered, and the filtrate added to the dry nucleoside (28 mg, 0.05 mmol). The reaction was controlled by TLC and monitored by the disappearance of the starting nucleoside. After completion of the reaction, tetrabutylammonium sait of pyrophosphate (150 mg) was added followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 hours at ambient température, the reaction was diluted with water (4 mL) and extracted with DCM (2x5 mL). The combined organic extracts were evaporated, dissolved in 5 mL of 80% HCOOH and left for 4 hours at 38°C. The reaction mixture was concentrated and distributed between water (5 mL) and DCM (5 mL). The aqueous fraction was loaded on the column HiLoad 16/10 with Q Sepharose High Performance. Séparation was done in a linear gradient of NaCl from 0 to IN in 50 mM TRIS-buffer (pH7.5). Two fractions were obtained. The triphosphate (56b-e) was eluted at 75-80%B. Desaltin was performed by RP HPLC on

180

Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50 mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer.

Table 3 - Triphosphates obtained from Example 53

Structure	MS (M-l)	P«x)	Ρ(β)	P(Y)
0 HqJ-q OyN-^¹ HÔ* F 55a	373.00	+3.64 (s)	NA	NA
0 o 0 H H ¹¹ « L z^NH HO-P-O-P-O-P-O^XyN^ OH OH OH^C,—0 HÔ* ^ZF 56a	532.95	-6.67 -6.74(d)	-21.87(0	-11.51 -11.63(d)
_____-NHj 0 0° il ιι II _n L z^N HO-P-O-P-O-P-O^/y^ Ah Ah Ah 7—'Λ—Λ ⁰ ^f Ht? ^ZF 56b	526.05	-6.33 -6.47(d)	-22.48(t)	-11.53 -1 l.64(d)
o o o /a H 'I a A ki Z^N HO-P-0-P-O-P-O^A.N^ Ah Ah Ah f-'W ⁰ HO- ^ZF 56c	516.00	-63.2(bs)	-22.45 (t)	-11.64(d)
nh₂o o 0 Æ >1 II \i_7 _H0„p_₀_p_₀_p_₀-· ₀ N-< 1 < «Y t o OH OH OHVJ-Z HÔ F 56d	524.4	-10.57 10.67(d)	-23.31(0	-11.31 -11.94(d)
nh₂ 0 0 0 Æ h h II \i_z Ho-p-o-P-o—p—o-xxr/i·^ 1 1 \| _c / 0 OH OH 0H^F7 HO F 56e	529.8	-6.17(bs)	21.96(bs)	ll.42(bs)

181

EXAMPLE 54

Préparation of Compound (57a)

[0413] 2’-Deoxy-2’-fluoro-4’-C-(ethenyl)guanosine (25a, 31 mg, 0.1 mmol) was dissolved in dry pyridine (3 mL). Isobutyric anhydrate (50 gL, 0,3 mmol) was added. The reaction mixture was kept at ambient température. After 40 hours, isobutyric anhydrate (100 gL, 0.6 mmol) was added, and the reaction mixture was ieft ovemight. The pyridine was evaporated. The residue was purified by silica gel chromatography using a gradient of methanol in DCM from 3% to 10% to yield 57a (20 mg, 50%). ‘H NMR (DMSO-d6) δ: 10.72 (s, IH), 7.88 (s, IH),

6.47 (s, 2H), 6.18-6.13 (dd, IH), 5.90-5.83 (dd, IH), 5.79-5.62 (m, 2H), 5.49-5.44 (d, iH), 5.355.32 (d, IH), 4.28-4.25 (d, IH), 4.12-4.10 (d, IH), 2.60-2.45 (m, 2H), 1.12-1.09 (m, 6H), 1.020.96 (m, 6H); m/z 452 (M+1).

182

EXAMPLE55

Préparation of Compound (58a)

584

DMTrO

HCÎ 'F

58-2

,0

NPMB

58-8

NH_Zô ΒηΟΎ>Ο_ν ^ΝΗ

BnO' 'F

58-9 [0414] Préparation of (58-2): To a solution of 58-1 (50.0 g, 205 mmol) in pyridine (250 mL) was added DMTrCl (75.0 g, 225.0 mmol). The solution was stirred at R.T. for 15 hours. MeOH (120 mL) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EA and washed with water. The organic layer was dried over Na₂SO₄and concentrated to give the crude DMTr protected dérivative (80.5 g, 89%) as a light yellow solid. Dried K₂COj (80.52 g, 583.2 mmol) and then PMBC1 (31.7 g, 109.2 mmol) 10 were added to a stirred solution of the DMTr protected dérivative (80 g, 146 mmol) in anhydrous

DMF (300 mL). The stirring was continued at ambient température for ovemight. The reaction was monitored by TLC. The mixture was diluted with EA and washed with water. The organic layer was dried over Na₂SO₄ and concentrated to give 58-2 (98.8 g, 90%) as light yellow solid.

[0415] Préparation of (58-3): NaH (10.4 g, 260.5 mmol) and BnBr (73.8 g, 434.2 mmol) were added to a stirred solution of 58-2 (98.8 g, 147.9 mmol) in anhydrous DMF (300 mL), and the stirring was continued at 25°C ovemight, The reaction was monitored by TLC. The reaction was quenched with water, extracted with EA and washed with brine. The solvent

183 was removed, and the residue was purified on silica gel (PE: EA= 10:1 to 3:1) to give the Bn protected dérivative (101.1 g, 90%) as a light yellow solid. The Bn protected dérivative (101.1g,

133.4 mmol) was dissoived in 80% HOAc (900 mL) at 25°C. The mixture was stirred at 25°C ovemight. The reaction was quenched with MeOH, and the solvent was removed to give the alcohol (42.1 g, 70%) as a white foam. To a solution of the alcohol (42.1 g, 92.6 mmol) in anhydrous CH3CN (300 mL) was added IBX (28.5 g, 121.7 mmol) at 25°C. The reaction mixture was refluxed for 1 hour and then cooled to 0°C. The precipitate was filtered-off, and the filtrate was concentrated to give 58-3 (39.2 g, 93%) as a yellow solid.

(0416] Préparation of (58-4): To a solution of 58-3 (39.2 g, 86.39 mmol) in 1,4dioxane (250 mL) was added 37% CH₂O (28.1 mL, 345.6 mmol) and 2N NaOH aqueous solution (86.4 mL, 172.8 mmol). The mixture was stirred at 25°C for 2 h and then neutralized with AcOH to pH = 7. To the reaction were added EtOH (200 mL) and NaBH₄ (19.7 g, 518.6 mmol). The mixture was stirred at 25°C for 30 mins. The reaction was quenched with saturated aqueous NH4CI. The mixture was extracted with EA, and the organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (PE: EA = 4:1 to 2:1) to give the diol dérivative (25.5 g, 55%) as a white solid. To a stirred solution of the diol dérivative (25.5 g, 52.5 mmol) in anhydrous pyridine (150 mL) and anhydrous CH3CN (150 mL) was added BzCl (6.6 g, 52.47 mmol) dropwise at 0°C. The mixture was then stirred at 25°C for 14 h. The reaction was quenched with H₂O, and the solution was concentrated. The residue was dissoived in EA and washed with NaHCOj. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on a silica gel column (PE/EA = 5:4) to give 58-4 (18.1 g, 60%) as a white foam.

[0417] Préparation of (58-5): Cs₂CO₃ (30.0 g, 92.0 mmol) and BnBr (10.4 g, 61.3 mmol) were added to a stirred solution of compound 58-4 (18.1g, 30.6 mmol) in anhydrous DMF (300 mL), and stirring was continued at 25°C ovemight. The reaction was quenched with NH4CI, extracted with EA and washed with brine. The solvent was removed to give the Bz protected dérivative (19.3 g, 95%) as a light yellow solid. To a stirred solution of the Bz protected dérivative (19.3 g, 28.4 mmol) in anhydrous MeOH (230 mL) was added NaOMe (24.9 g, 460 mmol) at 25°C for 1 h. The reaction was quenched with AcOH (10 mL) and concentrated. The residue was purified on a silica gel column (PE/EA = 1/2) to afford 58-5 (11.2 g, 54%) as a white solid.

[0418] Préparation of /58-6): To a stirred solution of 58-5 (200 mg, 0.347 mmol) in anhydrous DCM (5 mL) was added DMP (168 mg, 0.674 mmol) at 25°C. The mixture was stirred at 25°C for 2 h. The solvent was removed, and the residue was purified on a silica gel

184 column (PE: EA = 5:1 to 1:1) to give the aldéhyde dérivative (161 mg, 81%). To a stirred solution of the aldéhyde dérivative (200 mg, 0.348 mmol) in anhydrous THF (5 mL) was added MeMgBr (1.0 mL, 1.01 mmol) at -78°C. The mixture was stirred at -78°C for 1 h. The reaction was quenched with NHiCl and extracted with EA. The concentrated organic phase was purified by column chromatography (PE: EA = 5:1 to 1:1) to give 58-6 (135 mg, 65%).

[0419] Préparation of (58-7): To a solution of 58-6 (900 mg, 1.5 mmol) in DCM was added DMP (2.5 g, 6.0 mmol) at 0°C. After stirring at 0°C for I h, the mixture was quenched with Na₂S₂O₂. The solvent was removed, and the residue was purified on a silica gel column (PE: EA = 5:1 to I: I) to give the ketone dérivative (700 mg, 78%). To a solution of the ketone dérivative (700 mg, 1.52 mmol) in MeOH was added NaBHi in portions. After stirring at the same température for l h, the mixture was quenched with water. The solvent was removed, and the residue was purified on a silica gel column (PE: EA = 5:1 to 1:1) to give 58-7 (500 mg, 71%).

[0420] Préparation of (58-8): To a stirred solution of DAST (1.39 g. 8.68 mmol) in anhydrous toluene (15 mL) was added dropwise a solution of 58-6 (1.0 g, 1.73 mmol) at -78°C. The mixture was stirred at -78°C for 30 min. The solution was warmed to 25°C slowly and stirring continued ovemight. The mixture was poured into a saturated Na₂CO₂ solution. The concentrated organic phase was purified on a silica gel column (PE: EA=l0:l to 4:1) to give the fluoride dérivative (449 mg, 45%). A mixture of the fluoride dérivative (1.20 g, 2.07 mmol) and CAN (3.41 g, 6.23 mmol) in a 3:1 solution of MeCN and water (10 mL) was stirred at 25°C ovemight. Brine (10 mL) was added. and the mixture extracted with EA. The combined organic extracts were dried and evaporated under reduced pressure. Purification by chromatography on silica with PE: EA = 10:1 to 2:1 gave 58-8 as a yellow solid (475 mg, 50%).

[0421] Préparation of (58-9): To a stirred solution of 58-8 (550 mg, 210 mmol) in anhydrous MeCN (10 mL) were added TPSC1 (725 mg, 2.40 mmol), DMAP (293 mg, 2.40 mmol) and TEA (242 mg, 2.40 mmol) at 25°C. The mixture was stirred at 25°C ovemight. NH4OH (25 mL) was added and stirred for 2 h. The solvent was removed, and the residue was purified on a silica gel column (DCM: MeOH = 10:1) to give 58-9 (300 mg). ^lH NMR (CDjOD, 400 MHz) δ 7.70 (d, J = 8.4 Hz, IH), 7.25-7.36 (m, 10H), 6.13 (dd, J = 2.8, 16.8 Hz, IH), 5.40 (d, 7=7.6 Hz, IH), 5.15 (m, 1H),4.81 (d,7= 11.6 Hz, IH), 4.40-4.52 (m.4H), 3.82 (d, 7 = 8.8 Hz, 7H), 3.62 (d, 7 = 9.6 Hz, 7H). 1.35 (dd, 7 = 2.8, 14.4 Hz, 3H). ESI-MS: m/z 472.1 [M + H] + [0422] Préparation of (58a): A I M boron trichloride solution in CH₂C1₂ (3.2 mL;

3.2 mmol) was added dropwise to a solution of 58-9 (200 mg, 0.42 mmol) in anhydrous CH₂C1₂

185 (10 mL) at -78 C. The mixture was slowly (in 4 h) warmed to -30 °C and stirred at -30 to -20°C for 3 h. Ammonium acetate (1 g) and MeOH (5 mL) were added, and the resulting mixture allowed to warm to ambient température. The solvent was removed, and residue purified by RPHPLC (0-60% B; A: 50 mM aqueous TEAA, B: 50 mM TEAA in MeOH) to yield 58a (75 mg). ^lH NMR (CD₃OD) δ 7,97 (d, IH), 6.20 (dd, 1 H), 5.92 (d, 1 H), 5.22 (dt, 1 H), 4.98 (dq, 1 H), 4.58 (dd, 1 H), 3.73 (m, 2 H). 1.40 (dd, 3 H). ^l9F NMR (CD3OD) δ -205.80 (m, 1 F), -188.54 (m, 1 F). ESI-MS: m/z 290.4 [M - H]*.

EXAMPLE 56 Préparation of Compound (59a)

59-1

TBSO' 'F

59-2 >1H

ΗΟ-χ,Οχ/Η ------►

TBSÔ 'F

59-3

TBDPSO HO-

TBSÔ

59-4

TBDPSO'X O * t^NH < i 'z_ O

TBSO F ^u

59-5

[0423] Préparation of (59-2): To a solution of 59-1 (100.0 g, 406.5 mmol) in pyridine (750 mL) was added DMTrCl (164.9 g, 487.8 mmol). The solution was stirred at R.T. for 15 h. MeOH (300 mL) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na₂SO4 and concentrated. The residue was dissolved in DCM (500 mL). To this solution were added imidazole (44.3 g, 650.4 mmol) and TBSC1 (91.9 g, 609.8 mmol). The resulting reaction mixture was stirred at R.T. for 14 h. The reaction solution was washed with NaHCOj and brine. The organic layer was dried over Na₂SO4, and concentrated to give the crude product as a light yeliow solid. The crude product (236.4 g, 356.6 mmol) was dissolved in 80% HOAc aqueous solution (500 mL). The mixture was stirred at R.T. for 15 h. The mixture was diluted with EtOAc, washed with NaHCÜ3 solution and brine. The organic layer was dried over Na₂SO4 and purified on a silica gel column chromatography ( i-2% MeOH in DCM) to give 59-2 (131.2 g, 89.6%) as a üght yeliow solid. 'H NMR (DMSO-d6.400 MHz) δ i 1.39 (s, IH), 7.88 (d, J = 7.2 Hz, IH), 5.89 (dd, J= 18.0 Hz, J= 2.0 Hz, IH), 5.64 (d. J= 8.0 Hz, iH), 5.21 (dd, J_t-J₂- 7.2 Ηζ,ΙΗ), 5.18-5.03 (m, IH), 4.37-4.29 (m, IH), 3.86 (dd, J = 3.2 Hz, J = 3.2

186

Hz, 3H), 3.78-3.73 (m, 1H), 3.51-3.56 (m, 1H), 3.31 (s, 1H), 0.89 (s, 9H), 0.11 (s, 6H); ESI-MS: m/z 8O2[M + H]⁺.

[0424] Préparation of (59-3): To a solution of 59-2 (131.2 g, 364.0 mmol) in anhydrous CHjCN (1200 mL) was added IBX (121.2 g, 432.8 mmol) at R.T. The reaction mixture was refluxed for 3 h and then cooled to 0°C. The precipitate was filtered-off, and the filtrate was concentrated to give the crude aldéhyde (121.3 g) as a yellow solid. The aldéhyde was dissolved in 1,4-dioxane (1000 mL). 37% CH₂O (81.1 mL, 1.3536 mol) and 2M NaOH aqueous solution (253.8 mL, 507.6 mmol) were added. The mixture was stirred at R.T. for 2 h and then neutralized with AcOH to pH = 7. To the solution were added EtOH (400 mL) and NaBH4 (51.2 g, 1.354 mol). The mixture was stirred at R.T. for 30 mins and quenched with sat. aqueous NH4CI. The mixture was extracted with EA. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified by silica gel column chromatography (1-3% MeOH in DCM) to give 59-3 (51.4 g, 38.9 %) as a white solid.

[0425] Préparation of (59-4): To a solution of 59-3 (51.4 g, 131.6 mmol) in anhydrous DCM (400 mL) were added pyridine (80 mL) and DMTrCl (49.1 g, 144.7 mmol) at 0°C. The reaction was stirred at R.T. for 14 h, and then treated with MeOH (30 mL). The solvent was removed, and the residue was purified by silica gel column chromatography (1-3% MeOH in DCM) to give the mono-DMTr protected intermediate as a yellow foam (57.4 g, 62.9%). To the mono-DMTr protected intermediate (57.4 g, 82.8 mmol) in CH₂C1₂ (400 mL) was added imîdazole (8.4 g, 124.2 mmol) and TBDPSC1 (34.1 g, 124.2 mmol). The mixture was stirred at R.T. for 14 h. The precipîtated was filtered off, and the filtrate was washed with brine and dried over Na₂SO4. The solvent was removed to give the residue (72.45 g) as a white solid, which was dissolved in 80% HOAc aqueous solution (400 mL). The mixture was stirred at R.T. for 15 h. The mixture was diluted with EtOAc, washed with NaHCOj solution and brine. The organic layer was dried over Na₂SO4 and purified by silica gel column chromatography (1-2% MeOH in DCM) to give 59-4 (37.6 g, 84.2%) as a white solid. 'H NMR (CDjOD, 400 MHz) δ 7.76 (d, J = 4.0 Hz, 1H), 7.70 (dd, J= 1.6 Hz, J= 8.0 Hz, 2H), 7.66-7.64 (m, 2H), 7.48-7.37 (m, 6H), 6.12 (dd, J= 2.8 Hz, J= 16.8 Hz, 1H), 5.22 (d, J= 8.0 Hz, lH).5.20-5.05 (m, 1H), 4.74 (dd, J=5.6 Hz, J = 17.6 Hz, IH), 4.16 (d, J = 12.0 Hz, IH), 3.87-3.80 (m,2H), 3.56 (d, J = 12.0 Hz, lH), 1.16 (s, 9H), 0.92 (s, 9H), 0.14 (s, 6H).

[0426] Préparation of (59-5): To a solution of 59-4 (3.0 g, 4.78 mmol) in anhydrous DCM (100 mL) was added Dess-Martin periodinane (10.4 g, 23.9 mmol) at 0°C under nitrogen. The reaction mixture was stirred at R.T. for 5 h. The mixture was poured into NaHCOj and Na₂S₂O₃ (1:1) aqueous solution. The organic layer was dried over anhydrous Na₂SO4 and

187 concentrated to give a residue. The residue was purified on a silica gel column (20% EtOAc in PE) to give the intermediate (2.5 g, 83.1 %) as a white solid.

[0427] To a mixture of bromotriphenyl(propyl)phosphorane (6.45 g, 16.8 mmol) in anhydrous THF (3 mL) was added t-BuOK (16.8 mL, 16.8 mmol) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 50 mins. A solution of the above intermediate (1.5 g, 2.4 mmol) in anhydrous THF (3 mL) was added dropwise at 0°C under nitrogen. The reaction mixture was stirred at R.T. for 3 h. The reaction was quenched by NH4CI aqueous solution and extracted with EtOAc. The organic layer was dried over anhydrous Na₂SO4 and concentrated to give a residue. The residue was purified on a silica gel column (20% EtOAc in PE) to give 59-5 (1.3 g, 83%) as a white solid.

[0428] Préparation of (59a): To a solution of 59-5 (300 mg, 0.45 mmol) in anhydrous CH3CN (2 mL) were added TPSCl (341 mg, 1.13 mmol), DMAP (138 mg, 1.13 mmol) and NEt₃ (571 mg, 5.65 mmol) at R.T. The reaction mixture was stirred at R.T. for 2 h. NH4OH (1 mL) was added, and the reaction mixture was stirred for 1 h. The mixture was diluted with EA and washed with water. The organic layer was dried and concentrated to give a residue. The residue was purified on a silica gel column (2% MeOH in DCM) to give the cytidîne dérivative (285 mg, 95.0%) as a white solid.

[0429] To a solution of the cytidîne dérivative (280 mg, 0.43 mmol) in MeOH (10 mL) was added NH4F (1.0 g) at R.T. The reaction mixture was refluxed for 12 h. The mixture was filtered, and the filtrate was concentrated. The residue was purified on a silica gel column (10% MeOH in DCM) to give 59a (81 mg, 61%) as a white solid. ’H NMR (CD₃OD, 400 MHz) £8.11 (d,J=8.0Hz, 1H),5.91 (dd,J= 1.2 Hz,J= 17.6 Hz, 1H), 5.90 (d, 7.6 Hz, 1H),5.57-

5.59 (m, 2H), 4.82-4.96 (m, 1H), 4.42 (dd, 4.8 Hz, J= 24.4 Hz, 1H), 3.72 (d, J = 12.4 Hz, IH) 3.58 (d, J= 12.4 Hz, 1H), 2.31-2.41 (m, 2H), 0.99 (t, J= 7.6 Hz, 3H). ESI-TOF-MS: m/z

300.1 [M + H]*.

EXAMPLE 57 Préparation of Compound (60a)

TBDPSO-X CL

TBSO 'F ⁰

59-5

TBDPSO

TBSO

60-1

[0430] Préparation of (60-1): To a solution of 59-5 (450 mg, 0.69 mmol) in MeOH (10 mL) was added Pd/C (200 mg) at R.T. The reaction mixture was stirred R.T. for 1 h under

188

Hî (balloon). The mixture was filtered, and the filtrate was concentrated to give crude 60-1 (440 mg, 97.1%) as a white solid.

[0431] Préparation of (60a): To a solution of 60-1 (440 mg, 0.67 mmol) in anhydrous CHjCN (2 mL) were added TPSC1 (510 mg, 1.68 mmol), DMAP (205 mg, 1.68 mmol) and NEtj (338 mg, 3.35 mmol) at R.T. The reaction mixture was stirred at R.T. for 2 h. NH4OH (1 mL) was added, and the reaction was stirred for 1 h. The mixture was dîluted with EA and washed with water. The solvent was removed. The crude product was purified on a silica gel column (2% MeOH in DCM) to give the cytidine dérivative (205 mg, 46.5%) as a white solid.

[0432] To a solution of the cytidine dérivative (205 mg, 0.31 mmol) in MeOH (6 mL) was added NH4F (0.6 g) at R.T. The reaction mixture was refluxed ovemîght. After cooling to R.T., the mixture was filtered. The filtrate was concentrated, and the residue was purified on a silica gel column (10% MeOH in DCM) to give 60a (59 mg, 62.8 %) as a white solid. ^lH NMR (CDjOD. 400 MHz) £8.09 (d, J = 7.6 Hz, IH), 6.01 (dd, J = 3.2 Hz, J= 15.6 Hz, IH). 5.89 (d, 7.2 Hz, IH), 4.95-5.12 (m, IH), 4.41 (dd, J= 5.2 Hz, J= 17.2 Hz, IH), 3.75 (d, J= 12.0 Hz, IH) 3.56 (d, J= 11.6 Hz, IH), 1.73-1.80 (m, IH), 1.55-1.63 (m, IH), 1.40-1.46 (m. 4H), 0.92 (t, 7.6 Hz, 3H). ESl-MS: m/z 301.8 [M + H] ⁺.

EXAMPLE 58

Préparation of Compound (61a)

TBDPSO

59-4

TBSO'

TBDPSO

51-1

[0433] Préparation of (61-1): To a solution of 59-4 ( 1.5 g, 2.39 mmol) in anhydrous

DCM (100 mL) was added Dess-Martin periodinane (5.2 g, 11.95 mmol) at 0°C under nitrogen. The reaction mixture was stirred at R.T. for 5 h. The mixture was poured into NaHCOj and NaiSiOj solution and washed with brine. The organic layer was dried with anhydrous NaiSOj, and concentrated to give the crude intermediate (1.5 g) as a white solid.

189 [0434] To a solution of the crude intermediate (1.5 g, 2.39 mmol) in THF (12 mL) was added méthylmagnésium bromide (2.4 mL, 7.2 mmol) dropwise at 0°C. The resulting mixture was stirred at (f C for 2 h. After the starting material was consumed, the reaction was quenched with saturated NH4CI. The reaction mixture was extracted with DCM. The organic layer was washed with brine, dried and concentrated to give crude 61*1 (1.5 g).

[0435] Préparation of (fit-2): To a solution of 61-1 (1.5 g, 2.39 mmol) in anhydrous

DCM (50 mL) was added Dess-Martin periodinane (4.5 g, 10.6 mmol). The reaction mixture was stirred at R.T. ovemight. The mixture was poured into NaHCOj and NajSjOj aqueous solution. The organic layer was separated, washed with brine, dried and concentrated to give a residue. The residue was purified on a silica gel column (10% EtOAc in PE) to give the intermediate (907 mg, 58.6%) as a white solid.

[0436] To a mixture of bromo(methyl)triphenylphosphorane (5.0 g, 14 mmol) in anhydrous THF (8 mL) was added t-BuOK (12.6 mL, 12.6 mmol) at 0°C under nitrogen. The mixture was stirred at R.T. for 50 mins. A solution of the above intermediate (900 mg, 1.4 mmol) în anhydrous THF (4 mL) was added dropwise at 0°C under nitrogen. The reaction mixture was stirred at R.T. for 3 h. The reaction mixture was quenched with NH4CI aqueous solution and extracted with DCM. The organic layer was separated, washed with brine, dried and concentrated to give a residue. The residue was purified on a silica gel column (5% EtOAc in PE) to give 61-2 (700 mg, 78.0%) as a white solid.

[0437] Préparation of (61a): To a solution of 61-2 (298 mg, 0.46 mmol) in anhydrous CH3CN (5.5 mL) were added TPSC1 (346.5 mg, 1.14 mmol), DMAP (139.6 mg, 1.14 mmol) and NEtj (115.6 mg, 1.14 mmol) at R.T. The reaction mixture was stirred at R.T. for 2 h. NH4OH (1 mL) was added, and the mixture was stirred for another 1 h. The mixture was diluted with DCM and washed with water. The organic layer was separated, washed with brine, dried and concentrated to give a residue. The residue was purified on a silica gel column (2% MeOH in DCM) to give the cytidine dérivative (250 mg, 85.0%) as a white solid.

[0438] To a solution of the cytidine dérivative (250 mg, 0.39 mmol) in MeOH (10 mL) was added NH4F (1.0 g) at R.T. The reaction was refluxed for 12 h. The mixture was filtered, and the filtrate was concentrated. The residue was purifîed on a silica gel column (10% MeOH in DCM) to give fila (55 mg, 49%) as a white solid. *H NMR (CDjOD, 400 MHz) <78.11 (d, 7 = 7.6 Hz, IH), 6,21 (dd, 7=4.2 Hz, J- 14.0Hz, IH), 5.91 (d,7=7.6 Hz, IH), 5.10 (dt, J=

4.8 Hz, 7 = 53.6 Hz, IH), 5.13 (brs, IH), 5.00 (brs, IH), 4.46 (dd, J= 4.8 Hz, J= 11.6 Hz, IH), 3.83 (d, J= ! 1.6 Hz, IH), 3.54 (d, J= 11.6 Hz, IH). 1.84 (s, 3H). ESI-MS: m/z 285.9 [M + H] ⁺.

190

EXAMPLE 59 Préparation of Compound (62a)

nh₂

H ^ZHÔ 'F

62a [0439] Préparation of (62-1): To a solution of 61*2 (400 mg, 0.63 mmol) in MeOH (10 mL) was added Pd/C (400 mg) at R.T. The reaction was stirred at R.T. for 5 h under H₂(balloon). The mixture was filtered, and the filtrate was concentrated to give crude 62-2 (350 mg, 87%) as a white solid.

[0440] Préparation of (62a): To a solution of 62-1 (350 mg, 0.55 mmol) in anhydrous CH₃CN (6 mL) were added TPSC1 (414 mg, 1.4 mmol), DMAP (166.8 mg, 1.4 mmol) and NEt₃ (138.1 mg, 1.4 mmol) at R.T. The réaction mixture was stirred at R.T. for 2 h. NH4OH (1 mL) was added, and the reaction was stirred for another 1 h. The mixture was diluted with EA and washed with water. The organic layer was separated, dried and concentrated to give a residue. The residue was purified on a silica gel column (2% MeOH in DCM) to give the cytidine dérivative (300 mg, 85%) as a white solid.

[0441] To a solution of the cytidine dérivative (300 mg, 0.47mmol) in MeOH (10 mL) was added NH4F (1.5g) at R.T. The reaction mixture was refluxed ovemight. After cooling to R.T., the mixture was filtered. The filtrate was concentrated. The crude product was purified on a silica gel column (10% MeOH in DCM) to give 62a (83 mg, 61%) as a white solid. *H NMR (CD₃OD. 400 MHz) J8.12 (d, J = 7.6 Hz, IH), 6.22 (dd, J= 6.4 Hz, J = 12.4 Hz, IH),

5.94 (d, J= 7.6 Hz, IH), 5.25 (dt, J= 5.6 Hz, J= 54.0 Hz, IH), 4.38 (t, J = 4.8 Hz, IH), 3.72 (d, J= 11.6 Hz, IH), 3.67 (d,J= 11.6 Hz, IH), 2.31-2.42 (m, IH), 0.99 (2d, J = 7.2 Hz,6H). ESIMS: m/z 287.8 [M + H]⁺.

191

EXAMPLE 60

Préparation of Compound (63a)

Cl— MMTrO 'F

TfO TfOMMTrO 'F

TBSO Cl— MMTrd

MMTrO

NHDMTr

MMTrO

NHDMTr

MMTrO 'F

63-9

NHDMTr

TBSO ClMMTrÜ ‘

63-8

MMTrO [0442] Préparation of (63-2): To a solution of 63-1 (50 g, 203 mmol) in anhydrous 5 pyridine (200 mL) was added TBDPS-C1 (83.7 g, 304 mmol). The reaction was allowed to proceed ovemight at R.T. The solution was concentrated under reduced pressure to give a residue. The residue was partitîoned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over magnésium sulfate and concentrated under reduced pressure to give 5'-OTBDPS ether as a white foam (94 g ).

[0443] To a solution of the 5-OTBDPS ether (94.0 g, 194.2 mmol) in anhydrous

DCM (300 mL) were added silver nitrate (66.03 g, 388.4 mmol) and collidine (235 mL, 1.94 mol). The mixture was stirred at R.T. After most of silver nitrate was dissolved (-15 min), the mixture was cooled to 0°C. Monomethoxytrityl chloride (239.3 g, 776.8 mmol) was added as a single portion, and the mixture was stirred ovemight at R.T. The mixture was filtered through

Celite, and the filtrate was diluted with MTBE. The solution was washed successively with IM citric acid, diluted brine and 5% sodium bicarbonate. The organic solution was dried over sodium sulfate and concentrated under vacuum to give the fully protected intermediate as a yellow foam.

192 [0444] The fully protected intermediate was dîssolved in toluene (100 mL), and the solution was concentrated under reduced pressure. The residue was dîssolved in anhydrous THF (250 mL) and treated with TBAF (60 g, 233 mmol). The mixture was stirred for 2 hours at R.T., and the solvent was removed under reduced pressure. The residue was taken into ethyl acetate, and the solution was washed with saturated sodium bicarbonate and brine. After drying over magnésium sulfate, the solvent was removed in vacuum. The residue was purified by column chromatography (PE: EA= 5:1,1:1) to give 63-2 (91 g, 86.4%) as a white foam.

[0445] Préparation of (63-3): To a solution of 63-2 (13.5 g, 26 mmol) in DCM (100 mL) was added pyridine (6.17 mL, 78 mmol). The solution was cooled to 0°C and Dess-Martin periodinane (33.8 g, 78 mmol) was added as a single portion. The reaction mixture was stirred for 4 h at R.T. The reaction was quenched with Na₂S₂O₂ solution (4%) and sodium bicarbonate aqueous solution (4%) (the solution was adjusted to pH 6, -150 mL). The mixture was stirred for 15 mîn. The organic layer was separated, washed with diluted brine and concentrated under reduced pressure. The residue was dîssolved in dioxane (100 mL), and the solution was treated with 37% aqueous formaldéhyde (21.2 g, 10 eq) and 2N aqueous sodium hydroxide ( 10 eq). The réaction mixture was stirred at R.T. ovemight. After stirring for 0.5 h at R.T., the excess of aqueous sodium hydroxide was neutralized with saturated with NH4CI (-150 mL). The mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic phase was separated, washed with brine, dried over magnésium sulfate and concentrated. The residue was purified by column chromatography (MeOH: DCM= 100:1-50:1) to give 63-3 (9.2 g, 83.6%) as a white foam.

[0446] Préparation of (63-4): 63-3 (23 g, 42.0 mmol) was co-evaporated with toluene twice. The residue was dîssolved în anhydrous DCM (250 mL) and pyridine (20 mL). The solution was cooled to -35°C. Triflic anhydride (24.9 g, 88.1 mmol) was added dropwise over 10 mins. The reaction was stirring for 40 min at -35°C. When TLC (PE: EA= 2:1 and DCM: MeOH= 15:1) showed that the reaction was complété, the reaction was quenched with water (50 mL) at 0°C. The mixture was stirred 30 mins, extracted with EA. The organic phase was dried over Na₂SC>4 and filtered through a silica gel pad. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (PE: EA= 100:1-1:1) to give 63-4 (30.0 g, 88.3%) as a brown foam.

[0447] Préparation of (63-5): 63-4 (30 g, 36.9 mmol) was co-evaporated twice with toluene. The resulting bis-triflate was dîssolved in anhydrous DMF (150 mL), cooled to 0°C and treated with sodium hydride (60% in minerai oil; 1.5 g, 40.6 mmol, 1.1 eq). The réaction mixture was stirred at R.T. for I h until TLC (DCM: MeOH = 15:1) showed the disappearance

193 of the bis-triflate and formation of the 2,5’-anhydro intermediate. Lithium chloride (4.6 g, 110.7 mmol, 3 eq) was added, and the stirring was continued for 2 h. The mixture was taken into 100 mL of half saturated ammonium chloride and ethyl acetate. The organic phase was separated, washed with diluted brine and concentrated under reduced pressure to give 63-5.

[0448] Préparation of (63-6): 63-5 was dissoived in THF (150 mL), and the solution was treated with IN aqueous sodium hydroxide (—41 mL, 40.1 mmol, 1.1 eq). The mixture was stirred at R.T. for 1 h. The reaction was monitored by LCMS. The reaction was diluted with half saturated sodium bicarbonate (-60 mL) and extracted with ethyl acetate. The organic phase was dried (magnésium sulfate) and concentrated under reduced pressure.

Purification of the residue by column chromatography (DCM: MeOH= 300:1-60:1) gave 63-6 (18.3 g, 87.6%) as a yellow foam.

[0449] Préparation of (63-7); To a solution of 63-6 (18.3 g, 32.33 mmol) in anhydrous DCM (150 mL) was added TBS-C1 (17.7 g, 64.6 mmol) and imidazole (6.6 g, 97 mmol). The reaction was allowed to proceed overnight at R.T. The reaction was diluted with 15 water and extracted with DCM. The organic layer was separated, washed with brine, dried over Na₂SO₄ and concentrated. Purification of the residue by column chromatography (DCM: MeOH=300:1-80:1) gave 63-7 (18.4 g, 83.7%) as a white foam.

[0450] Préparation of (63-8): A solution of 63-7 (18.4 g, 27.1 mmol), DMAP (6.6 g, 54.0 mmol) and TEA (5.4 g,54.0 mmol) in MeCN (450 mL) was treated with 2,4,620 triispropylbenzenesulfonyl chloride (TPSCI, 16.3 g, 54.0 mmol). The mixture was stirred at R.T. for 3 h. NHj H₂O (70 mL) was added, and the mixture was stirred for 2 h. The solution was evaporated under reduced pressure, and the residue was purified on a silica gel column (DCM: MeOH= 100:1 to 15:1) to give 63-8 (18.0 g) as a light yellow solid.

[0451] Préparation of (63-9): To a solution of 63-8 (18.0 g, 26.5 mmol) in anhydrous DCM (150 mL) was added coîlîdine (8.1 g, 66.3 mmol, 2.5 eq), silver nitrate (4.5 g,

26.5 mmol, 1.0 eq) and DMTrCl (13.4 g, 39.7 mmol, 1.5 eq). The reaction was allowed to proceed overnight at R.T. The mixture was fiitered. The filtrate was washed with brine and extracted with DCM. The organic layer was separated, dried over Na₂SO₄ and concentrated. The residue was purified by column chromatography (PE: EA= 60:1-3:1) as a yellow foam. The foam was dissoived in THF (150 mL), and TBAF (10.4 g, 39.7 mmol, 1.5 eq) was added. The reaction was allowed to proceed overnight at R.T. The mixture was concentrated, washed with brine and extracted with EA. The organic layer was separated, dried over Na₂SO₄ and concentrated. Purification of the residue by column chromatography (PE: EA =60:l-EA) gave 63-9 (21.3 g, 92.4%) as a yellow foam.

194 [0452] Préparation of (63-10): To a solution of 63-9 (2.0 g, 2.3 mmol) in anhydrous DCM (20 mL) was added Dess-Martin periodinane (1.95 g, 4.6 mmol) at 0°C under nitrogen. The reaction was stirred at R.T. for 5 h. The mixture was diluted with EtOAc (100 mL) and washed with a mixture of saturated aqueous NaiS₂O₃ and saturated aqueous NaHCO₃. The 5 crude product was purified by column chromatography on silica gel (PE: EtOAc = 2: I) to give 63-10 (1.8 g, 90%) as a yellow solid.

[0453] Préparation of (63-11): To a solution of tetramethyl methylenediphosphonate (390 mg, 1.68 mmol) in anhydrous THF (10 mL) was added NaH (84 mg, 2.1 mmol) at 0°C under nitrogen. The reaction was stirred at 0ⁿC for 30 min. A solution of 10 63-10 (1.2 g, 1.4 mmol) in anhydrous THF (10 mL) was added dropwise at 0°C. The reaction mixture was stirred at R.T. for 1 h. The reaction was quenched by saturated aqueous NH4CI, and the crude product was purified by column chromatography on silica gel (DCM: MeOH - 150: 1) to give 63-11 (1.2 g, 88.2%) as a yellow solid. *H NMR (DMSO-d6,400 M Hz) δ 8.51 (s, IH), 7.46-7.09 (m, 22H), 6.88-6.82 (m, 6H), 6.62 (q, J; = 17.2 Hz, J₂ = 22.4 Hz, IH), 6.12 (d, J = 7.2 15 Hz, IH), 5.86-5.75 (m, 2H), 5.43 (d, J - 25.2 Hz, IH), 4.63 (dd, J = 4.8 Hz, J = 21.2 Hz, IH), 4.45 (d,J = 12.0 Hz, IH), 3.94 (d,J= 12.0 Hz, IH), 3.72 (s, 9H), 3.53 (q, J = 11.2 Hz,J= 16.0 Hz, 6H). ESI-MS: m/z 971.59 [M + H]⁺.

[0454] Préparation of (63a): A solution of 63-11 (1.0 g, 1.03 mmol) in 80% HOAc (46 mL) was stirred at 80-90°C for 2 h. The solvent was removed, and the crude product was 20 purified by column chromatography on silica gel (DCM: MeOH =20: 1) to give an intermediate (337 mg, 82.3%) as a white solid. The intermediate was dissolved in MeOH and wet Pd/C (300 mg) was added. The reaction mixture was stirred under H₂ (1 atm) for ! h and then filtered. The solvent was removed, and the residue was purified on a silica gel column (DCM: MeOH= 20:1) to give 63a (192 mg, 63.97o) as a white solid. *H NMR (CD₃OD, 400 MHz) £7.60 (d, J = 7.6 25 Hz, ! H), 5.87 (d, J - 7.2 Hz, IH), 5.70(dd, J-2.0 Hz, J-21.6 Ηζ,ΙΗ), 5.31(m, IH), 4.67 (dd, J = 5.6 Hz, .7 = 19.6 Ηζ,ΙΗ), 3.80(m, 2H), 3.75 (2d,J= 2.4 Hz, 6H), 1.92-2.20 (m, 4H). ^3IP NMR (CD₃OD, 162 MHz) δ 35.77. ESI-MS: m/z 400.0 [M + H]⁺.

195

EXAMPLE 61 Préparation of Compound (64a)

O O

Il II

64-2

64-1

MMTrÔ 'F

63-10

NHDMTr

64-3

[0455] Préparation of (64-2): To a solution of 64-1 (1.0 g, 4.3 mmol) in THF (20 mL) was added NaH (120 mg, 3.0 mmol), and the reaction mixture was stirred at 0°C for 1 h. Selectfluor (1.2 g, 3.4 mmol) was added into the reaction mixture. The crude product was purified on a silica gel column and eluted with EA to give 64-2 (500 mg, 57%) as a white solid. 'H NMR (CDjOD, 400 MHz) £5.65 (dt, J = 14.0 Hz, J = 44.8 Hz, 1H), 3.90 (d, J = 9.6 Hz, 12H).

[0456] Préparation of (64-3): To a solution of compound 64-2 (390 mg, 1.68 mmol) in anhydrous THF (10 mL) was added NaH (84 mg, 2.1 mmol) at 0ⁿC under nitrogen. The reaction mixture was stirred at 0°C for 30 mins. A solution of 63-10 (1.2 g, 1.4 mmol) in anhydrous THF (10 mL) was added dropwise at 0°C. The réaction mixture was stirred at R.T. for 1 h. The reaction was quenched with saturated aqueous NH₄C1 and concentrated to give a residue. The residue was purified on a silica gel column (DCM: MeOH= 150: 1) to give crude 64-3 (1.2 g, 88.2%) as a yellow solid.

[0457] Préparation of (64a): A solution of crude 64-3 (230 mg, 0.23 mmol) in 80% HOAc (3 mL) was stirred at 80-90°C for 2 h. The crude product was purified on a silica gel column (eluted with DCM: MeOH= 20:1) to give 64a (54 mg, 53.7%) as a white solid. *H NMR (DMS0.400 MHz) £7.69 (d, J = 7.2 Hz, 1H), 7.37 (d, J= 1.6 Hz, 2H), 6.62-6.78 (m, 1H), 6.40 (d, J = 5.6 Hz, 1H), 6.03-6.07 (m, 1H), 5.77 (d, J = 7.6 Hz, 1H), 5.61-5.64 (m, 1H), 5.48-5.51 (m, 1H), 4.60-4.64 (m, 1H), 4.38 (d, J = 11.6 Hz, 1H), 3.98 (d, J = 11.6 Hz, 1H), 3.75 (2d, J =

11.6 Hz, 6H). ESI-MS: m/z 416.3 [M + H]⁺.

196

EXAMPLE 62 Préparation of Compound (65a)

64-3

65a [0458] A solution of crude 64-3 (230 mg, 0.23 mmol) in 80% HOAc (3 mL) was stirred at 80-90°C for 2 h. The crude product was purified on a silica gel column (eluted with DCM: MeOH= 20: l) to give 64a (52 mg, 33.7%) as a white solid. ^lH NMR (DMSO, 400 MHz) £7.59 (d, J = 7.2 Hz, IH), 7.32 (s, 2H), 6.25-6.28 (m, IH), 5.86-6.02 (m, 2H), 5.73 (s, IH), 5.31 (d, 14.0 Hz, IH), 4.72 (d, J = 16.4 Hz, IH), 3.90 (d, J= 10.0 Hz, IH), 3.73 (2d, J= 11.6 Hz,

6H).

EXAMPLE 63

Préparation of Compound (66a)

[0459] A solution of 64a (130 mg, 0.3 mmol) in EA:MeOH (5:1,20 mL) was stirred under H₂ (15 Psi) at R.T. for 2 h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified on a silica gel column (DCM: MeOH= 20: l) to give 66a (70 mg, 54%) as a white solid. *H NMR (DMSO, 400 MHz) £7.61 (d, J =7.2 Hz, IH), 5.87 (d, J =

7.2 Hz, IH), 5.58-5.80 (m. IH), 5.26-5.47 (m, 2H), 4.97-5.03 (m, IH), 5.58-5.80 (m, IH), 3.73-

3.94 (m, 6H), 2.33-2.59 (m, 2H). ES1-MS: m/z 418.3 [M + H]⁺.

197

EXAMPLE 64

Préparation of Compound (67a)

O O H H Γ° °Ί ¹ 67-1 ¹	O O il h —- 0-— r°n ¹ 67-2 ¹
NHDMTr H	NHDMTr ? _F H	Hd··' V ⁰ 6Ta
α-Λ_7 ⁰ MIWTrO' ΐ 63-10	⁰ MMTrO 'F 67-3

[0460] Préparation of (67-2): To a solution of 67-1 (2.0 g, 6.9 mmol) in THF (20 mL) was added NaH (110 mg, 2.8 mmol), and the reaction mixture was stirred at 0°C for t h. Selectfluor (5.0 g, 13.6 mmol) was added into the reaction mixture. The reaction was quenched with saturated NHjCl and extracted with EA. The organic layer was separated, dried and concentrated to give the crude product. The crude product was purified on a silica gel column (eluted with EA) to give 67-2 (600 mg, 28.3%) as a white solid. *H NMR (CDjOD, 400 MHz) J

5.65 (dt, J = 14.0 Hz, J = 44.8 Hz, IH), 4.24-4.46 (m, 8H), L35-1.39 (m, 12H).

[0461] Préparation of (67-3): To a solution of 67-2 (2.14 g, 7.0 mmol) in anhydrous THF (10 mL) was added NaH (84 mg, 2.1 mmol) at 0°C under nitrogen. The reaction mixture was stirred at 0°C for 30 mins. A solution of 63-10 (3.0 g, 3.5 mmol) in anhydrous THF (10 mL) was added in dropwise at 0°C. The reaction mixture was stirred at R.T. for I h. The reaction was quenched with saturated aqueous NH4CI and concentrated to give a residue. The residue was purified on a silica gel column (DCM: MeOH=l50: 1) to give crude 67-3 (2.9 g, 79.5%) as a yellow solid.

[0462] Préparation of (67a): A solution of crude 67-3 (1.0 g, 0.98 mmol) in 80% HOAc (25 mL) was stirred at 80-90°C for 2 h. The crude product was purified on a silica gel column (eluted with DCM: MeOH= 20:1) to give 67a (133 mg, 32.5%) as a white solid. ^lH NMR (DMSO, 400 MHz) δ7.67 (d, J = 7.2 Hz, IH), 7.34 (d, J = 12.8 Hz, 2H), 6.33-6.69 (m, IH), 6.05 (d, J = 6.8 Hz, IH), 6.00-6.05 (m, IH), 5.76 (d, J = 7.6 Hz, IH), 5.45-5.61 (m, IH), 4.60-4.63 (m, IH), 4.08-4.14 (m, 5H), 1.23-1.29 (m, 6H). ^3,P NMR (DMSO, 162 MHz) δ 1.93, 1.30. ESI-MS: m/z 466.1 [M + Na]⁺.

198

EXAMPLE 65

Préparation of Compound (68a)

NH₂ [0463] To a solution of 67a (130 mg, 0.29 mmol) in MeOH (20 mL) was stirred under H2 (15 Psi) at R.T. for 2 h. The reaction mixture was filtered and concentrated to give a residue. The residue was purified on a silica gel column (eluted with DCM: MeOH= 20:1) to give a mixture of diastereomers of 68a (90 mg, 69.2%) as a white solid. *H NMR (DMSO, 400 MHz) J7.61-7.68 (m, IH), 7.28-7.38 (m. 2H), 5.89-5.95 (m, IH), 5.58-5.79 (m, 2H), 5.18-5.39 (m, 2H), 4.53-4.85 (m, IH), 4.04-4.39 (m,4H), 3.71-3.83 (m. 2H), 2.21-2.35 (m, 2H), 1.21-1.27 (m, 6H). ^3IP NMR (DMSO, 162 MHz) δ 18.2, 18.02, 17.73, 17.56. ESI-MS: m/z 446.1 [M + H]*

EXAMPLE 66

Préparation of Compound (69a)

MMTrO 'F

63-4

MMTrO' F

69-2 .0

NH

MMTrO ^V°y^N^₀

MeS—‘V_7 MMTrO' F

TfO- \_J MMTrCÏ 'F

69-1

MMTrO' 'F

69-4

69-3

[0464] Préparation of (69-1): 63-4 (3.0 g. 3.69 mmol) was co-evaporated twice with toluene. The resulting bis-triflate was dissolved in anhydrous DMF (20 mL). The solution was cooled to 0°C and treated with sodium hydride (60% in minerai oil; 177 mg, 0.43 mmol). The reaction was stirred at R.T. for 1 h (TLC (PE: EA =2:1) showed complété disappearance of the bis-triflate and clean formation of the 2’,5'-anhydro intermediate). The reaction mixture was used for the next step without any further workup

199 [0465] Préparation of (69-2): To the above stirred reaction mixture was added NaSMe (9.0 g, 0.13 mmol) and 15-Crown-5 (4.87 g, 22.14 mmol) at 0°C under nitrogen. The solution was stirred at R.T. for 2 h (TLC (PE: EA= 1:1) showed the reaction was complété). The reaction was quenched with water. The mixture was extracted by EtOAc, washed with brine, and dried over MgSO₄. The mixture was filtered and concentrated to give a residue. The residue was purified on a silica gel column (PE: EA= 5:2) to give 69-2 (1.23 g, 59.0%) as a white foam.

[0466] Préparation of (69-3): To a stirred solution of 69-2 (1.34 g, 2.32 mmol) in anhydrous DCM (10 mL) was added MMTrCl (1.32 g, 4.64 mmol), AgNO3 (1.17 g, 6.96 mmol) and Colüdine (1.41 g, 11.6 mmol) at R.T. under nitrogen. The reaction mixture was stirred at R.T. for 1 h (TLC (PE: EA= 1:1) showed the reaction was complété). The mixture was filtered and concentrated. The residue was purified on a silica gel column (PE: EA= 8:1) to give 69-3 (1.31 g, 66.5%) as a white foam.

[0467] Préparation of (69-4): To a solution of 69-3 (900 mg, 1.06 mmol) in anhydrous MeCN (9 mL) was added DMAP (259 mg, 2.12 mmol), TEA (214 mg, 2.12 mmol) and TPSC1 (640 mg. 2.12 mmol) at R.T. under nitrogen. The reaction mixture was stirred at R.T. for 2 h (TLC (DCM: MeOH=10:l) showed the reaction was complété). NH4OH (10 mL) was added, and the reaction mixture was stirred for another 1 h (LCMS showed the reaction was complété). The solution was diluted with water, extracted with EtOAc. The organic layer was washed with IM HCl, saturated NaHCOj and brine, and dried over MgSO₄. The mixture was filtered and concentrated to give a residue. The residue was purified on a silica gel column (DCM: MeOH= 70:1) to give 69-4 (870 mg, 68.5%) as a white solid.

[0468] Préparation of (69a): 69-4 (800 mg, 0.95 mmol) was dissolved in 80% HOAc aq. (50 mL). The reaction mixture was heated to 75°C ovemight (LCMS showed the reaction was complété). The reaction mixture was concentrated and purified on a silica gel column (DCM: MeOH= 15:1) to give 69a (180 mg. 62.5%) as a white solid. *H NMR (CDjOD, 400 MHz) δ 8.05 (d, J = 7.2 Hz, IH), 6.11 (dd, J =3.2 Hz J = 15.6 Hz, IH), 5.87 (d, J = 7.6 Hz, IH), 5.05 (dt, J = 4.8 Hz, J = 53.6 Hz, IH), 4.47 (dd, J =5.2 Hz J = 17.6 Hz, IH), 3.83 (d, J = 12.0 Hz, 2H), 2.84 (d, J - 14.4 Hz, 2H), 2.15 (s, 3H). ESI-MS: m/z 305.8 [M + H] *

200

EXAMPLE 67

Préparation of Compound (70a)

MMTrO 'F

63-5

[0469] To a solution of 63-5 (100 g, 182.5 mmol) in MeCN (2 L) was added 6N HCl aq. (15 g). The mixture was stirred at 40”C for 7 h, and then neutralized to pH = 5-6 with a 25% ammonia solution (-8 g). The mixture was filtered to give a solid, which was further washed by PE to give an intermediate (32.2 g, 60%) as a white solid. To a mixture of the intermediate (32.2 g, 109.5 mmol), TEA (22.1 g, 219 mmol) and DMAP (1.34 g, 11 mmol) in MeCN (1 L) was added with isobutyric anhydrous (69.2 g, 438 mmol). The mixture was stirred at R.T. for 3 h. The reaction was quenched by the addition of water (200 mL) and extracted with 2-Me-THF (800 mL). The organic layer was washed with saturated NaHCOj and brine. The organic layer was dried and concentrated to give a residue, which was purified by a silica gel column (10% toluene in heptane) to give 70a (42.3 g, 89%) as a white solid. ^lH NMR (CDjOD, 400 MHz) 8

7.65 (d, J = 8.0 Hz, IH), 5.95 (dd, J = 2.8, 20.4 Hz, IH), 5.55-5.74 (m, 3H), 4.33-4.41 (m, 2H), 3.88 (s, 2H), 2.57-2.72 (m, 2H), 1.14-1.22 (m, 12H).

EXAMPLE 68 Préparation of Compound (71a) fÎlH

TfO'X_zO_s/ ^N^ TfO—°

MMTrO' 'F

63-4

MMTrÔ F

71-1

MMTrO Xz°x/^N M Br-ÆX °

MMTrO F

71-2 nh₂ —HO' F

71a

201 [0470] Préparation of /71-t): To a solution of 63-4 (4.2 g, 5.17 mmol) in DMF (50 mL) at 0°C was added NaH (227 mg of 60% dispersion, 5.7 mmol). The mixture was stirred at 0°C for 2 h ,and then LiBr (1.34 g, 15.5 mmol) was added. The mixture was stirred ovemight at R.T., diluted with EA (150 mL) and washed successively with water and brine. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified on a silica gel column eluted with 10% EA in PE to give 71-1 as a yellow solid (2 g, 66%) [0471] Préparation of /71-2): To a solution of 71-1 (1.74 g, 2.9 mmol) in THF (20 mL) at 0°C was added IN NaOH (3.2 mL, 3.2 mmol), and the mixture was stirred at 0°C for 2 h. The mixture was partitioned between EA (100 mL) and water (20 mL), and the organic layer was dried over Na₂SC>4 and evaporated to dryness. The residue was purified on a silica gel column eluted with 20% EA in PE to give the S'-OH dérivative as a yellow solid (1.6 g, 90%).

[0472] To a solution of 5'-OH dérivative (2.3 g, 3.76 mmol) in anhydrous DCM (20 mL) were added collidine (0.8 g, 6.7 mol) and MMTrCt (2.7 g, 8.7 mmol). The reaction mixture was stirred at R.T. ovemight. The mixture was filtered and washed successively with saturated aqueous NaHCOj and brine, dried over Na₂SO4 and concentrated. The residue was purified on a silica gel column eluted with 10% EA in PE to give 71-2 as a yellow solid (2.4 g, 73%).

[0473] Préparation of /71a): To a solution of 71-2 (2.4 g, 2.72 mmol) in anhydrous CHjCN (30 mL) were added TPSC1 (1.65 g, 5.44 mmol), DMAP (0.663 g, 5.44 mmol) and NEtj ( 1.5 mL) at R.T. The mixture was stirred at R.T. for 3 h, and 28% aqueous ammonia (30 mL) was added. The mixture was stirred for t h. The mixture was diluted with EA (150 mL) and washed successively with water, saturated aqueous NaHCOj and brine. The solvent was removed, and the residue was purified on a silica gel column eluted with 2% MeOH in DCM to give a cytidîne dérivative as a yellow solid (1.5 g, 62%).

[0474] The cytidine dérivative (1.35 g, 1.5 mmol) was dissoived in 80% AcOH (40 mL), and the mixture was stirred at 60°C for 2 h. The mixture was concentrated, and the residue was purified on a silica gel column using 5% MeOH in DCM as elute to give 71a as a white solid (180 mg, 35 %). *H NMR (MeOD, 400 MHz) £8.00 (d, J = 7.2 Hz, IH), 6.12 (dd, J = 3.6 Hz, J = 15.6 Hz, IH), 5.88 (d, J =7.6 Hz, lH),5.l0(dd, ./ = 4.8 Hz, J= 53.2 Hz, lH),4.59(dd, J = 5.2 Hz, J = 16.4 Hz, IH), 3.95 (d, J = 11.6 Hz, IH), 3.76 (d, J = 11.6 Hz, IH), 3.70 (d, J =

11.6 Hz, IH), 3.63 (d, J- 11.2 Hz. IH); ES1-TOF-MS: m/z 337.9 [M + H]⁺.

202

EXAMPLE 69

Préparation of Compound (72a)

MMTrO

MMTrO Cl— MMTrO'

72-3

MMTrO ’ ClMMTrO'

72-4

MMTrO [0475]

Préparation of (72-1): To a solution of 63-6 (1.0 g, 1.8 mmol ) in 1,4 dioxane (2 mL) was added TEA (3 mL) and 37% HCHO (3 mL). The reaction mixture was stirred for 10 h at 60°C. The reaction was concentrated to dryness under vacuum, and the residue was purified by column on a silica gel column (DCM: MeOH = 100:1-30:1) to give 72-1 (470 mg, 45%) as a white foam. *H NMR (DMSO-d6, 400 MHz) <711.4 (s, IH), 7.27-7.49 (m,

13H), 6.89 (d, J = 8.8 Hz, 2H), 4.90-4.95 (m, IH), 4.58 (dd, J = 5.2 Hz, J = 23.6 Hz, IH), 3.96

4.07 (m, 4H), 3.73 (s, 3H), 3.50-3.62 (m, IH), 3.37-3.39 (m, IH), ESI-TOF-MS: m/z 596.9 [M + H]⁺.

[0476] Préparation of (72-2): To a solution of 72-1 (430 mg, 0.72 mmol) in dioxane (2 mL) was added 30% CH3COOH (0.7 mL) and PtO₂(290 mg). The reaction mixture was stirred under H₂ (latm) at R.T. for 2 h. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified on a silica gel column (DCM: MeOH = 100:1-30:1) to give 72-2 (268 mg, 64%) as a white foam. ‘H NMR (DMSO-d6, 400 MHz) <7 11.3 (s, IH), 7.27-7.46 (m, 13H), 6.88 (d, J « 8.8 Hz, 2H), 5.78 (d, J = 20.8 Hz, IH), 5.06-5.08 (t, J = 20.8 Hz, IH), 4.49 (dd, J = 4.2 Hz , J - 24.4 Hz, IH), 3.94-4.04 (m, 2H), 3.70 (s, 3H),

3.59-3,63 (m, IH), 3.52-3,53 (m, IH), 3.34-3.40 (m, IH), 1.66 (s, 3H). ESI-TOF-MS: m/z 580.9 [M + H]⁺.

[0477] Préparation of (72-3): To a solution of 72-2 (260 mg, 0.45 mmol) in anhydrous DCM (3 mL) was added AgNO₃ (228 mg, 1.35 mmol), collidine (223 mg, 1.8 mmol) and MMTrCl (456 mg, 1.35 mmol). The mixture was stirred at R.T. for 10 h . The reaction mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified on a silica gel column (PE: EA = 50:1-3:1) to give 72-3 (303 mg, 80%) as a white foam.

203 [0478] Préparation of (72-4): To a solution of 72-3 (300 mg, 0.35 mmol) in anhydrous CH₃CN (3 mL) was added DMAP (107 mg, 0.88 mmol), TEA ( 141 mg, 1.4 mmol) and TPSC1 (106 mg, 0.35 mmol) at R.T. The reaction mixture was stirred at R.T. for 4 h. NHjOH (1 mL) was added, and the mixture was stirred at R.T. for another 1 h. The solvent was removed, and the residue was partitioned by EA and water. The organic layer was washed by brine twice, dried and concentrated to give a residue. The residue was purified on a silica gel column (PE: EA = 50:1-3:1) to give 72-4 (270 mg, 90%) as a white foam.

[0479] Préparation of (72a): 72-4 (260 mg, 0.31 mmol) in 10 mL of 60% HCOOH was stirred at R.T. for 2 h. The solvent was removed, and the residue was washed with EA to give 72a (31 mg, 32%) as a white powder. ‘H NMR (MeOD, 400 MHz) J7.85 (d, J = 0.8 Hz, IH), 6.12 (dd, J = 4.0 Hz, J= 15.2 Hz, IH), 5.08-5.22 (m, 1H),4.58 (dd,J=4.8 Hz, J- 14.8 Hz, IH), 3.92 (d, J= 15.6 Hz, IH), 3.74-3.84 (m, 3H), 1.94 (d, J = 0.8 Hz, IH). ESI-TOF-MS: m/z 307.9 [M + Hf.

EXAMPLE 70 Préparation of Compound (73a)

ΊΗ _______MMTrO 'F

63-6

H(5 F

73-1

73-3

4H

BzO^Vz°V^N^ C!—°

BzO' ¥

73-2

[0480] Préparation of (73-1): 63-6 (600 mg, 1.06 mmol) in formic acid (5 mL, 80% in water) was stirred at R.T. ovemight. Completion of the reaction was determined by TLC (DCM: MeOH= 10:1). The solvent was removed to give crude 73-1 (290 mg, 93.2%).

[0481] Préparation of (73-2): To a solution of 73-1 (290 mg, 0.98 mmol) in pyridine (5 mL) and acetonitrile (5 mL) was added BzCl (371 mg, 2.65 mmol). The reaction mixture was stirred at 0°C for 0.5 h. The reaction was warmed to R.T. and stirred for 2 h.

Completion of the reaction was determined by LCMS. The reaction was quenched with water and extracted with EA. The organic layer was washed with brine, dried over MgSOu, filtered

204 and concentrated. The residue was purified on a silica gel column (DCM: MeOH= 200:1) to give 73-2 (245 mg, 49.8%) as a white solid.

[0482] Préparation of (73-3): To a solution of 73-2 (245 mg, 0.49 mmol) in anhydrous acetonitrile (2.5 mL) was added TPSC1 (394 mg, 0.98 mmol), DMAP (119.5 mg, 0.98 mmol) and TE A (98 mg, 0.98 mmol). The mixture was stirred at R.T. for 3 h. NH₂OHHC1 (68 mg, 0.98 mmol) and DBU (368 mg, 1.47 mmol) were added, and the reaction mixture was stirred at R.T. for 2 h. The reaction mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with IM HCl, saturated NaHCOj and brine, dried and concentrated. The residue was purified on a silica gel column (DCM: MeOH= 20:1) to give 733 (49 mg, 32.9%) as a white solid.

[0483] Préparation of (73a): 73-3 (49 mg, 0.1 mmol) in NHj/MeOH (30 mL) was stirred at R.T. for 2 days. The solvent was removed. The residue was purified on a silica gel column (DCM: MeOH= 30: l) to give 73a (12.9 mg, 44.0%) as a white solid. *H NMR (DMSOd_6t 400 MHz) δ 10.07 (brs, IH), 9.68 (brs, IH), 7.02 (d, J = 8.0 Hz, IH), 6.06 (dd, J = 6.4 Hz, J = 13.6 Hz, IH), 5.94 (d, J =5.6 Hz, 1 H), 5.60 (d, J = 8.4 Hz, 1 H), 5.36 (t, J = 5.2 Hz, IH), 5.16 (dt, J = 5.2 Hz, J = 53.6 Hz, IH), 4.31-4.35 (m, IH), 3.58-3.76 (m, 2H), 3.57-3.58 (m, 2H). ESITOF-MS: m/z 308.1 [M - Hf.

EXAMPLE 71 Préparation of Compound (74a)

MMTrÔ F

63-6

Cl—'VJ °

MMTrÔ F

74-1

74a \h ______► MMTrO'A^Oy^N

MMTrÔ F

74-2 [0484] Préparation of(74-l): To a solution of 63-6 (1.2 g, 2.12 mmol) in anhydrous

DCM (20 mL) were added collidine (750 mg, 6.51 mol) and MMTrCl (2.6 g, 8.5 mmol). The reaction mixture was stirred at R.T. ovemight. The reaction was filtered and washed

205 successively with saturated aqueous NaHCO₃ and brine, dried over Na₂SO₄ and concentrated. The residue was purified on a silica gel column eluted with 10% EA in PE to give 74-1 as a yellow solid (1.4 g, 72%).

[0485] Préparation of (74-2): To a stirred solution of 74-1 (600 mg, 0.715 mmol) in anhydrous acetonitrile (6 mL) were added TPSC1 (432 mg, 1.43 mmol), DMAP (174 mg, 1.43 mmol) and TEA (144 mg, 1.43 mmol). The mixture was stirred at R.T. for 2 h. Completion of the reaction was determined by TLC (DCM: MeOH= 10:1). CH₃NH₂ (310 mg, 10 mmol) was added dropwise at 0°C. The reaction mixture was stirred at R.T. for 2 h. The mixture was diluted with water and extracted with EtOAc. The combined organic layer was washed with IM

HCl, saturated NaHCO₃ and brine. The solvent was removed, and the residue was purified by prep-TLC (DCM: MeOH= 10; t) to give 74-2 (307 mg, 50.45%) as a white solid.

[0486] Préparation of (74a): 74-2 (300 mg, 0.352 mmol) in formic acid (10 mL, 80% in water) was stirred at R.T. ovemight. Completion of the reaction was determined by TLC (DCM: MeOH= 10:1). The solvent was removed to dryness. The residue was dissolved in 20 15 mL of methanol. Ammonia (0.5 mL) was added, and the mixture was stirred at R.T. for 5 mins.

The solvent was removed, and the residue was washed with PE (5X) to give 74a (103 mg, 95.3%) as a white solid. Ή NMR (DMSO-J₆.400 MHz) £7.79 (d, J = 4.8 Hz, IH), 7.72 (d, J =

5.2 Hz, IH), 6.10 (dd, J - 4.4 Hz, J = 14.8 Hz, IH), 5.97 (brs, IH), 5.73 (d, J = 7.6 Hz, IH), 5.39 (brs, IH), 5.08 (dt, J = 4.2 Hz, J = 53.2 Hz, IH), 4.37-4.40 (m, 1H), 3.73 (s, 2H), 3.54-3.70 (m, 2H), 2.73 (d, J = 4.4 Hz, 3H). ESI-TOF-MS: m/z 308.1 [M + H]⁺.

206

EXAMPLE 72 Préparation of Compound (75a)

H₃C(H₂C)₁₇-Br

75-1

•._i/^O(CH₂)₁₇CH₃

75-3

H₃C(H₂C)₁₇-O‘''''Y^ODMTr

--- OH

75-4

N(i-Pr)₂

HaCtHaQiT-O'^Y^OH ----------^CN _ ^r OBn ”

75-5

N(kPr)₂

H₃C(H₂C)₁₇-O^XY^O'%^x^^xCN

OBn

75-6

NHDMTr

75-7

[0487] Préparation of (75-3): To a stirred solution of 75-1 (20.0 g, 151 mmol) in 5 anhydrous THF (200 mL)was added NaH (7.8 g, 196 mmol) in portions at 0°C. The mixture was stirred for i h, and 75-2 (65.0 g, 196 mmol) was added dropwise at 0°C. The mixture was stirred at R.T. for 10 h. The reaction was quenched with water and extracted with EA. The reaction was washed with brine, and the organic layer was concentrated to obtain crude 75-3 (72

g)· [0488] Préparation of (75-4): Crude 75-3 (72 g, 151 mmol) was dissolved with

80% CH3COOH (300 mL) and stirred for 10 h. The solvent was removed under reduced pressure. The residue was dissolved in EA and washed with saturated NaHCOj and brine successively. The organic layer was dried over Na^SCL and concentrated to dryness. The residue was purified on a silica gel column to give the crude intermediate, which was dissolved in anhydrous pyridine (80 mL) and DCM (400 mL). A solution of DMTrCl (56.0 g, 166 mmol) în DCM (150 mL) was added dropwise at 0°C. The mixture was stirred at R.T. for 10 h. The reaction mixture was concentrated to dryness, and the residue was purified by column on silica gel (PE: EA= 2:1) to give 75-4 (58.5 g, 61%).

207 [0489] Préparation of (75-5): To a stirred solution of 75-4 (10.0 g, 15.5 mmol) in anhydrous DMF (80 mL) was added NaH (0.8 g, 20 mmol) at 0°C. The mixture was stirred at R.T. for 1 h, and BnBr (33.8 g, 20 mmol) was added. The reaction mixture was stirred at R.T. for 10 h. The reaction was quenched with water and extracted with EA. The reaction was washed with brine, and the organic layer was concentrated to give the crude intermediate (10.5 g, 92%) as a white foam. The crude intermediate (10.2 g, 13.8 mmol) in 80% CH3COOH (100 mL) was stirred at R.T. for 12 h. The solvent was removed. The residue was dissoived in EA, washed with saturated NaHCOj and brine successively, dried and concentrated to give a residue. The residue was purified on a silica gel column twice (PE: EA= 3:1) to give 75-5 (4.2 g, 70%) as a white foam.

[0490] Préparation of (75-6): To a solution of 75-5 (4.0 g, 9.2 mmol) in anhydrous CH3CN (30 mL) was added DIPEA (6.1 g, 47.6 mmol) and 2-cyanoethyl N,Ndiisopropylchlorophosphoramidite (2.8 g, 11.9 mmol). The mixture was stirred at R.T. for 2 h. The solvent was removed, and residue was partitioned by EA and saturated NaHCO₃. The organic layer was dried over MgSO₄ and concentrated to give a residue. The residue was purified on a silica gel column (PE: EA= 3:1) to give 75-6 (5.1g, 88 %) as a white solid.

[0491] Préparation of (75-7): To a solution of 75-6 ( 1.0 g, 1.6 mmol) and 63-9 (925 mg, 1.1 mmol) in anhydrous MeCN (1 mL) was added tetrazole (12 mL, 0.45M in MeCN, 5.5 mmol) dropwise at R.T. After stirred for 3 h, TBDPH (0.96 mL, 5M 4.8 mmol) was added. The reaction mixture was stirred at R.T. for t h. The mixture was diluted with EA and washed with saturated Na₂SÜ3 and brine, dried over anhydrous Na₂SO₄ and concentrated. The residue was purified by silica gel chromatography (PE/EA = 50:1 to 1:1) to give 75-7 (1.1 g, 73.3%) as a white solid.

[0492] Préparation of (75a): 75-7 (1.0 g, 0.7 mmol) in 60% HCOOH (3 mL) was stirred at R.T. for 12 h. The solvent was removed. The residue was dissoived in EA and washed with saturated NaHCO3 and brine successively, dried and concentrated to give a residue. The residue was purified twice on a silica gel column (DCM : MeOH= 30:l) to give crude 75a (510 mg, 86%) as a white foam. To a solution of crude 75a (275 mg, 0.33 mmol) in C₂H₃OH was added a few drops IN NaOH until pH-7.0. The mixture was stirred for 0.5 h. The mixture was concentrated to give a residue. The residue was purified by HPLC (MeCN and water, neutral system) to give 75a (sodium sait, 170 mg, 64%) as a white solid. *H NMR (CD3OD, 400 MHz) δ 8.01 (d, J= 7.6 Hz, IH), 7.23-7.37 (m, 5H), 6.22 (dd, J = 3.6 Hz, J= 14.4 Hz, IH), 6.01 (d, J =

7.6 Hz, IH), 5.01-5.16 (m, IH), 4.63-4.72 (m, 2H), 4.52-4.11 (m, IH), 4.23-4.29 (m, IH), 3.91 4.09 (m, 3H), 3.69-3.81 (m, 3H), 3.51-3.60 (m, 2H), 3.41-3.45 (m, 2H), 1.48-1.55 (m, 2H), 1.2117044

208

1.35 (m, 32H), 0.87-0.91 (m, 3H). ^3,P NMR (CD₃OD, 162 MHz) δ -0.223. ESI-TOF-MS: m/z

788.3 [M - H]⁺.

EXAMPLE 73 Préparation of Compound (76a)

AcÔ 'F

76-2

Ynh

HO F

73-1

Η.Η

--AcÔ 'F

76-1

[0493] Préparation of (76-1): To a solution of 73-1 (4.1 g, 13.95 mmol) in pyridine (40 mL) was added Ac₂O (3.13 g, 30,68 mmol) at R.T., and the mixture was stirred ovemight. The mixture was concentrated, and the residue was purified on a silica gel column (PE: EA= 3:1) to give 76-1 (4.0 g, 75.9%).

[0494] Préparation of (76-2): To a solution of 76-1 (1.3 g, 3.44 mmol) in pyridine (20 mL) was added NBS (1.22 g, 6.88mmol) at R.T., and the mixture was stirred ovemight. The mixture was concentrated, and the residue was purified on a silica gel column (PE: EA= 4:1) to give 76-2 (1.43 g, 72.2%).

[0495] Préparation of (76-3): To a solution of 76-2 (770 mg, 1.68 mmol) in dioxane (10 mL) was added MCéSn₂ (1.1 g, 3.36 mmol) and (PPh₃)₂PdCl₂ (100 mg) under N₂atmosphère. The mixture was heated at 80°C for 4 h. The mixture was concentrated, and the residue was purified on a silica gel column to give an intermediate (400 mg, 43.96%). To a solution of the intermediate (330 mg, 0.61 mmol) in anhydrous MeCN (3 mL) was added Selectflour® (462 mg, 1.34 mmol) at R.T. The mixture was stirred at R.T. for 2 days. The mixture was concentrated, and the residue was purified on a silica gel column (PE: EA= 4:1) to give 76-3 (100 mg, 41.5%).

[0496] Préparation of (76a): To a solution of 76-3 (100 mg, 0.25 mmol) in MeCN (2 mL) was added DMAP (62 mg, 0.51 mmol), TEA (51 mg, 0.51 mmol) and TPSC1 (153 mg, 0.51 mmol). The mixture was stirred at R.T. for 0.5 h. NH₃.H₂O (0.75 mL) was added. The

209 mixture was stirred at R.T. for 0.5 h. The mixture was extracted with EtOAc and washed with IN HCl and brine. The organic layer was dried and concentrated. The residue was purified on a silica gel column (PE: EA= 1:1) to give an intermediate (60 mg, 60.1%). The intermediate (50 mg, 0.13 mmol) in NHj/MeOH (5 mL) was stirred at R.T. for 3 h. The mixture was concentrated, and the residue was purified on a silica gel column (MeOH: DCM= 1:10) to give 76a (30 mg, 76.2%). 'H NMR (CDjOD, 400 MHz) £8.25 (d, 6.8 Hz, 1H), 6.09 (d, J = 16.0

Hz, 1H), 5.00 (dt, J = 4.0 Hz, J = 53.2 Hz, 1H), 4.48-4.54 (m, 1H), 3.73-3.95 (m, 4H). ESI-TOFMS: m/z 312.1 [M + H]⁺.

EXAMPLE 74

Préparation of Compound (77a)

77-1

[0497] 77-1 (680 mg, 0.8 mmol) and triphenylphosphine (312 mg, 1.2 mmol) were dîssolved in the mixture of 5 mL of dioxine and 0.25 mL of dry éthanol. A solution of diisopropyl azadicarboxylate (40% w solution in toluene, 1.28 mmol) in 3 mL of dioxane was added, and the mixture was stirred at R.T. for 2 h. The mixture was evaporated to dryness. The residue was dîssolved in 10 mL of THF, cooled down to 4°C and 2 équivalents of TBAF in THF were added. The mixture was warmed up to R.T. and the solvent was evaporated. The resulting nucleoside was treated with 80% HCOOH at R.T. for 3 h, and then the acid was evaporated. Isolated by isocratic silica gel chromatography using mixture of DCM (950 mL), MeOH (50 mL), and NHiOH (2.5 mL) for elution gave 77a (80mg, 30%). H'-NMR (DMSO-D₆) 6: 8.06 (s, IH), 6.41 (s, 2H), 6.11-6.06 (dd, 1H), 5.98-5.89 (dd, 1H), 5.65-5.64 (d, 1H), 5.34-5.26 (m, 2H), 5.18-5.11 (m, 1H), 4.58-4.50 (dt, 1H), 4.42-4.36 (q, 2H), 3.50-3.28 (m, 2H), 1.30 (t, 3H). MS: 384 (M-1+HC00H).

210

EXAMPLE 75

Préparation of Compound (78a)

TBSCÎ ''F

78-2

TBsd ''F

78-3

NHMMTr

TBSO' '?

78-4

NHMMTr

TBSO’ *?

78-5

NHMMTr

[0498] Préparation of (78-2): To a solution of 78-1 (10.0 g, 37.17 mmol) in anhydrous pyridine (100 mL) was added imidazole (9.54 g, 140.4 mmol) and TBSCI (21.1 g,

140.4 mmol) at 25°C. The solution was stirred at 25°C for 15 h. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc (200 mL) and washed with water and brine. The organic layer was separated, dried over anhydrous NaiSO.» and filtered. The filtrate was concentrated in vacuo to give a residue. The residue was purified by a silica gel column (PE/EA = 10:1 to 2:1) to give an intermediate (11.8 g, 64%). To an ice-cold solution of the intermediate (11.8 g, 23.7 mmol) in CH₂C1₂ (150 mL) was added a solution of ptoluenesulfonic acid monohydrate (8.2 g, 47.5 mmol) in small portion under N₂. The mixture was stirred at 25°C for 30 min, and then washed with saturated aq. NaHCOj. The organic layer was separated, dried over anhydrous Na₂SO4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified by silica gel (PE/EA = 10:1 to 1:1) to give 78-2 (6.7 g, 74%) as a solid.

[0499] Préparation of (78-3): To a solution of 78-2 (6.7 g, 17.5 mmol) in anhydrous pyridine (50 mL) was added TMSC1 (2.8 g, 26.2 mmol) in small portions at 0°C under N₂. The reaction mixture was stirred at 25°C ovemight. AgNOj (77.8 g, 510 mmol) and MMTrCl (156.8 g, 510 mmol) in anhydrous pyridine (50 mL) was added in small portions under N₂. The reaction mixture was stirred at 25°C ovemight. Ammonia (30 mL) was added, and the reaction mixture was stirred for 30 min. The mixture was filtered through a Buchner funnel, and the filtrate was washed with saturated NaHCOj solution and brine. The organic layer was separated, dried over anhydrous Na₂SO4, filtered and concentrated. Chromatography on silica gel (PE:EA = 10:1 to 2:1) gave an amine protected dérivative (6.1 g, 53%). To a solution of pyridine (142 mg, 1.8 mmol) in anhydrous DMSO (2 mL) at 0°C was added TFA (1.3 mg, 0.9 mmol)

211 dropwise. The mixture was stîrred at 25 C until a clear solution formed. The solution was then added into a solution of the amine protected dérivative (1.0 g, 1.5 mmol) and DCC (0.95 g, 4.6 mmol) in anhydrous DMSO at 0°C dropwise. Stirring was continued at 25°C for 10 h. Water (10 mL) was added, and the mixture was stîrred at 25°C for 1 h. The precipitate was removed by filtration, and the filtrate was extracted with EtOAc (20 mL). The organic layer was washed with brine (20 mL) and then dried over NaîSO4. The solvent was removed, and the residue was purified on a silica gel column (EA:PE = 10:1 to 2:1) to give the aldéhyde dérivative (850 mg, 85%). To a solution of the aldéhyde dérivative (2.6 g, 4.0 mmol) in 1,4-dioxane (30 mL) was added 37% CH2O (1.3 g, 16.0 mmol) and 2N NaOH aqueous solution (3.0 mL, 6.0 mmol). The mixture was stîrred at 25°C for 2 h and then neutralîzed with AcOH to pH=7. To the reaction were added EtOH (10 mL) and NaBHt (912 mg, 24.0 mmol). The reaction was stîrred for 30 mins, and then quenched with saturated aqueous NH4CI. The mixture was extracted with EA, and the organic layer was dried over Na₂SO4. Purification by silica gel column chromatography (EA: PE= 10:1 to 2:1) gave 78-3(1.1 g, 40%) as a yellow solid.

[0500] Préparation of (78-4): A stîrred solution of 78-3 (685 mg, 1.0 mmol) in anhydrous CH3CN (5 mL) and anhydrous pyridine (5 mL) was cooled to 0°C. BzCl (126 mg, 0.9 mmol) was added, and the reaction mixture was stirred at 25°C. After 1.5 h, water (5 mL) was added. The resulting mixture was extracted with DCM (2x30 mL). The combined extracts were washed with a saturated aqueous solution of NaHCOj (20 mL), dried over MgSOj, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (DCM: MeOH = 200:1 to 50:1) to give the Bz-protected dérivative (679 mg, 86%). To a stirred solution of Bz-protected dérivative (432 mg, 0.55 mmol) in anhydrous DMF (5 mL) was added imidazole (258 mg, 3.85 mmol) and TBSC1 (240.0 mg, 1.65mmol). The mixture was stirred for 15 h. Water ( 10 mL) was added, and the mixture was extracted with EA. The combined extracts were washed with aqueous solution of NaHCOj (60 mL) and brine (60 mL), dried over MgSO4, and evaporated under reduced pressure to give the two-TBS protected dérivative (680 mg, 137 %). The two-TBS protected dérivative (680 mg, 0.75 mmol) was dissolved in anhydrous CH3OH (5 mL), and NaOCHs (162 mg, 3.0 mmol) was added. The reaction mixture was stirred at 35°C for 2 h. The reaction was quenched with 80 % AcOH (3 mL) and extracted with DCM (2x50 mL). The combined cxtracts were washed with aqueous solution of NaHCO₃ (20 mL), dried over MgSO4, and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (EA: PE = 20:1 to 3:1) to give 78-4 (239 mg, 40%) as a white foam.

212 [0501] Préparation of (78-5): 78-4 (239 mg, 0.30 mmol) was co-evaporated with toluene three times to remove H₂O. To a solution of 78-4 in DCM (5 mL) was added DMAP (182 mg, 1.50 mmol) and TfCl (69 mg, 0.45 mmol) at 0°C under N₂. The mixture was stirred 0°C for 40 mins. Completion of the reaction was determined by LCMS. The mixture was concentrated to give the crude Tf-derivative (353 mg). To a solution of the Tf-derivative in DMF (5 mL) was added LiCl (31 mg, 0.76 mmol) at 0°C under N₂. The mixture was stirred at 25°C for 40 mins. The mixture was washed with NaHCO₃ and extracted with EA. The combined organic layer was dried over Na₂SÛ4 and concentrated to give crude 78-5 (268 mg) as a light yellow oil.

[0502] Préparation of (78a): To a solution of 78-5 (268 mg, 0.328 mmol) in MeOH (5 mL) was added NH4F (37 mg, 0.984 mmol) at 25°C for 4 h. The solution was filtered and evaporated to dryness. The residue was dissolved in HCOOH (20 mL) and H₂O (4 mL) at 25°C. The mixture was stirred at 25°C for 1 h and concentrated. The mixture was dissolved in MeCN and purified by prep-HPLC to give 78a (32 mg) as a white solid. *H NMR (MeOD, 400 MHz) £ 8.33 (s, IH), 8.20 (s, IH), 6.32 (dd, J = 5.6, 12.4 Hz, IH), 5.77 (m, IH), 4.69 (m, IH), 3.85 (m, IH). ESI-MS: m/z 317.9 [M + H]*.

EXAMPLE 76 Préparation of Compound (79a)

TBDPSO

HO—

TBSCî' >

78-4

TBDPSO

TBSO

TBSO'

TBDPSO

79-3

HO F

79a [0503] Préparation of (79-1): To a solution of 78-4 (1.1 g, 1.33 mmol) in anhydrous DCM (6.6 mL) at 0°C under nitrogen was added Dess-Martin periodinane (1.45 g, 3.33 mol). The mixture was stirred at 25°C for 4 h. The solvent was removed in vacuum, and the residue triturated with methyl-t-butyl ether (30 mL). The mixture was filtered through a pad of MgSO», and the organic solvent was stirred with an equal volume of Na₂S₂O₃ in 30 mL of saturated NaHCO₃ until the organic layer became clear (approx. 10 min). The organic layer was

213 separated, washed with brine, and dned over MgSO₄. Pnor to removing the solvent in vacuum, the residue was purified on a silica gel column (PE: EA« 7:1) to give 79-1 (750 mg, 75%) as a white solid.

[0504] Préparation of (79-2): To a stirred solution of methyl-triphenylphosphonium bromide (1.74 g, 4.89 mmol) in anhydrous THF (8 mL) was added n-BuLi (1.91 mL, 4.89 mmol, 2.5 M in THF) at -78°C dropwise. The mixture was stirred at 0°C for 1 h. 79-1 (750 mg, 0.81 mmol) was added, and the mixture stirred at 25°C ovemight. The reaction was quenched with saturated NH^C! (30 mL), and extracted with EtOAc (2x30 mL). The combined organic phase was washed with brine, dried with MgSO₄, filtered and evaporated to dryness to give a light white solid. The solid was purified by column chromatography (PE: EA = 5:1) to give 79-2 (440 mg, 60%).

[0505] Préparation of (79-3): To a solution of 79-2 (440 mg, 0.48 mmol) in MeOH (8 mL) was added Pd/C (500 mg, 10%) at R.T. under hydrogen atmosphère. The mixture was stirred at R.T. for 1.5 h. The mixture was filtered, and the filtrate was concentrated to dryness. Crude 79-3 (365 mg. 83%) was used for the next step without further purification.

[0506] Préparation of (79a): 79-3 (365 mg, 0.40 mmol) in MeOH (50 mL) was added NH4F (5.6 g, 0.15 mmol), and the solution was heated to refluxed ovemight. Completion of the reaction was determined by LCMS. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified on a silica gel column (PE: EA = 3:1) to give the amine protected dérivative (173 mg, 77%) as a white solid. The amine protected dérivative (100 mg, 0.18 mmol) in formic acid (4.4 mL) was stirred at 25°C ovemight. The solution was concentration to dryness, and the residue was purified on a silica gel column (PE: EA = 1:3) to give 79a (40 mg, 90%) as a white solid. 'H NMR (400MHz, CDjOD) £8.25 (s, IH), 8.09 (s, IH), 6.14 (dd, J= 6.0, 12.8 Hz, IH), 5.58 (m, IH), 4.45-4.48 (m, IH), 3.60 (q, 2H), 1.66-1.74 (m, 2H), 0.88(t, 3 H); ESI-MS: m/z 297.9 [M + H]*.

214

EXAMPLE 77 Préparation of Compound (80a)

78-3

BnO

DMTrO-

BnO

HO—

TBSO

F

80-3

NHMMTr

[0507] Préparation of (80-1): To a solution of 78-3 (4.4 g, 6.4 mmol) in anhydrous pyridine (5 mL) and DCM ( 25 mL). A solution of DMTrCl (2.37 g, 7.04 mmol) in DCM (5 mL) was added dropwise at 0°C under N₂. After 2 h, the reaction was quenched with CHjOH and concentrated to dryness. The residue was purified on a column of silica gel (PE: EA = 100:1 to 2:1) to obtain the DMTr protected dérivative (4.3 g, 68%). The DMTr protected dérivative (2.2 g, 2.5 mmol) in IM TB AF (2.5 mL) of THF (2.5 mL) solution was stirred at 25°C for 3 h. The solvent was removed in vacuum, and the residue was purified by column chromatography (PE/EA= 50:1 to 1:2) to give the diol dérivative (1.86 g, 96%). To a solution of the diol dérivative (1.3 g, 1.5 mmol) in anhydrous THF (5 mL) was added NaH (132 mg, 3.3 mmol) at 0°C. The mixture was stirred for 1 h, and TBI (276 mg, 0.75 mmol), and BnBr (558 mg, 3.3 mmol) was added. The mixture was stirred for 10 h at 25°C. The reaction was quenched with water, and the solvent was evaporated. The mixture was extracted with EA and brine. The organic layer was dried over Na^SOj, and evaporated to afford the crude product. The product was purified by silica gel (PE/EA = 100:1 to 3:1) to afford 80-1 (1.4 g, 90%) as a white foam.

[0508] Préparation of (80-2): To a solution of 80-1 (1.3 g, 1.23 mmol) in anhydrous DCM (17 mL) was added CI2CHCOOH (1.57 g, 12.3 mmol) at -78°C. The mixture was stirred at -20-10°C for 40 mîns. The reaction was quenched with saturated NaHCOj, and diluted with DCM (50 mL). The mixture was washed with brine, and the organic solution was dried over NajSOj and concentrated in vacuum. The residue was purified on a silica gel column (PE/EA = 100:1 to 1:1) to give 80-2 (652 mg, 70%) as a white foam.

[0509] Préparation of (80-3): To a solution of 80-2 (630 mg, 0.84 mmol) in anhydrous DCM (5 mL) was added DAST (1.35 g, 8.4 mmol) at -78°C. The mixture was gradually warmed to 0°C. The reaction was quenched with saturated NaHCOj. The mixture was

215 diluted with DCM (50 mL) and washed with brine. The organic solution was dried over Na₂SO₄and concentrated in vacuum. The residue was purified on a silica gel column (PE/EA = 100:1 to 2:1) to give 80-3 as a white solid (302 mg, 48%).

[0510] Préparation of (80a): A mixture of 80-3 (210 mg, 0.28 mmol) and Pd(OH)₂(200 mg) in methanol (3 mL) was stirred at 0°C at 40 psi H₂ for 20 h. Pd(OH)₂ was filtered off, and the filtrate was concentrated to dryness. The residue was purified by column (DCM/MeOH = 10:1) to give 80a (12 mg). *H NMR (400MHz, CDjOD) <78.33 (s, IH), 8.20 (s, IH), 6.33 (dd, J= 6.0, 13.2 Hz, IH), 5.79 (t, J- 5.6 Hz, IH), 5.66 (t, J= 5.2 Hz, IH), 4.52-4.80 (m, 3H), 3.803.82 (m, 2H). ESI-MS: m/z 302.0 [M + H] ⁺.

EXAMPLE 78

Préparation of Compound (81a)

81-1 81-2 81-3

anhydrous pyridine (200 mL) was added imidazole (19.1 g, 280 mmol) and TBSCi (42.1 g, 281 mmol) at 25°C. The solution was stirred at 25°C for 15 h, and then concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and then filtered. The filtrate was concentrated to dryness to give the TBS protected dérivative (36.4 g, 99%). The TBS protected dérivative (36.5 g, 71.1 mmol) was dissolved in THF (150 mL). H₂O (100 mL), and then AcOH (300 mL) were added. The solution was stirred at 80°C for 13 h. The reaction was cooled to

R.T., and then concentrated to dryness under reduced pressure to give 81-2 (31.2 g, 61%) as a white solid.

216 [0512] Préparation of (81-3): To a solution of 81-2 (31.2 g, 78.2 mmol) in anhydrous pyridine (300 mL) was added Ac₂O (11.9 g, 117.3 mmol). The mixture was stirred at 25°C for 18 h. MMTrCl (72.3 g, 234.6 mmol) and AgNOj (39.9 g, 234.6 mmol) were added, and the solution was stirred at 25°C for 15 h. H₂O was added to quench the reaction and the solution was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na₂SO4 and filtered. The filtrate was concentrated in vacuum to give a residue, which was purified by silica gel (DCM:MeOH = 200:1 to 50:1) to give the MMTr protected amine dérivative (35.2 g, 63%). The MMTr protected amine dérivative (35.2 g, 49.3 mmol) was dissolved in NHj/MeOH (300 mL). The mixture was stirred at 25°C for 20 h. The solution was evaporated to dryness, and purified by a silica gel column (DCM: MeOH = 100:1 to 50:1) to give 81-3 as a yellow solid (28.6 g, 87%). .

[0513] Préparation of (81-4): To a solution of 81-3 (12.0 g, 17.9 mmol) in anhydrous DCM (200 mL) was added Dess-Martin periodinane (11.3 g, 26.8 mmol) at 0°C. The mixture was stirred at 0°C for 2 h, and then at R.T. for 2 h. The mixture was quenched with a saturated NaHCOj and Na₂S₂O₂ solution. The organic layer was washed with brine (2X) and dried over anhydrous Na₂SO4. The solvent was evaporated to give the aldéhyde (12.6 g), which was used directly in the next step. To a solution of the aldéhyde (12.6 g, 18.0 mmol) in 1,4dioxane (120 mL) was added 37% HCHO (11.6 g, 144 mmol) and 2N NaOH aqueous solution (13.5 mL, 27 mmol). The mixture was stirred at 25°C ovemight. EtOH (60 mL) and NaBHi (10.9 g, 288 mmol) were added, and the reaction was stirred for 30 mins. The mixture was quenched with saturated aqueous NH₄C1, and then extracted with EA. The organic layer was dried over Na₂SO₄, and purified by silica gel column chromatography (DCM: MeOH = 200:1 to 50:1) to give 81-4 (7.5g, 59%) as a yellow solid.

[0514] Préparation of (81-5): To a solution of 81-4 (3.8 g, 5.4 mmol) in DCM (40 mL) was added pyridine (10 mL) and DMTrCl (1.8 g, 5.4 mmol) at 0°C. The solution was stirred at 25°C for 1 h. MeOH (15 mL) was added, and the solution was concentrated. The residue was purified by silica gel column chromatography (DCM: MeOH » 200:1 to 50:1) to give the MMTr protected dérivative (3.6 g, 66%) as a yellow solid. To a solution of the MMTr protected dérivative (3.6 g, 3.6 mmol) in anhydrous pyridine (30 mL) was added TBDPSC1 (2.96 g, 10.8 mmol) and AgNOj (1.84 g, 10.8 mmol). The mixture was stirred at 25°C for 15 h. The mixture was filtered and concentrated. The mixture was dissolved in EtOAc and washed with brine. The organic layer was dried over Na₂SO₄-, and then purified by silica gel column chromatography (DCM: MeOH = 200:1 to 50:1) to give the TBDPS protected dérivative (3.8 g.

217

85.1%) as a solid. To a solution of the TBDPS protected dérivative (3.6 g, 2.9 mmol) in anhydrous DCM (50 mL) was added C1₂CHCOOH (1.8 mL) in anhydrous DCM (18 mL). The mixture was stirred at -78°C for 1 h. C1₂CHCOOH (3.6 mL) was added at -78°C. The mixture was stirred at -10°C for 30 mins. The mixture was quenched with saturated aqueous NaHCOî and extracted with DCM. The organic layer was dried over Na₂SO₄, and then purified by silica gel column chromatography (DCM: MeOH » 200:1 to 50:1) to give 81*5 (2.2 g, 80%).

[0515] Préparation of (81-6): To an ice cooled solution of 81-5 (800 mg, 0.85 mmol) in anhydrous DCM (20 mL) was added pyridine (336 mg, 4.25 mmol) and Tf₂O (360 mg, 1,28 mmol) dropwise. The reaction mixture was stirred at 0°C for 15 mins. The reaction was quenched by ice water and stirred for 30 mins. The mixture was extracted with EtOAc, washed with brine (50 mL) and dried over MgSO₄. The solvent was evaporated to give the crude bis(triflate) dérivative. To the bis(triflate) dérivative (790 mg, 0.73 mmol) in anhydrous DMF (35 mL) was added LiCl (302 mg, 7.19 mmol). The mixture was heated to 40°C and stirred ovemîght. Completion of the reaction was determined by LCMS. The solution was washed with brine and extracted with EtOAc. The combined organic layers were dried over MgSO₄, and the residue was purified on a silica gel column (DCM/MeOH = 100:1) to give 81-6 (430 mg, 61%).

[0516] Préparation of (81a): To 81-6 (470 mg, 0.49 mmol) in MeOH (85 mL) was added NH₄F (8.1 g, 5.92 mmol), and the solution was heated to reflux ovemight. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified on a silica gel column (DCM/MeOH « 20:1) to give the diol (250 mg, 84%) as a white solid. The diol (130 mg, 0.21 mmol) in formic acid (5 mL) was stirred at 25°C ovemight. The solution was concentration to dryness, and the residue in MeOH (30 mL) was stirred at 70°C ovemight. Completion of the reaction was determined by LCMS and HPLC. The solvent was removed, and the crude product was washed with EtOAc to give 81a (58 mg, 81%) as a white solid. *H NMR (DMSO-î/₀, 400 MHz) <5 10.73 (br, IH), 7.98 (s, IH), 6.58 (br, 2H), 6.08 (q, J = 4.8, 9.2 Hz, 2H), 5.64 (dt, 5.6, 52.8 Hz, IH), 5.40 (m, IH), 4.52 (m, IH), 3.80-3.82 (m, 2H), 3.64 (q, 2H). ESI-MS: m/z 333.8 [M +Hf, 666.6 [2M +H]⁺

218

EXAMPLE 79

Préparation of Compound (82a)

82-3 ^82a [0517] Préparation of (82-1): To a solution of 81-4 (310 mg, 0.33 mmol) în anhydrous DCM (10 mL) was added pyridine (130 mg, 1.65 mmol) and Tf₂O (139 mg, 0.49 mmol) diluted by DCM dropwise at 0°C. The mixture was stirred at 0°C for 15 mins. The reaction was quenched with ice cold water. The organic layer was separated and washed with brine. The organic layer was dried over Na₂SC>4 and evaporated to give to give the triflate dérivative (420mg crude), which was used directly in the next step. To a solution of the triflate dérivative (420 mg crude) in anhydrous pentan-2-one was added Nal (396 mg, 2.64 mmol). The mixture was stirred at 40°C for 3 h, and then dissoived with EtOAc. The organic layer were washed with Na₂S₂0j twice and washed with brine. The organic layer was dried over Na₂SÛ4 and evaporated to give a residue. The residue was purified by a column (DCM: MeOH = 300:1 to 100:1) to give 82-1 (195 mg, 56% for two steps).

[0518] Préparation of (82-2): To a solution of 82-1 (650 mg, 0.62 mmol) in MeOH (10 mL) was added NH4F (45.8 g, 12.4 mmol). The mixture was refluxed ovemight. The mixture was filtered and evaporated to dryness. The residue was purified on a silica gel column (DCM/MeOH = 200:1 to 20:t) to give 82-2 (250 mg, 58%).

[0519] Préparation of (82-3): To a stirred solution of 82-2 (300 mg, 0.43 mmol), EtjN (217 mg, 2.15 mmol) in anhydrous MeOH (10 mL) was added 10% Pd/C (50 mg). The mixture was stirred in a hydrogénation apparatus (30 psi hydrogen) at R.T. ovemight. The catalyst was filtrated off, and the filtrate was evaporated to give a residue. The residue was purified on a silica gel column (DCM/MeOH = 200:1 to 20:1) to afford 82-3 as a white solid (l80mg, 73%).

[0520] Préparation of (82a): 82-3 (110 mg, 0.19 mmol) was dissoived în HCOOH (18 g) and H₂O (6 g) at 25°C, and stireed for 1 h. The solution was evaporated to dryness, dissoived in MeOH (30 mL). The mixture was stirred at 60°C for 12 h. The solution was

219 evaporated to dryness, and dissolved in EtOAc (50 mL). The mixture was stirred at 60 C for l h. The mixture was filtered and washed with EtOAc to give 82a as a white solid (45,3 mg, 80%). *H NMR (400MHz, MeOD) £8.00 (s, IH), 6.11-6.15 (m, IH), 5.35-5.50 (m, IH), 4.53-

4.59 (m, IH), 3.54-3.64 (m, 2H), 1.26 (s, 3H). ESI-MS: m/z 299.76 [Μ + 1 ]⁺, 598.66 [2M + 1]⁺.

EXAMPLE 80 Préparation of Compound (83a)

[0521] Préparation of (83-1): 81-1 (5.7 g. 20 mmol) was co-evaporated with pyridine three times, and then dissolved in pyridine (20 mL). The mixture was cooled to 0°C and Ac₂O (5.8 mL, 60 mmol) was added dropwise. The mixture was stirred at 25°C for 10 h, and then cooled to 0°C. AgNO₃ (8.5 g, 50 mmol), and then MMTrCl (15.5 g, 50 mmol) were added in portions. The mixture was stirred at 25°C for 10 h. The reaction was quenched with saturated NaHCOj and extracted with EA. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography (DCM/MeOH =

100:1 to 50:1) to afford the Ac protected dérivative (12.1 g, 93%) as a light yellow solid. The

Ac protected dérivative (12.1 g) was dissolved in methanolic NH₃ (saturated). The mixture was stirred at 25°C for 14 h. The solvent was removed, and the residue was purified on a silica gel column (DCM/MeOH = 80:1 to 30:1) to give 83-1 (9.2 g, 87%).

[0522] Préparation of (83-2): To a stirred solution of 83-1 (9.2 g, 16.5 mmol) in dry THF (300 mL) was added imidazole (9.0 g, 132 mmol) and PPh₃ (34.8 g, 132 mmol). A solution of I₂ (26.0 g, 103 mmol) in THF (100 mL) was added dropwise under N₂ at 0°C. The mixture was stirred at 25°C for 18 h and then quenched with a Na₂S₂O₃ solution. The mixture was extracted with EtOAc. The organic layer was dried over Na₂SO₄ and concentrated. The residue was purified on a silica gel column (DCM/MeOH = 80:1 to 30:1) to give the iodide dérivative (10.3 g, 93%) as a light yellow solid. To a stirred solution of the iodide dérivative (10.2 g, 15.3 mmol) in dry THF (300 mL) was added DBU (4.7 g, 30.1 mmol). The mixture was

220 stirred at 60 C for 8 h. The solution was diluted with a NaHCOj solution and extracted with EtOAc. The organic layer was dried over Na₂SO4 and concentrated. The residue was purified on a silica gel column (PE/EtOAc= 3:1 to 1:3) to afford 83-2 (6.2 g, yield 76%).

[0523] Préparation of (83-3): To a stirred solution of 83-2 (5.42 g, 10 mmol) in anhydrous CHjOH (100 mL) was added PbCOj (13.7 g, 53.1 mmol). A solution of I₂ (12.3 g, 48.9 mmol) in CH3OH (300 mL) was added dropwise at 0°C. The mixture was stirred at 25°C for 10 h. The solution was quenched with a Na₂S₂0j solution and extracted with DCM. The organic layer was washed with a NaHCOj solution, dried over Na₂SÛ4 and concentrated to give a residue. The residue was purified by HPLC (0.1% HCOOH in water and MeCN) to give the desired methoxyl dérivative (2.4 g, 34%). To a stirred solution of the methoxyl dérivative (2.4 g,

3.4 mmol) in dry pyridine (20 mL) was added BzCl (723 mg, 5.2 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 1 h. The solution was quenched with a NaHCOj solution and extracted with EtOAc. The organic layer was dried over Na₂SÛ4 and concentrated. Purified by a silica gel column (ΡΕ/EtOAc = 5:1 to 1:1 ) afforded 83-3 (2.1 g, 77%) as a white solid.

[0524] Préparation of (83a): 83-3 (2.0 g, 2.5 mmol), BzONa (3.6 g, 25 mmol) and 15-crown-5 (5.5 g, 25 mmol) were suspended in DMF (50 mL). The mixture was stirred at 110125°C for 5 days. The precipitate was removed by filtration, and the filtrate was diluted with EA. The solution was washed with brine and dried over Na₂SO4. The solvent was removed, and the residue was purified on a silica gel column (PE/EA = 10/1 to 2/1) to afford the crude Bz protected dérivative (1.6 g, 80%). The Bz protected dérivative (1.6 g, 2.0 mmol) was dîssolved in methanolic ammonia (100 mL), and the mixture was stirred at 25°C for 20 h. The solvent was removed, and the residue was purified by a silica gel column (DCM/MeOH = 100:1 to 20:1) to the diol dérivative as a white solid (410 mg, 35%). The diol dérivative (200 mg, 0.34 mmol) was dîssolved in HCOOH (24 g) and H₂O (6 g) at 25°C, and the mixture was stirred at 25°C for 1 h. The solution was evaporated to dryness, and dîssolved in MeOH (30 mL). The mixture was stirred at 60°C for 12 h. The solution was evaporated to dryness and dîssolved in EtOAc (50 mL). The mixture was stirred at 60°C for 1 h. The mixture was then filtered and washed with EtOAc to give 83a as a white solid (46.1 mg, 43%). ’H NMR (CDjOD, 400MHz) £7.92 (s, 1H), 6.22 (dd, J = 1.6, 18.8 Hz, 1H), 5.17-5.32 (m, 1H), 4.89-4.91 (m, 1H), 3.77 (m, 2H), 3.44 (s, 3H). ESI-MS: m/z 316.1 [M + H]⁺.

221

EXAMPLE 81

Préparation of Compound (84a)

ΒζΟ^γθ^Ο

Bzô \

84-1

BzO

BzÔ >

84-2

Ν=γ^Ν F NHMMTr 84-4 [=Λ ,o HO-VzO^Ny^f Uf\^nh ^F NHMMTr

84-5

- H^F N^^NHTBSÔ F NHMMTr

84-6

TBD PSO^\z°y» N ='''V^-F N«s/^NHTBSÔ 'F NHMMTr

84-9 ₀ ^{HCÎ F} NHMMTr

84-10

O ^H<3' ^F nh₂

84a [0525] Préparation of (84-2): To a stirred solution of 84-1 (100.0 g, 265.9 mmol) in dry THF (1000 mL) was added Li(O-f-Bu)₃AlH (318.9 mL, 318.9 mmol) at -78°C under N₂. The mixture was stirred at -78°C for 1 h and then at R.T for 1 h. The reaction mixture was cooled to -50°C and quenched with ice and a saturated NH₄C1 solution. The mixture was extracted with EtOAc. The organic layer was dried over NaiSQj and concentrated to afford the t '-OH dérivative (100.5 g) as a white solid. To a stirred solution of the l'-OH dérivative (100.5 g, 265.9 mmol) in dry DCM (600 mL), NEt₃ (110 mL) and MsCl (45.5 g, 298.0 mmol) were added dropwise at 0°C. The mixture was stirred at R.T. for 2 h. The mixture was quenched with ice water at 0°C and extracted with DCM. The organic layer was dried over Na₂SO4, concentrated and purified on a silica gel column (PE: EA = 50:1 to 5:1) to afford 84-2 (l 13.4 g, yield: 93.9%) as a white solid.

[0526] Préparation of (84-3): To a suspension of compound 6-chloro-9W-purin-2amine (70.1 g, 414,7 mmol), HMDS (480 mL) and (NHihSQu (0.8 g) was added dry DCE (400 mL). The mixture was refluxed under N₂ for 18 h and then cooled to R.T. To the silylated 2amino-6-chloropurine solution was added 84-2 (78.0 g, 171.Immol) and TMSOTf (60 mL, 331.9 mmol). The mixture was refluxed ovemight, concentrated and neutralized with a NaHCO₃ solution. The resulting precipitate was filtered, and the filtrate was extracted with

222

EtOAc. The organic layer was dried over Na₂SO₄ and concentrated. Chromatography on a silica gel column (PE: EA = 5:1 to 2:1) gave 84-3 (10.8 g, yield: 11.9%) as a light yellow solid.

[0527] Préparation of (84-4): To a suspension of 84-3 (30.0 g, 56.6 mmol) in DCM (300 mL) were added MMTrCl (34.9 g, ! 13.2 mmol) and AgNOj (19.3 g, 113.2 mmol). The reaction mixture was cooled to 0°C, and collidine (18.0 g, 150 mmol) was added. The resulting suspension was stined at R.T. for 12 h. The suspension was filtered. The filtrate was extracted with DCM and washed with a NaHCOj solution. The organic layer was dried over Na₂SO₄ and concentrated. Purification by a silica gel column (PE: EA = 20:1 to 3:1) to give 84-4 (35.0 g, yield: 77.9%) as a light yellow solid. *H NMR (CDClj, 400 MHz) â 7.94-7.96 (m, 4H), 7.057.58 (m, I8H), 6.62-6.67 (m, 2H), 6.55 (dd, J = 6.0 Hz, J = 9.6 Hz, IH), 5.60-5.66 (m, IH), 4.69-4.76 (m, 2H), 4.55-4.58 (m, IH), 3.64 (s, IH). ESI-MS: m/z 802 [M + H]⁺.

[0528] Préparation of (84-5): To a stirred solution of 84-4 (35.0 g, 43.6 mmol) in dry MeOH (400 mL) was added NaOMe (23.5 g, 436 mmol) and 2-mercapto-ethanol (30.6 g,

392.4 mmol). The mixture was refluxed ovemight. The pH was adjusted to 9-10 with CO₂. The precipitate was filtered, and the filtrate was concentrated. Purification on a silica gel column (PE: EA = 10:1 to 1:1) gave pure 84-5 (24.0 g, yield 95.7%) as a light yellow solid.

[0529] Préparation of (84-6): To a solution of 84-5 (24.0 g, 41.7 mmol) in pyridine (250 mL) was added DMTrCl (28.2 g, 83.5 mmol) at 0°C. The solution was stirred at R.T. for 15 h. MeOH (50 mL) was added, and the mixture was concentrated to dryness under reduced pressure. The residue was dissolved in EtOAc and washed with water. The organic layer was dried over Na₂SO₄, filtered, concentrated and purified by a silica gel column (DCM: MeOH = 200:1 to 50:1) to give a first intermediate (27.6 g) as a yellow solid. To a solution of the first intermediate (27.6 g, 31.5 mmol) in DCM (200 mL) was added imidazole (4.3 g, 63 mmol) and TBSC! (9.5 g, 63 mmol). The mixture was stirred at R.T. for 12 h. The solution was washed with NaHCOj and brine. The organic layer was dried over Na₂SO₄, filtered, concentrated and purified by a silica gel column (DCM: MeOH = 200:1 to 100:1) to give a second intermediate (30.2 g) as a yellow solid. To a solution of the second intermediate (30.2 g, 30.4 mmol) in anhydrous DCM (50 mL) was added C1₂CHCOOH (20 ml) in anhydrous DCM (500 mL). The mixture was stirred at -78°C for ! h. C1₂CHCOOH (30 mL) was added at -78°C. The mixture was stirred at -20°C for 2 h. The mixture was quenched with saturated aqueous NaHCOj and extracted with DCM. The organic layer was dried over Na₂SO₄, and then purified by a silica gel column (DCM: MeOH - 200:1 to 30:1) to give 84-6 (18.0 g, 62.5%) as a white solid. *H NMR (400MHz, MeOD) £8.27 (s, IH), 7.16-7.38 (m, 12H), 6.79-6.83 (m, 2H), 6.42 (dd, J= 4.4 Hz, J

223 = 10.0 Hz, 1H), 4.54-4.62(m, 1H), 3.92 (d, J= 8.8 Hz, 2H), 3.74 (s, 3H), 3.70-3.72 (m, 1H), 0.92 (s, 9H), 0.11-0.13 (m, 6H). ESI-LCMS: m/z 690.0 [M + HJ*.

[0530] Préparation of (84-7): 84-6 (7.0 g, 10.0 mmol) was added to a suspension of DMP (10.6 g, 25 mmol) in anhydrous CH₂C1₂ (100 mL) at 0°C. The mixture was stirred at 25°C 5 for 2 h. The solvent was removed in vacuo, and the residue triturated with diethyl ether (100 mL). The mixture was filtered through a pad of MgSO₄. The organic solvent was stirred with an equal volume of Na₂S₂O₃.5H₂O in 100 mL of saturated NaHCOj until the organic layer became clear (10 min). The organic layer was separated, washed with brine, and dried over MgSO₄. The solvent was removed in vacuo to give a third intermediate as a red solid (6.5 g, 10 95%). To a solution of the third intermediate (6.5 g, 9.5 mmol) in 1,4-dioxane (80 mL) was added 37% CH₂O (6.0 mL, 60 mmol) and 2N NaOH aqueous solution (9.5 mL, 19 mmol). The mixture was stirred at 25°C for 2 h and then neutralized with AcOH to pH 7. EtOH (30 mL) and NaBH₄ (3.8 g, 100 mmol) were added, and the mixture was stirred for 30 mins. The mixture was quenched with saturated aqueous NH4CI, and then extracted with EA. The organic layer 15 was dried over Na₂SO4. Purification by a silica gel column (DCM: MeOH = 200:1 to 30:1) gave 84-7 (4.2 g, 58.3%) as a yellow solid.

[0531] Préparation of (84-8): To a solution of 84-7 (4.2 g, 5.8 mmol) in DCM (50 mL) was added pyridine (5 mL) and DMTrCl (1.9 g, 5.8 mmol) at -20°C. The solution was stirred at 0°C for 2 h. The reaction mixture was treated with MeOH (15 mL), and then 20 concentrated. The residue was purified by a silica gel column (DCM: MeOH = 200:1 to 50:1 ) to give the fourth intermediate (1.3 g) as a yellow solid. To a solution of the fourth intermediate (1.3 g, 1.3 mmol) in anhydrous pyridine (15 mL) was added TBDPSC1 (1.1 g, 3.9 mmol) and AgNOj (0.68 g, 4.0 mmol). The mixture was stirred at 25°C for 15 h. The mixture was filtered, concentrated, dissolved in EtOAc and washed with brine. The organic layer was dried over 25 Na₂SO4. Purification by a silica gel column (DCM: MeOH = 200:1 to 100:1) gave a fïfth intermediate (1.4 g) as a solid. To a solution of the fifth intermediate (1.4 g, 1.1 mmol) in anhydrous DCM (50 mL) was added C1₂CHCOOH (0.7 ml) in anhydrous DCM (18 mL). The mixture was stirred at -78°C for 1 h. C1₂CHCOOH (1.5 ml) was added at -78°C, and the mixture was stirred at -20°C for 1.5 h. The mixture was quenched with saturated aqueous NaHCOj and 30 extracted with DCM. The oiganic layer was dried over Na₂SO₄. Purification by a silica gel column (DCM: MeOH = 200:1 to 50:1) gave 84-8 (650 mg, 11.6%) as a white solid.

[0532] Préparation of (84-9): To a solution of pyridine (521 mg, 6.59 mmol) in anhydrous DMSO (5 mL) was added TFA (636 mg, 5.58 mmol) dropwise at 10°C under N₂. The mixture was stirred until a clear solution formed. To this solution (0.8 mL) was added a

224 mixture of 84-8 (650 mg, 0.68 mmol) and DCC (410 mg, 2.0 mmol) în anhydrous DMSO (5 mL) at R.T. under N₂. The mixture was stirred at 20 °C ovemight. Water (30 mL) was added. The mixture was diluted with DCM (30 mL) and filtered. The filtrate was extracted with DCM. The organic layers were washed with saturated aqueous NaHCCh, dried over Na₂SÛ4 and concentrated in vacuo. The crude product was purified on a silica gel column (PE: EA = 10:1 to 1:1) to give the sixth intermediate (600 mg) as a yellow solid. To a stirred solution of Methyltriphenyl-phosphonium bromide (714 mg, 2.0 mmol) in anhydrous THF (5 mL) was added nBuLi (0.8 mL, 2.0 mmol, 2.5 M in THF) at -78°C dropwise over 1 min. Stirring was continued at 0 °C for 1 h. The sixth intermediate (600 mg, 0.63 mmol) was added to the mixture, and the mixture was stirred at 25°C for 15 h. The reaction was quenched with saturated NH₄C1 (20 mL) and extracted with EtOAc. The combined organic phase was dried with Na₂SO₄, filtered and evaporated to dryness to give a light yellow oil. The oil was purified by column chromatography (DCM: MeOH = 200:1 to 50:1) to give 84-9 (250 mg, 38.5%) as a yellow solid.

[0533] Préparation of (84-10): 84-9 (250 mg, 0.26 mmol) was dissolved in THF (5.0 mL). TBAF (131 mg, 0.5 mmol) was added at 20°C, and stirring was continued for 2 h. The solution was evaporated to dryness. The residue was dissolved in EA (50 mL) and washed with water (2X). The solution was evaporated to dryness, and purified by a silica gel column (PE: EA = 10:1 to 1:2) to give 84-10 (57.6 mg, 36.9%) as a white solid. *H NMR (400MHz, MeOD) Ô 8.34 (s, IH), 7.15-7.38 (m, 12H), 6.79-6.82 (m, 2H),6.44 (dd, J= 2.0 Hz, J= 10.0 Hz, IH), 6.01 (dd, J= 11.2 Hz, J= 17.6 Hz, 1H),5.51 (dd.J= 1.6 Hz,J= 17.2 Hz, IH), 5.35 (dd, J=

1.6 Hz, J= 17.2 Hz, 1 H), 4.68-4.76 (m, IH), 3.74 (s, 3H), 3.63(dd, J= 2.0 Hz,J= 12.8 Hz, IH) 3.52(dd. J= 2.0 Hz, J= 12.8 Hz, ÏH). ESI-LCMS: m/z 602.0 [M + H]*.

[0534] Préparation of (84a): A solution of 84-10 (27 mg) in 1.5 mL of 80% formic acid stood at R.T. for 4.5 h and then concentrated to dryness. The residue was mixed with water and lyophilized. MeOH (1.5 mL) and TEA (0.1 mL) were added, and the mixture was concentrated. The precipitate from MeOH and EtOAc was filtered and washed with EtOAc to give 84 (9.3 mg) as a slightïy-amber solid. *H NMR (CD3OD. 400 MHz) £8.44 (s, IH), 6.57 (d, J - 10.8 Hz, IH), 6.05 (dd, J= 17.6 Hz, 10.8 Hz, IH), 5.45 (dd, J= 17.6 Hz, J= 1.6 Hz, IH), 5.37 (dd, J = 10.8 Hz, 1.6 Hz, IH), 4.78 (dd, J = 18.4 Hz, 17.2 Hz, IH), 3.67 (d, J = 12.4 Hz, IH), 3.56 (dd, ./=12.4 Hz, 2.0 Hz, IH); ESI-MS: m/z 328.4 [M -Hf.

225

EXAMPLE 82

Préparation of Compound (85a)

NHDMT

85-2 [0535] Préparation of (85-2): A mixture of 85-1 (200 mg; 0.22 mmol) in pyridine (2.5 mL) and isobutyric anhydride (44 pL; 1.2 equiv) was stirred R.T. overnight. The mixture was concentrated, and the residue partitioned between EtOAc (50 mL) and water. The organic layer was washed with IN citric acid, water, saturated aqueous NaHCO₃ and brine. The mixture was dried with Na^SOj. The solvent was evaporated and the residue was purified on a silica column (10 g column) using hexanes/EtOAc (30 to 100% gradient) to give 85-2 (0.16 g, 75%).

[0536] Préparation of (85a): A solution of 85-2 (0.16 g; 0.16 mmol) in 80% aq. HCOOH (5 mL) was stirred at R.T. for 3 h. The solvent was evaporated and then co-evaporated with toluene. Purification on a silica column (10 g column) with CH2CI2 /MeOH (4-10% gradient) gave 85a (43 mg, 74%). 'H-NMR (DMSO-ds): δ 7.75 (d, 1 H), 7.33 (d, 2 H), 6.07 (dd.

H), 5.75 (d, t H), 5.55 (dd, 1 H), 5.43 (dt, 1 H), 5.43 (t, 1 H), 3.79 (dd, 2 H), 3.63 (ddd, 2 H),

2.64 (sept, 1 H), 1.12 (d, 6 H). MS: m/z = 362.1 [M+l]

EXAMPLE 83

Préparation of Compound (86a)

NHDMT

NH

NHDMT

^fO

86-2

86a [0537] Préparation of (86-2): 86-2 was prepared using a similar procedure for preparing 85-2 with the following: 86-1 (220 mg; 0.22 mmol), (2.5 mL), isobutyric anhydride (0.13 mL; 3.6 equiv), EtOAc (30 mL), and hexanes/EtOAc (30 to 100% gradient) to give 86-2 (175 mg, 85%).

[0538] Préparation of (86a): 86a was prepared using a similar procedure for preparing 85a with the following: 86-2 (117 mg; 0.13 mmol), 80% aq. HCOOH (4 mL) and

226

CH₂C1₂ /MeOH (4-10% gradient) to give 86a (36 mg, 77%). ¹ H-NMR (DMSO-dô): 6 7.58 (d, 1 H), 7.29 (d, 2 H), 6.00 (s, 1 H), 5.73 (d, 1 H), 5.24 (ddd, 1 H), 4.55 (dd, I H), 4.22 (dd, 2 H), 3.80 (dd, 2 H), 2.58 (sept, 1 H), 1.08, 1.07 (2d, 6 H). MS: m/z = 364 [M+1 ].

[0539] Préparation of (87*2): 87-2 was prepared using a similar procedure for preparing 46-2 with the following: 87-1 (178 mg, 0.3 mmol), hexanoic anhydride (0.14 mL, 2 equiv.), pyridine (3 mL) to give 87-2. (120 mg, 50%).

[0540] Préparation of (87a): 87a was prepared using a similar procedure for preparing 85a with the following: 87-2 (120 mg, 0.15 mmol), 80% aq. HCOOH and CH₂C1₂/MeOH (4-10% gradient) to give 87a (62mg, 85%). ¹ H-NMR (CDCh): 6 8.2 (br, 1 H), 7.42 (d.

H), 6.8 (br, l H), 6.03 (d, 1 H), 5.77 (dd, 1 H), 5.64 (dd, 1 H), 5.51 (ddd, I H), 4.43 (dd, 2 H),

3.82 (dd, 2 H), 2.41 (m, 2 H), 2.33 (m, 2 H), 1.64 (m, 4 H), 1.31 (m, 8 H), 0.82 (m, 6 H). MS:

m/z = 488 [M-l].

EXAMPLE 85 Préparation of Compound (88a)

NHOMT	NHDMT 1	NH, 1 *
Cl DMTO-t θΑ^Ν O	ex DMTO-y^o^ ^{0 r} ct-'-VJ	1X - w ⁰
H(J' V	0 >	d >
85-1	ΊΧο ¹ ΊΟ	ΊΧο ' Ί0
	88-2	88a
[0541]	Préparation of (88-2): 88-2 was prepared usine	a similar procedure for

preparing 85-2 with the following: 85-1 (220 mg; 0.24 mmol), pyridine (3 mL), dodecanoyc anhydride (0.12 g; 1.3 equiv), EtOAc (50 mL) and hexanes/EtOAc (25 to 80% gradient) to give 88-2 (0.22 g, 85%).

227 [0542] Préparation of (88a): 88a was prepared using a similar procedure for preparing 85a with the following: 88-2 (0.19 g; 0.17 mmol), 80% aq. HCOOH (5 mL) and CH₂C1₂ /MeOH (4-10% gradient) to give 88a (66 mg, 82%). ‘H-NMR (DMSO-dé): δ 7.77 (d, 1 H), 7.35 (d, 2 H), 6.07 (dd, t H), 5.77 (d, 1 H), 5.60 (dd, 1 H), 5.55 (ddd, 1 H), 5.43 (t, 1 H), 5 3.78 (dd, 2 H), 3.65 (ddd, 2 H), 2.41 (m, 2 H), 1.56 (m, 2 H), 1.24 (m, 16 H), 0.85 (m, 3 H).

MS: m/z = 474 [M-l].

EXAMPLE 86

Préparation of Compounds (89a) and (90a)

NHDMT nÂî

89-2

891

I

NHj -/¾ 'i' so* [0543] Préparation of (89-2): To a solution of 89-1 (175 mg; 0.18 mmol) in MeCN (2.5 mL) at 0°C was added TMSBr (0.28 mL; 10 equiv.). The mixture was stirred at R.T. for t h, evaporated and treated with water. The obtained white solid was filtered, dried and washed with CH2CI2. The white solid was then dissolved in NMP (2 mL) and treated with DIPEA (94 gL; 3 equiv.) and pivaloyloxymethyliodide (84 gL; 3 equiv.). The mixture was stirred at R.T. for 1 day, and then partitioned between water (20 mL) and rert-butyl methyl ether (TBME; 60 mL). The organic layer was washed with saturated aqueous NaHCOj, water and brine. The combined aqueous washings were back extracted with TBME (2 x 20 mL). The combined organic extract was dried and purified on a silica column (10 g column) with CH2CI2 /i-PrOH (220 10% gradient) to give 89-2 (42 mg, 26%).

[0544] Préparation of (89a): A solution of 89-2 in 80% aq. HCOOH was stirred at R.T. for 3 h. The solvent was evaporated and then co-evaporated with toluene. Purification on a silica column (10 g column) with CH₂Cl2 /MeOH (4-15% gradient) gave 89a (17 mg, 74%). ‘HNMR (CDjOD): δ 7.47 (d, 1 H), 6. 28 (dd, 1 H), 6.04 (dd, 1 H), 5.77-5.71 (m, 2 H), 5.53 (m, 4

228

H), 5.18 (ddd, 1 H), 5.60 (dd, 1 H), 3. 77 (dd, 2 H), 1.08 (m, 18 H). ^3IP-NMR (CDjOD): δ 17.64. MS: m/z = 598 [M+l].

[0545] Préparation of (90a): A mixture of 89a (12 mg; 0.02 mmol) in EtOH ( 1 mL) and Pd/C (10%; 2.5 mg) was stirred ovemight under an atmospheric pressure of hydrogen. The mixture was filtered through a Celite pad. The solvent was evaporated and the product was purified on a silica column (10 g column) with CH2CI2 /MeOH (4-17% gradient) to give 90a (6 mg, 50%). ’H-NMR (CDjOD): δ 7.51 (d, 1 H), 5.79 (d, 1 H), 5.65-5.54 (m, 5 H), 5.20 (ddd, 1 H), 5.60 (dd, 1 H), 3. 70 (dd, 2 H), 2.17-2.06 (m, 1 H), 2.02-1.87 (m, 3 H), 1.13 (m, 18 H). ³¹PNMR (CDjOD): δ 33.16. MS: m/z = 600 [M+l].

EXAMPLE 87

Préparation of Compound (91a)

Préparation of (91-2):

[0546]

To a solution of triethylammonium bis(i sopropy 1 ox ycarbon yloxymethyl Jphosphate (O.33mmol, prepared from 110 mg of bis(POC)phosphate and 0.1 mL of EtjN) in THF (2 mL) was added 86-1 (100 mg; 0.11 mmol), followed by diisopropylethyl amine (0.19 mL; 10 equiv), BOP-C1 (140 mg; 5 equiv) and 3-nîtro1,2,4-triazole (63 mg; 5 equiv). The mixture was stirred at R.T. for 90 mins., and then dîluted with CH2CI2 (30 mL). The mixture was washed with saturated aqueous NaHCOj and brine.

The mixture was dried with NajSOj. The solvent was evaporated, and the residue was purified on a silica column (10 g column) with hexanes/EtOAc (40-100% gradient) to give 91-2 (117 mg,

90%).

229 [0547] Préparation of (91a): 91a was prepared using a similar procedure for preparing 85a with the following: 91-2 (87 mg; 0.07 mmol), 80% aq. HCOOH (5 mL) and

CH₂CI₂ /MeOH (4-15% gradient) to give 91a (36 mg, 85%). ’H-NMR (CDjCN): δ 7.67 (dd, 1

H), 6.35 (dd, 1 H), 6.1 (br, 2 H), 5.82 (d, 1 H), 5.62 (m, 4 H), 5.22 (dm, 1 H), 4.98 (br, 1 H), 4.89 5 (m, 2 H), 4.49 (d, 1 H), 4.34 (m, 2 H), 3.88 (dd, 2H), 1.29 (d, 6 H), 1,28 (d, 6 H); ³¹P-NMR (CDjCN): δ -4.49. MS: m/z = 606[M+l].

EXAMPLE 88

Préparation of Compound (92a)

o

[0548] Préparation of (92-2) and (92-3): To a solution of triethylammonium bis(POM)phosphate (0.48 mmol, prepared from 176 mg of bis(POM)phosphate and 0.15 mL of EtjN) in THF (2 mL) was added 92-1 (150 mg; 0.18 mmol) followed by diisopropylethyl amine (0.31 mL; 10 equiv), BOP-C1 (229 mg; 5 equiv), and 3-nitro-l,2,4-triazole (103 mg; 5 equiv).

The mixture was stirred at R.T. for 90 mins., and then diluted with CH2CI2 (30 mL). The mixture was washed with saturated aqueous NaHCO₃ and brine. The mixture was dried with NaiSOj. The solvent was evaporated, and the residue was purified on a silica column (10 g

230 column) with CH2CI2 /i-PrOH (2-10% gradient) to obtain 92-2 (44 mg, 21%) and 92-3 (73 mg, 28%).

[0549] Préparation of (92a): A mixture of 92-2 and 92-3 (73 mg and 44 mg) and 80% aq. HCOOH (3 mL) was heated for 30 mins., at 35°C. The solvent was evaporated and 5 then coevaporated with toluene. The solvent was evaporated, and the residue was purified on a silica column ( 10 g column) with CH2CI2 /MeOH (4-10% gradient) to obtain 92a (40 mg, 75%). 'H-NMR (DMSO-D₆): δ 10.6 (br, 1 H), 7.76 (s, 1 H), 6.44 (br, 2 H), 5.99 (dd, 1 H), 5.83 (d, 1 H), 5.53-5.27 (2 m, 6 H), 4.39 (dt, 1 H), 4.04 (m, 2 H), 1.17 (s, 3 H), 1.06, 1.08 (2 s, 18 H). ^3,PNMR (DMSO-dô): δ-4.09. MS: m/z = 608 [M+l].

EXAMPLE 89

Préparation of Compound (93a)

Î fl _ ©

ΡΟΜΟ-Ρ-cP EtjNH HO—x _o N^n^NHMMT ____^0P0M___,

MMTd V

13-1 «3-2

93-3

O

[0550] Préparation of (93-2) and (93-3): 93-2 and 93-3 (68 mg and 80 mg, respectively) were prepared in the same manner from 93-1 (200 mg; 0.23 mmol) and bis(POM) phosphate (230 mg) with DIPEA (0.4 mL), BopCl (290 mg), and 3-nitro-l,2,4-triazole (130 mg) in THF (3 mL) as 92-2 and 92-3 from 92-1.

231 [0551] Préparation of (93a): 93-2 and 93-3 (68 mg and 80 mg, respectively) were converted into 93 (42 mg) with formic acid in the same manner as 92 from 92-2 and 92-3. *HNMR (DMSO-De): δ 7.73 (s, 1 H), 6.46 (br, 2 H), 6.04 (dd, 1 H), 5.91 (dd, 1 H), 5.87 (d, 1 H), 5.48 (d, 4 H), 5.33 (m, 1 H), 5.24 (ddd, I H), 4.60 (dt, 1 H), 4.07 (m, 2 H), 1.07, 1.06, 1.05 (4 s, 5 18 H). ^3,P-NMR (DMSO-d«): δ -4.37. MS: m/z = 620 [M+l].

EXAMPLE 90 Préparation of Compound (94a)

[0552] To a solution of 93a (53 mg; 0.09 mmol) in EtOH (2 mL) was added 10%

Pd/C (10 mg). The mixture stirred under hydrogen at atmospheric pressure for 1 h. The mixture was filtered through a Celite pad, and the filtrate evaporated. Purification on a silica column ( 10 g column) with CH2CI2 /MeOH (4-11% gradient) yielded 94a (45 mg, 81%). *H-NMR (DMSOD₆): δ 10.6 (br, 1 H), 7.81 (s, 1 H), 6.4 (br, 2 H), 5.97 (dd, 1 H), 5.85 (d, 1 H), 5.60-5.44 (m, 5

H), 4.37 (m, 1 H), 4.11 (ddd, 2 H), 1.66 (m, 2 H), 1.09, 1.06 (2 s, 18 H), 0.81 (7, 3 H); ³¹P-NMR (DMSO-d$): δ-4.10. MS: m/z = 622 [M+l],

232

EXAMPLE 91

Préparation of Compounds (95a) and (96a)

70a 95-1 95-2

[0553] Préparation of (95-1): To a solution of 5-Amino-2H-[l,2,4]triazin-3-one (180 mg, 1.5 mmol) in HMDS was added a catalytic amount of (NHj^SOj. The mixture was heated to reflux for 5 h. HMDS was evaporated to give a crude product. To a solution of the crude product in anhydrous CHjCN was added 70a (220 mg, 0.5 mmol) and TMSOTf (0.45 mL, 2.5 mmol). The mixture was heated to reflux for 24 h in a sealed tube. The reaction was quenched with NaHCOj and diluted with EA. The organic solvent was removed, and the residue was purified by prep-TLC first, and the by RP-HPLC (0.5% HCOOH in water and MeCN) to give the pure 95-1 (100 mg, 46%).

[0554] Préparation of (95-2): To a solution of 95-1 (80 mg, 0.18 mmol) in anhydrous CHjCN was added 1,2,4-trîazole (911 mg, 11.7 mmol) and TEA (1.45 g, 14.4 mmol). The mixture was cooled to 0°C and POClj was added. The reaction mixture was stirred at 25°C for 24 h. The solvent was evaporated and partitîoned with EA and water. The organic layer was concentrated to give the crude 95-2 (80 mg, 90%).

[0555] Préparation of (95a): 95-2 (90 mg, 0.18 mmol) was dissolved in 20 mL of saturated THF ammonia. The resulting solution was stirred at 25°C for 2 h. The solvent was removed, and the residue was purified on a silica gel column (EA: PE = 6:1) to give 95a as a white solid (70 mg, 70%).

[0556] Préparation of (96a): 95a (70 mg, 0.16 mmol) was dissolved in 20 mL of saturated MeOH ammonia. The resulting solution was stirred at 25°C for 2 h. The solvent was removed, and the residue was purified by RP-HPLC (0.5% HCOOH in water and MeCN) to give

233

96a (5 mg, 11%) as a white solid. Ή NMR (CDjOD, 400 MHz) £7.57 (s, IH), 6.35 (dd, J- 3.6 Hz, J = 15.6 Hz, IH), 5.45-5.47 (m, 1 H), 4.70 (dd, J = 4.8 Hz, J= 16.2 Hz, IH), 3.83 (s, 2H), 3.71 (d, J= 1.6 Hz, 2H). ESI-TOF-MS: m/z 295.1 [M + H]⁺.

EXAMPLE 92

Préparation of Compounds (97a-g)

[0557] Dry nucleoside (0.05 mmol) was dissolved in a mixture of DMF (3 mL) and DMA-DMF (0.04 mL, 0.1 mmol). The réaction was kept at ambient température for 4 h and then evaporated to dryness. The residue was dissolved in a mixture of PO(OMe)3 (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated in vacuum for 15 min. at 42°C, than cooled down to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCI3 (9μ1, 0.11 mmol). The mixture was kept at R.T. for 20-40 mins. The reaction was controlled by LCMS and monitored by the appearance of the corresponding nucleoside 5*-monophosphate. After completion of the reaction, tetrabutylammonium sait of pyrophosphate (150 mg) was added, followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 h at ambient température, the reaction was diluted with water (10 mL). The mixture was loaded on the column HiLoad 16/10 with Q Sepharose High Performance, and séparation was done in a linear gradient of NaCI from 0 to IN tn 50mM TRIS-buffer (pH7.5). The triphosphate (97a-f) was eluted at 75-80%B. The corresponding fractions were concentrated. The residue was dissolved in 5% ammonium hydroxide, kept for 15 min. at R.T. and concentrated. Desalting was achieved by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer.

234

Table 4 - Triphosphates obtained from Example 92

Structure	MS (M-l)	P(a)	M»)	P(7)
nh₂ O O O W., Il II II f N ' hÎ 'F 97a	528.0	-6.71 •6.82(d)	-21.43(0	-11.35 -11.47(d)
“ nh₂ h ji ° _m-p_o--O-P-O _vN-{ OH OH AhS-<_/ ° ^Z HO* * 97b	544.0	-6.25(bs)	-21.45(bs)	-11.44 -11.56(d)
nh₂ O O 0 HO-P-O-P-O-P-O-yo^ Ah Ah Ah ° ^S,Hâ *F 97c	575.7	-8.86 -9.00(d)	-22.95(0	-11.81 -11.94(d)
?H OH HO-P-O-P-O-JJ-O^. ₀ n-^ HO⁴ *F 97d	545.9	-9.41 -9.44(d)	-23.04 (t)	-12.00 -12.13(d)
NHï î Î^H ? HO-A-o-p-o-P-tv _oy«-< ^{0 0} °/=Λ_7 ⁰ \ H<? 97e	552.1	-10.32 -IO.44(d)	-23.26(t)	-11.84 -11.96(d)
NHi OOO ÇN ηο-^-ο-ρ-ο-^-ο-^Α>^ν-^ Ôh OH Ôh^<—T HO* F 97f	508.4	-8.30 (bs)	-22.72(bs)	-11.51 -11.63(d)
O o o J^™² HO-P-O-P-O-P-O r if ÔH ÔH ΟΗν^°γ*^Νγ^Ν 97fi	550.1	-9.17 -9.29 (d)	-23.04 (t)	•11.97 -12.09(d)

EXAMPLE 93

Préparation of Compounds (98a-e) and (99a) [0558] Dry nucleoside (0.05 mmol) was dissoived in a mixture of PO(OMe)j (0.7 mL) and pyridine (0.3 mL). The mixture was evaporated in vacuum for 15 mins. at 42°C, than cooled down to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCIj (9μ1,0.11 mmol). The mixture was kept at R.T. for 20-40 mins. The reaction was controlled by

235

LCMS and monitored by the appearance of the corresponding nucleoside 5*-monophosphate. After completion of the réaction, tetrabutylammonium sait of pyrophosphate (150 mg) was added, followed by DMF (0.5 mL) to get a homogeneous solution. After 1.5 h at ambient température, the réaction was diluted with water (10 mL) and loaded on the column HiLoad 5 16/10 with Q Sepharose High Performance. Séparation was done in a linear gradient of NaCl from 0 to IN în 50mM TRIS-buffer (pH7.5). The triphosphate (98a-e) was eluted at 75-80%B. The corresponding fractions were concentrated. Desaltîng was achieved by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of methanol from 0 to 30% in 50mM triethylammonium acetate buffer (pH 7.5) was used for elution. The 10 corresponding fractions were combined, concentrated and lyophilîzed 3 times to remove excess of buffer.

236

Table 5 — Compounds obtained from Example 93

Structure	MS (M-l)	P(a)	Ρ(β)	P(Y)
O O o n ΗΟ-Ρ-Ο-Ρ-Ο-Ρ-Ο-νΟ^Ν^Ύ ^{άΗ όΗ} « ^H0 F NH₂ 98a	538.0	-5.2! -5.33(d)	-20.56(1)	-11.09 -11.20(0
OH OH 0 —sN Cl—'J—/ Ht? F 98b	556.2	-10.85(bs)	-23.1l(bs)	-11.76 -11.88(d)
N Γ²ooo f y-i HO-P-O-P-O-P-O-» n N—(' J¹ÔH OH 0Η_ζ7θΆ^ ^Fho⁴ f 98c	540.4	-8.86(bs)	-23.84(t)	-11.68 -11.80(d)
,,ν ,^NH* ooo f y-4 HO-P-O-P-O-P-O-ao N-< J OH OH OFL-vi?f_T Ht? *F 98d	536.0	-9.35 -9.47(d)	-23.05(0	-11.60 -11.72(d)
e; î ?^H î fS. ψΤΗΜΗγ, ο o oci-^r\_y o Ht? *F 98e	545.9	-10.54 -10.66	-23.26	-11.80 -11.93(d)
ο ^Λιη 4 ► Ht? F 99a	357.2	1.42(s)	NA	NA

EXAMPLE 94 Préparation of Compound (100a)

H(J 'F

100-1

HCÏ 'F

100-2

HtJ F

100a [0559] Préparation of (100-2): To an ice-cold solution of 100-1 (22 mg; 0.055 mmol) in acetonitrile (0.5 mL) was added TMSBr (80 pL; 10 equiv.). The resuiting mixture was stirred at R.T. for 1 h. The mixture was concentrated, and the residue was partitioned between

237 water and diethyl ether. The aqueous layer was washed with Et₂O, neutralized with triethylammonium bicarbonate buffer and lyophilized to yield the triethylammonium sait of 100-

2.

[0560] Préparation of (100a): 100-2 was rendered anhydrous by coevaporating with pyridine and toluene. Anhydrous 100-2 was dissolved in HMPA (1 mL) and 1,1carbonyldiimidazole (32 mg; 0.2 mmol) was added. The mixture was stirred at R.T. for 6 h. A solution of tetrabutylammonium pyrophosphate (0.22 g; ~0.2 mmol) in DMF (2 mL) was added. The mixture was stirred ovemight at R.T. The mixture was diluted with triethylammonium acetate buffer and purified by RP-HPLC with a gradient 0-60% B (A: 50 mM aqueous TEAA, B: 50mM TEAA in MeOH) and repurified by RP-HPLC with a gradient 0-30% B to give 100a. ^3IP-NMR (D₂O): δ 3.22 (d, IP), -8.21 (br, 1 P), -22.91 (br, 1 P). MS: m/z = 528 (M-l).

EXAMPLE 95

	Préparation of Compound (100b)
nh₂	nh₂	° û n Q - ^Ho
o fi ci \ ^N MeO, q N—	⁰υ e n -

HO' 'F HO' F [0561] Préparation of (100-4): 100-4 was prepared from 100-3 (54 mg; 0.13 mmol) in acetonitrile (1.3 mL) with TMSBr (0.18 mL) using a similar procedure as described for the préparation of 100-2.

[0562] Préparation of (100b): 100b was prepared from 100-4 in HMPA (2 mL) with CDI (84 mg) and tetrabutylammonium pyrophosphate (0.5 g) in DMF (2 mL) using a similar procedure as described for the préparation of 100a. ³¹P-NMR (D₂O): δ 17.90 (d, IP), 9.00 (d. 1 P),-22.91 (t, 1 P). MS: m/z = 530(M-l).

EXAMPLE 96 Préparation of Compound (100c)

H(J F

100-5

100-6

100c

238 [0563] Préparation of (100-6): 100-6 was prepared from 100-5 (40 mg; 0.09 mmol) in acetonitrile (1 mL) with TMSBr (0.1 mL) using a similar procedure as described for the préparation of 100-2.

[0564] Préparation of (100c): 100c was prepared from 100-6 in HMPA (1.5 mL) 5 with CDI (50 mg) and tetrabutylammonium pyrophosphate (0.3 g) using a similar procedure as described for the préparation of 100a. ^3lP-NMR (D2O): δ -7.13 (br, IP), -10.14 (d, 1 P), -22.84 (br, 1 P). ¹⁹F-NMR (D2O): δ -117.53 (dd, 1 F), -197.8 (m, 1 F). MS: m/z = 545.5 (M-l).

EXAMPLE 97

Préparation of Compounds (IQOd) and (100e)

HCÎ 'F

100-7

100-8

100· [0565] Préparation of (100-8): To an ice-cold solution of diastereomers 100-7 (35 mg; 0.08 mmol) in acetonitrile (l mL) was added TMSBr (0.1 mL; 10 equiv.). The resulting mixture was stirred overnight at R.T. and then concentrated. The residue was partitioned 15 between water and CH₂C1₂. The aqueous layer was washed with CH₂C1₂, neutralized with triethylammonium bicarbonate buffer and lyophilized to yield the triethylammonium sait of 100-

8.

[0566] Préparation of (IQOd) and (100e): 100-8 was rendered anhydrous by coevaporating with pyridine and toluene. Anhydrous 100-8 was dissoived in DMF (1.5 mL) and 20 CDI (54 mg; 0.3 mmol) was added. The mixture was stirred at R.T. for 7 h. A solution of tetrabutylammonium pyrophosphate (0.3 g; -0.3 mmol) in DMF (4 mL) was added. The mixture was stirred at R.T for 3 days. The mixture was diluted with triethylammonium acetate buffer. Two consecutive RP-HPLC purifications with a gradient 0-60% B (A: 50 mM aqueous TEAA, B: 50mM TEAA in MeOH) and 0-40% B gave lOOd and 100e as single diastereomers.

100d: ^3tP-NMR (D₂O): δ 4.28 (dd, IP), -6.37 (d, 1 P), -22.36 (t, 1 P). MS: m/z = 548.1 (M-l).

100e: ^3IP-NMR (D₂O): δ 4.13 (dd, IP). -6.38 (d, I P), -22.46 (t, I P). MS: m/z = 548.1 (M-l).

239

EXAMPLE 98 Préparation of Compound (101a)

101-1

101-3 101« [0567] Préparation of (101-1): To a solution of 59-4 (1.5 g, 2.39 mmol) in anhydrous DCM (100 mL) was added Dess-Martin periodinane (5.2 g, 11.95 mmol) at 0°C under nitrogen. The mixture was stirred at R.T. for 5 h. The mixture was poured into NaHCO₃ and Na2S₂O₃ aq. Solution. The organic layer was washed with brine, dried over with anhydrous Na₂SO4, and concentrated to dryness to give the crude 101-1 (L5 g) as a white solid, which was used for the next step without further purification.

[0568] Préparation of (101-2): To a mixture of bromo(isobutyl)triphenylphosphorane (4.8 g, 12.03 mmol) in anhydrous THF (8 mL) was added t-BuOK(l 1.2 mL, 11.2 mmol) at 0°C under nitrogen. The mixture was stirred at R.T. for 1 h. A solution of 101-1 (1.0 g, 1.6 mmol) in anhydrous THF (4 mL) was added dropwise at 0°C. The mixture was stirred at R.T. for 3 h. The reaction was quenched with a NH4CI aq. solution and extracted with DCM. The organic layer was dried and concentrated to give a residue, which was purified by silica gel column chromatography (5% EtOAc in PE) to give 101-2 (793 mg, 74.4%) as a white solid.

[0569] Préparation of (101-3): To a solution of 101-2 (364 mg, 0.547 mmol) in anhydrous CH₃CN (6 mL) were added TPSC1 (414 mg, 1.37 mmol), DMAP (167 mg, L37 mmol) and NEt₃ (138 mg, L37 mmol) at R.T. The mixture was stirred at R.T. for 2 h. NH4OH (6 mL) was added, and the mixture was stirred for another 1 h. The mixture was diluted with DCM and washed with a NaHCO₃ aq. solution. The organic layer was separated and

240 concentrated to give a residue, which was purified by silica gel column chromatography (2% MeOH in DCM) to give 101-3 (347 mg, 95.0%) as white solid.

[0570] Préparation of (101a): To a solution of 27-3 (347 mg, 0.52 mmol) in MeOH (10 mL) was added NH4F (1.5 g) at R.T. The reaction mixture was refluxed for 12 h, and then filtered. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (10% MeOH in DCM) to give 101a (87 mg, 53%) as a white solid. *H NMR (CDjOD, 400MHz) £8.11 (d, J = 7.6 Hz, 1H), 6.03 (dd, J= 1.2,17.6 Hz, 1H), 5.88 (d, J =

7.2 Hz, 1H), 6.03 (dd, J = 1.6, 11.6 Hz, 1H), 5.39 (d, J = 10.8 Hz, 1H), 4.88 (dd, J = 3.2, 60.0 Hz, 1H), 4.41 (dd, J - 4.8, 24.4 Hz, 1H), 3.70 (d, J = 12.4 Hz, 1H), 3.57 (d, J = 12.0 Hz, 1H), 3.08-3.14 (m, 1H), 0.94-0.98 (m, 6H). ESI-MS: m/z 626.9 [2M + H]⁺.

EXAMPLE 99 Préparation of Compound (102a)

102-1 102-2

102-4 102a [0571] Préparation of (102-1): To a solution of 101-2 (1.0 g, 1.5 mmol) in MeOH (20 mL) was added NHjF (6 g) at R.T., and the mixture was refluxed ovemight. After cooling to R.T., the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (8 % MeOH in DCM) to give 102-1 (400 mg, 85%) as a white solid.

[0572] Préparation of (102-2): To a solution of 102-1 (400 mg, 1.27 mmol) in MeOH (10 mL) was added Pd/C (400 mg) at R.T. The mixture was stirred at R.T. under a balloon of H₂ for 1.5 h. The mixture was filtered, and the filtrate was concentrated in vacuo to give 102-2 (400 mg, 99 %) as a white solid.

[0573] Préparation of (102-3): To a solution of 102-2 (400 mg, 1.26 mmol) in anhydrous DMF (5 mL) were added imidazole (968 mg, 14.2 mmol), and TBSC1 (1.5 g, 10.0

241 mmol) at R.T. The mixture was stirred at 50°C ovemight. The mixture was diluted with DCM and washed with a NaHCOj aq. solution. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (10% EA in PE) to give 102-3 (676 mg, 98 %) as a white solid.

[0574] Préparation of (102-4): To a solution of 102-3 (676 mg, 1.24 mmol) in anhydrous CHjCN (6 mL) were added TPSC1 (941 mg, 13.11 mmol), DMAP (379 mg, 3.11 mmol) and NEtj (314 mg, 3.11 mmol) at R.T. The reaction was stirred at R.T. for 3 h. NH4OH (1 mL) was added, and the réaction was stirred for 4 h. The mixture was diluted with DCM and washed with a NaHCOj solution. The organic layer was dried and concentrated. The residue was purified by silica gel column chromatography (2% MeOH in DCM) to give 102-4 (450 mg, 67%) as a white solid.

[0575] Préparation of (102a): To a solution of 102-4 (450 mg, 0.83 mmol) in MeOH (10 mL) was added NH4F (2 g) at R.T. The reaction mixture was refluxed ovemight. After cooling to R.T., the mixture was filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (8 % MeOH in DCM) to give 102a (166.6 mg, 64%) as a white solid. *H NMR (CDjOD, 400MHz) £8.09 (d, J = 7.6 Hz, I H), 6.07 (d, J =

3.6 Hz, 1 H), 6.05 (d, J = 2.8 Hz, I H), 5.89 (d, J = 7.6 Hz, 1 H), 5.03 (dd, J = 5.2, 57.2 Hz, 1 H), 4.41 (dd, 7 = 4.2, 17.2 Hz, IH), 3.74 (d,7= 12.0 Hz, IH), 3.54 (d,7= 12.0 Hz, IH), 1.23-1.78 (m, 5H), 0.90 (d, 7 = 6.4 Hz, 6H). ESI-MS: m/z 631.1 [2M + H]⁺.

EXAMPLE 100

Préparation of Compound (103a)

103-1

103-2

242 [0576] Préparation of (103-21: 103-1 (3.8 g, 6.9 mmol) in 80% AcOH aq. was stirred at 50°C for 4 h. The mixture was concentrated to give a residue, which was purified by silica gel column chromatography (5% MeOH in DCM) to give the uridine dérivative (1.5 g, 78.2%?) as a white solid. To a solution of the uridine dérivative (1.5 g, 5.4 mmol) in Py (10 mL) was added AC2O (1.38 g, 13.5 mmol) at R.T. The mixture was stirred at R.T. for 12 h. The mixture was concentrated to give a residue, which was purified by silica gel column chromatography (20% EA in PE) to give 103-2 (1.3 g, 687o) as a white solid.

[0577] Préparation of (103-3): To a solution of N-(5-fluoro-2-hydroxy-l,2dihydropyrimidin-4-yl)benzamide (0.5 g, 2.1 mmol) in anhydrous PhCl (5 mL) was added ammonium sulfate (6 mg, 0.043 mmol), followed by HMDS (0.7 g, 4.3 mmol). The mixture was heated to 130°C for 8 h. The mixture was concentrated under vacuum to 2 mL, and then cooled to 0°C. TMSOTf (310 mg, 1.4 mmol) was then added. After stirring for 10 min at 0°C, 103-2 (150 mg, 0.4 mmol) in PhCl (5 mL) was added. The mixture was stirred at 130°C for 10 h. The mixture was concentrated, and the residue was re-dissolved in DCM (10 mL), washed with water (5 mL) and saturated NaHCOj. The organic layer was dried over NaîSCh, evaporated to dryness and the crude product was purified by silica gel column chromatography (60% PE in EA) to give 103-3 (30 mg, 16%) as a white solid.

[0578] Préparation of (103a): A solution of 103-3 (150 mg, 0.34 mmol) in NHi/MeOH (10 mL) was stirred at R.T. for 3 h. The mixture was concentrated, and the residue was purified by HPLC séparation (0.1% HCOOH in water and MeCN) to give 103a (60 mg, 60%) as a white solid. ^lH NMR (CD₃OD, 400MHz) £8.28 (d, J = 6.8 Hz, IH), 6.10 (dd, J = 2.0, 15.2 Hz, IH), 4.99-5.15 (m, IH), 4.62-4.65 (m, IH), 4.49-4.55 (m, 2H), 3.89 (dd, J = 1.6, 12.0 Hz, IH), 3.75 (dd,J=1.2, 12.0 Hz, IH). ESI-MS: m/z 613.1 [2M + Na]⁺.

EXAMPLE 101 Préparation of Compound (104a)

NHBz

103-3

[0579] Préparation of (104-1): 103-3 (150 mg. 0.31 mmol) was dissolved in 80% aqueous acetic acid (3 mL). The solution was heated to reflux for 2 h. The mixture was cooled to ambient température and diluted with water (5 mL), neutralized to pH>7 with saturated

243

NaHCOj and extracted with EA. The organic layer was dried and evaporated to dryness. The residue was purified by silica gel column chromatography (50% EA in PE) to give 104-1 (80 mg, 70%) as a white solid.

[0580] Préparation of (104a): 104-1 (80 mg, 0.22 mmol) in saturated NHj/MeOH (10 mL) was stirred at R.T. for 3 h. The mixture was concentrated, and the residue was purified by silica gel column chromatography (5% MeOH in DCM) to give 104a (40 mg, 60%) as a white solid. ^lH NMR (CDjOD, 400MHz) <78.30 (d, J = 6.8 Hz, 1 H), 6.18 (dd, J = 4.0, 14.0 Hz, IH), 5.13-5.65 (m, IH), 4.52-4.56 (m, IH), 3.980-3.95 (m, 2H), 3.76 (s, 3H). ESI-MS: m/z

319.1 [M + Na]⁺.

EXAMPLE 102

Préparation of Compound (105a) î O

-P-0 H I

°Y .X

BOP-Cl. DIPEA, triethylammonium (0. 065 mmol, prepared from 22 mg of

bis (isop ropyloxycarbonyloxyme thyl) phosphate bis(POC)phosphate and EtjN) in THF was added 105-1 (31 mg; 0.05 mmol). The resulting mixture evaporated, and the residue was rendered anhydrous by coevaporation with pyridine, followed by toluene. The anhydrous evaporated residue was dissolved THF ( l mL) and cooled tn an ice-bath. To the solution was added diisopropylethyl amine (35 gL; 4 equiv), followed by BOP-Cl (25 mg; 2 equiv) and 3-nitro-l,2,4-triazole (l l mg; 2 equiv). The mixture was stirred at 0°C for 90 min. The mixture was diluted with CH2CI2, washed with saturated aq. NaHCO₃ and

244 bnne, and dried with Na₂SO4. The evaporated residue was purifîed on silica (10 g column) with a CH₂CI₂ /i-PrOH solvent System (3-10% gradient) to give 105-2 (13 mg, 28%).

[0582] Préparation of f I05a): A solution of 105-2 ( 13 mg; 0.014 mmol) in 80% aq.

HCOOH (2 mL) was stirred at R. T. for 3 h. The mixture was evaporated and then coevaporated with toluene. The product was purifîed on silica (10 g column) with a CH₂Cl₂/MeOH solvent System (4-15% gradient) to give 105a (7 mg, 78%). *H-NMR (DMSO-d<i): δ 7.52 (d, 1 H), 7.28, 7.24 (2 br s, 2 H) 5.92 (dd, 1 H), 5.74 (d, 1 H), 5.69 (d, 1 H), 5.62 (d, 4 H), 4.97 (ddd, 1 H), 4.82 (m, 2 H), 4.38 (dt, 1 H), 4.07 (m, 2 H), 1.23 (m, 12 H), 1.04 (m, IH), 0.37 (m, 4 H). ^3,P-NMR (DMSO-dé): δ -4.51. ^l9F-NMR (DMSO-dJ: δ -199.23 (dt). MS: m/z = 598.4 (M+l).

EXAMPLE 103 Préparation of Compound (106a)

JL ⁰ ^χ'Ό^χΎ>^Χ’'^νΟ-Ρ-ΟΗ i

NHDMT	r°
Λ ο^ΗΟ_λΎ^Ν °	OyO Et₃N
ΒΟΡ-CI, DIPEA,
^Z HO 'F	NT; THF
106-1

80% aq HCOOH

[0583] Préparation of (106-1): 106-1 (15 mg; 30% yield) was prepared in the same manner from 43-5 (32 mg; 0.057 mmol) and bis(POC)phosphate (24 mg) with DIPEA (40 gL), BopCI (29 mg) and 3-nitro-l,2,4-triazole (13 mg) as 105-2 from 105-1.

[0584] Préparation of (106a): 106-1 (15 mg) was converted in formic acid to 106a (8 mg; 78% yield) in the same manner as 105-2 to 105a. ’H-NMR (DMSO-d^): δ 7.55 (d, 1 H), 7.32,7.27 (2 br s, 2 H) 6.06 (dd, 1 H), 5.84 (d, 1 H), 5.73 (d, 1 H), 5.61 (d, 4 H), 5.08 (ddd, 1 H), 4.83 (m, 2 H), 4.36 (m, 1 H), 4.21 (dd. H), 4.16 (dd, 1 H), 3.56 (d, 1 H), 3.49 (d, 1 H), 3.28 (s, 3 H), 1,25, 1.24 (2 d, 12 H). ^3,P-NMR(DMSO-d6): δ-4.45. MS: m/z = 602.4 (M+l).

245

EXAMPLE 104

Préparation of Compound (107a)

[0585] Préparation of (107-1): 107-1 (30 mg; 30% yield) was prepared in the same manner from 40-10 (65 mg; 0.115 mmol) and bis(POC)phosphate (49 mg) with DIPEA (80 gL), BopCI (58 mg) and 3-nitro-l,2,4-triazole (26 mg) as 105-2 from 105-1.

[0586] Préparation of (106a): 107-1 (30 mg) was converted in formic acid to 107a (15 mg; 73% yield) in the same manner as 105-2 to 105a. *H-NMR (DMSO-dé): 87.60 (d, 1 H), 10 7.36, 7.32 (2 br s, 2 H) 6.02 (m, 2 H), 5.74 (d, 1 H), 5.62 (m, 4 H), 5.17 (ddd, 1 H), 4.99 (dq, 1

H), 4.83 (m, 2 H), 4.61 (m, 1 H), 4.19 (m, 2 H), 1.40 (dd, 3 H), 1.24, 1.23 (2 d, 12 H). ^3,PNMR (DMSO-dJ: 8 -4.52. ^l9F-NMR (DMSO-do): 8-185.92 (m, 1 F), -200.48 (d, 1 F). MS: m/z = 604.3 (M+l).

EXAMPLE 105

Préparation of Compound (108a)

246 [0587] To a solution of 4*-ethyl-2'-fluorocytidine (50 mg, 0.183 mmol) in DMF (1 mL) were added DCC (113 mg, 0.55 mmol), isobutyric acid (48.5 μ!, 0.55 mmol) and DMAP (22 mg, 0.183 mmol). The mixture was stirred at R.T. ovemight. The mixture was filtered, and the filtrate was concentrated with a rotary evaporator until half of its original volume was achieved. EA was added to the mixture. The mixture was washed with water, followed by brine. The mixture was dried over anhydrous Na^SO.» and concentrated in vacuo to give a residue, which was purified by silica gel with DCM/ MeOH=95:5 to give 108a (40.8 mg, 54%) as a white solid. 'H NMR (DMSO-J6, 400 MHz) δ 7.67 (d, J = 7.2 Hz, 1H), 7.34 (br s, 2H), 5.85, 5.8 (2d, J = 21.2, 22 Hz, 1H), 5.72 (d, J = 7.6 Hz, 1H), 5.55-5.41 (m, 2H), 4.1 (q. 2H), 2.68-2.52 (m, 2H), 1.77-1.64 (m,2H), 1.13, 1.14 (2s, 2 x3H), 1.09-1.07 (m,6H), 0.96 (t, J = 7.6 Hz, 3H); MS m/z 414 (M-H⁺), 829 (2M+H⁺).

EXAMPLE 106

Préparation of Compound (109a)

[0588] 3’,5*-diacetylnucleoside (36 mg, 1 mmol) was dissolved in methanol saturated with NH4OH and kept ovemight at R.T. The solvent was evaporated, and the product isolated by column chromatography in gradient of methanol in DCM from 0 to 15% on a 10g Biotage cartridge. The product was 109a obtained (20 mg, 73%). ^lH-NMR (DMSO-dô): δ 11.4 (s, 1H), 11.84-11.82 (d, 1H); 6.10-6.05 (m, 1H), 5.95-5.83 (d, 1H), 5.71 (s, 1H), 5.65-5.63 (d, 1H), 5.37-3.36 (t, 1H), 5.26-5.20 (t, 1H), 5.11-5.07 (t, IH), 4.56-4.55 (m, 1H), 4.46-4.33 (m, 2H), 3.58-3.56 (m, 2H). MS 277.2 (M-H).

247

EXAMPLE 107

Préparation of Compound (110a)

[0589] Préparation of (110-1): To a solution of 70a (6.55 g, 2.1 mmol) and the benzoyl protected base moiety (2.3 g, 5.3 mmol) in PhCl (50 mL) was added TMSOTf (3.6 g,

16.1 mmol). After addition, the mixture was heated to I4O°C for 8 h. The mixture was cooled to R.T., and evaporated to give a residue. The residue was re-dissolved in DCM and washed with saturated NaHCOj and brine. The organic layer was dried and concentrated to give a residue, which was purified by silica gel column (40% EA in PE) to give 110-1 (300 mg, 10%) as a white solid.

[0590] Préparation of (110a): 110-1 (300 mg, 0.55 mmol) in 80% aqueous acetic acid (5 mL) was heated to reflux for 2 h. The mixture was cooled to ambient température and diluted with water (5 mL), and then extracted with EA. The organic layer was washed with saturated NaHCOj and brine. The mixture was dried and concentrated to give a residue, which was purified by silica gel column (10% EA in PE) to give the protected uridine dérivative (180 mg, 70%) as a white solid. The protected uridine dérivative (180 mg, 0.4 mmol) in saturated NHj/MeOH (10 mL) was stirred at R.T. for 3 h. The mixture was concentrated to give a residue, which was purified by préparative HPLC (0.1% HCOOH in water and MeCN) to give 110a (80 mg, 60%) as a white solid. ’H NMR (CD₃OD, 400MHz) £8.31 (d, J = 6.8 Hz, IH), 6.17 (dd, J - 4.0, 14.0 Hz, IH), 5.13-5.27 (m, IH), 4.52-4.56 (m, IH), 3.92 (dd, J = 12.0, 58.8 Hz, 2H). ESI-TOF-MS: m/z 334.7 [M + Na]⁺.

EXAMPLE 108

RSV Antiviral Assays [0591] CPE réduction assays are performed as described by Sidwell and Huffman et al., Appl Microbiol. (1971) 22(5):797-801 with slight modifications. HEp-2 cells (ATCC) at a concentration of 6000 cell/well are infected with RSV Long strain (ATCC) at a multiplicity of infection (m.o.i.) of 0.01, and each of the test compounds are provided to duplicate wells at final concentrations starting from 100 μΜ using 1/3 stepwise dilutions. For each compound, two

248 wells are set aside as uninfcctcd, untreatcd cell controls (CC), and two wclls per test compound receive virus only as a control for virus réplication (VC). The assay is stopped after 6 days, before ail of the cells in the virus-infected untreated control wells exhibited signs of virus cytopathology (giant cell formation, syncytia). At the end of the incubation, 20 μΐ of cell counting kit-8 reagent (CCK-8, Dojindo Molecular Technologies, Inc.) are added to each well. After 4 hour incubation, the absorbance is measured in each well according to manufacturées instruction, and the 50% effective concentration (EC50) is calculated by using régression analysis, based on the mean O.D. at each concentration of compound.

[0592] RT-PCR based assays were performed in HEp-2 cells (ATCC: CCL-23) at a concentration of 20000 cell/well were plated in 96 well plates and incubated ovemight. Each of the test compounds were 1/3 scrially diluted and dosed to HEp-2 cells in duplicates. The hîghest final concentration for each compound was 100 uM. After 24 hour compound pre-incubation, RSV A2 (ATCC: VR-1540) at MOI of 0.1 was added. Two wells per compound were set aside as uninfected, untreated cell controls (CC), and four wells per test compound received virus only as a control for virus réplication (VC). The assay was stopped 4 days after virus infection and conditioncd media was removed for viral RNA isolation. The quantitics of the RSV virus were measured by real-time PCR using a set of RSV spécifie primera and probe. The data was analyzcd with Prism software with EC50 defined as drug concentration that reduced the viral load 50% from the viral control (VC).

[0593] Standard RSV polymerase assays were conducted in the presence of 3 pL extract of RSV-infected cells in a reaction buffer containing 50mM tris-acetate pH 8, !20mM Kacetate, 4.5mM MgCh, 5% glycerol, 2mM EDTA, 50ug/mL BSA, and 3mM DTT. Varying concentration of test compounds were used to initiate RNA synthesis for 120 mins at 30°C„ and radioactive 33P GTP (15 uCi) was used as tracer. The reaction was stopped by adding 50 mM EDTA, and RNA samplcs were purified through G-50 size exclusion spin columns and phenolchloroform extraction. The radio-labeled RNA products were rcsolvcd by clcctrophoresis on a 6% polyacrylamide TBE gel, and visualized and quantitated after being exposed on a phosphorlmager screen. Polymerase inhibition experiments (IC50) were conducted the same way in the presence of increasing concentration of test compounds.

[0594] Compounds of Formula (I), Formula (Π) and Formula (ΠΙ) are active in the assay as noted in Tables 6 and 7. In Table 6, ‘A* indicates an ECjo < 2 μΜ, ‘B’ indicates an EC50 of >2 μΜ and < 10 μΜ and ‘C’ indicates an EC50 > 10 μΜ and < 50 μΜ. In Table 7, ‘A’ indicates an EC50 < I μΜ, ‘B’ indicates an EC50 of >1 μΜ and < 10 μΜ and ‘C* indicates an EC_So > 10 μΜ and < 100 μΜ.

249

Table 6 - Activitv of compounds as determined by RSV polymerase assay

No.	ECso	No.	ECso	No.	ECso	No.	EC$o	No.	ECso
35a	A	36i	B	56c	A	97b	A	97g	A
36a	A	36j	B	56da	A	97c	A	98b	A
36c	A	56a	B	56e	A	97d	A	98c	A
36e	A	56a	B	97a	A

Table 7 - Actîvity of compounds as determined by RT-PCR assay

No.	ECso	No.	ECso	No.	ECso	No.	ECso	No.	ECso	No.	ECso
la	C	14a	A	28a	B	48a	B	81a	B	106a	C
2a	C	20a	B	30a	A	50a	A	82a	A	108a	B
3a	A	21a	A	31a	B	52a	A	83a	B	-
4a	C	22a	C	33a	A	58a	C	85a	A	-
7a	A	23a	A	39a	B	69a	A	86a	A	-
9a	C	25a	C	41a	B	71a	A	87a	A	-
lia	B	26a	B	46a	B	73a	C	92a	C	-
13a	C	27a	B	45a	C	76a	A	105a	C	-

EXAMPLE 109 Influenza Antiviral Assay [0595] Human lung carcinoma A549 cells (ATCC, Manassas, VA) were plated at a density of 5 x I0⁴ cells/mL (5 x 10³ cells/well) in assay media (Ham’s Fl2 media supplemented 10 with 0.3% FBS, 1% penicillin/streptomycin (all Mediatech, Manassas, VA) and 1% DMSO (Sigma-Aldrich, St Louis, MO)) in black 96-well plates. After 24 hours, serially diluted test compounds were added to cells and incubated for an additional 24 hours. Cells were infected with 250 IU/well of Influenza strain A/WSN/33 (H1N1) (Virapur, San Diego CA) and incubated for 20 hours at 37°C, 5% CO₂. The cell culture supematant was aspirated off and 50 pL of 25 15 μΜ 2’-(4-Methylumbelliferyl)-a-D-N-acetylneuraminic acid (Sigma-Aldrich) dissolved in 33 mM MES, pH 6.5 (Emerald Biosystems, Bainbridge Island, WA) was added to the cells. After incubation for 45 mins at 30°C, reactions were stopped by addition of 150 pL stop solution (100 mM glycine, pH 10.5, 25% éthanol, all Sigma-Aldrich). Fluorescence was measured with excitation and émission filters of 355 and 460 nm, respectively, on a Victor X3 multi-label plate

250 reader (Perkîn Elmer, Waltham, MA). Cytotoxicity of uninfected parallel cultures was determined by addition of 100 pLof Ce IITiter-Glo® reagent (Promega, Madison, WI), and incubation for 10 mîns at R.T. Luminescence was measured on a Victor X3 multi-label plate reader.

[0596] Compounds of Formula (I), Formula (Π) and Formula (ΙΠ) are active in the assay as noted in Table 8, where ‘A* îndicates an EC50 < 20 μΜ, *B’ indicates an ECjq of >20 μΜ and < 100 μΜ and ‘C’ indicates an EC50 > 100 μΜ and < 250 μΜ.

Table 8 - Activity of compounds

No.	% Inhibition	No.	% Inhibition
la	C	20a	C
2a	C	21a	C
3a	C	22a	C
4a	C	23a	C
6a	C	25a	A
7a	C	26a	C
9a	C	27a	B
12a	C	28a	C
16a	c	30a	C
17a	c	31a	C
18a	c	39a	B

EXAMPLE 110

Influenza Pol Assay [0597] Recombinant influenza polymerase trimer is obtained as described (Aggarwal

S. et al., PLoS ONE 2010). Standard RNA poiymerization assays are conducted in the presence of 0.15 uM enzyme, 1.5 uM 50-mer oligonucleotide template, 400 uM AG primer and varying concentration of the test compounds are incubated together for 40 minutes at 30°C. Radioactive 33P GTP are used as the tracer and the radio-labeled RNA products are resolved by electrophoresis on a 15% polyacrylamide TBE gel. and is visualîzed and quantîtated after being exposed on a phosphorlmager screen. Polymerase inhibition experiments (IC50) are conducted the same way in the presence of increasing concentration of test compounds.

[0598] Although the foregoing has been described în some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the présent disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the présent disclosure, but rather to also cover ail modification and alternatives coming with the true scope and spirit of the invention.

Claims

I. A compound selected from Formula (I), Formula (II), and Formula (Ht), or a pharmaceutically acceptable sait of the foregoing:

(III) wherein:

B^,a B^,b and B^IC are independently an optionally substituted heterocyclic base or an

10 optionally substituted heterocyclic base with a protected amino group;

R^,a is selected from the group consisting of hydrogen, an optionally substituted acyl, an Z^1A ,2A ?3A

R^6AO“P“^ R^8AO—Ij³—R^1QA-P— optionallysubstituted O-linked aminoacid, OR^7A, R^9A and R^11A ;

the dashed line (----) of Formula (t) is absent, R^2A is selected from the group consisting of an unsubstituted C|^ alkyl, a halogen substituted Cu alkyl, a hydroxy substituted Ci_6 alkyl, an

15 alkoxy substituted C|_6 alkyl, a sulfenyl substituted alkyl, an optionally substituted alkenyl, an optionally substituted C24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted -O-C14 alkyl, an optionally substituted -O-C3-6 alkenyl, an optionally substituted -OC34 alkynyl and cyano, and R^3A is selected from the group consisting of OH, -OC(=O)R”^A and an optionally substituted O-Iînked amino acid;

253

R^tB is selected from the group consisting of O', OH, , an optionally substituted

N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative;

R^,c and R^2C are independently selected from the group consisting of O*. OH, an optionally substituted CY alkoxy, , an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; or «

ⁿ and R^2C is 0' or OH;

R^2b and R^3C are independently selected from the group consisting of an optionally substituted C|_6 alkyl, an optionally substituted C₂^ alkenyl, an optionally substituted C₂^ alkynyl, an optionally substituted C₂^ cycloalkyl, an optionally substituted -O-C^ alkyl, an optionally substituted -O-Cj^ alkenyl, an optionally substituted -O-Cj^ alkynyl and cyano;

R^4C is selected from the group consisting of OH, -OC(=O)R”^c and an optionally substituted O-linked amino acid;

R^4Ais fluoro or chloro;

R^3b and R^3C are independently a halogen;

R^3A, R^4B and R^6C are independently hydrogen or halogen;

R^6a, R^7a and R^8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted C₂.₂4 alkenyl, an optionally substituted C₂.₂4 alkynyl, an optionally substituted Cj^ cycloalkyl, an optionally substituted C₂^ cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aryl(Ci. e alkyl), an optionally substituted *-(€Η^ΙΪΑΗ^Ι6Α)ρ-Ο-€|.24 alkyl, an optionally substituted *- is absent or hydrogen; or

R^6A and R^7A are taken together to form a moiety selected from the group consisting of an optionally substituted wherein the oxygens connected to R^6A and R^7A, the phosphorus and the moiety form a six-membered to tenmembered ring system;.

10 R^9A is independently selected from the group consisting of an optionally substituted C1.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C₃^ cycloalkyl, an optionally substituted C₃^ cycloalkenyl, NR^30AR^3IA, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative;

R^IOA and R^1IA are independently an optionally substituted N-linked amino acid or an

15 optionally substituted N-linked amino acid ester dérivative;

R^I2A, r^I3A and R^t4A are independently absent or hydrogen;

each R^1ÎA, each R^I6A, each R^17A and each R^18A are independently hydrogen, an optionally substituted C1.24 alkyl or alkoxy;

255

R^I9A, _r20A _r22A _R23A _r5B. _r6B, _r8B_{( r}9B, _r9C _rI0C _r!2C _r13C i_nd_ependently selected from the group consisting of hydrogen, an optionally substituted Ci.₂4 alkyl and an optionally substituted aryl;

R^2IA, R^24A, R^7B, R^iob, R^iic and R^I4C are independently selected from the group consisting of hydrogen, an optionally substituted C|.₂4 alkyl, an optionally substituted aryl, an optionally substituted -O-Ci.₂₄ alkyl and an optionally substituted -O-aryl;

R²³*, R^29A, R^iib and R^I5C are independently selected from the group consisting of hydrogen, an optionally substituted Ci.₂4 alkyl and an optionally substituted aryl;

R^I6C, R^t7C and R^l8C are independently absent or hydrogen;

R^26A and R^27a are independently -ON or an optionally substituted substituent selected from the group consisting of C₂.g organyl carbonyl, C₂.g alkoxycarbonyl and C₂.gorganylaminocarbonyl;

R^28A is selected from the group consisting of hydrogen, an optionally substituted Ci.₂4-alkyl, an optionally substituted C₂.₂4 alkenyl, an optionally substituted C₂.₂₄ alkynyl, an optionally substituted C₃^ cycloalkyl and an optionally substituted C₃^cycloalkenyl;

R^30A and R^3IA are independently selected from the group consisting of hydrogen, an optionally substituted Ci.₂4-alkyl, an optionally substituted C₂.₂₄ alkenyl, an optionally substituted C₂.₂4 alkynyl, an optionally substituted C₃^ cycloalkyl and an optionally substituted C₃^ cycloalkenyl;

for Formula (III),-----is a single bond or a double bond;

when----is a single bond, each R^7C and each R^sc is independently hydrogen or halogen; and when---is a double bond, each R^7C is absent and each R^8C is independently hydrogen or halogen;

R”^a and R ^c are independently an optionally substituted Cu₂4-alkyl;

m and n are independently 0 or 1;

p and q are independently selected from the group consisting of 1,2 and 3;

r is 1 or 2;

Z^IA, Z^2A, Z^3A, Z^4A, Z^IB, Z^2B and Z^IC are independently O or S; and

R^8AO—P—| provided that when R^lA is R^9A wherein R^8A is an unsubstituted Cm alkyl or phenyl optionally para-substituted with a halogen or methyl and R^9A is methyl ester, ethyl ester,

256 isopropyl ester, n-butyl ester, benzyl ester or phenyl ester of an amino acid selected from the group consisting of glycine, alanine, valine, leucine, phenylalanine, tryptophan, méthionine and proline; R^3A îs OH; R^4A is fluoro; R^SA is fluoro or hydrogen; and B^,A is an unsubstituted uracil; then R^2Acannot be -OCH3;

provided that when R^lA is H; R^3A is OH; R^4A is fluoro; R^SA is fluoro; and B^IA is an unsubstituted cytosine; then R^2A cannot be allenyl; and provided that when R^lA is H; R^3A is OH; R^4A is fluoro; R^SA is fluoro; and B^,A is an unsubstituted cytosine; then R^2A cannot be ethynyl.
2. Thecompound ofClaim I, wherein thecompound isacompound ofFormula(I).

G

R^6AO—P—
(3. The compound of Claim 12, wherein R^6A and R^7A can be taken together to form a R³²* moiety selected from the group consisting of

258 optionally substituted aryl, an optionally substituted heteroaryl or an optionally substituted heterocyclyl.

14. The compound of any one of Claims 2-13, wherein Z^IA is O.

15. The compound of any one of Claims 2-13, wherein Z^IA is S.

r^8Ao—

16. The compound of Claim 2, wherein R^1A is R^9A .

17. The compound of Claim 16, wherein R^8A is selected from the group consisting of absent, hydrogen, an optionally substituted Ci-24 alkyl, an optionally substituted C224 alkenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C3.$ cycloalkyl and an optionally substituted C3M cycloalkenyl; and R^9A is independently selected from the group consisting of an optionally substituted C1-24 alkyl, an optionally substituted C2-24 alkenyl, an optionally substituted C2-24 alkynyl, an optionally substituted C3^> cycloalkyl, an optionally substituted C₃m cycloalkenyl and NR^3OAR^31A, wherein R^30A and R^3IA are independently selected from the group consisting of hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C3.6 cycloalkyl and an optionally substituted C3M cycloalkenyl.

18. The compound of Claim 16, wherein R^8A is absent, hydrogen or an optionally substituted aryl; and R^9A is an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative.

19. The compound of Claim 18, wherein R^9A is selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan, valine, omithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine, norleucîne and ester dérivatives thereof.

20.

259

The compound of Claim 18, wherein R^9A has the structure wherein R^33A is selected from the group consisting of hydrogen, an optionally substituted Ci_6-alkyl.

an optionally substituted C34 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(C_w alkyl) and an optionally substituted haloalkyl; R^34A is selected from the group consisting of hydrogen, an optionally substituted C^ alkyl, an optionally substituted C^ haloalkyl, an optionally substituted C34 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted aryUC^ alkyl); and R^33A is hydrogen or an optionally substituted CMalkyl; or R^34A and R^3ÎA are taken together to form an optionally substituted C3^ cycloalkyl.

21. The compound of any one of Claims 16-20, wherein Z^2A is O.

* *

22. The compound of any one of Claims 16-20, wherein Z is S.

23. The compound of Claim 2, wherein R^{1 A}is R^11A .

24. The compound of Claim 23, wherein R^t0A and R^,IA are both an optionally substituted

N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative.

25. The compound of Claim 24, wherein R^t0A and R^tiA are independently selected from selected from the group consisting of alanine, asparagine, aspartate, cysteîne, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, méthionine, phenylalanine, threonine, tryptophan, valine, omithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha propyl-glycine, norleucine and ester dérivatives thereof.

26. The compound of Claim 24, wherein R^i0A and R^1IA are independently hâve the structure wherein R^36A is selected from the group consisting of hydrogen, an optionally substituted C^-alkyl, an optionally substituted C34 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(CM alkyl) and an optionally substituted haloalkyl; R^37A is selected from the group consisting of hydrogen, an optionally substituted C^ alkyl, an optionally substituted C^ haloalkyl, an optionally substituted C₃^ cycloalkyl, an optionally substituted C₆aryl,

260 an optionally substituted Cio aryl and an optionally substituted aryl(Ci^ alkyl); and R^3SA is hydrogen or an optionally substituted C_M-alkyl; or R^37A and R^3gA are taken together to form an optionally substituted Cj^ cycloalkyl.

27. The compound of any one of Claims 23-26, wherein Z^3A is O.

28. The compound of any one of Claims 23-26, wherein Z^3A is S.

29.

The compound of Claim 3, wherein R^6A ïs

R^12AO—P--OR^13A ⁰ î

OR^14A ^m; and

R^7a is absent or hydrogen.

30. The compound of Claim 29, wherein m is 0, and R^I2A and R^t3A are independently absent or hydrogen.

3t. The compound of Claim 29, wherein m is t, and R^l2A, R^,3A and R^I4A are independently absent or hydrogen.

32. The compound of Claim 2, wherein R^IA is H.

33. The compound of Claim 2, wherein R^IA is an optionally substituted acyl.

34. The compound of Claim 33, wherein the optionally substituted acyl ts -C(=O)R^39A, wherein R^39A ïs selected from the group consisting of an optionally substituted C|.j₂ alkyl, an optionally substituted C₂.t₂ alkenyl, an optionally substituted C₂.|₂ alkynyl, an optionally substituted C₃_8 cycloalkyl, an optionally substituted C_s._g cydoalkenyl, an optionally substituted Co-io aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(CiMS alkyl), an optionally substituted heteroaryl(Ct^ alkyl) and an optionally substituted heterocyclyl(Ct-6 alkyl).

35. The compound of Claim 34, wherein R^39A is substituted or unsubstituted C|.i₂ alkyl.

36. The compound of Claim 2, wherein R^IA is an optionally substituted O-linked amino acid.

37. The compound of Claim 2, wherein R^IA is θ NH2 , wherein R^40A is selected from the group consisting of hydrogen, an optionally substituted C|^ alkyl, an optionally substituted Chaloalkyl, an optionally substituted C3^ cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci^ alkyl); and R^4IA is hydrogen

261 or an optionally substituted Cu-alkyl; or R⁴⁰* and R^41A are taken together to form an optionally substituted Cj-g cycloalkyi.

38. The compound of any one of Claims 2-37, wherein B^tA is selected from the group wherein:

R*² is selected from the group consisting of hydrogen, halogen and NHR^J2, wherein Rⁿ is selected from the group consisting of hydrogen, -C(=O)R^K2 and -C^OJOR¹²;

R⁸² is halogen or NHR^W2, wherein R^W2 is selected from the group consisting of hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted C₂-6 alkenyl, an optionally substituted Cj-g cycloalkyi, -C(=O)R^M2 and -C(=O)OR^N2;

R⁰² is hydrogen or NHR⁰², wherein R⁰² ïs selected from the group consisting of hydrogen, -C(=O)R^M and -C(=O)OR^Q2;

R^D2 is selected from the group consisting of hydrogen, halogen, an optionally substituted Ci-g alkyl, an optionally substituted C₂_6 alkenyl and an optionally substituted C₂_6 alkynyl;

R^K is selected from the group consisting of hydrogen, hydroxy, an optionally substituted C,-6 alkyl, an optionally substituted Cj.g cycloalkyi, -C(=O)R^R2 and-C(=O)OR^S2;

R¹ ² is selected from the group consisting of hydrogen, halogen, an optionally substituted Cj^alkyl, an optionally substituted Cj-galkenyl and an optionally substituted C₂_6 alkynyl;

Y² and Y³ are independently N or CR¹², wherein R¹² is selected from the group consisting of hydrogen, halogen, an optionally substituted Cj^-alkyl, an optionally substituted C₂.6-a!kenyl and an optionally substituted C₂^-alkynyl;

R^gi is an optionally substituted C]_6 alkyl;

5 R^H2 is hydrogen or N H R⁷², wherein Rⁿ is independently selected from the group consisting of hydrogen, -C(=O)R^U2 and -C(=0)0R^V2; and

R*², R^u, R^M2, R^N2, R^r, R^q2 R*², R^S2, R⁰² and R^V2 are independently selected from the group consisting of C|^ alkyl, C₂-6 alkenyl, C₂^ alkynyl, C₃^ cycloalkyl, C₃^ cydoalkenyl, Cé-io aryl, heteroaryl, heteroalicyclyl, aryl(C|^ alkyl), heteroary!(Ci^ alkyl) 10 and heteroalicyc!yl(C|^ alkyl).

O O

40.

The compound of Claim 38, wherein B^lA is

41. The compound of Claim 38, wherein B^1Ais

263

42.

43.

44.

45.

46.

The compound of Claim 38, wherein B^,A is

The compound of any one of Claims 2-42, wherein R^2a is a halogen substituted Ci-6 alkyl or a sulfenyl substituted Ci_6 alkyl, and R^3a OH.

The compound of Claim 43, wherein R^2A is a halogen substituted C i -6 alkyl.

The compound of any one of Claims 2-42, wherein R^2A is unsubstituted C_w alkyl.

The compound of any one of Claims 2-42, wherein R²* is an optionally substituted

C₂-6 alkenyl, an optionally substituted C2-6 alkynyl or an optionally substituted Cj^ cycloalkyl.

47. The compound of any one of Claims 2-42, wherein R^2A is an optionally substituted O-C1.6 alkyl, an optionally substituted -O-C₃^ alkenyl or an optionally substituted -O-C3-6 alkynyl.

48. The compound of any one of Claims 2-42, wherein R^2A is cyano.

49. The compound of any one of Claims 2-48, wherein R^3a is OH.

50. The compound of any one of Claims 2-48, wherein R^3A is -OC(=O)R ^A.

51. The compound of Claim 50, wherein R^a is an optionally substituted C|_₈ alkyl.

52. The compound of any one of Claims 2-48, wherein R^3A is O-linked amino acid.

53. The compound of Claim 52, wherein the O-linked amino acid is selected from the group consisting of alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucîne, lysine, méthionine, phenylalanine, threonine, tryptophan, valine, omithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gammaaminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucîne.

55. The compound of any one of Claims 2-54, wherein R^5A is hydrogen.

56. The compound of any one of Claims 2-54, wherein R^3A is halogen.

57. The compound of Claim 56, wherein R^3A is fluoro.

58. The compound of any one of Claims 2-57, wherein R^4A is fluoro.

59. The compound of Claim 1, wherein the compound is a compound of Formula (II).

60. The compound of Claim 1, wherein the compound is a compound of Formula (III).

61. The compound of Claim 2, wherein the compound of Formula (I) is selected from

265

62. The compound of Claim 2, wherein the compound of Formula (I) is _t or a pharmaceutically acceptable sait thereof.

266

R^,AO

The compound of Claim 2, wherein the compound

F , or a pharmaceutically acceptable sait thereof.

The compound of Claim 2, wherein the compound , or a pharmaceutically acceptable sait thereof.

The compound of Claim 2, wherein the compound of of of

Formula

Formula

Formula (I) (I) (D is is is , or a pharmaceutically acceptable sait thereof.

The compound of Claim 2, wherein the compound of Formula (I) is selected from the group consisting of:

267

268

Cl-----⁵

269

270 foregoing.

67. The compound of Claim 2, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.

68. The compound of Claim 2, wherein the compound of Formula (I) is nh₂ , or a pharmaceutically acceptable sait thereof.

271

69. The compound of Claim 2, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.

70. The compound of Claim 2, wherein the compound of Formula (1) is

Ho *F , or a pharmaceutically acceptable sait thereof.

71. The compound of Claim 2, wherein the compound of Formula (I) is selected from the group consisting of: o

274 (I) pharmaceutically acceptable sait of the foregoing.

The compound of Claim 2, wherein the compound of Formula , or a pharmaceutically acceptable sait thereof.

The compound of Claim 2, wherein the compound of Formula (I) is is , or a pharmaceutically acceptable sait thereof.

The compound of Claim 2, wherein the compound of Formula (I) is h₃c h

The compound , or a pharmaceutically acceptable sait thereof.

of Claim 2, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.

The compound of Claim 2, wherein the compound of Formula (I) is selected from the group consisting of:

o

279 or a pharmaceutically acceptable sait of the foregoing.

The compound of Claim 2, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.

78. The compound of Claim 2, wherein the compound of Formula (I) is

79. The compound of Claim 2, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait thereof.

281

80. The compound of Claim 59, wherein the compound of Formula (II) is selected from

81. The compound of Claim 60, wherein the compound of Formula (III) is selected from the

5 group consisting of:

282

82. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1-81, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

83. Use of an effective amount of a compound of any one of Claims 1-81, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 82 in the préparation of a médicament for amelîorating or treating a viral infection selected from a paramyxovirus viral infection and an orthomyxovirus viral infection in a subject identified as suffering from the viral infection.

♦

283

84. Use of an effective amount of a compound of any one of Claîms 1-81, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 82 in the préparation of a médicament for inhîbiting réplication of a virus selected from paramyxovirus and orthomyxovirus.

5 85. Use of an effective amount of a compound of any one of daims 1-81, or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 82 in the préparation of a médicament for contacting a cell infected with a virus selected from paramyxovirus and orthomyxovirus.

86. Use of an effective amount of a compound of any one of Claims 1-81, or a

10 pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 82 in the préparation of a médicament for ameliorating or treating a viral infection in combination with one or more agents comprising administering to or contacting a cell in a subject identified as suffering from the viral infection with an effective amount of the compound of any one of Claims 1-81, or a pharmaceutically acceptable sait thereof, or the pharmaceutical composition of Claim 82; and

15 wherein the viral infection is selected from a paramyxovirus viral infection and an orthomyxovirus viral infection.

87. The use of any one of Claims 83-86, wherein the viral infection is a paramyxovirus viral infection.

88. The use of Claim 87, wherein the paramyxovirus viral infection is a pneumoviral 20 infection.

89. The use of Claim 88, wherein the pneumoviral viral infection is a human respiratory syncytial virus infection.

90. The use of any one of Claims 83-86, wherein the viral infection is an orthomyxovirus viral infection.

25 91. The use of Claim 90, wherein the orthomyxovirus viral infection is influenza.

92. The use of Claim 86. wherein the orthomyxovirus viral infection is an influenza virus infection; and wherein the one or more agents is selected from the group consisting of amantadîne, rimantadine, zanamivir, oseltamivir, peramivir, laninamivir, favipiravir, fludase, ADS8902, IFN-b. beraprost and VGX-3400X.

30 93. The use of any one of Claims 91 -92, wherein the influenza is selected from the group consisting of influenza A, influenza B and influenza C.

t

284

94. The use of any one of Claims 91-92, wherein the influenza is selected from the group consisting of H INI andH3N2.

95. The use of Claim 86, wherein the paramyxovirus viral infection is a human respiratory syncytial virus infection; and wherein the one or more agents is selected from the group

3. The compound of Claim 2, wherein R*^A is OR^7A.
4. The compound of Claim 3, wherein R^6A and R^7A are both hydrogen or both absent.

5. The compound of Claim 3, wherein one of R^6A and R^7A is hydrogen, and the other of

R^6A and R^7A is selected from the group consisting of an optionally substituted C1.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Cj-β cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(Ci_6 alkyl) or both R^6A and R^7Aare independently selected from the group consisting of an optionally substituted C1.24 alkyl, an optionally substituted C2.24 alkenyl, an optionally substituted C2.24 alkynyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted C₃^ cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(C]^ alkyl).

6. The compound of Claim 3, wherein R^eA and R^7A are both an optionally substituted Ci-24 alkyl, both an optionally substituted C2-24 alkenyl, both *-(CR^,SAR^,6A)p-O-Ci.24 alkyl or both *-(CR^,7AR^18A)_<1-O-C2.24 alkenyl.

7. The compound of Claim 3, wherein R^6A and R^7A are both an optionally substituted aryl or both an optionally substituted aryl(C|^ alkyl).

257

The compound of Claim 3, wherein R^6A and R^7A are both

The compound of Claim 3, wherein R^6A and R^7A are both

The compound of

R^25A.

Claim 3, wherein

The compound of Claim 3, wherein R can be taken together to form a moiety selected from the group consisting of an optionally substituted and an optionally substituted , wherein the oxygens connected to R^6A and R^7A, the phosphores and

10 the moiety form a six-membered to ten-membered ring System.
5 consisting of ribavirin, palivizumab, RSV-1G1V, ALN-RSV01, BMS-433771, RFI-641, RSV6O4, MDT-637, BTA9881, TMC-353121, MBX-300, YM-53403, RV568 and a RSV-F Particle Vaccine.