OA17648A

OA17648A - Substituted nucleosides, nucleotides and analogs thereof.

Info

Publication number: OA17648A
Application number: OA1201500498
Authority: OA
Inventors: Natalia Dyatkina; Guangyi Wang; Leonid Beigelman; Vivek Kumar Rajwanshi
Original assignee: Alios Biopharma, Inc.
Priority date: 2013-06-26
Filing date: 2014-06-24
Publication date: 2017-05-15

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 paramyxovirus viral infection, with a nucleoside, a nucleotide and an analog thereof.

Description

SUBSTITUTED NUCLEOSIDES, NUCLEOTIDES AND ANALOGS THEREOF

INCORPORATION B Y REFERENCE TO ANY PRIORITY APPLICATIONS [0001] Any and ail applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the présent application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6.

REFERENCE TO SEQUENCE LISTING [0002] The présent application is filed with a Sequence Listing in Electronic format. The 10 Sequence Listing is provided as a file entitled ALIOS076.txt, created June 23, 2014, which is approximately 4 kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

BACKGROUND

Field [0003] The présent application relates to the fields of chemistry, biochemistry and medicine. More particularly, 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 20 treating a paramyxovirus viral infection with one or more nucleosides, nucléotides and analogs thereof.

Description [0004] Respiratory viral infections, including upper and lower respiratory tract viral 25 infections, infects and is the leading cause of death of millions of people each year. Upper 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.

[0005] 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 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 anti-metabolites, 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 [0006] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable sait thereof.

[0007] Some embodiments disclosed herein relate to methods of ameliorating and/or 10 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), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof. Other embodiments described herein relate to using one or more compounds of Formula (I), or a pharmaceutically 15 acceptable sait thereof, 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), or a pharmaceutically acceptable sait thereof, 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 20 cell infected with the paramyxovirus with an effective amount of one or more compounds of

Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof. 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 25 amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition that includes one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof.

[0008] Some embodiments disclosed herein relate to methods of ameliorating and/or treating a paramyxovirus 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 Formula (I), or a pharmaceutically

acceptable sait thereof), or a pharmaceutical 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 that can include contacting a cell infected with the virus with an effective amount of a compound 5 described herein or a pharmaceutically acceptable sait thereof (for example, one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof), or a pharmaceutical composition that includes one or more compounds described herein, in combination with one or more agents described herein.

BRIEF DESCRIPTION OF THE DRAWINGS [0009] Figure 1 shows example anti-RSV agents.

DETAILED DESCRIPTION [0010] Paramyxoviridae family is a family of single stranded RNA viruses. Several 15 généra of the paramyxoviridae family include respirovirus, rubulavirus, pneumovirus and metapneumovirus. These viruses can be transmitted person to person via direct or close contact with contaminated respiratory droplets or fomites.

[0011] Human Respiratory Syncytial Virus (RSV) is a species of pneumovirus and a négative single-stranded RNA virus. RSV can cause respiratory infections, and can be associated 20 with bronchiolitis and pneumonia. Symptoms of an RSV infection include coughing, sneezing, runny nose, fever, decrease in appetite, sore throat, headache and 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 25 of âge, an estimated 14,000 deaths and 177,000 hospitalizations hâve been attributed to RSV.

[0012] Treatment options for people infected with RSV are currently limited. Antibiotics, usually 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, 30 such as wheezing. RespiGam® (RSV-IGIV, Medlmmune, approved for high risk children younger than 24 months of âge) and Synagis® (palivizumab, Medlmmune, approved for high risk children younger than 24 months of âge) hâve been approved for prophylactic use against RSV, and Virzole® (ribavirin by aérosol, ICN pharmaceuticals) hâve been approved for the treatment of RSV.

[0013] Parainfluenza viruses are typically negative-sense RNA viruses. Species of respirovirus include human parainfluenza viruses 1 and 3; and species of rubulavirus include human parainfluenza viruses 2 and 4. Human parainfluenza virus includes four serotypes types (HPIV-1, HPIV-2, HPIV-3 and HPIV-4), and human parainfluenza virus 4 (HPIV-4) include two antigenic subgroups, A and B. Human parainfluenza viruses can cause upper and lower respiratory tract infections. Human parainfluenza virus 1 (HPIV-1) and human parainfluenza virus 2 (HPIV-2) can be associated with croup; human parainfluenza virus 3 (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 viruses.

[0014] A species of metapneumovirus is human metapneumovirus. Human metapneumovirus is a négative single-stranded RNA virus. Human metapneumovirus can cause respiratory tract infections, such as upper and lower respiratory tract infections in human, for example young children.

[0015] Respiratory infections include colds, croup, pneumonia, bronchitis and bronchiolitis. Symptoms can include a cough, runny nose, nasal congestion, sore throat, fever, diffïculty breathing, abnormally rapid breathing, wheezing vomiting, diarrhea and ear infections.

Définitions [0016] Unless defined 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 reference 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.

[0017] As used herein, any R group(s) such as, without limitation, R^1A, R^2A, R^3A, R^4A, r5A j^6A j^7A j^8A j^9A j^IOA j^llA j^12A j^13A j^14A j^15A j^16A j^17A j^18A j^19A j^20A j^21A j^22A p23A p24A j^25A j^26A j^27A j^28A j^29A j^30A j^31A j^32A j^33A j^34A j^35A j^36A j^37A j^38A 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, aryl, heteroaryl or heterocycle. For example, without limitation, if R^a and R^b of an NR^aR^b group are indicated to be taken together, it means that they are covalently bonded to one another to form a ring:

—Nf\ . ^Rb

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 defined previously.

[0018] 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 of 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) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, azido, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group and a di-substituted amino group.

[0019] 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, aryl, heteroaryl or heteroalicyclyl group. That is, the alkyl, alkenyl, alkynyl, ring(s) of the cycloalkyl, ring(s) of the cycloalkenyl, ring(s) of the aryl, ring(s) of the heteroaryl or ring(s) of the heterocyclyl 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-, (CH₃)₂CH-, CH₃CH₂CH₂CH₂-, CH₃CH₂CH(CH₃)- and (CH₃)₃C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these définitions is to be assumed.

[0020] As used herein, “alkyl” refers to a straight 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., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 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 1 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, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 10 tertiary butyl, pentyl and hexyl. The alkyl group may be substituted or unsubstituted.

[0021] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.

[0022] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or 15 branched hydrocarbon chain one or more triple bonds. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.

[0023] 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 20 ring(s) or 3 to 8 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted.

Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0024] 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 25 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 can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). A cycloalkenyl group may be unsubstituted or substituted.

[0025] 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 Cg-Cu aryl group, a C6-C_w aryl group, or a C₆ aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.

[0026] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring

System (a ring System with fully delocalized pi-electron System) that contain(s) one or more heteroatoms (for example, 1 to 5 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 10 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, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, 15 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.

[0027] 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 25 heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the définition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, 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 heterocyclyl or a heteroalicyclyl may be quaternized. Heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted. Examples 30 of such “heterocyclyl” or “heteroalicyclyl” groups include but are not limited to, 1,3-dioxin, 1,3dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,317648

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, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, 5 piperidine A-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4-piperidone, pyrazoline, pyrazolidine, 2-oxopyirolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4-methylenedioxyphenyl).

[0028] As used herein, “aralkyl” and “aryl(alkyl)” refer to an aryl group connected, as a 10 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-phenyl(alkyl), 3phenyl(alkyl) and naphthyl(alkyl).

[0029] 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 15 heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2thienyl(alkyl), 3-thienyl(alkyl), furyl(alkyl), thienyl(alkyl), pyrrolyl(alkyl), pyridyl(alkyl), isoxazolyl(alkyl), imidazolyl(alkyl) and their benzo-fused analogs.

[0030] A “heteroalicyclyl(alkyl)” and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group. The lower alkylene 20 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-thiopyran-4-yl(methyl), and 1,3-thiazinan-4-yl(methyl).

[0031] “Lower alkylene groups” are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not 25 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 définition of “substituted.” [0032] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), 30 heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are

methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tertbutoxy, phenoxy and benzoxy. An alkoxy may be substituted or unsubstituted.

[0033] As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, an. alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or 5 heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.

[0034] 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 2,2-dihydroxyethyl. A 10 hydroxyalkyl may be substituted or unsubstituted.

[0035] 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 tri-haloalkyl). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or 15 unsubstituted.

[0036] 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 20 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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(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 25 defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.

[0039] A “sulfonyl” group refers to an “SO₂R” 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 in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), 30 heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.

[0041] The ternis “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(R_A)-” group wherein each X is a halogen, and R_A hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).

[0045] The term “amino” as used herein refers to a -NH₂ 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 -N3 group.

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

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

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

[0052] A “carbonyl” group refers to a C=O group.

[0053] An “S-sulfonamido” group refers to a “-SO₂N(R_AR_B)” group in which R_A and R_Bcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.

[0054] An “N-sulfonamido” group refers to a “RSO₂N(R_A)-” group in which R and R_Acan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.

[0055] An “O-carbamyl” group refers to a “-OC(=O)N(R_AR_B)” group in which R_A and R_B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.

[0056] An “N-carbamyl” group refers to an “ROC(=O)N(Ra)-” group in which R and R_acan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.

[0057] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RaRb)” group in which Ra and R_b can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.

[0058] An “N-thiocarbamyl” group refers to an “ROC(=S)N(R_a)-” group in which R and

Ra can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.

[0059] A “C-amido” group refers to a “-C(=O)N(RaRb)” group in which Ra and R_B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, 15 heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.

[0060] An “N-amido” group refers to a “RC(=O)N(Ra)-” group in which R and R_A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or 20 unsubstituted.

[0061] 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 iodine.

[0062] 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, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.

[0063] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem.

11:942-944 (1972)).

[0064] 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 N-glycosidic 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 ribose 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 carbon 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 10 polymers and oligomers. In some instances, the nucleoside can be a nucleoside analog drug.

[0065] 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.

[0066] As used herein, the term “heterocyclic base” refers to an optionally substituted 15 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 20 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. 7methylguanine), theobromine, caffeine, uric acid and isoguanine. Examples of pyrimidine-bases include, but are not limited to, cytosine, thymine, uracil, 5,6-dihydrouracil and 5-alkylcytosine (e.g., 25 5-methylcytosine). An example of an optionally substituted triazole-base is l,2,4-triazole-3carboxamide. Other non-limiting examples of heterocyclic bases include diaminopurine, 8-oxo-N⁶alkyladenine (e.g., 8-oxo-N⁶-methyladenine), 7-deazaxanthine, 7-deazaguanine, 7-deazaadenine, N⁴,N⁴-ethanocytosin, N⁶,N⁶-ethano-2,6-diaminopurine, 5-halouracil (e.g., 5-fluorouracil and 5bromouracil), pseudoisocytosine, isocytosine, isoguanine, and other heterocyclic bases described in 30 U.S. Patent Nos. 5,432,272 and 7,125,855, which are incorporated herein by reference 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).

[0067] The term “-N-linked amino acid” refers to an amino acid that is attached to the indicated moiety via a main-chain amino or mono-substituted amino group. When the amino acid is 5 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. Nlinked amino acids can be substituted or unsubstituted.

[0068] 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 10 embodiments, the ester group has a formula selected from alkyl-O-C(=O)-, cycloalkyl-0-C(=0)-, aryl-O-C(=O)- and aryl(alkyl)-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)-, n-propyl-O-C(=O)-, isopropyl-O-C(=O)-, n-butyl-O-C(=O)-, isobutyl-O-C(=O)-, tert-butyl-O-C(=O)-, neopentyl-OC(=O)-, cyclopropyl-0-C(=0)-, cyclobutyl-0-C(=0)-, cycIopentyl-O-C(=O)-, cyclohexyl-O-C(=O)-, 15 phenyl-O-C(=O)-, benzyl-O-C(=O)-, and naphthyl-O-C(=O)-. N-linked amino acid ester dérivatives can be substituted or unsubstituted.

[0069] 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 main-chain 20 carboxylic acid group is not présent and the amino acid is attached via the oxygen. O-linked amino acids can be substituted or unsubstituted.

[0070] As used herein, the term “amino acid” refers to any amino acid (both standard and non-standard amino acids), including, but not limited to, α-amino acids, β-amino acids, γ-amino acids and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, 25 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.

[0071] The terms “phosphorothioate” and “phosphothioate” refer to a compound of the ? >

s=p—O—| general formula 0' ’ its protonated forms (for example,

0' and

and its tautomers (such as

SH

O=P—O—l I ^ξOH ).

[0072] As used herein, the term “phosphate” is used in its ordinary sense as understood by those skilled in the art, and includes its protonated forms (for example, OH OH

Q==P—O—O=P—O—

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.

[0073] 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 reactions. 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 reference 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-butoxycarbonyl (BOC), acetyl, or isobutyryl); arylalkylcarbonyls and arylalkoxycarbonyls (e.g., benzyloxycarbonyl); substituted methyl ether (e.g. methoxymethyl ether); substituted ethyl ether; a substituted benzyl ether; tetrahydropyranyl ether; silyls (e.g., trimethylsilyl, triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, tri-ÛOpropylsilyloxymethyl, [2-(trimethylsilyl)ethoxy]methyl or t-butyldiphenylsilyl); 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., 1,3-dioxane, 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; monomethoxytrityl (MMTr); 4,4'-dimethoxytrityl (DMTr); 4,4',4trimethoxytrityl (TMTr); and those described herein).

[0074] 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 5 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, 10 acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, ptoluensulfonic, 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 alkali 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, 15 tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.

[0075] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean 20 ‘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 exclude 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, 25 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, 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 30 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 k

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 5 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.

[0076] With respect to the use of substantially any plural and/or singular terms herein, 10 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 claims. The mere fact that certain measures are recited in mutually different 15 dépendent claims does not indicate that a combination of these measures cannot be used to advantage. Any reference signs in the claims should not be construed as limiting the scope.

[0077] 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-configuration or S-configuration or a mixture thereof. Thus, the compounds 20 provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric 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.

[0078] 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 phosphorothioate groups are intended to be included. Examples of tautomers of a phosphorothioate include the

O II	0’	o	OH
'I e ’S—P—O S-	=P—0	HS—P—Q	S=p—0
f. A following: O ,	0’ >	I A OH	¹ V and OH . 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.

[0079] 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).

[0080] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic 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, reference herein to a compound encompasses ail potential isotopic forms unless the context clearly dictâtes otherwise.

[0081] It is understood that the methods and combinations described herein include crystalline forms (also known as polymorphe, 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 solvated 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 nonstoichiometric 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.

[0082] 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 [0083] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable sait of the foregoing:

R^a,¹ pa2

(I) wherein: B^1A can be an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group; R^A can be hydrogen or deuterium; R^1A can be selected from hydrogen, an optionally substituted acyl, an optionally substituted O-linked amino ^1A y2A 2^3A r^6Ao—|R^8AO—P—r^1oa-p— acid, OR^7A, R^9A and R^11A ; R^al and R³² can be independently hydrogen or deuterium; R^2A can be a Ci_6 azidoalkyl or a Ci_6 aminoalkyl; R^3A can be selected from OH, OC(=O)R”^a and an optionally substituted O-linked amino acid; R^4A can be 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 C3-24 alkenyl, an optionally substituted C3.

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(Ci_6 alkyl), an optionally substituted *-(CR^15AR^16A)_p-O-Ci.₂4 alkyl, an optionally substituted *-

R^6A can be ^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 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^30AR^31A, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative; R^10A and R^11A can be independently an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative; R^12A, R^13A and R^14Acan be independently absent or hydrogen; each R^15A, each R^16A, each R^17A and each R^18A can be independently hydrogen, an optionally substituted C1-24 alkyl or alkoxy; R^19A, R^20A, R^22A and R^23Acan be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; R^21A and R^24A can be independently selected from hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl, an optionally substituted O-monocyclic heterocyclyl and ; R^25A and R^29A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; R^26Aand R^27A can be independently -C=N or an optionally substituted substituent selected from C2-8 organylcarbonyl, C2-s alkoxycarbonyl and C2_8 organylaminocarbonyl; R^28A can be selected from hydrogen, an optionally substituted C].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^31A 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; R”^A can be an optionally substituted Ci-24-alkyl; m and t can be independently 0 or 1; p and q can be independently selected from 1, 2 and 3; r can be 1 or 2; s can be 0, 1, 2 or 3; u can be 1 or 2; and Z^1A, Z^2A, Z^3A and Z^4A can be independently O or S.

£1A

6A II

R^6AO—Ij⁵—| [0084] In some embodiments, R^1A can be OR^7A. 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 skilled in the art understand that when R^6A and/or R^7A are absent, the associated oxygen(s) will hâve a négative charge. For example, when R^6A is absent, the 10 oxygen associated with R^6A will hâve a négative charge. In some embodiments, Z^1A can be O (oxygen). In other embodiments, Z^1A can be S (sulfur). In some embodiments, R^1A can be a monophosphate. In other embodiments, R^1A can be a monothiophosphate.

6A G r^6Ao—p—| [0085] In some embodiments, when R^1A is OR^7A, one of R^6A and R^7A can be hydrogen, and the other of R^6A and R^7A can be selected from an optionally substituted Ci.24 alkyl, an 15 optionally substituted C₃.₂4 alkenyl, an optionally substituted C₃.₂4 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 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 C1.24 alkyl. In other embodiments, both R^6A and R^7A can be independently 20 selected from an optionally substituted C1.24 alkyl, an optionally substituted C3_24 alkenyl, an optionally substituted C3_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 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 25 substituted C3_24 alkenyl. In some embodiments, R^6A and R^7A can be independently an optionally substituted version of the following: myristoleyl, myristyl, palmitoleyl, palmityl, sapienyl, oleyl, elaidyl, vaccenyl, linoleyl, α-linolenyl, arachidonyl, eicosapentaenyl, erucyl, docosahexaenyl, caprylyl, capryl, lauryl, stearyl, arachidyl, behenyl, lignoceryl and cerotyl.

[0086] In some embodiments, at least one of R^6A and R^7A can be *-(CR^15AR^16A)p-O-Ci_ 24 alkyl. In other embodiments, R^6A and R^7A can be both *-(CR^15AR^16A)p-O-Ci-24 alkyl. In some embodiments, each R^15A and each R^16A can be hydrogen. In other embodiments, at least one of R^15Aand R^16A can be an optionally substituted C1-24 alkyl. In other embodiments, at least one of R^15A and R^16a can be 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.

[0087] In some embodiments, at least one of R^6A and R^7A can be *-(CR^17AR^18A)q-O-C224 alkenyl. In other embodiments, R^6A and R^7A can be both *-(CR^17AR^t8A)q-O-C₂.₂₄ alkenyl. In some embodiments, each R^17A and each R^18A can be hydrogen. In other embodiments, at least one of R^17A and R^18a can be an optionally substituted C1.24 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^6Aand R^7A is *-(CR^15AR^16A)p-O-Ci_24 alkyl or *-(CR^17AR^18A)q-O-C₂.₂4 alkenyl, the C_b24 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, α-linolenyl, arachidonyl, eicosapentaenyl, erucyl and docosahexaenyl.

[0088]

In some embodiments, when R^1A is £1A 6A II r^6Ao—p—| or^7A

from

at least one of R^6A and R^7A

and the other of R^6A and R^7A can be selected from absent, 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, an optionally substituted C₃_6 cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted aryl(Ci_ alkyl).

. In some embodiments, both R^6A and R [0089] In some embodiments, at least one of R

When one or both of R

^20A can be independently selected from hydrogen, an optionally substituted C1-24 alkyl and an optionally substituted aryl; and R^21A can be selected from hydrogen, an optionally substituted C4.24 alkyl, an optionally substituted aryl, an optionally substituted -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted 10

Y°

O-heteroaryl, an optionally substituted -O-monocyclic heterocyclyl and ^L

In some embodiments, R^19A and R^20A can be hydrogen. In other embodiments, at least one of R^19Aand R^20A can be an optionally substituted C1-24 alkyl or an optionally substituted aryl. In some embodiments, R^21A can be an optionally substituted Ci_₂4 alkyl. In other embodiments, R^21A can be an optionally substituted aryl. In still other embodiments, R^21A can be an optionally substituted -OCi-24 alkyl or an optionally substituted -O-aryl. In some embodiments, R^21A can be an optionally substituted -O-C1.24 alkyl, an optionally substituted -O-aryl, an optionally substituted -Oheteroaryl or an optionally substituted -O-monocyclic heterocyclyl.

[0090] In some embodiments, both R^6A and R p22A p23A θ :^4àÇo

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

24A

_R24A , R^22A 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 C1-24 alkyl, an optionally substituted aryl, an optionally substituted -0-0μ₂4 alkyl, an optionally substituted -O-aryl, an optionally substituted -O-heteroaryl, an optionally substituted -Omonocyclic heterocyclyl and _4A ² ; 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^23A can be an optionally substituted Ci_24 alkyl or an optionally substituted aryl. In some embodiments, R^24A can be an optionally substituted C1-24 alkyl. In other embodiments, R^24A can be an optionally substituted aryl. In still other embodiments, R^24A can be an optionally substituted -O-Ci_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, s can be 0. In other embodiments, s can be 1. In still other embodiments, s can be 2. In yet still embodiments, s can be 3.

In some embodiments, s can be 0, and R^24A can

In some embodiments, u can be 1. In other embodiments, u can be 2. In some embodiments, one or both of R^6a and R^7A can be isopropyloxycarbonyloxymethyl (POC). In some embodiments, one or both of R^6a and R^7A can be pivaloyloxymethyl (POM). In some embodiments, R^6A and R^7A can be both a

isopropyloxycarbonyloxymethyl group, and form a bis(isopropyloxycarbonyloxymethyl) (bis(POC)) prodrug. In some embodiments, R^6A and R^7A can be both a pivaloyloxymethyl group, and form a bis(pivaloyloxymethyl) (bis(POM)) prodrug.

[0091] In some embodiments, both R^6A and R^7A can be R^26A wherein R^26A and R^27A can be independently -C=N or an optionally substituted substituent selected from C2-8 organylcarbonyl, C2-8 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 C₃.₆ cycloalkyl and an optionally substituted C3.6 cycloalkenyl; and r can be 1 or 2.

[0092] 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.

[0093] In some embodiments, R^6A and R^7A can be both an optionally substituted aryl(Ci_6 alkyl). In some embodiments, at least one of R^6A and R^7A can be an optionally substituted aryl(Ci_6 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(Ci_6 alkyl) can be a para-, ortho- or meta-substituted phenyl.

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

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

In some embodiments, R^25A can be hydrogen. In other embodiments, R^25A can be an optionally substituted C1.24 alkyl. In still other embodiments, R^25A can be an optionally substituted aryl. In some embodiments, R^25A can be a Cj.6 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl (branched and straightchained) and hexyl (branched and straight-chained). In some embodiments, t can be 0. embodiments, t can be 1. In some embodiments, one or both of R

In other

be a SIn some

In some embodiments, R^29A can acylthioethyl (SATE).

[0095] In some embodiments, R

embodiments, at least one of R^6A and R be hydrogen. In other embodiments, R^29A can be an optionally substituted Ci_₂4 alkyl. In some

embodiments, R^29A can be a C_M alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, 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. In some embodiments, R^6A and R^7A can be both a dioxolenone group and form a dioxolenone prodrug.

yiA

6A I· ï r^6Ao—p—| [0096] In some embodiments, R^1A can be OR^7A ; R^6A can be

R^7A can be absent or hydrogen; R^12A, R^13A and R^14A can be independently absent or hydrogen; and m can be 0 or 1. In some embodiments, m can be 0, and R^7A, R^12A and R^13A can be independently absent or hydrogen. In other embodiments, m can be 1, and R^7A, R^12A, R^13A and R^14A can be independently absent or hydrogen. Those skilled in the art understand that when m is 0, R^6A can be diphosphate, when Z^1A is oxygen, or an alphathiodiphosphate, when Z^1A is sulfur. Likewise, those skilled in the art understand that when m is 1, R^6a can be triphosphate, when Z^1A is oxygen, or an alpha-thiotriphosphate, when Z^1A is sulfur.

[0097] 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^1A 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 such as

In some embodiments, R^6A and R^7A can form a cyclosaligenyl (cycloSal) prodrug.

[0099] In some embodiments, R^6A and R^7A can be the same. In some embodiments, R^6A and R^7A can be different.

[0100] In some embodiments, Z^1A can be oxygen. In other embodiments, Z^1A can be sulfur.

_Z2A

8A 'I l r^8ao—p—| [0101] In some embodiments, R^1A can be R^9A . In some embodiments, R^8A can be selected from absent, 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; and R^9A can be independently selected from 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 C3-6 cycloalkenyl.

[0102] In some embodiments, R^8A can be hydrogen, and R^9A can be an optionally substituted Ci-6 alkyl. Examples of suitable C1-6 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 Nr3°^ar31a, _wh_erej_n r3oa _anj r31 a _can 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 C3.6 cycloalkyl and an optionally substituted C3.6 cycloalkenyl.

[0103] 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^9A can be an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid

AMENDED

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.

[0102] In some embodiments, R^8A can be hydrogen, and R^9A can be an optionally substituted Ci-6 alkyl. Examples of suitable Cj-g alkyls include methyl, ethyl, n-propyl, isopropyl, n5 butyl, isobutyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straightchained). In other embodiments, R^8A can be hydrogen, and R^9A can be NR^30AR^31A, wherein R³⁰ and •Ί!

R 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_6 cycloalkyl and an optionally substituted C3.6 cycloalkenyl.

[0103] 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^9A can 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 20 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, _R33A_O R^34A r35A / \ s

OA o HN---> _33A

R can hâve the structure *> wherein R can be selected from hydrogen, an optionally substituted Ci_g-alkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci_g alkyl) and an optionally substituted haloalkyl; R^34A can be 25 selected from hydrogen, an optionally substituted Cj.g alkyl, an optionally substituted Ci_g haloalkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted Cg aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci_6 alkyl); and R^35A can be hydrogen or an optionally substituted Ci^-alkyl; or R^34A and R^35A can be taken together to form an optionally substituted C₃_6 cycloalkyl.

[0104] 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-g-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 straight-chained). In some embodiments, R^33A can be methyl or isopropyl. In some embodiments, R^33A can be ethyl or neopentyl. In other embodiments, R^33A can be an optionally substituted C3.6 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^33A can be an optionally substituted aryl, such as phenyl and naphthyl. In yet still other embodiments, R^33A can be an optionally substituted aryl(C|.6 alkyl). In some embodiments, R^33A can be an optionally substituted benzyl. In some embodiments, R^33A can be an optionally substituted Ci-β haloalkyl, for example, CF3. In some embodiments, R^35A can be hydrogen. In other embodiments, R^35A can be an optionally substituted Ci_4-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^35A can be methyl. In some embodiments, R^34A and R^35A can be taken together to form an optionally substituted C3.6 cycloalkyl. Examples of optionally substituted C₃.e 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^35A, the carbon to which R^34A and R^35A are attached may be a chiral center. In some embodiment, the carbon to which R^34A and R^35A are attached may be a (R)chiral center. In other embodiments, the carbon to which R^34A and R^35A are attached may be a (S)chiral center.

y2A r^8Ao—p—1

I * [0105] In some embodiments, when R^1A is R^9A , Z^2A can be O (oxygen). In

Z^2A »A Î § _R8A₀—P--1 other embodiments, when R^1A is R^9A , Z^2A can be S (sulfur). In some embodiments, when

Γ r^8AO—ρ—

I

R^1A is R^9A , a compound of Formula (I) can be a phosphoramidate prodrug, such as an aryl phosphoramidate prodrug.

r^10A-p— [0106] In some embodiments, R^1A can be R^11A . In some embodiments, R^10A and 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^10A 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^11A 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^10A and

R^11a can independently hâve the structure s wherein R^36A can be selected from hydrogen, an optionally substituted Ci^-alkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Ci_6 alkyl) and an optionally substituted haloalkyl; R^37A can be selected from hydrogen, an optionally substituted Ci-6 alkyl, an optionally substituted Ci. 6 haloalkyl, an optionally substituted C3-6 cycloalkyl, an optionally substituted Cô aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci_6 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 cycloalkyl.

[0107] 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 OTA

Ci-6-alkyl, such as those described herein. In some embodiments, R can be hydrogen. In other embodiments, R^37A can be methyl. In some embodiments, R^36A 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 straight-chained). In some embodiments, R^36A can be methyl or isopropyl. In some embodiments, R^36A can be ethyl or neopentyl. In other embodiments, R^36a can be an optionally substituted C3.6 cycloalkyl. Examples of optionally substituted C3.6 cycloalkyl include optionally substituted variants of the following: cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. In an embodiment, R^36a can be an optionally substituted cyclohexyl. In still other embodiments, R^36A can 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^36A can be an optionally substituted benzyl. In some embodiments, R^36A can be an optionally substituted Cm 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, n-propyl, 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 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^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.

[0108]

Examples of suitable ’ groups include

Ο .

[0109] In some embodiments, R^10A and R^11A can be the same. In some embodiments, R^10a and R^nA can be different.

[0110] In some embodiments, Z^3A can be O (oxygen). In other embodiments, Z^3A can be

S (sulfur). In some embodiments, when R^1A is R^11A , a compound of Formula (I) can be a phosphonic diamide prodrug.

[0111] In some embodiments, R^1A can be hydrogen. In some embodiments, R^1A can be an optionally substituted acyl. In other embodiments, R^1A can be -C(=O)R^39A, wherein R^39A can be selected from an optionally substituted C1.12 alkyl, an optionally substituted C2.12 alkenyl, an optionally substituted C2-12 alkynyl, an optionally substituted C3.8 cycloalkyl, an optionally substituted C5.8 cycloalkenyl, an optionally substituted Cg-io aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(Ci_6 alkyl), an optionally substituted heteroaryl(Ci_6 alkyl) and an optionally substituted heterocyclyl(Ci_6 alkyl). In some embodiments, R^39A can be a substituted C4.12 alkyl. In other embodiments, R^39A can be an unsubstituted C1-12 alkyl.

[0112] 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, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alphapropyl-glycine and norleucine. In some embodiments, the O-linked amino acid can hâve the structure

wherein R^40A can be selected from hydrogen, an optionally substituted

C1-6 alkyl, an optionally substituted Ομ₆ haloalkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci6 alkyl); and R^41A can be hydrogen or an optionally substituted CM-alkyl; or R^40A and R^41A can be taken together to form an optionally substituted C₃_6 cycloalkyl. Those skilled in the art understand that when R^1A is an optionally substituted O-linked amino acid, the oxygen of R^1AO- of Formula (I) is part of the optionally substituted O-linked amino acid. For example, when R^1A is

the oxygen indicated with is the oxygen of R^1AO- of Formula (I).

[0113] When R^40A is substituted, R^40A 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^40A can be an unsubstituted Ci-6-alkyl, such as those described herein. In some embodiments, R^40A can be hydrogen. In other embodiments, R^40A can be methyl. In some embodiments, R^41A can be hydrogen. In other embodiments, R^41A can be an optionally substituted Ci.₄-alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and tert-butyl. In an embodiment, R^41A can be methyl. Depending on the groups that are selected for R^40A and R^41A, the carbon to which R^40A and R^41A are attached may be a chiral center. In some embodiment, the carbon to which R^40A and R^41A are attached may be a (R) -chiral center. In other embodiments, the carbon to which R^40A and R^41A are attached may be a (S) -chiral center.

,41A ^nh2 include the following:

[0114] Examples of suitable

[0115] As described herein, in some embodiments, R^2A can be a Cj-6 azidoalkyl. For example, R^2A can be an azidomethyl, azidoethyl, azidopropyl, azidobutyl, azidopentyl or azidohexyl. In other embodiments, R^2A can be a aminoalkyl, such as aminomethyl, aminoethyl, aminopropyl, aminobutyl, aminopentyl or aminohexyl.

[0116] The groups attached to the 3’-position of the pentose ring can vary. In some embodiments, R^3A can be OH. In other embodiments, 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, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alphapropyl-glycine and norleucine. In some embodiments, the O-linked amino acid can hâve the structure

, wherein R^42A can be selected from hydrogen, an optionally substituted

Ci-6 alkyl, an optionally substituted Ci-6 haloalkyl, an optionally substituted C3.6 cycloalkyl, an optionally substituted Cg aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci_ alkyl); and R^43A can be hydrogen or an optionally substituted Ci-4-alkyl; or R^42A and R^43A can be taken together to form an optionally substituted C3.6 cycloalkyl.

[0117] 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 Ci-6-alkyl, such as those described herein. In some embodiments, R^42A can be hydrogen. In other embodiments, R^42A can be methyl. In some embodiments, R^43A can be hydrogen. In other embodiments, R^43A can be an optionally substituted Ci.₄-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) -chiral center.

[0119] In still other embodiments, R^3A can be -OC(=O)R^A, wherein R ^A can be an optionally substituted C4.24 alkyl. In some embodiments, R ^A can be a substituted Ci_g alkyl. In other embodiments, R ^A can be an unsubstituted Cj.g alkyl. In still other embodiments, R^3A can be an optionally substituted -O-acyl. In yet still other embodiments, R^3A can be -OC(=O)R^44A, wherein R^44A can be selected from an optionally substituted Cj.u alkyl, an optionally substituted C2-12 alkenyl, an optionally substituted C2-12 alkynyl, an optionally substituted C₃_8 cycloalkyl, an optionally substituted C₅.₈ cycloalkenyl, an optionally substituted Cg-io aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted aryl(Ci_6 alkyl), an optionally substituted heteroaryl(Ci_6 alkyl) and an optionally substituted heterocyclyl(Ci_6 alkyl). In some embodiments, R^44A can be a substituted C1-12 alkyl. In other embodiments, R⁴^ can be an unsubstituted Cm₂ alkyl.

[0120] Various substituents can be présent at the 2’-position of the pentose ring. In some embodiments, R^5A can be hydrogen. In other embodiments, R^5A can be halogen, for example, fluoro or chloro. In some embodiments, R^4A can be halogen, such as fluoro or chloro. In some embodiments, R^5A can be hydrogen and R^4A can be halogen. In some embodiments, R^5A can be hydrogen and R^4A can be fluoro. In other embodiments, R^5A can be hydrogen and R^4A can be chloro. In other embodiments, R^4A and R^5A can both be halogen.

[0121] A variety of substituents can also be présent at the 5’-position of the pentose ring. In some embodiments, both R^al and R^a2 can be hydrogen. In other embodiments, R^al can be hydrogen and R^a2 can be deuterium. In still other embodiments, both R^al and R^a2 can be deuterium. For the Γ-position, in some embodiments, R^A can be hydrogen. In other embodiments, R^A can be deuterium.

[0122] In some embodiments, B^1A cannot be a substituted or unsubstituted thymine. In other embodiments, B^1A cannot be an unsubstituted uracil. In still other embodiments, B^1A cannot be cytosine. In some embodiments R^1A cannot be H. In some embodiments R^1A cannot be H when B^1A is an optionally substituted cytosine or an optionally substituted thymine. In some embodiments, Z^1A cannot be

In some embodiments, R^1A cannot be hydrogen when _R2A is azidomethyl, R^3A is hydroxy, R^4A is halogen (for example, fluoro), R^5A is hydrogen, R^A is hydrogen and B^1A is uracil. In some embodiments, R^1A cannot be hydrogen when R^2A is H2Nmethyl, R^3A is hydroxy, R^4A is halogen (for example, fluoro), R^5A is hydrogen, R^A is hydrogen and B^1A is uracil. In some embodiments, when R^2A is azidomethyl, R^3A is hydroxy, R^4A is halogen (for example, fluoro), R^5A is hydrogen and R^A is hydrogen. then B^1A cannot be uracil. In some embodiments, when R^2A is F^N-methyl, R^3A is hydroxy, R^4A is halogen (for example, fluoro), R^5A is hydrogen and R^A is hydrogen, then B^1A cannot be uracil. In some embodiments, a compound of

Formula (I), or a pharmaceutically acceptable sait, cannot be o

In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait, cannot be

[0123] 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^A2 can be selected from hydrogen, halogen and NHR^J2, wherein R^J2 can be selected from hydrogen, -C(=O)R^K2 and -C(=O)OR^L2; R^B2 can be halogen or NHR^W2, wherein R^w2 can be selected from hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted C₂-6 alkenyl, an optionally substituted C3.8 cycloalkyl, -C(=O)R^M2 and -C(=O)OR^N2; R^C2 can be hydrogen or NHR°²,

wherein R°² can be selected from hydrogen, -C(=O)R^P2 and -C(=O)OR^Q2; R^D2 can be selected from hydrogen, deuterium, halogen, an optionally substituted Ci-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2-6 alkynyl; R^E2 can be selected from hydrogen, hydroxy, an optionally substituted Ci_6 alkyl, an optionally substituted C3.g cycloalkyl, -C(=O)R^R2 and 5 C(=O)OR^S2; R^F2 can be selected from hydrogen, halogen, an optionally substituted C1-6 alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted C2_6 alkynyl; Y² and Y³ can be independently N (nitrogen) or CR¹², wherein R¹² can be selected from hydrogen, halogen, an optionally substituted Ci-6-alkyl, an optionally substituted C₂_6-alkenyl and an optionally substituted C2-6-alkynyl; R^G2 can be an optionally substituted Ci-e alkyl; R^H2 can be hydrogen or NHR^T2, 10 wherein R^T2 can be independently selected from hydrogen, -C(=O)R^U2 and -C(=O)OR^V2; and R^K2,

R^L2, R^M2, R^N2, R^P2, R^Q2, R^r2, R^S2, R^U2 and R^V2 can be independently selected from Ci_₆ alkyl, C₂.₆alkenyl, C2-6 alkynyl, C₃_6 cycloalkyl, C₃^ cycloalkenyl, Cg-io aryl, heteroaryl, heterocyclyl, aryl(Ci_6 alkyl), heteroaryl(Ci_6 alkyl) and heterocyclyl(Ci_6 alkyl). In some embodiments, the structures shown above can be modified by replacing one or more hydrogens with substituents selected from 15 the list of substituents provided for the définition of “substituted.”

O

[0124] In some embodiments, B^1A can be . In other embodiments,

uxrvxr

In yet still other embodiments, B^1A can be , for example,

I I · T)9 σνυν- or jwv« . In some embodiments, R can be hydrogen. In other embodiments,

B^1A can be άΑγ . In some embodiments, R^B2 can be NH2. In other embodiments, R^B2 can be NHR^W2, wherein R^w2 can be -C(=O)R^M2 or -C(=O)OR^N2 In still other embodiments, B^1A can be

[0125] In some embodiments, a compound of Formula (I) can hâve the structure:

or a pharmaceutically acceptable sait of the foregoing. In other embodiments, a compound of Formula (I) can hâve the structure:

or a pharmaceutically acceptable sait of the foregoing. In some embodiments of this paragraph, B^1A can be an optionally substituted purine base.

In other embodiments of this paragraph, B^1A can be an optionally substituted pyrimidine base. In some embodiments of this paragraph, B^1A can be guanine. In other embodiments of this paragraph,

B^1A can be thymine. In still other embodiments of this paragraph, B^1A can be cytosine. In yet still other embodiments of this paragraph, B^1A can be uracil. In some embodiments of this paragraph,

B^1A can be adenine. In some embodiments of this paragraph, R^1A can be hydrogen. In other embodiments of this paragraph, R^1A can be an optionally substituted acyl. In still other embodiments

of this paragraphe, R^1A can be mono-, di- or tri-phosphate. In yet other embodiments of this paragraph, R^1A can be phosphoramidate prodrug, such as an aryl phosphoramidate prodrug. In some embodiments of this paragraph, R^1A can be an acyloxyalkyl ester phosphate prodrug. In other embodiments of this paragraph, R^1A can be a S-acylthioethyl (SATE) prodrug. In still other 5 embodiments, R^1A can be a phosphonic diamide prodrug. In yet still other embodiments, of this paragraph, R^1A can be a cyclic l-aryl-l,3-propanyl ester (HepDirect) prodrug moiety. In some embodiments of this paragraph, R^1A be a cyclosaligenyl (cycloSal) prodrug.

[0126] Examples of suitable compounds of Formula (I) include, but are not limited to the following:

pharmaceutically acceptable sait of the foregoing.

[0127] Further examples of suitable compounds of Formula (I) include, but are not limited to the following:

[0128] Additional examples of a compound of Formula (I) include the following:

a pharmaceutically acceptable sait of the foregoing.

[0129] Examples of a compound of Formula (I) include the following:

pharmaceutically acceptable sait of the foregoing.

[0130] Further examples of a compound of Formula (I) include, but are not limited to the following:

Synthesis [0131] Compounds of Formula (I) and those described herein may be prepared in various ways. Some compounds of Formula (I) can be obtained commercially and/or prepared utilizing known synthetic procedures. General synthetic routes to the compounds of Formula (I), and some examples of starting materials used to synthesize the compounds of Formula (I) are shown and described herein. The routes shown and described herein are illustrative only and are not intended, 10 nor are they to be construed, to limit the scope of the claims 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; ail such modifications and alternate routes are within the scope of the claims.

Scheme 1

[0132] Compounds of Formula (I), where R^2A is a Ci_₆ azidoalkyl can be prepared from a nucleoside, for example, a nucleoside of Formula (A). In Scheme 1, R^a, R^3a, R^4a, R^5a and B^la can be 5 the same as R^A, R^3A, R^4A, R^5A and B^1A as described herein for Formula (I), PG¹ can be a suitable protecting group and LG¹ can be a suitable leaving group. The 5’-position of the nucleoside can be oxidized to an aldéhyde using methods known to those skilled in the art. Suitable oxidation conditions include, but are not limited to, Moffatt oxidation, Swern oxidation and Corey-Kim oxidation; and suitable oxidizing agents include, but are not limited to, Dess-Martin periodinane, 10 IBX (2-iodoxybenzoic acid), TPAP/NMO (tetrapropylammonium perruthenate/N-methylmorpholine

N-oxide), Swern oxidation reagent, PCC (pyridinium chlorochromate), PDC (pyridinium dichromate), sodium periodate, Collin’s reagent, ceric ammonium nitrate CAN, Na₂Cr₂O₇ in water,

Ag₂CO3 on celite, hot HNO₃ in aqueous glyme, O₂-pyridine CuCl, Pb(OAc)4-pyridine and benzoyl peroxide-NiBr₂. A hydroxymethyl group can be added to the 4’-position of the pentose ring along with the réduction of the aldéhyde to an alcohol. The hydroxymethyl group can be added via a condensation reaction using formaldéhyde and a base, such as sodium hydroxide. After addition of the hydroxymethyl group, réduction of the intermediate compound with a 4’-hydroxymethyl group can be conducted using a reducing reagent. Examples of suitable reducing agents include, but are

not limited to, NaBFU and LiAlHf. A suitable leaving group, such as a triflate, can be formed by replacing the hydrogen of the hydroxymethyl group attached to the 4’-position, and the oxygen attached to the 5’-position can be protected with a suitable protecting group (for example, by cyclization with the base, B^la, or with a separate protecting group). The leaving group can be 5 . replaced with an azido group using a métal azide reagent, for example, sodium azide.

Scheme 2

NW + POCI₃

u W

Scheme 3

(C)

8A 'I

R^8A0—P—Cl I r^9A

(C) o R^a\ R^a2

POCI₃	r^10A-p—ο—V	b^1a
amino acid or amino acid ester	r11A R^2Aiiii\''·'	~>ZniiiiR^a
	H-H--	A-R^5A
	4* R^3A<	^r^4A

[0133] Compounds of Formula (I) having a phosphorus containing group attached to the 5’-position of the pentose ring can be prepared using various methods known to those skilled in the 5 art. Examples of methods are shown in Schemes 2 and 3. In Schemes 2 and 3, R^a, R^2a, R^3a, R^4a, R^5aand B^la can be the same as R^A, R^2A, R^3A, R^4A, R^5A and B^1A as described herein for Formula (I). A phosphorus containing precursor can be coupled to the nucleoside, for example, a compound of Formula (B). As shown in Scheme 2, following the coupling of the phosphorus containing precursor, any leaving groups can be cleaved under suitable conditions, such as hydrolysis. Further 10 phosphorus containing groups can be added using methods known to those skilled in the art, for example using a pyrophosphate.

[0134] In some embodiments, an alkoxide can be generated from a compound of Formula (C) using an organometallic reagent, such as a Grignard reagent. The alkoxide can be coupled to the phosphorus containing precursor. Suitable Grignard reagents are known to those 15 skilled in the art and include, but are not limited to, alkylmagnesium chlorides and alkylmagnesium bromides. 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 trialkylamines (e.g., triethylamine)), optionally substituted pyridines (e.g. collidine) and optionally substituted imidazoles (e.g., N-methylimidazole)). Altematively, a phosphorus containing precursor can be added to the nucleoside 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) and iodine as the oxidizing agent and water as the oxygen donor.

[0135] A Ci_6 azidoalkyl at the 4’-position can be reduced to a Ci-β aminoalkyl. Various réduction agents/conditions known to those skilled in the art can be utilized. For example, the azido group can be reduced to an amino group via hydrogénation (for example, H₂-Pd/C or HCO2NH4Pd/C), Staudinger Reaction, NaBHVCoCh’ô H₂O, Fe/NH₄C1 or Zn/NH₄C1.

[0136] 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 sulfur can

Π H

R^6AO—P—Cl or OH R^8AO—P—Cl be part of the phosphores containing precursor, for example, R^7AO or 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-dioxide (Beaucage’s reagent), 3-((N,Ndimethylaminomethylidene)amino)-3H-l,2,4-dithiazole-5-thione (DDTT) and bis(3triethoxysilyl)propyl-tetrasulfide (TEST).

[0137] 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 2 and 3.

[0138] 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^la, can be protected with one or more suitable protecting groups. Suitable protecting groups are described herein. For example, when R^3a is a hydroxy group, R^3a can be protected with a triarylmethyl group or a silyl group. Likewise, any -NH and/or NH₂ groups présent on the B^la can be protected, such as with a triarylmethyl and a silyl group(s). Examples of triarylmethyl groups include but are not limited to, trityl, monomethoxytrityl (MMTr), 4,4'-dimethoxytrityl (DMTr), 4,4',4-trimethoxytrityl (TMTr),. 4,4',4-tris- (benzoyloxy) trityl (TBTr), 4,4',4-tris (4,5-dichlorophthalimido) trityl (CPTr), 4,4',4-tris (levulinyloxy) trityl (TLTr), p-anisyl-1- naphthylphenylmethyl, di-o-anisyl-1naphthylmethyl, p-tolyldipheylmethyl, 3-(imidazolylmethyl)-4,4'-dimethoxytrityl, 9-phenylxanthen

9-yl (Pixyl), 9-(p-methoxyphenyl) xanthen-9-yl (Mox), 4-decyloxytrityl, 4- hexadecyloxytrityl, 4,4'dioctadecyltrityl, 9-(4- octadecyloxyphenyl) xanthen-9-yl, l,r-bis-(4-methoxyphenyl)-l'pyrenylmethyl, 4,4',4-tris- (tert-butylphenyl) methyl (TTTr) and 4,4'-di-3, 5-hexadienoxytrityl. Examples of silyl groups include, but are not limited to, trimethylsilyl (TMS), ierributyldimethylsilyl (TBDMS), triisopropylsilyl (TIPS), tert-butyldiphenylsilyl (TBDPS), tri-wo-propylsilyloxymethyl and [2-(trimethylsilyl)ethoxy]methyl. 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 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 [0139] 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), or a pharmaceutically acceptable sait thereof) and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0140] 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.

[0141] The term “physiologically acceptable” defines a carrier, diluent or excipient that does not abrogate the biological activity and properties of the compound.

[0142] 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.

[0143] 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 5 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.

[0144] 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 10 ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.

[0145] 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 15 formulation and administration of the compounds described herein are known to those skilled in the art.

[0146] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, drageemaking, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the 20 active ingrédients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0147] Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aérosol, injection and parentéral delivery, including 25 intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.

[0148] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly 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 selectively by the organ.

[0149] 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 5 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 10 a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

Methods of Use:

[0150] Some embodiments described herein relate to a method of ameliorating, treating 15 and/or preventing a paramyxovirus 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), or a pharmaceutically acceptable sait thereof). In some embodiments, the subject is identified as suffering from a paramyxovirus viral infection.

[0151] Other embodiments described herein relate to a method of inhibiting viral réplication of a paramyxovirus, 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, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof). For example, a compound of Formula (I), or a pharmaceutically acceptable sait, can act as a chain-terminator and inhibit réplication of the virus.

[0152] In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a 30 pharmaceutically acceptable sait thereof) can be used to treat and/or ameliorate a paramyxovirus infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to prevent a paramyxovirus infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to inhibit the réplication of a paramyxovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to inhibit the polymerase complex of a paramyxovirus.

[0153] In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by a paramyxovirus infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate a lower respiratory viral infection caused by a paramyxovirus infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by a paramyxovirus infection (such as those described herein).

[0154] In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to a paramyxovirus infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate pneumonia due to a paramyxovirus infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a 5 pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate croup due to a paramyxovirus infection.

[0155] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that 10 includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) 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, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula 15 (I), or a pharmaceutically acceptable sait thereof) 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, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used to inhibit the réplication of a respiratory syncytial virus. In some 20 embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to inhibit the RSV polymerase complex.

[0156] In some embodiments, an effective amount of one or more compounds of 25 Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by RSV infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical 30 composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate a lower

respiratory viral infection caused by RSV infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or 5 ameliorate one or more symptoms of an infection caused by RSV infection (such as those described herein).

[0157] In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a 10 pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to a RSV infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or 15 ameliorate pneumonia due to a RSV infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate croup due to a RSV infection.

[0158] In some embodiments, an effective amount of one or more compounds of

Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to treat and/or ameliorate a HPIV-1 infection and/or HPIV-3 infection. In some embodiments, an effective amount of one or more compounds of 25 Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to prevent a HPIV-1 infection and/or HPTV-3 infection. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, or a pharmaceutically acceptable sait thereof, and/or a 30 pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used to inhibit the

réplication of HPIV-1 and/or HPIV-3. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to inhibit the HPIV-1 polymerase 5 complex and/or HPIV-3 polymerase complex.

[0159] In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to treat and/or ameliorate a HPIV-2 infection 10 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, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) 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 15 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), or a pharmaceutically acceptable sait thereof) can be used to inhibit the réplication of HPIV-2 and/or HPIV-4. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds 20 described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used to inhibit the HPIV-2 polymerase complex and/or HPIV-4 polymerase complex.

[0160] In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a 25 pharmaceutically acceptable sait thereof) can be used to treat and/or ameliorate a metapneumoviral infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to prevent a metapneumoviral infection. In some embodiments, 30 an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used to inhibit the réplication of a metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or more compounds described herein (e.g., a 5 compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used to inhibit the metapneumovirus polymerase complex. In some embodiments, including those of this paragraph, the metapneumovirus can be a human metapneumovirus.

[0161] In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that 10 includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate an upper respiratory viral infection caused by a virus selected from a RSV virus, a parainfluenza virus and a metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that 15 includes one or more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate a lower respiratory viral infection caused by a virus selected from a RSV virus, a parainfluenza virus and a metapneumovirus. In some embodiments, an effective amount of one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, and/or a pharmaceutical composition that includes one or 20 more compounds described herein (e.g., a compound of Formula (I), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate one or more symptoms of an infection caused by a virus selected from a RSV virus, a parainfluenza virus and a metapneumovirus (such as those described herein).

[0162] In some embodiments, an effective amount of one or more compounds of 25 Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate bronchiolitis and/or tracheobronchitis due to a RSV virus infection, a parainfluenza virus infection and a metapneumovirus infection. In some embodiments, an effective amount of one or more compounds 30 of Formula (I), 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), or a

pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate pneumonia due to a RSV virus infection, a parainfluenza virus infection and a metapneumovirus infection. In some embodiments, an effective amount of one or more compounds of Formula (I), 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), or a pharmaceutically acceptable sait thereof) can be used treat and/or ameliorate croup due to a RSV virus infection, a parainfluenza virus infection and a metapneumovirus infection.

[0163] The one or more compounds of Formula (I), or a pharmaceutically acceptable sait thereof, that can be used to treat, ameliorate and/or prevent a paramyxovirus viral infection can be a 10 compound of Formula (I), or pharmaceutically acceptable sait thereof, provided in any of the embodiments described in paragraphs [0083]-[0130).

[0164] As used herein, the terms “prevent” and “preventing,” mean lowering the efficiency of viral réplication and/or inhibiting viral réplication to a greater degree in a subject who receives the compound compared to a subject who does not receive the compound. Examples of 15 forms of prévention include prophylactic administration to a subject who has been or may be exposed to an infectious agent, such as a paramyxovirus (e.g., RSV).

[0165] 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 considered 20 treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.

[0166] The terms “therapeutically effective amount” and “effective amount” are used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or médicinal response indicated. For example, an effective amount of compound can be the amount 25 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 disclosed herein required as a dose will dépend 30 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.

[0167] Various indicators for determining the effectiveness of a method for treating a paramyxovirus viral infection are known to those skilled in the art. Example of suitable indicators 5 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.

[0168] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, is an amount that is effective to reduce viral titers to 10 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 Formula (I), or a pharmaceutically acceptable sait thereof, is an amount that is effective to reduce viral load compared to the viral load before administration of the compound of Formula (I), or a pharmaceutically acceptable sait thereof. For example, wherein the viral load is 15 measure before administration of the compound of Formula (I), or a pharmaceutically acceptable sait thereof, and again after completion of the treatment régime with the compound of Formula (I), or a pharmaceutically acceptable sait thereof (for example, 1 week after completion). In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be an amount that is effective to reduce viral load to lower than about 100 genome 20 copies/mL sérum. In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, 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 3log 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 Formula (I), or a pharmaceutically acceptable sait thereof. 25 For example, wherein the viral load is measure before administration of the compound of Formula (I), or a pharmaceutically acceptable sait thereof, and again after completion of the treatment régime with the compound of Formula (I), or a pharmaceutically acceptable sait thereof (for example, 1 week after completion).

[0169] In some embodiments, a compound of Formula (I), or a pharmaceutically 30 acceptable sait thereof, 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 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 Formula (I), or a pharmaceutically acceptable sait thereof, can resuit in a réduction of the réplication of a paramyxovirus 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 5 about 100 fold. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, 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 10 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.

[0170] In some embodiments, an effective amount of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, is an amount that is effective to achieve a sustained viral response, for example, non-detectable or substantially non-detectable paramyxovirus RNA (e.g., less 15 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.

[0171] After a period of time, infectious agents can develop résistance to one or more 20 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 in viral load réduction exhibited by a subject infected with a nonresistant strain. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable 25 sait thereof, can be administered to a subject infected with RSV that is résistant to one or more different anti-RSV agents (for example, ribavirin) to ameliorate and/or treat a RSV infection. In some embodiments, development of one or more résistant RSV strains can be delayed when subjects are treated with a compound of Formula (I), or a pharmaceutically acceptable sait thereof, compared to the development of one or more RSV strains résistant to other anti-RSV agents.

[0172] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, 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. For example, the percentage of subjects being treated with a compound of Formula (I), or a pharmaceutically acceptable sait thereof, that expérience complications can be 10% , 25%, 40%, 50%, 60%, 70%, 80% and 90% less compared to subjects being treated with ribavirin.

[0173] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, 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), or a pharmaceutically acceptable sait thereof, can be used in combination with one or more agents currently used for treating RSV. For example, the additional agent can be 10 ribavirin, palivizumab and RSV-IGIV. For the treatment of RSV, additional agents include but are not limited to ALN-RSV01 (an siRNA agent with the sense strand sequence (5' to 3') GGCUCUUAGCAAAGUCAAGdTdT (SEQ ID NO. 1) and the antisense strand sequence (5' to 3') CUUGACUUUGCUAAGAGCCdTdT (SEQ ID NO. 2), Alnylam Pharmaceuticals, U.S. Publication No. 2009/0238772, filed Dec. 15, 2008), BMS-433771 (l-cyclopropyl-3-[[l-(415 hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one), RFI-641 4,4-bis-{4,6-bis[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(l,3,5)triazin-2-ylamino}-biphenyl-2,2disulfonic-acid), RSV604 ((S)-l-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-lHbenzo[e][l ,4]diazepin-3-yl)urea), MDT-637 5,5'-bis[l-(((5-amino-lHtetrazolyl)imino)methyl)]2,2',4-methylidynetrisphenol), BTA9881 ((R)-9b-(4-chlorophenyl)-l-(420 fluorobenzoyl)-2,3-dihydro-lH-imidazo[r,2':l,2]pyrrolo[3,4-c]pyridin-5(9bH)-one), TMC-353121 (2- [ [6- [ [ [2-(3-HydroxypropyI)-5 -methylphenyl] amino] methyl] -2- [[3 -(morpholin-4yl)propyl]amino]benzimidazol-l-yl]methyl]-6-methylpyridin-3-ol) (Tibotec), MBX-300 ([2,2bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodiumoxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate), YM-53403 (6- [4-[(biphenyl-225 ylcarbonyl) amino]benzoyl} -N-cyclopropyl-5,6-dihydro-4H-thieno [3,2-d] [ 1 ] benzazepine-2carboxamide), motavizumab (Medi-524, Medhnmune), Medi-559 (Recombinant RSV A2 cp248/404/1030/ASH), Medi-534 (vector vaccine candidate recombinant bovine/human parainfluenza virus type 3 (PIV3)/RSV F2), Medi-557, RV568 and a RSV-F Particle Vaccine (Novavax).

[0174] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered with one or more additional agent(s) together in a single pharmaceutical composition. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered with one or more additional agent(s) as two or more separate pharmaceutical compositions. For example, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, 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 first pharmaceutical composition that includes a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and at least one of the other additional agent(s) can be in a second pharmaceutical composition.

[0175] The order of administration of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, with one or more additional agent(s) can vary. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered prior to ail additional agents. In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered prior to at least one additional agent. In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered concomitantly with one or more additional agent(s). In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered subséquent to the administration of at least one additional agent. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable sait thereof, can be administered subséquent to the administration of ail additional agents.

[0176] A potential advantage of utilizing a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) described in paragraph [0173], including pharmaceutically acceptable salts and prodrugs thereof, may be a réduction in the required amount(s) of one or more compounds of paragraph [0173] (including pharmaceutically acceptable salts and prodrugs thereof) that is effective in treating a disease condition disclosed herein (for example, RSV), as compared to the amount required to achieve same therapeutic resuit when one or more compounds described in paragraph [0173], including pharmaceutically acceptable salts and prodrugs thereof, are administered without a compound of Formula (I), or a pharmaceutically acceptable sait thereof. For example, the amount of a compound described in paragraph [0173], including a pharmaceutically acceptable sait and prodrug thereof, can be less compared to the amount of the compound described in paragraph [0173], including a 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), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) described in paragraph [0173], including pharmaceutically acceptable salts and prodrugs 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 barrier when a compound is administered as monotherapy.

[0177] Additional advantages of utilizing a compound of Formula (I), or a pharmaceutically acceptable sait thereof, in combination with one or more additional agent(s) described in paragraph [0173], including pharmaceutically acceptable salts and prodrugs thereof, may include little to no cross résistance between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) described in paragraph [0173] (including pharmaceutically acceptable salts and prodrugs thereof); different routes for élimination of a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) described in paragraph [0173] (including pharmaceutically acceptable salts and prodrugs thereof); little to no overlapping toxicities between a compound of Formula (I), or a pharmaceutically acceptable sait thereof, and one or more additional agent(s) described in paragraph [0173] (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 [0173] (including pharmaceutically acceptable salts and prodrugs thereof).

[0178] 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 vary 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.

[0179] 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 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, 5 as is needed by the subject. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0180] 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 10 human dosage is established, as will be the case for newly-discovered pharmaceutical compositions, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animais.

[0181] In cases of administration of a pharmaceutically acceptable sait, dosages may be 15 calculated as the free base. As will be understood by those of skill in the art, in certain situations it may be necessary to administer 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.

[0182] Dosage amount and interval may be adjusted individually to provide plasma 20 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 25 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.

[0183] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were

not adéquate (precluding toxicity). The magnitude of an administrated dose in 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 dose frequency, will also vary 5 according to the âge, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0184] Compounds disclosed herein can be evaluated for effîcacy 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 10 towards a cell Une, 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 model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The effîcacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human 15 clinical trials. When selecting a model to détermine effîcacy, 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 [0185] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

EXAMPLE 1

Préparation of Compound IA

HO F

1-1

MMTrÔ

[0186] Préparation of (1-2): To a solution of 1-1 (50 g, 203 mmol) in anhydrous 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 low pressure to give a residue, which was partitioned 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).

[0187] 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 15 mins, the mixture was cooled to 0°C, and monomethoxytrityl chloride (239.3 g, 776.8 mmol) was added as a single portion. After being stirred ovemight at R.T., the mixture was filtered through Celite and the filtrate was diluted with TBME. 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.

[0188] This fully protected intermediate was dissolved in toluene (100 mL) and the solution was concentrated under reduced pressure. The residue was dissolved in anhydrous THF (250 mL) and treated with TBAF (60 g, 233 mmol). The mixture was stirred for 2 h at R.T., and the solvent was removed under reduced pressure. The residue was taken into ethyl acetate and the

solution was washed first with saturated sodium bicarbonate and then with brine. After being dried over magnésium sulfate, the solvent was removed in vacuum and the residue was purified by column chromatography (50% EA in PE) to give 1-2 (91 g, 86.4%) as a white foam.

[0189] Préparation of (1-3): To a solution of 1-2 (13.5 g, 26 mmol) in DCM (100 mL) 5 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., and quenched by the addition of Na₂S₂O₃ solution (4%) and sodium bicarbonate aqueous solution (4%) (the solution was adjusted to pH 6, -150 mL). The mixture was stirred for 15 mins. The organic layer was separated, washed with diluted brine and concentrated under reduced 10 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. After stirring for 0.5 h at R.T., the excess of aqueous sodium hydroxide was removed with saturated NH4CI (-150 mL). The mixture was concentrated under reduced pressure, and the residue was partitioned between ethyl acetate and 5% sodium bicarbonate. 15 The organic phase was separated, washed with brine, dried over magnésium sulfate and concentrated. The residue was purified by column chromatography (2% MeOH in DCM) to give the diol 1-3 (9.2 g, 83.6%) as a white foam.

[0190] Préparation of (1-4): Compound 1-3 (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 20 solution was cooled to 0°C, and triflic anhydride (24.9 g, 88.1 mmol) was added dropwise over 10 mins. At this température, the reaction was stirred for 40 mins. The reaction was monitored by TLC (PE: EA= 2:1 and DCM: MeOH= 15:1). After completion, the reaction mixture was quenched with water (50 mL) at 0°C. The mixture was stirred for 30 mins, and extracted with EA. The organic phase was dried over Na₂SO4 and filtered through a silica gel pad. The filtrate was concentrated 25 under reduced pressure, and the residue was purified by column chromatography (50% EA in PE) to give 1-4 (30.0 g, 88.3%) as a brown foam.

[0191] Préparation of (1-5): To a stirred solution of 1-4 (4.4 g, 5.42mmol) in anhydrous DMF (50 mL) was added NaH (260 mg, 6.5 mmol) at 0°C under nitrogen atmosphère. The solution was stirred at R.T., for 1.5 h. The solution was used for the next step without any further workup.

[0192] Préparation of (1-6): To the stirred solution was added NaN₃ (1.5 g, 21.68 mmol) at 0°C under nitrogen atmosphère, and the resulting solution was stirred at R.T. for 1.5 h.

? 68

The reaction was quenched with water, extracted with EA, washed with brine, and dried over MgSC>4. The concentrated organic phase was used for the next step without further purification.

[0193] Préparation of (1-7): To a solution of 1-6 (3.0 g, 5.4 mmol) in anhydrous 1,4dioxane (18 mL) was added NaOH (5.4 mL, 2M in water) at R.T. The reaction mixture was stirred at R.T. for 3 h. The reaction was diluted with EA, washed with brine, and dried over MgSO4. The concentrated organic phase was purified on a silica gel column (30% EA in PE) to give 1-7 (2.9 g, 93%) as a white foam.

[0194] Préparation of (IA): Compound 1-7 (520 mg, 0.90 mmol) was dissolved in 80% of HCOOH (20 mL) at R.T. The mixture was stirred for 3 h, and monitored by TLC. The solvent was removed and the residue was treated with MeOH and toluene for 3 times. NH₃/MeOH was added, and the reaction mixture was stirred at R.T., for 5 mins. The solvent was concentrated to dryness and the residue was purified by column chromatography to give IA (120 mg, 44.4%) as a white solid. ESI-LCMS: m/z 302.0 [M+H]⁺, 324.0 [M+Na]⁺.

EXAMPLE 2

Préparation of Compound 2A

O \ NH °v^Nl 'F \ NI

MMTrO'

1-7 _zo /λ \ NH

ΜΜΤγΟΆ/⁰ \Z^N J n₃-a_7 °

MMTrO'' F

2-1 nh₂ \ N

MMTrO-A/° V^N J o

MMTrO'' ¥

2-2 [0195]

Préparation of (2-1): To a stirred solution of 1-7 (1.1 g, 2.88 mmol) in anhydrous DCM (10 mL) was added MMTrCl (1.77 g, 5.76 mmol), AgNO₃ (1.47 g, 8.64 mmol) and collidine (1.05 g, 8.64 mmol) at 25°C under a N₂ atmosphère. The reaction was refluxed for 12 h. MeOH (20 mL) was added and the solvent was removed to dryness. The residue was purified on a silica gel column (20% EA in PE) to give 2-1 (1.6 g, 85.1%) as a white foam.

[0196] Préparation of (2-2): To a stirred solution of 2-1 (800 mg, 0.947 mmol) in anhydrous MeCN (10 mL) were added TPSC1 (570 mg, 1.89 mmol), DMAP (230 mg, 1.89 mmol) and TEA (190 mg, 1.89 mmol) at R.T. The mixture was stirred for 12 h. NH4OH (25 mL) was added and the mixture was stirred for 2 h. The solvent was removed, and the residue was purified on a silica gel column as a yellow foam. Further purification by prep-TLC gave 2-2 (700 mg, 87.1%) as a white solid.

[0197] Préparation of (2A): Compound 2-2 (300 mg, 0.355 mmol) was dissolved in 80% of HCOOH (5 mL) at R.T. The mixture was stirred for 3 h, and monitored by TLC. The solvent was then removed and the residue was treated with MeOH and toluene (3 times). NHa/MeOH was added and the mixture was stirred at R.T., for 5 mins. The solvent was removed and the residue was purified by column chromatography to give 2A (124 mg, 82.6%) as a white solid. ESI-LCMS: m/z 301.0 [M+H]⁺, 601.0 [2M+H]⁺.

EXAMPLE 3

Préparation of Compound 14A

AA-1 AA-2 AA-3

[0198] Préparation of (AA-2): AA-1 (2.20 g, 3.84 mmol) was dissolved in 80% HCOOH (40 mL) at R.T. (18 °C). The mixture was stirred at R.T. for 12 h. The solvent was removed at low pressure. The residue was purified by column chromatography using 50% EA in Hexane to give AA-2 (1.05 g, 91.3%) as a white solid.

[0199] Préparation of (AA-3): To a stirred solution of AA-2 (1 g, 3.32 mmol) in anhydrous pyridine (20 mL) was added TBSC1 (747 mg, 4.98 mmol) and imidazole (451 mg, 6.64

mmol) at R.T. (16 °C) under N₂ atmosphère. The mixture was stirred at R.T. for 4 h. The resulting solution was concentrated to dryness under reduced pressure, and the residue was dissolved in EA (100 mL). The solution was washed with sat. NaHCO₃ solution and brine, and dried over anhydrous MgSO₄. The solution was concentrated to dryness, and the residue was purified on a silica gel 5 column using 20% EA in Hexane to give AA-3 (1.4 g, 79.5%) as a white solid.

[0200] Préparation of (AA-4): To a stirred solution of AA-3 (1.50 g, 2.83 mmol, 1.00 eq.) in anhydrous CH₃CN (28 mL) was added TPSC1 (1.71 g, 5.80 mmol, 2.05 eq.), DMAP (691.70 mg, 5.66 mmol, 2.00 eq.) and TEA (573.00 mg, 5.66 mmol, 2.00 eq.) at R.T. (15 °C). The mixture was stirred for 2 h. NH₃.H₂O (20 mL) was added, and the mixture was stirred for 3 h. The mixture 10 was extracted with EA (3 x 60 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified on a silica gel column (30% EA in PE) to give AA-4 (2.3 g, crude) as a yellow foam.

[0201] Préparation of (AA-5): To a stirred solution of AA-4 (1.90 g, 2.34 mmol) in anhydrous DCM (20 mL) was added DMTrCl (1.82 g, 3.49 mmol) and 2,4,6-trimethylpyridine (1.00 15 g, 8.25 mmol) at R.T. (15 °C) under N₂ atmosphère. The mixture was stirred at R.T. for 12 h.

MeOH (20 mL) was added. The mixture was filtered, and the filtrate was concentrated to dryness.

The residue was dissolved in EA (80 mL). The solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified on a silica gel column (5% MeOH in DCM) to give AA-5 (1.4 g, crude) as a white solid.

[0202] Préparation of (AA): AA-5 (2.40 g, 2.60 mmol) was dissolved in TB AF (10 mL, IM in THF). The mixture was stirred at R.T. (15 °C) for 30 mins. The mixture was concentrated to dryness, and the residue was dissolved in EA (60 mL). The solution was washed with brine, dried over MgSO₄ and concentrated under reduced pressure. The residue was purified on a silica gel column (5% MeOH in DCM) to give AA (1.50 g, 95.8%) as a white solid. ESI-MS: m/z

625.3 [M+Na]⁺.

[0203] Préparation of (14-1): To a solution of AA (60.0 mg, 99.57 pmol, 1.00 eq.) in pyridine (1 mL) was added isobutyric anhydride (31.50 mg, 199.13 μηιοί, 2.00 eq.) in 1 portion at R.T. (15 °C) under N₂ atmosphère. The mixture was stirred at R.T. for 12 h. The mixture was concentrated, and the residue was partitioned between EA and water. The combined organic phases 30 were washed with water and brine, and dried over anhydrous Na₂SO₄. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel chromatography (30% EA in PE) to afford 14-1 (59.00 mg, 79.77%) as a white solid.

[0204] Préparation of (14A): 14-1 (57.00 mg, 76.74 pmol, 1.00 eq.) was dissolved in 80% CH3COOH (8 mL). The solution was stirred at R.T. (15 °C) for 12 h. The mixture was concentrated to dryness. The residue was purified on a silica gel column (2.5% MeOH in DCM) to give 14A (23.00 mg, 68.05%) as a white foam. ESI-MS: m/z 441.2 [M+H]⁺, 463.2 [M+Na]⁺ .

EXAMPLE 4

Préparation of Compound 15A

15-1

15A [0205] Préparation of (15-1): 15-1 was prepared in similar manner as 14-1 using AA (60.00 mg, 99.57 μηιοί, 1.00 eq.) in pyridine (1 mL) and propionic anhydride (25.92 mg, 199.13 pmol, 2.00 eq.). 15-1 (white solid, 56.00 mg, 78.69%).

[0206] Préparation of (15A): Compound 15A was prepared in similar manner as 14A using 15-1 (54.00 mg, 75.55 pmol, 1.00 eq.) 15A (white foam, 18.00 mg, 57.78%). ESI-MS: m/z

413.1 [M+H]⁺.

EXAMPLE 5

[0207] Préparation of (16-1): 16-1 was prepared in similar manner as 14-1 using AA (62.00 mg, 102.89 μιηοΐ, 1.00 eq.) in pyridine (1 mL) and pentanoic anhydride (38.32 mg, 205.77 μιηοΐ, 2.00 eq.). 16-1 (white solid, 60.00 mg, 75.65%).

[0208] Préparation of (16A): Compound 16A was prepared in similar manner as 14A using 16-1 (75.00 mg, 97.30 pmol, 1.00 eq.) 16A (white foam, 28.00 mg, 61.43%). ESI-MS: m/z

469.2 [M+H]⁺.

EXAMPLE 6

Préparation of Compound 24A

[0209] Préparation of (24-1): To a stirred solution of AA-1 (300.0 mg, 497.83 pmol) in anhydrous pyridine (0.5 mL) was added DMTrCl (337.36 mg, 995.66 pmol) at R.T. (17 °C) under N₂ atmosphère. The solution was stirred at 50 °C~60 °C for 12 h. The mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in EA (40 mL). The solution was washed with brine, dried over anhydrous MgSCfi, and concentrated to dryness at low pressure. The residue was purified on a silica gel column using 20% EA in PE to give 24-1 (300 mg, 66.59%) as a white solid.

[0210] Préparation of (24-2): To a stirred solution of 24-1 (100.00 mg, 110.50 pmol) in anhydrous pyridine (0.5 mL) was added DMAP (6.75 mg, 55.25 μηιοί), DCC (22.80 mg, 110.50 μιηοΐ) and n-actanoic acid (31.87 mg, 221.00 pmol) at R.T. (18 °C) under N₂ atmosphère. The solution was stirred at R.T. for 12 h. The solution was concentrated to dryness under reduced pressure. The residue was purified on a silica gel column using 15% EA in PE to give 24-2 (98.00 mg, 86.0%) as a white foam.

[0211] Préparation of (24A): 24-2 (90.00 mg, 87.28 pmol) was dissolved in 80% CH3COOH (20 mL) at R.T. (16 °C). The mixture was stirred R.T. for 12 h. The reaction was quenched with MeOH, and the mixture was concentrated to dryness. The residue was purified on a silica gel column (5% MeOH in DCM) to give 24A (33.00 mg, 88.7%) as a white solid. ESI-MS: m/z 427.2 [M+H]⁺.

EXAMPLE 7

Préparation of Compound 25A

MMTrO'

25-1 25A [0212] Préparation of (BB-2): To a stirred solution of BB-1 (500.00 mg, 0.87 mmol) in anhydrous pyridine (1 mL) was added TBSC1 (236.5 mg, 1.57 mmol) at 20 °C under N₂. The solution was stirred at 50 °C~60 °C for 12 h. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA (50 mL). The solution was washed with sat. NaHCO3 solution and brine, and dried over anhydrous MgSO₄. The solution was filtered, and the fîltrate was concentrated to dryness. The residue was purified on a silica gel column to give BB-2 (510.00 mg, 85.06%) as a white solid.

[0213] Préparation of (BB-3): To a stirred solution of BB-2 (430.00 mg, 625.15 mmol) in anhydrous MeCN (6 mL) was added TPSC1 (368.65 mg, 1.25 mmol), DMAP (152.75 mg, 1.25 mmol) and TEA (126.52 mg, 1.25 mmol) at R.T. The mixture was stirred for 2 h. NHfiOH (8 mL) was added, and the mixture stirred for 3 h. The mixture was extracted with EA (3 x 40 mL). The organic phase was washed with brine, dried over anhydrous Na₂SO₄ and concentrated at low pressure. The residue was purified on a silica gel column (25% EA in PE) to give BB-3 (500 mg of crude) as a yellow foam.

[0214] Préparation of (BB-4): To a stirred solution of BB-3 (500 mg of crude, 0.72 mmol) in anhydrous DCM (7 mL) was added DMTrCl (365 mg, 1.0 mmol ) and collidine (305 mg,

2.5 mmol) and AgNC>3 (184 mg, 1.08 mmol) at R.T. (15 °C) under N2 atmosphère. The mixture was stirred at R.T. for 12 h. MeOH (5 mL) was added. The mixture was filtered, and the filtrate was concentrated to dryness. The residue was dissolved in EA (50 mL). The solution was washed with brine, dried over anhydrous Na₂SO4 and concentrated at low pressure. The residue was purified on a 5 silica gel column (5% MeOH in DCM) to give BB-4 (500 mg, 70.3%) as a white solid.

[0215] Préparation of (BB): BB-4 (1.00 g, 1.01 mmol) was dissolved in TBAF (5 mL, IM in THF) and stirred at R.T. for 30 mins. The mixture was diluted with EA (100 mL). The mixture was washed with water and brine, and dried over anhydrous MgSO4. The organic phase was concentrated to dryness. The residue was purified on the silica gel column (30% EA in PE) to 10 give BB (0.80 g, 91.5%) as a white solid. ESI-MS: m/z 873.7 [M+l]⁺.

[0216] Préparation of (25-1): To a solution of BB (100.00 mg, 114.29 pmol) in anhydrous pyridine (1.5 mL) was added DMAP (2.79 mg, 22.86 μιηοΐ), DCC (70.75 mg, 342.88 μπιοί) and n-octanoic acid (49.45 mg, 342.88 μιηοΐ) at R.T. (18 °C) under N₂ atmosphère. The solution was stirred at R.T. for 12 h. The solution was concentrated to dryness under reduced 15 pressure. The residue was purified on a silica gel column using 15% EA in PE to give 25-1 (95.00 mg, 83.03%) as a white foam.

[0217] Préparation of (25A): 25-1 (110.00 mg, 109.87 μιηοΐ) was dissolved in 80% CH3COOH (25 mL) at R.T. (15°C). The mixture was stirred for 12 h. The reaction was quenched with MeOH, and the solution was concentrated to dryness. The residue was purified on a silica gel 20 column (5% MeOH in DCM) to give 25A (30.00 mg, 64.03%) as a white solid. ESI-MS: m/z 427.2 [M+H]⁺.

EXAMPLE 8

Préparation of Compound 26A

nh₂

OAAZÎ 2HCI ^HzN °

HO F 26A [0218] Préparation of (26-1): To a solution of N-Boc-L-Valine (620.78 mg, 2.86 mmol) and TEA (144.57 mg, 1.43 mmol) in anhydrous THF (2.5 mL) was added BB (250.00 mg, 285.73 μιηοΐ). The mixture was co-evaporated with pyridine and toluene to remove water. The residue was dissolved in THF (2.5 mL). DIPEA (369.28 mg, 2.86 mmol) was added, followed by addition of BOP-C1 (363.68 mg, 1.43 mmol) and 3-nitro-lH-l,2,4-triazole (162.95 mg, 1.43 mmol) at R.T. (18 °C). The mixture was stirred at R.T. for 12 h and then diluted with EA (40 mL). The solution was washed with brine, dried over anhydrous Na₂SO₄ and concentrated to dryness at low pressure. The residue was purified on a silica gel column (30% EA in PE) to give 26-1 (220 mg, crude) as a white foam.

[0219] Préparation of (26-2): 26-1 (250.0 mg, 232.73 pmol) was dissolved in 80% CH3COOH (30 mL). The solution was heated to 50 °C and stirred for 12 h. The reaction was quenched with MeOH, and the solution was concentrated to dryness. The residue was purified on a silica gel column (5% MeOH in DCM) to give 26-2 (80.00 mg, 68.82%) as a white foam.

[0220] Préparation of (26A): 26-2 (78.00 mg, 156.16 pmol) was dissolved in HCl/dioxane (1.5 mL) and EA (1.5 mL) at R.T. (19 °C). The mixture was stirred at R.T. for 30 mins. The solution was concentrated to dryness at low pressure The residue was purified by prepHPLC to give 26A (23 mg, 31.25%) as a white solid. ESI-MS: m/z 400.20 [M+H]⁺,799.36 [2M+H]⁺.

EXAMPLE 9

Préparation of Compound 27 A

27A [0221] Préparation of (27-1): 27-1 was prepared in similar manner as 26-1 using BB 5 (250.0 mg, 276.25 μιηοΐ), (2S)-2-(tert-butoxycarbonylamino)-3-methyl-butanoic acid (360.11 mg,

1.66 mmol) and TEA (83.86 mg, 828.75 μιηοΐ). 27-1 (white foam, 220.0 mg, 72.12%).

[0222] Préparation of (27-2): 27-2 was prepared in similar manner as 26-2 using 27-1 (230.00 mg, 208.29 μιηοΐ, 1.00 eq.). 27-2 (white foam, 80.00 mg, 77.66%).

[0223] Préparation of (27A): 27A was prepared in similar manner as 26 using 27-2 10 (100.00 mg, 200.20 pmol, 1.00 eq.). 27A (white solid, 56 mg, 59.57 %). ESI-MS: m/z 400.0 [M+H]⁺, 422.1 [M+Na]⁺; 799.1 [2M+H]⁺, 821.2 [2M+Na]⁺.

EXAMPLE 10

Préparation of Compound 13A

A 13-1 13-2

13A [0224] Préparation of (13-1): To a solution of 2A (200 mg, 0.67 mmol) in anhydrous pyridine (5 mL) was added TBSC1 (120 mg, 0.8 mmol) at R.T. The mixture was stirred ovemight, and the reaction mixture was diluted with EA. The mixture was washed with NaHCO₃ aq. solution and brine. The organic layer was dried, filtered and concentrated to give residue, which was purified by silica gel column chromatography (5% MeOH in DCM to 25% MeOH in DCM to give 13-1 (153 mg, 55%) as a white solid.

[0225] Préparation of (13-2): To a solution of 13-1 (54 mg, 0.13 mmol) in anhydrous

DCM (2 mL) was added collidine (95 μΕ, 0.78 mmol), DMTrCl (262 mg, 0.78 mmol) and AgNO₃(66 mg, 0.39 mmol) at R.T. The mixture was stirred ovemight, and then diluted wit DCM (5 mL). The mixture was filtered through a pre-packed celite funnel, and the filtrate was washed with NaHCO₃ aq. solution, 1.0 M citric acid solution and then brine. The organic layer was dried over Na₂SO4, and concentrated at low pressure to give a residue. The residue was purified by silica gel column chromatography (25% EA in PE to 100 %EA) to give 13-2 (83.5 mg, 63.6%).

[0226] Préparation of (13-3): To a solution of 13-2 (83 mg, 0.081 mmol) in THF (1 mL), was added a IM solution of TB AF in THF (0.122 mL, 0.122 mmol) at ice bath température. The mixture was stirred for 1.5 h. The mixture was diluted with EA, and washed with water and brine. The organic layer was dried and concentrated to give the crude product, which was purified by silica gel column chromatography (DCM to 5% MeOH in DCM) to give 13-3 (66.6 mg, 91%) as a white foam.

[0227] Préparation of (13-4): 13-3 (66.6 mg, 0.074 mmol) was co-evaporated with toluene and THF (3x). Bis(POC)phosphate (33 mg, 0.96 mmol) was added, and then co-evaporated with toluene (3x). The mixture was dissolved in anhydrous THF (1.5 mL) and cooled in an ice bath (0 to 5 0C). 3-nitro-l,2,4-triazole (13 mg, 0.11 mmol), diisopropylethyl amine (54 μL, 0.3 mmol), and BOP-C1 (28 mg, 0.11 mmol) were added successively. The mixture was stirred 2 h at 0 to 5 °C, diluted with EtOAc, washed with 1.0M citric acid, sat. aq. NaHCO₃ and brine, and dried with Na2SO4. The residue was purified on silica (10 g column) with C^CLâ-PrOH (4-10% gradient) to give 13-4 (68 mg, 76%) as a white solid.

[0228] Préparation of (13A): 13-4 (68 mg, 0.07 mmol) was dissolved in 80% HCOOH. The mixture was stirred at R.T. for 2 h. The solvents were evaporated at R.T. and co-evaporated with toluene (3x). The residue was dissolved in 50% CH3CN/H2O, was purified on a reverse-phase HPLC (Cl8) using CH₃CN and H2O. The product was lyophilization to give 13A (4.8 mg, 14%) as a white foam. ESI-LCMS: m/z = 613.1 [M+H]⁺, 1225.2 [2M+H]⁺.

EXAMPLE 11

Préparation of Compound 17A

[0229] Préparation of (17-1): 17-1 (40.7 mg, 53%) was prepared in the same manner from 1-7 (50 mg, 0.087 mmol) and bis(isopropyloxycarbonyloxymethyl)phosphate (58 mg,0.175 mmol) with DIPEA (75 pL, 0.52 mmol), BOP-C1 (66.2 mg, 0.26 mmol), and 3-nitro-l,2,4-triazole (30 mg, 0.26 mmol) in THF (0.4 mL) in a similar manner as 13-4.

[0230] Préparation of (17A): 17-1 (40 mg, 0.045 mmol) was dissolved in_anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (34 pL, 0.135 mmol) was added at 0 to 5 °C. The mixture was stirred at R.T. for 3 h. Anhydrous EtOH (200 pL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene (3x). The residue was purified on silica (10 g column) with MeOH/CH₂C12 (5-7% gradient) and lypholized give 17A (15.4 mg, 76%) as a white foam. ESILCMS: m/z = 614.15 [M+H]⁺, 1227.2 [2M+H]⁺.

EXAMPLE 12

Préparation of Compound 18A

HO

MMTrCf ”F

1-7

[0231] Préparation of (18-1): To a stirred solution of 1-7 (80 mg, 0.14 mmol) in anhydrous CH3CN (2.0 mL) was added N-methylimidazole (0.092 mL, 1.12 mmol) at 0 °C (ice/water bath). A solution of phenyl (isopropoxy-L-alaninyl) phosphorochloridate (128 mg, 0.42 mmol, dissolved in CH₃CN (0.5 mL)) was then added (prepared according to a general procedure as described in McGuigan et al., J. Med. Chem. (2008) 51:5807-5812). The solution was stirred at 0 to 5 °C for h and then stirred at R.T. for 16 h. The mixture was cooled to 0 to 5 °C, diluted with EA followed by the addition of water (5 mL). The solution was washed with 1.0M citric acid, sat. aq. NaHCCh and brine, and dried with MgSCft. The residue was purified on silica (10 g column) with EA/hexanes (25-100% gradient) to give 18-1 (57.3 mg, 49 %) as a foam.

[0232] Préparation of (18A): 18-1 (57.3 mg, 0.07 mmol) was dissolved in_anhydrous CH₃CN (0.5 mL), and 4N HCl in dioxane (68 pL, 0.27 mmol) was added at 0 to 5 °C. The mixture was stirred at R.T. for 2 h, and anhydrous EtOH (100 pL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene (3x). The residue was purified on silica (10 g column) with MeOH/CH2C12 (1-7% gradient) and lypholized to give 18A (27.8 mg, 72%) as a white foam. ESILCMS: m/z = 571.1 [M+H]⁺, 1141.2 [2M+H]⁺.

EXAMPLE 13

Préparation of Compound 28A

[0233] Préparation of (28-1): 28-1 (68.4 mg, 44.7 %) was prepared from 1-7 (100 mg,

0.174 mmol) and bis(tert-butoxycarbonyloxymethyl)phosphate (126 mg, 0.35 mmol) with DIPEA (192 pL, 1.04 mmol), B0P-C1 (133 mg, 0.52 mmol), and 3-nitro-l,2,4-triazole (59 mg, 0.52 mmol ) in THF (1.5 mL) in the same manner as 13-4.

[0234] Préparation of (28A): 28A (31.4 mg, 67%) was prepared from 28-1 (68 mg, 0.077 mmol) in the same manner as 17A. ESI-LCMS: m/z = 627.15 [M+Na]⁺, 1219.25 [2M+H]⁺.

MMTrÔ F

1-7

EXAMPLE 14

Préparation of Compound 19A

[0235]

Préparation of (Ί9-1): To a solution of 1-7 (100 mg, 0.175 mmol) in anhydrous

CH₃CN (2 mL) was added 5-ethylthio-lH-tetrazole in CH₃CN (0.25M; 0.84 mL, 0.21 mmol). BisSATE-phosphoramidate (95 mg, 0.21 mmol) in CH₃CN (1 mL) was added at 0 to 5 °C dropwise. The mixture was stirred 2 h at 0 to 5 °C under Ar. A solution of 77% m-CPBA (78 mg, 0.35 mmol) in DCM (1 mL) was added, and the mixture stirred 2 h at 0 to 5 °C under Ar. The mixture was diluted with EtOAc (50 mL), washed with 1.0M citric acid, sat. NaHCO₃ and brine, and dried with

MgSOzt. The mixture was filtered, and the solvents were evaporated in vacuo. The residue was purified on silica (10 g column) with EA/hexanes (20-100% gradient) to give 19-1 (105 mg, 63.6 %) as a white foam.

[0236] Préparation of (19A): 19-1 (105 mg, 0.112 mmol) was dissolved in_anhydrous CH₃CN (0.8 mL), and 4N HCl in dioxane (84 pL, 0.334 mmol) was added at 0 to 5 °C. The mixture was stirred at R.T. for 2 h. Anhydrous EtOH (100 pL) was added. The solvents were evaporated at R.T., and co-evaporated with toluene (3x). The residue was purified on silica (10 g column) with MeOH/CH₂C12 (1-7% gradient) and lypholized to give 19A (42.7 mg, 57%) as a white foam. ESILCMS: m/z = 692.15 [M+Na]⁺, 1339.30 [2M+H]⁺.

EXAMPLE 15

Préparation of Compound 20A

[0237] Préparation of (20-2): 1-7 (100 mg, 0.174 mmol) was co-evaporated with anhydrous pyridine (3x), toluene (3x) and CH3CN (3x), and dried under high vacuum ovemight. 1-7 was dissolved in CH3CN (2 mL). A proton sponge (112 mg, 0.52 mmol), POC1₃ (49 uL, 0.52 mmol) were added at 0 to 5 °C. The mixture was stirred for 3 h at 0 to 5 °C to give intermediate 20-1. To this solution, L-alanine isopropyl ester hydrochloride (146 mg, 0.87 mmol), and TEA (114 uL, 1.74 mmol) were added. The mixture was stirred for 4 h at 0 to 5 °C. The mixture was stirred 2 h at 0 to 5 °C, then diluted with EtOAc. The mixture was washed with 1 .OM citric acid, sat. aq. NaHCO₃ and brine, and dried with IMasSCU. The residue was purified on silica (10 g column) with CH₂C12/MeOH (0-7% gradient) to give 20-2 (67 mg, 43.7%) as a white solid.

[0238] Préparation of (20A): 20-2 (65 mg, 0.074 mmol) was dissolved in_anhydrous CH3CN (0.5 mL), and 4N HCl in dioxane (55 pL, 0.22 mmol) was added at 0 to 5 °C. The mixture was stirred at R.T. for 1.5 h. A second portion of 4N HCl in dioxane (15 pL) was added, and the mixture stirred at R.T. for 2 h. Anhydrous EtOH (300 pL) was added. The solvents were evaporated at R.T. and co-evaporated with toluene (3x). The residue was dissolved in 50% CH3CN/H2O, was purified on a reverse-phase HPLC (Cl8) with CH3CN and water, and lyophilized to give 20A (9 mg, 20%) as a white foam. ESI-LCMS: m/z = 608.15 [M+H]⁺, 1215.3 [2M+H]⁺.

EXAMPLE 16

Préparation of Compound 23A

[0239] Préparation of (23-2): To a stirred solution of 1-7 (100 mg, 0.175 mmol) in anhydrous CH3CN (2.0 mL) was added N-methylimidazole (0.14 mL, 1.4 mmol) at 0 °C (ice/water bath). A solution of 23-1 (220 mg, 0.53 mmol, dissolved in 0.5 mL of CH3CN), (prepared according to a general procedure described in Bondada, L. et al., ACS Médicinal Chemistry Letters,(2913) 4(8):747-751) was added. The solution was stirred at 0 to 5 °C for 1 h and then stirred at R.T. for 16 h. The mixture was cooled to 0 to 5 °C, diluted with EA followed by addition of water (5 mL). The solution was washed with 1.0M citric acid, sat. aq. NaHCO₃ and brine, and dried with MgSO₄. The residue was purified on silica (10 g column) with EA/hexanes (25-100% gradient) to give 23-2 (56.4 mg, 33.7 %) as a white foam.

[0240] Préparation of (23A): 23-2 (56mg, 0.0585 mmol) was dissolved in_anhydrous CH3CN (0.7 mL), and 4N HCl in dioxane (44 pL, 0.176 mmol) was added at 0 to 5 °C. The mixture was stirred at R.T. for 2 h. 4N HCl in dioxane (20pL) was added. The mixture was stirred at R.T. for 2 h. Anhydrous EtOH (100 pL) was added. The solvents were evaporated at R.T. and coevaporated with toluene (3x). The residue was purified on silica (10 g column) with MeOH/CH2Cl₂(1-7% gradient) and lypholized to give 23A (27.6 mg, 69%) as a white foam. ESI-LCMS: m/z =

685.2 [M+H]⁺.

EXAMPLE 17

Préparation of Compound 29 A

NHDMTr

n₃—' MMTrÔ

NHDMTr

N₃-' } MMTrÔ

[0241] Préparation of (29-1): To a solution of BB (lOOmg, 0.114 mmol) in anhydrous CH₃CN (2 mL) were added a solution of bis-SATE-phosphoramidate (62.2 mg, 0.14 mmol) in CH3CN (1 mL) followed by 5-ethylthio-lH-tetrazole in CH3CN (0.25M; 0.56 mL, 0.14 mmol) at 0 to 5 °C dropwise. The mixture was stirred 2 h at 0 to 5 °C under Ar. A solution of 77% m-CPBA (49 mg, 0.22 mmol) in DCM (1 mL) was added, and the mixture was stirred 2 h at 0 to 5 °C under Ar. The mixture was diluted with EtOAc (50 mL), washed with 1.0M citric acid, sat. NaHCO₃, and brine, and dried with MgSCfr. The mixture was filtered and the solvents were evaporated in vacuo. The residue was purified on silica (10 g column) with EA/hexanes (10-100% gradient) to give 29-1 (72 mg, 50.8 %) as a white solid.

[0242] Préparation of (29A): 29-1 (72 mg, 0.056 mmol) was dissolved in_anhydrous CH3CN (1.0 mL), and 4N HCl in dioxane (87 pL, 0.35 mmol) was added at 0 to 5 °C. The mixture was stirred at R.T. for 2 h. Intermediate 29-2 was observed by LCMS. The solvents were evaporated at R.T. and co-evaporated with toluene (3x). The residue obtained was re-dissolved in 80% HCOOH (2 mL). The mixture was stirred at R.T. for 4.5 h. The solvents were evaporated at R.T. and co-evaporated with toluene (3x). Anhydrous EtOH (3x5 mL) was added. The residue was dissolved in 50% CH3CN/H2O, purified on a reverse-phase HPLC (Cl8) using CH3CN and H2O, and lyophilized to give 29A (19.2 mg) as a white foam. ESI-LCMS: m/z = 669.2 [M+H]⁺, 1337.25 [2M+H]⁺.

EXAMPLE 18

Préparation of Compound 30A

NHDMTr

[0243] Préparation of (30-1): 30-1 (98 mg, 72.6 %) was prepared in the same manner from BB (100 mg, 0.114 mmol) and bis(tert-butoxycarbonyloxymethyl)phosphate (83mg, 0.35 mmol) with DIPEA (126 pL, 0.69 mmol), BOP-C1 (87 mg, 0.34 mmol), and 3-nitro-l,2,4-triazole (39 mg, 0.34 mmol ) in THF (1.5 mL) in the same manner as 13-4.

[0244] Préparation of (30A): 30A (30.2 mg, 60%) was prepared from 30-1 (98 mg, 0.083 mmol) in the same manner as 17A. ESI-LCMS: m/z = 609.15 [M+H]⁺, 1217.3 [2M+H]⁺.

EXAMPLE 19

Préparation of Compound 21A

o ⁺ _zP-N(i-Pr)₂ΟΙ

21-1

[0245] Préparation of (21-3): A solution of 21-1 (4.7 g, 11.2 mmol; prepared according to the procedure Villard et al., Bioorg. Med. Chem. (2008) 16:7321-7329) and Et₃N (3.4 mL, 24.2 mmol) in THF (25 mL) was added dropwise over 1 h to a stirred solution of Λζ/Vdiisopropylphosphorodichloridite (1.0 mL, 5.5 mmol) in THF (35 mL) at -75 °C. The mixture was stirred at R.T. for 4 h. The mixture was filtered, and the fîltrate concentrated. The oily residue was purified on silica gel column with EtOAc/hexanes (2-20% gradient) to give 21-3 (1.4 g, 26%).

[0246] Préparation of (21-4): To a solution of 21-2 (50 mg, 0.08 mmol) and 21-3 (110 mg, 0.11 mmol) in CH₃CN (1.0 mL) was added 5-(ethylthio)tetrazole (0.75 mL, 0.16 mmol; 0.25 M in CH₃CN). The mixture was stirred at R.T. for 1 h. The mixture was cooled to -40 °C, and a solution of 3-chloroperoxybenzoic acid (37 mg, 0.16 mmol) in CH2CI2 (0.3 mL) was added. The mixture was warmed to R.T. over 1 h. The reaction was quenched with 7% Na2S2O₃ solution in sat aq. NaHCO₃. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed wit brine and dried with Na₂SO4. The solvent was evaporated, and the residue was purified on a silica gel column with EtOAc/hexanes (30-100% gradient) to give 21-4 (52 mg, 45%).

[0247] Préparation of (21A): A solution of 21-4 (52 mg, 0.036 mmol) in MeCN (0.5 mL) and HCl (45 μΕ; 4 N in dioxane) was stirred 20 h at R.T. The reaction was quenched with MeOH, and the solvents were evaporated. The residue was co-evaporated with toluene and purified on a silica gel column with MeOH/CH₂Cl₂ (4-10% gradient) to give 21A (14 mg, 51%). ESILCMS: m/z = 702 [M+H]⁺.

EXAMPLE 20

Préparation of Compound 22A

[0248] Préparation of (22-2): A mixture of 22-1 (0.14 g, 0.24 mmol; prepared according to the procedure described in WO 2008/082601, filed Dec. 28, 2007) and 21-2 (120 mg, 0.2 mmol) was rendered anhydrous by evaporating with pyridine and then dissolved in pyridine (3 mL). Pivaloyl chloride (48 pL) was added dropwise at -15 °C. The mixture was stirred at -15 °C for 2 h. The reaction was quenched with sat. aq. NH₄C1 solution and diluted with CH2CI2. The organic layer was washed with brine and dried with Na₂SO4. The solvents were evaporated, and the residue was purified on a silica gel column with EtOAc/hexanes (30-100% gradient) to give 22-2 (50 mg, 24%).

[0249] Préparation of (22-3): A mixture of 22-2 (43 mg; 0.04 mmol) in CC1₄ (0.8 mL), L-valine isopropyl ester hydrochloride (20 mg, 0.12 mmol) and Et₃N (33 μΐ, 0.24 mmol) was stirred at R.T. for 2 h. The mixture was diluted with EtOAc. The mixture was washed with sat. aq. NaHCO₃ and brine, and dried with Na₂SO₄. The solvents were evaporated, and the residue was purified on a silica gel column with i-PrOH/CH₂Cl₂ (2-10% gradient) to 22-3 (35 mg, 75%).

[0250] Préparation of (22A): A solution of 22-3 (35 mg, 0.03 mmol) in MeCN (0.4 mL) and HCl (40 pL; 4 N in dioxane) was stirred 4 h at R.T. The reaction was quenched with the addition of MeOH, and the solvents were evaporated. The residue was co-evaporated with toluene and purified on a silica gel column with MeOH/CH₂Cl₂ (4-10% gradient) to give 23A (11 mg, 56%). ESI-LCMS: m/z = 655 [M+H]⁺.

EXAMPLE 21

Préparation of Compound 7A

7-6

TBDPSO

TBSO

*· DMTrO

NHMMTr

[0251] Préparation of (7-2): To a solution of 7-1 (20.0 g, 70.1 mmol) in anhydrous 5 pyridine (230 mL) was added imidazole (19.1 g, 280.7 mmol) and TBSCl (42.1 g, 280.7 mmol) at 25 °C. The solution was stirred at 25 °C for 15 h. The mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in EA. A white solid was obtained and filtered. The filter cake was concentrated to dryness to give 7-2 (30.1g, 83%) as a white solid.

[0252] Préparation of (7-3): 7-2 (30.1 g, 58.7 mmol) was dissolved in THF (120 mL) 10 and H₂O (80 mL). HOAc (260 mL) was added, and was then stirred at 80 °C for 13 h. The mixture was cooled to R.T., and concentrated to dryness under reduced pressure. The residue was dissolved in EA and filtered. The filter cake was concentrated to dryness to give 7-3 (20.1 g, 86%) as a white solid.

[0253] Préparation of (7-4): 7-3 (20.1 g, 50.4 mmol) was dissolved in anhydrous 15 pyridine (200 mL). Ac₂O (7.7 g, 75.5 mmol) was added and then stirred at 25 °C for 18 h. MMTrCl

(46.5 g, 151.1 mmol) and AgNO₃ (25.5 g, 151.1 mmol) were added. The solution was stirred at 25 °C for 15 h. The reaction was quenched with water. The mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in EA. The solution was washed with brine. The organic layer was dried over Na₂SO₄ and filtered. The filtrate was concentrated in vacuum to dryness. The residue was purified on silica gel column (2% MeOH in DCM) to give 7-4 (21.5 g, 60%) as a white foam.

[0254] Préparation of (7-5): 7-4 (4.3 g, 6.0 mmol) was dissolved in NH₃/MeOH (40 mL). The mixture was stirred at 25 °C for 20 h. The solution was evaporated to dryness. The residue was purified on silica gel column (2% MeOH in DCM) to give 7-5 (3.1 g, 76.5 %) as a 10 yellow solid.

[0255] Préparation of (7-6): To a solution of 7-5 (3.1 g, 4.6 mmol) in anhydrous DCM (50 mL) was added Dess-Martin reagent (3.5 g, 8.2 mmol) at 0 °C. The mixture was stirred at 0 °C for 2 h, and then stirred at R.T. for 2 h. The reaction was quenched with saturated NaHCO₃ and Na₂S₂O₃ solution. The organic layer was washed with brine (2x) and dried over anhydrous Na₂SO₄.

The solvent was evaporated to give crude 7-6 (2.8 g) as a yellow foam.

[0256] Préparation of (7-7): To a solution of 7-6 (2.8 g, 4.2 mmol) in 1,4-dioxane (40 mL) was added 37% HCHO (2.7g, 33.5 mmol) and 2.0 N NaOH aqueous solution (3.0 mL, 6.0mmol). The mixture was stirred for 12 h at 25 °C. The mixture was treated with EtOH (20 mL) and NaBH4 (2.5 g, 66.9 mmol) and stirred for 30 mins. The reaction was quenched with sat. aq.

NH4CI and extracted with EA (50 mL). The organic layer was dried over Na₂SO₄. The concentrated organic phase was purified on silica gel column (2% MeOH in DCM) to give 7-7 (2.1g, 72.4%) as a yellow solid.

[0257] Préparation of (7-8): To a solution of 7-7 (2.1 g, 3.0 mmol) in DCM (20 mL) was added pyridine (5 mL) and DMTrCl (1.0 g, 3.0 mmol) at 0 °C. The solution was stirred at 25 °C for 1 h. The mixture was treated with MeOH (8 mL), and concentrated under reduced pressure. The residue was purified on silica gel column (2% MeOH in DCM) to give 7-8 (1.1 g, 36.7%) as a yellow solid.

[0258] Préparation of (7-9): To a solution of 7-8 (1.1 g, 1.Immol) in anhydrous pyridine (10 mL) was added TBDPSC1 (0.9 g, 3.3 mmol) and AgNO₃ (0.6 g, 3.3 mmol). The mixture was stirred at 25 °C for 15 h. The solid was removed by filtration, and the filtrate was concentrated at low pressure. The residue was dissolved in EA. The resulting solution was washed

with brine. The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified by column chromatography (2% MeOH in DCM) to give 7-9 (1.2 g, 88.2%) as a white foam.

[0259] Préparation of (7-10): To a solution of 7-9 (1.2 g, 1.0 mmol) in anhydrous DCM (15 mL) was added CLCHCOOH (0.6 mL) at -78 °C. The mixture was stirred at -20 °C for 1 h.

The reaction was quenched with sat. aq. NaHCO₃ and extracted with DCM. The organic layer was dried over Na₂SO₄ and concentrated at low pressure. The residue was purified on silica gel column (2% MeOH in DCM) to give 7-10 (693 mg, 76.3%) as a white foam.

[0260] Préparation of (7-11): To a solution of 7-10 (693 mg, 0.74 mmol) in anhydrous

DCM (25 mL) and pyridine (291 mg, 3.70 mmol) was added Tf₂O (312 mg, 1.1 mmol) in DCM (1 mL) dropwise at 0°C. The mixture was stirred at 0 °C for 15 mins. The reaction was quenched with ice water. The organic layer was separated and washed with brine. The organic layer was dried over anhydrous Na₂SO₄ and evaporated to give 7-11 (442 mg, crude) as a yellow foam.

[0261] Préparation of (7-12): To a solution of 7-11 (442 mg, 0.41 mmol) in anhydrous

DMF (5 mL) was added NaN₃ (134 mg, 2.1 mmol). The mixture was stirred at R.T. for 12 h. The reaction was quenched with water and extracted with EA (20 mL, 2x). The organic layer were washed with brine, dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified on a silica gel column (1% MeOH in DCM) to give pure 7-12 (313 mg, 78.6%) as a white foam.

[0262] Préparation of (7-13): A mixture of 7-12 (313 mg, 0.32 mmol) and NELF (240 mg, 6.5 mmol) in MeOH (10 mL) was stirred at 80 °C for 12 h. The mixture was cooled down to R.T. The solid was removed by filtration. The solvent was removed under reduced pressure, and the residue was purified on a silica gel column (5% MeOH in DCM) to give 7-13 (102 mg, 52%) as a white foam.

[0263] Préparation of (7A): 7-13 (102 mg, 0.17 mmol) was dissolved in CH₃COOH (80%). The mixture was stirred at 60 °C for 2 h and then cooled to R.T. The mixture was concentrated to dryness under reduced pressure. The residue was purified on silica gel column (5% to 10% MeOH in DCM) to give the crude product (67 mg). The crude product was purified by prepHPLC (0.1% NH4HCO3 in water and CH₃CN) to give 7A (37.5 mg, 66%) as a white solid. MS: m/z

341[M+H]⁺.

EXAMPLE 22

Préparation of Compound 31A

HO—'Λ_[

TBSri F

7-7

TBDPSO^\>\>

s- DMTrO—'' \__/

TBSri ΐ

31-3 ,=^N tbdpso'\_/ ^o _x>n Tfo—''A—( n=^ⁿ

TBSri F NHMMTr

31-5

31-7

31-1

TBDPSO[0264]

C n Ν=γ NHMMTr

31-6

31-4 r \ /⁰^

DMTrO—''’ \__f Ν=γ^Ν

TBSO' 'F NHMMTr

31-2

HOPréparation of (31-2): To a stirred solution of 7-7 (1.92 g, 27.3 mmol), PPh₃ (1.43 g, 54.7 mmol), EtOH (0.25 g, 54.7 mmol) in anhydrous dioxane (20 mL) was added DIAD (1.11 g, 54.7 mmol) dropwise at 0 °C. The solution was stirred at 25 °C for 15 h. The reaction was quenched with water and extracted with EA. The mixture was washed with water and brine. The organic layer was dried over Na₂SO4 and fîltered. The fîltrate was concentrated in vacuum to dryness, and the residue was purified on a silica gel column (2% to 5% MeOH in DCM) to give 31-1 (1.43 g, 71%) as a white foam.

[0265]

Préparation of (31-2): To a stirred solution of 31-1 (1.43 g, 19.6 mmol) in DMF (15 mL) was added TEA (0.59 g, 58.8 mmol) and DMTrCl (0.99 g, 29.4 mmol) at 0 °C. The solution was stirred at 25 °C for 12 h. The mixture was treated with MeOH (1 mL), and diluted with

EA. The solution was washed with water and brine. The organic layer was dried over anhydrous

NaSCfi, and concentrated to dryness. The residue was purified on a silica gel column (2% MeOH in DCM) to give 31-2 (1.13 g, 56%) as a yellow solid.

[0266] Préparation of (31-3): To a stirred solution of 31-2 (1.13 g, 1. Immol) in anhydrous pyridine (10 mL) was added TBDPSC1 (0.91 g, 3.3 mmol) and AgNO₃ (0.61 g, 3.3 mmol). The mixture was stirred at 25 °C for 15 h. The solid was removed by filtration, and the filtrate was diluted with EA (50 mL). The solution was washed with brine. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified on a silica gel column (2% MeOH in DCM) to give 31-3 (1.22 g, 88 %) as a white foam.

[0267] Préparation of (31-4): To a stirred solution of 31-3 (1.22 g, 1.0 mmol) in anhydrous DCM (15 mL) was added C1₂CHCOOH (0.6 mL) at -78 °C. The mixture was stirred at 20 °C for 1 h. The reaction was quenched with sat. aq. NaHCO₃ and extracted with DCM. The organic layer was dried over anhydrous Na₂SO₄, and concentrated at low pressure. The residue was purified by column chromatography (2% MeOH in DCM) to give 31-4 (0.52 g, 56%) as a white foam.

[0268] Préparation of (31-5): To a stirred solution of 31-4 (0.52 g, 0.5 mmol) in anhydrous DCM (15 mL) and pyridine (0.21 g, 2.5 mmol) was added Tf₂O (0.30 g, 1.0 mmol) in DCM (1 mL) dropwise at 0°C. The mixture was stirred at 0 °C for 15 mins. The reaction was quenched with ice water. The organic layer was separated and washed with water. The organic layer was dried over anhydrous Na₂SO4 and concentrated at low pressure to give 31-5 (442 mg 20 crude) as a yellow foam.

[0269] Préparation of (31-6): To a stirred solution of 31-5 (442 mg, 0.4 mmol) in anhydrous DMF (5 mL) was added NaN₃ (131 mg, 2.0 mmol). The mixture was stirred at RT for 12 h. The reaction was quenched with water and extracted by EA (20 Ml, 2x). The organic layer was washed with water and dried over Na₂SC>4. The organic phase was evaporated to dryness under 25 reduced pressure. The residue was purified on a silica gel column (l%MeOH in DCM) to give 31-6 (352 mg, 88%) as a white foam.

[0270] Préparation of (31-7): A mixture of 31-6 (352 mg, 0.35 mmol) and NH4F (392 mg, 10.6 mmol) in MeOH (10 mL) was stirred at 80 °C for 12 h. The mixture was cooled to R.T. The solid was removed by filtration. The solvent was concentrated under reduced pressure. The 30 residue was purified on a silica gel column (2% to 5%MeOH in DCM) to give crude 31-7 (151 mg).

The crude product was purified by prep-HPLC (0.1% NH4HCO3 in water and CH₃CN) to give 31-7 (71.5 mg, 32%) as a white solid. MS: m/z 641 [M+H]⁺.

[0271] Préparation of (31-8): A mixture of 31-7 (64 mg, 0.1 mmol) and bis(pivaloyloxymethyl)phosphate, after rendered anhydrous by evaporating with toluene, was dissolved in CH₃CN (1 mL) and cooled to 0 °C. BopCl (40 mg, 0.15 mmol) and NMI (40 pL, 0.5 mmol) were added. The mixture was stirred at 0 °C for 2 h. EtOAc was added, and the mixture was washed with 0.5 N aq. citric acid, sat. aq. NaHCO₃ and brine, and then dried with Na₂SO4. The solvents were removed, and the residue was purified on a silica gel column with 3% z-PrOH in CH₂C1₂ to 31-8 (38 mg, 40%).

[0272] Préparation of (31 A): A solution of 31-8 (30 mg, 0.03 mmol) in CH₃CN (0.3 mL) and HCl (30 pL; 4 N dioxane) was stirred at R.T. for 100 mins. The reaction was quenched with EtOH, and the mixture was evaporated. The crude residue was purified on a silica gel column with z-PrOH/CH₂Cl₂ (3-10% gradient) to yield 31A (10 mg, 50%). ESI-LCMS: m/z = 681 [M+H]⁺.

EXAMPLE 23

Préparation of Compound 32A

[0273] 2A (30 mg, 0.1 mmol) was hydrogenated in MeOH over 10% Pd/C at normal pressure. The catalyst was filtered off, and the filtrate was purified by RP HPLC on Synergy 4 micron Hydro-RP column (Phenominex). A linear gradient of MeOH from 0 to 20% in 50mM triethylammonium acetate buffer (pH 7.5) was used for elution. The corresponding fractions were combined, concentrated and lyophilized (3x) to remove excess of buffer to yield 32A (17 mg, 63%). ESI-LCMS: m/z = 275.2 [M+H]⁺, 297.1 [M+Na]⁺.

EXAMPLE 24

Préparation of Compound 8A

[0274] Préparation of (8-2): To a solution of 8-1 (3.0 g, 11.15 mmol) in anhydrous pyridine (90 mL) was added imidazole (3.03 g, 44.59 mmol) and TBSC1 ( 6.69 g, 44.59 mmol) at 25 °C under N₂ atmosphère. The solution was stirred at 25 °C for 15 h. The solution was concentrated to dryness under reduced pressure. The residue was dissolved in EA. The solution was washed with sat. NaHCO₃ and brine, and dried over anhydrous MgSO₄. The solvent was removed at low pressure to give crude 8-2 (4.49 g, 90 %) as a white solid.

[0275] Préparation of (8-3): To a stirred solution of 8-2 (3.5 g, 7.04 mmol) in a mixture of EA and EtOH (1:1, 55 mL) was added TsOH (10.7 g, 56.34 mmol) at 0 °C. The mixture was stirred at 30 °C for 8 h. Water (30 mL) was added, and the solution was removed to dryness. The residue was purified on a silica gel column (10% MeOH in DCM) to give 8-3 (1.75 g, 65%) as a white foam.

[0276] Préparation of (8-4): To a solution of 8-3 (3.4 g, 8.88 mmol) in anhydrous pyridine (17 mL) was added collidine (4.3 g, 35.51 mmol), AgNO₃ (5.50 g, 35.51 mmol) and

MMTrCl (8.02 g, 26.63 mmol) at 25 °C under N2. The mixture was stirred at 25 °C for 12 h. MeOH (20 mL) was added, and the solvent was removed to dryness at low pressure. The residue was purified on a silica gel column (10% EA in PE) to give 8-4 (5.76 g, 70%) as a white foam.

[0277] Préparation of (8-5): To a solution of 8-4 (2.0 g, 2.16 mmol) in anhydrous DCM (10 mL) was added C1₂CHCOOH (2.8 g, 21.57 mmol) dropwise at -78 °C. The mixture was warmed to -10 °C and stirred at this température for 20 mins. The reaction was quenched with sat.NaHCO3 at -10 °C. The mixture was extracted with DCM, washed with brine, and dried over anhydrous MgSCfi. The solution was concentrated at low pressure. The residue was purified on silica gel column (10% EA in PE) to give 8-5 (0.99 g, 70%) as a white foam.

[0278] Préparation of (8-6): To a stirred solution of 8-5 (3.5 g, 5.34 mmol) in anhydrous DMSO (35 mL) was added DCC (3.30 g, 16.03 mmol) and Py-TFA (1.03 g, 5.34 mmol). The mixture was stirred at 30 °C for 1 h. The reaction was quenched with cold water at 0 °C, and extracted with EA (3 x 60 mL). The precipitate was filtered. The organic layers were washed with brine (3x) and dried over anhydrous MgSCL. The organic phase was concentrated at low pressure to give crude 8-6 (3.5 g) as a yellow oil.

[0279] Préparation of (8-7): To a stirred solution of 8-6 (3.5 g, 5.34 mmol) in MeCN (35 mL) was added 37% HCHO (11.1 mL) and TEA (4.33 g, 42.7 mmol). The mixture was stirred at 25 °C for 12 h. The mixture was treated with EtOH (26 mL) and NaBHt (3.25 g, 85.5 mmol) and then stirred for 30 mins. The reaction was quenched with sat. aq. NH4CI and extracted with EA (3 x 60 mL). The organic layer was dried over anhydrous MgSCfi, and concentrated at low pressure. The residue was purified by column chromatography (from 10% EA in PE to 50% DCM in PE) to give 8-7 (1.46 g, 40%) as a white solid.

[0280] Préparation of (8-8): To a stirred solution of 8-7 (1.85 g, 2.7 mmol) in pyridine (24 mL) and DCM (9.6 mL) was added DMTrCl (1.3 g, 3.9 mmol) at -35 °C under N2 atmosphère. The solution was stirred at 25 °C for 16 h. The mixture was treated with MeOH (15 mL) and concentrated at low pressure. The residue was purified by column chromatography (EA in PE from 10% to 30%) to give 8-8 ( 1.60 g, 60 %) as a white solid.

[0281] Préparation of (8-9): To a solution of 8-8 (1.07 g, 1.08 mmol) in anhydrous pyridine (5 mL) was added AgNO₃ (0.65 g, 3.79 mmol) and TBDPSC1 (1.04 g, 3.79 mmol). The mixture was stirred at 25 °C for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in EA (50 mL). The resulting solution was washed with brine. The organic

layer was dried over anhydrous MgSO₄, and concentrated at low pressure. The residue was purified on a silica gel column (10% EA in PE) to give 8-9 (0.93 g, 70%) as a white foam.

[0282] Préparation of (8-10): To a stirred solution of 8-9 (1 g, 0.82 mmol) in anhydrous DCM (13.43 mL) was added CI2CHCOOH (2.69 mL) at -78 °C. The mixture was stirred at -10 °C for 20 mins. The reaction was quenched with sat. aq. NaHCCh and extracted with DCM. The organic layer was dried over anhydrous Na2SO₄, and concentrated at low pressure. The organic phase was purified by column chromatography (MeOH in DCM form 0.5% to 2%) to give 8-10 (0.48 g, 65%) as a solid.

[0283] Préparation of (8-11): To an ice cold solution of 8-10 (0.4 g, 0.433 mmol) in anhydrous DCM (2.7 mL) was added pyridine (171 mg, 2.17 mmol) and TÎ2O (183 mg , 0.65 mmol) by dropwise at -35 °C. The mixture was stirred at -10 °C for 20 mins. The reaction was quenched with ice water and stirred for 30 mins. The mixture was extracted with DCM (3 x 20 mL). The organic phase was washed with brine (100 mL), dried over anhydrous Na2SO₄, and concentrated at low pressure to give crude 8-11 (0.46 g), which was used for next step without further purification.

[0284] Préparation of (8-12): To a solution of 8-11 (0.46 g, 0.43 mmol) in anhydrous

DMF (2.5 mL) was added NaN3 (42 mg, 0.65 mmol). The mixture was stirred at 30 °C for 16 h. The solution was diluted with water and extracted with EA (3 x 30 mL). The combined organic layers were dried over anhydrous Na2SO₄, and concentrated at low pressure. The residue was purified on a silica gel column (EA in PE from 5% to 15%) to give 8-12 (0.31 g, 70%) as a solid.

[0285] Préparation of (8-13): To a solution of 8-12 (0.31 g, 0.33 mmol) in MeOH (5 mL) was added NH4F (0.36 g, 9.81 mmol) at 70 °C. The mixture was stirred at this température for 24 h. The mixture was evaporated to dryness. The residue was purified on silica gel column (MeOH in DCM from 0.5% to 2.5%) to give 8-13 (117 mg, 60%) as a white solid.

[0286] Préparation of (8A): 8-13 (300 mg, 0.50mmol) was dissolved in 80% of HOAc (20 mL). The mixture was stirred at 55 °C for 1 h. The reaction was quenched with MeOH and concentrated at low pressure. The residue was purified by prep-HPLC to give 8A (100 mg, 61.3 %) as a white solid. ESI-LCMS: m/z 325.1 [M + H]⁺.

EXAMPLE 25

Préparation of Compound 33A

DCM, R.T.

MMTrO

PPC, Ac₂Q, t-BuOH

MMTrO

33-3

33-4

TBSO

- N₃MMTrO'

33-5

NaBD₄ (4 eq.) THF, 40 °C, 12 h

33A [0287] Compound 33-3 was prepared according to the scheme provided above.

Compound 33A can be obtained using methods known to those skilled in the art, including those described in U.S. Publication No. 2012/0071434, filed September 19, 2011.

EXAMPLE 26 Préparation of Triphosphate Compounds [0288] Compounds 3A, 4A, 9A and 11 A: Dry nucleoside (0.05 mmol) 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 mins at a bath température of 42 °C, and then cooled down to R.T. N-Methylimidazole (0.009 mL, 0.11 mmol) was added followed by POCI3 (9 pL, 0.11 mmol), and the mixture was kept at R.T. for 40 mins. The reaction was controlled by LCMS and monitored by the appearance of the corresponding nucleoside 5’-monophosphate. After more than 50% of transformation was achieved, 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 (10 mL) and 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). Triphosphate was eluted at 75-80%B. Corresponding fractions were 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 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.

[0289] Compounds 5A, 6A, 10A and 12A: Nucleoside 5’-triphosphates with a 4’azidoalkyl group were dissolved in water (0.1 mL), methanol (3 mL) was added followed by 10%

Pd/C (3 mg). Hydrogen was bubbled through the solution for 2 h. The catalyst was filtered off, and

the filtrate was purified 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 for elution. The corresponding fractions were combined, concentrated and lyophilized 3 times to remove excess of buffer.

Table 1 - Triphosphates obtained from Example 25

Compound	³¹pnmr Pcx	³¹pnmr Ρβ	³¹PNMR Py	MS (M-l)
A.. ο ο o U L Il II II HO—P—0—P—0—P—0—» „ i 1 1 1 HO HO HO 7 n₃—* ---Ç Hcf T 3A	-10.95(d)	-23.38(0	-11.97(d)	540.4
nh₂ A ooo y l Il II II HO—P—0—P—0—P—0—» „ i 1 1 1 HO HO HO / N₃—J--Ç HC? % 4A	-5.36(d)	-20.72(t)	-11.40(d)	539.3
A ⁰⁰⁰ ü L Il II II HO—P—o—P—0—P—0—» 0 f HO HO HO / h₂n— / _V Hd F 5A	-6.68 -6.81(d)	-22.25(t)	-11.79 -11.92(d)	514.0
NH, A. ^{0 0 0} U. X Il II II HO—P—Ο—P—O—P—O-« „ f 1 1 1 HO HO HO /\ / H₂N—* / _% Hd F 6A	-5.95 -6.06(d)	-21.38(0	-11.53 -11.65(d)	513

Compound	³¹pnmr Pa	³¹pnmr Ρβ	³¹pnmr Py	MS (M-l)
0 ° ° ° n n n K. HO—P—0—P—0—P—0—* „ I* N nh₂ I I I y-o-V HO HO HO / h/ ^%f 9A	-10.31 -10.44(d)	-23.08(t)	-11.62 -11.84(d)	579
0 ⁰⁰⁰ x II l HO—P—0—P—0—P—O— HO HO HO ./K / h₂n—* /—Ç HC? F 10A	-9.94 -10.06(d)	-23.83(t)	-11.77 -11.89(d)	553
nh₂ 2<A_n ^{0 0 0} \ I il il n n'-'KmK HO—P—O—P—0—P—0—» o r ^N OH OH OH xK / Ns--* /---- § * HO F 11A	-10.79 -10.91(d)	-23.24(t)	-11.80 -11.92(d)	563.0
nh₂° ° ° ('tS ii il il i i i OH OH OH ___/ h₂n—* / v H(î f 12A	-6.48 -6.60(d)	-22.13(0	-11.76 -11.88(d)	537.0

EXAMPLE 27

Additional Compounds [0290] The foregoing synthèses are exemplary and can be used as a starting point to préparé a large number of additional compounds. Examples of compounds of Formula (I) that can be prepared in various ways, including those synthetic schemes shown and described herein, are provided below. Those skilled in the art will be able to recognize modifications of the disclosed synthèses and to devise routes based on the disclosures herein; ail such modifications and altemate routes are within the scope of the claims.

EXAMPLE 28 '

RSV Assay [0291] The RSV subgenomic replicon 395 HeLa was licensed from Apath (Brooklyn,

NY) and was originally developed by Dr. Mark Meeples of Center for Vaccines & Immunity, the Research Institute at Nationwide Children's Hospital in Columbus, Ohio. To generate subgenomic RSV replicon, three glycoprotein genes, those for SH, G, and F, from a full-length recombinant 10 GFP-expressing (rg) RSV antigenomic cDNA were deleted. In their place, a blasticidin S deaminase (bsd) gene was inserted. Through multiple steps, the RSV replicon was established in HeLa cells.

The 395 HeLa cells were cultured in Dulbecco’s Modified Eagle Medium (DMEM) containing 4500 mg/L D-glucose, L-glutamine, and 110 mg/L sodium pyruvate (Invitrogen, Cat. #11995-040).

The medium was further supplemented with 10% (v/v) fêtai bovine sérum (FBS) (Mediatech, Cat. 15 #35-010-CV), 1% (v/v) penicillin/streptomycin (Mediatech, Cat. #30-002-0), and 10 pg/mL of

Blasticidin (BSD) (Invivogen, Cat. code ant-bl-1). Cells were maintained at 37 °C in a humidified 5% CO2 atmosphère.

[0292] Détermination of 50% inhibitory concentration (EC50), 90% inhibitory concentration (EC₉₀) and 50% cytotoxic concentration (CC50) in RSV replicon cells were performed 20 by the following procedure. On the first day, 5000 RSV replicon cells per well were plated in a 96well plate. On the following day, compounds to be tested were solubilized in 100% DMSO to 100X

the desired final testing concentration. Each compound was serially diluted (1:3) up to 9 distinct concentrations. Compounds in 100% DMSO were reduced to 10% (v/v) DMSO by diluting 1:10 in cell culture media. A 10 pL sample of the compounds diluted to 10% (v/v) DMSO with cell culture media was used to treat the RSV replicon cells in 96-well format. The final DMSO concentration 5 was 1% (v/v). Cells were incubated with compounds for 7 days at 37 °C in a 5% CO₂ atmosphère.

In each assay, positive control that was previously characterized in the RSV replicon assay was included.

[0293] The Renilla Luciferase Assay System (Promega, Cat. #E2820) was used to measure anti-RSV replicon activity. Assay plates were set up as stated above. Luminescence was 10 recorded using a Perkin Elmer multilabel counter Victor3V. EC50, the concentration of the drug required for reducing RSV replicon RNA by 50% in relation to the untreated cell control value, was calculated from the plot of percentage réductions of the optical density (OD) value against the drug concentrations using the Microsoft Excel forecast function.

[0294] 395 HeLa cell prolifération assay (Promega; CellTiter-Glo Luminescent Cell

Viability Assay, Cat. #G7572) was used to measure cell viability. The CellTiter-Glo® Luminescent Cell Viability Assay is a homogeneous method to détermine the number of viable cells in culture based on quantitation of the ATP présent, which signais the presence of metabolically active cells. Assay plates were set up in the same format as noted above for the replicon assay. CellTiter-Glo reagent (100 pL) was added to each well and incubated at room température for 8 minutes.

Luminescence was recorded using a Perkin Elmer multilabel counter Victor3V. The CC50, the concentration of the drug required for reducing viable cells by 50% in relation to the untreated cell control value, was calculated from the plot of percentage réductions of the luminescence value against the drug concentrations using the Microsoft Excel forecast function.

[0295] Table Al includes compounds with an EC50 value that is less than 1 pM. Table 25 A2 includes compounds with an EC50 value that is equal to or higher than 1 pM and less than 50 pM. Other tested compounds disclosed herein had an EC50 value of 50 pM or greater.

Table Al

Compound		Compound	Compound
2A	14A	16A
13A	15A

102

Table A2

Compound 7A 17A 18A

Compound

19A

20A

21A

Compound

22A

23A

28A [0296] 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, 120mM K-acetate, 4.5mM MgC12, 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 samples were purified through G-50 size exclusion spin columns and phenol-chloroform extraction. The radio-labeled RNA products were resolved by electrophoresis 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.

[0297] Table A3 includes compounds with an IC50 value that is less than 1 μΜ against the polymerase. Table A4 includes compounds with an IC50 value that is equal to or higher than 1 μΜ and less than 50 μΜ against the polymerase. Other tested compounds disclosed herein had an IC50 value of 50 μΜ or greater against the polymerase.

Table A3

Table A4

EXAMPLE 29

Parainfluenza virus-3 (PIV-3) Plaque Assay [0298] MA-104 cells were grown in 24-well plates to a confluency of 90% in the presence of minimal essential medium (MEM) supplemented with 10% fêtai bovine sérum and

antibiotics (C-EMEM). The cells were then washed twice with non-complete minimal essential medium (NC-EMEM). Test articles were dissolved in DMSO to a stock concentration of 10 mM.

[0299] An aliquot of 0.5 mL of the test article at various concentrations was then inoculated in triplicate wells and incubated for 60 mins at 37 °C with 5% CO2 for the diffusion of 5 test article into MA-104 cells. After the incubation period, a stock of human PIV type 3 was thawed and diluted with NC-EMEM to achieve a viral concentration of 10⁴ pfu/mL. An aliquot of 0.1 mL was then inoculated into ail the wells except for the négative and test article toxicity control wells. Upon infection, the plates were incubated for 72 h at 37 °C at 5% CO2. After incubation, the plates were examined under microscopy to record cytotoxicity. The supernatants collected for viral 10 quantification using a standard plaque assay using MA-104 cells as the indicator cells.

[0300] To perform the plaques assay, MA-104 cells were grown to confluence in 24-well plates. The cells were washed with serum-free medium prior to inoculation of duplicate wells with serial 10-fold dilutions of supematant sample. After 1 h incubation at 37 °C, the samples were aspirated and 1.0 mL of methyl cellulose overlay media was added to each well. After 6 days of 15 culture, the cells were fixed and stained with 0.06% crystal violet in 1% glutaraldehyde and viral plaques enumerated. The data was analyzed with Prism software with EC50 defined as drug concentration that reduced the viral load 50% from the viral control (VC). Table B1 provides a listing of compounds of Formula (I) that are active against PIV-3 with an EC50 < 20 μΜ.

Table B1

No.

2A

14A

15A

16A

17A

18A

19A 28A

EXAMPLE 30

Human metapneumovirus (hMPV) TCIDso Assay [0301] LLC-MK2 cells were grown in 24-well plates to a confluency of 90% in the 5 presence of minimal essential medium (MEM) supplemented with 10% fêtai bovine sérum and antibiotics (C-EMEM). The cells were then washed twice with non-complete minimal essential medium (NC-EMEM). Test articles were dissolved in DMSO to a stock concentration of 10 mM.

[0302] An aliquot of 0.5 mL of the test article at various concentrations was then inoculated in triplicate wells and incubated for 60 mins at 37 °C with 5% CO₂ for the diffusion of 10 test article into LLC-MK2 cells. After the incubation period, a stock of human metapneumovirus was thawed and diluted with NC-EMEM to achieve a viral concentration of 10⁴ pfu/mL. An aliquot of 0.1 mL was then inoculated into ail the wells except for the négative and test article toxicity control wells. Upon infection, the plates were incubated for 7 days at 37 °C at 5% CO₂. After incubation, the plates were examined under microscopy to record cytotoxicity. The supernatants 15 collected for viral quantification using a standard TQD₅o assay using LLC-MK2 cells as the indicator cells. The data was analyzed with Prism software with EC50 defined as drug concentration that reduced the viral load 50% from the viral control (VC). Table Cl provides a listing of compounds of Formula (I) that are active against human metapneumovirus, with an EC50 < 20 μΜ.

Table Cl

No.

2A

7A

8A

No.

13A

14A

15A

No.

16A

17A

18A

No.

19A

28A [0303] Although the foregoing has been described in 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

1. A compound of Formula (I), or a pharmaceutically acceptable sait thereof, wherein:

B^1A is an optionally substituted heterocyclic base or an optionally substituted heterocyclic base with a protected amino group;

R^a is hydrogen or deuterium;

R^1A is selected from the group consisting of hydrogen, an optionally substituted

Z^1A Z^2A

R^6aO—Ij⁵—r^8Ao—P— acyl, an optionally substituted O-linked amino acid, OR^7A, R^9A and ^3A r1°^a-P--1

I ^ζ

R^11A ;

R^al and R^a2 are independently hydrogen or deuterium;

R^2A is a Ci_6 azidoalkyl or a C|.g aminoalkyl;

R^3A is selected from the group consisting of OH, -OC(=O)R”^A and an optionally substituted O-linked amino acid;

R^4a is halogen;

R^5A is hydrogen or halogen;

R^6A, R^7A and R^8A are independently selected from the group consisting of absent, hydrogen, an optionally substituted C1.24 alkyl, an optionally substituted C₃.₂4 alkenyl, an optionally substituted C3.24 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(Ci_6 alkyl), an optionally substituted

106 *-(CR^15AR^16A)p-O-Ci.24 alkyl, an optionally substituted *-(CR^17AR^18A)_q-O-Ci_24 alkenyl, consisting of 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 is independently selected from the group consisting of an optionally substituted Ci_₂4 alkyl, an optionally substituted C₂-24 alkenyl, an optionally substituted

C2-24 alkynyl, an optionally substituted C₃.₆ cycloalkyl, an optionally substituted C₃.₆cycloalkenyl, NR^30AR^31A, an optionally substituted N-linked amino acid and an optionally substituted N-linked amino acid ester dérivative;

R^10A and R^11A are independently an optionally substituted N-linked amino acid or

15 an optionally substituted N-linked amino acid ester dérivative;

R^12A, R^13A and R^14A are independently absent or hydrogen;

each R^15A, each R^16A, each R^17A and each R^18A are independently hydrogen, an optionally substituted Ci-24 alkyl or alkoxy;

107

R^19A, R^20A, R^22A and R^23A are independently selected from the group consisting of hydrogen, an optionally substituted Ci_₂₄ alkyl and an optionally substituted aryl;

R^21A and R^24a are independently selected from the group consisting of hydrogen, an optionally substituted Ci-₂₄ alkyl, an optionally substituted aryl, an optionally substituted -O-Ci.₂₄ alkyl, an optionally substituted -O-aryl an optionally substituted O-heteroaryl and an optionally substituted -O-monocyclic heterocyclyl;

R^25A and R^29A are independently selected from the group consisting of hydrogen, an optionally substituted Cj.₂₄ alkyl and an optionally substituted aryl;

R^26A and R^27A are independently -CsN or an optionally substituted substituent selected from the group consisting of C₂.g organylcarbonyl, C₂.g alkoxycarbonyl and C₂-s organylaminocarbonyl;

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_6 cycloalkyl and an optionally substituted C₃.₆ cycloalkenyl;

R^30A and R^31a are independently selected from the group consisting of hydrogen, an optionally substituted C].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”^a is an optionally substituted Ci_₂₄-alkyl;

m and t 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;

s is 0, 1, 2 or 3; and

Z^1A, Z^2A, Z^3A and Z^4A are independently O or S; and a compound of Formula (I), or a pharmaceutically acceptable sait, cannot be

108

2. The compound of Claim 1, wherein R^2A is azidomethyl.

3. The compound of Claim 1, wherein R^2A is aminomethyl.

Γ

R^6AO—P—

4. The compound of any one of Claims 1-3, wherein R^1A is OR^7A.

5. The compound of Claim 4, wherein R^6A and R^7A are both hydrogen.

6. The compound of Claim 4, wherein R^6A and R^7A are both absent.

7. The compound of Claim 4, wherein both R^6A and R^7A are independently selected from the group consisting of an optionally substituted C1-24 alkyl, an optionally substituted C3.24 alkenyl, an optionally substituted C3.24 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).

8. The compound of Claim 4, wherein _r6à and r^7A are both an optionally substituted C i_24 alkyl. 9. The compound of Claim 4, wherein R^6a and r^7A are both an optionally substituted C 5-24 alkenyl. 10. The compound of Claim 4, wherein R^6A and R^7A are both *- -(CR^15AR^16a)_p-O-Ci_ 24 alkyl. 11. The compound of Claim 4, wherein R^6A and R^7A are both *- -(CR^17AR^18A)_q-O-C₂- 24 alkenyl. 12. The compound of Claim 4, wherein _r6à and r^7A are both an optionally substituted aryl. 13. The compound of Claim 4, wherein r^6A and r^7a are both an optionally

substituted aryl(Ci-6 alkyl).

14.

15.

The compound of Claim 4, wherein R^6A and R^7A are both

R^24A and R^7A are both

16. The compound of Claim 4, wherein R^6A

O

17.

18.

The compound of Claim 4, wherein R^6A and R^7A are both R^29A .

The compound of Claim 4, wherein R^6A and R^7A are both

19. The compound of Claim 4, wherein R^6A and R^7A can be taken together to form a ★

moiety selected from the group consisting of an optionally substituted and an optionally substituted and R^7A, the phosphorus and the moiety form a six-membered to ten-membered ring System.

20. The compound of any one of Claims 1 to 19, wherein Z^1A is O.

21. The compound of any one of Claims 1 to 19, wherein Z^1A is S.

y2A _r8Aq--J--

22. The compound of Claim 1, wherein R^1A is R^9A

23. The compound of Claim 22, wherein R^8A is hydrogen, and R^9A is NR^30AR^31A, wherein R^30A and R^31A 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 C₃.₆ cycloalkyl and an optionally substituted

C3.6 cycloalkenyl.

110

24. The compound of Claim 22, wherein R^8A is 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.

25. The compound of Claim 22, wherein R^8A is an optionally substituted aryl; and

R^9A has the structure wherein R^33A is selected from the group consisting of hydrogen, an optionally substituted Ci^-alkyl, an optionally substituted C₃.₆ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Cp6 alkyl) and an optionally substituted haloalkyl; R^34A is selected from the group consisting of hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted Ci_6 haloalkyl, an optionally substituted C₃.₆ cycloalkyl, an optionally substituted Ce aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci_6 alkyl); and R^35A is hydrogen or an optionally substituted Cj^-alkyl; or R^34A and R^35A are taken together to form an optionally substituted C₃_6 cycloalkyl.

26. The compound of any one of Claims 22 to 25, wherein Z^2A is O.

27. The compound of any one of Claims 22 to 25, wherein Z^2A is S.

28. The compound of Claim 1, wherein R^{1 A} is R^11A .

29. The compound of Claim 28, wherein R^10A and R^11A are both an optionally substituted N-linked amino acid or an optionally substituted N-linked amino acid ester dérivative.

30. The compound of Claim 28, wherein R^10A and R^11A are independently hâve the structure wherein R^36A is selected from the group consisting of hydrogen, an optionally substituted Ci_6-alkyl, an optionally substituted C₃.₆ cycloalkyl, an optionally substituted aryl, an optionally substituted aryl(Cj.6 alkyl) and an optionally substituted haloalkyl; R^37a is selected from the group consisting of hydrogen, an optionally substituted Ci_₆ alkyl, an optionally substituted Ci_₆ haloalkyl, an optionally substituted C₃.₆ cycloalkyl, an optionally

111 substituted C(, aryl, an optionally substituted Cio aryl and an optionally substituted aryl(C].₆alkyl); and R^38A is hydrogen or an optionally substituted C_M-alkyl; or R^37A and R^38A are taken together to form an optionally substituted C₃.₆ cycloalkyl.

31. The compound of any one of Claims 28 to 30, wherein Z^3A is O.

32. The compound of any one of Claims 28 to 30, wherein Z^3A is S.

_6A G r^6Ao—p—|

33. The compound of Claim 1, wherein R^1A is OR^7A, and R¹⁶ is

O _R12Aq--p---OR^13A

L or^14A

34. The compound of Claim 33, wherein m is 0, and R^12A and R^13A are independently absent or hydrogen.

35. The compound of Claim 33, wherein m is 1, and R^12A, R^13A and R^14A are independently absent or hydrogen.

36. The compound of Claim 1, wherein R^1A is H.

37. The compound of Claim 1, wherein R^1A is an optionally substituted acyl.

38. The compound of Claim 1, wherein R^1A is an optionally substituted O-linked amino acid.

|-0 R^wyR^41A

39. The compound of Claim 1, wherein R^1A is θ , wherein R^40A is selected from the group consisting of hydrogen, an optionally substituted Cj^ alkyl, an optionally substituted C_A6 haloalkyl, an optionally substituted C₃.₆ cycloalkyl, an optionally substituted C₆aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci_6 alkyl); and R^41A is hydrogen or an optionally substituted Ci_4-alkyl; or R^40A and R^41A are taken together to form an optionally substituted C₃_6 cycloalkyl.

40. The compound of any one of Claims 1 to 39, wherein B^,A is selected from the group consisting of:

and JVVV * wherein:

_rA2 is selected from the group consisting of hydrogen, halogen and NHR^J2, 5 wherein R^J2 is selected from the group consisting of hydrogen, -C(=O)R^K2 and C(=O)OR^L2;

R^b2 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 C3.8 cycloalkyl, -C(=O)R^M2 and -C(=O)OR^N2;

10 R is hydrogen or NHR , wherein R is selected from the group consisting of hydrogen, -C(=O)R^P2 and -C(=O)OR^Q2;

R^D2 is selected from the group consisting of hydrogen, deuterium, halogen, an optionally substituted Ci_6 alkyl, an optionally substituted C₂.₆ alkenyl and an optionally substituted C2-6 alkynyl;

15 R^E2 is selected from the group consisting of hydrogen, hydroxy, an optionally substituted Ci_₆ alkyl, an optionally substituted C₃.₈ cycloalkyl, -C(=O)R^R2 and C(=O)OR^S2;

R^F2 is selected from the group consisting of hydrogen, halogen, an optionally substituted Ci_6alkyl, an optionally substituted C2-6 alkenyl and an optionally substituted 20 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 C].₆-alkyl, an optionally substituted C₂-6-alkenyl and an optionally substituted C2-6-alkynyl;

^c R is an optionally substituted Ci_6 alkyl;

R is hydrogen or NHR , wherein R is independently selected from the group consisting of hydrogen, -C(=O)R^U2 and -C(=O)OR^V2; and

R^K2, R^L2, R^M2, R^N2, R^P2, R^Q2 R^R2, R^S2’ R^U2 and R^v2 are independently selected from the group consisting of Ci_₆ alkyl, C₂.₆ alkenyl, C₂.₆ alkynyl, C₃.₆ cycloalkyl, C₃.₆cycloalkenyl, C₆-io aryl, heteroaryl, heterocyclyl, aryl(C]_₆ alkyl), heteroaryl(Ci.₆ alkyl) andheterocyclyl(Ci_₆ alkyl).

O

41. The compound of Claim 40, wherein B^1A is x/VW*

42. The compound of Claim 40, wherein B^1A JS ΆΛΛΓ

O

43. The compound of Claim 40, wherein B^1A is

44. The compound of Claim 40, wherein B^1A is

45. The compound of Claim 40, wherein B^1A is

114

46.

47.

48.

49.

The compound of Claim 40, wherein B

The compound of any one of Claims 1 to 46, wherein R^3A is OH.

The compound of any one of Claims 1 to 46, wherein R^3A is -OC(=O)R ”^A.

The compound of any one of Claims 1 to 46, wherein R^3A is O-linked amino acid.

50.

The compound of any one of Claims 1 to 46, wherein R^3A is wherein R^42A is selected from the group consisting of hydrogen, an optionally substituted Ci_6 alkyl, an optionally substituted Ci-6 haloalkyl, an optionally substituted C₃.₆ cycloalkyl, an optionally substituted C₆ aryl, an optionally substituted Cio aryl and an optionally substituted aryl(Ci_6 alkyl); and R^43A is hydrogen or an optionally substituted Ci-4-alkyl; or R^42A and R^43A are taken together to form an optionally substituted C3.6 cycloalkyl.

51. The compound of any one of Claims 1 to 50, wherein R^5A is hydrogen.

52. The compound of any one of Claims 1 to 50, wherein R^5A is halogen.

53. The compound of Claim 52, wherein R^5A is fluoro or chloro.

54. The compound of any one of Claims 1 to 53, wherein R^4A is fluoro.

55. The compound of any one of Claims 1 to 53, wherein R^4A is chloro.

56. The compound of any one of Claims 1 to 55, wherein R^al and R^a2 are both hydrogen.

57. The compound of any one of Claims 1 to 55, wherein R^al and R^a2 are both deuterium.

58. The compound of any one of Claims 1 to 57, wherein R^A is hydrogen.

59. The compound of any one of Claims 1 to 57, wherein R^A is deuterium.

60. The compound of any one of Claims 1 to 59, wherein a compound of Formula (I), or a pharmaceutically acceptable sait, cannot be

61. The compound of Claim 1, wherein the compound of Formula (I) is:

62. The compound of Claim 1, wherein the compound of Formula (I) is:

, or a pharmaceutically acceptable sait thereof.

63. The compound of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

nh₂

116 sait of the foregoing.

64. The compound of Claim 1, wherein the compound of Formula (I) is , or a pharmaceutically acceptable sait of the foregoing.

65. The compound of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

foregoing.

a pharmaceutically acceptable sait of the

66. The compound of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

118 a pharmaceutically acceptable sait of the foregoing.

67. The compound of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of: a pharmaceutically acceptable sait of the foregoing.

68. The compound of Claim 1, wherein the compound of Formula (I) is selected from the group consisting of:

120

HO

HO' ^0 ri

0' or a pharmaceutically acceptable sait of the foregoing.

5 69. A pharmaceutical composition comprising an effective amount of a compound of any one of Claims 1 to 68, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof.

70. Use of an effective amount of a compound of any one of Claims 1 to 68 or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 69 in the 10 préparation of a médicament for ameliorating or treating a paramyxovirus viral infection in a subject identified as suffering from the paramyxovirus viral infection.

71. Use of an effective amount of a compound of any one of Claims 1 to 68 or a pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 69 in the préparation of a médicament for inhibiting réplication of a paramyxovirus.

72. Use of an effective amount of a compound of any one of Claims 1 to 68 or a

5 pharmaceutically acceptable sait thereof, or a pharmaceutical composition of Claim 69 in the préparation of a médicament for contacting a cell infected with a paramyxovirus.

73. The use of any one of Claims 70 to 72, further comprising the use of one or more agents.

74. The use of any one of Claims 70 to 73, wherein the paramyxovirus viral infection 10 is a human respiratory syncytial virus infection.

75. The use of any one of Claims 73 to 74, wherein the paramyxovirus viral infection is a human respiratory syncytial virus infection; and wherein the one or more agents is selected from the group consisting of ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, BMS-433771, RFI-641, RSV604, MDT-637, BTA9881, TMC-353121, MBX-300, YM-53403, RV568 and a

15 RSV-F Particle V accine.

76. The use of any one of Claims 70 to 73, wherein the paramyxovirus viral infection is a human parainfluenza virus infection.

77. The use of Claim 76, wherein human parainfluenza virus infection is a human parainfluenza virus 3 infection.

20 78. The use of any one of Claims 70 to 73, wherein the paramyxovirus viral infection is a human metapneumovirus infection.